Formulation of boronic acid compounds

US 20040063623A1
Filed: 09/18/2003
Published: 04/01/2004
Est. Priority Date: 01/25/2001
Status: Active Grant

First Claim

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1. A compound of the formula (1):

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Abstract

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

in which Z¹and Z²are 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.

19 Citations

55 Claims

1. A compound of the formula (1):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
- - 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 Z¹and Z²together form a moiety derived from mannitol.
  - 7. The compound of claim 5, wherein Z¹and Z²together 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 R⁷is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—
      
      C(O)—
      
      or R⁷—
      
      S(O)₂—
      
      , R⁷can 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 R⁷is 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-C₈alkyl; and
      
      R³is C₁-C₆alkyl.
  - 12. The compound of claim 11, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
  - 13. The compound of claim 12, wherein Z¹and Z²together form a moiety derived from mannitol.
  - 14. The compound of claim 1, wherein R¹, R², and R³are each independently hydrogen, C₁-C₈alkyl, C₃-C₁₀cycloalkyl, C₆-C₁₀aryl, or —
    - CH₂—
      
      R⁵;
      
      R⁵in each instance is C₆-C₁₀aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀cycloalkyl, C₁-C₈alkoxy, or C₁-C₈alkylthio;
      
      wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵can 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-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.

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

17. A lyophilized compound of the formula (1):
- View Dependent Claims (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 34, 55)
- - 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 Z¹and Z²together form a moiety derived from mannitol.
  - 23. The compound of claim 20, wherein Z¹and Z²together 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 R⁷is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—
      
      C(O)—
      
      or R⁷—
      
      S(O)₂—
      
      , R⁷can 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 R⁷is 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-C₈alkyl; and
      
      R³is C₁-C₆alkyl.
  - 28. The compound of claim 27, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
  - 29. The compound of claim 28, wherein Z¹and Z²together form a moiety derived from mannitol.
  - 30. The compound of claim 17, wherein R¹, R², and R³are each independently hydrogen, C₁-C₈alkyl, C₃-C₁₀cycloalkyl, C₆-C₁₀aryl, or —
    - CH₂—
      
      R⁵;
      
      R⁵in each instance is C₆-C₁₀aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀cycloalkyl, C₁-C₈alkoxy, or C₁-C₈alkylthio;
      
      wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵can 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.
  - 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):
- View Dependent Claims (36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
- - 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 Z¹and Z²of 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 R⁷is alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—
      
      C(O)—
      
      or R⁷—
      
      S(O)₂—
      
      , R⁷can 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 R⁷is 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-C₆alkyl; and
      
      R³is C₁-C₆alkyl.
  - 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 R³are each independently hydrogen, C₁-C₈alkyl, C₃-C₁₀cycloalkyl, C₆-C₁₀aryl, or —
    - CH₂—
      
      R⁵;
      
      R⁵in each instance is C₆-C₁₀aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀cycloalkyl, C₁-C₈alkoxy, or C₁-C₈alkylthio;
      
      wherein the ring portion of any said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³, or R⁵can 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.

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Current Assignee
United States Department Of Health And Human Services (Government of the United States of America)
Original Assignee
GOV of The USA Represented By The Secretary Dept of Health and Human SVCS
Inventors
Lal Gupta, Shanker

Granted Patent

US 6,958,319 B2
Time in Patent Office

Days
Field of Search
US Class Current

514/8
CPC Class Codes

A61K 38/00   Medicinal preparations cont...

A61P 29/00   Non-central analgesic, anti...

A61P 31/18   for HIV

A61P 35/00   Antineoplastic agents

A61P 37/02   Immunomodulators

A61P 43/00   Drugs for specific purposes...

C07F 5/025   Boronic and borinic acid co...

C07F 5/04   Esters of boric acids

C07K 5/06191   containing heteroatoms diff...

C07K 5/0827   containing heteroatoms diff...

C07K 7/02   Linear peptides containing ...

Formulation of boronic acid compounds

First Claim

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Abstract

19 Citations

55 Claims

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Formulation of boronic acid compounds

First Claim

2 Assignments

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0 Petitions

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Abstract

19 Citations

55 Claims

Specification

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