Smith, Herman W.;

2,2-Difluoro-trans-4,5,13,14-tetrahydro-PGI.sub.1 compounds

The present invention relates to certain structural and pharmacological analogs of prostacyclin (PGI.sub.2) which are 2,2-difluoro-trans-4,5,13,14-tetradehydro-PGI.sub.1 compounds. These novel pharmacological agents are useful as smooth muscle stimulators.

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I claim:

1. A prostacyclin analog of the formula ##STR1## wherein Y.sub.2 is --C.tbd.C--. wherein Z.sub.2 is ##STR2## wherein g is the integer zero, one, or 2; wherein M.sub.1 is ##STR3## wherein R.sub.5 is hydrogen or alkyl with one to 4 carbon atoms, inclusive;

wherein L.sub.1 is ##STR4## or a mixture of ##STR5## 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 R.sub.1 is 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, two or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR6## 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; phenacyl, i.e., ##STR7## phenacyl substituted in the para position by chloro, bromo, phenyl, or benzamido; or a pharmacologically acceptable cation;

wherein R.sub.7 is ##STR8## 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 Z.sub.2 is a mixture of ##STR9##

3. 2,2-Difluoro(6RS)-trans-4,5,13,14-tetradehydro-PGI.sub.1, a prostacyclin analog according to claim 2.

4. A prostacyclin analog according to claim 1, wherein Z.sub.2 is ##STR10##

5. 2,2-Difluoro-trans-4,5,13,14-tetradehydro-6.alpha.-PGI.sub.1, a prostacyclin analog according to claim 4.

6. 2,2-Difluoro-15-methyl-trans-4,5,13,14-tetradehydro-6.alpha.-PGI.sub.1, a prostacyclin analog according to claim 4.

7. 2,2-Difluoro-16,16-dimethyl-trans-4,5,13, 14-tetradehydro-6.alpha.-PGI.sub.1, a prostacyclin analog according to claim 4.

8. 2,2,16,16-Tetrafluoro-trans-4,5,13,14-tetradehydro-6.alpha.-PGI.sub.1, a prostacyclin analog according to claim 4.

9. A prostacyclin analog according to claim 1, wherein Z.sub.2 is ##STR11##

10. A prostacyclin analog according to claim 9, wherein g is zero.

11. A prostacyclin analog according to claim 10, wherein ##STR12##

12. 2,2-Difluoro-17-phenyl-18,19,20-trinor-trans-4,5,13,14-tetradehydro-6.b e ta.-PGI.sub.1, a prostacyclin analog according to claim 11.

13. A prostacyclin analog according to claim 10, wherein ##STR13##

1 4. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-trans-4,5,13,14-tetradehydr o-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 13.

15. A prostacyclin analog according to claim 10, wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3 --.

16. A prostacyclin analog according to claim 15, wherein R.sub.5 is methyl.

17. 2,2-Difluro-15-methyl-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 16.

18. A prostacyclin analog according to claim 15, wherein R.sub.5 is hydrogen.

19. A prostacyclin analog according to claim 18, wherein at least one of R.sub.3 and R.sub.4 is fluoro.

20. 2,2,16,16-Tetrafluoro-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 19.

21. A prostacyclin analog according to claim 18, wherein at least one of R.sub.3 and R.sub.4 is methyl.

22. 2,2-Difluoro-16,16-dimethyl -trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 21.

23. A prostacyclin analog according to claim 18, wherein R.sub.3 and R.sub.4 are both hydrogen.

24. 2,2-Difluoro-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, methyl ester, a prostacyclin analog according to claim 23.

25. 2,2-Difluoro-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim 23.

26. 2,2-Difluoro-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, adamantanamine salt, a prostacyclin analog according to claim 23.

27. 2,2-Difluoro-trans-4,5,13,14-tetradehydro-6.beta.-PGI.sub.1, a prostacyclin analog according to claim 23.