US 2002/0165226 A1 · Estrogen receptor modulators

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.

A compound of the formula:

152
wherein R1 is selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclyl, CF3, —OR6, halogen, C1-5 alkylthio, thiocyanato, cyano, —CO2H, -COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2, and —SO2C1-5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclyl, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2 or —SO2C1-5 alkyl;
R2 is selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclyl, CF3, —OR6, halogen, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2, and —SO2C1-5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclyl, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2 or —SO2C1-5 alkyl;
R3 is selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclyl, CF3, —OR6, halogen, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2, and —SO2C1-5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclyl, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2 or —SO2C1-5 alkyl;
R4 is selected from the group consisting of hydrogen, C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl, heterocyclyl, CF3, —OR6, halogen, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2, and —SO2C1-5 alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclyl, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2 or —SO2C1-5 alkyl;
R5 is selected from the group consisting of C1-5 alkyl, C3-8 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl can be optionally substituted with C1-5 alkyl, C3-8 cycloalkyl, CF3, phenyl, heteroaryl, heterocyclyl, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONZ2, —SO2NZ2 or —SO2C1-5 alkyl;
X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone;
R6 is selected from the group consisting of hydrogen, C1-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C1-5 alkylcarbonyl, alkoxycarbonyl and CONZ2;
each Z is independently selected from the group consisting of hydrogen, C1-5 alkyl, and trifluoromethyl, wherein said alkyl can be optionally substituted with C1-5 alkyl, CF3, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONV2, —SO2NV2 or —SO2C1-5 alkyl;
both Zs and the nitrogen to which they are attached may be taken together to form a 3-8 membered ring, said ring may optionally contain atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may either be saturated or unsaturated, and the carbon atoms of said ring maybe optionally substituted with one to three substituents selected from the group consisting of C1-5 alkyl, CF3, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, —CONV2, —SO2NV2, and —SO2C1-5 alkyl;
each V is independently selected from the group consisting of C1-5 alkyl, CF3, —OR6, halogen, amino, C1-5 alkylthio, thiocyanato, cyano, —CO2H, —COOC1-5 alkyl, —COC1-5 alkyl, and —SO2C1-5 alkyl;
each n is independently an integer from one to five;
or a pharmaceutically acceptable salt or stereoisomer thereof.

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Estrogen receptor modulators

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Estrogen receptor modulators

Life of this patent

Abstract

Claims37