Inter-phenylene-PG carbonyl- or cyano-substituted amides

Abstract

The present invention relates to inter-phenylene PG carbonyl- or cyano-substituted amides. These compounds are pharmacological agents, being prolonged orally active platelet aggregation inhibitors in mammalian species. These compounds are accordingly useful for antithrombotic applications.

Description

Claims

1. A prostaglandin analog of the formula ##STR1## wherein D is ##STR2## wherein R.sub.8 is hydrogen or hydroxy; WHEREIN Y.sub.1 is

(1) trans-CH.dbd.CH--,

(2) cis--CH.dbd.CH--, or

(3) --CH.sub.2 CH.sub.2 --,

wherein g is one, 2, or 3;

Wherein Z.sub.3 is oxa or methylene, with the proviso that Z.sub.3 is oxa only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;

Wherein L.sub.1 is ##STR3## or a mixture of ##STR4## wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is methyl only when the other is hydrogen or methyl;

Wherein M.sub.1 is ##STR5## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is (1) --(CH.sub.2).sub.m --CH.sub.3, ##STR6## wherein h is zero to 3, inclusive, wherein m is one to 5, inclusive, s is zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, or alkoxy of one to 3 carbon atoms, the various T's being the same or different, with the proviso that not more than two T's are other than alkyl; and

wherein L.sub.2 is

amino of the formula --NR.sub.21 R.sub.22, wherein one R.sub.21 and R.sub.22 is hydrogen or alkyl of one to 12 carbon atoms, inclusive; and the other of R.sub.21 and R.sub.22 is

(i) phenyl substituted with zero, one, or 2 nitro, chloro, alkyl of one to 3 carbon atoms, inclusive, or hydroxy and at least one but not more than three carboxy or alkoxycarbonyl of one to 4 carbon atoms, inclusive, with the overall proviso that there be not more than 3 substituents;

(ii) carboxyalkyl of one to 4 carbon atoms, inclusive;

(iii) carbamoylalkyl of one to four carbon atoms, inclusive,

(iv) cyanoalkyl of one to 4 carbon atoms, inclusive;

(v) acetylalkyl of one to 4 carbon atoms, inclusive;

(vi) benzoylalkyl of one to 4 carbon atoms, inclusive, or

(vii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro.

2. A prostaglandin analog according to claim 1, wherein D is ##STR7##

3. A prostaglandin analog according to claim 2, wherein R.sub.8 is hydrogen.

4. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-11-deoxy-PGF.sub.1 .alpha., p-carboxyanilide, a prostaglandin analog according to claim 3.

5. A prostaglandin analog according to claim 2, wherein R.sub.8 is hydroxy.

6. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-PGF.sub.1 .alpha., p-carboxyanilide, a prostaglandin analog according to claim 5.

7. A prostaglandin analog according to claim 1, wherein D is ##STR8##

8. A prostaglandin analog according to claim 7, wherein R.sub.8 is hydrogen.

9. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-9-deoxy-PGD.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 8.

10. A prostaglandin analog according to claim 7, wherein R.sub.8 is hydroxy.

11. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-PGD.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 10.

12. A prostaglandin analog according to claim 1, wherein D is ##STR9##

13. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-9-deoxy-9,10-didehydro-PGD.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 12.

14. A prostaglandin analog according to claim 1, wherein D is ##STR10##

15. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-PGA.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 14.

16. A prostaglandin analog according to claim 1, wherein D is ##STR11##

17. A prostaglandin analog according to claim 16, wherein R.sub.8 is hydrogen.

18. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-11-deoxy-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 17.

19. A prostaglandin analog according to claim 16, wherein R.sub.8 is hydroxy.

20. A prostaglandin analog according to claim 19, wherein Y.sub.1 is cis--CH.dbd.CH--.

21. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-cis-13-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 20.

22. A prostaglandin analog according to claim 19, wherein Y.sub.1 is CH.sub.2 CH.sub.2 --.

23. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 22.

24. A prostaglandin analog according to claim 19, wherein Y.sub.1 is trans--CH.dbd.CH--.

25. A prostaglandin analog according to claim 24, wherein Z.sub.3 is methylene.

26. A prostaglandin analog according to claim 25, wherein Z.sub.3 is attached to the phenyl ring in the position meta to methylene.

27. 3,7-inter-m-Phenylene-4,5,6-trinor-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 26.

28. A prostaglandin analog according to claim 24, wherein Z.sub.3 is oxa.

29. A prostaglandin analog according to claim 28, wherein M.sub.1 is ##STR12##

30. 15-epi-3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 29.

31. A prostaglandin analog according to claim 28, wherein M.sub.1 is ##STR13##

32. A prostaglandin analog according to claim 31, wherein Z.sub.3 is attached to the phenyl ring in the position meta to methylene.

33. A prostaglandin analog according to claim 32, wherein R.sub.7 is ##STR14##

34. 3,7-inter-m-Phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-hexanor-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 33.

35. A prostaglandin analog according to claim 32, wherein R.sub.7 is ##STR15##

36. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,-19,20-heptanor-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 35.

37. A prostaglandin analog according to claim 32, wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3.

38. A prostaglandin analog according to claim 37, wherein m is 3.

39. A prostaglandin analog according to claim 38, wherein g is 3.

40. 2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 39.

41. A prostaglandin analog according to claim 38, wherein g is 1.

42. A prostaglandin analog according to claim 41, wherein at least one of R.sub.3 and R.sub.4 is methyl.

43. 3,7-inter-m-Phenylene-3-oxa-4,5,6,-trinor-16,16-dimethyl-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 42.

44. A prostaglandin analog according to claim 41, wherein at least one of R.sub.3 and R.sub.4 is fluoro.

45. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 44.

46. A prostaglandin analog according to claim 41, wherein R.sub.3 and R.sub.4 are both hydrogen.

47. A prostaglandin analog according to claim 46, wherein R.sub.5 is methyl.

48. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-15-methyl- PGE.sub.1, p-carboxyanilide, a prostaglandin analog according to claim 47.

49. A prostaglandin analog according to claim 46, wherein R.sub.5 is hydrogen.

50. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-PGE.sub.1, P-carboxyanilide, a prostaglandin analog according to claim 49.