Benzofused lactams and their use as antagonists of cholecystokinin are disclosed.

BACKGROUND OF THE INVENTION 
Cholecystokinin (CCK) is a neuropeptide composed of thirty-three 
aminoacids. [See: Mutt and Jorpes, Biochem. J. 125 678 (1971)]. The 
carboxyl terminal octapeptide (CCK-8) also occurs naturally and is fully 
active. CCK exists in both gastrointestinal tissue and the central nervous 
system. [V. Mutt, Gastrointestinal Hormones, G. B. J. Glass, Ed., Raven 
Press, N.Y., (1980) p. 169.] CCK is believed to play an important role in 
appetite regulation and CCK may be a physiological satiety hormone. [G. P. 
Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven 
Press, New York, 1984, p. 67.] 
Among additional effects of CCK are stimulation of colonic motility, 
stimulation of gall bladder contraction, stimulation of pancreatic enzyme 
secretion, and inhibition of gastric emptying. CCK reportedly co-exists 
with dopamine in certain mid-brain neurons and thus may also play a role 
in the functioning of dopaminergic systems in the brain as well as serving 
as a neurotransmitter in its own right. [See: A. J. Prange et al., 
"Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17 31, 33 
(1982) and references cited therein; J. A. Williams, Biomed. Res. 3 107 
(1982); and J. E. Morley, Life Sci. 30, 479 (1982).] 
CCK antagonists are useful in the treatment and prevention of CCK-related 
disorders of the gastrointestinal, central nervous and appetite regulatory 
systems of animals, especially humans. Three distinct chemical classes of 
CCK receptor antagonists have been reported. One class comprises 
derivatives of cyclic nucleotides; detailed structure-function studies 
have demonstrated that of the various members of this class, butyryl 
cyclic GMP, is the most potent. [See: N. Barlos et al., Am. J. Physiol., 
242, G161 (1982) and P. Robberecht et al., Mol., Pharmacol., 17, 268 
(1980).] The second class comprises peptide antagonists which are 
C-terminal fragments and analogs of CCK. Recent structure-function studies 
have shown that both shorter C-terminal fragments of CCK 
(Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2) as well as longer CCK 
fragments (CBz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) can function 
as CCK antagonists. [See: R. T. Jensen et al., Biochim. Biophys. Acta., 
757, 250 (1983) and M. Spanarkel et al., J. Biol. Chem., 258, 6746 
(1983).] The third class of CCK receptor antagonists comprises the amino 
acid derivatives; proglumide, a derivative of glutaramic acid and the 
N-acyl tryptophans including para-chlorobenzoyl-L-tryptophan (benzotript). 
[See W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) 
and R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269 (1983).] All of 
these compounds are relatively weak antagonists of CCK (IC.sub.50 
:10.sup.-4 -10.sup.-6 M). 
SUMMARY OF THE INVENTION 
It has now been found that the benzofused lactam compounds of this 
invention are antagonists of cholecystokinin (CCK). These CCK antagonists 
are useful in the treatment and prevention of CCK-related disorders of the 
gastrointestinal, central nervous and appetite regulatory systems of 
mammals, especially humans. 
DETAILED DESCRIPTION OF THE INVENTION 
An embodiment of the invention is a class of benzofused lactam compounds 
having the formula: 
##STR1## 
and pharmaceutically acceptable salts thereof wherein n is 1, 2 or 3, 
R.sub.4 is hydrogen, lower alkyl, aryl; 
R.sub.2 is hydrogen, 
R.sub.3 is H, halo, lower alkyl, or loweralkoxy, 
R.sub.1 is 
hydrogen; 
alkyl of from 1 to 12 carbon atoms which include branched, cyclic and 
unsaturated alkyl groups; 
substituted loweralkyl wherein the substituent can be halo, hydroxy, 
carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, 
loweraralkoxycarbonyl, amino, loweralkylamino, lowerdialkylamino, 
acylamino, carbonyl; 
substituted loweralkylamino wherein the substituent can be halo, hydroxy, 
alkoxy or cyano; arloweralkylamino; aryloxy; arylthio; aralkyloxy; 
aralkylthio; benzofused cycloalkyl or bicycloalkyl of from 8-12 carbon 
atoms; 
aryl or heteroaryl which may be mono-, di- or tri-substituted by 
loweralkyl, hydroxy, loweralkoxy, halo, amino, acylamino, loweralkylthio 
or aminoloweralkyl; 
benzofused cycloalkyl or bicycloalkyl of from 8 to 12 carbon atoms; 
arloweralkyl; arloweralkenyl; heteroloweralkyl and heteroloweralkenyl in 
which the aryl or heteroaryl rings may be mono-, di- or tri-substituted by 
halo, loweralkyl, hydroxy, loweralkoxy, amino, loweralkylamino, 
diloweralkylamino, aminoloweralkyl, acylamino, carboxy, haloloweralkyl, 
nitro, cyano or sulfonamido; 
aralkyl or heteroaralkyl which include branched loweralkyl groups; 
substituted aralkyl or substituted heteroaralkyl which include branched 
loweralkyl groups wherein the loweralkyl groups can be substituted by 
amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be 
substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, 
aroyl, arylthio, amino, aminoloweralkyl, loweralkanoylamino, aroylamino, 
lowerdialkylamino, loweralkylamino, hydroxy, hydroxyloweralkyl, 
trihaloloweralkyl, nitro, cyano, or sulfonamido; any of the arloweralkyl 
or alkenyl and heteroloweralkyl or alkenyl groups described above in which 
the aryl or heteroaryl ring is partially or completely hydrogenated; 
substituted loweralkyl having the formula R.sub.A.sup.1 (CH.sub.2).sub.n 
--Q--(CH.sub.2).sub.m wheren n is 0-2, m is 1-3, R.sub.A.sup.1 is aryl or 
heteroaryl optionally substituted by amino, lowerdialkylamino, 
loweralkylamino, hydroxy, hydroxyloweralkyl, aminoloweralkyl, 
trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, loweralkyl, halo, 
dihalo, and loweralkoxy, and Q is 0, is S, SO, SO.sub.2, N--R.sub.B.sup.1, 
CONR.sub.C.sup.1, NR.sub.C.sup.1 CO, CH.dbd.CH wherein R.sub.B.sup.1 is 
hydrogen, loweralkyl, aryl, aralkyl, loweralkanoyl, or aroyl, and 
R.sub.C.sup.1 is hydrogen, or loweralkyl; 
R.sub.5 is 
--OR.sub.6 or --NR.sub.7 R.sub.8 wherein R.sub.6, R.sub.7 and R.sub.8 can 
each independently be hydrogen; 
lower alkyl; 
substituted lower alkyl wherein the substituents are monohydroxy, dihydroxy 
or acylamino; 
acylloweralkyl; 
arloweralkyl; 
carboxyloweralkyl; 
carboxamidoloweralkyl; 
aryl of C.sub.6 or C.sub.10 ; 
heteroaryl, heteroarylalkyl and arylheteroalkyl wherein the aryl groups are 
C.sub.5 to C.sub.10 and the heteroatoms are O, N or S; 
the pharmaceutically acceptable salts thereof. 
Pharmaceutically acceptable salts are salts of Formula I with various 
inorganic and organic acids and bases. Such salts include ammonium salts, 
alkali metal salts like sodium and potassium salts, alkaline earth metal 
salts like the calcium and magnesium salts, salts with organic bases, 
e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino 
acids like arginine, lysine and the like, also salts with organic and 
inorganic acids such as HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, 
methanesulfonic, oxalic, pamoic, isethionic, toluenesulfonic, maleic, 
fumaric, camphorsulfonic, acetic or pivalic acids and the like. 
The salts may be prepared by conventional means, e.g., by reacting the free 
acid or free base forms of formula I with one or more equivalents of the 
appropriate base or acid in a suitable solvent or medium in which the salt 
is insoluble or in a solvent or medium in which the salt is insoluble, or 
in a solvent such as water which is then removed in vacuo or by 
freeze-drying or by exchanging the ions of an existing salt for another 
ion on a suitable ion exchange resin. 
The alkyl substituents recited above denote straight and branched chain 
hydrocarbons of C.sub.1 -C.sub.12 such as methyl, hexyl, propyl, dodecyl 
isopentyl, isopropyl, nopentyl, etc. 
Loweralkyl denotes alkyl groups of C.sub.1 to C.sub.8 such as ethyl, 
isobutyl, 4-methylpentyl, and the like. 
Alkenyl and alkynyl denote unsaturated hydrocarbon groups which are 
modified so that each contains a carbon to carbon double bond or triple 
bond, respectively, such as vinyl, 2-butenyl and 1-hexynyl. 
Cycloalkyl denotes rings composed of 5 to 8 methylene groups, each which 
may be substituted or unsubstituted with other hydrocarbon substituents, 
and include, for example, cyclopentyl, cycloheptyl, 4-methyl cyclohexyl, 
and the like. 
Benzofused cycloalkyl groups denote a cycloalkyl ring of 5 to 8 carbon 
atoms to which is fused a benzene ring such as indanyl or tetralyl groups. 
Bicycloalkyl denotes two cycloalkyl rings of 5 to 8 carbon atoms each 
joined together in any allowable way s h as perhydroindane, 
octahydronaphthalene, bicyclo 3:1:3 octane and spiro 4:0:4 nonane. 
The loweralkoxy substituent represents a loweralkyl group as described 
above attached through an oxygen bridge. 
The aralkyl and heteroaralkyl substituents recited above represent aryl or 
heteroaryl groups as herein defined attached through a straight or 
branched chain hydrocarbon of from one to six carbon atoms, for example, 
benzyl, phenethyl, 3,3-diphenylpropyl, 3-indolylmethyl, and the like. 
Halo means chloro, bromo, iodo, or fluoro. 
The aryl substituents are unsubstituted aromatic rings such as phenyl, 
naphthyl, or biphenyl. 
The heteroaryl substituent recited above represents any 5- or 6-membered 
aromatic ring containing from one to three heteroatoms selected from the 
group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, 
thienyl, furyl, imidazolyl, and thiazolyl; as well as any bicyclic group 
in which any of the above heterocyclic rings is fused to another aromatic 
ring, for example, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, 
benzothiazolyl, benzthienyl, and naphthyridyl. 
The acylamino substituent represents loweralkanoylamino and aroylamino. 
Preferred Formula I compounds are those where 
n is 1, 2 or 3, 
R.sub.5 is --OR.sub.6 or --NR.sub.7 R.sub.8 wherein R.sub.6, R.sub.7 and 
R.sub.8 are independently selected from hydrogen; lower alkyl, aryl, and 
arloweralkyl; 
R.sub.2 is 
hydrogen; 
carboxyloweralkyl; 
carboxamidoloweralkyl; 
R.sub.1 is as defined above; 
R.sub.4 is hydrogen, lower alkyl, aryl; and 
R.sub.3 is H, halo, lower alkyl, or lower alkoxy. 
More preferred compounds of Formula I are those where 
n is 1, 2 or 3, 
R.sub.5 is --OR.sub.6 or --NR.sub.7 R.sub.8 wherein R.sub.6, R.sub.7 and 
R.sub.8 are independently selected from hydrogen, lower alkyl, aryl, and 
arloweralkyl; 
R.sub.4 is hydrogen, lower alkyl, carboxyloweralkyl, carboxamidoloweralkyl; 
R.sub.2 is hydrogen; 
R.sub.1 is as defined above in the preferred group; 
R.sub.3 is H, halo, lower alkyl, lower alkoxy, or aryl. 
Most preferred compounds of Formula I are those where 
n is 1, 2 or 3, 
R.sub.4 is hydrogen, or lower alkyl; 
R.sub.1 is as defined above in the preferred group; 
R.sub.2 is hydrogen, 
R.sub.5 is --OR.sub.6 or --NR.sub.7 R.sub.8 wherein R.sub.6, R.sub.7 and 
R.sub.8 are independently selected from hydrogen, lower alkyl, benzyl, 
carboxyloweralkyl, carboxamidoloweralkyl; and, 
R.sub.3 is H, halo, lower alkyl or lower alkoxy. 
A preferred value of n in the above described sub-genera is 3 or 2, and 
more preferably 2. 
The preferred, more preferred and most preferred compounds of Formula I 
also include t pharmaceutically acceptable salts thereof. 
The pharmaceutically acceptable salts are salts of Formula I compounds with 
various inorganic and organic acids and bases. Such salts include ammonium 
salts, alkali metal salts like sodium and potassium salts, alkaline earth 
metal salts like the calcium and magnesium salts, salts with organic 
bases, e.g., dicyclohexylamine salts, N-methyl-Dglucamine, salts with 
amino acids like arginine, lysine and the like, and salts with organic and 
inorganic acids; e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, 
methanesulfonic, isethionic, pivalic, oxalic, toluenesulfonic, maleic, 
fumaric, camphorsulfonic acids and the like. 
The salts may be prepared by conventional means, e.g., reacting the free 
acid or free base form of the product with one or more equivalents of the 
appropriate base or acid in an appropriate solvent or reaction medium. 
An embodiment of this invention is the preparation of compounds of Formula 
I. 
Another embodiment is the use of the compounds of Formula I for the 
treatment and the prevention of disorders of the gastrointestinal, central 
nervous, and appetite regulatory systems of mammals, especially of man. 
Specifically, the Formula I compounds are useful in treatment and 
prevention of disorders of gastric acid secretion, gastrointestinal 
motility, pancreatic secretions, and dopaminergic functions. The compounds 
of Formula I are especially useful in the prevention and treatment of 
irritable bowel syndrome. 
A further embodiment is a composition comprising an effective amount of a 
compound of Formula I and a pharmaceutically acceptable carrier. 
The ability of the compounds of Formula I to antagonize CCK makes these 
compounds useful as pharmaceutical agents. These compounds will be 
especially useful in the treatment and prevention of disease states 
wherein CCK may be involved, for example, gastrointestinal disorders such 
as irritable bowel syndrome, ulcers, excess pancreatic or gastric 
secretion, acute pancreatitis, motility disorders, central nervous system 
disorders caused by CCK's interaction with dopamine such as neuroleptic 
disorders, tardive dyskinesia, Parkinson's disease, psychosis or Gilles de 
la Tourette Syndrome, and disorders of appetite regulatory systems. 
The compounds of Formula I or pharmaceutically acceptable salts thereof, 
can be administered to a human subject either alone, or preferably, in 
combination with pharmaceutically acceptable carriers or diluents, in a 
pharmaceutical composition, according to standard pharmaceutical practice. 
Thus, the compositions of the invention can contain other conventional 
pharmaceutically acceptable compounding ingredients, as necessary or 
desired. Conventional procedures for preparing such compositions in 
appropriate dosage forms can be utilized. Whatever the dosage form, it 
will contain a pharmaceutically effective amount of the present 
composition. 
The present compositions can be administered orally or other than orally; 
e.g., parenterally, by insu flation, topically, rectally, etc.; using 
appropriate dosage forms; e.g., tablets, capsules, suspensions, solutions, 
and the like, for oral administration; suspension emulsions, and the like, 
for parenteral administration; solutions for intravenous administration; 
and ointments, transdermal patches, and the like, for topical 
administration. 
Compositions intended for oral use may be prepared according to any method 
known to the art for the manufacture of pharmaceutical compositions and 
such compositions may contain one or more agents selected from the group 
consisting of sweetening agents, flavoring agents, coloring agents and 
preserving agents in order to provide pharmaceutically elegant and 
palatable preparation. Tablets containing the active ingredient in 
admixture with non-toxic pharmaceutically acceptable excipients may also 
be manufactured by known methods. The excipients used may be for example, 
(1) inert diluents such as calcium carbonate, sodium carbonate, lactose, 
calcium phosphate or sodium phosphate; (2) granulating and disintegrating 
agents such as corn starch, or alginic acid; (3) binding agents such as 
starch, gelatin or acacia, and (4) lubricating agents such as magnesium 
stearate, stearic acid or talc. The tablets may be uncoated or they may be 
coated by known techniques to delay disintegration and absorption in the 
gastrointestinal tract and thereby provide a sustained action over a 
longer period. For example, a time delay material such as glyceryl 
monostearate or glyceryl distearate may be employed. They may also be 
coated by the techniques described in U.S. Pat. Nos. 4,256,108; 
4,160,452; and 4,265,874 to form osmotic therapeutic tablets for 
controlled release. 
In some cases, formulations for oral use may be in the form of hard gelatin 
capsules wherein the active ingredient is mixed with an inert solid 
diluent, for example, calcium carbonate, calcium phosphate or kaolin. They 
may also be in the form of soft gelatin capsules wherein the active 
ingredient is mixed with water or an oil medium, for example peanut oil, 
liquid paraffin, or olive oil. 
Aqueous suspensions normally contain the active materials in admixture with 
excipients suitable for the manufacture of aqueous suspensions. Such 
excipients may be 
(1) suspending agents such as sodium carboxymethylcellulose, 
methylcellulose, hydroxypropylmethylcellulose, sodium alginate, 
polyvinylpyrrolidone, gum tragacanth and gum acacia; 
(2) dispersing or wetting agents which may be 
(a) a naturally-occurring phosphatide such as lecithin, 
(b) a condensation product of an alkylene oxide with a fatty acid, for 
example, polyoxyethylene stearate, 
(c) a condensation product of ethylene oxide with a long chain aliphatic 
alcohol, for example, heptadecaethyleneoxycetano 
(d) a condensation product of ethylene oxide with a partial ester derived 
from a fatty acid and a hexitol such as polyoxyethylene sorbitol 
monooleate, or 
(e) a condensation product of ethylene oxide with a partial ester derived 
from a fatty acid and a hexitol anhydride, for example polyoxyethylene 
sorbitan monooleate. 
The aqueous suspensions may also contain one or more preservatives, for 
example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; 
one or more flavoring agents; and one or more sweetening agents such as 
sucrose or saccharin. 
Oily suspension may be formulated by suspending the active ingredient in a 
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut 
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may 
contain a thickening agent, for example beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents and flavoring agents may be added to provide a 
palatable oral preparation. These compositions may be preserved by the 
addition of an antioxidant such as ascorbic acid. 
Dispersible powders and granules are suitable for the preparation of an 
aqueous suspension. They provide the active ingredient in admixture with a 
dispersing or wetting agent, a suspending agent and one or more 
preservatives. Suitable dispersing or wetting agents and suspending agents 
are exemplified by those already mentioned above. Additional excipients, 
for example, those sweetening, flavoring and coloring agents described 
above may also be present. 
The pharmaceutical compositions of the invention may also be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil such as 
olive oil or arachis oils, or a mineral oil such as liquid paraffin or a 
mixture thereof. Suitable emulsifying agents may be (1) naturallyoccurring 
gums such as gum acacia and gum tragacanth, (2) naturally-occurring 
phosphatides such as soy bean and lecithin, (3) esters or partial esters 
derived from fatty acids and hexitol anhydrides, for example, sorbitan 
monooleate, (4) condensation products of said partial esters with ethylene 
oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may 
also contain sweetening and flavoring agents. 
Syrups and elixirs may be formulated with sweetening agents, for example, 
glycerol, propylene glycol, sorbitol or sucrose. Such formulations may 
also contain a demulcent, a preservative and flavoring and coloring 
agents. 
The pharmaceutical compositions may be in the form of a sterile injectable 
aqueous or oleagenous suspension. This suspension may be formulated 
according to known methods using those suitable dispersing or wetting 
agents and suspending agents which have been mentioned above. The sterile 
injectable preparation may also be a sterile injectable solution or 
suspension in a non-toxic parenterally-acceptable diluent or solvent, for 
example as a solution in 1,3-butane diol. Among the acceptable vehicles 
and solvents that may be employed are water, Ringer's solution and 
isotonic sodium chloride solution. In addition, sterile, fixed oils are 
conventionally employed as a solvent or suspending medium. For this 
purpose any bland fixed oil may be employed including synthetic mono- or 
diglycerides. In addition, fatty acids such as oleic acid find use in the 
preparation of injectables. 
A composition of the invention may also be administered in the form of 
suppositories for rectal administration of the drug. These compositions 
can be prepared by mixing the drug with a suitable non-irritating 
excipient which is solid at ordinary temperatures but liquid at the rectal 
temperature and will therefore melt in the rectum to release the drug. 
Such materials are cocoa butter and polyethylene glycols. 
For topical use, creams, ointments, jellies, solutions or suspensions, 
etc., containing the compositions of the invention are employed. 
When a compound of Formula I or a salt thereof is used as an antagonist of 
CCK in a human subject, the daily dosage will normally be determined by 
the prescribing physician. Moreover, the dosage will vary according to the 
age, weight, and response of the individual patient, as well as the 
severity of the patient's symptoms. However, in most instances, an 
effective daily dosage will be in the range from about 0.5 mg to about 
1000 mg/kg and preferably 5 mg to about 500 mg/kg in a single or divided 
doses. On the other hand, it may be necessary to use dosages outside these 
limits in some cases. 
Therefore, it should be understood that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
activity of the specific compound exployed, the age, body weight, general 
health, sex, diet, time of administration, route of administration, rate 
of excretion, drug combination and the severity of the particular disease 
undergoing therapy. 
In Vitro Activity of Formula I 
The biological activity of the compounds of Formula I have been evaluated 
using an .sup.125 I-CCK receptor binding assay and in vitro isolated 
tissue preparations. 
Materials and Methods 
1. CCK Receptor Binding (Pancreas) 
CCK-33 was radiolabeled with .sup.125 I-Bolton Hunter reagent (2000 
Ci/mmole) as described by Sankara et al. (J. Biol. Chem. 254: 9349-9351, 
1979). Receptor binding was performed according to Innis and Snyder (Proc. 
Natl. Acad. Sci. 77: 6917-6921, 1980) with the minor modification of 
adding the additional protease inhibitors, phenylmethane sulfonyl fluoride 
and o-phenanthroline. The latter two compounds have no effect on the 
.sup.125 I-CCK receptor binding assay. 
Male Sprague-Dawley rats (200-350 g) were sacrificed by decapitation. The 
whole pancreas was dissected free of fat tissue and was homogenized in 20 
volumes of ice-cold 50 mM, Tris HCl (pH 7.7 at 25.degree. C.) with a 
Brinkmann Polytron PT 10. The homogenates were centrifuged at 48,000 g for 
10 min. Pellets were resuspended in Tris Buffer, centrifuged as above and 
resuspended n 200 volumes of binding assay buffer (50 mM Tris HCl, pH 7.7 
at 25.degree. C., 5 mM dithiothriethel, 0.1 mM bacitracin, 1.2 mM 
phenylmethane sulfonyl fluoride and 0.5 mM o-phenanthroline). For the 
binding assay, 25 .mu.l of buffer (for total binding) or unlabeled CCK-8 
sulfate to give a final concentration of l.mu.M (for nonspecific binding) 
or the compounds of Formula I (for determination inhibition of .sup.125 
I-CCK binding) and 25 .mu.l of .sup.125 I-CCK-33 (30,000-40,000 cpm) were 
added to 450 .mu.l of the membrane suspensions in microfuge tubes. All 
assays were run in duplicate or triplicate. The reaction mixtures were 
incubated at 37.degree. C. for 30 minutes and centrifuged in a Beckman 
Microfuge (4 minutes) immediately after adding 1 ml of ice-cold incubation 
buffer. The supernatant was aspirated and discarded, pellets were counted 
with a Beckman gamma 5000. 
2. CCK Receptor Binding (Brain) 
CCK-33 was radiolabeled and the binding was performed according to the 
description for the pancreas method with modifications according to Saito, 
et al. (J. Neurochem, 37, 483-490 (1981)). 
Male Hartley guinea pigs (300-500 g) were sacrificed by decapitation and 
the brains were removed and placed in ice-cold 50 mM, Tris HCl plus 7.58 
g/l Tritma-7.4 (pH 7.4 at 25.degree. C.) Cerebral cortex was dissected and 
used as a receptor source. Each gram of fresh guinea pig brain tissue was 
homogenated in 10 ml of Tris/Trizma buffer with a Brinkman polytron PT-10. 
The homogenates were centrifuged at 42,000 g for 15 min. Pellets were 
resuspended in Tri Buffer, centrifuged as above and resuspended in 200 
volumes of binding assay buffer (10 mM HEPES, pH 7.7 at 25.degree. C., 5 
mM MgCl.sub.2, 1 mM EGTA, 0.4% BSA (bovine serum albumin), 0.25 mg/ml 
bacitracin). For the binding assay, 25 .mu.l of buffer (for total binding) 
or unlabeled CCK-8 sulfate to give a final concentration of 1 .mu.M (for 
nonspecific binding) or the compounds of Formula I (for determination 
inhibition of .sup.125 I-CCK binding) and 25 .mu.l of .sup.125 I-CCK-33 
(30,000-40,000 cpm) were added to 450 .mu.l of the membrane suspensions in 
microfuge tubes. All assays were run in duplicate or triplicate. The 
reaction mixtures were incubated at 25.degree. C. for 2 hours and 
centrifuged in a Beckman Microfuge (4 minutes) immediately after adding 1 
ml of ice-cold incubation buffer. The supernatant was aspirated and 
discarded, pellets were counted with a Beckman gamma 5000. 
3. Isolated guinea pig gall bladder 
Male Hartley guinea pigs (400-600 g) were sacrificed by decapitation. The 
whole gall bladder was dissected free from adjacent tissues and cut into 
two equal halves. The gall bladder strips were suspended along the axis of 
bile duct in 5 ml organ bath under 1 g tension. The organ bath contained a 
Kreb's bicarbonate solution (NaCl 118 mM, KCl 4.75 mM, CaCl 2.54 mM, 
KH.sub.2 PO.sub.4 1.19 mM, Mg SO.sub.4 1.2 mM, NaHCO.sub.3 25 mM and 
dextrose 11 mM) maintained at 32.degree. C. and bubbled with 95% O.sub.2 
and 5% CO.sub.2. Isometric contractions were recorded using Statham (60 g; 
0.12 mm) strain gauges and a Hewlett-Packard (77588) recorder. The tissues 
were washed every 10 minutes for 1 hr to obtain equilibrium prior to the 
beginning of the study. CCK-8 was added cumulatively to the baths and 
EC.sub.50 's determined using egression analysis. After washout (every 10 
minutes for 1 hr), the compound of Formula I was added at least 5 minutes 
before the addition of CCK-8 and the EC.sub.50 of CCK-8 in the presence 
of the compound of Formula I similarly determined. 
4. Isolated longitudinal muscle of guinea pig ileum 
Longitudinal muscle strips with attached nerve plexus were prepared as 
described previously (Brit J. Pharmac. 23: 356-363, 1964; J. Physiol. 194: 
13-33, 1969). Male Hartley guinea pigs were decapitated and the ileum was 
removed (10 cm of the terminal ileum was discarded and the adjacent 20 cm 
piece was used). A piece (10 cm) of the ileum was stretched on a glass 
pipette. Using a cotton applicator to stroke tangently away from the 
mesentery attachment at one end, the longitudinal muscle was separated 
from the underlying circular muscle. The longitudinal muscle was then tied 
to a thread and by gently pulling, stripped away from the entire muscle. A 
piece of approximately 2 cm was suspended in 5 ml organ bath containing 
Krebs solution and bubbled with 95% O.sub.2 and 5% CO.sub.2 at 37.degree. 
C. under 0.5 g tension. CCK-8 was added cumulatively to the baths and 
EC.sub.50 values in the presence and absence of compounds of Formula I 
determined as described in the gall bladder protocol (above). 
In Vitro Results 
1. Effect of the Compounds of Formula I on .sup.125 I-CCK-33 Receptor 
Binding 
Compounds of Formula I inhibited specific .sup.125 I-CCK-33 binding in a 
concentration dependent manner with an IC.sub.50 less than or equal to 100 
.mu.M such as for example: 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminohomodihydr 
ocarbostyril, IC.sub.50 =2.4 .mu.M; 
1-carbomethoxymethyl-3-(1-carbomethoxy-3-phenyl-1-propyl)aminohomodihydroca 
rbostyril, IC.sub.50 =10 .mu.M; 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminohexahydrob 
enzazocine-2-one, IC.sub.50 =3 .mu.M; and 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-(3-indolyl)-1-propyl)aminohomod 
ihydrocarbostyril, IC.sub.50 =0.4 .mu.M. 
2. Effect of the compounds of Formula I on CCK induced contraction of 
guinea pig ileum or gall bladder 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-(3-indolyl)-1-propyl)aminohomod 
ihydrocarbostyril at 4.2 .mu.M shifted CCK dose response to the right 
approximately 2.6 fold without affecting maximal responses in guinea pig 
ileum. Ethyl-3-[(1-ethoxycarbonyl)-3-phenylpropyl)amino]-2,3.45, 
tetrahydro-2-oxo-1H-1-benzazepine-1-acetate at 26 .mu.M caused about 10 
times shift of CCK dose response in the guinea pig gall bladder without 
reducing maximal responses. These results indicates that the compounds of 
Formula I are competitive antagonists of CCK in these tissues. 
The compounds of this invention can also be administered in combination 
with antihypertensives and/or diuretics and/or calcium entry blockers. 
Typically, the individual daily dosages for these combinations can range 
from about one-fifth of the minimally recommended clinical dosages to the 
maximum recommended levels for the entities when they are given singly. 
The compounds of Formula I may be prepared by any convenient process. 
Useful processes are illustrated by the following reaction equations 
wherein R.sub.1 -R.sub.5 and n are as defined above unless otherwise 
indicated. 
##STR2## 
Process A 
Benzofused lactam II ring size ranging from 6 to 8 (n=1,2,3), prepared from 
a precursor ketone by a procedure of Blicke et al., J. Am. Chem. Soc., 76, 
2317 (1954), is converted to (III), with PX.sub.5 where X=Br or Cl 
[Nagasawa et al., J. Med. Chem., 14, 501 (1971)]. Reaction of (III) with 
sodium or lithium azide in a suitable solvent such as DMF or ethanol [see, 
for example, Brenner et al., Helv. Chem. Acta, 41, 181 (1958)] affords 
(IV) which can be alkylated with an iodoester (V) in the presence of a 
strong base, like sodium hydride, in a solvent such as DMF or THF to 
produce (VI). Reduction of (VI) with hydrogen and a suitable catalyst, 
such as palladium on carbon, affords (VII). Intermediate (VII) is then 
reductively coupled with a keto acid or ester (VIII) in a solvent such as 
ethanol using a catalyst such as palladium on carbon to afford (I') 
(R.sub.5 .noteq.H). Alternatively, sodium cyanoborohydride can be used to 
effect the reduction. 
Groups R.sub.5 may be modified by known methods, if desired. For example, 
if R.sub.6 =Et or t-Bu, the diester (I) can be converted to the monoester 
R.sub.6 =Et or H by treatment with trifluoroacetic acid. If R.sub.6 =Et, 
(I) can be converted to the diacid R.sub.6 =H by basic hydrolysis. 
Alternatively, (III) may be alkylated with (V) in the presence of a strong 
base, like sodium hydride, and the intermediate (IX) converted to (VI) by 
reaction with an azide salt as described above. 
Alternate Process for IX 
If desired, (IX) may be prepared by the alkylation of (X) [prepared from II 
using the alternate conditions of Nagasawa, above] with (V) to afford 
intermediate (XI). Treatment of (XI) with hydrogen and a catalyst, such as 
palladium on carbon, affords (IX). 
Process B 
Alternatively, IX (Y=Cl, Br; R.sub.6 .noteq.OH) may be converted to the 
iodo compound IX (X=I) by known methods, for example, sodium iodide in 
acetone. Reaction of this iodo lactam with an amino acid ester in a 
solvent such as toluene or DMF in the presence of a halide scavenger such 
as Ag.sub.2 O gives I (R.sub.6 .noteq.OH). 
Process C 
If desired, IV may be reduced with hydrogen in the presence of a suitable 
catalyst to afford XII which can be alkylated with a ketoester in the 
presence of hydrogen on a suitable catalyst to give XIII. Alternatively, 
sodium cyanoborohydride may be used. Alkylation of XIII to afford I' 
(R.sub.6 .noteq.OH) can be carried out with an iodoester in the presence 
of a strong base such as sodium hydride in a solvent such as THF. 
In the compound of Formula I, the carbon atoms to which R.sub.1, R.sub.2 
and R.sub.4 are attached and the ring carbon atom to which the 
##STR3## 
group is attached may be asymmetric. Thus, the compounds of this invention 
exist in diastereoisomeric forms or in mixtures thereof. The processes 
described above can utilize racemates, enantiomers or diastereomers as 
starting materials. When diastereomeric intermediates or products result 
from the synthetic procedures, the diastereomeric intermediates or 
products can be separated by chromatographic or fractional crystallization 
methods. When racemic mixtures result, they may be resolved by 
crystallization of salts of optically active acids or bases or by other 
methods known in the art. The part-structures 
##STR4## 
of Formula I can be in two configurations (S or R) and both are within the 
scope of this invention, although S is generally preferred. Both 
configurations at the carbon to which R.sub.2 is attached are encompassed 
within this invention.

The following Examples illustrate preparation of representative compounds 
of Formula I. All temperatures are in .degree. C. 
EXAMPLE 1 
A. t-Butoxycarbonylmethyl-3-aminodihydrocarbostyril 
##STR5## 
To a suspension of 2.42 gm NaH (50% oil dispersion washed 3.times.hexanes) 
in 50 ml of THF at 0.degree. C. was added solid 5 gm (0.025 mol) of 
3-aminodihydrocarbostyrilhydrochloride (T. J. McCord, Arch. of Biochem. & 
Biophys. 102 48 (1963)) stirring at 0.degree. C. until the evolution of 
hydrogen had ceased at which time the reaction mixture was warmed to room 
temperature and stirred a further 1 hour. To the stirred reaction mixture 
was added dropwise a solution of 6 gm of t-butyl iodoacetate in 20 ml of 
THF stirring a further 2 hours at room temperature at which time the 
reaction was quenched with 20 ml of saturated NaHCO.sub.3. The reaction 
mixture was diluted with 20 ml of H.sub.2 O and extracted 2.times.50 ml of 
9:1 ethylacetate:acetonitrile. The organic layers were combined, filtered 
through MgSO.sub.4 and concentrated in vacuo to give 5 gm of 
1-t-butoxycarbonylmethyl-3 -aminodihydrocarbostyril. 
NMR (CDCl.sub.3, TMS): 1.4 (s, 9H); 2.0-3.2 (m, 4H), 3.4-3.8 (m, 1H); 4.6 
(Q, 2H); 6.6-7.2 (m, 4H). 
IR: C.dbd.O 1738, 1680. 
B. 
1-Carbomethoxymethyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminodihydrocarbos 
tyril (racemate mixture) 
##STR6## 
A solution of 2.76 gm (0.010 mol) of 1-t-butoxycarbonylmethyl-3-amino 
dihydrocarbostyril, 10 gm of ethyl 4-phenyl-2-oxo-butyrate and 0.60 ml of 
acetic acid in 20 ml of absolute ethanol was stirred 1 hour at room 
temperature at which time was added dropwise over 8 hours a solution of 
1.57 gm of NaCNBH.sub.3 in 20 ml of ethanol. After stirring a further 4 
hours at room temperature the reaction mixture was concentrated in vacuo. 
The crude reaction mixture was partitioned between H.sub.2 O and 
ethylacetate. The aqueous layer was extracted 2.times. with ethylacetate 
and the combined organic layers filtered through MgSO.sub.4 and 
concentrated at reduced pressure. The reaction mixture was diluted with 20 
ml of trifluoroacetic acid and stirred 2 hours at room temperature after 
which it was concentrated at reduced pressure. The crude mono acid (B 
where CH.sub.3 is H) was taken up in 20 ml of saturated NaHCO.sub.3, 
washed 3.times.50 ml of ethyl acetate. The aqueous layer was concentrated 
in vacuo, redissolved in 30 ml of methanol, cooled to 0.degree. C., 
saturated with HCl gas, sealed, warmed to room temperature and stirred 
overnight at room temperature. The reaction mixture was subsequently 
concentrated in vacuo, diluted with saturated K.sub.2 CO.sub.3 and 
extracted 3 times with ethyl acetate. The combined organic fractions were 
filtered through MgSO.sub.4 and concentrated at reduced pressure. The 
crude reaction product B was chromatographed (silica, 2:1 ether:hexanes) 
and two diastereomeric B racemates were isolated. 
Racemate A: 500 mg. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.28. 
NMR (CDCl.sub.3, TMS) 1.2 (t, 3H): 1.8-2.2 (m, 3H); 2.6-3.1 (m, 6H); 
3.2-3.6 (m, 2H); 3.65 (s, 3H); 4.1 (Q, 2H); 4.6 (Q, 2H); 6.8-7.1 (s, 9H). 
Racemate B: 1.5 gm. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.20. 
NMR (CDCl.sub.3, TMS) 1.3 (s, 3H): 1.8-3.2 (m, 8H); 3.4-3.7 (m, 2H); 3.7 
(s, 3H); 4.1 (Q, 2H); 4.6 (Q, 2H); 6.8-7.2 (m, 9H). 
EXAMPLE 2 
1-Carboxymethyl-3-(1-carboxy-3-phenyl-1-propyl)dihydrocarbostyril 
##STR7## 
Racemate A 
A reaction mixture consisting of 900 mg (0.00212 mol) of the diester 
racemate A of Example 1, 2 ml of methanol and 2.2 ml of a 4N solution of 
NaOH in H.sub.2 O was stirred 12 hours at room temperature. Subsequently 
the reaction mixture was concentrated at reduced pressure. Upon 
acidification with acetic acid the diacid C precipitated out and was 
filtered, washed with H.sub.2 O and dried, giving 600 mg of the diacid C 
as its mono sodium salt. 
TLC (silica, 1:1:1:.5 H.sub.2 O:nB.sub.4 OH:EtOAc:HOAc): R.sub.f 0.50. 
An. Calc. for C.sub.21 H.sub.22 N.sub.2 O.sub.5 Na: 1.5 H.sub.2 O C, 58.27; 
H, 5.43; N, 6.47. Found: C, 58.11; H, 5.62; N, 6.02. 
EXAMPLE 3 
A. 3-Bromo-homodihydrocarbostyril 
##STR8## 
To a solution of 15 gm (0.093 mol) of homo dihydrocarbostyril (L. H. 
Briggs, J.C.S., 456 (1937)) in 200 ml of chloroform was added in 
increments over a period of an hour 19 gm of PCl.sub.5 at which time was 
added 140 mg of iodine followed by a slow dropwise addition of 90 ml of a 
1M solution of bromine in chloroform. The reaction mixture was warmed to 
room temperature where stirring was continued a further 1 hour. 
The crude reaction mixture was concentrated in vacuo and then partitioned 
between water, ice and chloroform. The aqueous layer was extracted 2 times 
with methylene chloride and the combined organic fractions were filtered 
through MgSO.sub.4 and concentrated in vacuo. The crude bromide D was 
chromatographed (silica, 2:1 ether:hexanes) to give 6.5 gm of pure D 
bromide. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.65. 
NMR (CDCl.sub.3, TMS): 2.4-3.0 (m, 4H); 4.4-4.7 t, 1H); 7.2 (s, 4H); 9.2 
(bs, 1H). 
IR: 1650 cm.sup.-1. 
mass spectrum: M.sup.+ 239, m/e: 241 (M.sup.+, +2); 160 (M.sup.+2, --Br); 
132 (--C.dbd.O). 
B. 3-Azido homodihydrocarbostyril 
##STR9## 
To a solution of 9.98 gm (0.0417 mol) of 3-bromo homodihydrocarbostyril in 
200 ml of DMF was added 10.8 gm of sodium azide stirring 12 hours at 
60.degree. C. at which time the DMF was removed at reduced pressure. To 
the crude reaction mixture was added 50 ml of water and the mixture was 
then extracted 3 times with 50 ml of chloroform. The combined organic 
fractions were combined, washed with 25 ml of a saturated solution of 
NaCl, filtered through MgSO.sub.4 and concentrated at reduced pressure. 
Chromatography (silica, 2:1 ether:hexanes) gave 7.92 gm of pure E azide. 
m.p. 150.degree.-151.degree. C. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.71. 
El. An. Calc. for C.sub.10 H.sub.10 N.sub.4 O. N, 27.71; C, 59.39; H, 4.98. 
Found: N, 27.27; C, 59.25; H, 4.98. 
NMR (CDCl.sub.3, TMS): 2.2-2.8 (m, 4H), 3.6-4.0 (dd, 1H); 7.2 (bs, 4H) 9.2 
(bs, 1H)IR N.sub.3 2130, CO 1678. 
mass spectrum: M.sup.+ 202, m/e 174 (M.sup.+ --N.sub.2 ; 146 (C.dbd.O). 
C. 1-t-Butoxycarbonylmethyl-3-azido homodihydrocarbostyril 
##STR10## 
To a suspension of 1 gm of sodium hydride (50% dispersion in oil washed 3 
times with hexanes) in 20 ml of THF at 0.degree. C. was added dropwise a 
solution of 4.2 gm (0.02 mol) of 3-azido homodihydro carbostyril and 3 ml 
of t-butyl iodo acetate in 20 ml of THF. The reaction was carefully 
monitored by TLC (silica, 2:1 ether:hexanes) until reaction was complete 
at which time the reaction was quenched with 30 ml of saturated NH.sub.4 
Cl, diluted with 20 ml H.sub.2 O and extracted 3 times with 50 ml 
CH.sub.2 Cl.sub.2. The combined organic layers were filtered, concentrated 
in vacuo and chromatographed (silica, 2:1 ether:hexanes) to give 4.5 gm of 
pure product F. 
m.p.: 103.degree.-104.degree. C. 
TLC (silica, 211 ether:hexanes): R.sub.f =0.74. 
El. An. Calc. for C.sub.16 H.sub.20 N.sub.4 O.sub. : N, 17.71; C, 60.74; H, 
6.37. Found: N, 17.39; C, 60.54; H, 6.61. 
NMR (CDCl.sub.3, TMS): 1.5 (s, 9H), 2.2-3.4 (m, 4H); 3.5-4.0 (overlapping 
doublets, 1H); 4.2-4.8 (ABQ, 2H); 7.2 (s, 4H). 
mass spectrum: M.sup.+ 316, m/e 288 (M.sup.+ --N.sub.2 ; 260 (M.sup.+ 
--C.sub.4 H.sub.9). 
D. 1-t-Butoxycarbonylmethyl-3-amino homodihydrocarbostyril 
##STR11## 
A solution of 8.01 gm of 1-t-butoxycarbonylmethyl-3-azido homo 
dihydrocarbostyril in 150 ml of absolute ethanol with 0.8 gm of Pd/C 10% 
was hydrogenated for 12 hr at room temperature and 40 lbs of H.sub.2. The 
reaction was subsequently filtered and the ethanol removed at reduced 
pressure to give 7.05 gm of pure amine G. 
m.p.: 107.degree.-109.degree. C. 
El. An. Calc. for C.sub.16 H.sub.22 N.sub.2 O.sub.3.1/2H.sub.2 O: N, 9.36; 
C, 64.19; H, 7.41 Found: N, 9.18; C, 64.17; H, 7.53. 
NMR (D.sub.2 O, CDCl.sub.3, TMS): 1.4 (s, 9H), 2.2-3.8 (m, 5H); 4.1-4.7 
(ABQ, 2H); 7.05 (bs, 4H). 
IR: C.dbd.O 1735, 1660. 
mass spectrum: M.sup.+ 290, m/e 262 (M.sup.+ --C.dbd.O); 234 M.sup.+ 
--C.sub.4 H.sub.8); 217 (M.sup.+ --C.sub.4 H.sub.9 O). 
E. 1-t-Butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl]-amino 
homodihydrocarbostyril (Racemate mixture) 
##STR12## 
A solution of 1 gm (0.00345 mol) of 1-t-butoxy carbonylmethyl-3-amino 
homodihydrocarbostyril, 3.5 gm of ethyl 4-phenyl-2-ox:obutyrate and 200 
.mu.l of acetic acid in 12 ml of absolute ethanol was stirred 1 hour at 
room temperature. To the stirred solution was added dropwise over a 12 
hour period a solution of 545 mg of NaCNBH.sub.3 in 12 ml of ethanol. 
After stirring a further 8 hours the reaction was concentrated at reduced 
pressure and partitioned between H.sub.2 O and ethyl acetate. After 
extracting twice with ethyl acetate the combined organic layers were 
filtered through MgSO.sub.4 and concentrated in vacuo. The crude reaction 
mixture was chromatographed (silica, 1:1 ether:hexanes) and two 
diastereomeric H racemates were isolated. 
Racemate Diester A: 450 mg. 
TLC (silica, 1:1, ether:hexanes): R.sub.f =0.31. 
NMR (CDCl.sub.3, TMS): 1.1-1.4 (t, 3H), 1.45 (s, 9H); 1.8-3.2 (m, 11H); 
3.9-4.3 (Q, 2H); 4.1-4.7 (ABQ, 2H); 7.1-7.3 (m, 9H). 
Racemate Diester B: 520 mg. 
TLC (silica, 1:1, ether:hexanes) R.sub.f =0.23. 
NMR (CDCl.sub.3, TMS): 0.9-1.2 (t, 3H), 1.4 (s, 9H); 1.8-3.4 (m, 11H); 
3.8-4.2 (Q, 2H); 4.1-4.7 (ABQ, 2H); 7.2 (s, 9H). 
EXAMPLE 4 
1-Carboxymethyl-3-(1-carboxy-3-phenyl-1-propyl)-aminohomodihydrocarbostyril 
##STR13## 
Racemate A 
250 mg of racemate iester A of Example 3 was stirred 2 hours with 5 ml of 
trifluoroacetic acid at which time the reaction mixture was concentrated 
in vacuo. The crude product in 1 ml of H.sub.2 O was treated with 600 
.mu.l of a 4N NaOH in H.sub.2 O solution and stirred 7 hours at room 
temperature. The crude reaction mixture was partially concentrated in 
vacuo at which time the monosodium salt of J precipitated out. The 
suspension was filtered, the solid washed with H.sub.2 O and dried under 
vacuum to give 125 mg of a diacid monosodium salt of J. 
TLC (silica, 1:1:1:.5, H.sub.2 O:ethylacetate:nBuOH:HOAc): R.sub.f =0.60. 
El. An. Calc. for C.sub.22 H.sub.23 N.sub.2 O.sub.5 Na.2.5H.sub.2 O: C, 
56.90; H, 5.82; N, 6.04. Found: C, 56.84; H, 5.64; N, 5.81. 
Racemate B 
550 mg of the racemate diester B of Example 3 was converted to the diacid J 
by the same procedure described above to give 250 mg of free diacid. 
TLC (silica, 1:1:1:.5, H.sub.2 O:ethylacetate:nBuOH:HOAc): R.sub.f =0.67. 
El. An. Calc. for C.sub.22 H.sub.23 N.sub.2 O.sub.5.1/4H.sub.2 O: C, 66.02; 
H, 5.75; N, 7.00. Found: C, 66.04; H, 6.13; N, 6.85. 
EXAMPLE 5 
1-Carbomethoxymethyl-3-(1-carbomethoxy-3-phenyl-1-propyl)aminohomodihydroca 
rbostyril 
##STR14## 
A solution of 1 gm of 1-carboxymethyl-3-(1-carboxy-3-phenyl-1-propyl)amino 
homodihydrocarbostyril (Racemate B of Example 4) in 20 ml of methanol was 
cooled to 0.degree. C. and saturated with HCl gas. The reaction mixture 
was then sealed and stirred overnight at room temperature. The reaction 
mixture was subsequently concentrated at reduced pressure and partitioned 
between a saturated aqueous solution of K.sub.2 CO.sub.3 and ethyl 
acetate. The aqueous layer was extracted two times with ethyl acetate and 
the combined organic fractions filtered through MgSO.sub.4 and 
concentrated at reduced pressure. The crude product was chromatographed 
(silica, 3:1 ether:hexanes) to give 700 mg of pure dimethyl ester K. 
TLC (silica, 3:1 ether:hexanes): R.sub.f =0.56. 
An. Calc. for C.sub.24 H.sub.28 N.sub.2 O.sub.5.1/4H.sub.2 O. N, 6.52; C, 
67.13; H, 6.52. Found: N, 6.28; C, 67.14; H, 6.60. 
NMR (CDCl.sub.3, TMS): 1.8-3.4 (m, 11H); 3.5 (s, 3H); 3.7 (s, 3H); 4.2-4.7 
(ABQ, 2H); 7.1 (bs, 9H). 
EXAMPLE 6 
1-Carboxymethyl-3-(1-carboethoxy-3-phenyl-1-propyl)amino 
homodihydrocarbostyril 
##STR15## 
A solution of 550 mg of 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl)amino 
homodihydrocarbostyril in 10 ml of trifluoroacetic acid was stirred at 
room temperature for 2 hours. The reaction mixture was concentrated in 
vacuo, diluted with water and concentrated a second time in vacuo to give 
a white solid. The solid was triturated with ether and filtered to give 
400 mg of the CF.sub.3 CO.sub.2 H salt of the desired product L. 
An. Calc. for C.sub.24 H.sub.28 N.sub.2 O.sub.5.CF.sub.3 CO.sub.2 H. H, 
5.34; C, 57.51; N, 5.16. Found: H, 5.46; C, 57.68; N, 5.03. 
NMR (CD.sub.3 OD): 1.2 (t, 3H); 2.0-3.0 (m, 9H); 3.6-4.2 (m, 4H); 4.5 (s, 
2H); 7.1-7.3 (overlapping singlets, 9H). 
EXAMPLE 7 
1-Carbobenzyloxymethyl-3-(1-carboxy-3-phenoxy-1-propyl)amino 
homodihydrocarbostyril 
##STR16## 
To a suspension of 1.90 gm of NaH (50% in oil washed 3 times with hexanes) 
in 40 l of THF at room temperature was added dropwise a solution of 6.5 gm 
of 3-amino homodihydrocarbostyril and 1.56 gm of benzyliodoacetate in 10 
ml of THF stirring a further 2 hr at room temperature. The reaction was 
subsequently quenched with 10 ml of H.sub.2 O and extracted two times with 
ethyl acetate. The combined organic fractions were filtered through 
MgSO.sub.4 and concentrated in vacuo to obtain 
1-carbobenzyloxymethyl-3-amino homodihydrocarbostyril. 
NMR (CDCl.sub.3, TMS): 1.8-3.0 (m, 6H); 3.1-3.4 (m, 1H); 4.6 (ABQ, 2H); 5.1 
(s, 2H); 7.0-7.3 (m, 9H). 
A solution of 5 gm of 1-carbobenzyloxymethyl-3-amino 
homodihydrocarbostyril, 16 gm of t-butyl-4-phenyl-2-oxobutyrate and 860 ml 
of acetic acid in 60 ml of absolute ethanol was stirred 1 hr at room 
temperature at which time was added dropwise over 18 hours a solution of 
2.4 gm of NaCNBH.sub.3 in 40 ml ethanol. The reaction mixture was 
concentrated in vacuo and partitioned between H.sub.2 O and ethyl acetate. 
The aqueous layer was extracted 2 times with ethyl acetate and the 
combined organic layers were filtered through MgSO.sub.4 and concentrated 
in vacuo. The crude reaction mixture was chromatographed (silica 1:1 
ether:hexanes) and the first diastereomeric racemate diester was isolated. 
NMR (CDCl.sub.3, TMS): 1.4 (s, 9H); 1.6-3.2 (m, l1H); 4.5 (ABQ, 2H); 4.6 
(s, 2H); 7.0-7.3 (m, 14H). 
Said diester in 5 ml of methylene chloride and 5 ml of trifluoro acetic 
acid was stirred 8 hr at room temperature at which time the reaction was 
concentrated in vacuo, redissolved in carbon tetrachloride and 
reconcentrated in vacuo to give 600 mg of monobenzyl ester M. 
NMR (CDCl.sub.3): 2.0-3.0 (m, 9H); 3.4-3.8 (m, 2H); 4.4 (bs, 2H); 5.0 (s, 
2H); 7.0-7.3 (m, 14H). 
EXAMPLE 8 
A. 3-Bromohexahydrobenzoazocin-2-one 
##STR17## 
To a solution of 15 gm (0.084 mol) of hexahydrobenzoazocin-2-one (Chemica 
Scandinavia, 18, 191 (1964)) in 150 ml of chloroform at 0.degree. C. was 
added 8.8 gm of PCl.sub.5 in increments over a period of an hour. 
Subsequently, to the reaction mixture was added 70 mg of iodine followed 
by slow dropwise addition of 84 ml of a 1M solution of bromine in 
chloroform. The reaction mixture was warmed to room temperature and 
stirred for 1 hour at which time it was concentrated at reduced pressure. 
To the crude product was added a mixture of ice and water and the mixture 
was extracted 3 times with methylene chloride. The combined organic 
fractions were filtered through MgSO.sub.4 and concentrated at reduced 
pressure. The solid bromide was recrystallized with a mixture of 
chloroform and hexanes to give 12 gm of pure product N. 
m.p.: 194.degree.-195.degree. C. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.36. 
An. Calc. for C.sub.11 H.sub.12 NOBr.1/4H.sub.2 O. N, 5.41; C, 51.08; H, 
4.68. Found: N, 5.29; C, 50.75; H, 4.53. 
NMR (CDCl.sub.3, TMS): 1.6-2.9 (m, 6H); 4.2-4.5 (bt, 1H); 7.2 (s, 4H); 8.5 
(bs, 1H). 
mass spectrum: M.sup.+ 253, m/e: 252 (p.sup.+ 2, 10%); 179 M.sup.+ --Br); 
146 (C.dbd.O). 
B. 3-Azidohexahydrobenzoazocine-2-one 
##STR18## 
To a solution of 10 gm (0.00394 mol) of 3-bromohexahydrobenzoazocine-2-one 
in 100 ml of dimethylformamide was added 10 gm of sodium azide and the 
resultant reaction mixture was stirred 12 hours at 60.degree. C. 
The DMF was then removed at reduced pressure and the crude product was 
partitioned between H.sub.2 O and methylene chloride. The aqueous layer 
was extracted 3 times with methylene chloride and the combined organic 
fractions were filtered through MgSO.sub.4 and concentrated at reduced 
pressure. The product was chromatographed (silica, 2:1 ether:hexanes) 
giving 8 gm of pure azide P. 
m.p: 142.degree.-143.degree. C. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.45. 
An. Calc. for C.sub.11 H.sub.12 N.sub.4 O.1/4H.sub.2 O. N, 25.36; C, 59.79; 
H, 5.44. Found: N, 25.17; C, 59.37; H, 5.39. 
NMR (CDCl.sub.3, TMS): 1.6-2.9 (m, 6H); 3.4-3.7 (bt, 1H); 7.2 (s, 4H); 8.5 
(bs, 1H); 
mass spectrum: m/e 188, (M.sup.+ --N.sub.2); 159 (C.dbd.O). 
C. 3-Azido-1-(t-butoxycarbonylmethyl)-hexahydrobenzoazocine-2-one 
##STR19## 
To a suspension of 1.86 gm of sodium hydride (50% suspension, prewashed 
with hexanes) in 40 ml THF at 0.degree. C. was added dropwise a solution 
of 8 gm (0.037 mol) of azide lactam and 5.63 ml of t-butyliodo acetate in 
40 ml of THF. The reaction was found to be complete upon the completion of 
the addition. (TLC, silica gel, 2:1 ether:hexanes). The reaction mixture 
was then quenched by the addition of 20 ml of saturated NH.sub.4 Cl. The 
solution was extracted three times with 50 ml portions of ethyl acetate. 
The combined organic fractions were filtered through MgSO.sub.4 and 
concentrated in vacuo. The crude product was purified by chromatography on 
silica gel using 2:1 ether:hexanes as eluant. The fractions containing the 
desired product were combined and concentrated at reduced pressure to give 
11 gm of the desired product Q. 
m.p.: 120.degree.-121.degree. C. 
TLC (silica, 2:1 ether:hexanes): R.sub.f =0.75. 
NMR (CDCl.sub.3, TMS): 1.5 (s, 9H); 1.9-3.0 (m, 6H); 3.35-3.6 (dd, 1H); 
4.0-4.6 (AB, 2H); 7.2 (s, 4H). 
An. Calc. for C.sub.14.sub.H.sub.22 N.sub.4 O.sub.3.1/2H.sub.2 O. N, 16.50; 
C, 60.11; H, 6.48. Found: N, 16.39; C, 60.29; H, 6.58. 
mass spectrum: m/e 302, (M.sup.+ --N.sub.2); 257 (M.sup.+ --OC.sub.4 
H.sub.9). 
D. 3-Amino-1-(t-butoxycarbonylmethyl)-hexahydrobenzoazocine-2-one 
##STR20## 
A solution of 9.5 gm (0.0287 mol) of azide lactam Q in 100 ml of absolute 
ethanol with 900 mg of 10% Pd/C was hydrogenated 12 hours at 40 lbs of 
hydrogen at room temperature. The reaction mixture was subsequently 
filtered and the filtrate concentrated in vacuo to give 98.7 gm of amine 
S. 
NMR (CDCl.sub.3, D.sub.2 O, TMS): 1.5 (s, 9H); 1.6-2.3 (m, 4H); 2.7-2.9 (t, 
3H); 3.2-3.4 (m, 1H); 4.0-4.6 (ABQ, 2H); 7.2 (s, 4H). 
E. 
1-t-Butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminohexahydro 
benzazocine-2-one (Racemate mixture) 
##STR21## 
A solution of 2 gm (0.0066 mol) of the 
3-amino-1-(t-butoxycarbonylmethyl)-hexahydrobenzoazocine-2-one, 6.7 gm of 
ethyl-4-phenyl-2-oxobutyrate and 377 ml of acetic acid in 20 ml of ethanol 
was stirred 1 hour at room temperature. To the stirring reaction mixture 
was slowly added over a period of 8 hours a solution of 1 gm of sodium 
cyano borohydride in 20 ml of ethanol. After stirring a further 8 hours 
the reaction was concentrated at reduced pressure and partitioned between 
water and ethyl acetate. After extracting twice with ethyl acetate the 
combined organic layers were filtered through MgSO.sub.4 and concentrated 
in vacuo. the crude reaction mixture was chromatographed (silica, 7:3 
hexanes:ethyl acetate) and two diastereomeric racemates of T were 
isolated. 
Racemate diester A: 1.7 gm. 
TLC (7:3 hexanes:ethyl acetate): R.sub.f =0.39. 
NMR (CDCl.sub.3, TMS): 1.2 (+, 3H), 1.5 (s, 9H), 1.6-3.2 (m, 13H), 4.1 (Q, 
2N), 4.3 (bs, 2H), 6.9-7.2 (m, 9H). 
Racemate diester B: 1 gm. 
TLC (7:3 hexanes:ethyl acetate): R.sub.f =0.28. 
NMR (CDCl.sub.3, TMS): 1.1 (+, 3H), 1.5 (s, 9H), 1.6-3.2 (m, 13H), 3.9 (Q, 
2N), 4.3 (bs, 2H), 7.0-7.2 (two overlapping bs, 9H). 
EXAMPLE 9 
1-Carboxymethyl-3-(1-carboxy-3-phenyl-1-propyl)aminohexahydrobenzoazocine-2 
-one 
##STR22## 
Racemate A 
The racemate A diester of Example 8, (1.7 gm (0.0035 mol) was stirred 1 
hour at room temperature with 5 ml of trifluoroacetic acid at which time 
the reaction mixture was concentrated at reduc:ed pressure. To the crude 
product in 7 ml of methanol was added 3.5 ml of a 4N solution of sodium 
hydroxide in water stirring continued overnight at room temperature. The 
reaction mixture was subsequently applied to a column of Dowex 50 
(H.sup.+) and eluted first with H.sub.2 O and then with 5% pyridine. The 
appropriate pyridine fractions were concentrated giving 600 mg of the 
diacid U racemate A. 
An. Calc. for C.sub.23 H.sub.26 N.sub.2 O.sub.5.1/2H.sub.2 O. C, 65.80; H, 
6.19; N, 6.67. Found: C, 66.01; H, 6.32; N, 6.65. 
NMR (D.sub.2 O=4.6): 1.5-3.2 (m, 12H), 4.1 (s, 2H), 6.8-7.2 (m, 9H). 
Racemate B 
The racemate B diester of Example 8 (1 gm, 0.002 mol) was converted to 500 
mg of the diacid U by the same procedure as described above. 
An. Calc. for C.sub.23 H.sub.26 N.sub.2 O.sub.5.1/2H.sub.2 O. N, 6.67; C, 
65.80; H, 6.19. Found: N, 6.62; C, 66.07; H, 6.27. 
NMR (D.sub.2 O=4.9): 1.6-3.4 (m, 12H), 4.2 (6s, 2H), 7.2-7.5 (m, 9H). 
EXAMPLE 10 
1-Carboethoxymethyl-3-(1-carboethoxy-3-phenyl-1-propyl)-amino 
homodihydrocarbostyril (Racemate A) 
##STR23## 
A solution of 100 mg of 
1-t-butoxycarbonylmethyl-3-(1-carboethoxy-3-phenyl-1-propyl)amino 
homodihydrocarbostyril (racemate A of Example 3) in 20 ml of ethanol was 
saturated with HCl gas, sealed and stirred overnight at room temperature. 
The reaction mixture was concentrated in vacuo and partitioned between 
ethylacetate and a saturated solution of K.sub.2 CO.sub.3 in H.sub.2 O. 
The H.sub.2 O layer was extracted 2 times with ethyl acetate, filtered 
through MgSO.sub.4 and concentrated at reduced pressure. The crude 
reaction product was chromatographed (silica, 2:1, ethylacetate:hexanes) 
to give 85 mg of product. 
TLC (silica, 3:1 ether:hexanes): R.sub.f =0.60. 
NMR (CDCl.sub.3, TMS): 1.1-1.5 (2t, 6H); 1.8-3.2 (m, 11H); 3.9-4.3 (2g, 
4H), 4.1-4.7 (ABq, 2H), 17.1-17.3 (m, 9H). 
EXAMPLE 11 
1-Benzyloxy-3-(1-carboethoxy-3-phenyl-1-propyl)amino homodihydrocarbostyril 
##STR24## 
To a solution of 200 mg of the monobenzylester M (Example 7) in 5 ml of 
methylene chloride at 0.degree. C. was added a solution of diazoethane in 
ether until TLC indicated reaction was complete. The reaction mixture was 
concentrated at reduced pressure and chromatographed (silica, 3:2, 
hexane:ethylacetate) to give 75 mg of the title diester product. 
TLC (silica, 3:2, hexane:ethylacetate): R.sub.p =0.50. 
NMR: (1.2 (t, 3H), 1.6-3.4 (m, 11H); 4.1 (9, 2H); 4.5 (ABq, 2H), 5.1 (s, 
2H), 7.0-7.3 (m, 14H). 
EXAMPLE 12 
1-t-Butoxycarbonylmethyl-3-(1-carboethoxy-3-(3)indolyl-1-propyl)amino 
homodihydrocarbostyril (Racemate Mixture) 
##STR25## 
A solution of 0.7 gm of 1-t-butoxycarbonylmethyl-3-amino 
homodihydrocarbostyril (Compound D, Example 3), 0.6 gm of 
ethyl-4-(.beta.-indolyl)-2-oxobutyrate and 0.27 ml of acetic acid in 10 ml 
of absolute ethanol was stirred 1 hour at room temperature. To the stirred 
solution was added dropwise over a 7 hour period a solution of 0.38 gm of 
NaCNBH.sub.3 in 10 ml of ethanol. Aftre stirring a further 12 hours, the 
reaction was concentrated at reduced pressure and partitioned between 
H.sub.2 O and ethyl acetate. After extracting twice with ethylacetate, the 
combined organic layers were filtered through MgSO.sub.4, concentrated in 
vacuo and chromatographed (silica, 1:1, ethylacetate:hexane) to afford two 
diasteriomeric racemates. 
Racemate A: 170 mg. 
TLC (silica, 1:1, ethylacetate:hexane): R.sub.f =0.52. 
NMR (CDCl.sub.3, TMS): 1.2 (t, 3H); 1.4 (s, 9H); 1.7-3.6 (m, 11H); 4.1 (9, 
2H); 4.4 (ABq, 2H); 6.7-7.4 (m, 9H); 8.2 (bs, 1H). 
mass spectrum: M.sup.+ 519. 
Racemate B: 200 mg. 
TLC (silica, 1:1, ethylacetate:hexane): R.sub.f =0.39. 
NMR (CDCl.sub.3, TMS): 1.1 (t, 3H); 1.4 (s, 9H); 1.8-3.5 (m, 11H); 4.0 (9, 
2H); 4.45 (ABq, 2H); 6.9-7.6 (m, 9H); 8.4 (bs, 1H). 
mass spectrum: M.sup.+ 519. 
EXAMPLE 13 
1-Carbomethoxymethyl-3-(1-carbomethoxy-3-phenyl-1-propyl)aminohexahydrobenz 
oazocine-2-one 
##STR26## 
The dimethyl ester W can be prepared from 
1-carboxymethyl-3-(1-carboxy-3-phenyl-1-propyl)aminohexahydrobenzoazocine- 
2-one using a process analogous to that described in Example 5. 
EXAMPLE 14 
1-Carboxymethyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminohexahydrobenzoazoci 
ne-2-one 
##STR27## 
The mono ethyl ester Y can be obtained from the t-butyl/ethyl diester 
(Racemate B of Example 9) by treatment with trifluoroacetic acid as in the 
analogous homodihydrocarbostyril Example 6. 
EXAMPLE 15 
1-Carbobenzyloxymethyl-3-(1-carboxy-3-phenyl-1-propyl)aminohexahydrobenzoaz 
ocine-2-one 
##STR28## 
The mono benzyl ester Z may be prepared from 3-amino hexahydrobenzoazocine 
by a sequence analogous to that described in Example 7. 
Examples of the various keto acids and keto esters having the formula: 
##STR29## 
which can be employed in the processes described above to prepare 
compounds of Formula I are illustrated below in Table I. 
TABLE I 
______________________________________ 
##STR30## 
______________________________________ 
(a) 
##STR31## 
(b) 
##STR32## 
(c) 
##STR33## 
(d) 
##STR34## 
(e) 
##STR35## 
(f) 
##STR36## 
(g) 
##STR37## 
(h) 
##STR38## 
(i) 
##STR39## 
(j) 
##STR40## 
(k) 
##STR41## 
(l) 
##STR42## 
(m) 
##STR43## 
(n) 
##STR44## 
(o) 
##STR45## 
______________________________________ 
Additional examples of the compounds of Formula I which can be synthesized 
by the procedures described herein are illustrated by, but not limited to, 
the compounds illustrated in Table II below: 
TABLE II 
__________________________________________________________________________ 
Additional Examples of Compounds of Formula I 
__________________________________________________________________________ 
(A) 
##STR46## 
(B) 
##STR47## 
(C) 
##STR48## 
(D) 
##STR49## 
(E) 
##STR50## 
(F) 
##STR51## 
(G) 
##STR52## 
(H) 
##STR53## 
(I) 
##STR54## 
(J) 
##STR55## 
__________________________________________________________________________