Claims
- 1. A fibrinogen receptor antagonist of the following formula ##STR63## and pharmaceutically acceptable salts thereof, where X is a 6-membered monocyclic nonaromatic ring system containing 2 nitrogen atoms either unsubstituted or substituted with hydrogen, C.sub.1-10 alkyl, and aryl C.sub.0-8 alkyl;
- Y and A are independently chosen from the group consisting of ##STR64## where m and n are integers independently chosen from 0-6, wherein A is attached to a ring atom of the ring comprising ##STR65## and Y is attached to a ring atom of the aromatic six-membered ring; B is chosen from the group consisting of: ##STR66## where p=0-2, and where R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently chosen from the group consisting of:
- hydrogen, fluorine, C.sub.1-8 alkyl, hydroxyl,
- C.sub.0-6 alkyl-CH.dbd.CH-C.sub.1-6 alkyl
- C.sub.0-6 alkyl-CH.dbd.CH.sub.2
- C.sub.0-6 alkyl-CH.dbd.CH-C.sub.0-6 alkylaryl
- C.sub.0-6 alkyl-C.tbd.C-C.sub.1-6 alkyl
- C.sub.0-6 alkyl-C.tbd.CH
- C.sub.0-6 alkyl-C.tbd.C-C.sub.0-6 alkylaryl
- hydroxy C.sub.1-6 alkyl, carboxy C.sub.0-6 alkyl,
- C.sub.1-6 alkyloxy, C.sub.3-8 cycloalkyl, aryl C.sub.1-6 alkyloxy,
- aryl C.sub.0-6 alkyl, C.sub.1-6 alkylcarbonyloxy,
- C.sub.0-6 alkylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylamino C.sub.0-6 alkyl,
- C.sub.0-6 dialkylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonyloxy,
- C.sub.1-8 alkylsulfonylamino C.sub.0-6 alkyl,
- C.sub.1-6 alkylaminocarbonyloxy,
- aryl C.sub.0-6 alkylaminocarbonyloxy,
- aryl C.sub.0-8 alkylsulfonylamino C.sub.0-6 alkyl,
- C.sub.1-8 alkyloxycarbonylamino C.sub.0-8 alkyl,
- aryl C.sub.0-8 alkyloxycarbonylamino C.sub.0-8 alkyl,
- C.sub.1-8 alkylcarbonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonylamino C.sub.0-6 alkyl,
- C.sub.0-8 alkylaminocarbonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-8 alkylaminocarbonylamino C.sub.0-6 alkyl,
- C.sub.0-8 alkylaminosulfonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-8 alkylaminosulfonylamino C.sub.0-6 alkyl,
- C.sub.1-6 alkylsulfonyl C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylsulfonyl C.sub.0-6 alkyl,
- C.sub.1-6 alkylcarbonyl C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonyl C.sub.0-6 alkyl,
- C.sub.1-6 alkylthiocarbonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylthiocarbonylamino C.sub.0-6 alkyl,
- C.sub.0-8 alkylaminocarbonyl C.sub.0-6 alkyl, and
- aryl C.sub.0-8 alkylaminocarbonyl C.sub.0-6 alkyl,
- unsubstituted or substituted with one or more substituents selected from R.sup.1 and R.sub.2, and ##STR67## where AA is an L- or D-amino acid, or its corresponding ester, connected through an amide linkage;
- R.sup.1, R.sup.2, R.sub.3 and R.sub.4 are independently selected from the group consisting of
- hydrogen,
- C.sub.1-10 alkyl,
- aryl C.sub.0-8 alkyl,
- amino C.sub.0-8 alkyl, C.sub.1-3 acylamino C.sub.0-8 alkyl,
- C.sub.1-6 alkylamino C.sub.0-8 alkyl,
- C.sub.1-6 dialkylamino C.sub.0-8 alkyl,
- C.sub.1-4 alkoxy C.sub.0-6 alkyl,
- carboxy C.sub.0-6 alkyl,
- C.sub.1-3 alkoxycarbonyl C.sub.0-6 alkyl,
- C.sub.1-4 alkylthio C.sub.0-6 alkyl,
- aryl C.sub.0-4 thio C.sub.0-6 alkyl,
- carboxy C.sub.0-6 alkyloxy, and
- hydroxy C.sub.0-6 alkyl; and
- R.sub.10 is chosen from the group consisting of:
- hydroxy,
- C.sub.1-8 alkyloxy,
- aryl C.sub.0-6 alkyloxy,
- C.sub.1-8 alkylcarbonyloxy C.sub.1-4 alkyloxy,
- aryl C.sub.1-8 alkylcarbonyloxy C.sub.1-4 alkyloxy,
- C.sub.1-8 alkylaminocarbonyl C.sub.1-4 alkyloxy,
- C.sub.1-8 dialkylaminocarbonyl C.sub.1-4 alkyloxy, and
- an L- or D- amino acid joined by an amide linkage, wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C.sub.1-6 alkyl.
- 2. A compound of claim 1 having the formula ##STR68## and pharmaceutically acceptable salts thereof, where Y and A are independently chosen from the group consisting of: ##STR69##
- 3. A compound of claim 2 having the formula ##STR70## and pharmaceutically acceptable salts thereof, where Y and A are independently chosen from the group consisting of: ##STR71## B is chosen from the group consisting of: ##STR72## where R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently chosen from:
- hydrogen, flourine, C.sub.1-8 alkyl, hydroxyl,
- hydroxy C.sub.1-6 alkyl,
- C.sub.0-6 alkylene-CH.dbd.CH-C.sub.1-6 alkyl,
- C.sub.0-6 alkylene-CH.dbd.CH.sub.2,
- C.sub.0-6 alkylene-CH.dbd.CH-C.sub.0-6 alkylaryl,
- C.sub.0-6 alkylene-C.tbd.C-C.sub.1-6 alkyl,
- C.sub.0-6 alkylene-C.tbd.CH,
- C.sub.0-6 alkylene-C.tbd.C-C.sub.0-6 alkylaryl,
- carboxy C.sub.0-6 alkyl, C.sub.1-6 alkyloxy, C.sub.3-8 cycloalkyl,
- aryl C.sub.0-6 alkyl,
- C.sub.1-6 alkylcarbonyloxy, C.sub.0-6 alkylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonyloxy,
- C.sub.0-6 dialkylamino C.sub.0-6 alkyl,
- C.sub.1-6 alkylaminocarbonyloxy,
- aryl C.sub.1-6 alkylaminocarbonyloxy,
- C.sub.1-8 alkylsulfonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylsulfonylamino C.sub.0-6 alkyl,
- C.sub.1-8 alkyloxycarbonylamino C.sub.0-8 alkyl,
- C.sub.1-8 alkylcarbonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonylamino C.sub.0-6 alkyl,
- C.sub.0-8 alkylaminocarbonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-8 alkylaminocarbonylamino C.sub.0-6 alkyl,
- C.sub.0-8 alkylaminosulfonylamino C.sub.0-6 alkyl,
- aryl C.sub.0-8 alkylaminosulfonylamino C.sub.0-6 alkyl,
- C.sub.1-6 alkylsulfonyl C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylsulfonyl C.sub.0-6 alkyl,
- C.sub.1-6 alkylcarbonyl C.sub.0-6 alkyl,
- aryl C.sub.0-6 alkylcarbonyl C.sub.0-6 alkyl,
- C.sub.1-6 alkylthiocarbonylamino C.sub.0-6 alkyl; and
- R.sub.10 is chosen from the group consisting of:
- hydroxy,
- C.sub.1-8 alkyloxy, and
- aryl C.sub.0-6 alkyloxy.
- 4. A compound of claim 3 having the formula ##STR73## and pharmaceutically acceptable salts thereof, where Y and A are independently chosen from the group consisting of: ##STR74##
- 5. A compound of claim 4 having the formula ##STR75## and pharmaceutically acceptable salts thereof, where B is chosen from the group consisting of: ##STR76##
- 6. A compound of claim 5 having the formula ##STR77## and pharmaceutically acceptable salts thereof, where where m is an integer independently chosen from 0 and 1.
- 7. A compound of claim 1 selected from the group consisting of:
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(S)-(3-pyridyl)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(S)-(3-pyridyl)-.beta.-alanine ethyl ester,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-methyl-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-(2-phenethyl)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-2(S)-(phenylsulfonylamino)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-2(R)-(phenylsulfonylamino)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-methyl-.beta.-alanine ethyl ester,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-(2-chlorobenzyl)-.beta.-alanine,
- N-{�7-(4-Benzylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-2(2-chlorobenzyl)-.beta.-alanine ethyl ester,
- N-{�7-(4-Benzylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-(2-chlorobenzyl)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3-(3-fluorophenyl)-.beta.-alanine,
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-(ethynyl)-.beta.-alanine ethyl ester, and
- N-{�7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl!acetyl}-3(R)-(ethynyl)-.beta.-alanine.
- 8. 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.
- 9. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 8.
- 10. A composition for inhibiting the aggregation of blood platelets in a mammal, comprising a compound of claim 1 in combination with two or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent and a pharmaceutically acceptable carrier.
- 11. A method for inhibiting the aggregation of blood platelets in a mammal, comprising administering to mammal the composition of claim 10.
Parent Case Info
This is a division of application Ser. No. 08/391,851 filed Feb. 22, 1995.
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Divisions (1)
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Number |
Date |
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Parent |
391851 |
Feb 1995 |
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