Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
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. A method of treating a metabolic disorder selected from the group consisting of 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, and improper modulation of leptin levels, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 , A 2 , A 3 , and A 4 are independently —C(R 9 )(R 10 )—;
A 5 is —C(R 11 )(R 12 )(R 13 );
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently H or D;
R 9 , R 10 , R 11 , R 12 , and R 13 each represent independently for each occurrence H or D; and
Z is D.
2. The method of claim 1 , wherein the metabolic disorder is non-alcoholic fatty liver disease.
3. The method of claim 2 , wherein the deuterium-enriched compound is administered orally.
4. The method of claim 2 , wherein the compound is a compound of Formula II-A having an optical purity of at least 75% enantiomeric excess, wherein Formula II-A is represented by:
or a pharmaceutically acceptable salt thereof, wherein Z is D.
5. The method of claim 4 , wherein the deuterium-enriched compound is in the form of a pharmaceutically acceptable salt.
6. The method of claim 5 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
7. The method of claim 4 , wherein the compound has an enantiomeric excess of at least 85%.
8. The method of claim 2 , wherein the compound is:
or pharmaceutically acceptable salt thereof, each having an optical purity of at least 90% enantiomeric excess.
9. The method of claim 2 , wherein the compound is:
having an optical purity of at least 90% enantiomeric excess.
10. The method of claim 2 , wherein the compound is:
hydrochloride having an optical purity of at least 90% enantiomeric excess.
11. The method of claim 2 , wherein the compound is:
or pharmaceutically acceptable salt thereof, each having an optical purity of at least 95% enantiomeric excess.
12. The method of claim 2 , wherein the compound is:
having an optical purity of at least 95% enantiomeric excess.
13. The method of claim 2 , wherein the compound is:
hydrochloride having an optical purity of at least 95% enantiomeric excess.
14. The method of claim 7 , wherein the deuterium-enriched compound is administered orally.
15. The method of claim 11 , wherein the deuterium-enriched compound is administered orally.
16. A method of treating a metabolic disorder selected from the group consisting of 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, and improper modulation of leptin levels, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the neurological disorder, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 , A 2 , A 3 , and A 4 are independently —C(R 9 )(R 10 )—;
A 5 is —C(R 11 )(R 12 )(R 13 );
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently H or D;
R 9 , R 10 , R 11 , R 12 , and R 13 each represent independently for each occurrence H or D; and
Z is D.
17. The method of claim 16 , wherein the disorder is non-alcoholic fatty liver disease.
18. The method of claim 17 , wherein the compound is a compound of Formula I-A having an optical purity of at least 75% enantiomeric excess, wherein Formula I-A is represented by:
or a pharmaceutically acceptable salt thereof, wherein Z is D.