TREA

Inter-phenylene-.omega.-aryl-PG amides

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Information

  • Patent Grant
  • 4205011
  • Patent Number
    4,205,011
  • Date Filed
    Thursday, April 20, 1978
    46 years ago
  • Date Issued
    Tuesday, May 27, 1980
    44 years ago
Information
Abstract
The present invention relates to inter-phenylene-.omega.-aryl-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

The present invention relates to inter-phenylene-.omega.-aryl-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-.omega.-aryl-PG amides of the unsubstituted inter-phenylene PG amides described in Ser. No. 788,455 now U.S. Pat. No. 4,100,192.





The present invention is particularly concerned with the following compounds:
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGF.sub.1.alpha., amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF.sub.1.alpha., amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-PGD.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGD.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-9,10-didehydro-PGD.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-15-phenoxy-4,5,6,17,18,19,20-heptanor-PGA.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGE.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-cis-13-PGE.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-PGE.sub.1, amide;
3,7-Inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide;
15-Epi-3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide;
3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide;
3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide;
2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-16-methyl-PGE.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-16-methyl-PGE.sub.1, amide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, n-propylamide;
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, ethylamide; and
3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, methylamide.
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--, or
  • (2) cis--CH.dbd.CH--,
  • wherein g is one, 2, or 3;
  • wherein Z.sub.3 is oxa or methylene;
  • wherein L.sub.1 is ##STR2## or a mixture of ##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 methyl only when the other is hydrogen or methyl;
  • wherein M.sub.1 is ##STR4## wherein R.sub.5 is hydrogen or methyl; 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) hydroxyalkyl 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.
  • wherein Z.sub.4 is
  • --(CH.sub.2).sub.h or oxa,
  • wherein h is zero to 3, inclusive, and
  • wherein 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.
  • 2. A prostaglandin analog according to claim 1, wherein D is ##STR5##
  • 3. A prostaglandin analog according to claim 2, wherein R.sub.8 is hydrogen.
  • 4. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGF.sub.1.alpha., 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-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF.sub.1.alpha., amide, a prostaglandin analog according to claim 5.
  • 7. A prostaglandin analog according to claim 1, wherein D is ##STR6##
  • 8. A prostaglandin analog according to claim 7, wherein R.sub.8 is hydrogen.
  • 9. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-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-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGD.sub.1, amide, a prostaglandin analog according to claim 10.
  • 12. A prostaglandin analog according to claim 1, wherein D is ##STR7##
  • 13. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-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 ##STR8##
  • 15. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGA.sub.1, 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-16-phenoxy-4,5,6,17,18,19,20-heptanor-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 Y.sub.1 is cis--CH.dbd.CH--.
  • 21. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-cis-13-PGE.sub.1, 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-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-PGE.sub.1, 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-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, 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-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, 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 Z.sub.4 is --(CH.sub.2).sub.h.
  • 34. 3,7-inter-m-Phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide, a prostaglandin analog according to claim 33.
  • 35. A prostaglandin analog according to claim 32, wherein Z.sub.4 is oxa.
  • 36. A prostaglandin analog according to claim 32, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
  • 37. A prostaglandin analog according to claim 36, wherein g is 3.
  • 38. 2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGE.sub.1, amide, a prostaglandin analog according to claim 37.
  • 39. A prostaglandin analog according to claim 36, wherein g is one.
  • 40. A prostaglandin analog according to claim 39, wherein at least one of R.sub.3 and R.sub.4 is methyl.
  • 41. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-16-methyl-PGE.sub.1, amide, a prostaglandin analog according to claim 49.
  • 42. A prostaglandin analog according to claim 39, wherein R.sub.3 and R.sub.4 are both hydrogen.
  • 43. A prostaglandin analog according to claim 42, wherein R.sub.5 is methyl.
  • 44. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-15-methyl-PGE.sub.1, amide, a prostaglandin analog according to claim 43.
  • 45. A prostaglandin analog according to claim 42, wherein R.sub.5 is hydrogen.
  • 46. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, n-propylamide, a prostaglandin analog according to claim 45.
  • 47. 3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, ethylamide, a prostaglandin analog according to claim 45.
  • 48.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE.sub.1, methylamide, a prostaglandin analog according to claim 45.
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 788,455, filed Apr. 18, 1977, now U.S. Pat. No. 4,100,192, issued July 11, 1978.

US Referenced Citations (6)
Number Name Date Kind
3933895 Nelson Jan 1976
3933897 Nelson Jan 1976
3933898 Nelson Jan 1976
3933899 Nelson Jan 1976
3933900 Nelson Jan 1976
4044043 Bernady et al. Apr 1977
Continuation in Parts (1)
Number Date Country
Parent 788455 Apr 1977