Johnson, Roy A.; Lincoln, Frank H.; Pike, John E.;

2-Decarboxy-2-hydroxymethyl-PGI.sub.2 compounds

The present invention relates to 2-decarboxy-2-hydroxymethyl-PGI.sub.2 compounds, having pharmacological activity. Particularly, the compounds described herein are useful as platelet aggregation inhibitors.

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We claim:

1. A compound of the formula ##STR2## or a mixture comprising that compound and the enantiomer thereof, wherein W.sub.2 is .alpha.--OH:.beta.--H, .alpha.--H:.beta.--OH, oxo, methylene, .alpha.--H:.beta.--H, or .alpha.--CH.sub.2 OH:.beta.--H;

wherein L is

(1) --(CH.sub.2).sub.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 oxo, .alpha.--H:.beta.--H, .alpha.--R.sub.8 :.beta.--OH, or .alpha.--OH:.beta.--R.sub.8,

wherein R.sub.8 is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R.sub.4 is

--C(R.sub.5)(R.sub.6)C.sub.g H.sub.2.sbsb.g --CH.sub.3,

--C(R.sub.5)(R.sub.6)--Z--(Ph I), or

--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 (Ph I); wherein (Ph I) is phenyl optionally substituted by one, 2, or 3 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, with the proviso that not more than two such substituents are other than alkyl and such substituents being 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 W.sub.2 is .alpha.-H:.beta.-OH.

3. A compound according to claim 1, wherein W.sub.2 is oxo.

4. A compound according to claim 1, wherein W.sub.2 is methylene.

5. A compound according to claim 1, wherein W.sub.2 is .alpha.-H:.beta.-H.

6. A compound according to claim 5, wherein L is --(CH.sub.2).sub.d --C(R.sub.2).sub.2, d being 3, 4, or 5, wherein Q is oxo or .alpha.--OH:.beta.--R.sub.8, 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, --CH.sub.2 --O--(Ph) or --C.sub.2 H.sub.4 --(Ph), wherein (Ph) is phenyl.

7. A compound according to claim 1, wherein W.sub.2 is .alpha.--CH.sub.2 OH:.beta.--H.

8. A compound according to claim 1, wherein W.sub.2 is .alpha.--OH:.beta.--H.

9. A compound according to claim 8, wherein L is --(CH.sub.2)d--C(R.sub.2).sub.2, d being 3, 4, or 5, wherein Q is oxo or .alpha.--OH:.beta.--R.sub.8, wherein R.sub.8 is hydrogen, methyl, or ethyl, and wherein R.sub.4 is n-pentyl, 1,1-dimethylpentyl, 1,1-difluoropentyl, --CH.sub.2 --O--(Ph) or --C.sub.2 H.sub.4 --(Ph), wherein (Ph) is phenyl.

10. (5Z)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.epoxy-.DELTA..sup.5 -PGF.sub.1, a compound according to claim 9.

11. A compound according to claim 8, wherein L is --(CH.sub.2).sub.d --C(R.sub.2).sub.2, d being 3, 4, or 5, wherein Q is oxo or .alpha.--OH:.beta.--R.sub.8, wherein R.sub.8 is hydrogen, methyl, or ethyl, and wherein R.sub.4 is cis--CH.sub.2 --CH.dbd.CH--CH.sub.2 CH.sub.3.