Inter-phenylene-PG-3,4-didehydropiperidylamides

Abstract

The present invention relates to inter-phenylene-PG 3,4-didehydropiperidylamides. These compounds are pharmacological agents, being prolonged orally active platelet aggregation inhibitors in mammalian species. These compounds are accordingly useful for antithrombotic applications.

Description

The present invention relates to inter-phenylene-PG 3,4-didehydropiperidylamides, the essential material constituting a disclosure of which is incorporated here by reference from U.S. Pat. 4,110,192. In particular, the present invention relates to inter-phenylene-PG 3,4-didehydropiperidylamides of the unsubstituted inter-phenylene PG amides described in U.S. Pat. 4,110,192.

The present invention particularly relates to the following compounds:

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-11-DEOXY-PGF.sub.1.alpha., 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGF.sub.1.alpha., 3,4-didehydropiperdyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-9-DEOXY-PGD.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGD.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-9-DEOXY-9,10-DIDEHYDRO-PGD.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGA.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINO-13,14-DIHYDRO-11-DEOXY-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-CIS-13-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINO-13,14-DIHYDRO-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGE.sub.1, 2,3-didehydropiperidyl amide;

15-EPI-3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-17-PHENYL-4,5,6,18,19,20-HEXANOR-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE- 3-OXA-16-PHENOXY- 4,5,6,17,18,19,20-HEPTANORPGE.sub.1, 3,4-didehydropiperidyl amide;

2A, 2B-DIHOMO-3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-16,16-DIMETHYL-PGE.sub.1, 3,4-didehydropiperidyl amide;

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-15-METHYL-PGE.sub.1, 3,4-didehydropiperidyl amide; and

3,7-INTER-M-PHENYLENE-3-OXA-4,5,6-TRINOR-PGE.sub.1, 3,4-didehydropiperidyl amide.

Claims

1. A prostaglandin analog of the formula ##STR1## 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 ##STR2## wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the provisio 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 ##STR3## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is

(1) --(CH.sub.2).sub.m --CH.sub.3, ##STR4## wherein h is zero to 3, inclusive, wherein m is one to 5, inclusive, s is zero, one, 2, or 3, 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 provision that not more than two T's are other than alkyl; and

wherein R.sub.21 and R.sub.22 are

(i) hydrogen

(ii) alkyl of one to 12 carbon atoms, inclusive;

(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(iv) aralkyl of 7 to 12 carbon atoms, inclusive;

(v) phenyl;

(vi) phenyl substituted with one, 2, or 3 chloro,

alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl or one to 4 carbon atoms, inclusive, or nitro;

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

(viii) carbamoylalkyl of one to 4 carbon atoms, inclusive;

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

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

(xi) benzoylalkyl of one to 4 carbon atoms, inclusive;

(xii) 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;

(xiii) pyridyl;

(xiv) pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;

(xv) pyridylalkyl of one to 4 carbon atoms, inclusive;

(xvi) pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive;

(xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive;

(xviii) dihydroxyalkyl of one to 4 carbon atoms; and

(xix) trihydroxyalkyl of one to 4 carbon atoms; with the

further proviso that not more than one of R.sub.21 and R.sub.22 is other than hydrogen or alkyl.

2. A prostaglandin analog according to claim 1, wherein ##STR5##

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., 2,3-didehydropiperidylamide, 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., 3,4dihydropiperidyl amide a prostaglandin analog according to claim 5.

7. A prostaglandin analog according to claim 1, wherein ##STR6##

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, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, a prostaglandin analog according to claim 10.

12. A prostaglandin analog according to claim 1, wherein ##STR7##

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

14. A prostaglandin analog according to claim 1, wherein ##STR8##

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

16. A prostaglandin analog according to claim 1, wherein ##STR9##

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-dihyro11-deoxy-PGF.sub.1, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, 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-dihydroPGE.sub.1, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, 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 ##STR10##

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

31. A prostaglandin analog according to claim 28, wherein M.sub.1 is ##STR11##

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 ##STR12##

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

35. A prostaglandin analog according to claim 32, wherein R.sub.7 is ##STR13##

36. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,-19,20-heptanor-PGE.sub.1, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, 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 3,4-dihydropiperidyl amide, 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, 3,4-dihydropiperidyl amide, a prostaglandin analog according to claim 49.