BORONATE ESTER COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF

• US 20130165390A1
• Filed: 11/02/2012
• Published: 06/27/2013
• Est. Priority Date: 06/17/2008
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Elliott, Eric L., Ferdous, Abu J., Kaufman, Michael J., Komar, Sonja A., Mazaik, Debra L., McCubbin, Quentin J., Palaniappan, Vaithianathan, Skwierczynski, Raymond D., Truong, Nobel T., Varga, Csanad M., Zawaneh, Peter N., Nguyen, Phuong M.
• Granted Patent: US 8,859,504 B2
• Time in Patent Office: Days
• US Class Current: 514/19.3
• 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 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07C 233/83 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 : Esters of boric acids
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Claims

1. A compound of formula (I):

2. The compound of claim 1, characterized by formula (II):

3. The compound of claim 2, wherein each of R^b3 and R^b4 independently is hydrogen, C_1-6 aliphatic, or —

(CH₂)_p—

CO₂H;

and p is 0, 1, or 2.

4. The compound of claim 3 wherein P is R^c—

C(O)—

, R^c—

O—

C(O)—

, R^c—

N(R^4c)—

C(O)—

, R^c—

S(O)₂—

, or R^c—

N(R^4c)—

S(O)₂—

;

R^c is selected from the group consisting of C_1-6 aliphatic, C_1-6 fluoroaliphatic, —

R^D, -T¹-R^D, and -T¹-R^2c;

T¹ is a C_1-6 alkylene chain substituted with 0-2 independently selected R^3a or R^3b, wherein the alkylene chain optionally is interrupted by —

C(R⁵)═

C(R⁵)—

, —

C≡

C—

, or —

O—

;

R^D is a substituted or unsubstituted mono- or bicyclic ring system;

R^2c is halo, —

OR⁵e, —

SR⁶, —

S(O)R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, —

N(R⁴)₂, —

NR⁴C(O)R⁵, —

NR⁴C(O)—

N(R⁴)₂, —

NR⁴CO₂R⁶, —

N(R⁴)SO₂R⁶, —

N(R⁴)SO₂N(R⁴)₂, —

O—

C(O)R⁵, —

OC(O)N(R⁴)₂, —

C(O)—

R⁵, —

CO₂R⁵, or —

C(O)N(R⁴)₂;

each R^3a independently is selected from the group consisting of —

F, —

OH, —

O(C_1-4 alkyl), —

CN, —

N(R⁴)₂, —

C(O)(C_1-4 alkyl), —

CO₂H, —

CO₂(C_1-4 alkyl), —

C(O)NH₂, and —

C(O)—

NH(C_1-4 alkyl);

each R^3b independently is a C_1-3 aliphatic substituted or unsubstituted with R^3a or R⁷;

or two substituents R^3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;

each R⁷ is a substituted or unsubstituted aromatic group; and

R^4c is hydrogen, C_1-4 alkyl, C_1-4 fluoroalkyl, or C_6-10 ar(C_1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

5. The compound of claim 3, wherein A is 0;

R^a1 is hydrogen, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b; and

m is 0.

6. The compound of claim 3, wherein P is R^c—

C(O)—

or R^c—

S(O)₂— and

R^c is —

R^D.

7. The compound of claim 6, wherein R^D is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrodrobenzoxazinyl.

8. The compound of claim 7, wherein R^D is substituted on substitutable carbon atoms with 0-1 R^d and 0-2 R^8d;

each R^d independently is C_1-6 aliphatic, C_1-6 fluoroaliphatic or halo; and

each R^8d independently is C_1-4 aliphatic, C_1-4 fluoroaliphatic or halo.

9. The compound of claim 4, wherein A is 0;

R^a is C_1-6 aliphatic, or —

(CH₂)_m—

CH₂—

R^B;

R^a1 is hydrogen, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

or R^c—

S(O)₂—

;

R^c is —

R^D; and

m is 0 or 1.

10. The compound of claim 9, wherein R^a is C_1-6 aliphatic.

11. The compound of claim 10, wherein R^a1 is —

CH₂—

R^B;

R^B is phenyl; and

R^D is 2-pyrazinyl.

12. The compound of claim 10, wherein R^a1 is —

CH(R^5a)—

OR^5b;

R^5a is C_1-6 aliphatic;

R^5b is hydrogen; and

R^D is 6-phenyl-2-pyridinyl-.

13. The compound of claim 10, wherein R^a1 is hydrogen, and

R^D is 2,5-dichlorophenyl.

14. The compound of claim 3, wherein Z¹ and Z² together form a moiety derived from citric acid.

15. The compound of claim 14, in a substantially crystalline form.

16. The compound of claim 14, characterized by formula (III), (IIIa), (IV), (IVa):

17. The compound of claim 16, wherein R^a is C_1-6 aliphatic.

18. The compound of claim 16, wherein A is 0;

R^a1 is hydrogen, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R⁵)—

OR^5b;

P is R^c—

C(O)—

; and

R^c is —

R^D.

19. The compound of claim 18, wherein R^D is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.

20. The compound of claim 18, wherein R^a is isobutyl.

21. The compound of claim 20, wherein R^a1 is —

CH₂—

R^B;

R^B is phenyl; and

R^D is 2-pyrazinyl.

22. The compound of claim 20, wherein R^a1 is hydrogen, and

R^D is 2,5-dichlorophenyl.

23. The compound of claim 20, wherein R^a1 is —

CH(R^5a)—

OR^5b;

R^5a is C_1-6 aliphatic;

R^5b is hydrogen; and

R^D is 6-phenyl-2-pyridinyl-.

24. A pharmaceutical composition comprising the compound of formula (I):

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition optionally further comprises a flow-aid, and optionally further comprises a buffer.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises about 0.2% to about 3% of the compound of formula (I), or a crystalline form thereof, about 86.5% to about 99.8% of a filler, optionally up to about 1.5% of a lubricant, optionally up to about 5% of a flow-aid, and optionally up to about 5% of a buffer, by weight as a percentage of total weight.

27. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises about 0.2% to about 3% of the compound of formula (I), or a crystalline form thereof;

about 97% to about 99.8% of a filler; and

optionally up to about 1.5% of a lubricant, by weight as a percentage of total weight.

28. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises about 0.25% to about 2% of the compound of formula (I), or a crystalline form thereof;

and about 98% to about 99.75% of a filler, by weight as a percentage of total weight.

29. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is an oral pharmaceutical dosage form.

30. The pharmaceutical composition of claim 29, wherein the oral pharmaceutical dosage form is a capsule.

31. The pharmaceutical composition of claim 25, wherein the compound of formula (I), or a crystalline form thereof, is present in an amount of about 0.2% to about 3%, by weight as a percentage of total weight.

32. The pharmaceutical composition of claim 25, wherein the compound of formula (I), or a crystalline form thereof, is present in an amount of about 0.25% to about 2%, by weight as a percentage of total weight.

33. The pharmaceutical composition of claim 25, wherein the filler is present in an amount of about 97% to about 99.8%, by weight as a percentage of total weight.

34. The pharmaceutical composition of claim 25, wherein the filler is present in an amount of about 98% to about 99.75%, by weight as a percentage of total weight.

35. The pharmaceutical composition of claim 25, wherein the filler is present in an amount of about 86.5% to about 99.8%, by weight as a percentage of total weight.

36. The pharmaceutical composition of claim 25, wherein the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, and mixtures thereof.

37. The pharmaceutical composition of claim 25, wherein the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, and mixtures thereof.

38. The pharmaceutical composition of claim 25, wherein the lubricant, when present, is present in an amount of up to about 1.5%, by weight as a percentage of total weight.

39. The pharmaceutical composition of claim 25, wherein the lubricant, when present, is present in an amount of about 1%, by weight as a percentage of total weight.

40. The pharmaceutical composition of claim 25, wherein the lubricant, when present, is selected from the group consisting of magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, talc, zinc stearate, calcium stearate, sucrose stearate, sodium stearyl fumarate, and mixtures thereof.

41. The pharmaceutical composition of claim 25, wherein the lubricant is magnesium stearate.

42. The pharmaceutical composition of claim 25, wherein the flow-aid, when present, is present in an amount of up to about 5%, by weight as a percentage of total weight.

43. The pharmaceutical composition of claim 25, wherein the flow-aid, when present is present in an amount of about 1%, by weight as a percentage of total weight.

44. The pharmaceutical composition of claim 25, wherein the flow-aid, when present, is talc.

45. The pharmaceutical composition of claim 25, wherein the buffer, when present, is present in an amount of up to about 5%, by weight as a percentage of total weight.

46. The pharmaceutical composition of claim 25, wherein the buffer, when present, is present in an amount of about 2%, by weight as a percentage of total weight.

47. The pharmaceutical composition of claim 25, wherein the buffer, when present, is sodium citrate.

48. The pharmaceutical composition of claim 25, wherein:

the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;

A is 0;

R^a is isobutyl;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

;

R^c is —

R^D;

m is 0 or 1;

the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof; and

the lubricant, when present, is magnesium stearate.

49. The pharmaceutical composition of claim 25, wherein

the compound of formula (I) is represented by compounds (I-1), (I-15), or (I-18):

50. The pharmaceutical composition of claim 25, wherein:

the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;

A is 0;

R^a is isobutyl;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

;

R^c is —

R^D;

m is 0 or 1;

the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof;

the lubricant, when present, is magnesium stearate;

the flow-aid, when present, is talc; and

the buffer, when present, is sodium citrate.

51. The pharmaceutical composition of claim 25, wherein

the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-18):

93. A method for treating cancer, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of any one of claims 24, 52, 57, 58, 59, 72, 77, and 87.

52. A pharmaceutical composition comprising the compound of formula (I-1):

53. The pharmaceutical composition of claim 52, wherein:

the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof; and

the lubricant, when present, is magnesium stearate.

54. The pharmaceutical composition of claim 52, wherein the crystalline form is Form 2.

55. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition optionally further comprises a flow-aid, and optionally further comprises a buffer.

56. The pharmaceutical composition of claim 55, wherein:

the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof;

the lubricant, when present, is magnesium stearate;

the flow-aid, when present, is talc; and

the buffer, when present, is sodium citrate.

57. A unit dose pharmaceutical composition comprising the compound of formula (I-1), or a crystalline form thereof, wherein the compound of formula (I-1) is present in an amount equivalent on a molar weight basis of about 0.1 mg to about 3.0 mg of the compound of formula (VIII-1).

58. A unit dose pharmaceutical composition comprising about 0.143 mg to about 4.3 mg of the compound of formula (I-1), or a crystalline form thereof, measured as about 0.1 mg to about 3.0 mg of the compound of formula (VIII-1), on a weight for weight basis.

59. A pharmaceutical composition comprising the compound of formula (I):

60. The pharmaceutical composition of claim 59, wherein the bulking agent is present in an amount of about 1% w/v to about 5% w/v.

61. The pharmaceutical composition of claim 59, wherein the bulking agent is present in an amount of about 3% w/v.

62. The pharmaceutical composition of claim 59, wherein the bulking agent is glycine.

63. The pharmaceutical composition of claim 59, wherein the buffer is sodium citrate, and citric acid.

64. The pharmaceutical composition of claim 59, wherein

the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;

A is 0;

R^a is isobutyl;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

;

R^c is —

R^D;

m is 0 or 1;

the bulking agent is glycine; and

the buffer is sodium citrate, and citric acid.

65. The pharmaceutical composition of claim 59 wherein

the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-18):

66. A pharmaceutical composition comprising the compound of formula (I) in a lyophilized powder:

67. The pharmaceutical composition of claim 66, further comprising a bulking agent, and a buffer.

68. The pharmaceutical composition of claim 67, wherein the bulking agent is glycine.

69. The pharmaceutical composition of claim 67, wherein the buffer is sodium citrate and citric acid.

70. The pharmaceutical composition of claim 67, wherein

the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;

A is 0;

R^a is isobutyl;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

;

R^c is —

R^D;

m is 0 or 1;

the bulking agent is glycine; and

the buffer is sodium citrate, and citric acid.

71. The pharmaceutical composition of claim 67, wherein

the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-18):

72. A unit dose pharmaceutical composition comprising the compound of formula (I-1), in a lyophilized powder:

73. The unit dose pharmaceutical composition of claim 72, wherein the compound of formula (I-1) is present in an amount equivalent on a molar weight basis of about 3.5 mg of the compound of formula (VIII-1).

74. The unit dose pharmaceutical composition of claim 72, wherein the pharmaceutical composition further comprises glycine, sodium citrate and citric acid.

75. The unit dose pharmaceutical composition of claim 74, wherein the amount of glycine present is about 0.01 g to about 0.50 g.

76. The unit dose pharmaceutical composition of claim 74, wherein the sodium citrate and citric acid is present in an amount equivalent to about 0.005 g to about 0.250 g of citrate ion.

85. A method for the preparation of a pharmaceutical composition of the compound (I-1) as a liquid pharmaceutical dosage form, said process comprising the step of reconstituting a lyophilized powder of the compound (I-1) according to claim 72 with water for injection.

77. A unit dose pharmaceutical composition comprising the compound of formula (I-15), in a lyophilized powder:

78. The unit dose pharmaceutical composition of claim 77, wherein the compound of formula (I-15) is present in an amount equivalent on a molar weight basis of about 3.5 mg of the compound of formula (VIII-15).

79. The unit dose pharmaceutical composition of claim 78, wherein the pharmaceutical composition further comprises glycine, sodium citrate and citric acid.

80. The unit dose pharmaceutical composition of claim 78, wherein the amount of glycine present is about 0.01 g to about 0.50 g.

81. The unit dose pharmaceutical composition of claim 78, wherein the sodium citrate and citric acid is present in an amount equivalent to about 0.005 g to about 0.250 g of citrate ion.

86. A method for the preparation of s pharmaceutical composition of the compound (1-15) as a liquid pharmaceutical dosage form, said method comprising the step of reconstituting a lyophilized powder of the compound (I-15) according to claim 77 with water for injection.

82. A method for preparation of a pharmaceutical composition of the compound (I-1) as a lyophilized powder, the method comprising the steps:

(f-1) combining;

i. water;

ii. the compound (I-1);

iii. glycine;

iv. sodium citrate; and

v. citric acid;

to form a mixture; and

(f-2) lyophilizing the mixture.

83. A method for the preparation of a pharmaceutical composition of the compound (1-15) as a lyophilized powder, the method comprising the steps

(g-1) combining:

i. an aqueous solvent mixture comprising water and tert-butyl alcohol;

ii. the compound (VIII-15);

iii. glycine;

iv. sodium citrate; and

v. citric acid;

to form a mixture; and

(g-2) lyophilizing the mixture.

84. The method of claim 83, wherein the tert-butyl alcohol in the aqueous solvent mixture is present in an amount of about 3% v/v to about 6% v/v tert-butyl alcohol.

87. A liquid pharmaceutical composition comprising the compound of formula (I):

88. The liquid pharmaceutical composition of claim 87, wherein the tonicity modifier, when present, is sodium chloride.

89. The liquid pharmaceutical composition of claim 87, wherein the buffer is sodium citrate, and citric acid.

90. The liquid pharmaceutical composition of claim 87 wherein:

the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;

A is 0;

R^a is isobutyl;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

P is R^c—

C(O)—

;

R^c is —

R^D;

m is 0 or 1;

the buffer is sodium citrate and citric acid; and

the tonicity modifier, when present, is sodium chloride.

91. A unit dose liquid pharmaceutical composition comprising the compound of formula

(I-1):

92. The unit dose liquid pharmaceutical composition of claim 91, further comprising sodium citrate, citric acid and sodium chloride.