US 4,306,075 A · Composition and process

A carbacyclin analog of formula XI:

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 .alpha.-R.sub.4 :.beta.-R.sub.3, 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 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 R.sub.7 is
(1) --C.sub.m H.sub.2.sbsb.m --CH.sub.3, wherein m is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three 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, two or three 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, or
(6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ;
wherein --C(L.sub.1)--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;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein R.sub.8 is hydroxy, hydroxymethyl, or hydrogen;
wherein
(1) R.sub.20, R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are all hydrogen with R.sub.22 being either .alpha.-hydrogen or .beta.-hydrogen,
(2) R.sub.20 is hydrogen, R.sub.21 and R.sub.22 taken together form a second valence bond between C-9 and C-6a, and R.sub.23 and R.sub.24 taken together form a second valence bond between C-8 and C-9 or are both hydrogen, or
(3) R.sub.22, R.sub.23, and R.sub.24 are all hydrogen, with R.sub.22 being either .alpha.-hydrogen or .beta.-hydrogen, and
(a) R.sub.20 and R.sub.21 taken together are oxo, or
(b) R.sub.20 is hydrogen and R.sub.21 is hydroxy, being .alpha.-hydroxy or .beta.-hydroxy;
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.6 -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) --NH--CO--R.sub.25,
(ii) --CO--R.sub.26,
(iii) --O--CO--R.sub.54, or
(iv) --CH.dbd.N--NH--CO--NH.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;
and 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)carboxyalkyl,
(vii) (C.sub.2 -C.sub.5)carbamoylalkyl,
(viii) (C.sub.2 -C.sub.5)cyanoalkyl,
(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)alkoxycarbonyl, or nitro,
(xi) pyridyl, optionally substituted by one, 2 or 3chloro, (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)alkyl,
(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 further proviso that not more than one of R.sub.51 and R.sub.52 is other than hydrogen or alkyl,
(b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, 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 R5.sub.3 is hydrogen or (C.sub.1 -C.sub.4)alkyl and R.sub.51 is other than hydrogen, but otherwise as defined above,
(d) sulfonylamino of the formula --NR.sub.53 SO.sub.2 R.sub.51, wherein R.sub.51 and R.sub.53 are as 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,
wherein Y.sub.1 is trans--CH.dbd.CH--, cis--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or --C.tbd.C--;
and
wherein Z.sub.4 is --CH.sub.2 -- or --(CH.sub.2).sub.f --CF.sub.2, wherein

60 more elements

A compound according to formula IX:

##STR2## 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 .alpha.-R.sub.4 :.beta.-R.sub.3, 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 M.sub.6 is .alpha.-OR.sub.10 :.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OR.sub.10, wherein R.sub.5 is hydrogen or methyl and R.sub.10 is an acid hydrolyzable protective group;
wherein R.sub.27 is
(1) --C.sub.m H.sub.2.sbsb.m --CH.sub.3, wherein m is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three 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.27 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, two or three 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(OR.sub.10)--CH.sub.3, wherein R.sub.10 is as defined above, or
(6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ;
wherein --C(L.sub.1)--R.sub.27 taken together is
(1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein R.sub.18 is hydrogen, hydroxy, hydroxymethyl, --OR.sub.10 or --CH.sub.2 OR.sub.10, wherein R.sub.10 is an acid-hydrolyzable protective group;
and wherein Y.sub.1 is trans--CH.dbd.CH--, cis--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or --C.tbd.C--.

13 more elements

A compound according to formula VIII:

##STR3## wherein R.sub.18 is hydrogen, hydroxy, hydroxymethyl, --OR.sub.10 or --CH.sub.2 OR.sub.10, wherein R.sub.10 is an acid-hydrolyzable protective group;
wherein
(1) R.sub.20, R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are all hydrogen with R.sub.22 being either .alpha.-hydrogen or .beta.-hydrogen,
(2) R.sub.20 is hydrogen, R.sub.21 and R.sub.22 taken together form a second valence bond between C-9 and C-6a, and R.sub.23 and R.sub.24 taken together form a second valence bond between C-8 and C-9 or are both hydrogen, or
(3) R.sub.22, R.sub.23, and R.sub.24 are all hydrogen, with R.sub.22 being either .alpha.-hydrogen or .beta.-hydrogen, and
(a) R.sub.20 and R.sub.21 taken together are oxo, or
(b) R.sub.20 is hydrogen and R.sub.21 is hydroxy, being .alpha.-hydroxy or .beta.-hydroxy;
wherein R.sub.33 is --CHO or --CH.sub.2 OR.sub.32, wherein R.sub.32 is hydrogen or a hydroxyl hydrogen replacing group;
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) --NH--CO--R.sub.25,
(ii) --CO--R.sub.26,
(iii) --O--CO--R.sub.54, or
(iv) --CH.dbd.N--NH--CO--NH.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;
and 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)carboxyalkyl,
(vii) (C.sub.2 -C.sub.5)carbamoylalkyl,
(viii) (C.sub.2 -C.sub.5)cyanoalkyl,
(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)alkoxycarbonyl, 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)alkyl,
(xiii) (C.sub.1 -C.sub.4)hydroxyalkyl,
(xiv) (C.sub.1 -C.sub.4)dihydroxyalkyl,
(xv) (C.sub.1 -C.sub.4)trihydroalkyl,
with the further proviso that not more than one of R.sub.51 and R.sub.52 is other than hydrogen or alkyl,
(b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, 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 as defined above,
(d) sulfonylamino of the formula --NR.sub.53 SO.sub.2 R.sub.51, wherein R.sub.51 and R.sub.53 are as 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 ;
and
wherein Z.sub.4 is --CH.sub.2 -- or --(CH.sub.2).sub.f --CF.sub.2, wherein f is zero, one, 2, or 3.

46 more elements

Composition and process

Life of this patent

Composition and process

Life of this patent

Abstract

Claims13