Novel 2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace

Claim 2

A process for preparing the compounds of formula wherein B₁ and B₂ are each independently hydrogen; hydroxy; -OR₂ wherein R₂ is a C₁-C₄ alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C₁-C₄ alkyl; or, where B₁ and B₂ are attached to adjacent carbon atoms, B₁ and B₂ can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; A is a bond, methylene, oxygen, sulfur, NR₄ or NCOR₅ wherein R₄ is hydrogen, a C₁-C₄ alkyl or an Ar-Y group and R₅ is -CF₃, a C₁-C₁₀ alkyl or an Ar-Y group; R₁ is -CH₂OC(O)C(CH₃)₃; R₃ is hydrogen; n is an integer 0 to 3; and Q is a group of the formula wherein Z is O, NH or S; and m is an integer 1 to 5. comprising reacting a compound of the formula wherein B₁, B₂, A, n and Q are as defined above, R₁ and R₃ are hydrogen with chloromethyl pivalate in the presence of a base.

Claim 3

A process for preparing the compounds of formula wherein B₁ and B₂ are each independently hydrogen; hydroxy; -OR₂ wherein R₂ is a C₁-C₄ alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C₁-C₄ alkyl; or, where B₁ and B₂ are attached to adjacent carbon atoms, B₁ and B₂ can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; A is a bond, methylene, oxygen, sulfur, NR₄ or NCOR₅ wherein R₄ is hydrogen, a C₁-C₄ alkyl or an Ar-Y group and R₅ is -CF₃, a C₁-C₁₀ alkyl or an Ar-Y group; R₁ is acetyl or benzoyl; R₃ is hydrogen; n is an integer 0 to 3; and Q is a group of the formula wherein Z is O, NH or S; and m is an integer 1 to 5. comprising reacting a compound of the formula wherein B₁, B₂, A, n and Q are as defined above, R₁ and R₃ are hydrogen with an acylating agent.

Claim 4

A process for preparing the compounds of formula wherein B₁ and B₂ are each independently hydrogen; hydroxy; -OR₂ wherein R₂ is a C₁-C₄ alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C₁-C₄ alkyl; or, where B₁ and B₂ are attached to adjacent carbon atoms, B₁ and B₂ can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; A is a bond, methylene, oxygen, sulfur, NR₄ or NCOR₅ wherein R₄ is hydrogen, a C₁-C₄ alkyl or an Ar-Y group and R₅ is -CF₃, a C₁-C₁₀ alkyl or an Ar-Y group; R₁ is acetyl or benzoyl; R₃ is -CH₂OC(O)C(CH₃)₃; n is an integer 0 to 3; and Q is a group of the formula wherein Z is O, NH or S; and m is an integer 1 to 5. comprising reacting a compound of the formula wherein B₁, B₂, A, R₁, n and Q are as defined above and R₃ is hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 5

A process for preparing the compounds of formula wherein B₁ and B₂ are each independently hydrogen; hydroxy; -OR₂ wherein R₂ is a C₁-C₄ alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C₁-C₄ alkyl; or, where B₁ and B₂ are attached to adjacent carbon atoms, B₁ and B₂ can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; A is a bond, methylene, oxygen, sulfur, NR₄ or NCOR₅ wherein R₄ is hydrogen, a C₁-C₄ alkyl or an Ar-Y group and R₅ is -CF₃, a C₁-C₁₀ alkyl or an Ar-Y group; R₁ is hydrogen; R₃ is -CH₂OC(O)C(CH₃)₃; n is an integer 0 to 3; and Q is a group of the formula wherein Z is O, NH or S; and m is an integer 1 to 5. comprising reacting a compound of the formula wherein B₁, B₂, A, R₃, n and Q are as defined above and R₁ is acetyl or benzoyl with ammonia.

Claim 6

A process for preparing the compounds of formula wherein B₁ and B₂ are each independently hydrogen; hydroxy; -OR₂ wherein R₂ is a C₁-C₄ alkyl or an Ar-Y group wherein Ar is aryl and Y is a hydrogen or C₁-C₄ alkyl; or, where B₁ and B₂ are attached to adjacent carbon atoms, B₁ and B₂ can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy; A is a bond, methylene, oxygen, sulfur, NR₄ or NCOR₅ wherein R₄ is hydrogen, a C₁-C₄ alkyl or an Ar-Y group and R₅ is -CF₃, a C₁-C₁₀ alkyl or an Ar-Y group; R₁ is -CH₂OC(O)C(CH₃)₃; R₃ is -CH₂OC(O)C(CH₃)₃; n is an integer 0 to 3; and Q is a group of the formula wherein Z is O, NH or S; and m is an integer 1 to 5. comprising reacting a compound of the formula wherein B₁, B₂, A, n and Q are as defined above and R₁ and R₃ are hydrogen with chloromethyl pivalate in the presence of a suitable base.

Claim 7

A process according to any of Claims 1 to 6 wherein Q is

Claim 8

A process according to Claim 7 wherein A is methylene.

Claim 9

A process according to Claim 1 wherein R₁ and R₃ are hydrogen, Q is and A is methylene.

Claim 10

A process according to Claim 9 wherein n is 0.

Claim 11

A process according to Claim 9 wherein n is 1.

Claim 12

A process according to Claim 9 wherein n is 2.

Claim 13

A process according to any of Claims 1 to 6 wherein Q is

Claim 14

A process according to Claim 13 wherein A is methylene.

Claim 15

A process according to Claim 1 wherein R₁ and R₃ are hydrogen, Q is and A is methylene.

Claim 16

A process according to Claim 15 wherein n is 0.

Claim 17

A process according to any of Claims 1 to 6 wherein A is -O-.

Claim 18

A process according to any of Claims 1 to 6 wherein A is -S-.

Claim 19

A process according to any of Claims 1 to 6 wherein A is -NH-.

Claim 20

A process according to any of Claims 1 to 6 wherein the compound to be produced is [4S-[4α, 7α(R*), 12bβ]]-7-[(2-Thio-2-oxoindan)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; 4S-[4α, 7α(R*), 12bβ]]-7-[(2-mercaptomethyl-2-oxoindan)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; [4S-[4α, 7α(R*), 12bβ]]-7-[(2-(2-mercaptoethyl)-2-oxoindan)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Thio-1-oxocyclopentane)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Thio-1-oxocyclohexane)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Thio-1-oxocyclopropane)methylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid; or [4S-[4α, 7α(R*), 12bβ]]-7-[(2-Thio-1-oxo-2-methyl)-2-propylamino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid.

Claim 21

A composition for nonpharmaceutical purposes comprising an assayable amount of a compound obtainable according to the process of any of Claims 1 to 20 in admixture or otherwise in association with an inert carrier.

Claim 22

A process for producing a pharmaceutical composition comprising mixing an effective immunosuppressive amount of a compound obtainable according to the process of any of Claims 1 to 20 with one or more pharmaceutically acceptable carriers or excipients.