Ketolide antibacterials

Details Ketolide antibacterials Ketolide antibacterials

2000-04-13

2002-10-01

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06458771

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. This work has produced a number of derivatives including the semi-synthetic antibiotic, clarithromycin, which is 6-O-methylerythromycin. 12,11 oxycarbonyl substituted imino chemical derivatives of erythromycin are described in U.S. Pat. No. 5,635,485. 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 products.
Recently, work surrounding the search for modified polyketide antibiotics expanded with the discovery and isolation of the modular polyketide synthases (PKS's); multifunctional enzymes related to fatty acid synthases, which catalyze the biosynthesis of polyketides through repeated reactions between acylthioesters to produce the polyketide chain. The entire biosynthetic gene cluster from
S. erythraea
has been mapped and sequenced by Donadio et al. in Industrial Microorganisms: Basic and Applied Molecular Genetics (1993) R. H. Baltz, G. D. Hegeman, and P. L. Skatrud (eds.) (Amer. Soc. Microbiol.) and the entire PKS is a modular assembly of three multifunctional proteins encoded by three separate genes. U.S. Pat. No. 5,672,491 discloses the use of cells transformed with recombinant vectors encoding a variety of PKS gene clusters, which can be used to produce a variety of active polyketides. The vectors can include native or hybrid combinations of PKS subunits, or mutants thereof, to produce a variety of polyketide compounds. Cell-free systems which effect the production of polyketides employing modular polyketide synthases are reported in WO 97/02358.
Using these techniques, production of erythromycin analogues in which C-13 bears a substitution other than the natural ethyl group have been reported, for example in WO 98/01571, WO 99/35157, WO 99/03986, and WO 97/02358. WO 98/0156 describes a hybrid modular PKS gene for varying the nature of the starter and extender units to synthesize novel polyketides, including erythromycin analogues. U.S. Pat. Nos. 5,824,513 and 6,004,787 further describe methods to produce polyketide structures by introducing specific genetic alterations to genes encoding PKS in the EryA sequence of
S. erythraea.
The present invention is concerned with novel chemical derivatives of unnatural erythromycin analogues prepared by manipulation of the modular PKS gene clusters.
SUMMARY OF THE INVENTION
This invention is concerned with new compounds of the formula I:
wherein:
X is H, F, Cl, Br, or I;
R
2
is selected from H, —COCH
3
and —COPhenyl;
R
6
is selected from H and —O—R
a
where R
a
is substituted or unsubstituted alkyl (C
1
-C
10
), substituted or unsubstituted alkenyl (C
2
-C
10
), or substituted or unsubstituted alkynyl(C
2
-C
10
);
R
13
is selected from H, (C
1
-C
8
) alkyl, 1-alkenyl (C
2
-C
8
), 1-alkynyl (C
2
-C
8
), substituted (C
1
-C
8
)alkyl, and —CH
2
—R″ where R″ is selected from H, (C
1
-C
8
) alkyl, substituted (C
1
-C
8
)alkyl, cycloalkyl, alkenyl (C
2
-C
8
), alkynyl (C
2
-C
8
), aryl, substituted-aryl, (C
1
-C
8
) alkylaryl, heterocyclo, and substituted heterocyclo; provided that R
13
can not be ethyl;
R is selected from H, aryl, substituted-aryl, heterocyclo, substituted-heterocyclo, cycloalkyl, C
1
-
8
-alkyl and C
1
-C
8
-alkenyl optionally substituted with one or more substituents selected from the group of aryl, substituted-aryl, heterocyclo, substituted-heterocyclo, hydroxy, C
1
-C
6
-alkoxy;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of the specified number of carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO
2
NH
2
), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH
2
) substituted carbamyl (e.g.CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, napthyl, and biphenyl groups, each of which may be substituted.
The term “alkylaryl” or “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “substituted aryl” refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term “cycloalkyl” refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C
3
-C
7
carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substitutents.
The terms “heterocycle”, “heterocyclic” and “heterocyclo” refer to an optionally substituted, fully saturated or unsaturated , aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-con

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