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Details for Patent: 4,210,748

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Details for Patent: 4,210,748

Title: Enlarged-hetero-ring prosta-cyclin analogs
Abstract:Prostaglandin (PG.sub.1, derivatives having (1) a 5-keto feature, for example ##STR1## or (2) a 9-deoxy-5,9-epoxy feature together with a 4-halo or 5-hydroxy feature, for example ##STR2## or a 4,5-didehydro feature, for example in an enol ether of the formula ##STR3## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.
Inventor(s): Johnson; Roy A. (Kalamazoo, MI)
Assignee: The Upjohn Company (Kalamazoo, MI)
Filing Date:Aug 11, 1978
Application Number:05/932,899
Claims:1. A 4Z compound of the formula ##STR22## wherein R.sub.20 is ##STR23## wherein L is --(CH.sub.2).sub.d --C(R.sub.2).sub.2 --

wherein d is zero to 5, R.sub.2 is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R.sub.2 is not methyl when the other is fluoro,

wherein

Q is ##STR24## wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R.sub.3 is (a) hydrogen (b) alkyl of one to 12 carbon atoms, inclusive, or (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR25## wherein R.sub.10 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wheren R.sub.11 is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation;

wherein R.sub.5 and R.sub.6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R.sub.5 and R.sub.6 is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R.sub.5 nor R.sub.6 is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR.sub.5 R.sub.6 -- and the phenyl ring;

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR.sub.7 -- wherein R.sub.7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein X is

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

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

(3) --C.tbd.C-- or

(4) --CH.sub.2 CH.sub.2 --;

including the lower alkanoates thereof.

2. A compound according to claim 1 wherein R.sub.20 is ##STR26##

3. A compound according to claim 1 wherein R.sub.20 is ##STR27##

4. A compound according to claim 1 wherein R.sub.20 is ##STR28##

5. A compound according to claim 1 wherein R.sub.20 is ##STR29##

6. A compound according to claim 1 wherein R.sub.20 is ##STR30##

7. A compound according to claim 1 wherein R.sub.20 is ##STR31##

8. A compound according to claim 1 wherein R.sub.20 is ##STR32##

9. A compound according to claim 8 wherein L is --(CH.sub.2).sub.n --, n being 2, 3, or 4, and wherein Q is ##STR33## wherein R.sub.8 is hydrogen, methyl, or ethyl.

10. A compound according to claim 9 wherein L is --CH.sub.2 CH.sub.2 --.

11. A compound according to claim 10 wherein R.sub.5 and R.sub.6 are hydrogen.

12. A compound according to claim 11 wherein "s" is zero.

13. A compound according to claim 12 wherein X is --C.tbd.C--.

14. A compound according to claim 12 wherein X is --CH.sub.2 CH.sub.2 --.

15. A compound according to claim 13 wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

16. A compound according to claim 12 wherein X is trans--CH.dbd.CH--.

17. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -17-phenyl-18,19,20-trinor-13,14-didehydro-PGF.sub.1, methyl ester, a compound according to claim 15.

18. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-PGF.sub.1, methyl ester, a compound according to claim 15.

19. A compound according to claim 14, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

20. A compound according to claim 19, wherein R.sub.3 is methyl.

21. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -17-phenyl-18,19,20-trinor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 20.

22. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 20.

23. A compound according to claim 19, wherein R.sub.3 is sodium.

24. A compound according to claim 16, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

25. A compound according to claim 24, wherein R.sub.3 is methyl.

26. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 25.

27. A compound according to claim 24, wherein R.sub.3 is sodium.

28. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 25.

29. A compound according to claim 12, wherein X is cis--CH.dbd.CH--.

30. A compound according to claim 29, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

31. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -17-phenyl-18,19,20-trinor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 30.

32. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-phenoxy-17,18,19,20-tetranor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 30.

33. A compound according to claim 11, wherein "s" is one.

34. A compound according to claim 33, wherein X is --CH.sub.2 CH.sub.2 --.

35. A compound according to claim 34, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

36. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF.sub. 1, methyl ester, a compound according to claim 35.

37. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 35.

38. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 35.

39. A compound according to claim 33, wherein X is trans--CH.dbd.CH--.

40. A compound according to claim 39, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

41. A compound according to claim 40, wherein R.sub.3 is methyl.

42. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 41.

43. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 41.

44. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGF.sub..alpha., methyl ester, a compound according to claim 41.

45. A compound according to claim 40, wherein R.sub.3 is sodium.

46. A compound according to claim 33, wherein X is cis--CH.dbd.CH--.

47. A compound according to claim 46, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

48. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 47.

49. A compound according to claim 10, wherein R.sub.5 and R.sub.6 are methyl.

50. A compound according to claim 49, wherein "s" is zero.

51. A compound according to claim 50, wherein X is --CH.sub.2 CH.sub.2 --.

52. A compound according to claim 51, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

53. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 52.

54. A compound according to claim 50, wherein X is trans--CH.dbd.CH--.

55. A compound according to claim 54, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

56. A compound according to claim 55, wherein R.sub.3 is methyl.

57. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16,16-dimethyl-17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 56.

58. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 56.

59. A compound according to claim 55, wherein R.sub.3 is sodium.

60. A compound according to claim 50, wherein X is cis--CH.dbd.CH--.

61. A compound according to claim 60, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

62. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 61.

63. A compound according to claim 10, wherein R.sub.5 and R.sub.6 are fluoro.

64. A compound according to claim 63, wherein "s" is zero.

65. A compound according to claim 64, wherein X is --CH.sub.2 CH.sub.2 --.

66. A compound according to claim 65, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

67. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 66.

68. A compound according to claim 64, wherein X is trans--CH.dbd.CH--.

69. A compound according to claim 68, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

70. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -16,16-difluoro-17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 69.

71. A compound according to claim 8, wherein L is --CH.sub.2 CF.sub.2 -- and wherein Q is ##STR34## wherein R.sub.8 is hydrogen, methyl, or ethyl.

72. A compound according to claim 71, wherein R.sub.5 and R.sub.6 are hydrogen.

73. A compound according to claim 72, wherein "s" is zero.

74. A compound according to claim 73, wherein X is --CH.sub.2 CH.sub.2 --.

75. A compound according to claim 74, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

76. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 75.

77. A compound according to claim 73, wherein X is trans--CH.dbd.CH--.

78. A compound according to claim 77, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

79. A compound according to claim 78, wherein R.sub.3 is methyl.

80. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 79.

81. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 79.

82. A compound according to claim 78, wherein R.sub.3 is sodium.

83. A compound according to claim 73, wherein X is cis--CH.dbd.CH--.

84. A compound according to claim 83, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

85. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 84.

86. A compound according to claim 71, wherein R.sub.5 and R.sub.6 are methyl.

87. A compound according to claim 86, wherein "s" is zero.

88. A compound according to claim 87, wherein X is --CH.sub.2 CH.sub.2 --.

89. A compound according to claim 88, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

90. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGF.sub.1 , methyl ester, a compound according to claim 89.

91. A compound according to claim 87, wherein X is trans--CH.dbd.CH--.

92. A compound according to claim 91, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

93. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.1, methyl ester, a compound according to claim 92.

94. A compound according to claim 87, wherein X is cis--CH.dbd.CH--.

95. A compound according to claim 94, wherein R.sub.3 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or sodium.

96. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-PGF.sub.1, methyl ester, a compound according to claim 95.

97. A 4E compound of the formula ##STR35## wherein R.sub.20 is ##STR36## wherein L is --(CH.sub.2).sub.d --C(R.sub.2).sub.2 -- wherein d is zero to 5, R.sub.2 is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R.sub.2 is not methyl when the other is fluoro,

wherein Q is ##STR37## wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R.sub.3 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR38## wherein R.sub.10 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R.sub.11 is hydrogen or benzoyl, or (n) a pharmacologically acceptable cation;

wherein R.sub.5 and R.sub.6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R.sub.5 and R.sub.6 is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R.sub.5 nor R.sub.6 is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR.sub.5 R.sub.6 -- and the phenyl ring;

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR.sub.7 -- wherein R.sub.7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein X is

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

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

(3) --C.tbd.C-- or

(4) --CH.sub.2 CH.sub.2 --; including the lower alkanoates thereof.
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