2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9745294-B2
Application number	US-201414571922-A
Country	US
Kind code	B2
Filing date	Dec 16, 2014
Priority date	May 31, 2007
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

A compound is represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher's; or Fabry's disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A method of decreasing glycated hemoglobin levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a phenyl group optionally substituted with one or more halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR 30 , —SR 30 , —N(R 31 ) 2 , Ar 1 , —V o —OR 30 , —V o —N(R 31 ) 2 , —V o —Ar 1 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —O—[CH 2 ] p —O—, —S—S[CH 2 ] p —S—, or —[CH 2 ] q —;
each V o is independently a C1-C10 alkylene group;
each V 1 is independently a C2-C10 alkylene group;
Ar 1 is an aryl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and
each R 30 is independently
i) hydrogen;
ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or
iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and
each R 31 is independently R 30 , —CO 2 R 30 , —SO 2 R 30 or —C(O)R 30 ; or
—N(R 31 ) 2 taken together is an optionally substituted non-aromatic heterocyclic group;
each p is independently 1, 2, 3 or 4;
each q is independently 3, 4, 5 or 6;
Y is —H;
—N(R 2 R 3 ) is a 5- or 6-membered non-aromatic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl,
haloalkyl, —OR 40 , —O(haloalkyl), —SR 40 , —NO 2 , —CN, —N(R 41 ) 2 , —NR 41 C(O)R 40 , —NR 41 C(O)OR 42 , —N(R 41 )C(O)N(R 41 ) 2 , —C(O)R 40 , —C(S)R 40 , —C(O)OR 40 , —OC(O)R 40 , —C(O)N(R 41 ) 2 , —S(O) 2 R 40 , —SO 2 N(R 41 ) 2 , —S(O)R 42 , —SO 3 R 40 , Ar 2 , V 2 —Ar 2 , —V 2 —OR 40 , —V 2 —O(haloalkyl), —V 2 —SR 40 , —V 2 —NO 2 , —V 2 —CN, —V 2 —N(R 41 ) 2 , —V 2 —NR 41 C(O)R 40 , —V 2 —NR 41 CO 2 R 42 , —V 2 —N(R 41 )C(O)N(R 41 ) 2 , —V 2 —C(O)R 40 , —V 2 —C(S)R 40 , —V 2 —CO 2 R 40 , —V 2 —OC(O)R 40 , —V 2 —C(O)N(R 41 ) 2 —, —V 2 —S(O) 2 R 40 , —V 2 —SO 2 N(R 41 ) 2 , —V 2 —S(O)R 42 , —V 2 —SO 3 R 40 , —O—V 2 —Ar 2 and —S—V 2 —Ar 2 ;
each V 2 is independently a C1-C4 alkylene group;
Ar 2 is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and
each R 40 is independently
i) hydrogen;
ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or
iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and
each R 41 is independently R 40 , —CO 2 R 40 , —SO 2 R 40 or —C(O)R 40 ; or
—N(R 41 ) 2 taken together is an optionally substituted non-aromatic heterocyclic group; and each R 42 is independently:
i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or
ii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl;
X is —(CR 5 R 6 ) n -Q-; Q
is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR 7 —, —NR 7 —, —NR 7 C(O)—, —NR 7 C(O)NR 7 —, —OC(O)—, —SO 3 —, —SO—, —S(O) 2 —, —SO 2 NR 7 —, or —NR 7 SO 2 —;
and R 4 is —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group; or
X is —O—, —S— or —NR 7 —; and R 4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group; or
X is —(CR 5 R 6 ) n —; and R 4 is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, —CN, —NCS, —NO 2 or a halogen; or
X is a covalent bond; and R 4 is a substituted or unsubstituted aryl group; and
R 5 and R 6 are each independently —H, —OH, —SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group;
n is 1, 2, 3, 4, 5 or 6; and
each R 7 is independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R 7 and R 4 taken together with the nitrogen atom of NR 7 R 4 form a substituted or unsubstituted non-aromatic heterocyclic group.

2. A method of inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a phenyl group optionally substituted with one or more halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR 30 , —SR 30 , —N(R 31 ) 2 , Ar 1 , —V o —OR 30 , —V o —N(R 31 ) 2 , —V o —Ar 1 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —O—[CH 2 ] p —O—, —S—[CH 2 ] p —S—, or —[CH 2 ] q —;
each V o is independently a C1-C10 alkylene group;
each V 1 is independently a C2-C10 alkylene group;
Ar 1 is an aryl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and
each R 30 is independently
i) hydrogen;
ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or
iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and
each R 31 is independently R 30 , —CO 2 R 30 , —SO 2 R 30 or —C(O)R 30 ; or
—N(R 31 ) 2 taken to ether is an optionally substituted non-aromatic heterocyclic group;
each p is independently 1, 2, 3 or 4;
each q is independently 3, 4, 5 or 6;
Y is —H;
—N(R 2 R 3 ) is a 5- or 6-membered non-aromati

Assignees

• Genzyme Corp

Inventors

• Siegel Craig
• Bastos Cecilia M
• Harris David J
• Dios Angeles
• Lee Edward
• Silva Richard
• Cuff Lisa M
• Levine Mikaela
• Celatka Cassandra A
• Vinick Frederic
• Jozefiak Thomas H
• Xiang Yibin
• Kane John
• Liao Junkai

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D319/18

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07D411/12

  linked by a chain containing hetero atoms as chain links · CPC title