Formulation of boronic acid compounds

• US 20020169114A1
• Filed: 01/25/2002
• Published: 11/14/2002
• Est. Priority Date: 01/25/2001
• Status: Active Grant

• Current Assignee: Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services, United States Department Of Health And Human Services
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Gupta, Shanker Lal
• Granted Patent: US 6,713,446 B2
• Time in Patent Office: Days
• US Class Current: 514/8
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention provides stable compounds prepared from boronic acid and lyophilized compounds thereof of the formula (1):

in which Z¹ and Z² are moieties derived from sugar. The invention also provides methods for preparing such compounds. Lyophilizing a mixture comprising a boronic acid compound and a moiety derived from sugar produces a stable composition that readily releases the boronic acid compound upon reconstitution in aqueous media.

Claims

1. A compound of the formula (1):

2. The compound of claim 1, wherein the sugar is a monosaccharide or disaccharide.

3. The compound of claim 1, wherein the sugar is a reduced sugar.

4. The compound of claim 3, wherein the reduced sugar is mannitol or sorbitol.

5. The compound of claim 1, wherein A is 0.

6. The compound of claim 1, wherein Z¹ and Z² together form a moiety derived from mannitol.

7. The compound of claim 5, wherein Z¹ and Z² together form a moiety derived from mannitol.

8. The compound of claim 1, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

9. The compound of claim 8, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

10. The compound of claim 9, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

11. The compound of claim 8, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

12. The compound of claim 11, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

13. The compound of claim 12, wherein Z¹ and Z² together form a moiety derived from mannitol.

14. The compound of claim 1, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂-R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

15. The compound of claim 1, wherein said compound is:

D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronate;

D-Mannitol N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl- L-tyrosine-L-leucine boronate;

or

D-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.

18. The compound of claim 17, wherein the sugar is a monosaccharide or disaccharide.

19. The compound of claim 17, wherein the sugar is a reduced sugar.

20. The compound of claim 17, wherein A is 0.

21. The compound of claim 19, wherein the reduced sugar is mannitol or sorbitol.

22. The compound of claim 17, wherein Z¹ and Z² together form a moiety derived from mannitol.

23. The compound of claim 20, wherein Z¹ and Z² together form a moiety derived from mannitol.

24. The compound of claim 17, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

25. The compound of claim 24, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

26. The compound of claim 25, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

27. The compound of claim 24, wherein

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

28. The compound of claim 27, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

29. The compound of claim 28, wherein Z¹ and Z² together form a moiety derived from mannitol.

30. The compound of claim 17, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂—

R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

31. The compound of claim 25, wherein said compound is:

D-Mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronate;

D-Mannitol N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronate;

D-Mannitol N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronate;

or

D-Mannitol N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronate.

33. The compound of claim 17, wherein the compound is stable at 0°

C. for at least one month.

34. The compound of claim 17, wherein the compound is stable at 40°

C. for at least one month.

36. The method of claim 35, wherein the sugar is a monosaccharide or disaccharide.

37. The method of claim 35, wherein the sugar is a reduced sugar.

38. The method of claim 37, wherein the reduced sugar is mannitol or sorbitol.

39. The method of claim 38, wherein the reduced sugar is mannitol.

40. The method of claim 35, wherein Z¹ and Z² of formula (1) together form a moiety derived from mannitol.

41. The method of claim 35, wherein P is R⁷—

C(O)—

, R⁷—

S(O)₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially saturated, or aromatic heterocycle.

42. The method of claim 41, wherein P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, and R⁷ is an aromatic heterocycle.

43. The method of claim 42, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

44. The method of claim 35, wherein

A is zero;

R is hydrogen or C₁-C₆ alkyl; and

R³ is C₁-C₆ alkyl.

45. The method of claim 44, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

46. The method of claim 35, wherein

R¹, R², and R³ are each independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or —

CH₂-R⁵;

R⁵ in each instance is C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵ can be optionally substituted.

47. The method of claim 35, wherein the compound of formula (3) is:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid;

or

N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid.

48. The method of claim 35, wherein the compound of formula (1) is D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

49. The method of claim 47, wherein the compound of formula (3) is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

50. The method of claim 35, wherein the mixture further comprises a water-miscible solvent.

51. The method of claim 50, wherein the water-miscible solvent is an alcohol.

52. The method of claim 51, wherein the alcohol is tert-butanol.

53. The method of claim 35, wherein the moiety derived from sugar and the compound of formula (3) are present in at least a 1:

1 ratio.

54. The method of claim 35, wherein the moiety derived from sugar and the compound of formula (3) are present in at least a 5:

1 ratio.

16. The compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

17. A lyophilized compound of the formula (1):

55. A lyophilized cake comprising the compound of claim 17.

32. The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

35. A method of preparing a lyophilized compound of the formula (1):