Claims for Patent: 6,555,542

Summary for Patent: 6,555,542

Title:	Sulfonamide lactam inhibitors of FXa and method
Abstract:	Sulfonamide lactams of the following formula ##STR1## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.4a, R.sup.5, R.sup.5a, R.sup.6, R.sup.6a, R.sup.7 and R.sup.8 are as described herein, are provided which inhibitors of Factor Xa and are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
Inventor(s):	O\'Connor; Stephen P. (Newtown, PA), Lawrence; Michael (Yardley, PA), Shi; Yan (Flourtown, PA), Stein; Philip D. (Pennington, NJ)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	10/059,621
Patent Claims:	1. A compound of formula II ##STR1069## or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrugs thereof, wherein Y and Y.sup.a are independently a bond, alkyl, alkenyl or alkynyl; X and X.sup.a are independently 2. A compound of claim 1 wherein Y a is bond or alkenyl. 3. A compound of claim 2 wherein R.sub.1 is aryl or heteroaryl either of which may be optionally substituted with one or more groups Z.sup.1, Z.sup.2 or Z.sup.3. 4. A compound of claim 3 wherein R.sup.9 is H, Z.sup.3d or when a group R.sup.11 is present R.sup.9 combines with R.sup.11 to form a single bond; R.sup.10 is H, Z.sup.1f, --Y.sup.2 --R.sup.11, Y.sup.2 --R.sup.2 or --Y.sup.12 --N(R.sup.11)--Z.sup.4 --Z.sup.9a ; Y.sup.2 is --(CH.sub.2).sub.u -- or --C(O)--(CH.sub.2)--; Z.sup.3d and Z.sup.1f are each independently H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, --OH, --OZ.sup.6, --C(O).sub.t H, --C(O).sub.t Z.sup.6, --S(O).sub.t Z.sup.6, -(alkyl)-OH, -(alkyl)-OZ.sup.6, -(alkyl)-C(O).sub.t H, -(alkyl)-C(O).sub.t Z.sup.6, -(alkyl)-S(O).sub.t Z.sup.6, --Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sup.6, --Z.sup.4 --N(Z.sup.10)--Z.sup.5 --H, --Z.sup.4 --N(Z.sup.9) --Z.sup.5 --NZ.sup.7 Z.sup.8, -(alkyl)-Z.sup.4 --NZ.sup.7 Z.sup.8, -(alkyl)-Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sup.6, -(alkyl)-Z.sup.4 --N(Z.sup.10)--Z.sup.5 --H, or -(alkyl)-Z.sup.4 --N(Z.sup.9)--Z.sup.5 --NZ.sup.7 Z.sup.8 any of which may be optionally further substituted where valence allows; R.sup.14 is a group D or H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, --OH, --OZ.sup.6, --C(O).sub.t H, --C(O).sub.t Z.sup.6, --S(O).sub.t Z.sup.6, -(alkyl)-OH, -(alkyl-OZ.sup.6, -(alkyl)- C(O).sub.t H, -(alkyl)-C(O).sub.t Z.sup.6, -(alkyl)-S(O).sub.t Z.sup.6, --Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sup.6, --Z.sup.4 --N(Z.sup.10)--Z.sup.5 --H, --Z.sup.4 --N(Z.sup.9)--Z.sup.5 --NZ.sup.7 Z.sup.8, -(alkyl)-Z.sup.4 --NZ.sup.7 Z.sup.8, -(alkyl)-Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sup.6, -(alkyl)-Z.sup.4 --N(Z.sup.10)--Z.sup.5 --H, or -(alkyl)-Z.sup.4 --N(Z.sup.9)--Z.sup.5 --NZ.sup.7 Z.sup.8 any of which may be optionally further substituted where valence allows. 5. A compound of claim 4 wherein Z.sup.4 is a bond, --C(O)--, --C(.dbd.NZ.sup.9a)--, --C(O)--C(O)-- or --C(O)O--; and Z.sup.5 is --C(O)--, --C(O)O-- or --SO.sub.2 --. 6. A compound of claim 5 wherein Z.sup.3d and Z.sup.1f are each independently H, alkyl, heteroaryl, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sub.4 --NZ.sup.7 --Z.sup.8, -(alkyl)-Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sub.6, -(alkyl)-Z.sup.4 --N(Z.sup.9)--Z.sup.5 --NZ.sup.7 Z.sup.8, --C(O).sub.t --Z.sup.6, -(alkyl)-C(O).sub.t Z.sup.6, -(alkyl)-OH, -(alkyl)-OZ.sup.6, or --S(O).sub.t Z.sup.6 ; and R.sup.14 is a group H, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sup.4 --NZ.sup.7 Z.sup.8, -(alkyl)- Z.sup.4 --N(Z.sup.10)--Z.sup.5 --Z.sup.6, -(alkyl)-Z.sup.4 --N(Z.sup.9)--Z.sup.5 --NZ.sup.7 Z.sup.8, --C(O).sub.t Z.sup.6, -(alkyl)-C(O).sub.t Z.sup.6, -(alkyl)-OH, -(alkyl)-OZ.sup.6, --S(O).sub.t Z.sup.6 or a group D. 7. A compound of claim 6 wherein R.sup.2 is H, alkyl, --C(O).sub.t H, --C(O).sub.t Z.sup.6, --Z.sup.4 --NZ.sup.7 Z.sup.8, -(alkyl)-C(O).sub.t H, -(alkyl)-C(O).sub.t Z.sup.6, or -(alkyl)-Z.sup.4 --NZ.sup.7 Z.sup.8 ; and R.sup.3, R.sup.4, R.sup.4a, R.sup.5, R.sub.5a, R.sup.6, and R.sup.6a are H. 8. A compound of claim 7 wherein R.sup.1 is ##STR1074## ##STR1075## any of which may be optionally substituted with one or more Z.sup.1, Z.sup.2 or Z.sup.3. 9. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable vehicle or carrier therefor. 10. A pharmaceutical composition of claim 9 further comprising at one additional therapeutic agent selected from prothrombolytic agents, thrombin inhibitors, platelet aggregation inhibitors, PAI-1 inhibitors, thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thromboxane receptor antagonists, thromboxane synthase inhibitors, serotonin-2-receptor antagonists, aspirin, hypolipodemic agents, antihypertensive agents, or combinations thereof. 11. A pharmaceutical combination of claim 10 wherein the additional therapeutic agent is streptokinase, releplase, activase, lanoteplase, urokinase, prourokinase, ASPAC, animal salivary gland plasminogen activators, warfarin, clopidogrel, aspirin, ticlopidine, ifetroban, XR-330, T-686, dipyridamole, cilostazol, picotamide or ketanserin or combinations thereof. 12. A method for treating Factor Xa-associated disorders selected from thromboses, coronary artery disease or cerebrovascular disease, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound of claim 1.

Details for Patent 6,555,542

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2021-01-30
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	11/13/1987		2021-01-30
Genentech, Inc.	CATHFLO ACTIVASE	alteplase	For Injection	103172	09/04/2001		2021-01-30