Novel mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace

Claim 2

A compound of the Formula (I) wherein A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen; -CH 2 0-C(0)C-(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl; or diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; B 1 and B 2 are each independently hydrogen; hydroxy; -OR s wherein R 5 is a C 1 -C 4 alkyl or an Ar-Y- group; or, where B 1 and B 2 are attached to adjacent carbon atoms, B 1 and B 2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; R 2 is hydrogen, C 1 -C 8 alkyl, -CH 2 0CH 2 CH 2 0CH 3 or an Ar-Y-group; R 3 is hydrogen, acetyl, -CH 2 O-C(O)C(CH 3 ) 3 or benzoyl; and n is an integer 0 or 1.

Claim 3

A compound according to Claim 1 wherein n is 1.

Claim 4

A compound according to Claim 1 wherein n is 0.

Claim 5

A compound according to Claims 1-3 wherein A 1 is COOR 4 .

Claim 6

A compound according to Claims 1-4 wherein R 2 is phenylmethyl.

Claim 7

A compound according to Claim 1, namely [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2(R)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2-thio-ethyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a]-[2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-oxo-2-thio-2-phenylethyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid, [6α(R*), 11 bβ]-6-[(S)-(1-oxo-2(R)-thio-3-phenylpropyl)amino]-1,2,3,5,6,7,11b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid, or [6α(R*), 11 bβ]-6-[(S)-(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,5,6,7,11b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid.

Claim 8

A compound of the Formula (II) wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR s wherein R 5 is a C 1 -C 4 alkyl or an Ar-Y- group wherein Ar is aryl and Y is a Co-C 4 alkyl; or, where B 1 and B 2 are attached to adjacent carbon atoms, B 1 and B 2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; R 2 is hydrogen, C 1 -C 8 alkyl, -CH 2 0CH 2 CH 2 0CH 3 or an Ar-Y-group; R 3 is hydrogen, acetyl, -CH 2 O-C(O)C(CH 3 ) 3 or benzoyl; R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group, -CH 2 0-C(O)C(CH 3 ) 3 or diphenylmethyl; and Z is -O-, -S-, wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y-group and R 7 is -CF 3 , a C 1 -C 1 alkyl or an Ar-Y-group.

Claim 9

A compound of the Formula (II) wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR s wherein R 5 is a C 1 -C 4 alkyl or an Ar-Y- group wherein Ar is aryl and Y is a Co-C 4 alkyl; or, where B 1 and B 2 are attached to adjacent carbon atoms, B 1 and B 2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; R 2 is hydrogen, C 1 -C 8 alkyl, -CH 2 0CH 2 CH 2 0CH 3 or an Ar-Y-group; R 3 is hydrogen, acetyl, -CH 2 O-C(O)C(CH 3 ) 3 or benzoyl; R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group, -CH 2 0-C(O)C(CH 3 ) 3 or diphenylmethyl; and Z is -O-, -S-, wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y-group and R 7 is -CF 3 , a C 1 -C 1 alkyl or an Ar-Y-group.

Claim 10

A compound according to Claim 7, namely [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexa hydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,5,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexa hydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexa hydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester.

Claim 11

A compound according to Claim 7 wherein Z is -O-.

Claim 12

A compound according to Claim 7 wherein Z is -S-.

Claim 13

A compound according to Claim 7 wherein Z is -NH-.

Claim 14

A process for preparing a compound of the Formula (I) according to any one of claims 1-6 wherein A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen; -CH 2 0-C(0)C-(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl; or diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; B 1 and B 2 are each independently hydrogen; hydroxy; -OR s wherein R 5 is a C 1 -C 4 alkyl or an Ar-Y- group; or, where B 1 and B 2 are attached to adjacent carbon atoms, B 1 and B 2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; R 2 is hydrogen, C 1 -C 8 alkyl, -CH 2 0CH 2 CH 2 0CH 3 or an Ar-Y-group; R 3 is hydrogen, acetyl, -CH 2 O-C(O)C(CH 3 ) 3 or benzoyl; and n is an integer 0 or 1, which comprises a) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is - COOR 4 , A 2 is hydrogen; R 3 is acetyl or benzoyl; and B 1 , B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein A 1 , A 2 , Bi, B 2 , n and R 2 are as defined above with thiolacetic acid or thiolbenzoic acid in the presence of triphenylphosphine and an oxidizing agent, b) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; R 3 is acetyl or benzoyl; and B 1 , B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is - COOR 4 , A 2 is hydrogen and R 3 , Bi, B 2 , n and R 2 are as defined above, with an acid, c) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; R 3 is hydrogen; and Bi, B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein R 3 is acetyl or benzoyl; and Bi, B 2 , A 1 , A 2 , n and R 2 are as defined above, with a base, d) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is -CH 2 O-C(O)C(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; R 3 is acetyl or benzoyl; and Bi, B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; Bi, B 2 , n, R 3 and R 2 are as defined above, in the presence of base, with the appropriate Ci-C 4 alkyl halide, chloromethyl pivalate or Ar-Y halide wherein Ar and Y are defined as above, e) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is -CH 2 0-C(0)C-(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl or diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; R 3 is hydrogen; and B 1 , B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein R 3 is acetyl or benzoyl and B 1 , B 2 , A 1 , A 2 , n, and R 2 are as defined above with ammonia, or f) if A 1 and A 2 are each independently hydrogen or -COOR 4 wherein R 4 is hydrogen; -CH 2 0-C-(O)C(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl or diphenylmethyl; with the proviso that where A 1 is hydrogen, A 2 is -COOR 4 , and where A 1 is -COOR 4 , A 2 is hydrogen; R 3 is -CH 2 O-C(O)C(CH 3 ) 3 ; and Bi, B 2 , R 2 and n are as defined above, reacting a compound of the formula wherein R 3 is hydrogen; and Bi, B 2 , A 1 , A 2 , n, and R 2 are as defined above, in the presence of base, with chloromethyl pivalate.

Claim 15

A process for preparing a compound of the Formula (II) according to any one of claims 7-11 wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR s wherein R 5 is a C 1 -C 4 alkyl or an Ar-Y- group wherein Ar is aryl and Y is a Co-C 4 alkyl; or, where B 1 and B 2 are attached to adjacent carbon atoms, B 1 and B 2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; R 2 is hydrogen, C 1 -C 8 alkyl, -CH 2 0CH 2 CH 2 0CH 3 or an Ar-Y-group; R 3 is hydrogen, acetyl, -CH 2 O-C(O)C(CH 3 ) 3 or benzoyl; R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group, -CH 2 0-C(O)C(CH 3 ) 3 or diphenylmethyl; and Z is -O-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y-group and R 7 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y-group, which comprises a) if R 3 is acetyl or benzoyl; R 4 is diphenylmethyl; and Z is -O-, -S-, wherein R 6 is hydrogen, and Bi, B 2 and R 2 are as defined above, reacting a compound of the formula wherein B 1 , B 2 , R 4 and Z are defined as above with a compound of the formula wherein R 3 and R 2 are defined as above in the presence of a coupling reagent, b) if R 3 is acetyl or benzoyl; R 4 is hydrogen; and Z is -O-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group; and R 7 is -CF 3 , C 1 -C 1 0 alkyl or an Ar-Y- group, and Bi, B 2 and R 2 are as defined above, reacting a compound of the formula wherein B 1 , B 2 , R 2 , R 3 and Z are defined as above; and R 4 is diphenylmethyl with an acid, c) if R 3 is hydrogen; R 4 is hydrogen; and Z is -0-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group; and R 7 is -CF 3 , C 1 -C 1 0 alkyl or an Ar-Y- group, and B 1 , B 2 and R 2 are as defined above, reacting a compound of the formula wherein B 1 , B 2 , R 2 , R 4 and Z are defined as above; and R 3 is acetyl with a base, d) if R 3 is acetyl or benzoyl; R 4 is -CH 2 0-C(0)(CH 3 ) 3 ; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C o -C 4 alkyl; and Z is -O-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group; and R 7 is -CF 3 , C 1 -C 1 0 alkyl or an Ar-Y- group, and B 1 , B 2 and R 2 are as defined above, reacting a compound of the formula wherein Bi, B 2 , R 2 , R 3 and Z are defined as above; and R 4 is hydrogen, in the presence of base, with the appropriate C 1 -C 4 alkyl halide, chloromethyl pivalate or Ar-Y halide wherein Ar and Y are defined as above, e) if R 3 is hydrogen; R 4 is -CH 2 0-C(0)(CH 3 ) 3 ; diphenylmethyl; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a C 0 -C 4 alkyl; and Z is -O-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group; and R 7 is -CF 3 , C 1 -C 1 o alkyl or on Ar-Y- group, and Bi, B 2 and R 2 are as defined above, reacting a compound of the formula wherein B 1 , B 2 , R 2 , R 4 and Z are defined as above; and R 3 is acetyl or benzoyl with ammonia, f) if R 3 is -CH 2 O-C(O)C(CH 3 ) 3 ; R 4 is hydrogen, -CH 2 0-C(0)(CH 3 ) 3 ; diphenylmethyl; a C 1 -C 4 alkyl; an Ar-Y- group wherein Ar is aryl and Y is a Co-C 4 alkyl; and Z is -O-, -S-, or wherein R 6 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group; and R 7 is -CF 3 , C 1 -C 1 0 alkyl or an Ar-Y- group, and B 1 , B 2 and R 2 are as defined above, reacting a compound of the formula wherein Bi, B 2 , R 2 , R 4 and Z are defined as above; and R 3 is hydrogen, in the presence of base, with chloromethyl pivalate.

Claim 16

A composition comprising an assayable amount of a compound according to any one of claims 1-11 in admixture or otherwise in association with an inert carrier.

Claim 17

A process for preparing a pharmaceutical composition which comprises combining a compound according to any one of claims 1 - 11 and a physiologically acceptable carrier.