2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9744153-B2
Application number	US-201615003207-A
Country	US
Kind code	B2
Filing date	Jan 21, 2016
Priority date	Oct 3, 2008
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

A compound for use in treating polycystic kidney disease 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 polycystic kidney disease in 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. Methods of treating in polycystic kidney disease 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 treating polycystic kidney disease in a subject, the method comprising administering to the subject an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is

 wherein r is 1, 2, 3 or 4;
Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group;
R 2 and R 3 are each independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R 2 and R 3 taken together with the nitrogen atom of N(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring; and
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. The method of claim 1 , wherein:
Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′; and
R and R′ are each independently —H; a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , lower alkoxy, lower haloalkoxy and aryl; or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group; or
R and R′ taken together with the nitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; —OH; —CN; —NCS; —NO 2; —NH 2 ; lower alkoxy; lower haloalkoxy; lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , lower alkoxy, lower haloalkoxy and aryl; and aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group.

3. The method of claim 2 , wherein:
—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.

4. The method of claim 3 , wherein R 5 and R 6 are each independently —H; —OH; a halogen; or a lower alkoxy or lower alkyl group.

5. The method of claim 4 , wherein Y is —H.

6. he method of claim 5 , wherein:
R 4 is an aliphatic or aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —NCS, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —NR 51 C(O)OR 52 , —N(R 51 )C(O)N(R 51 ) 2 , —C(O)R 50 , —C(S)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —S(O) 2 R 50 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 50 , —NR 51 SO 2 N(R 51 ) 2 , —NR 51 SO 2 R 52 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —NR 51 CO 2 R 52 , —V 4 —N(R 51 )C(O)N(R 51 ) 2 , —V 4 —C(O)R 50 ,
—V 4 —C(S)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —V 4 —S(O) 2 R 50 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 50 , —V 4 —NR 51 SO 2 N(R 51 ) 2 , —V 4 —NR 51 SO 2 R 52 , —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(S)—V 4 —N(R 51 ) 2 , —C(S)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —S(O) 2 —V 4 —N(R 51 ) 2 , —S(O) 2 —V 4 —Ar 3 , —SO 2 N(R 51 )—V 5 —N(R 51 ) 2 , —SO 2 N(R 51 )—V 4 —Ar 3 , —S(O)—V 4 —N(R 51 ) 2 , —S(O)—V 4 —Ar 3 , —S(O) 2 —O—V 5 N(R 51 ) 2 , —S(O) 2 —

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
• Jozefiak Thomas H
• Vinick Frederic
• Xiang Yibin
• Kane John
• Liao Junkai

Classifications

• A61P43/00

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

• C07D319/18 Primary

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D207/10 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title