2-acylaminopropoanol-type glucosylceramide synthase inhibitors

• US 9,744,153 B2
• Filed: 01/21/2016
• Issued: 08/29/2017
• 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:
  US15/003,207
• Publication Number:
  US 20160338996A1
• Time in Patent Office: 586 Days
• Field of Search: None
• 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 polycystic kidney disease in a subject, the method comprising administering to the subject an effective amount of a compound represented by the following structural formula:

2. The method of claim 1, wherein:

Y is —

H, —

C(O)R, —

C(O)OR or —

C(O)NRR′

; and

R and R′

are each independently —

H;

a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy and aryl;

or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group;

or

R and R′

taken together with the nitrogen atom of NRR′

form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of;

halogen;

—

OH;

—

CN;

—

NCS;

—

NO_2;

—

NH₂;

lower alkoxy;

lower haloalkoxy;

lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy and aryl; and

aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

CN, —

NCS, —

NO₂, —

NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group.

3. The method of claim 2, wherein:

—

N(R²R³) is a 5- or 6- membered non- aromatic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl,

haloalkyl, —

OR⁴⁰, —

O(haloalkyl), —

SR⁴⁰, —

NO₂, —

CN, —

N(R⁴¹)₂, —

NR⁴¹C(O)R⁴⁰, —

NR⁴¹C(O) OR⁴², —

N(R⁴¹)C(O)N(R⁴¹)₂, —

C(O)R⁴⁰, —

C(S)R⁴⁰, —

C(O)OR⁴⁰, —

OC(O)R⁴⁰, —

C(O)N(R⁴¹)₂, —

S(O)₂R⁴⁰, —

SO₂N(R⁴¹)₂, —

S(O)R⁴², —

SO₃R⁴⁰, Ar²,

V₂—

Ar², —

V₂—

OR⁴⁰, —

V₂—

O(haloalkyl), —

V₂—

SR⁴⁰, —

V₂—

NO₂, —

V₂—

CN, —

V₂—

N(R⁴¹)₂, —

V₂—

NR⁴¹C(O)R⁴⁰, —

V₂—

NR⁴¹CO₂R⁴², —

V₂—

N(R⁴¹)C(O)N(R⁴¹)₂, —

V₂—

C(O)R⁴⁰, —

V₂—

C(S)R⁴⁰, —

V₂—

CO₂R⁴⁰, —

V₂—

OC(O)R⁴⁰, —

V₂—

C(O)N(R⁴¹)₂—

, —

V₂—

S(O)₂R⁴⁰, —

V₂—

SO₂N(R⁴¹)₂, —

V₂—

S(O)R⁴², —

V₂—

SO₃R⁴⁰, —

O—

V₂—

Ar² and —

S—

V₂—

Ar²;

each V₂ is independently a C1-C4 alkylene group;

Ar² is an aryl 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 R⁴⁰ is independently

i) hydrogen;

ii) an aryl 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 R⁴¹ is independently R⁴⁰, —

CO₂R⁴⁰, —

SO₂R⁴⁰ or —

C(O)R⁴⁰;

or

—

N(R⁴¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; and

each R⁴² is independently;

i) an aryl 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

ii) 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.

4. The method of claim 3, wherein R⁵ and R⁶ are each independently —

H;

—

OH;

a halogen;

or a lower alkoxy or lower alkyl group.

5. The method of claim 4, wherein Y is —

H.

6. he method of claim 5, 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—

V₅N(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.

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

8. The method of claim 7, wherein R⁴ is an optionally substituted aryl group.

9. The method of claim 8, wherein R⁴ is selected from the group consisting of:

10. The method of claim 1, wherein r is 1 or 2.

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

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

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

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