Proteasome inhibitors and methods of using the same

• US 8,058,262 B2
• Filed: 02/03/2011
• Issued: 11/15/2011
• Est. Priority Date: 08/14/2003
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Bernardini, Raffaella, Bernareggi, Alberto, Cassara, Paolo G., Chatterjee, Sankar, D'Arasmo, Germano, De Munari, Sergio, Ferretti, Edmondo, Iqbal, Mohamed, Menta, Ernesto, Messina McLaughlin, Patricia A., Oliva, Ambrogio
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US13/020,425
• Publication Number:
  US 20110144033A1
• Time in Patent Office: 285 Days
• Field of Search: None
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds

Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Claims

1. A method for treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of Formula (I)

2. The method of claim 1 wherein R¹ is C₁-C₄ alkyl.

3. The method of claim 1 wherein R¹ is 2-propyl.

4. The method of claim 1 wherein R² is —

(CH₂)_aCH₂NHC(═

NR⁴)NH—

Y.

5. The method of claim 4 wherein a is 1, 2, 3, or 4.

6. The method of claim 4 wherein a is 2.

7. The method of claim 1 wherein R² is —

(CH₂)_dCH(R⁷)NR⁹R¹⁰.

8. The method of claim 7 wherein d is 0, 1, or 2.

9. The method of claim 7 wherein d is 0.

10. The method of claim 7 wherein R⁹ is H.

11. The method of claim 1 wherein R² is —

(CH₂)_eCH(R⁷)ZR⁸.

12. The method of claim 11 wherein Z is O.

13. The method of claim 12 wherein e is 0, 1, or 2.

14. The method of claim 12 wherein e is 0.

15. The method of claim 1 wherein Q is B(OH)₂ or a cyclic boronic ester wherein said cyclic boronic ester contains from 6 to 10 carbon atoms and contains at least one cycloalkyl moiety.

16. The method of claim 15 wherein Q is pinanediol boronic ester.

17. The method of claim 15 wherein Q is bicyclohexyl-1,1′

-diol boronic ester.

18. The method of claim 15 wherein Q is 1,2-dicyclohexyl-ethane-1,2-diol boronic ester.

19. The method of claim 1 wherein X is R^AC(═

O)—

.

20. The method of claim 1 wherein X is R^ANHC(═

O)—

.

21. The method of claim 1 wherein X is R^AS(═

O)₂—

.

22. The method of claim 1 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

23. The method of claim 1, wherein:

R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀ alkyl-C(═

O)—

, carbocyclyl-C(═

O)—

, heterocarbocyclyl-C(═

O)—

, carbocyclylalkyl-C(═

O)—

, heterocarbocyclylalkyl-C(═

O)—

, C₁-C₁₀ alkyl-S(═

O)₂—

, carbocyclyl-S(═

O)₂—

,

heterocarbocyclyl-S(═

O)₂—

, carbocyclylalkyl-S(═

O)₂—

,

heterocarbocyclylalkyl-S(═

O)₂—

, C₁-C₁₀ alkyl-NHC(═

O)—

,

carbocyclyl-NHC(═

O)—

, heterocarbocyclyl-NHC(═

O)—

,

carbocyclylalkyl-NHC(═

O)—

, heterocarbocyclylalkyl-NHC(═

O)—

,

C₁-C₁₀ alkyl-OC(═

O)—

, carbocyclyl-OC(═

O)—

, heterocarbocyclyl-OC(═

O)—

, carbocyclylalkyl-OC(═

O)—

, heterocarbocyclylalkyl-OC(═

O)—

, or an amino protecting group;

wherein R¹⁰ is optionally substituted with 1, 2, or 3 R²³;

alternatively, R⁹ and R¹⁰ together with the N atom to which they are attached form a heterocarbocyclyl group;

R^A is morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, isothiazolyl, or purinyl, each optionally substituted with 1-2 R²¹;

R²¹ is selected from the group consisting of;

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,

C₁-C₂₀ thialkoxy, —

OH, —

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂,

—

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

C(═

O)O-alkyl, —

C(═

O)alkyl,

—

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl,

carbocyclyl optionally substituted with 1-5 R²²; and

heterocarbocyclyl optionally substituted with 1-5 R²²;

R²³ is selected from the group consisting of;

C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I, haloalkyl, —

NH₂,

—

NHR^23a, —

N(R^23a)₂, —

N₃, —

NO₂, —

CN, —

CNO, —

CNS, —

C(═

O)OR^23a, —

C(═

O)R^23a,

—

OC(═

O)R^23a, —

N(R^23a)C(═

O)R^23a, —

C(═

O)N(R^23a)₂, ureido, —

OR^23a, —

SR^23a,

—

S(═

O)₂—

(C₁-C₆ alkyl), —

S(═

O)₂-aryl, and —

S(═

O)₂—

N(R^23a)₂; and

r is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

24. The method of claim 23 wherein R¹ is 2-propyl.

25. The method of claim 23 wherein Q is —

B(OH)₂.

26. The method of claim 23 wherein Q is pinanediol boronic ester.

27. The method of claim 23 wherein X is R^AC(═

O)—

.

28. The method of claim 23 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

29. The method of claim 1, wherein:

R¹ is C₁-C₈ alkyl;

R² is —

(CH₂)_aCH₂NHC(═

NH)NH—

Y, —

(CH₂)_cCH₂NHCONH₂, —

(CH₂)_dCH(R⁷)NR⁹R¹⁰, or —

(CH₂)_eCH(R⁷)ZR⁸;

a is 1, 2, 3, 4, or 5;

c is 1, 2, 3, 4, or 5;

d is 0, 1, or 2;

e is 0, 1, or 2;

R⁷ is H or methyl;

R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀ alkyl-C(═

O)—

,

carbocyclyl-C(═

O)—

, heterocarbocyclyl-C(═

O)—

, carbocyclylalkyl-C(═

O)—

,

heterocarbocyclylalkyl-C(═

O)—

, C₁-C₁₀ alkyl-S(═

O)₂—

, carbocyclyl-S(═

O)₂—

,

heterocarbocyclyl-S(═

O)₂—

, carbocyclylalkyl-S(═

O)₂—

,

heterocarbocyclylalkyl-S(═

O)₂—

, alkyl-NHC(═

O)—

,

carbocyclyl-NHC(═

O)—

, heterocarbocyclyl-NHC(═

O)—

,

carbocyclylalkyl-NHC(═

O)—

, heterocarbocyclylalkyl-NHC(═

O)—

,

C₁-C₁₀ alkyl-OC(═

O)—

, carbocyclyl-OC(═

O)—

, heterocarbocyclyl-OC(═

O)—

,

carbocyclylalkyl-OC(═

O)—

, heterocarbocyclylalkyl-OC(═

O)—

, or an amino protecting group;

wherein R¹⁰ is optionally substituted with 1, 2 or 3 R²³;

alternatively, R⁹ and R¹⁰ together with the N atom to which they are attached form a heterocarbocyclyl group;

Z is O or S;

Q is —

B(OH)₂, —

B(OR¹⁴)₂, or a cyclic boronic ester wherein said cyclic boronic ester contains from 6 to 20 carbon atoms and contains at least one cycloalkyl moiety;

R¹⁴ is H, C₁-C₄ alkyl, or cycloalkyl;

R^A is

morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, isothiazolyl, or purinyl, each optionally substituted with 1-2 R²¹;

R²¹ is selected from the group consisting of;

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,

C₁-C₂₀ thialkoxy, —

OH, —

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂,

—

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

C(═

O)O-alkyl, —

C(═

O)alkyl,

—

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl,

carbocyclyl optionally substituted with 1-5 R²², and

heterocarbocyclyl optionally substituted with 1-5 R²²;

R²³ is selected from the group consisting of;

C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I, haloalkyl, —

NH₂,

—

NHR^23a, —

N(R^23a)₂, —

N₃, —

NO₂, —

CN, —

CNO, —

CNS, —

C(═

O)OR^23a, —

C(═

O)R^23a,

—

OC(═

O)R^23a, —

N(R^23a)C(═

O)R^23a, —

C(═

O)N(R^23a)₂, ureido, —

OR^23a, —

SR^23a,

—

S(═

O)₂—

(C₁-C₆ alkyl), —

S(═

O)₂-aryl, and —

S(═

O)₂—

N(R^23a)₂;

r is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

30. The method of claim 1, wherein:

R¹ is C₁-C₄ alkyl;

R² is —

(CH₂)_aCH₂NHC(═

NH)NH—

Y, —

(CH₂)_cCH₂NHCONH₂, or —

(CH₂)_dCH(R⁷)NR⁹R¹⁰;

a is 1, 2, or 3;

c is 1, 2, or 3;

d is 0 or 1;

R⁷ is H or methyl;

R⁹ is H or C₁-C₁₀ alkyl;

R¹⁰ is H, C₁-C₁₀ alkyl, or an amino protecting group;

Y is H, CN, or NO₂;

Q is —

B(OH)₂, pinanediol boronic ester, bicyclohexyl-1,1′

-diol boronic ester, or 1,2-dicyclohexyl-ethane-1,2-diol boronic ester;

R²¹ is selected from the group consisting of;

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,

C₁-C₂₀ thialkoxy, —

OH—

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂,

—

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

C(═

O)O-alkyl, —

C(═

O)alkyl,

—

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl,

carbocyclyl optionally substituted with 1-5 R²², and

heterocarbocyclyl optionally substituted with 1-5 R²²;

r is 2, 3, 4, or 5.

31. The method of claim 30 wherein R¹ is 2-propyl.

32. The method of claim 30 wherein Q is —

B(OH)₂.

33. The method of claim 30 wherein Q is pinanediol boronic ester.

34. The method of claim 30 wherein X is R^AC(═

O)—

.

35. The method of claim 30 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

36. The method of claim 1, wherein:

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₇ cycloalkyl;

R² is —

CH₂NH₂ or —

CH₂NR⁹R¹⁰;

R⁹ is H or C₁-C₁₀ alkyl;

R¹⁰ is H, C₁-C₁₀ alkyl, carbocyclyl, heterocarbocyclyl, C₁-C₁₀ alkyl-C(═

O)—

,

carbocyclyl-C(═

O)—

, heterocarbocyclyl-C(═

O)—

, carbocyclylalkyl-C(═

O)—

,

heterocarbocyclylalkyl-C(═

O)—

, C₁-C₁₀ alkyl-S(═

O)₂—

, carbocyclyl-S(═

O)₂—

,

heterocarbocyclyl-S(═

O)₂—

, carbocyclylalkyl-S(═

O)₂—

,

heterocarbocyclylalkyl-S(═

O)₂—

, C₁-C₁₀ alkyl-NHC(═

O)—

,

carbocyclyl-NHC(═

O)—

, heterocarbocyclyl-NHC(═

O)—

,

carbocyclylalkyl-NHC(═

O)—

, heterocarbocyclylalkyl-NHC(═

O)—

,

C₁-C₁₀ alkyl-OC(═

O)—

, carbocyclyl-OC(═

O)—

, heterocarbocyclyl-OC(═

O)—

,

carbocyclylalkyl-OC(═

O)—

, heterocarbocyclylalkyl-OC(═

O)—

, or an amino protecting group;

wherein R¹⁰ is optionally substituted with 1, 2 or 3, R²³;

alternatively, R⁹ and R¹⁰ together with the N atom to which they are attached form a heterocarbocyclyl group;

R²¹ is selected from the group consisting of;

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy,

C₁-C₂₀ thialkoxy, —

OH—

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂,

—

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

C(═

O)O-alkyl, —

C(═

O)alkyl,

—

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl,

carbocyclyl optionally substituted with 1-5 R²², and

heterocarbocyclyl optionally substituted with 1-5 R²²;

R²³ is selected from the group consisting of;

C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, F, Cl, Br, I, haloalkyl, —

NH₂,

—

NHR^23a, —

N(R^23a)₂, —

N₃, —

NO₂, —

CN, —

CNO, —

CNS, —

C(═

O)OR^23a, —

C(═

O)R^23a,

—

OC(═

O)R^23a, —

N(R^23a)C(═

O)R^23a, —

C(═

O)N(R^23a)₂, ureido, —

OR^23a, —

SR^23a,

—

S(═

O)₂—

(C₁-C₆ alkyl), —

S(═

O)₂-aryl, and —

S(═

O)₂—

N(R^23a)₂;

r is 2, 3, 4, or 5.

37. The method of claim 36 wherein R¹ is 2-propyl.

38. The method of claim 36 wherein Q is —

B(OH)₂.

39. The method of claim 36 wherein Q is pinanediol boronic ester.

40. The method of claim 36 wherein X is R^AC(═

O)—

.

41. The method of claim 36 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

45. The method of claim 1, wherein the compound is boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl], or a pharmaceutically acceptable salt or boronic ester thereof.

46. The method of claim 1, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

47. The method of claim 23, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

48. The method of claim 29, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

49. The method of claim 30, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

50. The method of claim 36, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

54. The method of claim 45, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

55. The method of claim 1, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

56. The method of claim 23, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

57. The method of claim 29, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

58. The method of claim 30, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

59. The method of claim 36, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

63. The method of claim 45, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

64. The method of claim 1, wherein the cancer is multiple myeloma.

65. The method of claim 23, wherein the cancer is multiple myeloma.

66. The method of claim 29, wherein the cancer is multiple myeloma.

67. The method of claim 30, wherein the cancer is multiple myeloma.

68. The method of claim 36, wherein the cancer is multiple myeloma.

72. The method of claim 45, wherein the cancer is multiple myeloma.

73. The method of claim 1, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

74. The method of claim 23, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

75. The method of claim 29, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

76. The method of claim 30, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

77. The method of claim 36, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

81. The method of claim 45, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

82. The method of claim 72, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

42. A method for treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of Formula (I):

51. The method of claim 42, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

60. The method of claim 42, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

69. The method of claim 42, wherein the cancer is multiple myeloma.

78. The method of claim 42, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

43. A method for treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound selected from:

52. The method of claim 43, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

61. The method of claim 43, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

70. The method of claim 43, wherein the cancer is multiple myeloma.

79. The method of claim 43, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.

44. A method for treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound selected from:

53. The method of claim 44, wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

62. The method of claim 44, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

71. The method of claim 44, wherein the cancer is multiple myeloma.

80. The method of claim 44, comprising administering the compound in combination with one or more antitumor or anticancer agent and/or radiotherapy.