EP0000500B1 - Dérivés de, cephalosporine leur préparation et leurs compositions pharmaceutiques - Google Patents

Dérivés de, cephalosporine leur préparation et leurs compositions pharmaceutiques Download PDF

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Publication number
EP0000500B1
EP0000500B1 EP78100367A EP78100367A EP0000500B1 EP 0000500 B1 EP0000500 B1 EP 0000500B1 EP 78100367 A EP78100367 A EP 78100367A EP 78100367 A EP78100367 A EP 78100367A EP 0000500 B1 EP0000500 B1 EP 0000500B1
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Prior art keywords
amino
group
cephem
acid
carboxylic acid
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EP0000500A3 (en
EP0000500A2 (fr
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Karoly Dr. Kocsis
Peter Dr. Schneider
Bruno Dr. Fechtig
Riccardo Dr. Scartazzini
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Novartis AG
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Ciba Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to new acylamido-3-cephem-4-carboxylic acid compounds and their salts, processes for their preparation, pharmaceutical compositions containing these compounds with antibiotic activity and their therapeutic use for the treatment of infections, and new intermediates and their preparation.
  • the object of the present invention is to produce new 7 ⁇ -acylamino-3-cephem-4-carboxylic acid compounds which have novel acyl groups which are characterized by the presence of a terminal a-aminocarboxylic acid group.
  • the new compounds are characterized by an excellent effect against normal and resistant germs and have an unexpectedly long time in the body.
  • lower in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl and the like means that the corresponding groups, unless expressly defined otherwise, up to. 7, preferably up to 4 carbon atoms contain:
  • a group - (C n H 2n ) - is a branched or unbranched alkylene chain, and is in particular methylene, 1,2-ethylene, 1,3-propylene or 1,4-butylene, furthermore, for example, 1,1-ethylene, 1, 1-propylene, 1,2-propylene, 1,1-butylene, or 1,1-isobutylene.
  • An optionally substituted phenylene group A is in particular p-, but can also be o- or m-phenylene.
  • Substituents of the phenylene group are, for example, lower alkyl, such as methyl, hydroxy, lower alkoxy, such as methoxy, and / or halogen, such as fluorine, chlorine or bromine.
  • An optionally substituted thienylene group A is in particular 2,5-thienylene, furthermore 2,4-or 2,3-thienylene.
  • furylene group A is in particular 2,5-furylene, furthermore 2,4- or 2,3-furylene.
  • Substituents of the thienylene and furylene group A are, for example, lower alkyl, such as methyl, lower alkoxy, such as methoxy, and / or halogen, such as fluorine, chlorine or bromine.
  • Z is hydrogen
  • Y is preferably hydrogen or hydroxy, or else amino, or sulfo.
  • R ° contains 1-4 carbon atoms as optionally substituted lower alkyl.
  • Substituents of such a lower alkyl group R ° are, for example, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, hydroxy or acylated hydroxy, such as lower alkanoyloxy, e.g. Acetoxy, sulfo, and in particular free or also esterified carboxy.
  • R ° are, for example, methyl, ethyl, propyl, butyl, methoxymethyl, methoxyethyl, such as 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-haiogen, such as 2-chloroethyl, 3-halogen, such as 3 Chloropropyl, or 4-halogen, such as 4-chlorobutyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, in which the hydroxy group can be acylated, for example, by lower alkanoyl, such as acetyl, 2-sulfoethyl, 3-sulfopropyl, 2- Carboxyethyl, 3-carboxypropyl or 4-carboxybutyl, in which the carboxy group can be esterified, for example, by lower alkyl, such as methyl or ethyl.
  • a lower alkyl group R 1 contains 1-4 carbon atoms and is, for example, ethyl, propyl, butyl or in particular methyl.
  • a lower alkoxy group R 1 contains 1-4 C atoms and is, for example, methoxy, ethoxy, propoxy or butoxy.
  • R 1 as halogen is fluorine, bromine, iodine or preferably chlorine.
  • An esterified hydroxy or mercapto group R 2 is esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid.
  • Hydroxy groups R 2 esterified with lower aliphatic carboxylic acids are, in particular, lower alkanoyloxy, in particular acetyloxy, furthermore formyloxy, propionyloxy, valeryloxy, hexanoyloxy, heptanoyloxy or pivaloyloxy.
  • Mercapto groups R 2 esterified with lower aliphatic carboxylic acids are lower alkanoylthio, such as acetylthio, formylthio, propionylthio, valeroylthio, hexanoylthio, heptanoylthio or pivaloylthio.
  • N substituents are optionally substituted by halogen, for example chlorine, or by lower alkanoyl, for example acetyl or propionyl, lower alkyl, for example methyl, ethyl, 2-chloroethyl, or 2 -Acetoxyethyl.
  • halogen for example chlorine
  • lower alkanoyl for example acetyl or propionyl
  • lower alkyl for example methyl, ethyl, 2-chloroethyl, or 2 -Acetoxyethyl.
  • Hydroxyl groups R 2 esterified in this way are, for example, carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N- (2-chloroethyl) carbamoyloxy or N- (2-acetoxyethyl) carbamoyloxy.
  • Corresponding esterified mercapto groups R 2 are, for example, carbamoylthio, N-methylcarbamoylthio, N-ethylcarbamoylthio, N- (2-chloroethyl) carbamoylthio or N- (2-acetoxyethyl) carbamoylthio.
  • Lower alkoxy and lower alkylthio groups R 2 have in particular 1-4. C atoms, and are primarily methoxy, as well as ethoxy, n-propyloxy or isopropyloxy, furthermore straight-chain or branched. Butyloxy, or methylthio, and also ethylthio, n-propylthio or isopropylthio, and also straight-chain or branched butylthio.
  • Substituted by an optionally via a ring carbon atom to the mercapto group bound heterocyclic radical having from 1 to 4 ring nitrogen atoms and optionally a further ring hetero atom of the group oxygen and sulfur etherified mercapto groups R 2 are the substituents mentioned below are primarily optionally containing monocyclic five-membered diaza- , triaza, tetraza, thiaza, thiadiaza, thiatriaza, oxaza or oxadiazacyclic radicals of aromatic character.
  • Substituents of such heterocyclyl radicals are lower alkyl, in particular methyl, and also ethyl, n-propyl, isopropyl or straight-chain or branched butyl, or by hydroxyl, lower alkanoyloxy, halogen, such as chlorine, carboxy, lower alkoxycarbonyl, sulfo, amidated sulfo, amino, mono- or di-lower alkylamino, Niederalkanoylamino, or substituted by Niederalkanoylamino as substituted by carboxy or halogen lower alkyl, for example 2-hydroxyethyl, 2-acetoxyethyl, 2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, sulfomethyl, 2-sulfoethyl, sulfamethyl -Sulfamylethyl, 2-amino
  • heterocyclic radical is cycloalkyl, for example cyclopentyl or cyclohexyl, aryl, such as phenyl optionally substituted by halogen, for example chlorine or nitro, aryl-lower alkyl, for example benzyl, or heterocyclyl, such as furyl, for example 2-furyl, thie nyl, for example 2-thienyl, or oxazolyl, for example 2- or 5-oxazolyl, or functional groups, such as halogen, for example fluorine, chlorine or bromine, optionally substituted amino, such as optionally mono- or di-substituted amino, for example amino, by lower alkyl , Methylamino or dimethylamino, acylamino, such as lower alkanoylamino or lower alkanoylamino substituted by halogen or carboxy, such as acetylamino, 3-chloropropionylamino or 3-
  • Preferred heterocyclically etherified mercapto groups R 2 in which the heterocyclic radical represents a corresponding monocyclic, five-membered radical, include imidazolylthio, for example 2-imidazolylthio, triazolylthio optionally substituted by lower alkyl and / or phenyl, for example 1 H-1,2,3-triazole 4-ylthio, 1-methyl-1H-1,2,3-triazol-4-ylthio, 1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-triazol- 3-ylthio, 3-methyl-1-phenyl-1H-1,2,4-triazol-5-ylthio, 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio or 4-phenyl- 4H-1,2,4-triazol-3-ylthio, in particular tetrazolylthio optionally substituted as indicated, for example 1 H-tetrazol-5-
  • 1,2,3,4-thiatriazolyl-5-ylthio optionally substituted oxazolylthio or isoxazolylthio as indicated, for example 5-oxazolylthio, 4-methyl-5-oxazolylthio, 2-oxazolylthio, 4,5-diphenyl-2-oxazolylthio or 3 -Methyl-5-isoxazolylthio, or optionally substituted oxadiazolylthio as indicated, for example 1,2,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, Z-phenyl-1,3 , 4-oxadiazol-5-ylthio, 5- (4-nitrophenyl) -1,3,4-oxadiazol-2-ylthio or 2- (2-thienyl) -1,3,4-oxadiazole -5-ylthio.
  • Preferred heterocyclically etherified mercapto groups R 2 in which the heterocyclic radical represents a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical, include, inter alia, 1-oxido-pyridylthio optionally substituted by halogen, for example 1-oxido-2-pyridylthio or 4-chloro 1-oxido-2-pyridylthio, optionally substituted by hydroxy pyridazinylthio, for example 3-hydroxy-6-pyridazinylthio, optionally substituted by lower alkyl, lower alkoxy or halogen, N-oxido-pyridazinylthio, for example 2-oxido-6-pyridazinylthio, 3-chloro 1-oxido-6-pyridazinylthio, 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio, 3-ethoxy-1-oxid
  • Quaternary ammonium groups R 2 are quaternary ammonium groups derived from tertiary organic bases, preferably from corresponding aliphatic amines or primarily from corresponding heterocyclic nitrogen bases, which are linked to the methyl carbon atom via the nitrogen atom.
  • quaternary ammonium group R 2 which is derived from a tertiary organic base, the nitrogen atom is bound to the methyl carbon atom and is accordingly present in quaternized, positively charged form.
  • Quaternary ammonium groups include tri-lower alkylammonium, for example trimethylammonium, triethylammonium, tripropylammonium or tributylammonium, but in particular optionally substituted, for example lower alkyl, such as methyl, hydroxy-lower alkyl, such as hydroxymethyl, amino, substituted sulfonamido, such as 4-aminophenylsulfonamido, hydroxyl, halogen, such as fluorine Bromine or iodine, halogenated lower alkyl, such as trifluoromethyl, sulfo, optionally functionally modified carboxy, such as carboxy, lower alkoxycarbonyl, for example methoxycarbonyl, cyano,
  • Heterocyclic ammonium groups R 2 are primarily optionally lower alkyl, Hy d r ox y- lower alkyl, amino, substituted sulfonamido, hydroxy, halogen, trifluoromethyl, sulfo, carboxy, lower alkoxycarbonyl, cyano, lower alkanoyl, 1-lower alkyl-pyrrolidinyl or pyridinium containing N-substituted carbamoyl which is substituted by lower alkyl or hydroxy-lower alkyl, for example pyridinium, 2-, 3- or 4-methyl-pyridinium, 3,5-dimethyl-pyridinium, 2,4,6-trimethylpyridinium, 2-, 3- or 4-ethyl-pyridinium, 2-, 3- or 4-propyl-pyridinium or in particular 4-hydroxymethylpyridinium , furthermore 2-amino- or 2-amino-6-methyl-pyridinium, 2- (4-aminopheny
  • the functional groups present in compounds of the formula I are optionally protected by protective groups which are used in penicillin, cephalosporin and peptide chemistry.
  • Such protective groups are easy to remove, that is to say without undesirable side reactions taking place, for example solvolytically reductive, photolytically or even under physiological conditions.
  • carboxyl groups are Usually protected in esterified form, such ester groups being easily cleavable under mild conditions.
  • Suitable protected carboxyl groups are in particular lower alkoxycarbonyl, in particular tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. Adamantyloxycarbonyl, arylmethoxycarbonyl, wherein aryl is preferably one or two, optionally, e.g. by lower alkyl, especially tertiary lower alkyl, e.g. tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g.
  • Chlorine, and / or nitro, mono- or poly-substituted phenyl radicals such as optionally, e.g. substituted benzyloxycarbonyl as mentioned above, e.g. 4-nitro-benzyloxycarbonyl, or 4-methoxybenzyloxycarbonyl, or e.g. substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halogeno lower alkoxycarbonyl, e.g.
  • 2,2,2-trichloroethoxycarbonyl especially aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. benzoyl substituted by halogen such as bromine, e.g. Phenacyloxycarbonyl, or polyhaloaryloxycarbonyl, such as pentachlorophenyloxycarbonyl, in question.
  • Esterified carboxyl groups are also corresponding silyloxycarbonyl, in particular organic silyloxycarbonyl groups or corresponding stannyloxycarbonyl groups.
  • the silicon or tin atom preferably contains lower alkyl, especially methyl, furthermore lower alkoxy, e.g.
  • Suitable silyl or stannyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, also dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halosilyl, e.g. Methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, e.g. Dimethylchlorosilyl, or appropriately substituted stannyl compounds, e.g. Tri-n-butylstannyl.
  • Preferred as the protected carboxyl group is especially tert-butyloxycarbonyl, optionally, e.g. substituted benzyloxycarbonyl as mentioned e.g. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl.
  • An esterified carboxyl group which is cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group, in which acyl e.g. is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the residue of a lactone.
  • acyloxymethoxycarbonyl e.g. Acetyloxymethyloxycarbonyl or pivaloyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, e.g.
  • a protected amino group can e.g. are present in the form of an easily cleavable acylamino, triarylmethylamino, etherified mercaptoamino, 1-acyl-2-lower alkylidene amino, silyl or stannylamino group or as an azido group.
  • acyl is preferably the acyl radical of a carbonic acid semi-ester, such as lower alkoxycarbonyl, in particular tert.-lower alkoxycarbonyl, for example tert.-butyloxycarbonyl, polycycloalkoxycarbonyl, for example adamantyloxycarbonyl, arylmethoxycarbonyl, in which aryl is preferably one or two, optionally, for example by lower alkyl, in particular tert.
  • a carbonic acid semi-ester such as lower alkoxycarbonyl, in particular tert.-lower alkoxycarbonyl, for example tert.-butyloxycarbonyl, polycycloalkoxycarbonyl, for example adamantyloxycarbonyl, arylmethoxycarbonyl, in which aryl is preferably one or two, optionally, for example by lower alkyl, in particular tert.
  • alkyl for example tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and / or nitro
  • phenyl radicals such as optionally, for example as mentioned above, substituted benzyloxycarbonyl, for example 4-nitro-benzyloxycarbonyl , or, for example, as mentioned above, substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halogeno-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, in particular aroylmethoxycarbonyl, in which the aroyl group is preferably benzoyl optionally substituted, for example, by
  • Acyl in an acylamino group can also represent the corresponding residue of an organic sulfonic acid; such a radical is in particular arylsulfonyl, in which aryl is a phenyl radical which is optionally substituted, for example by lower alkyl, such as methyl, halogen, such as bromine or nitro, for example 4-methylphenylsulfonyl.
  • the aryl radicals are in particular optionally substituted phenyl radicals; a corresponding group is primarily trityl.
  • An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, in which aryl in particular optionally, e.g. phenyl substituted by lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen such as chlorine and / or nitro.
  • a corresponding amino protecting group is e.g. 4-nitrophenylthio.
  • acyl is preferably the corresponding residue of a lower alkane carboxylic acid, an optionally, e.g. benzoic acid substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro, or a carbonic acid semi-ester, such as a carbonic acid lower alkyl half ester.
  • Corresponding protective groups are primarily 1-lower alkanoyl-2-propylidene, e.g. 1-acetyl-2-propylidene, or 1-lower alkoxycarbonyl-2-propylidene, e.g. 1-ethoxycarbonyl-2-propylidene.
  • a silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which the silicon or tin atom is preferably lower alkyl, especially methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Contains chlorine as a substituent.
  • Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halosilyl, e.g.
  • an amino group can also be protected in protonated form; the anions are primarily those of strong inorganic acids such as hydrohalic acids, e.g. the chlorine or bromine anion, or of sulfonic acid, such as p-toluenesulfonic acid, in question.
  • hydrohalic acids e.g. the chlorine or bromine anion
  • sulfonic acid such as p-toluenesulfonic acid
  • amino protecting groups are the acyl residues of carbonic acid semiesters, especially tert-lower alkoxycarbonyl, optionally, e.g. substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halogeno-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, as indicated.
  • Hydroxy protecting groups are e.g. Acyl radicals, such as 2,2-dichloroacetyl or in particular one of the acyl radicals of carbonic acid semiesters mentioned in connection with a protected amino group, in particular 2,2,2-trichloroethoxycarbonyl, or organic silyl or stannyl radicals, and also easily removable 2-oxa- or 2-thia -aliphatic or -cycloaliphatic hydrocarbon radicals, primarily 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for example 1-methoxyethyl, 1-ethoxyethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacyclone-lower alkyl with 5-7 ring atoms, e.g.
  • Acyl radicals such as 2,2-dichloroacetyl or in particular one of the acyl radicals of carbonic acid
  • 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues as well as easily removable, optionally substituted ⁇ -phenyne-lower alkyl radicals, such as optionally substituted benzyl or diphenylmethyl, the substituents of the phenyl radicals being e.g. Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.
  • Halogen such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.
  • a protected sulfo group is primarily a sulfo group esterified with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, such as a lower alkanol, or with a silyl or stannyl radical, such as tri-lower alkylsilyl.
  • the hydroxyl group may be etherified like the hydroxyl group in an esterified carboxy group.
  • Salts are especially those of compounds of formula I with a free carboxyl group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and also heterocyclic bases for salt formation come into question, such as lower alkylamines, for example Triethylamine, hydroxy-lower alkylamines, e.g.
  • 2-hydroxyethylamine bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 2-diethylaminoethyl 4-aminobenzoic acid, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine, furthermore bases of the pyridine type, e.g. Pyridine, collidine or quinoline.
  • pyridine type e.g. Pyridine, collidine or quinoline.
  • Compounds of formula I with a basic group can include acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. Form trifluoroacetic acid, as well as with amino acids such as arginine and lysine.
  • acid addition salts e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. Form trifluoroacetic acid, as well as with amino acids such as arginine and lysine.
  • Compounds of the formula with a free carboxyl group and free amino group can also be in the form of internal salts, i.e. are in zwitterionic form.
  • the acyl residue on the 7 ⁇ -amino group contains one or optionally two centers of asymmetry.
  • the optionally present center of asymmetry closest to the 7-amino group namely when Y is hydroxyl, amino or sulfo and Z is hydrogen, is in the R, S or preferably in the R Configuration before.
  • the center of asymmetry at the terminal aminocarboxylic acid group can have the R, S or R, S configuration.
  • the compounds of the formula in which carboxyl groups are optionally esterified in physiologically cleavable form, and their pharmaceutically usable, non-toxic salts are valuable antibiotic substances which can be used in particular as antibacterial antibiotics.
  • they are effective in vitro against gram-positive and gram-negative microorganisms, such as against cocci, including Neisseria species, and anaerobes in minimum concentrations of about 0.02 mcg / ml and against Enterobacteriaceae in minimum concentrations of about 0.25 mcg / ml .
  • the invention relates in particular to the compounds of the formula I described in the examples, their pharmaceutically acceptable salts, and the starting materials and intermediates described therein.
  • the compounds of the present invention are obtained by methods known per se.
  • a tert-lower alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylme Convert the thoxycarbonyl group into the free carboxyl group by treatment with a suitable acidic agent, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole.
  • a suitable acidic agent such as formic acid or trifluoroacetic acid
  • a nucleophilic compound such as phenol or anisole.
  • An optionally substituted benzyloxycarbonyl group can be released, for example, by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst.
  • substituted benzyloxycarbonyl groups such as 4-nitrobenzyloxycarbonyl
  • benzyloxycarbonyl groups also by means of chemical reduction, for example by treatment with an alkali metal, for example sodium dithionite, or with a reducing metal, for example zinc, or metal salt, such as a chromium (II) salt, for example chromium II-chloride, usually in the presence of a hydrogen-donating agent capable of producing nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably water, being added to the free carboxyl group convict.
  • a hydrogen-donating agent capable of producing nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably water, being added to the free carboxyl group convict.
  • a 2-halogeno-lower alkoxycarbonyl group (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group) or an acylmethoxycarbonyl group into the free carboxyl group, whereby an aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide.
  • a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide.
  • a polyhaloaryloxycarbonyl group such as the pentachlorophenyloxycarbonyl group, is saponified to the free carboxyl group under mild basic conditions, such as by dilute sodium hydroxide solution or organic bases in the presence of water.
  • a carboxyl group protected, for example, by silylation or stannylation can be released in the usual way, for example by treatment with water or an alcohol.
  • a protected amino group is known in a manner known per se and in various ways depending on the type of protective group, e.g. released by solvolysis or reduction.
  • a 2-halogeno lower alkoxycarbonylamino group (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group), an acylmethoxycarbonylamino group or a 4-nitrobenzyloxycarbonylamino group can e.g.
  • a suitable chemical reducing agent such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonylamino group also by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate and a 4-nitrobenzyloxycarbonylamino group also by treatment with an alkali metal, e.g. Sodium dithionite, a diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or polycycloalkoxycarbonylamino group by treating e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonylamino group, e.g.
  • a hydrogenation catalyst such as a palladium catalyst, an aryl or aryl-lower alkylthioamino group e.g. by treatment with a nucleophilic reagent such as sulfurous acid, an arylsulfonylamino group e.g. by means of electrolytic reduction, a 1-acyl-2-lower alkylidene amino group or a triarylmethyl group e.g. by treatment with aqueous mineral acid, and an amino group protected with an organic silyl or stannyl group e.g. are released by hydrolysis or alcoholysis.
  • a hydrogenation catalyst such as a palladium catalyst
  • an aryl or aryl-lower alkylthioamino group e.g. by treatment with a nucleophilic reagent such as sulfurous acid, an arylsulfonylamino group e.g. by means of electrolytic reduction, a 1-acyl-2-lower alkylidene
  • An amino group protected in the form of an azido group is converted into the free amino group in a manner known per se by reduction, for example by catalytic hydrogenation with hydrogen and a hydrogenation catalyst, such as platinum oxide, palladium, or also Raney nickel, or also by zinc and acid, like acetic acid.
  • Catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon e.g. Methylene chloride, or in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 to 25 °, or at a reduced or elevated temperature.
  • a hydroxyl group protected by an acyl group, a silyl or stannyl group or by an optionally substituted a-phenyl-lower alkyl radical is released like an appropriately protected amino group.
  • One by 2,2-dichloroacety! Protected hydroxyl group is released by basic hydrolysis and a hydroxyl group protected by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is released by acidolysis.
  • a protected sulfo group is released analogously to a protected carboxyl group.
  • the protective groups are preferably selected so that they can all be split off simultaneously, for example acidolytically, such as by treatment with trifluoroacetic acid or formic acid, or reductively, such as by treatment with zinc and glacial acetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium / carbon Catalyst.
  • cleavage reactions described are carried out under conditions known per se, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.
  • an inert gas e.g. Nitrogen atmosphere.
  • a group R 1 can be replaced by another radical R 1 in a manner known per se or convert to another radical R 1 .
  • R 2 represents in a compound of formula I wherein R, represents a group of the formula -CH 2 R 2, for example a replaceable by nucleophilic substituents radical, or in a salt thereof, by treating a corresponding mercaptan or with a thio carboxylic acid compound to replace such a radical R 2 by an etherified or esterified mercapto group R 2 .
  • a suitable radical which can be replaced by an etherified mercapto group is, for example, a hydroxy group esterified by a lower aliphatic carboxylic acid.
  • esterified hydroxyl groups are especially acetyloxy, furthermore formyloxy.
  • the reaction of such a compound with a suitable mercaptan compound can be carried out under neutral or weakly basic conditions in the presence of water and, if appropriate, a water-miscible organic solvent.
  • the basic conditions can be achieved, for example, by adding an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. of sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate.
  • organic solvents e.g. water-miscible alcohols, e.g. Lower alkanols such as methanol or ethanol, ketones, e.g. Lower alkanons such as acetone, amides, e.g. Lower alkanecarboxamides such as dimethylformamide or nitriles e.g. Lower alkanoic acid nitriles such as acetonitrile and the like can be used.
  • Esterified hydroxyl groups R 2 in a compound of the formula I, in which R 1 is the group -CH 2 --R, where R 2 is a hydroxyl group esterified by the acyl radical of an optionally substituted half-amide of carbonic acid can be introduced, for example, by an appropriate compound of the formula I in which R 2 is free hydroxy (which is obtained, for example, by splitting off the acetyl radical from an acetyloxy group R 2 , for example by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupini i Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, for example from orange peel), with a suitable carbonic acid derivative, in particular with an isocyanate or Carbamic acid compound, such as a silyl isocyanate, for example
  • arbamic acid halide for example chloride (which lead to N-unsubstituted 3-aminocarbonyloxymethyl compounds), or then with an N-substituted isocyanate or with an N-mono or N, N-disubstituted carbamic acid compound, such as a corresponding carbamic acid halide, for example -chloride, is carried out, usually in the presence of a solvent or diluent and, if necessary, with cooling or heating, in a closed vessel and / or in an inert gas, for example nitrogen atmosphere.
  • the weakly acidic conditions can be adjusted by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or else sulfuric acid.
  • a suitable organic or inorganic acid for example acetic acid, hydrochloric acid, phosphoric acid or else sulfuric acid.
  • the above-mentioned water-miscible solvents can be used as organic solvents.
  • certain salts can be added to the reaction mixture, for example alkali metal salts, such as sodium and in particular potassium salts, of inorganic acids, such as hydrohalic acids, for example hydrochloric acid and in particular hydroiodic acid, and thiocyanic acid, or organic acids, such as lower alkane carboxylic acids, for example acetic acid .
  • alkali metal salts such as sodium and in particular potassium salts
  • inorganic acids such as hydrohalic acids, for example hydrochloric acid and in particular hydroiodic acid, and thiocyanic acid
  • organic acids such as
  • acids e.g. acetic acid
  • Quaternary ammonium groups R 2 can advantageously be prepared using an intermediate of the formula I in which R 2 represents a substituted, in particular an aromatically substituted, carbonylthio group and primarily the benzoylthio group.
  • Such an intermediate which is obtained, for example, by reacting a compound of the formula I in which R 2 in the radical R 1 is an esterified hydroxyl group, in particular a lower alkanoyloxy, for example acetyloxy, group with a suitable salt, such as an alkali metal, for example sodium salt, a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, for example thiobenzoic acid, is reacted with the tertiary amine, in particular a tertiary heterocyclic base, such as an optionally substituted pyridine, to give the quaternary ammonium compound.
  • the reaction is usually carried out in the presence of a suitable desulfurization agent, in particular a mercury salt, for example mercury-II perchlorate, and a suitable solvent or diluent or a mixture, if necessary, with cooling or heating, in a closed vessel and / or in an inert gas -, for example nitrogen atmosphere.
  • a suitable desulfurization agent in particular a mercury salt, for example mercury-II perchlorate
  • a suitable solvent or diluent or a mixture if necessary, with cooling or heating, in a closed vessel and / or in an inert gas -, for example nitrogen atmosphere.
  • a free carboxyl group in a compound of the formula obtained is converted into an esterified carboxyl group which can be cleaved under physiological conditions by esterification methods known per se, for example by adding a compound of the formula I in which other functional groups, such as amino, hydroxy, or sulfo groups, optionally in protected Form, or a functional derivative thereof which is reactive with respect to the carboxyl group to be esterified, or a salt thereof, with a corresponding alcohol or a reactive functional derivative thereof.
  • Salts of compounds of the formula can be prepared in a manner known per se.
  • salts of compounds of formula 1 with acidic groups e.g. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. form the sodium salt of ⁇ -ethyl-caproic acid or sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.
  • Acid addition salts of compounds of formula 1 are obtained in a conventional manner, e.g. by treatment with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of formula I which contain a free carboxyl group can e.g. by neutralizing salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.
  • Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.
  • the process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.
  • Any radicals which substitute the amino group and allow their acylation in a starting material of the formula II or IV are, for example, organic silyl or stannyl groups, and also ylidene groups which, together with the amino group, form a Schiff base.
  • the organic silyl or stannyl groups mentioned are e.g. the same, which are also able to form a protected carboxyl group with the 4-carboxyl group on the cephem ring.
  • ylidene groups mentioned are primarily arylmethylene groups, where aryl is especially for a carbocyclic, primarily monocyclic aryl radical, e.g. represents phenyl optionally substituted by nitro or hydroxy; such arylmethylene groups are e.g. Benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further optionally, e.g. carboxy substituted oxacycloalkylidene, e.g. 3-carboxy-2-oxacyclohexylidene.
  • the other functional groups present in the starting materials of the formulas II to VII can be protected by the protective groups already mentioned under the compounds of the formula I. All reactive functional groups which do not take part in the acylation reaction are preferably protected, but in particular any acylatable amino, hydroxyl and mercapto groups which may be present are protected.
  • suitable condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, are usually used -, N, N'-diisopropyl, N, N'-dicyclohexyl or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide
  • suitable carbonyl compounds for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenyl-isoxazolinium -3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate
  • an acylamino compound for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.
  • the condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, with cooling or if desired or necessary Heating and / or carried out in an inert gas atmosphere.
  • a solvent or diluent for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran
  • a reactive, ie amide-forming or ester-forming, functional derivative of an acid of the formula III, V or VII, in which all functional groups except the reacting acid group are or can be protected is primarily an anhydride of such an acid, including and preferably a mixed anhydride, but also an internal anhydride, ie a corresponding ketene or, in acid V, if W is the group -S0 2 NH-CO-, or if X is the group -NH- and W is the group -CO - or ⁇ CO ⁇ NHSO 2 - is a corresponding isocyanate.
  • Mixed anhydrides are, for example, those with inorganic acids, such as hydrohalic acids, ie the corresponding acid halides, for example chlorides or bromides, furthermore with hydrochloric acid, ie the corresponding acid azides, with a phosphorus-containing acid, for example phosphoric acid or phosphorous acid, or with a sulfur-containing acid, eg sulfuric acid, or with hydrocyanic acid.
  • hydrohalic acids ie the corresponding acid halides, for example chlorides or bromides
  • hydrochloric acid ie the corresponding acid azides
  • a phosphorus-containing acid for example phosphoric acid or phosphorous acid
  • sulfur-containing acid eg sulfuric acid, or with hydrocyanic acid.
  • mixed anhydrides are, for example, those with organic carboxylic acids, such as with lower alkane carboxylic acids which are optionally substituted, for example by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with half esters, in particular lower alkyl semesters of carbonic acid, such as the ethyl or isobutyl semesters of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, for example p-toluenesulfonic acid.
  • organic carboxylic acids such as with lower alkane carboxylic acids which are optionally substituted, for example by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with half esters, in particular lower alkyl semesters of carbonic acid, such as the ethyl or isobutyl semesters of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic
  • esters suitable for reaction with the amino, hydroxy or mercapto group in an acid of the formula 111, V or VIII, in which all functional groups except the reacting carboxyl group are or can be protected are activated esters, such as esters with vinylogenic alcohols (ie enols), such as vinylogenic lower alkenols, or aryl esters, such as 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters, such as benzotriazole, for example 1-benzotriazole ester, or diacylimino esters, such as succinylimino or phthalylimino esters.
  • Acylation with an acid derivative, such as an anhydride, especially with an acid halide can be carried out in the presence of an acid binding agent, e.g. an organic base such as an organic amine, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyldiisopropylamine, or N, N-di-lower alkyl-aniline, e.g. N, N-dimethylaniline, or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g.
  • an organic base such as an organic amine, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyldiisopropy
  • Pyridine an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.
  • an inorganic base e.g. an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.
  • acylations can be carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, such as a formamide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrile, e.g.
  • a carboxamide such as a formamide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrile, e.g.
  • a carboxamide such as a formamide, e.g. Dimethylformamide
  • an inert gas e.g. Nitrogen atmosphere.
  • a protected amino group may also be in ionic form, i.e. the starting material of formula 111, V or VII may be in the form of an acid addition salt, preferably with a strong inorganic acid such as a hydrohalic acid e.g. Hydrochloric acid, or sulfuric acid can be used.
  • a hydrohalic acid e.g. Hydrochloric acid, or sulfuric acid
  • an acid derivative can be formed in situ if desired. So you get e.g. a mixed anhydride by treating an acid of formula III, or an acid of formula V, wherein X-W represents the group -CO-, with appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine such as 4-methylmorpholine or a metal e.g. Alkali metal salt, with a suitable acid derivative, such as a corresponding acid halide of an optionally substituted lower alkane carboxylic acid, e.g. Trichloroacetyl chloride, or with a half ester of a carbonic acid halide, e.g. Chloroformic acid ethyl ester or isobutyl ester, and uses the mixed anhydride thus obtained without isolation.
  • a suitable acid derivative such as a corresponding acid halide of an optionally substituted lower alkane carboxylic acid, e.g. Trichloroace
  • hydrochloric acid receptors, solvents and reaction conditions are the same as those mentioned for the acylation of compounds of formula II or IV; for example, the reaction can take place in the presence of pyridine in methylene chloride and toluene at about 0 ° to about + 10 °.
  • an acid chloride of an acid of the formula VII, in which W is the group -CO-, and in which the 4-carboxyl group and in the groups -AC (Y) (Z) - and R 1 optionally existing additional functional groups are protected from a corresponding protected compound of formula IV, can be prepared by treatment with chlorosulfonyl isocyanate.
  • the 7 ⁇ -methoxy group R 3 can be introduced in a manner known per se, for example by sequentially treating the intermediate mentioned with an anion forming agent, an N-halogenating agent and methanol treated.
  • a suitable anion-forming agent is primarily an organometallic base, in particular an alkali metal base, primarily an organic lithium base.
  • organometallic bases such as an alkali metal base, primarily an organic lithium base.
  • Such compounds are, in particular, corresponding alcoholates, such as suitable lithium lower alkanolates, primarily lithium methylate, or corresponding metal hydrocarbon bases, such as lithium lower alkanes and lithium phenyl.
  • the reaction with the anion-forming organometallic base is usually carried out with cooling, e.g. from about 0 ° C to about -80 ° C, and in the presence of a suitable solvent or diluent, e.g. an ether such as tetrahydrofuran when using lithium methylate also in the presence of methanol and, if desired, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.
  • a suitable solvent or diluent e.g. an ether such
  • a sterically hindered organic hypohalite in particular chlorite, and primarily a corresponding aliphatic hypohalite, e.g. chlorite, such as a tertiary lower alkyl hypohalite, e.g. -chlorite.
  • the primary application is tert-butyl hypochlorite, which is reacted with the non-isolated product of the anionization reaction.
  • the N-halogenated intermediate compound is converted into a 7-acyliminocephem compound under the reaction conditions and without being isolated, and this is converted into a 7a-methoxy-cephem compound by adding methanol transferred.
  • the elements of hydrohalic acid, in particular hydrochloric acid must be split off from the N-halogenated intermediate; this is done with the addition of a hydrogen halide base, such as a suitable alkali metal lower alkanolate, e.g.
  • Lithium tert-butoxide this reaction usually taking place under the conditions of the anion and N-halogen compound-forming reaction, where one works in the presence of methanol and instead of the acylimino compound the 7a-methoxy-cephem compound can be obtained directly.
  • a compound of the formula I in which functional groups are in protected form is used with an excess of the anion-forming agent, e.g. Lithium methylate or phenyllithium, in the presence of methanol, then treated with the N-halogenating agent, e.g. tert-butyl hypochlorite, and thus directly receives the desired compound of formula I, in which functional groups are protected.
  • the anion-forming agent e.g. Lithium methylate or phenyllithium
  • the methanol can also be added subsequently, the dehydrohalogenation and the addition of methanol at somewhat higher temperatures than the anion and N-halogen compound forming reactions, e.g. at about 0 ° C to about -20 ° C, if necessary, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.
  • an inert gas e.g. Nitrogen atmosphere.
  • 3-cephem compounds if appropriate partially, can isomerize to 2-cephem compounds.
  • a 2-cephem compound obtained or a mixture of a 2- and a 3-cephem compound can be isomerized in a manner known per se to the desired 3-cephem compound.
  • This isomerization can be carried out, for example, by oxidizing the 2-cephem compound obtained or the mixture of the 2- and 3-cephem compound obtained in the 1-position and reducing the 1-oxides of the corresponding 3-cephem compounds thus obtainable.
  • Suitable oxidizing agents for the oxidation in the 1-position of cephem compound are, for example, inorganic peracids which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids with a Dissociation constant of at least 10- 5 , in question.
  • Suitable inorganic peracids are periodic and persulfuric acid.
  • Organic peracids are corresponding percarbonate and persulfonic acids which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid.
  • acetic acid is used as the solvent.
  • Suitable peracids are, for example, performic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluenesulfonic acid.
  • the oxidation can also be carried out using hydrogen peroxide with catalytic Amounts of an acid are carried out with a dissociation constant of at least 10- 5, wherein low concentrations, for example, can use 1-2% and less, but also large quantities of the acid.
  • the effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.
  • the above oxidation can be carried out in the presence of suitable catalysts.
  • suitable catalysts for example, the oxidation with percarboxylic acids by the presence of an acid having a dissociation constant of at least 10- 5 are catalyzed with their effectiveness depends on their strength.
  • Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid.
  • acetic acid, perchloric acid and trifluoroacetic acid Usually at least equimolar amounts of the oxidizing agent are used, preferably a slight excess of about 10% to about 20%.
  • the oxidation is carried out under mild conditions, for example at temperatures from approximately -50 ° C. to approximately + 100 ° C., preferably from approximately -10 ° C. to approximately + 40 ° C.
  • Oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds can also be accomplished by treating with ozone, further with organic hypohalite compounds such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite, which can be obtained in the presence of inert solvents such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -10 ° C to about + 30 ° C, with periodate compounds such as alkali metal periodates, e.g.
  • organic hypohalite compounds such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite, which can be obtained in the presence of inert solvents such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -10 ° C to about + 30 ° C, with periodate compounds such as alkali metal periodates, e.g.
  • Potassium periodate which is preferably used in an aqueous medium at a pH of about 6 and at temperatures from about -10 ° C to about + 30 ° C, with iodobenzene dichloride, which is in an aqueous medium, preferably in the presence of an organic base , e.g. Pyridine, and with cooling e.g. at temperatures from about -20 ° C to about 0 °, or with any other oxidizing agent suitable for converting a thioin to a sulfoxide moiety.
  • organic base e.g. Pyridine
  • the reduction of the 1-oxides of 3-cephem compounds can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent.
  • suitable reducing agents are: catalytically activated hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium, and which are optionally used together with a suitable support material, such as carbon or barium sulfate; reducing tin, iron, copper or manganese cations, which are in the form of corresponding compounds or complexes of inorganic or organic type, e.g.
  • Sodium or potassium dithionite, sodium or potassium iodide or iron-II-cyanide, or in the form of the corresponding acids, such as hydroiodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, furthermore esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as phosphorus sulfur compounds corresponding to these phosphoric acid compounds, in which organic residues are primarily aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups such as e.g.
  • Triphenylphosphine tri-n-butylphosphine, diphenylphosphinous acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzene phosphonic acid dimethyl ester, butanephosphonous acid methyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus trichloride reducing halosilane compounds which have at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups, e.g.
  • optionally substituted lower alkyl or phenyl groups such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc .; reducing quaternary chloromethylene iminium salts, in particular chlorides or bromides, in which the iminium group is substituted by a bivalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal hydrides, such as sodium borohydrides, in the presence of suitable activating agents, such as cobalt-II chloride, and also borane dichloride.
  • suitable activating agents such as cobalt-II chloride, and also borane dichloride.
  • activating agents which are used together with those of the abovementioned reducing agents which do not themselves have Lewis acid properties ie which are primarily used together with the dithionite, iodine or iron (II) cyanide and the non-halogen-containing trivalent phosphorus Reducing agents or used in the catalytic reduction are in particular organic carbon and sulfonic acid halides, furthermore sulfur, phosphorus or silicon halides with the same or greater second order hydrolysis constant as benzoyl chloride, for example phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide,
  • the reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of the reducing agent, e.g. Lower alkane carboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. Benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanecaronic acid esters or nitriles, e.g.
  • solvents or mixtures thereof the selection of which is primarily determined by the solubility of the starting materials and the choice of the reducing agent, e.g. Lower alkane carboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the
  • Ethyl acetate or acetonitrile, or amides of inorganic or organic acids e.g. Dimethylformamide or hexamethylphosphoramide, ether, e.g. Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. Acetone, or sulfones, especially aliphatic sulfones, e.g. Dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably not containing water. It is usually carried out at temperatures from about -20 ° C. to about 100 ° C., and the reaction can be carried out at lower temperatures if very reactive activating agents are used.
  • Such compounds of the formula III, with appropriately protected functional groups are prepared, for example, by using a compound of the formula wherein the amino group can optionally be substituted by a group permitting acylation, and functional groups present in the group -AC (Y) (Z) - are optionally protected, with intermediate protection of the carboxyl group, with a reactive functional derivative of an acid of the formula V.
  • the aminocarboxylic acid group HOOC-CH (NH 2 ) - is in protected form, or, if XW together mean a group -CO, also acylated with a corresponding free acid or with a salt thereof, and if desired, a compound obtained in a transferred other compound of formula III with appropriately protected functional groups.
  • the groups permitting the acylation, and also the protective groups of the aminocarboxylic acid group HOOC-CH (NH 2 ) - and the group -AC (Y) (Z) -, are the same as those mentioned under the compounds of the formulas II or IV and I.
  • the carboxyl protective groups already mentioned can also be used per se, but the carboxyl protective groups used for the intermediate protection in the present acylation must differ from the other protective groups which necessarily remain in the compounds of the formula III should differ in the type of their cleavage, so that they can be cleaved selectively after the present acylation reaction.
  • a hydrogenolytically removable protective group such as one of the optionally substituted benzyl groups mentioned, for example the benzyl or p-nitrobenzyl group
  • the other protective groups must not be able to be removed hydrogenolytically; they can be, for example, the abovementioned, only acidolytically removable tert-lower alkyl groups, such as tert-butyl or tert-lower alkoxycarbonyl groups, such as tert-butoxycarbonyl.
  • acylation can otherwise be carried out analogously to the acylation of compounds of the formula IV with an acid of the formula V or an appropriately protected and reactive functional derivative thereof.
  • a protective group optionally selectively, can be split off, or a functional group, optionally freed up by the acylation reaction, can be protected.
  • the a-hydroxy group can be oxidatively, as indicated for the oxidation of compounds XI to a-keto acids IX, for example with temporary protection of the carboxyl group as an ester, by treatment with manganese dioxide , are converted into an a-oxo group and in an available compound of the formula 111, in which Z and Y together represent the oxo group, this can be converted into the corresponding oximino group by treatment with a hydroxylamine of the formula H 2 NOR o , which reaction analogous to the conversion of a-keto acids of the formula IX into oximino compounds of the formula VIIIa.
  • R ° is hydrogen or optionally substituted lower alkyl represents.
  • the new, antibiotic compounds of formula IV mentioned can be used as antibacterial antibiotics.
  • they are in vitro against Enterobacteriaceen, e.g. Escherichia coli, effective in minimum concentrations of 0.8 mcg / ml and against cocci in minimum concentrations of 0.1 mcg / ml.
  • Enterobacteriaces such as Escherichia coli
  • cocci in minimal doses of 15 mg / kg.
  • the new connections can therefore, e.g. in the form of antibiotic preparations for the treatment of infections caused by enterobacteria such as Escherichia coli and cocci.
  • acylation of corresponding protected compounds of the formula II with an acid of the formula VIII or with a reactive functional derivative thereof, the removal of the protective groups, the conversion of a group R 1 into another group R j , and the introduction of the methoxy group R 3 , and the salt formation can be carried out in a manner analogous to that indicated for the acylation of appropriately protected compounds of the formula II or IV with an acid of the formula II or V and the corresponding subsequent operations.
  • Acids of the formula V, reactive functional derivatives thereof, the precursors of the formula and correspondingly protected derivatives are known or can be prepared by methods known per se, for example in situ.
  • Reactive functional derivatives of acids of formula VII in which the 4-carboxyl group and optionally in the radical R 1 and in the grouping -AC (Y) (Z) - functional groups present can be present in protected form, are known in a manner known per se protected compounds of formula IV prepared.
  • Acids of the formula VIII and corresponding reactive functional and protected derivatives thereof are known in some cases or can be prepared by methods known per se.
  • A is in particular one of the preferred groups mentioned under formula, primarily 2,5-furylene, 2,5-thienylene or 1,4-phenylene.
  • the amino protective group in a compound of the formula IX is one of the abovementioned, for example one of the acyl groups mentioned under formula I which are stable during the reaction and can subsequently be split off easily, in particular the trifluoroacetyl group.
  • the reaction of the a-keto acid with the hydroxylamine compound H 2 NOR " is carried out in a customary manner, for example by the two reactants in a solvent, such as water or an organic solvent, such as an alcohol, for example methanol, at a slightly elevated or reduced temperature
  • a solvent such as water or an organic solvent, such as an alcohol, for example methanol
  • the hydroxylamine compound can, also in situ, from one of its salts, for example a hydrohalide, such as hydrochloride, by treatment with an inorganic base, such as an alkali metal hydroxide, for example sodium hydroxide, or an organic base , such as a tertiary amine, for example a trinierderalkylamine, such as triethylamine or ethyldiisopropylamine, or a heterocyclic tertiary base, such as pyridine, are liberated.
  • an inorganic base such as an alkali metal hydroxide, for example sodium
  • the protective group can be split off by customary methods mentioned above, a trifluoroacetyl group, for example by alkaline saponification.
  • the free amino group can be converted into one of the protected amino groups mentioned by customary methods mentioned above, for example by treatment with an acid anhydride, such as the anhydride of carbonic acid monobut.butyl ester in the presence of base the corresponding N-acyl, e.g. N-tert-butoxycarbonyl compound.
  • an acid anhydride such as the anhydride of carbonic acid monobut.butyl ester in the presence of base the corresponding N-acyl, e.g. N-tert-butoxycarbonyl compound.
  • Functional derivatives of compounds of the formula Villa in which the amino group is protected, which are reactive with respect to the carboxyl group, are the same as those mentioned under the acids of the formula III, and are in particular anhydrides, such as mixed anhydrides with the inorganic or organic acids mentioned, or activated esters, such as those with the alcohols mentioned.
  • Acid halides are e.g. prepared by reacting a compound of the formula VIIIa with a protected amino group or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride.
  • a halogenating agent for example phosphorus pentachloride, thionyl chloride or oxalyl chloride.
  • the reaction is preferably carried out in a non-aqueous solvent or solvent mixture, such as a carboxamide, e.g. Dimethylformamide, and / or in the presence of a base such as a tertiary amine such as tri-lower alkylamine, e.g. Triethylamine, or a tertiary cyclic amine such as N-methyl-morpholine.
  • Symmetrical anhydrides or mixed anhydrides other than halides Compounds of the formula VIIIa with a protected amino group can be prepared, for example, by a corresponding compound having a free carboxyl group, preferably a salt, in particular an alkali metal, for example sodium, or ammonium, for example triethylammonium salt thereof, with a reactive derivative such as a halide , for example the chloride, one of the acids mentioned, for example a lower alkyl haloformate, such as isobutyl chloroformate, or an optionally halogenated lower alkane carboxylic acid chloride, for example trichloroacetyl chloride.
  • a salt in particular an alkali metal, for example sodium, or ammonium, for example triethylammonium salt thereof
  • a reactive derivative such as a halide
  • a halide for example the chloride
  • one of the acids mentioned for example a lower alkyl haloformate,
  • Activated esters of compounds of formula VIIIa with a protected amino group can e.g. be prepared by using a corresponding compound with a free carboxyl group in the presence of a carbodiimide, e.g. one of the above carbodiimides, such as N, N-dicyclohexylcarbodiimide, with an optionally, e.g. phenol substituted by nitro or halogen, such as chlorine, e.g. Nitrophenol, e.g. 4-nitrophenol or 2,4-dinitrophenol, or polyhalophenol, e.g. 2,3,4,5,6-pentachlorophenol, or reacted with 1-hydroxybenzotriazole.
  • a carbodiimide e.g. one of the above carbodiimides, such as N, N-dicyclohexylcarbodiimide
  • Nitrophenol e.
  • the ⁇ -keto acids of the formula IX are new and also a subject of the present invention. They can be prepared in a manner known per se by working in a compound of the formula in which m and A have the meanings given under formula VIIIa and in which the amino group is in protected form, the methyl group is oxidized to a carboxyl group, or in an a-hydroxy acid of the formula in which m and A have the meanings given under formula VIIIa and in which the amino group is in protected form, the a-hydroxy group is oxidized to an a-oxo group.
  • a starting compound of the formula X or XI the amino group is protected, for example, by one of the acyl protective groups mentioned, in particular by the trifluoroacetyl group.
  • the oxidation of a compound X is carried out with one of those for the conversion of aromatic acetyl compounds, i.e. Aryl methyl ketones, in corresponding a-keto acids, i.e. Arylglyoxylic acids, suitable oxidizing agents carried out in the usual way.
  • Suitable oxidizing agents are, for example, oxidizing oxides or oxygen-containing acids, such as those of selenium, sulfur, manganese, chromium or nitrogen, or salts of corresponding acids, in particular alkali metal salts, such as potassium salts thereof, the salts optionally in the presence of mineral acids, such as hydrochloric acid or sulfuric acid, be used, hydrogen peroxide, or oxygen in the presence of a catalyst, such as platinum on carbon.
  • oxidizing oxides or oxygen-containing acids such as those of selenium, sulfur, manganese, chromium or nitrogen, or salts of corresponding acids, in particular alkali metal salts, such as potassium salts thereof, the salts optionally in the presence of mineral acids, such as hydrochloric acid or sulfuric acid, be used, hydrogen peroxide, or oxygen in the presence of a catalyst, such as platinum on carbon.
  • Highlighting oxidizing agents are selenium dioxide or the selenic acid, permanganic salts such as potassium permanganate, dichromic salts such as potassium dichromate and nitrous acid which are generated in situ from an inorganic nitrite salt such as a corresponding alkali metal salt or alkaline earth metal salt, e.g. Sodium salt, and an acid such as hydrochloric acid or sulfuric acid.
  • permanganic salts such as potassium permanganate
  • dichromic salts such as potassium dichromate and nitrous acid which are generated in situ from an inorganic nitrite salt such as a corresponding alkali metal salt or alkaline earth metal salt, e.g. Sodium salt
  • an acid such as hydrochloric acid or sulfuric acid.
  • the oxidation is carried out in water or an optionally water-miscible, optionally water-containing organic solvent, such as pyridine, acetic acid, an ether, such as tetrahydrofuran or dioxane, or else an alcohol, such as a lower alkanol, for example methanol or ethanol, at temperatures of about 0 ° up to about 100 °, usually carried out at elevated temperatures, ie at about 60-90 0 .
  • an optionally water-miscible, optionally water-containing organic solvent such as pyridine, acetic acid, an ether, such as tetrahydrofuran or dioxane, or else an alcohol, such as a lower alkanol, for example methanol or ethanol
  • Oxidizing oxides such as those of manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium trioxide, e.g.
  • a sterically hindered alcohol such as aluminum or potassium tert-butoxide
  • isopropoxide or phenoxide in the presence of a ketone such as acetone, cyclohexanone or fluorenone.
  • a ketone such as acetone, cyclohexanone or fluorenone.
  • the oxidation is carried out in water or an optionally water-miscible, optionally water-containing solvent at temperatures from about 0 ° to about 100 °.
  • the pharmacologically useful compounds of the present invention can e.g. be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients, which are preferably suitable for parenteral administration.
  • the pharmacologically active compounds of the present invention are used in the form of injectable, e.g. intravenously, administrable preparations or infusion solutions.
  • injectable e.g. intravenously, administrable preparations or infusion solutions.
  • Such solutions are preferably isotonic aqueous solutions or suspensions, these being e.g. from lyophilized preparations, which the wiki substance alone or together with a carrier material, e.g. Mannitol can be prepared before use.
  • the pharmaceutical preparations can be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.
  • the present pharmaceutical preparations which, if desired, may contain other pharmacologically valuable substances, are used in a manner known per se, e.g. by means of conventional solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active substance.
  • daily doses of approximately 0.5 g to approximately 5 g SC are used. for the treatment of warm-blooded animals weighing approximately 70 kg.
  • the suspension is poured onto an ice-cold mixture of petroleum ether (300 ml) and diethyl ether (150 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • the product can be further purified by dissolving it in water and evaporating it, or in cases involving ethanol.
  • a voluminous precipitate precipitates out of the initially clear solution.
  • the suspension is poured onto an ice-cold mixture of petroleum ether (1000 ml) and diethyl ether (500 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • the starting material can be produced as follows:
  • the crude product is purified by chromatography on 15 times the amount of silica gel.
  • the fractions with methylene chloride-methyl acetate (9: 1) as the eluent are combined and the 7 ⁇ - ⁇ 2 - [4 - ((2R) - 2 - BOC - Amino - 2 - t.butoxycarbonylvesthoxycarbonylamino) phenyl] acetylamino ⁇ - 3 - methyl - 3-cephem-4-carboxylic acid diphenylmethyl ester precipitated from ethyl acetate solution with a mixture of petroleum ether and ether.
  • the suspension is concentrated on a rotary evaporator at 40 ° within 15 minutes to about 50 ml and poured onto an ice-cold mixture of petroleum ether (500 ml) and ether (250 ml).
  • the trifluoroacetate obtained is filtered off with suction, washed with ether and dried at room temperature in a high vacuum.
  • the sodium 7 ⁇ - ⁇ 2 - [4 - ((2R) - 2 - amino - 2 - carboxyethoxycarbonylamino) phenyl] acetylamino ⁇ cephalosporanic acid salt is obtained from the trifluoroacetate by the procedure of Example 1.
  • the starting material can be produced as follows:
  • the suspension is poured onto an ice-cold mixture of petroleum ether (800 ml) and ether (400 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried at room temperature in a high vacuum.
  • the starting material can be produced as follows:
  • the crude product is purified by chromatography on a 30-fold amount of silica gel.
  • the fractions with methylene chloride-methyl acetate (7: 3) and (3: 2) as eluent are combined and the 7 ⁇ - ⁇ 2 - [4 - ((2R) - 2 - BOC - amino - 2 - t.butoxycarbonylvesthoxycarbonylamino) phenyl] acetylamino ⁇ - 3 - carbamoyloxymethyl - 3 - cephem - 4 - carboxylic acid - diphenylmethyl ester precipitated from ethyl acetate solution with a mixture of petroleum ether and ether.
  • F. 95 ⁇ 114 ° (slow decomposition); DS (eluent: ethyl acetate - toluene - ethanol - (47: 47: 5)): Rf 0.34.
  • the compound obtained according to Example 5a) can also be prepared as follows:
  • the starting material can be obtained as follows.
  • the suspension is poured onto an ice-cold mixture of petroleum ether (600 ml) and ether (300 ml), the trifluoroacetate obtained is filtered off with suction, washed with ether and dried at room temperature in a high vacuum.
  • the suspension obtained is poured onto an ice-cold mixture of petroleum ether (400 ml) and diethyl ether (200 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried at room temperature in a high vacuum.
  • Solution II is then pipetted into solution 1 and, after addition of 0.2 ml (1.4 mmol) of triethylamine, the mixture is stirred for 1 1/2 hours. After shaking with 2 N sulfuric acid and brine, the organic phase is dried over sodium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel (system methylene chloride / ethyl acetate 9: 1).
  • Solution I is added to solution II and the mixture is stirred for 1 hour at 0 ° under nitrogen. After shaking with 2 N sulfuric acid, sodium bicarbonate and brine, the organic phase is dried over sodium sulfate, filtered and evaporated in vacuo.
  • the starting material can be produced as follows:
  • Solution II is then pipetted into solution I and, after adding 0.2 ml (1.4 mmol) of triethylamine, the mixture is stirred for 1 1/2 hours. After shaking with 2 N sulfuric acid and brine, the organic phase is dried over sodium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel (system methylene chloride / ethyl acetate 9: 1).
  • Solution I is added to solution II and the mixture is stirred for 1 hour at 0 ° under nitrogen. After shaking with 2 N sulfuric acid, sodium bicarbonate and brine, the organic phase is dried over sodium sulfate, filtered and evaporated in vacuo.
  • the starting material is produced as follows:
  • a suspension of 0.75 g of aminophenylacetic acid in 2.91 g of pyridine is mixed with 1.29 g of trimethylchlorosilane, a clear solution being formed and the temperature rising to 38 °. After stirring for 20 minutes at 40-45 °, the mixture is cooled to 0 ° (solution B).
  • solution B is added dropwise to solution A and then stirred for a further 30 minutes at 0 ° and 1 hour at + 22 °.
  • the mixture is poured onto 80 ml of 0.2 M dipotassium hydrogenphosphate solution with stirring, the methylene chloride is removed in vacuo and the remaining aqueous phase is extracted at room temperature in the cold with ethyl acetate. Evaporation of the organic phase gave 2 - [4 - ((2R) - 2 - BOC - Amino - 2 - diphenylmethoxycarbonyläthoxycarbonylaminosulfonylamino) phenyl] acetic acid in the form of a foam.
  • the suspension is then stirred in an ice bath for a further 3 hours, then suction filtered through Celit and the filter cake is washed with a large amount of ethyl acetate.
  • the filtrate is washed successively with plenty of water, 1 N sodium hydrogen carbonate and water.
  • the ethyl acetate solution is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator at 45 ° and the residue is purified by chromatography on a 25-fold amount of silica gel.
  • the suspension is poured onto an ice-cold mixture of petroleum ether (500 ml) and diethyl ether (250 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and rocked under high vacuum at room temperature.
  • the trifluoroacetate obtained is the 7ß - ((2R, S) - 2 - [4 - ((2R) - 2 - Amino - 2 - carboxyäthoxycarbonylamino) phenyl] - 2 - hydroxyacetylaminof - 3 - carbamoyloxymethyl - 3 - cephem - 4 - carboxylic acid analogously to Example 1a) converted into the corresponding sodium salt.
  • Example 1 5a The suspension is then stirred in an ice bath for a further 2 hours and worked up as in Example 1 5a).
  • the crude product is purified by chromatography on 30 times the amount of silica gel.
  • the fractions with methylene chloride-methyl acetate (17: 3) as eluent are combined and the 7 ⁇ - ⁇ (2R, S) - 2 - [4 - ((2R) - 2 - BOC - amino - 2 - tert.-butoxycarbonylethoxycarbonylamino) phenyl] - 2 - hydroxy - acetylamino ⁇ - 3 - [(1 - methyl - 1 H - tetrazol - 5 - yl) - thiomethyl] - 3 - cephem - 4 - carboxylic acid - diphenylmethyl ester from ethyl acetate solution with a mixture of petroleum ether and diethyl
  • Trifluoroacetic acid is added for 75 minutes Room temperature stirred in the absence of atmospheric moisture. The suspension is then poured onto an ice-cold mixture of petroleum ether (500 ml) and diethyl ether (250 ml), the resulting trifluoroacetate of 7 ⁇ - ⁇ (2R, S) - 2 - [ 4 - ((2R) - Amino - 2 - carboxyethoxycarbonylamino ) phenyl] - 2 - hydroxyacetylarnino ⁇ - 3 - [(1 - methyl - 1 H - tetrazol - 5 - yl) - thiomethyl] - 3 - cephem - 4 - carboxylic acid filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • a voluminous precipitate precipitates out of the initially clear solution.
  • the suspension is then poured onto an ice-cold mixture of petroleum ether (400 ml) and diethyl ether (200 ml), the resulting trifluoroacetate of 7 ⁇ - ⁇ (2R) - 2 - [4 - ((2R) - 2 - Amino - 2 - carboxyethoxycarbonylamino ) phenyl] - 2 - hydroxyacetylamino ⁇ - 3 - [(1 - methyl - 1 H - tetrazol - 5 - yl) - thiomethyl] - 3 - cephem - 4 - carboxylic acid filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • the starting material can be produced as follows:
  • Example 17d The suspension is then worked up using the method of Example 17d.
  • the crude product is purified by chromatography on 30 times the amount of silica gel.
  • the fractions with chloroform-methyl acetate (4: 1) as the eluent are combined and the product is crystallized from chloroform.
  • the suspension is poured onto an ice-cold mixture of petroleum ether (400 ml) and diethyl ether (200 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • the crude product is purified by filtration on 10 times the amount of silica gel.
  • DS eluent: ethyl acetate
  • Rf 0.38.
  • the reaction mixture is diluted with methylene chloride, washed successively with water, 1N sodium hydrogen carbonate and water, dried over sodium sulfate and the solvent is evaporated off on a rotary evaporator at 45 °.
  • the product is purified by chromatography on a 20-fold amount of silica gel. The fractions with methylene chloride-methyl acetate (20: 1) as eluent are combined.
  • the grease is quickly dissolved by adding 10 ml of ice-cold trifluoroacetic acid, then poured onto an ice-cold mixture of petroleum ether (500 ml) and diethyl ether (250 ml).
  • the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried in a high vacuum at room temperature.
  • the suspension is then filtered off with suction, the filtrate is mixed with a mixture of 1.4 liters of petroleum ether and 0.7 liters of diethyl ether and the resulting product is filtered off with suction.
  • the filter cake is suspended in a mixture of ethanol (150 ml) -diethyl ether (150 ml) -petrol ether (150 ml), suction filtered and dried under high vacuum at room temperature.
  • the crude product is stirred with 250 ml of methylene chloride, the insoluble part is separated off, the clear solution is evaporated on a rotary evaporator at 45 ° and the remaining foam is chromatographed on 25 times the amount of silica gel.
  • the starting material can be produced as follows:
  • solution B is added dropwise to solution A within 5 minutes, 1.3 ml of N-methylmorpholine are then added, and the mixture is stirred at 0 ° for 30 minutes and at 25 ° for 3 hours.
  • the solution is washed with ice water and saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator.
  • the crude product is purified on silica gel with diethyl ether as the eluent, from which (2R) - 2 - BOC - amine - 2 - [3 - (2R) - 2 - BOC - amino - 2 - diphenylmethoxycarbonylethoxycarbonylamino) phenylacetic acid is isolated as a colorless amorphous powder .
  • DS: Rf 96 0.9.
  • Solution B cooled to 0 °, is added dropwise to solution A within 5 minutes and, after the addition of 0.95 ml (8.8 mmol) of N-methylmorpholine, is stirred for 30 minutes at 0 ° and 2 hours at room temperature.
  • the reaction mixture diluted with 400 ml of ethyl acetate is washed with ice water and saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator.
  • the foamy residue is purified on silica gel with diethyl ether as the eluent and gives the 7 ⁇ - ⁇ (2R, S) - 2 - hydroxy - 2 - [3 - ((2R) - 2 - BOC - amino - 2 - diphenylmethoxycarbonylvesthoxycarbonylamino) phenyl] - acetylamino ⁇ - 3 - carbamoyloxymethyl - 3 - cephem -4 - carboxylic acid - diphenylmethyl ester as an amorphous powder.
  • the aqueous phase is adjusted to pH 3 with 1 N sodium hydroxide solution and, for purification of the crude product, chromatographed on an Amberlite XAD-2 column with water isopropanol 9: 1 as the eluent.
  • solution B is added dropwise to solution A within 5 minutes, 1.3 ml (12 mmol) of N-methylmorpholine are then added, and the mixture is stirred at 0 ° for 30 minutes and at 25 ° for 1 hour.
  • the reaction mixture diluted with ethyl acetate (600 ml) is extracted with 3 ⁇ 150 ml ice water, dilute hydrochloric acid and saturated sodium chloride solution.
  • the organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator.
  • the crude product obtained is purified on silica gel with diethyl ether-ethyl acetate 9: 1 as the eluent.
  • the suspension obtained is poured onto an ice-cold mixture of petroleum ether (1 liter) and diethyl ether (500 ml), the trifluoroacetate obtained is filtered off with suction, washed with diethyl ether and dried at room temperature under a high vacuum.
  • the starting material can be produced as follows:
  • the aqueous phase is separated off with 20% citric acid solution acidified (pH 3) and extracted three times with ethyl acetate. The organic extracts are combined, washed once with brine, dried over sodium sulfate and the solvent is evaporated on a rotary evaporator at 45 °.
  • the crude product is purified by filtration on 10 times the amount of silica gel.
  • the fractions with methylene chloride-methyl acetate (10: 0.5) as eluent are combined.
  • the 4 - ((4R) -4-BOC-amino-4-t-butoxycarbonylbutyrylamino) phenylacetic acid benzyl ester obtained is recrystallized from a mixture of ethyl acetate and petroleum ether. F. 101-104 ° (decomposition).

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Claims (13)

1. Composés d'acide acylamino-3-cephem-4-carboxylique de formule
Figure imgb0030
où l'indice n représente un nombre entier allant de 1 à 4, l'indice m 0 ou 1, X un oxygène, un soufre ou le groupe -NH-, W un groupe -CO-, ―CO―NHSO2― ou ―SO2NH―CO―, ou X-W ensemble un groupe -CO- ou ―CO―NHSO2―, A un phénylène éventuellement substitué par un alcoyle inférieur, un hydroxy, un alcoxy inférieur et/ou un halogène, un thiénylène ou un furylène éventuellement substitué par un alcoyle inférieur, un alcoxy inférieur et/ou un halogène, Y un hydrogène, un hydroxyle, un formyloxy, un amino ou un sulfo se présentant éventuellement sous forme de sel et Z un hydrogène, ou Y et Z ensemble un groupe oxo ou un groupe =N-0-RO, où R° représente un hydrogène ou un alcoyle inférieur éventuellement substitué par un alcoxy inférieur, un halogène, un hydroxy, un hydroxy acylé, un sulfo, un carboxy ou un carboxy estérifié par un alcoyle inférieur, R1 un hydrogène, un alcoyle inférieur en C1 à C4, un alcoxy inférieur en C1 à C4, un halogène ou , un groupe de formule ―CH2―R2, où R2 représente un groupe hydroxy, un groupe hydroxy ou mercapto estérifié par un acide carboxylique aliphatique inférieur, par l'acide carbamique ou un acide carbamique susbtitué sur l'atome d'azote par un alcoyle inférieur, un alcoyle inférieur halogéné ou un alcanoyle inférieur-alcoyle inférieur, un alcoxy inférieur, un alcoyle inférieur-thio ou un groupe mercapto éthérifié par un radical hétérocyclique, lié au groupe mercapto par l'intermédiaire d'un atome de carbone du noyau, ayant de 1 à 4 atomes d'azote dans son noyau, et éventuellement dans son noyau un autre hétéroatome du groupe de l'oxygène et du soufre, qui peut être mono- ou polysubstitué par un alcoyle inférieur, un hydroxyalcoyle, inférieur, un alcanoyloxy inférieur-alcoyle inférieur, un alcoyle inférieur halogéné, un carboxyalcoyle, inférieur, un alcoxycarbonyle inférieur-alcoyle inférieur, un sulfoalcoyle inférieur, un sulfoalcoyle inférieur amidé, un amino-alcoyle inférieur, un mono- ou di-alcoyle inférieur- aminoalcoyle inférieur, un acylaminoalcoyle inférieur, un cycloalcoyle, un aryle, un arylalcoyle inférieur, un hétérocyclyle, un halogène, un amino, un mono-ou di-alcoyle inférieur-amino, un alcanoyle inférieur-amino, un halogène-alcanoyle inférieur-amino, un carboxy-alcanoyle inférieur-amino, un nitro, un hydroxy, un alcoxy inférieur, un carboxy, un alcoxycarbonyle inférieur, un carbamoyle, un carbamoyle substitué par un N-mono-alcoyle inférieur ou un N,N-dialcoyle inférieur, un cyano, un oxo ou un oxydo, ou un groupe ammonium quaternaire, les radicaux décrits comme inférieurs comprenant, sauf définition expresse ontraite, ceux qui ont de 1 à 7 atomes de carbone, et R3 représente un hydrogène ou un méthoxy, où les groupes carboxyle sont éventuellement estérifiés sous forme physiologiquement séparable, et leurs sels.
2. Composés de formule [I] selon la revendication 1, où le groupe ―[CnH2n]― est non ramifié et où les indices n et m ont la signification donnée, X représente un oxygène ou le groupe -NH-, W un groupe --CO- ou ―CO―NHSO2―, ou X-W ensemble un groupe -CO- ou ―CO―NHSO2―, A représente un p- ou un m-phénylène, un 2,5-thiénylène ou un 2,5-furylène, Y représente un hydrogène, un hydroxyle, un amino ou un sulfo et Z représente un hydrogène, ou Y et Z représentent ensemble un groupe =N-O-R°, où R° est un hydrogène ou un méthyle, R1 un alcoyle inférieur, un alcoxy inférieur, ou un groupe de formule ―CH2―R2, où R2 représente un alcanoyloxy inférieur, un carbamoyloxy, un N-alcoyle inférieur-carbamoyloxy, un triazolylthio, un tétrazolylthio, un thiazolylthio, un thiatriazolylthio, un thiadiazolylthio, un oxazolylthio, un oxadiazolylthio, ou un pyridinio, où les radicaux hétérocycliques peuvent être éventuellement substitués par un alcoyle inférieur, un N,N-dialcoyle inférieur- aminoalcoyle inférieur, un carboxyalcoyle inférieur, un sulfoalcoyle inférieur, un amino, un carboxyalcanoyle inférieur-amino ou un carbamoyle, et R3 représenté un hydrogène ou un méthoxy, et leurs sels.
3. Composés de formule I selon les revendications 1 ou 2, où le groupe ―[C2H2n]― est non ramifié et où les indices n et m ont la signification donnée, X représente un oxygène ou le groupe -NH-, W représente un groupe -CO- ou ―CONHSO2―, ou bien où X-W représentent ensemble un groupe -CO- ou ―CONHSO2―, A représente un p- ou un m-phénylène ou encore, lorsque m vaut 1, un 2,5-thiénylène ou un 2,5-furylène, Y représente un hydrogène, un hydroxyle, un amino ou un sulfo et Z représente un hydrogène, ou bien où Y et Z représentent ensemble un groupe =N-0-R°, où R° est un hydrogène ou un méthyle, R1 représente un méthyle, un méthoxy ou un groupe de formule ―CH2―R2, où R2 représente un acétoxy, un carbamoyloxy, un 1-méthyl-1H-tétrazol-5-yl-thio, un 1-sulfométhyl-1H-tétrazol-5-ylthio, un 1-carboxyméthyl-1H-tétrazolylthio, un 1-(2-diméthylamino- éthyl)-1H-tétrazol-5-ylthio, un 2-méthyl-1,3,4-thiadiazol-5-ylthio, un 4-carbamoylpyridinio, et R3 un hydrogène ou un méthoxy, et leurs sels.
4. L'acide 7β - {2 - / 4 - [2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/acétyl - aminol - 3 - / [1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl / - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - / 4 - [[2S] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/acétylamino} - 3 - / [1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl / - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - / 4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/acétylamino}-3 - méthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - / 4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/acétylamino} - céphalosporanique,
l'acide 7β - {2 -/4 - [[5R,S] - 5 - amino - 5 - carboxypentylaminocarbonylamino]phényl/acétyl - amino) - céphalosporanique,
l'acide 7β - {2 /4 - [[3R] - 3 - amino - 3 - carboxypropionylamino] - phényl/acétylaminol - 3 -/ [1 - méthyl - 1 H - tétrazol - 5 - yl]thiométhyl/ - 3 - cephem - 4 - carboxylique,
l'acide 7/3 - {2 - /4 - [[3R] - 3 - amino - 3 - carboxypropionylamino]phényl/acétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - /5 - [[2R] - 2 - amino - 2 - carboxyéthoxycrbonylaminométhyl] - 2 - furyl/ - 2 - syn - méthoxyiminoacétylamino} - 3 - /[1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl/ - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - /5 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylaminométhyl] - 2 - furyl/ - 2 - syn - méthoxyiminoacétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7/3 - {2 -/5 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylaminométhyl] - 2 - thiényl/ - 2 - syn - méthoxyiminoacétylamino} - 3 - acétoxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylaminosulfonylamino]phényl/ - acétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {[2R,S] - 2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/ - 2 - hydroxyacétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {[2R,S] - 2 - /4 - [[2R] - amino - 2 - carboxyéthoxycarbonyl]phényl/ - 2 - hydroxy - acétylamino} - 3 - /[1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl/ - 3 - cephem - 4 - carboxylique,
le 7β - /4 - [2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino] - phénylacétamido/ - 3 - [4 - carbamoyl - pyridiniométhyl] - 3 - cephem - 4 - carboxylate, et
l'acide 7β - {2 - /4 - [[4R] - 4 - amino - 4 - carboxybutyrylamino] - phényl/acétylamino} - 3 -/ [1 - méthyl - 1 H - tétrazol - 5 - yl]thiométhyl/ - 3 - cephem - 4 - carboxylique,
l'acide 7a - méthoxy - 7β - {2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/ - acétylamino} - 3 - /[1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl/ - 3 - cephem - 4 - carboxylique,
l'acide 7β - {[2R,S] - 2 -/4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/ - 2 - sulfo acétylamino} - 3 - /[1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl/ - 3 - cephem - 4 - carboxylique,
l'acide 7ß - {[2R] - 2 - amino - 2 - /3 - [2R] - 2 - amino - 2 - carboxy - éthoxycarbonylamino] - phényl/acétylamino} - 3 - méthoxy - 3 - cephem - 4 - carboxylique,
l'acide 7β - {[2R,S] - 2 - hydroxy - 2 - /3 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino] - phényl/acétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique,
l'acide 7β - {[2R,S] - 2 - hydroxy - 2 - /3 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino] - phényl/acétylamino} - 3 - méthoxy - 3 - cephem - 4 - carboxylique,
l'acide 7β - /5 - [[2R] - 2 - amino - 2 - carboxy - éthoxycarbonylaminométhyl] - thién - 2 - yl - acétamido/ - 7α - méthoxy - 3 - [1 - méthyl - 1 H - tétrazol - 5 - ylthiométhyl] - 3 - cephem - 4 - car - boxylique, et leurs sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 3.
5. L'acide 7β - {2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino] - phényl/acétyl - amino) - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique et ses sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 3.
6. L'acide 7β - {[2R] - 2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/ - 2 - hydroxyacétylamino} - 3 - /[1 - méthyl - 1 H - tétrazol - 5 - yl] - thiométhyl/ - 3 - cephem - 4 - carboxy - lique et ses sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 3.
7. L'acide 7β - {[2R] - 2 - /4 - [[2R] - 2 - amino - 2 - carboxyéthoxycarbonylamino]phényl/ - 2 - hydroxyacétylamino} - 3 - carbamoyloxyméthyl - 3 - cephem - 4 - carboxylique et ses sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 3.
8. Les sels de sodium de l'un des composés mentionnés dans les revendications 1 à 7.
9. Préparations pharmaceutiques contenant l'un des composés revendiqués dans l'une des revendications 1 à 8.
10. Corps et mélanges de corps selon l'une des revendications 1 à 9 aux fins d'application au traitement d'infections provoquées par des bactéries ou des coques gram-positifs et gram-négatifs.
11. Composés d'acide acylamido-3-cephem-4-carboxylique de la formule I définie dans la revendication 1, où au moins l'un des groupes fonctionnels se présente sous forme protégée, ainsi que leurs sels.
12. Procédé de préparation de composés d'acide acylamido-3-cephem-4-carboxylique de la formule 1 définie dans la revendication 1, où les groupes carboxyle sont éventuellement estérifiés sous forme physiologiquement séparable, et de leurs sels, caractérisé en ce qu'on libère le[s] groupe[s] fonctionnel[s] dans un composé de départ correspondant à la formule I, où au moins l'un des groupes fonctionnels présents est protégé, si on le désire, en ce qu'on transforme un groupe carboxyle libre en un groupe carboxyle estérifié physiologiquement séparable, et/ou, si on le désire, en ce qu'on dédouble un mélange d'isomères obtenu pour donner les isomères isolés, et/ou, si on le désire, en ce qu'on transforme un composé obtenu en un sel ou un sel obtenu en un composé libre ou en un autre sel..
13. Procédé de préparation de composés d'acide acylamino-3-cephem-4-carboxylique de formule 1 défini dans la revendication 1, où au moins l'un des groupes fonctionnels se présente sous forme protégée, caractérisé en ce que
a] dans un composé de formule
Figure imgb0031
où le groupe amino est éventuellement substitué par un groupe permettant l'acylation, et où le groupe 4-carboxyle et éventuellement d'autres groupes fonctionnels présents dans le radical R1 se présentent sous forme protégée, on acyle le groupe amino par traitement avec un acide de formule
Figure imgb0032
 où le groupement acide carboxylique aminé HOOC―CH[NH2]― et éventuellement d'autres groupes fonctionnels présents dans le groupement ―A―C[Y][Z]― se présentent sous forme protégée, ou avec un dérivé d'acide fonctionnel réactif ou avec un de ses sels, ou
b] dans un composé de formule
Figure imgb0033
où le groupe amino peut être éventuellement substitué par un groupe permettant l'acylation, et où le groupe 4-carboxyle et éventuellement d'autres groupes fonctionnels présents dans le radical R1 et dans le groupement ―A―C[Y][Z]― peuvent se présenter sous forme protégée, on acyl le groupe amino par traitement avec un dérivé fonctionnel réactif d'un acide de formule
Figure imgb0034
où le groupement acide carboxylique aminé HOOC―CH[NH2]― se présente sous forme protégée, ou bien lorsque X-W représentent ensemble un groupe -CO-, également avec un acide libre correspondant ou avec un de ses sels, ou
c] dans un composé de formule
Figure imgb0035
où X représente un oxygène, un soufre ou le groupe -NH-, et où le groupement acide carboxylique aminé HOOC-CH[NH2)- se présente sous forme protégée, on acyle le groupe -X-H- avec un dérivé fonctionnel réactif d'un composé de formule
Figure imgb0036
où le groupe 4-carboxyle et éventuellement d'autres groupes fonctionnels présents dans le radical R1 et dans le groupement ―A―C[Y][Z]― peuvent se présenter sous forme protégée et, si on le désire, en ce qu'on protège dans un composé obtenu les groupes fonctionnels non encore protégés ou en ce qu'on échange un groupe protecteur contre un autre, et/ou, si on le désire, en ce qu'on échange dans un radical R1 un groupe R2 contre un autre groupe R2, et/ou, si on le désire, en ce qu'on transforme un composé obtenu où R3 est un hydrogène en un composé où R3 est un méthoxy, et/ou, si nécessaire, en ce qu'on isomérise un composé 2-cephem obtenu ou un mélange obtenu d'un composé 2-cephem et d'un composé 3-cephem en un composé 3-cephem, et/ou, si on le désire, en ce qu'on dédouble un mélange d'isomères obtenu pour donner les isomères isolés.
EP78100367A 1977-07-18 1978-07-11 Dérivés de, cephalosporine leur préparation et leurs compositions pharmaceutiques Expired EP0000500B1 (fr)

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US4313945A (en) * 1978-11-23 1982-02-02 Ciba-Geigy Corporation 7-Thiazolyl-acetamido-cephem derivatives with terminal aminocarboxylic acid grouping
US4464366A (en) * 1979-12-19 1984-08-07 Ciba Geigy Corporation Cephem compounds having a terminal aminocarboxylic acid grouping and containing an azacyclyl(thio)ureido group
EP0059683A3 (fr) * 1981-02-27 1982-12-01 Ciba-Geigy Ag Acides 7-acylamido-3-céphem-4 carboxyliques, leur préparation, compositions pharmaceutiques les contenant et leur application
US4751299A (en) * 1983-11-18 1988-06-14 Takeda Chemical Industries, Ltd. Optically active β-lactams and method of their production
GB2167434B (en) * 1984-11-20 1988-09-14 Witton Chem Co Ltd Dispersing agents for coal slurries
EP2167071B1 (fr) * 2007-06-13 2020-03-18 Wayne State University Board Of Governors Solution de baclofène pour administration thérapeutique en faible volume
WO2008157308A2 (fr) 2007-06-13 2008-12-24 Wayne State University Board Of Governors Solution zwittérionique pour administration thérapeutique en faible volume

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US4007173A (en) * 1973-05-07 1977-02-08 Smithkline Corporation α-amino-α-(ureidophenyl)acetamidocephalosporins
AR205537A1 (es) * 1973-05-10 1976-05-14 Fujisawa Pharmaceutical Co Procedimiento para la preparacion de derivados de acido 7-substituido fenilglicinamido - 3 - substituido - 3 - cefem - 4 - carboxilicos
FR2235695B1 (fr) * 1973-07-06 1982-03-26 Fujisawa Pharmaceutical Co
US3919206A (en) * 1973-09-25 1975-11-11 Yeda Res & Dev 7-(Halomethylaryl)acetamidocephalosporin derivatives
US3929778A (en) * 1974-08-08 1975-12-30 Squibb & Sons Inc {8 (Acylcarbamoyl) thioacetyl{9 {0 cephalosporin derivatives
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ES471812A1 (es) 1979-10-16
EP0016900A1 (fr) 1980-10-15
US4467101A (en) 1984-08-21
IL55152A (en) 1982-07-30
AU522514B2 (en) 1982-06-10
IE47032B1 (en) 1983-11-30

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