Patent EA-000165-B1 (EA)
Title: Cephalosporines having in position 7 substituted benzyloxyimino radical, method preparation and administration thereof
Inventor: ASZODI JOSEF
IPC: C07D501/00
Filed: 1996-08-15
Abstract: 1 Cephalosporin of general formula (1):   isomer syn as intercomplex solts or salts of inorganic or organic salts or bases, wherein R1, R<2>, R<3> and R<5>, identical or different, represent a hydrogen atom, a halogen atom or radical chosen from the group consisting from radicals: hydroxy, alkyl including from 1 to 4 carbon atoms optionally substituted by one or several halogen atoms alkyloxy including from 1 to 4 carbon atoms, mercapto-radical, alkylthio-radical including from 1 to 4 carbon atoms, nitro, cyano, amino, alkylamino comprising from 1 to 4 carbon atoms, dialkylamino, comprising from 2 to 8 carbon atoms, carbamoyl, (alkylamino) carbonyl comprising from 2 to 5 carbon atoms, (dialkylamino) carbonyl comprising from 3 to 9 carbon atoms, carboxy, alkoxycarbonyl comprising from 2 to 5 carbon atoms, acyloxy radical comprising from 1 to 8 carbon atoms     in which Rx and Ry, identical or different, represent a hydrogen atom or alkyl radical, including from 1 to 4 carbon atoms, R4 represents hydroxy radical or acyloxy radical including from 1 to 8 carbon atoms R7 represents a hydrogen atom or alkyloxycarbonyl readical, in which alkyloxy radical includes from 1 to 3 carbon atoms, A represents a hydrogen atom, an equivalent of alcali or alcali earth metals, magnesium, ammonium or aminated organic base, or A represents the residue of ester readily cleavable group, or CO2A represents CO2<-> wherein a wavy line designates, that CH2R6 group may be in position E or Z, and R6 represents, as quartenary ammonium one of below radicals:         in case, that if, when A represents COO-, R1 represents carboxy radical, R2 and R5 hydrogen, R3 and R4 are correspondingly hydroxy or acyloxy (C1-8) hydroxy or acyloxy (C1-8) radical and R6 represents   R7 represents hydrogen, and in case, when A represents COO, R1, R2 and R5 represent hydrogen, R3 and R4 hydroxy or acyloxy (C1-8) radical and R6 represents     R7 represents alkyloxycarbonyl radical. 2. Compounds of general formula (I) according to Claim 1 wherein R6 represents radical such as quinoleinium, isoquinoleinium, 4-(methylthio) pyridinium, thieno[2,3-b]pyridinium, 1-methyl pyrrolidinium, N-methyl N-ethyl N-(2-amino 2-oxoethyl) aminium, imidazo-1,2-a-pyridinium or radical 6,7-dihydro-5H-l-pyrindinium. 3. Compounds of general formula (I) according to Claim 1 or 2 wherein each of R3 and R4 represents hydroxy radical 4. Compounds of general formula (I) according to Claim 1, 2 or 3 wherein each of R2 and R5 represents a chlorine or fluorine atom. 5. Compounds of general formula (I) according to Claim 1, 2 or 3 wherein R2 represents a fluorine atom. 6. Compounds of general formula (I) according to Claim 1, 2 or 3 wherein R2 represents metoxy raqdical, and one of R1 and R5 represent a chlorine atom. 7. Compounds of general formula represented by the following compounds: intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-difluorine 3,4 -dihydroxyphenyl) mehoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4.2.0]oct-2-en-3-yl) 2-propenyl) quinoleinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl)- ((2,5-dichlorine 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicycio[4,2,0]oct-2-en-3-yl) 2-propenyl) quinoleinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-difluorine 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) imidazo(1,2-a) pyridinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-dichlorine 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) imidazo(1,2-a) pyridinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-difluorine 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H-1 -pyrindinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((2,5-dichlorine 3,4 -dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H-1 -pyrindinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((5-fluorine -3,4- dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-aza-bicycio[4,2,0]oct-2-en-3-yl) 2-propenyl) quinoleinium, intercomplex salt (6R-(3-(E) 6alpha, 7beta-(Z))) 1-(3-(7-(((2-amino 4-thiazolyl) ((methoxycarbonyl) -3,4- dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-aza-bicycio[4,2,0]oct-2-en-3-yl) 2-propenyl) quinoleinium, 8. Method of obtaining compounds of general formula (I) wherein aldehyde of aromatic series of formula (II):     in which R1, R2, R3, R4 and R5 such as defined in Claim 1 if necessary protected in their functional groups and thus transformed in aldehyde of aromatic series of formula (IIp)   in which R1p, R2p, R3p, R4p and R5p have correspondingly values R1, R2, R3, R4 and R5, as defined above, or protected functional group wherein said aldehyde of formula (IIp) either treated by a reducing agent to obtain alcohol of formula (III)     or gomolog in alpha-hydroxy acid of formula (III1) :   which is esterified to alpha-hydroxy ester of formula (III2):   in which Alc represents alkyl radical, including from 1 to 4 carbon atoms, ester of formula (III2) or alcohol of formula are treated by N-hydroxyphtalimide, if nescessary in the presense of activating agent to obtain derivative of formula (IV):   which is subjected to hydrolysis to obtain 0-substituted hydroxylamine of formula (V) :   which is condensed using derivative 2-(2-aminothiazol-4-yl) 2-oxoacetic acid of formula (VI) :   in which R8 represents a hydrogen atom or protecting group amino function to obtain a derivative alpha-alk-oxyiminoacetic acid syn form of formula (VII) :   which, if necessary, is transformed in functional derivative, then a compound of formula (VII) or functional derivative thereof is subjected to aminating using ester chlorhydrate 7-amino 3-(3-halogen 1-propenyl) 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid of formula (VIII):       in which R9 represents the residue of readily cleavable ester thus obtaining a derivative 7-(N-substituted amido) - 3 -(3 halogen -1- propenyl) 8 -oxo 5 - thia 1 azabicyclo - [4,2,0] oct - 2- en - 2 carboxylic acid of formula (IX):     which, if necessary, is transformed in 3-(3-iodopropenyle) analogue of formula (X):   which is treated by the base of formula R6 to obtain a compound of formula (XI):   from which, if necessary, isomers (E) or (Z) are selected or transform (Z) isomers into (E) isomers or compound of formula (XI) subject, if necessary, to one or several below reactions in the given sequence : a) removal by hydrolysis or by thiourea treatment of all or part ester protecting groups and protecting groups of amino-radical or hydroxylic radicals, b) ecterification or salification of carboxylic radical using the base c) salification of amino-radical using acid, d) separation of compounds in the form of mixture R,S to R and S isomers. 9. Method of obtaining compounds of general formula (I) wherein 0 -substituted hydroxylamine of formula (V) is subjected to condensing with a compound of formula (XII) :   to obtain a compound of formula (XI) described in Claim 8, from which, if necessary, isomers (E) or (Z) are selected or transform (Z) isomers into (E) isomers or compound of formula (XI) subject, if necessary, to one or several below reactions in the given sequence : a) removal by hydrolysis or by thiourea treatment of all or part ester protecting groups and protecting groups of amino-radical or hydroxylic radicals, b) ecterification or salification of carboxylic radical using the base c) salification of amino-radical using acid, d) separation of compounds in the form of mixture R,S to R and S isomers. 10. Use compounds of formula (I) and salt thereof with acids as a pharmaseutical composition. 11. Use according to Claim 10 wherein compounds of formula (I) according to Claims 2-8 or salts thereof with acids as a pharmaceutical composition. 12. A pharmaceutical composition comprising said compound according to Claims 10 or 11.