Carboxyalkyl substituted inhibitors of enkephalinase and ACE

Claim 2

A compound of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 is hydrogen or -CH 2 OC(O)C(CH 3 ) 3 ; R 1 is hydrogen, C 1 -C 4 alkyl or -CH 2 0C(O)-C(CH 3 ) 3 ; and n is an integer 1 to 3.

Claim 3

A compound according to Claim 1 wherein A is methylene.

Claim 4

A compound according to Claim 1 or 2 wherein n is 1.

Claim 5

A compound according to Claim 1, 2 or 3 wherein R 1 and R 3 are hydrogen.

Claim 6

A compound according to Claim 1 wherein A is -O-.

Claim 7

A compound according to Claim 1 wherein A is -S-.

Claim 8

A compound according to Claim 1 wherein A is -NH-.

Claim 9

A compound of Claim 1 wherein the compound is [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxymethyl carboxy)methyl-3-phenylpropyl)-amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-thiazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-azazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-N4-trifluoroacetyl-azazino[3,4-a][2]benzazepine-4-carboxylic acid or [6a(R*), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7,11 b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid, methyl ester or [6a(R*), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7,11b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid.

Claim 10

A pharmaceutical composition containing a compound according to any one of claims 1 to 8.

Claim 11

A pharmaceutical composition according to claim 9 useful in producing an endorphin- or enkephalin-mediated analgesic effect.

Claim 12

A pharmaceutical composition according to claim 9 useful in producing an ANP-mediated hypotensive effect.

Claim 13

A pharmaceutical composition according to claim 9 useful in producing an ANP-mediated diuretic effect.

Claim 14

A pharmaceutical composition according to claim 9 useful in treating congestive heart failure.

Claim 15

A pharmaceutical composition according to claim 9 useful in inhibiting ACE.

Claim 16

A pharmaceutical composition according to claim 14 useful in producing a hypotensive effect.

Claim 17

A pharmaceutical composition according to claim 14 useful in producing a cognition enhancing effect.

Claim 18

A pharmaceutical composition according to claim 14 useful in treating congestive heart failure.

Claim 19

A composition comprising an assayable amount of a compound of Claim 1 in admixture or otherwise in association with an inert carrier.

Claim 20

A pharmaceutical composition according to claim 9 useful in effecting immunosuppression. Claims for the following Contracting State : ES

Claim 21

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 ' is hydrogen; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 * is t-butyl with an acid.

Claim 22

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 ' is hydrogen; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 * is t-butyl with an acid.

Claim 23

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 " is -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 ' and R 3 ' are hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 24

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 " is -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 ' and R 3 ' are hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 25

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 "' is C 1 -C 4 alkyl; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, R 3 ' and n are as defined above and R 1 "' is C 1 -C 4 alkyl with palladium/carbon in the presence of hydrogen.

Claim 26

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 "' is C 1 -C 4 alkyl; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, R 3 ' and n are as defined above and R 1 "' is C 1 -C 4 alkyl with palladium/carbon in the presence of hydrogen.

Claim 27

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 "' is C 1 -C 4 alkyl; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, m and R 1 "' are as defined above and R 3 ' is hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 28

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 "' is C 1 -C 4 alkyl; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, m and R 1 "' are as defined above and R 3 ' is hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 29

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 ' is hydrogen; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, n and R 3 " are as defined above and R 1 "' is C 1 -C 4 alkyl with a base.

Claim 30

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 " is -CH 2 OC(O)C(CH 3 ) 3 ; R 1 ' is hydrogen; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A, n and R 3 " are as defined above and R 1 "' is C 1 -C 4 alkyl with a base.

Claim 31

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 " is -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 " is CH 2 0C(O)-C(CH 3 ) 3 with palladium/carbon in the presense of hydrogen.

Claim 32

A process for preparing the compounds of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen, a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 ' is hydrogen; R 1 " is -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3, comprising reacting a compound of the formula wherein B 1 , B 2 , A and n are as defined above and R 1 " is CH 2 0C(O)-C(CH 3 ) 3 with palladium/carbon in the presense of hydrogen.

Claim 33

A process according to any one of claims 1 to 6 wherein in the compound prepared A is methylene.

Claim 34

A process according to any one of claims 1 to 7 wherein in the compound prepared n is 1.

Claim 35

A process according to any one of claims 1 to 6 wherein in the compound prepared A is -O-.

Claim 36

A process according to any one of claims 1 to 6 wherein in the compound prepared A is -S-.

Claim 37

A process according to any one of claims 1 to 6 wherein in the compound prepared A is -NH-.

Claim 38

A compound of Claim 1 wherein the compound is [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-pheny!propyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7a(R * ), 12bβ]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl or [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxymethyl carboxy)-methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-thiazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-azazino[3,4-a[2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-N4-trifluoroacetyl-azazino[3,4-a][2]benzazepine-4-carboxylic acid or [6a(R * ), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7,11b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid, methyl ester or [6a(R * ), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7 11 b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid.

Claim 40

The method according to claim 13 wherein the pharmaceutical composition prepared is useful in inhibiting enkephalinase.

Claim 41

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in producing an endorphin- or enkephalin-mediated analgesic effect.

Claim 42

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in producing an ANP-mediated hypotensive effect.

Claim 43

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in producing an ANP-mediated diuretic effect.

Claim 44

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in the treatment of congestive heart failure.

Claim 45

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in inhibiting ACE.

Claim 46

A method according to claim 19 wherein the pharmaceutical composition prepared is useful in producing a hypotensive effect.

Claim 47

A method according to claim 19 wherein the pharmaceutical composition prepared is useful in producing a cognition enhancing effect.

Claim 48

A method according to claim 19 wherein the pharmaceutical composition prepared is useful in treating congestive heart failure.

Claim 49

A composition comprising an assayable amount of a compound of claim 1 in admixture or otherwise in association with an inert carrier.

Claim 50

A method according to claim 13 wherein the pharmaceutical composition prepared is useful in effecting immunosuppression.

Claim 51

Claims for the following Contracting State : GR

Claim 52

A compound of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen- a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 is hydrogen or -CH 2 0C(0)C(CH 3 ) 3 ; R 1 is hydrogen, C 1 -C 4 alkyl or -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3.

Claim 53

A compound of the formula wherein B 1 and B 2 are each independently hydrogen; hydroxy; -OR 2 wherein R 2 is a C 1 -C 4 alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C 1 -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; A is a bond, methylene or oxygen, sulfur or NR 4 or NCOR s wherein R 4 is hydrogen- a C 1 -C 4 alkyl or an Ar-Y- group and R 5 is -CF 3 , a C 1 -C 1 o alkyl or an Ar-Y- group; R 3 is hydrogen or -CH 2 0C(0)C(CH 3 ) 3 ; R 1 is hydrogen, C 1 -C 4 alkyl or -CH 2 0C(0)-C(CH 3 ) 3 ; and n is an integer 1 to 3.

Claim 54

A compound according to Claim 1 wherein A is methylene.

Claim 55

A compound according to Claim 1 or 2 wherein n is 1.

Claim 56

A compound according to Claim 1, 2 or 3 wherein R 1 and R 3 are hydrogen.

Claim 57

A compound according to Claim 1 wherein A is -O-.

Claim 58

A compound according to Claim 1 wherein A is -S-.

Claim 59

A compound according to Claim 1 wherein A is -NH-.

Claim 60

A compound of Claim 1 wherein the compound is [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7α(R*), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-(methylcarboxy)methyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl ester or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid, pivaloyloxymethyl or [4S-[4a, 7a(R*), 12bβ]]-7-[(1-Oxo-2-(pivaloyloxymethylcarboxymethyl carboxy)methyl-3-phenylpropyl)-amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-oxazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-thiazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-azazino[3,4-a][2]benzazepine-4-carboxylic acid or [4S-[4a, 7a(R * ), 12bβ]]-7-[(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-hexahydro-6-oxo-1 H-[1,4]-N4-trifluoroacetyl-azazino[3,4-a][2]benzazepine-4-carboxylic acid or [6a(R * ), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7,11 b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid, methyl ester or [6a(R*), 11bβ]-6-[(S)-(1-Oxo-2-carboxymethyl-3-phenylpropyl)amino]-1,2,3,5,6,7,11b-heptahydro-5-oxo- pyrrolo[2,1-a][2]benzazepine-3(S)-carboxylic acid.

Claim 62

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in inhibiting enkephalinase.

Claim 63

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in producing an endorphin- or enkephalin-mediated analgesic effect.

Claim 64

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in producing an ANP-mediated hypotensive effect.

Claim 65

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in producing an ANP-mediated diuretic effect.

Claim 66

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in treating congestive heart failure.

Claim 67

A method according to claim 9 wherein the pharmaceutical composition prepared is useful in inhibiting ACE.

Claim 68

A method according to Claim 15 wherein the pharmaceutical composition prepared is useful in producing a hypotensive effect.

Claim 69

A method according to Claim 15 wherein the pharmaceutical composition prepared is useful in producing a cognition enhancing effect.

Claim 70

A method according to Claim 15 wherein the pharmaceutical composition prepared is useful in treating congestive heart failure.

Claim 71

A composition comprising an assayable amount of a compound of claim 1 in admixture or otherwise in association with an inert carrier.

Claim 72

A method according to Claim 9 wherein the pharmaceutical composition is useful in effecting immunosuppression.