6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts and compositions and method of use thereof

6,11-Substituted-6,11-dihydrobenzo[b]quinolizinium salts, pharmaceutical compositions containing them and methods for the treatment or prevention of neurodegenerative disorders or neurotoxic injuries utilizing them.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
The invention relates to 6,11-substituted-6,11-dihydrobenzo[b]quinolizinium 
salts, to compositions containing the same and to the method of use 
thereof in the treatment or prevention of neurodegenerative disorders or 
neurotoxic injuries. 
(b) Information Disclosure Statement 
Fields, U.S. Pat. No. 3,517,073 issued Jun. 23, 1970, discloses compounds 
of the formula: 
##STR1## 
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 when taken 
separately, is hydrogen, lower alkyl, lower aryl, lower acyloxy, lower 
alkoxy, nitro, halogen, lower acylamino, di(lower alkyl) amino; one group 
of R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, and R.sup.3 and R.sup.4, 
preferably R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4, each group when 
taken together, represents a fused ring system containing up to three 
6-member carbocyclic and nitrogen-containing heterocyclic rings at least 
one of which is an aromatic ring, and having no more than two nuclear 
nitrogens in any ring, which may be unsubstituted or substituted with one 
or more of the substituents defined by R.sup.1, R.sup.2, R.sup.3 and 
R.sup.4 ; each of R.sup.5 and R.sup.6, when taken separately is hydrogen, 
lower alkyl or lower aryl; each of R.sup.7 and R.sup.8, when taken 
separately, is hydrogen; R.sup.7 and R.sup.8, when taken together, 
represent a fused ring system as defined hereinbefore; R.sup.9, when taken 
individually, is methylene or lower alkyl, lower aryl, lower alkenyl, 
halogen, or cyano substituted methylene; R.sup.10, when taken 
individually, is a protected carbonyl group; R.sup.9 and R.sup.10, when 
taken together, represent a fused aromatic carbocyclic or heterocyclic 
ring system, whose valence bonds are from adjacent carbons, containing up 
to three 6-membered carbocyclic and nitrogen-containing heterocyclic rings 
having no more than two nitrogens in any ring and which may be substituted 
with one or more of the substituents defined by R.sup.1, R.sup.2, R.sup.3 
and R.sup.4. Among the compounds specifically disclosed are 
12,12-diethoxy-11-methyl-9,10-ethano-9,10-dihydro-4a-azoniaanthracene 
perchlorate and 9,10-(O-benzeno)-9,10-dihydro-5-methyl-4a-azoniaanthracene 
perchlorate. Also disclosed are compounds of the formula: 
##STR2## 
wherein R.sup.1 -R.sup.10 are as defined above and m is an odd integer 
having a value of from 1 to 5, inclusive. Among the compounds specifically 
disclosed are 
12,12-diethoxy-11-methyl-9,10-ethano-4a-aza-1,2,3,4,4a,9,9a,10-octahydroan 
thracene perchlorate acid salt, 
9,10-(O-benzeno)-5-methyl-4a-aza-1,2,3,4,4a,9,9a,10-octahydroanthracene 
and 12,12-diethoxy-9,10-ethano-11-bromo-4a-aza-1,2,3,-4,4a,9,9a,10-octahyd 
roanthracene. The above-described compounds are disclosed as being 
intermediates in the synthesis of 2-napthol derivatives and various 
anthracene derivatives. 
Fields et al., J. Org. Chem. 1968, 33(1), 390-395, disclose a series of 
sixteen Diels-Alder adducts prepared from a 4a-azoniaanthracene ion and 
various dienophiles. Among the compounds specifically disclosed are 
12-ethyl,12-hydroxymethyl and 
12-ethylene-9,10-dihydro-4a-azonia-9,10-ethanoanthracene bromides; 
12-phenyl-12-(4-morpholinyl), 12-methyl-12-(1-methylethylene), 
12,12-diethoxy-11-bromo and 
12-diethylamino-11-phenyl-9,10-dihydro-4a-azonia-9,10-ethanoanthracene 
perchlorates, as well as 9,10[1',2']cyclopentyl and 
9,10[2',3']tetrahydropyranyl-9,10-dihydro-4a-azoniaanthracene 
perchlorates. No utility is disclosed for these compounds. 
Fields and Regan, J. Org. Chem. 1971, 36(20), 2986-2990, disclose compounds 
of the formula: 
##STR3## 
wherein R is H, Br, or OAc, as intermediates in the synthesis of 
substituted 8-tert-butyl-1-(2-pyridyl)napthalenes. 
Fields and Regan, J. Org. Chem. 1971, 36(20), 2991-2994, disclose compounds 
of the formula: 
##STR4## 
wherein R is H, CH.sub.3, C.sub.6 H.sub.5, or Br, as intermediates in the 
synthesis of 2-pyridylnapthols. 
Fields, J. Org. Chem. 1971, 36(20), 3002-3005, discloses a series of 
substituted 12,12-diethoxy-9,10-ethano-9,10-dihydro-4a-azoniaanthracenes 
and the corresponding derivatives wherein the pyridinium moiety is 
partially or completely reduced, as intermediates in the synthesis of 
substituted 2-napthols. Among the compounds specifically disclosed is 
12,12-diethoxy-5,11-dimethyl-9,10-ethano-9,10-dihydro-4a-azoniaanthracene 
perchlorate. Also disclosed is a series of substituted 
9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracenes and the corresponding 
derivatives wherein the pyridinium moiety is partially or completely 
reduced, as intermediates in the synthesis of substituted anthracenes. 
Among the compounds specifically disclosed is 
9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracene perchlorate. 
Westerman and Bradsher, J. Org. Chem. 1971, 36(7), 969-970, disclose 
compounds of the formula: 
##STR5## 
wherein R is CH.sub.3, CH(CH.sub.3).sub.2, H, F, I, Cl, Br, CO.sub.2 H, 
CO.sub.2 CH.sub.3, or NO.sub.2. No utility is disclosed for these 
compounds. 
Bradsher and Day, J. Het. Chem. 1973, 10, 1031-1033, disclose four 
Diels-Alder adducts prepared from acridizinium perchlorate and 
cyclopentadiene, methyl vinyl ether, norbornadiene and maleic anhydride. 
No utility is disclosed for these compounds. 
Fields and Regan, J. Org. Chem. 1970, 35(6), 1870-1875, disclose compounds 
of the formula: 
##STR6## 
wherein R is H, CH.sub.3 or C.sub.6 H.sub.5. Also specifically disclosed 
are 
9,10-dihydro-12,12-dimethoxy-11,11-dimethyl-4a-azonia-9,10-ethanoanthracen 
e perchlorate and 
9,10-dihydro-9,11-dimethyl-12,12-diethoxy-4a-azonia-9,10-ethanoanthracene 
perchlorate. The compounds are said to be intermediates in the synthesis 
of 9,10-dihydro-12-oxo-4a-azonia-9,10-ethanoanthracenes. 
Fields et al., J. Org. Chem. 1971, 36(20), 2995-3001, disclose 
9,10-dihydro-4a-azonia-9,10-O-benzenoanthracene perchlorate and several 
analogs as intermediates in the synthesis of various 
9-(2-pyridyl)anthracenes. 
Fields and Miller, J. Het. Chem. 1970, 7, 91-97, disclose a compound of the 
formula: 
##STR7## 
as an intermediate in the synthesis of the corresponding 5,8-dione salt. 
Bradsher and Stone, J. Org. Chem. 1968, 33(2), 519-523, disclose a series 
of Diels-Alder adducts prepared from an acridizinium ion and maleic 
anhydride, maleate esters, fumarate esters and various para-substituted 
styrenes in which the para substituent is H, CH.sub.3, OCH.sub.3 or 
NO.sub.2. No utility is disclosed for these compounds. A substantially 
similar disclosure for the preparation of Diels-Alder adducts from 
acridizinium bromide and maleic anhydride, maleate or fumarate esters can 
be found in Bradsher and Solomons, J. Am. Chem. Soc. 1958, 80, 933-934. 
Bradsher and Stone, J. Org. Chem. 1969, 34(6), 1700-1702, disclose 
compounds of the formula: 
##STR8## 
wherein R is H, or CH.sub.3 ; R' is H, or CH.sub.3 ; R" is OCH.sub.3, 
CH.sub.3, H, or NO.sub.2 ; and X.sup.- is perchlorate; without an 
indication of utility. Also disclosed are the Diels-Alder adducts obtained 
from acridizinium perchlorate and diethyl maleate, diethyl fumarate or 
dimethyl maleate, without an indication of utility. 
Burnham and Bradsher, J. Org. Chem. 1972, 37(3), 355-358, disclose 
compounds of the formula: 
##STR9## 
wherein R.sup.1 is Ph, and R.sup.2 is OEt; or R.sup.1 is H, and R.sup.2 is 
OEt, OBu, OAc, N-carbazolyl or 1-pyrrolidin-2-one, without an indication 
of utility 
Parham et al., J. Org. Chem. 1972, 37(3), 358-362, disclose compounds of 
the formula: 
##STR10## 
wherein R is H.sub.2, (CH.sub.2).sub.3, C(O)NHC(O), C(O)N(CH.sub.3)C(O), 
C(O)OC(O), CH.sub.2 OCH.sub.2, or CH.sub.2 NH.sub.2.sup.+ CH.sub.2, 
without an indication of utility. 
Bradsher et al., J. Am. Chem. Soc. 1977, 99(8), 2588-2591, disclose 
compounds of the formula: 
##STR11## 
wherein: R.sup.1 .dbd.R.sup.2 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 
.dbd.Me, and R.sup.2 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H, and R.sup.2 .dbd.Me; and R.sup.1 .dbd.H, 
and R.sup.2 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.Me. No utility is disclosed for 
these compounds. 
Bradsher et al., J. Org. Chem. 1978, 43(5), 822-827, disclose compounds of 
the formula: 
##STR12## 
wherein: R.sup.1 is OEt and R is Me, H, F, Cl, CO.sub.2 Me or NO.sub.2 ; 
R.sup.1 is O--Ph--p--X, wherein X is CH.sub.3, OCH.sub.3, H, C(O)CH.sub.3, 
or NO.sub.2, and R is hydrogen; and R.sup.1 is N-carbazolyl and R is 
hydrogen. No utility is disclosed for these compounds. 
Westerman and Bradsher, J. Org. Chem. 1978, 43(15), 3002-3006, disclose a 
series of Diels-Alder adducts prepared from an acridizinium ion and 
various unsymmetrical alkenes, without an indication of utility. Among the 
compounds specifically disclosed are 
6,11[2',3']indanyl-6,11-dihydroacridizinium tetrafluoroborate, and 
12-phenyl-13-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridizinium 
tetrafluoroborate. 
Westerman and Bradsher, J. Org. Chem. 1979, 44(5), 727-733, disclose a 
series of Diels-Alder adducts prepared from a substituted or unsubstituted 
acridizinium cation and various polarizable alkenes without an indication 
of utility. Among the compounds specifically disclosed are 
12,12-diphenyl-6,11-dihydro-6,11-ethanoacridizinium perchlorate or 
bromide, 9-methyl-6,11[2',3']indanyl-6,11-dihydroacridizinium 
tetrafluoroborate, and 7,10-dimethyl-12-phenyl-12-(4-morpholinyl), 
9-methyl-12-phenyl-12-(4-morpholinyl), 12-(2-pyridyl), and 
9-methyl-12-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridizinium 
tetrafluoroborates. 
Bradsher et al., J. Org. Chem. 1979, 44(8), 1199-1201, disclose a series of 
Diels-Alder adducts prepared from a substituted or unsubstituted 
acridizinium ion and cyclopropene or 1-methylcyclopropene, without an 
indication of utility. 
Hart et al., Tetrahedron Letters 1975, 52, 4639-4642, disclose a compound 
of the formula: 
##STR13## 
as an intermediate in the synthesis of 1,4,5,8,9-pentamethylanthracene. 
SUMMARY OF THE INVENTION 
The invention relates to compounds of the Formula I: 
##STR14## 
wherein: R.sup.1 is hydrogen, or lower-alkyl; 
R.sup.2 is hydrogen, or from one to four, the same or different, halogen 
substituents in any of the 7-,8-,9- or 10-positions; 
A is cycloalkenyl, or said ring substituted at any available carbon atom 
thereof by lower-alkylidene; and 
X.sup.- is an anion; or a hydrate thereof; or a stereoisomer thereof; with 
the proviso that when R.sup.1 and R.sup.2 are hydrogen and X.sup.- is 
Br.sup.-, or ClO.sub.4.sup.-, A cannot be [3',4']cyclopentenyl. 
The compounds of Formula I bind to the PCP receptor and are thus useful in 
the treatment or prevention of neurodegenerative disorders or neurotoxic 
injuries. 
Preferred compounds of Formula I above are those wherein: 
R.sup.1 is hydrogen, or methyl; 
R.sup.2 is hydrogen or a bromide or fluorine substituent in any of the 
7-,8-,9- or 10-positions; 
A is cyclopentenyl, or cyclohexenyl ring, or said cyclopentenyl ring 
substituted on any available carbon atom thereof by lower-alkylidene; and 
X.sup.- is an anion; 
Particularly preferred compounds of Formula I above are those wherein: 
R.sup.1 is hydrogen, or methyl; 
R.sup.2 is hydrogen or 9-Br or 9-F; 
A is a [3',4']cyclohexenyl, [3',4']cyclopentenyl, or 
[5'-isopropylidene-[3',4']cyclopentenyl] ring; and 
X.sup.- is an anion. 
The invention further relates to pharmaceutical compositions which comprise 
a compound of Formula I: 
##STR15## 
wherein: R.sup.1 is hydrogen, or lower-alkyl; 
R.sup.2 is hydrogen, or from one to four, the same or different, 
substituents in any of the 7-,8-,9- or 10-positions selected from the 
group consisting of halogen, nitro, lower-alkoxy, hydroxy, and 
lower-alkyl; 
A is a member selected from the group consisting of cycloalkenyl, 
tetrahydrofuranyl, cycloalkyl, cycloalkenyl substituted at any available 
carbon atom thereof by lower-alkylidene; and phenyl; and 
X.sup.- is an anion; 
or a hydrate thereof; or a stereoisomer thereof; together with a 
pharmaceutically acceptable carrier, adjuvant, diluent, or vehicle; with 
the following provisos a) when R.sup.1 is hydrogen, R.sup.2 is 9-nitro and 
X.sup.- is ClO.sub.4.sup.-, A cannot be [3',4']cyclopentenyl; b) when 
R.sup.1 is hydrogen, R.sup.2 is 7,10-dihydroxy and X.sup.- is Br.sup.-, A 
cannot be [3',4']cyclopentenyl; (c) when R.sup.1 and R.sup.2 are hydrogen 
and X.sup.- is ClO.sub.4.sup.-, A cannot be phenyl; and (d) when R.sup.1 
is hydrogen, R.sup.2 is 9-methyl and X.sup.- is ClO.sub.4.sup.-, A cannot 
be phenyl. 
The invention further relates to a method for the treatment or prevention 
of neurodegenerative disorders or neurotoxic injuries which comprises 
administering to a patient in need of such treatment an effective amount 
of a compound of the formula: 
##STR16## 
wherein: R.sup.1 is hydrogen, or lower-alkyl; 
R.sup.2 is hydrogen, or from one to four, the same or different, 
substituents in any of the 7-,8-,9- or 10-positions selected from the 
group consisting of halogen, nitro, lower-alkoxy, hydroxy, and 
lower-alkyl; 
A is a member selected from the group consisting of cycloalkenyl, 
tetrahydrofuranyl, cycloalkyl, cycloalkenyl substituted at any available 
carbon atom thereof by lower-alkylidene; and phenyl; and 
X.sup.- is an anion; 
or a hydrate thereof; or a stereoisomer thereof; with the following 
provisos a) when R.sup.1 is hydrogen, R.sup.2 is 9-nitro and X.sup.- is 
ClO.sub.4.sup.-, A cannot be [3',4']cyclopentenyl; b) when R.sup.1 is 
hydrogen, R.sup.2 is 7,10-dihydroxy and X.sup.- is Br.sup.-, A cannot be 
[3',4']cyclopentenyl; (c) when R.sup.1 and R.sup.2 are hydrogen and 
X.sup.- is ClO.sub.4.sup.-, A cannot be phenyl; and (d) when R.sup.1 is 
hydrogen, R.sup.2 is 9-methyl and X.sup.- is ClO.sub.4.sup.-, A cannot be 
phenyl. 
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
The term lower-alkyl as used herein means linear or branched hydrocarbon 
chains having one to about four carbon and thus includes methyl, ethyl, 
isopropyl, n-butyl, sec-butyl, and the like. 
The term halogen as used herein means bromine, chlorine, iodine, and 
fluorine. 
The term lower-alkoxy as used herein means linear or branched alkyloxy 
substituents having one to about four carbon atoms and thus includes 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and the like. 
The term cycloalkenyl as used herein means C.sub.5 through C.sub.7 
unsaturated monocyclic hydrocarbon residues and thus includes 
cyclopentenyl, cyclohexenyl and cycloheptenyl. 
The term cycloalkyl as used herein means C.sub.5 through C.sub.7 
unsaturated monocyclic hydrocarbon residues and thus includes cyclopentyl, 
cyclohexyl and cycloheptyl. 
The term lower-alkylidene as used herein means linear or branched 
hydrocarbon chains having one to about four carbon atoms and thus includes 
methylidene, ethylidene, propylidene, isopropylidene, sec-butylidene and 
the like. 
The term anion (X.sup.-) as used herein means the anion of an organic acid 
(includes anions of organic monoacids, as well as monoanions of organic 
diacids) which is at least as strong as acetic acid, and thus includes 
anions of such acids as acetic acid, methanesulfonic acid, toluenesulfonic 
acid, trifluoromethanesulfonic acid, (-)-dibenzoyl-L-tartaric acid 
[(-)-DBT], (+)dibenzoyl-D-tartaric acid [(+)-DBT], and the like; or it 
means an inorganic acid anion such as chloride, bromide, perchlorate, 
PF.sub.6.sup.- and the like, preferably chloride. 
The numbering system used throughout the specification is shown in the ring 
system which is illustrated below. Ring systems of this type are usually 
named in the chemical literature as a 
6,11-substituted-6,11-dihydrobenzo[b]quinolizinium 
##STR17## 
nolizinium or a 6,11-dihydro-6,11-substituted acridizinium. It should be 
noted, however, that in some of the earlier chemical literature references 
(see references cited in Information Disclosure Statement) ring systems of 
this type were numbered as shown below, and were named as a 
9,10-substituted-9,10-dihydro-4a-azoniaanthracene, or a 
9,10-dihydro-4a-azonia-9,10-substituted 
##STR18## 
anthracene. Throughout this specification, however, we will use the former 
numbering system, and we will name the compounds as 
6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts. 
The synthesis of the compounds of the invention may be outlined as shown in 
Scheme A: 
Scheme A 
##STR19## 
A suitably substituted benzo[b]quinolizinium salt of Formula I can be 
treated with an excess of an appropriate cyclic diene or olefin of the 
Formula III, in a suitable solvent, e.g. acetonitrile, sulfolane, 
nitromethane, water, or alcoholic solvents, e.g. methanol, or mixtures of 
said solvents, at a temperature in the range of about room temperature up 
to the boiling point of the solvent or solvent mixture used to produce the 
6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts of Formula I 
where A is cycloalkenyl, tetrahydrofuranyl, cycloalkyl, or cycloalkenyl 
substituted at any available carbon atom thereof by lower-alkylidene. The 
corresponding compounds of the Formula I wherein A is a phenyl ring can be 
prepared by procedures which are known in the art of chemistry, for 
example, treating an appropriately substituted benzo[b]quinolizinium salt 
of Formula II in a suitable solvent, e.g. acetonitrile, concurrently with 
an excess of isoamyl nitrite and anthranilic acid (forms benzyne in situ) 
in the same solvent, followed by the addition of ether to precipitate the 
compounds of Formula I wherein A is phenyl (see, for example, Fields et 
al., J. Org. Chem. 1971, 36(20), 2995-3001). 
If desired, the compounds of Formula I can be converted into other 
compounds of Formula I which possess various different anions (X.sup.-) by 
a) treating a solution of a compound of the Formula I in water with at 
least one molar equivalent of the alkali metal salt of an organic acid 
anion or an inorganic acid anion, M.sup.+ X.sup.-, wherein the acid of the 
salt used is a stronger acid than the corresponding acid of the initial 
acid anion (X.sup.-), and wherein M.sup.+ is an alkali metal, e.g. 
lithium, sodium or potassium; b) passing a compound of the Formula I 
wherein X.sup.- is other than Cl.sup.- through a Dowex.RTM. 1.times.2-200 
ion-exchange resin (Dowex.RTM.-1-chloride) column to produce compounds of 
the Formula I wherein X.sup.- is Cl.sup.- ; or c) by passing a compound of 
the Formula I through a suitable ion-exchange resin column (prepared, for 
example, by treating Dowex.RTM. 1X2-200 ion-exchange resin with a suitable 
organic acid or inorganic acid) to provide various compounds of Formula I 
wherein X.sup.- is other than Cl.sup.-, ClO.sub.4.sup.- or PF.sub.6.sup.-. 
It will be appreciated that the compounds of the Formula I can possess one 
or more asymetric carbon atoms and are thus capable of existing in a 
number of stereoisomeric forms, e.g. enantiomers, diastereomers, and 
geometric isomers. Unless otherwise specified herein, the, invention is 
intended to extend to each of these stereoisomeric forms, and to mixtures 
thereof, including the racemates. In some cases there may be advantages, 
e.g. greater potency, to using a particular enantiomer when compared to 
the other enantiomer or the racemate in the treatment or prevention of 
neurodegenerative disorders or neurotoxic injuries, and such advantages 
can be readily determined by those skilled in the act. The different 
stereoisomeric forms may be separated one from the other by the methods 
described hereinbelow: 
The diastereomers/geometric isomers can be separated by conventional 
procedures which are well known in the art of chemistry such as 
chromatography, fractional crystallization and the like. The separation of 
enantiomers can be accomplished by a) chiral chromatography, or b) 
treating a racemic mixture of a compound of Formula I with the potassium 
salt of (+)-dibenzoyl-D-tartaric acid (K.sup.+ [(+)-DBT]) to afford a 
compound of Formula I as the .sup.- [(+)-DBT] salt; fractional 
crystallization of the .sup.- [(+)-DBT] salt to afford a single 
diastereomer of the .sup.- [(+)-DBT] salt, and then conversion of the 
single diastereomer of the .sup.- [(+)-DBT] salt into various other 
non-chiral anions (X.sup.-) by following the procedures described 
hereinabove for the conversion of compounds of the Formula I into other 
compounds of the Formula I with various different anions (X.sup.-), to 
produce the compounds of the Formula I as a single enantiomer; or c) 
treating a racemic mixture of a compound of Formula I with the potassium 
salt of (-)-dibenzoyl-L-tartaric acid (K.sup.- [(-)-DBT]) to afford a 
compound of Formula I as the .sup.- [(-)-DBT] salt and then proceeding as 
described hereinabove in part b to afford the compounds of Formula I as 
the other enantiomer. 
The suitably substituted benzo[b]quinolizinium salts of the Formula II, 
which are required for the synthesis of the compounds of the Formula I, 
are either known and can thus be prepared by procedures which are known in 
the art of chemistry (see for example, Bradsher and Parham, J. Org. Chem., 
1963, 28, 83-85; Bradsher and Jones, J. Am. Chem. Soc., 1957, 79, 6033-34; 
Bradsher et al., J. Het. Chem. 1964, 1, 30-33; and Bradsher and Parham, J. 
Het. Chem. 1964, 1, 121-124); or if they are novel, they can be prepared 
by the procedures described in the an or those,described hereinbelow and 
illustrated in Schemes B and C. In Scheme B, at least one molar equivalent 
of an appropriately substituted benzyl halide (IV), wherein Z is a 
halogen, preferably chlorine, bromine, or iodine, is treated with one mole 
of an appropriately substituted 
Scheme B 
##STR20## 
stituted 2-(1,3-dioxolan-2-yl)pyridine (V), in the presence of a solvent, 
e.g. sulfolane, or acetone, at a temperature in the range of about room 
temperature up to the boiling point of the solvent used, to produce the 
pyridinium salt (VI). The pyridinium salt (VI) can then be treated with an 
excess of an acid, e.g. polyphosphoric acid, 48% hydrobromic acid, or a 
mixture of polyphosphoric acid and methanesulfonic acid at a temperature 
in the range of about 40.degree. C. up to the boiling point of the acid, 
or acid mixture used, to produce the compounds of the Formula VII (Formula 
II wherein Z.sup.- .dbd.X.sup.- .dbd.halogen). The compounds of the 
Formula VII can then be converted into compounds of the Formula II which 
possess various anion groups, X.sup.-, by (a) treating a compound of the 
Formula VII, either as a solution in water, or neat, with or adding it to 
an aqueous solution containing at least one molar equivalent of the alkali 
metal salt of an organic acid anion or an inorganic acid anion, M.sup.+ 
X.sup.-, wherein the acid of the salt used is a stronger acid than the 
corresponding acid of the initial acid anion, and wherein M.sup.+ is an 
alkali metal, preferably potassium, lithium, or sodium, and X.sup.- is as 
defined hereinabove; at a temperature in the range of about room 
temperature up to the boiling point of the aqueous solution, or (b) adding 
the alkali metal salt, M.sup.+ X.sup.-, as a solid, to, or treating it 
with a solution of the compound of Formula VII in water, at a temperature 
in the range of about room temperature up to the boiling point of the 
aqueous solution. 
Alternatively, the benzo[b]quinolizinium salts of Formula II can be 
prepared as shown in Scheme C. A suitably substituted benzyl alcohol 
(VIII) is treated with at least two molar equivalents of a lower-alkyl 
alkali metal, preferably n-BuLi, optionally in the presence of at least 
one mole of a second base, e.g. tetramethylethylenediamine, followed by 
addition of an excess of a suitable pyridine derivative (IX), in an 
organic solvent, such as ether; at room temperature or below, preferably 
at a temperature in the range of about room temperature to about 
-30.degree. C., to afford diol X. The diol X can then be treated 
Scheme C 
##STR21## 
with a) an excess of an acid, e.g. 45% hydrobromic acid in acetic acid, at 
a temperature in the range of room temperature up to the boiling point of 
the acid used, or b) an excess of trifluoromethanesulfonic anhydride 
((TF).sub.2 O), in a suitable solvent, at about room temperature or above, 
or c) at least one molar equivalent of a phosphorous oxyhalide, preferably 
phosphorous oxychloride, at about room temperature or above, to produce 
the compounds of the Formula II, which can in turn be converted into other 
benzo[b]quinolizinium salts of the Formula II which possess various 
different anion groups, X.sup.-, by following the procedures described 
hereinabove. It will be noted that the method described hereinabove in 
Scheme C is the preferred method when it is desired to prepare compounds 
of the Formula II which contain substituents in the 6-, 10-, and/or 
11-positions. 
The appropriately substituted cyclic diene or olefin (III), the alkali 
metal salts of an organic acid anion or an inorganic acid anion (M.sup.+ 
X.sup.-), benzyl halide (IV), 2-(1,3-dioxolan-2-yl)pyridine (V), benzyl 
alcohol (VIII) and pyridine derivative (IX) are commercially available, or 
they can be prepared by procedures well known in the art, or by the 
procedures described hereinbelow. 
The compounds of Formula I are quinolizinium salts in which it is preferred 
that the salts are pharmaceutically acceptable salts, that is, salts whose 
anions (X.sup.-) are relatively innocuous to the animal organism in 
pharmaceutical doses of the salts, so that the beneficial properties 
inherent in the compounds of the Formula I are not vitiated by side 
effects ascribable to the anions. In practicing the present invention it 
is convenient to use the anions (X.sup.-) of organic acids such as 
methanesulfonic acid and toluenesulfonic acid, or the anions of inorganic 
acids such as hydrobromic acid and hydrochloric acid. However, other 
appropriate pharmaceutically acceptable salts within the scope of the 
invention are those derived from the anions (X.sup.-) of other organic 
acids, organic diacids, or inorganic acids. 
The structures of the compounds of the invention were established by the 
mode of synthesis, and by one or more of elemental analysis, and infrared, 
nuclear magnetic resonance and mass spectroscopy. The course of the 
reactions and the identity and homogeneity of the products were assessed 
by one or more of thin layer chromatography (TLC), high pressure liquid 
chromatography (HPLC), or gas-liquid chromatography (GLC).

The following examples will further illustrate the invention without, 
however, limiting it thereto. All melting points (m.p.) are in degrees 
centigrade (.degree. C.) and are uncorrected. 
Example 1 
To a mixture of benzo[b]quinolizinium bromide (10 g, 0.04 mol) (Bradsher 
and Parham, J. Org. Chem. 1963, 28, 83-85, Example VIIa) in 100 mL of 
acetonitrile/methanol (3:1) was added 3.55 g (0.044 mol) of 
1,3-cyclohexadiene in 5 mL of acetonitrile/methanol (3:1) and the 
resulting solution was stirred at room temperature for 3 hours. The 
solvent was removed in vacuo and the residue was recrystallized from ethyl 
acetate/methylene chloride (3.times.) to afford 9.3 g (67%) of 
6,11[3',4']-cyclohexenyl-6,11-dihydrobenzo[b]quinolizinium bromide 
(Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; A.dbd.[3',4']-cyclohexenyl; 
X.sup.- .dbd.--Br.sup.-), as an off-white solid, m.p. 
285.degree.-290.degree. C. 
Example 2 
A solution containing 11-methyl-benzo[b]quinolizinium perchlorate (1.0 g, 
3.4 mmol) (Bradsher and Parham, J. Org. Chem., 1963, 28, 83-85, Example 
VIII) and cyclopentadiene (2 mL, 23.4 mmol) in acetonitrile (40 mL) was 
stirred at room temperature for 2 hours. The solvent was removed in vacuo 
and the residue was triturated with ethyl acetate. The solid product was 
filtered to afford 1.2 g (97%) of 
11-methyl-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
perchlorate. 
Example 3 
A solution of 8-methoxybenzo[b]quinolizinium perchlorate (3.2 g, 10.3 mmol) 
(Bradsher and Jones, J. Am. Chem. Soc, 1957, 79, 6033-34) in acetonitrile 
(100 mL) and methanol (35 mL) was cooled to 0.degree. C. under nitrogen 
and cyclopentadiene (3.9 g, 59 mmol) was added. The mixture was stirred at 
room temperature overnight, followed by refluxing the reaction mixture for 
an additional 4 hours. The solvent was removed in vacuo and the residue 
was triturated with methanol, filtered, and the yellow solid thus obtained 
was washed with ether to afford 1.8 g (46%) of 
8-methoxy-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
perchlorate (Formula I: R.sup.2 .dbd.8-OCH.sub.3 ; R.sup.1 .dbd.H; 
A.dbd.[3',4']-cyclopentenyl; X.sup.- .dbd.ClO.sub.4.sup.-). 
Example 4 
A mixture of 2-(1,3-dioxolan-2-yl)pyridine (15.1 g, 0.1 mol) and 
4-bromobenzyl-bromide (25.0 g, 0.1 mol) in tetramethylene sulfone (25 mL) 
was refluxed for 2 hours and allowed to stand for 16 hours. The reaction 
mixture was diluted with ethyl acetate (500 mL) and the solid product thus 
obtained was isolated by filtration to yield 37 g (92%) of 
1-(4-bromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (Formula VI: 
R.sup.2 .dbd.4-Br; R.sup.1 .dbd.H; Z.sup.- .dbd.Br.sup.-) as a white 
solid. 
(b) 
A mixture of 1-(4-bromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (37 
g, 0.092 mol) in 48% HBr (300 mL) was refluxed with stirring for 24 hours. 
The reaction mixture was concentrated in vacuo and cold water (200 mL) was 
added to the residue. A yellow solid precipitated, which was isolated by 
filtration to yield 7.7 g (25%) of 9-bromobenzo[b]quinolizinium bromide 
(Formula VII: R.sup.2 .dbd.9-Br; R.sup.1 .dbd.H; Z.sup.- .dbd.Br.sup.-). 
(c) 
To a mixture of 9-bromobenzo[b]quinolizinium bromide (7.7 g (0.0227 mol) in 
acetonitrile (75 mL) and nitromethane (75 mL) was added with stirring a 
solution of methanol (30 mL) and cyclopentadiene (10 mL). The mixture was 
stirred for 7 hours and allowed to stand for 16 hours. The solvent was 
removed in vacuo and the residue was triturated with acetonitrile and the 
solid product thus obtained was isolated by filtration. The product was 
recrystallized from ethanol to yield 7.2 g (78%) of 
9-bromo-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium bromide 
(Formula I: R.sup.1 .dbd.H; R.sup.2 .dbd.9-Br; A.dbd.[3',4']cyclopentenyl; 
X.sup.- .dbd.Br.sup.-), as a white solid, m.p. 277.degree.-9.degree. C. 
(dec). 
Example 5 
(a) 
A mixture of 4-fluorobenzylbromide (17.5 g, 0.093 mol), sulfolane (25 mL) 
and 2-(1,3,-dioxolan-2-yl)pyridine (14.0 g, 0.093 mol) was stirred at room 
temperature for 2 hours, and then allowed to stand for 72 hours. The 
reaction mixture was diluted with ethyl acetate (200 mL) and the precipate 
thus obtained was collected by filtration and washed with ether to afford 
31.08 g (98%) of 1-(4-fluorobenzyl)-2-(1,3,-dioxolan-2-yl)pyridinium 
bromide (Formula VI: R.sup.2 .dbd.4-F; R.sup.1 .dbd.H; Z.sup.- 
.dbd.Br.sup.-). 
(b) 
1-(4-Fluorobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (31 g, 0.091 
mol) was added to a mixture of polyphosphoric acid (350 g) and 
methanesulfonic acid (100 mL) at 40.degree. C. and the resulting: mixture 
was heated at 105.degree. C. for 2 hours. The mixture was poured onto ice 
and the solution was treated with charcoal. The mixture was added to an 
excess of sodium perchlorate and the solution was chilled and allowed to 
stand for 16 hours. A precipitate formed, which was collected by 
filtration to afford 15.9 g (59%) of 9-fluorobenzo-[b]quinolizinium 
perchlorate (Formula II: R.sup.2 .dbd.9-F; R.sup.1 .dbd.H; X.sup.- 
.dbd.ClO.sub.4.sup.-), as a yellow solid, m.p. 168.degree.-173.degree. C. 
(c) 
To a mixture of 9-fluorobenzo[b]quinolizinium perchlorate (15.94 g, 0.0535 
mol) in 100 mL of acetonitrile was added with stirring 18 g (0.27 mol) of 
cyclopentadiene. The reaction mixture was stirred at room temperature for 
3 hours, then allowed to stand at room temperature for 16 hours. The 
solvent was removed in vacuo and the residue was triturated with ether. 
The ether was decanted, and the solid residue was stirred with ethyl 
acetate. The solid was collected by filtration and recrystallized from 
acetonitrile/ether to yield 14.73 g (75.5%) of 
9-fluoro-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo-[b]quinolizinium 
perchlorate (Formula I: R.sup.1 .dbd.H; R.sup.2 .dbd.9-F; 
A.dbd.[3',4']cyclopentenyl; X.sup.- .dbd.ClO.sub.4.sup.31 ), as a white 
solid, (m.p. 204.degree.-5.degree. C.). 
Example 6 
To a suspension of 9-nitrobenzo[b]quinolizinium perchlorate (2.6 g, 8 mmol) 
(Bradsher et al., J. Het. Chem. 1964, 1, 30-33) in acetonitrile (20 mL) 
was added cyclopentadiene (2.6 g, 0.039 mol). The mixture was stirred 
until a homogeneous solution was obtained and the solution was filtered. 
The solvent was removed in vacuo and the residue thus obtained was 
recrystallized from acetonitrile to afford 1.3 g (42%) of 
9-nitro-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
perchlorate (Formula I: R.sup.2 .dbd.9-NO.sub.2 ; R.sup.1 .dbd.H; 
A.dbd.[3',4']cyclopentenyl; X.sup.- .dbd.ClO.sub.4.sup.-), as a white 
powder, m.p. 235.degree.-237.degree. C. (dec.). 
Example 7 
A mixture of benzo[b]quinolizinium bromide (4.0 g, 15.4 mmol) (Bradsher and 
Parham, J. Org. Chem. 1963, 28, 83-85, Example VIIa), dihydropyran (40 mL) 
and tetramethylene sulfone (20 mL) was heated to reflux for 6 hours, and 
then stirred at room temperature overnight. The mixture was diluted with 
ethyl acetate (40 mL) and the precipitate thus obtained was collected by 
filtration to afford 3.5 g (66%) of 
6,11[2',3']tetrahydropyranyl-6,11-dihydrobenzo[b]quinolizinium bromide, as 
a white solid. 
Example 8 
A mixture of benzo[b]quinolizinium bromide (2.6 g, 10 mmol) (Bradsher and 
Parham, J. Org. Chem. 1963, 28, 83-85, Example VIIa), and 2,3-dihydrofuran 
(10 mL, 132 mmol) was heated to reflux and tetramethylene sulfone (10 mL) 
was added. The mixture was cooled to room temperature and stirred for 2 
hours. The solvent was removed in vacuo, and the residue was stirred with 
ethyl acetate. A solid was collected by filtration and dried to afford 
0.36 g (10%) of 
6,11[2',3']tetrahydrofuranyl-6,11-dihydrobenzo[b]-quinolizinium bromide 
(Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; A.dbd.[2',3']tetrahydrofuranyl; 
X.sup.- .dbd.Br.sup.-), as a tan solid, m.p. 195.degree.-200.degree. C. 
Example 9 
To a solution of benzo[b]quinolizinium bromide (31 g, 0.12 mol) (Bradsher 
and Parham, J. Org. Chem. 1963, 28, 83-85, Example VIIa), in 
acetonitrile/methanol (3/1, 1000 mL) at room temperature was added in one 
portion freshly distilled cyclopentadiene (39.6 g, 0.6 mol). The mixture 
was stirred for 1.5 hours, and the solvent was removed in vacuo. The solid 
residue was slurried with ethyl acetate and the product was collected by 
filtration and the residue was recrystallized from 
methanol/tertbutylmethyl ether to afford 26.0 g (38%) of 
6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium bromide 
(Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; A.dbd.[3',4']cyclopentenyl; 
X.sup.- .dbd.Br.sup.-). 
Example 10 
(a) 
A mixture of 2-(1,3-dioxolan-2-yl)pyridine (19 g, 0.126 mol) and 
p-methoxybenzyl bromide (30 mL) in sulfolane (50 mL) was stirred at room 
temperature for 4.5 days. The reaction mixture was diluted with ethyl 
acetate and cooled while stirring. The solvent was decanted to isolate an 
opaque oil. The oil was triturated with ethyl acetate (3.times.) and a 
glassy solid was filtered to yield 15.72 g (40.6%) of 
1-(4-methoxybenzyl-2-(1,3-dioxolan-2-yl)-pyridinium chloride (Formula VI: 
R.sup.2 .dbd.4-OCH.sub.3 ; R.sup.1 .dbd.H; Z--.dbd.Cl--). 
(b) 
A mixture of 1-(4-methoxybenzyl)-2-(1,3-dioxolan-2-yl)pyridinium chloride 
(15 g, 0.049 mol) in 300 g of polyphosphoric acid was allowed to react at 
120.degree. C. for 3 hours. The reaction mixture was poured onto ice with 
stirring. The mixture was neutralized with dibasic sodium phosphate and an 
aqueous solution of lithium perchlorate (1.1 equiv.) was added. The 
precipitated solid was filtered and dried to yield 
9-methoxybenzo[b]quinolizinium perchlorate (Formula II: R.sup.2 
.dbd.OCH.sub.3 ; R.sup.1 .dbd.H; X.sup.- .dbd.ClO.sub.4.sup.-), as a 
yellow solid. 
(c) 
A mixture of 13 g (0.042 mol) of 9-methoxybenzo[b]quinolizinium perchlorate 
and 30 mL (0.497 mol) of cyclopentadiene in 300 mL of methanol was stirred 
at room temperature for 24 hours. Additional cyclopentadiene (10 mL) was 
added and the reaction mixture was stirred for an additional 24 hours. The 
solvent was concentrated in vacuo and the dark residue was triturated with 
hexane and ethyl acetate respectively. The product was collected by 
filtration to afford crude 
9-methoxy-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
perchlorate (Formula I: R.sup.2 .dbd.9.dbd.OCH.sub.3 ; R.sup.1 .dbd.H; 
A.dbd.[3',4']cyclopentenyl X.sup.- .dbd.ClO.sup.-). 
Example 11 
(a) 
To a solution of 3-methoxybenzylalcohol (50.0 g, 0.36 mol) in ether (1.1 L) 
at -20.degree. C. was added n-BuLi (76.0 mL, 0.756 mol) at such a rate 
that the internal temperature of the reaction was maintained at less than 
-10.degree. C. When the addition of n-BuLi was complete, the mixture was 
warmed to room temperature and stirred for 2 hours. The mixture was cooled 
to 0.degree. C. and tetramethylethylene diamine (42.0 g, 0.36 mol) was 
added. The reaction mixture was cooled to -30.degree. C. and 
2-pyridinecarboxaldehyde (58.0 g, 0.36 mol) was added over 5 minutes. The 
reaction was warmed to 0.degree. C. over a 30 minute period and was then 
quenched with water (500 mL). The mixture was chilled for 24 hours, and 
the product was collected by filtration and washed with ether. The product 
was recrystallized from ethanol to afford 30.0 g (34%) of 
.alpha.-[2-(hydroxymethyl)-6-methoxyphenyl]-2-pyridinemethanol (Formula X: 
R.sup.2 .dbd.6-OCH.sub.3 ; R.sup.1 .dbd.H). The mother liquor from the 
recrystallization step was concentrated, diluted with ether and 
refrigerated for 16 hours. A solid precipitated, which was collected by 
filtration to afford an additional 13.1 g of the desired product for a 
total of 43.1 g (49%). 
(b) 
A solution of 
.alpha.-[2-(hydroxymethyl)-6-methoxyphenyl]-2-pyridinemethanol (13.1 g, 
0.053 mol) in 45% hydrobromic acid in acetic acid (75 mL) was refluxed for 
20 hours. Additional 45% hydrobromic acid in acetic acid (25 mL) was added 
and refluxing was continued for another 4 hours. The reaction mixture was 
cooled, poured into CH.sub.2 Cl.sub.2 (700 mL) and stirred for several 
minutes. A solid precipitated, which was collected by filtration to afford 
9.0 g (59%) of 10-methoxybenzo[b]quinolizinium bromide (Formula II: 
R.sup.2 .dbd.10-OCH.sub.3 ; R.sup.3 .dbd.R.sup.4 .dbd.H; X.sup.- 
.dbd.Br.sup.-). The filtrate was concentrated in vacuo to afford 4.0 g 
(27%) of 10-hydroxybenzo[b]quinolizinium bromide (Formula II: R.sup.2 
.dbd.10-OH; R.sup.1 .dbd.H; X.sup.- .dbd.Br.sup.-). 
(c) 
10-Methoxybenzo[b]quinolizinium bromide (4.0 g, 0.014 mol) was added to 150 
mL of warm 10% potassium hexafluorophosphate in water. After stirring for 
5 minutes, the precipitate which formed was collected by filtration and 
washed with warm water, then hexane, to afford 3.0 g (61%) of 
10-methoxybenzo[b]quinolizinium hexafluorophosphate (Formula II: R.sup.2 
.dbd.10-OCH.sub.3 ; R.sup.1 .dbd.H; X.sup.- .dbd.PF.sub.6.sup.-). 
(d) 
To a solution of 10-methoxybenzo[b]quinolizinium hexafluorophosphate (3.0 
g, 8.4 mmol) in methanol/acetonitrile (3/1, 250 mL) was added freshly 
distilled cyclopentadiene (25 mL). The mixture was stirred at room 
temperature for 2 hours, and then was allowed to stand for 16 hours. The 
solvent was removed in vacuo and the residue was triturated with ethyl 
acetate and filtered to afford 2.6 g (74%) of 
10-methoxy-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
hexafluorophosphate (Formula I: R.sup.2 .dbd.10-OCH.sub.3 ; R.sup.1 
.dbd.H; A.dbd.[3',4']cyclopentenyl; X.sup.- .dbd.PF.sub.6.sup.-). 
Example 12 
(a) 
A mixture of 2-(1,3-dioxolan-2-yl)pyridine (3.9 g, 0.026 mol), 
1-iodoethylbenzene (6.0 g, 0.026 mol) and acetone (50 mL) was stirred at 
room temperature under nitrogen. The acetone was removed, and sulfolane 
(50 mL) and additional 1-iodoethylbenzene (0.5 equivalents) was added and 
the mixture was stirred for 24 hours. The mixture was diluted with ethyl 
acetate, and the precipitate which formed was collected by filtration to 
afford 3.7 g (37%) of 1-(1-phenylethyl)-2-(1,3-dioxolan-2-yl)pyridinium 
iodide (Formula VI: R.sup.2 .dbd.H; R.sup.1 .dbd.CH.sub.3 ; Z.sup.- 
.dbd.I.sup.-). 
(b) 
A mixture of 1-(1-phenylethyl)-2-(1,3-dioxolan-2-yl)pyridinium iodide (3.5 
g, 9 mmol) and 48% hydrobromic acid (20 mL) was refluxed for 16 hours. The 
solvent was removed in vacuo to afford 1.9 g (76%) of 
6-methylbenzo[b]quinolizinium bromide (Formula VII: R.sup.2 .dbd.H;R.sup.1 
.dbd.CH.sub.3 ; Z.sup.- .dbd.Br.sup.-). 
(c) 
A mixture of 6-methylbenzo[b]quinolizinium bromide (1.8 g, 7 mmol), 
cyclopentadiene (2.6 g, 0.039 mol) and methanol was stirred at room 
temperature for 48 hours. The solvent was removed in vacuo and the residue 
was dissolved in water, washed with ether, treated with charcoal and 
filtered through celite. Sodium perchlorate (857 mg, 7 mmol) was added to 
the filtrate and the solution was cooled. A solid precipitated, which was 
collected by filtration and washed with ether to afford 365 mg (15%) of 
6-methyl-6,11[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium 
perchlorate, .1/2 H.sub.2 O (Formula I: R.sup.2 .dbd.H; R.sup.1 
.dbd.CH.sub.3 ; A.dbd.[3',4']cyclopentenyl; X.sup.- ClO.sub.4.sup.-), as a 
tan solid, m.p. 239.degree.-241.degree. C. (dec.). 
Example 13 
A mixture of benzo[b]quinolizinium bromide (5.0 g, 0.02 mol), (Bradsher and 
Parham, J. Org. Chem. 1963, 28, 83-85, Example VIIa), methanol (3 mL), 
water (40 mL) and cyclopentene (3.3 mL, 0.04 mL) was heated to 65.degree. 
C. in a sealed tube for 2 hours. Additional methanol (5.0 mL) was added 
and heating was continued at 65.degree. C. for 8 hours. Additional 
methanol (3.0 mL) was again added and the mixture was heated at 65.degree. 
C. for about 17 hours. The solvent was removed in vacuo and the residue 
was purified by column chromatography on silica eluting with ethyl 
acetate/PAW (1/1, wherein PAW is pyridine/acetic acid/water (55/20/25) to 
afford two fractions, each of which contains a single geometric isomer, as 
well as a third fraction which contains 4.0 g of a mixture of both 
isomers. Each of the isomers was individually treated with water (20 mL), 
followed by sodium perchlorate to afford 0.2 g (2.8%) of 
6,11[1',2']cyclopentyl-6,11-dihydrobenzo[b]quinolizinium perchlorate.1/2 
hydrate (Example 13(a)) (Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; 
A.dbd.[1',2']cyclopentyl; X.sup.- .dbd.ClO.sub.4.sup.-), as one geometric 
isomer, and 0.88 g (12%) of 
6,11[1',2']cyclopentyl-6,11-dihydrobenzo[b]quinolizinium perchlorate.1/2 
hydrate (Example 13(b) (Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; 
A.dbd.[1',2']cyclopentyl; X.sup.- .dbd.ClO.sub.4.sup.-), as the other 
geometric isomer. The first isomer was isolated as a white solid, m.p. 
198.degree.-201.degree. C. and the second isomer was isolated as a tan 
solid, m.p. 217.degree.-222.degree. C. 
Example 14 
(a) 
Benzo[b]quinolizium bromide (508.5 g, 1.95 mol) was dissolved in distilled 
water (5L) with heating on a steam bath and potassium hexafluorophosphate 
(367.2 g, 1.95 mol) in water (1.1 L) was poured into this solution in 
portions. The mixture was stirred at ambient temperature for 3 hours, then 
in an ice-bath for 1 hour. The precipitate which formed was collected by 
filtration, washed with water and dried at 60.degree. C. in vacuo to 
afford 601 g (94.8%) of benzo[b]quinolizinium hexafluorophosphate (Formula 
II: R.sup.1 .dbd.R.sup.2 .dbd.H; X.sup.- .dbd.PF.sub.6.sup.-). 
(b) 
A solution of 5 g (0.0163 mol) of benzo[b]quinolizinium hexafluorophosphate 
and 5 g (0.047 mol) of 6,6-dimethylfulvene in nitromethane (60 mL) was 
allowed to reflux for 1 hour and cooled. A brown solid product (700 mg) 
formed, which was isolated by filtration and purified by column 
chromatography on silica eluting with methanol/methylene chloride (1:10) 
and ethyl acetate. The product isolated was passed through Dowex(Cl.sup.- 
; 1.times.2-200; 50 g resin, 1000 mL water). The purified product in water 
was treated with NaClO.sub.4 and the precipitated perchlorate was filtered 
and dried to yield 254 mg (4%) of 
6,11-[5'-isopropylidene-[3',4']cyclopentenyl]-6,11-dihydrobenzo[b]quinoliz 
inium perchlorate (Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; 
A.dbd.[5'-isopropylidene-[3',4']cyclopentenyl]; X.sup.- ClO.sub.4.sup.-). 
Following procedures similar to those described hereinabove, or by 
following procedures which are known in the art, the following known 
compounds (Examples 15a-15d) were prepared and, unexpectedly, they were 
found to bind to the PCP receptor and are thus useful in the treatment or 
prevention of neurodegenerative disorders or neurotoxic injuries. 
Example 15 
(a) 
6,11-[3',4']cyclopentenyl-6,11-dihydrobenzo[b]quinolizinium bromide 
(Formula I: R.sup.1 .dbd.R.sup.2 .dbd.H; A.dbd.[3',4']cyclopentenyl; 
X.sup.- .dbd.Br.sup.-). 
(b) 
7-Nitro-6,11-benzeno-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula 
I: R.sup.1 .dbd.H; R.sup.2 .dbd.7-NO.sub.2 ; A.dbd.phenyl; X.sup.- 
ClO.sub.4.sup.-). 
(c) 
7-Hydroxy-10-tert-butyl-6,11-benzeno-6,11-dihydrobenzo[b]quinolizinium 
perchlorate (Formula I: R.sup.1 .dbd.H; R.sup.2 
.dbd.7-OH,10-C(CH.sub.3).sub.3 ; A.dbd.phenyl; X.sup.- ClO.sub.4.sup.-). 
(d) 
7-Methyl-6,11-benzeno-6,11-dihydrobenzo[b]quinolizinium perchlorate 
(Formula I: R.sup.1 .dbd.H; R.sup.2 .dbd.7-CH.sub.3 ; A.dbd.phenyl; 
X.sup.- ClO.sub.4.sup.-). 
BIOLOGICAL TEST RESULTS 
Representative examples of the compounds of the invention have been found 
to possess valuable pharmacological properties. In particular, they have 
been found to bind to the PCP receptor and are thus non-competitive 
blockers (antagonists) of the effects which excitatory amino acids, such 
as glutamate, have upon the NMDA receptor. The compounds of the invention 
are thus useful in the treatment or prevention of neurodegenerative 
disorders such as Huntington's disease, Alzheimer's disease, amyotrophic 
lateral sclerosis, Down's Syndrome, senile dementia, glutaric acidaemia 
type I multi-infarct dementia, Parkinson's disease, vital encephalopathies 
(which include, but are not limited thereto, dementia associated with HIV 
infections) and neuronal damage associated with uncontrolled seizures, as 
well as in the treatment or prevention of neurotoxic injuries associated 
with ischemic, hypoxic; or hypoglycemic conditions. Representative 
examples of such ischemic, hypoxic, or hypoglycemic conditions include 
strokes or cerebrovascular accidents, carbon monoxide poisoning, 
hyperinsulinemia, cardiac arrest, drownings, suffocation, spinal or head 
trauma, coronary artery bypass graft, neonatal anoxic trauma, and 
perinatal asphyxia. 
The compounds of the invention are particularly useful in the treatment or 
prevention of neurotoxic injuries associated with ischemic, hypoxic; or 
hypoglycemic conditions, and especially ischemic, hypoxic, or hypoglycemic 
conditions which are associated with stroke. 
The pharmacological properties of representative examples of the compounds 
of the invention was demonstrated by conventional in vitro biological test 
procedures such as the following: 
[.sup.3 H]TCP Radioreceptor Assay (internal screen) 
[.sup.3 H]TCP binding to PCP recognition sites was performed as described 
by Vignon et al. Brain Research 1983, 280, 194-197. Male Sprague-Dawley 
rats were sacrificed by decapitation, and whole brains were homogenized in 
10 volumes (wt/vol) of cold Tris-HCl buffer (50 mM, pH 7.7) using a 
Brinkmann Polytron (setting 6, 30 sec). The homogenate was centrifuged at 
40,000.times.g for 10 min at 4.degree. C. The supernatant was decanted, 
and the homogenization and centrifugation steps were repeated twice as 
described above. Following this, the pellet was resuspended in Tris-HCl (5 
mM, pH 7.7) at a tissue concentration of 0.5-0.75 g/ml, and one ml 
aliquots were frozen at -70.degree. C. until use. The binding 
characteristics for PCP recognition sites were not altered by the freezing 
of membrane suspensions. 
On the day of the assay, membrane aliquots were thawed, resuspended in 
fresh 5 mM Tris-HCl buffer at a tissue concentration of 1 mg/ml, and 
stored on ice until use. Each assay tube contained 100 .mu.l of [.sup.3 
H]TCP at a final concentration of approximately 1 nM, 100 .mu.l of various 
concentrations of the compounds of interest, 500 .mu.l of the tissue 
suspension and 300 .mu.l of buffer to a final assay volume of 1 ml and a 
final protein concentration of 0.5 mg/tube. Non-specific binding was 
defined by addition of a final concentration of 100 .mu.M PCP to blank 
tubes. All tubes were incubated at room temperature for 25 min before 
termination of the reaction by rapid filtration over Whatman GF/B glass 
fiber filters that had been presoaked in a solution of 0.5% 
polyethylenimine for at least 1 hr prior to use. Filters were washed with 
three 4 ml volumes of cold Tris buffer. Following addition of 
scintillation cocktail, the amount of bound radioactivity was determined 
by liquid scintillation spectrometry using a Beckman LS 5000TA liquid 
scintillation counter with an efficiency for tritium of approximately 55%. 
Inhibition constants (K.sub.i values) were calculated using the 
EBDA/LIGAND program (McPherson, J. Pharmacol. Meth. 1985, 14, 213-228), 
purchased from Elsevier/Biosoft, Inc. Results are reported as K.sub.i 
values which are expressed as the mean of at least two separate 
determinations; or as a percent (%) inhibition of binding at 10 .mu.M. 
Representative compounds of the invention were also tested in an external 
[.sup.3 H]TCP radioreceptor assay using the following protocol: 
[.sup.3 H]TCP Radioreceptor Assay (external screen) 
A procedure similar to that described above, for the [.sup.3 H]TCP 
radioreceptor assay (internal screen) was utilized except that the whole 
rat forebrain membranes were incubated at 25.degree. C. for 60 minutes 
rather than at room temperature for 25 minutes, before termination of the 
reaction. The results are reported as a percent (%) inhibition of binding 
at 10 .mu.M. 
Antagonism of NMDA-induced Neurotoxicity in Cultured Neurons 
Preparation of Cultured Cortical Neurons 
Pregnant, Swiss-Webster mice were obtained from Taconic Farms (Germantown, 
N.Y.) and sacrificed 16 days post conception. Fetuses were removed and 
placed in a sterile dish containing Hank's balanced salt solution (HBSS), 
pH 7.4. Brain cortices were dissected, meninges were removed, the tissue 
was minced and placed into a solution of HBSS containing 0.25% (w/v) 
trypsin at 37.degree. C. for 15 minutes. Tissue was then triturated with a 
sterile pasteur pipet, diluted with minimal essential media (Gibco 
330-1430), pH 7.4, supplemented with 10% horse serum, 10% fetal calf 
serum, 2 mM 1-glutamine, 21 mM d-glucose, 2.2 g/L sodium bicarbonate, 1000 
U/ml penicillin, and 1,000 .mu.g/ml streptomycin. Cells were plated onto 
Falcon primaria 96 well plates at a final density of 50,000 cells/well and 
incubated at 37.degree. C. in the presence of 5% (v/v) carbon dioxide. 
After 5 days, plating media was replaced with maintenance media containing 
minimal essential media (Gibco 330-1430), pH 7.4, supplemented with 10% 
horse serum, 10% 1-glutamine, 21 mM d-glucose, 2.2 g/l sodium bicarbonate, 
1,000 U/ml penicillin, 1,000 .mu.g/ml streptomycin, and 10 .mu.M cytosine 
arabinoside. On days 7 and 10, media was replaced with maintenance media 
as above lacking the cytosine arabinoside. Experiments were conducted on 
day 13. 
Neuroprotection Assessment 
Day 13 cultured cortical neurons were washed twice with minimal essential 
media, pH 7.4 and then exposed for 30 minutes to 500 .mu.M 
N-methyl-D-aspartic acid (NMDA) with or without varying concentrations of 
test agents. Dizocilpine (MK-801) at a final concentration of 10 .mu.M 
MK-801 was routinely included as a positive control. MK-801 and test 
agents were prepared in minimal essential media supplemented with 21 mM 
d-glucose and 2.2 g/L sodium bicarbonate (MEM). After 30 minutes, media 
was replaced with MEM alone. Exposure of neurons to test agents was 
limited to the NMDA treatment period. Twenty-four hours after removal of 
NMDA, an aliquot of media from each well was removed for assessment of 
cell injury by determining lactate dehydrogenase (LDH) activity by the 
method of Wroblewski and LaDue Proc. Soc. Exp. Biol. Med. 1955, 90, 
210-213. The results are expressed as an IC.sub.50 (in nM) value 
(concentration causing 50% inhibition) for the antagonism of NMDA-induced 
neurotoxicity. 
Table 1 summarizes the results obtained from the testing of representative 
compounds of the invention in the [.sup.3 H]TCP radioreceptor assay 
(internal screen and external screen) as well as in the antagonism of 
NMDA-induced neurotoxicity in cultured neurons. 
TABLE 1 
______________________________________ 
[.sup.3 H]TCP 
[.sup.3 H]TCP 
(internal screen) 
(external Antagonism of 
K.sub.i (nM) or 
screen) Per- 
NMDA-induced 
Example 
Percent Inhibition 
cent Inhibition 
neurotoxicity 
Number @10 .mu.M (%) @10 .mu.M 
(IC.sub.50 in nM) 
______________________________________ 
1 245 -- -- 
4(c) 1626 -- -- 
5(c) 806 -- -- 
8 8494 -- -- 
12(c) 93.4 -- -- 
13(a) 1565 -- -- 
13(b) 366 -- 8400 
14(b) 367 -- -- 
15(a) 464 92% -- 
15(b) 37% 9% -- 
15(c) 10% 24% -- 
15(d) 52% 11% -- 
______________________________________ 
The compounds of the invention can be prepared for pharmaceutical use by 
conventional pharmaceutical procedures that are well known in the art; 
that is, by formulating a pharmaceutical composition which comprises 
compounds of the invention or their pharmaceutically acceptable salts 
together with one or more physiologically acceptable carriers, adjuvants, 
diluents or vehicles, for oral administration in solid or liquid form, 
parenteral administration, topical administration or aerosol inhalation 
administration, and the like. 
Solid compositions for oral administration include compressed tablets, 
pills, powders and granules. In such solid compositions, the active 
compound is admixed with at least one inert diluent such as starch, 
calcium carbonate, sucrose or lactose. These compositions may also contain 
additional substances other than inert diluents, e.g., lubricating agents, 
such as magnesium stearate, talc and the like. 
Liquid compositions for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups and elixirs 
containing inert diluents commonly used in the art, such as water and 
liquid paraffin. Besides inert diluents such compositions may also contain 
adjuvants, such as wetting and suspending agents, and sweetening, 
flavoring, perfuming and preserving agents. According to the invention, 
the compounds for oral administration also include capsules of absorbable 
material, such as gelatin, containing said active component with or 
without the addition of diluents or excipients. 
Preparations according to the invention for parenteral administration 
include sterile aqueous, aqueous-organic, and organic solutions, 
suspensions and emulsions. Examples of organic solvents or suspending 
media are propylene glycol, polyethylene glycol, vegetable oils such as 
olive oil and injectable organic esters such as ethyl oleate. These 
compositions can also contain adjuvants such as stabilizing, preserving, 
wetting, emulsifying and dispersing agents. 
Preparations according to the invention for topical administration or 
aerosol inhalation administration include dissolving or suspending a 
compound of the invention in a pharmaceutically acceptable vehicle such as 
water, aqueous alcohol, glycol, oil solution or oil-water emulsion, and 
the like. 
If desired, the compounds of the invention can further be incorporated into 
slow release or targeted delivery systems such as polymer matrices, 
liposomes, and microspheres. 
The percentage of active component in such compositions may be varied so 
that a suitable dosage is obtained. The dosage administered to a 
particular patient is variable depending upon the clinician's judgment 
using as criteria: The route of administration, the duration of treatment, 
the size and physical condition of the patient, the potency of the active 
component and the patient's response thereto. An effective dosage amount 
of the active component can thus readily be determined by the clinician 
after a consideration of all criteria and using his best judgment on the 
patient's behalf.