Thrombin inhibitors
View Patent ↗Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein Q is CH 2 , NR 4 , O, S, S(O) or S(O 2 ), wherein R 4 is H, C 1-6 alkyl, aryl, or C 3-8 cycloalkyl; R 1 is a heterocycle or —(CR 5 R 6 ) 1-2 NH 2 , wherein R 5 and R 6 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH; R 2 is OH, NH 2 or NHSO 2 CH 3 ; R 3 is C 1-6 alkyl.
1. A compound of the formula I
or a pharmaceutically acceptable salt thereof, wherein
Q is S, S(O) or S(O 2 );
R 1 is a heterocycle or —(CR 5 R 6 ) 1-2 NH 2 , wherein R 5 and R 6 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH;
R 2 is OH, NH 2 or NHSO 2 CH 3 ; and
R 3 is C 1-6 alkyl.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula Ia
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is tetrazole or —CH 2 NH 2 .
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 NH 2 .
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OH.
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —C(CH 3 ) 3 .
7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
9. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, having the formula Ib
10. A compound of claim 1 , or pharmaceutically acceptable salt thereof, which is
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide,
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1-oxide, or
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1,1-dioxide.
11. A salt of claim 10 which is
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide trifluoroacetate,
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1-oxide trifluoroacetate, or
(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1,1-dioxide trifluoroacetate.
12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
13. A method for inhibiting thrombin in blood comprising adding to the blood a composition of claim 12 .
14. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to the blood a composition of claim 12 .
15. A method for inhibiting thrombus formation in blood comprising adding to the blood a composition of claim 12 .
16. A method for treating venous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a composition of claim 12 .
17. A method for treating deep vein thrombosis in a mammal comprising administering to the mammal a composition of claim 12 .
18. A method for treating thromboembolic stroke in humans and other mammals comprising administering to the mammal a composition of claim 12 .