Anti-estrogenic compounds and compositions
AssigneeEndorecherche, Inc.
InventorsFernand Labrie, Yves Merand
Life of this patent
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Abstract
Inhibitors of sex steroid activity, for example those having the general structure ##STR1## may be used as part of a pharmaceutical composition to provide antiestrogenic effects and/or to suppress estrogen synthesis. Such pharmaceutical compositions are useful for the treatment of breast cancer or other diseases whose progress is aided by activation of sex steroid receptors.
Claims66
A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of a sex steroid activity inhibitor having, as part of its molecular structure, an estrogenic nucleus of the formula:
- ##STR131## wherein said sex steroid activity inhibitor includes, as another part of its molecular structure, a side chain of the formula R.sup.1 (B--R.sup.2).sub.x LG substituted onto a ring carbon of said estrogenic nucleus to form:
- ##STR132## wherein x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three intervening atoms, and wherein:
- R.sup.1 is phenylene and R.sup.2 is alkylene;
- Radical B is either absent or selected from the group consisting of --O--, --S--, --Se--, --NR.sup.30 --, --CR.sup.30 OR.sup.30 --, (R.sup.30 being hydrogen or lower alkyl);
- L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lower alkyl, --CONR.sup.4 --, --CSNR.sup.4 --, --NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5 CONR.sup.4 --, --NR.sup.5 C(NR.sup.60)NR.sup.4 --, --SO.sub.2 NR.sup.4 --, --CSS--, --SCS--, --(NO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5 COO--, --NR.sup.5 SO.sub.2 --, --O--, --NR4--, --S--, --SO--, and --SO.sub.2 -- (R.sup.4 and R.sup.5 being independently selected from the group consisting of hydrogen and lower alkyl;
- and R.sup.60 being selected from the group consisting of hydrogen, nitrile and nitro);
- G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl, (lower) alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10) aryl, (C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of the foregoing;
- wherein Z is selected from the group consisting of lower alkylene, halogeno lower alkylene, --(CH.sub.2).sub.n O--, --(CH.sub.2).sub.n S--, --(CH.sub.2).sub.n CO--, --(CH.sub.2).sub.n NR.sub.22 --, (wherein R.sub.22 is hydrogen or lower alkyl and n is an integer from 0 to 3);
- wherein R.sup.3 and R.sup.10 are independently selected from the group consisting of hydrogen, hydroxyl, and a substituent convertible to hydroxyl in vivo;
- and
- wherein R.sup.6 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl.
A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an unsubstituted sex steroid activity inhibitor selected from the group consisting of:
- 2-(4'-hydroxyphenyl)-1-methyl-3-(4"-(2"'-piperidinoethoxy)phenyl)-3,4-dihyd ronaphtalene (EM 765) ##STR133## 2-(4'-hydroxyphenyl)-1-methyl-3-(4"-(2"'-piperidinoethoxy)benzyl)-3,4-dihy d ronaphtalene (EM 431) ##STR134## and N-pyrrolidinyl-11-(7'-hydroxy-3'-(4"-hydroxyphenyl)-4'-methyl-2H-benzothio pyran-2'-yl) undecanamide (EM 941) ##STR135##
A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of unsubstituted sex steroid activity inhibitor 7-hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-(2"'-piperidinoethoxy)phenyl )-2H-benzopyran (EM 343) ##STR136##
A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of a compound having the following molecular structure:
- ##STR138## wherein R.sup.3 and R.sup.10 are independently selected from the group consisting of hydroxyl and a substituent convertible in vivo to hydroxyl.
A sex steroid activity inhibiting compound having, as part of its molecular structure, an estrogenic nucleus of the formula:
- ##STR139## wherein said compound includes, as another part of its molecular structure, a side chain of the formula R.sup.1 (B--R.sup.2).sub.x LG substituted onto a ring carbon of said estrogenic nucleus to form:
- ##STR140## wherein x is an integer from 0 to 6, wherein at least one of L and G is a polar moiety distanced from said ring carbon by at least three intervening atoms, and wherein:
- R.sup.1 is phenylene and R.sup.2 is alkylene;
- Radical B is either absent or selected from the group consisting of --O--, --S--, --Se--, --NR.sup.30 --, --CR.sup.30 OR.sup.30 -- (R.sup.30 being hydrogen or lower alkyl);
- L is either a moiety which together with G, forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of lower alkyl, --CONR.sup.4 --, --CSNR.sup.4 --, --NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5 CONR.sup.4 --, --NR.sup.5 C(NR.sup.60)NR.sup.4 --, --SO.sub.2 NR.sup.4 --, --CSS--, --SCS--, --(NO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5 COO--, --NR.sup.5 SO.sub.2 --, --S--, --NR.sup.4 --, --S--, --SO--, and --SO.sub.2 -- (R.sup.4 and R.sup.5 being independently selected from the group consisting of hydrogen and lower alkyl;
- and R.sup.60 being selected from the group consisting of hydrogen, nitrile and nitro);
- G is either a moiety which together with L forms a heterocyclic ring having at least one nitrogen atom or is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7) cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl, (lower) alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and fluoro-substituted analogs of the foregoing;
- wherein Z is selected from the group consisting of lower alkylene, halogeno lower alkylene, --(CH.sub.2).sub.n O--, --(CH.sub.2).sub.n S--, --(CH.sub.2).sub.n CO--, --(CH.sub.2).sub.n NR.sub.22 --, (wherein R.sub.22 is hydrogen or lower alkyl and n is an integer from 0 to 3);
- wherein R.sup.3 and R.sup.10 are independently selected from the group consisting of hydrogen, hydroxyl, and a substituent convertible in vivo to hydroxyl;
- and
- wherein R.sup.6 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl.
An unsubstituted sex steroid activity inhibiting compound having the molecular structure:
- ##STR141## 2-(4'-hydroxyphenyl)-1-methyl-3-(4"-(2"'-piperidinoethoxy) phenyl)-3,4-dihydronaphtalene (EM 765).
An unsubstituted sex steroid activity inhibiting compound having the molecular structure:
- ##STR142## 7-hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-(2"'-piperidinoethoxy)phenyl ) -2H-Benzopyran (EM 343).
A compound having the following molecular structure:
- ##STR145## wherein R.sup.3 and R.sup.10 are independently selected from the group consisting of hydroxyl and a substituent convertible in vivo to hydroxyl.
Dependencies are inferred from the claim text.