2-acylaminopropoanol-type glucosylceramide synthase inhibitors

• US 9,272,996 B2
• Filed: 08/27/2012
• Issued: 03/01/2016
• Est. Priority Date: 10/03/2008
• Status: Expired due to Fees

• 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., Jozefiak, Thomas H., Vinick, Frederic, Xiang, Yibin, Kane, John, Liao, Junkai
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US13/595,251
• Publication Number:
  US 20120322786A1
• Time in Patent Office: 1,282 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 271/12 to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 317/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 319/20 with substituents attached to the hetero ring
• CPC Class Codes: C07D 333/16 by oxygen atoms
• CPC Class Codes: C07D 407/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

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.

Claims

1. A method of treating a subject having polycystic kidney disease, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

2. The method of claim 1, wherein:

R⁴ is an aliphatic or aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar³, Ar³—

Ar³, —

OR⁵⁰, —

O(haloalkyl), —

SR⁵⁰, —

NO₂, —

CN, —

NCS, —

N(R⁵¹)₂, —

NR⁵¹C(O)R⁵⁰, —

NR⁵¹C(O)OR⁵², —

N(R⁵¹)C(O)N(R⁵¹)₂, —

C(O)R⁵⁰, —

C(S)R⁵⁰, —

C(O)OR⁵⁰, —

OC(O)R⁵⁰, —

C(O)N(R⁵¹)₂, —

S(O)₂R⁵⁰, —

SO₂N(R⁵¹)₂, —

S(O)R⁵², —

SO₃R⁵⁰, —

NR⁵¹SO₂N(R⁵¹)₂, —

NR⁵¹SO₂R⁵², —

V₄—

Ar³, —

V—

OR⁵⁰, —

V₄—

O(haloalkyl), —

V₄—

SR⁵⁰, —

V₄—

NO₂, —

V₄—

CN, —

V₄—

N(R⁵¹)₂, —

V₄—

NR⁵¹C(O)R⁵⁰, —

V₄—

NR⁵¹CO₂R⁵², —

V₄—

N(R⁵¹)C(O)N(R⁵¹)₂, —

V₄—

C(O)R⁵⁰, —

V₄—

C(S)R⁵⁰, —

V₄—

CO₂R⁵⁰, —

V₄—

OC(O)R⁵⁰, —

V₄—

C(O)N(R⁵¹)₂—

, —

V₄—

S(O)₂R⁵⁰, —

V₄—

SO₂N(R⁵¹)₂, —

V₄—

S(O)R⁵², —

V₄—

SO₃R⁵⁰, —

V₄—

NR⁵¹SO₂N(R⁵¹)₂, —

V₄—

NR⁵¹SO₂R⁵², —

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(S)—

V₄—

N(R⁵¹)₂, —

C(S)—

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, —

S(O)₂—

V₄—

N(R⁵¹)₂, —

S(O)₂—

V₄—

Ar³, —

SO₂N(R⁵¹)—

V₅—

N(R⁵¹)₂, —

SO₂N(R⁵¹)—

V₄—

Ar³, —

S(O)—

V₄—

N(R⁵¹)₂, —

S(O)—

V₄—

Ar³, —

S(O)₂—

O—

V₅—

N(R⁵¹)₂, —

S(O)₂—

O—

V₄—

Ar³, —

NR⁵¹SO₂—

V₄—

N(R⁵¹)₂, —

NR⁵¹SO₂—

V₄—

Ar³, —

O—

[CH₂]_p′

—

O—

, —

S—

[CH₂]_p′

—

S—

, and —

[CH₂]_q′

—

;

each V₄ is independently a C1-C10 alkylene group;

each V₅ is independently a C2-C10 alkylene group;

each Ar³ is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and

each R⁵⁰ is independently

i) hydrogen;

ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl;

or

iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each R⁵¹ is independently R⁵⁰, —

CO₂R⁵⁰, —

SO₂R⁵⁰ or —

C(O)R⁵⁰;

or

—

N(R⁵¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; and

each R⁵² is independently;

i) an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl;

or

ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and

each p′

is 1, 2, 3 or 4; and

each q′

is 3, 4, 5 or 6.

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

4. The method of claim 3, 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(R³)₂, —

S—

V_o—

Ar¹, —

S—

V₁—

N(R³¹)₂, —

N(R³¹)—

V_o—

Ar¹, —

N(R³¹)—

V₁—

N(R³)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.

5. The method of claim 4, wherein —

N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of 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 and C1-C5 dialkylamino.

6. The method of claim 2, represented by the following structural formula:

7. The method of claim 6, represented by the following structural formula:

8. The method of claim 7, represented by the following structural formula:

9. The method of claim 2, represented by the following structural formula:

10. The method of claim 9, represented by the following structural formula:

11. The method of claim 10, represented by the following structural formula:

12. The method of claim 2, represented by the following structural formula:

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

14. The method of claim 2, represented by the following structural formula (XI) or (XII):

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

16. The method of claim 2, represented by the following structural formula: