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US 6,472,372 B1Granted
6-O-Carbamoyl ketolide antibacterials
AssigneeOrtho-McNeil Pharmaceuticals, Inc.
InventorsTodd C. Henninger, Xiaodong Xu
Life of this patent
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Abstract
6-O-Carbamoyl ketolide antibacterials of the formula: wherein R1, R2, R3, R4, R5, R6, X, X′, Y, and Y′ are as described herein and in which the substituents have the meaning indicated in the description. These compounds are useful as antibacterial agents.
Claims37
A compound of Formula 1
- wherein
- R1 and R2 are independently selected from the group consisting of hydrogen, optionally substituted C1-C8-alkyl, optionally substituted —CH2C2-C8-alkenyl, and optionally substituted —CH2C2-C8-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COORa, —OCORa, —ORa, —SRa, —SORa, —SO2Ra, —NRaRb, —CONRaRb, —OCONRaRb, —NHCORa, —NHCOORa, and —NHCONRaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
- provided that R1 and R2 are not both hydrogen;
- R3 is hydrogen;
- R4 is selected from the group consisting of hydrogen, halogen, and hydroxy;
- R5 is hydrogen or a hydroxy protecting group;
- R6 is selected from the group consisting of hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl,
- heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or
- alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
- X and X′, together with the carbon atom to which they are attached, form C═O, C═NRc, or C═NORc, wherein Rc is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
- and
- Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NRc, or C═NORc, wherein Rc is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
- or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
10 more elements
Compound of formula 1′ or 1″:
- wherein
- R1 and R2 are independently selected from the group consisting of hydrogen, substituted C1-C8-alkyl, substituted —CH2C2-C8-alkenyl, and substituted —CH2C2-C8-alkynyl, wherein the substituents are selected from the group consisting of CN, nitro, -COORa, —OCORa, —ORa, —SRa, —SORa, —SO2Ra, —NRaRb, —CONRaRb, —OCONRaRb, —NHCORa, —NHCOORa, and —NHCONRaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
- provided that R1 and R2 are not both hydrogen;
- R3 is hydrogen;
- R4 is selected from the group consisting of hydrogen, halogen, and hydroxy;
- or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, ester or pro-drugs thereof.
3 more elements
A process for the preparation of a compound having the formula:
- wherein
- R5 is hydrogen or a hydroxy protecting group;
- R7 is a hydroxy protecting group;
- and
- R6 is selected from the group consisting of hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
- the process comprising:
- a) treating a compound having the formula
- wherein R8 is a hydroxy protecting group and R6 and R7 are as previously defined, with trichloroacetylisocyanate in an inert solvent to give a compound having the formula
- wherein R6, R7, and R8 are as previously defined;
- b) treating the compound obtained in step (a) with a suitable base in an aqueous solvent mixture to give a compound having the formula
- wherein R5, R6, and R7 are as previously defined;
- c) optionally treating the compound obtained in step (b) with an equilibrating base;
- and
- d) when R5 is hydrogen, optionally protecting the 2′-hydroxy with a hydroxy protecting group.
11 more elements
A process for the preparation of a compound having the formula:
- wherein
- R1 is selected from the group consisting of hydrogen, optionally substituted C1-C8-alkyl, optionally substituted —CH2C2-C8alkenyl, and optionally substituted —CH2C2-C8-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COORa, —OCORa, —ORa, —SRa, —SORa, —SO2Ra, NRaRb, —CONRaRb, —OCONRaRb, —NHCORa, —NHCOORa, and —NHCONRaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
- R5 is hydrogen or a hydroxy protecting group;
- R6 is selected from the group consisting of hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
- the process comprising:
- a) treating a compound having the formula
- wherein
- R7 is a hydroxy protecting group, and R5 and R6 are as previously defined, with a suitably substituted aldehyde, an acid, and a silane reducing agent;
- b) when R5 is hydrogen, protecting the 2′-hydroxy with a hydroxy protecting group;
- c) oxidizing the 3-hydroxy group;
- and
- d) optionally deprotecting the 2′-hydroxy group.
9 more elements
A process for the preparation of a compound having the formula:
- wherein
- R1 is selected from the group consisting of hydrogen, optionally substituted C1-C8-alkyl, optionally substituted —CH2C2-C8-alkenyl, and optionally substituted —CH2C2-C8-alkynyl, wherein the substituents are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COORa, —OCORa, —ORa, —SRa, —SORa, —SO2Ra, —NRaRb, —CONRaRb, —OCONRaRb, —NHCORa, —NHCOORa, and —NHCONRaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
- R5 is hydrogen or a hydroxy protecting group;
- R6 is selected from the group consisting of hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
- the process comprising:
- a) treating a compound having the formula
- wherein R8 is a hydroxy protecting group, and R1 and R6 are as previously defined, with a fluorinating agent in the presence of a base;
- and
- b) optionally deprotecting the 2′-hydroxy group.
6 more elements
Dependencies are inferred from the claim text.