Enantiomerically purified gper angonist for use in treating disease states and conditions

Abstract

The present disclosure provides 1) an enantiomerically purified compound SRR G-1, or a derivative thereof, including specific crystal forms, salts and co-crystals that modulates G protein-coupled estrogen receptor activity, 2) pharmaceutical and cosmetic compositions comprising an enantiomerically purified SRR G-1, or a derivative thereof, and 3) methods of treating or preventing disease states and conditions and cosmetic conditions mediated through these receptors and related methods thereof in humans and animals.

What is claimed is: 
     
         1 . A compound comprising the formula of: 
       
         
           
           
               
               
           
         
         1-((3 aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one, or a derivative thereof, wherein the chiral purity of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one, or a derivative thereof, is about 90% or greater. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is crystalline as evidenced by XRPD analysis or amorphous as evidenced by XRPD analysis or a mixture of crystalline and amorphous material. 
     
     
         3 . The compound of  claim 1 , wherein the chiral purity of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one, or a derivative thereof, is substantially free of its opposite enantiomer. 
     
     
         4 . The compound of  claim 1  wherein the form of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one is selected from crystalline Form A that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 5.75, about 20.54, about 20.71, about 21.25, and about 21.86; crystalline Form B that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 13.98, about 15.44, about 19.67, about 21.55, and about 22.05; crystalline Form C that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 10.73, about 12.77, about 13.49, about 16.09, and about 20.60; is amorphous; or combinations thereof. 
     
     
         5 . The compound of  claim 1  wherein the crystalline form of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one is selected from crystalline Form A that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 5.75, about 20.54, about 20.71, about 21.25, and about 21.86; crystalline Form B that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 13.98, about 15.44, about 19.67, about 21.55, and about 22.05; crystalline Form C that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 10.73, about 12.77, about 13.49, about 16.09, and about 20.60; or combinations thereof. 
     
     
         6 . The compound of  claim 5  wherein the crystalline form of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one is crystalline Form A that is characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 5.75, about 20.54, about 20.71, about 21.25, and about 21.86. 
     
     
         7 . The compound of  claim 6  wherein the crystalline form of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one is crystalline Form A that is further characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 5.75, about, 9.56, about 10.53, about 17.03, about 20.54, about 20.71, about 21.25, about 21.86, about 24.67, and about 28.06. 
     
     
         8 . The compound of  claim 7  wherein the crystalline form of 1-((3aS,4R,9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-1-one is crystalline Form A that is further characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.20) at about 5.75, about, 9.56, about 10.53, about 10.81, about 13.02, about 14.66, about 14.79, about 16.23, about 17.03, about 20.54, about 20.71, about 21.25, about 21.86, about 24.67, and about 28.06. 
     
     
         9 . The compound of  claim 1  wherein the derivative thereof is a salt or co-crystal. 
     
     
         10 . The compound of  claim 1  wherein the derivative thereof is selected from salts or co-crystals formed with benzenesulfonic acid, with (+)-(1S)-camphor-10-sulfonic acid, with ethane-1,2-disulfonic acid, with hydrochloric acid, with methanesulfonic acid, with naphthalene-2-sulfonic acid, with naphthalene-1,5-disulfonic acid, with sulfuric acid, with p-toluenesulfonic acid, or combinations thereof. 
     
     
         11 . The compound of  claim 10  wherein the derivative thereof is a salt or co-crystal formed with benzenesulfonic acid. 
     
     
         12 . The compound of  claim 10  wherein the derivative thereof is a salt or co-crystal formed with (+)-(1S)-camphor-10-sulfonic acid. 
     
     
         13 . The compound of  claim 10  wherein the derivative thereof is a salt or co-crystal formed with naphthalene-2-sulfonic acid. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         15 . A cosmetic composition comprising a therapeutically effective amount of the compound of  claim 1  and a cosmetically acceptable carrier, adjuvant, or vehicle. 
     
     
         16 . A method of treating or preventing a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a derivative thereof. 
     
     
         17 . The method of  claim 16  wherein the disease or disorder is selected from the group consisting of cancer, endometritis, prostatitis, polycystic ovarian syndrome, urinary incontinence, hormone-related disorders, hearing disorders, hot flashes, profuse sweating, hypertension, stroke, ischemia, myocardial infarction, dilated cardiomyopathy, obesity, insulin resistance, osteoporosis, atherosclerosis, symptoms of menopause, inflammation, rheumatoid arthritis, osteoarthritis, lymphoproliferative disorders, myeloproliferative disorders, eosinophilia, histiocytosis, paroxysmal nocturnal hemoglobinuria, systemic mastocytosis, venous thrombosis, embolisms, depression, insomnia, anxiety, neuropathy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, inflammatory bowel disease, Crohn's disease, celiac disease, proteinuric renal disease, vascular disease, and thymic atrophy. 
     
     
         18 . A method of preventing or reducing the likelihood of pregnancy after intercourse comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of  claim 14 . 
     
     
         19 . The method of  claim 16 , wherein the subject is a human or an animal. 
     
     
         20 . A method of treating or preventing type 2 diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a derivative thereof. 
     
     
         21 . The method of  claim 17  wherein the cancer is selected from the group consisting of reproductive cancers, hormone-dependent cancers, leukemia, colorectal cancer, prostate cancer, breast cancer, ovarian carcinoma, endometrial cancer, uterine carcinosarcoma, stomach cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, cervical cancer, cervix uteri cancer, corpus uteri cancer, ovary cancer, testicular cancer, bladder cancer, renal cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, uveal melanoma, triple negative breast cancer, multiple myeloma, melanoma, acute leukemia, lymphocytic leukemia, hairy cell leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, non-small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms's Tumor, neuroblastoma, cancer of the mouth/pharynx, cancer of the esophagus, cancer of the larynx, kidney cancer, lymphoma, Burkitt lymphoma, sarcoma, angiosarcoma, glioblastoma, medulloblastoma, astrocytoma, and Merkel cell carcinoma. 
     
     
         22 . A method of increasing, or preventing or reversing loss of, skin pigmentation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a derivative thereof. 
     
     
         23 . A method of skin protection in a subject in need thereof comprising administering to a subject a therapeutically effective amount of the compound of  claim 1 , or a derivative thereof. 
     
     
         24 . The compound of  claim 1 , or a derivative thereof, further comprising one or more additional therapeutic agents selected from the group consisting of an anti-obesity agent, an immunotherapy agent, a chemotherapy agent, a targeted kinase inhibitor, a histone deacetylase inhibitor, an anti-infective agent, a bromodomain inhibitor, and combinations thereof. 
     
     
         25 . The method of  claim 17  wherein the cancer or cells causing or involved in the disease or disorder expresses GPER. 
     
     
         26 . A method of treating or preventing cancer, preventing the reoccurrence of cancer, or inhibiting the progression of cancer in a subject in need thereof comprising administering to a subject a therapeutically effective amount of the compound of  claim 1 , or a derivative thereof.