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Details for Patent: 4,202,972

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Details for Patent: 4,202,972

Title: .DELTA..sup.2 -Prostacyclin analogs
Abstract:Enlarged-hetero-ring prostacyclin analogs having a .DELTA..sup.2 feature are disclosed, for example ##STR1## said analogs 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 23, 1978
Application Number:05/936,295
Claims:1. A 4Z compound of the formula ##STR18## wherein R.sub.20 is ##STR19## wherein Q is ##STR20## 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, (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, ##STR21## 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.4 is ##STR22## wherein C.sub.g H.sub.2g is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR.sub.5 R.sub.6 -- and terminal methyl, 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--) or C.sub.j H.sub.2j wherein C.sub.j H.sub.2j is 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 Q is ##STR23## wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R.sub.20 is ##STR24##

3. A compound according to claim 2 wherein R.sub.20 is ##STR25##

4. A compound according to claim 3 wherein Q is ##STR26## wherein R.sub.8 is hydrogen, methyl, or ethyl.

5. A compound according to claim 4 wherein R.sub.4 is ##STR27## wherein C.sub.g H.sub.2g is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR.sub.5 R.sub.6 -- and terminal methyl, 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.

6. A compound according to claim 4 wherein R.sub.4 is ##STR28## 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--) or C.sub.j H.sub.2j wherein C.sub.j H.sub.2j is 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.

7. A compound according to claim 1 wherein R.sub.3 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, or (c) a pharmacologically acceptable cation.

8. A compound according to claim 7 wherein R.sub.3 is methyl or sodium.

9. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -PGF.sub.1, methyl ester, a compound according to claim 8.

10. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -PGF.sub.1, sodium salt, a compound according to claim 8.

11. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -(15S)-15-methyl-PGF.sub.1, methyl ester, a compound according to claim 8.

12. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -(15S)-15-methyl-PGF.sub.1, sodium salt, a compound according to claim 8.

13. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16,16-dimethyl-PGF.sub.1, methyl ester, a compound according to claim 8.

14. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16,16-dimethyl-PGF.sub.1, sodium salt, a compound according to claim 8.

15. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -13,14-dihydro-PGF.sub.1, methyl ester, a compound according to claim 8.

16. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -13,14-dihydro-PGF.sub.1, sodium salt, a compound according to claim 8.

17. A compound according to claim 12 wherein R.sub.3 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, or (c) a pharmacologically acceptable cation.

18. A compound according to claim 17 wherein R.sub.3 is methyl or sodium.

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

20. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -17-phenyl-18,19,20-trinor-PGF.sub.1, sodium salt, a compound according to claim 18.

21. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 18.

22. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, sodium salt, a compound according to claim 18.

23. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 22.

24. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF.sub.1, sodium salt, a compound according to claim 18.

25. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyloxy)-17,18,19,20-tetranor-PG F.sub.1, methyl ester, a compound according to claim 18.

26. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -16-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyloxy)-17,18,19,20-tetranor-PG F.sub.1, sodium salt, a compound according to claim 18.

27. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, methyl ester, a compound according to claim 18.

28. (4Z)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, sodium salt, a compound according to claim 18.

29. A 4E compound of the formula ##STR29## wherein R.sub.20 is ##STR30## wherein Q is ##STR31## 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, (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, ##STR32## 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.4 is ##STR33## wherein C.sub.g H.sub.2g is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR.sub.5 R.sub.6 -- and terminal methyl, 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--) or C.sub.j H.sub.2j wherein C.sub.j H.sub.2j is 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.

30. A compound according to claim 29, wherein Q is ##STR34## wherein R.sub.8 is hydrogen, methyl, or ethyl,

wherein R.sub.20 is ##STR35## and wherein R.sub.4 is ##STR36## wherein C.sub.g H.sub.2g is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR.sub.5 R.sub.6 -- and terminal methyl, 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.

31. (4E)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -PGF.sub.1, methyl ester, a compound according to claim 30.

32. (4E)-9-Deoxy-5,9.alpha.-epoxy-.DELTA..sup.4 -trans-.DELTA..sup.2 -PGF.sub.1, sodium salt, a compound according to claim 30.
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