Enantiomerically purified gper agonist 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.

1 . A method of treating a disease or disorder in a subject in need thereof, comprising:
 a) administering to the subject a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         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
 SRR G-1 
 
       
       or a pharmaceutically acceptable salt thereof,
 wherein the compound comprises a crystalline Form A 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, wherein the crystalline Form A has a melt onset of about 176° C., wherein the crystalline Form A is anhydrous, wherein the crystalline Form A exhibits low hygroscopicity, and wherein the crystalline Form A exhibits a calculated density of about 1.485 g cm −3 , and 
 b) alleviating one or more symptoms associated with the disease or disorder in the subject. 
 
     
     
         2 . The method of  claim 1 , wherein the compound is a free base. 
     
     
         3 . The method of  claim 1 , wherein activation of G-protein coupled estrogen receptor (GPER) by the compound alleviates the one or more symptoms associated with the disease or disorder. 
     
     
         4 . The method of  claim 1 , wherein cells causing or involved in the disease or disorder express G-protein coupled estrogen receptor (GPER). 
     
     
         5 . The method of  claim 1  further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of an immunotherapy agent, a chemotherapy agent, a targeted kinase inhibitor, a histone deacetylase inhibitor, a bromodomain inhibitor, and combinations thereof. 
     
     
         6 . The method of  claim 1 , wherein the subject is a human or an animal. 
     
     
         7 . The method of  claim 1 , 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. 
     
     
         8 . The method of  claim 7 , wherein the disease or disorder is cancer. 
     
     
         9 . The method of  claim 8 , 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. 
     
     
         10 . A method of treating type 2 diabetes in a subject in need thereof, comprising:
 a) administering to the subject a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         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
 SRR G-1 
 
       
       or a pharmaceutically acceptable salt thereof,
 wherein the compound comprises a crystalline Form A 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, wherein the crystalline Form A has a melt onset of about 176° C., wherein the crystalline Form A is anhydrous, wherein the crystalline Form A exhibits low hygroscopicity, and wherein the crystalline Form A exhibits a calculated density of about 1.485 g cm −3 ; and 
 b) alleviating one or more symptoms of type 2 diabetes in the subject. 
 
     
     
         11 . A method of increasing or preventing loss of skin pigmentation in a subject in need thereof, comprising:
 a) administering to the subject a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         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
 SRR G-1 
 
       
       or a pharmaceutically acceptable salt thereof,
 wherein the compound comprises a crystalline Form A 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, wherein the crystalline Form A has a melt onset of about 176° C., wherein the crystalline Form A is anhydrous, wherein the crystalline Form A exhibits low hygroscopicity, and wherein the crystalline Form A exhibits a calculated density of about 1.485 g cm −3 ; and 
 increasing or preventing loss of skin pigmentation in the subject. 
 
     
     
         12 . A method of skin protection in a subject in need thereof comprising:
 a) administering to a subject a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         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
 SRR G-1 
 
       
       or a pharmaceutically acceptable salt thereof,
 wherein the compound comprises a crystalline Form A 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, wherein the crystalline Form A has a melt onset of about 176° C., wherein the crystalline Form A is anhydrous, wherein the crystalline Form A exhibits low hygroscopicity, and wherein the crystalline Form A exhibits a calculated density of about 1.485 g cm −3 ; and 
 b) increasing skin pigmentation in the subject. 
 
     
     
         13 . A method of treating cancer in a subject in need thereof comprising:
 administering to a subject a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         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
 SRR G-1 
 
       
       or a pharmaceutically acceptable salt thereof,
 wherein the compound comprises a crystalline Form A 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, wherein the crystalline Form A has a melt onset of about 176° C., wherein the crystalline Form A is anhydrous, wherein the crystalline Form A exhibits low hygroscopicity, and wherein the crystalline Form A exhibits a calculated density of about 1.485 g cm −3 ; and 
 b) alleviating one or more symptoms associated with the cancer in the subject.