Bicyclic lactams

A compound of the formula:

• ##STR82## wherein:
• R and R.sub.2 are hydrogen, loweralkyl, aryl, or aryl lower alkyl;
• R.sub.1 is
• alkyl, alkenyl, alkynyl, and unsubstituted cycloalkyl of 1-10 carbon atoms;
• substituted lower alkyl wherein the substituent can be hydroxy, lower alkylthio, amino, alkylamino, diloweralkylamino, acetylamino, and benzoylamino;
• substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m -- wherein n is 0-2, m is 1-3, R.sub.A is aryl or heteroaryl optionally substituted by alkyl, halo, dihalo, amino, cyano, hydroxy, or alkoxy, and Q is O, S, N--R.sub.B, CONR.sub.C, NR.sub.C CO, or CH.dbd.CH, wherein R.sub.B is hydrogen, lower alkyl, aryl loweralkyl, lower alkanoyl, benzoyl, or 1-naphthoyl and R.sub.C is hydrogen or lower alkyl;
• aryl lower alkyl or heteroaryl loweralkyl which include branched lower alkyl groups;
• substituted aryl lower alkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl substituents can be amino, acetylamino, benzoylamino, or hydroxy and the aryl and heteroaryl substituents can be lower alkyl, halo, dihalo, amino, cyano, hydroxy, lower alkoxy, amino loweralkyl, or hydroxyloweralkyl;
• and
• the pharmaceutically acceptable salts thereof, wherein in said R, R.sub.1 and R.sub.2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, or biphenyl;
• and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

A compound of the formula:

• ##STR83## wherein:
• R and R.sub.2 are independently hydrogen, loweralkyl, aryl, or aryl lower alkyl;
• R.sub.1 is
• alkyl of 1-10 carbon atoms which include branched alkyl groups;
• substituted lower alkyl wherein the substituent can be amino, acetylamino, benzoylamino, or lower alkylthio;
• substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m -- wherein n is 0-1, m is 1-2, R.sub.A is phenyl optionally substituted by halo, dihalo, alkoxy, or cyano, and Q is O or S;
• aryl lower alkyl or heteroaryl loweralkyl;
• substituted aryl lower alkyl or substituted heteroaryl loweralkyl wherein the aryl and heteroaryl substituents are halo, dihalo, cyano, hydroxy, hydroxy lower alkyl, amino, and amino lower alkyl;
• and,
• the pharmaceutically acceptable salts thereof, wherein in said R, R.sub.1 and R.sub.2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, or biphenyl;
• and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

A compound of the formula:

• ##STR84## wherein:
• R and R.sub.2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl;
• and,
• R.sub.1 is
• alkyl of 1-8 carbon atoms which include branched alkyl groups;
• substituted lower alkyl wherein the substituent can be amino or loweralkylthio;
• substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m -- wherein n is 0, m is 1, R.sub.A is phenyl, and Q is 0 or S;
• aralkyl wherein the aryl is phenyl or napthyl and the alkyl group contains 1 to 3 carbon atoms, or heteroaralkyl wherein the heteroaryl group is indole, thiophene, imidazole, pyridine, quinoline or isoquinoline and the alkyl group contains 1 to 3 carbon atoms;
• substituted aralkyl wherein the aryl is a phenyl group, the alkyl contains 1 to 3 carbon atoms, and the phenyl substituents can be halo, hydroxy, phenoxy, lower alkoxy, amino, or aminomethyl;
• and,
• the pharmaceutically acceptable salts thereof.

A process for producing a compound having the formula:

• ##STR96## wherein:
• R and R.sub.2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl;
• R.sub.1 is
• hydrogen;
• alkyl, alkenyl, alkynyl, and unsubstituted cycloalkyl of from 1 to 12 carbon atoms;
• substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, aryl loweralkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, acetylamino, or benzoylamino;
• substituted lower alkyl having the formula R.sub.A (CH.sub.2).sub.n --Q--(CH.sub.2).sub.m wherein n is 0-2, m is 1-3, R.sub.A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino loweralkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, and lower alkoxy, and Q is O, S, N--R.sub.B, CONR.sub.C, NR.sub.C CO, CH.dbd.CH wherein R.sub.B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, or benzoyl or 1-naphthoyl, and R.sub.C is hydrogen or lower alkyl;
• aryl;
• substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, hydroxy, halo, or dihalo;
• aryl lower alkyl or heteroaryl loweralkyl which include branched lower alkyl groups;
• substituted aryl lower alkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acetylamino, benzoylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, arylthio, amino, amino lower alkyl, lower alkanoylamino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl nitro, cyano, or sulfonamido;
• wherein in said R, R.sub.1 and R.sub.2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, or biphenyl;
• and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl;
• which process comprises:
• synthesizing a bicyclic lactam having the formula:
• ##STR97## wherein R.sub.2 is as defined above, by oxidizing a protected phthalimido derivative (III) to form the aldehyde, 5-formyl-2(S)-phthalimido pentanoic acid (IV);
• condensing said aldehyde (IV) to form a diastereomeric mixture of thiazolidines (V);
• treating said mixture of thiazolidines (V) to effect ring closure thereof and obtain said lactam (VIII);
• and,
• subsequently reductively alkylating said lactam with .alpha.-keto acids and esters, followed by removal of protecting groups, if any, to yield products of Formula I and, if desired, isolating the biologically more active diastereomer by chromatography or crystallization and, if further desired, preparing a pharmaceutically acceptable salt therefrom by conventional means.