Glucosylceramide synthase inhibitors and therapeutic methods using the same

Patent metadata

Field	Value
Publication number	US-10202340-B2
Application number	US-201615546320-A
Country	US
Kind code	B2
Filing date	Feb 1, 2016
Priority date	Feb 2, 2015
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

Abstract

Glucosylceramide synthase inhibitors and compositions containing the same are disclosed. Methods of using the glucosylceramide synthase inhibitors in the treatment of diseases and conditions wherein inhibition of glucosylceramide synthase provides a benefit, like Gaucher disease and Fabry disease, also are disclosed.

First claim

What is claimed:

1. A compound having a structure

wherein R 1 , independently, is selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkyl substituted with one to five fluoro atoms, OC 1-3 alkyl, OC 1-3 alkyl substituted with one to five fluoro atoms, cyclopropyl, CH 2 cyclopropyl, Ocyclopropyl, and OCH 2 cyclopropyl;
NR 2 R 2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one;
R 3 is H, F, or Cl;
G is (CH 2 ) n ;
m is 1 or 2; and
n is 1 or 2,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 , independently is —OCH 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —F, —CF 3

3. The compound of claim 1 , wherein m is 2, and R 1 is F and —OCH 3 .

4. The compound of claim 1 , wherein R 3 is H.

5. The compound of claim 1 wherein —NR 2 R 2′ is

6. The compound of claim 1 wherein

is

7. The compound of claim 1 selected from the group consisting of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(3-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluoro-3-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(cyclopropylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; and 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

9. A method of treating a disease or condition wherein inhibition of GCS provides a benefit comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof, wherein the disease or condition is a Gaucher disease, Fabry disease, Sandhoff disease, Tay-Sachs disease, Parkinson's disease, type 2 diabetes, hypertrophy or hyperplasia associated with diabetic neuropathy, an elevated plasma TNF-α level, an elevated blood glucose level, an elevated glycated hemoglobin level, a glomerular disease, lupus, a disorder involving cell growth, a disorder involving cell division, a collagen vascular disease, atherosclerosis, renal hypertrophy in a diabetic individual, a growth of arterial epithelial cells, an infection, a tumor, and an autosomal dominant or recessive form of a polycystic kidney disease.

10. The method of claim 9 wherein the Gaucher disease is type I, type II, or type III Gaucher disease, and the glomerular disease is selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis, and membranous nephropathy.

11. A method of inhibiting glucosylceramide synthase or lowering a glycosphinolipid concentration in an individual in need thereof comprising administering a therapeutically effective amount of a compound of claim 1 to the individual.

Assignees

• Univ Michigan Regents

Inventors

• Larsen Scott D
• Abe Akira
• Shu Liming
• Wilson Michael William
• Keep Richard F
• Sun Duxin
• Shayman James A

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title