Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone

Abstract

The invention provides enantiopure deuterium-enriched pioglitazone, pharmaceutical compositions, and methods of treating neurological disorders, cancer, respiratory disorders, metabolic disorders, and other disorders using enantiopure deuterium-enriched pioglitazone. A preferred aspect of the invention provides methods of treating Alzheimer's disease, non-small cell lung cancer, hepatocellular carcinoma, and chronic obstructive pulmonary disease using enantiopure deuterium-enriched pioglitazone.

1 - 87 . (canceled) 
     
     
         88 . A compound represented by 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         having an optical purity of at least 75% enantiomeric excess, 
         wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%. 
       
     
     
         89 . The compound of  claim 88 , wherein the abundance of deuterium is at least 75%. 
     
     
         90 . The compound of  claim 88 , wherein the abundance of deuterium is at least 90%. 
     
     
         91 . The compound of  claim 88 , having an optical purity of at least 90% enantiomeric excess. 
     
     
         92 . A compound represented by 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         having an optical purity of at least 75% enantiomeric excess, 
         wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%. 
       
     
     
         93 . The compound of  claim 92  wherein the abundance of deuterium is at least 75%. 
     
     
         94 . The compound of  claim 92 , wherein the abundance of deuterium is at least 90%. 
     
     
         95 . The compound of  claim 92 , having an optical purity of at least 90% enantiomeric excess. 
     
     
         96 . A method of treating a neurological disorder selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, Down syndrome, neurodegeneration, adrenoleukodystrophy, Huntington's disease, stroke, traumatic brain injury, substance abuse, spinal cord injury, neuronal injury, major depression or bipolar disorder comorbid with metabolic syndrome, and a neurological disorder caused by functional mitochondrial impairment, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 88 . 
     
     
         97 . A method of treating a disorder selected from the group consisting of cancer, a metabolic disorder, a symptom of hepatitis, a cardiovascular disease, polycystic ovary syndrome, and a skin defect caused by exposure to ultraviolet radiation, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 88 . 
     
     
         98 . The method of  claim 97 , wherein the metabolic disorder is non-alcoholic fatty liver disease, viral hepatitis, liver cirrhosis, liver fibrosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, beta cell depletion, insulin resistance in a patient with congenital adrenal hyperplasia treated with a glucocorticoid, dysmetabolism in peritoneal dialysis patients, reduced insulin secretion, improper distribution of brown fat cells and white fat cells, obesity, or improper modulation of leptin levels. 
     
     
         99 . A method of treating a neurological disorder selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, autism spectrum disorder, depression, mild cognitive impairment, Down syndrome, neurodegeneration, adrenoleukodystrophy, Huntington's disease, stroke, traumatic brain injury, substance abuse, spinal cord injury, neuronal injury, major depression or bipolar disorder comorbid with metabolic syndrome. and a neurological disorder caused by functional mitochondrial impairment, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 92 . 
     
     
         100 . A method of treating a disorder selected from the group consisting of cancer, a metabolic disorder, a symptom of hepatitis, a cardiovascular disease, polycystic ovary syndrome, and a skin defect caused by exposure to ultraviolet radiation, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 92 . 
     
     
         101 . The method of  claim 100 , wherein the metabolic disorder is non-alcoholic fatty liver disease, viral hepatitis, liver cirrhosis, liver fibrosis, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, beta cell depletion, insulin resistance in a patient with congenital adrenal hyperplasia treated with a glucocorticoid, dysmetabolism in peritoneal dialysis patients, reduced insulin secretion, improper distribution of brown fat cells and white fat cells, obesity, or improper modulation of leptin levels. 
     
     
         102 . A method of synthesizing the compound F1, the method comprising reaction of E1 with d 6 -DMSO and triethylamine followed by d 4 -MeOH