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WO2003031441A1 - Composes a actions multiples - Google Patents

Composes a actions multiples Download PDF

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Publication number
WO2003031441A1
WO2003031441A1 PCT/EP2002/010765 EP0210765W WO03031441A1 WO 2003031441 A1 WO2003031441 A1 WO 2003031441A1 EP 0210765 W EP0210765 W EP 0210765W WO 03031441 A1 WO03031441 A1 WO 03031441A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
oxo
mmol
phenyl
oxazolidin
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PCT/EP2002/010765
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English (en)
Inventor
Christian Hubschwerlen
Jean-Luc Specklin
Original Assignee
Morphochen Aktiengesellschaft Für Kombinatorische Chemie
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Publication of WO2003031441A1 publication Critical patent/WO2003031441A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention refers to novel multiple action compounds, that is, to compounds which contain at least two pharmaceutically active components in one molecule.
  • S. aureus is ⁇ -lactam, quinolone and now even partly vancomycin resistant.
  • S. pneumoniae is becoming resistant to penicillin and even to new macrolides.
  • Enteroccocci are quinolone and vancomycin resistant and ⁇ -lactams were never efficacious against these strains.
  • the only alternative is to use oxazolidinone (e.g. linezolid) but this compound is not baetericidal .
  • linezolid oxazolidinone
  • resistance already appears in clinical practice.
  • microorganisms that are causing persistent infections are increasingly being recognized as causative agents or cofactors of severe chronic diseases like peptic ulcers or heart diseases.
  • the compounds according to the present invention are compounds with multiple, especially dual pharmaceutical activities.
  • pharmaceutical activity comprises any bioactivity of a compound or substance and such compounds or substances can be, e.g. therapeutically active, prophylactically active and/or pharmacologically or physiologically active substances with a beneficial activity for humans, animals or plants. Most preferred it refers to therapeutical activity, beneficial for humans. Moreover, they can be used as well as disinfectants .
  • the present invention refers to a compound with at least two components each of which is capable of exerting a pharmaceutical activity, localized or systemic, irrespective of whether therapeutic, diagnostic or prophylactic in nature .
  • Such components preferably are each known medicaments from known medicament classes or classes of medicaments in clinical or preclinical trial or classes of medicaments under research or development or close analogues of them. Examples of such medicaments are disclosed in US Patent 5,656,286 of Noven Pharmaceuticals as printed in columns 11 to 32, which are incorporated herein by reference.
  • antiinfective components especially antiviral, antifungal or antibacterial components.
  • the present invention refers to coupling of two or more known medicaments like antibiotics to form a chemical compound containing both or all of these medicaments.
  • the components are preferably linked in a manner known per se to a chemist or biochemist.
  • a substituent like a H (or any other) -atom or group like a known leaving group of each medicament (component) can be replaced by a covalent bond, a spacer etc. as disclosed in the present invention.
  • two components can be linked by one bond, double bond etc., or one spacer etc.
  • two medicaments (components) etc. or parts thereof can be connected in a way that they share one (e.g. structural) element necessary for their pharmaceutical activity.
  • the links are preferably such that they - and especially preferred also the complete compounds
  • Physiological conditions per se are known in the art. They can differ according to the target or locus of the target.
  • the term "physiological conditions" according to the present invention preferably refers to
  • pH-value in the range from 1 to 10, more preferably from 4 to 9, still more preferably from 6 to 8;
  • - a temperature in the range from 36 to 40 °C, more preferably in the range from 36,5 to 38 C and especially preferably from 36,7 to 37 °C;
  • physiological conditions most preferably refers to the conditions in the blood of healthy humans.
  • stable preferably refers to a degradation of less than 10% preferably less than 5% of the compounds of the present invention within at least 30 min preferably within at least 60 min, more preferably within at least 8 hours and especially preferred within at least 24 hours after administration in the blood of humans. That means that the stable links (covalent bonds, elements or spacers) and preferably also the complete compounds are stable, preferably in the human body or blood, for this period of time so that the compounds can exert their pharmaceutical activity.
  • Examples of the compounds of the present invention are compounds of Formula (I) that are, e.g., useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria:
  • A is a direct bond, a NH, 0, S, SO, S0 2 , S0 2 NH, P0 4 , -NH-C0-NH-, -C0-NH-, -CO-, -C0-0-, -NH-C0-0-, an alkylen group, a heteroalkylen group, an arylen group, a heteroarylen group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups;
  • X is CR5 or N;
  • Y is CR6 or N;
  • U is F or Cl;
  • n is 0, 1, 2 or 3;
  • Rl is H, F, Cl, Br, I, OH, NH 2 , an alkyl group or a heteroalkyl group;
  • R2 is H, F or Cl;
  • R3 is H, an alky
  • R3 is an ethyl, a 2-propyl, a C3-C6 cycloalkyl, a phenyl or a pyridyl group. All these groups may be substituted by one or more fluorine atoms or amino groups.
  • A is a cycloalkylen or a alkylcycloalkylen group that contains 2 , 3 or 4 nitrogen atoms and may be substituted by one, two or more fluorine atoms and the nitrogen atoms may be substituted by an alkyl or an acyl group.
  • A is selected from the following groups which may be further substituted by one, two or more fluorine atoms or by an alkyl group which may be substituted by one, two or more fluorine atoms, and wherein the amino groups may be substituted by an alkyl or an acyl group:
  • the compounds according to the present invention have a higher stability than corresponding compounds of the prior art which are unstable under physiological conditions possibly causing the unwanted release of an active ingredient before the compounds reach their targets.
  • Such prior art compounds specifically do not have the requested stability under physiological conditions.
  • the at least two components are pharmaceutically active themselves, they maintain their activity when combined to one molecule, if either one of the components is not pharmaceutically active before, it becomes pharmaceutically active when combined with another component to one compound according to the present invention. Accordingly, all components according to the present invention, that is, when incorporated into one molecule, are pharmaceutically active.
  • a pharmaceutically active component is e.g. a chemical scaffold like a hydrocarbon chain or a hydrocarbon ring carrying at least one pharmacophore .
  • "Pharmacophore” is a commonly used term in the art and is defined as containing at least one functional group which is oriented in space in a specific manner and is responsible for a biological activity. Such pharmacophores are, e.g., described in B ⁇ hm, Hans-Joachim, et al . , irkstoffdesign, Heidelberg; Berlin; Oxford; Spektrum, Akad. Verl., 1996.
  • Compounds of the present invention can have one or more of the following modes of action:
  • At least two components have pharmaceutical activities
  • One component can act as the actual active ingredient while another component can inhibit enzymes etc. which can degrade the active ingredient or inhibit its action;
  • At least two components can act as inhibitors in the same biological pathway or in different pathways. In both cases synergy may occur; - One component releases a second component after having exerted its own pharmaceutical role.
  • a further advantage of the compounds of the present invention is due to the fact that multiple diseases can be cured with one compound (medicament) so that the comfort and compliance of the patients is largely increased. This is especially important when different pathogenic bacteria have to be treated with different antibiotics. Moreover, the problem of resistance development is minimized.
  • the compounds of the present invention can contain at least two components which share one (structural) element.
  • the at least two components share one element like a phenyl ring, which is - contrary to a spacer -necessary for the activity of the at least two components.
  • the at least two, preferably two, components contain preferably only one such element.
  • at least two components or pharmacophores can be forged into one compound according to the present invention, which is preferably stable under physiological conditions .
  • the compounds of the present invention can contain at least two components which are connected with a covalent bond which is preferably stable under physiological conditions .
  • the compounds of the present invention can contain at least two components which are linked (connected) with a spacer.
  • spacer is per se known in the art.
  • a spacer is any chemical element or group capable of linking the at least two pharmaceutically active components of the present invention and can e.g.
  • Such links are preferably stable under physiological conditions .
  • alkyl refers to a saturated or unsaturated (i.e. alkenyl and alkinyl having one, two or more double and/or triple bonds) straight or branched chain alkyl group, containing from one to ten, preferably one to six carbon atoms for example methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl n-hexyl, 2 , 2-dimethylbutyl, n- octyl; ethenyl (vinyl) , propenyl (allyl) , iso-propenyl, n- pentyl, butenyl, isoprenyl or hexa-2-enyl; ethinyl, propinyl or butinyl groups. Any alkyl group as defined herein may be substituted with one
  • heteroalkyl refers to an alkyl group as defined herein where one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorous or sulphur atom for example an alkoxy group such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy or tert .
  • an alkoxyalkyl group such as methoxymethyl , ethoxymethyl , 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl
  • an alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino or diethylamino
  • an alkylthio group such as methylthio, ethylthio or isopropylthio or a cyano group.
  • heteroalkyl furthermore refers to a group derived from a carboxylic acid or carboxylic acid amide such as acetyl, propionyl, acetyloxy, propionyloxy, acetylamino or propionylamino, a carboxyalkyl group such as carboxymethyl, carboxyethyl or carboxypropyl, a carboxyalkyl ester, an alkylthiocarboxyamino group, an alkoxyimino group, an alkylammothiocarboxyamino group or an alkoxycarbonylamino group.
  • Any heteroalkyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, NH 2 , OH, SH or N0 2 .
  • cycloalkyl refers to a saturated or unsaturated (having one, two or more double and/or triple bonds) , cyclic group with one, two or more rings, having three to 14 ring- carbon atoms, preferably from five or six to ten ring-carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentenyl or cyclohex-2-enyl groups.
  • Any cycloalkyl group as defined herein may be substituted with one, two or more substituents, for example F, Cl, Br, I, OH, NH 2 , SH, N 3 , N0 2 , alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino or cyanide.
  • substituents for example F, Cl, Br, I, OH, NH 2 , SH, N 3 , N0 2 , alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino or cyanide.
  • heterocycloalkyl refers to a cycloalkyl group as defined herein where one, two or more ring-carbon atoms are replaced by one or more oxygen, nitrogen, phosphorous or sulphur atoms for example piperidino, morpholino or piperazino groups.
  • aryl refers to an aromatic cyclic group with one or more rings, having five to 14 ring-carbon atoms, preferably from five or six to ten ring-carbon atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one or more substituents, for example F, Cl, Br, I, OH, NH 2 , SH, N 3 , N0 2 , alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino or cyanide .
  • heteroaryl refers to an aryl group as defined herein where one, two or more carbon atoms are replaced by an oxygen, nitrogen, boron, phosphorous or sulphur atom, for example 4-pyridyl, 2-imidazolyl , 3-pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2 , 3-triazolyl, 1 , 2 , 4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl , indazolyl, tetrazolyl, pyrazinyl, pyridinyl , pyrimidinyl and pyridazinyl groups .
  • arylalkyl, alkylaryl and heteroarylalkyl refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups .
  • At least two components of the inventive compounds can have the same or different pharmaceutical and/or therapeutical effects. Accordingly they can prevent, alleviate or cure the same or different diseases.
  • all components have different pharmaceutical and/or therapeutical effects .
  • all components have the same pharmaceutical and/or therapeutic effect.
  • This embodiment is especially preferred, since such compounds can have a multiple effect on the same microorganism thereby circumventing a possible resistance mechanism.
  • the pharmaceutical or therapeutic effect is not especially restricted; the advantage of providing at least two pharmaceutically active components applies to all known diseases .
  • the compounds according to the present invention contain at least one or two pharmaceutically active components which have antibiotic activity. It is especially preferred that all pharmaceutically active components have antibiotic activities.
  • the present invention also relates to pharmaceutically acceptable salts, or solvates and hydrates, respectively, and to compositions and formulations of such compounds.
  • the present invention describes procedures to produce pharmaceutically useful agents, which contain these compounds, as well as the use of these compounds for the production of pharmaceutically useful agents .
  • Examples of such pharmaceutically acceptable sufficiently basic salts of the compounds of the present invention are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleinic and salicylic acid.
  • examples of such pharmacologically acceptable sufficiently acidic salts of the compounds of the present invention may form alkali or earth alkaline metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, N-methyl-D- aminomethane (meglumin) , piperidine, morpholine, tris- (2- hydroxyethyl) amine, lysine or arginine salts.
  • Compounds according to the present invention may be solvated, especially hydrated.
  • the hydratisation can occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds.
  • the compounds can contain asymmetric C-atoms and may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
  • the present invention also relates to pro-drugs which are composed of a compound according to the present invention and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, aralkyloxy- , acyl- or acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl, acetyloxy, alkylcarboxyoxymethyl or 2- (alkyloxycarbonyl) -2-alkylideneethyl .
  • pharmacologically acceptable protective group which will be cleaved off under physiological conditions
  • an alkoxy-, aralkyloxy- , acyl- or acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl, acetyloxy, alkylcarboxyoxymethyl or 2- (alkyloxycarbonyl) -2-alkylideneeth
  • the present invention refers to pharmaceutical compositions, containing at least one compound according to the present invention optionally in combination with pharmaceutically acceptable carriers, adjuvants and/or diluents.
  • the pharmaceutical components according to the present invention may also contain additional known medicaments like antibiotics.
  • carriers, adjuvants or diluents are: water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, petroleum, vegetable, animal or synthetic oils, glycofurol 75, 2-hydroxypropyl- ⁇ -cyclodextrin sulphobutylether- ⁇ -cyclodextrin.
  • therapeutically useful agents that contain compounds of the present invention, their solvates, salts and formulations are also comprised in the scope of the present invention.
  • compounds of the present invention will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g.
  • the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g.
  • lactose sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • excipients e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols.
  • excipients as are e.g. water, alcohols, aqueous saline, aqueous dextrose, cyclodextrins, glycofurol 75, polyols, glycerin, vegetable, petroleum, animal or synthetic oils.
  • excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols.
  • compressed gases suitable for this purpose as are e.g. oxygen, nitrogen and carbon dioxide.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilisation, e.g. UV stabilizers, emulsifiers, sweetener, aromatisers, salts to change the osmotic pressure, buffers, coating additives and antioxidants .
  • a daily dosage per patient of about 1 mg to about 4000 mg especially about 100 mg to 2 g is usual with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being treated or prevented.
  • the daily dosage can be administrated in a single dose or can be divided over several doses.
  • An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg can be contemplated.
  • the compounds, pro-drugs or pharmaceutical compositions of the present invention can e.g. be used for the treatment or prevention of viral, fungal or bacterial infections.
  • the compounds of Formula (I) can be obtained by reacting an oxazolidinone bearing a group A as defined above, that contains an amine with a 7-chloro quinolone derivative.
  • the quinolone reactant may be activated prior to its use by forming a complex with a Lewis acid like BF 3 -etherate or any boron containing complex like boron acetate.
  • the reaction is performed in a polar solvent like acetonitrile, l-methyl-2- pyrrolidone, water, DMSO in presence of an organic base like triethylamine, N,N' dimethyl-p-toluidine, DBU, DABCO between 20 and 200°C preferably between 80 and 130°C.
  • the product can be prepared from the corresponding 7-chloro-quinolone by substitution with a 4-nitrophenyl derivative bearing a group containing an amine and subsequent construction of the oxazolidinone through reduction of the nitro group, reaction with benzyl chloroformate, deprotonation with n-BuLi and reaction with a glycitol ester.
  • EXAMPLE 1 7- (4 - ⁇ 4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3 yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -1-cyclopropyl-6-fluoro-4- oxo-1, 4-dihydro-quinoline-3 -carboxylic acid:
  • EXAMPLE 2 9- (4- ⁇ 4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3- yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -8-fluoro-3-methyl-6-oxo- 2 , 3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid:
  • EXAMPLE 3 7- ( (3R, S) -3 - ⁇ 4- [ (5S) -5- (acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenylcarbamoyl ⁇ -piperazin-1-yl) -1- cyclopropy1-6-fluoro-4-oxo-1,4-dihydro-quinoline-3 -carboxylic acid.
  • the solvents were evaporated, the residue dissolved in 10 ml water, neutralized with sodium bicarbonate, and the water layer evaporated to dryness.
  • the residue was digested in a 1/1 dichloromethane/methanol solution, the insoluble salts filtered, and the filtrate evaporated.
  • the residue was digested in ethyl acetate and the solid filtered.
  • the mixture was poured in ether, the solid filtered and dried.
  • the solid was purified by chromatography, using a dichloromethane/methanol 9/1 mixture with 1% acetic acid. The fractions with a rf of 0.1 were collected and evaporated.
  • EXAMPLE 4 7- [ (3R) -3 - ⁇ 4 - [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenylamino ⁇ -pyrrolidin-1-yl] - lcyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-quinoline-1-carboxylic acid.
  • the suspension was diluted with 100ml ether, the solid was filtered, washed with ether and hexane and dried.
  • the solid was suspended in 10 ml THF, 4.87g BOC anhydride (, 30 mmol) was added and the reaction stirred at rt . for 3 h and monitored by TLC.
  • the reaction was diluted with ethyl acetate, the org layer washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was crystallized from an ether/hexane mixture .
  • the catalyst was filtered, the filtrate evaporated to dryness, and the residue was dissolved in 100 ml of acetone. 25 ml of a saturated solution of sodium bicarbonate was added, than a 0°C 3.63 ml of benzyl chloroformate (25.8 mmol) .
  • the reaction was stirred over night at rt and monitored by TLC.
  • the acetone was evaporated, the water layer extracted twice with ethyl acetate, the org layer washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness.
  • the residue was purified by chromatography, using a 1/1 ethyl acetate/hexane mixture as eluent .
  • the reaction was diluted with water and washed with water and brine.
  • the org. layer was dried over Mg sulfate, filtered and the filtrate evaporated .
  • the solid residue was dissolved in 10 ml of DMF and 1.38g sodium azide (10.8 mmol) was added and the mixture stirred under inert gas at 80°C for 20 hrs.
  • the DMF was evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and evaporated.
  • the reaction was stirred at rt for 2hrs and monitored by TLC.
  • the solvents were evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness.
  • EXAMPLE 5 7- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -6-fluoro-l- (5- fluoro-pyridin-2-yl) -4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid:
  • the DMSO was evaporated and the crude product was digested in 10 ml water and filtered. The residue was purified by chromatography using a CH 2 Cl 2 /MeOH 5% mixture.
  • EXAMPLE 6 7- (4- ⁇ (5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3 ⁇ yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -1- (2 , 4-difluoro-phenyl) -6- fluoro-4-oxo-l, 4-dihydro-quinoline-3 -carboxylic acid:
  • the yellow oil was dissolved in 20 ml of THF, reacted with 315 mg of a 50 % NaH suspension in oil (6.56 mmol) and stirred at reflux for 20 hrs.
  • the solution was diluted with ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated.
  • EXAMPLE 7 7- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -1-cyclo- propyl- 8-methoxy-4 -oxo-1,4-dihydro-quinoline-3 -carboxy1ic acid:
  • the crystals were suspended in 3 ml of acetic anhydride (MW: 102.9,28 mmol) and 354 mg anhydrous boric acid (MW: 61.83, 5.6mmol) and 10 mg zinc chloride (MW: 136.28, 0.07mmol) were added. The mixture was stirred at 80°C for two hours. The reaction was poured on lOg ice in 20 ml water and stirred. The colorless crystals were filtered.
  • acetic anhydride MW: 102.9,28 mmol
  • anhydrous boric acid MW: 61.83, 5.6mmol
  • 10 mg zinc chloride MW: 136.28, 0.07mmol
  • EXAMPLE 8 9- (4 - ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin-l-yl) -8-fluoro-3 methyl-6-oxo-2, 3-dihydro-6H-l-oxa-3 , 3a-diaza-phenalene-5- carboxylic acid:
  • EXAMPLE 9 7- ⁇ (3RS) -3- [( ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -ethyl-amino) methyl] -piperazin- 1-yl ⁇ -l-cyclopropyl -6-fluoro-4-oxo-l, 4-dihydro-quinoline-3- carboxylic acid.
  • the solid was filtered, the filtrate concentrated and the solid deep red material filtered from the aqueous layer.
  • the solid was dissolved in ethyl acetate, washed twice with water and brine, dried over Mg sulfate, filtered and evaporated.
  • the deep red oily residue was dissolved in 100 ml acetone. 50 ml of saturated sodium bicarbonate solution was added. Under vigorous stirring, 1.17 ml of benzylchloroformate were added at 0°C. The reaction was stirred at rt over night, the acetone evaporated and the water layer extracted twice with ethyl acetate. The org. layer was washed with water and brine, dried over Mg S0 4 , filtered and the filtrate evaporated. The residue was purified by chromatography, using a 95/5 dichloromethane/methanol mixture as eluent . Yield: 3.1 g, quantitative.
  • the DMSO was evaporated, the residue dissolved in 10ml dichloromethane and the solid collected.
  • the solid was digested in 3 ml water, filtered and purified by prep HPLC. The fractions were concentrated by evaporation and the water freezed dried.
  • EXAMPLE 10 7- (4- ⁇ [ (5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin- 3-yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -l-cyclopropyl-6-fluoro-4- oxo-1, 4-dihydro- [1, 8] naphthyridine-3-carboxylic acid:
  • EXAMPLE 11 7- ⁇ 4- [2- (4- ⁇ 4- [5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin- 1-yl) -ethyl] piperazin-1-yl ⁇ -l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro- quinoline-3 -carboxylic acid:
  • the solid was suspended in 5,08 ml of acetic anhydride (5.2 mmol), 628 mg anhydrous boric acid (MW: 61.83, 1 mmol) and 20 mg zinc chloride (0.14 mmol) were added. The mixture was stirred at 80 °C for 20 hrs. The reaction was poured on 10 -g ice in 20 ml water and stirred. The solid was filtered.
  • EXAMPLE 12 7- [4- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -piperidin-1- yl] -l-cyclopropyl-6-fluoro-4-oxo-1, 4 -dihydro-quinoline-3- carboxylic acid:
  • the solid was dissolved in 200 ml toluene and 8.48g 4- amino-1-benzylpiperidine and 16.9 ml triethylamine were added. The suspension was stirred at 120°C for 72 hrs. The reaction was monitored by TLC. The solvents were evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over MG sulfate, filtered and evaporated. The residue was purified by chromatography, using a 9/1 dichloromethane / methanol mixture as eluent. The interesting fractions were collected and evaporated. The residue was crystallized from ethyl acetate/hexane mixture .
  • the reaction was stirred at room temperature and monitored by TLC.
  • the reaction was diluted with water and washed with water and brine.
  • the org. layer was dried over Mg sulfate, filtered and evaporated.
  • the oily residue was dissolved in 15 ml DMF. 100 mg of tetrabutyl ammonium iodide and 0.930 g sodium azide (14.32 mmol) were added and the mixture stirred under nitrogen at 80°C.
  • the reaction was monitored by TLC.
  • the DMF was evaporated, the residue dissolved in ethyl acetate and washed with water and brine.
  • the org. layer was dried over Mg sulfate, filtered and evaporated. The residue was crystallized from an ethyl acetate/ether mixture.
  • EXAMPLE 13 7-[(3R, 4R) and (3S, 4S) -3- ⁇ 4- [ (5S) -5- (Acetylaminomethyl) -2 -oxo-oxazolidin-3 -yl] -2-fluoro-phenyl ⁇ -4 -aminomethyl- pyrrolidin-1-yl] -1-eyelopropyl-6-fluoro-4-oxo-1,4-dihydro- quinolin-3 -carboxylic acid.
  • the reaction was diluted with ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was crystallized from an ethyl acetate / hexane mixture .
  • EXAMPLE 14 7- ⁇ 4- [2- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenyl ⁇ -piperazin-1-yl) -2-oxo-ethyl] piperazin-1-yl ⁇ -1-cyclopropyl-6-fluoro-4-oxo-1 , 4-dihydro- quinolone-3-carboxylic acid:
  • EXAMPLE 15 7- (3 - ⁇ 4- [5 (S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenylamino ⁇ -azetidin-1-yl) -1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1, 8] naphthyridine-3- carboxylic acid:
  • EXAMPLE 16 7- [ (3R) -3 - ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenylamino ⁇ -pyrrolidin-1-yl] -1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1,8] -naphthyridine-3- carboxylic acid:
  • EXAMPLE 17 7- [ (3R, 4S ) and (3S, 4R) -3 - ( -4 ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro- phenyl ⁇ piperazine-l-carbonyl) -4-aminomethyl-pyrrolidin-1-yl] -1- cyclopropyl-6-fluoro-4 -oxo-1, 4-dihydro-quinoline carboxylic acid
  • EXAMPLE 18 7-[(3R, 4S) and (3S, 4R) -3- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl ⁇ - piperazine-1-carbonyl) -4-aminomethyl-pyrrolidin-l-yl) 1- cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro- [1, 8] naphthyridine-3- carboxylic acid
  • the solution was heated at 150°C under stirring in a microwave oven for 10 min.
  • the reaction was monitored by TLC.
  • the DMSO was evaporated, the residue digested in water, filtered and the solid purified by chromatography, using dichloromethane / methanol mixture as eluent.
  • the intermediate was crystallized from acetonitrile.
  • the crystals were dissolved in a 1.25 M HCl and stirred at rt .
  • the reaction was monitored by TLC.
  • the methanol was evaporated and the residue purified by preparative HPLC.
  • the solid was filtered, washed with ether and hexane and dried.
  • the solid was diluted with 100 ml dichloromethane, 2.30 g BOC anhydride (MW: 218.25, 17.6 mmol) was added and the reaction stirred at RT over night and monitored by TLC.
  • the reaction was diluted with dichloromethane, the org. layer washed with water and brine dried over Mg sulfate and filtered. The filtrate was evaporated. The residue was purified by chromatography, using ethyl acetate as eluent.
  • EXAMPLE 22 1-Cyclopropyl-6-fluoro-7- (4- ⁇ 2-fluoro-4- [ (5R) -5- (methansulfonylamino-methyl) -2-oxo-oxazolidin-3-yl] -phenyl ⁇ - piperazin- 1-yl) -4-oxo-l , 4-dihydro- [1,8] naphthyridine-3- carboxylic acid.
  • EXAMPLE 23 7- (4- ⁇ 4- [ (5S) -5- (Acetylamino-methyl) -2 -oxo- oxazolidin-3-yl] -2-fluoro-phenylamino ⁇ -piperidin-1-yl) -1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro- [1,8] naphthyridine-3- carboxylic acid:
  • EXAMPLE 24 1-Cyclopropyl-6-fluoro-7- (4- ⁇ 2 -fluoro-4- [ (5S) -5- (methoxythiocarbonylamino-methyl) -2-oxo-oxazolidin-3-yl] - phenyl ⁇ -piperazin-1-yl) -4-oxo-l, 4-dihydro- [1, 8] -naphthyridine-3- carboxylic acid:
  • EXAMPLE 25 l-Cyclopropyl-6-fluoro-7- (4 - ⁇ 2-fluoro-4- ( (5S) -5- (methylsulfanylthiocarbonylamino-methyl) -2-oxo-oxazolidin-3 -yl] phenyl ⁇ -piperazin-1-yl) -4-oxo-l, 4dihydro- [1, 8] naphthyridine-3 - carboxylic acid:
  • EXAMPLE 26 l-Cyclopropyl-6-fluoro- ⁇ 4- [2 -fluoro-4 - ⁇ (5S) -2-oxo-5- thioureidomethyl-oxazolidin-3-yl ⁇ -phenyl] -piperazin-1-yl ⁇ -4-oxo- 1, 4-dihydro- [1, 8] naphthyridine-3 -carboxylic acid:
  • the reaction mixture was diluted with water and the solid filtered.
  • the solid was purified by chromatography using a 95/5 dichloromethane / methanol mixture with 1% acetic acid as eluent to leave 50 mg of an oily residue which was crystallized from a ETOAC/hexane mixture.
  • EXAMPLE 27 7- (4- ⁇ 4- [5 (S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenoxy ⁇ -piperidin-1-yl) -1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3 - carboxylic acid:
  • EXAMPLE 28 7- (4- ⁇ 4- [5 (S) -5- (Acetylamino-methyl) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenoxy ⁇ -piperidin-1-yl) -1- cyclopropyl-6-fluoro-4 -oxo-1, 4 -dihydro-quinoline-3 -carboxylic acid:
  • EXAMPLE 30 7- (4- ⁇ 4- [5 (S) -5 (Acetylamino-methyl ) -2-oxo- oxazolidin-3-yl] -2-fluoro-phenylsulfanyl ⁇ -piperidin-l-yl) -1- cyclopropyl-6-fluoro-4-oxo-1,4 -dihydro- [1,8] naphthyridine-3 - carboxylic acid:
  • compounds according to the present invention exhibit an improved action for the prevention, alleviation or treatment of diseases in the human or animal body.
  • the reasons for the improved action are not yet completely understood.
  • pathogenic organisms have defense mechanisms wherein different medicaments are neutralised by different means (active efflux, metabolic transformation or mutation (s) in the target.
  • the compounds of the present invention might no more be substrates for the various enzymes or receptors in charge of the detoxification of the bacteria. Further resistance through simultaneous mutation in the active sites of the two targets is unlikely or very difficult.

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Abstract

L'invention concerne de nouveaux composés à actions multiples, en d'autres termes, des composés qui contiennent au moins deux principes actifs sur le plan pharmaceutique encapsulés dans la même molécule. Ces composés présentent une stabilité supérieure à celle des composés homologues antérieurs.
PCT/EP2002/010765 2001-10-04 2002-09-25 Composes a actions multiples WO2003031441A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006055359A1 (fr) * 2004-11-12 2006-05-26 Allergan, Inc. Association de medicaments antibiotiques
JP2006526577A (ja) * 2003-04-30 2006-11-24 モルホケム アクツィエンゲゼルシャフト フューア コンビナートリッシュ ヒェミー 炭疽および他の感染を治療するためのオキサゾリジノン‐キノリンハイブリッド抗生物質の使用
JP2007516263A (ja) * 2003-12-18 2007-06-21 モルフォケム アクチェンゲゼルシャフト フュア コンビナトリシェ ヘミー オキサゾリジノン−キノロンハイブリッド抗生物質
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
WO2010081851A1 (fr) 2009-01-14 2010-07-22 Genoscience Pharma Composés de pipéridin-4-ylpipérazine pour le traitement d'une infection à vhc
US7880002B2 (en) * 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8124772B2 (en) 2003-09-03 2012-02-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
US8158797B2 (en) 2003-12-18 2012-04-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
US9402913B2 (en) 2013-03-08 2016-08-02 Allergan, Inc. Cyclosporine A steroid conjugates
US9402912B2 (en) 2013-03-08 2016-08-02 Allergan, Inc. Antibiotic conjugates directly linked with steroid drugs
EP3517527A4 (fr) * 2016-11-02 2019-08-28 Aktsionernoe Obshchestvo "Tatkhimfarmpreparaty" Compositions antimicrobiennes à base de dérivés de ciprofloxacine
US10723746B2 (en) 2013-05-28 2020-07-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibacterials for the parenteral treatment or prophylaxis of bacterial diseases

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WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
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DE19601265A1 (de) * 1996-01-16 1997-07-17 Bayer Ag 2-Oxo- und 2-Thio-1,2-dihydrochinolinyl-oxazolidinone
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
JP4805139B2 (ja) * 2003-04-30 2011-11-02 モルホケム アクツィエンゲゼルシャフト フューア コンビナートリッシュ ヒェミー 炭疽および他の感染を治療するためのオキサゾリジノン‐キノリンハイブリッド抗生物質の使用
US8513231B2 (en) 2003-04-30 2013-08-20 Morphochem Aktiengesellschaft fü Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
US8268812B2 (en) 2003-04-30 2012-09-18 Morphochem Aktiengesellschaft fül Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
JP2006526577A (ja) * 2003-04-30 2006-11-24 モルホケム アクツィエンゲゼルシャフト フューア コンビナートリッシュ ヒェミー 炭疽および他の感染を治療するためのオキサゾリジノン‐キノリンハイブリッド抗生物質の使用
US8124772B2 (en) 2003-09-03 2012-02-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
JP2007516263A (ja) * 2003-12-18 2007-06-21 モルフォケム アクチェンゲゼルシャフト フュア コンビナトリシェ ヘミー オキサゾリジノン−キノロンハイブリッド抗生物質
US9133213B2 (en) 2003-12-18 2015-09-15 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8501774B2 (en) 2003-12-18 2013-08-06 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
JP2012025748A (ja) * 2003-12-18 2012-02-09 Morphochem Ag Fuer Kombinatorische Chemie オキサゾリジノン−キノロンハイブリッド抗生物質
US8158797B2 (en) 2003-12-18 2012-04-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
WO2006055359A1 (fr) * 2004-11-12 2006-05-26 Allergan, Inc. Association de medicaments antibiotiques
US8168788B2 (en) 2004-12-29 2012-05-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US7880002B2 (en) * 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8648197B2 (en) 2004-12-29 2014-02-11 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
WO2010081851A1 (fr) 2009-01-14 2010-07-22 Genoscience Pharma Composés de pipéridin-4-ylpipérazine pour le traitement d'une infection à vhc
US9402913B2 (en) 2013-03-08 2016-08-02 Allergan, Inc. Cyclosporine A steroid conjugates
US9402912B2 (en) 2013-03-08 2016-08-02 Allergan, Inc. Antibiotic conjugates directly linked with steroid drugs
US10723746B2 (en) 2013-05-28 2020-07-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibacterials for the parenteral treatment or prophylaxis of bacterial diseases
US11261205B2 (en) 2013-05-28 2022-03-01 Morphochem Gmbh Oxazolidinone-quinolone hybrid antibacterial for the parenteral treatment of prophylaxis of bacterial diseases
EP3517527A4 (fr) * 2016-11-02 2019-08-28 Aktsionernoe Obshchestvo "Tatkhimfarmpreparaty" Compositions antimicrobiennes à base de dérivés de ciprofloxacine

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