US 4,668,814 AGranted

Interphenylene carbacyclin derivatives

AssigneeThe Upjohn Company

InventorPaul A. Aristoff

Life of this patent

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Abstract

A compound of the formula ##STR1## and intermediates useful in preparing same.

Claims11

Dependent claims

A compound of the formula

wherein X.sub.1 is
(1) --COOR.sub.1, wherein R.sub.1 is
(a) hydrogen;
(b) (C.sub.1 -C.sub.12) alkyl;
(c) (C.sub.3 -C.sub.10) cycloalkyl;
(d) (C.sub.7 -C.sub.12) aralkyl;
(e) phenyl, optionally substituted with one, 2 or 3 chloro or (C.sub.1 -C.sub.3) alkyl;
(f) phenyl substituted in the para position by
(i) --NHCOR.sub.25,
(ii) --COR.sub.26,
(iii) ##STR38## or (iv) --CH.dbd.N--NHCONH.sub.2 wherein R.sub.25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH.sub.2 ;
R.sub.26 is methyl, phenyl, --NH.sub.2, or methoxy;
R.sub.54 is phenyl or acetamidophenyl;
inclusive;
or
(g) a pharmacologically acceptable cation;
(2) --CH.sub.2 OH;
(3) --COL.sub.4, wherein L.sub.4 is
(a) amino of the formula --NR.sub.51 R.sub.52 wherein R.sub.51 and R.sub.52 are
(i) hydrogen,
(ii) (C.sub.1 -C.sub.12) alkyl,
(iii) (C.sub.3 -C.sub.10) cycloalkyl,
(iv) (C.sub.7 --C.sub.12) aralkyl,
(v) phenyl, optionally substituted with one 2 or 3 chloro, (C.sub.1 -C.sub.3) alkyl, hydroxy, carboxy, (C.sub.2 -C.sub.5) alkoxycarbonyl, or nitro,
(vi) (C.sub.2 -C.sub.5) cyanoalkyl,
(vii) (C.sub.2 -C.sub.5) carboxyalkyl,
(viii) (C.sub.2 -C.sub.5) carbamoylalkyl,
(ix) (C.sub.3 -C.sub.6) acetylalkyl,
(x) (C.sub.7 -C.sub.11) benzoalkyl, optionally substituted by one, 2 or 3 chloro, (C.sub.1 -C.sub.3) alkyl, hydroxy, (C.sub.1 -C.sub.3) alkoxy, carboxy, (C.sub.2 -C.sub.5) alkoxy carbonyl, or nitro,
(xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C.sub.1 -C.sub.3) alkyl, or (C.sub.1 -C.sub.3) alkoxy,
(xii) (C.sub.6 -C.sub.9) pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C.sub.1 -C.sub.3) alkyl, hydroxy, or (C.sub.1 -C.sub.3) alkoxy,
(xiii) (C.sub.1 -C.sub.4) hydroxyalkyl,
(xiv) (C.sub.1 -C.sub.4) dihydroxyalkyl,
(xv) (C.sub.1 -C.sub.4) trihydroxyalkyl, with the proviso that not more than one of R.sub.51 or R.sub.52 is other than hydrogen or alkyl;
(b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethylenimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C.sub.1 -C.sub.12) alkyl of one to 12 carbon atoms, inclusive;
(c) carbonylamino of the formula --NR.sub.53 COR.sub.51 wherein R.sub.53 is hydrogen or (C.sub.1 -C.sub.4) alkyl and R.sub.51 is other than hydrogen, but otherwise defined as above;
(d) sulfonylamino of the formula --NR.sub.53 SO.sub.2 R.sub.51, wherein R.sub.51 and R.sub.53 are defined in (c);
(4) --CH.sub.2 NL.sub.2 L.sub.3 wherein L.sub.2 and L.sub.3 are hydrogen or (C.sub.1 -C.sub.4) alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X.sub.1 is --CH.sub.2 NL.sub.2 L.sub.3 ;
(5) --CN;
wherein Z.sub.4 is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CF.sub.2 --, or --CH.sub.2 CF.sub.2 ;
wherein L.sub.20 is .alpha.-OH,.beta.-H;
.alpha.-H,.beta.-OH;
H,H;
.alpha.-CH.sub.3,.beta.-H;
.alpha.-CH.sub.2 OH,.beta.-H;
.dbd.O;
or .dbd.CH.sub.2 ;
wherein L.sub.60 is hydrogen or L.sub.20 and L.sub.60 taken together form a double bond between positions 10 and 11;
wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --, --SCH.sub.2 --, --C.tbd.C--, trans --CH.dbd.CH--, or cis --CH.dbd.CH--;
wherein ##STR39## taken together is ##STR40## wherein M.sub.1 is .alpha.-H:.beta.-H;
.dbd.O;
.alpha.-OH:.beta.-R.sub.5 ;
or .alpha.-R.sub.5 :.beta.-OH;
wherein R.sub.5 is hydrogen or methyl;
wherein L.sub.1 is
(1) .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or mixtures thereof 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;
(2) or when M.sub.1 is .alpha.-H:.beta.-H L.sub.1 is .alpha.-OH:.beta.-R.sub.3, .alpha.-R.sub.3 :.beta.-OH;
or a mixture of .alpha.-OH:.beta.-R.sub.3 and .alpha.-R.sub.3 :.beta.-OH wherein R.sub.3 is hydrogen, methyl, vinyl, or ethynyl;
wherein R.sub.7 is
(1) --C.sub.m H.sub.2m CH.sub.3, wherein m is an integer from one to 8, inclusive;
(2) phenoxy optionally substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3) alkyl, or (C.sub.1 -C.sub.3) alkoxy, 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;
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, 2 or 3 chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3) alkyl, or (C.sub.1 -C.sub.3) alkoxy, with the proviso, that not more than two substituents are other than alkyl;
(4) cis --CH.dbd.CH--CH.sub.2 CH.sub.3 ;
(5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3 ;
(6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ;
(7) --(CH.sub.2).sub.2 --CH.dbd.CH.sub.2 ;
wherein ##STR41## taken together is (1) (C.sub.4 -C.sub.7) cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl or (C.sub.1 -C.sub.5) alkenyl;
(2) 2-(2-furyl)ethyl;
(3) 2-(3-thienyl)ethoxy;
(4) 3-thienyloxymethyl;
(5) ##STR42## and the individual optical enantiomers thereof with the proviso that each compound is other than one formed when the substituents X.sub.1, Z.sub.4, L.sub.20, Y.sub.1, L.sub.1, and R.sub.7 have the following meanings:
wherein X.sub.1 is as defined above;
wherein Z.sub.4 is --CH.sub.2 --, --CF.sub.2, or --CH.sub.2 CF.sub.2 --;
wherein L.sub.20 is .alpha.-OH,.beta.-H;
.alpha.-H,.beta.-OH;
H,H;
.alpha.-CH.sub.2 OH,.beta.-H;
wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --, --C.tbd.C--, trans --CH.dbd.CH--, or cis --CH.dbd.CH--;
wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5, or .alpha.-R.sub.5 :.beta.-OH wherein R.sub.5 is hydrogen or methyl;
wherein L.sub.1 is
(1) .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, 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;
and
wherein R.sub.7 is as defined above except R.sub.7 is other than --(CH.sub.2).sub.2 --CH.dbd.CH.sub.2 and C(L.sub.1)R.sub.7 taken together is as defined above except C(L.sub.1)R.sub.7 is other than (C.sub.4 -C.sub.7) cycloalkyl optionally substituted with (C.sub.1 -C.sub.5) alkenyl.

80 more elements

A compound of formula ##STR43## wherein Q is cis-CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 COOH, or ##STR44## wherein alkyl has from 1 to 4 carbon atoms, Y.sub.2 is --SCH.sub.2 -- or CH.sub.2 CH.sub.2 --, M.sub.2 is .alpha.-H:.beta.-OR.sub.x, .alpha.-OR.sub.x :.beta.-H or H,H wherein R.sub.x is a protecting group;

L.sub.2 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3 or mixture thereof 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 when M.sub.2 is H,H, L.sub.2 is .alpha.-OR.sub.x :.beta.-R.sub.3, .alpha.-R.sub.3 :.beta.-OR.sub.x, or a mixture thereof wherien R.sub.3 is hydrogen, methyl, vinyl or ethynyl and R.sub.x is a protecting group;
and R.sub.7
(1) --C.sub.m H.sub.2m CH.sub.3, wherein m is an integer from one to 8, inclusive;
(2) phenoxy optionally substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3) alkyl, or (C.sub.1 -C.sub.3) alkoxy, 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;
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, 2 or 3 chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3) alkyl, or (C.sub.1 -C.sub.3) alkoxy, with the proviso that not more than two substituents are other than alkyl;
(4) cis-CH.dbd.CH--CH.sub.2 CH.sub.3 ;
(5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3 ;
(6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ;
(7) --C.sub.p H.sub.2p CH.dbd.CH.sub.2 wherein p is an integer from 2 to 6, inclusive;
or C--R.sub.7 taken together is
(1) (C.sub.4 -C.sub.7) cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl, or (C.sub.1 -C.sub.5)alkenyl;
(2) 2-(2-furyl)ethyl;
(3) 2-(3-thienyl)ethoxy;
(4) 3-thienyloxymethyl;
or
(5) ##STR45## and Q.sub.2 is ##STR46## wherein Y.sub.2, M.sub.2, L.sub.2 and R.sub.7 are as defined above or Q.sub.2 is --CO.sub.2 alkyl wherein alkyl has from 1 to 4 carbon atoms.

13 more elements

Dependencies are inferred from the claim text.

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