Ketolide antibacterials

A technology of alkyne and alkyl groups, which is applied in the field of ketolide antibacterial agents, and can solve problems such as the complexity of macrolide molecules

Inactive Publication Date: 2007-06-20
ORTHO MCNEIL PHARM INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the complexity of the macrolide molecule, medicinal chemistry efforts to achieve derivatives a...

Method used

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Examples

Experimental program
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Embodiment 10

[0137] Example 10 describes the preparation of C-2-halo compounds of the invention. Specifically, the compound to be halogenated is treated with a base and an electrophilic halogenating reagent such as pyridinium perbromide or N-fluorobenzenesulfonimide. Example 12 describes the removal of cladinose from a derivative of erythromycin A containing a C-6-O-allyl group and the oxidation of the resulting C-3-hydroxyl to a ketone. Example 13 illustrates the transformation of C-6-O-alkyl containing compounds into several intermediates useful in the synthesis of compounds of the invention. Example 14 describes the synthesis of compounds of formula I, where R = H, R 2 = H, X = H and R 6 =O-allyl. Example 15 describes the conversion of macrolides containing 6-O-alkyl and 11,12-cyclic carbamate functional groups to compounds of formula I by the Heck reaction followed by deprotection of the deoxyaminosugar. Example 16 describes the alkylation of the compound to the 6-O-propargyl inter...

Embodiment 21

[0139] Example 21 describes the synthesis of 1H-imidazo[4,5-b]pyridine-1-(4-amino-2-butene), an amine useful in the synthesis of compounds of the invention where R=1H - imidazo[4,5-b]pyridine.

[0140] Methods for converting 10,11-anhydro compounds into carbamate derivative compounds of the present invention are described in Examples 22 and 23. The amines used in the synthesis of carbamate derivative compounds of Formula I are either commercially available or can be readily prepared as described in Denis et al., Bioorg.Med.Chem.Lett.9:3075-3080 (1999). ground preparation.

Embodiment 1

[0142] Preparation of diketone thioesters

[0143] In this example, the preparation of N-acetyl for feeding recombinant Streptomyces host cells to produce 15-methyl and 14,15-dehydro-6-deoxyerythromycin ring B intermediate compounds is described. Method used for Cysteamine Thioate ("NACS"). The synthetic methods described below are also described in U.S. Patent Application Serial No. 09 / 492,733 (inventors G. Ashley, M. Burlingame, and I. Chan-Kai), which is incorporated herein by reference.

[0144] Thus, from (4S)-N-[(2S,3R)-2-methyl-3-hydroxyhexanoyl]-4-benzyl-2-oxazolidinone (Preparation D) with N-acetylcysteine Amine (Preparation B) reaction to prepare (2S,3R)-2-methyl-3-hydroxyhexanoate NACS (Preparation E), which is used to prepare 15-methyl-6-deoxyerythrolide ring B intermediate. In turn, N-acetyl cysteamine was prepared from N,S-diacetyl cysteamine (Preparation A). Preparation of (4S)-N-[(2S,3R)-2-methyl-3 from (4S)-N-propionyl-4-benzyl-2-oxazolidinone (propionyl-N...

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Abstract

The present invention includes compounds of the formula wherein: X is hydrogen or halide; R<2> is hydrogen, acyl, or a hydroxy protecting group; R<6> is hydrogen, hydroxyl, or -OR wherein R is a substituted or unsubstituted moiety selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, 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; R<13> is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of methyl; C3-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, 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;and, R is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, 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;and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. These compounds possess anti-infective activity and are useful for the treatment of bacterial and protozoal infections.

Description

[0001] This application claims U.S. Application Serial No. 09 / 548568, filed April 13, 2000, U.S. Application Serial No. 09 / 548584, filed April 13, 2000, and U.S. Application Serial No. 09 / 550045, filed April 14, 2000 and priority of US Application Serial No. 09 / 551,162, filed April 14, 2000, which is hereby incorporated by reference in its entirety. field of invention [0002] The present invention relates to a series of macrolide ketolide antibacterial agents, intermediates for their preparation and pharmaceutical compositions containing them. The compounds are analogs of erythromycin for the treatment of bacterial and protozoal infections and for the treatment of other conditions including gastric motility. Background of the invention [0003] Polyketides are a class of natural products that includes many compounds with antibacterial and other pharmacological properties. Erythromycin is a class of macrolide antibiotics first discovered in 1952 in the metabolites of Strept...

Claims

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Application Information

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IPC IPC(8): C07H17/08A61K31/7048A61P31/04
CPCC07H17/08Y02P20/55A61P31/04
Inventor D·赫拉斯塔T·C·亨宁格E·B·格兰特C·赫霍斯拉D·T·W·徐G·阿什莱
Owner ORTHO MCNEIL PHARM INC
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