Thiophene integrin inhibitors

• US 6,274,620 B1
• Filed: 06/07/2000
• Issued: 08/14/2001
• Est. Priority Date: 06/07/1999
• Status: Expired due to Fees

• Current Assignee: Biochem Pharma, Incorporated (Shire plc)
• Original Assignee: Biochem Pharma, Incorporated (Shire plc)
• Inventors: Préville, Patrice, Charron, Sylvie, Bubenik, Monica, Labrecque, Denis, Denis, Réal, Attardo, Giorgio, Falardeau, Guy, Zacharie, Boulos, Chan, Laval, Lamothe, Serge
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/588,574
• Time in Patent Office: 433 Days
• Field of Search: 514/448, 514/471, 514/275, 514/241, 514/423, 549/72, 549/487, 544/331, 544/180, 548/537
• US Class Current: 514/448
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 307/64 Sulfur atoms
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/34 Sulfur atoms
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention comprises compounds that are effective inhibitors of integrins, particularly αvβ3 and αvβ5 integrins. Particularly, the compounds are of formula I

and pharmaceutically acceptable salts thereof wherein X,Y₁ W, R1 to R5, A and B are defined according to the disclosure herein.

Claims

1. A compound of formula I:

and pharmaceutically acceptable salts thereof, wherein;

X is selected from the group consisting of O and S;

Y₁ is selected from the group consisting of O, S and N;

W is selected from the group consisting of carbonyl and sulfonyl;

R1 and R2 are independently selected from the group consisting of H, C_5-10aryl, C_5-10arylsulfonylamino, C_5-10cycloalkylsulfonylamino, C_5-10arylamino and C_5-10arylC_1-6alkyl with the proviso that R1 and R2 are not both H;

R3 is selected from the group consisting of H, C_1-8alkyl, C_1-8alkylamino C_0-8alkyl, C_1-8alkoxy, C_1-8alkylepoxy C_1-8alkylC_1-8alkyl-Y₂C(O)Y₃—

C_0-8alkyl, C_5-8aryl, C_5-8arylC_0-8alkyl-Y₂C(O)Y₃—

C_0-8alkyl, C_5-8aryl, C_1-8alkylC_5-8aryl, and C_5-8arylC_1-8alkyl, wherein Y₂ and Y₃ are independently O or N;

R4 and R5 are independently selected from the group consisting of H, halogen, C_1-6alkyl and C_1-6alkoxy;

A is selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_5-10aryl, C_3-10cycloakyl; and

B is selected from the group consisting of amino, C_1-6aminoalkyl, C_5-10arylamino, guanidino, C_1-6guanidinoalkyl, cyclic guanidino, urea, cyclic urea.

2. The compound of claim 1, wherein X is S.

4. The compound of claim 2, wherein R4 and R5 are H.

5. The compound of claim 2, wherein W is carbonyl.

6. The compound of claim 2, wherein R1 is H and R2 is C_5-10arylsulfonylamino.

7. The compound of claim 5, wherein R1 is H and R2 is selected from the group consisting of phenylsulfonylamino and trimethylphenylsulfonylamino.

8. The compound of claim 2, wherein R1 is H and R2 is C_5-10aralkyl.

9. The compound of claim 7, wherein R1 is H and R2 is benzyloxycarbonyl.

10. The compound of claim 2, wherein R1 is H and R2 is C_5-10arylamino.

11. The compound of claim 8, wherein R1 is H and R2 is pyrimidinylamino.

12. The compound of claim 2, wherein A is C_1-6alkyl.

13. The compound of claim 12, wherein A is —

(CH₂)₃—

.

14. The compound of claim 2, wherein A is C_2-6alkenyl.

15. The compound of claim 14, wherein A is —

(CH₂)_0-2—

C═

C—

(CH₂)_0-2—

.

16. The compound of claim 15, wherein A is —

CH═

CH—

CH₂—

.

17. The compound of claim 2, wherein A is C_2-6alkynyl.

18. The compound of claim 17, wherein A is —

(CH₂)_0-2—

C≡

C—

(CH₂)_0-2—

.

19. The compound of claim 18, wherein A is —

C≡

C—

CH₂—

.

20. The compound of claim 2, wherein A is C_5-10aryl.

21. The compound of claim 20, wherein A is selected from the group consisting of:

wherein R₁₂ is selected from the group consisting of H, C_1-6 alkyl, C_1-6alkoxy and NH₂.

22. The compound of claim 21, wherein A is selected from the group consisting of:

wherein R₁₂ is selected from the group consisting of H and NH₂.

23. The compound of claim 2, wherein B is selected from the group consisting of guanidino and C_1-6guanidinoalkyl.

24. The compound of claim 2, wherein B is selected from the group consisting of amino, C_1-6aminoalkyl, C_5-10arylamino.

25. The compound of claim 1, wherein either R1 or R2 are H with the proviso that both R1 and R2 are not H.

26. The compound of claim 1, wherein Y₁ is —

NH—

.

27. The compound of claim 1, wherein Y₁ is —

C—

.

28. The compound of claim 1, wherein R3 is selected from the group consisting of H, halogen, C_1-18alkyl, C_1-18alkylamino C_0-18alkyl, C_1-18hydroxyalkyl, C_1-18alkylether, C_1-18alkylthioether, C_1-18alkyl-Y₂C(O)Y₃—

C_0-18alkyl, C_1-18alkyl-C(O)Y₃—

C_0-18alkyl, C_1-18alkyl-Y₂C(O)—

C_0-18alkyl, C_5-12aryl, C_5-12arylC_0-18alkyl-Y₂C(O)Y₃—

C_0-18alkyl, C_1-18alkylC_5-12aryl, C_5-12arylC_1-18alkyl, —

C(O) C_1-18alkenyl, C_0-18alkyl-C_3-12cycloalkyl, C_1-18haloalkyl, and C_1-18alkynyl, wherein Y₂ and Y₃ are independently O, S or N.

29. The compound of claim 1, wherein R3 is selected from the group consisting of H, halogen, C_1-10alkyl, C_1-10alkylamino C_0-10alkyl, C_1-10hydroxyalkyl, C_1-10alkylether, C_1-10alkylthioether, C_1-10alkyl-Y₂C(O)Y₃—

C_0-10alkyl, C_1-10alkyl-C(O)Y₃—

C_0-10alkyl, C_1-10alkyl-Y₂C(O)-C_0-10alkyl, C_5-12aryl, C_5-12arylC_0-10alkyl-Y₂C(O)Y₃—

C_0-10alkyl, C_1-10alkylC_5-12aryl, C_5-12arylC_1-18alkyl, —

C(O) C_1-10alkenyl, C_0-10alkyl-C_3-12cycloalkyl, C_1-18haloalkyl, and C_1-10alkynyl, wherein Y₂ and Y₃ are independently O, S or N, wherein Y₂ and Y₃ are independently O, S or N.

30. The compound of claim 1, wherein R3 is selected from the group consisting of H, halogen, C_1-18alkyl, C_1-18alkylamino C_0-18alkyl, C_1-18hydroxyalkyl, C_1-18alkylether, C_1-18alkyl-C(O)Y₃—

C_0-18alkyl, C_1-18alkyl-Y₂C (O)—

C_0-18alkyl, C_5-12aryl, C_1-18alkylC_5-12aryl, C_5-12arylC_1-18alkyl, —

C(O)C_1-18alkenyl, C_0-18alkyl-C_3-12cycloalkyl, and C_1-18haloalkyl, wherein Y₂ and Y₃ are independently O, S or N.

31. The compound of claim 1, wherein R3 is selected from the group consisting of H, C_1-18alkyl, C_1-18alkylamino C_0-18alkyl, C_1-18hydroxyalkyl, C_1-18alkylether, C_5-12aryl, C_1-18alkylC_5-12aryl, and C_5-12arylC_1-18alkyl.

32. The compound of claim 1, wherein R3 is selected from the group consisting of H, C_1-18alkyl, C_1-18alkylaminoC_0-18alkyl, C_1-18hydroxyalkyl, and C_1-18alkylether.

33. The compound of claim 1, wherein R3 is C_1-18alkyl.

34. The compound of claim 1, wherein R3 is selected from the group consisting of C_1-18alkyl-Y₂C(O)Y₃—

C_0-18alkyl, C_1-18alkyl-C(O)Y₃—

C_0-18alkyl, C_1-18alkyl-Y₂C(O) C_0-18alkyl, C_5-12aryl C_0-18alkyl-Y₂C(O)Y₃—

C_0-18alkyl, wherein Y₂ and Y₃ are independently O, S or N.

35. The compound of claim 1, wherein Y₁ is —

NH— and

R3 is C_1-18alkyl.

36. The compound of claim 1, wherein Y₁ is —

O— and

R3 is C_1-18alkyl.

37. The compound of claim 1, wherein R3 is H.

38. The compound of claim 1, wherein R3 is selected from the group consisting of C_5-12aryl, C_1-18alkylC_5-12aryl, and C_5-12aryl C_1-18alkyl.

3. The compound of 1, wherein R1 and R2 are represented by the formula N—

Y₄—

R6 wherein

Y₄ is selected from the group consisting of —

CO₂—

, —

SO₂— and

—

(CH₂)_0-2—

;

R6 is selected from the group consisting of;

wherein R7, R8, R9, R10, R11 are independently selected from the group consisting of H, C_1-6alkyl, C_1-6alkoxy and halogen.