Chphalosporin-derived mercaptans as inhibitors of serine and metallo-beta-lactamases

• US 20060178357A1
• Filed: 02/06/2006
• Published: 08/10/2006
• Est. Priority Date: 02/10/2005
• Status: Abandoned Application

• Current Assignee: Hansong Chen, John D. Buynak
• Original Assignee: Hansong Chen, John D. Buynak
• Inventors: Chen, Hansong, Buynak, John D.
• Application Number:
  US11/348,066
• Publication Number:
  US 20060178357A1
• Time in Patent Office: Days
• US Class Current: 514/200
• CPC Class Codes: C07D 501/14 Compounds having a nitrogen atom directly attached in position 7

Abstract

Compounds of formula I: See Formula I in Figures Section
wherein R¹, R², R³, R⁴ and n have any of the values defined in the specification, and their pharmaceutically acceptable salts, are useful for inhibiting simultaneously serine and metallo-β-lactamase enzymes, for enhancing the activity of β-lactam antibiotics, and for treating β-lactam resistant bacterial infections in a mammal. The invention also provides pharmaceutical compositions, processes for preparing compounds of formula I, and novel intermediates useful for the synthesis of compounds of formula I.

Claims

1. A compound of formula (I)

See Formula I in the Figures Section

(I)

wherein

R¹ is hydrogen, (C₁-C₁₀)alkanoyl C(═

O)R, (C₁-C₁₀)alkoxycarbonyl C(═

O)OR, (C₁-C₁₀)carboxamido (C═

O)NHR, (C₁-C₁₀)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, or morpholinyl;

R² is hydrogen, (C₁-C₁₀)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, —

COOR, —

CONRR, cyano, —

C(═

O)R, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, morpholinyl, —

S(O)_nR, —

NRR, azido, or halo;

R³ is acetoxymethyl (CH₂OAc), carbamoyloxymethyl (CH₂O(C═

O)NH₂), hydrogen, methyl, halo, (C2-C10)alkyl, cyano, vinyl (—

CH═

CH2), (C1-C10)substituted vinyl (—

CH═

CHR), (C1-C10)alkanoylvinyl (—

CH═

CHCOR), (C1-C10)alkoxycarbonylvinyl (—

CH═

CHCO2R), (C1-C10)carboxaminovinyl (—

CH═

CHCONHR), (C2-C10)alkynyl, (C1-C10)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C10)substituted aryl, (C1-C10)alkyl, heteroaryl(C1-C10)alkyl, S(O)nR wherein n=0, 1, or 2, corresponding to the C3 sidechain sulfide, sulfoxide and sulfone and R is (C1-C10)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

R⁴ is hydrogen, acyloxymethyl (CH2O(C═

O)R), (C1-C10)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, aryl, or heteroaryl;

or a pharmaceutically acceptable salt thereof, especially including sodium, potassium, and lithium.

n is 0, 1, or 2;

2. The synergistic combination of a compound of Formula I with a β

-lactam antibiotic, including, but not limited to, members of the penicillin, cephalosporin, carbapenem, carbacephem, oxacephem, penem, and monobactam subcategories.