Claims
- 1. A fibrinogen receptor antagonist of the following formula ##STR63## and pharmaceutically acceptable salts thereof, where X is ##STR64## wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-10 alkyl, aryl C.sub.0-8 alkyl, oxo, thio, 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;
- Y and A are independently chosen from the group consisting of ##STR65## wherein R.sup.3 and R.sup.4 are selected from the group consisting of hydrogen, C.sub.1-10 alkyl, aryl C.sub.0-8 alkyl, oxo, thio, amino C.sub.0-8 alkyl, C.sub.1-3 acylamino C.sub.0-8 alkyl, C.sub.1-6 alkylamine C.sub.0-8 alkyl, C.sub.1-6 dialkylamine 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
- where m and n are integers independently chosen from 0-6, wherein 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=CH--C.sub.1-6 alkyl C.sub.0-6 alkyl--CH=CH.sub.2 C.sub.0-6 alkyl--CH=CH--C.sub.0-6 alkylaryl C.sub.0-6 alkyl--C.ident.C--C.sub.1-6 alkyl C.sub.0-6 alkyl.ident.C--CH C.sub.0-6 alkyl--C.ident.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 ##STR67## where AA is an L- or D-amino acid, or its corresponding ester, connected through an amide linkage;
- R.sup.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 alkylaminocarbonyt 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 X is ##STR69## wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-10 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, carboxy C.sub.0-6 alkyloxy hydroxy C.sub.0-6 alkyl C.sub.1-4 alkythio C.sub.0-6 alkyl, aryl C.sub.0-4 thio C.sub.0-6 alkyl, amino C.sub.0-3 alkyl, C.sub.1-6 alkylamino C.sub.0-3 alkyl, and C.sub.1-6 acylamino C.sub.0-3 alkyl;
- Y and A are independently chosen from the group consisting of: ##STR70## where m and n are integers independently chosen from 0-6, wherein, and Y is attached to a ring atom of the aromatic six-membered ring.
- 3. A compound of claim 2 having the formula ##STR71## and pharmaceutically acceptable salts thereof, where Y and A are independently chosen from the group consisting of: ##STR72## where m and n are integers independently chosen from 0-6, wherein A is attached to a ring atom of the ring comprising L, and Y is attached to a ring atom of the ring comprising Z;
- B is chosen from the group consisting of: ##STR73## where R5, R6, R.sup.7, R.sup.8 and R.sup.9 are independently chosen from: hydrogen, flourine, C.sub.1-8 alkyl, hydroxyl, hydroxy C.sub.1-6 alkyl, C.sub.0-6 alkyl--CH=CH--C.sub.1-6 alkyl, C.sub.0-6 alkyl--CH=CH.sub.2 C.sub.0-6 alkyl--CH=CH--C.sub.0-6 alkylaryl C.sub.0-6 alkyl--C.ident.C--C.sub.1-6 alkyl, C.sub.0-6 alkyl--C.ident.C--CH --C.sub.0-6 alkyl --C.ident.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.sup.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 ##STR74## and pharmaceutically acceptable salts thereof, where; Y and A are independently chosen from the group consisting of: ##STR75## where m and n are integers independently chosen from 0-6, wherein A is attached to a ring atom of the ring comprising L;
- B is chosen from the group consisting of: ##STR76## where R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently chosen from:
- hydrogen, flourine, C.sub.1-8 alkyl, hydroxyl, hydroxy C.sub.1-6 alkyl, C.sub.0-6 alkyl--CH=CH--C.sub.1-6 alkyl, C.sub.0-6 alkyl--CH=CH.sub.2 C.sub.0-6 alkyl--CH=CH--C.sub.0-6 alkylaryl C.sub.0-6 alkyl--C=C--C.sub.1-6 alkyl, C.sub.0-6 alkyl--C=C--CH C.sub.0-6 alkyl--C=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.sup.10 is chosen from the group consisting of:
- hydroxy, C.sub.1-8 alkyloxy, and aryl C.sub.0-6 alkyloxy.
- 5. A compound of claim 4 having the formula ##STR77## and pharmaceutically acceptable salts thereof, where X is ##STR78## wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-10 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, carboxy C.sub.0-6 alkyloxy hydroxy C.sub.0-6 alkyl C.sub.1-4 alkythio C.sub.0-6 alkyl, aryl C.sub.0-4 thio C.sub.0-6 alkyl, amino C.sub.0-3 alkyl, C.sub.1-6 alkylamino C.sub.0-3 alkyl, and C.sub.1-6 acylamino C.sub.0-3 alkyl;
- Y and A are independently chosen from the group consisting of: ##STR79## where m and n are integers independently chosen from 0-6, wherein; B is ##STR80## where R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently chosen from:
- hydrogen, flourine, C.sub.1-8 alkyl, hydroxyl, hydroxy C.sub.1-6 alkyl, C.sub.0-6 alkyl --CH=CH--C.sub.1-6 alkyl, C.sub.0-6 alkyl --CH=CH.sub.2, C.sub.0-6 alkyl--CH=CH--C.sub.0-6 alkylaryl, C.sub.0-6 alkyl --C.ident.C--C.sub.1-6 alkyl, C.sub.0-6 alkyl --C.ident.CH, C.sub.0-6 alkyl --C.ident.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.sup.10 is chosen from the group consisting of:
- hydroxy, C.sub.1-8 alkyloxy, and aryl C.sub.0-6 alkyloxy.
- 6. A compound of claim 5 having the formula ##STR81## and pharmaceutically acceptable salts thereof, where X is ##STR82## wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-10 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, carboxy C.sub.0-6 alkyloxy hydroxy C.sub.0-6 alkyl C.sub.1-4 alkythio C.sub.0-6 alkyl, aryl C.sub.0-4 thio C.sub.0-6 alkyl, amino C.sub.0-3 alkyl, C.sub.1-6 alkylamino C.sub.0-3 alkyl, and C.sub.1-6 acylamino C.sub.0-3 alkyl;
- Y and A are independently chosen from the group consisting of:
- --(CH.sub.2).sub.m--,
- where m is an integer independently chosen from 0 and 1, wherein A is attached to a ring atom of the ring comprising L;
- B is ##STR83## where R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently chosen from:
- hydrogen, flourine, C.sub.1-8 alkyl, hydroxyl, hydroxy C.sub.1-6 alkyl, C.sub.0-6 alkyl --CH=CH--C.sub.1-6 alkyl, C.sub.0-6 alkyl --CH=CH.sub.2, C.sub.0-6 alkyl --CH=OH--C.sub.0-6 alkylaryl, C.sub.0-6 alkyl --C.ident.C--C.sub.1-6 alkyl, C.sub.0-6 alkyl --C.ident.C--CH, C.sub.0-6 alkyl --C.ident.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 atkylaminosulfonylamino 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.sup.10 is chosen from the group consisting of:
- hydroxy, C.sub.1-8 alkyloxy, and aryl C.sub.0-6 alkyloxy.
- 7. A compound of claim 1 selected from the group consisting of:
- N-{[6-(Piperazin-1-yl)-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-b-alanine n-butyl ester; and
- N-{[6-(Piperazin-1-yl)-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-b-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.
- 12. A composition for inhibiting the binding of fibrinogen to blood platelets, in a mammal, comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
- 13. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 12.
- 14. A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising a compound of claim 13 and a pharmaceutically acceptable carrier.
- 15. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 14.
- 16. 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.
- 17. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 16.
- 18. A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
- 19. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 18.
- 20. A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising a compound of claim 6 and a pharmaceutically acceptable carrier.
- 21. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to the mammal a composition of claim 20.
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 |
Country |
Parent |
391851 |
Feb 1995 |
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