WO1997026260A1 - Isooxacephem derivatives - Google Patents

Isooxacephem derivatives Download PDF

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Publication number
WO1997026260A1
WO1997026260A1 PCT/EP1997/000057 EP9700057W WO9726260A1 WO 1997026260 A1 WO1997026260 A1 WO 1997026260A1 EP 9700057 W EP9700057 W EP 9700057W WO 9726260 A1 WO9726260 A1 WO 9726260A1
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Prior art keywords
oxo
amino
carboxylic acid
ene
aza
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PCT/EP1997/000057
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French (fr)
Inventor
Christian Hubschwerlen
Jean-Luc Specklin
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F. Hoffmann-La Roche Ag
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Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to JP9525647A priority Critical patent/JP2000503654A/en
Priority to EP97900972A priority patent/EP0879237A1/en
Priority to AU14399/97A priority patent/AU718495B2/en
Priority to BR9706980A priority patent/BR9706980A/en
Publication of WO1997026260A1 publication Critical patent/WO1997026260A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • Y—GENERAL 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to isooxacephem derivatives of the general formula I
  • Rl is hydrogen or an acyl group derived from a carboxylic acid
  • R is hydrogen, hydroxy, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy or a heterocyclic ring
  • the lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy and the heterocyclic ring being unsubstituted or substituted with at least one group selected from carboxy, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CONR21R22 ; -N(R22)COOR 23 , 22CO-, R220
  • the invention also relates to pharmaceutical compositions and methods of use of the above.
  • acyl group derived from a carboxylic acid refers to all organic radicals derived from an organic carboxylic acid by removal of the hydroxyl group.
  • group R 1 may be any one of many acyl radicals, certain acyl groups are preferred, as described below.
  • acyl groups are those groups which can be used to acylate ⁇ -lactam antibiotics, including 6-aminopenicillanic acid and derivatives and 7-aminocephalosphoranic acid and derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic
  • j 0, 1, 2 or 3;
  • R is hydrogen, lower alkyl, cycloaikyl, carbarn oyl-lower alkyl, aryl- lower alkyl;
  • RlO is hydrogen, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl or cycloalkenyl, the lower alkyl group or the lower alkenyl group being optionally substituted with at least one group selected from halogen, cyano, nitro, amino, mercapto, alkylthio or cyano- m ethyl thio;
  • RU is aryl unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl; a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy
  • the aliphatic acyl groups used in conjunction with Rl have the formula a, wherein R ⁇ O is as defined above.
  • Preferred aliphatic acyl groups are those wherein Rl is lower alkanoyl, particularly acetyl.
  • aromatic or heteroaromatic acyl groups used in conjunction with Ri have the formulae b to f, wherein j, RU and Rl are as defined above.
  • the aryl group in the residue R ⁇ is preferably phenyl.
  • heteroaromatic acyl groups suitable for the purposes of the present invention include those groups of the above formulae b to f wherein ⁇ is isoxazolyl, 2,6-dichlorophenyl-5-methyl-isoxazolyl, tetrazolyl, 1-methyl-tetrazolyl, 2-amino-4-thiazolyl, 2-amino-5-halo-4- thiazolyl, 4-aminopyridin-2-yl, 2-amino-l,3,4-thiadiazol-5-yl, 5-amino- l,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, 4-pyridinyl, 2,6-dichloro-4- pyridinyl or 2-amino-4-benzothiazolyl.
  • Preferred heteroaromatic acyl groups are those wherein Rl is a residue of the formula b, particularly 2,6-dichlorophenyl-5-methyl- isoxazol-4-yl-carbonyl. Also preferred are heteroaromatic acyl groups wherein Rl is a residue of the formula f, particularly 1-methyl-tetrazol- 5-yl-sulfanyl-acetyl.
  • the oxyimino-acyl groups used in conjunction with R ⁇ have the formula g, wherein R3 and R ⁇ are as defined above.
  • oxyimino-acyl groups of the formula g wherein RU is a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl or substituted with optionally substituted phenyl or fused together with a benzene ring.
  • the heterocyclic ring is preferably the thiazolyl ring or the thiadiazolyl ring.
  • R2 is as defined under formula I and R is as defined above.
  • R3 is preferably hydrogen, carbamoyl-lower alkyl or cycloaikyl, particularly hydrogen, carbamoyl-methyl or cyclopentyl.
  • Preferred compounds of formula II are such where R 2 is lower alkyl, cycloaikyl, aryl-lower alkyl, aryl or a heterocyclic ring, the lower alkyl, aryl-lower alkyl, aryl and the heterocyclic ring being unsubstituted or substituted with at least one group selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl or lower alkoxy.
  • R 2 is isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, phenyl, 3-nitrophenyl, 4- hydr oxy phenyl, 2-fluorophenyl, 2-methoxyphenyl, 4-nitrobenzyl, pyridinyl, N-methyl-pyridinium-2yl or 5-methyl-isoxazolyl.
  • lower alkyl refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
  • cycloaikyl a 3-7 membered saturated carbocyclic ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • lower alkoxy refers to alkoxy groups in the sense of the above description of the term lower alkyl. Examples include methoxy, ethoxy, n-propoxy and the like.
  • lower alkenyl refers to an unsubstituted or substituted hydrocarbon chain radical 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 and the like.
  • cycloalkenyl refers to a carbocyclic ring having at least one olefinic double bond.
  • lower alkynyl refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one olefinic triple bond.
  • halogen used herein refers to all four forms, that is chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro.
  • aryl is meant a radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen and can be substituted or unsubstituted.
  • the aromatic hydrocarbon can be mono- nuclear or polynuclear.
  • aryl radicals of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cumenyl, and the like.
  • aryl radicals of the polynuclear type include naphthyl, anthryl, phenanthryl, and the like.
  • the aryl group can have at least one substituent selected from, as for example, halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy or trifluorm ethyl.
  • substituents selected from, as for example, halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy or trifluorm ethyl. Examples include 2-fluorophenyl, 3- nitrophenyl, 4-nitrophenyl, 4-methoxy phenyl, 4-hydroxyphenyl and the like.
  • aryl-lower alkyl is meant a lower alkyl group containing an aryl group as for example benzyl.
  • aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
  • aryl-lower alkoxy is an oxygen radical having an aryl-lower alkyl substituent. (i.e., -O-lower-alkyl-aryl).
  • heterocyclic ring refers to an unsaturated or saturated, unsubstituted or substituted 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: pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
  • 1,3,4-thiadiazolyl 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- tetrazolyl, 2H-tetrazolyl, thienyl, furyl, hexamethyleneiminyl, oxepanyl, lH-azepinyl, thiophenyl, tetrahydrothiophenyl, 3H-l,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl, isoxazolyl, isothiazolyl, 4H-1,2,4- oxadiazinyl, 1,2,5-oxathiazinyl, 1,2,3,5-oxathiadiazinyl
  • Substituents for the heterocyclic ring include lower- alkyl, lower- alkoxy, halogen, trifluoromethyl, trichloroethyl, amino, mercapto, hydroxy, carboxy or carbamoyl.
  • Preferred examples of substituted heterocyclic rings include 5-methyl-isoxazol-3-yl, N-methyl- pyridinium-2yl, 1-methyl-tetrazolyl and the like.
  • the heterocyclic ring can also be substituted by an optionally substituted phenyl ring such as 2,6-dichlorophenyl. Preferred is 2,6- dichlorophenyl-5-methyl-isoxazolyl.
  • a further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, 1,1- dioxo-tetrahydrothien-3-yl.
  • the heterocyclic ring can also be fused together with a benzene ring.
  • substituted phenyl is meant phenyl mono or di- substituted.
  • 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 + ), and from the alkaline earth metals, for example, calcium (Ca ++ ) and magnesium (Mg ++ ), although cationic forms of other metals, such as iron (Fe ++ or Fe +++ ), aluminium (Al +++ ), 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), benzyltrimethyl- ammonium (N + (C6H5CH2)(CH3)3), phenyltriethylammonium (N+(C6H5)(CH 2 CH3)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.
  • amino protecting group refers to protecting groups conventionally used to replace an acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218-287. These examples include e.g. allyl, allyloxycarbonyl, t-butyl, t- butoxycarbonyl, benzyl, p-methoxybenzyl and p-nitro-benzyl. Preferred is allyloxycarbonyl.
  • carboxylic acid protecting group refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and
  • allyl diphenylmethyl, p- nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, t- butyldimethylsilyl. Preferred is allyl.
  • 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 phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoy
  • 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)carbonylJoxy] 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 2 of the isooxacephem ring.
  • the compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated.
  • the hydra tion 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 for the treatment and prophylaxis of infectious diseases. 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 coprecipitated aluminum hydroxide-calcium carbonate, dicalcium phosphate or lactose; disintegrating agents, such as maize starch; and lubricating agents, such as talc, calcium stearate, 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, 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.
  • In vitro activity was determined by minimum inhibitory concentration in a microorganism spectum by the agar dilution method in Mueller Hinton agar.
  • R 2 is as defined above under formula I or an ester or salt thereof, with acylating agents, or
  • R 1 and/or R 2 may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) or reducing a nitro group to amino in a compound having the formula IV in which R h is hydrogen or a carboxy protecting group, R f is as Rl and R ⁇ is as R 2 with the proviso that at least one of the following provisions is fulfilled: (i) R n is a carboxylic acid protecting group,
  • R f is a residue defined under R 1 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s),
  • R£ is a residue defined under R 2 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s), or a salt thereof, or
  • reaction of compounds III with acylating agents according to embodiment (a) can be carried out in a manner known per se.
  • acylating agents used in embodiment (a) are activated carboxylic acids such as acid chlorides, anhydrides, reactive esters such as N-hydroxysuccinimide esters, 2-benzothiazolyl thioesters, or 1- hydroxy-benzotriazole esters of the carboxylic acids.
  • carboxylic acids such as acid chlorides, anhydrides, reactive esters such as N-hydroxysuccinimide esters, 2-benzothiazolyl thioesters, or 1- hydroxy-benzotriazole esters of the carboxylic acids.
  • the 2- benzothiazolyl thioester may be reacted with the compound of the formula III in an inert organic solvent such as in dimethylformamide, methylene chloride, ethyl acetate and the like.
  • the 1-hydroxybenzo- triazole ester can be employed by reacting the carboxylic acid with 1- hydroxybenzotriazole and a carbodiimide, especially N,N'- dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
  • an inert organic solvent preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
  • the carboxy group in compounds of the formula III can be protected; for example, by esterification to form a readily cleavable ester such as allyl-, t-butyl-, benzhydryl-, p-nitrobenzyl, p-methoxybenzyl- ester.
  • a readily cleavable ester such as allyl-, t-butyl-, benzhydryl-, p-nitrobenzyl, p-methoxybenzyl- ester.
  • the 7-amino group in compounds of the formula III can be protected, for example, by those groups employed in peptide chemistry, such as allyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, trityl or benzhydryl. Preferred is allyloxycarbonyl.
  • reaction of a 7-amino compond of formula III with a carboxylic acid 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.
  • R2 is as defined above.
  • esters other than allylesters being used by cleaving off the allyloxycarbonyl-amino-protecting group, adding the acylating agent and cleaving off the ester-goup.
  • 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:
  • the amino protecting groups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl group or trityl group), using e.g. aqueous formic acid.
  • acid hydrolysis e.g. the t-butoxycarbonyl group or trityl group
  • Pd(0) - produced in situ by reduction of Pd-bis triphenylphosphin-dichloride with a trialkyl-tinhydride -
  • Pd- ⁇ -complex scavenger like dimedon, pyrrolidin, dialkylmalonat, trialkyltinhydride, in an aprotic solvent such as dichlor-methane, hexane, diethylether, toluol or tetrahy drofuran .
  • Possible hydroxy protecting groups are such as are commonly known in the art, e.g. benzyl or p-nitrobenzyl.
  • trityl or acetyl For protection of hydroxyimino groups trityl or acetyl can be employed.
  • 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.
  • protecting groups may be removed as follows: benzhydryl trifluoroacetic acid 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 acid at about 0 °C to 50°C;
  • t-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 °C to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about -40°C to room temperature;
  • a carboxylic acid 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 acid triamide, dimethyl sulfoxide or, especially, dimethylform amide.
  • the reaction is preferably carried out at a temperature in the range of about 0 °C to 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 acid 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 acid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C).
  • reaction scheme 1 shows the process for obtaining compounds in accordance with the invention, e.g. a compound of formula II.
  • a base which is either an inorganic base (sodium or potassium hydroxide, sodium or potassium carbonate etc.), an organic base (tertiary amines), an organolithium compound such as butyl lithium or phenyl lithium or an epoxide such as 1,2-butyleneoxide.
  • a base which is either an inorganic base (sodium or potassium hydroxide, sodium or potassium carbonate etc.), an organic base (tertiary amines), an organolithium compound such as butyl lithium or phenyl lithium or an epoxide such as 1,2-butyleneoxide.
  • the preferred solvents are in the case of inorganic base being used, water and water-miscible solvents (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.
  • the manufacture of the Wittig reagent (2) can be carried out in a manner known per se; for example, by cyclization of a N-substituted dibromide using a catalyst like Dowex as discribed in the European Patent Application EPA 0 620 255.
  • the carboxylic acid protecting group R n and the amino protecting group Rf are removed and the reaction conditions used are depending on the nature of the protecting groups.
  • amino protecting group being allyloxycarbonyl and the carboxy protecting group being the allyl ester
  • Pd(0) generated in situ is employed.
  • amino protecting group being t- butoxycarbonyl and the carboxy protecting group being benzhydryl
  • trifluoroacetic acid is employed, at temperature of about -20 °C to about room temperature.
  • the acylation of compound (4) can be carried out with an organic acid which is activated with known reagents, preferably anhydride, thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, bis-[benz- thiazolyl-(2)]disulfide, N-hydroxy benzotriazole or a 2-halo N-methyl- pyridinium 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-miscible solvent to inert solvents such as chloroform, dimethylformamide (DMF) or dimethyl- sulfoxide (DMSO) can be used.
  • the R3 group if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
  • Scheme 2 shows the manufacture of the isooxacephemaldehydes (1) of Scheme 1.
  • Examples 1-23 show the preparation of diallyl vinyl isooxacephems according to the Wittig reaction Scheme 1, 1 to 3. Subsequent thereto follow “Examples 24-51" which illustrate the manufacture of the end products of the present invention.
  • reaction mixture After 3 hours the reaction mixture is cooled to room temperature, diluted with 1.5 1 ethyl acetate and saturated with sodium chloride. The reaction mixture is adjusted to pH 7 by adding 2N sodium carbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 7:3 as eluent.
  • reaction mixture is stirred vigorously and 15.9 ml (15.6 g, 0.197 mol) pyridine are added.
  • a solution of 21 ml (23.81 g, 0.197 mol ) allylchloroformiate in 100 ml methylene chloride is added dropwise within 30 minutes raising the temperature to -10 °C.
  • the reaction mixture is stirred at -10 °C for a further 2 hours, diluted with 500 ml methylene chloride and extracted in succession with water (500 ml), 0.1 M HC1 (500 ml) and 20% sodium chloride solution (500 ml).
  • the organic phase is dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator.
  • the residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
  • the temperature is raised to -20 °C, kept at -20 °C for one hour, cooled again to -78 °C and treated with a saturated solution of ammonium chloride (200 ml).
  • the temperature is raised to 0 °C.
  • the reaction mixture is adjusted to pH 5 by adding 2N HC1.
  • 300 ml ethyl acetate are added.
  • the organic phase is washed with water (300 ml ) and aqueous sodium chloride solution (300 ml).
  • the organic solution is dried over magnesium sulphate and concentrated on a rotary evaporator.
  • the residue is chromatographed over silica gel using ethyl acetate/n-hexane 3:7 as eluent.
  • reaction is controlled via thin layer chromatography (eluent: ethyl acetate/n- hexane 1:1, Rf educt: 0.39, Rf product: 0.16). After 3 hours the reaction mixture is diluted with 100 ml methylenchloride. The organic phase is washed with 150 ml of a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
  • Dimethylformamide is evaporated.
  • the residue is taken up in 3 ml ethyl acetate.
  • the obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide.
  • 0.1 ml (0.2 mmol) 2N sodium 2-ethyl-capronate solution are added.
  • the solvent is evaporated, 1,5 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water- acetonitrile). The fractions containing the product are combined and lyophilized.
  • the obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide. Then 0.2 ml (0.4 mmol) 2N sodium 2-ethyl- capronate solution are added. The solvent is evaporated, 3 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water-acetonitrile). The fractions containing the product are combined and lyophilized.
  • HKcm' 1 3434, 1778, 1676, 1635, 1565, 1532, 1334.
  • the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(2- fluoro-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
  • the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(4-nitro- benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl] -4-oxa- 1-aza-bicyclo [4.2.0. ] oct- 2-ene-2-carboxylic acid sodium salt.
  • the trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(5- methyl-isooxazolyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt .

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Abstract

The present invention relates to isooxacephem derivatives of general formula (I), wherein R1 is hydrogen or an acyl group derived from a carboxylic acid; R2 is hydrogen, hydroxy, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy or a heterocyclic ring; the lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy and the heterocyclic ring being unsubstituted or substituted with at least one group selected from carboxy, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CONR?21R22, -N(R22)COOR23, R22CO-, R22¿OCO- or R22COO-, wherein R21 is hydrogen, lower alkyl, or cycloalkyl; R22 is hydrogen or lower alkyl; R23 is lower alkyl, lower alkenyl or a carboxylic acid protecting group; 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

Isooxacephem-Derivatives
The present invention relates to isooxacephem derivatives of the general formula I
Figure imgf000003_0001
wherein
Rl is hydrogen or an acyl group derived from a carboxylic acid; R is hydrogen, hydroxy, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy or a heterocyclic ring; the lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy and the heterocyclic ring being unsubstituted or substituted with at least one group selected from carboxy, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CONR21R22; -N(R22)COOR23, 22CO-, R220CO- or 22cOO-, wherein R * is hydrogen, lower alkyl, or cycloaikyl; R is hydrogen or lower alkyl; R23 {S lower alkyl, lower alkenyl or a carboxylic acid protecting group; 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.
The invention also relates to pharmaceutical compositions and methods of use of the above.
In the above compounds of formula I the substituent in position 3 can be present in the E-form having the formula la
Figure imgf000004_0001
or in the Z-form having the formula lb
Figure imgf000004_0002
The term "acyl group derived from a carboxylic acid" used in conjunction with R1 herein refers to all organic radicals derived from an organic carboxylic acid by removal of the hydroxyl group. Although the group R1 may be any one of many acyl radicals, certain acyl groups are preferred, as described below.
Exemplary acyl groups are those groups which can be used to acylate β-lactam antibiotics, including 6-aminopenicillanic acid and derivatives and 7-aminocephalosphoranic acid and derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic
Press (1972), Belgian Patent No. 866,038, published October 17, 1978, Belgian Patent No. 867,994, published December 11, 1978 and United States Patent No. 3,971,778, issued July 27, 1976.
The following list of acyl groups a to g for the residue R^ of formula I is presented to further exemplify the term "acyl", without intending to limit that term to only those groups set forth. o
Rl.-C -T-
O
R11 — (CH^C-y- b
O Rπ-CH-C-τ- C
R12
O Rπ-CH2- 0 — C-y- d
O
Rπ— O-CH2 — c-_- e
o
Rπ-S-CH2 — C-y- f
Figure imgf000005_0001
wherein
j is 0, 1, 2 or 3;
R is hydrogen, lower alkyl, cycloaikyl, carbarn oyl-lower alkyl, aryl- lower alkyl; RlO is hydrogen, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl or cycloalkenyl, the lower alkyl group or the lower alkenyl group being optionally substituted with at least one group selected from halogen, cyano, nitro, amino, mercapto, alkylthio or cyano- m ethyl thio; RU is aryl unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl; a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl, aminomethyl or substituted with optionally substituted phenyl or fused together with a benzene ring; Rl is amino, acylamino, hydroxy, sulfato, a carboxyl salt, protected carboxy or azido.
The aliphatic acyl groups used in conjunction with Rl have the formula a, wherein R^O is as defined above.
Preferred aliphatic acyl groups are those wherein Rl is lower alkanoyl, particularly acetyl.
The aromatic or heteroaromatic acyl groups used in conjunction with Ri have the formulae b to f, wherein j, RU and Rl are as defined above.
The aryl group in the residue R^ is preferably phenyl.
Examples for heteroaromatic acyl groups suitable for the purposes of the present invention include those groups of the above formulae b to f wherein ^ is isoxazolyl, 2,6-dichlorophenyl-5-methyl-isoxazolyl, tetrazolyl, 1-methyl-tetrazolyl, 2-amino-4-thiazolyl, 2-amino-5-halo-4- thiazolyl, 4-aminopyridin-2-yl, 2-amino-l,3,4-thiadiazol-5-yl, 5-amino- l,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, 4-pyridinyl, 2,6-dichloro-4- pyridinyl or 2-amino-4-benzothiazolyl.
Preferred heteroaromatic acyl groups are those wherein Rl is a residue of the formula b, particularly 2,6-dichlorophenyl-5-methyl- isoxazol-4-yl-carbonyl. Also preferred are heteroaromatic acyl groups wherein Rl is a residue of the formula f, particularly 1-methyl-tetrazol- 5-yl-sulfanyl-acetyl.
The oxyimino-acyl groups used in conjunction with R^ have the formula g, wherein R3 and R^ are as defined above.
Preferred are oxyimino-acyl groups of the formula g wherein RU is a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl or substituted with optionally substituted phenyl or fused together with a benzene ring. The heterocyclic ring is preferably the thiazolyl ring or the thiadiazolyl ring.
Most preferred is an amino substituted thiazolyl ring. The thus obtained subgroup of compounds of the invention consists of compounds of the formula II
Figure imgf000007_0001
wherein R2 is as defined under formula I and R is as defined above.
In formula II R3 is preferably hydrogen, carbamoyl-lower alkyl or cycloaikyl, particularly hydrogen, carbamoyl-methyl or cyclopentyl.
Preferred compounds of formula II are such where R2 is lower alkyl, cycloaikyl, aryl-lower alkyl, aryl or a heterocyclic ring, the lower alkyl, aryl-lower alkyl, aryl and the heterocyclic ring being unsubstituted or substituted with at least one group selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl or lower alkoxy.
Most preferred compounds of formula II are such wherein R2 is isobutyl, 2,2,2-trifluoroethyl, cyclopropyl, phenyl, 3-nitrophenyl, 4- hydr oxy phenyl, 2-fluorophenyl, 2-methoxyphenyl, 4-nitrobenzyl, pyridinyl, N-methyl-pyridinium-2yl or 5-methyl-isoxazolyl.
As used herein, the term "lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
By the term "cycloaikyl" is meant a 3-7 membered saturated carbocyclic ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "lower alkoxy" refers to alkoxy groups in the sense of the above description of the term lower alkyl. Examples include methoxy, ethoxy, n-propoxy and the like.
As used herein, "lower alkenyl" refers to an unsubstituted or substituted hydrocarbon chain radical 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 and the like.
As used herein, "cycloalkenyl" refers to a carbocyclic ring having at least one olefinic double bond.
As used herein, "lower alkynyl" refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one olefinic triple bond.
The term "halogen" used herein refers to all four forms, that is chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro.
By the term "aryl" is meant a radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen and can be substituted or unsubstituted. The aromatic hydrocarbon can be mono- nuclear or polynuclear. Examples of aryl radicals of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cumenyl, and the like. Examples of aryl radicals of the polynuclear type include naphthyl, anthryl, phenanthryl, and the like. The aryl group can have at least one substituent selected from, as for example, halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy or trifluorm ethyl. Examples include 2-fluorophenyl, 3- nitrophenyl, 4-nitrophenyl, 4-methoxy phenyl, 4-hydroxyphenyl and the like.
By the term "aryl-lower alkyl" is meant a lower alkyl group containing an aryl group as for example benzyl.
As used herein, "aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). As used herein, "aryl-lower alkoxy" is an oxygen radical having an aryl-lower alkyl substituent. (i.e., -O-lower-alkyl-aryl).
As used herein, "heterocyclic ring" refers to an unsaturated or saturated, unsubstituted or substituted 5-, 6-, or 7-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen, or sulfur. Exemplary heterocyclic rings include, but are not limited to, for example, the following groups: pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- tetrazolyl, 2H-tetrazolyl, thienyl, furyl, hexamethyleneiminyl, oxepanyl, lH-azepinyl, thiophenyl, tetrahydrothiophenyl, 3H-l,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl, isoxazolyl, isothiazolyl, 4H-1,2,4- oxadiazinyl, 1,2,5-oxathiazinyl, 1,2,3,5-oxathiadiazinyl, 1,3,4- thiadiazepinyl, 1,2,5,6-oxatriazepinyl, oxazolidinyl, tetrahydrothienyl, etc., and others. Substituents for the heterocyclic ring include lower- alkyl, lower- alkoxy, halogen, trifluoromethyl, trichloroethyl, amino, mercapto, hydroxy, carboxy or carbamoyl. Preferred examples of substituted heterocyclic rings include 5-methyl-isoxazol-3-yl, N-methyl- pyridinium-2yl, 1-methyl-tetrazolyl and the like.
The heterocyclic ring can also be substituted by an optionally substituted phenyl ring such as 2,6-dichlorophenyl. Preferred is 2,6- dichlorophenyl-5-methyl-isoxazolyl.
A further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, 1,1- dioxo-tetrahydrothien-3-yl.
The heterocyclic ring can also be fused together with a benzene ring.
By the term "substituted phenyl" is meant phenyl mono or di- substituted.
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 acid 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, calcium (Ca++) and magnesium (Mg++), although cationic forms of other metals, such as iron (Fe++ or Fe+++), aluminium (Al+++), 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), benzyltrimethyl- ammonium (N+(C6H5CH2)(CH3)3), phenyltriethylammonium (N+(C6H5)(CH2CH3)3), and the like, etc. Those 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.
The term "amino protecting group" refers to protecting groups conventionally used to replace an acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218-287. These examples include e.g. allyl, allyloxycarbonyl, t-butyl, t- butoxycarbonyl, benzyl, p-methoxybenzyl and p-nitro-benzyl. Preferred is allyloxycarbonyl.
The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and
Sons, Inc. 1981). These examples include e.g. allyl, diphenylmethyl, p- nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, t- butyldimethylsilyl. Preferred is allyl.
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 phthalidyl 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)carbonylJoxy] ethyl ester and 3,3-dimethyl-2-oxobutyl ester. It will be appreciated 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 2 of the isooxacephem ring.
Examples of salts of the compounds of formula I are defined under
"pharmaceutically acceptable salts" above.
The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydra tion 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 for the treatment and prophylaxis of infectious diseases. 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 coprecipitated aluminum hydroxide-calcium carbonate, dicalcium phosphate or lactose; disintegrating agents, such as maize starch; and lubricating agents, such as talc, calcium stearate, 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 acid 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, 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.
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:
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-2-oxo-l-(2,2,2-trifluoro-ethyl)-pyrrolidin-3- ylidenmethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 24).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-2-oxo-l-phenyl-pyrrolidin-3-ylidenmethyl]-4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt
(Example 25).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 26).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(cyclopropyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 27).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-0X0-3- [(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt
(Example 28).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-0X0-3- [(E)- l-(5-methyl-isooxazolyl)-2-oxo-pyrroli din-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 29).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(3-nitrophenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 30).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-0X0-3- [(E)- l-(4-hyroxyphenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 31).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[(E)-l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicy clo [4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 32).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[2-oxo-l-(2-pyridinyl)-pyrrolidin-3-ylidenemethyl]-8-oxo- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt
(Example 33).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[(E)-l-(l-methyl-pyridinium-2-yl)-2-oxo-pyrrolidin-3- ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicy clo [4.2.0.] oct-2-ene-2-carboxylic acid (Example 34).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[l-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 35).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 36).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino] -3- [(E)- l-(4-phenyl)-2-oxo-pyrrolidin-3-ylidene- methyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 37).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-cyclopropyl-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 38).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicyclo [4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 39).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-
8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 40).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(3-nitrophenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 41).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 42).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 43).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 44).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(3-nitro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 45).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(pyridin-2-yl)-2-oxo-pyrrolidin-3- ylidenemethyl] -4-oxa- 1-aza-bicyclo [4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 46).
E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 47).
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 48).
(E)-(6S,7S)-7-[[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-yl- carbonyl] -amino] -3- [(E)- l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl] -4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt
(Example 49).
(6S,7S)-3-((E)-l-Isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7[2-(l- methyl-lH-tetrazol-5-ylsulfanyl)-acetylamino)-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 50).
(6S,7S)-7-Acetylamino-3-((E)-l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt (Example 51). The results appear below:
Minimum Inhibiting Concentration Values (mg/1)
Example S.aureus S.aureus E.faecalis E.faecium E.coli E. cloacae No. 6538 887 ATCC 25922 908SSΪ
29212 QK 5/90
8
Figure imgf000017_0002
Figure imgf000017_0001
Figure imgf000017_0003
1 4 4 - 16 32 1 2
2 1 2 0.5 16 2 8
3 1 1 1 32 1 2
4 1 1 0.5 16 1 4
5 1 1 1 16 2 2
6 0.5 1 0.5 16 1 2
7 1 0.5 2 16 2 2
8 1 1 1 32 1 2
9 1 _ _ >32
0 _ 2 8
1 4 16
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 III
Figure imgf000018_0001
in which R2 is as defined above under formula I or an ester or salt thereof, with acylating agents, or
(b) for the manufacture of a compound of formula I in which R1 and/or R2 may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) or reducing a nitro group to amino in a compound having the formula IV
Figure imgf000019_0001
in which Rh is hydrogen or a carboxy protecting group, Rf is as Rl and Rε is as R2 with the proviso that at least one of the following provisions is fulfilled: (i) Rn is a carboxylic acid protecting group,
(ii) Rf is a residue defined under R1 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s),
(iii) R£ is a residue defined under R2 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s), 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.
The reaction of compounds III with acylating agents according to embodiment (a) can be carried out in a manner known per se.
Examples of acylating agents used in embodiment (a) are activated carboxylic acids such as acid chlorides, anhydrides, reactive esters such as N-hydroxysuccinimide esters, 2-benzothiazolyl thioesters, or 1- hydroxy-benzotriazole esters of the carboxylic acids. For instance, the 2- benzothiazolyl thioester may be reacted with the compound of the formula III in an inert organic solvent such as in dimethylformamide, methylene chloride, ethyl acetate and the like. The 1-hydroxybenzo- triazole ester can be employed by reacting the carboxylic acid with 1- hydroxybenzotriazole and a carbodiimide, especially N,N'- dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.
The carboxy group in compounds of the formula III can be protected; for example, by esterification to form a readily cleavable ester such as allyl-, t-butyl-, benzhydryl-, p-nitrobenzyl, p-methoxybenzyl- ester.
The 7-amino group in compounds of the formula III can be protected, for example, by those groups employed in peptide chemistry, such as allyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, trityl or benzhydryl. Preferred is allyloxycarbonyl.
The reaction of a 7-amino compond of formula III with a carboxylic acid 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.
Compound of the formula III can be obtained by palladium assisted deprotection of the corresponding allylester IVa
Figure imgf000020_0001
wherein R2 is as defined above.
or in case of esters other than allylesters being used by cleaving off the allyloxycarbonyl-amino-protecting group, adding the acylating agent and cleaving off the ester-goup.
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
The amino protecting groups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl group or trityl group), using e.g. aqueous formic acid. In the case of an allyloxycarbonyl protecting group Pd(0) (- produced in situ by reduction of Pd-bis triphenylphosphin-dichloride with a trialkyl-tinhydride -) is employed at a temperature in the range of about -30°C to +40°C in the presence of a Pd-π-complex scavenger like dimedon, pyrrolidin, dialkylmalonat, trialkyltinhydride, in an aprotic solvent such as dichlor-methane, hexane, diethylether, toluol or tetrahy drofuran .
.Removal of hydroxy protecting groups
Possible hydroxy protecting groups are such as are commonly known in the art, e.g. benzyl or p-nitrobenzyl.
For protection of hydroxyimino groups trityl or acetyl can be employed.
These protecting groups are e.g. removed as follows:
-trityl in acidic solvents like 90% formic acid at about 0 °C to 50 °C or triethylsilane in trifluoroacetic acid at about -20 °C to 25°C; in organic solutions of hydrochloric acid at about -50 °C to 25°C;
-acetyl with weak inorganic bases like sodium bicarbonate in ethanol/water at about 0 °C to 50°C;
-benzyl, p-nitrobenzyl with hydrogen or a hydrogen donor like cyclohexene or cyclohexadiene and a catalyst like Pd/C in solvents like alcohols, dichloromethane, ethyl acetate, acetic acid, dimethylformamide etc, or mixtures of these at about 0 °C to 50°C.
Removal of protecting groups at the carboxy 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 acid 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 acid at about 0 °C to 50°C;
t-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-nitrobenzyl sodium sulfide in acetone/water at about 0 °C to room temperature; or hydrogen with Pd C in an alcohol such as ethanol or in tetrahydrofuran;
p-methoxybenzyl formic acid at about 0 °C to 50°C; or trifluoroacetic acid 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 acid, 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 acid 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 acid triamide, dimethyl sulfoxide or, especially, dimethylform amide. The reaction is preferably carried out at a temperature in the range of about 0 °C to 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 acid 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 acid 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 scheme 1 below. Scheme 1 shows the process for obtaining compounds in accordance with the invention, e.g. a compound of formula II.
Scheme 1
Alloc-HN
Figure imgf000024_0001
Pd(0) deprotection
Figure imgf000024_0002
Figure imgf000024_0003
(5)
Figure imgf000024_0004
Scheme 1
Wittig reaction 1 to 3
The reaction of known 3-isooxacephem aldehyde (1) wherein the 7- amino-protecting group is allyloxycarbonyl and the carboxy protecting group is allyl with a Wittig reagent (2) yields the coupling product (3).
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 compound such as butyl lithium or phenyl lithium or an epoxide such as 1,2-butyleneoxide. The preferred solvents are in the case of inorganic base being used, water and water-miscible solvents (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.
The manufacture of the Wittig reagent (2) can be carried out in a manner known per se; for example, by cyclization of a N-substituted dibromide using a catalyst like Dowex as discribed in the European Patent Application EPA 0 620 255.
Deprotection 3 to 4
The carboxylic acid protecting group Rn and the amino protecting group Rf are removed and the reaction conditions used are depending on the nature of the protecting groups.
In the case of the amino protecting group being allyloxycarbonyl and the carboxy protecting group being the allyl ester, Pd(0) generated in situ is employed. In the case of the amino protecting group being t- butoxycarbonyl and the carboxy protecting group being benzhydryl, trifluoroacetic acid is employed, at temperature of about -20 °C to about room temperature.
Acylation 3 to 4
The acylation of compound (4) can be carried out with an organic acid which is activated with known reagents, preferably anhydride, thionyl chloride, oxalyl chloride, dicyclohexylcarbodiimide, bis-[benz- thiazolyl-(2)]disulfide, N-hydroxy benzotriazole or a 2-halo N-methyl- pyridinium 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-miscible solvent to inert solvents such as chloroform, dimethylformamide (DMF) or dimethyl- sulfoxide (DMSO) can be used. The R3 group, if necessary, can be further deprotected with a reaction condition suitable for the removal of the protecting group.
The 2-carboxylic function of compound (5) is converted to the prodrug esters which are readily hydrolyzable in vivo.
Scheme 2 shows the manufacture of the isooxacephemaldehydes (1) of Scheme 1.
Scheme 2
dihydropyran
Figure imgf000027_0001
(1 )
Figure imgf000027_0002
(2) (3) (4)
Figure imgf000027_0003
(9) (1 0)
Z= benzyloxycarbonyl,; THP= tetrahydropyranyl; DMB= 2,4-dimethoxybenzyl; Alloc =allyloxycarbonyl; TBDMS= tert-butyldimethylsilyl; DEAD= diethylazodicarboxylate
The manufacture of starting materials according to Scheme 2 are illustrated in the following description termed "Preparations 1-9".
Examples 1-23 show the preparation of diallyl vinyl isooxacephems according to the Wittig reaction Scheme 1, 1 to 3. Subsequent thereto follow "Examples 24-51" which illustrate the manufacture of the end products of the present invention.
I Preparation of the key-aldehydes
Preparation 1 (1 to 2, Scheme 2)
1:1 Mixture of (3S,4S)-[l-(2,4-Dimethoxy-ben2yl)-2-oxo-4[(R)-and (S)-tetrahydropyran-2-yloxymet^^ acid benzyl ester
1 g ( 5.25 mmol) p-toluenesulfonic acid mono-hydrate is added to a suspension of 107 g (0.267 mol) benzyl-(2S,3S)-l-(2,4-dimethoxybenzyl)-2- (hydroxymethyl)-4-oxo-3-azetidinyl-carbamate in 1 1 tetrahydrofuran.
41.6 ml (38,6 g; 0,458 mol) 3,4-dihydro-2H-pyran are added dropwise within two hours at room temperature. The reaction mixture is stirred for six days. The reaction is controlled via thin layer chromatography (eluent: ethyl acetate/n-hexane 1:1, Rf educt: 0.09, Rf product: 0.18). The solvent is removed on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 1:1 as eluent. The obtained oil is stirred in n- hexane. The obtained crystals are filtered off and dried at high vacuum.
Yield: 110 g (85%) white crystals.
IR (cm-1): 3294, 1758, 1686, 1546, 1293, 1267
MS (ISP): 485.3 (M+H)+; 507.2 (M+Na)+
Preparation 2 (2 to 3, Scheme 2)
1:1 Mixture of (3S,4S) [-2-Oxo-4-[(R)-and-[(S)-tetrahydropyran-2- yloxyιnethyl]-azetid--πι^-yl] »_rbaιnic acid benzyl ester
110 g (0.227 mol) of a 1:1 mixture of (3S,4S)-[l-(2,4-dimethoxy- benzyl)-2-oxo-4[(R)-and -[(S)-tetrahydropyran-2-yloxymethyl]-azetidin-3- yl]-carbamic acid benzyl ester are dissolved in 1 1 acetonitrile and diluted with 0.5 1 water. The reaction mixture is heated to 80 °C. Then 128 g (0.467 mol) potassium persulfate are added in two portions within two hours. The reaction mixture is adjusted to pH 5.5 by adding 2N sodium carbonate solution. After 3 hours the reaction mixture is cooled to room temperature, diluted with 1.5 1 ethyl acetate and saturated with sodium chloride. The reaction mixture is adjusted to pH 7 by adding 2N sodium carbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 7:3 as eluent.
Yield: 60 g (79%) yellow oil.
IR (cm-1): 3294, 1764, 1718, 1536, 1252
MS (ISP): 335.2 (M+H)+; 352.2 (M+NH4)+; 357.2 (M+Na)+
Preparation 3 (3 to 4, Scheme 2)
1:1 mixture of (3S,4S) [-2-Oxo-4-[(R)-and-[(S)-tetrahydropyran-2- yloxyιnethyl]-azetidiι_-3-yl]-carbamic acid allyl ester
60 g (0.179 mol) of a 1:1 mixture of (3S,4S) [-2-oxo-4-[(R)-and-[(S)- tetrahydropyran-2-yloxymethyl]-azetidin-3-yl]-carbamic acid benzyl ester are dissolved in 800 ml ethyl acetate and hydrogenated over 5 g palladium-charcoal (10%Pd). The suspension is stirred under hydrogen at normal pressure. The catalyst is filtered off over glass fiber under suction and the filtrate is concentrated on a rotary evaporator. The obtained colourless oil is dried at high vacuum, dissolved in 700 ml methylene chloride and cooled to -20 °C. The reaction mixture is stirred vigorously and 15.9 ml (15.6 g, 0.197 mol) pyridine are added. A solution of 21 ml (23.81 g, 0.197 mol ) allylchloroformiate in 100 ml methylene chloride is added dropwise within 30 minutes raising the temperature to -10 °C. The reaction mixture is stirred at -10 °C for a further 2 hours, diluted with 500 ml methylene chloride and extracted in succession with water (500 ml), 0.1 M HC1 (500 ml) and 20% sodium chloride solution (500 ml). The organic phase is dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
Yield: 44.8 g (88%) colourless oil.
πUcm-1):3293, 1764, 1724, 1537, 1259
MS (ISP): 285,3 (M+H)+; 302,3 (M+NH4)+; 307,2 (M+Na)+ Preparation 4 (4 to 5, Scheme 2)
1:1 mixture of (3S^S)-[3~aUyloxycarbonylaπ_ino-2-oxo-4-[(R)- and[(S)-tetiΩhydιxκpyran-2-yloxymethyl]-azetid-n-l-yl]-acetic acid allyl ester
12.3 g (0.089 mol) potassium carbonate are added to a solution of a
1:1 mixture of (3S,4S) [-2-oxo-4-[(R)-and-[(S)-tetrahydropyran-2- yloxymethyl]-azetidin-3-yl]-carbamic acid allyl ester (19.5 g; 0.068 mol) in 200 ml dimethylformamide. Then 13.5 g (0.075 mol) bromoacetic acid allyl ester are added dropwise at room temperature. The reaction mixture is stirred for 48 hours and filtered off over glass fiber under suction. The filtrate is concentrated on a rotary evaporator. The residue is taken up in 500 ml ethyl acetate and extracted with 20% sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
Yield: 16 g (61%) colourless oil.
IR (cm"1): 3312, 1770, 1726, 1535, 1420, 1248 MS (ISP): 383.2 (M+H)+; 405.2 (M+Na)+
Preparation δ (5 to 6, Scheme 2)
1:1 mixture of 2-[(3S,4S)-3-AUyloxycarbonylanιino-2-oxo-4[(R)-and -[(S)-tetrahydro-pyrøm-2-yloxymeth^^ sUylanyloxy)-3-oxo-butyric acid allyl ester
24 g (0.063 mol) of a 1:1 mixture of (3S,4S)-[3-allyloxycarbonyl- amino-2-oxo-4-[(R)-and[(S)-tetrahydro-pyran-2-yloxymethyl]-azetidin-l- yl] -acetic acid allyl ester are dissolved in 300 ml tetrahydrofuran and cooled to -78 °C. A solution of 1 M bis-trimethylsilyl-litium-amide in tetrahydrofuran (63 ml, 0.063 mol) is added dropwise at -78 °C. After 30 minutes 8.03 ml (0.063 mol) trimethylchlorsilan are added dropwise and the reaction mixture is stirred for a further 45 min. Then a further solution of 1 M bis-trimethylsilyl litium-amide in tetrahydrofuran (126 ml, 0.126 mol) is added dropwise. After 30 minutes 14.4 g (0.0689 mol) tert.-butyl-dimethylsilyloxy-acetylchloride are added. The reaction mixture is stirred for a further 2 hours at -78 °C. The temperature is raised to -20 °C, kept at -20 °C for one hour, cooled again to -78 °C and treated with a saturated solution of ammonium chloride (200 ml). The temperature is raised to 0 °C. The reaction mixture is adjusted to pH 5 by adding 2N HC1. Then 300 ml ethyl acetate are added. The organic phase is washed with water (300 ml ) and aqueous sodium chloride solution (300 ml). The organic solution is dried over magnesium sulphate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using ethyl acetate/n-hexane 3:7 as eluent.
Yield: 24 g (70%) colourless oil.
IR (cm'1): 3316, 2949, 1775, 1734, 1650, 1527, 1251 MS (ISP): 555.3 (M+H)+; 572.4 (M+NH4)+
Preparation 6 (6 to 7, Scheme 2)
2-[(3S,4S)-3-AUyloxyc!arbonylanmiC-2-hydroxynaethyl-4-oxo- asretidin-l-yl]^(teιi butyl-sUylanylo_c^)-3-oxo-butyric acid allyl ester
15.5 g (0.060 mol) magnesium bromide-diethyletherate are added portionwise at 0 °C to a solution of a 1:1 mixture of 2-[(3S,4S)-3- Allyloxycarbonylamino-2-oxo-4[(R)-and -[(S)-tetrahydro-pyran-2- yloxymethyl]-azetidin-l-yl]-4-(tert-butyl-silylanyloxy)-3-oxo-butyric acid allyl ester (11.6 g, 0.020 mol) in 300 ml diethylether. After 2 hours 150 ml water are added at 0 °C. The organic phase is washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
Yield: 5.9 g (62%) yellow oil.
IR (cm-1): 3403, 1735, 1648, 1520, 1254 MS (El): 470 (M); 413 (M-tBu) Preparation 7 (7 to 8, Scheme 2)
(6S S)-7-AUyloxyc5arbonylaι no-3-(tert-butyl-dimethyl- sUanyloxymethyl)-8 >xo-4-oxa-l-aza-bicyclo[4^.0.] oct-2-ene-2-<»rboxylic acid allyl ester
To a solution of 2-[(3S,4S)-3-Allyloxycarbonylamino-2- hydroxymethyl-4-oxo-azetidin-l-yl]-4-(tert-butyl-silylanyloxy)-3-oxo- butyric acid allyl ester (5.9 g, 0.0125 mol) in 100 ml tetrahydrofuran 4.9 g (18.8 mmol) triphenylphosphin are added at -30 °C. After 5 minutes 2.7 ml (17.5 mmol) azodicarboxylic acid diethyl ester are added dropwise. The temperature is raised to 0 °C and the reaction mixture is stirred for
30 minutes at 0 °C. Then 20 ml saturated ammonium chloride solution are added. The reaction mixture is diluted with 150 ml ethyl acetate. The organic phase is dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 3:7 as eluent.
Yield: 3.4 g (60%) yellow oil.
IR (cm-1): 3320, 1785, 1717, 1616, 1540, 1467 MS (ISP): 453.3 (M+H)+; 470.3 (M+NH4)+
Preparation 8 (8 to 9, Scheme 2)
6S,7S)-7-AUyloxycarbOnylaπιino-3-hyό xyn ethyl-8-oxo^-oxa-l- aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid allyl ester
3.4 g (7.5 mmol) (6S,7S)-7-Allyloxycarbonylamino-3-(tert-butyl- dimethyl-silanyloxymethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester are dissolved in 20 ml acetonitrile. The solution is cooled to 0 °C. 7.5 ml (0.015 mol) 2 N HF in acetonitrile are added. The reaction mixture is warmed to room temperature and is stirred for 3 hours. The obtained solution is cooled to 0 °C and diluted with 100 ml ethyl acetate. The solution is adjusted to pH 6.5 by adding saturated sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 1:1 as eluent. Yield: 2.3 g (88%) oil.
IR(cm-1): 3474, 3330, 1777, 1710, 1611, 1540
MS (ISP): 321.2 (M+H-H20); 339.2 (M+H)+; 361.1 (M+Na)+
Preparation 9 (9 to 10, Scheme 2)
(6S,7S)-7-AUyloxycarbx>nylaπιiιιo-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxy_ic acid allyl ester
845 mg (2.5 mmol) (6S,7S)-7-Allyloxycarbonylamino-3- hydroxymethyl-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester are dissolved in 20 ml methylene chloride. At 0 °C 47 mg (0.39 mmol) potassium bromide, 106 mg (1.26 mmol) sodium bicarbonate and 5 ml water are added. Then 59.7 mg (0.38 mmol) 2,2,6,6-tetramethylpiperidine-l-oxyl are added. The reaction mixture is stirred vigorously and 2.5 ml 12% sodium hypochlorite solution are added dropwise. After 30 minutes at 0 °C the reaction mixture is diluted with 100 ml methylene chloride. The organic phase is washed with 500 ml 50% sodium chloride solution, dried over magnesium sulfate and filtered off. The solvent is evaporated.
Yield: 780 mg yellow oil.
IR (cm-1): 3341, 1793, 1720, 1687, 1587, 1534, 1382 MS (ISP): 337.2 (M+H)+; 359.2 (M+Na)+
II Preparation of diallyl vinyl isooxacephems. Wittig reaction Scheme 1. 1 to 3
Example 1
(E)-(6S,7S)-7-AUyloxycarbonylaιm^o-8-oxo-3-[2-oxo-l-(2^-trifluoro- ethyl)-pyrιx)Ud n-3-yUdenιnethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester
780 mg (2.5 mmol) (6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester are dissolved in 30 ml of a 1:1 mixture of ethylenchloride and 1,2- butylenoxide. Then 1.4 g (2.75 mmol) [2-Oxo-l-(2,2,2,-trifluoro-ethyl)-3- pyrrolidinyl]-triphenyl-phosphonium bromide are added. The white suspension is stirred vigorously and warmed to 40°C. The reaction is controlled via thin layer chromatography (eluent: ethyl acetate/n- hexane 1:1, Rf educt: 0.39, Rf product: 0.16). After 3 hours the reaction mixture is diluted with 100 ml methylenchloride. The organic phase is washed with 150 ml of a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the residue is chromatographed over silica gel using ethyl acetate/n-hexane 1:1 as eluent.
Yield: 950 mg (78%) amorphous solid.
IR (cm-1): 3426, 1779, 1711, 1646, 1566, 1535, 1390
MS (ISP): 486.2 (M+H)+; 503.2 (M+NH4)+ 508.1 (M+Na)+
According to the procedure set forth in the preceding example the following additional compounds are prepared:
Example 2
(E)-(6S,7S)-7-AQyloxycarbonylamino-8-oxo-3-[2-oxo-l-phenyl- pyπx)Udm-3-ylidenπιethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [2- oxo-l-phenyl)-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR (cm-1): 3436, 1776, 1710, 1640, 1530, 1391, 1309 MS (ISP): 480.2 (M+H)+
Example 3
(E)-(6S S)-7-AUyloxycarbonylamino-3-[l-(4-mtro-benzyl)-2-oxo- py-TOUdin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4^.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [2- oxo-l-(4-nitrobenzyl)-3-pyrrolidinyl]-triphenylphosphonium bromide. IR (cm-1): 3423, 1779, 1712, 1522, 1387, 1347 MS (ISP): 539.2 (M+H)+; 556.2 (M+Na)+
Example 4
(E)-(6S,7S)-7-AUyloxycarbonylamino-3-[l-cyclopropyl-2-oxo- pyrroKdin-3-ylideneπιethyl]-8-oxo-4-oxa-l-aza-bicyclo[4^.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [1- (cyclopropyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR (cm'1): 3430, 1780, 1712, 1643, 1562, 1388
MS (ISP): 444.4 (M+H)+
Example 5
(E)-(6S S)-7-AUyloxycarbonylai-_mo-^ 3-yUdenemethyl)-8-oxc>-4-oxa-l-aza-bicyclo[4.2^ acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [1- (isobutyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR (cm"1): 3496, 1782, 1712, 1643, 1563, 1387, 1252 MS (ISP): 458.4 (M+H)+
Example 6
CE)-(6S,7S)-7-AUyloxycarbOnylaπιmc^[l-(ό^methyl-isooxazol-3-yl)-2-oxo- pyriOUd--tι-3-yUdeneιnethyl]-8^xo- oxa-l-a-Ea-bicyclo[4.2.0 oct 2-ene-2^ carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [l-(5- methyl-isooxazol-3-yl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR(cm'1): 3403, 1777, 1714, 1644, 1610, 1508, 1385 MS (ISP): 485.2 (M+H)+ Example 7
(E)-(6S,7S)-7-AUyloxycarbonylaπώιo-3-[l-(3-nitrophenyl)-2-oxo- pyrι >Ucun-3-yUdenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [l-(3- nitrophenyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR cπr1): 3421, 1778, 1710, 1642, 1610, 1560, 1346 MS (ISP): 525.0 (M+H)+; 547.1 (M+Na)+
Example 8
(E)-(6S,7S)-7-AUyloxycarbony]amino-3 ^ pyπOUdin-3-yUdeneιne hyl]-8H xo-4 )xa-l-aza-bicyclo[4^.0J oct 2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [l-(2- fluoro-phenyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
HKcm"1): 3404, 1782, 1711, 1645, 1565, 1533, 1504, 1389 MS (ISP): 498.2 (M+H)+
Example θ
(E)-(6S,7S)-7-AUyloxycarbonylammc^-[2κ>xo-l-(2 yridmyl)- pyπx Uόlin-3-yUdeneπιethyl]-8 )xo-4-oxa-l-aza-bicyclo[4^ ] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [l-(2- pyridinyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR (cm"1): 3404, 1778, 1712, 1642, 1567, 1528, 1469, 1435, 1386, 1337, 1309,
1242
MS (ISP): 481.3 (M+H)+ Example 10
(E)-(6S S)-7-AUyloxycarbonylamino-3-[l-(2-methoxy-phenyl)-2-oxo- py-TθUdin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [l-(2- methoxy-phenyl)-2-oxo-3-pyrrolidinyl]-triphenylphosphonium bromide.
IR (cm-1): 3434, 1781, 1711, 1644, 1562, 1504, 1388, 1253 MS (ISP): 510.2 (M+H)+
Example 11
(E)-(6S,7S)-7-AUyloxycarbonylaιnmo-3 l-(4-hydroxy-phenyl)-2-oxo- pyιτoUdm-3-ylideneπιethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester
(6S,7S)-7-allyloxycarbonylamino-3-formyl-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester is reacted with [2- oxo-l-(4-"tert"-butoxycarbonyloxy-phenyl)-3-pyrrolidinyl]- triphenylphosphonium bromide to obtain (E)-(6S,7S)-7- allyloxycarbonylamino-3-[l-(4-"tert"-butoxycarbonyloxy-phenyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid allyl ester.
IR (cm"1): 3424, 1761, 1719, 1509, 1392, 1149 MS (ISP): 596.3 (M+H)+.
595 mg (1 mmol) (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(4-"tert"- butoxycarbonyloxy-phenyl)-2-oxo-pvrrolidin-3-ylidenemethyl]-8-oxo-4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester are dissolved in 2 ml dichloromethane. At 25 °C 2 ml formic acid are added.
After 28 hours the solvent is evaporated. The residue is dissolved in a mixture of dichloromethane / methanol (9:1) and washed with water.
The organic phase is dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator. The residue is purified by chromatography over silica gel using dichloromethane / methanol (95:5) as eluent.
Yield: 121 mg (24.4%) amorphous solid.
IR (cm"1): 3405, 1775, 1709, 1636, 1514, 1391 MS (ISP): 496.1 (M+H)+; 518.0 (M+Na)+
II liberation of the betaine: Scheme 1.3 to 4
Example 13
(E)-(6S,7S)-7-Ammo-8-oxo-3-[2^xo-l-(2^ 2-trifluoro-ethyl)- pyrroUdm-3-yUdennιethyl]-4-oxa-l-aza-bicyclo[4.2.0 oct-2-ene-2- carboxylic acid
330 mg (0.679 mmol ) (E)-(6S,7S)-7-allyloxycarbonylamino-8-oxo-3-[2-oxo- l-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-ylidenmethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester are dissolved in 15 ml tetrahydrofuran. At room temperature 10 mg (2 mol%, 0.0136 mmol) palladium-bis-(triphenylphosphin)-dichloride and 0.54 ml (3.39 mmol) 2-ethylcaproic acid are added. Within 3 minutes 0.90 ml (988 mg, 3.39 mmol ) tributyltinhydride are added dropwise. After 10 minutes yellow crystals are obtained. The suspension is stirred for further two hours and the crystals are filtered off under suction, washed with 20 ml tetrahydrofuran and 30 ml ethyl acetate and dried at high vacuum. Yield: 220 mg (89%)
IR (cm"1): 3433,1773, 1692, 1643, 1565, 1266, 1155 MS (ISP): 362.1 (M+H)+; 384.2 (M+Na)+
According to the procedure set forth in the preceding example the following additional compounds are prepared:
F,v«τnple ;14
(E)-(6S,7S)-7-Ammo-3-[l-(4-nitro-benzyl)--i )xo-pyrroUdin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(4-nitro- benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo
[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester. IR(cm"1):3433,1766, 1679,1638, 1603, 1520, 1347 MS (ISP): 415.2 (M+H)+
Example15
(E).(6S,7S)-7-Ammo-8-oxo-3-[2-oxo-l henyl-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4^2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-8-oxo-3-[2-oxo-l- phenyl)-pyrrolidin-3-ylidenmethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene- 2-carboxylic acid allyl ester.
Example 16
(E)-(6S,7S)-7-Ammc^(l<yclopropyl-2-oxo-pyrroUdin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-cyclopropyl- 2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2- ene-2-carboxylic acid allyl ester.
IR (cm-1): 3433,1768, 1683, 1638, 1563, 1404, 1364 MS (ISN): 318.3 (M-H)"
Example 17
(E)-(6S,7S)-7-Ammo-3-(l-isobutyl-2-oxo-pyιτolidin-3-ylidenemethyl)- 8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] octr2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-(l-isobutyl-2- oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2- ene-2-carboxylic acid allyl ester.
IR (cm"1): 3431, 1806, 1771, 1682, 1644, 1558, 1406, 1360 MS (ISN): 334.3 (M-H)-
Example 18
(E)-(6S,7S)-7-Ammo-3-[l-(5-methyl-isooxazol-3-yl)-2-oxo yπ )Udin- 3-yHdenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4-2O oct-2-ene-2-carboxylic acid Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(5-methyl- isooxazolyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester.
IR (cm-1): 3436,1799, 1701, 1608, 1508, 1457 MS (ISN): 359.3 (M-H)-; 376.3 (M-H+NH3)-
Example 19
(E)-(6S S)-7-Ammo-3-[l-(3-mtrophenyl)-2 xo-pyiToUdin-3-yUdene- methyl]-8-oxo-4 >xa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(3- nitrophenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester.
IR (cm-l): 3432,1766, 1689, 1634, 1529, 1394, 1347 MS (ISN): 399.2 (M-H)-; 416.3 (M-H+NH3)-
Example20
(E)-(6S,7S)-7-Ammo^ 1-(4-hyclroxyphenyl)-2 )xo-pyιτoUd -3- yUdene-ιnethyl]-8<>xo-4H>xa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(4-hydroxy- phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester.
IR (cm"1): 3430,1770, 1679, 1634, 1514, 1401, 1337 MS (ISN): 370.2 (M-H)".
Example 21
(E)-(6S,7S)-7-Ammo-3 1-(2-fluoι >-phenyl)-2-oxo-pyrrondin-3- ylidene-methyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(2-fluoro- phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester. IR(cm"1): 3432,1774, 1692, 1638, 1564, 1504, 1400 MS (ISP): 374.2 (M+H)+.
Example22
(E)-(6S S)-7-Ammo-3 2-oxo-l-(2 yridmyl) yrroUdin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[ 2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[2-oxo-l-(2- pyridinyl)-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester.
IR (cm"1): 3434,1773, 1691, 1635, 1587, 1469, 1436, 1391
MS (ISN): 355.3 (M-H)"; 372.3 (M-H+NH3)-.
Example 23
(E)-(6S S)-7-Ammo^-[l-(2-met-rιoxy henyl)-2-oxo-ρyrroUdin-3- yUdene-met^yl]-8κ)xo-4-oxa-l-aza-bicyclo[4»2.0.] oct-2-ene-2-carboxylic acid
Starting from (E)-(6S,7S)-7-allyloxycarbonylamino-3-[l-(2-methoxy- phenyl)-2-oxo-py rrolidin-3 -ylidenemethyl] -8-oxo-4-oxa- 1-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid allyl ester.
IR (cm-1): 3434,1770, 1686, 1636, 1595, 1503, 1400 MS (ISP): 386.2 (M+H)+;
ul Acylation of the betaine: Scheme 1.4 to 5
Example 24
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-thiazo^ acetylammo]-8-oxo-3-[0E)-2-oxo-l-(2 _,2 ι^ ylidenmethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000042_0001
To a suspension of 90 mg (0.25 mmol) (E)-(6S,7S)-7-amino-8-oxo-3- [2-oxo-l-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-ylidenmethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid in 8 ml dimethylformamide 33 mg (0.27 mmol) (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxvimino- thioacetic acid-S-benzothiazol-2-yl ester are added at room temperature according to the European Patent Application EPA-0 620 225 or to H.Tsubouchi et al., J. Med. Chem. 1995, 38, 2152-57. The reaction mixture is stirred for 20 hours at room temperature.
Dimethylformamide is evaporated. The residue is taken up in 3 ml ethyl acetate. The obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide. Then 0.1 ml (0.2 mmol) 2N sodium 2-ethyl-capronate solution are added. The solvent is evaporated, 1,5 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water- acetonitrile). The fractions containing the product are combined and lyophilized.
Yield : 51 mg (33%) light yellow lyophilizate.
IR (cm-1): 3430, 1758, 1668, 1638, 1532, 1392
MS (ISP): 599.3 (M+H)+; 621.2 (M+Na)+
According to the procedure set forth in the preceding example the following additional compounds are prepared:
Example 25
(E)-(6S/7S)-7-[(-9-2-(2-Ammo-tWa-røl^ acetylamino]-8^xo-3-[0E)-2κ)xo-l henyl yrroUdm-3-yUdemnethyl]- oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000043_0001
Starting from (E)-(6S,7S)-7-amino-8-oxo-3-[2-oxo-l-phenyl- pyrrolidin-3-ylidenemethyl] -4-oxa- 1-aza-bicyclo [4.2.0. ] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3430, 1759, 1668, 1630, 1596, 1532, 1392 MS (ISP): 593.3 (M+H)+
Example 26
(E)-(6S,7S)-7 (Z)-2-(2-Am o-tWazol-4-yl)----cyclopeniyloxyimm acsetylamino]-8-oxo-3-[(E)-l-(4-nit_x>-be---_yl)-2-oxo-pyr^ ylidenemethyl]-4-oxa-l-aza-bicyclo[4»2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000043_0002
Starting from (E)-(6S,7S)-7-amino-3-[l-(4-nitro-benzyl)-2-oxo- pyrrolidin-3-ylidenem ethyl] -8-oxo-4-oxa- 1-aza-bicyclo [4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
πKcm"1): 3427, 1759, 1669, 1636, 1604, 1529, 1390, 1345 MS (ISP): 652.4 (M+H)+; 674.4 (M+Na)+ Example 27
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-tωazol-4-yl)-2κ;yclopentyloxyimino- ac«tylaπ_ino]-8-oxo-3-[(E)-l-(cydopι >pyl)-2-oxo-pynx>Udin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000044_0001
Starting from (E)-(6S,7S)-7-amino-3-(l-cyclopropyl-2-oxo-pyrrolidin- 3-ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3420, 1759, 1665, 1631, 1603, 1532, 1391 MS (ISP): 557.2 (M+2H-Na)+; 579.3 (M+H)+
Example 28
(E)-(6S,7S)-74(Z)-2-(2-Ai-i o-ttoazo acetylammo]-8-oxo-3-[(E)-l-(isobutyl)-2-oxc-pyjToUd -3-yUdenem 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000044_0002
Starting from (E)-(6S,7S)-7-amino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino-thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3428, 2959, 1759, 1665, 1635, 1533, 1390 MS (ISP): 573.3 (M+H)+; 595.3 (M+Na)+
Example 29
(E)-(6S,7S)-7 (Z)-2-(2-Ammo-thiazol-4-y^^ acetylanuΗθ]-8-oxo-3-[(E)-l-(5^methyl-isooxazolyl)-2-oxc-pyπx>Hόm ylidenemethyl]-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000045_0001
Starting from (E)-(6S,7S)-7-amino-3-[l-(5-methyl-isooxazolyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm-1): 3418, 1759, 1608, 1506, 1382
MS (ISP): 598.3 (M+2H-Na)+; 620 (M+H)+
Example 30
(E)-(6S S)-7 (Z)--^(2-Atnino-tWazol-4-yl)-2-cyclopentyloxyimino- acetylaπ_mo]-8-oxo-3-[(E)-l-(3-mtrophenyl)-2-oxo-py-τoHd ylidenemethyl]-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000046_0001
Starting from (E)-(6S,7S)-7-amino-3-[l-(3-nitrophenyl)-2-oxo- pyrrolidin-3-ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicyclo [4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm'1): 3437, 1758, 1626, 1529, 1388, 1346 MS (ISP): 638.3 (M+2H-Na)+; 660-3 (M+H)+
Example 31
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-tWazol-4-yl)-2-cyclopenryloxyimmo- acetylammo] ^xo-3-[(E) -(4-hyιx>xyphen^ yUdenemethyl]-4rθxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000046_0002
Starting from (E)-(6S,7S)-7-amino-3-[l-(4-hydroxy-phenyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
DKcm"1): 3435, 1758, 1629, 1513, 1392 MS (ISP): 609.3 (M+H)+ Example 32
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-tω.ιzol-4-yl)-2κ;yclopentyloxy-- _dno- acetylamino]--3-[(E)-l-(2-fluoro-phenyl)-2 >xo-pyrroUdin-3- yUdenemethyl]-8<)xo-4-oxa-l-aza-bicyclo[4-2O oct 2-ene-2 ;arboxylic acid as sodium salt
Figure imgf000047_0001
Starting from (E)-(6S,7S)-7-amino-3-[l-(2-fluoro-phenyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3430, 1757, 1675, 1610, 1530, 1390 MS (ISP): 611.4 (M+H)+
Example 33
(E)-(6S S)-7-[(Z)--^(2-Ammo-thiazol^yl)-2 ;yclopentyloxyi-iuno- acety_bammo]-3-[2-oxc-l-(2 yrid yl)-pyrπ
4Oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000047_0002
Starting from (E)-(6S,7S)-7-amino-3-[2-oxo-l-(2-pyridinyl)- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid IR (cm"1): 3439, 1761, 1631, 1586, 1534, 1386. MS (ISP): 616.3 (M+Na)+; 594.4 (M+H)+
Example 34
(E)-(6S/7S)-7-[(_9-2-(2-An _mo-tWazo^ acetylam o]-3 (E) -(l-methyl yrid-mum-2-yl)-2-oxo-pyιτoUdm
Figure imgf000048_0001
acid
Figure imgf000048_0002
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[2-oxo-l-(2-pyridinyl)-pyrrolidin-3-ylidenem ethyl] -8-oxo-
4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid (Example 33) is reacted with methyl iodide.
IR (cm"1): 3428, 1780, 1686, 1634, 1569, 1382. MS (ISP): 608.4 (M+H)+
Example 35
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-tl-ia-M)l-4-yl)-2-cyclopentyloxyim acetyla-_r_ino] Ml-(2-methoxy he
8-oxo-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000048_0003
Starting from (E)-(6S,7S)-7-amino-3-[l-(2-methoxy-phenyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid.
IR (cm"1): 1758, 1672, 1601, 1503, 1390. MS (ISP): 623.5 (M+H)+
Example 36
(E)-(6S S)-7 (Z)-2-(2-Amino-thiazol^-yl)-2- carbamoy--meti_oxyimmcr-acetylam ^ pynOUdin-3-yUdenenietiiyl]-8H)xc^oxa-l-a-»-bicyclo[4.2O oct 2-ene-2- carboxylic acid as sodium salt
Figure imgf000049_0001
Starting from (E)-(6S,7S)-7-amino-3-[l-(4-nitro-benzyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2- carbamoylmethoxyimino-thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3429, 1759, 1672, 1634, 1603, 1522, 1390, 1346 MS (ISP): 641.3 (M+H)+; 663.3 (M+Na)+
Example 37
(E)-(6S,7S)-7-[(Z)-2-(2-Aιm^o-t-ύazol-4-yl)-2-carbamoylmethoxy- i-ncdncHacetylamino]-3 (E)-l-(4-phenyl)-2-oxo-pyrroUdin-3- yUdeneιnethyl]-8-oxo-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000050_0001
Starting from (E)-(6S,7S)-7-amino-8-oxo-3-[2-oxo-l-phenyl- pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2- carbamoylmethoxyimino-thioacetic acid-S-benzo-thiazol-2-yl ester.
IR (cm"1): 3429, 1757, 1674, 1629, 1594, 1533, 1390 MS (ISP): 582.3 (M+H)+; 604.2 (M+Na)+
Example 38
(E)-(6S S)-7-[(Z)-2-(2-Amino-t_ύa-røl-4-yl)-2-carbamoylmethoxy- iιmno-acetylamino]-3-[0E)-l-cyclop-x>pyl-2 )xo-pyιτoUdm yUdeneπιethyl]-8<>xc-4 >xa-l-aza-bicyclo[4^.0.] oct-2-ene-2-carboxylic acid as sodium salt.
Figure imgf000050_0002
Starting from (E)-(6S,7S)-7-amino-3-(l-cyclopropyl-2-oxo-pyrrolidin- 3-ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-carbamoylmethoxyimino- thioacetic acid-S-benzothiazol-2-yl ester.
πKcπr1): 3426, 3199, 1758, 1672, 1630, 1563, 1535, 1392 MS (ISP): 546.2 (M+H)+; 568.2 (M+Na)+ Example 39
(E)-(6S S)-7-[(Z)-2-(2-Ammo-thiazol-4-yl)-2-carbamoylmethoxy- iπ-ino-acetyla_-cu ιo]-3-[(E) -(5-met^y sooxa_-θlyl)-2-oxo-^ ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000051_0001
Starting from (E)-(6S,7S)-7-amino-3-[l-(5-methyl-isooxazolyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2- carbamoylmethoxyimino-thioacetic acid-S-benzothiazol-2-yl ester.
IR (cm"1): 3432, 3197, 1760, 1679, 1608, 1562, 1534, 1506, 1385 MS (ISP): 587.2 (M+H)+; 609.2 (M+Na)+
Example 40
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-thiazol-4-yl)-2-carbamoylmethoxy- immo-acetylammo]-3-[(E)-l-i-- butyl-2-ox
8-oxo-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000051_0002
Starting from (E)-(6S,7S)-7-amino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-carbamoylmethoxyimino- thioacetic acid-S-benzothiazol-2-yl ester
IR (cm"1): 3424, 3196, 1758, 1672, 1634, 1534, 1390 MS (ISP): 562.2 (M+H)+; 584.3 (M+Na+H)+
Example 41
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-thiazol-4-yl)-2-carbamoylmethoxy- im o-acetylammo]-3-[(E)-l-(3-mtro^ y enemethyl]-8-oxc-4^xa-l-aza-bicyclo[4.2.0 cκ;t-2-ene-2 5arboxylic acid as sodium salt
Figure imgf000052_0001
Starting from (E)-(6S,7S)-7-amino-3-[(3-nitrophenyl)-2-oxo- pyrrolidin-3-ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicyclo [4.2.0.] oct-2-ene-2- carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2- carbamoylmethoxyimino-thioacetic acid-S-benzothiazol-2-yl ester
IR (cm-1): 3437, 1759, 1675, 1632, 1529, 1345
MS (ISP): 649.2 (M+H)+; 671.3 (M+Na)+
Example 42
(E)-(6S,7S)-7-[(Z)-2-(2-Anrn o-tWazol^yl)-2-hydroxyimino- acetylammo]-8-oxθτ3-[(E)-l-(2-methoxy-phenyl)-2-oxo-pynx)Udin-3- yUdenemethyl]- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000052_0003
Figure imgf000052_0002
To a suspension of 200 mg ( 0.519 mmol) (E)-(6S,7S)-7-amino-8-oxo- 3-[2-oxo-l-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3-ylidenmethyl]-4-oxa-l- aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid in 8 ml dimethylacetamide (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid-benzotriazol-1-yl ester is added at room temperature according to "the Journal of
Antibiotics, Vol XLIII, p 1564, 1990". The reaction mixture is stirred for 20 hours at room temperature. Dimethylformamide is evaporated. The residue is taken up in 150 ml ethyl acetate/water (1:1). The organic phase is separated and extracted three times with water (50 ml) and dried over magnesium sulfate. The solvent is evaporated and the residue is taken up in ethyl acetate/ n-hexane. (E)-(6S,7S)-7-[(Z)-2-(2- Amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(E)-l-(2- methoxy-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is obtained.
Yield: 204 mg (49%) light yellow crystals.
IR (cm-1): 3437, 1775, 1677, 1635, 1503, 1395 MS (ISP): 797.5 (M+H)+; 814.5 (M+NH4)+
204 mg (0.255 mmol) (E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2- trityloxyimino-acetylamino]-8-oxo-3-[(E)-l-(2-methoxy-phenyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid are dissolved in 1 ml formic acid at room temperature. After 1 hour formic acid is removed in vacuum at 20 °C. The residue is taken up in 100 ml diethylether. The obtained crystals are filtered off over glass fiber under suction and dissolved in 3 ml dimethylformamide. Then 0.2 ml (0.4 mmol) 2N sodium 2-ethyl- capronate solution are added. The solvent is evaporated, 3 ml water are added and the aqueous phase is chromatographed over a polymeric hydrophobic gel (eluent: water-acetonitrile). The fractions containing the product are combined and lyophilized.
Yield : 50 mg (34%) light yellow lyophilizate.
IR (cm"1): 3430, 1758, 1666, 1630, 1532, 1503, 1391.
MS (ISP): 555.2 (M+H)+; 572.4 (M+NH4)+ 577.3 (M+Na)+ Example43
(E)-(6S,7S)-7-[(Z)-_^(2-Ammo-ιMazoW-yl)-2-hy6-roxyimino- acetylammo]-8^xo^[(E)-l-(isκ)butyl)-2 )xo-py-TθUd-_n-3-yUdenemethyll- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000054_0001
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-trityloxyimino- acetylamino]-8-oxo-3-[(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-(l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid and (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid- benzotriazol-1-yl ester.
HKcm'1): 3434, 1778, 1676, 1635, 1565, 1532, 1334.
MS (ISP): 747.5 (M+H)+; 764.5 (M+NH4)+ 769,5 (M+Na)+
The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2-
Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l- (isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
IR (cm"1): 3429, 1757, 1664, 1632, 1534, 1390 MS (ISP): 505.2 (M+H)+; 522.2 (M+NH4)+; 527.2 (M+Na)+
Example 44
(E)-(6S,7S)-7-[(Z)-2-(2-Aπm o^tMa2θl -yl)-2-hyό^xyimm acetylaπιino]-8H)xo^-[(E)-l-(2--iuo-X)-phenyl)-2 .xo-pyrroUdin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000055_0001
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]- 8-oxo-3-[(E)-l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa- l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-[l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicy clo [4.2.0.] oct-2-ene-2-carboxylic acid with (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid- benzotriazol-1-yl ester.
IR (cm"1): 3435, 1777, 1682, 1633, 1503, 1397 MS (ISP): 785.4 (M+H)+; 807.4 (M+Na)+
The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(2- fluoro-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
IR (cm"1): 3422, 1758, 1669, 1609, 1532, 1504, 1392.
MS (ISP): 543.1 (M+H)+; 560.2 (M+NH4)+
Example 45
(E)-(6S S)-7 (Z)-2-(2-Aιnmo-thiazol -yl)-2-hyd- )xyiπι o- acetylammo]-8<>xo^-[(E)-M3-mtιx>-phenyl)^ ylidenemethyl]-4-oxa-l-aza-bicyclo[4^.0.] oct-2-ene-2-carboxylic acid as sodium salt
Figure imgf000055_0002
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylamino]-8-oxo-3-[(E)-l-(3-nitro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-[l-(3-nitrophenyl)-2-oxo- pyrrolidin-3-ylidenemethyl] -8-oxo-4-oxa- 1-aza-bicy clo [4.2.0. ] oct-2-ene-2- carboxylic acid with (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid-benzotriazol-1-yl ester.
IR (cm"1): 3437, 1758, 1626, 1529, 1388,1346.
MS (ISP): 812.4 (M+H)+; 829.4 (M+NH4)+ ; 834.3 (M+Na)+
The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(3-nitro- phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-
2-ene-2-carboxylic acid sodium salt .
IR (cm"1): 3434, 1758, 1668, 1617, 1529, 1388.
MS (ISP): 570.2 (M+H)+; 587.3 (M+NH4)+; 592.2 (M+Na)+
Example 46
(E)-(6S,7S)-7-[(Z)-2-(2-Ammo-tMazol^yl)-2-hyd oxyimino- acetylammo]*oxo^ (E)-l-(pyrid--α-2-yl)-2<>xo-pyrι Udin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4-2.0.] oct-2-ene-2-carboxylic acid as sodium salt.
Figure imgf000056_0001
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylamino]-8-oxo-3-[(E)-l-(pvridin-2-yl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-[l-(pyridin-2-yl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid with (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid-benzotriazol-1-yl ester.
IR (cm"1): 3430, 1775, 1684, 1630, 1532, 1389,1309. MS (ISP): 768.4 (M+H)+ ; 790.4 (M+Na)+ The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l- (pyridin-2-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
IR (cm"1): 3427, 1758, 1666, 1628, 1533, 1386. MS (ISP): 526.1(M+H)+
Example 47
(E)-(6S,7S)-7 (Z)-2-(2-Ammo mazol- yl)-2-hydroxyimino- acety]ammo]-8^xo M(E)-l-(4-mtro-^ ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxy-ic acid as sodium salt.
Figure imgf000057_0001
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylamino]-8-oxo-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-[l-(4-nitro-benzyl)-2-oxo- pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2- carboxylic acid with (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetic acid-benzotriazol-1-yl ester.
IR(cm'1): 3435, 1778, 1678, 1636, 1522, 1346.
MS (ISP): 826.5(M+H)+; 843.5 (M+NH4)+; 848.4 (M+Na)+
The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(4-nitro- benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl] -4-oxa- 1-aza-bicyclo [4.2.0. ] oct- 2-ene-2-carboxylic acid sodium salt.
IR(cm"1): 3430, 1756, 1665, 1633, 1521, 1346.
MS (ISP): 584.3(M+H)+ Example 48
(E)-(6S S)-7 (Z)-2-(2-Ammo-tmazol^yl)-2-hydroxyimino- acetylami.no]-θ )xo^-[(E)-l-(5-nιethyl-isooxazolyl)-2-oxc-pyπx)Ud -3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4 2.0.] oct-2-ene-2-carboxylic acid as sodium salt.
Figure imgf000058_0001
(E)-(6S,7S)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetylamino]-8-oxo-3-[(E)-l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is prepared by reacting (E)-(6S,7S)-7-amino-3-[l-(5-methyl-isooxazolyl)-2- oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2- ene-2-carboxylic acid with (Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino- acetic acid-benzotriazol-1-yl ester.
IR (cm"1): 3435, 1776, 1685, 1609, 1505, 1386. MS (ISP): 772.4(M+H)+; 794.3 (M+Na)+
The trityl-protecting group is cleaved off to give (E)-(6S,7S)-7-[(Z)-2-(2- amino-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-l-(5- methyl-isooxazolyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt .
IR (cm"1): 3435, 1758, 1609, 1506, 1384.
MS (ISP):530.1(M+H)+; 552.2 (M+Na)+
Example 49
(E)-(6S,7S)-7-[[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-yl- carbonyl]-ammo]-3-[(E)-l-(isobutyl)-2 )xo-pyrroKό--n-^^ oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt.
Figure imgf000059_0001
5.02 g (18.45 mmol) 3-(2,6-dichloro-phenyl)-5-methyl-isoxazole-4- carboxylic acid ( CAS Reg. No 3919-76-4, Beilstein 5-27, 6-27) are dissolved in 140 ml acetonitrile. 2.8 g (27.6 mmol) N-methyl-morpholine are added. Then 7.36 g 2,2'-dithiobisbenzothiazole are added. A solution of 5.36 g (32.3 mmol) triethylphosphite in 15 ml acetonitrile are added dropwise within two hours at 0 °C. The solution is cooled to -10 °C. The obtained crystals are filtered off under suction, washed with acetonitrile and ether. 3-(2,6-dichloro-phenyl)-5-methyl-isoxazole-4-carbothioic acid
S-benzothiazol-2-yl ester is obtained.
Yield : 6.59 g (84.7 %)
IR (cm-1): 3436, 1669, 1575, 1425 MS (E.I. + I) = 420 (M.)
(E)-(6S,7S)-7-[[3-(2,6-dichloro-phenyl)-5-methyl-isoxazol-4-yl-carbonyl]- amino]-3-[(E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-4-oxa-l- aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt is prepared by reacting (E)-(6S,7S)-7-amino-3-( l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid with 3-(2,6-dichloro-phenyl)-5-methyl-isoxazol-4-carbothioic acid S- benzothiazol-2-yl ester.
IR (cm"1): 3429, 1761, 1667, 1601, 1561, 1391.
MS (ISP): 589.2, 591.2(M+H)+; 606.2, 608.2 (M+NH4)+; 611.2, 613.2
(M+Na)+
Example 50
(6S,7S)^-((E) -lsobutyl-2-oxo-pyrroUdin-3-ylidenemethyl)-7[2-(l- πιethyl-lH-tet3^ιzol-5-ylsulfanyl)-acetyla-mno)-8 >xo-4-o bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid as sodium salt.
Figure imgf000060_0001
5.2 g (885 mmol) (l-methyl-lH-tetrazol-5-ylsulfanyl)-acetic acid ( CAS Reg. No 55862-52-7; Saito, Seiki et al, Synlett (1993), 2, 139-40 ; 29) are dissolved in 100 ml dimetylformamide. Then 3.44 g (32.84 mmol) N- hydroxysuccinimide are added. Then 6.78 g N,N'-dicyclohexylcarbodi- imid are added. After a view minutes white crystals are obtained. The suspension is stirred for further five days. The crystals are filtered off. Dimethylformamide is is removed in vacuum. The residue is is taken up in 60 ml ethyl acetate at 60 °C, filtered off, washed with 30 ml ethylacetate (three times) and dried at high vacuum. 1-Methyl-1H- tetrazol-5-ylsulfanyl)-acetic acid 2,5-dioxo-pyrrolidin-l-yl ester is obtained.
Yield: 6.54 g ( 80.7 %)
IR (cm"1): 3497, 1740, 1627, 1415, 1199 MS (E.I. + QI) = 272 (M + H)+
(6S,7S)-3-((E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7[2-(l-methyl- lH-tetrazol-5-ylsulfanyl)-acetylamino)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt is prepared by reacting (E)- (6S,7S)-7-amino-3-(l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid with (1-methyl-lH- tetrazol-5-ylsulfanyl)-acetic acid 2,5-dioxo-pyrrolidin-l-yl ester.
IR (cm"1): 3434, 1759, 1677, 1641, 1597, 1393.
MS (ISP): 492.2(M+H)+; 509.1 (M+NH4)+; 514.0(M+Na)+
Example 51
(6S,7S)-7-Acetylamino^((E) -isobutyl-2-oxo-pyι oUdin-3- yUdeneιnethyl)-β >xo-4^xa-l-aza-bicyclo[4^.0.] oct-2^ne-2 «u,boxylic acid as sodium salt
Figure imgf000061_0001
(E)-(6S,7S)-7-amino-3-(l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8- oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid is reacted with acetanhydride.
IR (cm"1): 3439, 1760, 1674, 1640, 1599,1556, 1392.
MS (ISP): 378.2(M+H)+; 395.3 (M+NH4)+; 400.2(M+Na)+

Claims

Clai s
1. Isooxacephem derivatives of the general formula I
Figure imgf000062_0001
wherein
R1 is hydrogen or an acyl group derived from a carboxylic acid; R is hydrogen, hydroxy, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy or a heterocyclic ring; the lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl, aryloxy, aryl-lower alkoxy and the heterocyclic ring being unsubstituted or substituted with at least one group selected from carboxy, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CONR21R22, -N(R22)CO0R23, R22CO-, R220CO- or R22cOO-, wherein R21 is hydrogen, lower alkyl, or cycloaikyl; R 2 is hydrogen or lower alkyl; R23 is lower alkyl, lower alkenyl or a carboxylic acid protecting group; 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 with the 3-substituent in the E-form, having the formula la
Figure imgf000062_0002
wherein R1 and R are as defined in claim 1.
3. Compounds of claim 1 with the 3-substituent in the Z-form, having the formula lb
Figure imgf000063_0001
wherein R1 and R are as defined in claim 1.
4. Compounds of any one of claims 1-3, wherein R1 is a residue of one of the formulae a to g
O
R10-C-$- a
Figure imgf000063_0002
O Rπ-CH-C -s-
>12
R11— CH2-0 — C-$-
R"-0-C CHH22 —— .+■
o
R» — S-CH, — C i-÷-
Figure imgf000063_0003
wherein
j is 0, 1, 2 or 3;
R3 is hydrogen, lower alkyl, cycloaikyl, carbamoyl-lower alkyl, aryl- lower alkyl; R1^ is hydrogen, lower alkyl, cycloaikyl, lower alkoxy, lower alkenyl or cycloalkenyl, the lower alkyl group or the lower alkenyl group being optionally substituted with at least one group selected from halogen, cyano, nitro, amino, mercapto, alkylthio or cyano- methylthio;
R11 is aryl unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl or aminomethyl; a heterocyclic ring unsubstituted or substituted with at least one group selected from halogen, hydroxy, nitro, amino, cyano, carboxy, lower alkyl, lower alkoxy, carbamoyl, trifluoromethyl, aminomethyl or substituted with optionally substituted phenyl or fused together with a benzene ring; R^ is amino, acylamino, hydroxy, sulfato, a carboxyl salt, protected carboxy or azido.
5. Compounds of claim 4, wherein R1 is a residue of formula a.
6. Compounds of claim 5, wherein R1 is acetyl.
7. Compounds of claim 4, wherein R1 is a residue of formula b.
8. Compounds of claim 7, wherein R1 is 2,6-dichlorophenyl-5- methyl-isoxazol-4-yl-carbonyl
9. Compounds of claim 4, wherein R1 is a residue of formula f.
10. Compounds of claim 9, wherein R1 is l-methyl-tetrazol-5-yl- sulfanyl-acetyl.
11. Compounds of claims 4, wherein R1 is a residue of formula g.
12. Compounds of claim 11, having the formula II
Figure imgf000064_0001
wherein R2 is as defined in claim 1 and R^ is as defined in claim 4.
13. Compounds of claim 12, wherein R is hydrogen, carbamoyl- lower alkyl or cycloaikyl.
14. Compounds of claim 13, wherein R3 is hydrogen, carbamoylmethyl, or cyclopentyl.
15. Compounds of any one of claims 1-14, wherein R2 is lower alkyl, cycloaikyl, aryl-lower alkyl, aryl or a heterocyclic ring, the lower alkyl, aryl-lower alkyl, aryl and the heterocyclic ring being unsubstituted or substituted with at least one group selected from halogen, hydroxy, amino, nitro, cyano, lower alkyl, lower alkoxy.
16. Compounds of claim 15, wherein R2 is isobutyl, 2,2,2- trifluoroethyl, cyclopropyl, phenyl, 3-nitrophenyl, 4-hydroxyphenyl, 2- fluorophenyl, 2-methoxyphenyl, 4-nitrobenzyl, pyridinyl, N-methyl- pyridinium-2-yl or 5-methyl-isoxazolyl.
17. Compounds of claiml,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-2-oxo-l-(2,2,2-trifluoro-ethyl)-pyrrolidin-3- ylidenmethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-0X0-3- [(E)-2-oxo-l-phenyl-pyrrolidin-3-ylidenmethyl] -4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(cyclopropyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt, (E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-8-oxo-3-[(E)-l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-0X0-3- [(E)- l-(3-nitrophenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -8-oxo-3- [(E)- l-(4-hyroxyphenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]~3-[(E)-l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[2-oxo-l-(2-pyridinyl)-pyrrolidin-3-ylidenemethyl]-8-oxo- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino]-3-[(E)-l-(l-methyl-pyridinium-2-yl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-cyclopentyloxyimino- acetylamino] -3-[l-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3-ylidenemethyl] -
8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(4-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-cyclopropyl-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]- 8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-carbamoylmethoxy- imino-acetylamino]-3-[(E)-l-(3-nitrophenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(2-fluoro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl] -4-oxa- 1-aza-bicy clo [4.2.0.] oct-2-ene-2-carboxy lie acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino] -8-0X0-3- [(E)-l-(3-nitro-phenyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt, (E)-(6S,7S)-7-[(Z)-2-(2,Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(pvridin-2-yl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-l-(4-nitro-benzyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino- acetylamino] -8-0X0-3- [(E)- l-(5-methyl-isooxazolyl)-2-oxo-pyrrolidin-3- ylidenemethyl]-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(E)-(6S,7S)-7-[[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-yl- carbonyl]-amino]-3-[(E)-l-(isobutyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-4- oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(6S,7S)-3-((E)-l-Isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7[2-(l- methyl-lH-tetrazol-5-ylsulfanyl)-acetylamino)-8-oxo-4-oxa-l-aza- bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt,
(6S,7S)-7-Acetylamino-3-((E)-l-isobutyl-2-oxo-pyrrolidin-3- ylidenemethyl)-8-oxo-4-oxa-l-aza-bicyclo[4.2.0.] oct-2-ene-2-carboxylic acid sodium salt.
18. A pharmaceutical preparation, particularly for the treatment and prophylaxis of infectious diseases containing a compound of any one of claims 1-17 and a pharmaceutically inert carrier.
19. Process for the manufacture of compounds of any one of claims
1-17, which process comprises
(a) treating a compound having the formula III
Figure imgf000068_0001
in which R2 is as defined in claim 1, or an ester or salt thereof, .with acylating agents, or
(b) for the manufacture of a compound of formula I in which R1 and/or R2 may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) or reducing a nitro group to amino in a compound having the formula IV
Figure imgf000069_0001
in which Rh is hydrogen or a carboxy protecting group, Rf is as R1 and Rε is as R2 with the proviso that at least one of the following provisions is fulfilled: (i) Rn is a carboxylic acid protecting group,
(ii) Rf is a residue defined under R1 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s),
(iii) RS is a residue defined under R2 having nitro, protected amino, protected hydroxy and/or protected carboxylic group(s), 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.
20. Compounds of any one of claims 1-17 for use as pharmaceutically active substances particularly for the treatment and prophylaxis of infectious diseases.
21. The use of the compounds of any one of claims 1-17 as medicaments or for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.
22. Compounds of any one of claims 1-17, whenever prepared according to the process claimed in claim 19 or by an obvious chemical equivalent thereof.
23. The novel compounds, formulations, processes and methods substantially as described herein.
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