GB2106519A - Aminooxazolyl compounds - Google Patents

Aminooxazolyl compounds Download PDF

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GB2106519A
GB2106519A GB08227774A GB8227774A GB2106519A GB 2106519 A GB2106519 A GB 2106519A GB 08227774 A GB08227774 A GB 08227774A GB 8227774 A GB8227774 A GB 8227774A GB 2106519 A GB2106519 A GB 2106519A
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amino
carboxy
lower alkyl
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Riccardo 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Description

SPECIFICATION Aminooxazolyl compounds, processes for their manufacture, pharmaceutical preparations containing these compounds, and the use of the latter The present invention relates to novel 7p-aminooxazolylacetamino-3-cephem-4-carboxylic acid compounds, processes for their manufacture, pharmaceutical preparations containing these compounds, and their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds, and to novel intermediates and processes for their manufacture.
The present invention relates to 7,3-aminooxazolylacetamino-3-cephem-4-carboxylic acid compounds of the formula
in which n is an integer from 0 to 2, A represents carbonyl, methylene, or a methylene group that is substituted by amino, protected amino, hydroxy, protected hydroxy, sulpho, protected sulpho or by a group of the formula =N-O-R4 in which R4 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, carbamoyl or substituted carbamoyl, R, represents hydrogen, lower alkyl, lower alkoxy, halogen, or a group of the formula -CH2-R2 in which R2 represents hydroxy, mercapto, esterified hydroxy or mercapto, etherified hydroxy or mercapto, or an ammonia group, and R3 represents carboxy or protected carboxy, hydrates and salts of compounds of the formula I, processes for the manufacture of compounds of the formula I, pharmaceutical preparations containing compounds of the formula I and the use of compounds of the formula I for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.
In the description of the present invention, the term "lower" used in connection with groups for example lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc., means that the respective groups, unless expressly defined to the contrary, contain up to 7, and preferably up to 4, carbon atoms.
In the formula I, the index n represents especially 0. If n represents 1, the 1 -oxido group may be in the a- or ,B-position, or, in compounds of the formula I the 1 -oxido group may be in both positions.
The oxazolyl radical substituted in the 2-position by the amino group may also be present in tautomeric form as a dihydrooxazolyl radical substituted by an imino group, or as a mixture of both tautomers. The position of the equilibrium between the two tautomers depends on external parameters such as temperature, solvent and pH value. In the present description, the aminooxazolyl radical is referred to only as an aminooxazolyl radical. The dihydroiminooxazolyl tautomer is, however, also included.
The general definitions used hereinbefore and hereinafter have, within the scope of the present description, preferably the following meanings: Lower alkyl R1 contains from 1 to 4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl.
Lower alkoxy R, contains from 1 to 4 carbon atoms and is, for example, ethoxy, propoxy, butoxy or especially methoxy.
Halogen R, is fluorine, bromine, iodine or preferably chlorine.
Esterified hydroxy or mercapto R2 is a hydroxy or mercapto group that is esterified by an aliphatic carboxylic acid, by an aliphatic carboxylic acid that is substituted by acyl, for example lower alkanoyl, for example acetyl, or by carbamic acid: for example lower alkanoyloxy, for example acetoxy, lower alkanoyl-lower alkanoyloxy, for example acetylacetoxy, or carbamoyloxy, or lower alkanoylthio, for example acetylthio orformylthio, or carbamoylthio, respectively.
Esterified hydroxy or mercapto R2 is furthermore a hydroxy or mercapto group that is esterified by an N-substituted carbamic acid.
N-substituents are, for example, lower alkyl, for example methyl or ethyl, or lower alkyl substituted by halogen, for example chlorine, or by lower alkanoyloxy, for example acetoxy, for example 2-chloroethyl or 2-acetoxyethyl.
Hydroxy or mercapto R2 esterified by an N-substituted carbamic acid is, for example, N methylcarbamoyloxy, N-ethylcarbamoyloxy, N-(2-chloroethyl)-carbamoyloxy, N-(2-acetoxyethyl)carbamoyloxy or N-methylcarbamoylthio.
Etherified hydroxy or mercapto R2 is a hydroxy or mercapto group that is etherified by an aliphatic hydrocarbon radical, for example lower alkoxy having from 1 to 4 carbon atoms, for example methoxy or ethoxy, or lower alkylthio having from 1 to 4 carbon atoms, for example methylthio.
Etherified mercapto R2 is likewise etherified by a hetetocycle that is bonded via a ring carbon atom to the sulphur atom of the mercapto group, for example by a monocyclic hetetocycle that has from 1 to 4 nitrogen hetero atoms and optionally an additional oxygen or sulphur atom, or by a bicyclic hetetocycle having from 1 to 5 nitrogen hetero atoms. Such an etherified mercapto group is hereinafter called "heterocyclyithio group R2".
A heterocylic radical in a heterocyclylthio group R2 is especially an aromatic monocyclic, five- or six-membered diaza-, triaza-, tetraaza-, thiaza, thiadiaza-, thia-, oxaza- or oxadiaza-cyclyl radical or is an aromatic or partially saturated bicyclic aza-, diaza-, triaza-, tetraaza- or pentaza-bicyclyl radical containing five or six ring atoms per ring.
Substituents of the mentioned heterocyclic radical in a heterocyclylthio group R2 are, for example, lower alkyl, for example ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, especially methyl, lower alkenyl, for example allyl, or lower alkyl, for example methyl or ethyl, which is substituted by the following groups: Hydroxy; esterified hydroxy, for example lower alkanoyloxy, for example acetoxy; or halogen, for example fluorine or chlorine; lower alkylphosphonyl, for example methyl- or ethyl-phosphonyl, di-lower alkylphosphonyl, for example dimethyl- or diethyl-phosphonyl, each optionally in salt form, for example in alkali metal, for example sodium, salt form; carboxy or sulpho each optionally in salt form, for example in alkali metal or ammonium salt form, for example in sodium salt form; esterified carboxy, for example lower alkyoxycarbonyl, for example ethoxycarbonyl; sulphamoyl; amino; lower alkylamino, for example methylamino or ethylamino; di-lower alkylamino, for example dimethylamino or diethylamino; acylamino, for example lower alkanoylamino, for example acetamino; or lower alkanoylamino substituted by carboxy or halogen, for example chlorine, for example carboxyacetamino or chloracetamino.
Such a substituted lower alkyl radical is, for example: hydroxy-lower alkyl, for example hydroxymethyl or 2-hydroxyethyl, acetoxy-lower alkyl, for example acetoxymethyl or 2-acetoxyethyl, halo-lower alkyl, for example chloromethyl, 2-chloroethyl, 2,2,2-trichloroethyl or trifluoromethyl, lower alkylphosphono-lower alkyl, for example ethylphosphonomethyl, di-lower alkylphosphono-lower alkyl, for example diethylphosphonomethyl, carboxy-lower alkyl, for example carboxymethyl or 2carboxyethyl, sulpho-lower alkyl, for example sulphomethyl or 2-sulphoethyl, lower alkoxycarbonyllower alkyl, for example ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, sulphamoyl-lower alkyl, for example sulphamoylmethyl or 2-sulphamoylethyl, amino-lower alkyl, for example aminomethyl or 2aminoethyl, lower alkylamino-lower alkyl, for example methylaminomethyl or 2-methylaminoethyl, dilower alkylamino-lower alkyl, for example dimethylaminomethyl or 2-dimethylaminoethyl, lower alkanoylamino-lower alkyl, for example 2-acetaminoethyl, carboxy-lower alkanoylamino-lower alkyl, for example 3-carboxypropionylaminoethyl or 2-carboxyacetaminoethyl, or halo-lower alkanoylaminolower alkyl, for example 3-chloropropionylaminoethyl or 2-chloracetaminoethyl.
Functional groups or modified, for example protected, functional groups, for example halogen, for example fluorine, chlorine or bromine, unsubstituted or substituted amino, for example amino that is unsubstituted or mono- or di-substituted by lower alkyl, for example methyl or ethyl, for example amino, methylamino or dimethylamino, acylamino, for example lower alkanoylamino, for example acetamino, or lower alkylsulphonylamino, for example mesylamino, or lower alkanoylamino substituted by halogen, for example chlorine, or by carboxy, for example 3-chloropropionylamino or 3carboxypropionylamino, nitro, hydroxy, lower alkoxy, for example methoxy or ethoxy, carboxy, esterified carboxy, for example lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, optionally substituted, for example mono- or di-lower alkylated, carbamoyl, for example methylcarbamoyl or dimethylcarbamoyl, or cyano, and also oxo or oxido, are likewise substituents of the heterocyclic radical in a heterocyclylthio group R2.
A heterocyclylthio group R2 in which the heterocyclic radical is an aromatic monocyclic fivemembered radical, is, inter alia, imidazolylthio, for example 2-imidazolylthio; triazolylthio, or triazolylthio that is substituted by lower alkyl, for example methyl, and/or phenyl, for example 1 H-i 2,3- triazol-5-ylthio-l -methyl-l H-l ,2,3-triazol-4-ylthio, 1 H-l ,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4- triazol-3-ylthio or 4,5-dimethyl-4H-l ,2,4-triazol-3-ylthio; tetrazolylthio, for example 1 H-tetrazol-5ylthio, or tetrazolylthio that is substituted by lower alkyl, for example methyl or ethyl, or by substituted lower alkyl, for example ethyl- or diethyl-phosphonomethyl, carboxyethyl, sulphomethyl, 2-sulphoethyl, 2-dimethylaminoethyl or by cyanomethyl, for example 1 -methyl-l H-tetrazol-5-lythio, 1 -ethyl- or 1 diethyl-phosphonyl methyl-i H-tetrazol-5-ylthio, 1 -carboxymethyl- 1 H-tetrazol-5-ylthio, 1 -(2- carboxyethyl)-l H-tetrazol-5-ylthio, 1-sulphomethyl-1 H-tetrazol-5-ylthio, 1 -(2-sulphoethyl)-1 Htetrazol-5-ylthio, 1 -(2-dimethylaminoethyl)- 1 H-tetrazol-5-ylthio, or 1 -cyanomethyl- 1 H-tetrazol-5-ylthio; thiazolylthio or thiazolylthio substituted by lower alkyl, for example methyl, for example 2-thiazolylthio or 4,5-dimethyl-2-thiazolylthio; isothiazolylthio, for example 3-isothiazolylthio, 4-isothiazolylthio or 5isothiazolylthio; thiadiazolylthio or thiadiazolylthio substituted by lower alkyl, for example methyl, for example 1 ,2,3-thiadiazol-4-ylthio, 1 ,2,3-thiadiazol-5-ylthio, 1 ,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4thiadiazol-5-ylthio, 1 ,2,4-thiadiazol-5-ylthio or 1 ,2,5-thiadiazol-3-yithio; thiatriazolylthio, for example 1 ,2,3,4-thiatriazol-5-ylthio; oxazolylthio or oxazolylthio substituted by lower alkyl, for example methyl, for example 2- or 5-oxazolylthio, or 4-methyl-5-oxazolylthio; isooxazolylthio substituted by lower alkyl, for example methyl, for example 3-methyl-5-isoxazolylthio; or oxidiazolylthio or oxidiazolylthio substituted by lower alkyl, for example methyl, for example 1 ,2,4-oxidiazol-5-ylthio or 2-methyl-1,3,4oxidiazol-5-ylthio.
A heterocyclylthio group R2 in which the hetero-cyclic radical is an aromatic monocyclic sixmembered radical contains 1 to 3 nitrogen atoms and is, for example, 5,6-dioxotetrahydro-astriazinylthio or 5,6-dioxotetrahydro-as-triazinylthio that is substituted by lower alkyl, for example methyl, carboxy-lower alkyl, for example carboxymethyl, or by sulpho-lower alkyl, for example sulphomethyl, for example 1-or 2-methyl-5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-methyl5,6-dioxo-1 ,4,5,6-tetrahydro-as-triazin-3-ylthio, 1 - or 2-carboxymethyl-5,6-dioxo- 1 ,2,5,6-tetrahydro- as-triazin-3-ylthio, 4-ca rboxymethyl-5,6-dioxo-1 ,4,5,6-tetra hydro-as-triazin-3-ylthio, 1- or 2 sulphomethyl-5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-sulphomethyl-5,6-dioxo-l ,4,5,6tetrahydro-as-triazin-3-ylthio.
A heterocyclylthio group R2 in which the heterocyclic radical is an aromatic or partially saturated bicyclic radical containing five or six ring atoms per ring is, for example, indolylthio, indolylthio substituted by lower alkyl, for example methyl, for example indol-2-ylthio or N-methylindol-2-ylthio, isoindolylthio, for example isoindol-2-ylthio, quinolylthio, for example 2-, 4- or 8-quinolylthio, benzimidazolylthio, benzimidazolylthio substituted by lower alkyl, for example methyl, or by carboxylower alkyl, for example carboxymethyl, for example 1-methyl-, 1-carboxymethyl- or 1 -(2- carboxyethyl)-benzimidazol-2-ylthio, benztriazolylthio, benztriazolylthio substituted by lower alkyl, for example methyl, or by carboxy-lower alkyl, for example carboxymethyl, for example 1-methyl- or 1 ca rboxymethyl-l H-benzo[d]triazol-5-ylthio, or especially tetrazolopyridazinlythio, tetrazolopyridazinylthio substituted by lower alkyl, for example methyl or ethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, carbamoyl, lower alkylcarbamoyl, for example methylcarbamoyl, di-lower alkylcarbamoyl, for example dimethylcarbamoyl, amino, lower alkylamino, for example methylamino, or by di-lower alkylamino, for example dimethylamino or diethylamino: for example 8-methyl-, 8-ethyl-, 8-carboxy-, 8-carboxymethyl-, 8-(2-carboxyethyl)-, 8-carba moyl-, 8-(N-methylca rba moyl)-, 8-(N,Ndimethylcarbamoyl)-, 8-amino-, 8-dimethylamino- or 8-diethylamino-tetrazolo[ 1 ,5-b]pyridazin-6ylthio.
An ammonia group R2 is derived from a tertiary organic base, for example from an aliphatic amine or, preferably, from a heterocyclic nitrogen base and is bonded via the nitrogen atom to the methylene group in the 3-position of the cephem nucleus. The positive charge at the quaternary nitrogen atom is compensated for example by the negatively charged carboxylate group in the 4-position of the cephem nucleus.
An ammonio group R2 that is derived from an aliphatic amine is, for example, tri-lower alkylammonio, for example trimethyl or triethyl-ammonio.
An ammonio group R2 that is derived from anunsubstituted or substituted heterocyciic nitrogen base is, for example, 1 -pyrazolio that is unsubstituted or substituted in the 2-position by lower alkyl, for example methyl or ethyl, lower alkenyl, for example vinyl or allyl, carboxy-lower alkyl, for example carboxymethyl, lower alkoxycarbonyl-iower alkyl, for example methoxycarbonylmethyl, sulpho-lower alkyl, for example sulphomethyl, amino-lower alkyl, for example 2-aminoethyl, or di-lower alkylaminolower alkyl, for example 2-dimethylaminoethyl: for example 2-methyl- or 2-ethyl-l -pyrazolio, 2-allyl- or 2-vinyl-l -pyrazolio, 2-carboxymethyl- 1 -pyrazolio, 2-methoxycarbonylmethyl-l -pyrazolio, 2 sulphomethyl-l -pyrazolio, 2-(2-aminoethyl)-1 -pyrazolio or 2-(2-dimethylaminoethyi)-l -pyrazolio.
An ammonio group R2 that is derived from a heterocyclic nitrogen base is likewise, for example, 1 -triazolio or 1-triazolio that is substituted in the 3-position by lower alkyl, for example methyl or ethyl, carboxy-lower alkyl, for example carboxymethyl or di-lower alkylamino-lower alkyl, for example 2dimethylaminoethyl: for example 3-methyl-l -triazolio, 3-carboxymethyl-i -triazolio or 3-(2 dimethylaminoethyl)-1 -triazolio.
An ammonia group R2 that is derived from an unsubstituted or substituted heterocyclic nitrogen base is likewise, for example, pyridinlo, or pyridinio that is mono-, or di-substituted by lower alkyl, for example methyl, carbamoyl, lower alkylcarbamoyl, for example methylcarbamoyl, hydroxy-lower alkyl, for example hydroxymethyl, lower alkoxy-lower alkyl, for example methoxymethyl, cyano-lower alkyl, for example cyanomethyl, carboxy-lower alkyl, for example carboxymethyl, sulpho-lower alkyl, for example 2-sulphoethyl, carboxy-lower alkenyl, for example 2-carboxyvinyl, carboxy-lower alkylthio, for example carboxymethylthio, thiocarbamoyl, halogen, for example bromine or chlorine, carboxy, sulpho or by cyano: for example lower alkylpyridinio, for example 2-, 3- or 4-methylpyridinio or 2-, 3 or 4 ethyl-pyridinio, carbamoylpyridinio, for example 3- or 4-carbamoylpyridinio, lower.
alkylcarbamoylpyridinio, for example 3- or 4methylcarbamoylpyridinio, di-lower alkylcarbamoylpyridinio, for example 3- or 4-dimethylcarbamoylpyridinio, hydroxy-lower alkylpyridinio, for example 3- or 4-hydroxymethylpyridinio, lower alkoxy-lower alkylpyridinio, for example 4 methoxymethylpyridinlo, cyano-lower alkylpyridinio, for example 3-cyanomethylpyridinio, carboxylower alkylpyridinio, for example 3-carboxymethylpyridinio, sulpho-lower alkylpyridinio, for example 4 (2-sulphoethylpyridinio), carboxy-lower alkenylpyridinio, for example 3-(2-carboxyvinyl)-pyridinio, carboxy-lower alkylthiopyridinio, for example 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, for example 4-thiocarbamoylpyridinio, halopyridinio, for example 3-bromo- or 4-bromo-pyridinio, carboxypyridinio, for example 4-carboxypyridino, sulphopyridinio, for example 3-sulphopyridinio, cyanopyridinio, for example 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, for example 3carboxymethyl-4-carbamoylpyridinio, aminocarbamoylpyridinio, for example 2-amino-5 carba moylpyridinio, carboxycarbamoylpyridinio, for example 3-carboxy-4-carba moylpyridinio, cyanohalomethylpyridinio, for example 3-cyano-4-trifluoromethylpyridinio, and aminocarboxypyridinio, for example 2-amino-3-carboxypyridinio.
A quaternary ammonio group R2 is preferably 2-lower alkyl -pyrazolio, for example 2-methyl-i - pyrazolio, 2-carboxy-lower alkyl -pyrazolio, for example 2-carboxymethyl- 1 -pyrazolio, 3-lower alkyl 1-triazolio, for example 3-methyl-l -triazolio, pyridinio or pyridinio that is substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4-hydroxymethylpyridinio, 4carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3or 4-carbamoylpyridinio.
R3 defined as "protected carboxy" is carboxy esterified by one of the carboxy-protecting groups described hereinafter, especially carboxy that can be cleaved under physiological conditions.
In a methylene group A that is substituted by amino, hydroxy or sulpho each present in protected form the relevant aminomethylene, hydroxymethylene or sulphomethylene group is protected by the amino-, hydroxy or sulpho-protecting groups described in the following.
The group of the formula -0-B4 is in syn- (or Z-) position or anti- (or E-) position, the syn- (or Z) position being preferred. In the syn-position, -0-B4 is directed towards the cephalosporin nucleus and, in the anti-position, in the opposite direction.
Lower alkyl R4 has preferably from 1 to 4 carbon atoms and is for example, ethyl, propyl, butyl or especially methyl.
Cycloalkyl R4 has preferably from 3 to 8, especially from 3 to 6, ring members and is, for example, cyclobdtyl, cyclopentyl, cyclohexyl or especially cyclopropyl.
Substituents of a lower alkyl group or cycloalkyl group R4 are, inter alia, free or etherified hydroxy, for example lower alkoxy, primary, secondary or tertiary amino, for example amino or di-lower alkylamino, free or functionally modified, for example esterified, amidated or protected, carboxy or sulpho, and ureidocarbonyl optionally N-substituted by lower alkyl. Preferably a substituted lower alkyl and cycloalkyl group R4 is substituted by a carboxy or sulpho group, these preferably being positioned at the carbon atom that is bonded to the oxygen atom of the oxyimino group.
Substituted lower alkyl or cycloalkyl R4 is, for example, 2-aminoethyl, 2-dimethylaminoethyl, carboxymethyl, 1- or 2-carboxyethyl, 1-, 2 or 3-carboxyprop-1 -yl, 1- or 2-carboxyprop-2-yl, 2- carboxycycloprop-2-yl or 1- or 2-carboxycyclobut- 1 -yl, as well as a corresponding sulpho-substituted lower alkyl or cycloalkyl group.
The carboxy and sulpho groups in the radical R4 may, for example, be esterified by lower alkyl, for example methyl or ethyl, or by a physiologically removable group, for example pivaloyloxymethyl, or amidated by NH3, a primary or secondary amine, for example a mono- or di-lower alkylamine, for example methyl- or ethyl-amine or dimethyl- or diethyl-amine, or protected by the conventional protecting groups mentioned further below.
Substituted carbamoyl R4 is, for example, a group of the formula --C(=O))-NHR, in which R represents lower alkyl, for example methyl, ethyl or 1- or 2-propyl; carboxy-lower alkyl, for example carboxymethyl, 1- or 2-carboxyethyl or 1-, 2- or 3-carboxypropyl in which the carboxy group is in free form or is protected by one of the customary carboxy-protecting groups or is esterified, for example, by lower alkyl, for example methyl, ethyl, n-propyl or isopropyl, or n- or tert.-butyl; sulpho-lower alkyl, for example sulphomethyl, 1- or 2-sulphoethyl or 1-, 2- or 3-sulphopropyl in which the sulpho group is in free form or is protected by one of the customary sulpho-protecting groups or is esterified, for example, by lower alkyl, for example methyl or ethyl; hydroxy-lower alkyl, for example hydroxymethyl, 2hydroxyethyl or 21our 3-hydroxypropyl in which the hydroxy group is in free form or is protected by one of the customary hydroxy-protecting groups or, for example, is acylated, for example acetylated; amino-lower alkyl, for example 2-aminoethyl, 2- or 3-aminopropyl or 2-, 3- or 4-aminobutyl in which the amino group is in free form or is protected by one of the customary amino-protecting groups or, for example, acylated, for example acetylated; aryl-lower alkyl, for example phenyl-lower alkyl, for example benzyl or 1- or 2-phenethyl; halo-lower alkyl, for example fluoro-, chloro- or bromo-lower alkyl, for example 2-chloropropyl, or 4-chloro-butyl; or aryl, for example phenyl, or phenyl substituted from one to three times by lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or by nitro.
The functional groups in the compounds of the formula I, especially carboxy and amino, and also hydroxy and sulpho, groups, are optionally protected by conventional protecting groups used in penicillin, cephalosporin and peptide chemistry.
Such protecting groups can be readily removed, that is to say without undesired secondary reactions taking place, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.
Protecting groups of this type and the manner in which they are removed are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, in "The Peptides", vol. 1, Schröder and Lübke, Academic Press, London, New York, 1965, and in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.
A carboxy group, for example the carboxy group R3, or a carboxy group present in R4 is usually protected in esterified form, the ester group being readily cleaved under mild conditions. A carboxy group protected in esterified form is esterified especially by a lower alkyl group that is branched in the position or substituted in the 1- or 2-position by suitable substituents.
A protected carboxy group that is esterified by a lower alkyl group branched in the position is, for example, tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals in which aryl is phenyl that is unsubstituted or mono- or poly-substituted, for example, by lower alkyl, for example tert.-lower alkyl, for example tert.-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyioxycarbonyl, or diphenylmethoxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example diphenylmethoxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl.
A protected carboxy group that is esterified by a lower alkyl group suitably substituted in the 1- or 2-position is, for example, lower alkoxy-lower alkoxy-carbonyl, for example methoxymethoxycarbonyl, 1 -methoxyethoxycarbonyl or 1 -ethoxymethoxycarbonyl, lower alkylthio-lower alkoxycarbonyl, for example 1 -methylthiomethoxycarbonyl or 1 -ethylthioethoxycarbonyl, aroylmethoxycarbonyl in which the aroyl group is benzoyl that is unsubstituted or substituted, for example by halogen, such as bromine, for example phenacyloxycarbonyl, and also 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxywarbonyl or 2iodoethoxycarbonyl.
A carboxy group may also be protected in the form of an organic silyloxycarbonyl group. A silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can alternatively be substituted only by two lower alkyl groups, for example methyl groups, and the carboxy group or amino group of a second molecule of the formula I. Compounds having such protecting groups can be manufactured, for example, by using dimethyldichlorosilane as silylating agent.
A preferred protected carboxy group is, for example, tert.-lower alkoxycarbonyl, for example tert.butoxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted as mentioned above, for example 4-nitrobenzyloxy-carbonyl, or diphenylmethoxycarbonyl.
An esterified carboxy group R3 that can be cleaved under physiological conditions is especially an acyloxy-lower alkoxycarbonyl group in which acyl is, for example, the acyl group of an organic carboxylic acid, especially of an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the radical of a lactone.
Such a group is, for example, lower alkanoyloxy-lower alkoxycarbonyl, for example lower alkanoyloxy-methoxycarbonyl or lower alka noyloxyethoxycarbonyl, for example acetoxymethoxycarbonyl, piva loyloxymethoxycarbonyl or 2-(propionyloxy)-ethoxycarbonyl, lower a I koxycarbonyloxy- lower alkoxycarbonyl, for example 1 -(ethoxycarbonyloxy)-ethoxycarbonyl or tert.-butoxycarbonyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially cg-amino-lower al kanoyloxymethoxyca rbonyl, for example g lycyloxymethoxycarbonyl, L-va lyloxymethoxycarbonyl' or L leucyloxymethoxycarbonyl, also phthalidyloxycarbonyl, for example 2-phthalidyloxycarbonyl, or indanyloxycarbonyl, for example 5-indanyloxycarbonyl.
An amino group, for example the amino group in the 2-position of the oxazolyl radical can be protected, for example, in the form of a readily cleavable acylamino, arylmethylamino., etherified mercaptoamino, 2-acyl-lower alk-1 -enylamino or silylamino group.
In a readily cleavable acylamino group, acyl is, for example, the acyl group of an organic carboxylic acid having up to 1 8 carbon atoms, especially ofan alkanecarboxylic acid that is unsubstituted or substituted, for example by halogen or aryl, or of benzoic acid that is unsubstituted or substituted, for example by halogen, lower alkoxy or nitro, or of a carbonic acid semiester.Such an acyl group is, for example, lower alkanoyl, for example formyl, acetyl or propionyl, halo-lower alkanoyl, for example 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, benzoyl that is unsubstituted or substituted, for example by halogen, lower alkoxy or nitro, for example benzoyl, 4-chiorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the position of the lower alkyl radical or suitably substituted in the 1- or 2-position.
Lower alkoxycarbonyl branched in the position of the lower alkyl radical is, for example, tert.lower alkoxycarbonyl, for example tert.-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals in which aryl is preferably phenyl that is unsubstituted or mono or polysubstituted, for example by lower alkyl, especially tert.-lower alkyl, for example tert.-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example unsubstituted or substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl.
Lower alkoxycarbonyl suitably substituted in the 1- or 2-position is, for example, aroylmethoxycarbonyl in which aroyl is benzoyl that is unsubstituted or substituted, for example by halogen, for example bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl in which each of the substituents, independently of one another, represents an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 1 5 carbon atoms that is unsubstituted or substituted, for example by lower alkyl, lower alkoxy, aryl, halogen or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl each of which is unsubstituted or substituted as mentioned above: for example 2-tri-lower alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(n-butyl-dimethylsilyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.
Further acyl groups coming into consideration as amino-protecting groups are also acyl groups of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, for example dicyclohexylphosphoryl, diphenylphosphoryl, diphenyl-lower alkylphosphoryl that is unsubstituted or substituted, for example by nitro, for example debenzylphosphoryl or di-4nitrobenzylphosphoryl, phenoxyphenylphosphonyl, di-lower alkylphosphinyl, for example diethylphosphinyl, or diphenylphosphinyl.
In an arylmethylamino group that is mono-, di- or especially tri-arylmethylamino, the aryl radicals are especially phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- and especially trityl-amino.
In an etherified mercaptoamino group, the etherified mercapto group is especially arylthio or aryl- lower alkylthio in which aryl is especially phenyl that is unsubstituted or substituted, for example by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, halogen, for example chlorine, and/or nitro. Such an amino-protecting group is, for example, 4-nitrophenylthio.
In a 2-acyl-lower alk-l-enyl group that may be used as an amino-protecting group, acyl is, for example, the acyl group of a lower alkanecarboxylic acid, or of a benzoic acid that is unsubstituted or substituted, for example by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, halogen, for example chlorine, and/or nitro, or especially the acyl group of a carbonic acid semiester, for example of a carbonic acid lower alkyl semiester. Such amino-protecting groups are especially lower alkanoylprop-l -en-2-yl, for example 1 -acetylprop-i -en-2-yl, or lower al koxycarbonylprop- 1 -en-2-yl, for example 1 -ethoxycarbonylprop- 1 -en-2-yl.
A silylamino group is, for example, a tri-lower alkylsilylamino group, for example trimethylsilylamino. The silicon atom of the silylamino group can alternatively be substituted only by two lower alkyl groups, for example methyl groups, and the amino group or carboxy group of a second molecule of the formula I. Compounds having such protecting groups can be manufactured, for example, by using dimethyldichlorosilane as silylating agent.
An amino group may also be protected in protonated form. As anions there come into consideration especially those of strong inorganic acids, such as hydrohalic acids, for example the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acid.
A preferred amino-protecting group is, for example, the acyl radical of a carbonic acid semiester, especially tert.-butoxycarbonyl, or benzyloxycarbonyl that is unsubstituted or substituted, for example as indicated, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, or trityl or formyl.
A hydroxy group, for example the hydroxy group in the hydroxyimino group =N-O-B4 (R4=hydrogen) may be protected, for example, by an acyl group, for example lower alkanoyl substituted by halogen, for example 2,2-dichloroacetyl, or may be protected especially by an acyl radical of a carbonic acid semiester mentioned in connection with protected amino groups.A preferred hydroxyprotecting group is, for example, 2,2,2-trichloroethoxycarbonyl, an organic silyl radical having the above-mentioned substituents, also a readily removable etherifying group, such as tert.-lower alkyl, for example tert.-butyl, a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical, for example 1 lower alkoxy-lower alkyl or lower alkylthio-lower alkyl, for example methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1 -methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl having from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl or a corresponding thia analogue, and also unsubstituted or substituted 1 -phenyl-lower alkyl, for example unsubstituted or substituted benzyl or diphenylmethyl, the phenyl radicals being substituted, for example by halogen, such as chlorine, lower alkoxy, for example methoxy, and/or nitro.
A sulpho group, for example a sulpho group in R2, is preferably esterified by an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, for example by lower alkanol, for example tert.-butanol, or by a silyl group, for example by tri-lower alkylsilyl. A sulpho group is protected, for example, analogously to a carboxy group.
Salts of compounds according to the invention are especially pharmaceutically acceptable nontoxic salts of compounds of the formula I.
Such salts are formed, for example, from the acid groups in compounds of the formula I, for example carboxy or sulpho groups, and are especially metal or ammonium salts, for example alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and also ammonium salts that are formed with ammonia or suitable organic amines, there coming into consideration for the salt formation especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di-, or poly-amines, and also heterocyclic bases.Such bases are, for example, lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethyidiaminoethyl ester, lower alkyleneamines, for example 1 -ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, and also bases of the pyridine type, for example pyridine, collidine or quinoline.
The basic groups in the compounds of the formula I, for example amino groups, can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example trifluoroacetic acid, and also with amino acids, such as arginine and lysine.
If several acid groups, for example two carboxy groups, or several basic groups, for example two amino groups, are present in compounds of the formula I, mono- or poly-salts can be formed, If the compounds of the formula I have at least one acid group, for example the carboxy group R3, and at least one basic group in free form, for example, the free amino group in the 2-position of the oxazolyl radical, compounds of the formula I may be present in the form of internal salts. In compounds of the formula I, one acid and one basic group may be in the form of an internal salt and additional acid and/or basic groups may be present in the-form of, for example, acid addition and/or base addition salts.
For the purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts. Only pharmaceutically acceptable non-toxic salts are used therapeutically and these are therefore preferred.
The compounds of the formula I in which the functional groups are in free form and the carboxy groups are optionally in physiologically cleavable esterified form/ and their pharmaceutically acceptable non-toxic salts are valuable antibiotic active substances that can be used especially as antibacterial antibiotics.For example, they are effective in vitro against gram-positive and gram-negative microorganisms, including strains producing p-lactamase, for example- against gram-positive cocci, for example Staphyloccus aureus, or streptococci, for example Streptococcus pyogenes, Streptococcus pneumoniae or Streptococcus faecalis, against gram-negative cocci, for example Neisseria gonorrhoeae, in minimum concentrations of from approximately 0.001 Xug/ml to approximately 32 yg/ml, against gram-negative bacteria, for example Pseudomonas aeruginosa, Haemophilus influenzae and against enterobacteria, for example Escherichia coli, Proteus spp. Klebsiella pneumoniae, Serratia marcescens or Enterobacter cloacae, in minimum concentrations of from approximately 0.005 ,ug/ml to approximately 1 32 ssg/ml. In vivo, when administered subcutaneously to mice, they are effective against systemic infections caused by gram-positive bacteria such as Staphylococcus aureus in a dosage range of from approximately 1.3 to approximately 55 mg/kg and against systemic infections caused by gram-negative bacteria such as enterobacteria, for example Escherichia coli, in a dosage range of from approximately 0.63 to 30 mg/kg.
In the following test report, the effectiveness of compounds of the formula I is demonstrated with reference to selected compounds: Test report I. Tested Compounds: 1. The sodium salt of 3-(l-methyl-l H-tetrazol-5-ylthiomethyl)-7jB-[2-(2-amino-4-oxazolyl)-2- Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid (Example 5a) 2. The sodium salt of 3-(1 -carboxymethyl-l H-tetrazol-5-ylthiomethyl)-7p-[2-(2-amino-4- oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid (Example 6a) 3.The dihydrochloride of 3-[ 1 -(2-dimethylaminoethyl)- 1 H-tetrazol-5-ylthiomethyl]-7p-[2-(2- amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid (Example 7) 4. The dihydrochloride of 3-[1 -(2-dimethylaminoethyl)-l H-tetrazol-5-ylthiomethyl]-7P-[2- (2-amino-4-oxazolyi-2-E-methoxyiminoacetam ino]-3-cephem-4-ca rboxylic acid (Example 7) 5. 3-(4-Carbamoylpyridinomethyl)7p-[2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3- cephem-4-carboxylate (Example 8) 6. The sodium salt of 3-acetoxymethyl-7P-[2-(2-a mino-4-oxazolyl-2-Z-hydroxyi mino- acetamino]-3-cephem-4-carboxylic acid (Example 9a) 7. The sodium salt of 3-acetoxymethyl-7,B-[2-(2-amino-4-oxazolyl)-2-Z-(2-carboxyprop-2- yloxyimino)-acetamino]-3-cephem-4-carboxylic acid (Example 1 Oa) 8. 3-Acetoxymethyl-7/3-[2-(2-a m ino-4-oxazolyl)-2-Z-(2-tert.-butoxycarbonylprop-2- yloxyimino)-acetamino]-3-cephem-4-carboxylic acid (Example 1 Ob) 9. The sodium salt of 3-pyridiniomethyl-7/3-[2-(2-amino-4-oxazolyl)-2-Z-(2-carboxyprop-2- yloxyimino)-acetamino]-3-cephem-4-carboxylate (Example 1 1 ) 1 0. The sodium salt of 3-(4-carbamoylpyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2- carboxyprop-2-yloxyimino)-acetamino]-2-cephem-4-carboxylate (Example 12) 11.The sodium salt of 7-[2-(2-a mino-4-oxazolyl)-2-Z-(2carboxyprop-2-yloxyi mino)- acetamino]-3-cephem-4-carboxylic acid (Example 1 3a) 1 2. The sodium salt of 7p-[2-(2-amino-4-oxazolyl)-2-Z-(2-tert.-butoxyCarbonylprop-2- yloxyimino)-acetamino]-3-cephem-4-carboxylic acid (Example 1 3b) 1 3. The sodium salt of 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid (Example 1 a) 14.The sodium salt of 7,B-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem- 4-carboxylic acid (Example 2a) 15. 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (Example 3a) 16. 3-[3-Chloropyridiniomethyl 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3cephem-4-carboxylate (Example 15) 1 7. The sodium salt of 3-(4-carboxylatepyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylate (Example 16) 18. The sodium salt of 3-carbamoyloxymethyl-7,3-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid (Example 1 7a).
II. Experimental: A. The antibiotic activity of the test compounds in vitro was established by the agar dilution method according to Ericsson, H. M. and Sherris, S. C., 1971, Acta Path. Microb. Scand. Section B, Suppl. No.217, vol. 1-90, in DST agar. The minimum concentrations still inhibiting the growth of the test organisms (MlC=minimum inhibiting concentrations) are given in micrograms per millilitre ( g/ml) for the tested compounds in Table 1.
B. The chemotherapeutic activity in vivo against systemic infections in female SPF, MF2 mice was established according to the method of Zak, O., etal., 1979, Drugs Exptl. Clin. Res. 5,45-59. The EDso values found in milligrams substance per kilogram mouse (mg/kg) for a number of microorganisms are indicated in Table 2 for the test compounds administered subcutaneously (s.c.).
III. Test results: Table 1: antibiotic activity (in vitro)
MIC [yg/mll Streptococcus Test p yo genes Escherichia Proteus compound Aronson coli 205 rettgeri 856 1 0.005 0.1 0.005 2 0.1 0.5 0.005 3 0.02 0.1 0.02 4 0.05 8 2 5 0.02 0.2 0.02 6 0.005 0.1 0.02 7 0.05 0.2 0.01 8 0.02 4 1 9 0.5 1 0.2 10 0.2 0.5 0.5 11 0.2 0.2 0.01 12 0.02 4 0.2 13 0.01 0.1 0.005 14 0.01 0.2 0.005 15 0.2 8 0.1 16 0.02 0.5 n.t. 17 0.05 0.5 0.02 18 0.02 j 0.1 0.01
n.t.: not tested.
Table 2: chemotherapeutic activity (in vivo)
EDso tmg/kg, s,cj Test Staphylococcus Escherichia compound aureus 10b cold 205 1 12 1.5 2 55 0.63 3 28 1.7 5 5.5 2.4 6 1,35 1.0 7 > 30 > ,",,30 8 > 30 > 30 9 > 30 5.6 10 > 30 1.6 11 > 30 4.4 12 > 30 > 30 13 5 1 14 30 9 15 30 14 16 5.5 2 17 > 30 n.t.
18 8 > 30 n.t.: not tested Compounds of the formula I in which the functional groups are protected are used as intermediates for the manufacture of compounds of the formula I in which the functional groups are in free form or in which the 4-carboxy group is in the form of a carboxy group that can be cleaved under physiological conditions.
The present invention relates especially to compounds of the formula I in which n represents 0, R, represents hydrogen, lower alkyl, for example, methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group -CH2-R2 in which R2 represents lower alkanoyloxy, for example acetoxy; carbamoyloxy;N-lower alkylcarbamoyloxy; an aromatic monocyclic five or six-membered diaza-, triaza-, tetraaza-, thiaza-, thiadiaza-, thia-, oxaza-, or oxadiaza-cyclyl radical, for example triazolylthio, for example 1 H-l ,2,3-triazol-5-ylthio, tetrazolylthio, for example 1 H-tetrazol-5-ylthio, thiazolylthio, thiadiazolylthio, for example 1 ,3,4-thiediazol-5-ylthio, oxazolylthio, oxadiazolylthio, or 5,6dioxotetrahydro-as-triazinylthio, for example 5,6-dioxo-l ,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6 dioxo-l ,4,5,6-tetrahydro-as-triazin-3-ylthio, which may be substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example, dimethyl-aminomethyl or 2-dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, carboxy-lower alkyl, for example carboxymethyl, amino, carboxy-lower alkylamino, for example 2-carboxyethylamino, or by carbamoyl, or ammonio, for example 2-lower alkyl- 1 -pyrazolio, for example 2-methyl-i -pyrazolio, 2-carboxylower alkyl-i - pyrazolio, for example 2-carboxymethyl-1 -pyrazolio, 3-lower alkyl -triazolio, for example 3-methyl-i - triazolio, pyridinio, pyridinio substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxylower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl: for example 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3- or 4-carbamoylpyridinio, R3 represents carboxy or carboxy that can be cleaved under physiological conditions, for example acyloxy-lower alkoxycarbonyl, for example lower alkanoyloxy-lower alkoxycarbonyl, for example lower alkanoyloxymethoxycarbonyl or lower alkanoyloxy-ethoxycarbonyl, for example pivaloyloxymethoxycarbonyl or 2-(propionyloxy)ethoxycarbonyl, or lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1 -(ethoxycarbonyloxy)ethoxyca rbonyl or tert.-butoxycarbonyloxymethoxyca rbonyl, and A represents amino, aminomethylene, hydroxymethylene, sulphomethylene, or a methylene group substituted by a group of the formula =N-O-B4 in which R4 represents hydrogen, lower alkyl, for example methyl, hydroxy-lower alkyl, for example 2-hydroxyethyl, amino-lower alkyl, for example 2aminoethyl, carboxy-lower alkyl, for example 2-carboxy-2-propyl, carbamoyl, lower alkylcarbamoyl, for example methylcarbamoyl, or amino-lower alkyl, for example 2-aminoethyl, wherein the group of the formula -0-R4 is in the syn- (orZ-) position, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I having salt-forming groups.
The present invention relates chiefly to compounds of the formula I in which n represents 0, B1 represents hydrogen, lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group -CH2-B2 in which R2 represents lower alkanolyoxy, for example acetoxy; carbamoyloxy; triazolylthio, for example 1 H-l ,2,3-triazol-5-ylthio; tetrazolylthio, for example 1 H-tetrazol-5-ylthio; tetrazolylthio substituted by lower alkyl, for example methyl, di-lower alkylaminolower alkyl, for example 2-dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl carboxy-lower alkyl, for example carboxymethyl, or by carbamoyl: for example 1 -methyl-l H-tetrazol-5ylthio, 1-sulphomethyl-1 H-tetrazol-5-ylthio, 1 -carboxymethyl-1 H-tetrazol-5-ylthio or 1 -(2- dimethylaminoethyl)-1 H-tetrazol-S-ylthio; thiadiazolylthio, for example 1 ,3,4-thiadiazol-5-ylthio, thiadiazolylthio substituted by lower alkyl, for example methyl, for example 2-methyl-l ,3,4-thiadiazol5-ylthio; 5,6-dioxotetrahydrotriazin-3-yl-thio substituted by lower alkyl, for example methyl, for example 2-methyl-5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo-1 ,4,5,6-tetrahydroas-triazin-3-ylthio; pyridinio; or pyridinio substitued by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl: for example 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3-or 4carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3- or 4-carbamoylpyridinio, R3 represents carboxy, or carboxy that can be cleaved under physiological conditions, for example acyloxy-lower alkoxycarbonyl, for example lower alkanoyloxy-lower alkoxycarbonyl, for example lower alkanoyloxymethoxycarbonyl or lower al kanoyloxyethoxycarbonyl, for example pivaloyloxymethoxycarbonyl or 2-(propionyloxy)-ethoxycarbonyl, or lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1 -(ethoxycarbonyloxy)-ethoxyca rbonyl or tert.-butoxycarbonyloxymethoxycarbonyl, and A represents a methylene group substituted by a group of the formula =N-0-B4 in which R4 represents hydrogen, lower alkyl, for example methyl, carboxy-lower alkyl, for example 2-carboxy-2-propyl, carbamoyl or lower alkylcarbamoyl, for example methylcarbamoyl, wherein the group of the formula -0-B4 is in the syn- (orZ-) position, and salts especially pharmaceutically acceptable salts, of compounds of the formula I having salt-forming groups.
The present invention relates most especially to compounds of the formula I in which n represents 0, R, represents hydrogen, lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group -CH2-B2 in which R2 represents lower alkanoyloxy, for example acetoxy; ca rbamoyloxy; tetrazolylthio, for example 1 H-tetrazol-5-ylthio; tetrazolylthio substituted by lower alkyl, for example methyl, di-lower alkylaminolower alkyl, for example 2-dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, or by carboxy-lower alkyl, for example carboxymethyl: for example 1 -methyl-l H-tetrazol-5-ylthio, 1 -(2dimethylaminoethyl)-1 H-tetrazol-5-ylthio, 1 -carboxymethyl-1 H- tetrazol-5-ylthio, 1 -sulphomethyl-1 H- tetrazol-5-ylthio, or 1 -carboxymethyl-i H-tetrazol-5-ylthio; thiadiazolylthio, for example 1,34 thiadiazol-5-ylthio; thiadiazolylthio substituted by lower alkyl, for example methyl, for example 2 methyl ,3,4-thiadiazol-5-ylthio; 5,6-dioxotetrahydro-as-triazinylthio substituted by lower alkyl, for example methyl, for example 2-methyl-5,6-dioxo-l ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl 5,6-dioxo- 1 ,4,5,6-tetrahydro-as-triazin-3-ylthio; pyridi nio; or pyridi nio substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or brornine, or by carbamoyl: for example 3- or 4-hydroxymethylpyridinio, 4carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3or 4-carbamoylpyridinio, R3 represents carboxy, lower alkanoyloxy-lower alkoxycarbonyl, for example lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethoxycarbonyl, for example pivaloyloxymethoxycarbonyl or 2-(propionyloxy)-ethoxycarbonyl or lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1 -(ethoxycarbonyloxy)-ethoxycarbonyl or tert.butoxycarbonyloxymethoxycarbonyl, and A represents a methylene group substituted by a group of the formula =N-0-B4 in which R4 represents lower alkyl, for example methyl, carboxy-lower alkyl, for example 2-carboxy-2-propyl, carbamoyl or lower alkylcarbamoyl, for example methylcarbamoyl, wherein the group of the formula -0-B4 is in the svn- or (Z-) position, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I having salt-forming groups.
The invention relates above all to the compounds of the formula I described in the Examples, and their salts, especially their pharmaceutically acceptable salts.
Compounds of the formula I and salts of such compounds having a salt-forming group are manufactured, for example, by a) in a compound of the formula
in which n, R, and R3 have the meanings given under formula I and the 7,B-amino group is in free form or is protected by a group that permits acylation, and in which functional groups present in R, are protected, or in a salt thereof, acylating the 7amino group by reaction with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula
in which A has the meaning given under formula I, and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in A are optionally protected, or with a salt thereof, or b) for the manufacture of a compound of the formula I in which n represents 0, isomerising a 2cephem compound of the formula
in which R,, R3 and A have the meanings given under formula I, and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in R, and A are optionally protected, or isomerising a salt thereof, to form the corresponding 3-cephem compound, or c) condensing a compound of the formula
in which n, Rr, R3 and A have the meanings given under formula I and X represents halogen, and functional groups present in R1 and A are optionally protected, or condensing a salt thereof, with urea, or d) for the manufacture of a compound of the formula I in which A represents methylene substituted by hydroxyimino, treating a compound of the formula
in which n, R1 and R3 have the meanings given under formula I, and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in R1 are optionally protected, or a salt thereof, with a nitrosating agent, and, if desired, converting a resulting compound of the formula i into a different compound of the formula I and/or converting a resulting compound in which n represents 0 into a compound in which n represents 1 or 2 and/or converting a resulting compound in which n represents 1 or 2 into a compound in which n represents 0 and/or converting functional groups present in protected form in a resulting compound into free functional groups and/or converting a resulting salt into the free compound or into a different salt and/or converting a resulting free compound into a salt and/or separating a resulting mixture of isomers into the individual isomers.
Process a) acylation: In a starting material of the formula II, a functional group, for example a carboxy, amino or hydroxy group, present in R1 is protected by one of the protecting groups mentioned hereinbefore.
The 7amino group in a starting material of the formula II is optionally protected by a group that permits acylation. Such a group, forms a Schiff's base. An organic silyl group is, for example, one which, together with the amino groupo, form a Schiff's base. An organic silyl group is, for example, one that is also capable of forming a protected carboxy group with a carboxy group R3. This is especially a tri-lower alkylsilyl group, especially trimethylsilyl. In the silylation for the protection of a 4-carboxy group in a starting material of the formula ll, if an excess of the silylating agent is used, the amino group may likewise be silylated.An ylidene group is especially a 1 -aryl-lower alkylidene group, especially a 1-arylmethylene group, wherein aryl represents especially a carbocylic, primarily a monocyclic, aryl radical, for example phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or nitro.
An acylating agent that introduces the acyl radical of a carboxylic acid of the formula III is the carboxylic acid of the formula Ill itself or a reactive functional derivative or a salt thereof. In a starting material of the formula Ill, a functional group present in R4, for example a carboxy, amino or hydroxy group, which is not to participate in the acylation, is protected by one of the protecting groups mentioned hereinbefore.
In a starting material of the formula Ill, any amino group present may also be protected in ionic form, for example in the form of an acid addition salt which is formed, for example, with a strong inorganic acid, such as a hydrohalic acid, for example hydroch!oric acid, or sulphuric acid, or with an organic acid, for example p-toluenesulphonic acid.
If a free acid of the formula Ill is used for acylation, the reaction is usually carried out in the presence of suitable condensation agents, such as carbodiimides, for example N,N'-diethyl-N,N'dipropyl-, N,N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1 ,2-oxazolium compounds, such as 2-ethyl-5-phenyl 1 ,2-oxazolium 3'-sulphonate or 2-tert.-butyl-5-methyl-1 ,2-oxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1 -ethoxycarbonyl-l ,2-dihydroquinoline.
The condensation reaction is carried out preferably in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary while cooling or heating, for example within a temperature range of from approximately40 C to approximately + 1 00 C, preferably from approximately 20C0 to approximately +500C, and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
A reactive, i.e. carboxamide-forming, functional derivative of a carboxylic acid of the formula Ill is especially an anhydride of such an acid, preferably a mixed anhydride. A mixed anhydride is formed, for example, by condensation with another acid, for example an inorganic acid, for example a hydrohalic acid, and is, for example, the corresponding carboxylic acid halide, for example the carboxylic acid chloride or bromide. A mixed anhydride is furthermore formed by condensation with hydrazoic acid and is, for example, the carboxylic acid azide. Other inorganic acids that are suitable for the formation of the mixed anhydride are phosphorus-containing acids, for example phosphoric acid, diethylphosphoric acid or phosphorous acid, sulphur-containing acids, for example sulphuric acid or hydrocyanic acid.A reactive functional derivative of a carboxylic acid of the formula Ill is furthermore formed by condensation with an organic carboxylic acid, for example with an unsubstituted lower alkanecarboxylic acid or a lower alkanecarboxylic acid substituted by halogen, for example fluorine or chlorine, for example pivalic acid or trifluoroacetic acid, with a lower alkyl semiester of carbonic acid, for example the ethyl or isobutyl semiester of carbonic acid, or with an organic, for example aliphatic or aromatic sulphonic acid, for example methanesulphonic acid orp-toluenesulphonic acid.
A reactive functional derivative of a carboxylic acid of the formula Ill is likewise an activated ester of the carboxylic acid of the formula Ill, which is formed, for example, by condensation with a vinylogous alcohol, i.e. with an enol, for example a vinylogous lower alkenol; an iminomethyl ester halide, for example dimethyliminomethyl ester chloride, produced from the carboxylic acid of the formula Ill and, for example, dimethyl-( 1 -chloroethylidene)-iminium chloride of the formula [(CH3)2NG+=C(Cl)CH3]ClD-, which in turn can be obtained, for example, from N,N-dimethylacetamide and phosgene or oxalyl chloride; an aryl ester, for example a phenyl ester substituted by halogen, for example chlorine, and/or by nitro, for example a pentachlorophenyl, 4-nitrophenyl or 2,3-dinitrophenyl ester; an Nheteroaromatic ester, for example N-benztriazole ester; or an N-diacylimino ester, for example an Nsuccinylimino or N-phthalylimino ester.
The acylation with a reactive functional derivative of the carboxylic acid of the formula Ill, for example with a corresponding anhydride, especially an acid halide, is carried out preferably in the presence of a suitable acid-binding agent, for example a suitable organic base. A suitable organic base is, for example, an amine, for example a tertiary amine, for example tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or N,N-di-lower alkylaniline, for example N,Ndimethylaniline, or a cyclic tertiary amine, for example an N-lower akylated morpholine, for example Nmethylmorpholine, or is, for example, a base of the pyridine type, for example pyridine.A suitable acidbinding agent is, further, 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 bicarbonate, or is an oxirane, for example a 1 ,2-lower alkylene oxide, such as ethylene oxide or propylene oxide.
The acylation with a reactive functional derivative of the carboxylic acid of the formula Ill is carried out preferably in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, if necessary or desired at reduced or elevated temperature, for example in a temperature range of from approximately40 C to approximately + 1 000C, preferably from approximately 00C to approximately +500 C, and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
The acylation of a compound of the formula II can also be effected by using a suitable reactive functional derivative of the acid of the formula III in the presence of a suitable acylase. Such acylases are known and can be formed by a number of microorganisms, for example by acetobacter, such as Acetobacter aurantium, achromobacter, such as Achromobacter aeris, aeromonas, such asAeromonas hydrophila, or bacillus, such as Bacillus Megaterium 400.In such an enzymatic acylation, there is used as reactive functional derivative especially an amide, ester or thioester, such as a lower alkyl ester, for example a methyl or ethyl ester, of the carboxylic acid of the formula lil. Such an acylation is usually carried out in a nutrient medium containing the corresponding microorganism, in a filtrate of the culture broth or, optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous medium optionally containing a buffer, for example in a temperature range of from approximately 200C to approximately 400C, preferably at approximately 370C.
A reactive functional derivative of an acid of the formula Ill used in the acylation reaction can, if desired, be formed in situ. Thus, for example, a mixed anhydride can be produced in situ by reacting an acid of the formula III in which functional groups are optionally protected, or a suitable salt thereof, for example an ammonium salt, which is formed, for example, with an organic base, such as pyridine or 4methylmorpholine, or a metal salt, for example an alkali metal salt, for example a sodium salt, with a suitable derivative of another acid, for example an acid halide of a lower alkanecarboxylic acid that is unsubstituted or substituted by halogen, for example chlorine, for example trichloroacetyl chlorine, with a semiester of a carbonic acid semihalide, for example chloroformic acid ethyl ester or isobutyl ester, or with a halide of a di-lower alkylphosphoric acid, for example diethylphosphorobromidate, which can be formed by reacting triethyl phosphite with bromine. The mixed anhydride so obtained can be used in the acylation reaction without being isolated.
Process b) (isomerisation): In a 2-cephem starting material of the formula IV, the optionally protected 4-carboxy group is preferably in the a-configuration.
2-Cephem compounds of the formula IV can be isomerised by treating with a weakly basic agent and isolating the corresponding 3-cephem compound. Suitable isomerising agents are, for example, organic, nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, especially bases of the pyridine type, such as pyridine itself, and picolines, collidines or lutidines, and also quinoline, tertiary aromatic bases, for example those of the aniline type, such as N,N-di-lower alkylanilines, for example N,N-dimethylaniline or N,N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as tri-lower alkylamines, for example trimethylamine or N,N-diisopropylethylamine, N-lower alkylazacycloalkanes, for example N-methylpiperidine, or N,N-dilower alkyl phenyl-lower alkylamines, for example N,N-dimethylbenzylamine, and also mixtures of such basic agents, such as the mixture of a base of the pyridine type and a tri-lower alkylamine, for example pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, especially of mediumstrength to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, for example sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, and other analogous bases or mixtures of such basic agents can also be used.
Isomerisation of 2-cephem compounds of the formula IV with basic agents is carried out preferably in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, it being possible for the bases used as reactants which are liquid under the reaction conditions to serve, at the same time, as solvents, optionally while cooling or heating, preferably within a temperature range of from approximately30 C to approximately +1000C, in an inert gas atmosphere, for example a nitrogen atmosphere, and/or in a closed vessel.
3-cephem compounds of the formula I obtainable in this manner can be separated from 2 cephem starting materials which may still be present in a manner known per se, for example by adsorption and/or crystallisation.
The isomerisation of 2-cephem compounds of the formula IV to the corresponding 3-cephem compound is preferably carried out by oxidising these in the l-position, and if desired optionally separating isomeric mixtures of the l-oxides formed and reducing the resulting l-oxides of the corresponding 3-cephem compounds.
Suitable oxidising agents for the oxidation in the position of 2-cephem compounds of the formula IV are inorganic peracids that have a reduction potential of at least 1.5 volts and consist of non-metallic elements, organic peracids or mixtures consisting of hydrogen peroxide and acids, especially organic carboxylic acids, having a dissociation constant of at least 10-5. Suitable inorganic peracids are, for example, periodic acid and persulphuric acid. Organic peracids are, for example, percarboxylic and persulphonic acids which are added as such or can be formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid. In this case it is expedient to use a large excess of the carboxylic acid if, for example, acetic acid is used as solvent.Suitable peracids are, for example, performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3chloroperbenzoic acid, monoperphthalic acid orp-toluenepersulphonic acid.
The oxidation can likewise be effected using hydrogen peroxide with catalytic amounts of an acid having a dissociation constant of at least 10-5, it being possible to use low concentrations, for example 12% and lower, or alternatively relatively large amounts of the acid. In this case the effectiveness of the mixture depends chiefly 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 may be carried out in the presence of suitable catalysts. Thus, for example, the oxidation with percarboxylic acids can be catalysed by the presence of an acid having a dissociation constant of at least 10-5, the effectiveness of this acid as catalyst being dependent on its strength.
Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually, at least equimolar amounts of the oxidising agent, and preferably a slight excess of from approximately 10% to approximately 20%, are used, it being possible alternatively to use relatively large excesses, i.e.
up to 10 times the amount or more of the oxidising agent. The oxidation is carried out under mild conditions, for example at temperatures of from approximately50 C to approximately +1 000C, preferably from approximately -i 00C to approximately +400 C.
The reduction of l-oxides of 3-cephem compounds can be carried out in a manner known per se by treating with a reducing agent, if necessary in the presence of an activating agent. As reducing agents there come into consideration, for example: catalytically activated hydrogen, there being used noble metal catalysts that contain palladium, platinum or rhodium and which are optionally employed together with a suitable carrier, such as carbon or barium sulphate; tin, iron, copper or manganese cations having a reducing action, which are used in the form of inorganic or organic compounds or complexes, for example in the form of tin(ll) chloride, fluoride, acetate or formate, iron(ll) chloride, sulphate, oxalate or succinate, copper(l) chloride, benzoate or oxide, or manganese(ll) chloride, sulphate, acetate or oxide, or in form of complexes, for example with ethylenediaminetetraacetic acid or nitrilotriacetic acid; dithionite, iodide or iron(ll) cyanide anions having a reducing action, which are used in the form of corresponding inorganic or organic salts, such as alkali metal dithionite, iodide or iron(ll) cyanide, for example sodium or potassium dithionite, sodium or potassium iodide or sodium or potassium iron(ll) cyanide, or in the form of the corresponding acids, such as hydriodic acid; trivalent inorganic or organic phosphorus compounds having a reducing action, such as phosphines, also esters, amides and halides of phosphonous, phosphinous or phosphorous acid, and also phosphorus-sulphur compounds corresponding to these phosphorus-oxygen compounds, wherein organic radicals in these compounds are especially aliphatic, aromatic or araliphatic radicals, for example optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, such as, for example, triphenylphosphine, tri-nbutylphosphine, diphenylphosphonous acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonous acid dimethyl ester, butanephosphonous acid methyl ester, phosphoric acid triphenyl ester, phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide etc.; halosilane compounds having a reducing action that have at least one hydrogen atom bonded to the silicon atom and may contain, apart from halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups, for example optionally substituted lower alkyl or phenyl, such as chlorosilane, bromosilane, di- or tri-chlorosilane, di- or tri-bromosilane, diphenylchlorosilane or dimethylchlorosilane, or also halosilane compounds in which all the hydrogen atoms are replaced by organic radicals, such as a tri-lower alkylhalosilane, for example trimethylchlorosilane or trimethyliodosilane, or cyclic sulphur-containing silanes, such as 1 ,3-dithia-2,4disilacyclobutanes or 1 ,3,5-trithia-2,4,6-trisilacyclohexanes, of which the silicon atoms are substituted by hydrocarbon radicals, such as, especially, lower alkyl, for example 2,2,4,4-tetramethyl-1,3-dithia- 2,4-disilacyclobutane or 2,2,4,4,6,6-hexamethyl-1,3,5-trithia-2,4,6-trisilacyclohexane, etc.; quaternary chloromethyleneiminium salts having a reducing action, especially chlorides or bromides, in which the iminium group is substituted by one bivalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl, such as N-chloromethylene-N,N-diethyliminium chloride or Nchloromethylene-pyrrolidinium chloride; or complex metal hydrides having a reducing action, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt(ll) chloride, and also borane dichloride.
As activating agents which are used with those of the above-mentioned reducing agents that do not themselves have any, or that have only faint, properties of Lewis acids, i.e. those which are used primarily together with dithionite, iodide or iron(ll) cyanide reducing agents and the trivalent phosphorus reducing agents that do not contain halogen, or are used in the catalytic reduction, there may be mentioned especially organic carboxylic and sulphonic acid halides, also sulphur, phosphorus or silicon halides having a second order hydrolysis constant which is the same as or greater than that of benzoyl chloride, for example phosgene, oxalyl chloride, acetyl chloride or bromide, chloroacetyl chloride, pivaloyl chloride, 4-methoxybenzoyl chloride, 4-cyanobenzoyl chloride,p-toluenesulphonyl chloride, methanesulphonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous acid dichloride, dimethylchlorosilane or trichlorosilane, also suitable acid anhydrides, such as trifluoroacetic acid anhydride, or cyclic sultones, such as ethanesultone, propanesultone, 1 ,3-butanesultone or 1,3hexanesultone.
The reduction is carried out preferably in the presence of solvents or mixtures thereof, the choice of which is determined chiefly by the solubility of the starting materials and the chosen reducing agents; thus, for example, lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the case of catalytic reduction and, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanecarboxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides of inorganic or organic acids, for example dimethylformamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydrofuran or dioxan, ketones, for example acetone, or sulphones, especially aliphatic sulphones, for example dimethylsulphone or tetramethylenesulphone, etc., together with the chemical reducing agents, these solvents preferably containing no water. The reaction is usually carried out at temperatures of from approximately20 C to approximately 1 000C, it being possible when using very reactive activating agents, to carry out the reaction also at lower temperatures.
Process c) (ring closure): In a starting material of the formula V, X represents halogen, preferably chlorine, also bromine, iodine or fluorine. A compound of the formula V having a salt-forming group, for example R3 representing carboxy, may be used in the form of a salt, for example in the form of an alkali metal or ammonium salt, for example a lithium, sodium, potassium, tri-lower alkylammonium, for example trimethylammonium ortriethylammonium salt.
The urea is added in an equivalent amount or in excess.
The reaction is generally carried out in a solvent, such as water or an organic inert solvent, or a mixture thereof. Suitable as organic solvents are alcohols, such as methanol, ethanol or isopropanol, ketones, such as acetone, ethers, such as dioxan or tetrahydrofuran, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, esters, such as ethyl acetate, or amides, such as dimethylformamide or dimethylacetamide, and the like. If a free compound of the formula V is used, the reaction can be carried out in the presence of a base.
Suitable bases are alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonates, such as sodium or potassium carbonate, or organic tertiary nitrogen bases, such as trilower alkylamines, for example trimethylamine, triethylamine, ethyl-diisopropylamine, pyridine and the like. The reaction temperature is above room temperature, preferably between 60 and the boiling temperature of the reaction mixture.
The reaction can also be carried out in stages, by first of all forming an open-ring intermediate, for example of the partial formula NH2-C(=NH)-OH2-CO-A-, which is then in the second stage dehydrated by heating.
Process d) (formation of the unsubstituted hydroxyimino group): In a starting material of the formula VI the functional groups are protected. Suitable nitrosating agents are nitrous acid and derivatives thereof, such as nitrosyl halides, for example nitrosyl chloride or nitrosyl bromide, salts of nitrous acid, such as alkali metal salts, for example sodium or potassium nitrite, or especially esters of nitrous acid, for example a lower alkyl ester, for example butyl, pentyi or especially isoamyl nitrite. If a salt of nitrous acid is used as nitrosating agent, the reaction is carried out preferably in the presence of a strong inorganic or organic acid, for example hydrochloric acid, sulphuric acid, formic acid or acetic acid.If an ester of nitrous acid is used, the reaction is carried out preferably in the presence of a strong base, such as an alkali metal alkanolate.
The nitrosation is carried out in a suitable solvent, such as water, a carboxylic acid, for example acetic acid, a lower alkanol, for example methanol or ethanol, an ether, for example dioxan or tetrahydrofuran, or a hydrocarbon, for example hexane or benzene, or in mixtures thereof, if necessary while cooling or heating, especially in a temperature range of from approximately --1 50C to approximately room temperature, and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
Subsequent operations: R1 conversions: In a resulting compound of the formula I in which functional groups are optionally protected, in a manner known per se a group R, can be replaced by another radical R1 or converted into another radical R1. Thus, for example, it is possible in a compound of the formula I in which B1 represents a group of the formula -CH2-B2 and R2 represents, for example, a radical replaceable by nucleophilic substituents, or in a salt thereof, to replace such a radical R2 by an etherified mercapto group, for example a heterocyclylmercapto group, or an esterified mercapto group R2 by treatment with a mercaptan compound, for example a heterocyclylmercaptan compound, or with a thiocarboxylic acid compound.
A suitable radical replaceable by nucleophilic substituents, for example by an etherified mercapto group is, for example, a hydroxy group esterified by a lower aliphatic carboxylic acid. Such an estedfied hydroxy group is especially acetoxy and acetoacetoxy.
The reaction of such a compound of the formula I with a suitable mercaptan compound, for example a heterocyclylmercaptan compound, can be carried out under acidic, neutral or weakly basic conditions. In the case of acidic conditions the reaction is carried out in the presence of concentrated sulphuric acid, which is optionally diluted by an inorganic solvent, for example polyphosphoric acid. In the case of neutral or weakly basic conditions the reaction is carried out in the presence of water and optionally a water-miscible organic solvent.
The basic conditions can be established, for example, by the addition of an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium potassium or calcium hydroxide, carbonate or bicarbonate. There may be used as organic solvents, for example, water-miscible alcohols, for example lower alkanols, such as methanol or ethanol, ketones, for example lower alkanones, such as acetone, amides, for example lower alkanecarboxylic acid amides, such as dimethylformamide, or nitriles, for example lower alkanoic acid nitriles, for example acetonitrile.
In a compound of the formula I in which R1 represents a group of the formula -CH2-R2 in which R2 represents free hydroxy, the free hydroxy group can be esterified by the acyl radical of an optionally N-substituted carbamic acid. The esterification of the free hydroxy group with an isocyanate compound, for example halosulphonyl isocyanate, for example chlorosulphonyl isocyanate, or with a carbamic acid halide, for example carbamic acid chloride, results in N-unsubstituted 3 carbamoyloxymethyl cephalosporins of the formula I.The esterification of the free hydroxy group with an N-substituted isocyanate compound or with an N-mono- or N,N-di-substituted carbamic acid compound, for example a correspondingly substituted carbamic acid halide, for example an N-mono- or N,N-di-substituted carbamic acid chloride, results in N-mono- or N,N-di-substituted 3carbamoyloxymethyl cephalosporins of the formula I. The reaction is usually carried out in the presence of a solvent or diluent and, if necessary, while cooling or heating, in a closed vessel and optionally under an inert gas atmosphere, for example a nitrogen atmosphere.The compound of the formula I in which R1 represents a group of the formula -CH2-B2 in which R2 represents free hydroxy can be produced from a compound of the formula I by removing the acetyl radical from an acetoxy group R2, for example by hydrolysis in weakly basic medium for example in an aqueous sodium hydroxide solution at a pH of 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme selected from Rhizobium tritolii, Rhizobium lupinii, Rhizobiumjaponicum or Bacillus subtilis or a suitable citrus esterase, for example from orange peel.
Also, a compound of the formula I in which R1 represents a -CH2-R2 group, R2 representing, for example, the above-defined radical replaceable by nucleophilic substitution, can be reacted with a tertiary organic base, especially an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH value of approximately 6.5, in the presence of water and optionally in a water-miscible organic solvent, to form compounds of the formula I in which R1 represents a radical of the formula -CH2-B2 and R2 represents an ammonio group. The weakly acidic conditions can be established by the addition of a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or sulphuric acid. There may be used as organic solvents, for example, the afore mentioned water-miscible solvents.To increase the yield certain salts may be added to the reaction mixture, for example alkali metal salts, such as sodium and, especially, potassium salts, of inorganic acids, such as hydrohalic acids, for example hydrochloric acid and especially hydriodic acid, as well as thiocyanic acid, or of organic acids, such as lower alkanecarboxylic acids, for example acetic acid.
Suitable salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate. Salts of suitable anion exchangers can also be used for this purpose, for example liquid ion exchanges in salt form, such as, for example, Amberlite LA-1 (liquid secondary amines with a molecular weight of 351 - 393; oil-soluble and water-insoluble; meq/g=2.5--2.7, for example in acetate form), with acids, for example acetic acid.
Ammonio groups R2 can advantageously be produced using an intermediate of the formula I in which R2 represents a substituted, but especially an aromatic substituted, carbonylthio group and, more especially, a benzoylthio group. Such an intermediate, which can be obtained, for example, by reacting a compound of the formula I in which R2 in the radical R1 represents an esterified hydroxy group, especially a lower alkanoyloxy group, for example acetoxy, with a suitable salt, for example an alkali metal salt, for example a sodium salt, of a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, for example thiobenzoic acid, is reacted with a tertiary amine, especially a tertiary heterocyclic base, such as an optionally substituted pyridine, to yield the corresponding compound with an ammonio group.The reaction is usually carried out in the presence of a suitable desulphurising agent, especially a mercury salt, for example mercury(ll) perchlorate and of a suitable solvent or diluent or a mixture thereof, if necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
Oxidation of the hydroxymethylene group A: In a resulting compound of the formula (I), a hydroxymethylene group A can be oxidised to an oxomethylene group. The oxidation can, optionally with the protection of a free amino and carboxy group, be carried out in a manner known per se, that is to say in a manner known for the oxidation of hydroxy groups to oxo groups.There come into consideration as oxidising agents oxides, for example of manganese, chromium, nitrogen or sulphur, such as manganese dioxide, chromium trioxide, for example Jones reagent or chromium trioxide in the presence of acetic acid, sulphuric acid or pyridine, di-nitrogen tetraoxide, dimethyl sulphoxide optionally 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 hydroxmethylene group can also be converted into the oxomethylene group by Oppenauer oxidation, that is to say by treatment with the salt of a sterically hindered alcohol, such as aluminium or potassium tert.-butoxide, isopropoxide or phenoxide in the presence of a ketone, such as acetone, cyclohexanone or fluorenone. A further possible method of converting the hydroxymethylene group into the oxomethylene group is by dehydration, for example with Raney nickel.
Depending on the oxidising agent, the oxidation is carried out in water or an optionally watercontaining organic solvent at temperatures of from approximately 0 to approximately 1000.
Reaction of the carbonyl group A with a hydroxylamine derivative: In a resulting compound of the formula (I) in which A represents a carbonyl group, the carbonyl group can, optionally with protection of functional groups, be converted by treatment with hydroxylamine or O-methylhydroxylamine into a hydroxyiminomethylene or methoxyiminomethylene group respectively.
The reaction of the carbonyl group with the hydroxylamine compound is carried out in customary manner, for example by allowing the two reactants to react in a solvent, such as water, or an organic solvent, such as an alcohol, for example methanol, at slightly elevated or reduced temperature, optionally in an inert gas atmosphere, such as a nitrogen atmosphere. The hydroxylamine compound car also be freed in situ from one of its salts, for example a hydrohalide, such as a hydrochloride, by treatment with un inorganic base, such as an alkali metal hydroxide, for example sodium hydroxide, or with an organic base, such as a tertiary amine, for example a tri-lower alkylamine, such as triethylamine or ethyl-diisopropylamine, or with a heterocyclic tertiary base, such as pyridine.
Conversion to the 1-oxide, 1-dioxide and 1-sulphide: A compound of the formula I in which the index n is 0 can be converted by the oxidising agents described in process b) into the corresponding oxide in which the index n is 1.
A compound of the formula I in which the index n is O or 1 can be converted into the corresponding l-dioxide in which n is 2 by reaction with agents that convert sulphide or sulphoxide groups into sulphone groups.
Such agents are especially hydrogen peroxide, organic peracids, especially aliphatic percarboxylic acids, for example, peracetic acid, perbenzoic acid, chloroperbenzoic acid, for example mchloroperbenzoic acid, or monoperphthalic acid, oxidising inorganic acids or their salts, for example nitric acid, chromic acid, potassium permanganate, or alkali metal hypochlorite, for example sodium hypochlorite, or anodic oxidation may be used.The oxidation is carried out preferably in a suitable inert solvent, for example a halogenated hydrocarbon, for example methylene chloride, chloroform or carbon tetrachloride, an alcohol, for example methanol or ethanol, a ketone, for example acetone, an ether, for example diethyl ether, dioxan or tetrahydrofuran, an amide, for example dimethylformamide, a sulphone, for example dimethyl sulphone, a liquid organic carboxylic acid, for example acetic acid, or in water or a mixture of these solvents, especially an aqueous mixture, for example aqueous acetic acid, at room temperature, or while cooling or gently heating, i.e. at from approximately --200 to approximately +900, preferably at from approximately +180 to approximately +300.The oxidation can also be carried out in stages by first of all oxidising at low temperature, that is to say at from approximately --200 to approximately 00, by the addition of an equivalent amount of oxidising agent, to the sulphoxide stage, which is optionally isolated, then, in a second stage, oxidising the sulphoxide to the sulphone, that is the 1,1-dioxide of the formula (I), preferably at elevated temperature, by the addition of a further equivalent amount of oxidising agent.
For working up, excess oxidising agent that may still be present can be eliminated by reduction, especially by treatment with a reducing agent, such as a thiosulphate, for example sodium thiosulphate.
A oxide of the formula I in which the indexn is 1, and a l-dioxide in which the index n is 2, can be converted by the reducing agents described in process b) into the corresponding 1 -sulphide in which the index n is 0.
The removal of protecting groups: In a resulting compound of the formula I in which one or more functional groups are protected, these, for example protected carboxy, amino, hydroxy and/or sulpho groups, may be liberated in a manner known per se, optionally in stages or simultaneously, by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reductions, especially hydrogenolysis.
A protected carboxy group is liberated in a manner known per se and, depending on the nature of the protecting groups, by various methods, but preferably by means of solvolysis or reduction. Thus, tert.-lower alkoxycarbonyl, or lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the position by lower alkoxy or lower alkylthio, or optionally substituted diphenylmethoxycarbonyl can be converted into free carboxy, for example, by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylenethioglycol. Optionally substituted benzyloxycarbonyl can be liberated, for example, by means of hydrogenolysis, i.e. by treating with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst.Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can be converted into free carboxy also by means of chemical reduction, for example by treatment with an alkali metal dithionite, for example sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(ll) salt, for example chromium(ll) chloride, usually in the presence of a hydrogen-yielding agent that, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as a lower alkanecarboxylic acid optionally substituted, for example, by hydroxy, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or of an alcohol or thiol, water preferably being added.By treatment with a reducing metal or metal salt, as described above, it is possible also to convert 2-halo-lower alkoxycarbonyl (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxy, it being possible to cleave aroylmethoxycarbonyl also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide.Substituted 2silylethoxycarbonyl can also be converted into free carboxy by treatment with a salt of hydrofluoric acid yielding the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, in the presence of a macrocyclic polyether ("Crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower alkylarylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethyl sulphoxide or N,N-dimethylacetamide. Carboxy esterified by an organic silyl group, such as tri-lower alkylsilyl, for example trimethylsilyl, can be liberated in the customary manner by solvolysis, for example by treatment with water, an alcohol or an acid.
A protected amino group is liberated in a manner known per se and, depending on the nature of the protecting group, by various methods, but preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino, optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably saltforming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.lower alkoxycarbonylamino or 2-tri-substituted silylethoxycarbonylamino can be liberated by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino can be liberated, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino, formylamino or 2-acyl-lower alk-i -en-i -ylamino can be liberated, for example, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic acid, acetic acid or trifluoroacetic acid optionally in the presence of water, and an amino group protected by an organic silyl group can be liberated, for example, by hydrolysis or alcoholysis.An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea and by subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treatment with a salt of hydrofluoric acid yielding fluoride anions, as indicated above in connection with the liberation of a correspondingly protected carboxy group.
A phosphoramido, phosphonamido or phosphinamido group can be converted into the free amino group, for example by treatment with a phosphorus-containing acid, such as a phosphoric, phosphonic or phosphinic acid, for example orthophosphoric acid or polyphosphoric acid, an acid ester thereof, for example monomethyl, monoethyl, dimethyl or diethyl phosphate, or monomethylphosphonic acid, or an an hydroxide thereof, such as phosphorus pentoxide.
A hydroxy group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1 -phenyl-lower alkyl is liberated in the same manner as a correspondingly protected amino group. A hydroxy group protected by 2,2-dichloroacetyl is liberated, for example by basic hydrolysis, while a hydroxy group etherified by tert.lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is liberated by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
A protected, especially esterified, sulpho group is liberated analogously to a protected carboxy group.
The cleaving reactions described are carried out under conditions known per se, if necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
Preferably, when several protected functional groups are present, the protecting groups are so selected that more than one such group can be removed simultaneously, for example by acidolysis, such as by treatment with trifluoroacetic acid or formic acid, or by reduction, such as by treatment with zinc and acetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium-on-carbon catalyst.
Esterification of a free carboxy group: The conversion of a free carboxy group, for example the free carboxy group R3, into an esterified carboxy group, especially into a carboxy group that can be cleaved under physiological conditions, is effected according to esterification methods known per se. For example, a compound of the formula I in which the carboxy group to be esterified is in free form and other functional groups, for example amino or hydroxy groups, are in protected form, or a compound of the formula I in which the carboxy group to be esterified is in the form of a reactive functional derivative, or a salt of a compound of the formula I, is reacted with the corresponding alcohol or a reactive functional derivative of this alcohol.
In the case of esterification of a compound of the formula I in which the carboxy group to be esterified is in free form, there are used with the desired alcohol the same condensation agents, for example carbodiimides, the same solvents and the same reaction conditions as are used for the acylation according to process a).
A compound of the formula I in which the carboxy group to be esterified is in the form of a reactive functional derivative is, for example, a mixed anhydride or an activated ester, which can be obtained in the manner described under process a) (acylation) by condensation of the carboxylic acid of the formula I with an inorganic acid, a carboxylic acid, a semi-ester of carbonic acid, a sulphonic acid or by condensation with a vinylogous alcohol.
A reaction functional derivative of the alcohol to be esterified is especially the ester, which is formed by condensation with a strong inorganic or organic acid, for example the corresponding halide, for example chloride, bromide or iodide, or the corresponding lower alkyl, or aryl, for example the methylsulphonyloxy or 4-methylsulphonyloxy compound.
In the case of the esterification of a compound of the formula I in which the carboxy group to be esterified is in the form of a reactive functional derivative, there are used with the corresponding alcohol, or in the case of esterification of a compound of the formula I in which the carboxy group to be esterified is in free form, there are used with a reactive functional derivative of the corresponding alcohol, the same solvents and the same reaction conditions as for the acylation with a reactive functional derivative of a carboxylic acid of the formula III according to process a).
A compound of the formula I in which the carboxy group to be esterified is in the form of a reactive functional derivative can also be produced in situ analogously to the method described in process a) (acylation) and can be reacted with the corresponding alcohol without being isolated.
Salt formation: Salts of compounds of the formula I can be manufactured in a manner known per se. Thus, salts of compounds of the formula I can be formed, for example, by reaction of the acid groups with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of aethylcaproic acid, or sodium carbonate, or with ammonia or a suitable organic amine, preferably stoichiometric quantities or only a small excess of the salt-forming agent being used. Acid addition salts of compounds of the formula I are obtained in the customary manner, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with liquid ion exchangers.
Salts can be converted in the customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts can be converted, for example, by treatment with a suitable basic agent.
In all of the reactions mentioned hereinbefore that are carried out under basic conditions, all or some 3-cephem compounds can be isomerised to 2-cephem compounds. A resulting 2-cephem compound or a mixture of a 2- and a 3-cephem compound can be isomerised in a manner known per se to the desired 3-cephem compound.
Mixtures of isomers can be separated into the individual isomers in a manner known per se, for example by fractional crystallisation, chromatography, etc.
The process also includes those embodiments according to which compounds formed as intermediates are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage; furthermore, starting materials may be used in the form of derivatives or formed during the reaction.
Preferably, the starting materials and the reaction conditions are so chosen that the compounds described above as being especially preferred are obtained.
Pharmaceutical preparations: The pharmacologically acceptable compounds of the formula I, their hydrates or salts can be used for the manufacture of pharmaceutical preparations.
Pharmaceutical preparations contain an effective amount of the pure active ingredient of the formula I alone or an effective amount of the active ingredient of the formula I in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable preferably for parenteral administration.
Preferably, the active ingredients of the formula I of the present invention are used in the form of injectable, for example intravenously administrable, preparations or in the form of infusion solutions.
Such solutions are preferably isotonic aqueous solutions or suspensions which can be produced before use, for example from lyophilised preparations that contain only the active ingredient or the active ingredient together with a carrier, for example mannitol. The pharmaceutical preparations are preferably sterilised and may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question which, if desired, may contain other pharmacologically valuable substances, contain from approximately 0. 1% to 100%, especially from approximately 1% to approximately 50%, and in the case of lyophilisates up to 100%, of the active ingredient.
The pharmaceutical preparations are produced in a manner known per se, for example by means of conventional dissolving or lyophilising processes.
Use: Compounds of the formula I, their hydrates or pharmaceutically acceptable salts can be used as antibiotically active agents in the form of pharmaceutical preparations in a method for the therapeutic treatment of the human or animal body, for example for the treatment of infections that are caused by gram-positive or gram-negative bacteria and cocci, for example by enterobacteria, for example Escherichia coli, Kiebsiella pneumoniae or Proteus spp..
Depending on the nature of the infection and the condition of the infected organism, daily doses of from approximately 0.5 g to approximately 5 g are used s.c., i.v. or i.m. for the treatment of warmblooded animals (man and animals) weighing approximately 70 kg.
Starting materials: The starting materials used in the process for the manufacture of compounds of the present invention are either known or, if novel, can be produced in a manner known per se.
Starting materials of the formula Il and corresponding compounds having protected functional groups are known or can be produced in a manner known per se.
Starting materials of the formula Ill and the esters and reactive derivatives thereof are novel and the invention relates also to these.
The carboxylic acid of the formula Ill or reactive functional derivatives thereof used for the introduction of the acyl radical of a carboxylic acid of the formula Ill can be produced in a manner known per se. They are obtained, for example, by reacting with urea a compound of the formula
in which X represents halogen and A has the meanings given under formula I, and the carboxy group is present in esterified form or is protected by a customary carboxy-protecting group, and, if desired, in a resulting compound, removing the carboxy-protecting group and/or protecting the amino group in the 2-position of the oxazolyl radical and/or protecting a functional group in A and/or converting the group A into a different group A.
In a compound of the formula VII X is preferably chlorine or bromine, or also iodine or fluorine.
The carboxy group is in esterified form, for example in the form of methyl or ethyl ester, or is protected by one of the afore-mentioned customary protecting groups, for example by the tert.-butyl radical. The reaction of a compound of the formula VII with urea may be carried out substantially under the same conditions as those mentioned in process c), dimethylformamide being preferred as solvent. Preferably, the reaction is carried out at temperatures of above approximately 800 up to the boiling point of the reaction mixture. it is possible to react with urea compounds of the formula VII in which A represents, for example, carbon, unsubstituted methylene or methylene substituted by a group of the formula -N-0-B4, for example methoxyimino.
The amino group in the 2-position of the oxazolyl radical in a resulting compound of the formula Ill may subsequently be converted into an amino group protected, for example, by tert.-butoxycarbonyl.
If, in the acylation according to process a), the free carboxylic acid of the formula III is to be used, the protected carboxy group is previously converted into a free carboxy group. In a compound of the formula III, a carbonyl group A may subsequently be converted by a hydroxylamine compound of the formula H2N-0-R4 into a methylene group A substituted by a group of the formula =N-O-R4 analogously to the processes described above under subsequent operations. In a compound of the formula III, an unsubstituted methylene group A may subsequently be converted by a suitable nitrosating agent, for example sodium nitrite, into a methylene group A substituted by a hydroxyimino group =N-O-H analogously to the processes described above under subsequent operations.
Compounds of the formula IV to VII are known or, if novel, can be manufactured according to processes known per se.
The present invention relates also to novel starting compounds, as well as intermediates and processes for their manufacture.
The following Examples illustrate the invention; temperatures are given in degrees Centigrade; BOC: tert.-butoxycarbonyl.
Example 1: a) The sodium salt of 3-acetoxymethyl-7/3-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid 0.26 g of 3-acetoxymethyl-7p-[2-(2-BOC-a mino-4-oxazolyl)-2-Z-methoxyi minoacetamino]-3- cephem-4-carboxylic acid diphenylmethylester in 1.1 ml of methylene chloride is stirred at room temperature for one hour with 1.1 ml of trifluoroacetic acid and 0.2 ml of anisole, 50 ml of ice-cold toluene are added and the solution is then concentrated by evaporation in vacuo. After digesting the residue with ether and drying, the corresponding trifluoroacetic acid salt is obtained in the form of a yellowish powder. The salt is taken up in 5 ml of methanol and then 0.2 ml of a 3-molar methanolic sodium ethyl hexanoate solution is added.In order to precipitate the sodium salt, diethyl ether is added, the precipitate formed is filtered off, washed with ether and dried. The title compound is obtained in the form of a light beige powder. Bf""'0.23 (silica gel; n-butanol/acetic acid/water; 67:10:23); UV (H2O): AmaX=213 nm (17200) and 261 nm (12100).
b) 3-acetoxymethyl-7p-[2-(2-BOC-amino-4-oxazolyl)-2 -methoxyiminoacetamino]-3- cephem-4-carboxylic acid diphenylmethyl ester 0.09 ml of dimethylformamide is added at --100 to 0.1 ml of oxalyl chloride in 4 ml of methylene chloride, the mixture is stirred for 30 minutes and then 2-(2-BOC-amino-4-oxazolyl)-2-Zmethoxyiminoacetic acid and 0.14 ml of N-methylmorpholine are added. Stirring is continued for a further 30 minutes at approximately --50 to 10 and a solution consisting of 526 mg of 3 acetoxymethyl-7p-amino-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.14 ml of Nmethylmorpholine in 5 ml of methylene chloride is added to the reaction mixture and allowed to react for two hours at approximately 00.For working up, the reaction mixture is concentrated and the residue is taken up in ethyl acetate and extracted by shaking in succession with approximately 0.5N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying the organic phase over sodium sulphate and concentrating by evaporation, the title compound is obtained as a crude product which is purified by preparative thick layer chromatography (silica gel, ethyl acetate). Bf approximately 0.53 (silica gel; ethyl acetate); IR (methylene chloride): 3400, 1785, 1 758b, 1 740sh, 1 680 and 1 630 cm-1.
The starting materials are manufactured as follows: c) 2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid A solution of 1.2 g of potassium hydroxide in 10 ml of water is added to 1 g of 2-(2-BOC-amino 4-oxazolyl)-2-Z-methoxyiminoacetic acid methyl ester in 20 ml of ethanol and the whole is stirred for 50 minutes at room temperature. The reaction mixture is then concentrated in vacuo, diluted with ethyl acetate and acidified with 1N hydrochloric acid to pH 1-2. The organic phase is separated off, extracted by shaking with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation.After digesting the residue with a mixture of ethyl acetate and hexane, the title compound is obtained in the form of a yellowish powder. Bf approximately 0.38 (silica gel; n butanol/acetic acid/water; 67:10:23); IR (Nujol): 3400b, 1735b, 1710 and 1640 cm-'.
d) 2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid methyl ester 2.0 g of 2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid methyl ester are suspended in 3.05 g of di-tert.-butyl dicarbonate, the suspension is heated to 1000 and 0.1 g of 4dimethylaminopyridine is added. The whole is allowed to react for 7 minutes at 1000, is cooled and the reaction mixture is diluted with ethyl acetate and extracted twice with saturated sodium chloride solution; the organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo.
The crude product is chromatographed over 100 g of silica gel, toluene and 1 5% ethyl acetate being used to elute the title compound which is then crystallised out from ether. Melting point: 142 1460C; IR (CH2CI2): 3415, 1740, 1715sh, 1638, 1515 cm-l; UV (EtOH): AmaX=227 nm (16000) and 261 nm (7900).
e) 2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid methyl ester 47.6 g of 4-bromo-2-methoxyiminoacetoacetic acid methyl ester and 120 g of urea in 480 m; of dimethylformamide are heated at 1000 for 1 hour, an additional 30 g of urea are added and the whole is allowed to react for a further hour at 1000. The dark reaction mixture is poured into ice-water, extracted exhaustively with ethyl acetate and the organic phase is shaken three times with water and twice with saturated sodium chloride solution and dried over sodium sulphate. After concentrating by evaporation in vacuo, the title compound is crystallised out from an ethyl acetate/diethyl ether mixture.
Melting point: 142--1470; IR (Nujol): interalia 3438,3181, 1701, 1680, 1588cm1.
Example 2: a) The sodium salt of 7/3-[2-(2-amino-4-oxazolyl)-2nZ-methoxyiminoacetamino]-3-cephem-4- carboxylic acid 0.43 g of 7X3-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester in 2.05 ml of methylene chloride is stirred at room temperature for one hour with 2.05 ml of trifluoroacetic acid and 0.37 ml of anisole; 50 ml of ice-cold toluene are added and the whole is then concentrated by evaporation in vacuo. After digesting the residue with ether and drying, the corresponding trifluoroacetic acid salt is obtained in the form of a yellowish powder. The salt is taken up in 10 ml of methanol and then 0.4 ml of a 3-molar methanolic sodium ethyl hexanoate solution is added.In order to precipitate the sodium salt, diethyl ether is added, the precipitate formed is filtered off and then washed with ether and dried. The title compound is obtained in the form of a beige powder. Bf approximately 0.24 (silica gel; n-butanol/acetic acid/water; 67:10:23); UV (in water): Ajax=205 nm (17600) and 260 nm (8400).
b) 7ss-[3-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester 0.18 ml of dimethylformamide is added to 0.2 ml of oxalyl chloride in 8 ml of chloroform at 100; the mixture is left to stand for 30 minutes and then 570 mg of 2-(2-BOC-amino-4-oxazolyl)-2 Z-methoxyiminoacetic acid and 0.28 ml of N-methylmorpholine are added.Stirring is continued for 30 minutes at approximately from --50 to10 . A solution consisting of 0.84 g of 7p-amino-3-cephem- 4-carboxylic acid diphenylmethyl ester and 0.28 ml of N-methylmorpholine in 10 ml of methylene chloride is added to the reaction mixture and the whole is then allowed to react further for 45 minutes at from DO to 5 . For working up, the reaction mixture is concentrated, the residue is taken up in ethyl acetate and is extracted by shaking in succession with approximately 0.5N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution.After drying the organic phase over sodium sulphate and concentrating by evaporation, the title compound is obtained as a crude product which is purified by preparative thick layer chromatography (silica gel, ethyl acetate). Bf approximately 0.3 (silica gel; ethyl acetate/toluene; 1:1); IR (in methylene chloride): bands at 3402, 1788, 1755. 1730, 1680, 1628 and 1512 cm-'; UV (in ethanol): Ajax=260 nm (7000sh); 215 nm (sh).
Example 3: a) 7ss-[2-(2-amino-4-oxazolyl)-2-Z0methoxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester A mixture of 0.11 ml of chloromethyl pivalate and 0.45 g of sodium iodide in 1.5 ml of acetone is stirred for 3 hours at room temperature. 0.10 g of the sodium salt of 7P-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid in 3 ml of dimethylformamide is then added to the suspension and the whole is stirred for a further hour at room temperature. The reaction mixture is diluted with ethyl acetate, extracted by shaking with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate 1:1 and ethyl acetate and yields 7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
b) 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride The pivaloyloxymethyl ester is converted into the hydrochloride salt by treatment with a saturated HCI solution in methylene chloride and precipitation with ether. Rf~0.25 (ethyl acetate); IR (CH2CI2): bands at 3490, 3380,1780,1751,1677, cm-'.
Example 4: a) 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyliminoacetamino]-3-cephem-4-carboxylic acid 1 (ethoxyearbonyloxy)-ethyl ester A mixture of 0.75 g of 7,B-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3- cephem-4-carboxylic acid 1-(ethoxycarbonyloxy)-ethyl ester, 3.9 ml of trifluoroacetic acid and 3.9 ml of methylene chloride is stirred for 1 hour at room temperature, cold toluene is added and the solution is concentrated by evaporation under reduced pressure. A toluene-chloroform mixture is added to the residue, the whole is concentrated by evaporation, a toluene/ether mixture is added and concentration by evaporation is carried out once again. The residue is crystallised from ether.The trifluoroacetate of the title compound melts at 147C1 50 with decomposition; IR spectrum (Nujol): bands at 1790, 1745, 1730, 1670, 1640 and 1540 cm-l. The trifluoroacetate salt is taken up in ethyl acetate and washed twice with cold saturated sodium bicarbonate solution. After drying the organic phase over sodium sulphate, the solution is concentrated under reduced pressure. The residue is chromatographed (silica gel 60; methylene chloride/ethanol) and the title compound is obtained with an Bf value of 0.62 (silica gel 60; methylene chloride/ethanol 9:1).
b) 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid 1 -(ethoxycarbonyloxy)-ethyl ester The 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid 1 -(ethoxycarbonyloxy)-ethyl ester used as starting material can be manufactured as follows: 1.8 g of sodium iodide are added to a solution of 0.45 g of 1 -chloroethyl-ethyl carbonate in 10 ml of acetone. The mixture is stirred for 2 1/2 hours at room temperature and then a solution of 1.16 g of 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid and 0.38 g of 1 ,5-diazabicyclo[5,4,0]-undec-5-ene in 20 ml of acetone is added. The reaction mixture is stirred for 4 hours at room temperature, diluted with ethyl acetate and washed with saturated sodium chloride solution.The organic phase is dried over sodium sulphate and concentrated by evaporation under reduced pressure. The residue is purified by column chromatography (silica gel 60; methylene chloride/ethanol).
Example 5: a) The sodium salt of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid 5.5 g of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[2-(2-BOC-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester in 22 ml of methylene chloride are stirred at room temperature for 1 hour with 22 ml of trifluoroacetic acid and 3.9 ml of anisole; 200 ml of ice-cold toluene are added and the whole is concentrated by evaporation in vacuo.
After digesting the residue and drying in ether, the corresponding trifluoroacetic acid salt is obtained in the form of a yellowish powder. The salt is suspended in 50 ml of water and the pH is adjusted to 7.0 by adding 1 N NaOH solution. The cloudy solution is chromatographed over a column 4 cm in diameter filled with 400 ml of Amberlite XAD-2 adsorber resin. After eluting with 12% aqueous isopropanol solution, purifying the product-containing fractions that are uniform according to thin layer chromatography and lyophilising, the title compound is obtained. RF~0.2 (silica gel; n-butanol/glacial acetic acid/water; 67:10:23); IR (Nujol): inter alia 3330, 1770, 1667, 1606 cm-l: UV (H2O):AmaX=270 nm (15000).
b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z methoxyiminoacetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester 1.40 ml of oxalyl chloride in 42 ml of methylene chloride are added at approximately 10 to 1.26 ml of dimethylformamide in 14 ml of methylene chloride; the mixture is stirred for 45 minutes at .from --50 to --100 and then 3.99 g of 2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid and 1.96 ml of N-methylmorpholine are added.Stirring is continued for a further 30 minutes at from 5 to - 1 00. A solution prepared from 7.3 g of 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7ss-amino-3- cephem-4-carboxylic acid diphenylmethyl ester and 1.96 ml of N-methylmorpholine in 70 ml of methylene chloride is then added to this reaction mixture and the whole is allowed to react for 45 minutes at from 0 to 5 . For working up, the reaction mixture is concentrated, taken up in ethyl acetate and extracted by shaking in succession with 0.5N hydrochloric acid, saturated NaHCO3 solution and saturated sodium chloride solution.After drying over sodium sulphate and concentrating by evaporation, the crude product is obtained and chromatographed over 200 g of silica gel. After eluting with toluene and toluene solution with increasing portions of ethyl acetate (1 0%-25%) and concentrating by evaporation, the title compound is obtained in the form of a yellow foam. Rf~0.55 (ethyl acetate; silica gel); l(OH2Ol2):lntera,ia341O, 1793,1758,1730,1684, 1632 cm1;UV (EtOH): AmaX=261 nm (16200).
Example 6: a) The disodium salt of 3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl-7ss-[2-(2-amino-4 oxazolyl)-2-Z-methoxyiminoacetam ino]-3-cephem-4-carboxylic acid 3.5 g of 3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z methoxyiminoacetamino]-3-cephem-4-carboxylic acid are stirred at room temperature for one hour in 16.6 ml of methylene chloride and 1 6.6 ml of trifluoroacetic acid, and 100 ml of ice-cold toluene are added. The mixture is then concentrated by evaporation, the residue is digested with ether, filtered off and dried. The trifluoroacetic acid salt is suspended in water, the solution is adjusted to pH 7 and chromatographed over Amberlite XAD-2# adsorber resin.After eluting with water, combining the fractions that are uniform according to thin layer chromatography and lyophilising, the pure title compound is obtained. Rf~0.55 (silylated silica gel UPC12; water/acetonitrile; 95:5); IR (Nujol): inter alia 3325b, 1768, 1665, 1628 cm- ; UV (H2O) : #max=268 nm (14000).
b) The disodium salt of 3-( 1 -carboxymethyl-1 H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-BOC-amino- 4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid A solution of 1.1 5 ml of oxazolyl chloride in 13 ml of methylene chloride is added dropwise at -25 in the course of 10 minutes to 0.92 ml of dimethylformamide in 13 ml of methylene chloride; the mixture is stirred for 30 minutes at -25 and then a solution of 2.85 g of 2-(2-BOC-amino-4-oxazolyl)2-Z-methoxyiminoacetic acid and 1.34 ml of N-methylmorpholine in 28 ml of methylene chloride is added. Stirring is continued for a further 30 minutes at -25 (solution A).
A suspension of 4.48 g of 3-( 1 -carboxymethyl- 1 H-tetrazol-5-ylthiomethyl)-7ss-amino-3-cephem- 4-carboxylic acid in 40 ml of methylene chloride is stirred for 1.5 hours with 11.70 ml of bis (trimethylsilyl)-acetamide (BSA) at room temperature; 1.60 ml of N-methylmorpholine are added and the solution is cooled to -25 (solution B).
Solution B is added dropwise to solution A and the mixture is then allowed to react for three hours at room temperature. For working up, the reaction mixture is poured into ice-water, the pH is adjusted with 1 N sodium hydroxide solution to pH 7 and the aqueous phase is extracted by shaking three times with ethyl acetate. After separating the phases, the aqueous phase is extracted twice more with an ethyl acetate/acetone (4:1) mixture. The organic phases are combined, extracted by shaking with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained in the form of a brown powder. For purification, the crude product is chromatographed over 100 g of silica gel which has been deactivated beforehand by the addition of 5% water.After eluting with ethyl acetate containing 25% CH2Cl2, pure ethyl acetate, and ethyl acetate containing 10% acetone, the title compound is obtained. Rf~0.2 (silica gel; n-butanol/glacial acetic acid/water; 67:10:23).
Example 7: 3-11 -(2-dimethylaminoethyl)-l H-tetrazol-5-ylthiomethyl]-7,B-[2-(2-amino-4-oxazolyl)-2-Z- methoxyim inoacetamino]-3-cephem-4-carboxylic acid dihydrochloride 4.62 g of the sodium salt of 3-acetoxymethyl-7ss-p2-(2-amino-4-oxazolyl)-2-Z-methoxyimino- acetamino]-3-cephem-4-carboxylic acid (Example 1 a)) are added to a solution, heated to 700, of 29.96 g of a sodium iodide and 2.25 g of 1 -(2-dimethylaminoethyl)-1 H-tetrazol-5-yl mercaptan in 15 ml of water and 0.93 my of glacial acetic acid. The mixture is stirred for 75 minutes at 700 under a nitrogen atmosphere.The brown-coloured reaction solution is then poured into 200 ml of ice-water, adjusted to pH 5.5 with 1 N sodium hydroxide solution and chromatographed over a column filled with Amberlite XAD-2# adsorber resin. After eluting with water and an aqueous solution containing increasing proportions of isopropanol (5-1 5%) and combining the fractions that are uniform according to thin layer chromatography, the title compound and the corresponding 2-E compound are obtained. After again chromatographing over silylated silica gel (Opti UPC,2) and eluting with a water/acetonitrile (9:1) mixture, the title compound, which is uniform according to thin layer chromatography, and the corresponding 2-E compound are obtained and are each taken up in methylene chloride, treated with HCI-containing methylene chloride and added dropwise to ether. The precipitate formed is filtered off and dried. 2-Z compound: Bf""O.45 (silica gel OPTI UPC-12; H2O/acetonitrile; 4:1); IR (Nujol): inter alia 3320, 1782, 1718, 1680, 163Scm1;UV(H20):max=270 nm (14500); NMB (d-DMSO); oxazole-H at #=7.75, N-OCH3 at #=3.95. 2-E compound: Rf~0.25 (silica nel OPTI UPC-12; H20/acetonitrile; 4:1) IR (Nujol): inter alia 330, 1784, 1718, 1682, 1632 cm-'; UV (H2O): 270sh (6500); NMR (d-DMSO): oxazole-H at #=8.35. CH30-N at S=4.15.
Example 8: 3-(4carbamoyIpyridiniomethyI)-7-[2-(2-amino-4-oxazoIyl)-2-Z-methoxyiminoacetaminoi-3- cephem-4-carboxylate 3.46 g of the sodium salt of 3-acetoxymethyl-7j5-[2-(2-amino-4-oxazolyl)-2-Z-methoxyimino- acetamino]-3-cephem-4-carboxylic acid (Example 1 a)) are added to a solution, heated to 700, of 22.5 g of sodium iodide and 1.24 g of isonicotinamide in 11.25 ml of water and 0.43 ml of glacial acetic acid. The reaction mixture is stirred for one hour at 700 under a nitrogen atmosphere. After cooling, the brown-coloured reaction solution is adjusted to pH 5.2 with 1 N sodium hydroxide solution and chromatographed over a column filled with Amberlite XAD-2 adsorber resin.After eluting with a 12% aqueous isopropanol solution, combining the product-containing fractions that are uniform according to thin layer chromatography and lyophilising, the title compound is obtained in the form of a yellowish lyophilisate. Rf: 0.6 (silylated silica gel UPC12; water/acetonitrile; 4:1); IR (Nujol): inter alia 3340b, 1776, 1655, 1615 cm-'; UV (H2O): 212 nm (22300), 261 nm (15400).
Example 9: a) The sodium salt of 3-acetoxymethyl-7p-[2-(2-amino-4-oxazolyl)-2-Z-hydroxyimino- aceta mino]-3-cephem-4-carboxylic acid 4.2 g of 3-acetoxymethyl-7p-[2-(2-BOC-a mino-4-oxazolyl)-2-Z-(2-tetra hydropyranyloxyi mino)acetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester in 16 ml of methylene chloride are stirred for one hour at room temperature with 1 6.5 ml of trifluoroacetic acid and 2.8 ml of anisole, 100 ml of ice-cold toluene are added to the brown-coloured reaction mixture and the whole is concentrated by evaporation in vacuo. After drying and digesting the residue in ether, the corresponding trifluoroacetic acid salt is obtained in the form of a yellowish powder.The salt is suspended in 50 ml of water and the pH value is adjusted to 7.4 by adding 2N sodium hydroxide solution. The cloudy solution is chromatographed over a column 3.5 cm in diameter filled with Amberlite XAD-28 adsorber resin.
After eluting with a 12% aqueous isopropanol solution, combining the product-containing fractions that are uniform according to thin layer chromatography and lyophilising, the title compound is obtained. R;-0.45 (silylated silica gel OPTI-UPC12; water/acetonitrile; 4:1); IR (Nujol): interalia 3325b, 1770, 1665, 1608 cm-': UV (H20): 209 (20000); 260 (12200).
b) 3-acetoxymethyl-7P-[2-(2-BOC-am ino-4-oxazolyl)-2-Z-(2-tetrahydropyranyloxyimino) acetam ino]-3-cephem-4-carboxylic acid diphenyl methyl ester 1.0 ml of oxalyl chloride in 30 ml of methylene chloride is added at --50 to 0.9 ml of dimethylformamide in 40 ml of methylene chloride, the mixture is stirred for 20 minutes at from -5 to -100 and then 3.55 g of 2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-tetrahydropyranyloxyimino)-acetic acid and 1.4 ml of N-methylmorpholine are added. Stirring is continued for a further 30 minutes at --100.
A solution of 4.39 g of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.4 ml of N-methylmorpholine in 44 ml of methylene chloride is then added to the reaction mixture and the whole is allowed to react for 30 minutes at --50 and for 75 minutes at 00. For working up, the reaction mixture is concentrated, taken up in ethyl acetate and extracted by shaking in succession with 0.5N hydrochloric acid, saturated NaHCO3 solution and saturated sodium chloride solution. After drying over sodium sulphate and concentrating by evaporation, the crude product is obtained and chromatographed over 250 g of silica gel.After eluting with toluene and toluene solution with increasing portions of ethyl acetate (1 0%-50%), combining the product-containing fractions that are uniform according to thin layer chromatography and concentrating by evaporation, the title compound is obtained. Rf~0.5 (silica gel; ethyl acetate); IR (CH2CI2): inter alia 3410,1796,1748, 1683, 1631 cm-'; UV (EtOH): #max=258 nm (15100).
The starting materials are manufactured as follows: c) 2-(2-BOC-a mino-4-oxazolyl-2-Z-(tetrahydropyranyloxyimino)-acetic acid A solution of 11.66 g of potassium hydroxide in 100 ml of water, and 158 ml of ethanol are added in succession to a solution of 15.8 g of 2-(2-BOC-amino-4-oxazolyl)-2-Z-(2 tetrahydropyranyloxyimino)-acetic acid methyl ester in 1 58 ml of ethanol and the whole is stirred for 30 minutes at approximately 1 5 C. For working up, concentration is effected in vacuo, the aqueous phase is extracted twice with ethyl acetate, adjusted to pH 2.4 with 2N hydrochloric acid and the aqueous phase is extracted four times with an ethyl acetate/acetone (4:1 ) mixture.The combined organic phases are shaken with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is digested with hexane, filtered off and dried. The title compound is obtained in the form of a light yellow micro crystalline powder having a melting range of 122--1250.
d) 2-(2-BOC-amino-4-oxazolyl )-2-Z-(2-tetrahydropyranyloxyi mino)-acetic acid methyl ester 1.0 g of dimethylaminopyridine is added in portions to 1 8.4 g of 2-(2-amino-4-oxazolyl)-2-Z-(2tetrahydropyranyloxyimino)-acetic acid methyl ester and 44.7 g of di-tert.-butyl dicarbonate. The mixture is stirred at room temperature for 4 hours. For working up, the reaction mixture is diluted with ethyl acetate, extracted by shaking in succession with water, saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation.
After eluting with toluene and toluene solution with increasing portions of ethyl acetate (5%-i 0%) and combining the product-containing fractions that are uniform according to thin layer chromatography and concentrating by evaporation, the title compound is obtained. Ref~0.58 (silica gel; toluene/ethyl acetate; 1:1).
e) 2-(2-amino-4-oxazolyl)-2-Z-(2-tetrahydropyranyloxyimino)-acetic acid methyl ester 181.8 g of 4-bromo-2-Z-(2-tetrahydropyranyloxyimino)-acetic acid methyl ester are heated for 1 hour at 1000 in 900 ml of dimethylformamide and 354.4 g of urea. The reaction mixture is then poured into ice-water, salted out with sodium chloride and extracted four times with ethyl acetate. The combined organic extracts are extracted by shaking with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained in the form of a dark oil which is purified by chromatography over silica gel. After eluting with toluene/ethyl acetate (2:1 to 1:1), the uniform title compound is obtained and is crystallised from ether.
Melting range: 1 45 0--1 49 0 (with decomposition).
f) 4-bromo-2-Z-(2-tetrahydropyranyloxyimino)-acetoacetic acid methyl ester The crude 4-bromo-2-Z-hydroxyiminoacetoacetic acid methyl ester obtainable according to Example 1 g) is dissolved in 1.65 litres of dioxan and stirred for 1 5 hours at room temperature with 20.1 ml of 3,4-dihydro-2H-pyrane and 0.69 g of p-toluenesulphonic acid monohydrate. For working up, the reaction mixture is concentrated, the residue is taken up in ethyl acetate, extracted by shaking with water and saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. A dark red oil comprising the title compound is obtained. Ref~0.6 and 0.54 (silica gel, toluene/ethyl acetate 1:1).
g) 4-bromo-2-Z-hydroxyiminoacetoacetic acid methyl ester A solution of 50.9 ml of bromine in 200 ml of chloroform is added at 400 in the course of one hour to 2-Z-hydroxyiminoacetoacetic acid methyl ester in 550 ml of chloroform and then stirred for a further 1.5 hours at room temperature. For working up, the reaction mixture is extracted by shaking three times with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The crude title compound is obtained and is further processed directly without purification. (Example 9f). Ref~0.29 (silica gel; toluene/ethyl acetate; 1:1).
Example 10: a) The sodium salt of 3acetoxymethyI-7[2-(2-amino-4-oxazolyI)-2J-(2-carboxyprnp-2- yloxyimino)-acetaminoj-3-cephem-4-carboxylic acid 9.3 g of 3-acetoxymethyl-7-[2-(2-a mino-4-oxazolyl)-2-Z-(2-80C-prop-2-yloxyimino)- acetamino]-3-cephem-4-carboxylic acid in 10 ml of methylene chloride are stirred at room temperature for 75 minutes with 34 ml of trifluoroacetic acid and 5.8 ml of anisole; 200 ml of ice-cold toluene are added and the mixture is concentrated by evaporation in vacuo. After digesting the residue in ether and drying, a beige powder is obtained which is suspended in 50 ml of water.After adjusting the pH value to 7.5 with 1 N sodium hydroxide solution, the solution is chromatographed over a column 3 cm in diameter filled with 200 ml of Amberlite XAD-28 adsorber resin. After eluting with water, combining the product-containing fractions that are uniform according to thin layer chromatography and lyophilising, the title compound is obtained. Rf~0.23 ; (silica gel; n-butanol/glacial acetic acid/water; 67:10:23); IR (Nujol): 33SOb, 1770, 1668, 1600 cm-'; UV (H2O): may=264 nm (12700); 210 nm(sh).
b) 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxyimino) acetamino]-3-cephem-4-carboxylic acid A mixture of 2.5 g of 3-acetoxymethyl-7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2- yloxyimino)-acetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester, 25 ml of methylene chloride, 4.5 ml of trifluoroacetic acid and 0.48 ml of anisole is stirred at room temperature for 75 minutes, diluted with ice-cold toluene and concentrated by evaporation in vacuo. Digestion of the residue with ether, filtering off and drying yields the corresponding trifluoroacetic acid salt in the form of a beige powder. This powder is suspended in 10 ml of ice-cold methanol, and 2 ml of a 3-molar methanolic sodium α-ethyl hexanonate solution are added. After decanting the oily precipitate formed, the residue is digested in ether and an ether/hexane (1:1) mixture, filtered off and dried. The resulting crude product is chromatographed by means of thick layer chromatography over silylated silica gel plates (UPC,2, eluant: water/acetonitrile; 3:1). After eluting the product-containing zone with 50 ml of an acetonitrile/water (1:1) mixture, filtering through a millipore filter and concentrating by evaporation, the pure title compound is obtained and is dissolved and reprecipitated from an acetone/ether mixture.
Rf,-0.4 (silica gel; n-butanol/glacial acetic acid/water; 67:10:23); IR (Nujol): 3320b, 1 770sh, 1730, 1674, 1598 cm-'; UV (H2O): 210 nm(sh); 263 nm (10900).
c) 3-acetoxymethyl-7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino) acetamino]-3-cephem-4-carboxylic acid diphenylmethyl ester 1.0 ml of oxalyl chloride in 30 ml of methylene chloride is added at approximately --50 to 0.9 ml of dimethylformamide in 40 my of oxazolyl chloride, the mixture is stirred for 20 minutes at from --50 to -10" and then 3.55 g of 2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetic acid and 1.4 ml of N-methylmorpholine are added.The reaction mixture is stirred for a further 30 minutes at approximately 100, then a solution of 4.39 g of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.4 ml of N-methylmorpholine in 44 ml of methylene chloride is added and the whole is allowed to react for 30 minutes at --50 and for 75 minutes at 0 . For working up, the reaction mixture is concentrated, taken up in ethyl acetate and extracted by shaking in succession with 0.5N hydrochloric acid, saturated NaHCO3 solution and saturated sodium chloride solution. After drying over sodium sulphate and concentrating by evaporation, the crude product is obtained in the form of a brownish foam which is chromatographed over 250 g of silica gel.After eluting with toluene and toluene solution containing increasing proportions of ethyl acetate (10%-50%), combining the product-containing fractions that are uniform according to thin layer chromatography and concentrating by evaporation, the title compound is obtained. Rf,-0.52 (silica gel; toluene/ethyl acetate; 1:1); IR (CH2CI2): her alia 3420, 1800, 1745, 1690, 1633 cm-1; UV (EtOH): #max=258 nm (15400).
The starting materials are manufactured as follows: d) 2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyi mino)-acetic acid A solution of 7.08 g of KOH in 50 ml of water, and also 75 ml of ethanol are added to 10.55 g of 2-(2-bis-(BOC)-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetic acid methyl ester in 75 ml of ethanol. The mixture is stirred for one hour at room temperature. It is then concentrated in vacuo, adjusted to a pH value of approximately 1.6 with 4N hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases are extracted by shaking with water and aqueous saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. After crystallising the crude product, the title compound is obtained in the form of a light yellow powder.
Melting range: 1 400 to 1440 (with decomposition).
e) 2-(2-bis-( BOC)-a mino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetic acid methyl ester 0.9 g of 4-dimethylaminopyridine is added to 30.2 g of 2-(2-amino-4-oxazolyl)-2-Z-(2-BOCprop-2-yloxyimino)-acetic acid methyl ester suspended in 60.5 g of di-tert.-butyl dicarbonate and the mixture is stirred for one hour at room temperature. It is then diluted with ethyl acetate, extracted by shaking with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. After chromatographing the oily residue over 600 g of silica gel, eluting with toluene and toluene solution with increasing portions of ethyl acetate (2.5%5%) and concentrating by evaporation, the title compound, which is uniform according to thin layer chromatography, is obtained.
UV (C2H5OH) : #max=211 nm (10500) and 254 nm (9200) ; IR (CH2Cl2) : 1812, 1783, 1748, 1600, 1587 cm-.
f) 2-(2-a mino-4-oxazolyl-2-Z-(2-BOC-prop-2-yloxyimino)-acetic acid methyl ester While cooling with ice, a solution of 8.31 g of 2-(2-amino-4-oxazolyl)-2-Z-hydroxyiminoacetic acid methyl ester in 45 ml of dimethyl sulphoxide is added to a solution of 11.25 g of bromoisobutyric acid tert.-butyl ester and 1 6.2 g of potassium carbonate in 45 ml of dimethyl sulphoxide. The reaction mixture is then stirred for 18 hours at room temperature. For working up, the reaction mixture is poured into ice-water, extracted with ethyl acetate and the organic phase is extracted by shaking with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. After crystallising the residue from ether, the title compound is obtained in the form of yellowish crystals. Melting range: 1560--1600.
g) 2-(2-amino-4-oxazolyl)-2-Z-hydroxyiminoacetic acid methyl ester 26.9 g of 2-(2-amino-4-oxazolyl-2-Z-(2-tetrahydropyranyloxyimino)-acetic acid methyl ester in 300 ml of methylene chloride are stirred for two hours at room temperature with 300 ml of trifluoroacetic acid, then cold toluene is added and the whole is concentrated by evaporation in vacuo.
The residue is taken up in ethyl acetate, extracted in succession with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. After crystallising the oily residue from ether, the title compound is obtained. Melting range: 1510--1550 (with decomposition).
Example 11: The sodium salt of 3-pyridinomethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-carboxyprop-2 yloxyimino)-acetamino]-3-cephem-4-carboxylate 1.2 ml of glacial acetic acid, 1.1 5 ml of pyridine and 5.55 g of the sodium salt of 3acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl-2-Z-(2-carboxyprop-2-yloxyimino)-acetamino]-3-cephem-4carboxylic acid are added to a solution, heated to 700, of 30 g of sodium iodide in 1 6 ml of water. The mixture is stirred for 1.5 hours under a nitrogen atmosphere. After cooling, the pH value is adjusted to 5.1 by adding 1 N sodium hydroxide solution and the mixture is chromatographed over a column 4.5 cm in diameter filled with approximately 750 ml of Amberlite XAD-2(E) adsorber resin.After eluting with a 10% aqueous isopropanol solution, combining the producting-containing fractions that are uniform according to thin layer chromatography, digesting and concentrating by evaporation with acetone, the title compound is obtained in the form of a yellow powder.Rf~0.47 (silylated silica gel UPC12; water/acetonitrile; 6:1); IR (Nujol): inter alia 3345, 1770, 1665, 1 600b cm-'; UV (H20): imaX=255 nm (12000) Example 12: The sodium salt of 3-(4-carbamoylpyridinomethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2 carboxyprop-2-yloxyi mino)-acetamino]-3-cephem-4-carboxylate 1.1 6 g of isonicotinamide, 0.8 ml of glacial acetic acid and 3.88 g of the sodium salt of 3acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamino]-3-cephem-4carboxylic acid are added in succession to a solution, heated to 700, of 21 g of sodium iodide in 11 ml of water. The mixture is stirred for 1.5 hours under a nitrogen atmosphere.After cooling, the pH value is adjusted to 5.3 by adding 1 N sodium hydroxide solution and the mixture is chromatographed over a colum 4.5 cm in diameter filled with 650 ml of Amberlite XAD-2(b) adsorber resin. After eluting with water and combining the product-containing fractions that are uniform according to thin layer chromatography, concentrating by evaporation and digesting several times with acetone to remove isonicotinamide still present, the title compound is obtained. Rf~0.6 (silylated silica gel UPC12 ; water/acetonitrile; 6:1); IR (Nujol): inter alia 3320b, 1770, 1665, 1 600b cm-'; UV (H2O) AmaX 220 nm (18600) and 261 nm (15400).
Example 13: a) The sodium salt of 7p[2-(2-amino4-oxazolyl)-2J-(2-carboxyprnp-2-yloxyi mino)- acetamino]-3-cephem-4-carboxylic acid 3.04 g of 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetamino]-3- cephem-4-carboxylic acid diphenylmethyl ester, 1 5 ml of trifluoroacetic acid, 2.0 ml of anisole and 3.0 ml of methylene chloride are stirred for 1.5 hours at room temperature and then 100 ml of ice-cold toluene are added to the mixture and the whole is concentrated by evaporation in vacuo. After digesting and drying, the corresponding trifluoroacetic acid salt is obtained and is dissolved in 5 ml of methanol and then 3 ml of a 3-molar methanolic sodium methyl hexanoate solution are added.To complete precipitation, ether is added and the whole is filtered and then washed with ether. The resulting precipitate is dissolved in water, the pH value is adjusted to 7.5 with 1 N sodium hydroxide solution and the solution is chromatographed over a column 3.5 cm in diameter filled with 250 ml of Amberlite XAD-28 adsorber resin. After eluting with a 10% aqueous isopropanol solution, combining the product-containing fractions that are uniform according to thin layer chromatography and lyophilising, the title compound is obtained. Rf~0.25 (silica gel; n-butanol/glacial acetic acid/water; 67:10:23); IR (Nujol): 3350b, 1770, 1668b, 1595 cm-'; UV (H2O) AmaX 264 nm (9700).
b) The sodium salt of 7p-[2-(2-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetamino]- 3-cephem-4-carboxylic acid 5.0 g of 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetamino]-3- cephem-4-carboxylic acid diphenylmethyl ester in 50 ml of methylene chloride are stirred for three hours at room temperature under a nitrogen atmosphere with 1.05 ml of anisole and 6.25 ml of trifluoroacetic acid, 200 ml of ice-cold toluene are added and the mixture is concentrated by evaporation in vacuo. After digesting the residue and concentrating by evaporation, the corresponding trifluoroacetic acid salt is obtained which is suspended in SO ml of water, adjusted to a pH value of 7.3 with 1 N NaOH and chromatographed over a column filled with 500 ml of Amberlite XAD-20 adsorber resin. After eluting with water and an aqueous solution containing increasing proportions of isopropanol (5%50%), combining the product-containing fractions that are uniform according to thin layer chromatography, concentrating by evaporation and drying, the title compound is obtained.
Rf~0.44 (silica gel; n-butanol/glacial acetic acid/water; 67:10:23); IR (Nujol): inter alia 3340b, 1764, 1737,1668, 16OOcm1;UV(H20):2OSnm(2O800);262nm(100O0).
c) 7ss-[2-(2-BOC-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetamino]-3-cephem-4 carboxylic acid diphenylmethyl ester 1.35 ml of dimethylformamide and 1.5 ml of oxalyl chloride are allowed to react for 30 minutes at approximately -10 in 100 ml of methylene chloride; 6.2 g of 2-(2-BOC-amino-4-oxazolyl)-2-Z-(2 BOC-prop-2-yloxyimino)-acetic acid and 2.1 ml of N-methylmorpholine are added and the whole is reacted for a further 30 minutes at from 5 to --100. A solution of 5.5 g of 7p-amino-3-cephem-4- carboxylic acid diphenylmethyl ester and 2.1 ml of N-methylmorpholine in 55 ml of methylene chloride is then added to the reaction mixture and the whole is allowed to react for 30 minutes at 5. For working up, the reaction mixture is concentrated, taken up in ethyl acetate and extracted by shaking in succession with 0.1 N hydrochloric acid, saturated NaHC03 solution and saturated sodium chloride solution. After drying over sodium sulphate, the crude product is obtained and is chromatographed over 250 g of silica gel. After eluting with toluene and toluene solution containing increasing proportions of ethyl acetate (10%-20%), combining the product-containing fractions that are uniform according to thin layer chromatography and concentrating by evaporation, the title compound is obtained. Rf~0.55 (silica gel; toluene/ethyl acetate; 1:1); IR (CH2Cl2): 3418, 1800, 1758, 1733, 1685, 1632 cm-1; UV (EtOH): #max=260 nm (sh) (6700).
Example 14: a) 7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2)BOC-prop-2-yloxyimino)-acetamino]-3-cephem-4carboxylic acid pivaloyloxymethyl ester 0.8 g of the sodium salt of 7p-[2-(2-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)- acetamino]-3-cephem-4-carboxylic acid in 8 ml of dimethylformamide is allowed to react for 30 minutes at 0 with 0.4 ml of iodomethyl pivalate, is stirred while adding a phosphate buffer having a pH of 8 and is extracted with ethyl acetate. The organic phase is extracted by shaking with saturated NaHCO3 solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The crude product is chromatographed over 17 g of silica gel.After eluting with toluene and toluene solution containing increasing proportions of ethyl acetate (1 0%-50%), combining the product-containing fractions that are uniform according to thin layer chromatography and concentrating by evaporation, the title compound is obtained.
b) 7ss-[2-(2)-amino-4-oxazolyl)-2-Z-(2-BOC-prop-2-yloxyimino)-acetamino]-3-cephem-4pivaloyloxymethyl ester hydrochloride In order to convert into the hydrochloride, the pivaloyloxymethyl ester obtainable according to Example 14a) is dissolved in 5 ml of ether, 1.6 ml of 0.5N hydrochloric acid in methylene chloride are added and the whole is precipitated out with hexane. After filtering, dissolving and reprecipitating from ether/hexane (1:1) and drying, the title compound is obtained. Rf~0.39 (silica gel, ethyl acetate).
Example 15: 3-(3-chloropyridinomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3cephem-4-carboxylate 1.7 g of the sodium salt of 3-acetoxymethyl-7/3-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid and 0.21 ml of acetic acid are added to a solution, pre-heated to 700, of 11.25 g of sodium iodide and 560 mg of 3-chloropyridine in 5.6 ml of water. After stirring for one hour at 700 under a nitrogen atmosphere, the soiution is adjusted to pH 5.2 with 1 N sodium hydroxide solution and chromatographed over Amberlite ER-1808. The title compound is obtained having an Rf value of 0.69 (UPC,2 plates; water/acetonitrile; 4:1); UV (water): AmaX=215 nm (shoulder) and 265 nm (14000).
Example 16: The sodium salt of 3-(4-carboxylate-pyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2 methoxyiminoacetamino]-3-cephem-4-carboxylate 1.7 g of the sodium salt of 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid and 0.21 ml of acetic acid are added to a solution, pre-heated to 700, of 11.25 g of sodium iodide and 610 mg of isonicotinic acid in 5.6 ml of water. After stirring for one hour at 700 under a nitrogen atmosphere, the solution is adjusted to pH 7.2 with 1 N sodium hydroxide solution and chromatographed over Amberlite ER-180(!). The title compound is obtained having an Rf value of 0.75 (UPC,2 plates, water/acetonitrile; 4:1); UV (water): Amax=2 1 6 nm (21200) and 260 nm (13300).
Example 17: a) The sodium salt of 3-carbamoyloxymethyl-7,B-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid A solution of 4.5 g of 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3 carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of methylene chloride is stirred for 1 hour with 1 9.7 ml of trifluoroacetic acid and 3.3 ml of anisole; 250 ml of ice-cold toluene are added and the whole is concentrated by evaporation. After digesting the residue with ether, filtering off with suction and drying, the trifluoroacetic acid salt of the title compound is obtained in the form of a beige powder. It is suspended in 20 ml of water.The solution is adjusted to pH 7.2 with 1 N sodium hydroxide solution at 0 and chromatographed over Amberlite ER-180(!). The title compound is obtained having an Revalue of 0.77 (silica gel 60; n-butanol/acetic acid/water; 67:10:23); UV (water): Ajax 212 nm (18000) and 260 nm (12400).
b) 3-carbamoyloxymethyl-7ss-[2-(2-BOC-a m ino-4-oxazolyl )-2-Z-methoxyiminoacetamino-3- cephem-4-carboxylic acid diphenylmethyl ester Under a nitrogen atmosphere, a mixture of 1 ml of oxalyl chloride, 0.9 ml of dimethylformamide and 40 ml of methylene chloride is stirred for 30 minutes at approximately from -5 to -10 and then 2.85 g of 2-(2-tert.-butoxycarbonylamino-4-oxazolyl)-2-Z-methoxyiminoacetic acid and 1.4 ml of Nmethylmorpholine are added. After stirring for a further 30 minutes at this temperature, a solution of 4.39 g of 3-ca rba moyloxymethyl-7P-a mino-3-cephe m4-carboxylic acid diphenylmethyl ester and 1.4 ml of N-methylmorpholine in 45 ml of methylene chloride is added.The mixture is reacted for a further 30 minutes at approximately -5 and for a further 1 hour at 00. The reaction mixture is concentrated, the residue is taken up in ethyl acetate and extracted by shaking in succession with 1 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtering and concentrating by evaporation, the title compound is obtained in crude form. It is purified by column chromatography (silica gel 60; toluene/ethyl acetate) and melts at 700.
Example 18: 3-carbamoyloxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4carboxylic acid pivaloyloxymethyl ester 2.6 g of the sodium sa It of 3-ca rbamoyloxymethyl-7p-[2-(2-a mino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid are added at 0 to a solution of 2.3 g of iodomethyl pivalate in 15 ml of dimethylformamide and the whole is stirred for 3 hours at room temperature. The reaction mixtures is diluted with ethyl acetate, extracted by shaking in succession with 25 ml of water,10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo.The residue is purified by column chromatography (silica gel 60: methylene chloride/ethanol).
The title compound has an Rf value of 0.75 (silica gel 60; methylene chloride/ethanol; 9:1); IR (methylene chloride) : 790, 740, 1685, 1600 and 1525 cm-.
Example 19: 3-pyridiniomethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4carboxylate 1.7 g of the sodium salt of 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid and 0.21 ml of acetic acid are added to a solution, pre-heated to 700, of 11.25 g of sodium iodide and 0.4 g of pyridine in 5.6 ml of water. The mixture is stirred for 1 hour at 700, is adjusted to pH 5.2 with 1 N sodium hydroxide solution and chromatographed over Amberlite MZMB. The title compound is obtained having an Rf value of 0.25 (UPCa2 plates, water/acetonitrile 4:1); UV spectrum (water): #max=257 (13000).
Example 20: a) 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid tert.butoxycarbonylmethyl ester A mixture of 0.75 g of 7,l3-[2-(2-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3- cephem-4-carboxylic acid tert.-butoxycarbonylmethyl ester, 3.9 ml of trifluoroacetic acid and 3.9 ml of methylene chloride is stirred for 1 hour at room temperature, cold toluene is added and the whole is concentrated by evaporation under reduced pressure. This procedure is repeated with a toluene/chloroform mixture and a toluene/ether mixture. The residue is crystallised from ether. The trifluoroacetate salt of the title compound melts at 1 45--1 480 with decomposition; IR spectrum (Nujol) : bands at 1785, 1740, 1660, 1630, 1540 cm-.
The trifluoroacetate salt is taken up in ethyl acetate and washed twice with cold saturated sodium bicarbonate solution. After drying the organic phase over sodium sulphate, the solution is concentrated under reduced pressure. The residue is chromatographed (silica gel 60; methylene chloride/ethanol) and the title compound is obtained having an Rf value of 0.21 (silica gel 60; methylene chloride/ethanol 9:1).
b) 7ss-[2-12-BOC-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid tert.-butoxycarbonylmethyl ester 1.0 g of potassium phthalimide is added at 200 to a mixture of 2.3 g of 7ss-[2-(2-BOC-amino-4- oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid and 1 8 ml of N,Ndimethylacetamide. After cooling to 00, 1.33 g of iodoacetic acid tert.-butyl ester are added. After stirring for 30 minutes, 50 ml of ethyl acetate and 50 ml of water are added, the pH is adjusted to 7 with 1 N sodium hydroxide solution and the ester phase is separated off. Extraction is carried out again with ester, the combined ester phases are washed with saturated sodium chloride solution, dried and concentrated by evaporation under reduced pressure.The residue is purified by column chromatography (silica gel 60; methylene chloride/ethanol.
Example 21: 3-carbamoyloxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4carboxylic acid 1 -(ethoxycarbonyloxy)-ether ester A mixture of 1.76 g of 1-(1 -chloroethyl)-ethyl carbonate, 1.99 g of sodium iodide and 15 ml of absolute acetone is heated under reflux for 35 minutes. The acetone is distilled off under reduced pressure. The residue is partitioned between 25 ml of water and 25 ml of ether, the ether phase is separated off and washed with water and an aqueous sodium chloride solution. The ether solution is dried and concentrated by evaporation under reduced pressure.The 1 -(1 -iodoethyl)-ethyl carbonate which remains is dissolved in 5 ml of dimethylformamide and this solution is added to a solution of 1.15 g of the sodium salt of 3-carbamoylmethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid in 8 ml of dimethylformamide. The mixture is stirred for 1 hour at room temperature and then 50 ml of ethyl acetate are added. The organic phase is washed in succession with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The ethyl acetate phase is dried over magnesium sulphate and filtered. The solvent is distilled off under reduced pressure. The residue is purified by column chromatography (silica gel 60; methylene chloride/ethanol).The title compound has an Rf value of 0.47 (silica gel 60; methylene chloride/ethanol 9:1); IR spectrum (methylene chloride): bands at 1790, 1765, 1740, 1675, 1655, 1586 cm-'.
Example 22: 3-carbamoyloxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyi minoacetamino]-3-cephem-4carboxylic acid propionyloxymethyl ester 1.25 g of propionic acid iodomethyl ester are added at 0 to a solution of 2.3 g of the sodium salt of 3-carbamoyl-7p-[2-(2-a mino-4-oxazolyl)-2-Z-methoxyiminoaceta mino]-3-cephem-4-ca rboxylic acid in 15 ml of absolute dimethylformamide. After stirring for 2 hours at 00, the reaction mixture is diluted with 100 ml of ethyl acetate and washed in succession with water and saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over sodium sulphate, the solution is concentrated by evaporation under reduced pressure and the residue remaining is chromatographed (silica gel 60; methylene chloride/ethanol).In this manner the title compound is obtained having an Rf value of 0.47 (silica gel 60; methylene chloride/ethanol 9:1); IR spectrum (KBr): bands at 1785, 1735, 1660,1600 cm-'.
Example 23: In a manner analogous to that described in Examples 4a, 20a and 21 , the following esters can be manufactured: '3-carbamoyloxymethyl-7ss-12-(2-amino-4-oxazoiyl)-2-Z-methoxyiminoacetamino]-3-cephem-4- carboxylic acid 1-(propionyloxy)ethyl ester-IR (CH2CI2): 1790, 1760, 1740, 1675, 1655, 1520 cm-'; Rf: approximately 0.44 (silica gel, CH2CI2/EtOH 9:1)- 7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxylminoacetamino]-3-cephem-4-carboxylic acid 1 (propionyloxy)-ethyl ester-IR (CH2CI2): 1792, 1760, 1740, 1660, 1640, 1520 cm-'; Rf:: approximately 0.61 (silica gel, CH2CI2/EtOH 9:1)- 3-(1 -methyl- 1 H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-am ino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid 1 -(propionyloxy)-ethyl ester-IR (CH2CI2): 790, 1765, 1742, 1678, 1655, 1785 cm-1; Rf: approximately 0.23 (silica gel, CH2CI2/EtOH 9:1)- 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester-IR (CH2CI2) : 1785, 1740, 1670, 1620, 1520 cm~1; Rf: approximately 0.38 (silica gel, CH2CI2/EtOH 9::1)- 7ss-[2-(2-amino-4-oxazolyl)-2-hydroxyiminoacetamino]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester-IR (CH2CI2): 1790, 1745, 1675, 1625, 1548 cm-'; R,: approximately 0.42 (silica gel, CH2CI2/EtOH 9:1)- 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Zmethoxyiminoacetamino]-3-cephem-4-carboxylic acid 1-(ethoxycarbonyloxy)-ethyl ester -IR (CH2Cl2) : 1785, 1745, 1673, 1620, 1545 cm- ; Rf : approximately 0.28 (silica gel, CH2Cl2/EtOH 9:1) 7ss-[2-(2-amino-4-oxazolyl)-2-hydroxyiminoacetamino]-3-cephem-4-carboxylic acid 1 (ethoxycarbonyloxy)-ethyl ester-IR (CH2CI2): 1788, 1762, 1740, 1672, 1640, 1555 cm-'; Rf: approximately 0.38 (silica gel, CH2Cl2/EtOH 9:1).
Example 24: In a manner analogous to that described in Examples 1-3 and 5-19, the following compounds can be obtained using suitable starting materials: The sodium salt of 3-(1 ,3,4-thiadiazol-5-ylthiomethyl)-7p-[2-(2-amino-4-oxazOiyl)2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid-UV (#max) : 215 (16800). 257 (13200) nm ; Rf : approximately 0.78 (UPC12 plates, H2O/CH3CN) The sodium salt of 3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7ss-[2-(2 amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid -UV (#max) : 218 (17400), 265 (14200) nm; Rf: approximately 0.63 (UPC,2 plates, H20/OH3CN)- 3-(4-hydroxymethylpyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino] 3-cephem-4-carboxylate-UV (#max) : 216 (s), 262 (13800) nm; Rf: approximately 0.72 (UPC,2 plates, H20/OH3CN)- The sodium salt of 3-carbamoyloxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z- hydroxyiminoacetamino]-3-cephem-4-carboxylic acid-UV (#max) : 21 (18100), 260 (13400) nm ;Rf approximately 0.68 (UPC,2 plates, H20/CH3CN)- The sodium salt of 7ss-[2-amino-4-oxazolyl-2-hydroxyiminoacetamino]-3-cephem-4-carboxylic acid-UV (may) 207 (17400), 261 (12800) nm; Rf: approximately 0.72 (UPC,2 plates, H20/CH3CN)- The sodium salt of 3 (1 methyl 1H tetrazol 5 ylthiomethyl) 7ss-[2-(2-amino-4-oxazolyl)-2hydroxyiminoacetamino]-3-cephem-4-carboxylic acid-UV (#max) : 216 (s), 264 (14400) nm ; Rf : approximately 0.63 (UPC,2 plates, H20/CH3CN)- The sodium salt of 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-aminoethoxyimino)- acetamino]-3-cephem-4-carboxylic acid-UV (#max) : 213 (15800), 262 (13600) nm; Rf : approximately 0.65 (UPC,2 plates, H20/CH3CN)- The sodium salt of 3-acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-hydroxyethoxyimino)- acetamino]-3-cephem-4-carboxylic acid-UV (#max) : 212 (16200), 260 (13500) nm; Rf : approximately 0.68 (UPC,2 plates, H20CH3CN).
Example 25 Dry ampoules or phials containing 0.5 g of active ingredient, for example 3-acetoxymethyl-7ss-[2- (2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid, can be manufactured as follows: Composition (for 1 ampoule or phial): active ingredient 0.5 g mannitol 0.05 g A sterile aqueous solution consisting of the active ingredient and the mannitol is filled under aseptic conditions into 5 ml ampoules or 5 ml phials and these are then sealed and examined.

Claims (54)

Claims
1. 7ss-Aminooxazolylacetamino-3-cephem-4-carboxylic acid compounds of the formula
in which n is an integer of from 0 to 2, A represents carbonyl, methylene, or a methylene group that is substituted by amino, protected amino, hydroxy, protected hydroxy, sulpho, protected sulpho or by a group of the formula =N-O-R4 in which R4 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, carbamoyl or substituted carbamoyl, R1 represents hydrogen, lower alkyl, lower alkoxy, halogen, or a group of the formula -CH2-R2 in which R2 represents hydroxy, mercapto, esterified hydroxy or mercapto, etherified hydroxy or mercapto, or an ammonio group, and R3 represents carboxy or protected carboxy, hydrates and salts of compounds of the formula I.
2. 7ss-Aminooxazolylacetamino-3-cephem-4-carboxylic acid compounds of the formula I according to claim 1 in which n represents an integer of from 0 to 2, A represents carbonyl or a methylene group that is substituted by amino, protected amino, hydroxy, protected hydroxy, sulpho, protected sulpho or by a group of the formula =N--OO-R, in which R4 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, carbamoyl or substituted carbamoyl, and R1, R2 and R3 have the meanings given in claim 1, hydrates and salts of these compounds.
3. 7/3-Aminooxazolyiacetamino-3-cephem-4-carboxylic acid compounds of the formula I according to claim 1 in which n represents an integer of from 0 to 2, A represents carbonyl or a methylene group that is substituted by amino, protected amino, hydroxy, protected hydroxy, sulpho, protected sulpho or by a group of the formula =N--OO-R, in which R4 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, carbamoyl or substituted carbamoyl, and R1, R2 and R3 have the meanings given in claim 1, hydrates and salts of these compounds.
4. Compounds according to claim 1 of the formula I in which n represents 0, R1 represents hydrogen, lower alkyl, lower alkoxy, halogen, or a group -CH2-B2 in which R2 represents lower alkanoyloxy; carbamoyloxy; N-lower alkylcarbamoyloxy; an aromatic monocyclic five- or six-membered diaza, triaza-, tetraaza-, thiaza-, thiadiaza-, thia-, oxaaza or oxadiazacyclyl radical, which may be substitued by lower alkyl, di-lower alkylamino-lower alkyl, sulpho-lower alkyl, carboxy-lower alkyl, amino, carboxy-lower alkylamino, or by carbamoyl; or ammonio;R3 represents carboxy or carboxy that can be cleaved under physiological conditions; and A represents amino, aminomethylene, hydroxymethylene, sulphomethylene, or a methylene group substituted by a group of the formula -N-OR4 in which R4 represents hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl, carbamoyl, lower alkylcarbamoyl or amino-lower alkyl, wherein the group of the formula -0-R4 is in the syn- or (Z-) position, and salts of compounds of the formula I having saltforming groups.
5. Compounds according to claim 4 of formula I in which n represents 0, R1 represents hydrogen, methyl, methoxy, chlorine, or a group -CH2-R2 in which R2 represents acetoxy; carbamoyloxy; Nlower alkyl-carbamoyloxy; triazolylthio; tetrazolylthio; thiazolylthio; thiadiazolylthio; oxazolylthio; oxadiazolylthio or 5,6-dioxotetrahydro-as-triazinylthio which aromatic radicals may be substituted by lower alkyl, di- lower-alkylamino-lower alkyl, sulpho-lower alkyl, carboxy-lower alkyl, amino, carboxylower alkylamino or by carbamoyl; 2-lower alkyl-1 -pyrazolio, 2-carboxy-lower alkyl-1 -pyrazolio, 3lower alkyl-1 -triazolio, pyridinio, pyridinio substituted by hydroxy-lower alkyl, carboxy, carboxy-lower alkyl, halogen, or by carbamoyl;R3 represents carboxy, acyloxy-lower alkoxycarbonyl or lower alkoxycarbonyloxy-lower aikoxycarbonyl; and A represents amino, amino-methylene, hydroxymethylene, sulphomethylene, or a methylene group substituted by a group of formula =N--OO-R, in which R4 represents hydrogen, methyl, 2-hydroxyethyl, 2-aminoethyl, 2-carboxy-2-propy carbamoyl, methylcarbamoyl, 2-aminoethyl, wherein the group -0-B4 is in the syn- or (Z-) position and salts of compounds of the formula I having salt-forming groups.
6. Compounds according to claim 5 of formula I in which R1 represents hydrogen, methyl, methoxy, chlorine, or a group -CH2-B2 in which R2 is acetoxy, carbamoyloxy, N-lower alkylcarbamoyloxy, 1 H-1 ,2,3-triazol-5-ylthio, 1 H-tetrazol-5-ylthio, 1 ,3,4-thiadiazol-5-ylthio, 5,6-dioxo 1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6-dioxo-1 ,4,5,6-tetrahydro-as-triazin-3-ylthio which aromatic radicals may be substituted by methyl, dimethylaminomethyl or 2-dimethylaminoethyl, sulphomethyl, carboxymethyl, 2-carboxyethylamino or by carbamoyl; 2-methyl-1-pyrazolio, 2carboxymethyl-1-pyrazolio, 3-methyl-1-tnazolio, pyridinio, pyridinio substituted by hydroxymethyl, carboxy, carboxymethyl, chlorine, bromine or by carbamoyl;R3 represents carboxy, lower alkanoyloxylower alkoxyca rbonyl, 1 -(ethoxycarbonyloxy)ethoxycarbonyl or tert.-butoxyca rbonyloxymethoxy carbonyl; and n and A are as defined in claim 5; and salts of compounds of formula I having saltforming groups.
7. Compounds according to claim 6 of formula I in which n and A are as defined in claim 6 and R, represents hydrogen, methyl, methoxy, chlorine or a group -CH2-R2 in which R2 is acetoxy, carbamoyloxy, N-lower alkylcarbamoyloxy, 1 H-1 ,2,3-triazol-5-ylthio, 1 H-tetrazol-5- ylthio, 1,3,4thiadiazol-5-ylthio, 5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio, or 5,6-dioxo-1 ,4,5,6-tetrahydro- as-triazin-3-ylthio which aromatic radicals may be substituted by methyl, dimethylaminomethyl or 2dimethylaminoethyl, sulphomethyl, carboxymethyl, 2-carboxyethylamino or by carbamoyl; 3- or 4hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio 3or 4-bromopyridinio or 3- or 4-carbamoylpyridinio;R3 represents carboxy or lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethoxycarbonyl; and salts of compound of formula I having salt forming groups.
8. Compounds according to claim 7 of formula I in which n, A, B1 and R2 are as defined in claim 7 and R3 represents carboxy, pivaloyloxymethoxycarbonyl or 2-(propionyloxy)-ethoxycarbonyl; and salts of compounds of formula I having salt-forming groups.
9. Compounds according to claim 2 of the formula I in which n, A, R1, R2 and R4 have the meanings given in claim 4 and R3 represents carboxy or acyloxy-methoxycarbonyl, or lower alkoxycarbonyloxy-lower alkoxycarbonyl; and salts of these compounds.
10. Compounds according to claim 9 of formula I in which n, A, R1, R2 and R4 are as defined in claim 9 and B3 is carboxy, lower alkanoyloxymethoxycarbonyl or 1 -(ethoxycarbonyloxy)ethoxycarbonyl; and salts of these compounds.
11. Compounds according to claim 10 of the formula I in which n, A,R1, R2 and Rq have the meanings given in claim 10 and R3 represents carboxy, pivaloyloxymethoxycarbonyl or 1 (ethoxyca rbonyloxy)-ethoxycarbonyl; and sa Its of these compounds.
12. Compounds according to claim 4 of the formula I in which n represents 0, R1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2-B2 in which R2 represents lower alkanoyloxy; carbamoyloxy; triazolylthio; tetrazolylthio; tetrazolylthio substituted by lower alkyl, dilower alkylamino-lower alkyl, sulpho-lower alkyl, carboxy-lower alkyl, or by carbamoyl: thiadiazolylthio; thiadiazolylthio substituted by lower alkyl; 5,6-dioxotetrahydrotriazin-3-ylthio substituted by lower alkyl; pyridinio; or pyridinio substituted by hydroxy-lower alkyl, carboxy, carboxy-lower alkyl, halogen or by carbamoyl:R3 represents carboxy, or carboxy that can be cleaved under physiological conditions; and A represents a methylene group substituted by a group of the formula =N-0-B4 in which R4 represents hydrogen, lower alkyl, carboxy-lower alkyl, carbamoyl or lower alkylcarbamoyl, wherein the group of the formula -0-B4 is in the syn- (orZ-) position; and salts of compounds of the formula I having salt-forming groups.
1 3. Compounds according to claim 1 2 of the formula I in which n represents 0; R1 represents hydrogen, methyl, methoxy, chlorine or a group -CH2-B2 in which R2 represents acetoxy; carbamoyloxy; l-H-l .2,3-triazol-5-ylthio; 1 -H-tetrazol-5-yl-thio; 1 -H-tetrazol-5-yl-thio substituted by methyl, 2-dimethylaminoethyl, sulphomethyl, carboxymethyl or carbamoyl; 1 ,3,4-thiadiazol-5-ylthio; 1 ,3,4-thiadiazol-5-ylthio substituted by methyl; 5,6-dioxotetrahydrotriazin-3-ylthio substituted by methyl; pyridinio, or pyridinio substituted by hydroxymethyl, carboxy, carboxymethyl, chlorine, bromine or by carbamoyl; B3 is carboxy or acyloxy-lower alkoxycarbonyl or lower alkoxycarbonyloxy-lower alkoxycarbonyl; and A represents a methylene group substituted by a group of formula =N-0-B4 in which R4 represents hydrogen, methyl, 2-carboxy-2-propyl, carbamoyl or methylcarbamoyl wherein the group of formula -0-R4 is in the syn- (orZ-) position; and salts of compounds of formula I having salt-forming groups.
14. Compounds according to claim 1 3 wherein B1 is hydrogen, methyl, methoxy, chlorine or a group -CH2-R2 in which R2 represents acetoxy, carbamoyloxy, l-H-l ,2,3-triazol-5-ylthio, 1-methyl 1 H-tetrazol-5-ylthio, 1 -sulphomethyl-1 H-tetrazol-5-ylthio, 1 -carboxymethyl-1 H-tetrazol-5-ylthio, or 1 (2-dimethyla minoethyl)-l H-tetrazol-5-ylthio; 1 ,3,4-thiadiazol-5-ylthio, or 2-methyl-l ,3,4-thiadiazol-5ylthio; 2-methyl-5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo-l ,4,5,6- tetrahydro-as-triazin-3-ylthio; pyridinio; 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4 carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3- or 4-carbamoylpyridinio; R3 represents carboxy or lower alkanoyloxy-lower alkoxycarbonyl, 1 -(ethoxycarbonyloxy)- ethoxycarbonyl or tert.butoxycarbonyloxy-methoxycarbonyl; and n and A are as defined in claim 9; and salts of compounds of formula I having salt-forming groups.
1 5. Compounds according to claim 14 of formula I wherein n, A, R1 and R2 are as defined in claim 1 4 and B3 is carboxy, pivaloyloxymethoxycarbonyl or 2-(propionyloxy)-ethoxycarbonyl; and salts of formula I having salt-forming groups.
16. Compounds according to claim 9 of the formula I in which n, A, R1, R2 and R4 have the meanings given in claim 1 2 and R3 represents carboxy, lower alkanoyloxymethoxycarbonyl or lower alkoxycarbonyl-oxy-lower alkoxy-carbonyl; and salts of these compounds.
1 7. Compounds according to claim 1 6 wherein R3 represents carboxy, pivaloyloxymethoxycarbonyl or 1 -(ethoxycarbonyloxy)-ethoxycarbonyl; and salts of these compounds.
18. Compounds according to claim 11 of the formula I in which n, A, R,, R2 and R4 have the meanings given in claim 12, and R3 represents carboxy, pivaloyloxymethoxycarbonyl or 1 (ethoxycarbonyloxy)-ethoxycarbonyl; and salts of these compounds.
1 9. Compounds according to claim 1 2 of the formula I in which n represents 0, B1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2R2 in which R2 represents lower alkanoyloxy, carbamoyloxy; tetrazolylthio; tetrazolylthio substituted by lower alkyl, di-lower alkylamino lower alkyl, sulpho-lower alkyl, or by carboxy-lower alkyl; thiadiazolylthio: thiadiazolylthio substituted by lower alkyl; 5,6-dioxo-tetrahydro-as-triazinylthio substituted by lower alkyl; pyridinio; or pyridinio substituted by hydroxy-lower alkyl, carboxy, carboxy-lower alkyl, halogen or by carbamoyl: R3 represents carboxy, lower alkanoyloxy-lower alkoxycarbonyl, or lower alkoxycarbonyloxy-lower alkoxycarbonyl and A represents a methylene group substituted by a group of the formula =N-O-B4, in which R4 represents lower alkyl, carboxy-lower alkyl, carbamovl or lower alkylcarbamoyl, wherein the group of the formu la --OO-R, is in the syn- (orZ-) position; and salts of compounds of the formula I having salt-forming groups.
20. Compounds according to claim 1 9 of formula I in which n represents 0, B1 represents hydrogen, methyl, methoxy, chlorine, or a group -CH2-2 in which R2 represents acetoxy, carbamoyloxy, 1 H-tetrazol-5-ylthio, 1 H-tetrazol-5-ylthio substituted by methyl, 2dimethylaminoethyl, sulphomethyl, or carboxymethyl; 1 ,3,4-thiadiazol-5-ylthio or 2-methyl-1,3,4thiadiazol-5-ylthio; 2-methyl-5,6-dioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo 1 ,4,5,6-tetrahydro-as-triazin-3-ylthio; pyridinlo; pyridinio substituted by hydroxymethyl, carboxy, carboxymethyl, chlorine, bromine, or carbamoyl;R3 is carboxy, lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethoxycarbonyl; and A represents a methylene group substituted by a group of formula =N-O-B4 in which R4 is methyl, 2-carboxy-2-propyl, carbamoyl or methylcarbamoyl wherein the group of formuia-O-R4 is in the syn- (or Z-) position; and salts of compounds of formula I having salt-forming groups.
21. Compounds according to claim 20 of the formula I in which n, A, B 2and R4 have the meanings given in claim 19 and R3 represents carboxy, lower alkanoyloxy-methoxycarbonyl or lower alkoxycarbonyloxy-lower alkoxycarbonyl; and salts of these compounds.
22. Compounds according to claim 21 of the formula I in which n, A, R,, R2 and R4 have the meanings given in claim 19 and R3 represents carboxy, pivaloyloxymethoxycarbonyl or 1 (ethoxycarbonyloxy)-ethoxycarbonyl; and salts of these compounds.
23. Compounds of formula I according to any of the preceding claims wherein the salts are pharmaceutically acceptable salts.
24.3-Acetoxymethyl-7ss-[2-(2-amino-4-oxazol6yl)-2-Z-methoxyiminoacetamino]-3-cephem-4carboxylic acid according to claim 19.
25. 7ss-[2-(2-Amino-4-oxazolyl)-2Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 19.
26. The sodium salts of compounds according to claim 24 or 25.
27. 3-(1-Methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Zmethoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 21.
28. 3-( 1 -Carboxymethyl-1 H-tetrazol-5-ylthio-methyl )-7,B-[2-(2-amino-4-oxazolyl-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 21.
29. 3-[1 -(2-Dimethylaminoethyl)-1 H-tetrazol-5-ylthiomethyl]-7,B-[2-(2-a mi no-4- oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 21.
30. 3-[1 -(2-Dimethylaminoethyl)-1 H-tetrazol-5-ylthiomethyl]-7/3-[2-(2-amino-4-oxazolyl)-2-E- methoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 21.
31. 3-(4-Carbamoylpyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]3-cephem-4-carboxylate according to claim 21.
32. 3-Acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-hydroxyiminoacetamino]-3-cephem-4carboxylic acid according to claim 21.
33.3-Acetoxymethyi-7p-[2-(2-am ino-4-oxazolyl)-2-Z-(2-ca rboxyprop-2-yloxyimino)-acetamino]3-cephem-4-carboxylic acid according to claim 21.
34. 3-Acetoxymethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-(2-tert.-butoxycarbonylprop-2 yloxyimino)-acetaminoj-3-cephem-4-carboxylic acid according to claim 21.
35. 3-(3-Chloropyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3cephem-4-carboxylate according to claim 21.
36. The sodium salt of 3-(4-carboxylatepyridiniomethyl)-7ss-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylate according to claim 21.
37. The sodium salt of 3-carbamoyloxymethyl-7,B-[2-(2-amino-4-oxazolyl)-2-Z- methoxyiminoacetamino]-3-cephem-4-carboxylic acid according to claim 21.
38. The sodium salts of compounds according to claims 27, 28, 32, 34, 36 or 37.
39. Teh mono
39. The mono- or di-hydrochlorides of compounds according to claim 29 or 30.
40. 3-Pyridiniomethyl-7ss-[2-(2-amino-4-oxazolyl)-2-Z-methoxyiminoacetamino]-3-cephem-4carboxylate according to claim 22.
41. 7P-[2-(2-Amino-4-oxazolyl)-2-Z-methoxyim acid tert.butoxycarbonyl methyl ester according to claim 22.
42. 3-Carbamoyloxymethyl-7P-[2-(2-amino-4-ox cephem-4-carboxylic acid 1 -(ethoxycarbonyloxy)-ethyl ester according to claim 22.
43. Compounds of formula I substantially as described with reference to any of Examples 1 to 24.
44. Process for the manufacture of 7,3-aminooxazolylacetamino-3-cephem-4-carboxylic acid compounds of the formula I according to claim 1, in which n, R,, R2, R3, A and R4 have the meanings given in claim 1, hydrates and salts of these compounds, characterised in that a) in a compound of the formula
in which n, R, and R3 have the meanings given under formula I, and the 7,5-amino group is in free form or is protected by a group that permits acylation, and in which functional groups present in R, are protected, or in a salt thereof, the 7amino group is acylated by reaction with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula
in which A has the meanings given under formula I and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in A are optionally protected, or with a salt thereof, or b) for the manufacture of a compound of the formula I in which n represents 0, a 2-cephem compound of the formula
in which R,, R3 and A have the meanings given under formula I, and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in R, and A are optionally protected, or a salt thereof, is isomerised to form the corresponding 3-cephem compound, or c) a compound of the formula
in which n, R,, R3 and A have the meanings given under formula I and X represents halogen, and functional groups present in R, and A are optionally protected, or a salt thereof, is condensed with urea, or d) for the manufacture of a compound of the formula I in which A represents methylene substituted by hydroxyimino, a compound of the formula
in which n, R, and R3 have the meanings given under formula I and the amino group in the 2-position of the oxazolyl radical as well as functional groups present in R, are optionally protected, or a salt thereof, is treated with a nitrosating agent, and, if desired, a resulting compound of the formula I is converted into a different compound of the formula I and/or a resulting comnound in which n represents 0 is converted into a compound in which n represents 1 or 2, and/or a resulting compound in which n represents 1 or 2 is converted into a compound in which n represents 0 and/or functional groups present in protected form in a resulting compound are converted into free functional groups and/or a resulting salt is converted into the free compound or into a different salt and/or a resulting free compound is converted into a salt and/or a resulting mixture of isomers is separated into the individual isomers.
45. Process according to claim 44 substantially as described with reference to any of Examples 1 to 24.
46. Compounds of formula I when produced by a process claimed in claim 44 or 45.
47. Pharmaceutical preparations containing compounds of the formula I according to claim 1, hydrates or pharmaceutically acceptable salts of such compounds.
48. Pharmaceutical composition according to claim 47 substantially as described with reference to Example 25.
49. Compounds of the formula I according to claim 1 for use in the treatment of bacterial infections in the human or animal body.
50. Carboxylic acids of the formula
in which A represents carbonyl, methylene or a methylene group that is substituted by amino, protected amino, hydroxy, protected hydroxy, sulpho, protected suipho or by a group of the formula =N-0-B4 in which R4 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, carbamoyl or substituted carbamoyl, and in which the amino group, and also functional groups present in A, are optionally protected, reactive functional derivatives and salts thereof.
51. 2-(2-Amino-4-oxazolyl)-2-Z-methoxyiminoacetic acid, in which the amino group is optionally protected, according to claim 50.
52. 2-(2-Amino-4-oxazolyl)-2-hydroxyiminoacetic acid, in which the hydroxy and/or the amino group are optionally protected, according to claim 50.
53. 2-(2-Amino-4-oxazolyl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetic acid, in which the carboxy and/or the amino group are optionally protected, according to claim 50.
54. Process for the manufacture of carboxylic acids of the formula III in which A has the meaning given in claim 50, and of reactive functional derivatives and salts thereof, characterised in that a compound of the formula
in which X represents halogen and A has the meanings given under formula I and the carboxy group is present in esterified form or is protected by a customary carboxy-protecting group, is reacted with urea and, if desired, in a resulting compound the carboxy-protecting group is removed and/or the amino group in the 2-position of the oxazolyl radical is protected and/or a functional group in A is protected and/or the group A is converted into a different group A.
GB08227774A 1981-09-30 1982-09-29 Aminooxazolyl compounds Expired GB2106519B (en)

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US4698338A (en) * 1986-02-19 1987-10-06 Eli Lilly And Company 7[2-(2-aminothiazol-4-yl)-2-benzyloximino]acetamido-3[4-alkyl-5-oxo-6-hydroxy-3,4-dihydro-1,2,4-triazin-3-yl]thiomethyl cephalosporins
HUT53892A (en) * 1989-04-07 1990-12-28 Technologishen Kom Za Promy Mi Process for producing synaminothiazolyl and synaminooxazolyl derivatives
US20110118462A1 (en) * 2009-11-18 2011-05-19 Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory N-heterocyclic substituent-containing antibiotic, preparation and use thereof

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GB1399086A (en) * 1971-05-14 1975-06-25 Glaxo Lab Ltd Cephalosporin compounds
CA1088049A (en) * 1975-06-03 1980-10-21 Takashi Masugi 3-substituted-7-substituted alkanamido-3-cephem-4- carboxylic acid compounds and processes for preparation thereof
US4382932A (en) * 1981-09-08 1983-05-10 Eli Lilly And Company Isoquinolinium substituted cephalosporins
US4430499A (en) * 1981-09-08 1984-02-07 Eli Lilly And Company 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido]cephalosporin antibiotics
US4382931A (en) * 1981-09-08 1983-05-10 Eli Lilly And Company 3'-Substituted quinolinium cephalosporins
US4388316A (en) * 1981-10-02 1983-06-14 Eli Lilly And Company Amino-substituted oxazole, oxadiazole and isoxazole-substituted cephalosporins
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