Bicyclic lactams

Claim 2

A compound of the formula: ##STR81## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl; R 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 lower alkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, acetylamino, or benzoylamino; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, and lower alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, benzoyl, or 1-naphthoyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl, or 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 alkanoyl amino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; and, the pharmaceutically acceptable salts thereof, wherein in said R, R 1 and R 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.

Claim 3

A compound of the formula: ##STR82## wherein: R and R 2 are hydrogen, loweralkyl, aryl, or aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by alkyl, halo, dihalo, amino, cyano, hydroxy, or alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, or CH═CH, wherein R B is hydrogen, lower alkyl, aryl loweralkyl, lower alkanoyl, benzoyl, or 1-naphthoyl and R 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 1 and R 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.

Claim 4

A compound of the formula: ##STR82## wherein: R and R 2 are hydrogen, loweralkyl, aryl, or aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by alkyl, halo, dihalo, amino, cyano, hydroxy, or alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, or CH═CH, wherein R B is hydrogen, lower alkyl, aryl loweralkyl, lower alkanoyl, benzoyl, or 1-naphthoyl and R 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 1 and R 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.

Claim 5

A compound of the formula: ##STR83## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, or aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0-1, m is 1-2, R 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 1 and R 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.

Claim 6

A compound of the formula: ##STR83## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, or aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0-1, m is 1-2, R 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 1 and R 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.

Claim 7

A compound of the formula: ##STR84## wherein: R and R 2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl; and, R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0, m is 1, R 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.

Claim 8

A compound of the formula: ##STR84## wherein: R and R 2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl; and, R 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 A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0, m is 1, R 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.

Claim 9

A compound of claim 4 which has the formula: ##STR85##

Claim 10

A compound of claim 5 which is: [3R-[3α,6α(S*),9aα]]-6-[(1-carboxy-3-phenylpropyl) amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid.

Claim 11

A compound of claim 4 which has the formula: ##STR86##

Claim 12

A compound of claim 7 which is: [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid.

Claim 13

A compound of claim 4 which has the formula: ##STR87##

Claim 14

A compound of claim 9 which is: [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid.

Claim 15

A compound of claim 4 which has the formula: ##STR88##

Claim 16

A compound of claim 11 which is: [3R-[3α,6α(S*),9aα]]-6-[[1-ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid.

Claim 17

A compound of claim 4 which has the formula: ##STR89##

Claim 18

A compound of claim 13 which is: n-Butyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 19

A compound of claim 4 which has the formula: ##STR90##

Claim 20

A compound of claim 15 which is: Ethyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 21

A compound of claim 4 which has the formula: ##STR91##

Claim 22

A compound of claim 17 which is: Ethyl [3R-[3α,6α(S*),9aα]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 23

A compound of claim 4 which has the formula: ##STR92##

Claim 24

A compound of claim 19 which is: Benzyl [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 25

A compound of claim 4 which has the formula: ##STR93##

Claim 26

A compound of claim 21 which is: Phenyl [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 27

A compound of claim 4 which has the formula: ##STR94##

Claim 28

A compound of claim 23 which is: n-Butyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 29

A compound of claim 4 which has the formula: ##STR95##

Claim 30

A compound of claim 25 which is: Benzyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 31

A process for producing a compound having the formula: ##STR96## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R 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 B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, or benzoyl or 1-naphthoyl, and R 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 1 and R 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 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 α-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.

Claim 32

A process for producing a compound having the formula: ##STR96## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl; R 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 A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R 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 B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, or benzoyl or 1-naphthoyl, and R 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 1 and R 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 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 α-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.

Claim 33

A compound having the formula: ##STR98## wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl, said alkyl groups having 1-6 carbon atoms and said aryl being selected from the group consisting of phenyl, naphthyl, or biphenyl.

Claim 34

A compound having the formula: ##STR98## wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl, said alkyl groups having 1-6 carbon atoms and said aryl being selected from the group consisting of phenyl, naphthyl, or biphenyl.

Claim 35

A compound having the formula: ##STR99## wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl, said alkyl groups having 1-6 carbon atoms and said aryl being selected from the group consisting of phenyl, naphthyl, or biphenyl.

Claim 36

A compound having the formula: ##STR99## wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl, said alkyl groups having 1-6 carbon atoms and said aryl being selected from the group consisting of phenyl, naphthyl, or biphenyl.