Carbamic acid compounds comprising an ether linkage as HDAC inhibitors

• US 6,960,685 B2
• Filed: 09/27/2001
• Issued: 11/01/2005
• Est. Priority Date: 09/29/2000
• Status: Expired due to Fees

• Current Assignee: TopoTarget UK Limited (Onxeo S.A.)
• Original Assignee: TopoTarget UK Limited (Onxeo S.A.)
• Inventors: Kalvinsh, Ivars, Lolya, Daina, Finn, Paul W, Starchenkov, Igor, Loza, Einars, Watkins, Clare J, Romero-Martin, Maria Rosario, Harris, C. John, Semenikhina, Valentina, Bokaldere, Rasma M, Duffy, James E. S.
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US10/381,794
• Publication Number:
  US 20040198830A1
• Time in Patent Office: 1,496 Days
• Field of Search: 562/621, 562/623, 514/575
• US Class Current: 562/623
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Abstract

This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula:
wherein: A is an aryl group; Q¹ is a covalent bond or an aryl leader group; J is an amide linkage selected from: —NR¹C(═O)— and —C(═O)NR¹—; R¹ is an amido substituent; X is an ether heteroatom, and is —O— or —S—; and, R² and R³ are each independently an ether group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.

Claims

1. A compound of the formula:

wherein;

A is an aryl group;

Q¹ is a covalent bond or an aryl leader group;

J is an amide linkage selected from;

R¹ is an amido substituent;

X is an ether heteroatom, and is —

O—

or —

S—

; and

,

R² and R³ are each independently an ether group; and

wherein;

A, is a C_5-20aryl group, and is unsubstituted or substituted;

the aryl leader group, if present, is a C_1-7alkylene group and is unsubstituted or substituted;

the amido substituent, R¹, is hydrogen, C_1-7alkyl, C_3-20heterocyclyl, or C_5-20aryl;

each of the ether groups, R² and R³, is independently C_1-7alkylene; and

is unsubstituted;

and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

2. A compound according to claim 1, wherein J is —

NR¹CO— and

X is —

O—

.

3. A compound according to claim 1, wherein J is —

NR¹CO— and

X is —

S—

.

4. A compound according to claim 1, wherein Q¹ is an aryl leader group, J is —

NR¹CO— and

X is —

O—

.

5. A compound according to claim 1, wherein Q¹ is an aryl leader group, J is —

NR¹CO— and

X is —

S—

.

6. A compound according to claim 1, wherein Q¹ is a covalent bond, J is —

NR¹CO— and

X is —

O—

.

7. A compound according to claim 1, wherein Q¹ is a covalent bond, J is —

NR¹CO— and

X is —

S—

.

8. A compound according to claim 1, wherein J is —

CONR¹— and

X is —

O—

.

9. A compound according to claim 1, wherein J is —

CONR¹— and

X is —

S—

.

10. A compound according to claim 1, wherein Q¹ is a covalent bond, J is —

CONR¹— and

X is —

O—

.

11. A compound according to claim 1, wherein Q¹ is a covalent bond, J is —

CONR¹— and

X is —

S—

.

12. A compound according to claim 1, wherein Q¹ is an aryl leader group, J is —

CONR¹— and

X is —

O—

.

13. A compound according to claim 1, wherein Q¹ is an aryl leader group, J is —

CONR¹— and

X is —

S—

.

14. A compound according to claim 1, wherein the aryl leader group, Q¹, is an aliphatic C_1-7alkylene group.

15. A compound according to claim 1, wherein the aryl leader group, Q¹, is a partially unsaturated aliphatic C_2-7alkylene group.

16. A compound according to claim 1, wherein the aryl leader group, Q¹, is selected from:

—

CH₂—

, —

CH═

CH—

, and —

CH═

CH—

CH═

CH—

.

17. A compound according to claim 1, wherein the aryl leader group, Q¹, is unsubstituted or substituted with one or more groups selected from:

halo, hydroxy, ether, C_5-20aryl, acyl, amido, and oxo.

18. A compound according to claim 1, wherein the aryl leader group, Q¹, is unsubstituted.

19. A compound according to claim 1, wherein each of the ether groups, R² and R³, is independently an aliphatic C_1-7alkylene group.

20. A compound according to claim 1, wherein each of the ether groups, R² and R³, is independently a saturated aliphatic C_1-7alkylene group.

21. A compound according to claim 1, wherein each of the ether groups, R² and R³, is independently —

(CH₂)_n—

, wherein n is an integer from 1 to 5.

22. A compound according to claim 1, wherein the group R²—

X—

R³ is independently selected from the following;

—

CH₂—

O—

CH₂— and

—

CH₂—

S—

CH₂—

;

—

CH₂—

O—

CH₂CH₂— and

—

CH₂—

S—

CH₂—

CH₂;

—

CH₂CH₂—

O—

CH₂— and

—

CH₂CH₂—

S—

CH₂—

;

—

CH₂—

O—

CH₂CH₂CH₂— and

—

CH₂—

S—

CH₂CH₂CH₂—

;

—

CH₂CH₂—

O—

CH₂CH₂— and

—

CH₂CH₂—

S—

CH₂CH₂—

;

—

CH₂CH₂CH₂—

O—

CH₂— and

—

CH₂CH₂CH₂—

S—

CH₂—

;

—

CH₂—

O—

CH₂CH₂CH₂CH₂— and

—

CH₂—

S—

CH₂CH₂CH₂CH₂—

;

—

CH₂CH₂—

O—

CH₂CH₂CH₂— and

—

CH₂CH₂—

S—

CH₂CH₂CH₂—

;

—

CH₂CH₂CH₂—

O—

CH₂CH₂— and

—

CH₂CH₂CH₂—

S—

CH₂CH₂—

;

—

CH₂CH₂CH₂CH₂—

O—

CH₂— and

—

CH₂CH₂CH₂CH₂—

S—

CH₂—

;

—

CH₂—

O—

CH₂CH₂CH₂CH₂CH₂— and

—

CH₂—

S—

CH₂CH₂CH₂CH₂CH₂—

;

—

CH₂CH₂—

O—

CH₂CH₂CH₂CH₂— and

—

CH₂CH₂—

S—

CH₂CH₂CH₂CH₂—

;

—

CH₂CH₂CH₂—

O—

CH₂CH₂CH₂— and

—

CH₂CH₂CH₂—

S—

CH₂CH₂CH₂—

;

—

CH₂CH₂CH₂CH₂—

O—

CH₂CH₂— and

—

CH₂CH₂CH₂CH₂—

S—

CH₂CH₂—

;

—

CH₂CH₂CH₂CH₂CH₂—

O—

CH₂— and

—

CH₂CH₂CH₂CH₂CH₂—

S—

CH₂—

.

23. A compound according to claim 1, wherein A is a C_5-20aryl group derived from one of the following:

benzene, pyridine, furan, indole, pyrrole, imidazole, naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole.

24. A compound according to claim 1, wherein A is a phenyl group unsubstituted or substituted with one or more of the following groups:

fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

25. A compound according to claim 1, wherein the amido substituent, R¹, is —

H.

26. A compound according to claim 1, selected from the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof:

27. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carder or diluent.

28. A compound of the formula:

wherein;

A is an aryl group;

Q¹ is a covalent bond or an aryl leader group;

J is an amide linkage selected from;

R¹ is an amido substituent;

X is an ether heteroatom, and is —

O—

or —

S—

; and

,

R² and R³ are each independently an ether group; and

wherein;

A, is a C_5-20aryl group, and is unsubstituted or substituted;

the aryl leader group, if present, is a C_1-7alkylene group and is unsubstituted or substituted;

the amido substituent, R¹, is hydrogen, C_1-7alkyl, C_3-20heterocyclyl, or C_5-20aryl;

R² is independently C_5-20arylene;

R³ is independently C_1-7alkylene;

each of the ether groups, R² and R³is unsubstituted;

and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

29. A compound according to claim 28, wherein J is —

NR¹CO— and

X is —

O—

.

30. A compound according to claim 28, wherein J is —

NR¹CO— and

X is —

S—

.

31. A compound according to claim 28, wherein J is —

CONR¹— and

X is —

O—

.

32. A compound according to claim 28, wherein J is —

CONR¹— and

X is —

S—

.

33. A compound according to claim 28, wherein Q¹ is an aryl leader group, J is —

CONR¹— and

X is —

O—

.

34. A compound according to claim 28, wherein the aryl leader group, Q¹, is an aliphatic C_1-7alkylene group.

35. A compound according to claim 28, wherein the aryl leader group, Q¹, is a partially unsaturated aliphatic C_2-7alkylene group.

36. A compound according to claim 28, wherein the aryl leader group, Q¹, is a partially unsaturated linear C_2-7alkylene group.

37. A compound according to claim 28, wherein the aryl leader group, Q¹, is selected from:

—

CH₂—

, —

CH═

CH—

, and —

CH═

CH—

CH═

CH—

.

38. A compound according to claim 28, wherein the aryl leader group, Q¹, is unsubstituted or substituted with one or more groups selected from:

halo, hydroxy, ether, C_5-20aryl, acyl, amido, and oxo.

39. A compound according to claim 28, wherein the aryl leader group, Q¹, is unsubstituted.

40. A compound according to claim 28, wherein R² is independently C_5-6arylene.

41. A compound according to claim 28, wherein R² is phenylene.

42. A compound according to claim 28, wherein R³ is independently an aliphatic C_1-7alkylene group.

43. A compound according to claim 28, wherein R³ is independently a saturated aliphatic C_1-7alkylene group.

44. A compound according to claim 28, wherein R³ is independently —

(CH₂)_n—

, wherein n is an integer from 1 to 5.

45. A compound according to claim 28, wherein the group —

R²—

X—

R³—

is;

46. A compound according to claim 28, wherein A is a C_5-20aryl group derived from one of the following:

benzene, pyridine, furan, indole, pyrrole, imidazole, naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole.

47. A compound according to claim 28, wherein A is a phenyl group unsubstituted or substituted with one or more of the following groups:

fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

48. A compound according to claim 28, wherein the amido substituent, R¹, is —

H.

49. A compound according to claim 28, selected from the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof:

50. A composition comprising a compound according to claim 28 and a pharmaceutically acceptable carrier or diluent.

51. A compound of the formula:

wherein;

A is an aryl group;

Q¹ is an aryl leader group;

J is an amide linkage selected from;

R¹ is an amido substituent;

X is an ether heteroatom, and is —

O—

; and

,

R² and R³ are each independently an ether group; and

wherein;

A, is a C_5-20aryl group, and is unsubstituted or substituted;

the aryl leader group, if present, is a C_1-7alkylene group and is unsubstituted or substituted;

the amido substituent, R¹, is hydrogen, C_1-7alkyl, C_3-20heterocyclyl, or C_5-20aryl;

R² is independently C_5-20arylene;

R³ is independently C_1-7alkylene;

each of the ether groups, R² and R³, is unsubstituted or substituted

and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

52. A compound according to claim 51, wherein J is —

NR¹CO—

.

53. A compound according to claim 51, wherein J is —

CONR¹—

.

54. A compound according to claim 51, wherein the aryl leader group, Q¹, is an aliphatic C_1-7alkylene group.

55. A compound according to claim 51, wherein the aryl leader group, Q¹, is a partially unsaturated aliphatic C_2-7alkylene group.

56. A compound according to claim 51, wherein the aryl leader group, Q¹, is a partially unsaturated linear C_2-7alkylene group.

57. A compound according to claim 51, wherein the aryl leader group, Q¹, is selected from:

—

CH₂—

, —

CH═

CH—

, and —

CH═

CH—

CH═

CH—

.

58. A compound according to claim 51, wherein the aryl leader group, Q¹, is unsubstituted or substituted with one or more groups selected from:

halo, hydroxy, ether, C_5-20aryl, acyl, amido, and oxo.

59. A compound according to claim 51, wherein the aryl leader group, Q¹, is unsubstituted.

60. A compound according to claim 51, wherein R² is independently C_5-6arylene.

61. A compound according to claim 51, wherein R² is phenylene.

62. A compound according to claim 51, wherein R³ is independently an aliphatic C_1-7alkylene group.

63. A compound according to claim 51, wherein R³ is independently a saturated aliphatic C_1-7alkylene group.

64. A compound according to claim 51, wherein R³ is independently —

(CH₂)_n—

, wherein n is an integer from 1 to 5.

65. A compound according to claim 51, wherein the group —

R²—

X—

R³—

is;

66. A compound according to claim 51, wherein A is a C_5-20aryl group derived from one of the following:

benzene, pyridine, furan, indole, pyrrole, imidazole, naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole.

67. A compound according to claim 51, wherein A is a phenyl group unsubstituted or substituted with one or more of the following groups:

fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

68. A compound according to claim 51, wherein the amido substituent, R¹, is —

H.

69. A compound according to claim 51, selected from the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: