Nanomolar β-lactamase inhibitors

• US 7,271,186 B1
• Filed: 12/09/2003
• Issued: 09/18/2007
• Est. Priority Date: 12/09/2002
• Status: Expired due to Fees

• Current Assignee: Northwestern University, University of Modena, Italy
• Original Assignee: Northwestern University, University of Modena
• Inventors: Shoichet, Brian K., Prati, Fabio
• Primary Examiner(s): McKane; Joseph K.
• Assistant Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US10/731,738
• Time in Patent Office: 1,379 Days
• Field of Search: 548/190, 548/199, 549/83, 514/370, 514/438, 564/123
• US Class Current: 514/370
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

New carboxyphenyl-glycylboronic acid transition-state analog inhibitors, representative of a class of compounds effective against class C β-lactamase AmpC. The new compounds improve inhibition by over two-orders of magnitude compared to analogous glycylboronic acids, with Ki values as low as 1 nM.

Claims

1. A β

-lactamase inhibitor compound having a formula

2. A β

-lactamase inhibitor compound of claim 1 wherein said R₁ substituent further comprises at least one of a hydroxy, halogen, alkoxy, amino, amido, nitro, nitrile, azo, acyl, carboxy, sulfoxy, sulfonyl, formyl, alkenyl, branched or unbranched alkyl, cycloalkyl, aminoalkyl, alkoxylalkyl, carboxylalkyl, arylalkyl, haloalkyl, azoalkyl, amidoalkyl, alkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, amidocarbonyl, arylcarboxamido, arylamino, arylcarbonyl, arylalkoxy, amidocarbonyl, carboxycarbonyl, cycloalkenyl and heterocyclyl moiety.

3. A β

-lactamase inhibitor compound of claim 2 wherein said R₁ substituent comprises a thiophene-2-yl moiety.

4. A β

-lactamase inhibitor compound of claim 1 wherein said R₂ substituent further comprises at least one of a carboxyl, formyl, sulfonyl, sulfoxy, heterocyclyl, cycloalkenyl, alkoxy, alkenyl, amino, amido, nitro, nitrile, azo, acyl, branched or unbranched alkyl, cycloalkyl, aminoalkyl, amidoalkyl, alkoxyalkyl and arylalkoxy moiety.

5. A β

-lactamase inhibitor compound of claim 4 wherein R₂ is phenyl comprising one of a 3-carboxylate, a 3-formyl, a 3-sulfonate and a 3-heterocyclyl moiety.

6. A β

-lactamase inhibitor compound having a formula

7. A β

-lactamase inhibitor compound of claim 6 wherein said R₁ substituent further comprises at least one of a hydroxy, halogen, alkoxy, amino, amido, nitro, nitrile, azo, acyl, carboxy, sulfoxy, sulfonyl, formyl, alkenyl, branched or unbranched alkyl, cycloalkyl, aminoalkyl, alkoxylalkyl, carboxylalkyl, arylalkyl, haloalkyl, azoalkyl, amidoalkyl, alkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, amidocarbonyl, arylcarboxamido, arylamino, arylcarbonyl, arylalkoxy, amidocarbonyl, carboxycarbonyl, cycloalkenyl and heterocyclyl moiety.

8. A β

-lactamase inhibitor compound of claim 6 wherein said R₂ substituent further comprises at least one of a hydroxy, halogen, alkoxy, amino, amido, nitro, nitrile, azo, acyl, carboxy, sulfoxy, sulfonyl, formyl, alkenyl, branched or unbranched alkyl, cycloalkyl, aminoalkyl, alkoxylalkyl, carboxylalkyl, arylalkyl, haloalkyl, azoalkyl, amidoalkyl, alkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, amidocarbonyl, arylcarboxamido, arylamino, arylcarbonyl, arylalkoxy, amidocarbonyl, carboxycarbonyl, cycloalkenyl and heterocyclyl moiety.

9. A β

-lactamase inhibitor compound of claim 8 wherein R₂ comprises phenyl substituted at the 3-position thereof.

10. A β

-lactamase inhibitor compound having a formula

11. A β

-lactamase inhibitor compound of claim 10 wherein said R₂ substituent further comprises at least one of a carboxy, formyl, sulfonyl and heterocyclyl moiety.

12. A β

-lactamase inhibitor compound of claim 11 wherein said R₂ substituent is substituted at the 3-position thereof.