US 2008/0167334 A1 · Compounds for binding to ERalpha/beta and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof

Abstract

The current invention is in the field of molecular biology/pharmacology and provides compounds which modulate the effects of GPR30 as well as the classical estrogen receptors alpha and beta (ERα and ERβ). These compounds may function as agonists and/or antagonists of one or more of the disclosed estrogen receptors. Diseases which are mediated through one or more of these receptors include cancer (particularly breast, reproductive and other hormone-dependent cancers, leukemia, colon cancer, prostate cancer), reproductive (genito-urological) including endometritis, prostatitis, polycystic ovarian syndrome, bladder control, hormone-related disorders, hearing disorders, cardiovascular conditions including hot flashes and profuse sweating, hypertension, stroke, obesity, osteoporosis, hematologic diseases, vascular diseases or conditions such as venous thrombosis, atherosclerosis, among numerous others and disorders of the central and peripheral nervous system, including depression, insomnia, anxiety, multiple sclerosis, neuropathy, neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, as well as inflammatory bowel disease, Crohn's disease, coeliac (celiac) disease and related disorders of the intestine. A contraceptive indication to prevent or reduce the likelihood of pregnancy after intercourse is a further aspect of the present invention.

A compound according to the chemical structure I:

Where X is ═N—, O, S, or N—R, with the proviso that when X is N—R and R is a bond, N together with R1 forms a 5- to 7-membered optionally substituted heterocyclic group;
R is a bond, H, OH, NO2, an optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (amide), an optionally substituted —C(O)—O—(C1-C6) alkyl (urethane), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted
—C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheterocycle);
R1, R2 and R5 are each independently selected from H, OH, NO2, halogen (F, Br, Cl or I), a C1-C6 optionally substituted carboxylic acid group, an optionally substituted O—(C1-C6)alkyl, optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheterocycle);
R3 and R4 are each independently selected from H, OH, NO2, halogen (F, Br, Cl or I), a C1-C6 optionally substituted carboxylic acid group, an optionally substituted O—(C1-C6)alkyl, an optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheteroaryl) or R3 and R4 together form a 5- or 6-membered optionally substituted carbocyclic (which may be saturated or unsaturated), optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group;
R6 and R7 are each independently absent or are selected from H, OH, NO2, halogen (F, Br, Cl or I), a C1-C6 optionally substituted carboxylic acid group, an optionally substituted O—(C1-C6)alkyl, an optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheteroaryl), or together R6 and R7 form a 4-, 5-, 6- or 7-membered optionally substituted carbocyclic (which may be saturated or unsaturated), an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group, or a 5- to 9-membered optionally substituted carbocyclic or heterocyclic bicyclic group, with the proviso that R7 is not absent when both R7′ and R7″ are also absent;
R6′ is absent, H, a C1-C6 optionally substituted hydrocarbyl group (preferably H, CH3 or CH2CH3) or together with R6 forms a ═O group;
R7′ is absent, H, optionally substituted hydrocarbyl group (preferably H, CH3 or CH2CH3), or together with R7 forms a ═O group;
R7″ is absent, H, OH, halogen (F, Br, Cl or I), an optionally substituted O—(C1-C6)alkyl, an optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheteroaryl);
R8′ is absent (when the carbon to which R8′ is attached and the carbon to which R6 is attached form an optional double bond), H, CH3 or CH2CH3;
R10, R11, R12 and R13 are each independently H, OH, NO2, halogen (F, Br, Cl or I), a C1-C6 optionally substituted carboxylic acid group, unsubstituted or substituted O—(C1-C6)alkyl, unsubstituted or substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted —C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheteroaryl);
R14 is H, OH, NO2, halogen (F, Br, Cl or I), a C1-C6 optionally substituted carboxylic acid group, an optionally substituted O—(C1-C6)alkyl, optionally substituted C1-C6 hydrocarbyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, an optionally substituted —C(O)—(C1-C6) alkyl (ketone), an optionally substituted —C(O)—O—(C1-C6) alkyl (ester), an optionally substituted O—C(O)—(C1-C6) alkyl (ester), an optionally substituted —C(O)—NH(C1-C6) alkyl (urea), an optionally substituted —C(O)—N(C1-C6)dialkyl, an optionally substituted —C(O)—NH(aryl), an optionally substituted —C(O)—N(diaryl), an optionally substituted —C(O)—NH(heteroaryl), an optionally substituted
—C(O)—N(diheteroaryl), an optionally substituted —C(O)—NH(heterocycle) or an optionally substituted —C(O)—N(diheterocycle) or together with the carbon to which R7 is attached forms a 5-, 6- or 7-membered optionally substituted carbocyclic (which may be saturated or unsaturated), optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic ring;
or a stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof.

11 more elements

Compounds for binding to ERalpha/beta and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof

Life of this patent

Compounds for binding to ERalpha/beta and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof

Life of this patent

Abstract

Claims36