Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease

Patent metadata

Field	Value
Publication number	US-9481671-B2
Application number	US-201414255634-A
Country	US
Kind code	B2
Filing date	Apr 17, 2014
Priority date	Jul 28, 2008
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject comprises administering to the subject an effective amount of a glucosylceramide synthase inhibitor.

First claim

What is claimed is:

1. A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a glucosylceramide synthase inhibitor represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a substituted or unsubstituted aryl 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, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms; and
R 4 is an optionally substituted aryl group or an optionally substituted straight chained aliphatic group.

2. The method of claim 1 ,
wherein R 4 is an optionally substituted aryl group.

3. The method of claim 2 , wherein:
R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of 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— and —[CH 2 ] q —;
Ar 1 is a phenyl 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 30 is independently
i) hydrogen;
ii) a phenyl 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 31 is independently R 30 , or —N(R 31 ) 2 is an optionally substituted non-aromatic heterocyclic group.

4. The method of claim 3 , wherein:
—N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

5. The method of claim 4 , wherein R 4 is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl,
Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 50 , —C(O)O R 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —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 —C(O)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —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(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 , —O—[CH 2 ] p′ —O— and —[CH 2 ] q′ —.

6. The method of claim 5 , wherein R 4 is selected from the group consisting of:

wherein:
each of rings A-Z5 is optionally substituted with.

7. The method of claim 6 , wherein:
—N(R 2 R 3 ) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

8. The method of claim 7 , wherein:
the phenyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH 2 ] p O—; and
each of rings A-U is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR 50 , —Ar 3 , —V 4 —Ar 3 , —V—OR 50 , —O(C1-C10 haloalkyl), —V 4 —O(C1-C10 haloalkyl), —O—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— and —[CH 2 ] q′ —.

9. The method of claim 8 , wherein:
—N(R 2 R 3 ) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; and
each of rings A-U is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH 2 ] p′ —O— and —[CH 2 ] q ′—.

10. The method of claim 6 , wherein R 4 is

and wherein phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar 3 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

11. The method of claim 1 ,
wherein R 4 is an optionally substituted straight chained aliphatic group.

12. The method of claim 11 , wherein R 4 is a straight chained C1-C20 alkyl group optionally substituted with hydroxy.

13. The method of claim 12 , wherein:
R 1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of 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— and —[CH 2 ] q —;
Ar 1 is a phenyl 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 30 is independently
i) hydrogen;
ii) a phenyl group optionally substituted with one or more substituents selected from the group consi

Assignees

• Genzyme Corp

Inventors

• Ibraghimov-Beskrovnaya Oxana
• Natoli Thomas A

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/4245

  Oxadiazoles · CPC title

• A61K31/453

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title