Aryl sulfonic pyridoxines as antiplatelet agents
View Patent ↗Aryl sulfonic pyridoxine compounds with antiplatelet aggregation characteristics for the treatment of cardiovascular and cardiovascular related disease, are described. The methods are directed to administering pharmaceutical compositions comprising aryl sulfonic pyridoxines.
1. A compound of the formula:
wherein
A)
R 1 is —OH; —O-alkyl; —(CH 2 ) n′ OH where n′ is an integer from 1 to 8; alkyl; cycloalkyl; or O-alkyl-aryl-R 4 , where R 4 is —CN or amidine;
R 2 is (CH 2 ) n -aryl-R 5 where n is an integer from 0 to 8 and R 5 is SO 2 NH 2 or SO 2 NHC(CH 3 ) 3 ; (CH 2 ) n -aryl-aryl-R 5 , where n and R 5 are as defined above, or —(CH 2 ) n —NH-aryl-R 5 , where n and R 5 are as defined above; and
R 3 is —(CH 2 ) n OH where n is as defined above; (CH 2 ) n —NH-aryl-R 5 , where n and R 5 are as defined above; (CH 2 ) n —NH—CO-aryl-R 5 where n and R 5 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 5 where n and R 5 are as defined above; or (CH 2 ) n —NH—CO-aryl-aryl-R 5 where n and R 5 are as defined above; or
B)
R 1 is —OH; —O-alkyl; —(CH 2 ) n′ OH where n′ is an integer from 1 to 8; alkyl; cycloalkyl; or O-alkyl-aryl-R 4 , where R 4 is —CN or amidine;
R 2 is alkyl; —(CH 2 ) n′ OH where n′ is as defined above; —(CH 2 ) n COOH where n is an integer from 0 to 8; —(CH 2 ) n COO(CH 2 ) n CH 3 where n is as defined above; (CH 2 ) n -aryl-R 5 where n is as defined above and R 5 is SO 2 NH 2 or SO 2 NHC(CH 3 ) 3 ; (CH 2 ) n -aryl-aryl-R 5 , where n and R 5 are as defined above, or —(CH 2 ) n -NH-aryl-R 5 , where n and R 5 are as defined above;
R 3 is (CH 2 ) n —NH-aryl-R 5 , where n and R 5 are as defined above; (CH 2 ) n —NH—CO-aryl-R 5 where n and R 5 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 5 where n and R 5 are as defined above; or (CH 2 ) n —NH—CO-aryl-aryl-R 5 where n and R 5 are as defined above
and
R 1 and R 2 when taken together form a compound of formula II,
wherein R 3 is as defined above;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein an alkyl is substituted with one or more of fluorine, chlorine, alkoxy groups having 1 to 8 carbon atoms, or amido groups having from 1 to 8 carbon atoms.
3. The compound of claim 2 , wherein the alkoxy group is methoxy or ethoxy.
4. The compound of claim 2 , wherein the amido group is acetamido.
5. The compound of claim 1 , wherein an aryl group is a phenyl group or a naphthyl group.
6. The compound of claim 1 , wherein an aryl group is substituted with one or more of fluorine, chlorine, bromine, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkoxyalkyl groups having 1 to 8 carbon atoms, or amido groups having 1 to 8 carbon atoms.
7. The compound of claim 6 , wherein the alkyl group is methyl or ethyl.
8. The compound of claim 6 , wherein the alkoxy group is methoxy or ethoxy.
9. The compound of claim 6 , wherein the amido group is acetamido.
10. The compound of claim 1 , wherein an aryl group is substituted with one or more functional groups.
11. The compound of claim 10 , wherein the functional group is a hydroxy group, carboxy group, or acetoxy group.
12. A compound of the formula
wherein
R 1 is OH, OCH 3 , or OCH 2 —(4-tert-Butyl-phenyl), or
R 2 is CH 2 OH or
where R 8 is as defined above;
W is (CH 2 ) n where n′=1, 2 or 3;
X is (CH 2 ) n where n=0, 1, 2, or 3, or C═O;
Y is C—H, C—F, or N; and
R 1 and R 2 when taken together form a compound of formula
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein the compound is 3-{4-Hydroxymethyl-5[(2′-sulfamoyl-biphenyl-4-ylamino-methyl]-pyridin-3-yloxymethyl}-benzamidine.
14. A method of inhibiting platelet aggregation comprising administering the compound of claim 1 .
15. The method of claim 14 , wherein said compound is administered enterally, parenterally, or by inhalation.
16. A method of inhibiting platelet aggregation comprising administering the compound of claim 12 .
17. The method of claim 16 , wherein the compound is 3-{4-Hydroxymethyl-5[(2′-sulfamoyl-biphenyl-4-ylamino-methyl]-pyridin-3-yloxymethyl}-benzamidine.
18. The method of claim 15 , wherein the compound is administered concurrently with another therapeutic agent.
19. The method of claim 18 , wherein said other therapeutic agent is an anti-platelet agent, glycoprotein IIb/IIIa inhibitor, or anticoagulant.
20. The method of claim 19 , wherein said anti-platelet agent is clopidogrel, aspirin, or dipyridamole.
21. The method of claim 19 , wherein said glycoprotein IIb/IIIa inhibitor is eptifibatide.
22. The method of claim 19 , wherein said anticoagulant is unfractionated heparin, low molecular weight heparins, hirudin, or argatroban.
23. A method of inhibiting platelet aggregation in a mammal post-surgically comprising administering a therapeutically effective amount of the compound according to claim 1 following a surgical procedure.
24. A method of claim 23 , wherein the surgical procedure is a hip replacement, invasive cardiovascular surgery, or angioplasty.
25. A method of claim 24 wherein the invasive cardiovascular surgery is coronary artery bypass graft or heart valve replacement.
26. A method of claim 23 , wherein the angioplasty is coronary, pulmonary, peripheral, intracranial, extracranial carotid, renal, and aortic angioplasty.
27. The method of claim 23 , wherein the compound is administered concurrently with another therapeutic agent.
28. The method of claim 23 , wherein the compound is coated on a medical device.
29. The method of claim 28 , wherein the medical device is an intravascular stent or catheter.
30. A method of inhibiting platelet aggregation in a mammal post-surgically comprising administering a therapeutically effective amount of the compound according to claim 12 following a surgical procedure.
31. A method of claim 30 , wherein the surgical procedure is a hip replacement angioplasty, or invasive cardiovascular surgery.
32. A method of claim 31 , wherein the invasive cardiovascular surgery is coronary artery bypass graft or heart valve replacement.
33. A method of claim 31 , wherein the angioplasty is coronary, pulmonary, peripheral, intracranial, extracranial carotid, renal, and aortic angioplasty.
34. The method of claim 30 , wherein the compound is administered concurrently with another therapeutic agent.
35. The method of claim 30 , wherein the compound is coated on a medical device.
36. The method of claim 35 , wherein the medical device is an intravascular stent or catheter.