9,11-Dideoxy-10-oxa-TXB intermediates

Abstract

The present invention relates to novel compositions of matter and particularly provides 9,11-dideoxy-10-oxa-TXB intermediates for preparing corresponding thromboxane analogs. These thromboxane analogs are useful for a variety of pharmacologically useful purposes, most particularly as anti-thrombotic agents.

Description

DESCRIPTION

Background of the Invention

The present invention relates to novel compositions of matter the preparation and use of which is incorporated here by reference from U.S. Ser. No. 019,752. Particularly the present invention provides novel analogs of the thromboxanes. Most particularly, the present invention specifically relates to novel 9,11-dideoxy-10-oxa-TXB intermediates for preparing corresponding thromboxanes.

PRIOR ART

Thromboxane B.sub.2 is known in the art. See Samuelsson, Proceedings of the National Academy of Sciences USA 71:3400-3404 (1974). Likewise, numerous analogs of thromboxane B.sub.2 and their use as reproductive cycle control agents is known in the art. See U.S. Pat. No. 4,070,384, issued Jan. 24, 1978.

Further, certain 11-oxa prostaglandin-type compounds are known in the art. See particularly Belgian Pat. No. 830,423 (Derwent Farmdoc CPI No. 01971X) and Tetrahedron Letters 43:3715-3718 (1975).

Other heterocyclic ring analogs of the prostaglandins include the 9.alpha.,11.alpha.- or 11.alpha.,9.alpha.-epoxymethano-9,11-dideoxy-PGF-type compounds described in U.S. Pat. Nos. 3,950,363 and 4,028,354. Finally related azo and epoxyimino compounds are known in the art. See U.S. Pat. No. 4,112,224.

SUMMARY OF THE INVENTION

The present invention particularly provides

A thromboxane intermedate of formula IV, V, VI, or VII ##STR1## wherein Y.sub.1 is (1) trans--CH.dbd.CH--,

(2) cis--CH.dbd.CH--, (3) --CH.sub.2 CH.sub.2 --, or (4) --C.tbd.C--, wherein M.sub.1 is .alpha.--R.sub.5 :.beta.--OH, .alpha.--OH:.beta.--R.sub.5, or .alpha.--H:.beta.-H, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.--R.sub.3 :.beta.--R.sub.4, .alpha.--R.sub.4 :.beta.--R.sub.3, or a mixture of .alpha.--R.sub.3 :.beta.--R.sub.4 and .beta.--R.sub.3 :.alpha.--R.sub.4, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro; wherein g is one, 2, or 3; wherein R.sub.7 is (1) --(CH.sub.2).sub.m --CH.sub.3, wherein m is an integer from one to 5 inclusive; (2) phenoxy; (3) phenoxy substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, icnlusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (4) phenyl; (5) phenyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (6) phenylmethyl, phenylethyl, or phenylpropyl; or (7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different; wherein M.sub.7 is .alpha.--R.sub.5 :.beta.--OR.sub.10, .alpha.--OR.sub.10 :.beta.--R.sub.5, or .alpha.--H:.beta.--H, wherein R.sub.10 is a stable, acid hydrolyzable blocking group; wherein R.sub.12 is alkyl of one to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; or phenyl substituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms, and wherein R.sub.34 is a stable, hydrogenolyzable blocking group.

Claims

1. A thromboxane intermediate of formula IV, V, VI, or VII ##STR2## wherein Y.sub.1 is (1) trans--CH.dbd.CH--,

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

(3) --CH.sub.2 CH.sub.2 --, or

(4) --C.tbd.C--,

wherein M.sub.1 is .alpha.--R.sub.5 :.beta.--OH, .alpha.--OH:.beta.--R.sub.5, or .alpha.--H:.beta.--H, wherein R.sub.5 is hydrogen or methyl;

wherein L.sub.1 is .alpha.--R.sub.3 :.beta.--R.sub.4, .alpha.--R.sub.4 :.beta.--R.sub.3, or a mixture of .alpha.--R.sub.3 :.beta.--R.sub.4 and .beta.--R.sub.3 :.alpha.--R.sub.4, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro;

wherein g is one, 2, or 3;

wherein R.sub.7 is

(1) --(CH.sub.2).sub.m --CH.sub.3, wherein m is an integer from one to 5 inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, icnlusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl; or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;

wherein M.sub.7 is .alpha.--R.sub.5 :.beta.--OR.sub.10, .alpha.--OR.sub.10 :.beta.--R.sub.5, or .alpha.--H:.beta.--H, wherein R.sub.10 is a stable, acid hydrolyzable blocking group;

wherein R.sub.12 is alkyl of one to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; or phenyl substituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms, and

wherein R.sub.34 is a stable, hydrogenolyzable blocking group.