Fibrinogen receptor antagonists for inhibiting aggregation of blood platelets

Claim 2

A fibrinogen receptor antagonist of the formula ##STR86## wherein: X is ##STR87## Y is ##STR88## wherein n=0-5 and j=0-3; Z is --CO 2 R 2 , ##STR89## wherein R 10 is C 1-8 alkyl, aryl, arylC 1-8 alkyl, u is C or N, v is C or N, R is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC 1-5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C -8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkyloxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 1 is attached bear only one heteroatom; R 1 is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC -5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, aminoC 1-3 alkyl, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C 1-8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkoxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 1 is attached bear only one heteroatom; R 2 is hydrogen, C 1-12 alkyl, unsubstituted or substituted, with one or more C 1-6 alkyl groups, ##STR90## where R 9 is C 1-6 alkyl, branched or unbranched, or phenyl, and wherein R 9 , when appearing more than once, can be the same or different; m is 1-4, or the pharmaceutically acceptable salts thereof, or optical isomer thereof.

Claim 3

A fibrinogen receptor antagonist of claim 1 having the formula ##STR91## wherein: X is ##STR92## Y is ##STR93## wherein n=0-5; Z is --CO 2 R 2 , ##STR94## wherein R 10 is C 1-8 alkyl, aryl, arylC 1-8 alkyl, u is C or N, v is C or N, R is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodi, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC 1-5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, aminoC 1-3 alkyl, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C 1-8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkyloxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 1 is attached bear only one heteroatom; R 1 is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC 1-5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, aminoC 1-3 alkyl, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C 1-8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkyloxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl) amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 1 is attached bear only one heteroatom; R 2 is hydrogen, C 1-12 alkyl, unsubstituted or substituted, with one or more C 1-6 alkyl groups, ##STR95## where R 9 is C 1-6 alkyl, branched or unbranched, or phenyl, and where R 9 , when appearing more than once, can be the same or different; k is 1-4; and m is 1-4, or the pharmaceutically acceptable salts thereof, or optical isomer thereof.

Claim 4

A fibrinogen receptor antagonist of claim 2 having the formula ##STR96## wherein: X is ##STR97## Y is ##STR98## wherein n=1-3; Z is --CO 2 H, R is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC 1-5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, aminoC 1-3 alkyl, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylChd 0-4alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C 1-8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkyloxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 1 is attached bear only one heteroatom; R 1 is hydrogen, C 0-6 alkyl, either unsubstituted or substituted, with one or more groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C 1-5 alkylcarbonyl(C 0-8 alkyl)amino, arylC 1-5 alkylcarbonyl(C 0-8 alkyl)amino, aryloxy, C 1-10 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, aminoC 1-3 alkyl, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, C 1-8 alkylsulfonyl(C 0-8 alkyl)amino, aryl C 0-10 alkylsulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylsulfonyl, C 0-8 alkylsulfonyl, hydroxycarbonylC 0-5 alkyl, C 1-8 alkyloxycarbonyl(C 0-8 alkyl)amino, arylC 0-10 alkyloxycarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyl(C 0-8 alkyl) amino, arylC 0-8 alkylaminocarbonyl(C 0-8 alkyl)amino, C 0-8 alkylaminocarbonyloxy, arylC 0-10 alkylaminocarbonyloxy, C 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, arylC 0-8 alkylaminosulfonyl(C 0-8 alkyl)amino, C 0-8 alkylaminosulfonyl, and arylC 0-8 alkylaminosulfonyl; provided that the carbon atom to which R or R 11 is attached bear only one heteroatom; k is 1; and m is 1-4, or the pharmaceutically acceptable salts thereof, or optical isomer thereof.

Claim 5

A compound of claim 1 selected from the group consisting of: ##STR99## or pharmaceutically acceptable salts thereof.

Claim 6

A compound which is: ##STR100## or pharmaceutically acceptable salts thereof.

Claim 7

A compound which is: ##STR100## or pharmaceutically acceptable salts thereof.

Claim 8

A compound of claim 4 which is: ##STR101## or pharmaceutically acceptable salts thereof.

Claim 9

A compound of claim 4 which is: ##STR102## or pharmaceutically acceptable salts thereof.

Claim 10

A compound of claim 4 which is: ##STR103## or pharmaceutically acceptable salts thereof.

Claim 11

A compound of claim 4 which is ##STR104## or pharmaceutically acceptable salts thereof.

Claim 12

A compound of claim 1 which is: ##STR105## or pharmaceutically acceptable salts thereof.

Claim 13

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Claim 14

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

Claim 15

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compound of claim 5 and a pharmaceutically acceptable carrier.

Claim 16

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compound of claim 6 and a pharmaceutically acceptable carrier.

Claim 17

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compound of claim 7 and a pharmaceutically acceptable carrier.

Claim 18

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

Claim 19

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compound of claim 9 and a pharmaceutically acceptable carrier.

Claim 20

A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the compounds of claim 10 and a pharmaceutically acceptable carrier.