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US 2006/0025327 A1Published application
Hybrid molecules QA, wherein Q is an aminoquinoline and a is an antibiotic or a resistance enzyme inhibitor, their synthesis and their uses as antibacterial agent
AssigneePalumed S. A. & Centre National de la Recherche Scientifique CNRS
InventorsMuriel Sanchez, Bernard Meunier
Life of this patent
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Abstract
Aminoquinoline-antibiotic hybrid compounds in the form of hybrid molecules QA, wherein Q is an aminoquinoline and A is an antibiotic or a resistance enzyme inhibitor, their synthesis and their uses as antibacterial agent. This compound is defined by the general formula (I): Q-(Y1)p—(U)p′—(Y2)p″-A (I) in which Q represents an aminoquinoline, (Y1)p—(U)p′—(Y2)p″— is an optional spacer arm and A is an antibiotic, one of its derivatives or precursors, or a resistance enzyme inhibitor. The invention unexpectedly enables the activity of the antibiotic to be improved.
Claims43
A compound of the formula (I):
- Q-(Y1)p—(U)p′—(Y2)p″-A (I)
- wherein
- Q is an aminoquinoline-type molecule;
- A is selected from the group consisting of an antibiotic residue, a derivative of an antibiotic residue, a precursor of an antibiotic residue, a salt of an antibiotic residue, an hydrate of an antibiotic residue, a prodrug of an antibiotic residue, a prodrug salt of an antibiotic residue, a resistance enzyme inhibitor, a resistance enzyme inhibitor salt, and a resistance enzyme inhibitor hydrate, and A and Q are linked together by a covalent bond represented by —(Y1)p—(U)p′—(Y2)p″—, the covalent bond being direct or indirect by the use of a spacer arm.
1 more element
A compound of the formula (I):
- Q-(Y1)p—(U)p′—(Y2)p″-A (I)
- wherein
- Q is an aminoquinoline of the following formula (II) or (III):
- with
- n and n′ being, independently of each other, selected from the consisting of 0, 1, 2 and 3,
- R1a and R1b being one or more substituents, identical or different, occupying any position and representing moieties selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, sulfate, sulfonate, phosphate, phosphonate, nitro, cyano, aryl, heteroaryl, heteroalkyl, alkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonamido, alkylsulfonylamino, alkylamido, alkylcarboxy, alkoxycarbonyl, and alkylcarbonylamino, said alkyl group comprising 1 to 6 carbon atoms, saturated or unsaturated, linear, branched or cyclic, and optionally containing one or more moieties selected from the group consisting of amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, hydroxyimine, ether and thioether moieties, said moieties optionally bearing 1 to 4 substituents, identical or different, selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, carbonyl, amine, nitro, aryl, and heteroaryl,
- R2a and R2b being substituents, identical or different, optionally forming a cyclic structure together or with Y1, Y2, U or A and being selected from the group consisting of a hydrogen atom, and a linear, branched or cyclic C1 to C6 alkyl moiety optionally containing one or more moieties selected from the group consisting of amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether and thioether moieties, said moieties optionally bearing 1 to 4 substituents, identical or different, selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, carbonyl, amine, nitro, aryl, and heteroaryl,
- p, p′, p″ are, independently of each other, 0 or 1,
- Y1 and Y2, identical or different, are selected from the group consisting of a saturated or unsaturated, linear, branched or cyclic C1 to C6 alkyl chain optionally containing one or more moieties selected from the group consisting of amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, hydroxyimine, ether and thioether moieties, said moieties optionally forming a cyclic structure with R2 including N of the aminoquinoline part Q and/or the U function, the C1 to C6 alkyl chain optionally bearing 1 to 4 substituents, identical or different, selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, carbonyl, amine, nitro, hydroxyimine, aryl and heteroaryl, said C1 to C6 chain optionally substituted with 1 to 4 moieties selected from the group consisting of alkyl, alkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, alkylamido, alkylcarboxy, alkoxycarbonyl, alkylaminocarbonyl, and alkoxyimine type, said alkyl group comprising 1 to 6 carbon atoms, linear, branched or cyclic optionally containing one or more moieties selected from the group consisting of amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether, thioether, aryl and heteroaryl,
- U is a function is selected from the consisting of an amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, ether, thioether, thiocarbonyl, sulfonate, alkoxyimine (C═N—OR) and alkoxyiminocarbonyl (C(O)—C═N—OR) function with R representing a hydrogen atom or a linear, branched or cyclic C1 to C6 alkyl moiety optionally containing one or more moieties selected from the group consisting of amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether and thioether moieties,
- said aryl moiety being an aromatic ring having 5 to 6 members optionally bearing one or more substituents selected from the group consisting of:
- halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, nitro and cyano;
- said heteroaryl moiety being an aromatic ring having 5 to 6 members comprising 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said heteroaryl moiety optionally bearing one or more substituents selected from the group consisting of:
- halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, nitro and cyano;
- A is selected from the group consisting of an antibiotic residue, a derivative of an antibiotic residue, a precursor of an antibiotic residue, a resistance enzyme inhibitor, a salt of an antibiotic residue, an hydrate of an antibiotic residue, a prodrug of an antibiotic residue and a salt of a prodrug of an antibiotic residue.
12 more elements
An aminoquinoline compound which is coupled via a covalent bond to an antibiotic, wherein the aminoquinoline is selected from the group consisting of:
- (2S,5R,6R)-6-{[1-(7-Chloro-quinolin-4-yl)-piperidine-4-carbonyl]-amino}-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester;
- (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[3-(quinolin-8-ylamino)-propionylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester;
- (2S,5R,6R)-6-[2-(7-Chloro-quinolin-4-ylamino)-acetylamino]-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester;
- (2S,5R,6R)-6-[3-(7-Chloro-quinolin-4-ylamino)-propionylamino]-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester;
- (6R,7R)-3-Acetoxymethyl-7-[2-(7-chloro-quinolin-4-ylamino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-[2-(7-chloro-quinolin-4-ylamino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride;
- (6R,7R)-3-Acetoxymethyl-7-[2-(7-chloro-quinolin-4-ylamino)-acetylamino]-5,8-dioxo-5λ4-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride;
- (6R,7R)-3-Acetoxymethyl-7-[2-(7-chloro-quinolin-4-ylamino)-acetylamino]-5,8-dioxo-5λ4-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-[3-(7-chloro-quinolin-4-ylamino)-propionylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-[3-(7-chloro-quinolin-4-ylamino)-propionylamino]-5,8-dioxo-5×4-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-[3-(7-chloro-quinolin-4-ylamino)-propionylamino]-5,8-dioxo-524-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride;
- (6R,7R)-3-Acetoxymethyl-7-[4-(7-chloro-quinolin-4-ylamino)-butyrylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-{[1-(7-chloro-quinolin-4-yl)-piperidine-4-carbonyl]-amino}-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-3-Acetoxymethyl-7-{[1-(7-chloro-quinolin-4-yl)-piperidine-4-carbonyl]-amino}-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride;
- (6R,7R)-3-Acetoxymethyl-7-[2-(7-trifluoromethyl-quinolin-4-ylamino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
- (6R,7R)-3-Acetoxymethyl-7-[2-(2-methyl-quinolin-4-ylamino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- and
- 7-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1.4-dihydro-quinoline-3-carboxylic acid.
15 more elements
Dependencies are inferred from the claim text.