WO1996026943A1 - Derivatives of 3-pyrrolidylidene-2-one-cephalosporines - Google Patents

Derivatives of 3-pyrrolidylidene-2-one-cephalosporines Download PDF

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Publication number
WO1996026943A1
WO1996026943A1 PCT/EP1996/000667 EP9600667W WO9626943A1 WO 1996026943 A1 WO1996026943 A1 WO 1996026943A1 EP 9600667 W EP9600667 W EP 9600667W WO 9626943 A1 WO9626943 A1 WO 9626943A1
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oxo
compounds
salts
formula
compound
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PCT/EP1996/000667
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French (fr)
Inventor
Ingrid Heinze-Krauss
Hans Richter
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F.Hoffmann-La Roche Ag
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Priority to BR9607046A priority Critical patent/BR9607046A/en
Priority to AU48771/96A priority patent/AU4877196A/en
Priority to US08/875,563 priority patent/US5925632A/en
Priority to EP96904802A priority patent/EP0812323A1/en
Priority to JP8525987A priority patent/JPH11501017A/en
Publication of WO1996026943A1 publication Critical patent/WO1996026943A1/en
Priority to MXPA/A/1997/006187A priority patent/MXPA97006187A/en
Priority to FI973500A priority patent/FI973500A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to cephalosporin derivatives of the general formula I
  • Rl is hydrogen, lower alkyl, aralkyl, cycloalkyl, R 3 CO- or
  • R 4 and R 5 are each independently hydrogen or lower alkyl, or R 4 and R 5 taken together form a cycloalkyl group;
  • R 3 is hydrogen or lower alkyl and
  • R 6 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group.
  • R 2 is isobutyl, sec. butyl, 2,2-dimethyl-propyl, 2-ethyl-butyl, cyclobutyl- methyl, cyclopentyl-methyl or cyclohexyl-methyl; n is 0, 1 or 2; X is CH or N
  • n is 1.
  • R 1 is preferably hydrogen or cyclopentyl.
  • X is preferably CH.
  • the compounds of the formula I are preferably in the Z-form at the oximino group and E-form for the substitutent in position 3.
  • Preferred compounds of formula I include:
  • the invention also relates to pharmaceutical compositions and methods of use of the above.
  • lower alkyl refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
  • aralkyl is meant an alkyl group containing an aryl group. It is a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl hydrogen atom is substituted by a monocydic aryl group, e.g., phenyl, tolyl, etc.
  • cydoalkyl is meant a 3-7 membered saturated carbocyclic moiety, e.g., cydopropyl, cyclobutyl, cydohexyl, etc.
  • lower alkenyl refers to unsubstituted or substituted hydrocarbon chain radicals having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl etc.
  • carboxylic add protecting group refers to protecting groups conventionally used to replace the addic proton of a carboxylic add. Examples of such groups are benzyhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
  • salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino add salts.
  • preferred metal salts are those derived from the alkali metals, for example, lithium (Li + ), sodium (Na+) and potassium (K+), and from the alkaline earth metals, for example, caldum (Ca ++ ) and magnesium (Mg ++ ), although cationic forms of other metals, such as iron (Fe++ or Fe +++ ), aluminium (A1+++), and zinc (Zn ++ ) are within the scope of this invention.
  • Examples of quaternary ammonium salts derived from organic bases include tetramethylammonium (N+(CH3)4), tetraethylammonium (N + (CH2CH3)4), benzyltrimethylammonium (N+(C6H5CH2)(CH3)3), phenyltriethylammo ium (N+(C6H5)(CH 2 CH3)3), and the like, etc.
  • salts derived from amines indude salts with N-ethyl- piperidine, procaine, dibenzylamine, N.N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino adds such as, for example, salts with arginine or lysine.
  • 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-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyloxymethyl, 1- ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the ph halidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoyloxy-al
  • esters e.g., the benzyl and cyanomethyl esters
  • Other examples of such esters are the following: (2,2-dimethyl-l-oxopropoxy)methyl ester; 2-[(2- methylpropoxy)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-[[(cyclohexyloxy)carbonyl]oxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester.
  • the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound, for example, at the carboxy group in position 1 and at a carboxy group -COOR 6 .
  • 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 invention are useful as antibiotics having potent and broad antibacterial activity. They also possess good oral absorption properties.
  • the products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for enteral (oral) administration.
  • the products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories.
  • compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non- toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.
  • compositions of suitable oral or parenteral dosage forms can contain, as optional ingredients, any of the various adjuvants which are used ordinarily in the production of pharmaceutical preparations.
  • fillers such as copredpitated aluminum hydroxide-caldum carbonate, dicaldum phosphate or lactose; disintegrating agents, such as maize starch; and lubricating agents, such as talc, caldum s tear ate, and the like.
  • Suitable as such carrier materials are not only inorganic, but also organic carrier materials.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance; no carriers are, however, required in the case of soft gelatine capsules).
  • Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose.
  • Suitable carrier materials for suppositiories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • solubilizers As pharmaceutical adjuvants there are contemplated the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.
  • the compounds of formula I and their salts, or hydrates can preferably be used 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 solution.
  • the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human, a daily dosage of about 10 mg to about 4000 mg, espedally about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appredating 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.
  • In vitro activity was determined by minimum inhibitory concentration in a microorganism spectum by the agar dilution method in Mueller Hinton agar.
  • R 1 and X are defined above, or R 1 is a reactive functional derivative thereof, or
  • R 2 is defined above, R f is hydrogen or an amino protecting group, RS is hydrogen or a hydroxy protecting group, R h is hydrogen or a carboxy protecting group, provided that at least one of R f , R6 and R h is a corresponding protecting group or a salt thereof, or
  • the reaction of compounds II and III or a reactive derivative of III according to embodiment (a) can be carried out in a manner known per se.
  • the carboxy group in compounds II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester) or benzhydryl ester.
  • the carboxy group can also be protected in the form of one of the aforementioned readily hydrolyzable esters.
  • the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.
  • the amino group present in the acylating agent of formula III can be protected.
  • Possible protecting groups are, for ⁇ example, protecting groups which are cleavable by add hydrolysis (e.g. the tert.- butoxycarbonyl or trityl groups) or by basic hydrolysis (e.g. the tr ⁇ luoroacetyl group).
  • Preferred protecting groups are the chloroacetyl, bromoacetyl and iodoacetyl groups, espedally the chloroacetyl group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea.
  • the 7-amino group in compounds II can be protected, for example, by a silyl protecting group such as the trimethylsilyl group.
  • a free carboxylic add in reacting a 7-amino compound of formula II with a carboxylic add of formula IU or a reactive functional derivative thereof, for example, a free carboxylic add can be reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicydohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide, and subsequently the ester group can be deaved off.
  • Oxazolium salts e.g. N-ethyl-5-phenyl-isoxazolium-3 - sulphonate
  • carbodiimide such as dicydohexylcarbodiimide
  • an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloro
  • a salt of an add of formula II e.g. a trialkylammonium salt such as the triethylammonium salt
  • a reactive functional derivative of a carboxylic add of formula HI as mentioned earlier in an inert solvent (e.g. one of the aforementioned solvents).
  • an add halide, preferably the chloride, of a carboxylic add of formula DI is reacted with an amine of formula II.
  • the reaction is preferably carried out in the presence of an arid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine.
  • an arid-binding agent for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine.
  • the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan.
  • the reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or hexamethylphosphoric add triamide.
  • an aprotic organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or hexamethylphosphoric add triamide.
  • acylation where the amino group present in the acylating agent of formula IU. need not be protected, involves the use of a 2-benzothiazolyl thioester or a 1-hydroxybenzotriazole ester of the carboxylic add.
  • the 2-benzthiazolyl thioester may be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g.
  • the 1-hydroxybenzotriazole ester can be employed by reacting the carboxylic add with 1-hydroxybenzotriazole and a carbodiimide, espedally N,N - dicydohexylcarbodiimide or in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
  • reaction of a 7-amino compond of formula II with the carboxylic addof formula HI or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.
  • Embodiment (b) of the process of the present invention involves deprotection (removal) of protected amino, hydroxy or carboxylic groups present in a compound of formula IV and can be carried and as follows:
  • Possible amino-protecting groups are those employed in peptide chemistry, such as an alkoxycarbonyl group, e.g., t-butoxycarbonyl, etc., a substituted alkoxycarbonyl group, e.g., trichloroethoxycarbonyl etc., an optionally substituted aralkyloxycarbonyl group, e.g., p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, an aralkyl group such as trityl or benzhydryl or a halogen- alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifiuoroacetyl.
  • an alkoxycarbonyl group e.g., t-butoxycarbonyl, etc.
  • a substituted alkoxycarbonyl group e.g., trichloroethoxycarbonyl etc.
  • Preferred protecting groups are t-butoxycarbonyl (t-BOC) and trityl.
  • the amino protecting groups may be deaved off by add hydrolysis (e.g. the t-butoxycarbonyl or trityl group), e.g. aqueous formic add, or by basic hydrolysis (e.g. the trifiuoroacetyl group).
  • hydrolysis e.g. the t-butoxycarbonyl or trityl group
  • basic hydrolysis e.g. the trifiuoroacetyl group.
  • the chloroacetyl, bromoacetyl and iodoacetyl groups are deaved off by treatment with thiourea.
  • Amino-protecting groups which are deavable by add hydrolysis are preferably removed with the aid of a lower alkanecarboxylic add which may be halogenated.
  • a lower alkanecarboxylic add which may be halogenated.
  • formic add or trifluoroacetic add is used.
  • the reaction is carried out in the add or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride.
  • the add 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, bromoacetyl and iodoacetyl protecting groups can be
  • Possible hydroxy protecting groups are such as are commonly known in the art, e.g.
  • R 1 hydrogen in compounds of formula D, usually trityl, lower alkanoyl, preferably acetyl, tetrahydropyranyl protecting groups are employed
  • -trityl in addic solvents like 90% formic add at about 0 to 50°C or triethylsilane in trifluoroacetic add at about -20 to 25°C; in organic solutions of hydrochloric add at about -50 to 25°C; -acetyl with weak inorganic bases like sodium bicarbonate in ethanol/water at about 0 to 50°C; -tetrahydropyranyl with weak organic adds like p-toluenesulfonic add in an alcohol, e.g. ethanol, at about 0°C to the boiling point of the mixture; Removal of protecting groups at the carboxv function
  • ester protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, the ester protecting group being exemplified by, for example, t-butyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, allyl, etc.
  • a carboxylic arid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group.
  • the reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine.
  • the esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric arid triamide, dimethyl sulfoxide or, especially, dimethylformamide.
  • the reaction is preferably carried out at a temperature in the range of about 0-40°C.
  • the manufacture of the salts and hydrates of the compounds of formula I or the hydrates of said salts in accordance with embodiment (d) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic arid of formula I or a salt thereof with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like).
  • a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like).
  • salt formation is brought about by the addition of an organic or inorganic salt.
  • the temperature at which the salt formation is carried out is not critical.
  • the salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C.
  • a completely or partially anhydrous carboxylic arid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C).
  • the preferred solvents in the case of inorganic base being used, are water and water-misrible solvent (acetone, tetrahydrofuran, or alcohols etc.); in the case of organic base being used, an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran; in the case of organolithium being used, benzene or tetrahydrofuran; and in the case an epoxide being used, the epoxide itself (e.g. 1,2-butyleneoxide).
  • the temperature for the reaction ranges from -20°C to 80°C. The preferred conditions are exemplified in the examples.
  • the E isomer is the predominant product. Invariably, less than 10% Z-isomer is formed, the amount depending on the reagents and conditions.
  • Compound 4 is converted to the sulfoxide 5 with an oxidizing agent which can be hydrogen peroxide or a perarid, preferably m-chloroperbenzoic arid.
  • an oxidizing agent which can be hydrogen peroxide or a perarid, preferably m-chloroperbenzoic arid.
  • the temperature ranges from -20°C to room temperature and any suitable solvent, preferably chlorinated hydrocarbon or benzene can be used.
  • the de-oxygenation of the sulfoxide 5 is carried out in the presence of phosphorus tribromide in dimethylformamide or in the mixed solvent of dimethylformamide and N-methylacetamide.
  • the reaction temperature for the reaction is from about -40 to about 0°C.
  • the protecting groups R r and R 10 are removed and the reaction conditions used are depending on the nature of the protecting groups.
  • R 10 being t-butoxycarbonyl and R r being benzhydryl
  • trifluoroacetic arid is employed, at temperature of about -20°C to about room temperature (about 22°C).
  • the acylation of compound 7 can be carried out with an organic arid which is activated with known reagents, preferably tbionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, bis-[benzthiazolyl-(2)]disulfide, N-hydroxy benzotriazole or a 2-halo N-methylpyridinium salt.
  • the reaction is carried out with or without the base (inorganic or organic bases) depending on the method of activation and a wide range of solvents, from water and water-mis ⁇ ble solvent to inert solvents such as chloroform, dimethylformamide (DMF) or dimethyl- sulfoxide (DMSO) can be used.
  • the R 1 group if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
  • RP can be any such esters known in the art by esterification with the corresponding alcohol of RP or by treating with the corresponding halide of RP and a base; the preferred esters are exemplified in the examples.
  • the R 1 group if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
  • reaction-temperatures range from -10 to 100°C.
  • Cyclization of the N-substituted dibromoamides (2) can be accomplished under the usual phase transfer catalytic conditions using catalysts like Dowex 2x10, tetraalkylammonium salts, tetraalkylarylammonium salts, crown ethers etc. with bases like aqueous sodium or potassium hydroxide, sodium or potassium carbonate etc.
  • strong bases like sodium hydride, lithium diisopropylamide, potassium t-butoxide can be used in solvents like tetrahydrofuran, dichloromethane, dimethoxyethane or diethylether at reaction temperatures between -78 and +80°C.
  • the direct conversion of the add chlorides into the bromolactams is possible when the first step (1 to 2) is carried out in biphasic solvent mixtures like water/dichloromethane or water/chloroform etc. together with sodium or potassium hydroxide as base.
  • a catalyst like Dowex 2x10, tetralkylammonium salts, tetraalkylarylammonium salts, crown ethers etc. is added when the amide (2) has formed according to TLC or HPLC analysis.
  • the temperatures range between 0 and 50°C.
  • the triphenylphosphonium salts (4) can be prepared by treating the bromolactams with triphenylphosphine in solvents like tetrahydrofuran, toluene, benzene, ethylacetate, dichloromethane, dichloroe thane, chloroform etc. at temperatures between 0 and 150°C.
  • the aqueous phase was extracted thrice with 20 ml dichloromethane, and the combined organic phases were washed once with 20 ml water, once with 20 ml brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting colourless oil was chromatographed on silica gel (0.040-0.063 mm) with ethyl acetate/n-hexane 1:1 as eluent.
  • rac-2,4-dibromo-N-(2,2-dimethyl-propyl)-butyramide was synthesized from 10 g (0.115 mol) neopentylamine and 27.6 g (0.104 mol) 2,4-dibromo butanoic arid chloride.

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Abstract

Cephalosporin derivatives of general formula (I) wherein R1 is hydrogen, lower alkyl, aralkyl, cycloalkyl, R3CO- or -C(R4R5)CO2R6; where R?4 and R5¿ are each independently hydrogen or lower alkyl, or R?4 and R5¿ taken together form a cycloalkyl group; R3 is hydrogen or lower alkyl and R6 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group. R2 is isobutyl, 2,2-dimethyl-propyl or cyclohexyl-methyl; n is 0, 1 or 2; X is CH or N; as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula (I) and of their esters and salts.

Description

Derivatives of 3-pyrrolidylidene-2-one-cephalosporines
The present invention relates to cephalosporin derivatives of the general formula I
Figure imgf000003_0001
wherein
Rl is hydrogen, lower alkyl, aralkyl, cycloalkyl, R3CO- or
-C(R R5)CO2R6; where R4 and R5 are each independently hydrogen or lower alkyl, or R4 and R5 taken together form a cycloalkyl group; R3 is hydrogen or lower alkyl and R6 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group.
R2 is isobutyl, sec. butyl, 2,2-dimethyl-propyl, 2-ethyl-butyl, cyclobutyl- methyl, cyclopentyl-methyl or cyclohexyl-methyl; n is 0, 1 or 2; X is CH or N
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
In above compounds of formula I the substituent in position 3 can be present in the E-form formula la or in the Z-form formula lb
la
Figure imgf000003_0002
Figure imgf000004_0001
In a particular embodiment of the compounds of formula I n is 1. Moreover R1 is preferably hydrogen or cyclopentyl. X is preferably CH. The compounds of the formula I are preferably in the Z-form at the oximino group and E-form for the substitutent in position 3.
Preferred compounds of formula I include:
(6R,7R)-7-[(Z)-2-(2-aιmno-t a2θl-4-yl)-2-hydroxyiminoacetylamino]-3- [(E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
Figure imgf000004_0002
(6R,7R)-7-[(Z)-2-(2-a--nino-tl-dazol-4-yl)-2-(hydroxyimmoacetylamino]-3- [(E)-l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and
Figure imgf000004_0003
(6R,7R)-7-[(Z)-2-(2-ammo-thiazol-4-yl)-2-(hydroxyimmoacetylamino]-3- [(E)-l-cyclohexylnιethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Figure imgf000005_0001
The invention also relates to pharmaceutical compositions and methods of use of the above.
As used herein, the term 'lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
By the term "aralkyl" is meant an alkyl group containing an aryl group. It is a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl hydrogen atom is substituted by a monocydic aryl group, e.g., phenyl, tolyl, etc.
By the term "cydoalkyl" is meant a 3-7 membered saturated carbocyclic moiety, e.g., cydopropyl, cyclobutyl, cydohexyl, etc.
As used herein, "lower alkenyl" refers to unsubstituted or substituted hydrocarbon chain radicals having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl etc.
The term "carboxylic add protecting group" refers to protecting groups conventionally used to replace the addic proton of a carboxylic add. Examples of such groups are benzyhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino add salts. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li+), sodium (Na+) and potassium (K+), and from the alkaline earth metals, for example, caldum (Ca++) and magnesium (Mg++), although cationic forms of other metals, such as iron (Fe++ or Fe+++), aluminium (A1+++), and zinc (Zn++) are within the scope of this invention. Examples of quaternary ammonium salts derived from organic bases include tetramethylammonium (N+(CH3)4), tetraethylammonium (N+(CH2CH3)4), benzyltrimethylammonium (N+(C6H5CH2)(CH3)3), phenyltriethylammo ium (N+(C6H5)(CH2CH3)3), and the like, etc. Those salts derived from amines indude salts with N-ethyl- piperidine, procaine, dibenzylamine, N.N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino adds such as, for example, salts with arginine or lysine.
As readily hydrolyzable 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. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyloxymethyl, 1- ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the ph halidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g., the acetamidomethyl ester). Other esters (e.g., the benzyl and cyanomethyl esters) can also be used. Other examples of such esters are the following: (2,2-dimethyl-l-oxopropoxy)methyl ester; 2-[(2- methylpropoxy)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-[[(cyclohexyloxy)carbonyl]oxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester. It will be appredated by those of ordinary skill in the art that the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound, for example, at the carboxy group in position 1 and at a carboxy group -COOR6.
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 invention are useful as antibiotics having potent and broad antibacterial activity. They also possess good oral absorption properties.
The products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for enteral (oral) administration. The products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories.
Pharmaceutical compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non- toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.
It is contemplated that the compounds are ultimately embodied into compositions of suitable oral or parenteral dosage forms. The compositions of this invention can contain, as optional ingredients, any of the various adjuvants which are used ordinarily in the production of pharmaceutical preparations. Thus, for example, in formulating the present compositions into the desired oral dosage forms, one may use, as optional ingredients, fillers, such as copredpitated aluminum hydroxide-caldum carbonate, dicaldum phosphate or lactose; disintegrating agents, such as maize starch; and lubricating agents, such as talc, caldum s tear ate, and the like. It should be fully understood, however, that the optional ingredients herein named are given by way of example only and that the invention is not restricted to the use hereof. Other such adjuvants, which are well known in the art, can be employed in carrying out this invention.
Suitable as such carrier materials are not only inorganic, but also organic carrier materials. Thus, for tablets, coated tablets, dragees and hard gelatine capsules there can be used, for example, lactose, maize starch or derivatives thereof, talc, stearic add or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance; no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for suppositiories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
As pharmaceutical adjuvants there are contemplated the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. The compounds of formula I and their salts, or hydrates, can preferably be used 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 solution.
Depending on the nature of the pharmacologically active compound the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human, a daily dosage of about 10 mg to about 4000 mg, espedally about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appredating 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.
Representative compounds of the present invention were tested.
In vitro activity was determined by minimum inhibitory concentration in a microorganism spectum by the agar dilution method in Mueller Hinton agar.
The following compounds were tested:
A : (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl 2-hydroxyiminoacetylamino]- 3-[(E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic add trifluoroacetate
B: (6R,7R)-7-[(Z)-2-(2-am o-tmazol-4-yl)-2-(hydroxyiminoacetylamino]- 3-[(E>l-(2,2-d--methyl-propyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-l-azabicydo[4.2.0]oct-2-ene-2-carboxylic add trifluoroacetate and
C: (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-(hydroxyiminoacetylamino]- 3-[(E)-l-cydohexyln ethyl-2-oxo-pyrrolid--n-3-ylidenemethyl]-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic add trifluoroacetate.
The antibacterial Spectrum appears below: MIC : Minimum Inhibiting Concentration Values
Antibacterial Spectrum (MIC, μg ml)
A B C Cefdinir Ceftriaxone
S. aureus 6538 1 1 1 0.5 4
S. aureus 734 MRSA 4 16 8 >32 >32
S. pyogenes B15 <0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06
S. pneumoniae Q19 <0.06 ≤0.06 <0.06 0.25 <0.06
S. agalactiae QK44 0.25 0.5 0.25 0.25 ≤0.06
S. viridans group 016 ≤0.06 1 0.5 2 0.25
E. faecalis 6 1 2 2 8 >32
L. monocytogenes BK23 4 4 4 16 >16
H. influenzae 1 0.5 <0.06
M. catarrhalis RA21 1 16 16 1 1
N. meningitidis 69480 <0.06 <0.01
E. coli 25922 0.25 1 1 0.25 ≤0.06
K pneumoniae 418 0.5 1 1 0.12 ≤0.06
E. doacae 908SSi 0.5 2 2 32 0.25
E. cloacae 908R 16 32 16 >32 >32
C. freundϋ 902 0.25 1 1 16 0.25
C. freundϋ 43 4 8 8 >32 32
P. mirabilis 2117 0.25 0.25 0.5 0.12 ≤0.06
P. vulgaris 1028 4 0.5 1 0.12
M. morganϋ 6H-137 0.25 0.5 4 8 ≤0.06
S. marcescens 69438 1 4 4 16 0.25
P. aeruginosa 27853 >32 16
X. maltophilia 1AC739 >32 >32 >32 >32 >32
Actinetobacter sp. 51-156 16 32 16 >32 32
Cefdinir [6R-[6a,7b(Z)]]-7-(2-Amino-4-thiazolyl)[(hydroxyimino)]acetyl] amino]-3-ethenyl-8-oxo-5-thia-l-azabicyclo-[4.2.0]oct-2-ene-2- carboxylic add
Ceftriaxone: [6R-[6a,7KZ)]]-7-([[2-Amino-4-t azolyl)(methoxyimino)acetyl] amino]-8-oxo-3-[[(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-l,2,4- triazin-3-yl)thio] methyl]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylic add The compounds of the formula I in accordance with the invention as well as their pharmaceutical acceptable salts, hydrates, or readily hydrolyzable esters can be manufactured in accordance with the invention by (a) treating a compound having the formula II
Figure imgf000010_0001
in which R2 and n are defined above,
Figure imgf000010_0002
in which R1 and X are defined above, or R1 is a reactive functional derivative thereof, or
(b) cleaving off the amino, hydroxy and or carboxy protecting group in a compound having the formula IV
Figure imgf000010_0003
in which R2 is defined above, Rf is hydrogen or an amino protecting group, RS is hydrogen or a hydroxy protecting group, Rh is hydrogen or a carboxy protecting group, provided that at least one of Rf , R6 and Rh is a corresponding protecting group or a salt thereof, or
(c) for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic add of formula I to a corresponding esterification, or (d) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salts.
The reaction of compounds II and III or a reactive derivative of III according to embodiment (a) can be carried out in a manner known per se. The carboxy group in compounds II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester) or benzhydryl ester. The carboxy group can also be protected in the form of one of the aforementioned readily hydrolyzable esters. Furthermore, the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. The amino group present in the acylating agent of formula III can be protected. Possible protecting groups are, for θ example, protecting groups which are cleavable by add hydrolysis (e.g. the tert.- butoxycarbonyl or trityl groups) or by basic hydrolysis (e.g. the trϋluoroacetyl group). Preferred protecting groups are the chloroacetyl, bromoacetyl and iodoacetyl groups, espedally the chloroacetyl group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea. The 7-amino group in compounds II can be protected, for example, by a silyl protecting group such as the trimethylsilyl group.
In reacting a 7-amino compound of formula II with a carboxylic add of formula IU or a reactive functional derivative thereof, for example, a free carboxylic add can be reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicydohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide, and subsequently the ester group can be deaved off. Oxazolium salts (e.g. N-ethyl-5-phenyl-isoxazolium-3 - sulphonate) can be used in place of carbodiimides in the foregoing reaction.
According to another embodiment, a salt of an add of formula II (e.g. a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of a carboxylic add of formula HI as mentioned earlier in an inert solvent (e.g. one of the aforementioned solvents).
According to a further embodiment, an add halide, preferably the chloride, of a carboxylic add of formula DI is reacted with an amine of formula II. The reaction is preferably carried out in the presence of an arid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or hexamethylphosphoric add triamide. When a silylated compound of formula II is used, the reaction is carried out in an anhydrous medium.
Advantageous alternatives for acylation, where the amino group present in the acylating agent of formula IU. need not be protected, involves the use of a 2-benzothiazolyl thioester or a 1-hydroxybenzotriazole ester of the carboxylic add. For instance, the 2-benzthiazolyl thioester may be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g.
°) methylene chloride, in acetone, ethyl acetate or in a mixture of such solvents with water. The 1-hydroxybenzotriazole ester can be employed by reacting the carboxylic add with 1-hydroxybenzotriazole and a carbodiimide, espedally N,N - dicydohexylcarbodiimide or
Figure imgf000012_0001
in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
The reaction of a 7-amino compond of formula II with the carboxylic addof formula HI or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.
Embodiment (b) of the process of the present invention involves deprotection (removal) of protected amino, hydroxy or carboxylic groups present in a compound of formula IV and can be carried and as follows:
Removal of amino protecting groups
Possible amino-protecting groups are those employed in peptide chemistry, such as an alkoxycarbonyl group, e.g., t-butoxycarbonyl, etc., a substituted alkoxycarbonyl group, e.g., trichloroethoxycarbonyl etc., an optionally substituted aralkyloxycarbonyl group, e.g., p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, an aralkyl group such as trityl or benzhydryl or a halogen- alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifiuoroacetyl.
Preferred protecting groups are t-butoxycarbonyl (t-BOC) and trityl.
The amino protecting groups may be deaved off by add hydrolysis (e.g. the t-butoxycarbonyl or trityl group), e.g. aqueous formic add, or by basic hydrolysis (e.g. the trifiuoroacetyl group). The chloroacetyl, bromoacetyl and iodoacetyl groups are deaved off by treatment with thiourea.
Amino-protecting groups which are deavable by add hydrolysis are preferably removed with the aid of a lower alkanecarboxylic add which may be halogenated. In particular, formic add or trifluoroacetic add is used. The reaction is carried out in the add or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride. The add 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, bromoacetyl and iodoacetyl protecting groups can be
l o deaved off using thiourea in addic, neutral or alkaline medium at about 0°C- 30°C.
Removal of hvdroxv protecting groups
Possible hydroxy protecting groups are such as are commonly known in the art, e.g.
- for protection of hydroxyimino groups (R1 = hydrogen in compounds of formula D, usually trityl, lower alkanoyl, preferably acetyl, tetrahydropyranyl protecting groups are employed
These protecting groups are e.g. removed as follows:
-trityl in addic solvents like 90% formic add at about 0 to 50°C or triethylsilane in trifluoroacetic add at about -20 to 25°C; in organic solutions of hydrochloric add at about -50 to 25°C; -acetyl with weak inorganic bases like sodium bicarbonate in ethanol/water at about 0 to 50°C; -tetrahydropyranyl with weak organic adds like p-toluenesulfonic add in an alcohol, e.g. ethanol, at about 0°C to the boiling point of the mixture; Removal of protecting groups at the carboxv function
As ester protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, the ester protecting group being exemplified by, for example, t-butyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, allyl, etc.
These protecting groups may be removed as follows:
benzhydryl trifluoroacetic add with anisol, phenol, cresol or triethylsilane at about -40°C to room temperature; hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; BF3- etherate in acetic add at about 0 to 50°C; t-butyl formic add or trifluoroacetic add with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about -10°C to room temperature; p-nitrobenzyl sodium sulfide in acetone/water at about 0 to room temperature; or hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; p-methoxybenzyl formic add at about 0 to 50°C; or trifluoroacetic add and anisol, phenol or triethylsilane at about -40°C to room temperature; allyl palladium(O) catalyzed transalkylation reaction in the presence of sodium or potassium salt of 2-ethyl hexanoic arid, see for example J.
Org. Chem. 1982, 47_ 587. In order to manufacture a readily hydrolyzable ester of the carboxylic acids of formula I in accordance with embodiment (c) of the process provided by the present invention, a carboxylic arid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric arid triamide, dimethyl sulfoxide or, especially, dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0-40°C.
The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of said salts in accordance with embodiment (d) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic arid of formula I or a salt thereof with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). Correspondingly, salt formation is brought about by the addition of an organic or inorganic salt. The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C.
The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous carboxylic arid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C).
Exemplary of the process for obtaining products in accordance with the invention are the following reaction schemes 1 and 2 below.
2, Scheme 1
Figure imgf000015_0001
Scheme 1 1 or 2 + 3 → 4
The reaction of known 2-cephem aldehyde (1) or 3-cephem aldehyde (2) where Rr is a carboxy protecting group as defined under Rn above and R10 is an amino protecting group with a Wittig reagent, exemplified by structure 3, yields the coupling product 4. The reaction is carried out in the presence of a base which is either an inorganic base (sodium or potassium hydroxide, sodium or potassium carbonate etc.), an organic base (tertiary amines), an organolithium
|3 such as butyl lithium or phenyllithium or an epoxide such as 1,2-butyleneoxide. The preferred solvents, in the case of inorganic base being used, are water and water-misrible solvent (acetone, tetrahydrofuran, or alcohols etc.); in the case of organic base being used, an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran; in the case of organolithium being used, benzene or tetrahydrofuran; and in the case an epoxide being used, the epoxide itself (e.g. 1,2-butyleneoxide). The temperature for the reaction ranges from -20°C to 80°C. The preferred conditions are exemplified in the examples.
In the normal Wittig Reaction according to scheme 1, the E isomer is the predominant product. Invariably, less than 10% Z-isomer is formed, the amount depending on the reagents and conditions.
4 → 5
Compound 4 is converted to the sulfoxide 5 with an oxidizing agent which can be hydrogen peroxide or a perarid, preferably m-chloroperbenzoic arid. The temperature ranges from -20°C to room temperature and any suitable solvent, preferably chlorinated hydrocarbon or benzene can be used.
5 → β
The de-oxygenation of the sulfoxide 5 is carried out in the presence of phosphorus tribromide in dimethylformamide or in the mixed solvent of dimethylformamide and N-methylacetamide. The reaction temperature for the reaction is from about -40 to about 0°C.
The protecting groups Rr and R10 are removed and the reaction conditions used are depending on the nature of the protecting groups. In the case of R10 being t-butoxycarbonyl and Rr being benzhydryl, trifluoroacetic arid is employed, at temperature of about -20°C to about room temperature (about 22°C).
7 → 8
The acylation of compound 7 can be carried out with an organic arid which is activated with known reagents, preferably tbionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, bis-[benzthiazolyl-(2)]disulfide, N-hydroxy benzotriazole or a 2-halo N-methylpyridinium salt. The reaction is carried out with or without the base (inorganic or organic bases) depending on the method of activation and a wide range of solvents, from water and water-misάble solvent to inert solvents such as chloroform, dimethylformamide (DMF) or dimethyl- sulfoxide (DMSO) can be used. The R1 group, if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
8 → 9
The 2-carboxylic function of compound 8 is converted to the prodrug esters which are readily hydrolyzable in vivo. RP can be any such esters known in the art by esterification with the corresponding alcohol of RP or by treating with the corresponding halide of RP and a base; the preferred esters are exemplified in the examples. The R1 group, if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
Scheme 2
Figure imgf000017_0001
(1) (2)
Figure imgf000017_0002
(4) (3) n = 1 or 2 R2 = as defined above Ph = phenyl
The processes in scheme 2 are carried out as follows:
l to 2
The known dibromo arid chlorides (1, n = 1, 2) can be converted to the amides (2) using the appropriate amines or aminehydrohalides and inorganic bases such as sodium or potassium hydroxide, sodium or potassium carbonate etc., organic bases such as sodium methoxide or tertiary amines such as
>>5 triethylamine, dϋsopropylethylamine etc. The reaction is carried out in biphasic solvent mixtures like water/dichloromethane or water/chloroform etc., when inorganic bases are used. In case of organic bases or tertiary amines being used, an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran etc. is preferred. The reaction-temperatures range from -10 to 100°C.
2 to 3
Cyclization of the N-substituted dibromoamides (2) can be accomplished under the usual phase transfer catalytic conditions using catalysts like Dowex 2x10, tetraalkylammonium salts, tetraalkylarylammonium salts, crown ethers etc. with bases like aqueous sodium or potassium hydroxide, sodium or potassium carbonate etc.
Alternatively, strong bases like sodium hydride, lithium diisopropylamide, potassium t-butoxide can be used in solvents like tetrahydrofuran, dichloromethane, dimethoxyethane or diethylether at reaction temperatures between -78 and +80°C.
l to 3
The direct conversion of the add chlorides into the bromolactams is possible when the first step (1 to 2) is carried out in biphasic solvent mixtures like water/dichloromethane or water/chloroform etc. together with sodium or potassium hydroxide as base. A catalyst like Dowex 2x10, tetralkylammonium salts, tetraalkylarylammonium salts, crown ethers etc. is added when the amide (2) has formed according to TLC or HPLC analysis. The temperatures range between 0 and 50°C.
3 to 4
The triphenylphosphonium salts (4) can be prepared by treating the bromolactams with triphenylphosphine in solvents like tetrahydrofuran, toluene, benzene, ethylacetate, dichloromethane, dichloroe thane, chloroform etc. at temperatures between 0 and 150°C.
7 Example 1
(a) rac-2,4-I-Hbromo-N-isobutyl-butvramide
1.52 g (20.8 mmol) Isobutylamine were dissolved in 3 ml of water, and 13 ml dichloromethane were added. The mixture was cooled to 0°C and vigorously stirred. A solution of 5.0 g (18.9 mmol) of 2,4-dibromobutanoic arid chloride (J. Med. Chem., 1987, 30, 1995) in 3 ml dichloromethane was added within 5 min. Thereafter a solution of 0.83 g (20.8 mmol) NaOH in 1.5 ml water was added at a rate resulting in the temperature remaii-ing between 7 and 10°C. After complete addition, stirring was continued for 3h at this temperature. Finally the phases were separated and the aqueous phase was extracted thrice with 15 ml dichloromethane. The combined organic phases were washed once with 17 ml 0.5M HC1, once with 14 ml 5% sodium bicarbonate solution and once with 10 ml brine and dried over magnesium sulfate. After evaporation of the solvent a colourless solid was obtained.
Yield: 4.5 g (78.9%)
IR (Film): 3310, 1654, 1552 cm"1 MS (El): 299 (M)
(b) rac-3-Bromo-l-isobutyl-pyrrolidine-2-one 4.48 g (14.9 mmol) rac-2,4-Dibromo-N-isobutyl-butyramide were dissolved in 40 ml dichloromethane, then 17.3 ml of 50% sodium hydroxide solution and 0.48 g Dowex 2x10 were added. The mixture was stirred vigorously for 4h at room temperature. Afterwards the mixture was poured into 50 ml ice/water and the phases were separated. The aqueous phase was extracted thrice with 20 ml dichloromethane, and the combined organic phases were washed once with 20 ml water, once with 20 ml brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting colourless oil was chromatographed on silica gel (0.040-0.063 mm) with ethyl acetate/n-hexane 1:1 as eluent.
Yield: 2.74 g (83%) beige crystals IR(KBr): 2960, 1694 cm*l MS(EI): 219 (M)
(c) ι^c-(l-Isobutyl-2 >xo-pyrrOUdin-3-yl)-triphenyl-phosphoniu bromide 2.74 g (12.4 mmol) rac-3-Bromo-l-isobutyl-pyrrolidine-2-one were dissolved in 12 ml THF, and 3.43 g (13.1 mmol) triphenylphosphine were added. The mixture was then refluxed for 3 days under argon atmosphere. After cooling to room temperature, the suspension was filtered with suction, the white crystals were washed with ice-cold THF and then dried under high vacuum.
Yield: 4.8 g (80%) ER(KBr): 2768, 1683, 1436 cm-1 MS(ISP): 402.4 (M+)
(d) (E)-(2R,6R-7R)-7-tert-Butoxycarbonylamino-3-(l-isobutyl-2-oxo- pyrιx»Hdin-3-yUdenemethyl)-8-oxo-5-t a-l-aza-bicyclo[4.2.0]oct-3-ene-2- carboxylic acid benzhydryl ester The suspension of 20.3 g (41.1 mmol) [6R-(6a,7b)]-7-[[(l,l- dimethylethoxy)carbonyl]amino]-3-formyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct- 3-ene-2-carboxylic add diphenylmethyl ester and 23.8 g (49.3 mmol) rac-(l- isobutyl-2-oxo-pyrrolidin-3-yl)-triphenyl-phosphoniunι bromide in 160 ml 1,2- butylene oxide was refluxed for 2h. After cooling to room temperature the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (0.040-0.063 mm) with ethyl acetate n-hexane 1:1 as eluent. The product was then recrystallized from CH2Cl2/n-hexane.
Yield: 26.5 g (86.3%) white powder IR(KBr): 1781, 1742, 1712, 1680 cm'l MS(ISP): 618.4(M+H+)
Microanalysis: C34H39N3O6S
C H N S calc 66.11 6.36 6.80 5.19 calc.#) 63.28 6.15 6.43 4.91 found 63.25 6.18 6.36 5.12
#) corr. values with 0.42 mol CH2CI2
(e) (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert-butoxycarbonylamino-3-(l- isobutyl-2-ox< pyrrolidin-3-ylidenemethyl)-5,8-dioxo-5-thia- 1-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
The solution of 11.3 g (18.3 mmol) (E)-(2R,6R,7R)-7-tert- butoxycarbonylamino-3-(l-isobutyl-2-oxo-pyrrohdin-3-ylidenemethyl)-8-oxo-5- thia-l-aza-bicyclo[4.2.0]oct-3-ene-2-carboxyUc add benzhydryl ester in 100 ml dichloromethane was cooled to 0°C and treated dropwise with a solution of 4.5 g
(18.3 mmol) m-chloroperoxybenzoic add (70-75%) in 80 ml dichloromethane while keeping the temperature below 4°C. After stirring for an additonal hour at this temperature, 50 ml of a 10% aqueous sodium thiosulfate solution was added and the phases were separated. The aqueous phase was extracted thrice with ι<9 50 ml dichloromethane and the combined organic extractions were washed successively with aqueous solutions of 10% sodium thiosulfate and saturated sodiτun bicarbonate and finally water. After drying over magnesium sulfate the drying agent and solvent were removed, and the residue was purified by flash silica gel chromatography (0.040-0.063 mm, ethyl acetate/n-hexane 3:1), yielding the desired product as a yellow oil.
Yield: 10.2g(87.8%)
IR(KBr): 1796, 1722, 1685 cm'l
MS: 634.4(M+H+)
(f) (E)-(6R,71l)-7-teι^Butoxycarbonylamino-3-(l-isobutyl-2-oxo- pyrιx>Udin-3-yUdenemethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic acid benzhydryl ester
A solution of 22.7 g (35.8 mmol) (EM5R,6R,7R and (5S,6R,7R>7-tert- butoxycarbonylamino-3-( l-isobutyl-2-oxo-pyrrolidin-3-yhdenemethyl)-5,8-dioxo- 5-thia-l-aza-bicyclo[4.2.01oct-2-ene-2-carboxylic acid benzhydryl ester in dichloromethane (230 ml), N-methyl acetamide (32 ml) and N,N-dimethyl formamide (34 ml) was cooled to -30°C and treated with 13.6 ml (143 mmol) of phosphorus tribromide in dichloromethane (35 ml), while maintaining the temperature below -25°C. The solution was stirred for 1 hour at this temperature and then poured into a stirred solution of ice water (11) and dichloromethane (650 ml). The aqueous layer was separated and reextracted thrice with dichloromethane (250 ml each). The combined organic extractions were washed with an aqueous solution of saturated sodium bicarbonate, water and finally brine. After drying over magnesium sulfate, filtration and evaporation of the solvent, the residue was crystallized from dichloromethane n- hexane to give the desired compound as a white powder.
Yield: 22.9 g (99.1%) IR(KBr): 1786, 1721, 1685 cm'l MS: 618.4 (M+H+)
(g) (E)-(6-^7R)-7-Amino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (E)-(6R,7R)-7-tert-Butoxycarbonylamino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic arid benzhydryl ester (21.9 g, 35.0 mmol) was dissolved in 240 ml dichloromethane and 23 ml anisole. At 2°C 120 ml trifluoroacetic arid were added dropwise while maintaining the temperature below 5°C. After complete addition the ice-bath was removed and the solution was stirred at ambient temperature for 2.5 hours. The volatile material was then removed under reduced pressure and the remaining yellow oil was added slowly to 400 ml of diethyl ether, in which the product started to preripitate. After 1.5 hours the suspension was filtered under argon atmosphere and the remaining crystals were stirred in 150 ml of ethyl acetate for 2 hours. The suspension was filtered under argon giving the desired product as a yellow crystalline powder.
Yield: 11.2 g (74.5%) ER(KBr): 1782, 1680, 1623 cm"1 MS(ISP): 352.3 (M+H+) Microanalysis: C18H22F3N3O6S
C H N S F calc 46.45 4.76 9.03 6.89 12.25 calc.#) 51.52 5.54 10.83 8.26 4.70 found 50.93 5.57 10.53 8.13 4.31
#) corr. values with 0.32 mol CF3COOH
(h) (6R,7R)-7 (Z)-2-(2.Amino-thiazol-4.yl)-2-trit loxyimino- acetylamino]-3-[(E)-l-isobutyl-2-K3xo-pyiriOUdin-3-yUdenemethyl]-8-oxo- 5-thia- l-aza-bicyclo[4.-2.0]oct-2-ene-2-carboxylic acid
482 mg (1.26 mmol) (E)-(6R,7R)-7-Amino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add trifluoroacetate was suspended in dimethylformamide (21 ml) and stirred for 1 h at room temperature. During this time a solution was formed to which 765 mg (1.39 mmol) of 2-(2-aminothiazol-4-yl)-(Z)-2-trityloxyimino-acetic add 1- benzotriazole ester were added and the reaction mixture was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure and the remainining residue was taken up in ethyl acetate. The solution was washed twice with water followed by brine and dried over magnesium sulfate. After filtration and evaporation of the solvent the semi-solid residue was treated with 50 ml diethyl ether and stirred for 30 min. The solid was filtered, washed with diethyl ether and n-hexane and dried under high vacuum.
Yield: 610 mg (64.5%)
IR(KBr): 1784, 1675, 1626 cm"1 MS(ISP): 763.2 (M+H+)
2.0 (i) (6R,7R)-7-[(Z)-2-(2-Amino-tWazoW-yl)-2-hydroxyimino- acetylaiDino]-3-[(E)-l-isobutyl-2-oxo yιτolidin-3-ylidenemethyl]-8-oxo- 5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
16.8 ml (219.4 mmol) Trifluoroacetic acid was cooled to 0°C, and 2.0 g (2.62 mmol) (6R,7R)-7-[(Z)-2-(2-ammo-thiazol-^-yl)-2-trityloxvimino- acetylaιmno]-3-[(E)-l-isobutyl-2-oxo-pyrroHdin-3-ylidenemethyl]-8-oxo-5-thia-l- aza-bicydo[4.2.0]oct-2-ene-2-carboxylic arid were added portionwise, keeping the temperature below 5°C. After 5 min. at that temperature, 0.96 ml (6.06 mmol) of triethylsilane were added dropwise and the reaction mixture was stirred for lh at 0°C. During this time a beige suspension was formed which was poured with stirring into 100 ml of diethyl ether. After lh the crystals were collected by filtration and retreated with 50 ml diethyl ether. After 1.5 hours the product was filtered and dried under high vacuum.
Yield: 1.17 g (86%) beige crystalline powder IR(KBr): 1778, 1670, 1633 cm-1 MSCISP): 521.3 (M+H+) Microanalysis: C21H24N6O6S2
C H N S F calc. 48.45 4.65 16.14 12.32 0.00 calc.#) 45.35 4.22 14.32 10.92 5.65 found**) 45.24 4.46 14.33 10.75 5.59
#) corr. values with 0.58 mol CF3COOH ##) corr. values with 2.0% H2O
(j) (6R,7R)-7-[(Z)-2-(2-Anύno-thiaz l-4-yl)-2-cyclopentyloxyimino- acetylam ol-3-[(E)-l-isobutyl-2-oxo yπ )Udin-3-ylidenemethyl]-8-oxo- 5-thia- l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
A suspension of 3.0 g (7.70 mmol) (E)-(6R,7R)-7-amino-3-(l-isobutyl-2- oxo-pyrroUdin-3-ylidenemethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic arid trifluoroacetate in 125 ml of dimethylformamide was stirred for 50 min. at room temperature. During this time most of the starting material dissolved. Then 3.47 g (8.58 mmol) (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyl- oxyimino-thioacetic arid 5-benzothiazol-2-yl ester were added and the reaction mixture was stirred for 18 hours. The solvent was removed under reduced pressure, the crystals were collected by filtration and digerated in 25 ml ethyl acetate for lh, and 100 ml diethyl ether for 1.5 hours.
Yield: 2.92 g (60.8%) beige crystals IR(KBr): 1783, 1676, 1629 cm"1
MSCISP): 589.4 (M+H+)
Microanalysis: C26H32N6O6S2
C H N s calc. 53.05 5.48 14.28 10.89 found*) 52.18 5.50 14.04 10.74
#) corr. values with 1.29% H2O
Exam ie 2
(a) rac-2,4-IMbromo-N-(2^-dimethyl ]Opyl)*'butyramide
In analogy to 1(a), rac-2,4-dibromo-N-(2,2-dimethyl-propyl)-butyramide was synthesized from 10 g (0.115 mol) neopentylamine and 27.6 g (0.104 mol) 2,4-dibromo butanoic arid chloride.
Yield: 32.4 g (98.5%) colourless powder IR(KBr): 3302, 1656, 1566 cm"1 MS(EI): 298 (M-CH3)
(b) ι^c-3-Bκ>mo-l-(2 2-dimeΛyl-propyl) yrro dine-2-one In analogy to 1(b), rac-3-bromo-l-(2,2-dimethyl-propyl)-pyrrolidine-2-one was synthesized by cyclisation of 64.5 g (0.205 mol) rac-2,4-dibromo-N-(2,2- dimethyl-propyD-butyramide.
Yield: 30.9 g (64.5%) white powder πt(KBr): 1693, 1413 cm"1 MS(ISP): 218 (M-CH3)
(c) ι»c-[l-(2,2-Dimethyl-propyl)-2-oxo yrroHdin-3-yl]-triphenyl- phosphonium bromide
In analogy to 1(c), rac-[l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3-yl]- triphenyl-phosphonium bromide was synthesized from 16.1 g (68.7 mmol) rac-3- bromo-l-(2,2-dimethyl-propyl)-pyrroHdine-2-one and 19.8 g (75.6 mmol) of triphenylphosphine.
Yield: 31.5 g (92.2%) colourless powder IR(KBr): 2776, 1684, 1482 cm"1 MSCISP): 416.4 (M+)
(d) (E)-(2R,6R, )-7-teι^Butoxycarbonylamino-3-[l-(2,2-dimethyl- p«>pyl)-2-oxo-pyrrolidin-3-ylidenemethyll -8-oxo-5-thia- 1-aza- bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester In analogy to 1(d), (E)-(2R,6R,7R)-7-tert-but0xycarbonylamino-3-[l-(2,2- dinιethyl-propyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicydo[4.2.0]oct-3-ene-2-carboxylic arid benzhydryl ester was synthesized from 30.6 g (61.6 mmol) rac-[l-(2,2-dimethyl-propyl)-2-oxo-pyrroUdin-3-yl]-triphenyl- phosphonium bromide and 25.4 g (51.3 mmol) [6R-(6a,7b)]-7-[[(l,l- dimethylethoxy)carbonyl]amino]-3-formyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct- 3-ene-2-carboxylic arid diphenylmethyl ester.
Yield: 18.2 g (56.0%) yellow foam IR(KBr): 1783, 1743, 1718 cm"l MSCISP): 632.4 (M+H+)
(e) (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert-butoxycarbonylamino-3-[l- (2^-dinιethyl-propyl)-»2-oxo-pyrroUdin-3-ylidenenιethyl]-'5,8-dioxo-5- thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
In analogy to 1(e), (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert- butoxycarbonylam o-3-[l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-5,8-dioxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic arid benzhydryl ester were synthesized from 18.2 g (28.8 mmol) (E)-(2R,6R,7R)-7- tert-butoxycarbonylamino-3-[l-(2,2-di-methyl-propyl)-2-oxo-pyrroHdin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic add benzhydryl ester and 7.1 g (28.8 mmol) m-chloroperoxybenzoic arid (70-75%).
Yield: 12.0 g (64.3%) yellow foam IR(KBr): 1798, 1723, 1689 cm"* MSdSP): 648.3 (M+H+)
(f) (E)-(6R,71l)-7-tert-Butoxycarbonylamino-3-[l-(2^.dimethyl.propyl)- 2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5- thia- l-aza-bicyclo[4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester
In analogy to 1(f), (E)-(6R,7R)-7-tert-butoxycarbonylamino-3-[l-(2,2- diπιethyl-propyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicyclo[4.2.01oct-2-ene-2-carboxylic arid benzhydryl ester was synthesized from 12.0 g (0.185 mol) (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert- butoxycarbonylammo-3-[l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-5,8-dioxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add benzhydryl ester by reduction with 20.1 g (0.74 mol) phosphorus tribromide.
Yield: 9.5 g (82.9%) pale yellow powder. IR(KBr): 1786, 1721, 1692 cm"1 MSCISP): 632.4 (M+H+) (g) (E)-(6R,7R)-7-Aιnino-3-[l-(2^-dimethyl i >pyl)-2.oxo yrroUdin-3- ylidenemethyll-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
In analogy to 1(g), (E)-(6R,7R>7-amino-3-[l-(2,2-dimethyl-propyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic add trifluoroacetate was synthesized by deprotection of 9.50 g (0.15 mol) (E>(6R,7R)-7-tert-butoxycarbonylamino-3-[l-(2,2-dimethyl-propyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic add benzhydryl ester in 48.5 ml (0.63 mol) trifluoroacetic arid and 10 ml anisole.
Yield: 4.7 g (85.4%) brownish powder ERCKBr): 1783, 1681, 1626 cm'l MSdSP): 366.4 (M+H+) Microanalysis: C17H23N3O4S
C H N S F calc. 55.87 6.34 11.50 8.77 0.00 calc.#) 54.97 6.20 11.20 8.54 1.30 found 55.38 5.89 11.34 8.49 1.69 #) corr. values for 2.52% H2O, 2.61% CF3COOH and 0.65 residue
(h) (6R,7R)-7-[(Z)-2-(2-Amino-tWazol-4.yl)-2-trityloxyimino- acetylamino] -3-[ (E )- l-(2,2-dimethyl-propyl) -2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
In analogy to 1(h), (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylammol-3-[(E)-l-(2,2-dήnethyl-propyl)-2-oxo-p rroUdin-3-ylidenemethyl]- 8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic arid was synthesized from 1.0 g (2.62 mmol) (E)-(6R,7R)-7-amino-3-[l-(2,2-dimethyl-propyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic add trifluoroacetate (content of trifluoroacetic arid: 4.25%) and 1.59 g (2.90 mmol) 2-(2-aminothiazol-4-yl)-(Z)-2-trityloxyimino-acetic arid 1- benzotriazole ester.
Yield: 1.41 g (71.6%) white crystals ER(KBr): 1785, 1683, 1624 cπr1 MSdSP): 777.2 (M+H+)
(i) (6R, )-7-[(Z)-2.(2-Amino-*flύazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-l-(2,2-d-methyl iropyl)-2-oxo-pyrro-idin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carbox lic acid trifluoroacetate
Analogously to l(i), (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2- hydroxyimino-acetylarnino]-3-[(E)-l-(2,2-d--methyl-propyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic arid trifluoroacetate was synthesized by deprotection of 1.41 g (1.80 mmol) (6R,7R)- 7-[(Z)-2-(2-ammo-tmazol-^-yl)-2-trityloxyimino-acetylamino]-3-[(E)-l-(2,2- dimethyl-propyl)-2-oxo-pyιτolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicyclo[4.2.01oct-2-ene-2-carboxylic arid in 11.6 ml (151.5 mmol) trifluoroacetic acid and 0.67 ml (4.17 mmol) of triethylsilane.
Yield: 0.93 g (96.6%) beige crystals IR(KBr): 1781, 1669, 1633 cm"l MSdSP): 535.2(M+H+) Microanalysis: C22H26N6O6S2
C H N s F calc. 49.43 4.90 15.72 11.99 0.00 calc.#) 44.25 4.17 12.85 9.80 9.12 found 44.19 4.32 12.81 9.56 9.11 #) corr. values with 1.39% H2O and 18.2% CF3COOH
(j) (6R,7R)-7-[(Z)-2-(2-Amino-thiaz l-4-yl)-2-*cyclopentyloxyimino- acetylanιinol-3-[(E)-l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.01oct-2-ene-2-carboxylic acid
In analogy to l(j), (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2- cyclopentyloxyimino-acetylamino]-3-[(E)-l-(2,2-dimethyl-propyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic arid was synthesized by reaction of 1.0 g (2.62 mmol) (EM6R,7R)-7- amino-3-[l-(2,2-dimethyl-propyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic arid trifluoroacetate (content of trifluoroacetic arid: 4.25%) and 1.16 g (2.90 mmol) (Z)-2-(2-amino-thiazol-4-yl)- 2-cyclopentyloxyimino-thioacetic add 5-benzothiazol-2-yl ester.
Yield: 1.28 g (81.0%) beige powder IR(KBr): 1782, 1679, 1628 cπr1 MSdSP): 603.3 (M+H+) Microanalysis: C27H34N6O6S2
C H N S calc. 53.81 5.69 13.94 10.64
3 S found*) 53.17 5.39 13.65 10.40
#) corr. values with 1.4% H2O and 0.6% residue
Example 3
(a) rac-2,4-IMbromo-N-cyclohexyljnethyl-butyramide In analogy to 1(a), rac-2,4-dibromo-N-cydohexylmethyl-butyramide was synthesized from 4.71 g (41.6 mmol) (aminomethyl)cyclohexane and 10.0 g (37.8 mmol) 2,4-dibromo butanoic add chloride.
Yield: 11.4 g (90%) beige crystals IR(KBr): 1786, 1649, 1568 cm"l MSCISP): 342 (M)
(b) rac-3-Bromo-l-cyclohexylmethyl-pyrrolidine-2-one
In analogy to 1(b), rac-3-bromo-l-cyclohexylmethyl-pyrrohdine-2-one was synthesized by cydization of 11.4 g (33.4 mmol) rac-2,4-dibromo-N- cyclohexylmethyl-butyramide.
Yield: 8.3 g (85.9%) white crystals IR(KBr): 2923, 1690 cm"1 MSdSP): 261 (M)
(c) rac-[l*H-yclohexyJ-methyl-2-oxo-pyιτoHdin-3-yl]-triphenyl- phosphonium bromide
In analogy to 1(c), rac-[l-cyclohexylmethyl-2-oxo-pyrrolidin-3-yl]- triphenyl-phosphonium bromide was synthesized from 8.30 g (31.9 mmol) rac-3- bromo-l-cyclohexylmethyl-pvrrolidine-2-one and 9.20 g (35.1 mmol) triphenylphosphine .
Yield: 15.3 g (91.6%) white crystals IR(KBr): 1685, 1437 cm"1 MS(ISP): 442.4 (M+) Microanalysis: C29H33BrNOP
C H N calc. 66.67 6.37 2.68 found*) 65.95 6.42 2.53
#) corr. values with 1.68% H2O
,r (d) (E)-(2R,6R,7R)-7-tert-Butoxycarbonylamino-3-[ 1-cyclohexylmethyl- 2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia- l-aza-bicyclo[4.2.0] oct-3- ene-2-carboxylic acid benzhydryl ester
In analogy to 1(d), (E)-(2R,6R,7R)-7-tert-butoxycarbonylamino-3-[l- cydohexylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicydo[4.2.0]oct-3-ene-2-carboxylic arid benzhydryl ester was synthesized from 14.0 g (26.8 mmol) rac-[l-cyclohexylmethyl-2-oxo-pyrrolidin-3-yl]-triphenyl- phosphonium bromide and 11.0 g (22.2 mmol) [6R-(6a,7b)]-7-[[(l,l- dimethylethoxy)carbonyl]amino]-3-formyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct- 3-ene-2-carboxylic arid diphenylmethyl ester.
Yield: 12.5 g (85.4%) yellow foam IR(KBr): 1783, 1743, 1718 cnr* MSdSP): 658.4 (M+H+)
(e) (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert-butoxycarbonylamino-3-[l- cyclohexylmethyl-2-oxo-pyrι >Ud-Ln-3-yUdenemethyl]-5,8-dioxo-5-thia-l- aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester
In analogy to 1(e), (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert- butoxycarbonylamino-3-[l-cydohexylmethyl-2-oxo-pyrrolidin-3-yhdenemethyl]- 5,8-dioxo-5-thia-l-aza-bicydo[4.2.0]oct-2-ene-2-carboxylic arid benzhydryl ester were synthesized from 12.5 g (19.0 mmol) (E)-(2R,6R,7R)-7-tert- butoxycarbonylan --no-3-[l-cyclohexylπιethyl-2-oxo-pyrrolidin-3-yhdenenιethyl]- 8-oxo-5-thia-l-aza-bicydo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester and 4.70 g (19.0 mmol) m-chloroperoxybenzoic arid (70-75%).
Yield: 6.6 g (51.6%) pale yellow foam IR(KBr): 1797, 1723, 1686 cπr* MSdSP): 674.3 (M+H+)
(f) (E)-(6R,7R)-7-tert-Butoxycarbonylamino-3-[l-cyclohexylmethyl-2- oxo-pyrrohdin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylic acid benzhydryl ester
In analogy to 1(f), (E)-(6R,7R)-7-tert-butoxycarbonylamino-3-[l-cyclo- hexylmethyl-2-oxo-pyrrolidin-3-yhdenemethyl]-8-oxo-5-thia-l-aza-bicyclo- [4.2.0]oct-2-ene-2-carboxylic add benzhydryl ester was synthesized from 6.60 g (9.80 mmol) (E)-(5R,6R,7R)- and (5S,6R,7R)-7-tert-butoxycarbonylamino-3-[l- cyclohexylmeti yl-2-oxo-pyrroUdin-3-ylidenemethyl]-5,8-dioxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic add benzhydryl ester by reduction with 10.6 g (39.2 mmol) phosphorus tribromide. Yield: 5.6 g (86.9%) colourless crystals IR(KBr): 1785, 1719, 1683 cm-1 MSdSP): 658.4 (M+H+)
(g) GB)-(6R 7R)-7-Amino-3-[l-cyclohexylmethyl-2-oxo-pyrrolidin-3- ylidenemethyl] -8-oxo-5-thia- l-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylic acid trifluoroacetate
In analogy to Kg), (E)-(6R,7R)-7-amino-3-[l-cyclohexylmethyl-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicydo[4.2.0]oct-2-ene-2- carboxyhc arid trifluoroacetate was synthesized by deprotection of 5.60 g (8.50 mmol) (E)-(6R,7R)-7-tert-butoxycarbonylamino-3-[l-cyclohexylmethyl-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic arid benzhydryl ester in 27.4 ml (357.8 mmol) trifluoroacetic arid and 5.5 ml anisole.
Yield: 3.1 g (93.9%) brown crystals IR(KBr): 2923, 1781, 1680 cm-1 MSdSP): 392.4 (M+H+) Microanalysis: C19H25N3O4S
C H N S F calc. 58.29 6.44 10.73 8.19 0.00 calc.*) 57.09 6.26 10.39 7.92 1.62 found 57.15 6.29 10.23 7.77 1.64
#) calc. values for 0.82% H2O and 3.24% CF3COOH
(h) (6R,7R)-7-[(Z)-2-(2-Aιnino-thiazol-4-yl)-2-trityloxyimino- acetylamύιo]-3-[(E)-l-κ-yclohexylmethyl-2* >xo-pyπOUd-in-3- ylidenemethyl] -8-oxo- 5- thia- 1 -aza-bicyclo[4.2.0] oct-2-ene-2-carboxylic acid In analogy to 1(h), (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylaminol-3-[(E)-l-cyclohexylπιethyl-2-oxo-pvrroHdin-3-ylidenemethyl]-8- oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add was synthesized from 1.0 g (2.43 mmol, content of trifluoroacetic acid: 4.77%) (E)-(6R,7R)-7-amino-3- [l-cyclohexylmethyl-2-oxo-pyrrolidin-3-yhdenemethyl]-8-oxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate and 1.48 g (2.70 mmol) 2-(2-aminothiazol-4-yl)-(Z)-2-trityloxyimino-acetic arid 1-benzotriazole ester.
Yield: 0.92 g (47.2%) beige powder IR(KBr): 1784, 1679, 1625 cm'l MSdSP): 803.3 (M+H+) (i) (6B,71l)-7-[(Z)-2-(2-Amino-tWazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-l-cyclohexyhnethyl-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate
Analogously to l(i), (6R,7R)-7-[(Z 2-(2-amino-thiazol-4-yl)-2-hydroxy- imino-acetylamino]-3-[(E)-l-cyclohexylmethyl-2-oxo-pyrrolidin-3-ylidene- methyll-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate was synthesized by deprotection of 0.87 g (1.08 mmol) (6R,7R)- 7-[(Z 2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-3-[(E)-l- cydohexylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 6.94 ml (90.6 mmol) trifluoroacetic arid and 0.40 ml (2.49 mmol) triethylsilane.
Yield: 0.54 g (88.9%) beige crystalline powder IR(KBr): 1779, 1670, 1634 cm"l MSdSP): 561.2 (M+H+) Microanalysis: C24H28N6O6S2
C H N s F calc. 51.42 5.03 14.99 11.44 0.00 calc.*) 46.33 4.34 12.48 9.52 8.39 found 46.34 4.38 12.43 9.27 8.39
#) calc. values for 1.84% H2O and 16.8% CF3COOH
(j) (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylanιinol-3-[(E)-l-cyclohexybnethyl-2-oxo-pyιτohdin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Analogously to l(j), (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2- cyclopentyloxyimino-acetylamino]-3-[(E)-l-cyclohexylmethyl-2-oxo-pyrrolidin- 3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.01oct-2-ene-2-carboxylic add was synthesized by reaction of 1.0 g (2.43 mmol; content of trifluoroacetic add: 4.77%) (E)-(6R,7R)-7-amino-3-[l-cyclohexylmethyl-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic add trifluoroacetate and 1.08 g (2.70 mmol) (Z)-2-(2-amino-thiazol-4-yl)-2- cyclopentyloxyimino-thioacetic add 5-benzothiazol-2-yl ester.
Yield: 1.26 g (78.7%) light brown powder IR(KBr): 1780, 1674, 1629 cm-1 MSdSP): 629.4 (M+H+) Microanalysis: C29H36N6O6S2
C H N S calc. 55.40 5.77 13.37 10.20 found*) 54.47 5.69 13.09 10.12
#) corr. values with 1.52% H2O

Claims

Claims
1. Cephalosporin derivatives of the general formula I
Figure imgf000033_0001
wherein R is hydrogen, lower alkyl, aralkyl, cycloalkyl, R3CO- or
-C(R4R5)C0 R6; where R4 and R5 are each independently hydrogen or lower alkyl, or R4 and R5 taken together form a cycloalkyl group; R3 is hydrogen or lower alkyl and R6 is hydrogen, lower alkyl, lower alkenyl or a carboxyhc add protecting group.
R2 is isobutyl, 2,2-dimethyl-propyl or cyclohexyl-methyl; n is 0, 1 or 2;
X is CH or N; as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
2. Compounds of claim 1, wherein R1 is hydrogen and n is 1.
3. Compounds of any one of daims 1 or 2, wherein R2 is isobutyl.
4. Compounds of any one of claims 1 or 2, wherein R2 is 2,2-dimethyl- propyl.
5. Compounds of any one of claims 1 or 2, wherein R2 is cyclohexyl- methyl.
6. Compounds of any one of claims 1-5 with the 3-substituent in the Z-form.
7. (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-hydroxyiminoacetylamino]-3-
[(E)- l-isobutyl-2-oxo-pyrrohdin-3-yhdenemethyl]-8-oxo-5-thia- 1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic add, as well as pharmaceutically acceptable salts of this compound and hydrates of said compound and salts.
3 /
8. (6R,7R)-7-[(Z)-2-(2-amino-tlήazo -yl)-2-(hydroxyiminoacetylamino]-3- [(E)-l-(2,2-d_bιιethyl-propyl)-2-oxo-pyrroHdin-3-yUdenemethyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic add, as well as pharmaceutically acceptable salts of this compound and hydrates of said compound and salts.
9. (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-(cydopentyloxyimino- acetylamino]-3-[(E)-l-cyclohexylmethyl-2-oxo-pyrroUdin-3-ylidenemethyl]-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic add, as well as pharmaceutically acceptable salts of this compound and hydrates of said compound and salts.
10. Compounds of the formula II
Figure imgf000034_0001
in which R2 and n are defined above, or esters or salts thereof.
11. Compounds of the formula HA
Figure imgf000034_0002
in which R2 and n are defined above, p is 0 or 1 and R10 is an amino protecting group, or esters or salts thereof.
12. A pharmaceutical preparation containing a compound according to any one of claims 1-9, particularly for the treatment and prophylaxis of infectious diseases.
13. Process for the manufacture of the compounds according to any one of claims 1-9, which process comprises (a) treating a compound having the formula E
Figure imgf000035_0001
in which R2 and n are defined above, or an ester or salt thereof, with a carboxylic add of the general formula III
Figure imgf000035_0002
in which R1 and X are defined above or R1 is a reactive functional derivative thereof, or
(b) cleaving off the amino, hydroxy and/or carboxy protecting group in a compound having the formula IV
^OR8
N
Figure imgf000035_0003
COORh O
in which R2 is defined above, Rf is hydrogen or an aminoprotecting group, RS is hydrogen or a hydroxy protecting group, Rn is hydrogen or a carboxy protecting group, provided that at least one of Rf , R and Rh is a corresponding protecting group or a salt thereof, or
(c) for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification, or
(d) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salts.
14. Compounds according to any one of claims 1-9, whenever prepared according to the process claimed in claim 13 or by an obvious chemical equivalent thereof.
15. Compounds as in any one of claims 1-9 as pharmaceutically active substances for the treatment and prophylaxis of illnesses, particularly for the treatment and prophylaxis of infectious diseases.
16. The use of the compounds according to any one of claims 1-9 in the treatment and prophylaxis of iHnesses, particularly in the treatment and prophylaxis of infectious diseases.
17. The use of the compounds according to any one of claims 1-9 for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.
18. The novel compounds, formulations, processes and methods substantially as described herein.
-3
PCT/EP1996/000667 1995-02-27 1996-02-16 Derivatives of 3-pyrrolidylidene-2-one-cephalosporines WO1996026943A1 (en)

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US08/875,563 US5925632A (en) 1995-02-27 1996-02-16 Derivatives of 3-pyrrolidylidene-2-one-cephalsporines
EP96904802A EP0812323A1 (en) 1995-02-27 1996-02-16 Derivatives of 3-pyrrolidylidene-2-one-cephalosporines
JP8525987A JPH11501017A (en) 1995-02-27 1996-02-16 Derivatives of 3-pyrrolidyliden-2-one-cephalosporin
MXPA/A/1997/006187A MXPA97006187A (en) 1995-02-27 1997-08-13 Derivatives of 3-pirrolidiliden-2-ona-cefalospori
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WO1997026260A1 (en) * 1996-01-16 1997-07-24 F. Hoffmann-La Roche Ag Isooxacephem derivatives
EP0812846A1 (en) * 1996-06-10 1997-12-17 F. Hoffmann-La Roche Ag Preparation of cephem- and isooxacephem derivatives
EP0831093A1 (en) * 1996-09-23 1998-03-25 F. Hoffmann-La Roche Ag 1-Carba-(dethia)-Cephalosporin Derivatives
EP0841339A1 (en) * 1996-11-06 1998-05-13 F. Hoffmann-La Roche Ag Vinylpyrrolidinon cephalosporin derivatives
EP0911030A2 (en) * 1997-09-15 1999-04-28 F.Hoffmann-La Roche Ag Antimicrobial composition comprising a vinyyl pyrrolidinon derivative and a carbapenem antibiotic or a beta-lactamase inhibitor
US5939410A (en) * 1996-09-23 1999-08-17 Hoffmann-La Roche Inc. 1-carba-(dethia)-cephalosporin derivatives
GB2351378A (en) * 2000-10-04 2000-12-27 Robert James Withey Electronic multimedia information processor
WO2001079211A1 (en) * 2000-04-13 2001-10-25 Otsuka Kagaku Kabushiki Kaisha Process for the preparation of a 3-vinylcephem compound

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US5811419A (en) * 1996-01-16 1998-09-22 Hoffmann-La Roche Inc. Isooxacephem-derivatives
WO1997026260A1 (en) * 1996-01-16 1997-07-24 F. Hoffmann-La Roche Ag Isooxacephem derivatives
US5919939A (en) * 1996-06-10 1999-07-06 Hoffmann-La Roche Inc. Preparation of cephem and isooxacephem derivatives
US5883247A (en) * 1996-06-10 1999-03-16 Hoffmann-La Roche Inc. Preparation of cephem and isooxacephem derivatives
EP0812846A1 (en) * 1996-06-10 1997-12-17 F. Hoffmann-La Roche Ag Preparation of cephem- and isooxacephem derivatives
US5939410A (en) * 1996-09-23 1999-08-17 Hoffmann-La Roche Inc. 1-carba-(dethia)-cephalosporin derivatives
EP0831093A1 (en) * 1996-09-23 1998-03-25 F. Hoffmann-La Roche Ag 1-Carba-(dethia)-Cephalosporin Derivatives
EP0841339A1 (en) * 1996-11-06 1998-05-13 F. Hoffmann-La Roche Ag Vinylpyrrolidinon cephalosporin derivatives
US6294668B1 (en) 1996-11-06 2001-09-25 Hoffman-La Roche Inc. Vinylpyrrolidinone cephalosporin derivatives
EP0911030A2 (en) * 1997-09-15 1999-04-28 F.Hoffmann-La Roche Ag Antimicrobial composition comprising a vinyyl pyrrolidinon derivative and a carbapenem antibiotic or a beta-lactamase inhibitor
EP0911030A3 (en) * 1997-09-15 1999-10-13 F.Hoffmann-La Roche Ag Antimicrobial composition comprising a vinyyl pyrrolidinon derivative and a carbapenem antibiotic or a beta-lactamase inhibitor
US6150350A (en) * 1997-09-15 2000-11-21 Hoffman-La Roche Inc. Antimicrobial compositions
JPH11140087A (en) * 1997-09-15 1999-05-25 F Hoffmann La Roche Ag Antimicrobial composition
JP4621311B2 (en) * 1997-09-15 2011-01-26 バジリア ファルマスーチカ アーゲー Antibacterial composition
WO2001079211A1 (en) * 2000-04-13 2001-10-25 Otsuka Kagaku Kabushiki Kaisha Process for the preparation of a 3-vinylcephem compound
GB2351378A (en) * 2000-10-04 2000-12-27 Robert James Withey Electronic multimedia information processor

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