COMBINATION THERAPY USING ENANTIOPURE, OXY-SUBSTITUTED, DEUTERIUM-ENRICHED 5-(BENZYL)-5-DEUTERO-THIAZOLIDINE-2,4-DIONES FOR TREATMENT OF MEDICAL DISORDERS
The invention provides combination therapy using enantiopure deuterium-enriched pioglitazone, pharmaceutical compositions, and methods of treating nonalcoholic steatohepatitis, diabetes, fibrotic disorders, and other disorders using the combination therapy.
1 - 50 . (canceled)
51 . A method of treating nonalcoholic steatohepatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of (i) a deuterium-enriched compound of Formula I, or a pharmaceutically acceptable salt thereof, having an optical purity of at least 75% enantiomeric excess; and (ii) a second therapeutic agent, to treat the nonalcoholic steatohepatitis, wherein the compound of Formula I is represented by:
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 H or D, provided that the abundance of deuterium in Z is at least 30%.
52 . The method of claim 51 , wherein the second therapeutic agent comprises vitamin E, pentoxifylline, metformin, obeticholic acid, simtuzumab, aramchol, GFT-505, IMM-124E, cenicriviroc, metreleptin, sitagliptin, GR-MD-02, SHP626, or a pharmaceutically acceptable salt thereof.
53 . The method of claim 51 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are H.
54 . The method of claim 51 , wherein A 1 , A 2 , A 3 , and A 4 are -CH 2 -.
55 . The method of claim 51 , wherein A 5 is CH 3 .
56 . The method of claim 51 , wherein the deuterium-enriched compound is a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, having an optical purity of at least 75% enantiomeric excess, wherein the compound of formula (I-A) is represented by:
wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
57 . The method of claim 51 , wherein the abundance of deuterium in Z is at least 60%.
58 . The method of claim 51 , wherein the deuterium-enriched compound has an enantiomeric excess of at least 85%.
59 . The method of claim 51 , wherein the deuterium-enriched compound is:
or pharmaceutically acceptable salt thereof, each having an optical purity of at least 90% enantiomeric excess.
60 . The method of claim 51 , wherein the deuterium-enriched compound is in the form of a hydrochloride salt.
61 . A method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of (i) a deuterium-enriched compound of Formula I, or a pharmaceutically acceptable salt thereof, having an optical purity of at least 75% enantiomeric excess; and (ii) a second therapeutic agent, to treat the liver cancer, wherein the compound of Formula I is represented by:
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 H or D, provided that the abundance of deuterium in Z is at least 30%.
62 . The method of claim 61 , wherein the second therapeutic agent comprises sorafenib, OMP-54F28, trametinib, TRC 105, tremelimumab, tivozanib, glass microspheres containing radioactive yttrium-90, refametinib, regorafenib, erlotinib, vorinostat, PD-033299, TKM-080301, tivantinib, ramucirumab, DCB-BO1202, LY2875358, galunisertib, erismodegib, cabozantinib, nivolumab, MSC2156119J, temsirolimus, OPB-111077, DCR-MYC, CC-223, donafenib, INC280, CC-122, oprozomib, CF102, SGI-110, artesunate, dalantercept, lenvatinib, colchicine, metformin, pentamidine, or a pharmaceutically acceptable salt thereof.
63 . The method of claim 61 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are H.
64 . The method of claim 61 , wherein A 1 , A 2 , A 3 , and A 4 are -CH 2 .
65 . The method of claim 61 , wherein A 5 is CH 3 .
66 . The method of claim 61 , wherein the deuterium-enriched compound is a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, having an optical purity of at least 75% enantiomeric excess, wherein the compound of formula (I-A) is represented by:
wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
67 . The method of claim 61 , wherein the abundance of deuterium in Z is at least 60%.
68 . The method of claim 61 , wherein the deuterium-enriched compound has an enantiomeric excess of at least 85%.
69 . The method of claim 61 , wherein the deuterium-enriched compound is:
or pharmaceutically acceptable salt thereof, each having an optical purity of at least 90% enantiomeric excess.
70 . The method of claim 51 , wherein the deuterium-enriched compound is in the form of a hydrochloride salt.