Inter-phenylene-13,14-dihydro-PG amides

Abstract

The present invention relates to inter-phenylene-13,14-dihydro-PG 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

SPECIFICATION

The present invention relates to inter-phenylene-13,14-dihydro-PG amides, the essential material constituting a disclosure of which is incorporated here by reference from Ser. No. 788,455. In particular, the present invention relates to inter-phenylene-13,14-dihydro-PG amides of the unsubstituted inter-phenylene PG amides described in Ser. No. 788,455 now U.S. Pat. No. 4,100,192.

Claims

1. A prostaglandin analog of the formula ##STR1## wherein D is ##STR2## wherein R.sub.8 is hydrogen or hydroxy; wherein g is one, 2, or 3;

wherein Z.sub.3 is oxa or methylene;

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 m is one to 5, inclusive; 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 or nitro;

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

(viii) dihydroxyalkyl of one to 4 carbon atoms; or

(ix) 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 D is ##STR6##

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-13,14-dihydro-11-deoxy-PGF.sub.1, amide, 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-13,14-dihydro-11-deoxy-PGF.sub.1, amide, a prostaglandin analog according to claim 5.

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

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-13,14-dihydro-9-deoxy-PGD.sub.1, 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-13,14-dihydro-PGD.sub.1, amide, a prostaglandin analog according to claim 10.

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

13. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-9-deoxy-9,10-didehydro-PGD.sub.1, amide, a prostaglandin analog according to claim 12.

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

15. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGA.sub.1, amide, a prostaglandin analog according to claim 14.

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

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, 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 Z.sub.3 is methylene.

21. A prostaglandin analog according to claim 20, wherein Z.sub.3 is attached to the phenyl ring in the position meta to methylene.

22. 3,7-inter-m-Phenylene-4,5,6-trinor-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 21.

23. A prostaglandin analog according to claim 19, wherein Z.sub.3 is oxa.

24. A prostaglandin analog according to claim 23, wherein M.sub.1 is ##STR11##

25. 15-epi-3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 24.

26. A prostaglandin analog according to claim 23, wherein M.sub.1 is ##STR12##

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

28. A prostaglandin analog according to claim 27, wherein m is 3.

29. A prostaglandin analog according to claim 28, wherein g is 3.

30. 2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 29.

31. A prostaglandin analog according to claim 28, wherein g is one.

32. A prostaglandin analog according to claim 31, wherein at least one of R.sub.3 and R.sub.4 is methyl.

33. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-16,16-dimethyl-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 32.

34. A prostaglandin analog according to claim 31, wherein at least one of R.sub.3 and R.sub.4 is fluoro.

35. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 34.

36. A prostaglandin analog according to claim 31, wherein R.sub.3 and R.sub.4 are both hydrogen.

37. A prostaglandin analog according to claim 36, wherein R.sub.5 is methyl.

38. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-15-methyl-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 37.

39. A prostaglandin analog according to claim 36, wherein R.sub.5 is hydrogen.

40. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, n-propylamide, a prostaglandin analog according to claim 39.

41. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, ethylamide, a prostaglandin analog according to claim 39.

42. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, methylamide, a prostaglandin analog according to claim 39.

43. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim 39.