Modulators of the gpr119 receptor and the treatment of disorders related thereto

Abstract

The present invention relates to the GPR119 receptor agonists: 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzanide; -fluoro-4-(5-fluoro-6-(4-(3-(2-fluoro-propan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide; and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as a single pharmaceutical agent or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

1 .- 57 . (canceled) 
     
     
         58 . An anhydrous crystalline form of the compound 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide, wherein the anhdrous crystalline form has a powder X-ray diffraction (XRPD) pattern comprising peaks, in terms of 2θ, at 13.6°±0.2°, 20.1±0.2°, and 25.0°±0.2°. 
     
     
         59 . The anhydrous crystalline form of  claim 58 , wherein the anhdrous crystalline form has a XRPD pattern comprising peaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 20.1°±0.2°, 25.0°±0.2°, and 27.2°±0.2°. 
     
     
         60 . The anhydrous crystalline form of  claim 58 , wherein the anhdrous crystalline form has a XRPD pattern comprising peaks, in terms of 2θ, at 8.6°±0.2°, 13.6°±0.2°, 18.3°±0.2°, 20.1°±0.2°, 21.1°±0.2°, 25.0°±0.2°, and 27.2°±0.2°. 
     
     
         61 . The anhydrous crystalline form of  claim 58 , having a XRPD pattern substantially as shown in  FIG. 6 . 
     
     
         62 . The anhydrous crystalline form of  claim 58 , having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an extrapolated onset temperature between about 143.9° C. and about 153.9° C. 
     
     
         63 . The anhydrous crystalline form of  claim 58 , having a DSC thermogram comprising an endothermic peak with an extrapolated onset temperature at about 148.9° C. 
     
     
         64 . The anhydrous crystalline form of  claim 58 , having a DSC thermogram substantially as shown in  FIG. 7 . 
     
     
         65 . The anhydrous crystalline form of  claim 58 , having a thermogravimetric analysis (TGA) profile substantially as shown in  FIG. 7 . 
     
     
         66 . The anhydrous crystalline form of  claim 58 , having a dynamic moisture sorption (DMS) analysis profile substantially as shown in  FIG. 8 . 
     
     
         67 . A composition comprising the anhydrous crystalline form of  claim 58  and a pharmaceutically acceptable carrier. 
     
     
         68 . A method for increasing the secretion of an incretin or increasing a blood incretin level in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the anhydrous crystalline form of  claim 58 . 
     
     
         69 . The method according to  claim 68 , wherein the incretin is GLP-1. 
     
     
         70 . The method according to  claim 68 , wherein the incretin is GIP. 
     
     
         71 . The method according to  claim 68 , wherein the incretin is PYY. 
     
     
         72 . A method for the treatment of a disorder selected from a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; and obesity; in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the anhydrous crystalline form of  claim 58 . 
     
     
         73 . A method for increasing the secretion of an incretin or increasing a blood incretin level in an individual in need thereof, comprising administering to the individual the anhydrous crystalline form of  claim 58  in combination with a second pharmaceutical agent. 
     
     
         74 . The method of  claim 73 , wherein the second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an anti-diabetic peptide analogue. 
     
     
         75 . A method for the treatment of a disorder selected from a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; and obesity; in an individual in need thereof, comprising administering to the individual the anhydrous crystalline form of  claim 58  in combination with a second pharmaceutical agent. 
     
     
         76 . The method of  claim 75 , wherein the second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an anti-diabetic peptide analogue. 
     
     
         77 . A method of treating a condition characterized by low bone mass selected from: osteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget's disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine, and loss of height, wherein the method comprises administering to an individual in need thereof an effective amount of the anhydrous crystalline form of  claim 58 . 
     
     
         78 . A method of treating a neurological disorder selected from stroke and Parkinson's disease, wherein the method comprises administering to an individual in need thereof an effective amount of the anhydrous crystalline form of  claim 58 . 
     
     
         79 . A method of treating a metabolic-related disorder selected from: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glycosuria, metabolic acidosis, a cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP-1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-neuron disease, traumatic brain injury, spinal cord injury, and obesity, wherein the method comprises administering to an individual in need thereof an effective amount of the anhydrous crystalline form of  claim 58 . 
     
     
         80 . A method of treating type 2 diabetes, wherein the method comprises administering to an individual in need thereof an effective amount of the anhydrous crystalline form of  claim 58 .