2-acylaminopropoanol-type glucosylceramide synthase inhibitors

• US 9,745,294 B2
• Filed: 12/16/2014
• Issued: 08/29/2017
• 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:
  US14/571,922
• Publication Number:
  US 20150225393A1
• Time in Patent Office: 987 Days
• Field of Search: None
• 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 method of decreasing glycated hemoglobin levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

4. 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, —

NR⁵¹ SO₂—

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.

5. The method of claim 4, wherein the compound is represented by the following structural formula:

6. The method of claim 4, wherein the compound is represented by the following structural formula:

7. The method of claim 4, wherein the compound is represented by the following structural formula:

8. The method of claim 4, wherein the compound is represented by the following structural formula:

9. The method of claim 4, wherein the compound is represented by one of the following structural formulas:

10. The method of claim 4, wherein the compound is represented by the following structural formula:

2. 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 a compound represented by the following structural formula:

11. The method of claim 2, 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, —

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(R⁵)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.

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

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

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

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

16. The method of claim 11, wherein the compound is represented by one of the following structural formulas:

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

3. A method of treating a subject having Tay-Sachs, Gaucher'"'"'s or Fabry'"'"'s disease, comprising administering to the subject a therapeutically effective of a compound represented by the following structural formula:

18. The method of claim 3, 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—

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(R⁵)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(R⁵)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.

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

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

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

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

23. The method of claim 18, wherein the compound is represented by one of the following structural formulas:

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