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

• US 9,481,671 B2
• Filed: 04/17/2014
• Issued: 11/01/2016
• 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 A.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US14/255,634
• Publication Number:
  US 20140336174A1
• Time in Patent Office: 929 Days
• Field of Search: 514/233.8, 514/321, 514/365, 514/422
• US Class Current: 1/1
• 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 glucosylceramide synthase inhibitor represented by the following structural formula:

2. The method of claim 1,

wherein R⁴ is an optionally substituted aryl group.

3. The method of claim 2, 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, —

OR³⁰, —

SR³⁰, —

N(R³¹)₂,

Ar¹, —

V_o—

OR³⁰, —

V_o—

N(R³¹)₂, —

V_o—

Ar¹, —

O—

V_o—

Ar¹, —

O—

V₁—

N(R³¹)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³¹)₂, —

O—

[CH₂]_p—

O—

, —

S—

[CH₂]_p—

S— and

—

[CH₂]_q—

;

Ar¹ 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 R³⁰ 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 R³¹ is independently R³⁰, or —

N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

4. The method of claim 3, wherein:

—

N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

5. The method of claim 4, wherein R⁴ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl,

Ar³, —

OR⁵⁰, —

O(haloalkyl), —

SR⁵⁰, —

NO₂, —

CN, —

N(R⁵¹)₂, —

NR⁵¹C(O)R⁵⁰, —

C(O)R⁵⁰, —

C(O)O R⁵⁰, —

OC(O)R⁵⁰, —

C(O)N(R⁵¹)₂, —

V₄—

Ar³, —

V—

OR⁵⁰, —

V₄—

O (haloalkyl), —

V₄—

SR⁵⁰, —

V₄—

NO₂, —

V₄—

CN, —

V₄—

N(R⁵¹)₂, —

V₄—

NR⁵¹C(O)R⁵⁰, —

V₄—

C(O)R⁵⁰, —

V₄—

CO₂R⁵⁰, —

V₄—

OC(O)R⁵⁰, —

V₄—

C(O)N(R⁵¹)₂—

, —

O—

V₄—

Ar³, —

O—

V₅—

N(R⁵¹)₂, —

S—

V₄—

Ar³, —

S—

V₅—

N(R⁵¹)₂, —

N(R⁵¹)—

V₄—

Ar³, —

N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

N(R⁵¹)₂, —

NR⁵¹C(O)—

V₄—

Ar³, —

C(O)—

V₄—

N(R⁵¹)₂, —

C(O)—

V₄—

Ar³, —

C(O)O—

V₅—

N(R⁵¹)₂, —

C(O)O—

V₄—

Ar³, —

O—

C(O)—

V₅—

N(R⁵¹)₂, —

O—

C(O)—

V₄—

Ar³, —

C(O)N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

C(O)N(R⁵¹)—

V₄—

Ar³, —

O—

[CH₂]_p′

—

O— and

—

[CH₂]_q′

—

.

6. The method of claim 5, wherein R⁴ is selected from the group consisting of:

7. The method of claim 6, wherein:

—

N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

8. The method of claim 7, wherein:

the phenyl group represented by R¹ 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—

[CH₂]_pO—

; 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, —

OR⁵⁰, —

Ar³, —

V₄—

Ar³, —

V—

OR⁵⁰, —

O(C1-C10 haloalkyl), —

V₄—

O(C1-C10 haloalkyl), —

O—

V₄—

Ar³, —

O—

[CH₂]_p′

—

O— and

—

[CH₂]_q′

—

.

9. The method of claim 8, wherein:

—

N(R²R³) is pyrrolidinyl,

10. The method of claim 6, wherein R⁴ is

11. The method of claim 1,

wherein R⁴ is an optionally substituted straight chained aliphatic group.

12. The method of claim 11, wherein R⁴ is a straight chained C1-C20 alkyl group optionally substituted with hydroxy.

13. The method of claim 12, 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, —

OR³⁰, —

SR³⁰, —

N(R³¹)₂,

Ar¹, —

V_o—

OR³⁰, —

V_o—

N(R³¹)₂, —

V_o—

Ar¹, —

O—

V_o—

Ar¹, —

O—

V₁—

N(R³¹)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³¹)₂, —

O—

[CH₂]_p—

O—

, —

S—

[CH₂]_p—

S— and

—

[CH₂]_q—

;

Ar¹ 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 R³⁰ 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 R³¹ is independently R³⁰, or —

N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

14. The method of claim 13, wherein:

—

N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

15. The method of claim 14, wherein:

—

N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

16. The method of claim 15, wherein:

the phenyl group represented by R¹ 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—

[CH₂]_p—

O—

.

17. The method of claim 16, wherein:

—

N(R²R³) is pyrrolidinyl,

18. The method of claim 12, wherein R⁴ is a straight chained C6-C8 alkyl group.

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

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

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

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

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