Novel antihypertensive agent

Claim 2

Compounds of the formula and the pharmaceutically acceptable salts thereof wherein R and R 1 are independently (a) hydrogen; (b) C 1 -C 6 alkyl; (c) substituted C 1 -C 6 alkyl wherein the substituents are hydroxy, C 1 -C 4 alkyloxy and di-(C 1 -C 4 )-alkylamino; (d) C 6 to C 12 aryl; (e) substituted C 6 to C 12 aryl wherein the substituents are C 2 -C 6 alkyl, halo (F, Cl, Br, 1), and C 1 -C 4 alkyloxy; (f) hetero (C 4 to C 9 ) aryl wherein the heteroatom can be one of 0, N or S; (g) substituted hetero (C 4 to C 9 )aryloxy wherein the heteroatom can be one of O, N or S and the substituents are C 1 -C 6 alkyl, halo (F, Br, Cl, I) and C 1 -C 4 alkyloxy; R 2 is (a) hydrogen; (b) C 1 -C 8 straight or branched alkyl; (c) C 2 -Cs straight or branched alkenyl; (d) C 2 -C 8 straight or branched alkynyl; (e) C 3 -C 10 cycloalkyl; (f) C 6 or C 10 aryl (C l -C 4 )alkyl; (g) substituted C 1 -C 8 alkyl which can optionally contain an 0, S, S=O, O=S=O, C=O, CONR 2 , S0 2 NR 2 , NRCO, NRCONR 2 , OCONR 2 , NRCOOR or -NR 2 group wherein R is as defined above and wherein there can be 1-3 substituents selected from halo (F, Br, Cl, I), carboxamido, C 1 -C 4 alkoxy carbonyl, mercapto, amino, and R wherein R is as defined above; R 3 is H, C 1 -C 12 alkyl, phenyl and benzyl; R 4 is the residue of a natural amino acid including H, C 1 -C 12 alkyl, phenyl or benzyl; and R 3 and R 4 each taken together with the carbon atoms to which they are attached form a 6 to 8 membered fused ring moiety, optionally having a sulfur or oxygen atom in said ring; R 5 and R 6 each independently are (a) hydrogen, hydroxy; (b) halo (F, Br, Cl, I); (c) C 1 -C 6 alkyl; (d) C 1 -C 6 alkyloxy.

Claim 3

Compounds of claim I wherein the diastereomeric configuration is as follows:

Claim 4

Compounds of claim 2 having the formula wherein X is CH 2 , O or S.

Claim 5

A compound of claim 3 wherein R 5 and R 6 are hydrogen.

Claim 6

A compound of claim 3 wherein R 5 is hydroxy and R 6 is hydrogen.

Claim 7

A compound of claim 3 wherein R is H.

Claim 8

A compound of claim 6 wherein R 2 is phenethyl.

Claim 9

A compound of claim 7 wherein X is CH 2 .

Claim 10

A compound of claim 8 wherein R 1 is ethyl .

Claim 11

A compound of claim 9 wherein X is S.

Claim 12

A compound of claim 9 wherein X is O.

Claim 13

A compound of claim 3 wherein R is H, R 1 is ethyl, X is CH 2 , R 2 is phenethyl, R 5 and R 6 are H.

Claim 14

A compound of claim 3 wherein R is H, R 1 is ethyl, X is S, R 2 is phenethyl, and R 5 and R 6 are H.

Claim 15

A compound of claim 3 wherein R and R 1 are H, X is CH 2 , R 5 and R 6 are H and R 2 is phenethyl.

Claim 16

A compound of claim 3 wherein R and R 1 are ethyl, X is CH 2 , R 5 and R 6 are H and R 2 is phenethyl.

Claim 17

A compound of claim 3 wherein R and R 1 are H, X is S, R 5 and R 6 are H and R 2 is phenethyl.

Claim 18

A compound of claim 3 wherein R and R 1 are ethyl, X is S, R 5 and R 6 are H and R 2 is phenethyl.

Claim 19

A process for preparing compounds of the formula and the pharmaceutically acceptable salts thereof wherein R and R 1 are independently (a) hydrogen; (b) C 1 -C 6 alkyl; (c) substituted C 1 -C 6 alkyl wherein the substituents are hydroxy, C 1 -C 4 alkyloxy and di-(C 1 -C 4 )-alkylamino: (d) C 6 to C 12 aryl; (e) substituted C 6 to C 12 aryl wherein the substituents are C 2 -C 6 alkyl, halo (F, Cl, Br, I), and C 1 -C 4 alkyloxy; (f) hetero (C 4 to Cs) aryl wherein the heteroatom can be one of O, N or S; (g) substituted hetero (C 4 to C 9 )aryloxy wherein the heteroatom can be one of O, N or S and the substituents are C 1 -C 6 alkyl, halo (F, Br, Cl, I) and C 1 -C 4 alkyloxy; R 2 is (a) hydrogen; (b) C 1 -C 8 straight or branched alkyl; (c) C 2 C 8 straight or branched alkenyl; (d) C 2 -C 8 straight or branched alkynyl; (e) C 3 -C 10 cycloalkyl: . (f) C 6 or C 10 aryl (C 1 -C 4 )alkyl; (g) substituted C 1 -C 8 alkyl which can optionally contain an O, S, S=O, O=S=O, C=O, CONR z , SO 2 NR 2 , NRCO, NRCONR 2 , OCONR 2 , NRCOOR or -NR 2 group wherein R is as defined above and wherein there can be I-3 substituents selected from halo (F, Br, Cl, I), carboxamido, C 1 -C 4 alkoxy carbonyl, mercapto, amino, and R wherein R is as defined above; R 3 is H, C 1 -C 12 alkyl, phenyl and benzyl; R 4 is the residue of a natural amino acid including H, C 1 -C 12 alkyl, phenyl or benzyl; and R 3 and R 4 each taken together with the carbon atoms to which they are attached form a 6 to 8 membered fused ring moiety, optionally having a sulfur or oxygen atom in said ring. R 5 and R s each independently are (a) hydrogen, hydroxy: (b) halo (F, Br, CI, I); (c) C 1 -C 6 alkyl; - (d) C 1 -C 6 alkyloxy which comprises coupling a fused lactam of the formula with compounds A, B or C of the formulae wherein the definition of R' and R'i corresponds to those of R and R 1 but with the exclusion of the meaning hydrogen, and Y is oxygen and following said coupling optionally removing one or both of the R' and R' 1 ester groups, said coupling with a compound of formula A being effected by contacting the reactants together in the presence of a base, said coupling with a compound of formula B being effected by contacting the reactants together in the presence of a molecular sieve to form a Schiff's base and reducing said Schiff's base preferably with sodium cyanoborohydride, said coupling with a compound of formula C being effected according to a 1,4-Michael addition reaction, followed by the reduction of Y using catalytic hydrogenation techniques.

Claim 20

A process for preparing compounds of the formula and the pharmaceutically acceptable salts thereof wherein R and R 1 are independently (a) hydrogen; (b) C 1 -C 6 alkyl; (c) substituted C 1 -C 6 alkyl wherein the substituents are hydroxy, C 1 -C 4 alkyloxy and di-(C 1 -C 4 )-alkylamino: (d) C 6 to C 12 aryl; (e) substituted C 6 to C 12 aryl wherein the substituents are C 2 -C 6 alkyl, halo (F, Cl, Br, I), and C 1 -C 4 alkyloxy; (f) hetero (C 4 to Cs) aryl wherein the heteroatom can be one of O, N or S; (g) substituted hetero (C 4 to C 9 )aryloxy wherein the heteroatom can be one of O, N or S and the substituents are C 1 -C 6 alkyl, halo (F, Br, Cl, I) and C 1 -C 4 alkyloxy; R 2 is (a) hydrogen; (b) C 1 -C 8 straight or branched alkyl; (c) C 2 C 8 straight or branched alkenyl; (d) C 2 -C 8 straight or branched alkynyl; (e) C 3 -C 10 cycloalkyl: . (f) C 6 or C 10 aryl (C 1 -C 4 )alkyl; (g) substituted C 1 -C 8 alkyl which can optionally contain an O, S, S=O, O=S=O, C=O, CONR z , SO 2 NR 2 , NRCO, NRCONR 2 , OCONR 2 , NRCOOR or -NR 2 group wherein R is as defined above and wherein there can be I-3 substituents selected from halo (F, Br, Cl, I), carboxamido, C 1 -C 4 alkoxy carbonyl, mercapto, amino, and R wherein R is as defined above; R 3 is H, C 1 -C 12 alkyl, phenyl and benzyl; R 4 is the residue of a natural amino acid including H, C 1 -C 12 alkyl, phenyl or benzyl; and R 3 and R 4 each taken together with the carbon atoms to which they are attached form a 6 to 8 membered fused ring moiety, optionally having a sulfur or oxygen atom in said ring. R 5 and R s each independently are (a) hydrogen, hydroxy: (b) halo (F, Br, CI, I); (c) C 1 -C 6 alkyl; - (d) C 1 -C 6 alkyloxy which comprises coupling a fused lactam of the formula with compounds A, B or C of the formulae wherein the definition of R' and R'i corresponds to those of R and R 1 but with the exclusion of the meaning hydrogen, and Y is oxygen and following said coupling optionally removing one or both of the R' and R' 1 ester groups, said coupling with a compound of formula A being effected by contacting the reactants together in the presence of a base, said coupling with a compound of formula B being effected by contacting the reactants together in the presence of a molecular sieve to form a Schiff's base and reducing said Schiff's base preferably with sodium cyanoborohydride, said coupling with a compound of formula C being effected according to a 1,4-Michael addition reaction, followed by the reduction of Y using catalytic hydrogenation techniques.

Claim 21

A process according to claim 18 for producing compounds of the formula wherein R', R' 1 and R' 1 have the same meanings as R, R 1 and R 2 but for the meaning hydrogen, which comprises coupling a fused lactam of the formula with a reactant of the formulae and optionally hydrolyzing off the R' 1 and R' ester functions once said coupling has taken place wherein R2 is phenethyl, X is CH 2 , O, or S, R 5 and R 6 are as defined in claim 16, R' 1 and R' are other than H, said coupling with a compound of formula B being effected by contacting the reactants together in the presence of a molecular sieve to form a Schiff's base and reducing said Schiff's base preferably with sodium cyanoborohydride, said coupling with a compound of formula C being effected according to a 1,4-Michael addition reaction, followed by the reduction of Y using catalytic hydrogenation techniques.

Claim 22

A process for preparing compounds of the formula wherein Q is (H,H) or or an N-protecting group, R is as defined in claim 17 except it cannot be H, and X is CH2, S, or O which comprises subjecting a compound of the formula to a Friedel-Kraft cyclization, and optionally removing any N-protecting group, said cyclization being effected with a Lewis acid.

Claim 23

A process of claim 18 wherein the Lewis acid is a perfluoroalkylsulfonic acid.

Claim 24

A process of claim 18 wherein Q is phthalimido.

Claim 25

A process of claim 20 wherein the phthalimido protecting group is removed by reaction with hydrazine hydrate.

Claim 26

A compound of claims 1 to 17 for use as a medicine.

Claim 27

Use of a compound of claims 1 to 17 for preparing a medicament for treating hypertension.

Claim 28

A pharmaceutical composition which comprises a compound of claims 1 to 17 in admixture with a pharmaceutically acceptable carrier.

Claim 29

A medicament which comprises a compound of claims 1 to 17 for conjunctive administration with another antihypertensive and/or diuretic and/or calcium entry blocker.

Claim 30

A pharmaceutical composition which comprises a compound of claims 1 to 17 and one or two other active ingredients selected from another antihypertensive, a diuretic and a calcium entry blocker.