2-acylaminopropoanol-type glucosylceramide synthase inhibitors

• US 8,940,776 B2
• Filed: 08/27/2012
• Issued: 01/27/2015
• Est. Priority Date: 05/31/2007
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• 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
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US13/595,349
• Publication Number:
  US 20120322787A1
• Time in Patent Office: 883 Days
• Field of Search: 514/364, 514/365, 514/367, 514/380, 514/422, 514/424, 514/428, 548/131, 548/159, 548/204, 548/245, 548/518, 548/526, 548/527, 548/541, 548/571
• US Class Current: 514/364
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 295/125 with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• 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 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 411/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• 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 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.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1, wherein —

N(R²R³) is a pyrrolidinyl group optionally substituted with one or more substituents selected from halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino or C1-C5 dialkylamino.

3. The compound of claim 2, represented by the following structural formula:

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. A method of treating a subject having type 2 diabetes, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. A method of treating a subject having renal hypertrophy or hyperplasia associated with diabetic nephropathy, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. A method of decreasing plasma TNF-α

in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. A method of lowering blood glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. A method of decreasing glycated hemoglobin levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. 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 the compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. A method of treating a subject with Tay-Sachs, Gaucher'"'"'s or Fabry'"'"'s disease, comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound is a (1R,2R) stereoisomer.

13. The compound of claim 2, wherein R⁷ is —

H, and R⁴ is an optionally substituted aryl or arylalkyl group.

14. The compound of claim 13, wherein R⁴ is an aryl or arylalkyl group each optionally and independently substituted with one or more substituents selected from 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)OR⁵⁰, —

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—

or —

[CH₂]_q′

—

, wherein arylalkyl includes straight and branched saturated chains containing one to six carbon atoms.

15. The compound of claim 3, wherein R⁸ is selected from:

16. The compound of claim 15, wherein —

N(R²R³) is an unsubstituted pyrrolidinyl group.

17. The compound of claim 16, wherein each of rings A-Z5 is optionally substituted with one or more substituents selected from halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —

O—

[CH₂]_p—

O—

or —

[CH₂]_q—

.

18. The compound of claim 17, wherein:

—

N(R²R³) is pyrrolidinyl; and

the phenyl group represented by R¹ is optionally substituted with one or more substituents selected from —

OH, —

OCH₃, —

OC₂H₅ or —

O—

[CH₂]_p—

O—

.

19. The compound of claim 1, represented by one of the following structural formulas: