7A-Homo-4-oxo-PGI.sub.1 compounds

Abstract

This invention relates to certain 7a-homo-4-oxo-PGI.sub.1 compounds. These novel prostacyclin-type compounds are useful for pharmacological purposes.

Description

The present invention relates to 7a-homo-4-oxo-PGI.sub.1 compounds whose preparation and use is described in Ser. No. 857,106, filed Dec. 5, 1977, now issued as U.S. Pat. No. 4,126,744.

The essential material constituting a disclosure of these 7a-homo-4-oxo-PGI.sub.1 compounds is incorporated here by reference from U.S. Pat. No. 4,126,744.

Claims

1. A prostacyclin analog of the formula ##STR1## wherein .about. represents attachment of the side chain in the alpha or beta configuration or a mixture of alpha and beta configurations;

Wherein g is the integer one, 2, or 3;

Where R.sub.8 is hydrogen, hydroxy, or hydroxymethyl;

Wherein Y.sub.1 is

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

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

(3) --ch.sub.2 ch.sub.2 --, or

(4) --C.tbd.C--,

wherein M.sub.1 is ##STR2## wherein R.sub.5 is hydrogen or alkyl with one to 4 carbon atoms, inclusive,

Wherein L.sub.1 is ##STR3## 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 fluoro only when the other is hydrogen or fluoro;

Wherein Z.sub.1 is

(1) --COOR.sub.1 wherein R.sub.1 is hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; hydrocarbylaralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR4## WHEREIN R.sub.25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH.sub.2 ; R.sub.26 is methyl, phenyl, --NH.sub.2, or methoxy; and R.sub.27 is hydrogen or acetamido; inclusive, phenacyl, i.e., ##STR5## phenacyl substituted in the para position by chloro, bromo, phenyl, or benzamido; of a pharmacologically acceptable cation;

(2) --CH.sub.2 OH; or

(3) --COL.sub.4, wherein L.sub.4 is

(a) amino of the formula --NR.sub.21 R.sub.22 ; wherein R.sub.21 and R.sub.22 are hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; carboxyalkyl of one to 4 carbon atoms, inclusive; carbamoylalkyl of one to 4 carbon atoms, inclusive; cyanoalkyl of one to 4 carbon atoms, inclusive; acetylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl of one to 4 carbon atoms, inclusive; 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; pyridyl; 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; pyridylalkyl of one to 4 carbon atoms, inclusive; pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, or alkoxy of one to 3 carbon atoms, inclusive; hydroxyalkyl of one to 4 carbon atoms, inclusive; dihydroxyalkyl of one to 4 carbon atoms, and 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;

(b) cycloamino selected from the group consisting of ##STR6## wherein R.sub.21 and R.sub.22 are as defined above; (c) carbonylamino of the formula --NR.sub.23 COR.sub.21, wherein R.sub.23 is hydrogen or alkyl of one to 4 carbon atoms and R.sub.21 is as defined above;

(d) sulfonylamino of the formula --NR.sub.23 SO.sub.2 R.sub.21, wherein R.sub.21 and R.sub.23 are as defined above; or

(e) hydrazino of the formula --NR.sub.23 R.sub.24, wherein R.sub.23 is as defined above and R.sub.24 is amino of the formula --NR.sub.21 R.sub.22, as defined above, or cycloamino, as defined above; and

wherein R.sub.7 is

(1) --(CH.sub.2).sub.m --CH.sub.3, ##STR7## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two T's are other than alkyl.

2. A prostacyclin analog according to claim 1, wherein R.sub.8 is hydroxymethyl.

3. 7a-Homo-11-deoxy-11.alpha.-hydroxymethyl-4-oxo-6.alpha.- or 6.beta.-PGI.sub.1, a prostacyclin analog according to claim 2.

4. A prostacyclin analog according to claim 1, wherein R.sub.8 is hydrogen.

5. 7a-Homo-11-deoxy-4-oxo-6.alpha.- or 6.beta.-PGI.sub.1, a prostacyclin analog according to claim 4.

6. A prostacyclin analog according to claim 1, wherein R.sub.8 is hydroxy.

7. A prostacyclin analog according to claim 6, wherein Y.sub.1 is cis --CH.dbd.CH--, --C.tbd.C--, or --CH.sub.2 CH.sub.2 --.

8. 7a-Homo-cis-13-4-oxo-PGI.sub.1, a prostacyclin analog according to claim 7.

9. 7a-Homo-13,14-Didehydro-4-oxo-6.alpha.- or 6.beta.-PGI.sub.1, a prostacyclin analog according to claim 7.

10. 7a-Homo-13,14-Dihydro-4-oxo-6.alpha.- or 6.beta.-PGI.sub.1, a prostacyclin analog according to claim 7.

11. A prostacyclin analog according to claim 6, wherein Y.sub.1 is trans --CH.dbd.CH--,

12. A prostacyclin analog according to claim 11, wherein the C-6 side chain is a mixture of alpha and beta isomers.

13. 7a-Homo-(6RS)-4-oxo-PGI.sub.1, a prostacyclin analog according to claim 1.

14. A prostacyclin analog according to claim 11, wherein the C-6 side chain is in the alpha configuration.

15. 7a-Homo-4-oxo-6.alpha.-PGI.sub.1, a prostacyclin analog according to claim 14.

16. A prostacyclin analog according to claim 11, wherein the C-6 side chain is in the beta configuration.

17. A prostacyclin analog according to claim 16, wherein g is two.

18. 2a,7a-Dihomo-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 17.

19. A prostacyclin analog according to claim 16, wherein g is one or 3.

20. A prostacyclin analog according to claim 19, wherein g is one.

21. A prostacyclin analog according to claim 20, wherein R.sub.7 is ##STR8##

22. 7a-Homo-17-phenyl-18,19,20-trinor-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 21.

23. A prostacyclin analog according to claim 20, wherein R.sub.7 is ##STR9##

24. 7a-Homo-16-phenoxy-17,18,19,20-tetranor-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 23.

25. A prostacyclin analog according to claim 20, wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3 --.

26. A prostacyclin analog according to claim 25, wherein m is 3.

27. A prostacyclin analog according to claim 26, wherein X.sub.1 is --COL.sub.4.

28. 7a-Homo-4-oxo-6.beta.-PGI.sub.1, amide, a prostacyclin analog according to claim 27.

29. A prostacyclin analog according to claim 27, wherein X.sub.1 is --CH.sub.2 OH.

30. 7a-Homo-2-decarboxy-2-hydroxymethyl-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 29.

31. A prostacyclin analog according to claim 26, wherein X.sub.1 is --COOR.sub.1.

32. A prostacyclin analog according to claim 31, wherein R.sub.5 is methyl.

33. 7a-Homo-15-methyl-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 32.

34. A prostacyclin analog according to claim 31, wherein R.sub.5 is hydrogen.

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

36. 7a-Homo-16,16-difluoro-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 35.

37. A prostacyclin analog according to claim 34, wherein at least one of R.sub.3 and R.sub.4 is methyl.

38. 7a-Homo-16,16-dimethyl-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 37.

39. A prostacyclin analog according to claim 34, wherein R.sub.3 and R.sub.4 are both hydrogen.

40. 7a-Homo-4-oxo-6.beta.-PGI.sub.1, methyl ester, a prostacyclin analog according to claim 39.

41. 7a-Homo-4-oxo-6.beta.-PGI.sub.1, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim 39.

42. 7a-Homo-4-oxo-6.beta.-PGI.sub.1, adamantanamine salt, a prostacyclin analog according to claim 39.

43. 7a-Homo-4-oxo-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 39.