11a-Homo-PG intermediates for preparing 11a-methano TXA.sub.2 compounds

Abstract

The present invention provides novel thromboxane analogs and intermediates. Particularly, the present invention provides novel 11a-homo-PG intermediates for preparing 11a-methano TXA.sub.2 compounds.

Description

BACKGROUND OF THE INVENTION

The present invention provides novel thromboxane analogs and intermediates. Particularly, the present invention provides novel 11a-homo-PG intermediates for preparing 11a-methano TXA.sub.2 compounds. The essential material constituting a disclosure of the preparation and use of the compounds described above is incorporated here by reference from the U.S. Ser. No. 035,143 now U.S. Pat. No. 4,128,378.

PRIOR ART

Known in the art are the cyclohexane analogs of PGF.sub.2.alpha. and PGE.sub.2, e.g., 10a-homo-PGF.sub.2.alpha. and 10a-homo-PGE.sub.2. See Crossley, N. S., Tett. Lett. 36:3327-3330 (1971). Also racemic 11a-homo-PGE.sub.1 is described by Floyd, M. B., et al., J. Org. Chem. 44:71-75 (1979). A related cyclohexene is describewd by Muchowski, J. M., et al., Prostaglandins 75:297-302 (1975) and certain 11-deoxy-11a-homo PG's are described in Derwent Farmdoc CPI 29086Y, abstracting French Pat. No. 2,327,768.

SUMMARY OF THE INVENTION

The present invention particularly provides a thromboxane intermediate of formula V, VI, VII, VIII, IX, or X, ##STR1##

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; phenyl; or phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms;

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, and 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 the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro, or wherein -C(M.sub.1)-C(L.sub.1)- is trans--CH.dbd.CH--;

wherein Z.sub.1 is

(1) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, (2) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --, (3) cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, (4) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 --, (5) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2 --, (6) --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, (7) --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.g --CH.sub.2 --, or (8) trans--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -CH.dbd.CH-; (9) --(m-Ph)--O--(CH.sub.2).sub.g --, or (10) --(m-Ph)--CH.sub.2 --(CH.sub.2).sub.g --, wherein g is one, 2, or 3 and -(m-Ph)- is meta-phenylene; and

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, inclusive, 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, inclusive, 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.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel 11a-methano-TXA analogs of the present invention are all highly active as inhibitors of thromboxane synthetase and accordingly are useful for anti-inflammatory, anti-asthma, and anti-thrombotic indications.

Claims

1. A thromboxane intermediate of formula V, VI, VII or VIII, ##STR2## 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.5 is hydrogen or methyl and 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; phenyl; or phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms;

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 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 the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro,

wherein Z.sub.1 is

(1) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --,

(2) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --,

(3) cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --,

(4) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 --,

(5) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2 --,

(6) --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --,

(7) --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.g --CH.sub.2 --, or

(8) trans--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --CH.dbd.CH--;

(9) --(m-Ph)--O--(CH.sub.2).sub.g --, or

(10) --(m-Ph)--CH.sub.2 --(CH.sub.2).sub.g --,

wherein g is one, 2, or 3 and -(m-Ph)- is meta-phenylene; and

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, inclusive, 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, inclusive, 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.