US2007142270A1PendingUtilityA1
Aryl Sulfonic Pyridoxines as Antiplatelet Agents
Est. expiryOct 28, 2024(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/12A61P 9/06A61P 7/02A61P 43/00A61P 7/10A61P 31/04A61P 9/10A61P 11/00C07D 491/04C07D 213/66
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Claims
Abstract
Aryl sulfonic pyridoxine compounds with inhibition of serine protease activity and antiplatelet aggregation characteristics for the treatment of cardiovascular and cardiovascular related diseases are described. The methods are directed to administering pharmaceutical compositions comprising aryl sulfonic pyridoxines.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting serine protease activity comprising:
administering a compound of the formula: wherein 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; or R 5 where R 5 is (CH 2 ) n -aryl-R 6 where n is as defined above and R 6 is SO 2 NH 2 or SO 2 NHC(CH 3 ) 3 ; (CH 2 ) n -aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-aryl-R 6 , where n and R 6 are as defined above; or —(CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; R 3 is alkyl; —(CH 2 ) n′ OH where n′ is as defined above; or R 5 where R 5 is (CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-R where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 where n and R 6 are as defined above; or (CH 2 ) n —NH—CO-aryl-aryl-R 6 where n and R 6 are as defined above; further wherein
R 2 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above, and R 3 is R 5 ; or
R 2 is R 5 and R 3 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above; and
R 1 and R 2 when taken together form compounds of formula II, wherein R 7 and R 8 are independently H or CH 3 , and R 5 is as defined above; or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein said serine protease is Factor Xa.
3 . The method of claim 1 , wherein said serine protease is Factor IIa.
4 . The method of claim 1 , wherein said serine protease is trypsin.
5 . The method of claim 1 , wherein at least one 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.
6 . The method of claim 5 , wherein the alkoxy group is methoxy or ethoxy.
7 . The method of claim 5 , wherein the amido group is acetamido.
8 . The method of claim 1 , wherein the aryl group is a phenyl group or a naphthyl group.
9 . The method of claim 1 , wherein the 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.
10 . The method of claim 9 , wherein the alkyl group is methyl or ethyl.
11 . The method of claim 9 , wherein the alkoxy group is methoxy or ethoxy.
12 . The method of claim 9 , wherein the amido group is acetamido.
13 . The method of claim 1 , wherein the aryl group is substituted with one or more functional groups.
14 . The method of claim 13 , wherein the functional group is a hydroxy group, carboxy group, or acetoxy group.
15 . A method of inhibiting serine protease activity comprising:
administering a compound of the formula wherein R 1 is OH; OCH 3 ; OCH 2 -(4-tert-Butyl-phenyl); or where R 4 is —CN or amidine; R 2 is (CH 2 ) m OH, where m=0 to 8; or R 5 , where R 5 is where W is (CH 2 ) n where n=1, 2, or 3; where X is C=0 or (CH 2 ) n′ , where n′=0, 1, 2, or 3; Y is CH, CF, or N; and R 6 is R 3 is (CH 2 ) m OH, where m is as defined above; or R 5 , where R 5 is as defined above; further wherein
R 2 is (CH 2 ) m OH, where m is as defined above, and R 3 is R 5 ; or
R 2 is R 5 and R 3 is (CH 2 ) m OH, where m is as defined above; and
R 1 and R 2 when taken together form a compound of formula IV wherein R 7 and R 8 are independently H or CH 3 ; and R 5 is as defined above; or a pharmaceutically acceptable salt thereof.
16 . The method of claim 15 , wherein said serine protease is Factor Xa.
17 . The method of claim 15 , wherein said serine protease is Factor Ia.
18 . The method of claim 15 , wherein said serine protease is trypsin.
19 . The method of claim 15 , wherein said compound is administered enterally, parenterally, or by inhalation.
20 . The method of claim 15 , wherein the compound is administered concurrently with another therapeutic agent.
21 . The method of claim 20 , wherein said other therapeutic agent is an anti-platelet agent, glycoprotein IIb/IIIa inhibitor, or anticoagulant.
22 . The method of claim 21 , wherein said anti-platelet agent is clopidogrel, aspirin, or dipyridamole.
23 . The method of claim 21 , wherein said glycoprotein IIb/IIIa inhibitor is eptifibatide.
24 . The method of claim 21 , wherein said anticoagulant is unfractionated heparin, low molecular weight heparin, hirudin, or argatroban.
25 . A method of inhibiting in vitro serine protease activity comprising:
contacting an isolated cell with a compound of the formula: wherein 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; or R 5 where R 5 is (CH 2 ) n -aryl-R 6 where n is as defined above and R 6 is SO 2 NH 2 or SO 2 NHC(CH 3 ) 3 ; (CH 2 ) n -aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-aryl-R 6 , where n and R 6 are as defined above; or —(CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; R 3 is alkyl; —(CH 2 ) n′ OH where n′ is as defined above; or R 5 where R 5 is (CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-R 6 where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 where n and R 6 are as defined above; or (CH 2 ) n —NH—CO-aryl-aryl-R 6 where n and R 6 are as defined above; further wherein
R 2 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above, and R 3 is R 5 ; or
R 2 is R 5 and R 3 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above; and
R 1 and R 2 when taken together form compounds of formula II, wherein R 7 and R 8 are independently H or CH 3 , and R 5 is as defined above; or a pharmaceutically acceptable salt thereof.
26 . A method of inhibiting serine protease activity comprising:
contacting an organism with a compound of the formula: wherein 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; or R 5 where R 5 is (CH 2 ) n -aryl-R 6 where n is as defined above and R 6 is SO 2 NH 2 or SO 2 NHC(CH 3 ) 3 ; (CH 2 ) n -aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-aryl-R 6 , where n and R 6 are as defined above; or —(CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; R 3 is alkyl; —(CH 2 ) n OH where n′ is as defined above; or R 5 where R 5 is (CH 2 ) n —NH-aryl-R 6 , where n and R 6 are as defined above; (CH 2 ) n —NH—CO-aryl-R 6 where n and R 6 are as defined above; (CH 2 ) n —NH-aryl-aryl-R 6 where n and R 6 are as defined above; or (CH 2 ) n —NH—CO-aryl-aryl-R 6 where n and R 6 are as defined above; further wherein
R 2 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above, and R 3 is R 5 ; or
R 2 is R 5 and R 3 is alkyl or —(CH 2 ) n′ OH where n′ is as defined above; and
R 1 and R 2 when taken together form compounds of formula II, wherein R 7 and R 8 are independently H or CH 3 , and R 5 is as defined above; or a pharmaceutically acceptable salt thereof.
27 . A compound of the formula
wherein
R 1 is OH; OCH 3 ; OCH 2 -(4-tert-Butyl-phenyl); or
where R 4 is —CN or amidine;
R 2 is (CH 2 ) m OH, where m=0 to 8; or R 5 , where R 5 is
where W is (CH 2 ) n where n=1, 2, or 3; where X is C=0 or (CH 2 ) n′ , where n′=0, 1, 2, or
3; Y is CH, CF, or N; and R 6 is
R 3 is (CH 2 ) m OH, where m is as defined above; or R 5 , where R 5 is as defined above;
further wherein
R 2 is (CH 2 ) m OH, where m is as defined above, and R 3 is R 5 ; or
R 2 is R 5 and R 3 is (CH 2 ) m OH, where m is as defined above; and
R 1 and R 2 when taken together form a compound of formula IV
wherein R 7 and R 8 are independently H or CH 3 ; and R 5 is as defined above; or a pharmaceutically acceptable salt thereof.
28 . A method of treating cardiovascular or related diseases in a mammal comprising administering a therapeutically effective amount of a compound of claim 27 .
29 . The method of claim 29 , wherein the compound is administered concurrently with another therapeutic agent.
30 . The method of claim 29 , wherein said other therapeutic agent is an anti-platelet agent, glycoprotein IIb/IIIa inhibitor, or anticoagulant.
31 . The method of claim 30 , wherein said anti-platelet agent is clopidogrel, aspirin, or dipyridamole.
32 . The method of claim 30 , wherein said glycoprotein IIb/IIIa inhibitor is eptifibatide.
33 . The method of claim 30 , wherein said anticoagulant is unfractionated heparin, low molecular weigh heparins, hirudin, or argatroban.Join the waitlist — get patent alerts
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