Brain-specific drug delivery

The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: PA0 (a) compounds of the formula EQU [D--DHC] (I) PA0 wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine.revreaction.pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR1## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH.sub.2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH.sub.2 or OH function group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and PA0 (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine.revreaction.pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entitles [D--QC].sup.+ X.sup.- are also disclosed.

FIELD OF THE INVENTION 
The present invention relates to a dihydropyridine/pyridinium salt type or 
redox system for the site-specific or sustained delivery (or both) of a 
wide variety of drug species to the the brain. More especially, this 
invention relates to the discovery that a biologically active compound 
coupled to a lipoidal carrier moiety comprising a dihydropyridine nucleus 
readily and easily penetrates the blood-brain barrier ("BBB") and attains 
increased levels of concentration in the brain; oxidation of the 
dihydropyridine carrier moiety in vivo to the ionic pyridinium salts 
prevents its elimination from the brain, while elimination from the 
general circulation is accelerated, resulting in significant and 
prolongedly sustained brain-specific drug activity, whether ascribable to 
the cleavage of the [D--QC].sup.+ entity and sustained release of the drug 
in the brain and/or to [D--QC].sup.+ itself. 
BACKGROUND OF THE INVENTION 
The delivery of drug species to the brain is ofttimes seriously limited by 
transport and metabolism factors and, more specifically, by the functional 
barrier of the endothelial brain capillary wall deemed the blood-brain 
barrier, BBB. Site-specific delivery and sustained delivery of drugs to 
the brain are even more difficult, and to date (i.e. prior to the dates of 
applicant's earlier copending applications) no useful simple or generic 
techniques to achieve such phenomena are known to the art. 
Indeed, the barriers separating plasma from the brain and cerebrospinal 
fluid (CSF) are complex systems involving passive and active transport and 
subserve a number of important functions. The boundary between plasma and 
the central nervous system (CNS) is much less permeable than that between 
plasma and other tissue cells to a variety of water soluble substances, 
such as organic electrolytes, organic acids and bases, as well as to large 
molecules such as proteins. Such a barrier also provides a path for 
clearance from the brain of the breakdown products of cellular metabolism. 
The CNS and its fluids can be considered basically a three-compartment 
system: the blood or the plasma, CSF and brain tissue. There is a 
diffusion-controlled exchange between CSF and the extracellular fluid (CF) 
of the brain. It has also been suggested that the permeabilities of 
blood-CSF and blood-brain barriers are practically identical with respect 
to drugs and other foreign substances. Mayer et al, J. Pharmacol. and Exp. 
Therap., 125, 185 (1959). 
The BBB is, moreover, basically the result of the fact that the endothelial 
cells in the brain capillaries are joined by continuous, tight 
intercellular junctions, such that material has to pass through the cells 
rather than between them in order to move from blood to brain. It is 
interesting that there are areas within the brain, such as the subfornical 
body and the postremia, in which the capillary cells are not closely 
linked so that they lack the characteristics of the BBB. They provide the 
entry of small amounts of compounds which would not ordinarily enter the 
barriers. Hoffman and Olszewzki, Neurology (Minneap.), 11, 1081 (1961). 
Foreign compounds which enter organs other than the central nervous system 
with ease, may penetrate the CNS slowly or hardly at all. A number of 
theories concerning the nature of the barrier have been proposed. The 
widely accepted concept describes the boundary as a fat-like layer 
interspersed with small pores, although the BBB is not a simple, 
anatomically well-defined unitary physical entity. Shuttleworth, Prog. 
Exp. Tumor Res., 17, 279 (1972). Penetration of such a barrier may occur 
by several processes: lipid soluble substances may passively penetrate 
into the cells, while small molecules such as water and urea may pass 
through the pores. In addition to these simple physical processes, 
carrier-mediated and active transport processes govern the movement of 
many molecules through the BBB. Thus, it is generally accepted that lipid 
solubility, degree of ionic dissociation or protonation and the ability of 
temporary combination with membrane constituents affect delivery through 
the BBB. It has been shown, for example, that in the class of 
barbiturates, a quantitative correlation could be established between 
their ease to pass into the brain (as reflected by the different times of 
onset of anesthetic action) and their lipid/water partition coefficient. 
Mark et al, J. Pharmacol. and Exp. Therap., 123, 79 (1957). The role of 
lipid solubility in drug penetration through the BBB is also exemplified 
by the better absorption of the sparingly water-soluble thiamine propyl 
disulfide (TPD) as compared to the water-soluble thiamine hydrochloride 
(THCl). Thomson et al, Ann. Int. Med., 74,Z 529 (1971). Some materials 
such as glucose and amino acids are transported by active mechanism, 
characterized by saturation, bidirectional molecular specificity, 
bidirectional competitive inhibition and bidirectional countertransport. 
Fishman, Am. J. Physiol., 206, 836 (1964). 
Changes in permeability of the BBB can be caused by several pathological 
and toxicological processes. Pardridge, Connor and Crawford, CRC Crit. 
Rev. Toxicol., 179 (1975). A general increase in the barrier permeability, 
such as a nonspecific breakdown of the barrier has, however, severe 
consequences, including cerebral edema. 
It too is well documented that the BBB is relatively impermeable to the 
ionized forms of drugs and other molecules. Drugs which are weak organic 
electrolytes appear to pass from blood to CSF to reach a steady state 
ratio characteristic of each molecule according to its pK.sub.a and the 
existence of a normal pH gradient between blood and CSF. It is clear that 
it is the most difficult for quaternary pyridinium or ammonium salt to 
penetrate the BBB. 
And removal of substances from the brain and CSF is obviously a significant 
factor in regulating drug concentrations in the CNS. There are several 
efflux processes: bulk flow via the arachnoid villi, diffusion of lipid 
soluble substances into brain and blood, active transport and metabolism 
by adjacent meninges. Once a drug or metabolite enters the CSF from blood 
or brain by simple diffusion, it may rapidly be removed, either by 
nonselective bulk flow or by active transport mechanism associated with 
the choroid plexus or other nondefined structures in the CSF compartment. 
It is generally accepted that highly lipid-soluble drugs leave the CSF 
more rapidly than poorly lipid-soluble ones, but the barrier to passage of 
compounds from CSF has only superficial similarity to the blood-CSF 
barrier. 
Drug elimination processes from the brain are significantly directly 
related to drug accumulation in the brain. It is generally assumed that 
efflux in the opposite direction involves almost the same processes as for 
entry, except that the role of the bulk flow and the metabolic processes 
in the brain are not to be overlooked. 
The two elimination processes studied in the earlier literature and which 
can be said to have a certain bearing on the present invention involve 
elimination from the brain of ionic species. Thus, it is found that 
non-metabolized ionic species, such as the acetate ion, have a three times 
slower elimination rate from the CSF than from the blood. Freundt, Arz., 
Forsch., 23, 949 (1973). An even more dramatic change in the elimination 
rate was found in the case of a quaternary piperidinium salt. The 
quaternary salt, formed in situ after delivery of a haloalkylamine, which 
undergoes cyclization to the quaternary salt, in the brain, as well, was 
found to have an at least ten times slower elimination rate from the brain 
than from the rest of the body. It was concluded by the authors [Ross and 
Froden, Eur. J. Pharmacol., 13, 46 (1970)] that the outflow rate of the 
quaternary salt corresponded to the inflow rate. Similar results were 
obtained for the erythrocytes: the efflux of the quaternary salt was very 
slow. Ross, J. Pharm. Pharmacol., 27, 322(1975). 
And while it too has been suggested to deliver a drug species, specifically 
N-methylpyridinium-2-carbaldoxime chloride (2-PAM), into the brain, the 
active nucleus of which in and of itself constitutes a quaternary 
pyridinium salt, by way of the dihydropyridine latentiated prodrug form 
thereof, such approach was conspicuously delimited to relatively small 
molecule quaternary pyridinium ring-containing drug species and did not 
provide the overall ideal result of brain-specific, sustained release of 
the desired drug, with concomitant rapid elimination from the general 
circulation, enhanced drug efficacy and decreased toxicity. Hence, no 
"trapping" in the brain of the 2-PAM formed in situ resulted, and 
obviously no brain-specific, sustained delivery occurred as any 
consequence thereof: the 2-PAM was eliminated as fast from the brain as it 
was from the general circulation and other organs. Compare U.S. Pat. Nos. 
3,929,813 and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5, pp. 
685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156; Shek, 
Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. A more 
recent extension of this approach is described by Brewster, Dissertation 
Abstracts International, Vol. 43, No. 09, March 1983, p. 2910B. It has 
also been speculated to deliver, e.g., an antitumor agent, into the brain 
by utilizing a dihydropyridine/pyridinium redox carrier moiety therefor, 
but this particular hypothesis necessarily entails derivatizing the 
dihydropyridine/pyridinium carrier with a substituent itself critically 
designed to control the release rate of the active drug species from the 
quaternary derivative thereof, as well as being critically functionally 
coordinated with the particular chemical and therapeutic activity/nature 
of the anti-tumor drug species itself; Bodor et al, J. Pharm. Sci., supra. 
See also Bodor, "Novel Approaches for the Design of Membrane Transport 
Properties of Drugs", in Design of Biopharmaceutical Properties Through 
Prodrugs and Analogs, Roche, E. B. (ed.), APhA Academy of Pharmaceutical 
Sciences, Washington, D.C., pp. 98-135 (1976). Moreover, the hypothesis 
does not include any indication of what chemical transformations would be 
needed to link any specific antitumor agent (or indeed any specific drug) 
to an appropriate carrier moiety. 
Accordingly, acutely serious need exists in this art for a truly effective 
generaic but nonetheless flexible method for the site-specific, or 
sustained delivery, or both, of drug species to the brain, while at the 
same time avoiding the aforesaid noted and notable disadvantages and 
drawbacks associated with penetration of the blood-brain barrier, with 
dihydropyridine latentiated prodrug forms of drug species themselves 
comprising a pyridinium salt active nucleus, and with the necessity for 
introducing critically coordinated and designed, release rate-controlling 
substituents onto any particular drug carrier moiety. This need has been 
addressed by applicant's earlier copending applications referred to 
hereinabove, and especially by the Serial Nos. 379,316 and 516,382, and is 
also addressed by the present application. 
It is also known to this art that Parkinsonism, a striatal dopamine 
deficiency syndrome [H. Ehringer and O. Hornykiewicz, Klin. Wsch., 38, 
1236 (1960)], cannot be treated directly with dopamine, for dopamine and 
related catecholamines also do not cross the blood-brain barrier ([B. E. 
Roos and G. Steg, Life Sci., 3, 351 (1964)]. L-Dopa, considered as a 
prodrug for dopamine, was first discovered to be useful in the treatment 
of Parkinsonism more than twenty years ago [A. Barbeau, Excepta Medica, 
Int. Congr. Ser., 38, 152 (1961); W. Birkmayer and O. Hornykiewicz, Wien. 
Klin. Wochnenschr., 73, 787 (1961)]. Indeed, L-Dopa is considered to be 
the best available treatment for Parkinsonism, but, unfortunately, at the 
expense of a wide variety of undesirable side effects [A. Barbeau, TIPS, 
2, (11), 297 (1981]. The peripheral side effects of L-Dopa, which range 
from nausea and vomiting to cardiac arrythmias and hypotension, appear to 
be due to one or more of the metabolic products thereof, rather than 
L-Dopa per se. L-Aromatic amino acid decarboxylase enzyme is responsible 
for the major metabolism of L-Dopa, whether prior, during or after 
absorption. Concurrent administration of L-Dopa with an inhibitor of 
aromatic amino acid decarboxylase, which should not be able to penetrate 
the BBB, reduces the decarboxylation of L-Dopa in peripheral tissues. Such 
reduction allows higher proportions of L-Dopa to reach the CNS and at the 
same time diminishes the peripheral side effects considerably, 
particularly vomiting and cardiac arrythmias, but a number of serious side 
effects still persist [A. Barbeau, TIPS, supra; A. Barbeau ad M. Roy, 
Neurology, 26, 399 [(1976)]. Attempts have also been made to alleviate the 
well-known dissolution, absorption and metabolism problems of L-Dopa [H. 
Ninterberger, Biochem. Med., 5, 412 (1971); H. Shindo, T. Komai, K. 
Tanaka, E. Nakajima and N. Miyakoshi, Chem. Pharm. Bull., 21, 826 (1973); 
C. O. Rutledge and M. M. Hoehn, Nature (London), 244, 447 (1973); R. L. 
Bronaugh, R. J. McMurty, M. M. Hoehn and C. O. Rutledge, Biochem. 
Pharmacol., 24, 1317 (1975)], employing prodrug approaches [N. Bodor, K. 
B. Sloan, T. Higuchi and K. Sasahara, J. Med. Chem., 20, 1435 (1977); A. 
M. Felix, D. P. Winter, S. S. Wang, I. D. Kulesha, W. R. Pool, D. L. Hane 
and H. Sheppard, J. Med. Chem., 17, 422 (1974)]. 
Additional, dopamine agonists, which are used in the treatment of 
hyperproclactinemia associated with pituitary adenomas or amenorrhea [R. 
F. Spark and G. Dickenstein, Ann. Int. Med., 90, 949 (1979)], also induce 
unwanted side effects. 
Thus, especially acutely serious need exists in this art to deliver a 
dopaminergic agent directly and specifically to the brain, in a sustained 
manner, and there elicit the desired dopaminergic response, e.g., for the 
treatment of the Parkinsonism or hyperprolactinemia. This need has been 
addressed by applicant's earlier copending applications referred to above, 
and especially by the Ser. No. 461,543, and is also addressed by the 
present application. 
SUMMARY AND OBJECTS OF THE INVENTION 
Accordingly, a major object of the present invention is the provision of a 
generic method for the specific and/or target enhanced delivery to the 
brain of a wide variety of drug species and to achieve brain-specific drug 
delivery by effecting the bidirectional transport of the drug species into 
and out of the brain employing dihydropyridine.revreaction.pyridinium salt 
carrier type redpox systems. 
Another object of the invention is to provide for brain specific drug 
delivery utilizing a dihydropyridine.revreaction.pyridinium salt carrier 
type redox system, shich drug/carrier system is characterized by enhanced 
drug efficacy and decreased toxicity. Indeed, consistent herewith systemic 
toxicity is significantly reduced by accelerating the elimination of the 
drug/quaternary carrier system, and even central toxicity is reduced by 
providing a low level, sustained release of the active drug species in the 
brain. 
Yet another object of this invention is the provision of a chemical 
delivery system for the site-specific and sustained release of drug 
species to the brain, and one in which a special pro-prodrug reduced form 
of an active drug species is actually delivered to the body of a patient, 
not a prodrug as such and not a drug/carrier entity necessarily comprised 
of critically tailored release rate-controlling substituent(s). 
Yet another object of this invention is to provide enhanced delivery to the 
brain of a wide variety of centrally acting agents which are not 
themselves able to penetrate the blood-brain barrier to any considerable 
extent. 
Briefly, the present invention features a 
dihydropyridine.revreaction.pyridinium salt carrier redox system for the 
specific and sustained delivery of drug species to the brain according to 
the following Scheme 1: 
##STR2## 
Consistent with the foregoing Scheme 1, any drug species [D] is coupled to 
a quaternary pyridinium salt carrier [QC].sup.+ and the prodrug 
([D--QC.sup.+ which results is then reduced chemically to the lipoidal 
dihydro pro-prodrug form [D--DHC]. Alternatively, the drug species [D] can 
be directly coupled to the dihydro carrier [DHC] in certain instances to 
yield said pro-prodrug form [D--DHC]. After administration of the [D--DHC] 
in vivo, it is rapidly distributed throughout the body, including the 
brain . The dihydro form [D--DHC] is then in situ oxidized (rate constant, 
k.sub.1) (by the NAD.revreaction.NADH system) to the ideally inactive 
original [D--QC].sup.+ quaternary salt prodrug, which, because of its 
ionic, hydrophilic character, is rapidly eliminated from the general 
circulation of the body, while the blood-brain barrier prevents its 
elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). 
Enzymatic cleavage of the [D--QC] that is "locked" in the brain effects a 
sustained delivery of the drug species [D], followed by its normal 
elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ 
will also be rapidly eliminated from the brain (k.sub.6 &gt;&gt;k.sub.2). 
Because of the facile elimination of [D--QC.sup.+ from the general 
circualtion, only minor amounts of drug are released in the body (k.sub.3 
&gt;&gt;k.sub.4); [D] is released primarily in the brain (k.sub.4 &gt;k.sub.2). The 
overall result is a brain-specific, sustained release of the target drug 
species. Cf. Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372; 
The Friday Evening Post, Aug. 14, 1981, Health Center Communications, 
University of Florida, Gainesville, Fla; Chemical & Engineering News, Dec. 
21, 1981, pp. 24-25; Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. 
See also Bodor et al, J. Med. Chem., Vol. 26, March 1983, pp. 313-317; 
Bodor et al, J. Med. Chem., Vol. 26, April 1983, pp. 528-534; Bodor et al, 
Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (April 1983); 
Bodor et al, Science, Vol. 221, July 1983, pp. 65-67; and Bodor et al, J. 
Pharm. Sci., Vol. 73, No. 3, March 1984, pp. 385-388. 
In accord with the foregoing, the present invention provides compounds 
adapted for the site-specific/sustained delivery of a centrally acting 
drug species to the brain, said compounds being: 
(a) compounds of the formula 
EQU [D--DHC] (I) 
wherein [D] is centrally acting drug species, and [DHC] is the reduced, 
biooxidizable, blood-brain barrier penetrating lipoidal form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier, with the 
proviso that when [DHC] is 
##STR3## 
wherein R is lower alkyl or benzyl and [D] is a drug species containing a 
single NH.sub.2 or OH functional group, the single OH group when present 
being a primary or secondary OH group, said drug species being linked 
directly through said NH.sub.2 or OH functional group to the carbonyl 
function of [DHC], then [D] must be other than a sympathetic stimulant, 
steroid sex hormone or long chain alkanol; or 
(b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) 
wherein [D] is a centrally acting drug species and [DHC] is the reduced, 
biooxidizable, blood-brain barrier penetrating lipoidal form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier. 
In another aspect, the present invention provides compounds having the 
formula 
EQU [D--QC].sup.+ X.sup.- (II) 
wherein X.sup.- is the anion of a non-toxic pharmaceutically acceptable 
acid, [D] is a centrally acting drug species and [QC].sup.+ is the 
hydrophilic, ionic pyridinium salt form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier, with the 
proviso that when [QC].sup.+ is 
##STR4## 
wherein R is lower alkyl or benzyl and [D] is a drug species containing a 
single NH.sub.2 or OH functional group, the single OH group when present 
being a primary or secondary OH group, said drug species being linked 
directly through said NH.sub.2 or OH functional group to the carbonyl 
function of [QC].sup.+, then [D] must be other than a sympathetic 
stimulant, steroid sex hormone or long chain alkanol. 
The present invention further provides a generic method for specific and/or 
target enhanced delivery to the brain of a wide variety of centrally 
acting drug species, such brain-specific drug delivery being effected via 
the bidirectional transport of the drug species into and out of the brain 
by means of dihydropyridine.revreaction.pyridinium salt carrier type redox 
systems. 
In yet another aspect, the present invention provides, as an effective 
dopaminergic chemical delivery system, compounds having the formula 
EQU [D--DHC] (I) 
and non-toxic pharmaceutically acceptable salts thereof, wherein [D] is a 
dopamine having the structural formula 
##STR5## 
in which each Y is independently hydrogen or a hydrolytically or 
metabolically cleavable hydroxyl protective group, and [DHC] is the 
reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of 
a dihydropyridine.revreaction.pyridinium salt redox carrier. 
In still another aspect, the present invention provides compounds having 
the formula 
EQU [D--QC].sup.+ X.sup.- (II) 
wherein X.sup.- is defined above and [D] is a dopamine having the 
structural formula 
##STR6## 
in which each Y is independently hydrogen or a hydrolytically or 
metabolically cleavable hydroxy protective group, and [QC].sup.+ is the 
hydrophilic, ionic pyridinium salt form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier. 
Briefly, one presently preferred chemical delivery system for dopamine 
according to this invention has the structure (2) in the following Scheme 
2, wherein the amino function of dopamine is appropriately linked to the 
dihydropyridine-type carrier system, while the catechol function is 
advantageously protected, for example, as a corresponding ester function, 
e.g., the dipivalyl ester illustrated. The brain-specific delivery of 
dopamine, or the otherwise eliciting of a dopaminergic response, requires 
a succession of processes, including oxidation of the dihydropyridine ring 
to the corresponding pyridinium salt (for example, structure 3), which 
provides the basis for "locking-in" in the brain the molecule, hydrolysis 
of the, e.g., pivalyl esters (see structure 4) likely via the 3- and/or 
4-monopivalyl esters and, finally, the release of dopamine (1) from 4, 
which can be either a hydrolysis or a reductive process [a possible 
reductive release of dopamine was very recently suggested by a model for a 
presynaptic terminal, L. L. Miller, A. N. K. Lau and E. K. Miller, J. Am. 
Chem. Soc., 104, 5242 (1982)]. 
##STR7## 
As per the above Scheme 2, for the brain specific delivery of dopamine (1), 
structure 2 is one chemical delivery system consistent herewith, and 4 is 
one precursor locked in the brain and eliminated rapidly from the rest of 
the body. Structures 3 depict intermediates formed during the stepwise 
hydrolysis and oxidation processes.

DETAILED DESCRIPTION OF THE INVENTION 
More particularly in accord with the present invention, the following 
definitions are applicable: 
The term "lipoidal" as used herein is intended to designate a carrier 
moiety which is lipid-soluble or lipophilic. 
The expression "hydroxyl protective group" is intended to designate a group 
which is inserted in place of the hydrogen atom(s) of an OH group or 
groups in order to prevent premature metabolism of said OH group or groups 
prior to the compound's reaching the desired site in the body. Typical 
hydroxyl protective groups contemplated by the present invention (e.g., 
for Y in the case of the dopamine derivatives) are acyl groups and 
carbonates. 
When the hydroxyl protective group is acyl (i.e., when it is an organic 
radical derived from a carboxylic acid by removal of the hydroxyl group), 
it preferably represents an acyl radical selected from the group 
consisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl having one or 
two double bonds and 3 to 8 carbon atoms; 
##STR8## 
wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, 
one, two or three; phenoxyacetyl; pyridinecarbonyl; and 
##STR9## 
wherein r is zero, one, two or three and phenyl is unsubstituted or is 
substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 
1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 
carbon atoms or alkanoylamino having 2 to 6 carbon atoms. 
When the acyl group is alkanoyl, there are included both unbranched and 
branched alkanoyl, for example, acetyl, propionyl, butyryl, isobutyryl, 
valeryl, isovaleryl, 2-methylbutanoyl, pivalyl (pivaloyl), 
3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl and the 
like. Pivalyl, isobutyryl and isovaleryl are especially preferred. 
When the acyl group is alkenoyl, there are included, for example, crotonyl, 
2,5-hexadienoyl and 3,6-octadienoyl. 
When the acyl group is 
##STR10## 
there are included cycloalkanecarbonyl and cycloalkanealkanoyl groups 
wherein the cycloalkane portion can optionally bear 1 or 2 alkyl groups as 
substituents, e.g. cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, 
cyclopropaneacetyl, .alpha.-methylcyclopropaneacetyl, 
1-methylcyclopropaneacetyl, cyclopropanepropionyl, 
.alpha.-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropionyl, 
cyclobutanecarbonyl, 3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 
2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl, 
cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl and 
cycloheptanepropionyl. Cyclohexanecarbonyl is especially preferred. 
When the acyl group is pyridinecarbonyl, there are included picolinoyl 
(2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl 
(4-pyridinecarbonyl). 
When the acyl group is 
##STR11## 
there are included, for example, benzoyl, phenylacetyl, 
.alpha.-phenylpropionyl, .beta.-phenylpropionyl, p-toluyl, m-toluyl, 
o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 
2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, 
p-isobutylphenylacetyl, .beta.-(p-ethylphenyl)propionyl, p-anisoyl, 
m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxyphenylacetyl, 
m-isobutoxyphenylacetyl, m-diethylaminobenzoyl, 3-methoxy-4-ethoxybenzoyl, 
3,4,5-trimethoxybenzoyl, p-dibutylaminobenzoyl, p-n-butoxybenzoyl, 
2,4,6-triethoxybenzoyl, 3,4-diethoxyphenylacetyl, 
.beta.-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl, 
p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 
2,4,6-trichlorobenzoyl, p-chlorophenylacetyl, 
.alpha.-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl, 
2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, 
.beta.-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl, 
3-chloro-4-ethoxybenzoyl, .beta.-(3-methyl-4-chlorophenyl)propionyl, 
p-dimethylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, 
o-acetamidobenzoyl, m-propionamidobenzoyl, 
3-chloro-4-acetamidophenylacetyl and p-acetamidophenylpropionyl. 
When the hydroxyl protective group is a carbonate grouping, it has the 
structural formula 
##STR12## 
i.e., it is an organic radical which can be considered to be derived from 
a carbonic acid by removal of the hydroxyl group from the COOH portion. Y' 
preferably represents alkyl having 1 to 7 carbon atoms; alkenyl having one 
or two double bonds and 2 to 7 carbon atoms; 
EQU cycloalkyl--C.sub.r H.sub.2r -- 
wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, 
one, two or three; phenoxy; 2-, 3- or 4-pyridyl; or 
EQU phenyl--C.sub.r H.sub.2r -- 
wherein r is zero, one, two or three and phenyl is unsubstituted or is 
substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 
1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 
carbon atoms or alkanoylamino having 2 to 6 carbon atoms. Most preferably, 
Y' is C.sub.1 -C.sub.7 alkyl, particularly ethyl or isopropyl. 
Similarly, the expression "carboxyl protective group" is intended to 
designate a group which is inserted in place of the hydrogen atom(s) of a 
COOH group or groups in order to prevent premature metabolism of said COOH 
group or groups prior to the compound's reaching the desired site in the 
body. Typical carboxyl protecting groups are the groups encompassed by Y' 
above, especially C.sub.1 -C.sub.7 alkyl, particularly ethyl, isopropyl 
and t-butyl. While such simple alkyl esters and the like are often useful, 
other carboxyl protecting groups may be selected in order to achieve 
greater control over the rate of in vivo hydrolysis of the ester back to 
the acid and thus enhance drug delivery. To that end, carboxyl protecting 
groups such as the following may be used to replace the hydrogen of the 
--COOH group: 
##STR13## 
wherein alk is C.sub.1 -C.sub.6 straight or branched alkylene and the 
alkyl radical is straight or branched and contains 1 to 7 carbon atoms 
(e.g. 
##STR14## 
The expression "amino protective group" as used herein is intended to 
designate a group which is inserted in place of the hydrogen atom(s) of an 
amino group or groups in order to prevent unwanted reaction of the amino 
function(s) during chemical synthesis. Such protective groups are 
well-known in the art and include t-butoxycarbonyl and carbobenzoxy (i.e. 
benzyloxycarbonyl). Other appropriate amino protective groups will be 
apparent to those skilled in the art. Unlike the instant hydroxyl and 
carboxyl protective groups described above, which not only prevent 
unwanted chemical reaction but also protect those hydroxyl and carboxyl 
functions from premature metabolism in vivo, the amino protective groups 
are primarily intended for use during synthesis and are typically removed 
by well-known procedures at an appropriate stage of the synthetic pathway 
after they have achieved their protective function and are no longer 
needed. Occasionally, however, an amino protective function will be 
retained in the compound of formula (I) to also protect the amino group in 
vivo. 
The term "drug" as used herein means any substance intended for use in the 
diagnosis, cure, mitigation, treatment or prevention of disease or in the 
enhancement of desirable physical or mental development and conditions in 
man or animal. 
By "centrally acting" drug species, active agent or compound as utilized 
herein, there is of course intended any drug species or the like, a 
significant (usually, principal) pharmacological activity of which is CNS 
and a result of direct action in the brain. 
Exemplary such centrally acting drug species are the CNS-amines and other 
nervous system agents, whether sympathetic or parasympathetic, e.g., 
phenylethylamine (a stimulant), dopamine (a neurotransmitter and 
dopaminergic agent used, e.g., in the treatment of Parkinsonism or 
hyperprolactinemia), tyramine (a stimulant), L-DOPA (a dopamine precursor 
used, for example, in the treatment of Parkinsonism); muscle relaxants, 
tranquilizers and antidepressants, e.g., benzodiazepine tranquilizers such 
as diazepam and oxazepam and phenothiazine tranquilizers such as 
carphenazine, fluphenazine and the like; mild and strong analgesics and 
narcotics; sedatives and hypnotics; narcotic antagonists; vascular agents; 
stimulants; anesthetics; small peptides, such as the di-, tri-, tetra and 
pentapeptides, and other small 2-20 amino acid unit containing peptides, 
e.g. the enkephalins (for example, Tyr-Gly-Gly-Phe-Leu), which, besides 
being analgesics, initiate epileptic activity in the brain at doses that 
are about tenfold lower than for effecting analgesic activity; larger 
peptides, such as pituitary hormones and related agents; growth-promoting 
substances; antiepileptic and anticonvulsant drugs generally, including 
hydantoins such as phenytoin and ethotoin, barbituates such as 
phenobarbital; hormones, such as the steroid hormones, e.g., estradiol, 
testosterone, 17 .alpha.-ethylnyl testosterone (ethisterone), and the like 
(recent studies on histological mapping of hormone-sensitive and specific 
steroid binding cells in the brain have underscored the importance of the 
steroid action in the brain on sexual behavior); amphetamine-like drugs; 
anticancer and anti-Parkinsonism agents; antihypertensives; agents to 
enhance learning cpacity and the memory processes, including treatment of 
dementias, such as Alzheimer's disease; antibacterials; centrally acting 
hypotensive agents; centally acting prostaglandins, such as PGD.sub.2 ; 
diagonstic agents, such as radio-pharmaceuticals; monoamine oxidase (MAO) 
inhibitor drugs; CNS or brain important/essential amino acids, such as 
tryptophan (which is an antidepressant as well as a nutrient); and any 
like centrally acting compounds. For the purposes of this invention, dopa 
or L-DOPA is not classified as an amino acid but rather as a CNS amine and 
dopaminergic agent used, e.g. in the treatment of Parkinsonism. 
Other illustrative ultimate species of centrally acting drug entities are: 
amphetamine, dextroamphetamine, levamphetamine, aletamine, cypenamine, 
fencamfamin, fenozolone, zylofuramine, methamphetamine, phenmetrazine and 
phentermine, which are sympathomimetic amines/cerebral stimulants and 
appetite suppressants; etryptamine, a cerebral stimulant; codeine, 
oxycodone, pentazocine, anileridine, hydromorphone, morphine and 
oxymorphone, which are narcotic analgesics; desipramine, nortriptyline, 
octriptyline, maprotiline, opipramol and protriptyline, which are cerebral 
stimulants/tricylic antidepressants of the dibenzazepine type used, e.g., 
in endogenous depressions; clonidine and methyldopa, which are 
sympatholytic agents used, e.g., in hypertension; biperiden, cycrimine and 
procyclidine, which are centrally acting anticholinergics; 
tranylcypromine, a sympathomimetic cerebral stimulant/MAO inhibitor and 
antidepressant; acetophenazine, carphenazine, fluphenazine, perphenazine 
and piperacetazine, which are phenothiazine-type tranquilizers; 
benzoctamine, a sedative/muscle relaxant which structurally is an analogue 
of the phenothiazine tranquilizers; chlordiazepoxide, clorazepate, 
nitrazepam and temazepam, which are benzodiazepine-type tranquilizers; 
noracymethadol, a narcotic analgesic of the methadone type; piminodine, a 
narcotic analgesic of the meperidine type; tracazolate, a 
sedative/hypotensive; prizidilol, a centrally acting hypotensive; 
sulpiride, an antidepressant/psychotropic; haloperidol and clopenthixol, 
which are tranquilizers; norepinephrine, a sympathetic 
stimulant/adrenergic agent; nalorphine and naloxone, narcotic antagonists; 
hydralazine, a hypotensive; ethotoin, phenobarbital and aminoglutethimide, 
anticonvulsants; epinephrine, an adrenergic agent; ethamivan, a medullary 
stimulant; bemegride, a barbiturate antagonist; amiphenazole, a stimulant; 
iopydol, iodopyracet, idouppurate (o-iodohippuric acid), iodamide and 
iopanoic acid, which are radiodiagnostics; ephedrine, pseudoepherdrine, 
oxymetazoline and phenylephrine, which are sympathomimetic amines and 
decongestants; estradiol, estrone and estriol, the natural estrogens; 
amoxicillin, oxacillin, carbenicillin, benzylpenicillin, 
phenoxymethylpenicillin, methicillin, nafcillin, ticarcillin, 
bacampicillin, epicillin, hetacillin, pivampacillin, the methoxymethyl 
ester of hetacillin, and ampicillin, which are penicillin-type 
antibiotics; amobarbital, a sedative; trihexyphenidyl, a centrally acting 
antichloinergic; hydroxyzine, a tranquilizer; chlortetracycline, 
demeclocycline, minocycline, doxycycline, oxytertracycline, tetracycline 
and methacycline, which are tetracycline-type antibiotics; flurazepam, 
bromazepam, demoxepam and lorazepam, benzodiazepine tranquilizers; 
phenytoin, an anticonvulsant; glutethimide, a mild hypnotic/sedative; 
clindamycin, lincomycin, nalidixic acid, oxolinic acid and 
phenazopyridine, antibacterials/antibiotics; bethanidine and guanethidine, 
hypotensives/sympatholytics; captopril, a hypotensive; methyprylon, a mild 
hypnotic; amedalin, bupropion, cartazolate, daledalin, difluanine, 
fluoxetine and nisoxetine, which are cerebral stimulants; propranolol, a 
.beta.-blocker antihypertensive; dicloxacillin, a penicillin-type 
antibacterial; butalbital, a barbiturate sedative; GABA, .gamma.-vinyl 
GABA, .gamma.-acetylenic GABA, neurotransmitters for possible use in 
epilepsy; valproic acid and its metabolites such as 
5-hydroxy-2-n-propyl-pentanoic acid, 4-hydroxy-2-n-propylpentanoic acid, 
3-hydroxy-2-n-propylpentanoic acid, for use as anticonvulsants; 
valpromide, a valproic acid derivative for use as an anticonvulsant; 
apomorphine, a narcotic depressant/emetic which has been used in the 
treatment of photosensitive epilepsy; pholcodine, a narcotic antitussive; 
methotrexate, mitoxantrone, podophyllotoxin derivatives (etopside, 
teniposide), doxorubicin, daunamycin and cyclophosphamide, 
anticancer/antitumor agents; methylphenidate, a stimulant; thiopental, an 
anesthetic; ethinyl estradiol and mestranol, estrogens; meptazinol, 
cyclazocine, phenazocine, profadol, metopon, drocode and myfadol, which 
are narcotic analgesics; buprenorphine, nalbuphine, butorphanol, 
levallorphan, naltrexone, alazocine, oxilorphan and nalmexone, which are 
narcotic antagonists or agonist-antagonists; norgestrel and norethindrone, 
progestins; cephalothin, cephalexin, cefazolin, cefoxitin, moxalactam, 
ceforanide, cefroxadine and cephapirin, cephalosporin antibiotics; 
atenolol, nadolol, timolol and metoprolol, .beta.-blockers/hypotensives; 
ACTH (corticotropin), a hormone which stimulates glucocorticoid 
production; LHRH, a neurotransmitter which stimulates secretion of the 
pituitary hormones, LH and FSH, and has been used to induce ovulation as 
well as for fertility control/contraception; sulfadiazine and other 
sulfonamide antibiotics; ribavarin and acyclovir, antiviral agents; 
chlorambucil and melphalan, nitrogen mustard-type anticancer/antitumor 
agents; methotrexate and aminopterin, which are folic acid antagonist-type 
anticancer/antitumor agents; platinum coordination complexes, i.e. 
cisplatin analogue-type anticancer/antitumor agents; dactinomycin and 
mitomycin C, used in cancer chemotherapy; thioguanine, a purine/pyrimidine 
antagonist used in cancer treatment; vincristine and vinblastine, 
anticancer alkaloids; hydroxyurea and DON, anticancer urea derivatives; 
FSH, HCG and HCS, pituitary and nonpituitary gonadotropins, used, for 
example, in certain reproductive disorders; 
N,N'-bis(dichloracetyl)-1,8-octamethylenediamine (fertilysin), an agent 
for male fertility inhibition; levorphanol, a narcotic analgesic; 
benzestrol and diethylstilbestrol, synthetic estrogens; ethyl 
.beta.-carboline-3-carboxylate, a benzodiazepine antagonist; furosemide, a 
diuretic/antihypertensive; dipyridamole and nifedipine, coronary 
vasodilators; and progabide, a GABA-agonist and prodrug of GABA. Yet other 
ultimate species include non-steroidal antiinflammatory 
agents/non-narcotic analgesics, e.g. propionic acid derivatives, acetic 
acid derivatives, fenamic acid derivatives and biphenylcarboxylic acid 
derivatives. Specific NSAID's/non-narcotic analgesics contemplated for use 
herein include ibuprofen, naproxen, flurbiprofen, zomepirac, sulindac, 
indomethacin, fenbufen, fenoprofen, indoproxen, ketoprofen, fluprofen, 
bucloxic acid, tolmethin, alclofenac, fenclozic acid, ibufenac, 
flufenisal, pirprofen, flufenamic acid, mefenamic acid, clonixeril, 
clonixin, meclofenamic acid, flunixin, diclofenac, carprofen, etodolac, 
endosal, prodolic acid, sermetacin, indoxle, tetrydamine, diflunisal, 
naproxol, piroxicam, metazamide, flutiazin and tesicam. 
Preferred classes of centrally acting drugs for use herein are the central 
neurotransmitters, steroids, anticancer and antitumor agents, antiviral 
agents, tranquilizers, memory enhancers, hypotensives, sedatives, 
antipsychotics and cerebral stimulants (especially tricyclic 
antidepressants). Among the neurotransmitters, there can be mentioned 
amino acids, such as GABA, GABA derivatives and other omega-amino acids, 
as well as glycine, glutamic acid, tyrosine, aspartic acid and other 
natural amino acids; catecholamines, such as dopamine, norepinephrine and 
epinephrine; serotonin, histamine and tryptamine; and peptides such as 
neurotensin, luteinizing hormone-releasing hormone (LHRH), somatostatin, 
enkephalins such as met.sup.5 -enkephalin and leu.sup.5 -enkephalin, 
endorphins such as .gamma.-, .alpha.- and .beta.-endorphins, oxytocin M 
and vasopressin. Synthetic and semi-synthetic analogues, e.g. analogues of 
LHRH in which one or more amino acid(s) has/have been eliminated and/or 
replaced with one or more different amino acid(s), and which may be 
agonists or antagonists, are also contemplated, e.g. the primary and 
secondary amine LHRH analogues disclosed in U.S. Pat. Nos. 4,377,574, 
3,917,825, 4,034,082 and 4,338,305. Among the steroids, there can be 
mentioned anti-inflammatory adrenal cortical steroids such as 
hydrocortisone, betamethaxone, cortisone, dexamethaxone, flumethasone, 
fluprednisolone, meprednisone, methyl prednisolone, prednisolone, 
prednisone, triamcinolone, cortodoxone, fluroroctisone, flurandrenolone 
acetonide (flurandrenolide), paramethasone and the like; male sex hormones 
(androgens), such as testosterone and its close analogues, e.g. methyl 
testosterone (17-methyltestosterone); and female sex hormones, both 
estrogens and progestins, e.g. progestins such as norgestrel, 
norethindrone, norethynodrel, ethisterone, dimethisterone, allylestrenol, 
cingestol, ethynerone, lynestrenol, norgesterone, norvinisterone, 
ethynodiol, oxogestone and tigestol, and estrogens such as ethinyl 
estradiol, mestranol, estradiol, estriol, estrone and quinestrol and the 
like. Among the anticancer and antitumor agents, there can be mentioned 
Ara-AC, pentostatin (2'-deoxycoformycin), Ara-C (cytarabine), 
3-deazaguanine, dihydro-5-azacytidine, tiazofurin, sangivamycin, Ara-A 
(vitarabine), 6-MMPR, PCNU, spiromustine, bisbenzimidazole, L-alanosine 
(6-diazo-5-oxo-L-norleucine), DON, L-ICRF, trimethyl, TMM, 
5-methyltetrahydrohomofolic acid, glyoxylic acid sulfonylhydrazone, DACH, 
SR-2555, SR-2508, desmethylmisonidazole, mitoxantrone, menogarol, 
aclacinomycin A, phyllanthoside, bactobolin, aphidocolin, 
homoharringtonine, levonatradol, acivicin, streptozotocin, hydroxyurea, 
chlorambucil, cyclophosphamide, uracil mustard, melphalan, 5-FUDR 
(floxuridine), vincristine, vinblastine, cytosine arabinoside, 
6-mercaptopurine, thioguanine, 5-azacytidine, methotrexate, adriamycin 
(doxorubicin), daunomycin (daunorubicin), largomycine polypeptide, 
aminopterin, dactinomycin, mitomycin C, and podophyllotoxin derivatives, 
such as etoposide (VP-16) and teniposide. Among the antiviral agents, 
there can be mentioned ribavarin; acyclovir (ACV); amantadine (also of 
possible value as an anti-Parkinsonism agent); diarylamidines such as 
5-amidino-2-(5-amidino-2-benzofuranyl)indole and 
4',6-diimidazolino-2-phenylbenzo(b)thiophene; 2-aminooxazoles such as 
2-guanidino-4,5-di-n-propyloxazole and 2-guanidino-4,5-diphenyloxazole; 
benzimidazole analogues such as the syn and anti isomer of 
6[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazo 
l-2-amine; bridgehead C-nucleosides such as 
5,7-dimethyl-2-.beta.-D-ribofuranosyl-s-triazole(1,5-a)pyrimidine; 
glycosides such as 2-deoxy-D-glucose, glucosamine, 
2-deoxy-2-fluoro-D-mannose and 6-amino-6-deoxy-D-glucose; phenyl glucoside 
derivatives such as phenyl-6-chloro-6-deoxy-.beta.-D-glucopyranoside; 
(S)-9-(2,3-dihydroxypropyl)adenine; 6-azauridine; idoxuridine; 
trifluridine; BDVU (bisdihydroxyvinyluridine); and 
5,6-dichloro-1-.beta.-D-ribofuranosylbenzimidazole. Among the 
tranquilizers, there can be mentioned benzodiazepine tranquilizers, such 
as diazepam, oxazepam, lorazepam, chloridazepoxide, flurazepam, 
bromazepam, chlorazepate, nitrazepam and temazepam; hydantoin-type 
tranquilizers/anticonvulsants such as phenytoin, ethotoin, mephenytoin; 
phenothiazine-type tranquilizers such as acetophenazine, carphenazine, 
fluphenazine, perphenazine and piperacetazine; and others. Among the 
hypotensives, there can be mentioned clonidine, methyldopa, bethanidine, 
debrisoquin, hydralazine, and guanethidine and its analogues. Among the 
sedatives, tranquilizers and antipsychotics, there can be mentioned the 
many specific compounds of this type disclosed above, especially the 
phenothiazines and benzodiazepines and their analogues. Among the cerebral 
stimulants, there also can be mentioned the many specific compounds set 
forth hereinabove, particularly the sympathomimetic amine-type cerebral 
stimulants and the tricyclic antidepressants, especially preferred 
tricyclics being the dibenzazepines and their analogues. 
Also illustrative of the centrally acting drug species contemplated by this 
invention are centrally active metabolites of centrally acting drugs. Such 
metaolites are typified by hydroxylated metabolites of tricyclic 
antidepressants, such as the E- and Z-isomers of 10-hydroxynortriptyline, 
2-hydroxyimipramine, 2-hydroxydesipramine and 8-hydroxychlorimpramine; 
hydroxylated metabolites of phenothiazine tranquilizers, e.g. 
7-hydroxychlorpromazine; and desmethyl metabolites of N-methyl 
benzodiazepine tranquilizers, e.g. desmethyldiazepam. Other CNS active 
metabolites for use herein will be apparent to those skilled in the art, 
e.g. SL 75102, which is an active metabolite of progabide, a GABA agonist. 
Typically, these CNS active metabolites have been identified as such in 
the scientific literature but have not been administered as drugs 
themselves. In many cases, the active metabolites are believed to be 
comparable in CNS activity to their parent drugs; frequently, however, the 
metabolites have not been administered per se because they are not 
themselves able to penetrate the blood-brain barrier. 
As indicated hereinabove, diagnostic agents, including 
radiopharmaceuticals, are encompassed by the expression "centrally acting 
drug" or the like as used herein. Any diagnostic agent which can be 
derivatized to afford a compound of formula (I) which will penetrate the 
BBB and concentrate in the brain in its quaternary form (II) and can be 
detected therein is encompassed by this invention. The diagnostic may be 
"cold" and be detected by X-ray (e.g. radiopaque agents) or other means 
such as mass spectrophotometry, NMR or other non-invasive techniques (e.g. 
when the compound includes stable isotopes such as C13, N15, O18, S33 and 
S34). The diagnostic alternatively may be "hot", i.e. radiolabeled, such 
as with radioactive iodine (I 123, I 125, I 131) and detected/imaged by 
radiation detection/imaging means. Typical "cold" diagnostics for 
derivation herein include p-iodohippuric acid, iothalamic acid, iopydol, 
iodamide and iopanoic aicd. Typical radiolabeled diagnostics include 
diohippuric acid (I 125, I 131), diotyrosine (I 125, I 131), 
o-iodohippuric acid (I 131), iothalamic acid (I 125, I 131), thyroxine (I 
125, I 131), iotyrosine (I 131) and iodometaraminol (I 123), which has the 
structural formula 
##STR15## 
In the case of diagnostics, unlike the case of drugs which are for the 
treatment of disease, the "locked in" quaternary form will be the form 
that is imaged or otherwise detected, not the original diagnostic itself. 
Moreover, any of the centrally acting drugs encompassed by this invention 
which are intended for the treatment or prevention of medical disorders 
but which can be radiolabeled, e.g. with a radioisotope such as iodine, or 
labeled with a stable isotope, can thus be converted to a diagnostic for 
use herein. Put another way, any compound of formula (I) of this invention 
which can have incorporated into its structure such a radioactive or 
stable isotope [either directly or through incorporation of the isotope 
into the structure of the corresponding compound of formula (II)] can be 
used for diagnostic purposes. 
It will be apparent from the known structures of the many drug species 
exemplified above, that in many cases the selected drug will possess more 
than one reactive functional group, and, in particular, that the drug may 
contain hydroxyl or carboxyl or amino or other functional groups in 
addition to the groups to which the carrer will be linked, and that these 
additional groups will at times benefit from being protected during 
synthesis and/or during administration. The nature of such protection is 
described in more detail below. Obviously, such protected drug species are 
encompassed by the definition of "drug" set forth hereinabove. 
It too will be appreciated that by "dihydropyridine carrier" or "[DHC]", 
there is intended any nontoxic carrier moiety comprising, containing or 
including the dihydropyridine nucleus, whether or not a part of any larger 
basic nucleus, and whether substituted or unsubstituted, the only 
criterion therefor being capacity for BBB penetration and in vivo 
oxidation thereof to the corresponding quaternary pyridinium salt carrier 
[QC].sup.+. As aforesaid, the ionic pyridinium salt drug/carrier prodrug 
entity [D--OC].sup.+ which results from such in vivo oxidation is 
prevented from efflux from the brain, while elimination from the general 
circulation is accelerated. Subsequently, the covalent or equivalent bond 
coupling the drug species [D] to the quaternary carrier [QC].sup.+ is 
metabolically cleaved, which results in sustained delivery of the drug [D] 
in the brain and facile elimination of the carrier moiety [QC].sup.+. Such 
"covalent or equivalent bond" between the drug and the quaternary carrier 
can be a simple direct chemical bond, e.g., an amide, an ester, or any 
other like bond, or same can even be comprised of a linking group or 
function, e.g., a thiazolidine bridge or a peptide linkage, typically 
necessitated when the drug species is not susceptible to direct chemical 
coupling to either the dihydropyridine carrier or the quaternary carrier. 
Nonetheless, the bond in the formulae [D--QC].sup.+ and [D--DHC] is 
intended to be, and is hereby defined as inclusive of all such 
alternatives. And the cleavage of the [D--QC].sup.+ prodrug to sustainedly 
delivery the drug species [D] in the brain with concomitant facile 
elimination of the carrier moiety [QC].sup.+ is characteristically 
enzymatic cleavage, e.g., by esterase, amidase, cholinesterase, hydrolytic 
enzyme, or peptidase, albeit any type of in brain cleavage which might 
result, whether enzymatic, metabolic or otherwise, of course remains 
within the ambit of this invention. Thus, the drug release rate 
controlling parameter of the subject pro-prodrugs is imparted simply via 
the cleavable bonding between drug and carrier, and not by any release 
rate controlling substituent(s). 
The expression "non-toxic pharmaceutically acceptable salts" as used herein 
generally includes the nontoxic salts of compounds of formula (I), wherein 
[D] is a centrally acting drug species and [DHC] is the reduced, 
biooxidizable, blood-brain barrier penetrating form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier, formed with 
nontoxic, pharmaceutically acceptable inorganic or organic acids XH. For 
example, the salts include those derived from inorganic acids such as 
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the 
like; and the salts prepared from organic acids such as acetic, propionic, 
succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, 
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, 
sulfanilic, fumaric, methanesulfonic, toluenesulfonic and the like. The 
expression "anion of a non-toxic pharmaceutically acceptable acid" as used 
herein, e.g. in connection with structure (II), is intended to include 
anions of such inorganic or organic acids HX. 
In one embodiment according to this invention, simple nontoxic carrier 
systems [D--QC].sup.+ .revreaction.[D--DHC] are envisaged, utilizing a 
wide variety of models for D, such as those above outlined. Representative 
such carrier systems and models are: 
##STR16## 
wherein R.sub.2 is simply alkyl, e.g., CH.sub.3, or benzyl, albient 
virtually any other effective substituent is intended. (As depicted above, 
the isomeric dihydropyridine structure depends on the position of the 
substituent relative to the pyridine nitrogen.) Exemplary of such simple 
carrier systems are N-alkyl nicotinamide and nicotinate ester derivatives, 
tethered to such drug species as dopamine, melphalan and testosterone. The 
trigonelline (N-methylnicotinic acid) system is quite effective as a 
carrier; it also is readily eliminated from the circulation and is 
virtually non-toxic. 
Indeed, the present invention provides a flexible arsenal of 
dihydropyridine.revreaction.pyridinium salt redox carriers for the 
site-specific/sustained delivery of virtually any centrally acting drug 
species to the brain. Moreover, any dihydropyridine/pyridinium salt redox 
carrier entity is contemplated and intended hereby generically, and any 
such carrier moiety need not be, and is not, derivatized with a drug 
release rate controlling substituent critically tailored to meet, or be 
coordinated with, the chemical nature and deliveery requirements of the 
particular drug species sought to be preferentially administered to the 
brain. As utilized herein, the term "carrier" is to be understood as 
connoting just such a non-derivatized, non-drug/carrier coordinated 
entity, for consistent herewith it is the "carrier" entity itself and not 
the nature of any activity or release rate controlling/modifying 
substituent which is responsible for providing the desired brain-specific 
result. 
Additional examples of such redox carriers include the quaternary 
pyridinium alcohols (1), the analog isoquinoline acid and alcohol systems 
(2), and multicharged delivery forms, exemplified by structure 3 (D 
represents drug, Z a colvant link) and obviously the corresponding dihydro 
forms. 
##STR17## 
Yet other redox carriers include those comprising an acidic chain directly 
linked to the heterocyclic nitrogen, in quaternary or tertiary amine form. 
Also the hydroxide type carriers, e.g., the glucosamine analog indicated 
below. Representative are: 
##STR18## 
Preparation: 
##STR19## 
Method of: H. Lattre et al., Annalen, 579, 123 (1953). 
##STR20## 
Generally preferred dihydropyridine.revreaction.pyridinium salt redox 
carriers for use in the present invention include the following (where D 
represents the drug), and obviously the corresponding dihydro forms: 
(a) the pyridinium systems 
##STR21## 
in which the depicted substituent is in the 2-, 3- or 4- position, and 
R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, preferably 
methyl or benzyl; 
(b) the pyridinium system 
##STR22## 
in which R.sub.3 is C.sub.1 to C.sub.3 alkylene, i.e., (CH.sub.2).sub.n 
where n=1-3; 
(c) the isoquinolinium and quinolinium systems 
##STR23## 
in which R.sub.1 is defined as above; and 
(d) the quinolinium andisoquinolinium systems 
##STR24## 
in which R.sub.3 is defined as above. The corresponding dihydro forms of 
the foregoing preferred pyridinium salts are depicted below, wherein the 
position and identity of the structural variables are as indicated above: 
##STR25## 
In accord with the present invention, the sustained delivery of a drug to 
the brain in sufficient concentrations to achieve the desired 
pharmacological effect can be accomplished with much lower concentrations 
in the peripheral circulation and other tissues. The present invention of 
course will allow such treatment of any other organs or glands in which 
sufficient drug accumulates. Thus, for example, it is expected that the 
quaternary form (II) which is locked in the brain will be locked in the 
tests as well. See applicant's earlier copending Application Ser. No. 
475,493. 
The novel chemical delivery system of this invention begins with the 
preparation of the novel quaternary intermediates of formula (II). The 
preparation of those intermediates will be tailored to the particular drug 
portion and carrier portion to be combined, and especially to the nature 
of the chemical bond between them, e.g. whether the linkage is an ester or 
amide linkage, as well as to the presence or absence of other reactive 
functional groups (amino, mercapto, carboxyl, hydroxyl, hydroxy) in either 
the drug or carrier portion. Typicaly, if such other reactive groups are 
present, they are found in the drug portion. In any event, when such 
groups are present and it is desired to protect them, a step that 
introduces appropriate protecting groups can be incorporated at a suitable 
stage of the synthetic pathway. Typical protective groups are well known 
in the art and have been defined hereinabove. When carbonate protecting 
groups for hydroxy radicals are desired, the step of introducing the 
protecting groups will involve reacting the alcohol with a halocarbonate 
of the type ROCOCl or ROCOBr (formed by reaction of ROH with COCl.sub.2 or 
COBr.sub.2, R typically being lower akyl). For acyl protecting groups, the 
alcoholic hydroxyl is reacted with an acyl halides RCl or RBr, R being 
e.g., --COCH.sub.3 or --COC(CH.sub.3).sub.3. Yet other reaction schemes 
and reactants will be readily apparent to those skilled in the art, as 
well the appropriate means for removing such protective groups after they 
have achieved their function and are no longer needed. As already 
explained above, carboxyl and hydroxyl protecting groups are typically 
retained in the compounds of formulas (I) and (II) rather than being 
removed, so that they can perform their protective function in vivo as 
well. 
In forming the intermediates of formula (II), at least one amino, hydroxyl, 
mercapto, carboxyl, amide or imide group in a drug will be bonded to 
[QC.sup.+ ], the hydrophilic, ionic pyridinium salt form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier. 
In a preferred embodiment of the present invention, sustained delivery of 
drug to the brain in pharmacologically effective concentrations has now 
been demonstrated, paralleled with much lower concentrations in the 
peripheral circulation and other tissues, utilizing dopamine as the target 
drug species and a trigonelline-type carrier system, with the catechol 
moiety thereof in certain instances being acylated, e.g., acetylated or 
pivalylated. According to Scheme 3 which follows, one specific delivery 
system for dopamine, compound 5, on administratio (e.g., by injection) is 
distributed throughout the body and by reason of its lipophilic character 
facilely penetrates the blood-brain barrier and enters the CNS. Following 
oxidation both in the brain and in the other tissues, the corresponding 
hydrophilic quaternary salt (6) is formed. The quaternary salt 6 is 
essentially "locked in" the brain and its concentration is considered to 
increase with time until reaching a maximum, which depends primarily on 
the relative rates of entrance of the dihydro compound (5) to the brain 
(K.sub.1) as compared to K.sub.2 to the other tissues, the rate of 
oxidation of the dihydro form to the quaternary (K.sub.3 and K.sub.7) and 
the rates of its disappearance from the brain (K.sub.4 +K.sub.5). At the 
same time, the very water soluble quaternary forms) 6 is/are excreted 
readily via the kidney and the liver (K.sub.8 &gt;&gt;K.sub.4). Derivatives 6 
are considered to be essentially inactive forms (K.sub.8 &gt;&gt;K.sub.9), and 
thus systemic activity/toxicity is minimized. Hence, the concentration of 
5 and 6 in the blood rapidly increases. The ratio of the quateernary salt 
6 in the brain relative to the blood increases to the point where 6, or 
metabolites thereof, can only be found in the brain. The quaternary 6, 
whether in the brain, blood or other tissues, is deemed to release 
dopamine and the non-toxic compound, trigeonelline, depending upon the 
rates of site-specific conversion of the precursor 6 to the drug at each 
of these sites. The concentration of any released dopamine at any time is 
much higher in the brain than in the blood or other tissues. Also, as the 
enzymatic transformation of the quaternary precursor 6 to the drug 
(dopamine) is relatively slow, same permits a sustained release of 
dopamine. Too, the simultaneous protection/lipophilic derivatization of 
the catechol system in dopamine has also now been demonstrated. 
It will be appreciated that a compound of formula (I), suc as compound 5, 
may be administered as the free base, e.g. as depicted in Scheme 3, or in 
the form of a non-toxic pharmaceutically acceptable salt thereof, i.e., a 
salt which can be represented generally by the formula 
[D--DHC].HX 
and more specifically with respect to Scheme 3 by the formula 
##STR26## 
wherein HX is as defined befoe; and that, regardless of the actual form in 
which the compound is administered, it will be converted in vivo to a 
quaternary salt of formula (II), i.e. a salt of the compound 6 type, the 
anion X.sup.- being an anion present in vivo. It is not necessary that the 
anion be introduced as part of the compound administered. And even when 
the compound of formula I (e.g. compound 5) is used in its salt form, the 
anion of the formula (II) compound (e.g. of compound 6) is not necessarily 
the same as that present in the formula (I) compound. In any event, the 
exact identity of the anionic portion of the compound of formula (II), is 
immaterial to the in vivo transformation of (I) to (II), e.g. the depicted 
enzymatic transformation. 
##STR27## 
With specific reference to the immediately above, the 1,4-dihydropyridine 
derivatives (5) were prepared as in the following Scheme 4: 
##STR28## 
Similar schemes can be shown for the preparation of the other dopamine 
derivatives of the invention. The step which introduces the protecting 
groups is of course only required when it is desired to protect the 
catechol hydroxyl groups. Moreover, when carbonate rather than acyl 
protecting groups are desired, the step of introducing the protecting 
groups will involve reacting the catechol with a halocarbonate of the type 
Y'OCOCl or Y'OCOBr (formed by reaction of Y'OH with COCl.sub.2 or 
COBr.sub.2), rather than with an acyl halide YCl or YBr, Y and Y' being as 
generically defined hereinabove. Also, the order of steps shown in Scheme 
4 may be altered; quaternization, followed by reduction, need not be in 
the final two steps but may be carried out earlier in the reaction 
sequence. Yet other reaction schemes and reactants (e.g., using an 
anhydride rather than an acyl halide to convert 7 to 8) will be readily 
apparent to those skilled in the art, Scheme 4 being simply a preferred 
approach for the specific compounds there depicted. Variations of this 
approach are likewise applicable to preparing derivatives of other 
hydroxy-containing amines. 
In an attempt to ascertain whether any biotransformation of the free 
catechol is taking place by COMT (catechol-O-methyltransferase) either 
before or after oxiation, the possible O-methyl metabolites (9 and 10) 
were synthesized separately following Scheme 4 with 3-methoxytyramine 
hydrochloride as the starting material. 
##STR29## 
The stability of the 1,4-dihydropyridine derivatives (5) was determined in 
the presence of the oxidizing agents, alcoholic AgNO.sub.3 and hydrogen 
peroxide. The in vitro rates of oxidation of the 1,4-dihydropyridine 
derivative (5c) in 80% plasma, 20% brain homogenate, 20% liver homogenate 
and in whole blood were determined. 
The dihydropyridine derivative (5c) was then selected for the in vivo 
study. A solution in DMSO (dimethylsulfoxide) was injected through the 
jugular vein to a group of male Sprague-Dawley rats which were then 
sacrificed at various time intervals; their blood and brains were analyzed 
for the quaternary percursor of dopamine (6a). The in vivo dopaminergic 
activities of the selected compounds 5c vs. 6a were then determined. 
Consistent with the above, it was found that N-nicotinoyldopamine (7) could 
be obtained in good yields by coupling dopamine hydrobromide with 
nicotinic acid in pyridine as a solvent and with dicyclohexylcarbodiimide 
as the coupling agent. Attempts to prepare 7 by using dopamine free base 
were largely unsuccessful. As for the catechol protecting groups, the 
acetyl and pivalyl moieties were selected due to their rather different 
steric and partitioning parameters. Acylation could be accomplished with 
the acyl chlorides by using conventional methods. Reduction of the 
quaternaries (6a-c and 9) was accomplished by using sodium dithionite in 
mildly basic aqueous solution, (NaHCO.sub.3). It was observed that the 
dihydro compound obtained in the case of the quaternary 6b gave a faint 
green color with ferric ions, indicating partial hydrolysis of at least 
one of the acetyl moieties during reduction, even in the cold, weakly 
basic solution used as a medium. The dihydropyridine derivatives isolated 
(5a-c and 10) were determined to have the expected 1,4-dihydropyridine 
structure, based on their NMR and UV spectra. Attempts to prepare the 
.beta.-protonated enamine salts of the isolated dihydro derivatives were 
also largely unsuccessful, due to acid catalyzed addition reactions. The 
1,4-dihydropyridine derivatives (5a-c) were found to be relatively stable 
towards oxidation. Compound 5c was quantitatively oxidized to the 
corresponding quaternary salt 6c by H.sub.2 O.sub.2 or alcoholic 
AgNO.sub.3 solution. 
The diacetyl derivatives (5b and 6b) appeared to be labile to hydrolysis 
and therefore were not pursued in vitro. The dipivalyldihydro derivative 
(5c) was thoroughly investigated for its in vitro rates of disappearance 
and metabolic degradation in various biological fluids. It is evident that 
5c represents a rather complex case, as besides oxidation, a two-step 
hydrolysis will also take place. Scheme 5 illustrates the interconversion 
of the possible components. 
##STR30## 
FIGS. 1-4 illustrate the results of such an investigation. The apparent 
half-lives for the disappearance of 5c in biological fluids at 37.degree. 
C. were calculated. Although the process does not truly follow first order 
kinetics, the data fit very closely a pseudo first order process (FIG. 5). 
The obtained values, 51 min (80% plasma), 17 min (20% brain homogenate), 
18 min (whole citrated blood) and 6 min (20% liver homogenate), reflect an 
acceptable stability of the dihydro derivative 5c. The disappearance of 5c 
is accompanied by formation of some monoester (11) and dihydroxy dihydro 
form (5a) in all the media except the liver homogenate. The rate of 
hydrolysis of the first ester moiety is faster than the second and a 
reasonable amount of monoester 11 builds up with time. The monohydroxy 
quaternary 12 could not be detected except in the blood as a very small 
peak which does not change significantly with time. A steady increase in 
the concentration of the dihydroxy quaternary 6a was observed in all media 
except liver homogenate. Thus, it is established that this derivative, 6a, 
is forming as the main product of the various interconversion routes and 
it is the direct precursor thus concluded to be locked in the brain in the 
in vivo experiment. No formation of the methoxy derivatives 9 and 10 could 
be detected in any of the biological fluids studied; 5a and 6a do not 
appear to be good substrates for COMT. 
The first objective of the in vivo studies was to trace the appearance and 
disappearance of 6a in blood and brain following administration of 5c. 
FIG. 6 summarizes such results, and is consistent with the mechanism shown 
in Scheme 3. After one single injection of the 1,4-dihydropyridine 
derivative 5c to the rat, the dihydroxy quaternary 6a (ion), which is the 
only detectable derivative, could be seen to appear and then to disappear 
quickly from the blood, with a half-life of 27 min. On the contrary, the 
concentration of 6a (ion) is increasing in the brain steadily, reaching a 
maximum at about 30 min following administration. The descending portion 
indicates a half-life of disappearance from the brain of about 3.2 h. No 
formation of O-methyl metabolites (9, 10) could be detected in the brain. 
This confirms the in vitro results that 6a (or 5a) is not a good substrate 
for COMT. 
To determine whether dopamine itself was finally released in the brain upon 
completion of the aforesaid complex delivery process, 5c was administered 
intrajugularly and changes in brain-dopamine concentrations following that 
administration were studied. Some of the rats showed up to threefold 
increase in the dopamine concentrations, others practically none. Since it 
is possible (and even desired) that the intrinsic brain metabolism of the 
dopamine does not permit significant build-up of its concentration, 
specific pharmacologic activity was investigated, using change in the in 
vivo prolactin secretion. It is known that dopamine and its agonists 
decrease prolactin secretion following their binding to stereospecific 
receptors located on lactophors in the anterior pituitary (AP) gland [G. 
P. Mueller, J. W. Simpkins, J. Meites and K. E. Moore, Neuroendocrinology, 
20, 121 (1976); W. Wuttke, E. Cassell and J. Meites, Endocrinology, 88, 
737 (1971); J. A. Clemens, E. B. Smalstig and C. J. Shaar, Acta 
Endocrinol., 79, 230 (1975)]. This effect is dose-dependent and it can 
also be observed in vitro, incubating anterior pituitaries with dopamine 
or its agonists [R. M. MacLeod in "Frontiers in Neuroendocrinology", Ed. 
L. Martini and W. F. Ganong, Raven Press]. 
It was then determined that exposure of male rats to 17-.beta.-estradiol 
for two days elevated serum prolactin levels to greater than 150 ng/ml. 
Intravenous administration of 5c caused a 79% decrease in serum prolactin 
concentrations and this dramatic reduction was maintained through 120 min 
after treatment. In contrast, 6a had no significant effect on the serum 
prolactin concentrations by 15 min, and caused a 67% reduction by 30 min. 
Thereafter, serum prolactin levels increased progressively to levels which 
are not significantly different from vehicle injected controls, by 60 and 
120 min. These results are summarized in FIG. 7. The rapid onset and 
prolonged inhibitory effects of 5c on prolactin secretion is consistent 
with the time course of the appearance of 6a in the brain following 
administration of 5c. The "trapping" of 6a in the brain subsequent to I.V. 
injection of 5c provides a constant source of a potent dopaminergic agent, 
either dopamine or 6a itself. The significantly lower effect of 6a when 
administered I.V. does not unequivocally clarify which alternative is the 
more responsible. This was resolved by in vitro comparison of the relative 
activities of dopamine versus 6a. 
Fresh anterior pituitaries obtained from female rats were incubated with 
various concentrations of dopamine (DA) and 6a, repsectively, and their 
effects on the rate of release of prolactin were measured. It was found 
that at 2.times.10.sup.-8 M concentrations, neither DA nor 6a had any 
effect, but at 2.times.10.sup.-7 M, DA caused a 57% reduction of the 
prolactin rate secretion, while 6a had no effect. These results are 
summarized in the following Table I. 
TABLE I 
__________________________________________________________________________ 
Comparative in vitro activity of 6a vs. dopamine.sup.a 
Prolactin ng/mg./h.sup.b 
Dopamine (DA).sup.c 6a.sup.d 
DA DA 6a 6a 
Control 
2 .times. 10.sup.-8 M 
Control 
2 .times. 10.sup.-7 M 
Control 
2 .times. 10.sup.-8 M 
Control 
2 .times. 10.sup.-7 
__________________________________________________________________________ 
M 
344 .+-. 50 
355 .+-. 67 
282 .+-. 34 
121 .+-. 38* 
342 .+-. 38 
386 .+-. 29 
250 .+-. 30 
277 .+-. 32 
__________________________________________________________________________ 
.sup.a On freshly obtained anterior pituitary (AP) at 37.degree. C. All 
values are average of 9 separate APS. 
.sup.b Prolactin release rate of the incubated APS. 
.sup.c Weight of the APS: Control 4.6 .+-. 0.2 mg. DA treated 4.5 .+-. 0. 
mg. 
.sup.d Weight of the APS: Control 4.6 .+-. 0.3 6a treated 4.7 .+-. 0.4 
*P &lt; 0.05 
These results indicate that if 6a has any activity, it must be 
significantly less than that of DA. Based on the delayed onset of the 
activity when 6a was adminitered I.V. and considering the in vitro 
results, it logically follows that the high and prolonged activity of the 
6a locked in the brain following administration of 5c is due to the fact 
that 6a is slowly releasing the active DA in the brain. 
Accordingly, provided hereby is a potent, brain-specific dopaminergic agent 
comprising a lipophilic dihydropyridine carrier-type chemical delivery 
system of dopamine ["pro-prodrug" or "pro-pro-prodrug" in the case of the 
catechol protectiv group(s)], which penetrates the BBB passive transport. 
The rapid oxidation in the brain of the carrier moiety to the 
corresponding quaternary pyridinium salt results in an activated amide of 
dopamine. The oxidation process is much faster than amide cleavage of the 
beginning compound 5 or of 6. Moreover, the ionic nature of the activated 
quaternary salt results in a significant slowdown of the efflux of this 
specific form through the BBB, resulting in a selective concentration 
enhancement of the precursor 6a in the brain. Too, brain-specific 
dopaminergic activity is assured, logically as dopamine is released from 
this activated form upon hydrolytic, enzymatic or metabolic cleavage, as 
is facile excretion of the carrier moiety from the brain. 
In yet another embodiment of the invention, like synthesis of the analogous 
tyramine system has been carried out, and the corresponding determinations 
made. Such tyramine system is represented as follows: 
##STR31## 
Naturally, selection of the particular dihydropyridine .revreaction. 
pyridinium salt redox carrier to be used will depend on the chemical 
structure of the specific drug involved. And not only should the nature of 
the functional group which is to be linked to the carrier system be 
considered in selecting the carrier, but the manner in which the ultimate 
compound is prepared should be tailored to the presence of any other 
reactive groups in the molecule. The following examples of specific 
drug/carrier combinations and their manner of synthesis are set forth for 
the purpose of illustration only and are not to be considered limitative 
in any way whatsoever. 
Thus, in one specific illustration, the selected drug is testosterone and 
the selected carrier system is trigonelline 
.revreaction.dihydrotrigonelline; according to this embodiment, 
testosterone is reacted with nicotinoyl chloride, the resultant ester is 
then quaternized with methyl iodide, and the quaternary iodide is then 
reduced with Na.sub.2 S.sub.2 O.sub.4 to afford the testosterone-CDS 
(chemical delivery system) 
##STR32## 
Other steroids can be similarly derivatized, e.g., 
17.alpha.-ethynyltestosterone, estradiol and the like. 
Another specific illustration involves selecting melphalan and the same 
type of carrier system as above, but forming an amide rather than an ester 
linkage. Thus, melphalan is converted to its hydrobromide, which is 
reacted with nicotinic acid to afford the amide having the formula 
##STR33## 
which can be esterified, if desired (to increase lipoidal 
characteristics), followed by, when the ethyl ester is prepared, 
quaternizing same with methyl iodide to form 
##STR34## 
which can then be reduced to afford the melphalan-CDS 
##STR35## 
As one of several alternative schemes, melphalan can be derivatized by 
first esterifying it, e.g., to convert the carboxy function to the ethyl 
ester, then reacting the resultant melphalan ethyl ester with nicotinoyl 
chloride to form the amide of the formula 
##STR36## 
which can then be quaternized and the quarternary salt subsequently 
reduced as indicated above to afford to same melphalan-CDS as depicted 
above. 
Yet another specific illustration utilizes chlorambucil as the target drug, 
in which case the desired nicotinic acid carrier system is linked to the 
drug via a bridging group. Thus, nicotinic acid can be reacted with an 
appropriate di- or polyhydroxy compound such as ethylene glycol, propylene 
glycol or inositol and the resultant intermediate is linked via its free 
hydroxy group(s) to the carboxylic acid function of chlorambucil. That 
intermediate is then quaternized and the quaternary salt is reduced to 
afford the chlorambucil-CDS. In the case of nicotinic acid and ethylene 
glycol starting materials, the chlorambucil-CDS has the formula 
##STR37## 
On the other hand, when a polyhydroxy compound is reacted with nicotinic 
acid in the first step, a variety of products are possible. Thus, for 
example, when inositol is used, the final product may contain anywhere 
from 1 carrier/5 drug residues to 5 carrier/1 drug residue. In the case of 
the inositol trinicotinate intermediate 
##STR38## 
conditions for reacting same with chlorambucil can be selected so that 
one, two or three of the hydroxy functions react with the acid. When all 
three hydroxys react, the ultimate chlorambucil-CDS has the formula 
##STR39## 
and contain 3 drug residues and 3 carrier groupings. 
As another example, methotrexate, which has the structural formula 
##STR40## 
can be derivatized similarly to chlorambucil via its carboxy function(s), 
e.g., utilizing the inositol trigonellinates or a glucosamine analogue. 
As a further example, podophyllotoxin and its derivatives can be linked to 
a carrier system of this invention. These drugs can be represented by the 
structural formula 
##STR41## 
and can be derivatized by reacting the hydroxy group in podophyllotoxin 
(R.sub.4 .dbd.OH) or the hydroxy groups in the glycosidic portions in 
R.sub.4 with acidic type redox carriers, e.g., in a manner analogous to 
the testosterone-CDS depicted above. Known cisplatin analogues, in which 
typically the amino groups have been replaced with organic radicals, can 
be similarly derivatized according to the invention, the method of choice 
depending on the nature of the functional groups in the organic radicals. 
Similarly, syntheses and like determinations as regards the redox 
carrier-linked enkephalins can be carried out. First synthesized is the 
known leucine enkephalin XI. The quaternary pyridinium analog XII, the 
corresponding O-benzyl ether XIII and the amide XIV are next synthesized. 
##STR42## 
The O-benzyl pentapeptide ethyl ester derivative of XI is synthesized 
sequentially and then coupled with nicotinic acid, followed by 
methylation. Alternate methods involve introduction of carrier at an 
earlier stage in the synthesis. The reduction of XII and XIII results in a 
mixture of products due to the base sensitivity of the ester. Likewise 
prepared are the corresponding leucinol trigonelline ester XV and its 
dihydro derivative XVI. 
##STR43## 
Thus, the site-specific brain delivery of the enkephalins for the 
treatment of epilepsy is established consistent with the Scheme 1, as is 
their analgesic activity. 
Similarly, as regards the benzodiazepine tranquilizers, e.g.: 
##STR44## 
This reaction scheme utilizes conventional opening of the 7-member ring, 
accompanied by coupling of the drug to the carrier. The following drugs 
can be similarly derivatized to the corresponding dihydro derivatives: 
##STR45## 
Yet another example of tailoring chemical synthesis to the particular drug 
involved is shown in Scheme 6 below, which depicts synthesis of a 
radio-diagnostic, I 123 labeled metaraminol, carrier system. Note that in 
the case of radiolabeled compounds, the method of choice generally 
involved introducing the radioactive element toward the end of the 
reaction sequence, rather than using the radiolabeled parent drug itself 
as the starting material. 
##STR46## 
And in another preferred embodiment of the invention, there is provided the 
effective, selective and nontoxic treatment of epilepsy, based upon the 
mechanism illustrated in Scheme 1. Indeed, commencing from the 
"GABA-hypothesis" of epilepsy, the brain-specific, enhanced and sustained 
release of GABA (.gamma.-aminobutyric acid) itself, and various other 
compounds either directly or indirectly affecting the concentrations of 
GABA in the brain, is circumscribed consistent herewith. Model compounds 
include carboxylic acids, most specifically valproic acid, as well as some 
of the GABA analogs which inhibit irreversibly the GABA-T, such as 
.gamma.-vinyl and/or .gamma.-acetylenic GABA. Using the aforesaid 
trigonelline (N-methylnicotinic acid).revreaction.dihydrotrigonelline 
system, for example, the selected compounds can be effectively delivered 
per Scheme 1. Thus, representative target compounds are the 
dihydropyridine carrier-drug combinations 1 and the corresponding 
pyridinium carrier-drug species, for example, GABA and its esters: 
##STR47## 
Related derivatives for .gamma.-vinyl and .gamma.-acetylenic GABA are: 
##STR48## 
In the case of valproic acid, other alternatives are: 
##STR49## 
In another embodiment of like delivery system, applicable for both the GABA 
and related compounds and for the carboxylic acids, or for any other drug 
species to be linked to such a carrier, either directly or indirectly, 
i.e., mediated by a carboxylic acid, e.g., succinic acid, or other 
linkage, provided is a mono- or poly-substituted nontoxic polyol (such as 
inositol or sugars) having the 
trigonelline.revreaction.dihydrotrigonelline system and the compounds to 
be delivered linked to the same molecule as exemplified by the GABA case 
(5.revreaction.5a) and valproic acid (6.revreaction.6a): 
##STR50## 
R.sub.4 =H, GABA or valproic acid, but at least one of R.sub.4 is: 
##STR51## 
R.sub.4 can be partically replaced by additional GABA or valproic acid, 
changing the carrier/drug ratio as necessary. Some of the valproic acid 
metabolites can be coupled with carriers of the redox type, via the 
various hydroxy groups formed during the oxidative degradation: 
##STR52## 
Illustrative examples are the corresponding derivatives of the 5-, 4-, and 
3-hydroxy-2-n-propyl pentanoic acid derivatives. Additional carrier 
systems, such as the isoquinoline.revreaction.dihydroisoquinoline system, 
can also be developed consistent herewith. 
Moreover, based upon the observation that NADH content is significantly 
reduced in epileptic and like seizures, the use of the subject redox 
system (in reduced form) will bias the NAD.revreaction.NADH balance 
towards NADH during the dihydro carrier.fwdarw.quaternary transformation. 
Also, the brain-specific delivery of small peptides consistent herewith, 
e.g, the enkephalins, which have been found to initiate epileptic, 
seizures, has led to the design of a variety of long lasting potent 
antagonists. 
And the subject chemical delivery system is also useful for the delivery of 
other anticonvulsants in a sustained, brain-specific fashion, e.g., the 
benzodiazepines and hydrantoins, and those compounds, like apomorphine, 
which are useful in the treatment of photosensitive epilepsy. 
It will of course be appreciated in the immediately above regard that the 
drug treatment of epilepsy has always posed formidable problems. There are 
many different anticonvulsants available, some more specific for different 
types of seizures. Indeed, there exist a wide variety of opinions as to 
which is the most suitable drug for any particular type of seizure, and 
drug mixtures are typically employed. An inevitable result of the 
traditional therapy is the development of chronic toxicity, but such 
result is conspicuously avoided according to the present invention. 
It too will be appreciated that the desired therapeutic effects of all 
antiepileptic agents investigated, as well as their undesired toxic 
effects, reflect a statistically significant correlation with the drug 
levels in plasma. This correlation is based upon a close relationship 
between the drug concentrations in plasma and brain tissue. Hence, a 
primary attribute of this invention is to enable attainment of high and 
sustained brain levels of the selected active agents, essentially against 
the plasma-brain concentration gradient and independent of the drug 
concentration in the blood. 
GABA and related compounds are logical candidates. It has been shown that 
GABA neuron function is impaired in at least certain types of human 
epilepsy. Animal studies also showed that seizures are induced by 
reduction of GABA mneuron function to a critical degree by (1) inhibition 
of GABA synthesis, (2) blockade of GABA receptors or (3) inhibition of 
GABA-receptor mediated ionic events. In addition, enhancement of GABA 
synaptic activity (by direct receptor stimulation or by increasing GABA 
levels in the synapase) has a potent and wide spectrum anticonvulsant 
effect. These findings foreshadowed that an enhanced and sustained GABA 
brain delivery or a brain-specific delivery in a sustained manner of a 
good GABA-agonist would be efficacious in different forms of epilepsy. It 
is well known that GABA itself, when administered systemically, does not 
penetrate the normal blood-brain barrier to any significant extent. Among 
the potential sites at which drugs may act to influence GABA-mediated 
synaptic function, the first target is to effect the BBB transfer of GABA 
via redox delivery system. The second main target is to effect the 
catabolism of GABA. This invention, accordingly, specifically provides for 
the efficacious delivery of the GABA-T inhibitors, .gamma.-vinyl and 
.gamma.-acetylene-GABA, but the delivery of vaproic acid, specifically to 
the brain and without requiring high circulating blood levels, is also 
envisaged. In order to achieve the required activity, sodium valproate 
must have a relatively high, 50-100 .mu.g/ml, level in the blood. The 
value of valproic acid is well established in most types of epilepsy. It 
is evident that valproic acid produces significant increases in both brain 
and synaptosomal GABA concentrations. Valproic acid itself undergoes 
extensive metabolism. 
In capsule summary, the present invention provides for the significantly 
improved treatment of epilepsy, and concomitant reduction in toxicity of a 
number of antiepileptic drug species currently in use. And made available 
to the brain is a variety of important compounds, such as GABA and a 
wealth of GABA-ergic agents. 
Processes similar to those described hereinabove can be shown for the 
preparation of the other compounds of this invention. The acylation steps 
which introduce hydroxyl protecting groups are of course only needed when 
there are hydroxyl groups which it is desired to protect. Moreover, 
carbonate rather than acyl protecting groups could be introduced instead, 
as already discused hereinabove. Also, the order of steps may be altered; 
quaternization, followed by reduction, need not always constitute the 
final two steps but may be carried out earlier in the reaction sequence. 
Yet other reaction schemes, reactants, solvents, reaction conditions, etc. 
(e.g. using an anhydride rather than an acyl halide for the acylation 
step, or preparing a different acyl derivative e.g. the acetyl rather than 
the pivalyl derivative) will be readily apparent to those skilled in the 
art. Also, insofar as concerns the quaternary compounds, when an anion 
different from the one obtained is desired, the anion in the quaternary 
salt may be subjected to anion exchange via an anion exchange resin or, 
more conveniently, by use of the method of Kaminski et al, Tetrahedron, 
Vol. 34, pp. 2857-2859 (1978). According to the Kaminski et al method, a 
methanolic solution of an HX acid will react with a quaternary ammonium 
halide to produce the methyl halide and the corresponding quaternary.X 
salt. Moreover, the manner in which the ultimate compound is prepared 
should be tailored to the presence of any other reactive groups in the 
molecule. For example, when the parent drug contains an --OH or --NH.sub.2 
group to be derivatized as well as carboxy functions, such COOH functions 
will typically be esterified, e.g. converted to the corresponding ethyl 
ester, or otherwise suitably protected, usually prior to formation of the 
quaternary compound. Thus, a wide variety of synthetic approaches can be 
utilized, depending on the desired structure of the final product. And 
compounds containing more than one category of reactive functional groups 
may be derivatized in a variety of ways; for example, a compound 
containing reactive hydroxyl and carboxyl groups may have the hydroxyl 
group(s) protected and the carboxyl group(s) linked to the carrier, or the 
hydroxyl(s) may be linked to the carrier and the carboxyl(s) protected. 
Various illustrative synthetic schemes as applied to specific centrally 
acting drugs in accord with this invention are set forth below in the 
section entitled "Illustrative Synthetic Methods". While the sequence of 
reaction steps can be varied in many cases, in general, the final step 
(except in the case of optional salt formation or possibly in the case of 
radiolabeling) will be reduction of a quaternary compound of formula (II) 
to the corresponding dihydro compound of formula (I). The reduction is 
usually conducted at a temperature from about -10.degree. C. to room 
temperature, for a period of time from about 10 minutes to 2 hours, 
conveniently at atmospheric pressure. Typically, a large excess of 
reducing agent is employed, e.g., a 1:5 molar ratio of reducing agent to 
starting [D--QC].sup.+ compound. The process is conducted in the presence 
of a suitable reducing agent, preferably an alkali metal dithionite such 
as sodium dithionite or an alkali metal borohydride such as sodium 
borohydride or lithium aluminum borohydride, in a suitable solvent. Sodium 
dithionite reduction is conveniently carried out in an aqueous solution; 
the dihydro product [D-DHC] is usually insoluble in water and thus can be 
readily separated from the reaction medium. In the case of sodium 
borohydride reduction, an organic reaction medium is employed, e.g., a 
lower alkanol such as methanol, an aqueous alkanol or other protic 
solvent. 
In a presently preferred embodiment of the present invention, the centrally 
acting drug of which D is the residue is dopamine or L-DOPA or a protected 
counterpart thereof, and the instant redox system is thus designed to 
elicit a sustained and brainspecific dopaminergic (e.g. anti-Parkinsonism 
or anti-hyperprolactinemia) response in the animal to which the formula 
(I) derivative is administered. In an analogous fashion, the instant redox 
carrier system I.fwdarw.II in which D is the residue of any other 
centrally acting drug as defined herein is designed to elicit the kind of 
pharmacological response which would be obtained by delivery of the drug 
itself to the brain, i.e., when the centrally acting parent drug is an 
antitumor/anticancer agent, the instant redox system is employed to elicit 
an antitumor/anticancer response; when the parent drug is a sympathetic 
stimulant, the instant redox system is used to elicit a sympathetic 
stimulant or amphetamine-like response; when the parent drug is an 
anticonvulsant compound, the instant redox system is used to elicit an 
anticonvulsant response; when the parent drug is a tranquilizer, the 
instant system is used to elicit a tranquilizing response; when the parent 
drug is an antidepressant, the instant system is used to elicit an 
antidepressant response; and so forth. 
Suitable nontoxic pharmaceutically acceptable carriers for use with the 
topic compounds [D--DHC], e.g., those less toxic than the target drug 
species themselves, will be apparent to those skilled in this art. 
Compare, for example, Remington's Pharmaceutical Sciences, 4th Edition 
(1970). Obviously, the choice of suitable carriers will depend upon the 
exact nature of the particular dosage form selected, as well as upon the 
identity of the active drug species [D] and the compound to be 
administered. The therapeutic dosage ranges for administration of the 
compounds according to this invention will generally be the same as, or 
less than, those which would characteristically be used in this art for 
administration of the known drug species [D], per se. Naturally, such 
therapeutic dosage ranges will vary with the size of the patient, the 
condition for which the [D--DHC] compound is administered, the particular 
dosage form employed, and the like. The quantity of given dosage form 
needed to deliver the desired dose of [D] will of course depend upon the 
concentration of [D--DHC] in any given pharmaceutical composition/dosage 
form thereof. Obviously, in the case of diagnostic agents, the dosage of 
formula (I) compound used will be a quantity sufficient to deliver to the 
target body area a quantity sufficient to deliver an amount of 
radioisotope, stable isotope or the like which can be effectively detected 
by radioimaging or other detection means. The amount of radioisotope, 
stable isotope or the like present in the dosage form will be within or 
below the ranges conventionally used for diagnostic purposes. 
The ability of the topic compounds to cross the BBB and to be "locked into 
" the brain allows administration of the drug in a site-specific manner. A 
combination of the present dihydropyridine.revreaction.pyridinium salt 
redox system with a sustained release system will further enhance this 
site-specificity. Thus, a preferred embodiment of the invention comprises 
formulating the [D--DHC] compound or the salt of the [D--DHC] compound 
utilizing a sustained release carrier system and/or route of 
administration capable of slowly releasing the chemical, e.g. sustained 
release tablets and capsules for oral administration; subcutaneous 
injection, or implantation of drugs in solid pellet form (for example, 
distributed in a biodegradable polymer); intramuscular injection of the 
compound in solution in oil or suspended in a repository vehicle; a 
transdermal delivery device or form such as an ointment to be applied 
locally to the desired site (when the drug is susceptible of delivery 
through the skin), slow intravenous infusion and the like. The rate of 
release of compound from the sustained release system should be comparable 
to the rate of in vivo oxidation of the dihydro form of the redox system 
in order to achieve the greatest degree of enhancement of specificity. 
In applicant's copending application Ser. No. 632,314, filed July 19, 1984 
(itself a continuation-in-part of applicant's earlier Ser. Nos. 379,316, 
461,543, 475,493 and 516,382), the concept of applicant's redox carrier 
system was expanded to provide novel carrier-containing chelating agents, 
precursors thereto and radiopharmaceuticals derived therefrom, utilizing 
the dihydropyridine.revreaction.pyridinium salt type carriers disclosed 
herein and in the four earlier applications. The present application 
discloses several specific groups of carrier moieties only generically 
disclosed in its parent applications. The teachings of Ser. No. 632,314, 
which is incorporated by reference herein in its entirety and relied upon, 
can be readily combined with the teachings of the present application to 
expand the classes of chelating agents, precursors and 
radiopharmaceuticals defined therein to specifically include the new 
dihydropyridine.revreaction.pyridinium salt redox carriers disclosed in 
the present application. 
ILLUSTRATIVE SYNTHETIC METHODS 
I. 
Methods for Derivatizing --NH.sub.2 or --NH-- Functions in Drugs 
Method A 
The drug is reacted with nicotinoyl chloride, with nicotinic anhydride, or 
with nicotinic acid in the presence of a suitable coupling agent such as 
dicyclohexylcarbodiimide, in an appropriate organic solvent, to afford the 
corresponding nicotinamide. The nicotinamide is then quaternized, 
typically by treatment with methyl iodide in a suitable organic solvent, 
to afford the quaternary derivative of formula (II), which is then reduced 
by treatment with sodium dithionite or sodium borohydride as generally 
described hereinabove to afford the desired compound of formula (I). The 
representative drugs depicted below may be derivatized in this manner to 
the corresponding compounds of formulas (II) and (I). Compounds such as 
bupropion, difluamine, propranolol, ethyl .beta.-carboline-3-carboxylate, 
prizidilol, pseudoephedrine, 5-amidino-2-(5-amidino-2-benzofuranyl)indole, 
4',6-diimidazolino-2-phenylbenzo(b)thiophene, 
2-guanidino-4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenyloxazole, 
glucosamine, 6-amino-6-deoxy-D-glucose, somatostatin, vasopressin and 
6[[(hydroxyimino)phenyl]methyl]-1-[(methylethyl)sulfonyl-1H-benzimidazol-2 
-amine may be similarly derivatized. 
The foregoing procedure may be repeated using picolinic acid or its acid 
chloride or anhydride, or isonicotinic acid or its acid chloride or 
anhydride, in place of nicotinic acid or its acid chloride or anhydride, 
respectively, to convert drugs such as those specifically mentioned for 
derivatizing by this method to the corresponding picolinamides and 
isonicotinamides and then to the corresponding compounds of formulas (II) 
and (I). 
Alternatively, the drug may be reacted with an activated ester of nicotinic 
acid, picolinic acid or isonicotinic acid, e.g. a succinimidyl ester such 
as 
##STR53## 
and the procedure described above repeated to afford the identical 
products. As yet another alternative, the activated ester, e.g. the 
succinimidyl ester depicted above, may be quaternized (e.g. by treatment 
with methyl iodide) and the quaternized activated ester then reacted with 
the drug. The quaternary compound of formula (II) thus obtained may then 
be reduced as described in the first paragraph of this method to give the 
corresponding compound of formula (I). 
3 
Starting Material [DQC].sup.+ 
* [DDHC] 
##STR54## 
##STR55## 
##STR56## 
##STR57## 
##STR58## 
##STR59## 
##STR60## 
##STR61## 
##STR62## 
##STR63## 
##STR64## 
##STR65## 
##STR66## 
##STR67## 
##STR68## 
##STR69## 
##STR70## 
##STR71## 
##STR72## 
##STR73## 
##STR74## 
##STR75## 
##STR76## 
##STR77## 
##STR78## 
##STR79## 
##STR80## 
##STR81## 
##STR82## 
##STR83## 
##STR84## 
##STR85## 
##STR86## 
##STR87## 
##STR88## 
##STR89## 
##STR90## 
##STR91## 
##STR92## 
##STR93## 
##STR94## 
##STR95## 
##STR96## 
##STR97## 
##STR98## 
##STR99## 
##STR100## 
##STR101## 
##STR102## 
##STR103## 
##STR104## 
##STR105## 
##STR106## 
##STR107## 
##STR108## 
##STR109## 
##STR110## 
##STR111## 
##STR112## 
##STR113## 
##STR114## 
##STR115## 
##STR116## 
##STR117## 
##STR118## 
##STR119## 
##STR120## 
##STR121## 
##STR122## 
##STR123## 
##STR124## 
##STR125## 
##STR126## 
##STR127## 
##STR128## 
##STR129## 
##STR130## 
##STR131## 
##STR132## 
##STR133## 
##STR134## 
##STR135## 
##STR136## 
##STR137## 
##STR138## 
##STR139## 
##STR140## 
##STR141## 
##STR142## 
##STR143## 
##STR144## 
##STR145## 
##STR146## 
##STR147## 
##STR148## 
##STR149## 
##STR150## 
##STR151## 
##STR152## 
##STR153## 
##STR154## 
##STR155## 
##STR156## 
##STR157## 
##STR158## 
##STR159## 
##STR160## 
##STR161## 
##STR162## 
##STR163## 
##STR164## 
##STR165## 
##STR166## 
##STR167## 
##STR168## 
##STR169## 
##STR170## 
##STR171## 
##STR172## 
##STR173## 
##STR174## 
##STR175## 
##STR176## 
##STR177## 
##STR178## 
##STR179## 
##STR180## 
##STR181## 
##STR182## 
##STR183## 
##STR184## 
##STR185## 
##STR186## 
##STR187## 
##STR188## 
##STR189## 
##STR190## 
##STR191## 
##STR192## 
##STR193## 
##STR194## 
##STR195## 
##STR196## 
##STR197## 
##STR198## 
##STR199## 
##STR200## 
##STR201## 
##STR202## 
##STR203## 
##STR204## 
##STR205## 
##STR206## 
##STR207## 
##STR208## 
##STR209## 
##STR210## 
##STR211## 
##STR212## 
##STR213## 
##STR214## 
##STR215## 
*cation only depicted in this column throughout Illustrative Synthetic 
Methods 
Method B 
This is a variation of Method A used when the drug contains at least one 
--COOH function which is to be protected. 
The drug is first converted to the corresponding ethyl or t-butyl ester by 
conventional esterification techniques. That ester is then used as the 
starting material and Method A is repeated. 
Obviously, other esters may be similarly prepared in the first step by use 
of other esterifying agents. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Omega amino acids 
other than GABA, other natural amino acids such as glycine, tyrosine, 
aspartic acid and glutamic acid, small peptides (2-20 amino acids, e.g. 
met.sup.5 -enkephalin and leu.sup.5 -enkephalin), ceforanide, furosemide 
and the like may be similarly derivatized. 
The picolinamide and isonicotinamide quaternary and dihydro derivatives of 
the drugs specifically mentioned for derivatizing according to this method 
may be similarly prepared. See Method A. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR216## 
##STR217## 
##STR218## 
##STR219## 
##STR220## 
##STR221## 
##STR222## 
##STR223## 
##STR224## 
##STR225## 
##STR226## 
##STR227## 
##STR228## 
##STR229## 
##STR230## 
##STR231## 
##STR232## 
##STR233## 
##STR234## 
##STR235## 
##STR236## 
##STR237## 
##STR238## 
##STR239## 
##STR240## 
##STR241## 
##STR242## 
##STR243## 
##STR244## 
##STR245## 
##STR246## 
##STR247## 
##STR248## 
##STR249## 
##STR250## 
##STR251## 
##STR252## 
##STR253## 
##STR254## 
##STR255## 
##STR256## 
##STR257## 
Method C 
This is a variation of Method A used when the drug contains one or more OH 
functions which are to be protected. 
The drug is first reacted with excess trimethylacetyl chloride to convert 
the hydroxy group(s) to pivalyloxy group(s). (This process is generally 
conducted in the presence of a base; however, strongly acid conditions are 
used if an amine function is present.) That protected derivative is then 
used as the starting material and subjected to Method A. Alternatively, 
the first two steps may be reversed, i.e. the drug may be first converted 
to the nicotinamide, which may then be reacted with trimethylacetyl 
chloride to form the protected nicotinamide. 
Various other hydroxy protecting groups may be introduced in similar 
fashion. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). The corresponding 
picolinamide and isonicotinamide quaternary and dihydro derivatives may be 
similarly prepared. See Method A. Moreover, drugs such as atenolol, 
metoprolol, pentostatin (2'-deoxycoformycin), glucosamine, 
6-amino-6-deoxy-D-glucose and pseudoephedrine may be similarly 
derivatized. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR258## 
##STR259## 
##STR260## 
##STR261## 
##STR262## 
##STR263## 
##STR264## 
##STR265## 
##STR266## 
##STR267## 
##STR268## 
##STR269## 
##STR270## 
##STR271## 
##STR272## 
##STR273## 
##STR274## 
##STR275## 
##STR276## 
##STR277## 
##STR278## 
Method D 
This variation of Method A can be used when the drug contains one or more 
OH and COOH functions which are to be protected. The protecting groups, 
typically the ethyl or t-butyl ester and pivalyloxy groups, are introduced 
as described in Methods B and C, in the sequence considered most 
convenient. Obviously, other protecting groups can be introduced instead. 
The amine function is derivatized according to Method A. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). The corresponding 
picolinamide and isonicotinamide quaternary and dihydro derivatives may be 
similarly prepared. See Method A. 
__________________________________________________________________________ 
Starting Material 
[DQC].sup.+ [DDHC] 
__________________________________________________________________________ 
##STR279## 
##STR280## 
##STR281## 
##STR282## 
##STR283## 
##STR284## 
__________________________________________________________________________ 
Method E 
This method is of particular use when the --NH-- function is part of an 
amide or imide or a very low pKa primary or secondary amine. 
The drug is first reacted with an aldehyde [e.g. formaldehyde, 
benzaldehyde, acetaldehyde or chloral (Cl.sub.3 CCHO)]; for example, in 
the case of formaldehyde or chloral, one converts the --NH-- function to a 
##STR285## 
function, respectively, and thus forms a suitable bridging group. The 
resultant compound can then be derivatized in the same manner as any drug 
containing a reactive --OH group; for example, it is then reacted with 
nicotinic acid in the presence of a suitable coupling agent, or with 
nicotinoyl chloride or nicotinic anhydride, to form the corresonding 
nicotinic acid ester of the partial formula 
##STR286## 
respectively. The resultant intermediate is then quaternized and reduced 
as in Method A. The alternative process utilizing an activated ester or 
quaternary derivative thereof which is described in Method A may be 
utilized here as well. 
The representative starting drugs depicted below may be derivatized in this 
manner to the corresponding compounds of formulas (II) and (I). Drugs such 
as minocycline, doxycycline, oxytetracycline, tetracycline, methacycline, 
atenolol, sulfadiazine, dactinomycin, mitomycin, methylphenidate, ethyl 
.beta.-carboline 3-carboxylate, nifedipine, 3-deazaguanine, 
6-mercaptopurine, cyclophosphamide and progabide may be similarly 
derivatized. 
The foregoing procedure may be repeated using picolinic acid or its acid 
chloride or anhydride or activated ester, or isonicotinic acid or its acid 
chloride or anhydride or activated ester, in place of nicotinic acid or 
its acid chloride or anhydride, or activated ester, respectively, to 
convert drugs such as those specifically mentioned for derivatizing 
according to this method to the corresponding picolinic acid esters and 
isonicotinic acid esters and then to the corresponding compounds of 
formulas (II) and (I). 
As yet another alternative, the intermediate compound containing the 
##STR287## 
group or the like may be reacted with thionyl chloride to afford the 
corresponding compound containing a 
##STR288## 
or similar group. That derivative may then be reacted with a metallic salt 
(especially a silver or thallous salt) of nicotinic acid or the like 
(formed, e.g. by reacting nicotinic acid or the like with fresh silver 
hydroxide or oxide or with thallous ethoxide). The resultant nicotinic 
acid ester of the partial formula 
##STR289## 
or like derivative is then quaternized and subsequently reduced as in 
Method A. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR290## 
##STR291## 
##STR292## 
##STR293## 
##STR294## 
##STR295## 
##STR296## 
##STR297## 
##STR298## 
##STR299## 
##STR300## 
##STR301## 
##STR302## 
##STR303## 
##STR304## 
##STR305## 
##STR306## 
##STR307## 
##STR308## 
##STR309## 
##STR310## 
##STR311## 
##STR312## 
##STR313## 
##STR314## 
##STR315## 
##STR316## 
##STR317## 
##STR318## 
##STR319## 
##STR320## 
##STR321## 
##STR322## 
##STR323## 
##STR324## 
##STR325## 
##STR326## 
##STR327## 
##STR328## 
##STR329## 
##STR330## 
##STR331## 
##STR332## 
##STR333## 
##STR334## 
##STR335## 
##STR336## 
##STR337## 
##STR338## 
##STR339## 
##STR340## 
##STR341## 
##STR342## 
##STR343## 
##STR344## 
##STR345## 
##STR346## 
##STR347## 
##STR348## 
##STR349## 
##STR350## 
##STR351## 
##STR352## 
##STR353## 
##STR354## 
##STR355## 
##STR356## 
##STR357## 
##STR358## 
##STR359## 
##STR360## 
##STR361## 
##STR362## 
##STR363## 
##STR364## 
##STR365## 
##STR366## 
##STR367## 
##STR368## 
##STR369## 
##STR370## 
##STR371## 
##STR372## 
##STR373## 
##STR374## 
##STR375## 
##STR376## 
##STR377## 
##STR378## 
##STR379## 
##STR380## 
##STR381## 
##STR382## 
Method F 
This method is a variation of Method E which can be used when the --NH-- 
function is part of an amide or imide or low pKa primary or secondary 
amine and the drug contains one or more --COOH functions which is/are to 
be protected. Typically, the carboxyl group or groups is/are first 
converted to the corresponding pivaloyloxymethyl ester by known 
esterification techniques. Obviously, other esters may be similarly 
prepared. The ester is then used as the starting material and Method E is 
repeated. 
The representative starting drugs depicted below may be derivatized in this 
manner to the corresponding compounds of formulas (II) and (I). Drugs such 
as carbenicillin, phenoxymethylpenicillin, methicillin, nafcillin, 
ticarcillin, dicloxacillin, cefazolin, cefoxitin, moxalactam, aminopterin, 
furosemide, and 5-methyltetrahydrohomofolic acid may be similarly 
derivatized. 
The alternative procedures described in Method E may be used in Method F 
also. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR383## 
##STR384## 
##STR385## 
##STR386## 
##STR387## 
##STR388## 
##STR389## 
##STR390## 
##STR391## 
##STR392## 
##STR393## 
##STR394## 
##STR395## 
##STR396## 
##STR397## 
##STR398## 
Method G 
This is a variation of Method E used when the drug also contains one or 
more hydroxy functions which are to be protected. Typically, the drug is 
first reacted with excess trimethylacetyl chloride to convert the hydroxy 
group(s) to pivalyloxy group(s). That protected derivative is then used as 
the starting material and subjected to Method E. 
Other hydroxy protecting groups may be introduced in similar fashion. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). 
The alternative procedures described in Method E may be used in Method G 
also. 
__________________________________________________________________________ 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
__________________________________________________________________________ 
##STR399## 
##STR400## 
##STR401## 
##STR402## 
##STR403## 
##STR404## 
##STR405## 
##STR406## 
##STR407## 
__________________________________________________________________________ 
Method H 
Method A is followed, except that in the first step, the drug is reacted 
with 3-quinolinecarboxylic acid or its acid chloride or anhydride or 
activated ester instead of nicotinic acid or its acid chloride or 
anhydride or activated ester. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I), as may the 
remaining drugs mentioned with Method A. 
Similarly, Method H may be combined with Methods B, C, D, E, F or G to 
afford the corresponding derivatives, e.g., of the drugs listed with those 
methods. 
The foregoing procedure can be repeated using 4-isoquinolinecarboxylic acid 
or its acid chloride or anhydride or activated ester in place of 
3-quinolinecarboxylic acid or its acid chloride or anhydride or activated 
ester to convert drugs such as those mentioned with Methods A, B, C, D, E, 
F or G to the corresponding derivatives. 
The general procedures described above may be utilized to provide the 
1,2-dihydro derivatives as well as the depicted 1,4-dihydros. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR408## 
##STR409## 
##STR410## 
##STR411## 
##STR412## 
##STR413## 
##STR414## 
##STR415## 
##STR416## 
##STR417## 
##STR418## 
##STR419## 
##STR420## 
##STR421## 
##STR422## 
##STR423## 
##STR424## 
##STR425## 
##STR426## 
##STR427## 
##STR428## 
##STR429## 
##STR430## 
##STR431## 
##STR432## 
##STR433## 
##STR434## 
##STR435## 
##STR436## 
##STR437## 
##STR438## 
##STR439## 
##STR440## 
##STR441## 
##STR442## 
##STR443## 
Method I 
Method A is followed, except that in the first step, a reactant of the 
formula 
##STR444## 
is used in place of nicotinic acid. (That starting material may be 
prepared by reacting nicotinic anhydride, nicotinoyl chloride or nicotinic 
acid with glycolic acid.) 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I), as may the 
remaining drugs mentioned with Method A. 
Similarly, Method I may be combined with Methods B, C, D, E, F or G to 
afford the corresponding derivatives, e.g. of the drugs mentioned with 
those methods. 
The foregoing procedure can be repeated using picolinic acid or its acid 
chloride or anhydride, or isonicotinic acid or its acid chloride or 
anhydride, in place of nicotinic acid or its acid chloride or anhydride, 
respectively, in the preparation of the reactant depicted above. This 
variation affords a reactant of the formula 
##STR445## 
which can then be used in place of nicotinic acid to prepare derivatives 
of drugs such as those mentioned with Methods A, B, C, D, E, F or G. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR446## 
##STR447## 
##STR448## 
##STR449## 
##STR450## 
##STR451## 
##STR452## 
##STR453## 
##STR454## 
##STR455## 
##STR456## 
##STR457## 
##STR458## 
##STR459## 
##STR460## 
##STR461## 
##STR462## 
##STR463## 
##STR464## 
##STR465## 
##STR466## 
Method J 
Method A is followed, except that in the first step, a reactant of the 
formula 
##STR467## 
wherein n=1-3, preferably 2, is used in place of nicotinic acid. (That 
starting material may be prepared from nicotinamide, e.g. when n=2, by 
reacting 3-liodopropionic acid with nicotinamide.) The quaternary salt of 
formula (II) thus obtained may then be reduced as described in Method A. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method A. 
Similarly, Mehtod J may be combined with Methods B, C, D, E, F or G to 
afford the corresponding derivatives, e.g. of the drugs mentioned with 
those methods. 
The foregoing procedure can be repeated using picolinamide or 
isonicotinamide in place of nicotinamide in the preparation of the 
starting material. This variation affords a reactant of the formula 
##STR468## 
which can then be used in place of nicotinic acid in the procedure of this 
method, to afford the corresponding derivatives, e.g. of the drugs 
mentioned with Methods A, B, C, D, E, F or G. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR469## 
##STR470## 
##STR471## 
##STR472## 
##STR473## 
##STR474## 
##STR475## 
##STR476## 
##STR477## 
##STR478## 
##STR479## 
##STR480## 
##STR481## 
##STR482## 
##STR483## 
II. 
Methods for Derivatizing --OH and --SH Functions in Drugs 
Method K 
The drug is reacted with nicotinoyl chloride, with nicotinic anhydride, or 
with nicotinic acid in the presence of a suitable coupling agent such as 
dicyclohexylcarbodiimide, in an appropriate organic solvent, to afford the 
corresponding nicotinate. The nicotinate is then quaternized and 
subsequently reduced as described above in Method A. When the drug 
contains more than one reactive hydroxyl or thiol function, reaction 
conditions may be varied so that more than one hydroxyl or thiol function 
will be converted to nicotinate groupings. The alternative process 
utilizing an activated ester or quaternary derivative thereof which is 
described in Method A may be utilized here as well. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). 
2-Deoxy-D-glucose, 2-deoxy-2-fluoro-D-mannose, bisdihydroxyvinyluridine 
(BDVU), meptazinol, cyclazocine, phenazocine, metopon, myfadol, 
thioguanine, naltrexone, alazocine, oxilorphan, nalmexone and estriol may 
be similarly derivatized. 
The foregoing procedure may be repeated using picolinic acid or its acid 
chloride or anhydride or activated ester, or isonicotinic acid or its acid 
chloride or anhydride or activated ester, in place of nicotinic acid or 
its acid chloride or anhydride or activated ester, respectively, to 
convert drugs such as those specifically mentioned for derivatizing by 
this method to the corresponding picolinic acid esters or isonicotinic 
acid esters and then to the corresponding compounds of formulas (II) and 
(I). 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR484## 
##STR485## 
##STR486## 
##STR487## 
##STR488## 
##STR489## 
##STR490## 
##STR491## 
##STR492## 
##STR493## 
##STR494## 
##STR495## 
##STR496## 
##STR497## 
##STR498## 
##STR499## 
##STR500## 
##STR501## 
##STR502## 
##STR503## 
##STR504## 
##STR505## 
##STR506## 
##STR507## 
##STR508## 
##STR509## 
##STR510## 
##STR511## 
##STR512## 
##STR513## 
##STR514## 
##STR515## 
##STR516## 
##STR517## 
##STR518## 
##STR519## 
##STR520## 
##STR521## 
##STR522## 
##STR523## 
##STR524## 
##STR525## 
##STR526## 
##STR527## 
##STR528## 
##STR529## 
##STR530## 
##STR531## 
##STR532## 
##STR533## 
##STR534## 
##STR535## 
##STR536## 
##STR537## 
##STR538## 
##STR539## 
##STR540## 
##STR541## 
##STR542## 
##STR543## 
##STR544## 
##STR545## 
##STR546## 
##STR547## 
##STR548## 
##STR549## 
##STR550## 
##STR551## 
##STR552## 
##STR553## 
##STR554## 
##STR555## 
##STR556## 
##STR557## 
##STR558## 
##STR559## 
##STR560## 
##STR561## 
##STR562## 
##STR563## 
##STR564## 
##STR565## 
##STR566## 
##STR567## 
##STR568## 
##STR569## 
##STR570## 
##STR571## 
##STR572## 
##STR573## 
##STR574## 
##STR575## 
##STR576## 
##STR577## 
##STR578## 
##STR579## 
##STR580## 
##STR581## 
##STR582## 
##STR583## 
##STR584## 
##STR585## 
##STR586## 
##STR587## 
##STR588## 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR589## 
##STR590## 
##STR591## 
##STR592## 
##STR593## 
##STR594## 
##STR595## 
##STR596## 
##STR597## 
##STR598## 
##STR599## 
##STR600## 
##STR601## 
##STR602## 
##STR603## 
##STR604## 
##STR605## 
##STR606## 
##STR607## 
##STR608## 
##STR609## 
##STR610## 
##STR611## 
##STR612## 
##STR613## 
##STR614## 
##STR615## 
##STR616## 
##STR617## 
##STR618## 
##STR619## 
##STR620## 
##STR621## 
##STR622## 
##STR623## 
##STR624## 
##STR625## 
##STR626## 
##STR627## 
##STR628## 
##STR629## 
##STR630## 
##STR631## 
##STR632## 
##STR633## 
##STR634## 
##STR635## 
##STR636## 
##STR637## 
##STR638## 
##STR639## 
##STR640## 
##STR641## 
##STR642## 
##STR643## 
##STR644## 
##STR645## 
##STR646## 
##STR647## 
##STR648## 
This compound can be selectively hydrolyzed by known methods to the 
corresponding 17-monoester, which can be reduced to give the preferred 
17-monoester of formula (I). 
##STR649## 
##STR650## 
##STR651## 
##STR652## 
##STR653## 
##STR654## 
##STR655## 
##STR656## 
##STR657## 
##STR658## 
##STR659## 
##STR660## 
##STR661## 
##STR662## 
##STR663## 
##STR664## 
##STR665## 
##STR666## 
##STR667## 
##STR668## 
##STR669## 
##STR670## 
##STR671## 
##STR672## 
##STR673## 
##STR674## 
##STR675## 
##STR676## 
##STR677## 
##STR678## 
##STR679## 
##STR680## 
##STR681## 
##STR682## 
##STR683## 
##STR684## 
##STR685## 
##STR686## 
##STR687## 
##STR688## 
##STR689## 
##STR690## 
##STR691## 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR692## 
##STR693## 
##STR694## 
##STR695## 
##STR696## 
##STR697## 
##STR698## 
##STR699## 
##STR700## 
##STR701## 
##STR702## 
##STR703## 
##STR704## 
##STR705## 
##STR706## 
##STR707## 
##STR708## 
##STR709## 
.sup. 
##STR710## 
##STR711## 
##STR712## 
##STR713## 
##STR714## 
##STR715## 
##STR716## 
##STR717## 
##STR718## 
##STR719## 
##STR720## 
##STR721## 
##STR722## 
##STR723## 
##STR724## 
##STR725## 
##STR726## 
##STR727## 
##STR728## 
##STR729## 
##STR730## 
##STR731## 
##STR732## 
##STR733## 
##STR734## 
##STR735## 
##STR736## 
##STR737## 
##STR738## 
##STR739## 
##STR740## 
##STR741## 
##STR742## 
##STR743## 
##STR744## 
##STR745## 
##STR746## 
##STR747## 
##STR748## 
##STR749## 
##STR750## 
##STR751## 
##STR752## 
##STR753## 
##STR754## 
##STR755## 
##STR756## 
##STR757## 
##STR758## 
##STR759## 
##STR760## 
##STR761## 
##STR762## 
##STR763## 
##STR764## 
##STR765## 
##STR766## 
##STR767## 
##STR768## 
##STR769## 
##STR770## 
##STR771## 
##STR772## 
##STR773## 
##STR774## 
##STR775## 
##STR776## 
##STR777## 
##STR778## 
##STR779## 
##STR780## 
##STR781## 
##STR782## 
##STR783## 
##STR784## 
##STR785## 
##STR786## 
##STR787## 
##STR788## 
##STR789## 
##STR790## 
##STR791## 
##STR792## 
##STR793## 
##STR794## 
##STR795## 
##STR796## 
##STR797## 
##STR798## 
##STR799## 
##STR800## 
##STR801## 
##STR802## 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR803## 
##STR804## 
##STR805## 
##STR806## 
##STR807## 
##STR808## 
##STR809## 
##STR810## 
##STR811## 
##STR812## 
##STR813## 
##STR814## 
##STR815## 
##STR816## 
##STR817## 
##STR818## 
##STR819## 
##STR820## 
##STR821## 
##STR822## 
##STR823## 
##STR824## 
##STR825## 
##STR826## 
##STR827## 
##STR828## 
##STR829## 
##STR830## 
##STR831## 
##STR832## 
##STR833## 
##STR834## 
##STR835## 
##STR836## 
##STR837## 
##STR838## 
##STR839## 
##STR840## 
##STR841## 
##STR842## 
##STR843## 
##STR844## 
##STR845## 
##STR846## 
##STR847## 
##STR848## 
##STR849## 
##STR850## 
##STR851## 
##STR852## 
##STR853## 
##STR854## 
##STR855## 
##STR856## 
##STR857## 
##STR858## 
##STR859## 
##STR860## 
##STR861## 
##STR862## 
##STR863## 
##STR864## 
##STR865## 
##STR866## 
##STR867## 
##STR868## 
##STR869## 
##STR870## 
##STR871## 
##STR872## 
##STR873## 
##STR874## 
##STR875## 
##STR876## 
##STR877## 
##STR878## 
##STR879## 
##STR880## 
##STR881## 
##STR882## 
##STR883## 
##STR884## 
##STR885## 
##STR886## 
##STR887## 
##STR888## 
##STR889## 
##STR890## 
##STR891## 
##STR892## 
##STR893## 
##STR894## 
##STR895## 
##STR896## 
##STR897## 
##STR898## 
##STR899## 
##STR900## 
##STR901## 
##STR902## 
##STR903## 
##STR904## 
##STR905## 
##STR906## 
##STR907## 
##STR908## 
##STR909## 
##STR910## 
##STR911## 
##STR912## 
##STR913## 
##STR914## 
##STR915## 
##STR916## 
##STR917## 
Method K' 
This is an alternate process for derivatizing drugs containing secondary or 
tertiary hydroxyl functional groups. According to this process, the drug 
is reacted with chloral or other aldehyde capable of forming a hemiacetal 
therewith. In the case of chloral, this converts the --OH function(s) to 
##STR918## 
groupings. 
The --OH function(s) of the resultant hemiacetal can then be derivatized by 
any of the methods for derivatizing --OH groups disclosed hereinabove, 
e.g. by reaction with nicotinic acid or its acid chloride or anhydride as 
described in Method K. 
This process is of particular value when the --OH group(s) in the drug 
is/are sterically hindered and/or when it is desired to alter the rate of 
release of the drug from that obtained when the carrier is hooked directly 
to the drug's hydroxy function(s). 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Other drugs 
containing secondary or tertiary --OH groups which are disclosed herein, 
e.g. in connection with Method K, may be similarly derivatized. This 
method is of special interest for derivatizing steroids containing 
secondary or tertiary 17 .beta.-hydroxy substituents, especially steroid 
sex hormones, and most especially such hormones bearing a bulky 17 
.alpha.-substituent such as a 17 .alpha.-ethynyl grouping. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR919## 
##STR920## 
##STR921## 
##STR922## 
##STR923## 
##STR924## 
##STR925## 
##STR926## 
##STR927## 
##STR928## 
##STR929## 
##STR930## 
##STR931## 
##STR932## 
##STR933## 
##STR934## 
##STR935## 
##STR936## 
Method L 
This variation of Method K can be used when the drug contains an amino 
group which needs to be protected. Generally, the amino group is protected 
prior to any reaction of the hydroxyl function; typically, a 
benzyloxycarbonyl group is introduced in conventional manner to protect 
the amino function and then the process described in Method K is followed. 
Removal of the protecting group, also in conventional manner, takes place 
after protection is no longer needed, be it at the end of the synthetic 
pathway or earlier. Generally, the protecting group is removed before 
formation of the formula (II) quaternary. Occasionally, an amino 
protecting group will be utilized which need not be removed, for example, 
in the case of trifluoroacetyldoxorubicin below. 
The representative N- protected drugs depicted below may be derivatized in 
this manner to the corresponding compounds of formulas (II) and (I). Drugs 
such as norepinephrine, epinephrine, glucosamine, 
6-amino-6-deoxy-D-glucose and pseudoephedrine may be similarly 
derivatized. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR937## 
##STR938## 
##STR939## 
##STR940## 
##STR941## 
##STR942## 
##STR943## 
##STR944## 
##STR945## 
##STR946## 
##STR947## 
##STR948## 
##STR949## 
##STR950## 
##STR951## 
Method M 
This is a variation of Method K used when the drug contains a --COOH 
function which is to be protected. 
The drug is first converted to the corresponding ethyl or t-butyl ester by 
conventional esterification techniques. That ester is then used as the 
starting material and Method K is repeated. The --COOH group may be 
similarly converted to other ester groups. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Diflunisal, 
clorazepate and captopril may be similarly derivatized. 
The picolinic acid ester and isonicotinic acid ester quaternary and dihydro 
derivatives of the drugs specifically mentioned for derivatizing according 
to this method may be similarly prepared. See Method K. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR952## 
##STR953## 
##STR954## 
##STR955## 
##STR956## 
##STR957## 
##STR958## 
##STR959## 
##STR960## 
##STR961## 
##STR962## 
##STR963## 
##STR964## 
##STR965## 
##STR966## 
Method N 
Method K is followed, except that a reactant of the formula 
##STR967## 
wherein n=1-3, preferably 2, is used in place of nicotinic acid. The 
quaternary salt of formula (II) thus obtained may then be reduced as 
described in Method A. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I) as may the 
remaining drugs listed with Method K. 
Similarly, Method N may be combined with Method L or M to afford the 
corresponding derivatives, e.g. of the drugs mentioned with those methods. 
A starting material of the formula set forth immediately above can also be 
substituted for nicotinic acid in Method E, F or G to afford the 
corresponding derivatives, e.g of the drugs mentioned with those methods. 
Method N is of particular use in preparing derivatives of drugs in which 
the hydroxy function is hindered, e.g., biperiden, cycrimine, procyclidine 
and trihexyphenidyl. 
Alternatively, Method N may follow Method K except that it employs a 
reactant of the formula 
##STR968## 
(prepared as described in Method J), to afford derivatives of the drugs 
indicated with Method K. This altlernative form of Method N may also be 
combined with Method L or M, to afford the corresponding derivatives of 
the drugs mentioned with Method L or M, respectively. Also, these 
alternative Method N starting materials may be substituted for nicotinic 
acid in Method E, F or G to give the corresponding derivatives of the 
drugs mentioned with those methods. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR969## 
##STR970## 
##STR971## 
##STR972## 
##STR973## 
##STR974## 
##STR975## 
##STR976## 
##STR977## 
##STR978## 
##STR979## 
##STR980## 
##STR981## 
##STR982## 
##STR983## 
##STR984## 
##STR985## 
##STR986## 
##STR987## 
##STR988## 
##STR989## 
##STR990## 
##STR991## 
##STR992## 
##STR993## 
##STR994## 
##STR995## 
##STR996## 
##STR997## 
##STR998## 
##STR999## 
##STR1000## 
##STR1001## 
Method O 
Method K is followed, except that the drug is reacted with 
3-quinolinecarboxylic acid or its acid chloride or anhydride or activated 
ester instead of nicotinic acid or its acid chloride or anhydride or 
activated ester. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I), as may the 
remaining drugs mentioned with Method K. 
Similarly, Method O may be combined with Method L or M to afford the 
corresponding derivatives, e.g. of the drugs mentioned with those methods. 
The procedure of Method O may be repeated using 4-isoquinolinecarboxylic 
acid or its acid chloride or anhydride or activated ester in place of 
3-quinolinecarboxylic acid or its acid chloride or anhydride or activated 
ester, to afford the corresponding derivatives of drugs such as those 
indicated with Methods K, L, and M. 
3-Quniolinecarboxylic acid or its acid chloride or anhydride or activated 
ester or 4-isoquinolinecarboxylic acid or its acid chloride or anhydride 
or activated ester can also be substituted for nicotinic acid or its acid 
chloride or anhydride or activated ester in Method E, F or G, to afford 
the corresponding derivatives, e.g., of the drugs mentioned with those 
methods. 
The general procedures described above may be utilized to provide the 
1,2-dihydro derivatives as well as the depicted 1,4-dihydros. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR1002## 
##STR1003## 
##STR1004## 
##STR1005## 
##STR1006## 
##STR1007## 
##STR1008## 
##STR1009## 
##STR1010## 
##STR1011## 
##STR1012## 
##STR1013## 
##STR1014## 
##STR1015## 
##STR1016## 
##STR1017## 
##STR1018## 
##STR1019## 
##STR1020## 
##STR1021## 
##STR1022## 
##STR1023## 
##STR1024## 
##STR1025## 
##STR1026## 
##STR1027## 
##STR1028## 
##STR1029## 
##STR1030## 
##STR1031## 
##STR1032## 
##STR1033## 
##STR1034## 
##STR1035## 
##STR1036## 
##STR1037## 
##STR1038## 
##STR1039## 
Method P 
Method K is followed, except that a reactant of the formula 
##STR1040## 
is used in place of nicotinic acid. 
The representative drugs mentioned below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I), as may the 
remaining drugs mentioned with Method K. 
Similarly, Method P may be combined with Methods L and M to afford the 
corresponding derivatives, e.g. of the drugs mentioned with those methods. 
A starting material of the formula set forth immediately above can also be 
substituted for nicotinic acid in Method E, F or G to afford the 
corresponding derivatives, e.g. of the drugs mentioned with those methods. 
Alternatively, Method P may follow Method K except that it employs a 
reactant of the formula 
##STR1041## 
(prepared as described in Method I), to afford derivatives of the drugs 
indicated with method K. This alternative form of Method P may also be 
combined with Method L or M, to afford the corresponding derivatives of 
the drugs mentioned with Method L or M. also, these alternative Method P 
starting materials may be substituted for nicotinic acid in Method E, F or 
G to give the corresponding derivatives of the drugs specified wwith those 
methods. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1042## 
##STR1043## 
##STR1044## 
##STR1045## 
##STR1046## 
##STR1047## 
##STR1048## 
##STR1049## 
##STR1050## 
##STR1051## 
##STR1052## 
##STR1053## 
##STR1054## 
##STR1055## 
##STR1056## 
##STR1057## 
##STR1058## 
##STR1059## 
This compound can be subsequently selectively hydrolyzed by known 
methods to the corresponding 17-monoester of formula (II), which can be 
reduced to the corresponding preferred 17-monoester of formula (I). 
##STR1060## 
##STR1061## 
##STR1062## 
##STR1063## 
##STR1064## 
##STR1065## 
III. 
Methods for Derivatizing --COOH Functions in Drugs 
Method Q 
Nicotinic acid or an activated ester thereof is reacted with an aminoalkan 
ol 
EQU H.sub.2 N--Z'--OH 
wherein Z' is C.sub.1 -C.sub.8 straight or branched alkylene, e.g. 
2-aminoethanol, to afford the corresponding intermediate alcohol, e.g. in 
the case of 2-aminoethanol, an intermediate of the formula 
##STR1066## 
That alcohol is then reacted with a drug containing one or more --COOH 
functions, in the presence of a suitable coupling agent such as 
dicyclohexylcarbodiimide. The compound thus obtained is then quaternized 
and subsequently reduced as described above in Method A. 
Analogous starting materials can be readily prepared by reacting the 
selected aminoalkanol with picolinic acid, isonicotinic acid, 
3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic acid or the like to 
afford the desired intermediate, which can then be quaternized and 
subsequently reduced as described above. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Drugs such as 
methicillin, ticarcillin, oxacillin, dicloxacillin, glyoxylic acid 
sulfonyl hydrazone, 5-methyltetrahydrohomofolic acid, 
phenoxymethylpenicillin, fenbufen, fenoprofen, idoprofen, ketoprofen, 
fluprofen, bucloxic acid, tolmetin, alclofenac, fenclozic acid, ibufenac, 
meclofenamic acid, flufenamic acid, flufenisal, clonixin, carprofen, 
etodolac, flutiazin, pirprofen, furosemide, cefoxitin and clorazepate may 
be similarly derivatized. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1067## 
##STR1068## 
##STR1069## 
##STR1070## 
##STR1071## 
##STR1072## 
##STR1073## 
##STR1074## 
##STR1075## 
##STR1076## 
##STR1077## 
##STR1078## 
##STR1079## 
##STR1080## 
##STR1081## 
##STR1082## 
##STR1083## 
##STR1084## 
##STR1085## 
##STR1086## 
##STR1087## 
##STR1088## 
##STR1089## 
##STR1090## 
##STR1091## 
##STR1092## 
##STR1093## 
##STR1094## 
##STR1095## 
##STR1096## 
##STR1097## 
##STR1098## 
##STR1099## 
##STR1100## 
##STR1101## 
##STR1102## 
##STR1103## 
##STR1104## 
##STR1105## 
##STR1106## 
##STR1107## 
##STR1108## 
##STR1109## 
##STR1110## 
##STR1111## 
##STR1112## 
##STR1113## 
##STR1114## 
##STR1115## 
##STR1116## 
##STR1117## 
##STR1118## 
##STR1119## 
##STR1120## 
##STR1121## 
##STR1122## 
##STR1123## 
##STR1124## 
##STR1125## 
##STR1126## 
##STR1127## 
##STR1128## 
##STR1129## 
##STR1130## 
##STR1131## 
##STR1132## 
##STR1133## 
##STR1134## 
##STR1135## 
##STR1136## 
##STR1137## 
##STR1138## 
##STR1139## 
##STR1140## 
##STR1141## 
##STR1142## 
##STR1143## 
##STR1144## 
##STR1145## 
##STR1146## 
##STR1147## 
##STR1148## 
##STR1149## 
##STR1150## 
##STR1151## 
##STR1152## 
##STR1153## 
##STR1154## 
##STR1155## 
##STR1156## 
##STR1157## 
##STR1158## 
Method R 
This is a variation of Method Q used when the drug contains one or more 
--OH or --SH functions which are to be protected. 
The drug is first reacted with excess trimethylacetyl chloride to convert 
the hydroxy group(s) to pivalyloxy group(s). (Various other hydroxy 
protecting groups may be introduced in similar fashion.) The protected 
drug is then reacted with the intermediate alcohol 
##STR1159## 
in the presence of dicyclohexylcarbodiimide or other appropriate agent for 
coupling the --COOH function of the drug to the hydroxy function of the 
depicted intermediate. (Other intermediate alcohols can be employed, e.g. 
as described in Method Q.) The resultant compound is then quaternized and 
the quaternary subsequently reduced as in Method A. 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Drugs such as 
clorazepate, 4-hydroxy-2-n-propylpentanoic acid, 
3-hydroxy-2-n-propylpentanoic acid and captopril may be similarly 
derivatized. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1160## 
##STR1161## 
##STR1162## 
##STR1163## 
##STR1164## 
##STR1165## 
##STR1166## 
##STR1167## 
##STR1168## 
##STR1169## 
##STR1170## 
##STR1171## 
##STR1172## 
##STR1173## 
##STR1174## 
##STR1175## 
##STR1176## 
##STR1177## 
Method S 
This is a variation of Method Q used when the drug contains one or more 
amino functions which are to be protected. Generally, the amino group is 
protected prior to any reaction of the carboxyl function; typically, a 
benzyloxycarbonyl group is introduced in conventional manner to protect 
the amino function and then the N-protected drug is reacted with the 
intermediate alcohol as is Methods Q and R. Removal of the protecting 
group, in conventional fashion, takes place when protection is no longer 
needed, generally before formation of the formula (II) quaternary and 
subsequent reduction to the compound of formula (I). 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). GABA and other 
omega amino acids, other natural amino acids such as glycine, tyrosine, 
aspartic acid and glutamic acid, small peptides (e.g. met.sup.5 
-enkephalin and leu.sup.5 -enkephalin and other 2-20 amino acid unit 
peptides) and the like may be similarly derivatized. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1178## 
##STR1179## 
##STR1180## 
##STR1181## 
##STR1182## 
##STR1183## 
##STR1184## 
##STR1185## 
##STR1186## 
##STR1187## 
##STR1188## 
##STR1189## 
##STR1190## 
##STR1191## 
##STR1192## 
##STR1193## 
##STR1194## 
##STR1195## 
##STR1196## 
##STR1197## 
##STR1198## 
##STR1199## 
##STR1200## 
##STR1201## 
##STR1202## 
##STR1203## 
##STR1204## 
##STR1205## 
##STR1206## 
Method T 
This variation of Method Q can be used when the drug contains one or more 
NH.sub.2 and OH functions which are to be protected. The protecting 
groups, for example, benzyloxycarbonyl for amino functions and pivalyloxy 
for hydroxyl functions, are introduced as described in Methods R and S, in 
the sequence considered most convenient. (Obviously, other protecting 
groups can be introduced instead.) The carboxyl function(s) are then 
derivatized according to Method Q. Typically, the hydroxy protecting 
group(s) are introduced first and are retained throughout the process, 
while the amino protecting group(s) are generally removed earlier, 
frequently prior to formation of the quaternary derivative of formula 
(II). 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I). Amino acids 
containing hydroxyl functions (e.g. tyrosine) and small peptides 
containing such amino acids are also prime candidates for derivation in 
accord with this method. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1207## 
##STR1208## 
##STR1209## 
##STR1210## 
##STR1211## 
##STR1212## 
##STR1213## 
##STR1214## 
##STR1215## 
Method U 
The drug is first reacted with ethylene glycol (or other dihydroxyalkanol 
having up to 8 carbon atoms), in the presence of a suitable coupling agent 
such as dicyclohexylcarbodiimide, to convert the --COOH function(s) to the 
corresponding 
EQU --COOCH.sub.2 CH.sub.2 OH 
(or other 
##STR1216## 
group(s). That intermediate is then reacted with a compound of the formula 
##STR1217## 
or the like, prepared as described in Method J, in the presence of a 
coupling agent such as dicyclohexylcarbodiimide, to give the desired 
quaternary derivative of formula (II). Subsequent reduction to the 
corresponding dihydro derivative of formula (I) proceeds as described in 
Method A. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
The procedure described above may be repeated utilizing a reactant of the 
formula 
##STR1218## 
or the like, prepared as described in Method J, in place of the 
intermediate of the formula 
##STR1219## 
This procedure may also be adapted to preparation of derivatives of the 
drugs mentioned with Methods R, S and T. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1220## 
##STR1221## 
##STR1222## 
##STR1223## 
##STR1224## 
##STR1225## 
##STR1226## 
##STR1227## 
##STR1228## 
##STR1229## 
##STR1230## 
##STR1231## 
##STR1232## 
##STR1233## 
##STR1234## 
##STR1235## 
##STR1236## 
##STR1237## 
##STR1238## 
##STR1239## 
##STR1240## 
Method U' 
The drug is reacted with excess alcohol of the formula 
##STR1241## 
wherein n=1-3, preferably 2, to convert the --COOH function to the 
corresponding 
##STR1242## 
ester grouping. The resultant quaternary of formula (II) is then reduced 
as described in Method A. when the drug contains more than one reactive 
carboxyl function, reaction conditions may be varied so that more than one 
carboxyl function will be converted to ester groupings. (The starting 
alcohol may be prepared from nicotinamide, e.g. when n=2, by reacting 
2-iodoethanol with nicotinamide.) 
The representative drugs depicted below may be derivatized in this manner 
to the corresponding compounds of formulas (II) and (I), as may the 
remaining compounds mentioned with Method Q. 
The procedure described in the first paragraph of this method may utilize a 
starting alcohol of the formula 
##STR1243## 
(prepared from picolinamide or isonicotinamide, respectively) in place of 
the starting alcohol depicted in the first paragraph, to afford the 
corresponding derivatives of the drugs indicated with this method. 
This procedure may also be adapted to preparation of derivatives of the 
drugs mentioned with Methods R, S and T. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR1244## 
##STR1245## 
##STR1246## 
##STR1247## 
##STR1248## 
##STR1249## 
##STR1250## 
##STR1251## 
##STR1252## 
##STR1253## 
##STR1254## 
##STR1255## 
##STR1256## 
##STR1257## 
##STR1258## 
##STR1259## 
##STR1260## 
##STR1261## 
##STR1262## 
##STR1263## 
##STR1264## 
##STR1265## 
##STR1266## 
##STR1267## 
##STR1268## 
##STR1269## 
##STR1270## 
##STR1271## 
##STR1272## 
##STR1273## 
##STR1274## 
##STR1275## 
##STR1276## 
##STR1277## 
##STR1278## 
##STR1279## 
##STR1280## 
##STR1281## 
##STR1282## 
##STR1283## 
##STR1284## 
##STR1285## 
##STR1286## 
##STR1287## 
##STR1288## 
##STR1289## 
##STR1290## 
##STR1291## 
##STR1292## 
##STR1293## 
##STR1294## 
##STR1295## 
##STR1296## 
##STR1297## 
##STR1298## 
##STR1299## 
##STR1300## 
##STR1301## 
##STR1302## 
##STR1303## 
##STR1304## 
##STR1305## 
##STR1306## 
##STR1307## 
##STR1308## 
##STR1309## 
##STR1310## 
##STR1311## 
##STR1312## 
##STR1313## 
##STR1314## 
##STR1315## 
##STR1316## 
##STR1317## 
##STR1318## 
##STR1319## 
##STR1320## 
##STR1321## 
Method U" 
Method U' is repeated, except that the starting alcohol employed has the 
formula 
##STR1322## 
(That starting material may be prepared by reacting bromoglucose with 
nicotinamide.) 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
Alternatively, Method U" may utilize a starting alcohol of the formula 
##STR1323## 
(prepared by reacting bromoglucose with picolinamide or isonicotinamide), 
to afford the corresponding derivatives of the compounds mentioned with 
Method Q. 
This procedure may also be adapted to preparation of derivatives of the 
drugs mentioned with Methods R, S and T. 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR1324## 
##STR1325## 
##STR1326## 
##STR1327## 
##STR1328## 
##STR1329## 
##STR1330## 
##STR1331## 
##STR1332## 
##STR1333## 
##STR1334## 
##STR1335## 
##STR1336## 
##STR1337## 
##STR1338## 
##STR1339## 
##STR1340## 
##STR1341## 
##STR1342## 
##STR1343## 
##STR1344## 
##STR1345## 
##STR1346## 
##STR1347## 
##STR1348## 
##STR1349## 
##STR1350## 
Method U"' 
Method U' is repeated, except that the starting alcohol employed has the 
formula 
##STR1351## 
(That starting material may be prepared by reacting nicotinic acid with 
1,2-propylene glycol in the presence of dicyclohexylcarbodiimide.) 
The representative drugs listed below may be derivatized in this manner to 
the corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
The procedure of Method U"' may be repeated using a starting alcohol of the 
formula 
##STR1352## 
in place of the starting alcohol depicted above (prepared in an analogous 
manner using picolinic acid or isonicotinic acid in place of nicotinic 
acid in the reaction with 1,2-propylene glycol), to afford the 
corresponding derivatives of the drugs indicated in Method Q. 
This procedure may also be adapted to preparation of derivatives of the 
drugs mentioned with Methods R, S 
3 
Starting Material [DQC].sup.+ [DDHC] 
##STR1353## 
##STR1354## 
##STR1355## 
##STR1356## 
##STR1357## 
##STR1358## 
##STR1359## 
##STR1360## 
##STR1361## 
##STR1362## 
##STR1363## 
##STR1364## 
##STR1365## 
##STR1366## 
##STR1367## 
##STR1368## 
##STR1369## 
##STR1370## 
Method V 
A drug containing one --COOH function is reacted with an equivalent amount 
of inositol, in the presence of dicyclohexylcarbodiimide or other suitable 
coupling agent, to convert the --COOH function to a group of the structure 
##STR1371## 
Reaction of that intermediate with nicotinic acid, in the presence of a 
suitable coupling agent, or with an activated ester of nicotinic acid, 
affords an intermediate in which the original --COOH has been converted to 
##STR1372## 
wherein each R is H or 
##STR1373## 
the number of original hydroxy groups esterified varying with the amount 
of nicotinic acid employed. Subsequent quaternization and reduction are 
carried out as in Method A. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q which contain a single --COOH function. 
Alternatively, the above procedure may be repeated, replacing nicotinic 
acid with an analogous starting material, e.g. picolinic acid, 
isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic 
acid or the like. 
Repetition of the procedure of the first paragraph of this method utilizing 
a greater amount of the drug (e.g. 2 to 5 or more moles per mole of 
inositol) provides an intermediate containing from 2 to 5 acid residues 
and from 4 to 1 hydroxyl groups. That intermediate is then reacted with 
nicotinic acid to convert at least one hydroxyl group to the corresponding 
##STR1374## 
group. Subsequent formation of the quaternary and reduction proceed as in 
Method A. 
This procedure may also be adapted to preparation of derivatives of drugs 
mentioned with Methods R, S and T. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1375## 
##STR1376## 
##STR1377## 
##STR1378## 
##STR1379## 
##STR1380## 
##STR1381## 
##STR1382## 
##STR1383## 
##STR1384## 
##STR1385## 
##STR1386## 
##STR1387## 
##STR1388## 
##STR1389## 
##STR1390## 
##STR1391## 
##STR1392## 
##STR1393## 
##STR1394## 
##STR1395## 
##STR1396## 
##STR1397## 
##STR1398## 
##STR1399## 
##STR1400## 
##STR1401## 
##STR1402## 
##STR1403## 
##STR1404## 
Method W 
The drug is first reacted with 1,2-propylene glycol (or other 
dihydroxyalkanol having up to 8 carbon atoms), in the presence of a 
suitable coupling agent such as dicyclohexylcarbodiimide, to convert the 
--COOH function(s) to the corresponding 
##STR1405## 
(or other 
##STR1406## 
group(s). The resultant intermediate is then reacted with nicotinic acid, 
in the presence of an appropriate coupling agent, or with an activated 
ester of nicotinic acid, to give an intermediat of the partial formula 
##STR1407## 
Subsequent quaternization and reduction are carried out as in Method A. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
Alternatively, the above procedure may be repeated, replacing nicotinic 
acid with an analogous starting material, e.g. picolinic acid, 
isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic 
acid or the like. 
This process may of course also be adapted to the preparation of drugs such 
as those mentioned with Methods R, S and T. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1408## 
##STR1409## 
##STR1410## 
##STR1411## 
##STR1412## 
##STR1413## 
##STR1414## 
##STR1415## 
##STR1416## 
##STR1417## 
##STR1418## 
##STR1419## 
##STR1420## 
##STR1421## 
##STR1422## 
##STR1423## 
##STR1424## 
##STR1425## 
Method X 
Glucosamine, of the structural formula 
##STR1426## 
is reacted with nicotinic acid, using equimolar amounts of the reactants, 
in the presence of a suitable coupling agent such as 
dicyclohexylcarbodiimide, or with an activated ester of nicotinic acid. 
The resultant intermediate of the formula 
##STR1427## 
is then reacted with a drug containing one reactive --COOH function, in 
the presence of dicyclohexylcarbodiimide or other appropriate coupling 
agent, replacing one or more of the hydroxy groups with acid residue(s), 
the number of groups replaced varying with the relative amounts of 
reactants used. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q which contain a single --COOH group. 
Alternatively, the above procedure may be repeated, replacing nicotinic 
acid with an analogous starting material, e.g. picolinic acid, 
isonicotinic acid, 3-quinolinecarboxylic acid, 4-isoquinolinecarboxylic 
acid or the like. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1428## 
##STR1429## 
##STR1430## 
##STR1431## 
##STR1432## 
##STR1433## 
##STR1434## 
##STR1435## 
##STR1436## 
##STR1437## 
##STR1438## 
##STR1439## 
##STR1440## 
##STR1441## 
##STR1442## 
##STR1443## 
##STR1444## 
##STR1445## 
##STR1446## 
##STR1447## 
##STR1448## 
##STR1449## 
##STR1450## 
##STR1451## 
Method Y 
The procedure of Method W is repeated, using ethylene glycol in place of 
1,2-propylene glycol. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
Alternatively, nicotinic acid may be replaced in this process with an 
analogous starting material, as described in the third paragraph of Method 
W, and/or adapted to the preparation of derivatives of drugs such as those 
mentioned with Methods R, S and T. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1452## 
##STR1453## 
##STR1454## 
##STR1455## 
##STR1456## 
##STR1457## 
##STR1458## 
##STR1459## 
##STR1460## 
##STR1461## 
##STR1462## 
##STR1463## 
##STR1464## 
##STR1465## 
##STR1466## 
##STR1467## 
##STR1468## 
##STR1469## 
##STR1470## 
##STR1471## 
##STR1472## 
##STR1473## 
##STR1474## 
##STR1475## 
##STR1476## 
##STR1477## 
##STR1478## 
##STR1479## 
##STR1480## 
##STR1481## 
##STR1482## 
##STR1483## 
##STR1484## 
##STR1485## 
##STR1486## 
##STR1487## 
##STR1488## 
##STR1489## 
##STR1490## 
##STR1491## 
##STR1492## 
##STR1493## 
##STR1494## 
##STR1495## 
##STR1496## 
##STR1497## 
##STR1498## 
##STR1499## 
##STR1500## 
##STR1501## 
##STR1502## 
##STR1503## 
##STR1504## 
Method Z 
The process of the first paragraph of Method Q is repeated, using an 
aminoalkanol of the formula 
##STR1505## 
in place of 2-aminoethanol. 
The drugs depicted below may be derivatized in this manner to the 
corresponding compounds of formulas (II) and (I), as may the remaining 
drugs mentioned with Method Q. 
The process variation described in the second paragraph of Method Q may 
also be applied to Method Z. 
This process may of course also be adapted to the preparation of 
derivatives of drugs such as those mentioned with Methods R, S and T. 
3 
STARTING MATERIAL [DQC].sup.+ [DDHC] 
##STR1506## 
##STR1507## 
##STR1508## 
##STR1509## 
##STR1510## 
##STR1511## 
##STR1512## 
##STR1513## 
##STR1514## 
##STR1515## 
##STR1516## 
##STR1517## 
##STR1518## 
##STR1519## 
##STR1520## 
##STR1521## 
##STR1522## 
##STR1523## 
IV. 
Methods for Salt Formation 
An ether solution of a compound of formula (I) is treated with an 
equivalent amount of anhydrous p-toluenesulfonic acid dissolved in dry 
ether. Mixing at room temperature is continued until the iminium salt 
precipitates out of solution. The salt is then removed by filtration. 
Imminium salts which may be prepared in this manner include those derived 
from the following representative compounds of formula (I): 
##STR1524## 
In order to further illustrate the present invention and the advantages 
thereof, the following specific examples are given, it being understood 
that same are intended only as illustrative and in nowise limitative. 
In the examples immediately to follow, all melting points were taken on a 
Mel-Temp apparatus and are not corrected. Elemental analyses were 
performed at Atlantic Microlab, Inc., Atlanta, Ga. Infrared spectra were 
determined using a Beckman Acculab 1 double-beam recording 
spectrophotometer. NMR spectra were determined by means of a Varian T60A 
or FX100 spectrometer. All chemical shifts reported are in .delta. units 
(parts per million) relative to tetramethylsilane. Ultraviolet absorbance 
spectra were determined using a Cary Model 219 spectrophotometer. HPLC 
analysis were performed on Waters Associates Liquid chromatograph with 
Mode 6000A solvent delivery system, Model U6K injector and Model 440 
absorbance detector. And in all cases where Anal. C, H, N is indicated, 
the elementary analysis of the compound was found within .+-.0.4 of the 
calculated value. 
EXAMPLE 1 
Preparation of N-(.beta.-Phenethyl)nicotinamide 
To 10.25 g (0.083 mol) of nicotinic acid, 27.5 ml of thionyl chloride were 
gradually added. The mixture was stirred at room temperature for 10 min 
and then refluxed while stirring for 2 hrs. Excess thionyl chloride was 
then distilled off under reduced pressure. Dry benzene (over sodium, 50 
ml) was added and then distilled off under reduced pressure (to remove 
traces of SOCl.sub.2). A white crystalline acid chloride hydrochloride was 
left, which was used as such for the preparation of amides. 
To the solid acid chloride hydrochloride, 150 ml of dry and freshly 
distilled pyridine were added. To the stirred mixture, 10.45 ml (0.083 
mol) of phenethylamine were dropped over 15 min. The mixture was then 
heated on a water bath while stirring for 2 hrs. Pyridine was distilled 
off on rotavap. The brown oily residue was poured onto crushed ice. The 
cream-white solid which separated was filtered by suction, washed with 
cold water and dried in vacuum; yield 13.3 g (70%), m.p. 
79.degree.-80.degree. C.; ir (KBr) 3320 (NH) and 1630 cm.sup.-1 (C.dbd.O), 
NMR (CDCl.sub.3) .delta. 8.66 (bs, 1H, C.sub.4 pyridine proton), 8.46 (bd, 
1H, C.sub.6 pyridine proton), 8.0-7.6 (m, 1H, C.sub.4 pyridine proton), 
7.33-6.90 (bs, 6H, C.sub.6 H.sub.5 +C.sub.5 pyridine proton), 7.0-6.57 
(hump, 1H, CONH), 3.73 (g, 2H, 
##STR1525## 
2.97 (t, 2H, CH.sub.2 --.phi.). Anal. (C.sub.14 H.sub.14 N.sub.2 O) C, H, 
N. 
EXAMPLE 2 
Preparation of 1-Benzyl-3-(N-.eta.-phenethyl)carbamoylpyridinium bromide 
To a solution of 2.26 g (0.01 mol) of N-(.beta.-phenethyl)nicotinamide in 5 
ml of methanol, 1.4 ml (0.0114 mol) of benzyl bromide were added. The 
mixture was refluxed for 3 hours. Methanol was distilled off on rotavap. 
The yellow, oily residue left was scratched when it suddenly solidified 
into buff, gritty solid. Crystallized from acetone/ether, yield 3.7 g 
(95%), m.p. 142.degree.-144.degree. C., U.V. max (buffer pH 7.4) 210 and 
260 nm; ir (KBr) 3180 (NH) and 1670 cm.sup.-1 (C.dbd.O). NMR (CDCl.sub.3 
/DMSO-d.sub.6) .delta. 10.26 (bs, 1H, C.sub.2 pyridine proton), 9.53-8.90 
(m, 2H, C.sub.6 and C.sub.4 pyridine protons), 8.16-7.13 (m, 12H, 2C.sub.6 
H.sub.5 +CONH+C.sub.5 pyridine protons), 6.13 (s, 2H, 
##STR1526## 
3.96-3.50 (m, 2H, --N--CH.sub.2), 3.26-2.83 (m, 2H, CH.sub.2 --.phi.). 
Anal. (C.sub.21 H.sub.21 BrN.sub.2 O) C, H, N. 
EXAMPLE 3 
Preparation of 1-Methyl-3-(N-.beta.-phenethyl)carbamoyl iodide 
To a solution of 2.26 g (0.01 mol) of N-(.beta.-phenethyl)nicotinamide in 5 
ml of methanol, 1.3 ml (0.02 mol) in methyl iodide were added. The mixture 
was refluxed for 3 hrs. Methanol was distilled off on rotavap and the 
yellow, oily residue was cooled and scratched when a yellow gritty solid 
was obtained. Crystallized from acetone, yield 3.5 g (95%), m.p. 
134.degree.-136.degree. C., U.V. max (buffer pH 7.4) 210, 225 and 226 nm. 
Ir (KBr) 3240 (NH) and 1665 cm.sup.-1 (C.dbd.O). NMR (CDCl.sub.3 
/DMSO-d.sub.6) .delta. 9.63 (s, 1H, C.sub.2 pyridine proton), 9.4-8.9 (m, 
2H, C.sub.4 and C.sub.6 pyridine protons), 8.32-8.06 (m, 1H, C.sub.5 
pyridine proton), 4.6 (s, 3H, 
##STR1527## 
3.9-3.46 (m, 2H, --N--CH.sub.2), 3.2-2.8 (m, 2H, CH.sub.2 --.phi.). Anal. 
(C.sub.15 H.sub.17 IN.sub.2 O) C, H, N. 
EXAMPLE 4 
Preparation of 1-Benzyl-3-(N-.beta.-phenethyl)carbamoyl-1,4-dihydropyridine 
To a solution of 3.97 g (0.01 mol) of 
1-benzyl-3-(N-.beta.-phenethyl)carbamoylpyridinium bromide in 200 ml of 
deaerated water, 5.0 g (0.06 mol) of sodium bicarbonate and 200 ml of 
ether were added. The mixture was stirred in an ice bath and 7.1 g (0.04 
mole) of sodium dithionate were added gradually over a period of 5 min. 
The mixture was stirred for 3 hrs under nitrogen. The ether layer was then 
separated, washed with water, dried with Na.sub.2 SO.sub.4 and distilled 
under vacuo. Yield 2.3 g (72%) of bright yellow, viscous oil was obtained 
which gave positive test for dihydropyridine with alcoholic silver nitrate 
solution. U.V. max (buffer pH 7.4) 210 and 355 nm. NMR (CDCl.sub.3) 
.delta. two overlapping singlets at 7.2 (10H, 2C.sub.6 H.sub.5), 7.1 (bs, 
1H, C.sub.2 pyridine proton), 5.68 (doublet of doublets, 1H, J=8 and 2 
cps, C.sub.6 pyridine proton), 6.4-5.0 (hump, 1H, CONH), 4.84-4.60 (m, 1H, 
C.sub.5 pyridine proton), 4.35 (s, 2H, N--CH.sub.2), 3.5 (q, 2H, J-7.0, 
##STR1528## 
3.0 (bs, 2H, C.sub.4 pyridine proton) and 2.8 (t, 2H, J=7.0, CH.sub.2 
--.phi.). 
EXAMPLE 5 
Preparation of 1-Methyl-3-(N-.beta.-phenethyl)carbamoyl-1,4-dihydropyridine 
By the similar method described above, 
1-methyl-3-(N-.beta.-phenethyl)carbamoyl iodide (3.68 g, 0.01 mol) was 
reduced using sodium dithionate (7.1 g, 0.04 mol) and sodium bicarbonate 
(5.0 g, 0.06 mol). Yield 1.8 g (76%) of bright yellow, viscous oil which 
reduced alcoholic silver nitrate solution. U.V. max (buffer ph 7.4) 210, 
290 and 360 nm; NMR (CDCl.sub.3) .delta. 7.2 (s, 5H, C.sub.6 H.sub.5), 6.9 
(bs, 1H, C.sub.2 pyridine proton), 5.6 (doublet of doublets, 1H, J=8, 2 
cps, C.sub.6 pyridine proton), 5.3-5.1 (hump, 1H, CONH), 4.5-4.7 (m, 1H, 
C.sub.5 pyridine protons+N--CH.sub.3 +CH.sub.2 --.phi.). Anal. (C.sub.15 
H.sub.18 N.sub.2 O) C, H, N. 
EXAMPLE 6 
Preparation of Diethyl 3,5-pyridinedicarboxylate 
To suspension of 8.35 g (0.05 mol) of 3,5-pyridinedicarboxylic acid in 30 
ml of absolute ethanol, 10 ml of concentrated sulfuric acid were dropped 
while stirring. The mixture was then refluxed on a water bath for 5 hrs 
and poured onto crushed ice. The solution was then made alkaline by the 
addition of solid KHCO.sub.3 in small amounts. A white solid which 
separated was filtered, washed with water and dried. M.p. 
42.degree.-44.degree. C. The mother liquid was extracted with CH.sub.2 
Cl.sub.2 when another crop of the diester was obtained. The overall yield 
of the crude ester was 9.1 g (82%) of sufficient purity for the examples 
to follow. NMR (CDCl.sub.3) .delta. 9.62 (d, 2H, J-2 Hz, C.sub.2 and 
C.sub.6 pyridine protons), 8.76 (t, 1H, J=2 Hz, C.sub.4 pyridine proton), 
4.43 (q, 4H, J=7 Hz, 2 OCH.sub.2), 1.41 (t, 6H, J=7 Hz, 2 CH.sub.3). 
EXAMPLE 7 
Preparation of 5-Carboethoxy-3-pyridinecarboxylic acid 
To a solution of 10 g (0.045 mol) of diethyl 3,5-pyridinedicarboxylate in 
75 ml of ethyl alcohol, 25 ml of 2N alcoholic KOH were added while 
stirring. Stirring was continued for 1/2 hour at room temperature. To the 
mixture, 12.5 ml of 4N HCl were added while stirring. The solid which 
separated was filtered and washed with alcohol. The combined filtrate and 
washings were distilled on rotovap and the residue was washed with water, 
filtered and crystallized from ethanol. Yield 7.5 g (86%), m.p. 
180.degree.-182.degree. C., NMR (CDCl.sub.3 /DMSO-d.sub.6) .delta. 10.56 
(bs, 1H, COOH), 9.26 (d, 2H, J=2 Hz, C.sub.2 and C.sub.6 pyridine 
protons), 8.75 (t, 1H, J=2 Hz, C.sub.4 pyridine protons), 4.4 (q, 2H, J=7 
Hz, O--CH.sub.2), 1.42 (t, 3H, J=7 Hz, CH.sub.3). 
EXAMPLE 8 
Preparation of 5-Carboethoxy-3-(N-.beta.-phenethyl)carbamoylpyridine 
To 10 g (0.05 mol) of 5-carboethoxy-3-pyridinecarboxylic acid, 30 ml of 
thionyl chloride were added and the mixture was warmed on a water bath 
while stirring until clear (.congruent.3 hrs). Excess thionyl chloride was 
distilled under vacuum. The residue was cooled to room temperature and 50 
ml of sodium-dry benzene was added. The solution was cooled in an ice bath 
and a solution of 6.2 g (0.051 mol) of phenethylamine and 4 ml of pyridine 
in 50 ml of dry benzene was dropped while stirring over 1 hr and the 
mixture was left overnight at room temperature. The mixture was then 
washed with water until free from Cl.sup.- (tested by AgNO.sub.3 TS). The 
organic layer was dried with Na.sub.2 SO.sub.4 and distilled. The residue 
was crystallized from ether/pet. ether mixture. Yield 9.0 g (67%), m.p. 
159.degree.-161.degree. C.; ir (KBr) 3300 (NH), 1725 (ester CO) and 1650 
cm.sup.-1 (amide CO), NMR (CDCl.sub.3) .delta. 9.13-9.96 (two doublets, 
2H, J=2 Hz, C.sub.2 and C.sub.6 pyridine protons), 8.53 (t, 1H, J=2 Hz, 
C.sub.4 pyridine proton), 7.16 (s, 6H, C.sub.6 H.sub.5 +CONH), 4.36 (q, 
2H, J=7 Hz, OCH.sub.2), 3.4 (q, 2H, J=7 Hz, N--CH.sub.2), 2.9 (5, 2H, J=7 
Hz, CH.sub.2 --.phi.), 1.33 (t, 3H, J=7 Hz, CH.sub.3). Anal. (C.sub.17 
H.sub.18 N.sub.2 O.sub.3) C, H, N. 
EXAMPLE 9 
Preparation of 
5-Carboethoxy-1-methyl-3-(N-.beta.-phenethyl)carbamoylpyridinium iodide 
To a solution of 2.9 g (0.01 mol) of 
5-carboethoxy-3-(N-.beta.-phenethyl)carbamoylpyridine in 5 ml of acetone, 
3 ml of methyl iodide were added. The mixture was refluxed while stirring 
for 8 hrs and then left overnight. The yellow crystalline solid which 
precipitated was filtered, washed with acetone, dried and crystallized 
from acetone. Weight 3.5. g (82%), m.p. 168.degree.-170.degree. C., ir 
(KBr) 3250 (NH), 1725 (ester CO) and 1670 cm.sup.-1 (amide CO), U.V. max 
(buffer pH 7.4) 268 (weak plateau) and 268 nm (.epsilon.=53, 667), NMR 
(DMSO-d.sub.6) .delta. 9.53 (bs, 2H, C.sub.2 and C.sub.6 pyridine 
protons), 9.33-9.10 (m, 1H, C.sub.4 pyridine proton), 7.16 (s, 5H, C.sub.6 
H.sub.5), 4.63-4.26 (complex multiplet, 5H, 
##STR1529## 
3.56 (q, 2H, J=6 Hz, 
##STR1530## 
2.90 (t, 2H, J=6, CH.sub.2 --.phi.), 1.4 (t, 3H, J=7 Hz, CH.sub.3). Anal. 
(C.sub.18 H.sub.21 IN.sub.2 O.sub.3) C, H, N. 
EXAMPLE 10 
Preparation of 
5-Carboethoxy-1-methyl-3-(N-.beta.-phenethyl)carbamoyl-1,4-dihydropyridine 
This compound was prepared following the same procedure as in Example 4 
using 1.0 g (0.002 mol) of 
5-carboethoxy-1-methyl-3-(N-.beta.-phenethyl)carbamoylpyridinium iodide, 
1.0 g (0.012 mol) sodium bicarbonate and 1.42 g (0.008 mol) sodium 
dithionite. Yield, 0.60 g (84%) of orange-yellow viscous oil which reduced 
alcoholic silver nitrate, but very sowly. U.V. max (buffer pH 7.4) 205 and 
390 nm. NMR (CDCl.sub.3) 7.33 (s, 5H, C.sub.6 H.sub.5), 7.0 (s, 2H, 
C.sub.2 and C.sub.6 pyridine protons), 5.8-5.3 (hump, 1H, CONH), 4.2 (q, 
2H, J=7, O--CH.sub.2), 3.66 (q, 2H, J=7 Hz, 
##STR1531## 
3.16 (bs, 2H, C.sub.4 pyridine proton), 3.0 (q, 2H, J=7, CH.sub.2 
--.phi.), 1.4 (t, 3H, J=7, CH.sub.3). 
EXAMPLE 11 
Preparation of 3,5-Di(N-.beta.-phenethyl)carbamoylpyridine 
To a solution of 2.53 g (0.01 mol) of diethyl 3,5-pyridinedicarboxylate in 
10 ml of methanol, 3.0 g (0.025 mol) of phenethylamine were added. The 
mixture was refluxed overnight and then distilled. The residue was washed 
with very dilute HCl solution and water, dried and crystallized form 
ethanol. Yield 2.9 g (80%), m.p. 189.degree.-190.degree. C. NMR 
(CDCl.sub.3) .delta. 9.00 (d, J=2 Hz, 2H, 2,6-dipyridyl), 8.33 (5, J=2, 
1H, 4-pyridyl), 7.30 (s, 10H, 2 C.sub.6 H.sub.5), 6.93-6.40 (hump, 2H, 2 
COHN), 3.83 (q, J=7, 4H, 2 --N--CH.sub.2), 3.00 (t, J=7, 4H, 2 --CH.sub.2 
--.phi.). Anal. (C.sub.23 H.sub.23 N.sub.3 O.sub.2) C, H, N. 
EXAMPLE 12 
Preparation of 1-Methyl-3,5-di(N-.beta.-phenethyl)carbamoyl pyridinium 
iodide 
To a solution of 2.0 g (5.3 mmol) of 
3,5-di(N-.beta.-phenethyl)carbamoylpyridine in 10 ml of acetone, 2 ml of 
methyl iodide were added and the mixture was refluxed for 24 hrs. The 
yellow crystalline solid which separated was filtered, washed with acetone 
and dried. Weight 1.4 g (51%), m.p. 186.degree.-188.degree. C. U.V. 
spectrum of a solution in phosphate buffer 7.4 showed a plateau at 275 nm, 
a shoulder at 225 nm and a sharp peak at 203 nm (.epsilon.=67,356). Ir 
(KBr) 3240 (NH), 1665 and 1650 cm.sup.-1 (twin band, C.dbd.O). NMR 
(CDCl.sub.3 /D.sub.2 O) .delta. 9.35 (d, 2H, J=2, C.sub.2 and C.sub.6 
pyridine protons), 8.56 (d, 1H, J=2 Hz, C.sub.4 pyridine proton), 7.20 (s, 
10H, 2 C.sub.6 H.sub.5), 4.56 (s, 3H, 
##STR1532## 
3.66 (t, 4H, J=7 Hz, 2 --N--CH.sub.2), 2.96 (t, 4H, J=7 Hz, 2 CH.sub.2 
--.phi.). Anal. (C.sub.24 H.sub.26 IN.sub.3 O.sub.2). 
EXAMPLE 13 
Preparation of 
1-Methyl-3,5-di(N-.beta.-phenethyl)carbamoyl-1,4-dihydropyridine 
This compound was prepared following the same procedure as in Example 4, 
using 1 g (0.002 mol) of 1-methyl-3,5-di(N-.beta.-phenethyl)carbamoyl 
pyridinium iodide, 1.0 g (0.012 mol) sodium bicarbonate and 1.4 g (0.008 
mol) sodium dithionite. Yield 0.65 g (86%) of orange-yellow semisolid 
which could not be crystallized. Its alcoholic solution shows a slow 
reduction with alcoholic silver nitrate solution. U.V. max (buffer pH 7.4) 
388 and 210 nm. NMR (CDCl.sub.3) 7.13 (s, 5H, C.sub.6 H.sub.5), 6.76 (s, 
1H, C.sub.2 pyridine protons), 3.51 (q, 4H, J=7 Hz, 2 
##STR1533## 
3.06-2.60 (m, 9H, O--CH.sub.2 +C.sub.4 pyridine proton +N--CH.sub.3). 
EXAMPLE 14 
Preparation of N-Nicotinoyldopamine (compound 7) 
To a pyridine solution containing 11.7 g (0.05 mol) dopamine hydrobromide 
and 6.15 g (0.05 mol) nicotinic acid at 0.degree. C. were added 10.3 g 
(0.05 mol) dicyclohexylcarbodiimide (DCC). The reaction mixture was 
stirred at room temperature for 24 hours and the formed dicyclohexylurea 
was removed by filtration. The pyridine was removed in vacuo and the 
residue was crystallized from water at 0.degree. C. The product was 
isolated by filtration and dried over phosphorous pentoxide. 
Recrystallization from isopropanol gave 9.0 g (0.035 mol), 70% 
N-nicotinoyldopamine, m.p. 159.degree.-162.degree. C.; aqueous solution of 
the compound gave a green color with Fe.sup.+3 and reduced AgNO.sub.3 ; ir 
(KBr) 3300, 2960, 1725, 1630, 1590, 1520, 1430, 1290, 1190, 1115, 720 and 
710 cm.sup.-1 ; NMR (d.sub.6 -DMSO) .beta. 9.25-6.25 (m, 7H), 3.3 (m, 2H) 
and 2.65 (m, 2H) ppm. Anal. (C.sub.14 H.sub.14 N.sub.2 O.sub.3) C, H, N. 
EXAMPLE 15 
Preparation of 3-{N-[.beta.-(3,4-Diacetoxyphenyl)ethyl]}carbamoylpyridine 
To an ice cold suspension of 2.06 g (8 mmol) finely powdered 
nicotinoyldopamine in 50 ml of chloroform, 1.56 g (10 mmol) of acetyl 
chloride were dropped while stirring. The mixture was refluxed for 3 hrs, 
then filtered. The filtrate was washed with water until the washing did 
not give test for chloride ions with AgNO.sub.3 T.S. Chloroform was 
distilled on rotavap and the residue was crystallized from ether/pet. 
ether. Yield 2.2 g (81%) NMR (CDCl.sub.3) 8.90 (bs, 1H, C.sub.2 pyridine 
proton), 8.56 (bd, 1H, C.sub.6 pyridine proton), 8.16-7.83 (m, 1H, C.sub.4 
pyridine proton), 7.36-7.03 (m, 5H, C.sub.6 H.sub.3 +C.sub.5 pyridine 
proton +NH), 3.60 (q, 2H, J=7 Hz, 
##STR1534## 
2.90 (t, 2H, J=7 Hz, --CH.sub.2). 
EXAMPLE 16 
Preparation of 
3-{N-[.beta.-(3,4-Dipivalyloxyphenyl)ethyl]}carbamoylpyridine (compound 
8c) 
To a suspension of 5.16 g (0.02 mol) finely powdered nicotinoyldopamine in 
100 ml chloroform, 7.23 g (0.06 mol) trimethylacetyl chloride were added 
under stirring. The mixture was refluxed for 6 hrs and then filtered. The 
filtrate was washed with water free of chloride ions, then washed once 
with a 5% solution of NaHCO.sub.3, then with water. The chloroform was 
evaporated and the residue was chromatographed by using a silica gel G 
column and 2% methanol in chloroform as the eluent. The first fraction was 
collected and evaporated and the residue was crystallized from 
ether/petroleum ether. Yield, 6.2 g (73%) of a white crystalline solid, 
m.p. 112.degree.-114.degree. C., NMR (CDCl.sub.3) .delta. 9.06 (bs, 1H, 
C.sub.2 pyridine proton), 8.73 (bd, 1H, C.sub.6 pyridine proton), 
8.30-8.13 (m, 1H, C.sub.4 pyridine proton), 7.46-7.10 (m, 5H, C.sub.6 
H.sub.3 +C.sub.5 pyridine proton+CONH), 3.66 (q, 2H, J=6.25 Hz, 
--N--CH.sub.2), 3.0 (t, 2H, J=6 Hz, --CH.sub.2), 1.41 (s, 18H, 
2--C(CH.sub.3).sub.3). Anal. Calcd for C.sub.24 H.sub.30 N.sub.2 O.sub.5 : 
C, 67.58; H, 7.09; N, 6.56. Found: C, 67.61; H, 7.10; N, 6.54. 
EXAMPLE 17 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-dihydroxyphenyl)ethyl)]}carbamoylpyridinium 
iodide (compound 6a) 
To a solution of 1.26 g (5 mmol) of nicotinoyldopamine (7) in 10 ml of 
acetone, 1.41 g (10 mmol) of methyl iodide were added and the mixture was 
refluxed under stirring for 6 hrs. The acetone was removed and the residue 
was crystallized from methanol/ether. Yield, 1.7 g (87%), m.p. 
155.degree.-157.degree. C.(dec). Aqueous solution gave a green color with 
Fe.sup.+3, NMR (D.sub.2 O) .delta. 9.30-8.28 (ms, 4H, C.sub.5 H.sub.4 
N.sup.+), 7.00 (bs, 3H, C.sub.6 H.sub.3), 4.60 (s, 3H, --N.sup.+ 
--CH.sub.3), 3.80 (t, 2H, J=7 Hz, --N--CH.sub.2), 2.93 (t, 2H, J=7 Hz, 
CH.sub.2). Anal. Calcd for C.sub.15 H.sub.17 IN.sub.2 O.sub.3.H.sub.2 O: 
C, 43.11; H, 4.55; N, 6.70. Found: C, 43.83; H, 4.23; N, 6.81. 
EXAMPLE 18 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-diacetoxyphenyl)ethyl]}carbamoylpyridinium 
iodide (compound 6b) 
To a solution of 1.71 g (5 mmol) of 
3-{N-[.beta.-(3,4-diacetoxyphenyl)ethyl]}carbamoylpyridine (prepared like 
compound 8c), 1.41 g (10 mmol) of methyl iodide were added and the mixture 
was refluxed overnight under stirring. The acetone solution was then 
decanted from the insoluble oily residue. Ether was added to the acetone 
solution and the solid which separated was crystallized from 
acetone/ether. Yield, 1.9 g (78%) of yellow crystalline needles, m.p. 
171.degree.-173.degree. C. U.V. (methanol) 215, 265 nm; NMR (D.sub.2 O) 
.delta. 8.86-7.63 (ms, 4H, C.sub.5 H.sub.4 N.sup.+), 6.66 (bs, 3H, C.sub.6 
H.sub.3), 4.4 (s, 3H, --N.sup.+ --CH.sub.3), 3.50 (t, 2H, --N--CH.sub.2), 
3.03 (t, 2H, CH.sub.2), 2.21 (bs, 6H, 2 COCH.sub.3). Anal. Calcd for 
C.sub.19 H.sub.21 IN.sub.2 O.sub.5 : C, 47.12; H, 4.37; N, 5.78. Found: C, 
47.23; H, 4.38; N, 5.78. 
EXAMPLE 19 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-dipivalyloxyphenyl)ethyl]}carbamoylpyridinium 
iodide (compound 6c) 
To a solution of 5.0 g (11.7 mmol) of compound 8c in 20 ml of acetone, 3.3 
g (23.4 mmol) of methyl iodide were added and the mixture was refluxed 
under stirring for 6 hrs, then cooled. The orange crystalline solid which 
separated was filtered, washed with ether and crystallized for 
acetone/ether. Yield, 5.6 g (85%), m.p. 163.degree.-165.degree. C. U.V. 
(buffer pH 7.4) 270, 215 nm. NMR (DMSO-d.sub.6) .delta. 7.68-7.06 (ms, 7H, 
C.sub.5 N.sub.4 N.sup.+ +C.sub.6 H.sub.3 +NH), 4.56 (s, 3H, --N.sup.+ 
--CH.sub.3), 3.42 (q, 2H, J=7 Hz, --N--CH.sub.2), 3.19 (t, 2H, J=7 Hz, 
CH.sub.2), 1.32 (s, 18H, 2 --C(CH.sub.3).sub.3). Anal. Calcd for C.sub.25 
H.sub.33 IN.sub.2 O.sub.5 : C, 52.82; H, 5.85; N, 4.92. Found: C, 52.76; 
H, 5.87; N, 4.90. 
EXAMPLE 20 
Preparation of 
1-Methyl-3-{N-[.beta.-(4-hydroxy-3-methoxyphenyl)ethyl]}carbamoylpyridiniu 
m iodide (compound 9) 
N-nicotinoyl-3-methoxytyramine was prepared by following the procedure used 
for the preparation of compound 7. The isolated crude amide was 
quaternized directly with methyl iodide following the method used for the 
preparation of compound 6a. Crystallization from methanol gave a yellow 
crystalline compound, m.p 192.degree.-194.degree. C. with overall yield of 
84%, calculated on the basis of 3-methoxytyramine starting material. NMR 
(D.sub.2 O) closely similar to that of 6a except for the singlet at 
.delta. 3.66 for OCH.sub.3. 
EXAMPLE 21 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-dihydroxyphenyl)ethyl]}carbamoyl-1,4-dihydropyr 
idine (compound 5a) 
To an ice cold solution of 1.0 g (2.5 mmol) of compound 6a in 200 ml of 
deaerated water, 1.26 g (15 mmol) sodium bicarbonate were added. Nitrogen 
was bubbled into the mixtue and 1.74 g (10 mmol) of sodium dithionite were 
added gradually to the mixture under stirring. Stirring was continued for 
1 hr and the mixture was then extracted twice with 50 ml of ether. The 
ether extract was washed with water, dried with anhydrous Na.sub.2 
SO.sub.4 and evaporated to dryness. Yield, 0.36 g (54%) of a yellow solid, 
m.p. 90.degree.-93.degree. C. (dec.) which gave a green color with ferric 
chloride test and reduced alcoholic AgNO.sub.3 instantly. UV (CH.sub.3 OH) 
220, 350 nm. NMR (CDCl.sub.3 /D.sub.2 O) .delta. 7.2-6.9 (ms, 4H, C.sub.6 
H.sub.3 +C.sub.2 dihydropyridine proton), 5.6 (m, 1H, C.sub.6 
dihydropyridine proton), 4.6-4.4 (m, 1H, C.sub. 5 dihydropyridine proton), 
3.4 (m, 2H, --N--CH.sub.2), 3.1-2.7 (m, 7H, N--CH.sub.3 +C.sub.4 
dihydropyridine protons+CH.sub.2). Anal. Calcd for C.sub.15 H.sub.18 
N.sub.2 O.sub.3.1/2H.sub.2 O: C, 63.59; H, 6.76; N, 9.88. Found: C, 63.56; 
H, 6.85; N, 9.72. 
EXAMPLE 22 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-diacetoxyphenyl)ethyl]}carbamoyl-1,4-dihydropyr 
idine (compound 5b) 
To an ice cold solution of 1.4 g (3 mmol) of compound 6b in 200 ml of 
deaerated water, 1.5 g (18 mmol) of sodium bicarbonate was added. A stream 
of N.sub.2 was bubbled into the mixture and 2.1. g (12 mmol) of sodium 
dithionite were gradually added under stirring. Stirring was continued for 
30 min and then the mixture was extracted with ethyl acetate. The extract 
was washed with water, dried with anhydrous Na.sub.2 SO.sub.4 and 
evaporated to dryness. The yellowish semisolid mass remaining gave a faint 
green color with ferric chloride test indicating partial hydrolysis of the 
ester functions. It reduced alcoholic silver nitrate instantly. U.V. 
(CH.sub.3 OH) 220, 273 and 355 nm; NMR (CDCl.sub.3 /D.sub.2 O) .delta. 
7.13-6.80 (ms, 4H, C.sub.6 H.sub.3 +C.sub.2 dihydropyridine proton), 5.53 
(doublet of doublets, 1H, C.sub.6 dihydropyridine proton), 4.63-4.46 (m, 
1H, C.sub.5 dihydropyridine proton), 3.33 (t, 2H, J=6.5 Hz, 
--N--CH.sub.2), 3.06-2.66 (m, 7H, --N--CH.sub.3 +C.sub.4 dihydropyridine 
proton+CH.sub.2), 1.8 (s, .congruent.6H, 2COCH.sub.3). 
EXAMPLE 23 
Preparation of 
1-Methyl-3-{N-[.beta.-(3,4-dipivalyloxyphenyl)ethyl]}carbamoyl-1,4-dihydro 
pyridine (compound 5c) 
To a cold mixture of 2.0 g (3.5 mmol) of compound 6c, 200 ml of deaerated 
water and 100 ml of ethyl acetate, 1.14 g (14 mmol) of sodium bicarbonate 
and 2.43 g (14 mmol) of sodium dithionite were added. The mixture was 
stirred under N.sub.2 for 20 mins. The ethyl acetate layer was separated 
and the aqueous layer was re-extracted with 100 ml of ethyl acetate. The 
combined ethyl acetate was washed with cold deaerated water, dried over 
anhydrous Na.sub.2 SO.sub.4 and distilled on rotovapor. The viscous yellow 
oily residue was dissolved in 5 ml of acetone, filtered under N.sub.2 
atmosphere and then evaporated under reduced pressure. The solid residue 
was dried under vacuum over P.sub.2 O.sub.5 in N.sub.2 atmosphere. It 
reduced alcoholic AgNO.sub.3 instantaneously and gave no color with 
DeCl.sub.3 test. Yield, 1.3 g (83%) m.p. 45.degree.-48.degree. C.; UV 
(CH.sub.3 OH) 210 and 355 nm; NMR (CDCl.sub.3) .delta. 7.04-6.92 (m, 4H, 
C.sub.6 H.sub.3 +C.sub.2 dihydropyridine proton), 5.71-5.61 (doublet of 
doublets, 1H, C.sub.6 dihydropyridine proton), 4.81 (bs, 1H, CONH), 
4.60-4.51 (m, 1H, C.sub.5 dihydropyridine proton), 3.53 (q, 2H, J=6.3 Hz, 
--N--CH.sub.2), 2.36 (bs, 2H, C.sub.4 dihydropyridine proton), 2.91 (s, 
3H, N--CH.sub.3), 2.79 (t, 2H, J=6.3 Hz, CH.sub.2), 1.33 (s, 18H, 
CO--C(CH.sub.3).sub.3). Anal. Calcd for C.sub.25 H.sub.34 N.sub.2 O.sub.5. 
11/2H.sub.2 O: C, 63.9; H, 7.93; N, 5.96. Found: C, 63.4; H, 7.81; N, 
5.94. 
EXAMPLE 24 
Preparation of 
1-Methyl-3-{N-[.beta.-(4-hydroxy-3-methoxyphenyl)ethyl]}carbamoyl-1,4-dihy 
dropyridine (compound 10) 
This compound was prepared following the same method as for the preparation 
of compound 5c. The crude solid obtained showed the same NMR (CDCl.sub.3 
/D.sub.2 O) pattern as compound 5a, except for a peak at .delta. 3.5 for 
the OCH.sub.3 protons. It was sufficiently pure for the determination of 
its retention time following the HPLC method of analysis detailed in 
Example 37 below. No trials were made for its further crystallization or 
elemental analysis. 
EXAMPLE 25 
Preparation of N-Nicotinoyltyramine 
To an ice cold suspension of 3.69 g (0.03 mol) nicotinic acid in a solution 
of 5.2 g (0.03 mol) tyramine hydrochloride in 100 ml of pyridine, 6.18 g 
(0.03 mol) of dicyclohexylcarbodiimide (DCC) were gradually added while 
stirring. Stirring was continued at room temperature for 24 hrs and the 
formed dicyclohexylurea was removed by filtration. The pyridine was 
removed by distillation in vacuo and the residue was triturated with cold 
water, filtered and crystallized from 50% aqueous methanol. Yield, 6.25 g 
(86%), m.p. 179.degree.-181.degree. C. PMR (DMSO-d.sub.6 /D.sub.2 O) 
.delta. 9.0-8.66 (m, 2H, C.sub.2 and C.sub.6 pyridine protons), 8.33-8.10 
(m, 1H, C.sub.4 pyridine proton), 7.66-7.46 (m, 1H, C.sub.5 pyridine 
proton), 7.23-6.70 (m, rH, C.sub.6 H.sub.4), 3.56 (t, 2H, 
##STR1535## 
2.90 (t, 2H, CH.sub.2). Anal. (C.sub.14 H.sub.14 N.sub.2 O.sub.2) C, H, N. 
EXAMPLE 26 
Preparation of 3-{N-[.beta.-(4-pivalyloxyphenyl)ethyl]}carbamoylpyridine 
To an ice cold suspension of 4.84 g (0.02 mol) N-nicotinoyltyramine in 100 
ml chloroform, 3.6 g (0.03 mol) of trimethylacetyl chloride were dropped 
while stirring. The mixture was refluxed overnight and the non-reacted 
nicotinoyltyramine was filtered off. The filtrate was washed with water 
until free from chloride ions, washed once with 5% solution of NaHCO.sub.3 
and then with water. Chloroform was evaporated on rotavap and the residue 
was crystallized from ether/pet. ether. Yield 3.9 g (60%), m.p. 
80.degree.-82.degree. C. PMR (CDCl.sub.3) .delta. 8.66-6.93 (m, 8H, 
C.sub.5 H.sub.4 N+C.sub.6 H.sub.4), 3.56 (q, 2H, J=7 Hz, 
##STR1536## 
2.86 (5, 2H, J=7 Hz, CH.sub.2), 1.33 (s, 9H, C--(CH.sub.3).sub.3). 
EXAMPLE 27 
Preparation of 
1-Methyl-3-{N-[.beta.-(4-hydroxyphenyl)ethyl]}carbamoylpyridinium iodide 
To a solution of 1.21 g (5 mmol) of nicotinoyltyramine in 10 ml of acetone, 
1.41 g (10 mmol) of methyl iodide were added and the mixture was refluxed 
while stirring for 6 hrs. The fine, yellow solid which separated was 
filtered and crystallized from methanol ether. Yield 1.78 g (93%), m.p. 
208.degree.-210.degree. C. PMR (DMSO-d.sub.6 /D.sub.2 O) .delta. 9.23-8.26 
(m, 4H, C.sub.5 H.sub.4 N.sup.+), 7.33-6.83 (m, 4H, C.sub.6 H.sub.4), 4.50 
(s, 3H, 
##STR1537## 
3.70 (t, J=7 Hz, 2H, 
##STR1538## 
2.93 (t, J=7 Hz, 2H, CH.sub.2). 
EXAMPLE 28 
Preparation of 
1-Methyl-3-{N-[.beta.-(4-pivalyloxyphenyl)ethyl]}carbamoylpyridinium 
iodide 
To a solution of 1.63 g (5 mmol) of the product of Example 26 in 10 ml of 
acetone, 1.41 g (10 mmol) methyl iodide were added and the mixture was 
refluxed overnight while stirring. The acetone layer was separated by 
decantation and the yellowish, oily residue was crystallized from 
methanol/ether. Yield, 1.94 g (83%), m.p. 155.degree.-157.degree. C. PMR 
(D.sub.2 O) .delta. 9.16-8.00 (m, 4H, C.sub.5 H.sub.4 N.sup.+), 7.33-6.83 
(m, 4H, C.sub.6 H.sub.4), 4.40 (s, 3H, N.sup.+ --CH.sub.3), 3.5 (t, 2H, 
J=7 Hz, 
##STR1539## 
2.90 (t, 2H, J=7 Hz, CH.sub.2), 1.30 (s, 9H, C--(CH.sub.3).sub.3). Anal. 
(C.sub.20 H.sub.25 N.sub.2 O.sub.3 I) C, H, N. 
EXAMPLE 29 
Preparation of 
1-Methyl-3-{N-[.beta.-(4-hydroxyphenyl)ethyl]}carbamoyl-1,4-dihydropyridin 
To an ice cold solution of 1.15 g (3 mmol) of the product of Example 27 in 
200 ml of deaerated water, 1.5 g (18 mmol) sodium bicarbonate were added. 
While the mixture was bubbled with N.sub.2 gas, 2.09 g (12 mmol) of sodium 
dithionite were gradually added to the mixture. The mixture was stirred 
under N.sub.2 for 1 hr and then extracted twice, each with 100 ml of ethyl 
acetate. The combined extract was washed with water, dried over anhydrous 
Na.sub.2 SO.sub.4 and distilled on rotovap. Yield, 0.38 g (50%) of 
yellowish semisolid which reduced alcoholic AgNO.sub.3 TS instantaneously. 
(PMR as expected.) 
EXAMPLE 30 
Preparation of 
1-Methyl-3-{N-[.beta.-4-pivalyloxyphenyl)]}carbamoyl-1,4-dihydropyridine 
To an ice cold mixture of 2.34 g (5 mmol) of the product of Example 28, 200 
ml of deaerated water and 100 ml of ethyl acetate, 1.63 g (20 mmol) sodium 
bicarbonate and 3.47 g (20 mmol) sodium dithionite were added while 
stirring the mixture. Stirring was continued under N.sub.2 gas for 30 min. 
The ethyl acetate layer was separated and the aqueous layer was extracted 
with 100 ml of ethyl acetate. The combined ethyl acetate extract was 
washed with 100 ml cold deaerated water, dried over anhydrous Na.sub.2 
SO.sub.4 and evaporated on rotavap. The viscous, yellow residue was 
dissolved in 5 ml of acetone, filtered under N.sub.2 gas through folded 
filter paper and distilled on rotavap. The solid residue was dried under 
vacuo over P.sub.2 O.sub.5 in N.sub.2 atmosphere. It reduced alcoholic 
AgNO.sub.3 instantaneously. Yield, 1.06 g (62%). (PMR as expected.) 
EXAMPLE 31 
Preparation of 3,5-Pyridinedicarboxylic acid didecyl ester hydrochloride 
3,5-Pyridinedicarboxylic acid (9.6 g, 0.06 mole) was converted to the 
diacid chloride by treatment with excess SOCl.sub.2. The mixture was 
refluxed at 100.degree. C. for 6 hrs. Excess SOCl.sub.2 was distilled 
under reduced pressure and 25 ml of decyl alcohol dissolved in benzene 
were added. The solution was refluxed for 5 hrs after which benzene was 
distilled and the residue dissolved in ethyl ether. The organic phase was 
extracted with bicarbonate solution and later dried over Na.sub.2 
SO.sub.4. The ethyl ether solution was acidified with HCl (gas) and 24.2 g 
of compound (95% yield, m.p. 80.degree.-90.degree. C.) were obtained. 1H 
(NMR) CDCl.sub.3 /d.sub.6 DMSO .delta. 9.3 (3H, bs), 8.7 (1H, bs), 4.3 
(4H, bT) and 1.4 (38H, bm) ppm. 
EXAMPLE 32 
Preparation of Didecyl 3,5-dicarboxylate-1-methylpyridinium iodide 
The product of Example 31 (10 g, 0.025 mole) was dissolved in an ethyl 
ether/bicarbonate solution. The organic phase was rinsed with water and 
dried over Na.sub.2 SO.sub.4. The solvent was evaporated and the residue 
was dissolved in acetone and an excess of methyl iodide was added. The 
solution was refluxed for 8 hrs, after which the solvent was evaporated 
and ethyl ether was added to the residue. A yellow solid was obtained 
which was filtered and rinsed with more ethyl ether. The solid was 
recrystallized from a minimum amount of ethyl acetate to yield 12.5 g 
(85%) m.p. 104.degree.-105.degree. C. Analytical data: Theory: C, 57.04; 
H, 8.21. Found: C, 57.18; H, 8.09. Spectrophotometric data in methanol: 
.lambda.219 .epsilon.=2.7.times.10.sup.4 1/mol cm; .lambda.277 
.epsilon.=3.6.times.10.sup.3 1/mol cm. 
EXAMPLE 33 
(i) Oxidation by Hydrogen Peroxide: 
To 10 ml of 30% H.sub.2 O.sub.2 was added 0.2 g of the dihydropyridine 
derivative (products of Examples 4, 5, 10 or 13). The mixture was stirred 
and samples were taken to check the UV spectrum. Complete oxidation to the 
corresponding quaternary salts was observed. 
(ii) Oxidation by Silver Nitrate: 
To 5 ml of saturated methanolic AgNO.sub.3 solution was added 1 ml of 5% 
methanolic solution of the dihydropyridine derivative. The mixture was 
shaken and left for 5 min for complete precipitation of silver, 
centrifuged and an aliquot was taken to check the UV spectrum. Complete 
oxidation to the quaternary salts was observed. 
(iii) Calibration Curves 
UV study of the compounds prepared in Examples 2-5, 9, 10, 12 and 13 
revealed that they obey Beer's Law with good coefficients and at a wide 
range of dilution levels. The study was done at 350 nm for the dihydro 
derivatives and at 262 and 220 nm for all the quaternary and dihydro. 
EXAMPLE 34 
Kinetics of Oxidation of the Dihydro Derivatives 
In Plasma: 
0.2 ml of (6.25.times.10.sup.-4 M) freshly prepared solution of the dihydro 
derivative in methyl alcohol was diluted to 10 ml with 20% plasma (diluted 
whith phosphate buffer pH 7.4). The solution was kept at 37.degree. C. and 
UV spectrum was scanned from 400 nm to 300 nm every 10 min for 2 hrs 
against reference made by dilution of 0.2 ml methyl alcohol with 20% 
plasma to 10 ml. 
In Whole Blood: 
In each of 5 tubes, 0.1 ml of 10.times.10.sup.-4 M methanolic solution of 
the freshly prepared dihydro derivative, was added to 2 ml of fresh 
heparinized whole human blood and the tubes were kept at 37.degree. C. in 
a water bath. At the end of the time period to be investigated, 8 ml of 
acetonitrile was added, and the tubes were shaken vigorously and 
centrifuged. The extension of the supernatant solution at 350 nm was 
measured. A reference sample was made by addition of 0.1 ml of methyl 
alcohol instead of the sample solution following the same procedure. 
In Brain Homogenate: 
2.0 g of rat brain tissue were homogenized in 10 ml of phosphate buffer, pH 
7.4. The homogenate was centrifuged for 15 min at 3000 rpm, decanted, 
heated in a water bath at 50.degree. C. for 5 min and then centrifuged 
again. The supernatant solution was diluted to 100 ml with phosphate 
buffer, pH 7.4. 
Reference Sample: 
0.2 ml of methyl alcohol was diluted to 10 ml with the brain homogenate 
solution, and the solution was used to record the base line on a Cary 219 
spectrophotometer and as a reference for the dihydro derivative sample 
solution. 
Dihydro Derivative Sample Solutions: 
0.2 ml of 6.25.times.10.sup.-4 M methanolic solution of the freshly 
prepared dihydro derivative was diluted to 10 ml with the brain homogenate 
solution. The mixture was scanned at 37.degree. C. from 400 nm to 300 nm 
every 10 min for 2 hrs on a Cary 219 spectrophotometer. 
In Liver Homogenate: 
Liver Homogenate Solution: 
5.0 g of rat liver tissue were homogenized in 50 ml of phosphate buffer, pH 
7.4. The homogenate was centrifuged, decanted, heated in a water bath at 
50.degree. C. for 5 min and then centrifuged again. The supernatant 
homogenate was diluted to 250 ml with phosphate buffer, pH 7.4. 
Reference Sample: 
0.2 ml of methyl alcohol was diluted to 10 ml with the liver homogenate 
solution and the solution was used to record the base line on a Cary 219 
spectrophotometer and as a reference for the dihydro derivative sample 
solution. 
Dihydro Derivative Sample Solution: 
0.2 ml of 6.25.times.10.sup.-4 M solution of the freshly prepared dihydro 
derivative in methyl alcohol was diluted to 10 ml with liver homogenate 
solution. The mixture was scanned at 37.degree. C. from 400 nm to 300 nm 
every 5 min for 1 hr. 
TABLE II 
__________________________________________________________________________ 
Kinetics of Oxidation 
Medium K sec.sup.-1 
t1/2 m 
K sec.sup.-1 
t1/2 m 
__________________________________________________________________________ 
Comp. 
1-Methyl-3-(N--.beta.-phenethyl)- 
1-Benzyl-3-(N--.beta.-phenethyl)- 
carbamoyl-1,4-dihydropyridine 
carbomyl-1,4-dihydropyridine 
Plasma 1.8 .times. 10.sup.-4 
64.2 7.4 .times. 10.sup.-5 
156.1 
n = 13 r = .998 n = 12 r = .998 
Whole Blood 
8.4 .times. 10.sup.-4 
13.7 4.7 .times. 10.sup.-4 
24.4 
n = 5 r = .952 n = 5 r = .974 
Brain 4.1 .times. 10.sup.-4 
28.2 2.1 .times. 10.sup.-4 
55 
Homogenate 
n = 8 r = .996 n = 13 r = .999 
Liver 8.0 .times. 10.sup.-4 
14.4 7.5 .times. 10.sup.-4 
15.3 
Homogenate 
n = 7 r = .999 n = 5 r = .998 
Comp. 
5-Carboethoxy-1-methyl-3-(N--.beta.- 
1-Methyl-3,5-di(N--.beta.-phenethyl)- 
phenethyl)carbomyl-1,4-dihydro- 
carbamoyl-1,4-dihydropyridine 
pyridine 
Brain 8.4 .times. 10.sup.-6 
22.9 1.74 .times. 10.sup.-5 
11.1 
h 
Homogenate 
n = 6 r = .997 n = 6 r = .993 
Whole Blood 
4.9 .times. 10.sup.-5 
3.9 1.13 .times. 10.sup.-4 
1.7 h 
n = 5 r = .949 n = 5 r = .972 
__________________________________________________________________________ 
EXAMPLE 35 
In Vivo Study in 
1-Methyl-3-(N-.beta.-phenethyl)carbamoyl-1,4-dihydropyridine 
A group of rats of average weight (about 350 g) was injected through the 
jugular with a solution of the freshly prepared dihydro derivative in DMSO 
(0.05 g/ml solution) in a dose level of 125 mg/kg animal body weight. 
After the appropriate time period, 1 ml of blood was withdrawn from the 
heart and the animal was perfused with 20 ml of saline solution. The 
animal was decapitated. The brains were weighed, kept in the refrigerator 
overnight and homogenized in 2 ml of water. Acetonitrile, 8 ml, was added 
and the mixture was homogenized again and then centrifuged. The amount of 
the quaternary was determined from the HPLC spectrum in relation to a 
recovery experiment made by adding a specific amount of the quaternary to 
a blank brain and hybrid in the same manner of homogenization and 
extraction. 
Brain Results: 
______________________________________ 
Normalized value 
amt in mg/weight lb Normalized 
t in grams t value 
______________________________________ 
5 .055 40 .1132 
5 .0423 47 .125 
10 .099 66 .148 
15 .0553 90 .1626 
15 .100 90 .1294 
20 .0935 145 .0949 
21 .0743 180 .0838 
25 .101 185 .1001 
30 .1242 210 .0707 
32 .095 220 .0753 
33 .0778 
______________________________________ 
Blood Concentration: 
The blood withdrawn was left in the refrigerator overnight and 3 ml of 
saline was added and the mixture shaken, then 17 ml of acetonitrile was 
added and the mixture was shaken vigorously for 1 min and then 
centrifuged. The supernatant solution was injected directly into the HPLC. 
______________________________________ 
Results: 
t (m) 
mg/ml 
______________________________________ 
25 .0235 
40 .0117 
21 .0205 
33 .0058 
5 .0294 
75 .0058 
40 .0088 
15 .0235 
______________________________________ 
EXAMPLE 36 
Kinetics of Disappearance of the Quaternary from Brain Homogenate 
A fresh perfused rat brain was homogenized in 20 ml of phosphate buffer, pH 
7.4. A solution of 10.0 mg of 
1-methyl-3-(N-.beta.-phenethyl)carbamoylpyridinium iodide in 2 ml aqueous 
methanol (1:1) was added and the thoroughly mixed mixture was kept at 
37.degree. C. in a water-bath. At each time period, 1 ml of the mixture 
was taken and shaken thoroughly with 8 ml of acetonitrile, centrifuged and 
injected to HPLC. The amount of the quaternary in the same was determined 
in comparison with a sample taken at time 0. Linear regression of t 
against log C shows that K=4.8.times.10.sup.-5 sec.sup.-1, t1/2=3.50 h (in 
vivo exp.) which was found to be K=8.45.times.10.sup.-5 sec.sup.-1, 
t1/2=2.1 h, r=0.957. 
Studies of the Dopamine Derivatives 
EXAMPLE 37 
Analytical Methods: 
A high pressure liquid chromatography (HPLC) method was developed for the 
studies of the degradation of the dihydropyridine dopamine derivative. The 
chromatographic analysis was performed on a component system consisting of 
a Waters Associate Model 6000A solvent delivery system, Model U6K injector 
and Model 440 dual channel absorbance detector operated at 254 and 280 nm. 
A 30 cm.times.3.9 mm (internal diameter) reverse phase .mu.Bondapak 
C.sub.18 column (Waters Associates), operated at ambient temperature, was 
used for all separations. The mobile phase used for the separation of the 
dihydropyridine derivative, its degradation products and oxidation 
products consisted of 0.005M solution of 1-heptanesulfonic acid sodium 
salt (PIC B-7 Eastman Kodak) in CH.sub.3 CN; 0.01M aqueous dibasic 
ammonium phosphate (2.5:1). At a flow rate of 2.0 ml/min, 6a had a 
retention time for 5.1 min; 6c, 11.8 min, 5a, 1.7 min; 5c, 3.1 min. A peak 
was always shown at a retention time of 2.2 min which is believed to be a 
monodeacylated dihydropyridine derivative, since it eventually did result 
in 6a. 
EXAMPLE 38 
Determination of the Enzymatic Hydolytic Cleavage and Rate of Oxidation of 
Compound 5c 
In Human Plasma: 
The freshly collected plasma used was obtained at the Civitan Regional 
Blood Center, Inc. (Gainesville, Fla.) and contained about 80% plasma 
diluted with anticoagulant citrate phosphate dextrose solution U.S.P. The 
plasma was stored in a refrigerator and used the next day. One hundred 
.mu.l of a freshly prepared 0.61M solution of compound 5c in methanol was 
added to 20 ml of plasma, previously equilibrated to 37.degree. C. in a 
water bath and mixed thoroughly to result in an initial concentration of 
3.05.times.10.sup.-3 moles/liter. One ml samples of plasma were withdrawn 
from the test medium, added immediately to 5 ml of ice cold acetonitrile, 
shaken vigorously and placed in a freezer. When all samples had been 
collected, they were centrifuged and the supernatants were filtered 
through Whatman 1 filter papers and analyzed by HPLC. 
In Human Blood: 
The freshly collected heparinized blood was obtained at the Civitan 
Regional Blood Center, Inc. (Gainesville, Fla.). The blood was stored in a 
refrigerator and used the next day. One hundred .mu.l of a freshly 
prepared 0.19 solution of compound 5c in methanol was added to 20 ml of 
blood, previously equilibrated to 37.degree. C. in a water bath and mixed 
thoroughly to result in an initial concentration of 9.times.10.sup.-4 
moles/liter. One ml samples of blood were withdrawn from the test medium 
every 5 minutes, added immediately to 5 ml of ice cold acetonitrile, 
shaken vigorously and placed in a freezer. When all samples had been 
collected, they were centrifuged and the supernatants were filtered using 
Whatman 4 filter paper and analyzed by HPLC. 
In Rat Brain Homogenate: 
The brain homogenate was prepared by the following method. Five 
Sprague-Dawley rats were killed by decapitation and the brains were 
removed, weighed (total weight 9.85 g) and homogenized in 49.3 ml of 
aqueous 0.11M phosphate buffer, pH 7.4. The homogenate was centrifuged and 
the supernatant was used for the test. 100 .mu.l of 0.18M solution of 
compound 5c was mixed with 10 ml of homogenate, previously equilibrated to 
37.degree. C. in a water bath, to result in an initial concentration of 
1.8.times.10.sup.-3 moles/liter. Samples of 1.0 ml were withdrawn every 10 
minutes from the test medium, added immediately to 5 ml of ice cold 
acetonitrile and placed in a freezer. When all samples had been collected, 
they were centrifuged. Each supernatant was filtered through two Whatman 1 
filter papers and analyzed by HPLC. 
In Rat Liver Homogenate: 
The liver homogenate was prepared by the following method. Three 
Sprague-Dawley rats were killed by decapitation and the livers were 
removed, weighed and homogenized by tissue homogenizer in 0.11M aqueous 
phosphate buffer,pH 7.4, to make 20% liver homogenate. The homogenate was 
centrifuged and the supernatant was used for the test. 100 .mu.l of 0.1M 
solution of compound 5c in methanol were mixed with 20 ml of the 
homogenate, previously equilibrated to 37.degree. C. in a water bath, to 
result in an initial concentration of 9.times.10.sup.-4 moles/liter. 
Samples of 1.0 ml were withdrawn every 5 minutes from the test medium, 
added immediately to 5 ml of ice cold acetonitrile, shaken vigorously and 
placed in a freezer. When all samples had been collected, they were 
centrifuged and each supernatant was filtered through Whatman 1 filter 
paper and analyzed by HPLC. 
Rates of disappearance (overall oxidation and degradation) of compound 5c: 
______________________________________ 
(i) in Plasma: R = 2.25 .times. 10.sup.-4 sec.sup.-1 
t1/2 = 51.3 min 
r = 0.998 
n = (3 .times. 6) 
(ii) In 20% Brain Homogenate: 
R = 6.7 .times. 10.sup.-4 sec.sup.-1 
t1/2 = 17.2 min 
r = 0.996 
n = (3 .times. 6) 
(iii) 
In Blood: R = 6.3 .times. 10.sup.-4 
t1/2 = 18.2 min 
r = 0.997 
n = (3 .times. 7) 
(iv) In Liver: R = 1.93 .times. 10.sup.-3 
t1/2 = 5.9 min 
r = 0.950 
n = (3 .times. 5) 
______________________________________ 
EXAMPLE 39 
Determination of Concentration of Compound 6a in Brain and Blood after 
Parenteral Administration of 5c 
Male Sprague-Dawley rats of average weight of 150.+-.10 g were used. The 
rats were anesthetized with IM injection of Inovar and the jugular was 
exposed. Compound 5c was injected intrajugularly in the form of 10% 
solution in DMSO at a dose of 64.2 mg/kg (equivalent to 50 mg/kg compound 
6a). The injection was given at a rate of 24 .mu.l/min using a calibrated 
infusion pump. After appropriate time periods, 1 ml of blood was withdrawn 
from the heart and dropped immediately into a tared tube containing 3 ml 
acetonitrile, which was afterwards weighed to determine the weight of the 
blood taken. The animal was then perfused with 20 ml of saline solution, 
decapitated and the brain was removed. The weighed brain was homogenized 
with 0.5 ml of distilled water, 3 ml of acetonitrile was added and the 
mixture was rehomogenized thoroughly, centrifuged, filtered and then 
analyzed for compound 6a using the HPLC method. The tubes containing the 
blood were shaken vigorously, centrifuged, decanted and also analyzed for 
compound 6a using the HPLC method. Quantitation was done by using a 
recovery standard curve obtained by introducing a known amount of 6a in 
either brain homogenate or blood and then treated in the same manner. See 
FIG. 6 and the discussion thereof hereinabove. 
EXAMPLE 40 
Pharmacological studies: 
In vivo effect on pituitary prolactin secretion: 
Adult male rats (Charles Rivers, CD-1) weighing 200 to 225 g were provided 
food and water ad libitum for at least one week period to experimentation. 
To elevate serum prolactin levels, each rat received a single s.c. implant 
of a Silastic tube (1.57 mm interior diameter, 5 mm.times.3.15 mm overall 
size) packed with crystalline 17-.beta.-estradiol. Two days later the rats 
were lightly anesthetized with ether and a small incision was made over 
the right jugular vein for intravenous (I.V.) administration of the test 
drugs. Compound 6a was injected at a dose of 1 mg/kg body weight/ml saline 
and groups of six rats were decapitated at 15, 30, 60 and 120 min later to 
collect blood samples. Control rats (time 0) received an I.V. injection of 
the saline vehicle and were decapitated 30 min later. Compound 5c was 
dissolved in 10% ethanol in silane and was injected IV. Rats were 
decapitated at 15, 30 and 120 min later. Control (time 0) animals received 
the 10% ethanol vehicle and were sampled 30 min later. 
Trunk blood was collected, allowed to clot for 2 h and the serum was 
separated and stored at -20.degree. C. for subsequent assay for prolactin 
concentrations. Each serum sample was assayed in duplicate by the 
double-antibody radioimmunoassay procedure described by the National 
Pituitary Agency Hormone Distribution Program. Serum prolactin 
concentrations are expressed in terms of the PRL-RP-2 reference 
preparation provided. The intraassay coefficient of variation for 10 
replicate samples of pooled serum obtained from male rats was 13.8%. 
The effects of compounds 5c and 6a on serum prolactin concentrations were 
evaluated by one-way analysis of variance and Student-Newman Keuls tests. 
A probability level of less than 0.05 was selected for significance. See 
FIG. 7 and the discussion thereof hereinabove. 
The foregoing procedure was repeated, except for the following changes: 
Compound 5c (the dihydropyridine dipivalyl ester derivative of dopamine) 
was dissolved in 10% dimethylsulfoxide in saline and administered 
intravenously at a dosage of 1 mg/kg to groups of five or six rats; the 
rats were decapitated at 1, 2, 4, 8, 12 and 24 hours following 
administration. Compound 5a (the dihydropyridine dihydroxy derivative) was 
dissolved in 10% dimethylsulfoxide and administered intravenously at a 
dosage of 1 mg/kg to groups of six rats; the rats were decapitated at 1, 2 
and 4 hours after administration. Control groups of animals received 10% 
dimethylsulfoxide in saline and were sacrificed 2 hours later. Intravenous 
administration of 5c was found to maintain a dramatic reduction in serum 
prolactin concentrations for at least 12 hours following adinistration. 
Again, the rapid onset and very prolonged inhibitory effects of 5c on 
prolactin secretion is consistent with the time course of the appearance 
of 6a in the brain following administration of 5c and the "trapping" of 6a 
in the brain. Compound 5a did produce a significant reduction in serum 
prolactin concentration at 2 hours, but by 4 hours the prolactin levels 
had increased substantially; thus 5a did not show as prolonged an 
inhibitory effect as that exhibited by 5c. 
In vitro evaluation of the prolactin inhibitory effect of 6a: 
Adult female rats (Charles Rivers Lab.) weighing 225-250 g were maintained 
on food and water ad libitum. Animals were sacrificed by decapitation; 
their pituitary glands were quickly removed from the cranium. The anterior 
pituitary (AP) of each animal was dissected into two equal halves and 
placed into incubation media. (Gibco's Minimal Essential Media supplied by 
Grand Island Biological Co. was used.) The incubation was conducted at 
37.degree. C., under continuous aeration (95% O.sub.2, 5% CO.sub.2); the 
pH was 7.2. After one hour of preincubation, the media were discarded and 
replaced with fresh ones containing either DA (2.times.10.sup.-8 M), 6a 
(2.times.10.sup.-8) or ascorbic acid (10.sup.-4 M). In all cases, one-half 
of AP received the test drug; the other, the ascorbate control. After one 
hour, samples were taken from the media and the remaining media were 
discarded. Fresh media containing DA (2.times.10.sup.-7), 6a 
(2.times.10.sup.-7) and ascorbate, respectively, were then added. One hour 
later, the second samples were taken. After the 3 h incubation period, 
each half AP's were weighed. 
The samples were diluted 1:50 with phosphate buffered saline and then 
assayed in triplicate by the radioimmunoassay method described. The data 
are given as ng prolactin released/mg wet weight/h. Paired Student's 
T-test was used to evaluate the significance of the inhibitory effects of 
the test drugs on prolactin secretion. The control AP half and the drug 
treated half were employed in each pair comparison. See TABLE I and the 
discussion thereof hereinabove. 
Further in vitro evaluation of the prolactin inhibitor effect of 6a vs. 
dopamine: 
Eighteen female rats (Charles River Lab.) weighing 225-250 g were 
maintained on food and water ad libitum for one week. Animals were 
sacrificed by decapitation, the pituitary gland was removed from the 
cranium and the anterior pituitary (AP) was separated from the posterior 
and intermediate lobes. The AP was discussed into two equal halves and 
each half was placed in an incubation media consisting of Gibco's Minimal 
Essential Media containing 25 mM Hepes Buffer (Grand Island Biological 
Company, Grand Island, N.Y.). The media was maintained at a pH of 7.2 
under continuous aeration (95% O.sub.2, 5% CO.sub.2) at a temperature of 
37.degree. C. Following a one hour preincubation period, the media were 
discarded and replaced with fresh media containing either DA (10.sup.-6 M) 
or 6a (10.sup.-6 M). The control AP half received media containing 
10.sup.-4 M ascorbic acid, the vehicle for the drugs. After one hour, the 
media were sampled and the remaining media were discarded. Fresh media 
containing DA (10.sup.-5 M) or 6a (10.sup.-5 M) or ascorbic acid 
(10.sup.-4 M) were then added to the AP halves. One hour later, second 
samples were taken and the AP halves were weighed to the nearest tenth of 
a milligram. 
Samples of media were diluted 1:50 with phosphate buffered saline and then 
assayed in triplicate by radioimmunoassay methods. Data are expressed as 
ng prolactin released/mg net weight/h. Pair student's "t" tests were used 
to evaluate the significance of the effects of the drugs on the prolactin 
release rate. The control AP half and its respective drug-treated AP half 
were employed in each paired comparison. The results are tabulated below: 
__________________________________________________________________________ 
Prolactin ng/mg/h 
Dopamine (DA) 6a 
DA DA 6a 6a 
Control 
(10.sup.-6 M) 
Control 
(10.sup.-5 M) 
Control 
(10.sup.-6 M) 
Control 
(10.sup.-5 M) 
__________________________________________________________________________ 
306 .+-. 50 
128 .+-. 22 
219 .+-. 26 
59 .+-. 20 
349 .+-. 49 
301 .+-. 51 
205 .+-. 25 
206 .+-. 28 
__________________________________________________________________________ 
Thus, control AP halves released prolactin at a rate of 300 to 350 ng/mg 
wet weight/h during the first incubation period and about 200 ng/mg wet 
weight/h during the second incubation period. Dopamine (DA) concentration 
of 10.sup.-6 and 10.sup.-5 M caused a 58 and 73% decrease in prolactin 
secretion, respectively. In contrast, N-methylnicotinoyldopamine 6a did 
not alter the rate of prolactin secretion at concentrations of 10.sup.-6 
or 10.sup.-5 M. These results confirm the conclusions drawn from the 
earlier studies which were done at lower concentrations. 
In the examples immediately to follow, all melting points were taken on a 
Mel-Temp apparatus and are not corrected. Elemental analyses were 
performed at Atlantic Microlab, Inc., Atlanta, Ga. Infrared spectra were 
determined by using a Beckman Acculab 1 double-beam recording 
spectrophotometer. NMR spectra were determined by means of Varian T60A or 
FX100 spectrometers. All chemical shifts reported are in .delta. units 
(parts per million) relative to tetramethylsilane. Ultraviolet absorbance 
spectra were determined using a Cary Model 210 spectrophotometer. HPLC 
analyses were performed on a Beckman 345 ternary liquid chromatograph with 
Model 112 solvent delivery system, Model 210 injector, Model 160 
absorbance detector and Model 421 controller. 
EXAMPLE 41 
Preparation of Testosterone nicotinate (compound 41) 
Thionyl chloride (2 ml) was added to 0.7 g (5.7 mmol) of nicotinic acid and 
the mixture was refluxed for 3 hrs. Excess thionyl chloride was removed 
under reduced pressure. To the cold residue, 10 ml of dry pyridine was 
added, followed with 1.44 g (5.0 mmol) of testosterone. The mixture was 
heated with continuous stirring at 100.degree. C. over a watch bath for 4 
hrs. Pyridine was removed in vacuo and 5 ml of methanol was added to the 
oily residue. The mixture was cooled and the solid that crystallized was 
filtered and recrystallized from methanol/acetone mixture to give 1.4 g of 
41 as white crystals (yield 71%), m.p. 187.degree.-188.degree. C. This 
intermediate was used directly for the synthesis of the chemical delivery 
system. 
EXAMPLE 42 
Preparation of 
17.beta.-[(1-Methyl-3-pyridiniumcarbonyl)oxy]androst-4-en-3-one iodide 
(compound 42) (Testosterone-17-nicotinate N-methyl iodide) 
To a solution of 1.0 g (2.5 mmol) of testosterone nicotinate 41 in 15 ml of 
acetone, 1 ml of methyl iodide was added and the mixture was refluxed 
overnight. The yellow solid that separated was removed by filtration, 
washed with acetone and crystallized from methanol/ether to yield 1.25 g 
(92% yield) of pure 42 as yellow crystals, m.p. 215.degree.-220.degree. C. 
(dec.). U.V. (CH.sub.3 OH) .lambda. 270 nm (shoulder) .epsilon.=4579; 240 
(shoulder), .epsilon.=19375. NMR (CDCl.sub.3) .delta.10.0-8.3 (ms, 4H, 
pyridinium protons), 5.73 (s, 1H, C.sub.4 testosterone proton), 4.86 (s, 
3H, .sup.+ N--CH.sub.3), 2.40-1.06 (ms, 26H, testosterone skeleton 
protons). Analysis calculated for C.sub.26 H.sub.34 INO.sub.3 : C, 58.32; 
H, 6.40; N, 2.62. Found: C, 58.17; H, 6.48; N, 2.60. 
EXAMPLE 43 
Preparation of 
17.beta.-[(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)oxy]androst-4-en-3-one 
(compound 43) 
To an ice cold solution of 1.1 g (2 mmol) of testosterone nicotinate 
N-methyl iodide 42 in 150 ml of deaerated 10% aqueous methanol, 0.67 g (8 
mmol) of sodium bicarbonate and 1.37 g (8 mmol) of sodium dithionite were 
added. The mixture was stirred for 20 minutes and the pale yellow solid 
which separated was filtered, washed with water and dried over P.sub.2 
O.sub.5 under vacuum. Wt. 0.82 g (98% yield), m.p. 172.degree.-175.degree. 
C. UV (CH.sub.3 OH) .lambda. 356 nm, .epsilon.=9511; ir (KBr) 1700, 1660 
cm.sup.-1 (two C.dbd.O stretching). NMR (d.sub.6 -DMSO) .delta. 6.90 (bs, 
1H, C.sub.2 dihydropyridine proton), 5.83-5.70 (m, 1H, C.sub.6 
dihydropyridine proton), 5.56 (s, 1H, C.sub.4 testosterone proton), 
4.7-4.33 (m, 1H, C.sub.5 dihydropyridine proton), 3.26 (bs, 2H, C.sub.4 
dihydropyridine protons), 2.93 (s, 3H, N--CH.sub.3), 2.5-0.83 (m, 26H, 
testosterone skeleton protons with the angular methyl protons at 1.16 and 
0.83). Analysis calculated for C.sub.26 H.sub.35 NO.sub.3 : C, 76.25; H, 
8.61; N, 3.42. Found: C, 76.07; H, 8.65; N, 3.38. 
EXAMPLE 44 
Analytical Methods 
A high pressure liquid chromatograph (HPLC) method was developed for the 
studies of the degradation of the quaternary 42 and dihydropyridine 
derivative 43. The chromatographic analyses were performed on the Beckman 
described hereinabove. The absorbance detector was operated at 254 nm. A 
15 cm.times.4.6 mm (internal diameter), 5 .mu.m particle size ultrasphere 
reverse phase C.sub.18 column (Altex), operated at ambient temperature, 
was used for all separations. The mobile phase used for the separation of 
the dihydropyridine derivative, its degradation products and oxidation 
products consisted of 0.002M solution of 1-heptanesulfonic acid sodium 
salt (PIC B-7 Eastman Kodak) in CH.sub.3 CN, 0.01M aqueous dibasic 
ammonium phosphate (7:3). At a flow rate of 2.0 ml/min, compound 42 had a 
retention time of 12 min and compound 43, 5 min. For the analysis of 
testosterone in the in vivo brain delivery studies, a solvent system 
consisted of 0.002M solution of PIC B-7 in CH.sub.3 CN, 0.1M aqueous 
dibasic ammonium phosphate (1:1). At a flow rate of 2.0 ml/min, 
testosterone had a retention of 3.3 min and compound 42 had a retention 
time of 36.5 min (very broad peak). 
EXAMPLE 45 
Chemical Oxidation Studies 
(i) By Silver Nitrate: 1 ml of 5% methanolic solution of the 
dihydropyridine compound 43 was added to 5 ml of saturated methanolic 
AgNO.sub.3 solution. The mixture was shaken, left 10 minutes for complete 
oxidation, centrifuged and the UV spectrum checked. 
(ii) By Hydrogen Peroxide: To a standardized solution of H.sub.2 O.sub.2 
(0.18M) contained in a UV cuvette equilibrated at 37.degree. C., a 
solution of dihydropyridine compound 43 was added to the sample cuvette to 
make a concentration of approximately 5.times.10.sup.-6 M. The mixture was 
thoroughly mixed and monitored for the disappearance of the 
dihydropyridine maximum at 356 nm using a Cary 210 interfaced with an 
Apple II microprocessor and using an enzyme kinetic software package. 
(iii) By Diphenylpicrylhydrazyl Free Radical: To 2 ml of 
9.3.times.10.sup.-5 M solution of 2,2-diphenyl-1-picrylhydrazyl free 
radical in acetonitrile, equilibrated at 26.degree. C., 20 ml of 
1.5.times.10.sup.-2 M solution of the dihydropydine compound 43 in 
acetonitrile was added to make a final concentration of 
1.48.times.10.sup.-4 M. The mixture was monitored at 515 nm against a 
reference cuvette containing the same mixture in exactly the same 
concentrations, but previously prepared and left for at least 10 minutes 
and used as reference for A.infin.. The instrument used was a Cary 210 
interfaced with an Apple II microprocessor and using an enzyme kinetic 
software package. 
EXAMPLE 46 
Determination of In Vitro Rates of Oxidation of Compound 43 in Biological 
Media 
In Human Plasma: 
The freshly collected plasma used was obtained at the Civitan Regional 
Blood Center, Inc. (Gainesville, Fla.) and contained about 80% plasma 
diluted with anticoagulant citrate phosphate dextrose solution U.S.P. The 
plasma was stored in a refrigerator and used the next day. 100 .mu.l of a 
freshly prepared 0.024M solution of compound 43 in DMSO were added to 10 
ml plasma, previously equilibrated at 37.degree. C. in a water bath and 
mixed thoroughly to result in an initial concentration of 
2.4.times.10.sup.-4 moles/liter. One ml samples of plasma were withdrawn 
every 20 minutes from the test medium, added immediately to 5 ml of ice 
cold acetonitrile, shaken vigorously and placed in a freezer. When all 
samples had been collected, they were centrifuged and the supernatants 
were filtered through nitrocellulose membrane filters (por 0.45) and 
analyzed by HPLC, following appearance of 42 (Method A). 
In Human Blood: 
The freshly collected heparinized blood was obtained at the Civitan 
Regional Blood Center, Inc. (Gainesville, Fla.). The blood was stored in a 
refrigerator and used the next day. 100 .mu.l of a freshly prepared 0.048M 
solution of compound 43 in DMSO were added to 20 ml blood, previously 
equilibrated to 37.degree. C. in a water bath and mixed thoroughly, to 
result in an initial concentration of 2.4.times.10.sup.-4 moles/liter. One 
ml samples of blood were withdrawn from the test medium every 10 minutes, 
added immediately to 5 ml of ice cold acetonitrile, shaken vigorously and 
placed in a freezer. When all samples had been collected, they were 
centrifuged and the supernatants were filtered using nitrocellulose 
membrane filters (por 0.45) and analyzed by HPLC, following appearance of 
42 and disappearance of 43. 
In Rat Brain Homogenate: 
The brain homogenate was prepared by the following method. Five female 
Sprague-Dawley rats were killed by decapitation and the brains were 
removed, pooled, weighed (total weight 9.2 g) and homgenized in 36.8 ml of 
aqueous 0.11M phosphate buffer, pH 7.4. 100 .mu.l of 0.024M solution of 
compound 43 in DMSO were mixed with 20 ml of the homogenate, previously 
equilibrated to 37.degree. C. in a water bath, to result in an initial 
concentration of 2.4.times.10.sup.-4 moles/liter. Samples of 1.0 ml were 
withdrawn every 10 minutes from the test medium, added immediately to 5 ml 
of ice cold acetonitrile, shaken vigorously and placed in a freezer. When 
all samples had been collected, they were centrifuged and the supernatants 
were filtered through nitrocellulose membrane filter (por 0.45) and 
analyzed by HPLC (Method A). 
EXAMPLE 47 
In Vitro Determination of the Site-Specific Conversion of the Prodrug 42 to 
Testosterone 
A fresh brain homogenate was prepared as above described. 100 .mu.l of 
0.017M solution of the quaternary compound 42 in methanol were mixed with 
10 ml of the brain homogenate, previously equilibrated to 37.degree. C. to 
result in an initial concentration of 1.7.times.10.sup.-4 M. Samples of 
1.0 ml were withdrawn every 20 minutes from the test medium, added 
immediately to 5 ml of ice cold acetonitrile and placed in a freezer. When 
all the samples had been collected they were centrifuged and the 
supernatant was filtered through nitrocellulose membrane filter (por 0.45) 
and analyzed for the quaternary compound 42. 
EXAMPLE 48 
In Vivo Brain Delivery of Testosterone Following Administration of the 
Dihydro Compound 43 
Female Sprague-Dawley rats of average weight of 225.+-.10 g were used. The 
rats were anesthetized with IM injection of Innovar.sup.R (0.13 ml/kg) and 
the external jugular was exposed. Compound 43 was injected intrajugularly 
in the form of 2.5% solution in DMSO at a dose of 40 mg/kg (equivalent to 
52.3 mg quaternary 42 or 28.2 mg testosterone). The injection was given at 
a rate of 44.4 .mu.l/minute using a calibrated infusion pump. After 
appropriate time periods, 1 ml of blood was withdrawn from the heart and 
dropped immediately into a tared tube containing 5 ml acetonitrile which 
was later weighed to determine the weight of the blood taken. The animal 
was then perfused with 20 ml of saline solution, decapitated and the brain 
was removed. The weighed brain was homogenized with 1 ml of distilled 
water, 5 ml of acetonitrile was added and the mixture was rehomogenized 
thoroughly, centrifuged, filtered and then analyzed using the HPLC method. 
The tubes containing the blood were shaken vigorously, centrifuged, 
filtered and also analyzed using the HPLC method described at 0.05 
sensitivity limit for determination of the quaternary 42 and at 0.001 
sensitivity limit for determination of liberated testosterone. 
Quantitation was done using a recovery standard curve obtained by 
introducing a known amount of either compound 42 or testosterone in either 
brain homogenate or blood and then treating in the same manner of 
extraction and analysis. 
EXAMPLE 49 
In Vivo Brain Delivery of Testosterone Following its Administration 
Female Sprague-Dawley rats with an average weight of 225.+-.10 g were 
injected with testosterone at a dose level of 28.2 mg/kg following the 
same procedure previously described. Samples of brain and blood collected 
were analyzed for testosterone using HPLC. 
EXAMPLE 50 
In Vivo Brain Delivery of Quaternary 42 Following its Administration 
Following the same procedure, female Sprague-Dawley rats were injected I.V. 
with the quaternary solution (0.18%) in DMSO at a dose level of 13.0 mg/kg 
(it was found to be toxic at higher doses). The brain samples collected 
were analyzed for presence of the quaternary 42 using HPLC. 
EXAMPLE 51 
Results of Experiments of Examples 45-50 
The rates of oxidation of the dihydro derivative 43 with silver nitrate, 
hydrogen peroxide and diphenylpicrylhydrazyl free radical (DPP.) were 
determined. The reactions were carried out under pseudo first order 
conditions, either with higher concentrations of the oxidant in the case 
of hydrogen peroxide or higher concentrations of 43 in the case of the 
picryl reagent. With DPP., a reference sample was made using the same 
amounts as the test sample, but prepared 10 minutes before mixing and 
monitoring the test sample. This reference is used as a measure of 
A.infin. and these were the data used to calculate the kinetic parameters. 
The in vitro rates of oxidation of the dihydro derivative were also 
determined in biological fluids, e.g. 80% plasma, whole blood, 20% brain 
homogenate and 20% liver homogenate. The rate of disappearance of the 
ester 42 and appearance of testosterone in the medium was also determined. 
Finally, the in vivo brain delivery and blood concentration profile of the 
quaternary derivative and testosterone released, against time, was 
determined following a single injection of the dihydropyridine derivative 
43 to female rats. These results were compared to blood and brain kinetics 
of testosterone following administration of such. 
Chemical Oxidation of the Dihydropyridine Derivative 43 
(i) By Silver Nitrate: 
It was observed that this dihydro derivative 43 is more stable towards 
oxidation than the monophenethylamine type derivatives reported 
hereinabove; it takes a few minutes' standing for the silver to form. The 
product is exclusively the quaternary salt 42, as verified by the change 
in the UV and NMR spectra. 
(ii) By Hydrogen Peroxide: 
At low concentrations of the dihydro compound 43 (5.times.10.sup.-6 M), 
compared to the high concentration of the peroxide (0.18M), the oxidation 
proceeds according to a first order kinetics. k=2.7.+-.0.3.times.10.sup.-3 
sec.sup.-1 t.sub.1/2 =3.98.+-.0.7 min r=0.995 At higher concentrations, 
the dihydro compound is insoluble in H.sub.2 O.sub.2. 
(iii) By Diphenylpicrylhydrazyl (DPP.) Free Radical: 
The reaction was carried out under pseudo first order conditions using 
excess of the dihydropyridine derivative. With the concentrations used, 
all runs gave good first order plots over 3 half lives, with correlation 
coefficient better than 0.9998. k=4.87.+-.31.times.10.sup.-2 sec.sup.-1 
t.sub.1/2 =14.1.+-.0.6 seconds Trials to determine the second order rate 
constant using different concentrations of DPP. were unsuccessful. 
(iv) In Vitro Oxidation and Hydrolysis in Biological Media: 
Table III shows the rates, half-lives and correlation coefficient for the 
process of oxidation of the 1,4-dihydropyridine derivative 43 in different 
biological media. 
The rate of hydrolysis of the quaternary 42 in 20% brain homogenate was 
also determined and it was found to be 3.6.times.10.sup.-5 sec.sup.-1, 
corresponding to a half-life, t.sub.1/2, of 5:16 h. 
TABLE III 
______________________________________ 
Kinetics of in vitro oxidation 
of the dihydropyridine ester 43 to the 
quaternary derivative 42 in biological fluids..sup.a 
t1/2 
Medium k(sec.sup.-1) 
(min.) r Method.sup.b 
______________________________________ 
80% Plasma 8.12 .times. 10.sup.-5 
142 .959 A 
20% Brain Homogenate 
1.72 .times. 10.sup.-4 
67 .997 A 
Whole Blood 1.74 .times. 10.sup.-4 
66 .997 A,B 
______________________________________ 
.sup.a At 37.degree. C., initial concentration of [43] = 2.4 .times. 
10.sup.-4 M 
.sup.b Method A: Following appearance of 
Method B: Following disappearance of [43 
(v) In Vivo Administration of Compound 43 and Testosterone: 
FIG. 8 illustrates the concentration of the quaternary derivative 42 in 
brain and blood and concentration of testosterone released in the brain, 
following intravenous administration of the 1,4-dihydropyridine derivative 
43. Also, FIG. 8 shows the concentration of testosterone in brain and 
blood following administration of testosterone. Statistical analysis of 
the descending portions of the curves shown in FIG. 8 provides the 
following results: 
______________________________________ 
(1) Rates of disappearance of the quaternary compound 42: 
from brain = 2 .times. 10.sup.-3 min.sup.-1 
t.sub.1/2 = 5.7 hr r = .833 
from blood = 1.27 .times. 10.sup.-2 min.sup.-1 
t.sub.1/2 = 54 min r = .833 
(2) Rate of disappearance of released testosterone 
following administration of dihydro compound 43 = 
2.65 .times. 10.sup.-3 min.sup.-1 
t.sub.1/2 = 4.4 h 
r = .768 
(Results analyzed for up to 5 hrs, the data shown 
in FIG. 8 are for 3 hrs) 
(3) Rate of disappearance of testosterone following 
administration of testosterone: 
from brain = 5.5 .times. 10.sup.-2 min.sup.-1 
t.sub.1/2 = 12.6 min r = .994 
from blood = 4.74 .times. 10.sup.-2 min.sup.-1 
t.sub.1/2 = 14.5 min r = .959 
______________________________________ 
Thus, 
17.beta.-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]androst-4-en-3-one 
43 could be obtained in a high yield (more than 90%) from testosterone 
17.beta.-nicotinate by simple chemical procedures. The dihydro product 
obtained directly from the reduction reaction medium was found by HPLC to 
be quite pure and a single crystallization from hot methanol afforded an 
analytically pure product. No signs of oxidation were observed during 
crystallization, even from hot methanol, filtration or drying. The 
crystalline solid dihydro compound did not show signs of oxidation, 
decomposition or polymerization when tested by HPLC, during the 2-month 
shelf storage at ambient temperature under nitrogen. This compound 43 was 
found to be quantitatively oxidizable to the corresponding quaternary 
derivative 42, as identified by UV spectroscopy, whether by silver nitrate 
or hydrogen peroxide. The process of oxidation with silver nitrate is 
slower than that with the dihydropyridine derivative of phenethylamine 
reported hereinbelow. Oxidation with hydrogen peroxide or DPP., at pseudo 
first order conditions, was found to take place at measurable rates 
(t.sub.1/2 =3.98.+-.0.7 min and 14.1.+-.0.6 seconds, respectively) 
compared to the rates of oxidation of the corresponding phenethylamine and 
dopamine derivatives which were found to be too fast to be monitored using 
the same procedure. The in vitro investigation in biological fluids 
indicated a facile oxidative conversion of the dihydro form 43 to the 
corresponding quaternary 42, but at a slower rate than that of the 
analogous amides of phenethylamine or dopamine. 
Insofar as concerns the in vivo studies of compound 43, the results shown 
in FIG. 8 indicate that the dihydro derivative penetrates the BBB and is 
readily oxidized in the brain to the quaternary precursor 42. The in vivo 
rate of oxidation of the dihydro seems faster than that obtained from the 
in vitro experiment. No dihydro derivative could be detected in the brain 
without the sensitivity limits of the procedure. After 42 reaches its 
maximum concentration, within about 15 minutes, its concentration starts a 
decline phase corresponding to overall excretion and/or 
metabolismhydrolysis. The overall rate of this phase was calculated to be 
2.times.10.sup.-3 min.sup.-1 (t.sub.1/2 =5.7 h). In the same time, the 
concentration of 42 in blood was decreasing progressively from the 
beginning at a rate 1.27.times.10.sup.-2 min.sup.-1 or with a half life of 
54 min. Equimolar administration of testosterone using the same solvent 
(DMSO) and the same route of administration showed a rapid absorption of 
testosterone into the brain, reaching a maximum concentration within 5 
minutes, followed by fast clearance from both brain and blood (t.sub.1/2 
=12.6 min and 14.5 min respectively). The ratio of brain/blood 
concentration for testosterone was found to be 1.6 at 5 minutes and 1.8 at 
15 minutes from administration. The ratio of brain/blood concentration of 
the quaternary 42 was found to increase progressively with time (3.23 at 
15 min, 6.33 at 45 min and 12 at 3 hrs from administration). This 
indicates the predicted "lock in" property for the quaternary 42. 
Testosterone was found to be released from the quaternary ester 42 and 
could be detected in the brain following administration of the dihydro 
derivative 42. Analysis of the time concentration curve for release of 
testosterone indicated two phase kinetics for disappearance from the 
brain. The first phase is a fast descending one at a rate of 
1.2.times.10.sup.-2 min.sup.-1 followed by a slow clearance phase with a 
rate of 5.8.times.10.sup.-4 min.sup.-1 and a half life of about 20 hrs 
which corresponds to about 130 hrs for complete clearance from the brain. 
This result, if compared to that obtained by H. Frey, A. Aadvaag, D. 
Saahum and J. Falch, Eur. J. Clin. Pharmacol., 16, 345 (1979), for the 
clearance of testosterone from plasma after oral administration (about 6 
hrs), is very promising. Although the concentrations of testosterone in 
the brain following administration of compound 43 are low compared to that 
following administration of testosterone, this is by no means a 
disadvantage because such high concentration of testosterone may not be 
needed for receptor saturation. By dose manipulation of the dihydro 
derivative, a concentration of testosterone just sufficient for receptor 
saturation for a delayed period could be attained. 
In the examples immediately to follow, all melting points were taken on a 
Mel-Temp apparatus and are not corrected. Elemental analyses were 
performed at Atlantic Microlabs, Inc., Atlanta, Ga. Infrared spectra were 
determined by means of a Beckman Acculab 1 double-beam recording 
spectrophotometer. NMR spectra were determined by means of a Varian T60A 
spectrometer. All chemical shifts reported are in .delta. (parts per 
million) relative to tetramethylsilane. Ultraviolet absorbance spectra 
were determined using a Carey Model 219 spectrophotometer. HPLC analyses 
were performed on a Waters Associates Liquid chromatograph with Model 
6000A solvent delivery system, Model U6K injector and Model 440 absorbance 
detector. 
EXAMPLE 52 
Preparation of the 1-Methyl-3-carbamoylpyridinium derivative of 
Tyr-Gly-Gly-Phe-Leu-OC.sub.2 H.sub.5 (1-Methyl-3-carbamoylpyridinium 
derivative of leu.sup.5 -enkephalin ethyl ester) 
N-.alpha.-t-Butoxycarbonyl-O-benzyl-L-tyrosine (7 g, 0.019 mol) was 
dissolved in tetrahydrofuran in a three-neck round bottom flask which was 
cooled to approximately -10.degree. C. in an ice/acetone bath under a 
nitrogen atmosphere. N-methylmorpholine (6.3 ml, 0.06 mol) was added to 
the stirred solution, followed by 2.5 ml (0.019 mol) of isobutyl 
chloroformate. Immediately after the addition of isobutyl chloroformate, 
N-methyl morpholine hydrochloride precipitated. After 5 min, 3.7 g (0.019 
mol) of L-leucine ethyl ester hydrochloride, dissolved in 
dimethylformamide, were added. The reaction mixture was stirred at this 
temperature for an hour, after which the solvent was evaporated. The 
residue obtained was dissolved in ethyl acetate/water and the organic 
layer was extracted with sodium bicarbonate solution, water, 0.01N HCl and 
water. The organic layer was dried over Na.sub.2 SO.sub.4 and after 
evaporation of the solvent an oil was obtained. Crystallization from 
CHCl.sub.3 /petroleum ether yielded 7.4 g (0.014 mol, 76%) m.p. 
104.degree.-107.degree. C., of 
N-.alpha.-t-butoxycarbonyl-O-benzyl-L-tyrosylglycylglycine ethyl ester. 
.sup.1 H NMR (CDCl.sub.3) .delta. 7.2 (5H, s), 6.9 (4H, doublet of 
doublets), 5.0 (2H, s), 1.1 (12H, m). The ethyl ester was cleaved by 
treating 6.2 g (0.012 mol) of it with an equivalent amount of 2N NaOH in 
methanol. The solution was stirred at room temperature for half an hour 
after which the solvent was evaporated. An equivalent amount of 2N HCl was 
added to the cooled residue and the solid obtained was filtered and dried 
to yield 3.5 g (96%), m.p. 118.degree.-122.degree. C., of the free 
(t-butoxycarbonyl-O-benzyl)tyrosylglycylglycine. 
t-Butoxycarbonylphenylalanylleucine ethyl ester was prepared starting with 
6 g (0.019 mol) of t-butoxycarbonyl-L-phenylalanine, and 3.7 g (0.019 
mol) of leucine ethyl ester hydrochloride. Work up and crystallization 
from CHCl.sub.3 /petroleum ether yielded 6.5 g (84%), m.p. 
109.degree.-112.degree. C., of the desired compound. .sup.1 H NMR 
(CDCl.sub.3) .delta. 7.2 (5H, s), 6.4 (1H bm), 5.1 (1H, bm), 4.3 (4H, bm), 
3.1 (2H, bm), 1.3 (20H, m). 
The t-butoxycarbonyl protecting group was cleaved by treatment of 4.9 g 
(0.012 mol) of t-butoxycarbonylphenylalanylleucine ethyl ester with 60 ml 
of 33% trifluoroacetic acid/CH.sub.2 Cl.sub.2. The solution was stirred at 
room temperature for half an hour, after which the solvent was evaporated 
and the residue was treated with a bicarbonate solution which resulted in 
the formation of a solid. The solid, phenylalanylleucine ethyl ester, was 
filtered, rinsed with water and dried to yield 5.6 g (97%), m.p. 
150.degree.-154.degree. C. 
t-Butoxycarbonyl-O-benzyltyrosylglycylglycylphenylalanylleucine ethyl ester 
was prepared by the same method using 0.1 mol of starting materials, 
(t-butoxycarbonyl-O-benzyl)tyrosylglycylglycine and phenylalanylleucine 
ethyl ester. A white solid was obtained which was recrystallized from 
methyl alcohol/water to yield 4.9 g (63%), m.p. 149.degree.-152.degree. C. 
The t-butoxycarbonyl group of 
t-butoxycarbonyl-O-benzyltyrosylglycylglycylphenylalanylleucine ethyl 
ester was cleaved as previously described to give 
O-benzyl-tyr-gly-gly-phe-leu-OEt.TFA (trifluoroacetic acid) salt. Anal. 
calc. of C.sub.39 H.sub.48 O.sub.9 N.sub.5 F.sub.3.H.sub.2 O: C, 58.13; H, 
6.25; N, 8.69. Found: C, 58.06; H, 6.26; N, 8.69). 
Nicotinic acid (160 mg, 1.3 mmole) and O-benzyl-tyr-gly-gly-phe-leu-OEt.TFA 
salt (1 g, 1.3 mmole) were dissolved in pyridine and 268 mg (1.3 mmole) of 
dicyclohexylcarbodiimide were added. The mixture was stirred at room 
temperature for 24 hrs, after which the dicyclohexylurea was filtered and 
the pyridine distilled in vacuo. Water was added to the residue and the 
solid obtained was filtered and washed with more water. The solid 
N-nicotinoyl-O-benzylpentapeptide ethyl ester was recrystallized by 
methanol/water. .sup.1 H NMR gave the expected pattern. 
The N-nicotinoyl pentapeptide derivative (500 mg, 0.64 mmol) obtained above 
was dissolved in 10% formic acid/methanol, followed by addition of 500 mg 
of palladium black. The mixture was stirred overnight at room temperature, 
after which the solvent was evaporated. The residue was neutralized with a 
saturated NaHCO.sub.3 solution and extracted with ethyl acetate. The 
solvent was evaporated and the residue recrystallized from ethyl 
acetate/ethyl ether to yield 370 mg (0.54 mmol), 84% of product. .sup.1 H 
NMR gave the expected pattern, corresponding to 
##STR1540## 
Anal. calc. for C.sub.36 H.sub.44 O.sub.8 N.sub.6.4H.sub.2 O: C, 56.83; H, 
6.89; N, 11.04. Found: C, 56.88; H, 6.56; N, 10.48. That product (30 mg, 
0.44 mmol) was dissolved in acetone and an excess of methyl iodide was 
added. The solution was refluxed for 8 hrs, after which the solvent was 
evaporated and the residue was filtered from ethyl ether. A yellowish (260 
mg, 0.31 mm), 71%, product was obtained, corresponding to the 
1-methyl-3-carbamoylpyridinium derivative of leu.sup.5 -enkephalin ethyl 
ester. Anal. calc. for C.sub.37 H.sub.47 O.sub.8 N.sub.6 I: C, 53.50; H, 
5.70; N, 10.12. Found: C, 53.44; H, 4.77; N, 10.07. 
EXAMPLE 53 
Preparation of N[2-(3-Indolyl)ethyl]nicotinamide 
To a solution of 1.97 g (10 mmol) of tryptamine hydrochloride and 1.23 g 
(10 mmol) of nicotinic acid in 10 ml of dry pyridine at 0.degree. C. were 
added 2.20 g (10.7 mmol) of dicyclohexylcarbodiimide. The reaction mixture 
was stirred at room temperature for 24 hrs, and the formed 
dicyclohexylurea was removed by filtration (2.34 g). The pyridine was 
removed in vacuo, and 10 ml of methanol were added to the residue. 
Insoluble dicyclohexylurea in methanol was removed by filtration (0.05 g). 
The methanol was removed in vacuo and 10 ml of methylene chloride was 
added to the residue. Insoluble compound in methylene chloride was removed 
by filtration (0.04 g). The methylene chloride was removed in vacuo and 
the residue was crystallized from isopropanol. Recrystallization from 
methanol/isopropanol gave 1.92 g (72.5%) of 
N-[2-(3-indolyl)ethyl]nicotinamide as pale brown plates, m.p. 
150.degree.-152.degree. C. IR (KBr) 3280, 3050, 2940, 1646, 1526, 1412, 
1302, 1102, 740, 697 cm.sup.-1. Anal. calc. for C.sub.16 H.sub.15 N.sub.3 
O: C, 72.42; H, 5.91; N, 15.84. Found: C, 72.51; H, 5.74; N, 15.77. 
EXAMPLE 54 
Preparation of 1-Methyl-3-{[N-2-(3-indolyl)ethyl]}carbamoylpyridinium 
iodide 
To a solution of 1.06 g (4 mmol) of N-[2-(3-indolyl)ethyl]nicotinamide in 5 
ml of methanol, 1 ml (16 mmol) of methyl iodide was added. The mixture was 
refluxed for 5 hrs. The methanol and excess methyl iodide were removed in 
vacuo. The residue was recrystallized from methanol/isopropanol to yield 
1.42 g (87.4%) of 1-methyl-3{[N-2-(3-indolyl)ethyl]}carbamoyl pyridinium 
iodide as yellow needles, m.p. 215.degree.-217.degree. C. IR (KBr): 3280, 
3000, 2940, 1660, 1540, 1500, 1316, 1220, 735 cm.sup.-1. Anal. calc. for 
C.sub.17 H.sub.18 N.sub.3 OI: C, 50.13; H, 4.46; N, 10.32; I, 31.16. 
Found: C, 50.22; H, 4.49; N, 10.27; I, 31.06. The product has the 
structural formula: 
##STR1541## 
EXAMPLE 55 
Preparation of 
1-Methyl-3-{N-[2-(3-indolyl)ethyl]}carbamoyl-1,4-dihydropyridine 
To a solution of 0.61 g (1.5 mmol) of 
1-methyl-3{[N-2-(3-indolyl)ethyl]}carbamoylpyridinium iodide in 50 ml of 
deaerated water and 50 ml of ethyl acetate, 1.00 g (12 mmol) of sodium 
bicarbonate was added. The mixture was stirred in an ice bath and 1.65 g 
(8 mmol) of sodium dithionite was added gradually under nitrogen. The 
mixture was stirred for 6 hrs, the ethyl acetate layer was decanted and 
the water layer was extracted with ethyl acetate. The combined solution 
was washed with water, dried with anhydrous sodium sulfate and the solvent 
removed in vacuo. A yield of 
1-methyl-3{N-[2-(3-indolyl)ethyl]}carbamoyl-1,4-dihydropyridine of 0.29 g 
(69%) was obtained as a yellow semisolid, m.p. 40.degree.-70.degree. C. IR 
(KBr) 3250, 2900, 1670 cm.sup.-1. Anal. calc. for C.sub.17 H.sub.19 
N.sub.3 O.1/2H.sub.2 O: C, 70.32; H, 6.94; N, 14.47. Found: C, 70.47; H, 
6.76; N, 14.52. The product has the structural formula: 
##STR1542## 
EXAMPLE 56 
Preparation of 5-Benzyloxygramine 
A solution of 8.90 g (0.04 mol) of 5-benzyloxyindole in 40 ml of dioxane 
was added dropwise, over the course of 30 mins, to an ice-cooled, stirred 
mixture of 40 ml of dioxane, 40 ml of acetic acid, 3.2 ml of 37% aqueous 
formaldehyde (0.04 mol) and 8.8 ml of 25% aqueous dimethylamine (0.05 
mol). The solution was stirred and cooled for two hrs and then allowed to 
warm to room temperature overnight. The next day, 500 ml of water were 
added, and the turbid mixture which resulted was filtered after the 
addition of charcoal. The filtrate was made alkaline (to pH 8-9) with 400 
ml of 10% sodium hydroxide solution. The gramine quickly solidified and 
was filtered off after cooling in the refrigerator overnight. Washing with 
water, and drying gave 9.20 g (82.0%) of coarse powder, m.p. 
125.degree.-128.degree. C. Recrystallization from ethyl acetate gave 
slightly green glittering cubes, m.p. 136.degree.-137.degree. C., of the 
desired 5-benzyloxygramine. IR (KBr) 3110, 3020, 2920, 2840, 2800, 2755, 
1610, 1575, 1470, 1455, 1480, 1210, 1190, 1000 and 780 cm.sup.-1. 
EXAMPLE 57 
Preparation of 5-Benzyloxyindole-3-acetamide 
A solution of 8.41 g (0.03 mol) of 5-benzyloxygramine, 7.5 g (0.15 mol) of 
sodium cyanide, 120 ml of ethanol and 30 ml of water was refluxed for 90 
hours. The solution, which contained some precipitate, was diluted with 
200 ml of water and cooled in the refrigerator. The crystalline material 
which separated was washed thoroughly with water and dried, giving 4.40 g 
(52.3%) of a slightly brown sticky tan powder, m.p. 
137.degree.-140.degree. C. Recrystallization from methanol/benzene gave 
small needles, m.p. 156.degree.-158.degree. C., of 
5-benzyloxyindole-3-acetamide. IR (KB) 3400, 3290, 3180, 1645, 1610, 1580, 
1485, 1450, 1275, 1210, 1200 and 795 cm.sup.-1. 
EXAMPLE 58 
Preparation of 5-Benzyloxytryptamine hydrochloride 
4.21 (0.015 mol) of 5-benzyloxyindole-3-acetamide which were dissolved in 
200 ml of tetrahydrofuran were added gradually to a solution of 3.80 g 
(0.1 mol) of lithium aluminum hydride in 200 ml of ether over a 30 minute 
period and under a nitrogen atmosphere. The solution was refluxed for 24 
hrs. The excess hydride was decomposed with ethanol and then water was 
added to ensure complete decomposition of the precipitated complex. The 
ether layer was decanted and the residue was washed with fresh ether. The 
combined solution was washed with water and dried over solid potassium 
hydroxide. The solvent was evaporated in vacuo and the oily residue was 
taken up in ether and precipitated with hydrogen chloride gas. The pale 
purple 5-benzyloxytryptamine hydrochloride was recrystallized from 
ethanol/ether, yield 3.00 g (66.0%), m.p. 263.degree.-265.degree. C. IR 
(KBr) 3290, 3010, 2910, 1600, 1580, 1480, 1200, 1100 and 1000 cm.sup.-1. 
EXAMPLE 59 
Preparation of N-{2-[3-(5-benzyloxy)indolyl]ethyl}nicotinamide 
To a solution of 303 mg (1 mmol) of 5-benzyloxytryptamine hydrochloride and 
123 mg (1 mmol) of nicotinic acid in 5 ml of pyridine at 0.degree. C. was 
added 220 mg (1.07 mmol) of dicyclohexylcarbodiimide. The reaction mixture 
was stirred at room temperature for 24 hrs and the formed dicyclohexylurea 
was removed by filtration. The pyridine was removed in vacuo, and the 
residue was recrystallized from methanol/isopropanol. Yield 218 mg 
(58.9%), m.p. 192.degree.-194.degree. C. of 
N-{2-[3-(5-benzyloxy)indolyl]ethyl}nicotinamide. IR (KBr) 3280, 3050, 
2900, 1655, 1590, 1535, 1480, 1310, 1220, 1200, 1185, 1020, and 710 
cm.sup.-1. 
EXAMPLE 60 
Preparation of 
1-Methyl-3-N-{2-[3-(5benzyloxy)indolyl]ethyl}carbamoylpyridinium iodide 
To a solution of 185 mg (0.5 mmol) of 
N-{2-[3-(5-benzyloxy)indolyl]ethyl}nicotinamide in 2 ml of methanol there 
was added 0.2 ml (3.2 mmol) of methyl iodide. The mixture was refluxed for 
3 hrs. The methanol and excess methyl iodode were removed in vacuo. The 
residue of yellow solid gradually turned purplish. Yield 128 mg (50.0%), 
m.p. 228.degree.-230.degree. C., IR (KBr) 3210, 3020, 1670, 1495, 1480, 
1190, 1025, 1000, 770 cm.sup.-1. The product has the formula 
##STR1543## 
Catatylic hydrogenolysis, using palladium-on-charcoal catalyst, of 
1-methyl-3-N-{2-[3-(5-benzyloxy)indolyl]ethyl}carbamoylpyridinium iodide 
affords 1-methyl-3-N-{2-[3-(5-hydroxy)indolyl]ethyl}carbamoylpyridinium 
iodide. Subsequent esterification with trimethylacetyl chloride affords 
the corresponding pivalyl ester of the formula 
##STR1544## 
which can then be reduced as described hereinabove to the corresponding 
dihydro derivative of the formula 
##STR1545## 
EXAMPLE 61 
Peparation of 
1-Methyl-3-{{N-{1-ethoxycarbonyl-2-[4-bis(2-chloroethyl)aminophenyl]}ethyl 
}}carbamoylpyridine 
Melphalan ethyl ester hydrochloride (153 mg, 0.41 mmol) was dissolved in 
acetonitrile (5 ml). A mixture of dicyclohexylcarbodiimide (89 mg, 0.43 
mmol) and nicotinic acid (50.9 mg, 0.41 mmol) in acetonitrile (1 ml) and 
pyridine (1 ml) was added to the stirred solution of hydrochloride at 
0.degree. C. After approximately 5 minutes, the clear mixture became 
cloudy. The mixture was allowed to warm to room temperature and stirred 
for 44 hr, after which time the precipitate was removed by filtration. 
Solvents were removed at reduced pressure to give an orange oil which was 
taken into chloroform (15 ml) and washed with cold water (5 ml). Removal 
of solvent in vacuo gave 90 mg of a soft yellow solid (50% yield) which 
was used without further purification in the following step. 
.delta.(CDCl.sub.3): 9.3 (bs, 1H, pyridine H-2); 8.9-9.2 (m, 1H, pyridine 
H-4); 7.9-8.2 (m, 1H, pyridine H-6); 7.5 (m, 1H, pyridine H-5); 6.95 
(AB.sub.q, 4-H); 4.9-5.3 (m, 1H, C--H; 4.3 (q, 2H, OCH.sub.2); 3.5-3.9 
[bs, 8H, (CH.sub.2 CH.sub.2).sub.2 ]; 3.2 (dist. d, 2H, ArCH.sub.2); 1.3 
(t, 3H, CH.sub.3). The product has the formula: 
##STR1546## 
EXAMPLE 62 
Preparation of 
1-Methyl-3-{{N-{1-ethoxycarbonyl-2-[4-bis(2-chloroethyl)aminophenyl]}ethyl 
}}carbamoylpyridinium iodide 
The product of Example 61 (76.5 mg, 0.173 mmol) in acetone (10 ml) was 
treated with methyl iodide (0.1 ml, 1 mmol) and the mixture was heated at 
gentle reflux; further methyl iodide (0.1 ml) was added after 4 hours. 
Thin layer chromatography (CHCl.sub.3 :methanol, 10:1) showed several 
spots, including a quaternary compound at the origin. No further change in 
TLC was apparent after 6 hours, at which time heat was removed and 
solvents were evaporated in vacuo to leave a red-orange oil (118 mg). The 
oil was dissolved in d.sub.6 acetone and insoluble particles were removed 
by filtration through a cotton plug. .delta.[(CD.sub.3).sub.2 CO] 9.7 (bs, 
1H, pyridine H-2); 8.9-9.5 (m, 2-H, pyridine H-4, H-6); 8.1-8.4 (m, 1H, 
pyridine H-5); 4.8-5.1 (m, 1H, CH); 4.7 (s, 3H, N.sup.+ CH.sub.3); 4.2 
(q, 2H, OCH.sub.2); 3.75 [bs, 8H, (CH.sub.2 CH.sub.2).sub.2 ]; 3.2 (s, 
HOD+ArCH.sub.2); 1.25 (5, 3H, CH.sub.3). The product is further 
characterized by the structural formula: 
##STR1547## 
EXAMPLE 63 
Preparation of 
1-Methyl-3-{{N-{1-ethoxycarbonyl-2-[4-bis(2-chloroethyl)aminophenyl]}ethyl 
}}carbamoyl-1,4-dihydropyridine 
The product of Example 62 (101 mg, 0.174 mol) and sodium bicarbonate (5.8 
mg, 6.8 mmol), as a suspension in ice cold N.sub.2 deaerated water (15 ml) 
and methanol (2 ml), were treated with sodium dithionite (91 mg, 5.2 mmol) 
and ethyl acetate (20 ml). The original pale yellow suspension became 
yellow instantly, and after 2 hours the mixture was clear. Aqueous and 
organic layers were separated and the aqueous layer was extracted with 
ethyl acetate (4.times.20 ml). The combined organic layers were dried over 
sodium sulfate at 0.degree. C. in the dark. Removal of solvent in vacuo 
gave a yellow-orange oil which reduced methanolic AgNO.sub.3 : yield 77 
mg, 97%, .delta.(CDCl.sub.3) 6.5-5.9 (bd, 1H, pyridine H-6); 4.5-5.1 (m, 
2H, pyridine 4-5+C--H); 4.2 (q, 2H, OCH.sub.2); 3.75 [bs, 8H, (CH.sub.2 
CH.sub.2 ).sub.2 ]; 3.05-3.3 [m, 4H, CH.sub.2 Ar+pyridine H-4 (CH.sub.2)]; 
3.0 (s, 3H, NCH.sub.3); 1.3 (t, 3H, CH.sub.3). .lambda.max (methanol) 
356.5 nm. The product has the formula: 
##STR1548## 
EXAMPLE 64 
Preparation of 3-Nicotinoyloxyestra-1,3,5(10)-trien-17-one (Estrone 
Nicotinate) 
To nicotinic acid (41 g, 0.333 mol) at 0.degree. C. was added thionyl 
chloride (115 ml, 1.58 mol) with stirring. The mixture was refluxed for 
one hour, and the white crystalline product was filtered and washed 
sparingly with dry benzene. Excess thionyl chloride was azeotroped off 
with dry benzene immediately before use. Yield 90% (53.97 g) of nicotinoyl 
chloride hydrochloride; NMR, IR identical with literature values. 
To nicotinoyl chloride hydrochloride (2.65 g, 0.015 mol) in pyridine (20 
ml) at 0.degree. C. was added estrone (2 g, 0.0074 mol). The mixture was 
refluxed for one hour and then poured over 100 ml of ice cold water, 
filtered, and dried over P.sub.2 O.sub.5 under vacuum. Yield 72% (2.0076 
g), m.p. 207.degree.-210.degree. C. NMR (CDCl.sub.3) .delta.9.3-9.1 (br s, 
1H, C.sub.2 pyridinium proton), 8.8-8.6 (br d, 1H, C.sub.6 pyridinium 
proton, 8.4-8.2 (br d, 1H, C.sub.4 pyridinium proton), 7.5-7.1 (m, 2-H, 
C.sub.5 pyridinium proton+C.sub.1 estrone proton), 7.0-6.7 (m, 2H, 
C.sub.2,4 estrone protons), 3.2-1.3 (estrone skeletal protons, 15), 
1.0-0.9 (s, 3H, C.sub.18 estrone protons). IR (KBr) 1750-1730 cm.sup.-1 
(broad C.dbd.O stretching). Anal. calculated for C.sub.24 H.sub.25 
NO.sub.3 ; C, 76.76; H, 6.72; N, 3.73. Found: C, 76.37; H, 6.96; N, 3.67. 
The product is further characterized by the structural formula: 
##STR1549## 
EXAMPLE 65 
Preparation of 
3-[(1-Methyl-3-pyridiniumcarbonyl)oxy]estra-1,3,5(10)-trien-17-one iodide 
To estrone nicotinate (0.5 g, 0.0013 mol) in acetone (20 ml) was added 
methyl iodide (1 ml, 0.016 mol) and the mixture was refluxed overnight. 
The deep yellow precipitate was filtered, washed with acetone, and dried. 
Yield 90% (0.6226 g); m.p. 245.degree.-248.degree. C. (dec.). NMR (d.sub.5 
-DMSO) .delta.9.8-9.7 (br s, 1H, C.sub.2 pyridinium proton), 9.4-9.0 (m, 
2H, C.sub.4, C.sub.6 pyridinium protons), 8.4-8.0 (m, 1H, C.sub.5 
pyridinium proton), 7.4-7.2 (m, 1H, C.sub.1 estrone proton), 7.1-6.9 (m, 
2H, C.sub.2,4 estrone protons), 3.2.1.3 (estrone skeletal protons, 15), 
1.0-0.9 (s, 3H, C.sub.18 estrone protons). IR (KBr) 1755-1740 (broad 
C.dbd.O stretching). Anal. calculated for C.sub.25 H.sub.28 NO.sub.3 I: C, 
58.03; H, 5.47; N, 2.71. Found: C, 58.16; H, 5.51; N, 2.67. The product 
has the formula: 
##STR1550## 
EXAMPLE 66 
Preparation of 
3-[(1-Methyl-1,4-dihydro-3-pyridinylcarbonyl)oxy]estra-1,3,5(10)-trien-17- 
one 
To 3-[(1-methyl-3-pyridiniumcarbonyl)oxy]estra-1,3,5(10)-trien-17-one 
iodide (0.600 g, 1.16 mmol) in a 50:50 mixture of methanol and deaerated 
water (80 ml) were added NaHCO.sub.3 (0.58 g, 7.0 mmol) and Na.sub.2 
S.sub.2 O.sub.4 (0.81 g, 4.6 mmol). The mixture was stirred under N.sub.2 
for 2 hours. The precipitate was filtered, dissolved in methanol at room 
temperature, filtered, and then reprecipitated with deaerated water. This 
precipitate was then filtered and dried over P.sub.2 O.sub.5 under vacuum. 
Yield 67% (0.3029 g). The product decomposes over the range 
130.degree.-180.degree. C. NMR (CDCl) .delta.7.2-7.0 (m, 2H, C.sub.1 
estrone protons+C.sub.2 dihydro proton), 6.8-6.6 (m, 2H, C.sub.2,4 estrone 
protons), 5.8-5.3 (m, 1H, C.sub.6 dihydro proton), 5.0-4.6 (m, 1H, C.sub.5 
dihydro proton), 3.2-3.0 (m, 2H, C.sub.4 dihydro protons), 3.0-2.8 (s, 
3H, N--CH.sub.3), 2.5-1.2 (estrone skeletal protons, 15), 1.0-0.9 (s, 3H, 
C.sub.18 estrone protons). IR (KBr) 1745-1740 (C.dbd.O stretching). Anal. 
calculated for C.sub.25 H.sub.29 NO.sub.3 (+1/2H.sub.2 O): C, 74.96; H, 
7.56; , N 3.50. Found: C, 75.44; H, 7.27; N, 3.38. The product is further 
characterized by the structural formula: 
##STR1551## 
EXAMPLE 67 
Preparation of 17.beta.-Nicotinoyloxyestra-1,3,5(10)-trien-3-ol 3-methyl 
ether 
To nicotinoyl chloride hydrochloride (3.15 g, 0.017 mol) in pyridine (20 
ml) at 0.degree. C. was added estradiol 3-methyl ether (2 g, 0.0070 mol). 
After refluxing one hour, the mixture was poured over 100 ml of ice water, 
filtered and dried over P.sub.2 O.sub.5 under vacuum. Yield 76% (2.0674 
g), m.p. 140.degree.-142.degree. C. NMR (CDCl.sub.3) .delta.9.3-9.0 (br s, 
1H, C.sub.2 pyridinium proton, 8.8-8.6 (m, 1H, C.sub.6 pyridinium proton), 
8.4-8.1 (br d, 1H, C.sub.4 pyridinium proton), 7.5-7.0 (m, 2H, C.sub.5 
pyridinium proton+C.sub.1 estradiol proton), 6.8-6.5 (m, 2H, C.sub.2,4 
estradiol protons), 5.1-4.7 (m, 1H, C.sub.17.alpha. estradiol proton), 
3.8-3.6 (s, 3H, O--CH.sub.3), 3.0-1.2 (15H, estradiol skeletal protons), 
1.0-0.9 (s, 3H, C.sub.18 estradiol protons). IR (KBr) 1725 (C.dbd.O 
stretching). Anal. calculated for C.sub.25 H.sub.29 NO.sub.3 : C, 76.68; 
H, 7.48; N, 3.58. Found: C, 76.49; H, 7.50; N, 3.55. The product has the 
formula: 
##STR1552## 
EXAMPLE 68 
Preparation of 
17.beta.-[(1-Methyl-3-pyridiniumcarbonyl)oxy]estra-1,3,5(10)-trien-3-ol 
3-methyl ether iodide 
To 17.beta.-nicotinoyloxyestra-1,3,5(10)-trien-3-ol 3-methyl ether (1.5 g, 
0.0038 mol) in acetone (20 ml) was added methyl iodide (1 ml, 0.016 mol) 
and the mixture was refluxed overnight. The pale yellow precipitate was 
filtered, washed with acetone, and dried. Yield 76% (1.5595 g), m.p. 
230.degree.-234.degree. C. (dec.). NMR (d.sub.6 -DMSO) .delta.9.5-9.3 (br 
s, 1H, C.sub.2 pyridinium proton), 9.2-8.8 (m, 2H, C.sub.4,6 pyridinium 
protons), 8.3-8.0 (m, 1H, C.sub.5 pyridinium proton), 7.2-7.0 (m, 1H, 
C.sub.1 estradiol proton), 6.8-6.5 (m, 2H, C.sub.2,4 estradiol protons); 
5.2-4.8 (m, 1H, C.sub.17.alpha. estradiol proton), 4.6-4.4 (s, 3H, 
N--CH.sub.3), 3.8-3.6 (s, 3H,O--CH.sub.3), 3.0-1.2 (15H, estradiol 
skeletal protons), 1.0-0.9 (s, 3H, C.sub.18 estradiol protons). IR (KBr) 
1745 (C.dbd.O stretching). Anal. calculated for C.sub.26 H.sub.32 NO.sub.3 
I: C, 58.53; H, 6.06; N, 2.63. Found: C, 58.25; H, 6.07; N, 2.59. The 
title compound has the formula: 
##STR1553## 
EXAMPLE 69 
Preparation of 
17.beta.-[(1-Methyl-1,4-dihydro-3-pyridinylcarbonyl)oxy]estra-1,3,5(10)-tr 
ien-3-ol 3-methyl ether 
To 17.beta.-[(1-methyl-3-pyridiniumcarbonyl)oxy]estra-1,3,5(10)-trien-3-ol 
3methyl ether (0.600 g, 1.12 mmol) in a 50:50 mixture of methanol and 
deaerated water (80 ml) were added NaHCO.sub.3 (0.57 g, 6.7 mmol) and 
Na.sub.2 S.sub.2 O.sub.4 (0.78 g, 4.5 mmol). The mixture was stirred under 
N.sub.2 for 2 hours. The precipitate was filtered, dissolved in methanol 
at room temperature, filtered, and then reprecipitated with deaerated 
water. This precipitate was then filtered and dried over P.sub.2 O.sub.5 
under vacuum. Yield 74% (0.3383 g). The product decomposes over the range 
120.degree.-170.degree. C. NMR (CDCl.sub.3) .delta.7.3-7.2 (m, 1H, C.sub.1 
estradiol proton), 7.0-6.9 (s, 1H, C.sub.2 dihydro proton), 6.8-6.6 (m, 
2H, C.sub.2,4 estradiol protons), 5.8-5.6 (m, 1H, C.sub.6 dihydro proton), 
5.0- 4.6 (m, 2H, C.sub.5 dihydro proton+C.sub.17.alpha. estradiol proton), 
3.9-3.7 (s, 3H, O--CH.sub.3), 3.2-3.0 (m, 2H, C.sub.4 dihydro protons), 
3.0-2.8 (s, 3H, N--CH.sub.3), 2.4-1.2 (15H, estradiol skeletal protons), 
1.0-0.9 (s, 3H, C.sub.18 estradiol protons). IR (KBr) 1705 (C.dbd.O 
stretching). Anal. calculated for C.sub.26 H.sub.33 NO.sub.3 : C, 76.61; 
H, 8.18; N, 3.44. Found: C, 76.75; H, 8.43; N, 3.37. The product is 
further characterized by the structural formula: 
##STR1554## 
EXAMPLE 70 
Preparation of Estra-1,3,5(10-triene-3,17.beta.-diol 3,17-dinicotinate 
(Estradio 3,17.beta.-dinicotinate) 
Estradiol (2 g, 0.0073 mol) was added to nicotinoyl chloride hydrochloride 
(5.3 g, 0.029 mol) in dry pyridine (30 ml) at 0.degree. C. The mixture was 
refluxed for 1 hour and then poured over 100 ml of ice water, filtered and 
dried over P.sub.2 O.sub.5 under vacuum. Yield 90% (3.18 g), m.p. 
148.degree.-150.degree. C. NMR (CDCl.sub.3) .delta.9.2-9.0 (br s, 2H, 
C.sub.2 pyridinium protons), 8.7-8.3 (m, 2H, C.sub.6 pyridinium protons), 
8.4-8.0 (m, 2H, C.sub.4 pyridinium protons), 7.5-7.1 (m, 3H, C.sub.5 
pyridinium protons+C.sub.1 estradiol proton), 6.9-6.7 (m, 2H, C.sub.2,4 
estradiol protons), 5.0-4.7 (m, 1H, C.sub.17.alpha. estradiol proton), 
3.2-1.3 (estradiol skeletal protons, 15), 1.0-0.9 (s, 3H, C.sub.18 
estradiol protons). Ir (KBr) 1750, 1725 cm.sup.-1 (2 C.dbd.O stretching). 
Anal. calculated for C.sub.30 H.sub.31 N.sub.2 O.sub.4 : C, 74.50; H, 
6.47; N, 5.79. Found: C, 74.40; H 6.32; N, 5.75. The product has the 
formula: 
##STR1555## 
EXAMPLE 71 
Preparation of 
3,17.beta.-Bis[(1-methyl-3-pyridiniumcarbonyl)oxy]estra-1,3,5(10)-triene 
diiodide 
Methyl iodide (1 ml, 0.016 mol) was added to estradiol 
3,17.beta.-dinicotinate (1 g, 0.0021 mol) in acetone (20 ml) and the 
mixture was refluxed overnight. The deep yellow precipitate which formed 
was filtered, washed with acetone, and dried. Yield 72% (1.262 g), m.p. 
256.degree.-258.degree. C. (dec.). NMR (d.sub.6 -DMSO) .delta.9.6-9.2 (br 
s, 2H, C.sub.2 pyridinium protons), 9.2-8.7 (m, 4H, C.sub.4 +C.sub.6 
pyridinium protons), 8.4-8.0 (m, 2H, C.sub.5 pyridinium protons), 7.3-7.1 
(m, 1H, C.sub.1 estradiol proton), 7.1-6.9 (m, C.sub.2,4 estradiol 
protons), 5.0-4.7 (m, 1H, C.sub.17.alpha. estradiol proton), 4.5-4.3 (s, 
6H, N--CH.sub.3), 3.2-1.3 (estradiol skeletal protons, 15), 1.0-0.9 (s, 
3H, C.sub.18 estradiol protons). IR (KBr) 1750-1735 cm.sup.-1 (broad 
C.dbd.O stretching). Anal. Calculated for C.sub.32 H.sub.36 N.sub.2 
O.sub.4 I.sub.2 : (+1 H.sub.2 O): C, 48.99; H, 4.89; N, 3.57. Found: C, 
48.78; H, 4.66; N, 3.63. The product is further characterized by the 
structural formula: 
##STR1556## 
That compound was converted to the corresponding 3-hydroxy steroid of the 
formula 
##STR1557## 
by partial hydrolysis; the resultant 3-hydroxy compound was then reduced, 
as generally described hereinabove, to afford the corresponding dihydro 
derivative of the formula 
##STR1558## 
When that dihydro derivative was administered to male rats, the 
corresponding 3-hydroxy-17-quaternary derivative was found in the brain. 
EXAMPLE 72 
In Vitro Testing of Estrogenic Steroid Derivatives 
The products of Examples 66 and 69 both reduce methanolic silver nitrate. 
The product of Example 66 requires more time and some warming. 
The two above-mentioned dihydro derivatives show disappearance of UV 
absorption at 359 and 358 nm, respectively, upon addition of H.sub.2 
O.sub.2. Diphenylpicrazyl radical absorption at 516 nm can also be shown 
to decrease upon addition of ether of these compounds. 
Disappearance of the product of Example 66 in brain and plasma homogenates 
was studied using the Cary 210 and Apple II microprocessor. 
______________________________________ 
Brain Homogenate 
Concentration 
t1/2 (min.) 
k (sec.sup.-1) 
r 
______________________________________ 
2.68 .times. 10.sup.-4 M 
11.2 1.03 .times. 10.sup.-3 
0.9998 
1.18 .times. 10.sup.-4 M 
8.7 1.33 .times. 10.sup.-3 
0.9998 
4.07 .times. 10.sup.-5 M 
7.5 1.53 .times. 10.sup.-3 
0.9989 
______________________________________ 
______________________________________ 
Plasma Homogenate 
Concentration 
t1/2 (min.) 
k (sec.sup.-1) 
r 
______________________________________ 
1.43 .times. 10.sup.-4 M 
39.7 2.97 .times. 10.sup.-4 
0.992 
7.04 .times. 10.sup.-5 M 
52.7 2.19 .times. 10.sup.-4 
0.969 
2.75 .times. 10.sup.-5 M 
66.2 1.75 .times. 10.sup.-4 
0.953 
______________________________________ 
EXAMPLE 73 
Preparation of Estra-1,3,5(10)-triene-3,17.beta.-diol 17-nicotinate 
(Estradiol 17.beta.-nicotinate) 
0.5% Potassium bicarbonate in 95% methanol (60 ml) was added to estradiol 
3,17.beta.-dinicotinate (0.5 g, 0.0010 mol) and the slurry was stirred 
overnight at room temperature. Water (60 ml) was added and repeated 
extractions into chloroform were made, combined and dried over anhydrous 
sodium sulfate. The chloroform was removed in vacuo and the resulting 
pinkish-white solid was suspended in methanol at room temperature. The 
white powder thus obtained was separated by filtration and dried. Yield 
94% (0.3663 g), m.p. 221.degree.-222.degree. C. Anal. calc. for C.sub.24 
H.sub.27 NO.sub.3 : C, 76.36; H, 7.22; N, 3.71. Found: C, 76.20; H, 7.25; 
N, 3.70. The product has the formula: 
##STR1559## 
EXAMPLE 74 
Preparation of 
17.beta.-[(1-Methyl-3-pyridinium)carbonyloxy]estra-1,3,5(10)-trien-3-ol 
iodide 
Methyl iodide (2 ml, 0.032 mol) was added to 
estra-1,3,5(10)-triene-3,17.beta.-diol 17-nicotinate (2.0953 g, 0.0056 
mol) in acetone (200 ml) and the mixture was refluxed overnight. The pale 
yellow precipitate which formed was removed by filtration, washed with 
acetone and dried. Yield 83% (2.4203 g), m.p. 268.degree.-272.degree. C. 
(dec). Anal. calc. for C.sub.25 H.sub.29 NO.sub.3 I: C, 57.92; H, 5.65; N, 
2.70. Found: C, 57.70; H, 5.73; N, 2.68. The product has the formula: 
##STR1560## 
EXAMPLE 75 
Preparation of 
17.beta.-[(1-Methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-tr 
ien-3-ol 
To 17.beta.-[(1-methyl-3-pyridinium)carbonyloxy]estra-1,3,5(10)-trien-3-ol 
iodide (1.09 g, 0.0021 mol) in 50:50 t-butanol/deaerated water (150 ml) 
was added NaHCO.sub.3 (1.06 g, 0.0126 mol) and Na.sub.2 S.sub.2 O.sub.4 
(1.46 g, 0.0084 mol). The mixture was stirred under N.sub.2 for one hour. 
The precipitate which formed was removed by filtration, dissolved in ether 
and dried over anhydrous Na.sub.2 SO.sub.4. The ether was removed in 
vacuo. Yield 64% (0.2416 g). The product decomposes over the range 
115.degree.-130.degree. C. Anal. calc. for C.sub.25 H.sub.31 NO.sub.3 
(+1/2H.sub.2 O): C, 74.59; H, 8.03; N, 3.48. Found: C, 74.57; H, 8.04; N, 
3.40. The product is characterized by the structural formula: 
##STR1561## 
EXAMPLE 76 
Preparation of 17.alpha.-Ethynylandrost-4-en-17.beta.-ol-3-one 
17-nicotinate (Ethisterone nicotinate) 
Ethisterone (2.5 g, 8.0 mmol) was dissolved in 100 ml of dry pyridine. 
Excess nicotinoyl anhydride (2.5 g, 11.0 mmol) and a catalytic amount of 
DMAP were added. The solution was stirred for 5 days, then poured into ice 
water. The resulting white powder was removed by filtration and washed. 
Yield 85%, 2.84 g, m.p. 203.degree.-204.degree. C. The product has the 
formula: 
##STR1562## 
EXAMPLE 77 
Preparation of 
17.alpha.-Ethynyl-17.beta.-[(1-methyl-3-pyridinium)carbonyloxy]androst-4-e 
n-3-one iodide 
Ethisterone nicotinate (1 g, 1.79 mmol) was dissolved in 50 ml of 
acetonitrile. Methyl iodide (0.76 g, 5.3 mmol) was added and the solution 
was refluxed overnight. The yellow solid thus obtained was removed by 
filtration and washed. Yield 95%, 1.27 g. UV(CH.sub.3 OH) .lambda..sub.max 
=224 nm. The product has the formula: 
##STR1563## 
EXAMPLE 78 
Preparation of 
17.alpha.-Ethynyl-17.beta.-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy] 
androst-4-en-3-one 
The product of Example 77 (300 mg) was added to 100 ml of cold degassed 
water. Then, 0.135 g of NaHCO.sub.3 and 0.281 g of Na.sub.2 S.sub.2 
O.sub.4 were added and the solution was stirred for 30 minutes, then 
repeatedly extracted with chloroform. The chloroform layers were combined 
and dried over MgSO.sub.4. The solvent was removed under reduced pressure, 
yielding a yellow, high melting foam. Yield 0.11 g or 47%. UV(CH.sub.3 OH) 
.nu..sub.max =240 nm, others 208 nm, 362 nm. The compound has the 
structural formula: 
##STR1564## 
EXAMPLE 79 
Preparation of N-Nicotinoyltyrosine ethyl ester 
Nicotinic acid (12.3 g, 0.1 mol) was dissolved in dry pyridine (300 ml). 
The solution was cooled and dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was 
added. After dissolution, tyrosine ethyl ester hydrochloride (24.6 g, 0.1 
mol) was added and the solution was stirred overnight. The precipitated 
dicyclohexylurea (DCU) was removed by filtration. Additional DCU was 
removed by triturating the oil with hot water. The product was purified 
with acetone. Calculated for C.sub.17 H.sub.18 N.sub.2 O.sub.4.1/2H.sub.2 
O: C, 63.16; H, 5.88; N, 8.66. Found; C, 63.10; H, 5.96; N, 8.59. The 
product can also be named 
N-[1-ethoxycarbonyl-2-(4'-hydroxyphenyl)ethyl]nicotinamide. 
EXAMPLE 80 
Preparation of N-[(1-Methyl-3-pyridinium)carbonyl]tyrosine ethyl ester 
iodide 
N-Nicotinoyltyrosine ethyl ester (20 g, 0.06 mol) was dissolved in 200 ml 
of acetone. A two molar excess of methyl iodine (25.6 g, 0.18 mol) was 
added and the mixture was refluxed for 6 hours. The solvent was removed 
under reduced pressure to yield the desired product as a solid foam. NMR 
analysis confirmed the identity of the product, which has the structural 
formula 
##STR1565## 
and can also be named 
1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-hydroxyphenyl)ethyl}carbamoylpyr 
idinium iodide. 
EXAMPLE 81 
Preparation of 
1-Methyl-3{N-[(1'-ethoxycarbonyl)-2'-(4"-pivaloyloxyphenyl)ethyl]}carbamoy 
lpyridinium trifluoroacetate 
The product of Example 80 (6 g, 0.013 mol) was dissolved in 50 ml of cold 
trifluoroacetic acid at 0.degree. C. in an ice bath. Pivaloyl chloride 
(3.14 g, 0.026 mol) was slowly added and the solution was warmed to room 
temperature. After 24 hours, the solvent was removed under reduced 
pressure. The resulting dark oil was triturated with petroleum ether but 
no solidification occurred. Identity of the product was confirmed by NMR 
analysis. The product was dissolved in aqueous methanol (10%) and 
extracted with ethyl ether to remove a highly colored contaminate before 
using as the starting material in Example 83 below. 
EXAMPLE 82 
Preparation of 
1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxyphenyl)ethyl]}carba 
moylpyridinium trifluoroacetate 
The product of Example 80 (6 g, 0.013 mol) was dissolved in 50 ml of 
trifluoroacetic acid cooled to 0.degree. C. in an ice bath. To that 
solution with stirring, was slowly added isobutyryl chloride (2.77 g, 2.76 
ml). The solution was stirred overnight at ambient temperature and the 
solvent was removed under reduced pressure. The oil was stirred overnight 
with petroleum ether and then dried in vacuo, but no solidification 
occurred. Identity of the product was confirmed by NMR analysis. The 
product was dissolved in aqueous methanol (10%) and extracted with ethyl 
ether to remove a highly colored contaminant before using in Example 84 
below. 
EXAMPLE 83 
Preparation of 
1-Methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-pivaloyloxyphenyl)ethyl]}carbamo 
yl-1,4-dihydropyridine 
The product of Example 81 (4.07 g, 0.0079 mol) was dissolved in 100 ml of 
25% aqueous methanol. Nitrogen gas was bubbled through the solution. To 
the solution, stirring in an ice bath, was then added NaHCO.sub.3 (2.02 g, 
0.024 mol). Ethyl ether (100 ml) was added, followed by the addition of 
Na.sub.2 S.sub.2 O.sub.4 (4.12 g, 0.024 mol). The yellow biphasic solution 
was stirred for 30 minutes, then the layers were separated and the aqueous 
layer was extracted twice with 75 ml portions of ethyl ether. The combined 
organic fractions were dried over Na.sub.2 SO.sub.4 and the solvent was 
removed under reduced pressure to afford a solid foam which oxidized 
ethanolic silver nitrate. Anal. Calc. for C.sub.23 H.sub.20 N.sub.2 
O.sub.5.1/2H.sub.2 O: C, 65.23; H, 7.33. Found: C, 65.76; H, 7.28; N, 
6.95. 
EXAMPLE 84 
Preparation of 
1-Methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxyphenyl)ethyl]}carba 
moyl-1,4-dihydropyridine 
The product of Example 82 (2.20 g, 0.0044 mol) was dissolved in 100 ml of 
aqueous methanol. The solution was cooled in an ice bath with a stream of 
N.sub.2 passing through it. To this solution, NaHCO.sub.3 (1.11 g, 0.0132 
mol) and ether (100 ml) were added. Then, sodium dithionite (2.30 g, 
0.0132 mol) was added and the solution was stirred for 30 minutes. The 
layers were separated and the aqueous phase was washed with ethyl ether. 
The combined organic layers were dried over anhydrous Na.sub.2 SO.sub.4 
and reduced in volume. The resultant orange oil oxidized ethanolic silver 
nitrate. Identity of the product was confirmed by NMR analysis. 
EXAMPLE 85 
Preparation of 
1-Methyl-3-{N-[(1'-ethoxycarbonyl)-2'-4"-acetoxyphenyl)ethyl]}carbamoylpyr 
idinium trifluoroacetate 
The product of Example 80 (4.70 g, 0.01 mol) was dissolved in 30 ml of 
trifluoroacetic acid cooled in a water bath. Acetyl chloride (1.56 g, 0.02 
mol) was added, with stirring. The solution was then stirred overnight. 
The solvent was removed under reduced pressure and the resulting oil was 
dissolved in aqueous methanol and extracted with ethyl ether. The product 
was obtained as a pale yellow oil. Its identity was confirmed by NMR 
analysis. 
EXAMPLE 86 
Preparation of 
1-Methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-acetoxyphenyl)ethyl]}carbamoyl-1 
,4-dihydropyridine 
The product of Example 85 (2.76 g, 5.7 mmol) was dissolved in 25% aqueous 
methanol. The solution was stirred at 0.degree. C. while adding 
NaHCO.sub.3 (1.44 g, 0.017 mol). A layer of 100 ml of ethyl ether was 
added, followed by the addition of Na.sub.2 S.sub.2 O.sub.4 (2.98 g, 0.017 
mol). The system was stirred for 30 minutes, then the layers were 
separated. The aqueous layer was extracted with ether (2.times.50 ml), 
then the combined organic layers were extracted with cold degassed water. 
The ether layer was dried over Na.sub.2 SO.sub.4 and the solvent was 
removed under reduced pressure to given an orange oil. UV (CH.sub.3 OH) 
214 nm, 358 nm. Anal. calc. for C.sub.20 H.sub.24 N.sub.2 O.sub.5 O: C, 
64.52; H, 6.45; N, 7.53. Found: C, 63.90; H, 6.72; N, 7.70: I, 0.0. 
EXAMPLE 87 
Preparation of Valproic acid chloride (2-Propylpentanoyl chloride) 
To 4.32 g (30 mmol) of valproic acid in an ice bath, thionyl chloride (3.60 
g, 30 mmol) was slowly added, with stirring. The neat mixture was allowed 
to come to room temperature and then heated in a water bath at 50.degree. 
C. for 30 minutes. 50 Ml portions of dry benzene were twice added and 
removed under reduced pressure. The resultant product was used in 
subsequent reactions without further purification. 
EXAMPLE 88 
Preparation of Valproic acid 2-iodoethyl ester (2'-Iodoethyl 
2-propylpentanoate) 
To the product of Example 87 (4.87 g, 30 mmol), 2-iodoethanol (5.16 g, 30 
mmol) was added with stirring and cooling in an ice bath. The neat mixture 
was then heated to 100.degree. C. in a water bath for 10 minutes, then 
removed from the heat and stirred for an additional 10 minutes. The 
reaction mixture was then dissolved in 50 ml of ether, washed with water 
(1.times.30 ml), 5% NaOH (2.times.30 ml), and again with water (2.times.30 
ml). The ether layer was dried over anhydrous sodium sulfate and the 
solvent was removed under reduced pressure. A light yellow liquid product 
was obtained in 67% yield from valproic acid (6.0 g). Silver nitrate gave 
a bright yellow precipitate. NMR analysis confirmed the identity of the 
product. 
EXAMPLE 89 
Preparation of 1-[2'-(2"-Propyl)pentanoyloxy]ethyl-3-carbamoylpyridinium 
iodide 
The product of Example 88 (3.28 g, 11 mmol) and 50 ml of dimethylformamide 
were added to nicotinamide (1.22 g, 10 mmol). The mixture was heated to 
reflux for 3 hours, then was cooled. Removal of solvent under reduced 
pressure afforded a brown oily residue, which was stirred with ether (60 
ml) for 30 minutes, giving a yellow powder. The ether was decanted and a 
fresh portion of ether (50 ml) was added. The crude product was vacuum 
filtered under N.sub.2, then was recrystallized from isopropanol/ether to 
give 3.5 g of the desired product (84% yield), m.p. 
111.degree.-112.degree. C. The product has the formula: 
##STR1566## 
EXAMPLE 90 
Preparation of 
1-[2'-(2"-Propyl)pentanoyloxy]ethyl-3-carbamoyl-1,4-dihydropyridine 
To 50 ml of ice-cold degassed deionized water, the product of Example 89 
(420 mg, 1 mmol) was added. To that solution, NaHCO.sub.3 (366 mg, 4 mmol) 
and Na.sub.2 S.sub.2 O.sub.4 (696 mg, 4 mmol) were added, with stirring. 
Nitrogen gas was bubbled through the solution for 30 minutes. The aqueous 
solution was then extracted with ether (6.times.25 ml) until the ether 
layer was no longer yellow. The combined ether extracts were washed with 
water (1.times.50 ml) and dried over MgSO.sub.4. The ether layer was 
decanted from the drying agent and the solvent was removed under reduced 
pressure. To the oil residue, ether was added and then removed (10.times.5 
ml) on a vacuum pump. A foam was formed, which returned to an oil upon 
exposure to the atmosphere. Structure was confirmed by NMR analysis. 
EXAMPLE 91 
Preparation of 2-(3-Pyridyl)carbonylamino-3-(3,4-dihydroxy)phenylpropanoic 
acid ethyl ester 
L-DOPA ethyl ester (5 g, 17.8 mmol) in dry pyridine (20 ml) was treated 
with a solution containing dicyclohexylcarbodiimide (4 g, 10% excess) and 
nicotinic acid (2.21 g, 17.8 mmol) in dry pyridine (50 ml) at room 
temperature. The mixture was stirred for 24 hours, after which time the 
urea which formed was removed by filtration and washed with CH.sub.3 CN. 
Solvents were removed in vacuo to give an orange, highly hygroscopic foam. 
The crude product was taken up in CHCl.sub.3 (100 ml) containing 1 drop of 
methanol and washed with cold water (50 ml). Drying over MgSO.sub.4 and 
removal of solvent in vacuo left an orange foam, which was taken up in 
CH.sub.3 CN (15 ml). Insoluble material was removed by filtration through 
a glass wool plug. The filtrate was evaporated to dryness to give a 
hygroscopic yellow-orange foam which collapsed on exposure to the 
atmosphere. The product was taken up in CHCl.sub.3 (60 ml) and washed, 
first with 0.5% and then with 0.25% aqueous sodium bicarbonate. Drying 
over MgSO.sub.4 and evaporation to dryness left an orange foam which did 
not collapse on atmospheric exposure. NMR analysis confirmed that the 
product has the structure: 
##STR1567## 
EXAMPLE 92 
Preparation of 
2-(3-Pyridyl)carbonylamino-3-(3,4-dipivaloyloxy)phenylpropanoic acid ethyl 
ester 
The product of Example 91 (250 mg, .about.0.76 mmol) was taken up in 
CHCl.sub.3 (15 ml) and allowed to react with pivaloyl chloride (200 mg, 
10% excess) at gentle reflux overnight. Removal of volatiles in vacuo 
yielded a yellow foam, which was again treated with CHCl.sub.3. 
Triethylamine was added until complete solution was obtained, at which 
point pivaloyl chloride (200 mg, 10% excess) was added and the solution 
was heated at reflux for 4 hours, then allowed to cool overnight. Washing 
with water (50 ml), drying over MgSO.sub.4 and removal of solvent in vacuo 
gave an off-white foam which gave a negative FeCl.sub.3 test, indicating 
no free phenolic groups remained. The material was highly hydroscopic. NMR 
analysis confirmed the identity of the product. 
EXAMPLE 93 
Preparation of 
1-Methyl-3-{N-[1-ethoxycarbonyl-2-(3,4-dihydroxy)phenyl]}carbamoylpyridini 
um iodide 
The product of Example 91 (250 mg, 0.76 mmol) in CH.sub.3 CN (10 ml) was 
treated with methyl iodide (100 mg, 2-fold excess) at room temperature. 
The solution was stirred overnight, after which time the solvent was 
removed in vacuo to give a yellow foam, m.p. 75.degree.-82.degree. C. NMR 
analysis confirmed the identity of the quaternary salt. 
EXAMPLE 94 
Preparation of 
1-Methyl-3-{N-[1-ethoxycarbonyl-2-(3,4-dipivaloyloxy)phenyl]}carbamoylpyri 
dinium iodide 
The product of Example 92 (190 mg, 0.38 mmol) in CH.sub.3 CN (10 ml) was 
treated with CH.sub.3 I (250 mg, 5 equivalents) and the mixture was heated 
at gentle reflux, using an ice-cooled condenser. After 4 hours, heating 
was discontinued and volatiles were removed in vacuo to leave a yellow 
foam (200 mg, 82%). The material is hygroscopic and melts over a broad 
range. Testing with methanolic FeCl.sub.3 indicates that no free phenolic 
OH's remain. Identity of the product was confirmed by NMR analysis. 
EXAMPLE 95 
Preparation of 
1-Methyl-3-{N-[1-ethoxycarbonyl-2-(3,4-dipivaloyloxy)phenyl]}carbamoyl-1,4 
-dihydropyridine 
The product of Example 94 (180 mg, 0.28 mmol) in distilled water (20 ml) 
and ethanol (1.0 ml) at 0.degree. C. was treated with NaHCO.sub.3 (95 mg, 
4 equivalents) and Na.sub.2 S.sub.2 O.sub.4 (146 mg, 3 equivalents) under 
nitrogen. Ethyl ether (40 ml) was added and the mixture was stirred for 40 
minutes. Then the organic and aqueous layers were separated and the 
aqueous layer was reextracted with ethyl ether (3.times.20 ml). The 
combined organic layers were dried (MgSO.sub.4) and the solvent was 
removed in vacuo to leave an oily foam. The product was taken up in a 
minimum of CHCl.sub.3 and passed down a short neutral alumina column, 
using CHCl.sub.3 as eluant. The isolated material showed NMR and UV 
spectral properties in accord with the assigned structure: 
##STR1568## 
EXAMPLE 96 
Preparation of 4-Aminobutanoic acid benzyl ester hydrochloride 
GABA (4 g, 38.8 mmol) was suspended in 50 ml (0.48 mol) of benzyl alcohol. 
The reaction mixture was stirred, with cooling on an ice bath, while 20 ml 
SOCl.sub.2 was added dropwise over a 30 minute period. The mixture was 
slowly brought to the reflux temperature and refluxed for 4 hours. The 
resultant pink viscous solution was cooled to room temperature. Addition 
of 50 ml of ethyl ether and refrigeration overnight produced white 
crystals which were collected by filtration, recrystallized from a mixture 
of ethyl ether and ethanol and dried, m.p. 115.degree.-116.degree. C. 
EXAMPLE 97 
Preparation of 3-{N-[(3'-benzyloxycarbonyl)propyl]carbamoyl}pyridine 
Nicotinic acid (1.07 g, 8.7 mmol) was dissolved in a minimum amount of dry 
pyridine. Dicyclohexylcarbodiimide (1.97 g, 9.6 mmol) was dissolved in the 
mixture, with stirring. The solution was cooled to 0.degree. C. and 
4-aminobutanoic acid benzyl ester hydrochloride (2 g, 8.7 mmol) was added. 
After 30 minutes, the solution turned yellow and a precipitate was 
observed. Stirring was continued for 48 hours, after which time 1.8 g of 
dicyclohexylurea was removed from the yellow solution by filtration. The 
solution was evaporated to dryness and the residue was washed with 40 ml 
of ice cold water, extracted into ethyl acetate and dried over Na.sub.2 
SO.sub.4. Evaporation of solvent left the desired product as a sticky 
yellow oil. Identity of the product, which has the structural formula 
##STR1569## 
was confirmed by NMR analysis. 
EXAMPLE 98 
Preparation of 
1-Methyl-3-{N-[(3'-benzyloxycarbonyl)propyl]}carbamoylpyridinium iodide 
The product of Example 97 (0.92 g, 3.09 mmol) was dissolved in a minimum 
amount of acetone and cooled to 0.degree. C. Methyl iodide (0.40 ml, 6.4 
mmol) was added in one portion and the solution was slowly brought to the 
reflux temperature. The mixture was refluxed for 3 hours, then stirred 
overnight. Evaporation of solvent left a yellow oil which crystallized and 
which was recrystallized from acetone/ethyl ether. The light yellow 
crystals thus obtained were collected by filtration and dried. Anal. calc. 
for C.sub.18 H.sub.21 N.sub.2 O.sub.3 I.1/8H.sub.2 O: C, 48.86; H, 4.84; 
N, 6.33; I, 28.72. Found: C, 48.84; H, 4.81; N, 6.33; I, 28.94. UV 
(.lambda..sub.max)=264, 236 nm. NMR and IR analysis also confirmed the 
identity of the product. 
EXAMPLE 99 
Preparation of 
1-Methyl-3-{N-[(3'-benzyloxycarbonyl)propyl]}carbamoyl-1,4-dihydropyridine 
The product of Example 98 (200 mg, 0.45 mmol) was dissolved in 20 ml 
deaerated water. Sodium bicarbonate (0.23 g, 6-fold excess) was added to 
the solution, with stirring. Sodium dithonite (0.31 g) was added and a 
yellow color was observed. Ethyl acetate (30 ml) was added and the mixture 
was stirred for 11/2 hours. The organic layer, containing the yellow 
dihydro compound, was separated from the aqueous layer and dried over 
Na.sub.2 SO.sub.4. Evaporation of ethyl aetate left a yellow oil which 
reduced methanolic silver nitrate immediately. UV and NMR analysis 
confirmed the identity of the product, which has the formula 
##STR1570## 
EXAMPLE 100 
Preparation of 4-Aminobutanoic acid cyclohexyl ester hydrochloride 
GABA (8 g, 77.6 mmol) was suspended in 100 ml (0.96 mol) of cyclohexanol. 
Thionyl chloride (40 ml) was added dropwise to the mixture at 0.degree. C. 
The mixture was then refluxed for 4 hours, cooled and crystallized from 
ethyl ether. The white crystals obtained in this manner were filtered and 
dried. NMR analysis confirmed the identity of the product. 
EXAMPLE 101 
Preparation of 3-{N-[(3'-Cyclohexyloxycarbonyl)propyl]}carbamoylpyridine 
Nicotinic acid (2.2 g, 18 mmol) was suspended in 50 ml of dry pyridine. 
Dicyclohexylcarbodiimide (3.68 g, 17.9 mmol) was dissolved in the 
solution, with stirring. 4-Aminobutanoic acid cyclohexyl ester 
hydrochloride (4 g, 18 mmol) was added and the mixture was stirred for 48 
hours. Precipitated dicyclohexylurea was removed by filtration and the 
filtrate was evaporated to dryness. The residue was washed with 25 ml of 
ice cold water and extracted into ethyl acetate. The layers were separated 
and the organic layer was evaporated to dryness. NMR analysis confirmed 
the structure of the product. 
EXAMPLE 102 
Preparation of 
1-Methyl-3-{N'-[(3'-Cyclohexyloxycarbonyl)propyl]}carbamoylpyridinium 
iodide 
The product of Example 102 (1.74 g, 6 mmol) was dissolved in a minimum 
amount of acetone and the resulting white precipitate was filtered. Methyl 
iodide (1.5 ml, 24 mmol) was added in one portion to the solution, with 
stirring, at 0.degree. C. The mixture was allowed to gently reflux 
overnight. Filtration of a white precipitate and evaporation of the yellow 
filtrate produced a reddish oil, which was dissolved in acetone, filtered 
and evaporated to dryness. Anal. calc. for C.sub.22 H.sub.23 O.sub.3 
N.sub.2 I: C, 47.26; H, 5.79; N, 6.48; I, 29.38. Found: C, 47.03, H, 5.85; 
N, 6.44; I, 29.26. 
EXAMPLE 103 
Preparation of 
1-Methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl]}carbamoyl-1,4-dihydropyridin 
The product of Example 102 (0.11 g, 0.26 mmol) was dissolved in 25 ml of 
ice cold deaerated water. NaHCO.sub.3 (0.09 g, 4-fold excess) was added, 
followed by Na.sub.2 S.sub.2 O.sub.4 (0.14 g, 3-fold excess). Ethyl 
acetate (25 ml) was added and the mixture was stirred under nitrogen for 
30 minutes. The organic layer was extracted and dried to give an orange 
oil that reduced methanolic silver nitrate immediately. NMR analysis 
confirmed that the product has the structure: 
##STR1571## 
EXAMPLE 104 
Preparation of 3-{N-[(3'-Benzyloxycarbonyl)propyl]}carbamoylquinoline 
3-Quinolinecarboxylic acid (1.55 g, 9 mmol) was dissolved in 25 ml of dry 
pyridine. Dicyclohexylcarbodiimide (1.97 g, 9.6 mmol) was added and 
dissolved, with stirring. 4-Aminobutanoic acid benzyl ester hydrochloride 
(2.06 g, 9 mmol) was added and the mixture was stirred for 48 hours at 
room temperature. The precipitated urea was removed by filtration, the 
filtrate was evaporated to dryness and the residue was washed with 10 ml 
of ice cold water and extracted into ethyl acetate. That solution was 
dried over sodium sulfate. The solvent was evaporated, the remaining 
residue was dissolved in acetone, filtered and evaporated to dryness to 
give 2.2 g (70%) of the desired product. NMR analysis confirmed the 
structure of the product. 
EXAMPLE 105 
Preparation of 
1-Methyl-3-{N-[(3'-benzyloxycarbonyl)propyl]}carbamoylquinolinium iodide 
The product of Example 104 (1 g) was suspended in 25 ml of acetonitrile, 
the mixture was cooled on ice and 0.6 ml of CH.sub.3 I was added in one 
portion. Using an ice-water cooled condenser, the mixture was brought to a 
gentle reflux and refluxing was continued overnight on an oil bath. Thin 
layer chromatography confirmed that the resulting dark orange solution was 
the desired product. Addition of CH.sub.3 CN and evaporation on a rotovap 
produced a dark orange foam. Crystallization and recrystallization with 
acetone/ethyl ether gave the desired product as an orange powder, m.p. 
104.degree.-105.degree. C. Anal. calc. for C.sub.22 H.sub.23 N.sub.2 
O.sub.3 I.1/2H.sub.2 O: C, 52.91; H, 4.81; N, 5.61. Found: C, 52.92; H, 
4.84; N, 5.60. The product has the structure: 
##STR1572## 
EXAMPLE 106 
Preparation of 
1-Methyl-3-{N-[(3'-benzyloxycarbonyl)propyl]}carbamoyl-1,4-dihydroquinolin 
e 
The quaternary salt produced in Example 105 (200 mg, 0.41 mmol) was 
suspended in 10 ml deaerated water. Sodium bicarbonate (0.42 g) was added 
to the solution, with stirring, followed by 0.58 g of Na.sub.2 S.sub.2 
O.sub.4. A yellow color appeared immediately and the quaternary derivative 
dissolved. Ethyl acetate (20 ml) was added and the solution was stirred 
under nitrogen for 4 hours. The layers were separated and the yellow 
organic layer was dried over sodium sulfate and evaporated to dryness. The 
resulting yellow oil reduced methanolic silver nitrate immediately. The 
structure of the product was confirmed by NMR analysis to be: 
##STR1573## 
EXAMPLE 107 
Preparation of 3-{N-[(3'-Cyclohexylcarbonyl)propyl]}carbamoylquinoline 
3-Quinolinecarboxylic acid (1.55 g, 9 mmol) was dissolved in a minimum 
amount of dry pyridine. Dicyclohexylcarbodiimide (2.1 g, 10 mmol) was 
added and the solution turned yellow. 4-Aminobutanoic acid cyclohexyl 
ester hydrochloride (2 g, 9 mmol) was added and the mixture was stirred 
for 2 days. The precipitated urea was removed by filtration, the filtrate 
was evaporated to dryness and the residue was washed with 10 ml of ice 
cold water. Extraction into ethyl acetate, subsequent drying with Na.sub.2 
SO.sub.4 and evaporation produced a yellow solid, which was dissolved in 
acetone, filtered and evaporated to dryness. NMR was in good agreement 
with the expected spectrum. 
EXAMPLE 108 
Preparation of 
1-Methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl]}carbamoylquinolinium iodide 
The product of Example 107 (1.95 g, 5.7 mmol) was dissolved in acetone and 
2 ml of methyl iodide was added in one portion, with cooling on ice. The 
mixture was brought to reflux slowly and allowed to reflux overnight. The 
dark orange reaction mixture was subsequently crystallized from acetone 
and ether to give a dark orange powder. The structure of the product was 
confirmed by NMR and UV analyses. 
EXAMPLE 109 
Preparation of 
1-Methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl]}carbamoyl-1,4-dihydropyridin 
e 
The product of Example 108 (300 mg, 0.88 mmol) was suspended in 10 ml of 
deaerated water. NaHCO.sub.3 (1.22 g) was added, followed by Na.sub.2 
S.sub.2 O.sub.4 (0.09 g). The mixture turned yellow immediately. Ethyl 
acetate (20 ml) was added and the solution was stirred for 4 hours. The 
organic layer was dried and evaporated to dryness, leaving a yellow oil 
which reduced methanolic silver nitrate immediately. The product has the 
formula: 
##STR1574## 
EXAMPLE 110 
Preparation of L-Tryptophan ethyl ester hydrochloride 
A mixture of L-tryptophan (14.3 g, 0.07 mol) in 200 ml of ethanol 
containing .about.7 g of anhydrous HCl was refluxed for 5 hours. The 
mixture was cooled and the solid which separated was recrystallized from 
ethanol/ether. Yield 17.4 g (92.5%), m.p. 226.degree.-228.degree. C. The 
product has the formula: 
##STR1575## 
The product may also be named ethyl L-2-amino-3-indolepropionate. 
EXAMPLE 111 
Preparation of N-[1-Ethoxycarbonyl-2-(3'-indolyl)ethyl]nicotinamide 
To a solution of L-tryptophan ethyl ester hydrochloride (5.4 g, 0.02 mol) 
and nicotinic acid (2.5 g, 0.02 mol) in 30 ml of dry pyridine was added 
dicyclohexylcarbodiimide (4.5 g, 0.022 mol). The mixture was stirred for 
24 hours at room temperature, then the urea formed was removed by 
filtration. Pyridine was evaporated under vacuum and the residue was 
dissolved in 200 ml of methylene chloride. The solution was washed with 
10% NaHCO.sub.3 and water and methylene chloride was removed under vacuum. 
Yield 5.1 g (76%). NMR analysis confirmed the identity of the product. 
Anal. calc. for C.sub.19 H.sub.19 N.sub.3 O.sub.3.1/4H.sub.2 O: C, 66.75; 
H, 5.75; N, 12.29. Found: C, 66.59; H, 5.92; N, 12.25. 
EXAMPLE 112 
Preparation of 
1-Methyl-3-{N-[1'-ethoxycarbonyl-2'-(3"-indolyl)ethyl]}carbamoylpyridinium 
iodide 
The product of Example 111 (5 g, 0.015 mmol) was dissolved in 20 ml of 
methanol and methyl iodide (5 ml, 0.08 mol) was added. The mixture was 
refluxed for 5 hours, then methanol and excess methyl iodide were removed 
under vacuum. Yield 6.9 g (96%). Anal. calc. for C.sub.20 H.sub.22 N.sub.3 
O.sub.3 I.3/2H.sub.2 O: C, 47.44; H, 4.98; N, 8.30; I, 25.06. Found: C, 
47.44; H, 4.91; N, 8.29; I, 25.10. 
EXAMPLE 113 
Preparation of 
1-Methyl-3-{N-[1'-ethoxycarbonyl-2'-(3"-indolyl)ethyl]}carbamoyl-1,4-dihyd 
ropyridine 
To a solution of 0.96 g (2 mmol) of the product of Example 112 in 5 ml of 
methanol, 50 ml of deaerated water and 50 ml of ethyl acette was added 1 g 
(12 mmol of NaHCO.sub.3. To this ice-cold mixture kept under nitrogen was 
added 1.65 g (8 mmol) of sodium dithionite. The mixture was stirred for 3 
hours, then the ethyl acetate layer was separated and the aqueous layer 
was extracted with ethyl acetate. The combined ethyl acetate extracts were 
washed with water and dried over sodium sulfate. Ethyl acetate was removed 
under vacuum. Yield 0.52 g (73.6%). Anal. calc. for C.sub.20 H.sub.23 
N.sub.3 O.sub.3 : C, 67.97; H, 6.56; N, 11.89. Found: C, 67.67; H, 6.63; 
N, 11.79. The product has the structural formula: 
##STR1576## 
EXAMPLE 114 
Prepared of 
1-Methyl-3-{N-[.beta.-(3,4-dihydroxyphenyl)ethyl]carbamoyl}pyridinium 
iodide 
To a solution of 2 g (7.7 mmol) of nicotinoyldopamine in 40 ml of dry 
methanol was added 2.5 g (17.6 mmol) of methyl iodide. The reaction 
mixture was refluxed with stirring, for 6 hours. Methyl iodide (1.5 g, 
1.05 mmol) was added and refluxing was continued overnight. Methanol was 
removed and ethyl acetate was added, affording yellowish crystals of the 
desired product. Yield 2.4 g (77%), m.p. 173.degree.-174.degree. C. 
EXAMPLE 115 
Preparation of 
1-methyl-3-{N-[[.beta.-[3,4-bis(isobutyryloxy)phenyl]ethyl]]carbamoyl}pyri 
dinium trifluoroacetate 
To an ice-cold solution of the product of Example 114 (3 g, 7.5 mmol) in 30 
ml of trifluoroacetic acid, isobutyryl chloride (2.4 g, 22.5 mmol) was 
added slowly, with stirring. Stirring was continued overnight at room 
temperature. Trifluroracetic acid was evaporated under vacuum and the 
residue was crystallized from ethyl ether:hexane (3:1). Yield 1.2 g 
(30.4%), m.p. 87.degree.-91.degree. C. 
Substantial repetition of the procedure of the preceding paragraph, 
substituting trimethylacetyl chloride for the isobutyryl chloride used 
above, affords after appropriate purification, 
1-methyl-3-{N-[.beta.-(3,4-dipivalyloxyphenyl)ethyl]carbamoyl}pyridinium 
trifluoroacetate in 72% yield (4.0 g), m.p. 158.degree.-160.degree. C. 
EXAMPLE 116 
Preparation of 
1-Methyl-3-{N-[[.beta.-[3,4-bis(isobutyryloxy)phenyl]ethyl]]carbamoyl}-1,4 
-dihydropyridine 
A solution of 0.55 g (1 mmol) of 
1-methyl-3-{N-[[.beta.-[3,4-bis(isobutyryloxy)phenyl]ethyl]]carbamoyl}pyri 
dinium trifluoroacetate in 50 ml of deaerated water containing 10 ml of 
methanol was extracted three times with 30 ml portions of ether. To the 
resultant aqueous solution was added NaHCO.sub.3 (0.25 g, 3 mmol) and 50 
ml of ethyl ether and the mixture was kept under nitrogen. To this 
ice-cold mixture was added sodium dithionite (0.52 g, 3 mmol) and the 
mixture was stirred vigorously for 30 minutes. The ether layer was 
separated and the aqueous layer was extracted twice with ether. The 
combined ether extracts were washed with water and dried over sodium 
sulfate. Ether was removed under vacuum, leaving an oily product. NMR 
analysis confirmed that the product has the structural formula: 
##STR1577## 
EXAMPLE 117 
Preparation of 
5-[(3-Pyridyl)carbonyloxy]-3-{.beta.-ethoxycarbonyl-.beta.-[N-(3-pyridyl)c 
arbonylamino]ethyl}indole 
The ethyl ester hydrochloride of 5-hydroxytryptophan, i.e. ethyl 
L-2-amino-3-(5-hydroxyindolyl)propionate hydrochloride, was prepared by 
reacting 5-hydroxy-L-tryptophan with ethanol in the presence of HCl. To a 
solution of the ethyl ester hydrochloride (285 mg, 1 mmol) and nicotinic 
acid (246 mg, 2 mmol) in 3 ml of dry pyridine was added 
dicyclohexylcarbodiimide (430 mg, 2.1 mmol). The reaction mixture was 
stirred at room temperature for 24 hours and the urea formed was removed 
by filtration. Pyridine was removed in vacuo and the residue was dissolved 
in 1 ml of methanol and 20 ml of ethyl acetate. The ethyl acetate solution 
was washed with 10% NaHCO.sub.3 solution and then with water. Ethyl 
acetate was removed in vacuo and the residue was chromatographed on a 
silica gel column using 5% methanol in chloroform as the eluent. 
Chloroform was removed in vacuo to yield 270 mg (58.9%) of the desired 
product of the formula: 
##STR1578## 
EXAMPLE 118 
Preparation of 
5-[(1-Methyl-3-pyridinium)carbonyloxy]-3-{.beta.-ethoxycarbonyl-.beta.-[N- 
(1-methyl-3-pyridinium)carbonylamino]ethyl}indole diiodide 
The product of Example 117 (150 mg, 0.33 mmol) was dissolved in 20 ml of 
methanol and excess methyl iodide was added. The mixture was refluxed for 
4 hours and the methanol and excess methyl iodide were removed in vacuo to 
yield 230 mg (93.9%) of the desired product. Anal. calc. for C.sub.27 
H.sub.28 N.sub.4 O.sub.5 I.sub.2 : C, 43.68; H, 3.80; N, 7.55; I, 34.19. 
Found: C, 43.47; H, 3.86; N, 7.52; I, 34.08. NMR analysis confirmed that 
the product has the structure: 
##STR1579## 
EXAMPLE 119 
Preparation of 
5-[(1-Methyl-1,4-dihydropyridin-3-yl)carbonyloxy]-3-{.beta.-ethoxycarbonyl 
-.beta.[N-(1-methyl-1,4-dihydropyridin-3-yl]carbonylamino]ethyl}indole 
To a solution of the product of Example 118 (200 mg, 0.27 mmol) in 2 ml of 
methanol, 20 ml of deaerated water and 20 ml of ethyl acetate, 500 mg of 
sodium bicarbonate was added. The mixture was stirred in an ice bath under 
nitrogen and 0.7 g of sodium dithionite was added. The mixture was stirred 
for 5 hours. The ethyl acetate layer was decanted and the water layer was 
extracted with ethyl acetate. The combined ethyl acetate solution was 
washed with water, dried over amhydrous sodium sulfate and the solvent 
removed in vacuo to yield 110 mg (83.0%) of the desired product. NMR 
analysis confirmed that the product has the structural formula: 
##STR1580## 
EXAMPLE 120 
Preparation of N-[.beta.-Phenethyl) 2-bromoacetamide 
To a stirred solution of 2.263 g (0.0187 mol) of phenethylamine in 10 ml of 
8% sodium hydroxide solution, cooled to -10.degree. C., were introduced 
dropwise 3.14 g (0.02 mol) of bromoacetyl chloride. The reaction mixture 
was stirred at below -10.degree. C. for one hour. The precipitate produced 
was filtered, washed thoroughly with cold water, dried and recrystallized 
from chloroform, m.p. 60.degree.-61.degree. C., yield 3.2 g (71%); IR 
(KBr) 3280 (NH), 1675 (CO) cm.sup.-1. PMR further confirmed that the 
product has the structural formula: 
##STR1581## 
EXAMPLE 121 
Preparation of N-(.beta.-Phenethyl) 3-bromopropionamide 
The title compound was prepared similarly to the product of Example 120, 
but using 3-bromopropionyl chloride instead of bromoacetyl chloride. Yield 
85%, rrecrystallized from aqueous ethanol, m.p. 69.degree.-70.degree. C.; 
IR (KBr) 3315 (NH), 1640 (CO) cm.sup.-1. PMR further confirmed that the 
product has the structural formula: 
##STR1582## 
EXAMPLE 122 
Preparation of N-(.beta.-Phenethyl) 4-bromobutyramide 
The title compound was prepared similarly to the product of Example 120, 
but using 4-bromobutyryl chloride. Yield 80%, recrystallized from aqueous 
ethanol, m.p. 62.degree.-63.degree. C.; IR (KBr) 3100 (NH), 1635 (CO) 
cm.sup.-1. PMR further confirmed that the product has the structural 
formula: 
##STR1583## 
EXAMPLE 123 
Preparation of 
3-Carbamoyl-1-[N-(.beta.-phenylethyl)carbamoylmethyl]pyridinium bromide 
To a solution of 2.419 g (0.01 mol) of N-(.beta.-phenethyl) 
2-bromoacetamide in 20 ml dry acetonitrile were added 1.2 g (0.01 mol) of 
nicotinamide. The mixture was refluxed until disappearance on thin layer 
chromatography of the reactants (3 to 4 days). Plates of Silica Gel G and 
a chloroform:methanol (9:1) sys-tem were used. The acetonitrile was 
evaporated in vacuo and the residue was recrystallized from 
methanol/chloroform to yield the title compound (2.8 g, 77%), m.p. 
178.degree.-180.degree. C. UV max (methanol) 265 nm; IR (KBr) 3380 (NH), 
3250 (NH), 1690 (CO), 1655 (CO) cm.sup.-1. Anal. calc. for C.sub.16 
H.sub.18 BrN.sub.3 O.sub.2.H.sub.2 O: C, 50.27; H, 5.23; N, 10.98. Found: 
C, 50.25; H, 4.77; N, 10.62. PMR analysis further confirmed that the 
product has the structural formula: 
##STR1584## 
EXAMPLE 124 
Preparation of 
3-Carbamoyl-1-{2'-[N-(.beta.-phenylethyl)carbamoyl]ethyl}pyridinium 
bromide 
The title compound was prepared according to the procedure of Example 123, 
using N-(.beta.-phenethyl) 3-bromopropionamide and nicotinamide. Yield 
66%, recrystallized from ethanol/benzene, m.p. 120.degree.-122.degree. C. 
UV max (methanol) 266 nm; IR (KBr) 3280 (NH), 1695 (CO), 1640 (CO) 
cm.sup.-1. Anal. calc. for C.sub.17 H.sub.20 BrN.sub.3 O.sub.2 : C, 53.98; 
H, 5.33; N, 11.11. Found: C, 53.87; H, 5.35; N, 11.10. PMR further 
confirmed that the product has the structure: 
##STR1585## 
EXAMPLE 125 
Preparation of 
3-Carbamoyl-1-{3'-[N-(.beta.-phenylethylcarbamoyl]propyl}pyridinium 
bromide 
The title compound was prepared according to the procedure of Example 123, 
using N-(.beta.-phenethyl) 4-bromobutyramide and nicotinamide. Yield 83%, 
recrystallized from ethanol/acetone, m.p. 112.degree.-114.degree. C. UV 
max (methanol) 265 nm; IR (KBr) 3350 (NH), 3320 (NH), 1692 (CO), 1642 (CO) 
cm.sup.-1. Anal. calc. for C.sub.18 H.sub.22 BrN.sub.3 O.sub.2 : C, 55.11; 
H, 5.65; N, 10.71. Found: C, 54.93; H, 5.67; N, 10.70. PMR further 
confirmed the structure of the product to be: 
##STR1586## 
EXAMPLE 126 
Preparation of 
3-Carbamoyl-1-[N-(.beta.-phenylethyl)carbamoylmethyl]-1,4-dihydropyridine 
To a solution of 3.64 g (0.01 mol) of the product of Example 123 in 150 ml 
of deareated 15% aqueous methanol were added 5.04 g (0.06 mol) of sodium 
bicarbonate. The mixture was stirred in an ice bath, and 6.96 g (0.04 mol) 
of slodium dithionite were added over a period of 5 minutes. The reaction 
mixture was stirred for one hour under nitrogen and a pale yellow 
crystalline precipitate was formed. The precipitate was filtered, washed 
with water, and recrystallized from aqueous methanol, m.p. 
126.degree.-128.degree. C., yield 2.4 g (84%). UV max (methanol) 348 nm; 
IR (KBr) 3280 (NH), 1680 (CO), 1645 (CO) cm.sup.-1. Anal. calc. for 
C.sub.16 H.sub.19 N.sub.3 O.sub.2.3/4H.sub.2 O: C, 64.30; H, 6.91; N, 
14.06. Found: C, 64.32; H, 6.91; N, 14.06. The structure of the product 
was further confirmed by PMR to be: 
##STR1587## 
EXAMPLE 127 
Preparation of 
3-Carbamoyl-1-{2'-[N-(.beta.-phenylethyl)carbamoyl]ethyl}-1,4-dihydropyrid 
ine 
The product of Example 124 (3.78 g, 0.01 mol) was reduced according to the 
procedure described in Example 126 with sodium dithionite (6.96 g, 0.04 
mol). After completion of the reaction, the product was extracted with 
ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and 
the solvent was evaporated in vacuo. A yield of 2.4 g (80%) of the title 
compound was obtained as a yellowish amorphous powder, m.p. 
121.degree.-123.degree. C. UV max (methanol) 350 nm; IR (KBr) 3430 (NH), 
3260 (NH), 1670 (CO), 1630 (CO) cm.sup.-1. Anal. calc. for C.sub.17 
H.sub.21 N.sub.3 O.sub.2.3/4H.sub.2 O: C, 65.26; H, 7.24; N, 13.43. Found: 
C, 65.19; H, 6.87; N, 13.61. The structure of the product was further 
confirmed by PMR to be: 
##STR1588## 
EXAMPLE 128 
Preparation of 
3-Carbamoyl-1-{3'-[N-(.beta.-phenylethyl)carbamoyl]propyl}-1,4-dihydropyri 
dine 
The product of Example 125 (3.92 g, 0.01 mol) was reduced with sodium 
dithionite (6.96 g, 0.04 mol) according to the procedure of Example 126. A 
yield of 2.2 g (65%) of the title compound was obtained as an 
orange-yellow amorphous powder, m.p. 55.degree.-60.degree. C. UV max 
(methanol) 358 nm; IR (CHCl.sub.3) 3325 (NH), 1682 (CO), 1645 (CO) 
cm.sup.-1. Anal. calc. for C.sub.18 H.sub.23 N.sub.3 O.sub.2.3/4H.sub.2 O: 
C, 66.07; H, 7.49; N, 12.85. Found: C, 66.05; H, 7.56; N, 12.84. The 
structure of the product was further confirmed by PMR to be: 
##STR1589## 
EXAMPLE 129 
Preparation of 17.beta.-[(Bromoacetyl)oxy]androst-4-en-3-one 
(Testerosterone bromoacetate) 
To a solution of 2.884 g (0.01 mol) of testosterone in 30 ml of dry benzene 
was added 1.008 g (0.012 mol) of sodium bicarbonate; then, while stirring, 
there were introduced dropwise 1.888 g (0.012 mol) of bromoacetyl chloride 
over a 5 minute period. The reaction mixture was then stirred under reflux 
for 6 hours until no testosterone could be traced by TLC. (Plates of 
Silica Gel G and a CHCH.sub.3 /CH.sub.3 OH system were used.) The 
inorganic residue was filtered while hot, the filtrate was evaporated in 
vacuo and the residue was recrystallized from methanol, m.p. 
144.degree.-145.degree. C., yield 3.2 g (78%). IR (KBr) 1735 (C.dbd.O), 
1660 (C.dbd.O) cm.sup.-1. PMR as expected. The product has the formula: 
##STR1590## 
EXAMPLE 130 
Preparation of 17.beta.-[(3'-Bromopropionyl)oxy]androst-4-en-3-one 
(Testosterone .beta.-bromopropionate) 
The title compound was prepared according to the method of Example 129, but 
using 3-bromopropionylchloride. Yield 80%, recrystallized from methanol, 
m.p. 153.degree.-154.degree. C. IR (KBr) 1740 (C.dbd.O), 1667 (C.dbd.O) 
cm.sup.-1. PMR as expected. The product has the structural formula: 
##STR1591## 
EXAMPLE 131 
Preparation of 17.beta.-{(.+-.)[2'-Bromopropionyl]oxy}androst-4-en-3-one 
(Testosterone .alpha.-bromopropionate) 
The title compound was made according to Example 129, but using (.+-.) 
2-bromopropionyl chloride. Yield 80%, recrystallized from methanol, m.p. 
187.degree.-188.degree. C. IR (KBr) 1732 (C.dbd.O), 1658 (C.dbd.O) 
cm.sup.-1. PMR as expected. The product has the formula: 
##STR1592## 
Similarly prepared using 4-bromobutyryl chloride was 
17.beta.-[(4'-bromobutyryl)oxy]androst-4-en-3-one, having the formula: 
##STR1593## 
EXAMPLE 132 
Preparation of 
17.beta.-{[(3"-Carbamoyl-1"-pyridinium)acetyl]oxy}androst-4-en-3-one 
bromide 
To a solution of 4.09 g (0.01 mol) of testosterone bromoacetate in 30 ml of 
dry acetonitrile was added 1.22 g (0.01 mol) of nicotinamide. The mixture 
was refluxed until complete disappearance of the reactants (2 to 3 days) 
as detected by TLC (Plates and solvents as in Example 129). On cooling, a 
white crystalline precipitate was produced, which was filtered, washed 
with aetonitrile and recrystallized from acetonitrile. Yield 3.62 g (68%), 
m.p. 237.degree.-238.degree. C. UV max (methanol) 236.5 nm; IR (KBr) 3130 
(NH), 1745 (C.dbd.O), 1680 (C.dbd.O) cm.sup.-1 ; PMR as expected. Anal. 
calc. for C.sub.27 H.sub.35 BrN.sub.2 O.sub.4.1/2H.sub.2 O: C, 60.00; H, 
6.66; N, 5.18. Found: C, 59.87; H, 6.70; N, 5.17. The product has the 
formula: 
##STR1594## 
EXAMPLE 133 
Preparation of 
17.beta.-{[3'-(3"-Carbamoyl-1"-pyridinium)propionyl]oxy}androst-4-en-3-one 
bromide 
The title compound was prepared as the product of Example 132 using 
equimolar amounts of testosterone .beta.-bromopropionate and nicotinamide. 
Yield 60%, recrystallized from methanol/acetonitrile, m.p. 
215.degree.-216.degree. C. UV max (methanol) 238 nm; IR (KBr) 3150 (NH), 
1720 (C.dbd.O), 1670 (C.dbd.O) cm.sup.-1 ; PMR as expected. Anal. calc. 
for C.sub.28 H.sub.37 BrN.sub.2 O.sub.4 : C, 61.65; H, 6.79; N, 5.14. 
Found: C, 61.39; N, 6.89; N, 5.07. The product has the formula: 
##STR1595## 
EXAMPLE 134 
Preparation of 
17.beta.-{[(.+-.)2'-(3"-Carbamoyl-1"-pyridinium)propionyl]oxy}androst-4-en 
-3-one bromide 
The title compound was prepared as in Example 132 using equimolar amounts 
of testosterone .alpha.-bromopropionate and nicotinamide. Yield 60%, 
recrystallized from acetonitrile, m.p. 236.degree.-237.degree. C. UV max 
(methanol) 237 nm. IR (KBr) 3080 (NH), 1740 (C.dbd.O), 1670 (C.dbd.O) 
cm.sup.-1. PMR as expected. Anal. calc. for C.sub.28 H.sub.37 BrN.sub.2 
O.sub.4 : C, 61.65; H, 6.79; N, 5.14. Found: C, 61.52; H, 6.81; N, 5.12. 
The product has the formula: 
##STR1596## 
Similarly prepared using 17.beta.-[(4'-bromobutyryl)oxy]androst-4-en-3-one 
and nicotinamide was 
17.beta.-{[4'-(3"-carbamoyl-1"-pyridinium)butyryl]oxy}androst-4-en-3-one 
bromide, having the formula: 
##STR1597## 
EXAMPLE 135 
Preparation of 
17.beta.-{[(3"-Carbamoyl-1",4"-dihydropyridinyl)acetyl]oxy}androst-4-en-3- 
one 
To an ice-cold solution of 1.593 g (0.003 mol) of the product of Example 
132 in 150 ml of deaerated 25% aqueous methanol were added 1.512 g (0.018 
mol) of sodium carbonate and 2.088 g (0.012 mol) of sodium dithionite. The 
mixture was stirred for 30 minutes at 0.degree. C. under nitrogen. The 
dihydro product formed was extracted with dichloromethane, washed with 
water and dried over anhydrous slodium sulfate. The filtrate was flushed 
with dry nitrogen, and the solvent was evaporated in vacuo at ambient 
temperature. The residue was dried over P.sub.2 O.sub.5 under vacuum to 
yield 0.98 g (72%) of the title compound, m.p. 160.degree.-165.degree. C. 
Alcoholic solution shows immediate reduction to alcoholic solution of 
silver nitrate. UV max (methanol) 342 nm; IR (KBr) 3160 (NH), 1730 
(C.dbd.O), 1655 (C.dbd.O) cm.sup.-1. PMR as expected. Anal. calc. for 
C.sub.27 H.sub.36 N.sub.2 O.sub.4.3H.sub.2 O: C, 64.03; H, 8.30; N, 5.53. 
Found: C, 63.54; H, 7.94; N, 5.59. The product has the formula: 
##STR1598## 
EXAMPLE 136 
Preparation of 
17.beta.-{[3'-(3"-Carbamoyl-1",4"-dihydropyridinyl)propionyl]oxy}androst-4 
-en-3-one 
The title compound was prepared according to the method of Example 135, 
utilizing the product of Example 133 as starting material, in a 56% yield 
as a yellowish amorphous powder, m.p. 75.degree.-77.degree. C. The 
product's alcoholic solution shows immediate reduction to alcoholic 
solution of silver nitrate. UV max (methanol) 346 nm; IR (KBr) 3200 (NH), 
1725 (C.dbd.O), 1665 (C.dbd.O) cm.sup.-1 ; PMR as expected. Anal. calc. 
for C.sub.28 H.sub.38 N.sub.2 O.sub.4.3H.sub.2 O: C, 64.62; H, 8.46; N, 
5.38. Found: C, 64.59; H, 7.78; N, 5.19. The product has the formula: 
##STR1599## 
EXAMPLE 137 
Preparation of 
17.beta.-{[(.+-.)2'-(3"-Carbamoyl-1",4"-dihydropyridinyl)propionyl]oxy}and 
rost-4-en-3-one 
The title compound was prepared by the method of Example 135, using the 
product of Example 134, first paragraph, as starting material, in a 78% 
yield as a yellowish amorphous powder, m.p. 145.degree.-150.degree. C. Its 
alcoholic solution shows immediate reduction to alcoholic solution of 
silver nitrate. UV max (methanol) 344 nm; IR (KBr) 3160 (NH), 1725 
(C.dbd.O), 1655 (C.dbd.O) cm.sup.-1 ; PMR as expected. Anal. calc. for 
C.sub.28 H.sub.38 N.sub.2 O.sub.4.2H.sub.2 O: C, 66.93; H, 8.36; N, 5.57. 
Found: C, 66.79; H, 7.69; N, 5.43. The product has the formula: 
##STR1600## 
Similarly prepared from 
17.beta.-{[4'-(3"-carbamoyl-1"-pyridinium)butyryl]oxy}androst-4-en-3-one 
bromide was 
17.beta.-{[4'-(3"-carbamoyl-1",4"-dihydropyridinyl)butyryl]oxy}androst-4-e 
n-3-one, having the structural formula: 
##STR1601## 
EXAMPLE 138 
Preparation of 5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione 
Phenytoin (5 g, 0.02 mol) was suspended in 180 ml of water; 20 ml of 
formaldehyde (37% solution) and 0.25 g K.sub.2 CO.sub.3 were added and the 
mixture was stirred at 25.degree.-30.degree. C. for 24 hours. The white 
solid which formed was removed by filtration and washed repeatedly with a 
3% solution of formaldehyde, then air dried for 3 to 4 hours and over 
P.sub.2 O.sub.5 in a vacuum dessicator. Yield 91-93%, m.p. 
185.degree.-189.degree. C. Anal. calc. for C.sub.16 H.sub.14 N.sub.2 
O.sub.3 : C, 68.07; H, 5.00; N, 9.93. Found: C, 67.97; H, 5.05; N, 9.93. 
The product has the formula: 
##STR1602## 
EXAMPLE 139 
Preparation of 
5,5-Diphenyl-3-[(3'-pyridyl)carbonyloxymethyl]-2,4-imidazolidinedione 
The product of Example 138 (3.00 g, 0.011 mol) was dissolved in 150 ml of 
dry pyridine, then nicotinic anhydride (4.25 g, 0.019 mol) was added. The 
resultant solution was stirred at room temperature (25.degree.-30.degree. 
C.), under dry conditions, for 40 hours. The solution was poured into 2.5 
l of water and the resultant white solid was removed by filtration, washed 
well with water and dried over P.sub.2 O.sub.5 in a vacuum dessicator. 95% 
yield, m.p. 178.degree.-182.degree. C. Anal. calc. for C.sub.22 H.sub.17 
N.sub.3 O.sub.4 : C, 68.21; H, 4.42; N, 10.85. Found: C, 68.12; H, 4.43; 
N, 10.83. The product has the formula: 
##STR1603## 
EXAMPLE 140 
Preparation of 
5,5-Diphenyl-3-[(1'-methyl-3'-pyridinium)carbonyloxymethyl]-2,4-imidazolid 
inedione iodide 
The product of Example 139 (0.5 g, 0.0013 mol) was dissolved in 50 ml of 
acetonitrile, then 0.3 ml of methyl iodide was added and the reaction 
mixture was maintained at room temperature for 6 days. The solvent was 
removed by vacuum distillation and ethyl ether was added to the residue. 
The ether solution was refrigerated for 2 hours, then the yellow, 
hygroscopic crystals which formed were dried over P.sub.2 O.sub.5 in a 
vacuum dessicator, giving the desired product in 85% yield. UV and H.sup.1 
NMR spectra confirmed that the product has the structure: 
##STR1604## 
Repeating the above procedure in nitromethane at a 50.degree.-70.degree. C. 
bath temperature using excess methyl iodide, added gradually, for 5 to 6 
hours, afforded the same product in nearly quantitative yield. 
EXAMPLE 141 
Preparation of 
5,5-Diphenyl-3-[(1'-methyl-1',4'-dihydropyridin-3'-yl)carbonyloxymethyl]-2 
,4-imidazolidinedione: 
The quaternary salt obtained in Example 140 (0.4 g, 0.0008 mol) was 
dissolved in 40 ml of water, 3 ml of methanol and 15 ml of ethyl acetate. 
The reaction mixture was cooled to 0.degree. to 5.degree. C. and 
deaerated, then sodium bicarbonate (0.39 g, 0.0046 mol) and sodium 
dithionite (0.54 g, 0.0032 mol) were added. The mixture was stirred under 
nitrogen at 0.degree.-5.degree. C. for 35 minutes. The organic layer was 
removed and the aqueous layer was extracted twice with 15 ml portions of 
ethyl acetate and the organic solutions were extracted with 10 ml of cold 
deaerated water. After drying over Na.sub.2 SO.sub.4, the solvent was 
removed by vacuum distillation and the oily yellow solid was crystallized 
by addition of ether. Yield 70%. UV and H.sup.1 -NMR analyses confirmed 
that the product has the formula 
##STR1605## 
EXAMPLE 142 
Preparation of 3-Bromoacetyloxymethyl-5,5-diphenyl-2,4-imidazolidinedione 
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was 
dissolved in bromoacetylchloride (15 g, 8 ml, 0.096 mol) by heating in an 
oil bath (70.degree.-80.degree. C. bath temperature) for about 15 minutes, 
until the formation of HCl ceased. The mixture was cooled and 30 ml of 
ethyl ether were added. White crystals formed. The mixture was cooled to 
0.degree. C., then the crystals were removed by filtration and dried over 
P.sub.2 O.sub.5. Yield: 2.15 g (75%), m.p. 179.degree.-183.degree. C. 
Anal. calc. for C.sub.18 H.sub.15 N.sub.2 O.sub.4 Br: C, 53.61; H, 3.75; 
N, 6.95; Br, 19.82. Found: C, 53.60; H, 3.79; N, 6.92; Br, 19.90. The 
product has the formula: 
##STR1606## 
EXAMPLE 143 
Preparation of 
3-(3'-Bromopropionyl)oxymethyl-5,5-diphenyl-2,4-imidazolidinedione 
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (5 g, 0.018 mol) was 
reacted according to the procedure of Example 142 with 3-bromopropionyl 
chloride (6.8 g, 0.04 mol, 4 ml), using a bath temperature of 100.degree. 
C. A white crystalline product was obtained in 65% yield (4.9 g), m.p. 
133.degree.-134.degree. C. Anal. calc. for C.sub.19 H.sub.17 N.sub.2 
O.sub.4 Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.79; H, 
4.12; N, 6.69; Br, 19.25. The product has the formula: 
##STR1607## 
EXAMPLE 144 
Preparation of 
3-(2'-Bromopropionyl)oxymethyl-5,5-diphenyl-2,4-imidazolidinedione: 
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was 
dissolved in 2-bromopropionyl chloride (8.5 g, 5 ml, 0.05 mol) by heating 
for 30 minutes on a 100.degree.-110.degree. C. oil bath. The reaction 
mixture was cooled, 20 ml of ethyl ether were added, and the resultant 
solution was extracted with aqueous potassium carbonate, dried and then 
crystallized. The product was obtained as a solid white substance (1 g, 
34%), m.p. 112.degree.-115.degree. C. Anal. calc. for C.sub.19 H.sub.17 
N.sub.2 O.sub.4 Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 
54.77; H, 4.15; N, 6.69; Br, 19.25. The product has the formula: 
##STR1608## 
EXAMPLE 145 
Preparation of 
3-(3'-Carbamoyl-1'-pyridinium)acetyloxymethyl-5,5-diphenyl-2,4-imidazolidi 
nedione bromide: 
The product of Example 142 (2.02 g, 0.005 mol) dissolved in 15 ml of 
nitromethane was mixed with nicotinamide (0.61 g, 0.005 mol). The solution 
was stirred on a 90.degree.-100.degree. c. temperature oil bath for 2 
hours. The mixture was cooled to 60.degree.-70.degree. C. and the white 
crystals which had formed were removed by filtration and washed with 
nitromethane. Yield 61% (1.65 g), m.p. 193.degree.-197.degree. C. (dec). 
Anal. calc. for C.sub.24 H.sub.21 N.sub.4 O.sub.5 Br: C, 54.87; H, 4.03; 
N, 10.67; Br, 15.21. Found: C, 54.70; H, 4.05; N, 10.64; Br, 15.25. The 
product has the formula: 
##STR1609## 
EXAMPLE 146 
Preparation of 
3-[3'-(3"-Carbamoyl-1"-pyridinium)propionyloxymethyl]-5,5-diphenyl-2,4-imi 
dazolidinedione bromide 
The product of Example 143 (2.09 g, 0.005 mol) was dissolved in 15 ml 
acetonitrile, then nicotinamide (0.61 g, 0.005 mol) was added. The 
solution was refluxed for 6 days, then the solvent was removed. To the 
gum-like residue, 30 ml of ethyl ether was added and the mixture was 
stirred for 2 hours. The white substance which formed was removed by 
filtration ad washed with ether. Yield 78% (2.1 g); m.p. 
98.degree.-100.degree. C. (dec.); UV and H.sup.1 NMR as expected. The 
product has the formula: 
##STR1610## 
EXAMPLE 147 
Preparation of 
3-[2'-(3"-Carbamoyl-1"-pyridinium)propionyloxymethyl]-5,5-diphenyl-2,4-imi 
dazolidinedione bromide 
The product of Example 144 (0.69 g, 0.00165 mol) was dissolved in 8 ml of 
acetonitrile, then nicotinamide (0.2 g, 0.00165 mol) was added and the 
solution was refluxed for 22 hours. The silvent was removed from the 
resultant brown noncrystalline substance at 50.degree. C., then ethyl 
ether (15 ml) was added and the mixture was stirred for 2 hours. The light 
brown substance was removed by filtration and washed with ether. Yield 56% 
(0.5 g), m.p. 158.degree. C. (dec.). The product has the formula: 
##STR1611## 
EXAMPLE 148 
Preparation of 
3-[(3'-Carbamoyl-1',4'-dihydropyridin-1'-yl)acetyloxymethyl]-5,5-diphenyl- 
2,4-imidazolidinedione 
The product of Example 145 (0.52 g, 0.001 mol) was dissolved in a mixture 
of 60 ml of water and 30 ml of ethyl acetate. The mixture was cooled at 
5.degree. C. and deaerated, then sodium bicarbonate (0.5 g, 0.006 mol) and 
sodium dithionite (0.7 g, 0.004 mol) were added and the resultant mixture 
was stirred, with deaeration and cooling, for 30 minutes. The layers were 
separated and the aqueous layer was extracted with 30 ml of ethyl acetate. 
The organic solution was extracted with 20 ml of cooled, deaerated water. 
After drying over sodium sulfate, the solvent was removed. Yield 55% (0.25 
g) of yellow crystals, melting at 155.degree.-160.degree. C. (dec.). The 
product reduced alcoholic silver nitrate solution and has the formula: 
##STR1612## 
The products of Examples 146 and 47 can be similarly reduced to the 
corresponding dihydro derivatives. 
EXAMPLE 149 
Preparation of 
3-(3'-Pyridyl)acetyloxymethyl-5,5-diphenyl-2,4-imidazolidinedione 
3-Pyridylacetic acid hydrochloride (0.87 g, 0.005 mol) and 
5,5-diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (1.41 g, 0.005 mol) 
were dissolved in 14 ml of dry pyridine, then dicyclohexylcarbodiimide 
(1.03 g, 0.005 mol) in 2 ml of pyridine was added. The reaction mixture 
turned yellow. The mixture was stirred at room temperature for 24 hours, 
then the urea which formed was removed by filtration and the solvent was 
removed by vacuum distillation. Methylene chloride (10 ml) was added to 
the residue and, after 10 minutes, a small amount of urea was removee by 
filtration. The organic solution was extracted with potassium carbonate (1 
g) dissolved in 25 ml of water, then dried and concentrated. Ethyl ether 
was added to the oily residue, and white crystals formed. After cooling, 
the product was removed by filtration, washed with ether and dried. Yield 
65% (1.3 g), m.p. 157.degree.-161.degree. C. Anal. calc. for C.sub.23 
H.sub.19 N.sub.3 O.sub.4 : C, 68.82; H, 4.77; N, 10.49. Found: C, 68.49; 
H, 5.28; N, 10.39. The product has the structure: 
##STR1613## 
EXAMPLE 150 
Preparation of 
3-(1'-Methyl-3'-pyridinium)acetyloxymethyl-5,5-diphenyl-2,4-imidazolidined 
ione iodide 
The product of Example 149 (0.4 g, 0.001 mol) was dissolved in 20 ml of 
nitromethane, methyl iodide (0.9 g, 0.4 ml, 0.006 mol) was added and the 
mixture was warmed for 2 hours at 70.degree. C. on an oil bath. Removal of 
solvent by vacuum distillation afforded a yelllow crystalline product 
melting at 110.degree.-115.degree. C. Yield 100% (0.54 g). The product has 
the structure: 
##STR1614## 
That material can then be reduced using sodium dithionite as generally 
described hereinabove, to afford the corresponding dihydro derivative of 
the formula: 
##STR1615## 
EXAMPLE 151 
Preparation of 
10,11-Dihydro-N-methyl-N-(3-pyridyl)carbonyl-5H-dibenz(b,f)azepine-5-propa 
namine 
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was 
suspended in methylene chloride (12 ml) cooled to 5.degree. C. and sodium 
bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine 
hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred 
for 3 hours at 5.degree. C. The sodium chloride was removed by filtration 
and the organic solution was extracted with aqueous sodium bicarbonate, 
dried over sodium sulfate, filtered through Celite.TM. and concentrated. 
Ethyl ether (5 ml) was added to the oily residue and white crystals 
formed. Yield 62% (0.58 g), m.p. 84.degree.-86.degree. C. The product has 
the formula: 
##STR1616## 
EXAMPLE 152 
Preparation of 
10,11-Dihydro-N-methyl-N-(1-methyl-3-pyridinium)carbonyl-5H-dibenz(b,f)aze 
pine-5-propanamine iodide 
The product of Example 151 (0.3 g, 0.0008 mol) was dissolved in 10 ml of 
nitromethane, methyl iodide (0.7 g, 0.3 ml, 0.005 mol) was added and the 
mixture was maintained at 24 hours at room temperature. The solvent was 
removed by vacuum distillation, ethyl ether was added to the residue and 
hygroscopic crystals of the desired product were obtained. Yield 90% (0.37 
g), m.p. 110.degree. C. (dec.). The product has the formula 
##STR1617## 
The material can then be reduced as generally described hereinabove, to 
afford the corresponding dihydro derivative, 
10,11-dihydro-N-methyl-N-(1-methyl-1,4-dihydropyridin-3-yl)carbonyl-5H-dib 
enz(b,f)-azepine-5-propanamine, having the formula: 
##STR1618## 
EXAMPLE 153 
Preparation of N-Nicotinoyloxysuccinimide 
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 
0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide 
(6.75 g, 0.032 mol in 20 ml of dioxane was added. The reaction mixture was 
then stirred at room temperature for 3 hours. The dicyclohexylurea which 
precipitated was removed by filtration and the solvent was removed by 
rotary evaporation. The crude product was recrystallized from ethyl 
acetate to give light yellow crystals which are then washed with anhydrous 
ether. The product, obtained in 72% yield (5.2 g) and melting at 
129.degree.-131.degree. C., has the formula: 
##STR1619## 
EXAMPLE 154 
Preparation of N-[(1-methyl-3-pyridinium)carbonyloxy]succinimide iodide 
N-Nicotinoyloxysuccinimide (5.0 g, 0.0227 mol) was dissolved in 80 ml of 
dioxane and methyl iodide (4.24 ml, 0.0683 mol) was added. The reaction 
mixture was refluxed at 70.degree. C. overnight. The solution changed to a 
red color while a yellow precipitate formed. The precipitate was removed 
by filtration, washed thoroughly with anhydrous ether and dried. Yield 87% 
(7.134 g) of the quaternized product of the formula: 
##STR1620## 
EXAMPLE 155 
Preparation of 
2-Amino-1,9-dihydro-9-{[2-(1'-methyl-3'-pyridinium)carbonyloxyethoxy]methy 
l}-6H-purin-6-one iodide 
Acyclovir sodium salt was converted to the free acid by first dissolving it 
in water (10 ml) and then adding a few drops of 0.01M HCl, until some 
precipitation was observed. The precipitate was centrifuged and to the 
supernatant was added a few more drops of 0.01M HCl to ensure complete 
precipitation of the free acid. Complete precipitation was achieved with 
the pH at 11.00. The percipitate thus obtained was washed well with small 
amounts of ice-cold water and then with anhydrous ether and allowed to 
dry. 
The quaternized activated ester obtained in Example 154 (0.72 g, 0.002 mol) 
was dissolved in 50 ml of dimethylformamide and acyclovir (0.450 g, 0.002 
mol) in 50 ml of dimethylformamide was added. The reaction mixture was 
stirred at room temperature for 7 days, then one additional equivalent of 
the activated ester was added and the reaction mixture was stirred at 
50.degree. C. for 3 days. The volume of solvent was reduced by rotary 
evaporation and the residue was allowed to stand overnight. The light 
yellow crystals thus obtained were separated and dried. The product melted 
at 220.degree.-224.degree. C. and was assigned the structure depicted 
below: 
##STR1621## 
That product can then be reduced with sodium dithionite as generally 
described hereinabove, to afford the corresponding dihydro derivative, 
2-amino-1,9-dihydro-9-{[2-(1'-methyl-1',4'-dihydropyridin-3'-yl)carbonylox 
yethoxy]methyl}-6H-purin-6-one, having the formula: 
##STR1622## 
In the discussion to follow, the expression "at least one reactive 
functional group selected from the group consisting of amino, hydroxyl, 
mercapto, carboxyl, amide and imide" and portions of that expression are 
used. The functional groups designated in that expression have the 
following meanings: 
The word "amino" means a primary or secondary amino function, i.e. 
--NH.sub.2 or --NHR. The secondary amino function is also represented 
herein as --NH--, particularly since the exact identity of the R portion 
of --NHR is immaterial, R being a part of the drug residue D itself which 
is left unchanged by this invention. 
The word "hydroxyl" means an --OH function. 
The word "carboxyl" means a --COOH function. 
The word "mercapto" means an --SH function. 
The word "amide" means a carbamoyl (--CONH.sub.2) or substituted carbamoyl 
(--CONHR) or a sulfamoyl (--SO.sub.2 NH.sub.2) or substituted sulfamoyl 
(--SO.sub.2 NHR) functional group. The --CONHR and --SO.sub.2 NHR groups 
may also be represented herein as --CONH-- and --SO.sub.2 NH--, 
respectively, since the identity of R is immaterial, R being a part of the 
drug residue D is itself which is left unchanged by this invention. 
The word "imide" means a functional group having the structure 
##STR1623## 
that is, the structure which characterizes imides (i.e. compounds having a 
succinimide-type or phthalimide-type structure). 
The many different dihydropyridine.revreaction.pyridinium salt redox 
carrier moieties illustrated for use hereinabove are merely exemplary of 
the many classes of carriers contemplated by this invention. While the 
following list of carrier classes is not meant to be exhaustive (and, 
indeed, yet other carrier classes are illustrated both hereinabove and 
hereinbelow), the following major classes of quaternaries and the 
corresponding dihydro forms are prime examples of the moieties encompassed 
hereby: 
(1) For linkage to a drug having at least one hydroxyl or mercapto or 
primary or secondary amino functional grouping, replacing a hydrogen atom 
from at least one of said functional groupings with one of the following 
[QC.sup.+] groupings: 
##STR1624## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or 
C.sub.7 -C.sub.10 aralkyl; R.sub.3 is C.sub.1 to C.sub.3 alkylene; X is 
--CONR'R" wherein R' and R", which can be the same or different, are each 
H of C.sub.1 -C.sub.7 alkyl, or X is --CH--NOR"' wherein R"' is H or 
C.sub.1 -C.sub.7 alkyl; the carbonyl-containing groupings in formulas (a) 
and (c) and the X substituent in formula (b) can each be attached at the 
2, 3 or 4 position of the pyridinium ring; the carbonyl-containing 
groupings in formulas (d) and (f) and the X substituent in formula (e) can 
each be attached at the 2, 3 or 4 position of the quinolinium ring; and 
the carbonyl-containing groupings in formulas (g) and (j) and the X 
substituent in formula (h) can each be attached at the 1, 3 or 4 position 
of the isoquinolinium ring; 
(2) For linkage to a drug having at least one carboxyl functional grouping, 
replacing a hydrogen atom from at least one of said carboxyl groupings 
with one of the following [QC.sup.+ ] groupings: 
(a) When there are one or more --COOH groups to be derivatized: 
##STR1625## 
wherein Z' is C.sub.1 -C.sub.8 straight or branched alkylene, preferably 
C.sub.1 -C.sub.3 straight or branched alkylene; Q is --O-- or --NH--; 
R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 
-C.sub.10 aralkyl; R.sub.3 is C.sub.1 -C.sub.3 alkylene, X is --CONR'R" 
wherein R' and R", which can be the same or different, are each H or 
C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR"' wherein R"' is H or C.sub.1 
-C.sub.7 alkyl; the X substituent in formula (ii) and the 
carbonyl-containing groupings in formulas (i) and (iii) can each be 
attached at the 2, 3 or 4 position of the pyridinium ring; the x 
substituent in formula (v) and the carbonyl-containing groupings in 
formulas (iv) and (vi) can each be attached at the 2, 3 or 4 position of 
the quinolinium ring; and the X substituent in formula (viii) and 
carbonyl-containing groupings in formulasd (vii) and (ix) can each be 
attached at the 1, 3 or 4 position of the isoquinolinium ring; 
(b) Alternatively, when there is only one --COOH group to be derivatived: 
##STR1626## 
wherein .dottedcircle. is the skeleton of a sugar molecule; n.sup.iv is 
a positive integer equal to the total number of --OH functions in the 
sugar molecule from which said skeleton is derived; n.sup.v is a positive 
integer one less than the total number of --OH functions in the sugar 
molecule from which said skeleton is derived; each A in each of structures 
(xii), (xiii) and (xiv) can independently be hydroxy or D', D' being the 
residue of a centrally acting drug containing one reactive carboxyl 
functional group, said residue being characterized by the absence of a 
hydrogen atom from said carboxyl functional group in said drug; and each 
R'.sub.4 in each of structures (x) and (xi) can independently be hydroxy, 
##STR1627## 
wherein D' is defined as with structures (xii), (xiii) and (xiv); R.sub.1 
is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.10 
aralkyl; and the depicted carbonyl-containing groupings can be attached at 
the 2, 3 or 4 position of the pyridinium or quinolinium ring, or at the 1, 
3 or 4 position of the isoquinolinium ring; with the proviso that at least 
one R'.sub.4 in each of structures (x) and (xi) is 
##STR1628## 
wherein R.sub.1 and the position of the carbonyl-containing groupings are 
defined as above; and with the further proviso that when more than one of 
the R'.sub.4 radicals in a given compound are the aforesaid 
carbonyl-containing groupings, then all such carbonyl-containing groupings 
in said compound are identical. 
(3) For linkage to a drug having at least one --NH-- functional group which 
is part of an amide or imide structure or at least one low pKa primary or 
secondary amine functional group, replacing a hydrogen atom from at least 
one of said functional groupings with one of the following [QC.sup.+ ] 
groupings: 
##STR1629## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or 
C.sub.7 -C.sub.10 aralkyl; R is hydrogen, C.sub.1 -C.sub.7 alkyl, C.sub.3 
-C.sub.8 cycloalkyl, C.sub.1 -C.sub.7 haloalkyl, furyl, phenyl, or phenyl 
substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, 
lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower 
alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower 
alkylsulfinyl or lower alkylsulfonyl; R.sub.3 is C.sub.1 to C.sub.3 
alkylene; X is --CONR'R" wherein R' and R", which can be the same or 
different, are each H or C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR"' 
wherein R"' is H or C.sub.1 -C.sub.7 alkyl; the carbonyl-containing 
groupings in formulas (k) and (m) and the X substituent in formula (1) can 
each be attached at the 2, 3 or 4 position of the pyridinium ring; the 
carbonyl-containing groupings in formulas (n) and (p) and the X 
substituent in formula (o) can each be attached at the 2, 3 or 4 position 
of the quinolinium ring; and the carbonyl-containing groupings in formulas 
(q) and (s) and the X substituent in formula (r) can each be attached at 
the 1, 3 or 4 position of the isoquinolinium ring. Here and throughout 
this application, the expression "C.sub.1 -C.sub.7 haloalkyl" means 
C.sub.1 -C.sub.7 alkyl substituted by one or more halogen atoms. Also here 
and throughout this application, the alkyl radicals, including alkyl and 
alkylene portions of other radicals, can be straight or branched unless 
otherwise specified. 
Drugs containing secondary or tertiary hydroxyl functional groups can be 
linked to any of the [QC.sup.+ ] groupings (k) through (s) above in which 
the 
##STR1630## 
portion is derived from an aldehyde RCH.sub.2 O capable of reacting with 
said drug to form the corresponding hemiacetal, as discussed in more 
detail in Method K' hereinabove. 
The dihydro forms [DHC] corresponding to the aforementioned quaternaries 
are as follows: 
(1') For Group (1) above: 
##STR1631## 
wherein the dotted line in formulas (a'), (b') and (c') indicates the 
presence of a double bond in either the 4 or 5 position of the 
dihydropyridine ring; the dotted line in formulas (d'), (e') and (f') 
indicates the presence of a double bond in either the 2 or 3 position of 
the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 
-C.sub.7 haloalkyl or C.sub.7 -CH.sub.10 aralkyl; R.sub.3 is C.sub.1 to 
C.sub.3 alkylene; X is --CONR'R", wherein R' and R", which can be the same 
or different, are each H or C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR"' 
wherein R"' is H or C.sub.1 -C.sub.7 alky; the carbonyl-containing 
groupings in formulas (a') and (c') and the X substituent in formula (b') 
can each be attached at the 2, 3 or 4 position of the dihydropyridine 
ring; the carbonyl-containing groupings in formulas (d') and (f') and the 
X substituent in formula (e') can each be attached at the 2, 3 or 4 
position of the dihydroquinoline ring; and the carbonyl-containing 
groupings in formulas (g') and (j') and the X substituent in formula (h') 
can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline 
ring; 
(2') For Group (2) (a) above: 
##STR1632## 
wherein the dotted line in formulas (i'), (ii') and (iii') indicates the 
presence of a double bond in either the 4 or 5 position of the 
dihydropyridine ring; the dotted line in formulas (iv'), (v') and (vi') 
indicates the presence of a double bond in either the 2 or 3 position of 
the dihydroquinoline ring; Z' is C.sub.1 -C.sub.8 straight or branched 
alkylene, preferably C.sub.1 -C.sub.3 straight or branched alkylene; Q is 
--O-- or --NH--; R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 
haloalkyl or C.sub.7 -C.sub.10 aralkyl; R.sub.3 is C.sub.1 -C.sub.3 
alkylene; X is --CONR'R" wherein R' and R", which can be the same or 
different, are each H or C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR"' 
wherein R"' is H or C.sub.1 -C.sub.7 alkyl; the X substituent in formula 
(ii') and the carbonyl-containing grouping in formulas (i') and (iii') can 
each be attached at the 2, 3 or 4 position of the dihydropyridine ring; 
the X substituent in formula (v') and the carbonyl-containing groupings in 
formulas (iv') and (vi') can each be attached at the 2, 3 or 4 position of 
the dihydroquinoline ring; and the X substituent in formula (viii') and 
the carbonyl-containing groupings in formulas (vii') and (ix') can each be 
attached at the 1, 3 or 4 position of the dihydroquinoline ring. 
(3') For Group (2) (b) above: 
##STR1633## 
wherein the dotted line in formula (xii') indicates the presence of a 
double bond in either the 4 or 5 position of the dihydropyridine ring; the 
dotted line in formula (xiii') indicates the presence of a double bond in 
either the 2 or 3 position of the dihydroquinoline ring; .dottedcircle. 
is the skeleton of a sugar molecule; n.sup.iv is a positive integer equal 
to the total number of --OH functions in the sugar molecule from which 
said skeleton is derived; n.sup.v is a positive integer one less than the 
total number of --OH functions in the sugar molecule from which said 
skeleton is derived; each A in each of structures (xii'), (xiii'), (xiv') 
and (xiv") can independently be hydroxy or D', D' being the residue of a 
centrally acting drug containing one reactive carboxyl functional group, 
said residue being characterized by the absence of a hydrogen atom from 
said carboxyl functional group in said drug; and ech R.sub.4 in each of 
structures (x') and (xi') can independently be hydroxy, 
##STR1634## 
wherein the dotted line is defined as with structures (xii') and (xiii'); 
D' is defined as with structures (xii'), (xiii'), (xiv') and (xiv"); 
R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 
-C.sub.10 aralkyl; and the depicted carbonyl groupings can be attached at 
the 2, 3 or 4 position of the pyridinium or quinolinium ring or, except 
where otherwise specified, at the 1, 3 or 4 position of the isoquinolinium 
ring; with the proviso that at least one R.sub.4 in each of structures 
(x') and (xi') is 
##STR1635## 
wherein R.sub.1, the dotted lines and the position of the 
carbonyl-containing groupings are defined as above; and with the further 
proviso that when more than one of the R.sub.4 radicals in a given 
compound are the aforesaid carbonyl-containing groupings, then all such 
carbonyl-containing groupings in said compound are identical. 
(4') For Group (3) above: 
##STR1636## 
wherein R is hydrogen, C.sub.1 -C.sub.7 alkyl, C.sub.3 -C.sub.8 
cycloalkyl, C.sub.1 -C.sub.7 haloalkyl, furyl, phenyl, or phenyl 
substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, 
lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower 
alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower 
alkylsulfinyl or lower alkylsulfonyl; the dotted line in formulas (k'), 
(l') and (m') indicates the presence of a double bond in either the 4 or 5 
position of the dihydropyridine ring; the dotted line in formulas (n'), 
(o') and (p') indicates the presence of a double bond in either the 2 or 3 
position of the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl, 
C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -CH.sub.10 aralkyl; R.sub.3 is 
C.sub.1 to C.sub.3 alkylene; X is --CONR'R", wherein R' and R", which can 
be the same or different, are each H or C.sub.1 -C.sub.7 alkyl, or X is 
--CH.dbd.NOR" ' wherein R"' is H or C.sub.1 -C.sub.7 alkyl; the 
carbonyl-containing groupings in formulas (k') and (m') and the X 
substituent in formula (l') can each be attached at the 2, 3 or 4 position 
of the dihydropyridine ring; the carbonyl-containing groupings in formulas 
(n') and (p') and the X substituent in formula (o') can each be attached 
at the 2, 3 or 4 position of the dihydroquinoline ring; and the 
carbonyl-containing groupings in formulas (q') and (s') and the X 
substituent in formula (r') can each be attached at the 1, 3 or 4 position 
of the dihydroisoquinoline ring. 
The presently preferred dihydropyridine.revreaction.pyridinium salt redox 
carrier moieties of this invention are those wherein R.sub.1, when 
present, is C.sub.3 ; R.sub.3, when present, is --CH.sub.2 CH.sub.2 --; X, 
when present, is --CONH.sub.2 ; the depicted carbonyl-containing groupings 
in formulas (a) and (c) and the X substituent in formula (b) are attached 
at the 3-position; the depicted carbonyl-containing groupings in formulas 
(d) and (f) and the X substituent in formula (e) are attached at the 
3-position; the depicted carbonyl-containing groupings in formulas (g) and 
(j) and the X substituent in formula (h) are attached at the 4-position; 
Z', when present, is C.sub.2 or C.sub.3 straight or branched alkylene; Q, 
when present, is --NH--; the X substituent in formulas (ii) and (v) and 
the depicted carbonyl-containing groupings in formulas (i), (iii), (iv) 
and (vi) are attached at the 3-position; the X substituent in formula 
(viii) and the depicted carbonyl-containing groupings encompassed by 
formulas (x), (xi), (xii), (xiii) and (xiv) are in the 3-position of the 
pyridinium or quinolinium ring and in the 4-position of the isoquinolinium 
ring; all R'.sub.4 's in structures (x) and (xi) are --OH except for the 
one R.sub.4 in each structure which must be the carrier moiety; all A's in 
structures (xii), (xiii) and (xiv) are --OH; .dottedcircle. is the 
skeleton of a glucose molecule; R in formulas (k), (l) and (m) is 
hydrogen, methyl or CCl.sub.3 ; and the depicted carbonyl-containing 
groupings in formulas (k) through (s) are in the 3-position of the 
pyridinium or quinolinium ring and in the 4-position of the isoquinolinium 
ring; and the corresponding dihydro moieties. 
Especially preferred dihydropyridine.revreaction.pyridinium salt redox 
carrier moieties are the quaternaries of Group (1), structures (a), (b), 
(d), (e), (g) and (h); those of Group (2), structures (i), (ii), (iv), 
(v), (vii) (viii), (x) and (xii); and those of Group 3, structures (k), 
(l), (n), (o), (q) and (r); and the corresponding dihydro forms, most 
especially when they contain the preferred structural variables identified 
in the preceding paragraph. 
From the foregoing, it is apparent that the present invention provides two 
major classes of novel chemical compounds, i.e. the compounds of general 
formula (I) above, including their salts, and the compounds of general 
formula (II) above. Preferably, these two major clases consist of: 
Compounds of the formula 
EQU D--DHC].sub.n (Ia) 
and the nontoxic pharmaceutically acceptable salts thereof, wherein D is 
the residue of a centrally acting drug containing at least one reactive 
functional group consisting of amino, hydroxyl, mercapto, carboxyl, amide 
and imide, said residue being characterized by the absence of a hydrogen 
atom from at least one of said reactive functional groups in said drug; n 
is a positive integer equal to the number of said functional groups from 
which a hydrogen atom is absent; and [DHC] is the reduced, biooxidizable, 
blood-brain barrier penetrating lipoidal form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier; 
with the proviso that when the compound is other than a salt of a compound 
of formula (Ia), when n is 1, when [DHC] is 
##STR1637## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug of which D is the residue contains only 
one primary or secondary --OH functional group, no other --OH functional 
groups and no --NH.sub.2, --NH--, --SH or --COOH functional groups, then D 
must be the residue of a centrally acting drug other than a steroid sex 
hormone or long chain alkanol; 
and with the further proviso that when the compound is other than a salt of 
a compound of formula (Ia), when n is 1, when [DHC] is 
##STR1638## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug of which D is the residue contains only 
one --NH.sub.2 functional group and no other functional groups, then D 
must be the residue of a centrally acting drug other than a sympathetic 
stimulant; and 
Quaternary salts of the formula 
EQU D--QC.sup.+ ].sub.n qX.sup.-t (IIa) 
wherein D and n are as defined with formula (Ia); [QC.sup.+ ] is the 
hydrophilic, ionic pyridinium salt form of a 
dihydropyridine.revreaction.pyridinium salt redox carrier; X.sup.- is the 
anion of a pharmaceutically acceptable organic or inorganic acid; t is the 
valence of the acid anion; and q is the number which when multiplied by t 
is equal to n; 
with the proviso that when n is 1, when [QC.sup.+ ] is 
##STR1639## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug of which D is the residue contains only 
one primary or secondary --OH functional group, no other --OH functional 
groups and no --NH.sub.2, --NH--, --SH or --COOH functional groups, then D 
must be the residue of a centrally acting drug other than a steroid sex 
hormone or long chain alkanol; 
and with the further proviso that when n is 1, when [QC.sup.+ ] is 
##STR1640## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug of which D is a residue contains only 
one --NH.sub.2 functional group and no other functional groups, then D 
must be the residue of a centrally acting drug other than a sympathetic 
stimulant. 
Within each of the classes (Ia) and (IIa), the following subclasses are 
particularly noteworthy: 
(A) Compounds of formulas (Ia) and (IIa) wherein the D portion of the 
compound of formula (Ia) or (IIa) is identical to the corresponding 
portion of the centrally acting drug from which D can be considered to be 
derived, and the carrier is attached through an amino functional group in 
the drug. Preferred groups of compounds in this subclass include the 
following: 
(1) Cerebral stimulants, including sympathomimetic amine-type cerebral 
stimulants, such as amphetamine, dextroamphetamine, levamphetamine, 
aletamine, cypenamine, tyramine, phentermine, methamphetamine, 
fencamfamin, zylofuramine, phenethylamine, etryptamine and 
tranylcypromine; tricyclic antidepressant-type cerebral stimulants, 
especially dibenzazepines and their analogues, e.g. desipramine, 
nortriptyline, protriptyline, maprotiline, octriptyline, and many other 
cerebral stimulants, alerting agents and antidepressants of various types, 
as exemplified by amiphenazole, amedalin, cartazolate, daledalin, 
fluoxetine, nisoxetine, bupropion, difluamine and methylphenidate. 
(2) Neurotransmitters, such as dopamine, histamine, tryptamine and 
serotonin. 
(3) Narcotic analgesics, such as anileridine, noracymethadol and 
piminodine. 
(4) Hypotensives, such as clonidine, hydralazine, bethanidine, 
guanethidine, debrisoquin, propanolol and prizidilol. 
(5) Sympathomimetic amines, such as ephedrine, oxymetazoline and 
pseudoephedrine. 
(6) Anticancer and antitumor agents, such as doxorubicin and daunomycin. 
(7) Antiviral agents, such as amantadine, 
2-guanidino-4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenyloxazole, 
glucosamine and 6-amino-6-deoxy-D-glucose. 
(8) Antibiotic and antibacterial agents, such as phenazopyridine, 
bacampicillin and pivampicillin. 
(9) Sedatives, muscle relaxants, anticonvulsants, tranquilizers (including 
benzodiazepine tranquilizers) e.g. benzoctamine, tracazolate, 
chlordiazepoxide, tiletamine and aminoglutethimide. 
(10) Diagnostics, including radiolabeled diagnostics, e.g., 
iodometaraminol. 
(B) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amino function through which the 
carrier is attached and also contains at least one --OH functional group, 
and D in formula (Ia) or (IIa) contains, in place of the hydrogen atom of 
at least one of the --OH groups in the drug, at least one hydrolytically 
or metabolically cleavable hydroxyl protective group. Within subclass (B), 
preferred compounds are those in which D is a protected residue of a 
neurotransmitter, such as dopamine or serotonin; a cerebral stimulant, 
such as tyramine; a sympathomimetic amine, such as ephedrine, 
phenylephrine or pseudoephedrine; an adrenergic agent, such as 
norepinephrine or epinephrine; an anticancer or antitumor agent, such as 
pentostatin; an antiviral, such as glucosamine or 
6-amino-6-deoxy-D-glucose; or a hypotensive, such as atenolol or 
metoprolol. 
(C) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amino function through which the 
carrier is attached and also contains at least one --COOH functional 
group, and D in formula (Ia) or (IIa) contains, in place of the hydrogen 
atom of at least one of the --COOH groups, at least one hydrolytically or 
metabolically cleavable carboxyl protective group. Preferred compounds 
within this subclass are those in which D is a protected residue of 
anticancer and antitumor agents, e.g. melphalan, DON, L-alanosine and 
acivicin; antibiotics, especially penicillins such as amoxacillin and 
ampicillin and cephalosporins such as cephalexin, cefroxadine and 
ceforanide; hypotensives such as methyldopa and furosemide; dopaminergic 
agents such as L-DOPA; and amino acids and small peptides containing 2-20 
amino acid units, e.g. GABA, tyrosine and other natural amino acids, 
met.sup.5 -enkephalin, leu.sup.5 -enkephalin and the like. 
(D) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amino function through which the 
carrier is attached and also contains at least one --OH functional group 
and at least one --COOH functional group, and D in formula (Ia) or (IIa) 
contains, in place of the hydrogen atom of at least one of the --OH 
functional groups and at least one of the --COOH functional groups in said 
drug, respectively, at least one hydrolytically or metabolically cleavable 
hydroxyl protective group and at least one hydrolytically or metabolically 
cleavable carboxyl protective group. Of particular interest are the 
compounds in which D is a protected residue of a hypotensive, e.g. 
methyldopa; or a sympathetic stimulant/dopaminergic agent, e.g. levodopa. 
(E) Compounds of formulas (Ia) and (IIa) wherein the D portion of the 
compound of formula (Ia) or (IIa) is identical to the corresponding 
portion of the drug from which D can be considered to be derived and the 
carrier is attached through a hydroxyl or mercapto functional group in the 
drug. Preferred groups of compounds in this subclass include the 
following: 
(1) Tranquilizers, including benzodiazepines, such as oxazepam, temazepam 
and lorazepam; phenothiazines, such as carphenazine, fluphenazine, 
acetophenazine and the like; and other tranquilizers such as haloperidol, 
clopenthixol and hydroxyzine. 
(2) Steroids, including androgens, e.g. testosterone; progestins, e.g. 
norgestrel and norethynodrel; estrogens, e.g. natural estrogens such as 
estradiol and semisynthetic estrogens such as mestranol; and 
antiinflammatory steroids such as cortisone, hydrocortisone, triamcinolone 
and the like. 
(3) Narcotic analgesics, such as codeine, pentazocine and morphine. 
(4) Narcotic antagonists and mixed agonists/antagonists, e.g. nalorphine, 
naloxone, buprenorphine, nalbuphine and butorphanol. 
(5) Cerebral stimulants, including tricyclic antidepressants such as 
opipramol and centrally active hydroxylated metabolites of tricyclic 
antidepressants, e.g. 2-hydroxyimipramine. 
(6) Anticancer and antitumor agents, e.g. mitoxantrone, etoposide, 
hydroxyurea and Ara-AC. 
(7) Antivirals, e.g. ribavarin, acyclovir and trifluridine. 
(8) Non-steroidal antiinflammatory agents, clonixeril and naproxol. 
(9) Hypotensives, e.g. prizidilol and nadolol. 
(10) Diagnostics, e.g. iopydol. 
(F) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a hydroxyl or mercapto function 
through which the carrier is attached and also contains at least one amino 
functional group, and D in the formula (Ia) or (IIa) contains, in place of 
a hydrogen atom of at least one of the amino groups in the drug, at least 
one amino protective group. Of particular interest are derivatives of 
neurotransmitters, stimulants, sympathetic amines, anticancer or antitumor 
agents, adrenergic agents and antiviral agents. The stimulants include 
centrally active metabolites of tricyclic antidepressants (e.g. 
2-hydroxydesipramine). 
(G) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a hydroxyl or mercapto function 
through which the carrier is attached and also contains at least one 
carboxyl group, and D in formula (Ia) or (IIa) contains, in place of the 
hydrogen atom of at least one of the carboxyl groups in the drug, at least 
one hydrolytically or metabolically cleavable carboxyl protective group. 
Of particular interest here are the derivatives of valproic acid 
metabolite anticonvulsants and CNS prostaglandins. 
(H) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amide or imide or low pKa primary 
or secondary amine function through which the carrier is attached and the 
D portion of the compound of formula (Ia) or (IIa) is identical to the 
corresponding portion of the drug from which D can be considered to be 
derived. Especially significant members of this group are the hydantoin 
anticonvulsants, e.g. phenytoin, ethotoin and mephenytoin, as well as 
other anti-convulsants, e.g. phenobarbital, aminoglutethimide, progabide 
and valpromide; tranquilizers, e.g. benzodiazepine-type tranquilizers such 
as bromazepam and oxazepam, and centrally active N-desmethyl metabolites 
of N-methylated benzodiazepine tranquilizers; hypnotics; nonsteroidal 
antiinflammatory agents; anticancer agents such as cyclophosphamide; 
anti-depressants, such as sulpiride; antibiotics, especially 
tetracyclines; and antivirals, such as trifluridine. 
(I) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amide or imide or low pKa primary 
or secondary amine function through which the carrier is attached and the 
drug also contains at least one hydroxyl group, D in formula (Ia) or (IIa) 
containing, in place of the hydrogen atom of at least one hydroxyl group 
in the drug, at least one hydrolytically or metabolically cleavable 
hydroxyl protective group. Significant members of this group include 
antivirals such as trifluridine and benzodiazepine tranquilizers such as 
oxazepam. 
(J) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains an amide or imide or low pKa primary 
or secondary amine function through which the carrier is attached and the 
drug also contains at least one carboxyl functional group, D in formula 
(Ia) or (IIa) containing, in place of the hydrogen atom of at least one 
--COOH in the drug, at least one hydrolytically or metabolically cleavable 
carboxyl protective group. Especially significant members of this group 
include anticancer and antitumor agents, antibiotics (particularly 
penicillins and cephalosporins) and CNS anticholinergics. 
(K) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a --COOH function through which the 
carrier is attached, and the D portion of the compound of formula (Ia) or 
(IIa) is identical to the corresponding portion of the drug from which D 
can be considered to be derived. Especially significant members of this 
group include nonsteroidal antiinflammatory agents such as naproxen, 
ibuprofen and the like; diagnostics, including radiolabeled ones such as 
o-iodohippuric acid and iothalamic acid, as well as the corresponding 
"cold" compounds; CNS prostaglandins, such as PGD.sub.2 ; antibiotics, 
especially cephalosporins and pencillins; anticonvulsants, e.g., valproic 
acid and SL 75102; anticancer and antitumor agents, e.g. chlorambucil, 
DACH and methotrexate. 
(L) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a --COOH function through which the 
carrier is attached and the drug also contains at least one hydroxyl 
function, D in formula (Ia) or (IIa) containing, in place of the hydrogen 
atom of at least one --OH in the drug, at least one hydrolytically or 
metabolically cleavable hydroxyl protective group. Within this class, 
derivatives of valproic acid metabolite-type anticonvulsants and NSAID's 
are especially noteworthy. 
(M) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a --COOH function which the carrier 
is attached and the drug also contains at least one amino function, D in 
formula (Ia) or (IIa) containing, in place of a hydrogen atom of at least 
one of the amino functions in the drug, at least one amino protective 
group. Significant members of this group include penicillin antibiotics, 
cephalosporin antibiotics, anticancer and antitumor agents, amino acids 
and small peptides. 
(N) Compounds of formulas (Ia) and (IIa) wherein the drug from which D can 
be considered to be derived contains a --COOH function through which the 
carrier is attached and the drug also contains at least one amino function 
and at least one hydroxyl function, D in formula (Ia) or (IIa) containing, 
in place of a hydrogen atom of at least one amino function and in place of 
the hydrogen atom of at least one hydroxyl function, respectively, at 
least one amino protective group and at least one hydrolytically or 
metabolically cleavable hydroxyl protective group. Particularly 
significant members of this class include dopaminergic agents, hypotensive 
agents, antibiotics, hydroxyl-containing amino acids (e.g. tyrosine) and 
small peptides containing same. 
It is apparent from the foregoing that the present invention provides a 
wide variety of carrier moieties and compounds containing those carriers 
which are adapted for the site-specific and sustained delivery of 
centrally acting drugs to the brain. Many of the dihydro moieties which 
are depicted as structures (a') through (j"), (k') through (s"), (i') 
through (ix") and (x') through (xiv') hereinabove, and the corresponding 
quaternary forms, as well as compounds containing those carriers, are 
specifically contemplated by applicant's earlier copending applications, 
e.g. by Ser. No. 516,382. Moreover, applicant's earlier applications, and 
particularly Ser. No. 516,382, specifically contemplate some additional 
carrier moieties and derivatives containing same, and those additional 
carriers and derivatives are likewise within the ambit of this 
application. Among the classes of compounds specifically provided by both 
Ser. No. 516,382 and the present application, the following are 
particularly noteworthy: 
(A*) Compounds adapted for the side-specific/sustained delivery of a 
centrally acting drug species to the brain, said compounds being: 
(i) compounds of the formula 
EQU D*(--Q*).sub.n* (I') 
wherein D* is the residue of a centrally acting drug containing at least 
one --NH.sub.2 or --NH-- functional group, said residue being formed by 
removal of a hydrogen atom from at least one of the --NH.sub.2 or --NH-- 
functional groups in said drug; n* is a positive integer equal to the 
number of said --NH.sub.2 or --NH-- functional groups from which a 
hydrogen atom has been removed; and --Q* is a radical of the formula 
##STR1641## 
wherein the dotted line in formulas (a*), (b*), (c*), (d*) and (e*) 
indicates the presence of a double bond in either the 4 or 5 position of 
the dihydropyridine ring; the dotted line in formulas (g*), (i*), (k*), 
(l*) and (n*) indicates the presence of a double bond in either the 2 or 3 
position of the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl 
or C.sub.7 -C.sub.10 aralkyl; R.sub.3 is C.sub.1 to C.sub.3 alkylene; X is 
--CONR'R" wherein R' and R", which can be the same or different, are each 
H or C.sub.1 -C.sub.7 alkyl, or X is --CH.dbd.NOR"' wherein R"' is H or 
C.sub.1 -C.sub.7 alkyl; the 
##STR1642## 
groupings in formulas (a*), (b*), (c*) and (e*) and the X substituent in 
formula (d*) can each be attached at the 2, 3 or 4 position of the 
dihydropuyridine ring; the 
##STR1643## 
groupings in formulas (g*), (i*), (k*) and (n*) and the X substituent in 
formula (l*) can each be attached at the 2, 3 or 4 position of the 
dihydroquinoline ring; and the 
##STR1644## 
groupings in formulas (f*), (h*), (j*) and (o*) and the X substituent in 
formula (m*) can each be attached at the 1, 3 or 4 position of the 
dihydroisoquinoline ring; and 
(ii) non-toxic pharmaceutically acceptable salts of compounds of formula 
(I'); 
with the proviso that when the compound is other than a salt as defined in 
(ii) above, when n* is 1, when --Q* is 
##STR1645## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.20 aralkyl, 
and when the centrally acting drug from which D* is derived contains only 
one --NH.sub.2 functional group and no other functional groups, then D* 
must be the residue of a centrally acting drug other than a sympathetic 
stimulant. The corresponding compounds in which --Q* is (a*), (b*), (c*), 
(e*), (f*), (g*), (h*), (i*), (j*), (k*), (n*), (o*), (p*), (q*), (r*) or 
(t*) wherein R.sub.1 is C.sub.1 -C.sub.7 haloalkyl are also within the 
scope of class (A*) as defined herein. Within class (A*), preferred 
compounds are those wherein --Q* is a radical of the formula: 
##STR1646## 
Also preferred are those compounds of class (A*) wherein D* is the residue 
of hydralazine, bactobolin, clonidine, bethanidine, tranylcypromine, 
chlordiazepoxide, methamphetamine, phentermine, phenmetrazine, 
anileridine, protriptyline, daunamycin, dextroamphetamine, levamphetamine, 
amphetamine, phenylethylamine, doxorubicin, amantadine, mitoxantrone, 
tryptamine, desipramine or nortriptyline. 
(B*) Compounds of Class (A*) as defined above, wherein the centrally acting 
drug from which D* is derived also contains at least one --COOH functional 
group, and D* contains, in place of at least one of the --COOH functional 
groups in said drug, at least one --COOY' group wherein Y' is a 
hydrolytically or metabolically cleavable carboxyl protective group. 
Within Class (B*), preferred compounds are those in which Y' is C.sub.1 
-C.sub.7 alkyl and/or wherein D* is the residue of an amino acid or of a 
peptide containing 2 to 20 amino acid segments (especially an enkephalin 
or an endorphin). Also preferred are the compounds of Class (B*) wherein 
D* is the residue of tryptophan, ampicillin, cephalexin, melphalen, 
L-alanosine, DON, acivicin, GABA, .gamma.-vinyl GABA, or 
.gamma.-acetylenic GABA, met.sup.5 -enkephalin, leu.sup.5 -enkephalin, 
.gamma.-endorphin, .alpha.-endorphin, .beta.-endorphin, LH-RH, 
neurotensin, oxytocin M or vasopressin. 
(C*) Compounds of Class (A*) as defined above, wherein the centrally acting 
drug from which D* is derived also contains at least one --OH functional 
group, and D* contains, in place of at least one of the --OH functional 
groups in said drug, at least one --OY group wherein Y is a hydrolytically 
or metabolically cleavable hydroxyl protective group. Within Class (C*) 
preferred compounds are those wherein Y is an acyl group or a carbonate 
group and/or wherein D* is the residue of a neurotransmitter, especially a 
catecholamine. At the present time, preferred compounds in this general 
class include those in which D* is the residue of serotonin, 
norepinephrine, epinephrine, dopamine, tyramine or phenylephrine. 
(D*) Compounds of Class (A*) as defined above, wherein the centrally acting 
drug from which D* is derived also contains at least one --OH functional 
group and at least one --COOH functional group, and D* contains, in place 
of at least one of the --OH functional groups and at least one of the 
--COOH functional groups in said drug, at least one --OY group and at 
least one --COOY' group, respectively, wherein Y is a hydrolytically or 
metabolically cleavable hydroxyl protective group and Y' is a 
hydrolytically or metabolically cleavable carboxyl protective group. 
Within Class (D*) preferred compounds are those wherein Y is an acyl group 
or a carbonate group and/or Y' is C.sub.1 -C.sub.7 alkyl. Of particular 
interest are the compounds in which D* is the residue of methyldopa or 
levodopa. 
(E*) Compounds adapted for the site-specific/sustained delivery of a 
centrally acting drug species to the brain, said compounds being: 
(i) compounds of the formula 
EQU D"(--Q').sub.n' (I") 
wherein D" is the residue of a centrally acting drug containing at least 
one --NH-- functional group which is part of an amide or imide structure 
or at least one low pKa primary or secondary amine functional group, said 
residue being formed by removal of a hydrogen atom from at least one of 
said functional groups in said drug; n' is a positive integer equal to the 
number of said functional groups from which a hydrogen atom has been 
removed; and --Q' is a radical of the formula 
##STR1647## 
wherein the dotted lines indicate the presence of a double bond in either 
the 4 or 5 position of the dihydropyridine ring and in either the 2 or 3 
position of the dihydroquinoline ring; R.sub.1 is C.sub.1 -C.sub.7 alkyl 
or C.sub.7 -C.sub.10 aralkyl; R is hydrogen, C.sub.1 -C.sub.7 alkyl, 
C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.7 alkyl substituted by one or 
more halogen atoms, pyridyl, furyl, phenyl, or phenyl substituted by one 
or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, 
lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower 
alkyl)carbamoyl, lower alkylthio lower alkylsulfinyl or lower 
alkylsulfonyl; and the 
##STR1648## 
grouping can be in the 2, 3 or 4 position of the dihydropyridine ring, in 
the 2, 3 or 4 position of the dihydroquinoline ring and in the 1, 3 or 4 
position of the dihydroisoquinoline ring; and 
(ii) non-toxic pharmaceutically acceptable salts of compounds of formula 
(I"). Within Class (E*), preferred compounds are those wherein --Q is a 
radical of the formula 
##STR1649## 
wherein R is as defined above, especially when R is hydrogen, methyl, 
phenyl or trichloromethyl, and/or when D" is the residue of a tetracycline 
antibiotic containing a --CONH.sub.2 function. Of particular interest in 
this general class are those compounds wherein D" is the residue of 
cyclophosphamide, ethotoin, phenobarbital, chlortetracycline, 
glutethimide, uracil mustard, bemegride, aminoglutethimide, phenytoin, 
butalbital, demeclocycline, minocycline, doxycycline, oxytetracycline, 
ethyl .beta.-carboline 3-carboxylate, nifedipine, methylphenidate, 
3-deazaguanine, PCNU, spiromustine or L-ICRF. 
(F*) Compounds adapted for the site-specific/sustained delivery of a 
centrally acting drug species to the brain, said compounds being: 
(i) compounds of the formula 
EQU (D"'(--Q").sub.n" (I"') 
wherein D"' is the residue of a centrally acting drug containing at least 
one --OH-- or --SH functional group, said residue being formed by removal 
of a hydrogen atom from at least one of the --OH or --SH functional groups 
in said drug; n" is a positive integer equal to the number of said --OH or 
--SH functional groups from which a hydrogen atom has been removed; and 
--Q" is a radical of any one of formulas (a*) through (t*) inclusive as 
set forth in the definition of Class (A*) above, the structural variables 
in those formulas also being defined as in (A*) above; and 
(ii) non-toxic pharmaceutically acceptable salts of compounds of formula 
(I"'); 
with the proviso that when the compound is other than a salt as defined in 
(ii) above, when n" is 1, when --Q" is 
##STR1650## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug from which D"' is derived contains only 
one primary or secondary --OH functional group, no other --OH functional 
groups and no --NH.sub.2, --NH--, --SH or --COOH functional groups, then 
D"' must be the residue of a centrally acting drug other than a steriod 
sex hormone or long chain alkanol. The corresponding compounds in which 
--Q" is (a*), (b*), (c*), (e*), (f*), (g*), (h*), (i*), (j*), (k*), (n*), 
(o*), (p*), (q*), (r*) or (t*) wherein R.sub.1 is C.sub.1 -C.sub.7 
haloalkyl are also within the scope of class (F*) as defined herein. 
Within Class (F*), preferred compounds are those in which --Q" is a 
radical of any one of formulas (a*') through (o*') set forth in connection 
with Class (A*) hereinabove. Also preferred are those compounds wherein 
D"' is a steroid sex hormone, i.e., an androgen, estrogen or progestin. 
When D"' is the residue of an androgen, it is preferable the residue of 
testosterone or methyl testosterone or other known 
17.beta.-hydroxy-containing analogue of testosterone. When D"' is the 
residue of an estrogen, it is preferably the residue of a natural estrogen 
(estradiol, estrone or estriol) or of a known semi-synthetic estrogen 
having a 17.beta.-hydroxy substituent, such as ethinyl estradiol, 
mestranol or quinestrol. When D"' is the residue of a progestin, it is 
preferably the residue of a known semi-synthetic progestin having a 
17.beta.-hydroxy substituent, such as norethindrone, norgestrel, 
ethisterone, dimethisterone, allylestrenol, cingestol, ethynerone, 
lynestrenol, norgesterone, norvinisterone, ethynodiol, oxogestone, 
tigestol or norethynodrel. Within Class (F*), another preferred group of 
compounds consists of the compounds in which D"' is the residue of an 
anti-inflammatory steroid, especially a known anti-inflammatory steroid 
having a 21-hydroxy substituent, such as cortisone, hydrocortisone, 
betamethasone, dexamethasone, flumethasone, fluprednisolone, methyl 
prednisolone, meprednisone, prednisolone, prednisone, cortodoxone, 
fludrocortisone, paramethasone or triamcinolone. Yet another preferred 
group of Class (F*) compounds is the group in which D"' is the residue of 
a narcotic analgesic, narcotic antagonist or narcotic agonist-antagonist, 
especially when it is the residue of a known compound of this type bearing 
at least one hydroxy substituent, such as codeine, pentazocine, naloxone, 
oxycodone, hydromorphone, oxymorphone, nalorphine, morphine, levorphanol, 
meptazinol, cyclazocine, phenazocine, profadol, metopon, drocode, myfadol, 
buprenorphine, nalbuphine, butorphanol, levallorphan, naltrexone, 
alazocine, oxilorphan or nalmexone. Still another preferred group of Class 
(F*) compounds consist of compounds in which D"' is the residue of an 
anticancer or antitumor agent; preferably D"' is the residue of a 
podophyllotoxin derivative (especially etoposide or teniposide) or of 
Ara-AC, pentostatin, thioguanine, hydroxyurea, dihydro-5-azacytidine, 
tiazofurin, sangivamycin, Ara-A, 6-MMPR, trimethyl TMM, SR-2555, 
bisbenzimidazole, SR-2508, aclacinomycin A, phyllanthoside, 
6-mercaptopurine, desmethylisonidazole, menogarol, aphidicolin, 5-FUDR, 
trifluoroacetyl doxorubicin, cytosine arabinoside, 5-azacytidine, Ara-C or 
streptozotocin. Yet another preferred group of compounds within this 
general class consists of compounds in which D"' is the residue of an 
antiviral agent such as ribavarin, acyclovir, syn or 
anti-6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzi 
midazol-2-amine, 
5,7-dimethyl-2-.beta.-D-ribofuranosyl-s-triazole(1,5-a)pyrimidine, 
2-deoxy-D-glucose, 2-deoxy-2-fluoro-D-mannose, 
phenyl-6-chloro-6-deoxy-.beta.-D-glucopyranoside, 
(S)-9-(2,3-dihydroxypropyl)adenine, idoxuridine, 
5,6-dichloro-1-.beta.-D-ribofuranosylbenzimidazole or 
bisihydroxyvinyluridine. Another preferred group of compounds in Class 
(F*) consists of compounds in which D"' is the residue of a benzodiazepine 
or phenothiazine tranquilizer, especially those in which D"' is the 
residue of a known benzodiazepine such oxazepam, lorazepam or temazepam, 
or of a known phenothiazine such as acetophenazine, carphenazine, 
fluphenazine, perphenazine or piperacetazine. Other Class (F*) compounds 
of interest are those in which D"' is the residue of thiopental, 
haloperidol, opipramol, clopenthixol, ethamivan, hydroxyzine, apomorphine, 
iopydol, clindamycin, lincomycin, benzestrol, diethylstilbestrol, 
pholcodeine or dipyridamole. 
(G*) Compounds of Class (F*) as defined above, wherein the centrally acting 
drug from which D"' is derived also contains at least one --COOH 
functional group, and D"' contains, in place of at least one of the --COOH 
functional groups in said drug, at least one --COOY' group wherein Y' is a 
hydrolytically or metabolically cleavable carboxyl protective group. 
Within Class (G*), preferred compounds include those in which D"' is the 
residue of a valproic acid metabolite (such as 
5-hydroxy-2-n-propylpentanoic acid, 4-hydroxy-2-n-propylpentanoic acid or 
3-hydroxy-2-n-propylpentanoic acid), clorazepate or diflunisal. 
(H*) Compounds of Class (F*) as defined above, wherein --Q" is a radical of 
the formula 
##STR1651## 
and D"' is the residue of a centrally acting drug containing a hindered 
tertiary --OH functional group; especially when D"' is the residue of 
biperiden, cycrimine, procyclidine or trihexylphenidyl. 
(I*) Compounds adapted for the site-specific/sustained delivery of a 
centrally acting drug species to the brain, said compounds being: 
(i) compounds of the formula 
EQU D.sup.iv (--Q"').sub.n"' (I.sup.iv) 
wherein D.sup.iv is the residue of a centrally acting drug species 
containing at least one --COOH functional group, said residue being formed 
by removal of an --OH from at least one of the --COOH functional groups in 
said drug; n"' is a positive integer equal to the number of said --COOH 
functional groups from which an --OH has been removed; and --Q"' is a 
radical of the formula 
##STR1652## 
wherein Z' is C.sub.1 -C.sub.8 straight or branched alkylene; 
(ii) compounds of the formula 
##STR1653## 
wherein D.sup.iv is defined as above and each R.sub.4 * can independently 
be hydrogen, D.sup.iv or a radical of the formula 
##STR1654## 
with the proviso that at least one R.sub.4 * is a radical of the formula 
##STR1655## 
(iii) compounds of the formula 
##STR1656## 
wherein D.sup.iv is defined as above, .circle. is the skeleton of a 
sugar molecule, n.sup.iv is a positive integer equal to the total number 
of --OH functions in the sugar molecule from which said skeleton is 
derived, and R.sub.4 * can independently be hydrogen, D.sup.iv or a 
radical of the formula 
##STR1657## 
with the proviso that at least one R.sub.4 * is a radical of the formula 
and 
(iv) non-toxic pharmaceutically acceptable salts of compounds of formula 
(I.sup.iv), (I.sup.v) and (I.sup.vi). Within this class, preferred 
compounds are those in which z' is 
##STR1658## 
and/or in which .circle. is the skeleton of a pentose or hexose, 
especially when .circle. is 
##STR1659## 
Also preferred Class (I*) compounds are those in which D.sup.iv is the 
residue of an antibiotic, a radiodiagnostic, a non-steroidal 
anti-inflammatory agent or an anticancer or antitumor agent. At the 
present time, compounds of particular interest within this class are those 
in which D.sup.iv is the residue of cephalothin, valproic acid, cefoxitin, 
clorazepate, iodopyracet, iodouppurate, iodamide, iopanoic acid, nalidixic 
acid, amoxicillin, oxolinic acid, chlorambucil, glyoxylic acid 
sulfonylhydrazone, DACH, methotrexate, aminopterin, 
5-methyltetrahydrohomofolic acid, cefazolin, ibuprofen, naproxen, 
flurbiprofen, zomepirac, mefenamic acid, sulindac, diclofenac, 
indomethacin, benzylpenicillin, phenoxymethylpenicillin, methicillin, 
nafcillin, ticarcillin, furosemide, oxacillin, carbenicillin, 
dicloxacillin, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, 
bucloxic acid, tolmetin, alclofenac, fenclozic acid, ibufenac, 
meclofenamic acid, flufenamic acid or flufenisal. 
(J*) Compounds adapted for the site-specific/sustained delivery of an 
benzodiazepine tranquilizer to the brain, said compounds having the 
formula 
##STR1660## 
and the nontoxic pharmaceutically acceptable salts thereof, wherein --Q* 
is as defined in connection with Class (A*) above and X, Y and Z are 
identical to the corresponding groupings in a known benzodiazepine 
tranquilizer having the formula 
##STR1661## 
especially when --Q* is a radical of any one of formulas (a*') through 
(o*') set forth in connection with Class (A*) hereinabove. Presently 
preferred compounds in this class are those having the formula 
##STR1662## 
(K*) Non-toxic pharmaceutically acceptable quaternary salts having the 
formula 
EQU D*(--Q.sup.*.sym.).sub.n* Y.sub.n*.sup..crclbar. (II') 
wherein D* and n* are as defined in connection with Class (A*), Y.crclbar. 
is the anion of a non-toxic pharmaceutically acceptable acid and 
--Q.sup.*.sym. has the formula 
##STR1663## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl; 
R.sub.3 is C.sub.1 to C.sub.3 alkylene; X is --CONR'R" wherein R' and R", 
which can be the same or different, are each H or C.sub.1 -C.sub.7 alkyl, 
or X is --CH.dbd.NOR"' wherein R"' is H or C.sub.1 -C.sub.7 alkyl; the 
##STR1664## 
groupings in formulas (aa*), (bb*), (cc*) and (ee*) and the X substituent 
in formula (dd*) can each be attached at the 2, 3 or 4 position of the 
pyridinium ring; the 
##STR1665## 
groupings in formulas (gg*), (ii*), (kk*) and (nn*) and the X substituent 
in formula (ll*) can each be attached at the 2, 3 or 4 position of the 
quinolinium ring; and the 
##STR1666## 
groupings in formulas (ff*) (hh*), (jj*) and (oo*) and the X substituent 
in formula (mm*) can each be attached at the 1 3 or 4 position of the 
isoquinolinium ring; with the proviso that when n* is 1, when 
--Q.sup.*.sym. is 
##STR1667## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, 
and when the centrally acting drug from which D* is derived contains only 
one --NH.sub.2 functional group and no other functional groups, then D* 
must be the residue of a centrally acting drug other than a sympathetic 
stimulant. The corresponding compounds in which --Q.sup.*.sym. is (aa*), 
(bb*), (cc*), (ee*), (ff*), (gg*), (hh*), (ii*), (jj*), (kk*), (nn*), 
(oo*), (pp*), (qq*), (rr*) or (tt*) wherein R.sub.1 is C.sub.1 -C.sub.7 
haloalkyl are also within the scope of class (K*) as defined herein. 
Within this class of compounds, preferred compounds are those wherein 
--Q.sup.*.sym. has the formula: 
##STR1668## 
(L*) Non-toxic pharmaceutically acceptable quaternary salts having the 
formula 
EQU D"(--Q'.sup..sym.).sub.n' Y.sub.n'.sup..crclbar. (II") 
wherein D" and n' are as defined in connection with Class (E*) above, 
Y.sup..crclbar. is the anion of a non-toxic pharmaceutically acceptable 
acid and --Q'.sup..sym. has the formula 
##STR1669## 
wherein R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl; R 
is hydrogen, C.sub.1 -C.sub.7 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 
-C.sub.7 alkyl substituted by one or more halogen atoms, pyridyl, furyl, 
phenyl, or phenyl substituted by one or more halo, lower alkyl, lower 
alkoxy, carbamouyl, lower alkoxycarbonyl, lower alkanoyloxy, lower 
haloalkyl, mono (lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower 
alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; and the 
##STR1670## 
grouping can be in the 2, 3 or 4 position of the pyridinium ring, in the 
2, 3 or 4 position of the quinolinium ring and in the 1, 3 or 4 position 
of the isoquinolinium ring. 
(M*) Non-toxic pharmaceutically acceptable quaternary salts having the 
formula 
EQU D"'(--Q".sup..sym.).sub.n" Y.sub.n".sup..crclbar. (II"') 
wherein D"' and n" are as defined in connection with Class (F*) above, 
Y.sup..crclbar. is the anion of a non-toxic pharmaceutically acceptable 
acid and --Q".sup..sym. has any one of formulas (aa*) through (oo*) set 
forth in connection with Class (K*) above, wherein the various 
substituents are defined as in (K*) above; with the proviso that when n" 
is 1, when --Q".sup..sym. is 
##STR1671## 
where R.sub.1 is C.sub.1 -C.sub.7 alkyl or C.sub.7 -C.sub.10 aralkyl, and 
when the centrally acting drug from which D"' is derived contains only one 
primary or secondary --OH functional group, no other --OH functional 
groups and no --NH.sub.2, --NH--, --SH or --COOH functional groups, then 
D"' must be the residue of a centrally acting drug other than a steroid 
sex hormone or long chain alkanol. The corresponding compounds in which 
--Q".sup..sym. is (aa*), (bb*), (cc*), (ee*), (ff*), (gg*), (hh*), (ii*), 
(jj*), (kk*), (nn*), (oo*) (pp*) (qq*) (rr*) or (tt*) wherein R.sub.1 is 
C.sub.1 -C.sub.7 haloalkyl are also within the scope of class (M*) as 
defined herein. Within Class (M*), preferred compounds are those in which 
--Q".sup..sym. has any one of formulas (aa') through (oo') set forth in 
connection with Class (K*) above. 
(N*) Non-toxic pharmaceutically acceptable quaternary salts having the 
formula: 
EQU (i) D.sup.iv (--Q"'.sup..sym.).sub.n"' Y.sub.n"'.sup..crclbar.(II.sup.iv) 
wherein D.sup.iv an n"' are as defined in connection with Class (I*) above, 
Y.sup..crclbar. is the anin of a non-toxic pharmaceutically acceptable 
acid and --Q"'.sup..sym. has the formula 
##STR1672## 
wherein Z' is C.sub.1 -C.sub.8 straight or branched alkylene; 
##STR1673## 
wherein D.sup.iv is as defined in connection with Class (I*) above and 
each R.sub.4 *' can independently be hydrogen, D.sup.iv or 
##STR1674## 
wherein Y.sup..crclbar. is defined as above, with the proviso that at 
least one R.sub.4 *' is 
##STR1675## 
wherein D.sup.iv and .circle. are as defined in connection with Class 
(I*) above, and each R.sub.4 *' can independently be hydrogen, D.sup.iv or 
##STR1676## 
wherein Y.sup..crclbar. is defined as above, with the proviso that at 
least one R.sub.4 *' is 
##STR1677## 
Accordingly, provided hereby are not only a generic method and novel class 
of pro-prodrugs for the specific and/or target enhanced delivery to the 
brain of a wide variety of drug species via the bidirectional transport of 
the drug species into and out of the brain employing dihydropyridine 
.revreaction.pyridinium salt carrier redox systems, but also a system 
providing insight into the basic transport processes (both active and 
passive) of, and enzymatic activities in, the blood-brain barrier, as well 
as into the various processes specific to the function of the brain. 
Again, another very significant aspect of the bioreversible redox delivery 
system according to this invention is the toxicity implication, for 
significantly reduced is systemic toxicity by accelerating the elimination 
of the drug/quaternary carrier system. And even central toxicity is 
reduced by providing for low level, sustained release of the active drug 
species in the brain. Low toxicity is provided both as regards the 
quaternary carrier and in combination with the drug. Again, the present 
invention is not bases on a simple prodrug concept, as was the case with 
the earlier work done with 2-PAM In that case, a hydrophilic compound 
(2-PAM) was made lipoidal by making its dihydropyridine form (Pro-2-PAM) 
to enable its peenetration through lipoidal barriers. This allowed the 
compound to get into the brain as well as other organs, but this prodrug 
manipulation did not and could not result in any brain specificity. And 
while the possibility of carrying drugs to the brain was also hypothesized 
earlier, all the experimental evidence reported in the literature negates 
any possible specificity, for the only compound delivered to the brain 
(2-PAM via Pro-2-PAM) showed similar efflux properties from the brain as 
from the other organs. There is no suggestion in the art of the 
brain-specific delivery which has now been achieved and which is a result 
of a surprisingly slow in vivo oxidation of the dihydro carrier system 
compared to the one reported in the earlier 2-PAM.revreaction.Pro-2-PAM 
system. Indeed, a most surprising and unexpected feature of the present 
delivery system is that it will result in a build-up of the concentration 
of the intermediate charged species (quarternary form) in the brain even 
after one single bolus injection of the starting lipophilic chemical 
delivery system (dihydro form). There is a first portion of the brain 
level versus time curve which shows a significant increase in the brain 
(up to doubling or even more) from the starting overall concentration, and 
this process takes place against the concentration gradient; see, for 
examle, FIG. 6 (dopamine) and FIG. 8 (testosterone). The blood levels do 
simultaneously fall, and ater some time (for example, for 1 to 11/2 
hours) significantly higher concentrations of the precursor, now in its 
hydrophilic carrier (quaternary) form, will be found in the brain as 
compared to the rest of the body. This is brain-specific delivery; it is 
not simply delivery of something which otherwise cannot get to the brain, 
but is delivery of a given agent in an inactive form specifically to the 
brain, which then will subsequently lead to a sustained brain-specific 
delivery of the active specie itself. In the case of testosterone and 
dopamine, for example, slow enzymatic cleavage of the quaternary form 
"locked in" the brain provides sustained release of the drug itself. 
While the invention has been described in terms of various preferred 
embodiments, the skilled artisan will appreciate that various 
modifications, substitutions,omissions, and changes may be made without 
departing from the spirit thereof. Accordingly, it is intended that the 
scope of the present invention be limited solely by the scope of the 
following claims.