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Details for Patent: 4,191,824

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Details for Patent: 4,191,824

Title: 5-Halo PGI compounds
Abstract:Prostaglandin (PG.sub.1) derivatives having (1) a 6-keto feature, for example ##STR1## or (2) a 9-deoxy-6,9-epoxy feature together with a 5-halo or 6-hydroxy feature, for example ##STR2## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.
Inventor(s): Axen; Udo F. (Plainwell, MI)
Assignee: The Upjohn Company (Kalamazoo, MI)
Filing Date:Nov 09, 1978
Application Number:05/959,399
Claims:1. A compound of the formula ##STR3## or a mixture comprising that compound and the enantiomer thereof wherein R.sub.21 is ##STR4## wherein R.sub.13 is (a) hydrogen, (b) tetrahydropyranyl, (c) tetrahydrofuranyl, (d) 1-ethoxyethyl, (e) a group of the formula ##STR5## wherein R.sub.14 is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R.sub.15 and R.sub.16 are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R.sub.15 and R.sub.16 are taken together, --(CH.sub.2)a-- or --(CH.sub.2)b--O--(CH.sub.2)c-- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, and wherein R.sub.17 is hydrogen or phenyl, or (f) carboxyacyl including ##STR6## wherein "A" is alkyl of one to 4 carbon atoms, inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, and "e" is zero to 5, inclusive, provided that not more than two A's are other then alkyl, and that the total number of carbon atoms in the A's does not exceed 10 carbon atoms, ##STR7## wherein R.sub.30 is alkyl of one to 4 carbon atoms, inclusive, ##STR8## wherein "A" and "e" are as defined above, or ##STR9## wherein R.sub.31 is alkyl of one to 7 carbon atoms, inclusive, wherein L is

(1) --(CH.sub.2)d--C(R.sub.2).sub.2 --

(2) --CH.sub.2 --O--CH.sub.2 --Y-- or

(3) --CH.sub.2 CH.dbd.CH--

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, and Y is a valence bond, --CH.sub.2 --, or --(CH.sub.2).sub.2 --,

wherein Q is ##STR10## wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and R.sub.13 is as defined above,

wherein R.sub.1 is

(1) --COOR.sub.3

(2) --CH.sub.2 OH

(3) --CH.sub.2 N(R.sub.19)(R.sub.18) ##STR11## 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, ##STR12## 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.8 is hydrogen, methyl, or ethyl, and wherein R.sub.18 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R.sub.4 is ##STR13## wherein CgH.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 CjH.sub.2j wherein CjH.sub.2 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;

wherein R.sub.19 is chloro, bromo, or iodo with the proviso that R.sub.19 is not bromo when R.sub.20 is ##STR14## L is --(CH.sub.2).sub.3 --, R.sub.4 is n-pentyl, and X is --C.tbd.C--; 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 --.

2. A compound according to claim 1 wherein R.sub.13 is hydrogen.

3. A compound according to claim 2 wherein R.sub.21 is ##STR15##

4. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-11.beta.-PGF.sub.1, methyl ester, compounds according to claim 3.

5. A compound according to claim 2 wherein R.sub.21 is ##STR16##

6. A compound according to claim 2 wherein R.sub.21 is ##STR17##

7. A compound according to claim 2 wherein R.sub.21 is ##STR18##

8. A compound according to claim 2 wherein R.sub.21 is ##STR19##

9. A compound according to claim 2 wherein R.sub.21 is ##STR20##

10. A compound according to claim 2 wherein R.sub.21 is ##STR21## wherein L is ##STR22## n being 3, 4, or 5, wherein Q is or ##STR23## wherein R.sub.8 is limited to hydrogen, methyl, or ethyl, and wherein R.sub.4 is n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, ##STR24##

11. A compound according to claim 10 wherein R.sub.1 is ##STR25## wherein R.sub.19 and R.sub.18 are as defined in claim 1.

12. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, amide, compounds according to claim 11.

13. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, methylamide, compounds according to claim 11.

14. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, n-butylamide, comcpounds according to claim 11.

15. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, benzylamide, compounds according to claim 11.

16. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, anilide, compounds according to claim 11.

17. A compound according to claim 10 wherein R.sub.1 is --COOR.sub.3 wherein R.sub.3 is as defined in claim 1.

18. A compound according to claim 17 wherein X is --C.tbd.C--.

19. 5.xi.-Bromo-9-deoxy-6.xi.,9.alpha.-epoxy-15(R)-13,14-dideh ydro-PGF.sub.1, methyl ester, compounds according to claim 2.

20. A compound according to claim 17 wherein X is trans-CH.dbd.CH--.

21. A compound according to claim 20 wherein R.sub.3 is ##STR26## wherein R.sub.10 and R.sub.11 are as defined in claim 1.

22. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, p-phenylphenacyl ester, compounds according to claim 21.

23. A compound according to claim 20 wherein R.sub.3 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, or a pharmacologically acceptable cation.

24. A compound according to claim 23 wherein R.sub.3 is hydrogen, methyl, or a pharmacologically acceptable cation.

25. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, compounds according to claim 24.

26. 5.xi.-Bromo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, methyl ester, compounds according to claim 24.

27. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, methyl ester, compounds according to claim 24.

28. 5.xi.-Iodo-9-deoxy-6.xi.,9.al pha.-epoxy-17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, compounds according to claim 96.

29. A compound according to claim 1 wherein R.sub.13 is tetrahydropyranyl.

30. A compound according to claim 1 wherein R.sub.13 is carboxyacyl as defined in claim 1.

31. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, methyl ester, 11,15-bis(4-bromobenzoate), compounds according to claim 30.

32. A compound according to claim 2 wherein R.sub.4 is ##STR27##

33. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-17,18-didehydro-PGF.sub.1, methyl ester, compounds according to claim 32.

34. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-15-deoxy-PGF.sub.1, methyl ester, compounds according to claim 24.

35. 5.xi.-Iodo-9-deoxy-6.xi.,9.alpha.-epoxy-PGF.sub.1, p-(p-acetamidobenzamido)-phenyl ester, compounds according to claim 20.
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