WO2000032605A1 - Bi-pyrrolidinylvinyl (carba) cephalosporines - Google Patents

Bi-pyrrolidinylvinyl (carba) cephalosporines Download PDF

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Publication number
WO2000032605A1
WO2000032605A1 PCT/EP1999/009120 EP9909120W WO0032605A1 WO 2000032605 A1 WO2000032605 A1 WO 2000032605A1 EP 9909120 W EP9909120 W EP 9909120W WO 0032605 A1 WO0032605 A1 WO 0032605A1
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Prior art keywords
oxo
phenyl
hydrogen
carboxylic acid
methyl
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PCT/EP1999/009120
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English (en)
Inventor
Paul Hebeisen
Ingrid Heinze-Krauss
Hans Richter
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F. Hoffmann-La Roche Ag
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Priority to AU16549/00A priority Critical patent/AU1654900A/en
Publication of WO2000032605A1 publication Critical patent/WO2000032605A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D463/22—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by nitrogen atoms

Definitions

  • the present invention relates to (carba)cephalosporin derivatives of the general formula
  • R ⁇ R 2 are each independently hydrogen or lower alkyl
  • R J is hydrogen, hydroxy-lower alkyl or carbamoylmethyl
  • Z is phenylene, heterocyclylene or naphthylene
  • R 4 is halogen, phenyl, benzyl, naphthyl or heterocyclyl, the phenyl, benzyl, naphthyl or heterocyclyl being optionally substituted by at least one of halogen, hydroxy, optionally substituted lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl or carbamoyl;
  • Y is S, O, NH or CH 2 ;
  • s is 0 or 1;
  • R 5 , R 6 are each independently hydrogen or lower alkyl
  • R 7 is hydrogen, lower alkyl, lower cycloalkyl, formyl, acetyl or pivaloyl;
  • R 8 is hydrogen or halogen
  • the compounds of the present formula I are useful in the treatment and prophylaxis of infectious diseases caused by gram-positive bacteria. ' especially infectious diseases caused by sensitive and resistant staphylococci, pneumococci, enterococci and the like.
  • the invention is also concerned with the manufacture of compounds of formula I, with their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases, and with pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases.
  • R is methyl
  • R , 2 is hydrogen
  • R is hydrogen or carbamoylmethyl
  • Z is phenylene;
  • R 4 is phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl,
  • Y is S
  • X is CH or N
  • R 5 , R 6 are both hydrogen
  • R 7 is hydrogen
  • Also preferred compounds of formula I are in the E-form and have the additional pyrrolidine moiety connected via its 3',5'-positions, i.e. the compounds have the partial formula
  • halogen or halo refers to all four forms, that is chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro, unless specified otherwise.
  • lower alkyl used alone or in combination such as “lower alkylamino or di-lower alkylamino”, refers to both straight or branched saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl and the like.
  • lower alkoxy used alone or in combination such as “lower alkoxycarbonyl” refers to a straight or branched hydrocarbonoxy group wherein the "alkyl” portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n- propoxy and the like.
  • lower cycloalkyl is meant a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclohexyl, etc.
  • heterocyclyl refers to an unsaturated or saturated, unsubstituted or substituted 4-, 5-, 6- or 7-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen or sulfur.
  • heterocyclic rings include, but are not limited to, for example, the following groups; azetidinyl, pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl; furyl, 1H- azepinyl, thienyl, thi
  • Substituents for the heterocyclic ring include, for example, lower alkyls such as methyl, ethyl, propyl, etc., lower alkoxys such as methoxy, ethoxy, etc., halogens such as fluorine, chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxy, carbamoyl, or carboxy groups.
  • a further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, l,l-dioxo-tetrahydrothiophen-3-yl.
  • Heterocyclylene refers to a “heterocyclyl” residue as defined above but containing at least 2 carbon atoms and connected via two carbon bonds, such as 2,5-furylene, 2,5- thienylene, 2,4-pyridylene, 3,5-piperazylene, etc.
  • salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino acid salts.
  • preferred metal salts are those derived from the alkali metals, for example, lithium (Li + ), sodium (Na + ) and potassium (K + ).
  • Examples of quaternary ammonium salts derived from organic bases include tetramethyl- ammonium (N + (CH 3 ) 4 ), tetraethylammonium (N + (CH CH 3 ) 4 ), benzyltrimethyl- ammonium (N + (C 6 H 5 CH 2 )(CH3) 3 ), phenyltriethylammonium (N + (C 6 H 5 )(CH 2 CH 3 )3), and the like, etc.
  • salts derived from amines include salts with N-ethylpiperidine, procaine, dibenzylamine, N.N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine.
  • Especially preferred are hydrochlorides, sulfates, phosphates, lactates, mesylates or the inner salt.
  • esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group(s) of which (for example, the 2- carboxy group) is/are present in the form of readily hydrolyzable ester groups.
  • esters which can be of the conventional type, are the lower alkanoyloxy- alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxy ethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxy carbonyloxym ethyl, 1-ethoxy- carbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxy- methyl ester) and the lower alkanoylaminomethyl esters (e.g., the acetamidomethyl ester).
  • the lower alkanoyloxy- alkyl esters e.g., the acetoxymethyl, pival
  • esters e.g., the benzyl and cyanomethyl esters
  • Other examples of such esters are the following: (2,2-dimethyl-l-isopropoxy)methyl ester; 2-[(2-methyl- propoxy)carbonyl]-2-pentenyl ester; l-[[(l-methylethoxy)carbonyl]oxy]ethyl ester; l-(acetyloxy) ethyl ester; (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester; l-[[(cyclo- hexyloxy)carbonyl]oxy]ethyl ester; and 3,3-dimethyl-2-oxo-butyl ester.
  • the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound.
  • the compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated.
  • the hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
  • the compounds of the present formula I are useful in the treatment and prophylaxis of infectious diseases caused by gram-positive bacteria, especially infectious diseases caused by sensitive and resistant staphylococci, pneumococci, enterococci and the like.
  • the products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for parenteral administration, and for this purpose are preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate (e.g. glucose) solution.
  • the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, i.e. human and non-human.
  • a daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, 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 prevented or treated.
  • the daily dosage can be administered 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 following shows the minimum inhibitory concentrations (MIC; ⁇ g/ml) against a series of pathogenic microorganisms of two representative compounds of formula I.
  • R° is as R above except that R 7 may additionally represent a hydrox protecting group and the aminothia(dia)zol group may be protected, R 9 is hydrogen or a carboxy protecting group, R 10 is hydrogen or an allyloxycarbonyl protecting group, R 20 is hydrogen, lower alkyl or an allyloxycarbonyl protecting group and R 30 is hydrogen, protected hydroxy-lower alkyl or carbamoylmethyl, except that at least one of R 7 , R 9 , R 10 , R 20 and R 30 is a corresponding protecting or protected group,
  • the process of the present invention involves deprotection of a protected amino group in the 2-position of the thiazol or the thiadiazol ring and /or the protected pyrrolidin ring (R 10 as the protecting group), and/or protected hydroxy or carboxylic groups present in a compound of formula II and can be carried and as follows:
  • the amino protecting groups may be cleaved off by acid hydrolysis (e.g. the tert- butoxycarbonyl or trityl group), e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e.g. the phthalimido group).
  • the allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles.
  • the chloroacetyl group can be cleaved off by treatment with thiourea.
  • Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which maybe halogenated.
  • a lower alkanecarboxylic acid which maybe halogenated.
  • formic acid or trifluoroacetic acid is used.
  • the reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride.
  • the acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about -30°C to +40°C).
  • Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C.
  • the chloroacetyl protecting group can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C.
  • hydroxy protecting group refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilanyl, tert.-butyl-dimethylsilanyl, dimethylphenylsilanyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl and the like.
  • acetyl with weak inorganic bases like sodium bicarbonate in methanol or ethanol/water at about 0 to 50°C;
  • tetrahydropyranyl with weak organic acids like p-toluenesulfonic acid in an alcohol, e.g. ethanol, at about 0°C to the boiling point of the mixture.
  • carboxylic acid protecting group refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid.
  • carboxyl protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, for example, methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilanyl)ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethyl- silanyl, triethylsilanyl, tert-butyldimethylsilanyl, i-propyl-dimethylsilanyl.
  • Preferred are benzhydryl, tert-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
  • tert-butyl formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about -10°C to room temperature;
  • p-methoxybenzyl formic acid at about 0 to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about -40°C to room temperature;
  • the compounds of the invention can be manufactured according to the following reaction schemes 1-7.
  • Other compounds falling under the claims are obtainable in analogy thereto, in analogy to methods described in USP 5,523,400, EP 841,339 and EP 849,269 or in analogy to the examples given below.
  • TBDMS tert-butyl-dimethyl-silanyl
  • Ph phenyl
  • R l hydrogen or lower alkyl
  • R 20 hydrogen, lower alkyl or an allyloxycarbonyl protecting group
  • R 30 hydrogen, protected hydroxy-lower alkyl or carbamoylmethyl
  • the precipitated solid is collected by filtration and purified by column chromatography on MCI gel (75-150 ⁇ , Mitsubishi Kasei Corporation) with a gradient of water : acetonitrile (1 : 0, 4 : 1, 3 : 1, 2 : 1, 1 : 1).
  • the organic solvent is stripped off in a rotary evaporator and the aqueous phase is freeze-dried.
  • the pH of the reaction mixture is adjusted to 1 with 80% aqueous trifluoroacetic acid solution and stirred for 30 min.
  • the reaction mixture is concentrated under reduced pressure to give the desired compound as the trifluoroacetate salt which is used for the next step without further purification.
  • the crude amine from the step above (14.5 g, 0.05 mol) is dissolved in 450 ml dichloromethane and cooled to 0°C.
  • the pH of the solution is brought to 7 with triethylamine, then 5.84 ml (0.055 mol) allyl chloroformate are added dropwise.
  • the cooling bath is removed and the reaction mixture stirred at room temperature for an additional 1 hour.
  • the reaction mixture is poured on water and extracted.
  • the aqueous phase is reextracted twice with dichloromethane and the combined organic phases washed with water and brine and finally dried over magnesium sulfate.
  • the resulting oil (14.5 g, 32.0 mmol) is dissolved in 115 ml N.N-dimethylforrnamide and 2.50 g (38.4 mmol) sodium azide are added.
  • the solution is stirred overnight at 80°C and is then allowed to cool to room temperature.
  • the solvent is evaporated in a rotary evaporator and the residue dissolved in 120 ml ethyl acetate and extracted twice with 100 ml water.
  • the organic phase is dried over magnesium sulfate, filtrated and concentrated to a volume of about 60 ml, then 10.0 g (32.0 mmol) triphenylphosphine are added portionwise.
  • the solution is concentrated at 40°C in a rotary evaporator and the residue dissolved in 120 ml diethyl ether.
  • the solution is extracted with 68 ml aqueous 0.5M sodium hydroxide solution, and the aqueous phase is reextracted twice with each 40 ml diethyl ether.
  • the ethereal phases are dried over magnesium sulfate, filtrated and the solvent evaporated under reduced pressure.
  • the resulting residue is dissolved in 130 ml tetrahydrofuran, 50 ml 25% aqueous ammonium hydroxide solution added and the mixture stirred 24 hours at room temperature.
  • the organic solvent is stripped off and the aqueous phase is extracted with 80 ml ethyl acetate.
  • the aqueous phase is reextracted twice with each 30 ml ethyl acetate and the combined organic phases are extracted three times under each 40 ml 10% aqueous citric acid.
  • the pH of the aqueous phase is adjusted to 14 with 4M aqueous sodium hydroxide solution.
  • the aqueous phase is extracted four times with each 50 ml dichloromethane and the combined organic phases dried over magnesium sulfate, filtrated and evaporated. The resulting product can be used for the next step without further purification.
  • the phases are separated, the aqueous phase extracted twice with 40 ml dichloromethane and the combined organic phases washed twice with 20 ml water and dried over magnesium sulfate. After filtration the solvent is removed in a rotary evaporator. The residue is redissolved in 120 ml dichloromethane, them 180 ml 50% aqueous sodium hydroxide solution and 1.10 g Dowex 2x10 are added under vigorous stirring. After completion of the reaction (TLC) the phases are separated and the aqueous phase extracted twice with 60 ml dichloromethane. The combined organic phases are washed with 40 ml water, followed by brine, dried over magnesium sulfate and concentrated.
  • the resulting solid is dissolved in 40 ml dichloromethane and added under vigorous stirring to 450 ml n-hexane. After 1 hour the solvent is decanted off and the residue triturated with 450 ml diethyl ether. The resulting solid is collected by filtration, washed with n-hexane and diethyl ether and dried under high vacuum.
  • reaction mixture is stirred for 2.5 hours at room temperature, concentrated to a volume of 10 ml and poured on 150 ml ice-cold diethyl ether. The precipitated solid is collected by filtration, washed with diethyl ether and dried under high vacuum.
  • the precipitate is collected by filtration and dried under high vacuum.
  • the crude product is suspended in 10 ml water, and the pH is adjusted to 7 with IM aqueous sodium hydroxide solution.
  • the brown solution is purified by reversed phase chromatography (RP-18 LiChroPrep gel) with a gradient of water : acetonitrile (1 : 0, 4 : 1, 3 : 1, 2 : 1, 1 : 1).
  • the organic solvent is stripped off on a rotary evaporator and the pH of the aqueous phase is adjusted to 2 with IM hydrochloric acid.
  • the resulting solid is collected by filtration, washed with water and dried under high vacuum.
  • the resulting oily residue was purified by column chromatography on silica gel (MERCK, 0.040 - 0.063 mm) with a gradient of ethyl acetate : n-hexane (1 : 9 to 1 : 3) as eluent.
  • the reaction mixture was extracted three times with 5000 ml water, dried over magnesium sulfate, filtered and concentrated at a rotary evaporator.
  • the crude product was purified by column chromatography on silica gel (MERCK, 0.040 - 0.063 mm) with n-hexane : ethyl acetate (4 : 1) as eluent.
  • the crude product was purified by column chromatography on silica gel (MERCK, 0.040 - 0.063 mm) with a gradient of dichloromethane : ethyl acetate (50 : 1 to 20 : 1) as eluent.
  • the organic layer was washed successively with 1500 ml water, 5% sodium bicarbonate solution and brine. After drying over magnesium sulfate and filtration, the organic solvents were evaporated under reduced pressure.
  • the crude product was purified and the diastereomers were separated by column chromatography on silica gel (MERCK, 0.040 - 0.063 mm) with n-hexane : ethyl acetate (2 : 1 ) as eluent.
  • the solvent was evaporated at a rotary evaporator, the residue was distributed in 50 ml ethyl acetate and water (1/1 w/w) and extracted.
  • the aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed with water.
  • the filtrate was concentrated and at the same time the product starts to precipitate.
  • the solid material was collected by filtration, washed with diethyl ether and dried under high vacuum to give 1.20 g (77.1 %) of a beige solid.
  • Said starting material is obtained by reacting (E)-(6R,7R)-3-[(3 > S,5'R)- -allyloxycarbonyl- 5'- [4- [(allyloxycarbonyl-methyl-amino)-methyl] -phenyl] -2-oxo- [1, 3']bipyrrolidinyl-3- ylidenemethyl]-7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid with S-(2-benzothiazolyl) 2- [(triphenylmethyl) -amino] -4-thiazoleglyoxylate (Z)-O- (triphenylmethyl)oxime.
  • the reaction mixture was stirred for 1.5 h and then poured on 150 ml diethyl ether.
  • the solid material was collected by filtration and dried under high vacuum.
  • the crude product was suspended in 3 ml of water and the pH was adjusted to 1 with IM hydrochloric acid.
  • the solution was chromatographed on MCI gel (75-150 ⁇ , Mitsubishi Kasei Corporation) with water : acetonitrile (1 : 1) as eluent.
  • the fractions containing the product were pooled, concentrated at a rotary evaporator and the pH was adjusted to 7.1 with a 5% aqueous sodium bicarbonate solution.
  • the unsoluble material was filtered off and the filtrate was freeze-dried.
  • the lyophilisate was digested in a small amount of water, filtered and dried under high vacuum to yield 33 mg (16.1 %) of the desired product as a beige powder.
  • a lyophilisate of 1 g of active ingredient is prepared in the usual manner and filled into an ampoule.
  • the sterile water ampoule contains 10% propylene glycol.
  • the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.
  • active ingredient can be used one of the end products prepared according to the above Examples 1-8.

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  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Cephalosporin Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des dérivés de céphalosporine représentés par la formule (I). Dans ladite formule, R est R4 -Ys-(CR5R6)m- ou (formule a) R1, R2 sont chacun indépendamment hydrogène ou alkyle inférieur; R3 est hydrogène, hydroxy-alkyle inférieur ou carbamoylméthyle; Z est phénylène, hétérocyclylène ou naphthylène; R4 est halogène, phényle, benzyle, naphtyle ou hétérocyclyle, sachant que phényle, benzyle, naphtyle ou hétérocyclyle est éventuellement substitué par au moins l'un des éléments suivants : halogène, hydroxy, alkyle inférieur éventuellement substitué, alkoxy inférieur, amino, alkylamino inférieur, di-alkylamino inférieur, carboxy, alcoxycarbonyl inférieur ou carbamoyle; Q est S ou CH¿2?; Y est S, O, NH ou CH2; M vaut 0 ou 1; s vaut 0 ou 1; R?5, R6¿ sont chacun indépendamment hydrogène ou alkyle inférieur; X est CR8 ou N; R7 est hydrogène, alkyle inférieur, cycloalkyle inférieur, formyle, acétyle ou pivaloyle; R8 est hydrogène ou halogène. L'invention englobe les esters facilement hydrolisables des dérivés considérés, ainsi que les sels pharmaceutiquement acceptables, les hydrates, esters et sels de ces dérivés. L'invention concerne en outre la fabrication des produits considérés, et leur utilisation comme substances pharmaceutiquement actives, en particulier pour le traitement et la prophylaxie des maladies infectieuses. L'invention concerne enfin des préparations pharmaceutiques renfermant un produit représenté par la formule (I), utiles pour le traitement et la prophylaxie des maladies infectieuses.
PCT/EP1999/009120 1998-12-03 1999-11-25 Bi-pyrrolidinylvinyl (carba) cephalosporines WO2000032605A1 (fr)

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AU16549/00A AU1654900A (en) 1998-12-03 1999-11-25 Bi-pyrrolidinylvinl (carba) cephalosporins

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EP98122965.1 1998-12-03
EP98122965 1998-12-03
EP99119895.3 1999-10-07
EP99119895 1999-10-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004127A1 (fr) * 1999-07-07 2001-01-18 F. Hoffmann-La Roche Ag Derives de vinylpyrrolidinone a cycle thiazole substitue
US6384214B1 (en) * 1999-07-05 2002-05-07 Basilea Pharmaceutica Ag Process for producing cephalosporin derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0812846A1 (fr) * 1996-06-10 1997-12-17 F. Hoffmann-La Roche Ag Préparation de dérivés de céphem et isooxacéphem
EP0831093A1 (fr) * 1996-09-23 1998-03-25 F. Hoffmann-La Roche Ag Dérivés de 1-carba-(déthia)-céphalosporine
EP0838465A1 (fr) * 1996-10-22 1998-04-29 F. Hoffmann-La Roche Ag Dérivés de (lactamylvinyl)cephalosporin pyridinium substitués, leur préparation et leur utilisation comme antibiotiques
EP0841339A1 (fr) * 1996-11-06 1998-05-13 F. Hoffmann-La Roche Ag Dérivés de vinylpyrrolidone-céphalosporine
EP0849269A1 (fr) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinylpyrrolidin-cephalosporines substitues par des groupes basiques
EP0911030A2 (fr) * 1997-09-15 1999-04-28 F.Hoffmann-La Roche Ag Compositions antimicrobiennes contenant des dérivés de vinylpyrrolidinone-céphalosporine et un antibiotique carbapénème ou un inhibiteur du béta-lactamase

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EP0849269A1 (fr) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinylpyrrolidin-cephalosporines substitues par des groupes basiques
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Publication number Priority date Publication date Assignee Title
US6384214B1 (en) * 1999-07-05 2002-05-07 Basilea Pharmaceutica Ag Process for producing cephalosporin derivatives
WO2001004127A1 (fr) * 1999-07-07 2001-01-18 F. Hoffmann-La Roche Ag Derives de vinylpyrrolidinone a cycle thiazole substitue

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AU1654900A (en) 2000-06-19
AR023065A1 (es) 2002-09-04
PE20001402A1 (es) 2000-12-15
CO5150174A1 (es) 2002-04-29

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