|Title:||Enlarged hetero-ring prostacyclin 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|
|Claims:||1. A compound of the formula ##STR17## wherein W.sub.1 is .alpha.-OH:.beta.-H, .alpha.-H:.beta.-OH, oxo, methylene, .alpha.-H:.beta.-H, .alpha.-CH.sub.2 OH:.beta.-H; |
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 oxo, .alpha.-H:.beta.-H, .alpha.-OH:.beta.-R.sub.8 or .alpha.-R.sub.8:.beta.-OH
wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive,
wherein R.sub.3 is
(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,
(f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive,
(k) p-benzaldehyde semicarbazone,
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
(1) --CR.sub.5 R.sub.6 --CgH.sub.2g --CH.sub.3
(2) --CR.sub.5 R.sub.6 --Z--(Ph)
(3) cis-CH.sub.2 --CH.dbd.CH--CH.sub.2 CH.sub.3
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 (Ph); wherein (Ph) is phenyl or phenyl substituted by (T)s, 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; and
wherein X is
(3) --C.tbd.C-- or
(4) --CH.sub.2 CH.sub.2 --.
2. A compound according to claim 1, wherein W is .alpha.-OH:.beta.-H.
3. A compound according to claim 2, wherein L is --(CH.sub.2).sub.n --, n being 2, 3, or 4, wherein Q is oxo or .alpha.-OH:.beta.-R.sub.8, and wherein R.sub.8 is hydrogen, methyl, or ethyl, and wherein R.sub.4 is n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, phenoxymethyl or phenylethyl.
4. A compound according to claim 3, wherein X is trans-CH.dbd.CH--.
5. A compound according to claim 4, wherein R.sub.3 is --CHR.sub.11 --CO--R.sub.10.
6. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-epoxy-PGF.sub.1, p-phenylphenacyl ester, compounds according to claim 5.
7. A compound according to claim 4, wherein R.sub.3 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, or a pharmacologically acceptable cation.
8. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-epoxy-PGF.sub.1, compounds according to claim 7.
9. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-epoxy-PGF.sub.1, methyl ester, compounds according to claim 7.
10. 4.xi.-Bromo-9-deoxy-5.xi.,9.alpha.-epoxy-PGF.sub.1, methyl ester, compounds according to claim 7.
11. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-epoxy-15-keto-PGF.sub.1, methyl ester, compounds according to claim 7.
12. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-epoxy-15-deoxy-PGF.sub.1, methyl ester, compounds according to claim 7.
13. 4.xi.-Iodo-9-deoxy-5.xi.,9.alpha.-e poxy-17-phenyl-18,19,20-trinor-PGF.sub.1, methyl ester, compounds according to claim 1. /
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