Classifications

• • 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 action against normal and resistant germs.
• the present invention also relates to the corresponding carboxylic acids containing the novel acyl groups and their reactive functional derivatives to be used as starting materials, in which functional groups are optionally protected, and to processes for their preparation.
• 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, contain up to 7, preferably up to 4, carbon atoms.
• 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 phenyl 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 also 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-halogen, 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.
• 2-halogen such as 2-chloroethyl, 3-hal
• 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 alkanöylthio, 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.
• Etherified hydroxy and mercapto groups R 2 are etherified, for example, with an aliphatic hydrocarbon radical, and are in particular lower alkoxy, in particular with 1-4 C atoms, primarily methoxy, and also ethoxy, n-propyloxy or isopropyloxy, furthermore straight-chain or branched butyloxy, or Lower alkylthio, preferably with 1-4 C atoms, primarily methylthio, and ethylthio, n-propylthio or isopropylthio, and also straight-chain or branched butylthio.
• Etherified mercapto groups R 2 are, in particular, by an optionally substituted one via a ring carbon ether atom attached to the mercapto group, heterocyclic radical with 1 to 4 ring nitrogen atoms and optionally a further ring hetero atom from the group oxygen and sulfur.
• heterocyclic radicals are primarily optionally substituted, e.g. the below-mentioned substituent-containing monocyclic, five-membered diaza, triaza, tetraza, thiaza, thiadiaza, thiatriaza, oxaza or oxadiazacyclic radicals of aromatic character.
• Substituents of such heterocyclyl radicals include lower alkyl, especially methyl, and also ethyl, n-propyl, isopropyl or straight-chain or branched butyl, or hydroxy esterified by hydroxy, such as lower alkanoyloxy, halogen, such as chlorine, carboxy, esterified carboxy, such as lower alkoxycarbonyl, sulfo, amidated Sulfo, amino, mono- or di-lower alkylamino, acylamino, such as lower alkanoylamino, or by substituted lower alkyl, such as carboxy or halogen substituted lower alkanoylamino, for example 2-hydroxyethyl, 2-acetoxyethyl, 2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, 2 -Aethoxycarbonylethyl, sulfomethyl, 2-sulfoethy
• heterocyclic radical are 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, for example furyl, for example 2-furyl, thienyla for example 2-thienyl, or oxazolyl, for example 2- or 5-oxazolyl or functional groups, such as halogen, for example fluorophor chlorine or bromine, optionally substituted amino, such as optionally mono- or di-substituted amino substituted by lower alkyl, for example amino, methylamino or dimethylamino, acyl amino, such as lower alkanoylamino or lower alkanoylamino substituted by halogen or carboxy, such as acetylamino, 3-chloropropionylamino or 3-carboxypropiony
• 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 1H-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 1H-tetrazol
• 2-thiazolylthio 4- (2-thienyl) -2-thiazolylthio, 4, .5-dimethyl-2-thiazolylthio, 3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, in particular also optionally substituted thiadiazolylthio as indicated, for example 1,2,3-thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3,4-thiadiazol-2 -ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 2- (3-carboxypropionylamino) - 1,3,4-thiadiazol-5-ylthio, 1,2,4-thiadiazol-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thiatriazolylthio, for example 1,2,3,4-thiatriazolyl-5-ylthio, optionally substituted oxazolylthio or iso
• Preferred heterocyclically etherified mercapto groups R 22 in which the heterocyclic radical is a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical include 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-l-oxido-6
• 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, hydroxy, halogen, such as fluorine Bromine or iodine, halogeno lower alkyl, such as trifluoromethyl, sulfo, optionally functionally modified carboxy, such as carboxy, lower alkoxycarbonyl, for example methoxycarbonyl, cyano, optionally functional
• Heterocyclic ammonium groups R 2 are primarily optionally lower alkyl, hydroxy-lower alkyl, amino, substituted sulfonamido, hydroxy, halogen, trifluoromethyl, sulfo, carboxy, lower alkoxycarbonyl, cyano, lower alkanoyl, 1-lower alkyl-pyrrolidinyl or carbamoyl optionally substituted by lower alkyl or hydroxy-lower alkyl containing pyridinium, e.g.
• 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, reductively, 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, 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-lower alkyl for example tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and / or nitro, mono- or polysubstituted phenyl radicals, such as optionally, for example substituted benzyloxycarbonyl, for example 4-nitro, as mentioned above -benzyloxycarbonyl, or.
• 4-methoxybenzyloxycarbonyl or, for example, substituted di as mentioned above phenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halogeno-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, in particular aroylmethoxycarbonyl, in which the aroyl group is preferably optionally substituted, for example by halogen, such as bromine, with benzoyl , for example phenacyloxycarbonyl, or polyhaloaryloxycarbonyl, such as pentachlorophenyloxycarbonyl, in question.
• halogen such as bromine
• 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, in particular methyl, furthermore lower alkoxy, for example methoxy, and / or halogen, for example chlorine, as substituents.
• Suitable silyl or stannyl protective groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halosilyl, for example methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, for example Dimethylchlorosilyl, or appropriately substituted stannyl compounds, for example 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 means, for example, the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or in which acyloxymethyl forms the residue of a lactone.
• Such groups are lower alkanoyloxymethoxycarbonyl, for example acetyloxymethyloxycarbonyl or pivaloyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, in particular a-amino-lower alkanoyloxymethoxycarbonyl, for example glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, furthermore phthalidyloxycarbonyl, for example 2-phthalidyloxycarbonyl, or indanyloxycarbonl, for example 5-indylylcarbonyloxy.
• a protected amino group can e.g. in the form of an easily cleavable acylamino, triarylmethylamino, etherified mercaptoamino, l-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, substituted diphenylmethoxycarbonyl as mentioned above, 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 optionally, for example, by halogen s, such as
• Acyl in an acylamino group can also represent the corresponding residue of an organic sulfonic acid; such a residue is in particular arylsulfonyl, wherein aryl is a phenyl radical 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. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid 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 preferably contains lower alkyl, in particular methyl, furthermore lower alkoxy, for example methoxy, and / or halogen, for example chlorine, as substituents.
• silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halogen-silyl, eg methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, for example dimethyl-chlorosilyl, or appropriately substituted stannyl, for example tri-n-butylstannyl.
• 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 a-phenyl-lower alkyl radicals, such as optionally substituted benzyl or diphenylmethyl, where as substituents of the phenyl radicals 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 one with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol. such as a lower alkanol, or sulfo group esterified with a silyl or stannyl radical, such as tri-lower alkylsilyl.
• a sulfo group for example, the hydroxyl group, like the hydroXy group, may be etherified 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 the 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. 4-aminobenzoic acid-2-diethylaminoethyl ester, 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.
• Compounds of formula I with a basic group may 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.
• Compounds of formula I 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 possibly two centers of asymmetry.
• the optionally present asymmetry center 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 formula I in which carboxyl groups are optionally esterified in physiologically cleavable form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotically active 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 .
• gram-positive cocci such as Staphylococcus aureus (in minimum doses of about 3 mg / kg) and Streptococcus pneumoniae (in minimum doses of about 0.15 mg / kg)
• enterobacteria such as Escherichia coli (in minimum doses of about 8 mg / kg), Klebsiella pneumoniae and Proteus mirabilis (in minimum doses of about 0.3 mg / kg)
• Other gram-negative bacteria such as Pasteurella multocida (in minimum doses of 0.1 mg / kg ), effective.
• the new connections can therefore, e.g. in the form of antibiotic preparations for the treatment of infections caused by gram-positive or gram-negative bacteria and cocci, in particular by enterobacteria such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis.
• 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.
• these, for example protected carboxyl, amino, hydroxyl, mercapto and / or sulfo groups are used in a manner known per se, such as by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis , or by means of reduction, in particular hydrogenolysis or chemical reduction, if necessary gradually or simultaneously released.
• a tert.-lower alkoxyoarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group can be converted 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 which is capable of producing nascent hydrogen together with the metal, such as an acid, primarily acetic acid, and also formic acid, or an alcohol, preferably water, in the free carboxyl group Convict.
• a hydrogen-donating agent which is capable of producing nascent hydrogen together with the metal, such as an acid, primarily acetic acid, and also formic acid, or an alcohol, preferably water, in 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 formed under mild basic conditions, such as by dilute sodium hydroxide solution or organic. Bases in the presence of water, saponified to form the free carboxyl group.
• a carboxyl group slotted, for example by silylation or stannylation, can be released in a conventional manner, 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. by treating with an appropriate chemical reducing agent, such as zinc in the presence of aqueous acetic acid, also an aroylmethoxycarbonylamino group.
• an appropriate chemical reducing agent such as zinc in the presence of aqueous acetic acid, also an aroylmethoxycarbonylamino group.
• Treating with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and a 4-nitro-benzyloxycarbonylamino group also by treating 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.
• 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 treating with a nucleophilic reagent such as sulfurous acid, an arylsulfonylamino group e.g. by 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. be released by hydrolysis or alcoholysis.
• a hydrogenation catalyst such as a palladium catalyst
• an aryl or aryl-lower alkylthioamino group e.g. by treating with a nucleophilic reagent such as sulfurous acid, an arylsulfonylamino group e.g. by electrolytic reduction, a 1-acyl-2-lower alkylidene amino group or
• An amino group protected in 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 else by zinc and acid, such as acetic acid.
• the catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or also in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 to 25 °, or also in 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.
• a hydroxyl group protected by 2,2-dichloroacetyl 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 separated in a manner known per se replace another R 1 radical or convert it into another R 1 radical.
• R1 is a group of the formula -CH 2 -R 2 and R 2 is, for example, a radical which can be replaced by nucleophilic substituents, or in a salt thereof, by treatment with a corresponding mercaptan or with a thiocarboxylic acid compound to replace such a radical R 2 with 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 alkanecarboxylic acid camides 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 denotes the group -CH 2 -R 2 , where R 2 represents a hydroxyl group esterified by the acyl radical of an optionally substituted half-amide of carbonic acid, can be introduced, for example, by a corresponding compound of the formula I in which R 2 is free hydroxy (which can be obtained, for example, by splitting off the acetyl radical from an acetyl oxy 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 lupinii, Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, e.g.
• a suitable carbonic acid derivative in particular with an isocyanate or carbamic acid compound, such as a silyl isocyanate, e.g. silyl tetraisocyanate, a sulfonyl isocyanate, e.g. chlorosulfonyl isocyanate, or carbamic acid halide, e.g.
• a silyl isocyanate e.g. silyl tetraisocyanate
• a sulfonyl isocyanate e.g. chlorosulfonyl isocyanate
• carbamic acid halide e.g.
• N-substituted 3-aminocarbonyloxymethyl compounds lead), or then with an N-substituted isocyanate or with an N-mono- or N, N-disubstituted carbamic acid compounds, such as a corresponding carbamic acid halide, for example -chloride, -, wherein Usually in the presence of a solvent or diluent and, if necessary, with cooling n 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 become.
• a suitable organic or inorganic acid for example acetic acid, hydrochloric acid, phosphoric acid or else sulfuric acid become.
• 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
• acids for example 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 product which is obtained, for example, by reacting a compound of the formula I in which R 2 in the R 1 radical 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 thiocar- .bonic acid, such as an aromatic thiocarboxylic acid, for example thiobenzoic acid, can be obtained with the tertiary amine, in particular.
• a tertiary heterocyclic base such as an optionally substituted pyridine
• the reaction is usually carried out in the presence of a suitable desulphurizing agent, in particular a mercury salt, for example mercury silver-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 desulphurizing agent in particular a mercury salt, for example mercury silver-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.
• the conversion of a free carboxyl group in a compound of the formula I obtained into an esterified carboxyl group which can be cleaved under physiological conditions is carried out according to 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 I can be prepared in a manner known per se.
• salts of compounds of formula I 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 ⁇ -ethylcaproic 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 I 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 treatment 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 D n.
• Any residues present in a starting material of formula II or IV which substitute the amino group and allow their acylation 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.
• the amino group can also be silylated or stannylated.
• 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-hydroxybenzylideh or 4-nitrobenzylidene, further optionally, e.g. carboxy substituted oxacycloalkylidene, e.g. 3-carboxy-2-oxacyclohexylidene.
• the remaining 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, if appropriate, are protected from existing, acylatable amino, hydroxyl and mercapto groups.
• a free acid of formula III or V where all functional groups except the reacting carboxyl group are protected, are used for the acylation, suitable condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, are usually used.
• suitable condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, are usually used.
• 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.
• suitable carbonyl compounds for example carbonyldiimidazole
• isoxazolinium salts for example N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate and N-tert.
• -Butyl-5-methyl-isoxazolinium perchlorate or an acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.
• the condensation reaction is preferably carried out in a water-free reaction medium, preferably in the presence of a solvent or diluent, e.g. Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, carried out with cooling or heating and / or in an inert gas atmosphere.
• a solvent or diluent e.g. 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, and also with hydrochloric acid, ie the corresponding ones Acid azides, with a phosphorus-containing acid, for example phosphoric acid or phosphorous acid, or with a sulfur-containing acid, for example sulfuric acid, or with hydrocyanic acid.
• inorganic acids such as hydrohalic acids, ie the corresponding acid halides, for example chlorides or bromides
• hydrochloric acid ie the corresponding ones
• Acid azides with a phosphorus-containing acid, for example phosphoric acid or phosphorous acid, or with a sulfur-containing acid, for example sulfuric acid, or with hydrocyanic acid.
• mixed anhydrides are, for example, those with organic carboxylic acids, such as with lower alkane carboxylic acids 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 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
• esters suitable for reaction with the amino, hydroxy or mercapto group in an acid of the formula III, V or VII in which all functional groups.
• Pen are protected or can be protected from the reacting carboxyl group 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- Benztriazolester, or diacylimino esters, such as succinylimino or phthalylimino esters.
• the acylation with an acid derivative, such as an anhydride, in particular with an acid halide can be carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine.
• an acid-binding agent for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine.
• N, N-di-lower alkyl-aniline for example N, N-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylation ten "Mbrpholins, such as N-methylmorpholine, or a base of the pyridine type, for example pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example 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 for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example 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 III, 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.
• a mixed anhydride is obtained by treating an acid of the formula III, or an acid of the formula V, in which XW is the group -CO-, with appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, for example, with an organic amine, such as 4-methylmorpholine, or a metal, for example alkali metal salt, with a suitable acid derivative, such as a corresponding acid halide of an optionally substituted lower alkane carboxylic acid, for example trichloroacetyl chloride, or with a half ester of a carbonic acid half-halide, for example ethyl chloroformate or undisututobutyl ester uses the mixed anhydride thus available without isolation.
• An acid chloride of an acid of formula V, in which XW is a group -O-CO-, -S-CO- or -NH-CO- and in which the aminocarboxylic acid group HOOC-CH (NH 2 ) - is in protected form, for example in situ, are formed by using an amino carboxylic acid of formula VI, wherein X is oxygen, sulfur or the group -NH-, and the group HOOC-CH (NH 2 ) - in a protected form, in the presence of a hydrochloric acid acceptor in an inert organic Solvent or solvent mixture treated with phosgene.
• hydrochloric acid acceptors, 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 further functional groups are protected can be prepared from a correspondingly protected compound of the formula IV by treatment with chlorosulfonyl isocyanate.
• the 7a-methoxy group R 3 can be introduced in a manner known per se, for example by sequentially using said intermediate 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 base in particular 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, for example from about 0 ° C to about -80 ° C, and in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran, when using lithium methylate in the presence of methanol, and, if desired, in a closed vessel and / or in an inert gas, for example nitrogen atmosphere.
• a suitable solvent or diluent for example an ether such as tetrahydrofuran
• 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.
• hydrohalic acid in particular hydrochloric acid
• a hydrogen halide-releasing base such as a suitable alkali metal lower alkanolate, for example lithium tert-butoxide
• this reaction usually taking place under the conditions of the anion and N-halogen compound-forming reaction, in the presence of methanol work and instead of Acylimino compound can directly obtain the 7a-methoxy-cephem compound.
• the starting point is usually a compound of the formula I in which functional groups are in protected form, this is reacted with an excess of the anion-forming agent, for example lithium methylate or phenyllithium, in the presence of methanol, then treated with the N-halogenating agent, for example tert-butyl hypochlorite, and thus directly receives the desired compound of formula I, in which functional groups are protected.
• the methanol can also be added subsequently, the dehydrohalogenation and the addition of methanol being carried out at slightly higher temperatures than the reactions which form the anion and N-halogen compound, for example at about 0 ° C. to about -20 ° C., if necessary in a closed vessel and / or in an inert gas, for example 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 compounds 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 with a dissociation constant of at least 10 -5 , it being possible to use low concentrations, for example 1-2% or less, but also larger amounts of the acid.
• concentrations for example 1-2% or less, but also larger amounts 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.
• the oxidation with percarboxylic acids is catalyzed by the presence of an acid with a dissociation constant of at least 10-5, its effectiveness depending on its strength.
• Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid.
• acetic acid, perchloric acid and trifluoroacetic acid are, for example, acetic acid, perchloric acid and trifluoroacetic acid.
• 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 carrier 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 an inorganic or organic type, for example as tin (II) chloride, fluoride, acetate or formate, iron (II) chloride or sulfate , oxalate or succinate, copper (I) chloride, benzoate or oxide, or manganese (II) chloride, sulfate, acetate or oxide, or as complexes, for example with ethylenediaminetetraacetic acid or nitrol
• 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 than benzoyl chloride, for example phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivalinsänrechlorid, 4-methoxybenzoyl, 4-Cyanbenzoesaurechlorid, p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trich
• 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 alkane carboxylic acid esters or nitriles, e.g.
• the reducing agent e.g. Lower alkane carboxylic acids or esters thereof, such as acetic acid and ethyl acetate
• optionally substituted such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or
• 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. , in which the aminocarboxylic acid group HOOC-CH (NH 2 ) - is in protected form, or, when XW together represent a group -CO-, also acylated with a corresponding free acid or with a salt thereof, and if desired, a compound obtained converted into another 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 intermediate protection in the present acylation must differ from the other protective groups, which are necessarily to remain present in the compounds of the formula III, differ in the manner in which they are split off, so that after the present acylation reaction. can be split off selectively.
• a hydrogenolytically removable protective group such as one of the optionally substituted benzyl groups mentioned, for example the benzyl or p-nitrobenzyl group, is used for the intermediate protection of the carboxyl group, then the others may.
• Protective groups cannot be split off 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 in a compound of the formula III obtained, with appropriately protected functional groups, a protective group, optionally selectively, can be cleaved off, or a functional group that may have been released during the acylation reaction can be protected.
• the a-hydroxy group in which Z is hydrogen and Y is hydroxy, 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 ⁇ -oxc group and in an available compound of the formula III, in which Z and Y together denote the oxo group, this can be converted into the corresponding oximino group by treatment with a hydroxylamine of the formula H 2 NOR °, which reaction analogous to the conversion of a-keto acids of the formula IX into oximio compounds of the formula VIIIa
• R ° represents hydrogen or optionally substituted lower alkyl.
• the new, antibiotic compounds of formula IV mentioned can be used as antibacterial antibiotics.
• they are active in vitro against Enterobacteriaceen, for example Escherichia coli, in minimum concentrations of 0.8 mcg / ml and against cocci in minimum concentrations of 0.1 mc g / ml.
• Enterobacteriaces such as Escherichia coli
• cocci in minimal doses of 15 mg / kg.
• the new compounds can therefore be used accordingly, for example 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 splitting off of the protective groups, the conversion of a group R 1 into another group R 1 , 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 III or V and the corresponding subsequent operations.
• Acids of the formula V, reactive functional derivatives thereof, the precursors of the formula HOOC-CH (NH 2 ) - (C n H 2n ) XH (VI) and correspondingly protected derivatives are known or can be prepared by methods known per se, for example in situ , getting produced.
• 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 reaction-protected 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 I, 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 formulas mentioned under formula I, which is stable during the reaction and then easily cleavable acyl groups, in particular the trifluoroacetyl group.
• 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, optionally in an inert gas, such as nitrogen atmosphere.
• a solvent such as water or an organic solvent, such as an alcohol, for example methanol
• an inert gas such as nitrogen atmosphere.
• 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 such as sodium hydroxide or an organic base such as a tertiary amine such as a tri-lower alkylamine such as triethylamine , 'as will be set free or ethyldiisopropylamine, or a heterocyclic tertiary base pyridine.
• an inorganic base such as an alkali metal hydroxide such as sodium hydroxide
• an organic base such as a tertiary amine such as a tri-lower alkylamine such as triethylamine
• 'as will be set free or ethyldiisopropylamine, or a heterocyclic tertiary base pyridine.
• 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 mono-tert.butyl ester in the presence of base, in the corresponding N-acyl, e.g. N-tert-butoxycarbonyl compound.
• an acid anhydride such as the anhydride of carbonic acid mono-tert.butyl ester in the presence of base, in the corresponding N-acyl, e.g. N-tert-butoxycarbonyl compound.
• Acid halides for example, expectant prepared by reacting a compound of For VIIIa, by using a halogenating agent, for example psporpentachlorid, thione lchlorid or oxalyl amfact with maritzter Am i no g ru pp e, or a salt man.
• a halogenating agent for example psporpentachlorid, thione lchlorid or oxalyl amfact with maritzter Am i no g ru pp e, or a salt man.
• aqueous solvent or solvent mixture such as a carboxylic acid amide, for example dimethylformamide
• a base such as a tertiary amine, such as tr ederalkylamine, e.g. B. triethylamine, or a ter ren cyclic amine, such as N-methyl-morphclin,
• Symmetrical anhydrides or mixed anhydrides of compounds of the formula VIIIa with a protected amino group other than halcgenides can be prepared, for example, by adding a corresponding compound with a free carboxyl group, preferably a salt, in particular alkali metal, for example sodium, or ammonium, for example triethyl ammonium 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.
• 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
• 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, ie aryl methyl ketones, into the corresponding one a-Keto acids, ie arylglyoxylic acids, suitable oxidizing agents in the usual way.
• Suitable oxidizing agents are, for example, oxidizing oxides or oxygen-stoffhalti g e acids, such as those of selenium, sulfur, manganese, chromium or nitrogen, or salts of corresponding acids, hereby'Alkalimetall- such as potassium salts thereof, the salts thereof, optionally in the presence of mineral acids such as hydrochloric acid or sulfuric acid, hydrogen peroxide, or even oxygen in the presence of a catalyst such as platinum on carbon.
• oxidizing agents are selenium dioxide or the selenic acid, permanganic acid salts, such as potassium permanganate, dichromic acid salts, such as potassium dichromate, and nitrous acid, which in situ consist of an inorganic nitrite salt, such as a corresponding alkali metal salt or alkaline earth metal salt, for example sodium salt acid, and an acid Sulfuric acid.
• permanganic acid salts such as potassium permanganate
• dichromic acid salts such as potassium dichromate
• nitrous acid which in situ consist of an inorganic nitrite salt, such as a corresponding alkali metal salt or alkaline earth metal salt, for example sodium salt acid, and an acid 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 an alcohol, such as a lower alkanol, e.g. Methanol or ethanol, carried out at temperatures from about 0 ° to about 100 °, usually, at elevated temperatures, i.e. at about 60-90 °.
• an optionally water-miscible, optionally water-containing organic solvent such as pyridine, acetic acid, an ether, such as tetrahydrofuran or dioxane, or an alcohol, such as a lower alkanol, e.g. Methanol or ethanol
• a compound of the formula X is preferably oxidized with selenium dioxide in a solvent, such as pyridine, at about 80-90 °, or also in accordance with German Offenlegungsschrift No. 2,528,786, with sodium or potassium nitrite in aqueous hydrochloric, sulfuric or phosphoric acid .
• oxidation of ⁇ -hydroxy acids of the formula XI, in which the amino group is present in protected form, to the corresponding ⁇ -keto acids of the formula IX can also be carried out be carried out in a manner known per se, ie as is known for the oxidation of hydroxyl groups to oxo groups.
• Oxidizing oxides such as those of manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium trioxide, for example Jones reagent or chromium trioxide, are in turn present in the presence of acetic acid, sulfuric acid or pyridine, nitrous oxide, dimethyl sulfoxide, if appropriate in the presence of dicyclohexylcarbodiimide or oxygen, and peroxides , such as hydrogen peroxide, oxygen-containing acids, such as permanganic acid, chromic acid or hypochloric acid, or salts thereof, such as potassium permanganate, sodium or potassium dichromate or potassium hypochlorite.
• the a-hydroxy group can also be converted into the a-oxo group by the Oppenauer oxidation, ie by treatment with the salt of a sterically hindered alcohol, such as aluminum or potassium tert-butoxide, isopropoxide or phenoxide in the presence of a Ketones such as acetone, cyclohexanone or fluorenone.
• a sterically hindered alcohol such as aluminum or potassium tert-butoxide
• isopropoxide or phenoxide in the presence of a Ketones such as acetone, cyclohexanone or fluorenone.
• Another possibility of converting the a-hydroxy group into the a-oxo group is dehydration, for example with Raney nickel.
• 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 usable compounds of the present invention can be used, for example, for the preparation of pharmaceutical.
• Zeutician preparations are used which contain an effective amount of the active substance together or in a mixture with inorganic see or contain organic, solid or liquid, pharmaceutically usable carriers, which are preferably suitable for parenteral administration.
• the pharmacologically active compounds of the present invention are preferably used in the form of injectable, for example intravenous, administrable preparations or infusion solutions.
• injectable for example intravenous, administrable preparations or infusion solutions.
• Such solutions are preferably isotonic aqueous solutions or suspensions, these consisting, for example, of lyophilized preparations which contain the substance on their own or together with a carrier material, for example mannitol. can be made before use.
• the pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.
• the present pharmaceutical preparations which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1% up to about 50%, lyophilisates up to 100% of the active ingredient.
• a dose of about 0.5 g to about 5 g sc for the treatment of warm-blooded animals of about 70 k g weight.
• 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 obtained by dissolving it in water and evaporating it or precipitating it with ethanol to be cleaned further.
• 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 product can be further purified by dissolving it in water and evaporating it, or in cases involving ethanol.
• 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.
• solution B is added dropwise to solution A within 3 minutes and then stirred at 0 ° for 30 minutes and at + 20 ° for 30 minutes.
• the mixture becomes 0.3 liters to 1.3 liters.
• Phosphate buffer pH 7 stirred and extracted at pH 6 with ethyl acetate.
• 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.
• the suspension is filtered off, the filter cake is washed with a mixture of ethyl acetate-methyl acetate (1: 1) and the filtrate is concentrated on a rotary evaporator at 45 °.
• the solution is diluted with a lot of ethyl acetate-methyl acetate (1: 1) and washed successively with water, 1N sodium bicarbonate solution and water.
• the organic phase is dried over sodium sulfate.
• Solution II is then pipetted into solution I and, after adding 0.2 ml (1.4 mmol) of triethylamine, stirred for 11 ⁇ 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 aqueous phase is adjusted to pH 6.1 with 1N sodium hydroxide solution, concentrated to about 1 ml in vacuo and mixed with ethanol (about 20 ml), whereupon the sodium salt of 7 ⁇ - ⁇ 2- [5 - ((2R) -2-amino-2-carboxyethoxycarbonylaminomethyl) -2-furyl] -2-syn-methoximinoacetylamino ⁇ -3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid fails.
• DS: Rf 52A 0.05.
• Solution I is added to solution II and the mixture is left under nitrogen at 0 ° for 1 hour. After shaking with 2N sulfuric acid, sodium bicarbonate and saline, the organic phase is dried over sodium sulfate. filtered and evaporated in vacuo.
• the aqueous phase is adjusted to pH 6.1 with 1N sodium hydroxide solution, concentrated to about 1.5 ml in vacuo and mixed with 60 ml of ethanol, whereupon the sodium salt of 7 ⁇ - ⁇ 2- [5 - ((2R) -2- Amino-2-carboxy-ethoxycarbonylaminomethyl) -2-thienyl] -2-syn-methoximino-acetylamino ⁇ -3-acetoxymethyl-3-cephem-4-carboxylic acid fails.
• DS: Rf 52A 0.05.
• Solution II is then pipetted into solution I and, after adding 0.2 ml (1.4 mmol) of triethylamine, stirred for 11 ⁇ 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 2N sulfuric acid, sodium bicarbonate and brine, the organic phase is dried over sodium sulfate, filtered and evaporated in vacuo.
• 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 gives the 2- [4 - ((2R) -2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylaminosulfonylamino) phenyl] acetic acid in the form of a foam.
• This solution of the resulting mixed anhydride is at 0 ° to a solution of 1.62 g of 7 ⁇ -amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid-diphenylmethyl ester p-tosylate and 0.34 g of N-methylmorplfoline in 14 ml Dropped methylene chloride. After stirring for 11 ⁇ 2 hours at 0 ° and 1 hour at + 22 °, the mixture is stirred in 100 ml of 0.3 M potassium dihydrogenphosphate solution and freed from organic solvents in vacuo. The remaining aqueous phase is extranrerted at 0 ° and pH 2.0 with ethyl acetate.
• 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, 1N 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 25 times the 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 7 ⁇ - ⁇ (2R, S) -2- [4 - ((2R) -2-amino-2-carboxyethoxycarbonylamino) phenyl] -2-hydroxyacetylaminoJ-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid analogously to Example 1a) converted into the corresponding sodium salt.
• Example 15a The suspension is then stirred in an ice bath for a further 2 hours and worked up as in Example 15a).
• 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-hydroxyacetylamino ⁇ -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] - 3-cephem-4-carboxylic acid diphenylmethyl ester precipitated from ethyl acetate solution with a mixture of petroleum ether and diethyl ether.
• the suspension is 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-hydroxyacetylamino ⁇ -3 - [(1-methyl-1H-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 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 filter cake is mixed with a mixture of ethanol (150 ml) and diethyl ether (150 ml) petroleum ether (150 ml) slurried, suction filtered and dried in a high vacuum at room temperature, the crude product is stirred with 250 ml methylene chloride, the insoluble part is separated off, the clear solution is evaporated on a rotary evaporator at 45 ° and the remaining foam on the 25th times the amount of silica gel, the fractions with mead ethylene chloride-trifluoroethanol-water 7: 4: 0.2) are combined.
• 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, at 30 ° for 30 minutes. and stirred for 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-diphenylmethoxycarbonyl- ethoxycarbonylamino) phenyl ] -acetylamino ⁇ -3-carbamoyloxy-methyl-3 - cephem-4-carboxylic acid diphenylmethyl ester as an amorphous powder.
• the aqueous phase is adjusted to pH 3 with 1N 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. After removal of the solvents on a rotary evaporator, the 7 ⁇ - ⁇ (2R, S) -2-hydroxy-2- [3 - ((2R) -2-amino-2-carboxyethoxycarbonylamino) phenyl] acetylamino ⁇ -3-methoxy-3 is obtained -cephem-4-carboxylic acid in the form of the monohydrate.
• 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 oily (2R) -N-BOC-glutamic acid - (- y-benzyl ester) - ⁇ -tert-butyl ester is made from (2R) -N-BOC-glutamic acid- ⁇ -benzyl ester by reaction with 0-tert-butyl Isourea in methylene chloride (E. Vowinkel, Chem. Ber. 100, 16 (1967)).
• the crude product is purified by chromatography on 20 times the amount of silica gel.
• the reaction mixture is mixed with 3.0 g of solid N, N'-dicyclohexylcar bodiimid spiked.
• the suspension is filtered off with suction, the filter cake is washed with ethyl acetate, the filtrate is mixed with a lot of ethyl acetate and the tetrahydrofuran is removed by concentrating on a rotary evaporator at 45 °.
• the solution obtained is diluted with ethyl acetate and successively with water, 1N sodium bicarbonate solution and Washed water.
• the organic phase is dried over sodium sulfate and evaporated at 45 ° on a rotary evaporator.
• 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 the 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).
• Dry ampoules or vials containing 0.5 g of 7 ⁇ - ⁇ 2- [4 - ((2R) -2-amino-2-carboxyethoxycarbonylamino) phenyl] acetylamino ⁇ -3 - [(1-methyl-1H-tetrazol-5-yl ) -thiomethyl] -3-cephem-4-carboxylic acid sodium salt are prepared as follows:

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• 1978
  • 1978-07-11 EP EP78100367A patent/EP0000500B1/fr not_active Expired
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