Ketolide antibacterials

Details Ketolide antibacterials Ketolide antibacterials

2000-10-18

2003-07-08

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

Reexamination Certificate

active

06590083

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a series of ketolide antibacterials in the macrolide family, intermediates used in their manufacture and pharmaceutical compositions containing them. The compounds are erythromycin analogues useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
BACKGROUND OF THE INVENTION
Polyketides are a family of natural products that include many compounds possessing antibiotic and other pharmacologic properties. Erythromycins are a class of macrolide antibiotics originally discovered in 1952 in the metabolic products of a strain of
Streptomyces erythreus
. The antibiotic occurs in various glycosylated forms, designated A, B, C, and D. Since their discovery, many have worked to prepare derivatives of the molecule to improve or modify its properties. The focus of much of this work involved chemical modification of the naturally produced erythromycin molecule. For example, clarithromycin is a semi-synthetic antibiotic that is made by chemically modifying the hydroxyl group at C-6 to —OMe.
Ketolides are erythromycin derivatives where the C-3 cladinose sugar is chemically removed and the resulting free hydroxyl group converted into a keto group. For example, U.S. Pat. No. 6,124,269 describes ketolides with a cyclic carbamate group at C-11 and C-12 and an O-alkylaryl group at C-6. U.S. Pat. No. 5,635,485 also describes ketolides with a cyclic carbamate group at C-11 and C-12 but which have a —OMe group at C-6 and an alkylaryl group at the carbamate nitrogen. However, because of the complexity of the macrolide molecule, medicinal chemistry efforts to produce derivatives have been limited by the kinds of modifications that can be made to the naturally occurring erythromycins and their precursors.
Recently, the discovery and isolation of modular polyketide synthases (“PKS's”) have expanded the scope of macrolide structures that may be made. PKS's are multifunctional enzymes related to fatty acid synthases, which catalyze the formation of the polyketide chains through repeated reactions between its acylthioesters.
The
S. erythraea
PKS is an assembly of three multifunctional proteins encoded by three separate genes and is described by U.S. Pat. Nos. 5,824,513, 6,004,787, 6,060,234, and 6,063,561. The
S. erythraea
PKS product is 6-deoxyerythronolide B which is subsequently processed by additional tailoring enzymes to make erythromycins A-D. The collective assembly of the PKS gene and the genes for the tailoring enzymes are referred to as the biosynthetic gene cluster. The
S erythraea
PKS biosynthetic gene cluster is described by Donadio et al. in Industrial Microorganisms: Basic and Applied Molecular Genetics, (1993), R. H. Balz, G. D. Hegeman, and P. L. Skatrud (eds.), Amer. Soc. Microbiol.
Recombinant methods using vectors encoding a variety of PKS's, including the PKS from
S. erythraea
, to make novel polyketides are described by U.S. Pat. Nos. 5,672,491, 5,830,750, 5,672,491, 5,712,146, 5,962,290, 6,022,731, 6,066,721, and 6,077,696. PCT Publication No. WO 98/01546 describes additional methods for modifying the loading domain and thus varying the nature of the starter units that initiate polyketide synthesis. Methods for making polyketides in a cell-free system are described, for example by U.S. Pat. No. 6,080,555 and PCT Publication No. WO 97/02358. Using these techniques, erythromycin analogues where the naturally occurring ethyl group at C-13 is replaced with other groups have been reported, for example in PCT Publication Nos.: WO 97/23630; WO 98/01571, WO 99/35157, WO 00/03986, and WO 00/44761.
Due to the alarming increase in the incidence of resistant strains to currently used antibiotics, a need exists for novel compounds having antibiotic activity, particularly against resistant strains. The present invention fulfills this need by providing novel erythromycin derivatives. These compounds are generally the product of semi-synthesis or the chemical modification of unnatural erythromycin analogues that result from the manipulation of PKS gene clusters.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds that are expected to possess antibacterial activity against a broad-spectrum of bacterial strains and are thus useful for the treatment of bacterial infections in humans and animals. The present invention is concerned with 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
a
wherein R
a
is a substituted or unsubstituted moiety selected from the group consisting of C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, heterocyclo, aryl(C
1
-C
10
)alkyl, aryl(C
2
-C
10
)alkenyl, aryl(C
2
-C
10
)alkynyl, heterocyclo(C
1
-C
10
)alkyl, heterocyclo(C
2
-C
10
)alkenyl, and heterocyclo(C
2
-C
10
)alkynyl;
R
13
is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of methyl; C
3
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, heterocyclo, aryl(C
1
-C
10
)alkyl, aryl(C
2
-C
10
)alkenyl, aryl(C
2
-C
10
)alkynyl, heterocyclo(C
1
-C
10
)alkyl, heterocyclo(C
2
-C
10
)alkenyl, and heterocyclo(C
2
-C
10
)alkynyl;
and,
R is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, heterocyclo, aryl(C
1
-C
10
)alkyl, aryl(C
2
-C
10
)alkenyl, aryl(C
2
-C
10
)alkynyl, heterocyclo(C
1
-C
10
)alkyl, heterocyclo(C
2
-C
10
)alkenyl, and heterocyclo(C
2
-C
10
)alkynyl;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to novel erythromycin derivatives and intermediates thereto. In general, the inventive compounds possess antibacterial activity against Gram positive, Gram negative, and anaerobic bacteria, and are useful as broad-spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are effective against diverse strains including but not limited to
S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes
, enterococci,
Moraxella catarrhalis
and
H. influenzae
. Exemplary infections that may be treated include community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired long infections, and bone and joint infections.
Many of the inventive compounds contain one or more chiral centers. All of the stereoisomers are included within the scope of the invention, as pure compounds as well as mixtures of stereoisomers. Similarly, all geometric isomers are also included within the scope of the invention. Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succ

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