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

• US 8,729,075 B2
• Filed: 02/07/2013
• Issued: 05/20/2014
• Est. Priority Date: 07/28/2008
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Ibraghimov-Beskrovnaya, Oxana, Natoli, Thomas
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US13/762,102
• Publication Number:
  US 20130225573A1
• Time in Patent Office: 467 Days
• Field of Search: 514/233.8, 514/321, 514/365, 514/422
• US Class Current: 514/233.8
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/396 having three-membered rings, e.g. aziridine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 319/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

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.

Claims

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 compound represented by the following structural formula:

2. The method of claim 1, wherein the glomerular disease is mesangial proliferative glomerulonephritis.

3. The method of claim 1, wherein the glomerular disease is collapsing glomerulopathy.

4. The method of claim 1, wherein the glomerular disease is proliferative lupus nephritis.

5. The method of claim 1, wherein the glomerular disease is crescentic glomerulonephritis.

6. The method of claim 1, wherein the glomerular disease is membranous nephropathy.

7. The method of claim 1, wherein the compound is represented by the following structural formula:

8. The method of claim 1, wherein Q is —

O—

or —

C(O)—

.

9. The method of claim 8, wherein the compound is represented by the following structural formula:

10. The method of claim 8, wherein the compound is represented by the following structural formula:

11. The method of claim 1, wherein the compound is represented by the following structural formula:

12. The method of claim 11, wherein Q is —

O—

or —

C(O)—

.

13. The method of claim 12, wherein the compound is represented by the following structural formula:

14. The method of claim 1, wherein R¹ 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, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —

OH, C1-C6 alkoxy, —

O—

[CH₂]_p—

O— and

—

[CH₂]_q—

.

15. The method of claim 14, wherein the compound is represented by the following structural formula:

16. The method of claim 14, wherein the compound is represented by the following structural formula:

17. The method of claim 14, wherein the compound is represented by the following structural formula:

18. The method of claim 14, wherein the compound is represented by the following structural formula:

19. The method of claim 14, wherein the compound is represented by the following structural formula:

20. The method of claim 14, wherein the compound is represented by the following structural formula:

21. The method of claim 1, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof.

22. 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 compound represented by the following structural formula:

23. 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 compound represented by the following structural formula:

24. The method of claim 23, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof.