Inhibitors of β-lactamases and uses therefor

• US 6,448,238 B1
• Filed: 07/19/2000
• Issued: 09/10/2002
• Est. Priority Date: 06/13/1997
• Status: Expired due to Fees

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Shoichet, Brian K., Weston, Grady Scott
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/620,268
• Time in Patent Office: 783 Days
• Field of Search: 514/64, 514/330, 514/340, 514/451, 514/456, 514/481, 514/543
• US Class Current: 514/64
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 33/22 Boron compounds

Abstract

The invention provides novel non-β-lactam inhibitors of β-lactamases. In particular, the invention provides such inhibitors which are boronic acids of formula (1) which is set forth in the specification. These compounds may be used with β-lactam antibiotics to treat β-lactam-antibiotic-resistant bacterial infections. These compounds are also antibacterial by themselves. Finally, the invention provides a pharmaceutical composition comprising these compounds.

Claims

1. A method of treating a β

-lactam-antibiotic-resistant bacterial infection comprising administering to an animal suffering from such an infection

an effective amount of a compound having the formula;

2. The method of claim 1 wherein R is (4).

3. The method of claim 2 wherein atom 1 is S or O and the remaining atoms 2-6 are carbons.

4. The method of claim 3 wherein the compound is benzo[b]furan-2-boronic acid or benzo[b]thiophene-2-boronic acid.

5. The method of claim 1 wherein R is (6).

6. The method of claim 5 wherein the compound is benzo[b]thiophene-3-boronic acid.

7. The method of claim 1 wherein R is (11).

8. The method of claim 7 wherein X is O or NCH₃.

9. The method of claim 1 wherein R is (2).

10. The method of claim 9 wherein atom 1 is S and the remaining atoms 2-4 are carbons or atom 2 is S or O and the remaining atoms 1 and 3-4 are carbons.

11. The method of claim 10 wherein the compound is thiophene-2-boronic acid, 3-formylthiophene-2-boronic acid, 5-chlorothiophene-2-boronic acid, 4-methythiophene-2-boronic acid, 5-acetylthiophene-2-boronic acid, or R-3-tetrahydrofuranylboronic acid.

12. The method of claim 1 wherein R is (12).

13. The method of claim 12 wherein the compound is 3-(2-hydroxyphenylazo)benzeneboronic acid, 3-(4-hydroxyphenylazo)benzeneboronic acid, 2-hydroxy-5-(3-trifluoromethylphenylazo)benzeneboronic acid or 2,4,6-tris(5-(4-bromophenylazo)-2-hydroxyphenyl)boroxin.

14. The method of claim 1 wherein R is (3).

15. The method of claim 14 wherein the compound is m-nitrophenylboronic acid.

16. The method of claim 1 wherein the β

-lactam antibiotic is amoxicillin or ceftazidime.

17. A method of treating a bacterial infection comprising administering to an animal suffering from such an infection an effective amount of a compound having the formula:

18. The method of claim 17 wherein R is (2), (3), (4), (6), (11) or (12).

19. The method of claim 18 wherein the compound is 3-(2-hydroxyphenylazo)benzeneboronic acid, 3-(4-hydroxyphenylazo)benzeneboronic acid, 2-hydroxy-5-(3-trifluoromethylphenylazo)benzeneboronic acid, 2,4,6-tris(5-(4-bromophenylazo)-2-hydroxyphenyl)boroxin, thiophene-2-boronic acid, 3-formylthiophene-2-boronic acid, 5-chlorothiophene-2-boronic acid, 4-methylthiophene-2-boronic acid, 5-acetylthiophene-2-boronic acid, R-3-tetrahydrofuranylboronic acid, or benzo[b]furan-2-boronic acid, benzo[b]thiophene-2-boronic acid, benzo[b]thiophene-3-boronic acid, 4-(3-boronatophenylazo)homophthalic anhydride, or 4-(3-boronatoazo)homophthalimide.

20. A method of inhibiting a β

-lactamase comprising contacting the β

-lactamase with an effective amount of a compound having the formula;

21. The method of claim 20 wherein the β

-lactamase is produced by bacteria, and the bacteria are contacted with the compound or salt thereof.

22. The method of claim 20 wherein the contacting takes place in vitro.

23. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound having the formula:

 

(OH)₂—

B—

R 

 

(1)

wherein;

R is naphthalene, phenanthrene, or has one of the following formulas;

wherein;

ring system (2), (3), (4), (5), (6), (7), (8), (9), (10), (13) or (14) is aromatic or nonaromatic;

the atom center * is (R) or (S) in the case of chiral compounds;

positions 1, 2, 3, 4, 5, 6, 7 or 8 each independently is C, N, O or S;

R₁ through R₆ each independently is a lone pair, H, B(OH)₂, a halogen atom, CF₃, CH₂CF₃, CCl₃, CH₂CCl₃, CBr₃, CH₂CBr₃, NO₂, lower alkyl, CO₂H, CHCHCOOH, CH₂CH₂CH₂COOH, SO₃H, PO₃H, OSO₃H, OPO₃H, OH, NH₂, CONH₂, COCH₃, OCH₃, or phenyl boronic acid, except that R₂, R₃, R₄, R₅ and R₆ cannot all simultaneously be H, R₂ cannot be lower alkyl when R₃, R₄, R₅ and R₆ are H, R₃ cannot be NH₂, OH or lower alkyl when R₂, R₄, R₅ and R₆ are H, and R₄ cannot be lower alkyl when R₂, R₃, R₅ and R₆ are H;

R₇ is H, CF₃, CCl₃, CBr₃, CH₂CF₃, CH₂CCl₃, CH₂CBr₃, NO₂, COCH₃, OCH₃, lower alkyl, cyclic alkene, cyclic alkene substituted with one or more substituents R₈, heterocyclic alkene, or heterocyclic alkene substituted with one or more substituents R₈;

each R₈ is independently H, B(OH)₂, a halogen atom, CF₃, CCl₃, CBr₃, CH₂CF₃, CH₂CCl₃, CH₂CBr₃, NO₂,l lower alkyl, OH, NH_2, N(CH₃)₂, N(CH₃)CH₂CH₃, NHCOCH₃, COOH, CHCHCOOH, CH₂CH₂CH₂COOH, COCH₃, OCH₃, phenyl boronic acid, CONH₂, CONHCH₂COOH, CONHCH₂CONH₂, CONHCH₂CONHCH₂R₁₀, SO₂NH₂, SO₂NHCH₂COOH, SO₂NHCH₂CONH₂, or SO₂NHCH₂CONHCH₂R₁₀;

X is O, NH, NCH₃ or

Y is OH, NH₂, NCH₃, N(CH₃)₂, NHCOCH₃ or NHCOCH₂COOH;

R₉ is H, a halogen atom, CF₃, CCl₃, CBr₃, CH₂CF₃, CH₂CCl₃, CH₂CBr₃, NO₂, CO₂H, CHCHCOOH, CH₂CH₂CH₂COOH, SO₃H, PO₃H, OSO₃H, OPO₃H, OH, NH₂, CONH₂, COCH₃, OCH₃, phenyl boronic acid, lower alkyl, or a side chain of a standard amino acid; and

R₁₀ is a side chain of a standard amino acid;

pharmaceutically-acceptable salts thereof.

24. The composition of claim 23 wherein R is (4).

25. The composition of claim 24 wherein atom 1 is S or O and the remaining atoms 2-6 are carbons.

26. The composition of claim 25 wherein the compound is benzo[b]furan-2-boronic acid or benzo[b]thiophene-2-boronic acid.

27. The composition of claim 23 wherein R is (6).

28. The composition of claim 27 wherein the compound is or benzo[b]thiophene-3-boronic acid.

29. The composition of claim 23 wherein R is (11).

30. The composition of claim 29 wherein X is O or NCH₃.

31. The composition of claim 23 wherein R is (2).

32. The composition of claim 31 wherein atom 1 is S and the remaining atoms 2-4 are carbons or atom 2 is S or O and the remaining atoms 1 and 3-4 are carbons.

33. The composition of claim 32 wherein the compound is thiophene-2-boronic acid, 3-formylthiophene-2-boronic acid, 5-chlorothiophene-2-boronic acid, 4-methylthiophene-2-boronic acid, 5-acetylthiophene-2-boronic acid, or R-3-tetrahydrofuranylboronic acid.

34. The composition of claim 23 wherein R is (12).

35. The composition of claim 34 wherein the compound is 3-(2-hydroxyphenylazo)benzeneboronic acid, 3-(4-hydroxyphenylazo)benzeneboronic acid, 2-hydroxy-5-(3-trifluoromethylphenylazo)-benzeneboronic acid or 2,4,6-tris(5-(4-bromophenylazo)-2-hydroxyphenyl)boroxin.

36. The composition of claim 23 wherein R is (3).

37. The composition of claim 36 wherein the compound is m-nitrophenylboronic acid.

38. The composition of claim 23 further comprising a β

-lactam antibiotic.

39. The composition of claim 38 wherein the β

-lactam antibiotic is amoxicillin or ceftazidime.