Carbamic acid compounds comprising an amide linkage as HDAC inhibitors

• US 7,569,724 B2
• Filed: 09/27/2001
• Issued: 08/04/2009
• 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: Duffy, James E. S., Kalvinsh, Ivars, Moore, Kathryn G, Lolya, Daina, Dikovska, Klara, Ritchie, James, Amolins, Andris, Finn, Paul W, Starchenkov, Igor, Gailite, Vija, Vorona, Maxim, Loza, Einars, Watkins, Clare J, Romero-Martin, Maria Rosario, Andrianov, Victor, Harris, C. John, Semenikhina, Valentina, Bokaldere, Rasma M
• Primary Examiner(s): Andes; Janet L.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US10/381,791
• Publication Number:
  US 20040092598A1
• Time in Patent Office: 2,868 Days
• Field of Search: 564/155
• US Class Current: 564/155
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 233/49 having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/83 of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/36 having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• 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 259/08 having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07D 207/337 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 207/40 : 2,5-Pyrrolidine-diones
• CPC Class Codes: C07D 207/404 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• CPC Class Codes: C07D 209/14 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/16 : Tryptamines
• CPC Class Codes: C07D 209/18 : 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 209/22 : with an aralkyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 213/06 : containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
• CPC Class Codes: C07D 213/55 : Acids; Esters
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 233/04 : having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 233/08 : with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
• CPC Class Codes: C07D 235/14 : Radicals substituted by nitrogen atoms by nitro radicals C07D235/10
• CPC Class Codes: C07D 235/24 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 307/34 : having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 307/54 : 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 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 333/24 : 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 333/60 : 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 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the formula (1) wherein: A is an aryl group; Q1 is an aryl leader group having a backbone of at least 2 carbon atoms; J is an amide linkage selected from: —NR1C(═O)— and —C(═O)NR1-; R1 is an amido substituent; and, Q2 is an acid leader 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 selected from compounds of the following formula and pharmaceutically acceptable salts, amides, esters, ethers, and chemically protected forms thereof:

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

C(═

O)NR¹—

.

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

NR¹C(═

O)—

.

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

5. A compound according to claim 1, wherein Q¹ is a partially unsaturated linear C_2-7alkylene group.

6. A compound according to claim 1, wherein Q¹ is a partially unsaturated branched C_2-7alkylene group.

7. A compound according to claim 1, wherein Q¹ is a partially unsaturated alicyclic C_3-7alkylene group.

8. A compound according to claim 1, wherein Q¹ is not saturated at the carbon atom adjacent to J.

9. A compound according to claim 1, wherein Q¹ has a backbone of from 2 to 7 carbon atoms.

10. A compound according to claim 1, wherein Q¹ is unsubstituted.

11. A compound according to claim 1, wherein Q¹ is substituted.

12. A compound according to claim 1, wherein Q¹ is unsubstituted, or is substituted with one or more groups selected from:

halo, hydroxy, ether, phenyl, pyridyl, acyl, amido, and oxo.

13. A compound according to claim 1, wherein Q¹ is unsubstituted, or is substituted with one or more groups selected from:

—

F, —

Cl, —

Br, —

I, —

OH, —

OMe, —

OEt, —

OPr, -Ph, and ═

O.

14. A compound according to claim 1, wherein Q¹ is selected from:

15. A compound according to claim 1, wherein Q¹ is selected from:

—

CH═

CH— and

—

CH═

CH—

CH═

CH—

.

16. A compound according to claim 1, wherein Q² is a saturated C_3-10alkylene group.

17. A compound according to claim 1, wherein Q² is a partially unsaturated C_3-10alkylene group.

18. A compound according to claim 1, wherein Q² is an aliphatic C_3-10alkylene group.

19. A compound according to claim 1, wherein Q² is a linear C_3-10alkylene group.

20. A compound according to claim 1, wherein Q² is a branched C_4-10alkylene group.

21. A compound according to claim 1, wherein Q² is an alicyclic C_4-10alkylene group.

22. A compound according to claim 1, wherein Q² is a saturated aliphatic C_3-10alkylene group.

23. A compound according to claim 1, wherein Q² is a saturated linear C_3-10alkylene group.

24. A compound according to claim 1, wherein Q² is a saturated branched C_4-10alkylene group.

25. A compound according to claim 1, wherein Q² is a saturated alicyclic C_4-10alkylene group.

26. A compound according to claim 1, wherein Q² is a partially unsaturated aliphatic C_3-10alkylene group.

27. A compound according to claim 1, wherein Q² is a partially unsaturated linear C_3-10alkylene group.

28. A compound according to claim 1, wherein Q² is a partially unsaturated branched C_4-10alkylene group.

29. A compound according to claim 1, wherein Q² is a partially unsaturated alicyclic C_4-10alkylene group.

30. A compound according to claim 1, wherein Q² has a backbone of from 3 to 7 carbon atoms.

31. A compound according to claim 1, wherein Q² is unsubstituted.

32. A compound according to claim 1, wherein Q² is selected from:

—

(CH₂)₃—

, —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, and —

(CH₂)₇—

.

33. A compound according to claim 1, wherein Q² is selected from:

—

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, and —

(CH₂)₇—

.

34. A compound according to claim 1, wherein Q² is selected from:

—

(CH₂)₄—

, —

(CH₂)₅—

, and —

(CH₂)₆—

.

35. A compound according to claim 1, wherein Q² is selected from:

—

(CH₂)₅— and

—

(CH₂)₆—

.

36. A compound according to claim 1, wherein Q² is phenylene, or naphthalene-di-yl, and is optionally substituted.

37. A compound according to claim 1, wherein Q² is phenylene, and is optionally substituted.

38. A compound according to claim 1, wherein Q² is phenylene-C_1-7alkylene, or (naphthalene-di-yl)-C_1-7alkylene, and is optionally substituted;

and;

(i) the C_1-7alkylene moiety does not comprise a carbon-carbon triple bond;

or (ii) Q² has a backbone of less than 7 carbon atoms.

39. A compound according to claim 1, wherein Q² is phenylene-C_1-7alkylene, or (naphthalene-di-yl)-C_1-7alkylene, and is optionally substituted;

and;

(i) the C_1-7alkylene moiety does not comprise a carbon-carbon triple bond;

or (ii) Q² has a backbone of less than 6 carbon atoms.

40. A compound according to claim 1, wherein Q² is phenylene-C_1-2alkylene, or (naphthalene-di-yl)-C_1-2alkylene, -and is optionally substituted.

41. A compound according to claim 1, wherein Q² is phenylene-C_1-2alkylene, and is optionally substituted.

42. A compound according to claim 1, wherein Q² is phenylene-C_1-7alkylene, and is optionally substituted;

and;

(i) the C_1-7alkylene moiety does not comprise a carbon-carbon triple bond;

or (ii) Q² has a backbone of less than 7 carbon atoms.

43. A compound according to claim 1, wherein Q² is phenylene-meta-C_1-7alkylene or phenylene-para-C_1-7alkylene, and is optionally substituted;

and;

(i) the C_1-7alkylene moiety does not comprise a carbon-carbon triple bond;

or (ii) Q² has a backbone of less than 7 carbon atoms.

44. A compound according to claim 1, wherein Q² is substituted.

45. A compound according to claim 1, wherein Q² is selected from:

46. A compound according to claim 1, wherein Q² is:

47. A compound according to claim 1, wherein A is an optionally substituted naphthyl group.

48. A compound according to claim 1, wherein A is an optionally substituted phenyl group.

49. A compound according to claim 1, wherein A is a phenyl group which is unsubstituted, or is 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.

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

fluoro, chloro, bromo, iodo, trifluoromethyl, and nitro.

51. A compound according to claim 1, wherein R¹ is hydrogen or C_1-7alkyl.

52. A compound according to claim 1, wherein R¹ is —

H.

53. A compound according to claim 1, selected from the following compounds and pharmaceutically accepted salts thereof:

54. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

55. A method of inhibiting HDAC in a cell comprising said cell with an effective amount of a compound according to claim 1.

56. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

93. A compound according to claim 56, selected from the following compound, and pharmaceutically acceptable salts thereof:

57. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

58. A compound according to claim 57, wherein J is:

59. A compound according to claim 58, wherein A is phenyl, and is optionally substituted.

60. A compound according to claim 58, wherein A is phenyl, and is optionally 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.

61. A compound according to claim 58, wherein A is phenyl, and is optionally substituted with one or more of the following groups:

fluoro, chloro, bromo, methyl, hydroxyl, methoxy, and trifluoromethyl.

62. A compound according to claim 58, wherein A is naphthyl, and is optionally substituted.

63. A compound according to claim 58, wherein A is naphthyl, and is optionally 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.

64. A compound according to claim 58, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

65. A compound according to claim 59, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

66. A compound according to claim 60, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

67. A compound according to claim 61, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

68. A compound according to claim 62, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

69. A compound according to claim 63, wherein Q² is —

(CH₂)₅—

or —

(CH₂)₆—

.

70. A compound according to claim 58, wherein Q¹ is selected from:

71. A compound according to claim 59, wherein Q¹ is selected from:

72. A compound according to claim 60, wherein Q¹ is selected from:

73. A compound according to claim 61, wherein Q¹ is selected from:

74. A compound according to claim 62, wherein Q¹ is selected from:

75. A compound according to claim 63, wherein Q¹ is selected from:

76. A compound according to claim 64, wherein Q¹ is selected from:

77. A compound according to claim 65, wherein Q¹ is selected from:

78. A compound according to claim 66, wherein Q¹ is selected from:

79. A compound according to claim 67, wherein Q¹ is selected from:

80. A compound according to claim 68, wherein Q¹ is selected from:

81. A compound according to claim 69, wherein Q¹ is selected from:

82. A compound according to claim 57, selected from the following compound, and pharmaceutically acceptable salts thereof:

83. A compound according to claim 57, selected from the following compound, and pharmaceutically acceptable salts thereof:

84. A compound according to claim 57, selected from the following compound, and pharmaceutically acceptable salts thereof:

85. A compound according to claim 57, selected from the following compound, and pharmaceutically acceptable salts thereof:

86. A compound according to claim 57, selected from the following compound, and pharmaceutically acceptable salts thereof:

87. A pharmaceutical composition comprising a compound according to claim 57 and a pharmaceutically acceptable carrier or diluent.

88. A pharmaceutical composition comprising a compound according to claim 82 and a pharmaceutically acceptable carrier or diluent.

89. A pharmaceutical composition comprising a compound according to claim 83 and a pharmaceutically acceptable carrier or diluent.

90. A pharmaceutical composition comprising a compound according to claim 84 and a pharmaceutically acceptable carrier or diluent.

91. A pharmaceutical composition comprising a compound according to claim 85 and a pharmaceutically acceptable carrier or diluent.

92. A pharmaceutical composition comprising a compound according to claim 86 and a pharmaceutically acceptable carrier or diluent.