CH605994A5 - 7-Alpha-methoxy-penicillanic and cephalosporanic acid derivs - Google Patents

Abstract

7-Alpha-methoxy-penicillanic and cephalosporanic acid derivs with broad-spectrum antibacterial activity

Description

  

  
 



   The present invention relates to a process for the preparation of methoxylated aminomethyl heterocycles, in particular 6P-acylamino-6a-methoxy-penam-3-carhonic acid compounds and 7p-acylamino-7-methoxy-3-cephem4-carboxylic acid compounds of the formula
EMI1.1
 wherein X represents sulfur or oxygen, and wherein the grouping of the formula -S-A- is a radical of the formula
EMI1.2
 means in which R1 represents hydrogen or a radical of the formula -CH2-R2, in which R2 represents hydrogen, a free, etherified or esterified hydroxyl or mercapto group or a quaternary ammonium group, and R is hydroxyl or together with the carbonyl group -C (= O ) - represents an esterified carboxy group which is cleavable under physiological conditions, and salts thereof, and their further use.



   The radical X in the five-membered heterocycle is primarily sulfur, but can also be oxygen. The aminomethyl heterocycle therefore represents a 4- or 5-aminomethyl-2- or -3-thienyl radical, furthermore also a 3-aminomethyl-2thienyl or 2-aminomethyl-3-thienyl radical, or a corresponding furyl radical, for example the 4th - Or 5-aminomethyl-2-furyl radical.



   An etherified hydroxyl or mercapto group R2 is, for example, a hydroxyl or mercapto group etherified by a lower aliphatic hydrocarbon radical.



  An etherified mercapto group R2 can also be a mercapto group etherified by an optionally substituted heterocyclic radical having 1 to 4 ring nitrogen atoms and bonded to the sulfur via a ring carbon atom and optionally a further ring hetero atom from the group oxygen and sulfur.



   An esterified hydroxy or mercapto group R2 is esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid esterified hydroxyl or mercapto group.



   Quaternary ammonium groups R2 are derived from tertiary organic bases, preferably from corresponding aliphatic amines or primarily from corresponding heterocyclic nitrogen bases, which are linked via the nitrogen atom to the methyl carbon atom, quaternary ammonium group.



   Hydroxy and mercapto groups R2 etherified with an aliphatic hydrocarbon radical are, in particular, lower alkoxy, preferably having up to 7, in particular having up to 4 carbon atoms, primarily methoxy, and also ethoxy, n-propyloxy or isopropyloxy, furthermore straight-chain or branched butyloxy, pentyloxy, hexyloxy or heptyloxy, or lower alkylthio, preferably with up to 7, in particular with up to 4 carbon atoms, primarily methylthio, and also ethylthio, n-propylthio or isopropylthio, furthermore straight-chain or branched butylthio, pentylthio, hexylthio or heptylthio.



   In a mercapto group R2 etherified by the heterocyclic radical mentioned, it has aromatic properties or can be partially saturated. Substituents include lower alkyl, especially methyl, and also methyl, n-propyl, isopropyl or straight-chain or branched butyl, pentyl or hexyl, hydroxy-lower alkyl, for example hydroxymethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, aryl, as optionally by Halogen, for example chlorine, or nitro-substituted phenyl, aryl-lower alkyl, for example benzyl, or heterocyclyl, such as furyl, for example 2-furyl, thienyl, for example 2-thienyl, or oxazolyl, for example 2-oxazolyl, or functional groups, such as halogen, for example fluorine, chlorine or bromine, optionally substituted amino, such as amino monosubstituted or disubstituted by lower alkyl,

   for example amino, methylamino or dimethylamino, nitro, lower alkoxy, for example methoxy, alkoxy n-butyloxy or 2-ethylhexyloxy, or optionally functionally modified carboxy, such as carboxy, esterified carboxy, such as lower alkoxycarbonyl, for example methoxy or ethoxycarbonyl, optionally substituted, such as N-mono- or N, N-di-lower alkylated carbamoyl, for example N-methylcarbamoyl, or cyan, and also oxo or oxido, one or more of such substituents being primarily with ring carbon atoms, but also, especially lower alkyl and oxido Ring nitrogen atoms are connected, may be present.



   Such heterocyclic radicals are primarily substituted, for example the above-mentioned substituents, in particular lower alkyl, for example methyl, containing monocyclic, five-membered diaza, triaza, tetraza, thiaza, thiadiaza, thiatriaza, oxaza- or oxadiazacyclische Residues of aromatic character or corresponding, optionally substituted, for example the above-mentioned substituents containing residues with fused-on benzene ring, such as benzodiaza or benzooxazacyclic residues, optionally substituted, for example the above-mentioned substituents, primarily oxido-containing, monocyclic, six-membered monoaza- or diazacyclic Residues of aromatic character or corresponding, partially saturated, optionally substituted residues, for example the residues mentioned above, primarily oxo, containing residues,

   or optionally substituted, for example containing the above-mentioned substituents, bicyclic triaza or tetrazacyclic
Residues of aromatic character or corresponding partially saturated, optionally substituted, for example containing the above-mentioned substituents, primarily oxo
Leftovers.



   Preferred heterocyclically etherified mercapto groups R2, in which the heterocyclic radical is a corresponding monocyclic, five-membered radical or a corresponding benzoheterocyclic radical, include imidazolylthio, for example 2-imidazolylthio, optionally substituted by lower alkyl and / or phenyl, for example s- Triazol-3-ylthio, 5-methyl-s-triazol-2-ylthio, 1 Hl, 2,4-triazol-5-ylthio, 3-methyl-l-phenyl-1 Hi, 2,4-triazole 5-ylthio, 4,5-dimethyl-4H-1, 2,4-triazol-3-ylthio or 4-phenyl-4H-1,2,4-triazol-3-ylthio, optionally by lower alkyl, phenyl or halophenyl substituted tetrazolylthio, for example 1 H-tetrazol-5-ylthio, i-methyl-i H-tetrazol-5-yl-thio,

   I-phenyl-l H-tetrazol-5-ylthio or 1- (4-chlorophenyl) -l htetrazol-5-ylthio, optionally substituted by lower alkyl or thienyl thiazolylthio, for example 2-thiazolylthio, 4- (2-thienyl) - 2-thiazolylthio or 4,5-dimethyl-2-thiazolylthio, optionally substituted by lower alkyl thiadiazolylthio, for example 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1, 2,4-thiadiazol-5-ylthio, thiatriazolylthio, for example 1, 2,3,4-thiatriazolyl-5-ylthio, optionally substituted by lower alkyl or phenyl oxazolylthio or isoxazolylthio, for example 5-oxazolylthio, 4-methyl- 5oxazolylthio, 2-oxazolylthio, 4,5-diphenyl-2-oxazolylthio or 3-methyl-5-isoxazolylthio, optionally by lower alkyl, phenyl,

   Nitrophenyl or thienyl substituted oxadiazolylthio, for example 1,2,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, 2-phenyl-l, 3,4-oxadiazol- 5-ylthio, 5- (4-nitrophenyl) -l, 3,4-oxadiazol-2-ylthio or 2- (thienyl) -l, 3,4-oxadiazol-5-ylthio, optionally substituted by halogen-substituted benzimidazolylthio Example 2-benzimidazolylthio or 5-chloro-2-benzimidazolylthio, or optionally benuoxazolylthio substituted by halogen or nitro, for example 2-benzoxazolylthio, 5-nitro-2-benzoxazolylthio or 5-chloro-2-benzoxazolylthio.



   Preferred heterocyclically etherified mercapto groups R2, in which the heterocyclic radical is a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical, include, inter alia, halogen-substituted l-oxide-pyridylthio, for example 1-oxido-2-pyridylthio or 4-chloro -l-oxido-2-pyridylthio, optionally substituted by lower alkyl, lower alkoxy or halogen-substituted N-oxido-pyridazinylthio, for example 2-oxido-6-pyridazinylthio, 3-chloro-l-oxido-6-pyridazinylthio, 3- Methyl-2-oxido-6-pyridazinylthio, 3-methoxy-l-oxido-6 pyridazinylthio, 3-ethoxy-l-oxido-6-pyridazinylthio, 3-n-butyloxy-l -oxido-6-pyridazinylthio or 3- (2-ethylhexyloxy) -l-oxido- 6-pyridazinylthio,

   or 2-oxo-1,2-dihydro-pyrimidinylthio optionally substituted by lower alkyl, amino 'di-lower alkylamino or carboxy, for example 2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-methyl-2-oxo-1,2 dihydro-4-pyrimidinyl thio, 5-methyl-2-oxo-l, 2-dihydro4-pyrimidinylthio, 6-amino-2 oxo-1,2-dihydro-4-pyrimidinylthio, 6-dimethylamino-2-oxo-1 , 2-dihydro-4-pyrimidinylthio, 5-carboxy-2-oxo-1, 2-dihydro-4-pyrimidinylthio or 6-carboxy-2-oxo-l, 2dihydro4-pyrimidylthio.



   Preferred heterocyclic etherified mercapto groups R2, in which the heterocyclic radical is a corresponding to the bicyclic, optionally partially saturated radical, include triazolopyridylthio, for example
3-s-triazolo [4,3-a] pyridylthio or 5-v-triazolo [4,5-b] pyridylthio, or purinylthio optionally substituted by halogen and / or Niederal kyl, for example 2-purinylthio, 6-Pu rinylthio or 8-chloro-2-methyl-6-purinylthio, furthermore 2 oxo 1,2 dihydro-purinylthio, for example 2-oxo-1,2-dihydro-6-purinylthio.



   Hydroxy groups R2 esterified with aliphatic carboxylic acids are, in particular, lower alkanoyloxy, in particular acetyloxy, furthermore formyloxy, propionyloxy, valeryloxy, hexa noyloxy, heptanoyloxy or pivalyloxy.



   An esterified hydroxyl group R2 is also a hydroxyl group esterified by an optionally N-substituted half amide of carbonic acid. N-substituents are optionally halogen, for example chlorine, containing lower alkyl, for example methyl, ethyl or 2Chloräthyl, or lower alkanoyl, for example acetyl or propionyl. In this type esterified hydroxy groups R2 are for example
Carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyl oxy, N- (2-chloroethyl) carbamoyloxy or N-acetylcarbamoyl oxy.



   In a quaternary ammonium group R2, which is derived from a tertiary organic base, the nitrogen atom is bound to the methyl carbon atom and is accordingly in quaternized, positively charged form.



  Quaternary ammonium groups include tri-lower alkylammonium, for example trimethylammonium, triethylammonium, tripropylammonium or tributylammonium, but in particular optionally substituted, for example lower alkyl, such as methyl, hydroxy-lower alkyl, such as hydroxymethyl, amino, sulfonamido, such as p-aminobenzenesulfonamido, hydroxy, halogen, such as , Chlorine, bromine or iodine, halogenated lower alkyl, such as trifluoromethyl, sulfo, optionally functionally modified carboxy, such as carboxy, lower alkoxycarbonyl, for example methoxycarbonyl, cyano, optionally by lower alkyl, for example methyl or ethyl, or hydroxy-lower alkyl, for example hydroxymethyl, N-mono - or N, N-disubstituted carbamoyl, for example carbamoyl, N-methyl-carbamoyl or N, N-dimethyl-carbamoyl, optionally substituted by lower alkyl N-substituted hydrazinocarbonyl, for example hydrazinocarbonyl,

   Carboxy lower alkyl, such as carboxymethyl, lower alkanoyl, such as acetyl, or l-lower alkyl pyrrolidinyl, such as l-methyl-2-pyrrolidinyl, mono- or polysubstituted, monocyclic or bicyclic azacyclic ammonium groups of aromatic character, with 1 or 2 ring nitrogen and optionally a ring sulfur atom, such as Pyrimidinium, pyridazinium, thiazolium, quinolinium and primarily pyridinium.

 

   Heterocyclic ammonium groups R2 are primarily lower alkyl, hydroxy-lower alkyl, sulfonamido, hydroxy, halogen, trifluoromethyl, sulfo, carboxy, lower alkoxycarbonyl, cyano, lower alkanoyl, I-lower alkyl-pyrrolidinyl or optionally pyridinium containing N-substituted carbamoyl by lower alkyl or hydroxy-lower alkyl, for example Pyridinium, 2-, 3- or 4-methyl-pyridium, 3,5-dimethyl-pyridinium, 2,4,6-trimethyl-pyridinium, 2-, 3- or 4-ethyl-pyridinium, 2-, 3 - or 4-propyl-pyridinium or in particular 4-hydroxymethyl-pyridinium, furthermore 2-amino- or 2-amino-6-methyl-pyridinium, 2-sulfanilamido-pyridinium, 3-hydroxy-pyridinium, 3-fluoro-, 3 Chlorine, 3-iodine or in particular 3-bromo-pyridinium, 4-trifluoromethyl-pyridinium, 3-sulfo-pyridinium, 2-,

   3- or 4-carboxy- or 2,3-dicarboxypyridinium, 4-methoxycarbonyl-pyridinium, 3- or 4-cyanopyridinium, 3-carboxymethyl-pyridinium, 3- or 4-acetyl-pyridinium, 3- (1-methyl -2-pyrrolidinyl) pyridinium, and in particular 4-carbamoyl-, and 3-carbamoyl-, 3- or 4-N-methyl carbamoyl-, 4-N, N-dimethylcarbamoyl-, 4-N-ethylcarbamoyl-, 3- N, N-diethylcarbamoyl, 4-N-propylcarbamoyl-, 4-isopropylcarbamoyl- and 4-hydroxymethyl-carbamoyl-pyridinium, furthermore optionally appropriately substituted pyrimidinium, pyridazinium, thiazolium or quinolinium.



   In an esterified carboxyl group of the formula -C (= O) -R which is cleavable under physiological conditions, R is primarily an acyloxymethoxy group, in which acyl means, for example, the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or in which acyloxymethyl forms the rest of a lactone. Such groups R2 are lower alkanoyloxymethoxy, for example acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, in particular a-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, L-valyloxymethoxy or L-leucyloxymethoxy, and also phthalidyl.



   Salts are especially those of compounds of formula I with a free carboxy group -C (= O) -R, primarily metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and also heterocyclic bases for salt formation, such as lower alkylamines, for example triethylamine, Hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkylene amines,

   for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N, N'-dibenzyl-ethylenediamine, and also bases of the pyridine type, for example pyridine, collidine or quinoline. Compounds of the formula I can also form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example trifluoroacetic acid, and with amino acids, such as arginine and lysine. Compounds of the formula I with a free carboxyl group can also be present in the form of internal salts, that is to say in zwitterionic form.



   The compounds of formula I and their pharmaceutically usable, non-toxic salts are valuable, antibiotic substances which can be used in particular as antibacterial antibiotics. For example, they are against microorganisms, such as against gram-positive bacteria (with minimum concentrations in in vitro experiments of about 0.001 mg / ml), for example against Staphylococcus aureus (e.g. in mice in doses of about 2 to about 10 mg / kg sc), incl. against Pencillin-resistant Staphylococcus aureus (e.g. in vitro in dilutions of about 0.001 mg / ml), also against Bacillus subtilis, Bacterium megatherium and Bacterium cereus, and against gram-negative bacteria (with minimal concentrations at in vitro experiments from about 0.005 to about 0.03 mg / ml), for example against Escherichia coli (e.g.

  B. in mice in doses of about 20 to about 100 mg / kg sc), including against ampicillin, carbencillin and rifamycin-resistant Escherichia coli (e.g. in vitro in dilutions of about 0.005 mg / ml), also against Klebsiella pneumoniae, Salmonella typhimurium, incl. Ampicillin, carbenicillin and rifamycin-resistant Salmonella typhimurium (e.g. in vitro in dilutions of about 0.005 mg / ml), Proteus vulgaris, Proteus mirabilis, incl. Carbenicillin-resistant Proteus mirabilis , and Proteus rettgeri (in vitro in dilutions of approximately 0.03 mg / ml). The new compounds can therefore be used accordingly, for example in the form of antibiotically active preparations.



   The present invention relates primarily to those compounds of the formula 1 in which X is oxygen or, in particular, sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2thienyl radical, and also a 4- or 5-aminomethyl-2-furyl radical represents the grouping of the formula -SA- for a radical of the formula la, but in particular for a radical of the formula lb, in which R1 is the group of the formula -CH2-R2, and R2 is hydrogen, lower alkanoyloxy, especially acetyloxy, optionally substituted carbamoyloxy represents etherified mercapto or quaternary ammonium, and in which R represents hydroxy, and salts, in particular the non-toxic, pharmaceutically usable salts, especially the alkali metal or alkaline earth metal salts,

   as well as the inner salts of such compounds.



   The present invention relates primarily to compounds of the formula 1 in which X is oxygen or, in particular, sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl, furthermore a 4- or 5-aminomethyl 2-furyl radical, the grouping of the formula -SA- represents a radical of the formula Ia or Ib, where Rl is the group of the formula -CH2-R2 and R2 is hydrogen, lower alkanoyloxy, for example acetyloxy, optionally N-alkylated carbamoyloxy, for example Carbamoyloxy, optionally substituted heterocyclylthio, in which heterocyclyl represents a monocyclic, five-membered heterocyclic radical of aromatic character which is connected to the thiosulfur atom via a ring carbon atom, and which has 2 or 3 ring nitrogen atoms and optionally additionally a ring oxygen,

   Contains ring sulfur or ring nitrogen atom, such a radical may optionally be substituted by lower alkyl, in particular methyl, or wherein heterocyclyl is an unsaturated monocyclic, six-membered heterocyclic radical which is connected to the thiosulfur atom via a ring carbon atom and contains 2 ring nitrogen atoms, either one Ring nitrogen atom contains an oxo group or a ring carbon atom contains an oxo group, and such a heterocyclyl radical may optionally be substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, or halogen, for example chlorine, or a pyridinium radical which may be substituted by carboxy, Carbamoyl or hydrazinocarbonyl can be substituted, and in which R stands for hydroxy, and salts, in particular pharmaceutically usable, non-toxic salts,

   especially the alkali or alkaline earth metal salts, as well as the inner salts of such compounds.

 

   The invention particularly relates to 3-cephem compounds of the formula 1, in which X represents sulfur, and the aminomethyl-substituted heterocycle denotes a 4- or preferably 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA- the rest of the formula Ib means in which Rl represents the radical of the formula -CH2-R2, where R2 is hydrogen, acetyloxy, carbamoyloxy, optionally substituted by lower alkyl, for example methyl, thiadiazolylthio, for example 1,3,4-, which is connected to the thiosulfur atom via a ring carbon atom Thiadiazol-2-ylthio, 5-methyl-1,3, sthiadiazol-2-ylthio or 5-methyl-1, 2,4-thiadiazol-2-ylthio, or tetrazolylthio, for example 1-methyl-5-tetrazolylthio, optionally by lower alkyl, for example methyl, lower alkoxy, for example methoxy,

   or halogen, for example chlorine, substituted N-oxidopyridazinylthio connected via a ring carbon atom to the thiosulfur atom, for example 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio or 3-chloro 1-oxido-6-pyridazinylthio, or pyridinium optionally substituted by carbamoyl, for example pyridinium or 3-carbamoylpyridinium, and in which the group R represents hydroxy, and salts, in particular the non-toxic, pharmaceutically useful salts, especially the alkali or alkaline earth metal salts, as well as the inner salts of such compounds.



   The invention relates primarily to 3-cephem compounds of the formula 1 in which X is sulfur, and the amino-methyl-substituted heterocycle is a 4- or preferably 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA - The rest of the formula Ib means, wherein R stands for the rest of the formula -CH2-R2, where R2
Is hydrogen, acetyloxy, 1, 3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio or pyridinium, and in which R represents hydroxy, and salts, in particular the non-toxic, pharmaceutically usable salts, in particular the alkali or earth alkali metal salts, as well as the inner salts of such compounds.



   In particular, the invention relates to 3-acetyloxymethyl-7- [2- (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid,
3-acetyloxymethyl-7 p- [2- (4-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid,
3-acetyloxymethyl-75- [2- (5-aminomethyl-2-furyl) acetylamino7ct-methoxy-3-cephem-4-carboxylic acid,
7 p- [2- (5-aminomethyl-2-thienyl) acetylamino] -
7a-methoxy-3-methyl-3-cephem-4-carboxylic acid, 7ss- [2- (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-
3- (5-methyl-1, 3,4-thiadiazol-2-ylthiomethyl) -3- cephem-4-carboxylic acid, 72- (5-aminomethyl-2-thienyl) -acetylaminol7a-methoxy-
3- (5-methyl-1-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid and 7 p + 2- (5-aminomethyl-2-thienyl) acetylaminoI

   7a-methoxy-3-pyridiniummethyl-3-cephem-4-carboxylic acid, and their inner salts, which have excellent antibiotic effects at the doses indicated and accordingly in the form of antibiotic preparations
Find use.



   The new compounds of the present invention can be prepared in a manner known per se by working in a compound of the formula
EMI4.1
 wherein the amino group can be substituted by an acylation-permitting group, and wherein the grouping of the formula -SA- means a radical of the formula la or Ib, wherein R has the meaning given above, where a free hydroxyl group R can be temporarily protected , or in a salt thereof, the amino group by treatment with an acid of the formula
EMI4.2
 wherein the amino group is optionally protected, or acylated with a reactive functional acid derivative thereof or with a salt of such a compound, and converts protected amino of the aminomethyl group in a compound obtained into free amino, and, if desired or necessary,

   converts a free carboxyl group into a physiologically cleavable esterified carboxyl group of the formula -C (= O) -R, and / or, if desired, converts a salt obtained into the free compound or into another salt or a free compound obtained into a salt.



   Any residues which may be present and which allow the acylation of the amino group in a starting material of the formula II are, for example, organic silyl or stannyl groups, and also ylidene groups which, together with the amino group, form a Schiff base. The organic silyl or stannyl groups mentioned are the same ones which are also able to form the temporarily protected carboxyl group —C (= O) -R with the carboxyl group on the Penam or Cephem ring. In the silylation or stannylation of the carboxyl group, if an excess of the silylating or stannylating agent is used, the amino group can also be silylated or stannylated.



   The ylidene groups mentioned are primarily arylmethylene groups, in which aryl is in particular a carbocyclic, primarily monocyclic aryl radical, for example phenyl optionally substituted by nitro or hydroxy; such arylmethylene groups are, for example, benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene.



   A temporarily protected carboxyl group of the formula -C (= O) -R in a starting material of the formula II is primarily a preferably easily cleaved, esterified carboxyl group, in which R represents an etherified hydroxy group.



   An etherified hydroxy group R, which in the starting material of the formula II forms a, preferably easily cleavable, esterified carboxyl group with the carbonyl grouping of the formula -C (= O) - is, for example, preferably, primarily in a-, also in 5- Lower alkoxy group substituted and / or branched in the a position.

  Substituents of such a group are, for example, carbocyclic aryl, such as optionally, for example by lower alkyl, such as tert-butyl, phenyl, hydroxy, lower alkoxy, such as methoxy, and / or nitro-substituted phenyl, furyl, such as 2-furyl, aryloxy, as optionally, for example by Niederal koxy, such as methoxy, substituted phenyloxy, arylcarbonyl, such as optionally, for example by halogen, such as bromine, substituted benzoyl, cyan or acylamino, such as diacylamino, for example phthalimino or succinylimino; such substituents are preferably in the a position of the
Lower alkoxy group R, which, depending on the nature of the substituents, may contain one, two or more such radicals.

  Further substituents which are preferably in the B position of the lower alkoxy radical R are halogen, for
Example chlorine, bromine or iodine, where in such residues a single chlorine or bromine can easily be converted into iodine.

 

   Examples of the above, optionally substituted
Lower alkoxy groups R are tert-lower alkoxy, for example tert-butyloxy or tert-pentyloxy, optionally in
Phenyl radical, for example as indicated, substituted a-phenyl-lower alkoxy, such as 4-hydroxy-3,5-di-tert-butyl-benzyloxy,
2-biphenylyl-2-propyloxy, 4-methoxy-benzyloxy, 4,5-dimethoxy-2-nitro-benzyloxy or 4-nitro-benzyloxy, optionally substituted in the phenyl radicals, for example as indicated, in particular by lower alkoxy, for example methoxy Diphenylmethoxy, such as benzhydryloxy or 4,4'-dimethoxydiphenylmethoxy, and trityloxy, optionally in the phenyl radicals, for example as indicated, in particular by lower alkoxy.

   substituted bis-phenyloxymethoxy, such as bis4-methoxyphenyloxy-methoxy, 2-halogeno-lower alkoxy, such as 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, optionally, in particular, halogen-substituted phenacyloxy, such as phenacyloxy or 4-bromophenacyloxy, Cyanomethoxy, or diacyliminomethoxy, such as phthalyliminomethoxy or succinyliminomethoxy.



   An etherified hydroxyl group R which, together with the carbonyl group of the formula -C (= O) - forms a, preferably easily, cleavable esterified carboxyl group, can also mean a cycloalkoxy group, the a position of which is preferably a bridgehead carbon atom. Such a cycloalkoxy group R is, for example, l-adamantyloxy.



   Further radicals R are represented by organic silyloxy or stannyloxy groups, in which organic radicals, of which 1 to 3 may be present, in particular optionally substituted aliphatic hydrocarbon radicals, such as lower alkyl, for example methyl, ethyl, n-propyl or tert-butyl, or Halogen lower alkyl, for example chloromethyl or 2-chloroethyl, and optionally substituted cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as cycloalkyl, phenyl or phenyl-lower alkyl, and also organically substituted functional groups, such as etherified hydroxy groups, for example lower alkoxy, such as methoxy or ethoxy, and which may optionally contain, for example, halogen, such as chlorine, as further substituents.

  Such radicals R include tri-lower alkylsilyloxy, for example trimethylsilyloxy, or tert = butyldimethylsilyloxy, lower alkoxy-lower alkyl-halosilyloxy, for example chloromethoxy-methyl-silyloxy, or tri-lower alkylstannyloxy, for example tri-n-butylstannyloxy.



   The group R can also represent a phosphoryloxy group in which a substituted trivalent or pentavalent phosphorus atom together with the carboxyl group of the formula -C (= O) -O- forms an esterified carboxyl group. Substituents of the trivalent phosphorus include inter alia substituted hydrocarbon radicals, such as corresponding aliphatic or araliphatic hydrocarbon radicals, for example lower alkyl or halogeno-lower alkyl, such as methyl, ethyl or chloromethyl, or phenyl-lower alkyl, such as benzyl, etherified hydroxy or mercapto groups, such as by optionally substituted aliphatic, aromatic or araliphatic hydrocarbon radicals etherified hydroxy or mercapto groups, for example lower alkoxy or lower alkylthio, such as methoxy, ethoxy, methylthio or n-butylthio, optionally,

   for example by lower alkyl, lower alkoxy or halogen, substituted phenyloxy or phenylthio, or optionally, for example by phenyl-lower alkoxy or phenyl-lower alkylthio substituted by lower alkyl, lower alkoxy or halogen, for example benzyloxy or benzylthio, halogen, for example fluorine, chlorine or bromine, or a bivalent, optionally substituted and / or hydrocarbon radical interrupted by heteroatoms, such as oxygen or sulfur, such as a corresponding aliphatic or araliphatic radical, for example lower alkylene, such as 1,4-butylene or 1,5-pentylene, or 1-oxa-lower alkylene , for example 1-oxa-l, 4 pentylene or l-oxa-1,5-pentylene, or two, by a bivalent, optionally substituted hydrocarbon radical,

   such as a corresponding aliphatic, aromatic or araliphatic radical, such as lower alkylene or 1,2-phenylene, etherified hydroxy groups. Substituents of the pentavalent phosphorus are those of the trivalent phosphorus and additionally an oxo group.



   In a starting material of the formula II there may be, in addition to a carboxyl group of the formula —C (= O) -R, further free functional groups, such as a free hydroxyl group R2, if desired or necessary, usually in a protected, preferably light, state during the acylation reaction fissile form before; a free hydroxy group can, for example, in an easily cleavable etherified or esterified form, for example in the form of a lower alkoxy, for example methoxy, or a 2-oxacycloalkoxy, for example 2-tetrahydropyranyloxy group, or



  an acyloxy, such as a lower alkanoyloxy, for example acetyloxy, or suitable esterified hydroxycarbonyloxy group.



   In a starting material of formula III, the amino group is advantageously protected by any of the preferably easily removable amino protecting groups known in peptide or penicillin and cephalosporin chemistry. Such protective groups can be, for example, acyl, arylmethyl, 2-carbonyl-1-vinyl, arylthio or aryl-lower alkylthio, also arylsulfonyl, and organic silyl or stannyl groups. The amino group may also be in the form of the azido group. The starting material of formula III can also be used in the form of an acid addition salt in which the amino group is protected in the ionic form.



   An easily removable acyl group is, for example, the formyl group or the acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl group which is aliphatically substituted or branched and / or aromatically or heteroaromatically substituted on the carbon atom in the a-position to the oxy group or substituted by an arylcarbonyl, in particular benuoyl, radical Methoxycarbonylgruppe, or a lower alkoxycarbonyl group substituted in the p-position by halogen, such as tert. Lower alkoxycarbonyl, for example tert-butyloxycarbonyl, or tert-pentyloxycarbonyl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, 2-halogenoethoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a group which can be converted into the latter,

   such as 2-chloro or 2-bromoethoxycarbonyl, further preferably polycyclic, cycloalkoxycarbonyl, for example adamantyl oxycarbonyl, optionally substituted, for example, by lower alkyl, such as tert-butyl, hydroxy, lower alkoxy, such as methoxy and / or nitro, phenyl-lower alkoxycarbonyl, in particular special a-phenyl-lower alkoxycarbonyl, for example 4-methoxy-benzyloxycarbonyl, 4-hydroxy-3,5-bis-tert-butylbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or a4-biphenyl-a-methylethyloxycarbonyl, further optionally, for example, by Lower alkoxy, such as methoxy, substituted diphenylmethoxycarbonyl, for example diphenylmethoxycarbonyl, or furyl-lower alkoxycarbonyl, primarily a-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl.

  A
Acyl group for protecting the amino group can also be the appropriate residue of a suitable carboxylic acid, such as one
Aryl dicarboxylic acid, for example the phthaloyl radical, or a halogeno lower alkane carboxylic acid, for example the tri fluoroacetyl radical.



   Examples of readily removable arylmethyl groups include: optionally substituted polyarylmetamyl, such as triarylmethyl groups, for example optionally substituted by lower alkoxy, such as methoxy, especially optionally o- and or p-methoxy-substituted trityl.

 

   Easily cleavable 2-carbonyl-1-vinyl groups, which together with the amino group either form an enamine or the ketimine tautomeric thereto, are, for example, 2-lower alkoxycarbonyl-1-lower alkylvinyl groups, in particular the 2-methoxycarbonyl-1-methyl-1 - vinyl group.



   Easily cleavable arylthio or aryl-lower alkylthio groups are, for example, substituted phenylthio groups, for example substituted by nitro or halogen, for example chlorine, such as the o-nitrophenylthio or 2,4-dinitrophene nylthio or the pnetachlorophenylthio group, and also triarylmethylthiog the triphenylmethylthio group.



   An easily removable organic silyl or stannyl group can preferably optionally substituted, in particular aliphatic hydrocarbon radicals, such as lower alkyl, for example methyl, ethyl or tert-butyl, or halo-lower alkyl, for example 2-chloroethyl, furthermore functional groups, for example etherified or esterified hydroxy groups, such as lower alkoxy, for example methoxy or ethoxy, or halogen, for example chlorine, as substituents. Such silyl or stannyl radicals include tri-lower alkylsilyl, for example trimethylsilyl or tert.-
Butyldimethylsilyl, lower alkoxy-lower alkyl-halosilyl, for example chloro-methoxy-methyl-silyl, or tri-lower alkyl stannyl, for example tri-n-butyl-stannyl.



   The acylation of the free amino group or one substituted by an acylation group can be carried out in a known manner by treatment with an acid corresponding to the acyl radical of the formula III or a reactive functional derivative thereof.



   If a free acid of formula III, preferably with a protected amino group, is used for the acylation, suitable condensing agents, such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N ', are usually used. Diisopropyl, N, N'-dicyclohexyl or N-ethyl-N'-3 dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isocazolini salts, for example N-ethyl-5-phenyl-isoxazolinium-3'sulphonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or an acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline.



   The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned below, for example in methylene chloride, dimethylformamide or
Acetonitrile.



   An amide-forming, functional derivative of an acid of the formula III, preferably with a protected amino group, is primarily an anhydride of such an acid, including and preferably a mixed anhydride, but also an internal anhydride, that is to say the corresponding ketene.



   Mixed anhydrides are, for example, those with inorganic acids, such as hydrohalic acids, that is, the corresponding acid halides, for example chlorides or bromides, and also with hydrochloric acid, that is, the corresponding acid azides, with a phosphorus-containing acid, for example phosphoric acid or phosphorous
Acid, or with a sulfuric acid, for example
Sulfuric acid, or with hydrocyanic acid.

  Other mixed anhydrides are, for example, those with organic carboxylic acids, such as those substituted, for example, by halogen, such as fluorine or chlorine, with lower alkane carboxylic acids, for example pivalic acid or trichloroacetic acid, or with half esters, in particular lower alkyl esters of carbonic acid, such as Ethyl or isobutyl half esters of carbonic acid, or with organic, especially aliphatic or aromatic sulfonic acids, for example p-toluenesulfonic acid.



   Other suitable for reaction with the amino group
Acid derivatives of an acid of the formula III are reactive, activated esters, usually with a protected amino group in the aminomethyl group, such as esters with vinyl alcohols (ie enols), such as vinylogous lower alkenols, or aryl esters, such as 4-nitrophenyl or 2,4- Dinitrophenyl esters, heteroaromatic esters such as benzotriazole, for example
2-benzotriazolesters, or diacylimino esters, such as succinylimino or phthalyimino esters.



   Acylation with an acid derivative, such as an anhydride and in particular with an acid halide, can be carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example such as triethylamine, or N, N. -Di-lower alkyl-aniline, for example N, N-dimethylaniline, or a base of the pyridine type, for example pyridine of an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-A1-kylene oxide, such as ethylene oxide or propylene oxide.



   The above acylation can be carried out in an aqueous or preferably anhydrous solvent or solvent mixture, for example in a carboxamide, such as N, N-diniederalkylamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone , an ester, for example ethyl acetate or a nitrile, for example acetonitrile, or mixtures thereof, and, if necessary, at reduced or elevated temperature and / or in an inert gas, for example nitrogen atmosphere.



   In an acid of Formula III or in an acid derivative thereof, the amino group is usually in protected form and an acid derivative can be formed in situ if desired. For example, a mixed anhydride is obtained by treating an acid of formula III or a suitable salt thereof, such as an ammonium salt, for example with an organic amine, such as 4-methylmorpholine, or a metal, for example alkali metal salt, with a suitable acid derivative , such as a corresponding acid halide of an optionally substituted lower alkane carboxylic acid, for example trichloroacetyl chloride, or with a half ester of a carbonic acid halide, for example ethyl or isobutyl chloroformate, and uses the mixed anhydride thus obtainable without isolation.



   If desired or necessary, functional groups in a compound obtained can be converted into other functional groups in a manner known per se.



  First of all, in a compound obtainable according to the invention, a protected amino group in the aminomethyl substituent of the acylamino group must be released and / or a temporarily protected carboxyl group must be converted into a group of the formula -C (= O) -R; furthermore, if desired, a free carboxyl group of the formula -C (= O) -R can be converted into a physiologically cleavable carboxyl group of the formula -C (= O) -R and / or a group Rl in a grouping, in a manner known per se convert the formula Ib into another group Rl. These conversions are carried out in a manner known per se, the sequence in the case of multiple conversions being arbitrary and usually dependent on the type of residues to be converted or split off, and on the reactions used for this purpose.

  It is also possible to convert more than one protected functional group into the corresponding free functional groups at the same time. For example, by treating with a suitable acid, such as trifluoroacetic acid, optionally in the presence of anisole, a tert-butyloxycarbonylamino or diphenylmethoxycarbonylamino group in the aminomethyl substituent of the acylamino radical in the 6- or 7-position and one in a compound obtained can be obtained simultaneously , a temporarily protected carboxyl group-representing diphenylmethoxycarbonyl group in the 3- or 4-position of a obtained peanam or 3-cephem compound simultaneously in the amino or. Transfer carboxy group.



   A protected amino group can be converted into a free amino group in a manner known per se, usually by solvolysis or reduction.



   A formyl group as an amino protecting group can, for example, be treated with an acidic agent, for example p-toluenesulfonic or hydrochloric acid, with a weakly basic agent, for example dilute ammonia, or with a decarbonylating agent, for example tris (triphenylphosphine) - rhodium chloride, be split off.



   In an obtained compound, an acylamino group can easily be removed from an acyl group, such as an a-polybranched lower alkoxycarbonyl group, for example tert.-
Butyloxycarbonyl, furthermore a polycyclic cycloalkoxycarbonyl group, for example 1-adamantyloxycarbonyl, an optionally substituted diphenylmethoxycarbonyl group, for example diphenylmethoxycarbonyl, or an a-furyl lower alkoxycarbonyl group, furthermore also a 4-hydroxy-3,5bis-tert-butyl-benzyloxycarbonyl group, for example by
Treatment with a suitable acid, such as a strong, preferably aliphatic carboxylic acid, for example an optionally halogenated, in particular fluorinated, lower alkane carboxylic acid, primarily formic or trifluoroacetic acid, optionally in the presence of anisole,

   and a 2-halogeno-lower alkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a phenacyloxycarbonyl group by treatment with a chemical reducing agent such as a suitable reducing metal or a corresponding metal compound, for example zinc, or a chromium III compound, such as chloride or acetate, usually in the presence of a hydrogen-generating agent nascent with the metal or the metal compound, preferably in the presence of water-containing acetic acid.



  A phenacyloxycarbonyl group can also be split off by treatment with a suitable nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate.



   Furthermore, in a compound obtained, an amino group protected by a suitably substituted benzyloxycarbonyl group, such as 4-methoxy- or 4-nitrobenzyloxycarbonylamino, can be cleaved by hydrogenolysis, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palladium.



   A triarylmethyl group, such as the trityl group, can be cleaved off, for example, by treatment with an acidic agent, such as a mineral acid, for example hydrochloric acid.



   An amino group protected in the form of an enamine or a kautimine tautomeric thereto, and the abovementioned amino groups protected by arylthio, aryl-lower alkylthio and arylsulfonyl can be treated, for example, by treatment with an acidic agent, especially an aqueous acid, such as an organic carboxylic acid, for example ants -, acetic or propionic acid, or a mineral acid, for example hydrochloric or sulfuric acid, optionally in the presence of a water-miscible solvent, such as a lower alkanol, for example methanol, a ketone, for example acetone, an ether, for example tetrahydrofuran, or a nitrile, for example acetonitrile.

  The thio-protecting groups mentioned can be split off particularly quickly in the presence of additional reagents such as sodium thiosulfate, sulfurous acid, thioacetamide, thiourea and potassium iodide.



   An amino group protected with an organic silyl or stannyl group in a obtained compound can be released by treatment with an aqueous or alcoholic agent, for example with a lower alkanol such as methanol, or a mixture thereof; The cleavage of an amino group protected in this way usually takes place during the working up of the acylation product.



   An amino group in the form of an azido group in the aminomethyl substituent of a compound obtained can be obtained in a manner known per se by means of reduction, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a nickel or palladium catalyst, for example Raney nickel or palladium on carbon, under mild conditions, for example under atmospheric pressure and / or at room temperature or only slightly elevated temperature, further by treatment with a phosphine, such as a triarylphosphine, for example triphenylphosphine, or with tin-II-chloride in the amino group.



   The reaction products formed in the acylation of compounds of the formula II according to the invention, in which the amino group is substituted by a silyl or stannyl group, in which the organic silyl or stannyl group is still on the amide nitrogen, are customarily used in the working up, in particular under hydrolytic and / or or alcoholic conditions, for example as are customary in the elimination from organic silyl or stannyl groups from amino groups, converted into compounds of the formula I.



   The reaction products formed in the acylation of compounds of the formula II according to the invention, in which the amino group is substituted by a ylidene group, are likewise usually converted into compounds of the formula I during workup, in particular by hydrolysis, for example by treatment with water.



   In a compound of the formula I obtainable according to the invention with a temporarily protected, in particular esterified, carboxyl group of the formula -C (= O) -R, this can be released into the free state in a manner known per se by solvolysis or reduction, that is to say depending on the type of group R. Carboxyl group are transferred.

  A carboxyl group esterified by a suitable 2-halogeno lower alkyl, such as 2,2,2-trichloroethyl or 2-iodoethyl, or an arylcarbonylmethyl group, such as phenacyl, can, for example, be treated with a chemical reducing agent, such as a metal, for example zinc, or a reducing metal salt, such as a chromium II salt, for example chromium II acetate, usually in the presence of a hydrogen-donating agent which, together with the metal, can produce nascent hydrogen, such as an acid, primarily vinegar, and formic acid, preferably water being added, a carboxyl group esterified by an arylcarbonyl, for example phenacyl group, also converted into the free carboxyl group by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide.

  A carboxyl group esterified by a suitable arylmethyl group can be, for example, by irradiation, preferably with ultraviolet light, for example below 290 mole, if the arylmethyl group is, for example, optionally in the 3-, 4- and / or 5-position, for example by lower alkoxy and / or represents nitro groups-substituted benzyl radical, or with longer-wave ultraviolet light, for example above 290 mu, if the arylmethyl group is, for example, a benzyl radical substituted in the 2-position by a nitro group, are converted into the free carboxyl group, while one from, with one suitably branched lower alkyl group, for example tert-butyl, one with a suitable cycloalkyl group, such as l-adamantyl, or with a diphenylmethyl group, for example benzhydryl,

   esterified carboxyl group, for example by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, can release the carboxyl group. A hydrolytically cleavable, esterified carboxyl group, such as a carboxyl group esterified by a suitably substituted phenyl radical or a diacyliminomethyl radical, and also a carboxy group esterified by the 4-hydroxy-3,5-di-tert-butyl-benzyl radical, depending on the type of ester grouping , for example by treatment with an acidic or weakly basic aqueous agent, such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis,

   for example by treatment with hydrogen in the presence of a noble metal, for example palladium catalyst.



   A carboxyl group protected, for example, by silylation or stannylation and by phosphorylation can be released in a conventional manner, for example by hydrolysis or alcoholysis.



   In a compound of the formula 1 obtainable according to the invention which contains a free carboxyl group of the formula -C (= O) -R and in which the amino of the aminomethyl radical is optionally in a protected form, the free carboxyl group can be prepared in a manner known per se in a, under Cleavable, esterified carboxyl group can be converted to physiological conditions. For example, in a compound of formula I with a free carboxyl group or a salt thereof, for example an alkali metal such as sodium or potassium salt, or an alkaline earth metal such as calcium or magnesium salt, or an optionally substituted ammonium salt such as the triethylammonium salt by reaction with a suitable halide, for example chloride or bromide, into the corresponding esterified carboxyl group -C (= O) -R.



   Furthermore, a compound of the formula 1 obtainable according to the invention, in which the amino group in the aminomethyl substituent is preferably protected, and in which the grouping of the formula -SA- corresponds to a radical of the formula Ib, can be used in a manner known per se to convert the group R through a to replace another residue R1 or to convert it to another residue R1. For example, in a compound of the formula I with a radical of the formula Ib as a grouping of the formula -SA-, in which R1 is a group of the formula -CH2-R2, and R2, for example, a radical which can be replaced by nucelophilic substituents represents, or in a salt thereof, to replace such a radical R2 by an etherified mercapto group R2 by treatment with a mercaptan compound.

  A suitable radical which can be replaced by an etherified mercapto group is, for example, an esterified one, for example by a hydrohalic acid, such as hydrochloric or hydrobromic acid, or preferably by an organic carboxylic acid, such as an aliphatic (including formic acid), cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic aliphatic carboxylic acid, furthermore by a carbonic acid derivative, such as a carbonic acid ester, esterified hydroxy group.

  Such esterified hydroxyl groups are, for example, lower alkanoyloxy, in particular acetyloxy, optionally substituted by halogen, such as fluorine or chlorine, and also halogenated lower alkanoyloxy, such as haloacetyloxy, for example trifluoroacetyloxy, and also dichloroacetyloxy, furthermore formyloxy, or optionally substituted benzoyloxy, such as 4- Chlorobenzoyloxy.



   The reaction of such a compound with a suitable mercaptan compound can be carried out under neutral or weakly basic conditions in the presence of water and, if appropriate, a water-miscible organic solvent. The basic conditions can be adjusted, for example, by adding 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. Organic solvents which can be used are, 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 alkane carboxamides, such as dimethylformamide, and the like.



   Esterified hydroxyl groups R2 in a compound of formula 1, in which the group -SA- is the partial formula Ib, and R1 denotes the group -CH2-R2, where R2 represents a hydroxyl group esterified by an optionally substituted half amide of carbonic acid, can be used for Introduce an example by using a corresponding compound of formula 1, wherein R2 is free hydroxy (which e.g.

  B. by cleavage of the acetyl radical from an acetyloxy group R2, for example by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii , Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, for example from orange peel), with a suitable carbonic acid derivative, in particular with an isocyanate or carbamic acid compound, such as a silyl isocyanate, for example silyl tetraisocyanate, a sulfonyl isocyanate, for example chlorosulfonyl isocyanate, or carbamic acid halide, for example chloride (which lead to N-unsubstituted 3-aminocarbonyloxymethyl compounds),

   or then with an N-substituted isocyanate or with an N-mono- or N, N-disubstituted carbamic acid compounds, such as a corresponding carbamic acid halide, for example chloride, reacting, usually in the presence of a solvent or diluent and if necessary, with cooling or heating, in a closed vessel and / or in an inert gas, for example nitrogen atmosphere.



   Furthermore, a compound of formula 1, in which the group -SA- corresponds to a radical of formula Ib, where R2 represents, for example, the radical which can be replaced by nucleophilic substitution, with a tertiary organic base, in particular an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH of about 6.5, in the presence of water and optionally with a water-miscible organic solvent. The weakly acidic conditions can be adjusted by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or else sulfuric acid. For example, the above-mentioned water-miscible solvents can be used as organic solvents.

  To increase the yield, certain salts can be added to the reaction mixture, for example alkali metal salts, such as sodium and in particular potassium salts, of inorganic acids, such as hydrohalic acids, for example hydrochloric acid and in particular hydroiodic acid, and also thiocyanic acid, or organic acids, such as lower alkane carboxylic acids Example acetic acid. Representative of such salts are, for example, potassium iodide and potassium thiocyanate. Also salts of suitable anion exchangers, for example liquid ion exchangers in salt form, such as for example Amberlit LA-I (liquid secondary amines with a molecular weight of 351 to 393; oil-soluble and
Water-insoluble; meq.lg = 2.5 to 2.7, for example in acetate form), with acids, for example acetic acid, can be used for this purpose.



   Quaternary ammonium groups R2 can advantageously using an intermediate of formula 1, in which R2 of the radical Rl in a partial formula Ib stands for a substituted, in particular for an aromatically substituted carbonylthio group and primarily for the benzoylthio group.

  Such an intermediate, which can be obtained, for example, by reacting a compound of the formula
1, wherein -S-A- stands for partial formula Ib, wherein R2 in the rest
R1 is an esterified hydroxy group, and primarily one
Acyloxy, especially a lower alkanoyloxy, for example acetyloxy group means with a suitable salt, such as an alkali metal, for example sodium salt, a thio carboxylic acid, such as an aromatic thiocarboxylic acid
Example thiobenzoic acid can be obtained with the tertiary amine, especially a tertiary heterocyclic
Base, such as an optionally substituted pyridine, is converted, keeping the quaternary ammonium compound.

  The reaction is usually carried out in the presence of a suitable desulfurization agent, in particular a mercury salt, for example mercury-II-perchlorate, and a suitable solvent or diluent or a mixture, if necessary, with cooling or heating, in a closed vessel and / or in an inert gas, for example nitrogen atmosphere.



   Salts of compounds of the formula I can be prepared in a manner known per se. Thus one can form salts of compounds of formula I with acidic groups, for example by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of α-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably with stoichiometric amounts or only a small excess of the salt-forming agent used. Acid addition salts of compounds of formula I are obtained in a conventional manner, for example by treatment with an acid or a suitable anion exchange reagent.

  Internal salts of compounds of formula 1 which contain a free carboxyl group can be formed, for example, by neutralizing 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 into the free compounds in a conventional manner, metal and ammonium salts, for example by treatment with suitable acids, and acid addition salts, for example by treatment with a suitable basic agent.



   The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.



   Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as particularly preferred above are obtained.



   Starting materials of the formula II in which the amino group is optionally substituted by a group which permits acylation are known or can be prepared by known methods.



   So you can get compounds of formula 11 if you in corresponding compounds of formula
EMI9.1
 the amino group is converted into the diazo group, for example by treatment with a suitable diazotizing agent, in particular with nitrous acid or with nitrogen tetroxide, the diazo compound is treated with a halogen azide, for example bromoazide, and the 6-azido-6-halogeno-penam so obtainable or 7-AzidoJ-halogen-3-cephem compound, in which halogen is primarily bromine, and which may optionally be in the form of the 6- or 7-epimer mixture, with a suitable silver salt, such as silver-I-bortetrafluoride , in the presence of methanol.

  This gives the GP-azido-Ga-methoxy-penam or 713-AzidoJa-methoxy-3-cephem compound, in which the azido group is reductively, for example by catalytic hydrogenation in the presence of a noble metal catalyst such as platinum oxide or palladium on carbon and, if necessary, an activating agent, such as a cobalt salt, for example cobalt-II-acetate, are converted into the amino group. This sequence of reactions is described, for example, by Cama et al. J. Am. Chem.



  Soc., Vol. 94, 1408 (1972).



   In a resulting starting material of formula 11, the free amino group can be, for example, by silylation or stannylation, such as by treatment with a suitably substituted silyl halide, for example trimethylsilyl chloride, or by treatment with an aldehyde, in particular with an aryl carboxaldehyde, for example an optionally substituted benzaldehyde, be converted into a substituted amino group which permits acylation.



   Starting materials of the formula III can be prepared by methods known per se. For example, 5-aminomethyl-2-thienyl or 5-aminomethyl-2-furylacetic acid compounds can be obtained by using an aminomethylthiophene or furan, in which the amino group is preferably protected, for example by one of the protective groups mentioned, or an acid addition salt thereof, such as the hydrochloride, by treatment with a suitable acetylating agent, for example with an acetic anhydride, including an acetyl halide, such as acetyl chloride, or preferably with acetic anhydride, in the presence of a suitable catalyst, such as a Lewis acid, for example aluminum chloride or bromide, or an acid, such as polyphosphoric acid, or preferably trifluoroacetic acid, and acetylated their anhydride.

  The reaction can be carried out in an anhydrous solvent, such as an aromatic hydrocarbon, for example benzene, or an excess of the liquid reagents used, for example an excess of trifluoroacetic acid or acetic acid and / or their anhydrides. When using trifluoroacetic acid or trifluoroacetic anhydride, a free amino group can be acylated by the trifluoroacetyl radical at the same time.

 

   An acetylated aminomethylthiophene or furan compound in which the amino group is preferably protected, for example by the trifluoroacetyl radical, can, for example, by the Willgerodt or Willgerodt Kindler method, for example by heating with ammonium polysulfide or with a primary or secondary amine such as morpholine. and subsequent hydrolysis of the intermediate thioamide, are converted into a compound of formula (III).



   On the other hand, an acylated aminomethylthiophene or furan compound, in particular a compound in which the amino group is protected in the manner indicated, for example by the trifluoroacetyl radical, can be obtained by heating with thallium (III) nitrate in the presence of a lower alkanol, in particular methanol, and an acid , for example perchloric acid, can be converted into a lower alkyl ester, for example the methyl ester, of an acid of the formula III, from which the free acid can be prepared by hydrolysis.



   In the hydrolysis of a thioamide obtained according to Willgerodt or Willgerodt Kindler or an ester obtained according to the thallium (III) nitrate method, depending on the hydrolysis conditions and the type of amino protective groups which may be present, these can also be split off or, if desired, converted. The complete hydrolysis to a compound of formula III and the subsequent introduction of an amino protecting group can also be carried out in one step.

  For example, a methyl ester of a compound of formula III wherein the amino group is acylated with the trifluoroacetyl group, for example, can be obtained by treating with a base, for example an alkali metal hydroxide such as sodium hydroxide, in water or water together with a water-miscible organic solvent such as dioxane. first hydrolyzed and then treated in the same reaction mixture, for example with tert-butyloxycarbonyl azide, whereupon the desired thiophene or furanacetic acid with a tert-butyloxycarbonylaminomethyl group can be obtained after acidification and customary working up.



   Furthermore, 4-aminomethyl-2-thienyl or 4-aminomethyl-2-furylacetic acid compounds can be obtained, for example, by treating 2-acetyl-thiophene or 2-acetyl-furan, for example by treatment with formaldehyde or a derivative thereof, such as Paraformaldehyde, in the presence of a hydrohalic acid, such as hydrochloric acid, halogenomethylated, in particular chloromethylated, in the 2-acetyl-4-halomethylthiophene or

   2-Acetyl-4-halomethyl-furan compound, in which halogen primarily means chlorine, halogen in a manner known per se, for example by treatment with an alkali metal compound, for example potassium compound, a phthalimide and subsequent hydrazinolysis, or by treatment with a suitable azide, such as an alkali metal azide or ammonium azide, is converted into an optionally protected amino group and then the acetyl substituent is converted into the desired carboxymethyl radical, for example by the method described above.



   In a compound of formula III with an unprotected amino group, this can be converted into one of the protected amino groups mentioned by any known method. For example, an acyl radical as an amino protecting group can be introduced into the amino group, for example by the acylation process described above, and also by treatment with a carbonic acid halide or carbonic acid azide compound such as tert-butyloxycarbonyl azide. Furthermore, a triarylmethyl group can be introduced into the free amino group, for example by treatment with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine.



   An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a manner known per se, for example by treatment with a suitable silylating agent, such as a dihalodi-lower alkyl silane or tri-lower alkyl silyl halide, for example dichlorodimethylsilane or trimethylsilyl chloride, or an optionally N-mono-lower alkylated, N, N -di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkyl-silyl) -amine, (see for example British Patent No.

   1,073,530), or with a suitable stannylating agent, such as a bis (tri-lower alkyltin) oxide, for example bis (tri-n-butyltin) oxide, a tri-lower alkyltin hydroxide, for example triethyltin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetran-lower alkoxy-tin or tetran-lower alkyl-tin compound, and a tri-lower alkyl-tin halide, for example tri-n-butyl-tin chloride (see, for example, Dutch specification 67/11 107).



   An amino group can also be protected by introducing a 2-carbonyl-1-vinyl group, enamine or. Ketimine compounds are formed. Such groups can be obtained, for example, by treating the amine with a 1,3-dicarbonyl compound, for example with methyl acetoacetic acid or acetoacetic acid-N, N-dimethylamide, in an anhydrous medium, for example a lower alkanol such as methanol.



   Arylthio or aryl-lower alkylthio or arylsulfonyl protecting groups can be introduced into an amino group by treatment with an appropriate arylthio or aryl-lower alkylthio or arylsulfonyl halide, for example chloride.



   The reactive functional acid derivatives of an acid of the formula III can be prepared in a manner known per se. Acid halides are prepared, for example, by using a compound of formula III with an optionally protected amino group, or a salt thereof with a halogenating agent, for example with an acid halide such as fluoride or chloride, an inorganic, phosphoric or sulfur-containing acid Example, phosphorus pentachloride, thionyl chloride or oxalyl chloride. The reaction is preferably carried out in a non-aqueous solvent or solvent mixture, such as a carboxamide, for example dimethylformamide.

  The acid halide obtained does not need to be purified further, but can be reacted directly with the starting material of the formula II, using, for example, the same solvents or solvent mixtures which are used in the preparation of the acid halide.



   Symmetrical anhydrides or mixed anhydrides of compounds of formula III with optionally protected amino group different from halides can be prepared, for example, by adding a corresponding compound with a free carboxyl group, preferably a salt, in particular an alkali metal, for example sodium or ammonium -, for example triethylammonium salt thereof, with a reactive derivative such as a halide, for example the chloride, a suitable acid, for example a lower alkyl haloformate, for example isobutyl chloroformate, or a lower alkane carboxylic acid halide, for example trichloroacetic acid chloride.

 

   Activated esters of compounds of formula III with an optionally protected amino group can be prepared, for example, by a corresponding compound having a free carboxyl group in the presence of a carbodiimide, for example N, N'-dicyclohexylcarbodiimide, with an optionally, for example by nitro or halogen, such as chlorine, substituted phenol, such as a nitrophenol, for example 4-nitrophenol or 2,4-dinitrophenol, or a polyhalophenol, for example 2,3,4,5,6-pentachlorophenol.



   In the process according to the invention, as well as in any additional measures to be carried out, furthermore in the production of the starting materials, if necessary, free functional groups not participating in the reaction in the starting materials or in the compounds obtainable according to the process, as described above, for example free amino groups by acylation, tritylation or silylation, free hydroxyl or mercapto groups, for example by etherification or esterification, and free carboxyl groups, for example by esterification, including silylation, temporarily protected in a manner known per se and in each case after the reaction, if desired, in a manner known per se Are released by solvolysis or reduction.



   The pharmacologically usable compounds of the present invention can be used, for example, for the preparation of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are preferably suitable for parenteral administration .



   The pharmacologically active compounds of the present invention are preferably used in the form of injectable, for example intravenous, administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being able to be prepared, for example, from lyophilized preparations which contain the active substance on their own or together with a carrier material, for example mannitol. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

  The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1 % to about 50%, lyophilisates up to 1000 / o of the active ingredient.



   Unless otherwise defined, the term used in connection with the definition of organic radicals or compounds, for example in lower alkyl, lower alkanol and the like, means that the radicals or compounds in question have up to 7, preferably up to 4, carbon atoms.



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.



  example 1
A solution of 0.247 g of 3-acetyloxymethyl-7ss-azido-7a-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester (cama et al., J. Am. Chem. Soc. Vol. 94, p. 1408 [3972]; Deutsche Offenlegungsschrift 2 129 675) in 7.6 ml of tetrahydrofuran is hydrogenated in the presence of 0.167 g of platinum oxide and 0.076 g of cobalt II acetate at room temperature for 1 hour with hydrogen under a pressure of 2 atmospheres. The reaction mixture is filtered and the filtrate containing the 3-acetyloxymethyl-7ss-amino-7a-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester is used in the subsequent acylation step without further purification.



   A solution of 0.237 g (2 (5-tert-butyloxycarbonylaminomethyl-2-thienyl> acetic acid in 20 ml of methylene chloride is treated at -15 "with 0.095 ml of 4methylmorpholine followed by 0.119 ml of isobutyl chloroformate. The mixture is stirred for 15 minutes with - 15 "and then dropwise add the above solution of 3-acetyl oxymethyl-7ss-amino-7a-methoxy-3-cephem4-carboxylic acid di-phenylmethyl ester at the same temperature. The reaction mixture is stirred at 0 for 3 hours, then diluted with methylene chloride and washes with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride.

  The aqueous washing liquids are extracted with methylene chloride and the combined organic extracts are dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is subjected to a thick layer chromatogram (silica gel) which is developed with a 5: 3 mixture of toluene and ethyl acetate. The 3-acetyloxymetyl-7ss- [245-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylaminoj-7a-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester with Rf = 0.2 is obtained.



   The 2nd (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid can be prepared as follows:
A solution of 20 g of 2-thenylaminohydrochloride in a mixture of 100 ml of trifluoroacetic acid and 100 ml of acetic anhydride is stirred under the exclusion of moisture for 2 hours at 55 ". The reaction mixture is completely concentrated under reduced pressure, mixed with 50 ml of toluene and concentrated again. The crude product is dissolved in ethyl acetate, treated with activated carbon, filtered through silica gel and concentrated under reduced pressure.

  After recrystallization from diethyl ether, 2-acetyl-5-trifluoroacetylaminomethyl-thiophene, F. 83-84 "
A solution of 34.2 thallium (III) nitrate trihydrate in 100 ml of methanol is mixed with ice cooling with 40 ml of 700% aqueous perchloric acid above and a solution of 20 g of 2-acetyl-5-trifluoroacetylamino at +5 under a nitrogen atmosphere -thiophene added dropwise in 500 ml of methanol within 15 minutes. The solution is warmed to 50 and stirred at this temperature for 21 hours. The reaction mixture is cooled to about +5 and poured onto an ice-cold solution of 120 g dipotassium hydrogen phosphate in 300 ml water. It is filtered and the filter residue is washed with methanol.

  The filtrate is concentrated under reduced pressure to about 300 ml and three times with
150 ml of chloroform extracted. The extracts are washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in a water jet vacuum. There remains the methyl 2 (5-trifluoroacetylaminomethyl-2-thienyl) acetic acid;
Thin layer chromatogram (silica gel: system: toluene / ethyl acetate 60:40): Rf = 0.65; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93 u, 3.39, u, 5.75 u and 5.80 lt.



   40 ml of 2N aqueous solution are added to a solution of 9.7 g of methyl 2- (5-trifluoroacetylaminomethyl-2-thienyl) -acetate in 50 ml of dioxane under 20 under a nitrogen atmosphere
Given sodium hydroxide solution. Stir during two
Hours at 20 to 25, diluted with 50 ml of dioxane and gives
8.5 ml of tert-butyloxycarbonyl azide to the solution, followed by stirring at 20 to 25 for 16 hours. The reaction mixture is cooled to about 5 and with about 40 ml
20% aqueous phosphoric acid adjusted to pH 2.5. The mixture is concentrated to about 50 ml under reduced pressure and extracted three times with 200 ml of ethyl acetate each time.

  The extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, decolorized by treatment with an activated carbon preparation and concentrated under reduced pressure. It is recrystallized from diethyl ether and the 2 (5-tert-butyloxycarbonylamino-methyl-2-thienyl> acetic acid, mp 1141150.



   The 2 (5-tert-butyloxycarbonylaminomethyl-zthienyl) acetic acid can also be obtained as follows:
A solution of 1.34 g of N-hydroxymethyl acetamide (Einhorn, Ann. Chem., Vol. 343, 5.264 [1905]) kept at 0-5 "in 10 ml of trifluoroacetic acid is stirred in portions with 1.42 g of 2-thienylacetic acid are added. The mixture is stirred at 0-5 "for 2 hours and the trifluoroacetic acid is distilled off under reduced pressure. The residue is mixed with 30 ml of water and extracted twice with 50 ml of ethyl acetate. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and filtered through silica gel.

  The residue is crystallized from ethyl acetate and gives the 2- (5-acetylaminomethyl-2-thienyl) acetic acid, thin layer chromatogram (silica gel): Rf = 0.61 (system: butanol / acetic acid / water 45:45:10); Infrared absorption spectrum (mineral oil): characteristic bands at 2.95 u, 5.82 u,
6.23, t, 6.38 u.



   0.3 ml of a 2N aqueous sodium hydroxide solution is added to a solution of 0.6 g of 2- (5-acetylaminomethyl-2-thienyl) acetic acid in 5 ml of dioxane. The mixture is stirred for 12 hours at 55 to 60, cooled to 25, mixed with 0.2 ml of tert.
Butyloxycarbonyl azide, stirred for 16 hours at room temperature and isolated the 2- (5-tert-butyloxycarbonylamino methyl-2-thienyl) acetic acid according to the above
Procedure.



   Example 2
A solution of 0.90 g of 3-acetyloxymethyl-7a-methoxy-7- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] - 3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of tri fluoroacetic acid and 1.5 ml of anisole are left to stand for 30 minutes at 0 and with the addition of 20 ml of toluene
Evaporated water jet vacuum. The arrears with
10 ml of diethyl ether and 40 ml of petroleum ether triturated and filtered.

  The filter residue, which contains the trifluoroacetic acid salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid, is dried for 5 hours under high vacuum at room temperature and then dissolve it in 30 ml of methanol; the solution is decolorized by adding activated carbon and filtered.



   The filtrate is adjusted to pH 6.0 with triethylamine and then left to stand at 0-5 "for 2 hours. The precipitated inner salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) - is filtered. acetylamino] -7a-methoxy-3-ce phem-4-carboxylic acid and dries for 20 hours under high vacuum and at room temperature, F. over 180 (with decomposition); [a] j, = +177 + 1 "(c = 0.972 in a 0.15 molar aqueous potassium dihydrogenphosphate-dipotassium hydrogen phosphate buffer solution, pH 7.3 to 7.4); Thin layer chromatogram (silica gel):

  Rf = 0.12 (system: n-butanol / acetic acid / water 45:45:10); Ultraviolet absorption spectrum (in a 0.15 molar aqueous potassium dihydrogenphosphate-di potassium hydrogenphosphate buffer solution, pH 7.3 to 7.4): 1man =
241 m (E = 15 700) and Xmin = 214 mlt (e = 8700) infrared absorption spectrum (in mineral oil): characteristic bands at 5.66, u, 5.75, u, 6.00 1 *, 6.34 lt and 6.55, u.



   Example 3
A solution of 0.271 g of 2- (5-tert-butyloxycarbonylamino-methyl-2-thienyl) acetic acid in 5 ml of methylene chloride is obtained at 0 with 0.168 g of chloromethylene-dimethyl-ammonium chloride (obtained as a solid substance by reacting equimolar amounts of dimethylformamide and phosgene in methylene chloride) and the reaction mixture for 10
Stirred for minutes. 0.081 ml of pyridine is then added at 0, the mixture is stirred for 5 minutes at this temperature and the solution prepared by the process of Example 1 and containing the 3-acetyloxymethyl-7ss-amino-7a-methoxy-3 is added -cephem-4-carboxylic acid diphenylmethyl ester, too.

  The mixture is stirred at 0 for 30 minutes, then diluted with methylene chloride and washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. The aqueous washing liquids are extracted with methylene chloride and the combined organic extracts are dried over sodium sulfate, filtered and evaporated under reduced pressure.



  The residue is subjected to a thick layer chromatogram (silica gel) which is developed with a 5: 3 mixture of toluene and ethyl acetate. The 3-acetyloxymethyl-7ss- [2- (5-tert-butyloxyearbonylaminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf = 0.2 is obtained. which is identical to the product of the process described in Example 1.



  Example 4
A solution of 0.15 g of the inner salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid and 0.053 g of the sodium salt of 5-mercapto-1-methyl-tetrazole in 7 ml of acetone and 10 ml of water is mixed with 0.028 g of sodium hydrogen carbonate and heated to 60 for 5 hours. It is filtered, the filtrate is concentrated under reduced pressure to a volume of about 10 ml, adjusted to pH 5.5 with acetic acid and left to stand at 0-5 "for a few hours. The precipitate is filtered off and washed with acetone.

  The inner salt of 7llI2- (5-aminomethyl-% thienyl) -acetylamino] -7a-methoxy-3- (1-methyl-5-tetrazolyl-thiomethyl) -3-cephem-4-carboxylic acid is thus obtained drying under high vacuum for 12 hours; Thin layer chromatogram (silica gel): Rf = 0.25 (system: chloroform / methanol 1: 1).



   In another variant, the reaction is carried out in the presence of 0.028 g of sodium hydrogen carbonate and 0.055 g of potassium iodide.



  Example 5
Analogously to Example 1, 2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) acetic acid and the solution of 3-acetyloxymethyl-7ss-amino-7a-meth-oxy-3-cephem-4- obtainable according to Example 1 carbonic acid diphenylmethyl ester in the presence of 4-methylmorpholine and chloroformic acid isobutyl ester of crude 3-acetyloxymethyl-7a-methoxy-7PI2- (5-tert-butyloxy-carbonylaminomethyl-2-furyl) -acetylamino] - 3-cephem-4-carboxylic acid-diphenylmethyl ester are obtained.



  The crude product is chromatographed on 600 g of silica gel, the 3-acetyloxymethyl-7a-methoxy-7 P- [2 (5-tert-butyloxycarbonylaminomethyl-2-furyl) acetylamino] - being used with a 6: 4 mixture of toluene and ethyl acetate - 3-cephem 4-carboxylic acid diphenylmethyl ester eluted; Thin layer chromatogram (silica gel): Rf = 0.30 (system: toluene / ethyl acetate 6: 4); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92, u, 5.61, u, 5.76, u (broad), 6.24 lt and 6.67 Il.



   The starting material can be produced as follows:
A mixture of 50 g of furfurylamine and 150 ml of trifluoroacetic anhydride is stirred with the exclusion of moisture for 2 hours at room temperature. You give
Add 150 ml of acetic acid and continue stirring at 55 for 2 hours. The reaction mixture is completely concentrated under reduced pressure, 50 ml of toluene are added and the mixture is concentrated again. The crude product is dissolved in ethyl acetate, treated with activated carbon, filtered through silica gel and concentrated under reduced pressure. After recrystallization from diethyl ether, 2-acetyl-5-trifluoroacetaminomethyl-furan, F. 99-100 "; ultraviolet absorption spectrum (in ethanol): Xmax = 275 mlt (e = 15,500).

 

   A solution of 39.8 g thallium (III) nitrate trihydrate in
100 ml of methanol is cooled with ice with 50 ml 700 / above
Perchloric acid was added and a solution of 20 g of 2-acetyl-5-trifluoroacetamino methyl-furan in 500 ml of methanol was added dropwise within 15 minutes at +5 under a nitrogen atmosphere. The solution is heated to 50 and at this
Temperature stirred for 21k hours. The reaction mixture is cooled to about +5 and poured onto an ice-cold solution of 120 g dipotassium hydrogen phosphate in 300 ml water. It is filtered and the filter residue is washed with methanol. The filtrate is concentrated under reduced pressure to about 300 ml and extracted three times with 150 ml of chloroform.

  The extracts are washed with water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and
Water jet vacuum concentrated. The methyl 2- (5-trifluoroacetaminomethyl-2-furyl) .acetate remains, thin
Layer chromatogram (silica gel): Rf = 0.35 (system: toluene /
Ethyl acetate 60:40); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 lt, 3.39 lt and 5.80.



   To a solution of 18.4 g of 2- (5-trifluoroacetaminomethyl
2-furyl) -acetic acid methyl ester in 100 ml of dioxane are given at 20 under a nitrogen atmosphere 75 ml of a 2-n aqueous sodium hydroxide solution. Stir during 4
Hours at 20 to 25, diluted with 100 ml of dioxane and gives
34 ml of tert-butyloxycarbonyl azide to the solution, whereupon
Stir 20 to 25 for 16 hours. The reaction mixture is cooled to about 5 and adjusted to pH 2.5 with about 50 ml of 200 / above aqueous phosphoric acid. The mixture is concentrated to a volume of about 100 ml under reduced pressure and extracted three times with 200 ml of ethyl acetate each time.



   The extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, decolorized by treatment with an activated carbon preparation and concentrated. After recrystallization from diethyl ether, the 2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) acetic acid, mp 72-73.



   Example 6
A solution of 2.95 g of 3-acetyloxymethyl-7a-methoxy-7ss- [2- (5-tert.-butyloxyearbonylaminomethyl-2-furyl) acetylamino noI 3-cephem4-carboxylic acid diphenylmethyl ester in 3 ml of anisole and 12 ml Trifluoroacetic acid is left at 0 for 30 minutes and then evaporated with the addition of 100 ml of toluene in a water jet vacuum. The residue is triturated with 50 ml of diethyl ether and filtered.

  The filter residue, which contains the trifluoroacetic acid salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-furylS ace tylamino] -7α-methoxy-3-cephem-4-carboxylic acid, is dried for 5 hours under high vacuum Room temperature and then dissolves it in 30 ml of methanol, the solution is decolorized by adding activated carbon and filtered. The filtrate is adjusted to pH 6.0 with triethylamine and then left to stand at 0-5 "for 2 hours.

  The precipitated inner salt of 3-acetyloxymethyl-7B- [2- (5-aminomethyl-2-furyl) acetylamino] -7a-methoxy-3-cephem4-carboxylic acid is filtered off and dried for 20 hours under high vacuum and at room temperature, F. over 165 (with decomposition); Thin layer chromatogram (silica gel): Rf = 0.22 (system: chloroform / methanol 1: 1); Ultraviolet absorption spectrum (in 950 / above aqueous ethanol):

  Xmax = 222 m, u (e = 12 500) and # max2 = 266 m, u (E = 6200); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 lt 5.77, u, 5.91, u, 6.22 lt and 6.52.



  Example 7
In an analogous manner to Example 1, the following compounds are produced when the appropriate starting materials are selected:
Starting from 2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid, chloroformic acid isobutyl ester and 3-acetyloxymethyl-7p-amino-7a-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester, the inner salt of 3-acetyloxy methyl -7ss- [2- (3-aminomethyl-2-thienyl) acetylaminoj7a-methoxy-3-cephem4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf = 0.27 (system: n-butanol / acetic acid / water 45:45:10); Ultraviolet absorption spectrum (in water): Xmax = 237 mlt (e = 12 700); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.64 Fu, 5.57, u, 5.97 lt and 6.55 lt: proton resonance spectrum (formic acid d2):

   characteristic AB system at o = 7.17 and 7.38 (J = 5.5) of the two hydrogen substituents on the disubstinated thiophene ring; starting from 2- (4-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid, chloroformic acid isobutyl ester and 3-acetyloxymethyl-7ss-amino-7α-methoxy-3-cephem4carboxylic acid diephenylmethyl ester, the inner salt of 3-acetyl oxymethyl-7ss- [2- (4-aminomethyl-2-thienyl) acetylainino} 7a-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf = 0.27 (system: n-butanol / acetic acid / water 45:45:10); Ultraviolet absorption spectrum (in water) Xmax = 238 (e = 13 100); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.64 lt. 5.75 lt. 5.98 lt and 6.55; starting from 2- (5-tert-butyloxycarbonylamino methyl-2-thienyl) acetic acid, chloroformic acid isobutyl ester and 7ss-amino-7a-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl ) -3-cephem-4-carboxylic acid tert-butyl ester, the inner salt of 7ss {2- (5-aminomethyl-2-thienyl) acetylamino] - 7a-methoxy-3- (5-methyl-1, 3, 4-thiadiazol-2-ylthiomethyl) -3-cephem4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf = 0.11 (system: n-butanol / acetic acid / water 45:45:10); Ultraviolet absorption spectrum 0.1-n aqueous sodium hydrogen carbonate solution): Ämax = 242 mlt (± = 16 400); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 lt. 5.97 lt. 6.25 lt and 6.50; starting from 2- (5-tert-butyloxycarbonylaminoinethyl-2-thienyl) acetic acid, isobutyl chloroformate and 7ss-amino-3,7a-di-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester, the 7I3I2 (5-aminomethyl% thienyl) acetylamino 3,7a-dimethoxy3-cephem4-carboxylic acid:

  Ultraviolet absorption spectrum (in H2O): Xmax = 240 mlt (± = 14,000); Infrared absorption spectrum (in Nujol): bands at 3.03; 5.68; 6.03; 6.45; starting from 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid, chloroformic acid isobutyl ester and 3-aminocar bonyloxymethyl-7ss-amino-7a-methoxy-3-cephem4-carboxylic acid diphenylmethyl ester, the 3-aminocarbonyloxymethyl-7ss- [2 - (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem4-carboxylic acid; Ultraviolet absorption spectrum (in H2O) Xmax = 240 mlt (r = 14 700);

  Infrared absorption spectrum (in Nujol): characteristic bands at 2.80 (sh); 2.96 (sh); 2.98 (sh); 3.13; 3.80 (sh); 5.66 (s); 5.88 (sh); 5.93 (s); 6.24 (s) and 6.92; [a] 20 = +168 + 1 "(c = 1.002; water); starting from 245-tert.-butyloxycarbonylamino-2-thienyl) - acetic acid, isobutyl chloroformate and 7ss-amino-7a-methoxy-3-methylaminocarbonyl- diphenylmethyl ester of oxymethyl-3-cephem4-carboxylic acid, the 7ssi2- (5-aminomethyl-2-thienyl) acetylamino} 3-methylaminocarbonyloxymethyl-7-methoxy3-cephem4-carboxylic acid; ultraviolet absorption spectrum (in H2O) Xm x = 241 mlt (r 14 100); Infrared absorption spectrum (in Nujol):

  Bands at 2.97; 3.10; 5.68; 5.94; 6.50 FL; Analogously to Example 1, starting from 2- (5-tert-butyloxycarbonylamino-2-thienyl) acetic acid, isobutyl chloroformate and 7ss-amino-7α-methoxy-3-N- (2-chloroethyl) aminocarbonyloxymethyl-3 -cephem4-carboxylic acid diphenylmethyl ester, the 7I3- [2 (5-aminomethyl-2-thienylacetylaminol 3-N- (2-chloroethyl) -aminocarbonyloxymethyl- 7a-methoxy-3-cephem4-carboxylic acid; ultraviolet absorption spectrum (in H2O) Xm x = 242 mlt (e = 14 300);

  Infrared absorption spectrum (in Nujol): bands at 2.95; 3.10; 5.67; 5.87; 5.93; 6.48 lt; and starting from 2- (5-tert-butyloxyearbonylaminomethyl-2-thienyl) acetic acid, chloroformic acid isobutyl ester and 7ss-amino-7a-methoxy-3-methylthiomethyl-3-cephem-4-carboxylic acid diphenyl- methyl ester, the 7ss- [2- (5-aminomethyl-2-thienyl) acetylamino] - 7a-methoxy-3-methylthiomethyl-3-cephem-4-carboxylic acid. Ultraviolet absorption spectrum (in H2O): knllix = 240 ml: (1: = 10 200); Infrared absorption spectrum (in Nujol): bands at 2.95: 3.17: 5.63: 5.81: 5.97: 6.20: 6.59 which are usually obtained in the form of their internal salts.

 

  Example 8
1.0 g of 3-acetyloxymethyl-7ss- (3-carboxy-2-oxacyclohexyliden-imino) - 7a-methoxy-3-cephem-4-carboxylic acid are taken up in 20 ml of methylene chloride and at -10 "to +5" C with 0.70 g of 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid chloride and 0.40 ml of triethylamine are acylated. The acylation product extracted and dried with ethyl acetate is dissolved at 0-5 "in 4 ml of formic acid and 1 ml of trifluoroacetic acid. The mixture is concentrated to dryness in vacuo. Neutralization according to Example 4 gives the inner salt of 3-acetyloxymethyl-7ss - [* 45- aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid.

 

Claims (1)

PATENT CLAIM Process for the preparation of 6p-acylamino-6n-methoxy-penam-3-carboxylic acid compounds and 7ss-acylamino-7a-methoxy-3-cephem-4-carboxylic acid compounds of the formula EMI14.1 wherein X represents sulfur or oxygen, and wherein the grouping of the formula -S-A- is a radical of the formula EMI14.2 means in which R1 represents hydrogen or a radical of the formula -CH2-R2, in which R2 represents hydrogen, a free one. etherified or esterified hydroxy or mercapto group or a quaternary ammonium group. and R represents hydroxy or, together with the carbonyl grouping -C (= O) - an esterified carboxy group which is cleavable under physiological conditions, and salts thereof, characterized in that in a compound of the formula EMI14.3 wherein the amino group can be substituted by an acylation-permitting group, and wherein the grouping of the formula -SA- means a radical of the formula la or Ib, wherein R has the meaning given above, where a free hydroxyl group R can be temporarily protected , or in a salt thereof, the amino group by treatment with an acid of the formula EMI14.4 wherein the amino group is optionally temporarily protected, or acylated with a reactive functional acid derivative thereof or with a salt of such a compound, and optionally converting protected amino of the aminomethyl group into free amino in a compound obtained and / or, if desired, converting a salt obtained into the free compound or into another salt or a free compound obtained into a salt. SUB-CLAIMS 1. The method according to claim 1, characterized in that in a starting material of the formula II optionally present, the acylation of the amino groups radicals organic silyl or stannyl groups or aryl. methylene groups, which together with the amino group form a Schiff base. 2. The method according to claim 1, characterized in that a free carboxyl group of the formula -C (= O) -R in a compound of the formula I is converted into a physiologically cleavable esterified carboxyl group, such as a pivaloyloxymethoxycarbonyl group. 3. The method according to claim 1, characterized in that in a starting material, optionally in addition to a carboxyl group of the formula -C (= O) -R, free functional groups present are present in a temporarily protected, preferably easily cleavable form. 4. The method according to claim 1, characterized in that in a starting material amino of the aminomethyl group is protected by preferably easily removable amino protective groups or is in the form of the azido group. 5. The method according to claim 1, characterized in that one carries out the acylation of a starting material of the formula II by treatment with an acid of the formula III in the presence of a condensing agent. 6. The method according to claim 1, characterized in that the acylation of a starting material of the formula II by treatment with an anhydride, including a mixed or internal anhydride, an acid of the formula III, in particular the anhydride of such an acid with a hydrohalic acid, hydrochloric acid, a phosphoric or sulfur-containing acid, hydrocyanic acid, with an optionally substituted, for example by halogen, substituted lower alkane carboxylic acid or with a half ester of carbonic acid 7. The method according to claim I, characterized in that one carries out the acylation of a starting material of formula II by treatment with a reactive, activated ester of an acid of formula III. 8. The method according to claim I or one of the subclaims 1-7, characterized in that compounds of the formula I according to claim I or salts thereof are prepared in which X has the meaning given in claim I, and the rest of the formula -SA- for partial formula la or lb according to claim I, in which R has the meaning given in claim I, and Rs is hydrogen or the group -CH2-R2, in which R2 is hydrogen, hydroxy, a hydroxy or mercapto group etherified by a lower aliphatic hydrocarbon radical, a mercapto group etherified by an optionally substituted heterocyclic radical having 1 to 4 ring nitrogen atoms and optionally a further ring hetero atom from the group oxygen and sulfur, bonded to the sulfur via a ring carbon atom, by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid esterified hydroxy or mercapto group, or a quaternary ammonium group derived from a tertiary organic base and linked to the methyl carbon atom via the nitrogen atom. 9. The method according to claim I or one of the subclaims 1-7, characterized in that compounds of the formula I according to claim I or salts thereof are prepared in which X is oxygen or in particular sulfur and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl or a 4- or 5-aminomethyl-2-furyl radical, the grouping of the formula -SA represents a radical of the formula Ia or lb according to Claim 1, in which Rs is the group of the formula -CH2R2 and R2 is hydrogen, lower alkanoyloxy, optionally N-alkylated carbamoyloxy, optionally substituted heterocyclylthio, where heterocyclyl is a monocyclic, five-membered heterocyclic radical of aromatic character which is connected to the thiosulfur atom via a ring carbon atom, and which contains 2 or 3 ring nitrogen atoms and optionally additionally a ring oxygen atom, ring sulfur atom or ring nitrogen atom atom, such a radical may optionally be substituted by lower alkyl, or wherein heterocyclyl represents an unsaturated monocyclic, six-membered heterocyclic radical which is connected to the thiosulfur atom via a ring carbon atom and contains 2 ring nitrogen atoms, either a ring nitrogen atom containing an oxo group or a ring carbon atom containing an oxo group, and such a heterocyclyl radical may optionally be substituted by lower alkyl, lower alkoxy or halogen, or a pyridinium radical which may optionally be substituted by carboxy, carbamoyl or hydrazinocarbonyl , and where R is hydroxy. 10. The method according to claim I or one of subclaims 1-7, characterized in that 3-cephem compounds of the formula I according to claim 1 or salts thereof are prepared in which X is sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl means the grouping of the formula -SA- means the rest of the formula Ib according to claim I, in which Rl represents the rest of the formula -CH2R2, where R2 is hydrogen, acetyloxy, carbamoyloxy, optionally substituted by lower alkyl, thiadiazolylthio or tetrazolylthio bonded to the thiosulfur atom via a king carbon atom, optionally substituted by lower alkyl, lower alkoxy or halogen, N-oxidopyridazinylthio bonded to the thiosulfur atom via a ring carbon atom, or pyridinium optionally substituted by carbamoyl, and wherein R represents hydroxy. 11. The method according to claim 1 or one of the subclaims 1-7, characterized in that 3-cephem compounds of the formula I according to claim I or salts thereof, in which X is sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl means the grouping of the formula -SA- means the rest of the formula Ib according to claim 1, wherein Rl represents the rest of the formula -CH2R2, where R2 is hydrogen, acetyloxy, 1, 3,4-thiadiazole -2-ylthio, I-methyl-5-tetrazolylthio or pyridinium, and wherein R represents hydroxy. 12. The method according to claim I or one of the subclaims 1-7, characterized in that 3-acetyl oxymethyl-7p- [2- (5-aminomethyl-2-thienyl) acetylamino} 7a-methoxy-3-cephem4-carboxylic acid or salts thereof. 13. The method according to claim I or one of the subclaims 1-7, characterized in that 7p- [2- (5-aminomethyl-2-thienyl) acetylamino] - 7a-methoxy-3- (5-methyl-l- tetrazolylthiomethyl) - 3-cephem4-carboxylic acid or salts thereof. 14. The method according to claim I or one of the subclaims 1-7, characterized in that 713 [2- (5-aminomethyl-2-thienyl-acetylamino] - 7a-methoxy-3- (5 methyll, 3,4-thiadiazole-2 - ylthiomethyl) -3-cephem4-carboxylic acid or salts thereof PATENT CLAIM II Use of the compounds of the formula I obtained by the process of claim I, in which the group -SA- represents the partial formula Ib and R, a group -CH2-R2, in which R2 represents an esterified hydroxyl or mercapto group according to Claim 1, or their group Salts, characterized in that in such a compound, if appropriate with intermediate protection of free functional groups, such a radical R2 is converted into an etherified mercapto group R2 by treatment with a mercaptan compound. SUBJECT 15. Use according to claim II, characterized in that the 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyW acetylaminol-7a-methoxy-3-cephem4-carbon acid by treatment with 5- Mercapto-l-methyl-tetrazole was converted into the 7I3 + 2- (5-aminomethyl-2-thenyl> acetylaminoi 7a-methoxy3- (1-methyl-5-tetrazolyl-thiomethyl) -3-cephem4-carboxylic acid.