Dual antiplatelet/anticoagulant pyridoxine analogs

1. A compound of the formula:

wherein

R 1 is —(CR 7 R 8 ) m OH, where m is an integer from 0 to 8, where R 7 is H, halo, alkyl, cycloalkyl, hydroxyl, O-alkyl, or O-alkyl, or O-alkyl-aryl-R 6 , where R 6 is —NO 2 , —NH 2 , amidine, alkyl, cycloalkyl, —CN,

where R 9 is H, OH, or O-alkyl, and where R 8 is H, halo, alkyl, cycloalkyl, hydroxyl, O-alkyl, or O-alkyl-aryl-R 6 , where R 6 is as defined above;

—(CR 7 R 8 ) m O-alkyl, wherein m, R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m O-aryl-R 6 , where m, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m O-alkyl-aryl-R 6 , where m and R 6 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-R 6 , where n is an integer from 0 to 8, and where R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-aryl-R 6 where n, R 6 , R 7 and R 8 are as defined above;

—NH-aryl-R 6 , where R 6 is as defined above;

—(CR 7 R 8 ) n —CO—NH-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above; or

—(CR 7 R 8 ) n —CO—NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

R 2 is hydroxyl;

halo;

alkyl;

—(CR 7 R 8 ) m —X, where m, R 7 and R 8 are as defined above, where X is OH, F, Cl or Br;

—(CH 2 ) n COOH, where n is as defined above;

—(CR 7 R 8 ) m COO(CR 7 R 8 ) n CH 3 , where m, n, R 7 and R 8 are as defined above;

—(CR 7 R 8 ) m NH(CR 7 R 8 ) n COOH, where m, n, R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n -aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n -aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) m —CHF 2 , where m, R 7 and R 8 are defined as above;

—(CR 7 R 8 ) n —NH-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-aryl-R 6 where n, R 6 , R 7 and R 8 are as defined above;

NH-aryl-R 6 , where R 6 is as defined above;

—(CR 7 R 8 ) n —CO—NH-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above; or

—(CR 7 R 8 ) n —CO—NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

R 3 is —(CR 7 R 8 ) m OH, where m, R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m O-alkyl, where m, R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m O-aryl-R 6 , where m, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m O-alkyl-aryl-R 6 , where m and R 6 is as defined above;

—(CR 7 R 8 ) n OH, where n, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-aryl-R 9 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—NH-aryl-R 6 , where R 6 is as defined above;

—(CR 7 R 8 ) n —CO—NH-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above; or

—(CR 7 R 8 ) n —CO—NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

R 4 is H, aryl, cycloalkyl, arylalkyl, CHF 2 , CHO, or R 2 ;

R 5 is H, aryl, cycloalkyl, arylalkyl, CHF 2 , CHO, or R 2 ;

wherein aryl is phenyl or naphthyl; and

at least two of R 1 , R 2 , R 3 , R 4 , and R 5 have amidine groups;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.

3. A compound of the formula

wherein

R 1 is hydroxyl; O-alkyl; or

where R 6 is —NO 2 , —NH 2 , amidine, alkyl, cycloalkyl, —CN,

where R 9 is H, OH, or O-alkyl;

R 2 is CH 2 OH;

CH 2 OCH 3 ;

COOZ, where Z is OH, OCH 3 , OCH 2 CH 3 , or

 where R 6 is defined above;

CH 2 OBn;

CH 3 ;

CH 2 F;

CHF 2 ;

CH 2 —NH—(CH 2 ) m —CO 2 Z, where m′=0, 1, 2, 3, 4, or 5, and where Z is as defined above; or

(CH 2 ) n′ —CO 2 Z, where n′=1, 2 or 3, and where Z is as defined above;

A is O or NH;

W is C═O or (CH 2 ) n′ , where n′ is as defined above;

E is C═O; (CH 2 ) n′ , where n′ is as defined above; or CHR 10 , where R 10 is CH 2 COZ, where Z is as defined above;

Y is C—H, C—F, C—OCH 3 , C—OCF 3 , or C—CF 3 ;

R 4 is H;

halo;

aryl;

cycloalkyl;

arylalkyl;

CHF 2 ;

CHO;

alkyl;

—(CR 7 R 8 ) m —X, where m is an integer from 0 to 8, where R 7 is H, F, alkyl, cycloalkyl, hydroxyl, O-alkyl, or O-alkyl-aryl-R 6 , where R 8 is H, F, alkyl, cycloalkyl, hydroxyl, O-alkyl, or O-alkyl-aryl-R 6 , where R 6 is as defined above, and where X is OH, F, or Br;

—(CH 2 ) n COOH, where n is an integer from 0 to 8;

—(CR 7 R 8 ) m COO(CR 7 R 8 ) n CH 3 , where m, n, R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) m NH(CR 7 R 8 ) n COOH, where m, n, R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n -aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n -aryl-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n —CHF 2 , where n, R 7 and R 8 are defined as above;

—(CR 7 R 8 ) n —NH-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

—(CR 7 R 8 ) n —NH-aryl-aryl-R 6 , where n, R 6 , R 7 and R 8 are as defined above;

—(CR 7 R 8 ) n —NH—CO-aryl-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

NH-aryl-R 6 where R 6 is as defined above;

—(CR 7 R 8 ) n —CO—NH-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above; or

—(CR 7 R 8 ) n —CO—NH-aryl-aryl-R 6 , where n, R 6 , R 7 , and R 8 are as defined above;

R 5 is H, aryl, cycloalkyl, arylalkyl, CHF 2 , CHO, or R 4 , where R 4 is as defined above; and

at least two of R 1 , R 4 , R 5 , and R 6 have amidine groups;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein the compound is 4-{4-fluoromethyl-2-methyl-5-[(4-carbamimidoyl-benzyloxy)-methyl]-pyridin-3-yloxymethyl}-benzamidine.

5. The compound of claim 3 , wherein the compound is 4-{[5-(4-carbamimidoyl-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-benzamidine.

6. The compound of claim 3 , wherein the compound is 4-{[5-(3-carbamimidoyl-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-benzamidine.

7. The compound of claim 3 , wherein the compound is 3-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxymethyl)-2-methyl-pyridin-4-yl]-propionic acid ethyl ester.

8. The compound of claim 3 , wherein the compound is 6-({3-(4-carbamimidoyl-benzyloxy)-5-[(4-carbamimidoyl-phenylamino)-methyl]-2-methyl-pyridin-4-ylmethyl}-amino)-hexanoic acid.

9. The compound of claim 3 , wherein the compound is 6-({3-(4-carbamimidoyl-benzyloxy)-5-[(4′-carbamimidoyl-biphenyl-4-ylamino)-methyl]-2-methyl-pyridin-4-ylmethyl}-amino) hexanoic acid.

10. The compound of claim 3 , wherein the compound is 4-{[4,6-Bis-fluoromethyl-5-(3-amidine-benzyloxy)-pyridin-3-ylmethyl]-amino}-benzamidine.

11. The compound of claim 3 , wherein the compound is 4-{5-[(4-Carbamimidoyl-phenylamino)-methyl]-2,4-bis-fluoromethyl-pyridin-3-yloxymethyl}-benzamidine.

12. The compound of claim 3 , wherein the compound is 4-{[5-(3-Amidine-benzyloxy)-6-fluoro-methyl-4-methyl-pyridin-3-ylmethyl]-amino}-benzamidine.

13. The compound of claim 3 , wherein the compound is 4-{[4-Fluoromethyl-5-(3-amidine-benzyloxy)-6-methyl-pyridin-3-ylmethyl]-amino}-benzamidine.

14. The compound of claim 3 , wherein the compound is 4-{5-[(4-Carbamimidoyl-phenylamino)-methyl]-6-cyclopropyl-4-hydroxymethyl-2-methyl-pyridin-3-yloxymethyl}-benzamidine.

15. The compound of claim 3 , wherein the compound is 4-{[5-(3-Amidine-benzyloxy)-6-hydroxymethyl-4-methyl-pyridin-3-ylmethyl]-amino}-benzamidine.

16. The compound of claim 3 , wherein the compound is 3-{5-[(4-Carbamimidoyl-phenylamino)-methyl]-6-cyclopropyl-4-hydroxymethyl-2-methyl-pyridin-3-yloxymethyl}-benzamidine.

17. The compound of claim 3 , wherein the compound is 3-{5-[(4-Amidino-phenylamino)-methyl]-4-ethyl-2-methyl-pyridin-3-yloxymethyl}-benzamidine.

18. The compound of claim 3 , wherein the compound is 4-{5-[(3-amidino-phenylamino)-methyl]-2,4-dimethyl-pyridin-3-yloxy}benzamidine.

19. The compound of claim 3 , wherein the compound is 4-{[5-(3-Amidine-benzyloxy)-6-formyl-4-methyl-pyridin-3-ylmethyl]-amino}-benzamidine.

20. The compound of claim 3 , wherein the compound is 4-{[4,6-Dimethyl-5-(3-hydroxyamidine-benzyloxy)-pyridin-3-ylmethyl]-amino-}-N-hydroxybenzamidine.

21. The compound of claim 3 , wherein the compound is 4-{[5(3-Methoxyamidine-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-N-methoxybenzamidine hydrochloride.

22. The compound of claim 3 , wherein the compound is 4-{[5(3-Ethoxy-amidine-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-N-ethoxybenzamidine hydrochloride.