US 4,349,689 AGranted

Methano carbacyclin analogs

AssigneeThe Upjohn Company

InventorPaul A. Aristoff

Life of this patent

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Abstract

The present specification provides novel analogs of carbacyclin (CBA.sub.2), 6a-carba-prostacyclin (6a-carba-PGI.sub.2), which have pronounced prostacyclin-like pharmacological activity, e.g., as platelet anti-aggregatory agents. Specifically the novel chemical analogs of CBA.sub.2 are those substituted by fluoro (C-5), alkyl (C-9), interphenylene (C-5), and methano (C-6a,9). Further provided are benzindene analogs of CBA.sub.2 and substituted forms thereof, i.e., 9-deoxy-2',9-methano (or 2',9-metheno)-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGF.sub.1 compounds. Also provided are a variety of novel chemical intermediates, e.g., substituted bicyclo[3.3.0]octane intermediates, and chemical process utilizing such intermediates which are useful in the preparation of the novel CBA.sub.2 analogs.

Claims5

Dependent claims

A carbacyclin analog of formula X:

wherein n is one or 2;
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 R.sub.15 is hydrogen or fluoro;
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)benzoylalkyl, 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)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 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,
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.1 is
(1) --CH.sub.2 --(CH.sub.2).sub.f --C(R.sub.2).sub.2, wherein R.sub.2 is hydrogen or fluoro and f is zero, one, 2, or 3,
(2) trans--CH.sub.2 --CH.dbd.CH--,
(3) --(Ph)--(CH.sub.2).sub.g --, wherein (Ph) is 1,2-, 1,3-, or 1,4-phenylene and g is zero, one, 2, or 3,
with the proviso that Z.sub.1 is --(Ph)--(CH.sub.2).sub.g -- only when

59 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/219,106Filed 22 Dec 1980
Granted: 14 Sep 1982
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07C 59/66
Containing six-membered aromatic rings: the non-carboxylic part of the ether containing six-membered aromatic rings
C07C 405/0016
Analogues having the carboxyl group in the side-chains replaced by other functional groups: containing only hydroxy, etherified or esterified…
C07C 405/0083
Having the side-chains or their analogues or derivatives attached to a condensed ring system: which is only ortho or peri condensed, e.g. carbacyclins
C07D 309/12
Oxygen atoms: only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A carbacyclin analog of formula X:

wherein n is one or 2;
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 R.sub.15 is hydrogen or fluoro;
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)benzoylalkyl, 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)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 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,
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.1 is
(1) --CH.sub.2 --(CH.sub.2).sub.f --C(R.sub.2).sub.2, wherein R.sub.2 is hydrogen or fluoro and f is zero, one, 2, or 3,
(2) trans--CH.sub.2 --CH.dbd.CH--,
(3) --(Ph)--(CH.sub.2).sub.g --, wherein (Ph) is 1,2-, 1,3-, or 1,4-phenylene and g is zero, one, 2, or 3,
with the proviso that Z.sub.1 is --(Ph)--(CH.sub.2).sub.g -- only when

59 more elements

Facts

Application

06/219,106Filed 22 Dec 1980

Granted

14 Sep 1982

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07C 59/66
Containing six-membered aromatic rings: the non-carboxylic part of the ether containing six-membered aromatic rings
C07C 405/0016
Analogues having the carboxyl group in the side-chains replaced by other functional groups: containing only hydroxy, etherified or esterified…
C07C 405/0083
Having the side-chains or their analogues or derivatives attached to a condensed ring system: which is only ortho or peri condensed, e.g. carbacyclins
C07D 309/12
Oxygen atoms: only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers