GB2076803A - Substituted 7-(???-oxy-imino- acetamido)-cephalosporins and process for their preparation - Google Patents

Substituted 7-(???-oxy-imino- acetamido)-cephalosporins and process for their preparation Download PDF

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GB2076803A
GB2076803A GB8016252A GB8016252A GB2076803A GB 2076803 A GB2076803 A GB 2076803A GB 8016252 A GB8016252 A GB 8016252A GB 8016252 A GB8016252 A GB 8016252A GB 2076803 A GB2076803 A GB 2076803A
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syn
methoxy
isomer
cephem
carboxylic acid
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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Priority to BE0/204795A priority patent/BE888815A/en
Priority to JP7237981A priority patent/JPS5716890A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds having the general formula (I> <IMAGE> wherein: Z is -CN; -CONH2 or -COOR1, wherein R1 is hydrogen, C1-C6 alkyl or a carboxy-protecting group; A1 is a bond or has any of the meanings given below for A; in which case it can be the same as A or different therefrom, A is a branched or straight chain C1-C6 saturated or C2-C6 unsaturated aliphatic hydrocarbon radical, which may be unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, cyano, amino, -COR', where R' is hydrogen or C1-C6 alkyl, or -COOR1, wherein R1 is as defined above; R is hydrogen; a hydroxy-protecting group or a branched or straight chain C1-C6 saturated or C2-C6 unsaturated aliphatic hydrocarbon group, which may be unsubstituted or substituted by one or more substituents selected from a) hydroxy; b) cyano; c) C1-C6 alkyl; <IMAGE> wherein each of R2 and R3, which may be the same or different, is hydrogen, C1-C6 alkyl, C1-C6 aliphatic acyl or one of R2 and R3 is hydrogen and the other is an amino-protecting group; and e) -COOR1, wherein R1 is as defined above; Y is -O-COCH3 or -S-Het, wherein Het is an optionally substituted heterocyclic group T is a carboxy or esterified carboxy group; as well as the pharmaceutically and veterinarily acceptable salts thereof are useful antibacterial agents against gram-positive and gram-negative bacteria.

Description

SPECIFICATION Substituted 7-( a-oxy-i mino-acetamido)-cephalosporins and process for their preparation The present invention relates to new derivatives of 7- -oxy-imino-acetamido)-cephalosporins, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.
The compounds of the invention have the following formula (I)
wherein: Z is -CN; -CONH2 or -COOR1,wherei n R1 is hydrogen, C1-C6 alkyl or a carboxy protecting group; A1 is a bond or A; A is a branched or straight chain C1-C6 saturated or C2-C6 unsaturated aliphatic hydrocarbon radical, which may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, amino, -COR', where R' is hydrogen or C1-C6 alkyl, or -COOR1, wherein R1 is as defined above; R is hydrogen; a hydroxy protecting group or a branched or straight chain C1-C6 or C2-C6 unsaturated aliphatic hydrocarbon group, which may be unsubstituted or substituted by one or more substituents selected from a) hydroxy; b) cyano; c) C1-C6 alkyl;
wherein each of R2 and R3, which may be the same or different, is hydrogen, C1-C6 alkyl, C1-C6 aliphatic acyl or one of R2 and R3 is hydrogen and the other is an amino protecting group; and e) -COOR1, wherein R1 is as defined above; Y is --OO-COCH, or -5-Het, wherein Het is a') a pentatomic or hexatomic heteromonocyclic radical containing at least a double bond and at least a heteroatom chosen from N, S and 0; or b') a heterobicyclic radical formed by a hexatomic heteromonocyclic ring, containing 1 to 3 nitrogen atoms, condensed with either a pentatomic or a hexatomic heteromonocyclic ring; the heteromonocyclic and the heterobicyclic radicals defined above at points a') and b') being unsubstituted or substituted by one or more substituents selected from a") hydroxy; halogen; C1-C6 alkoxy,-SR' or-COR' wherein R' is as defined above; b") C1-C6 alkyl, optionally substituted by one or more substituents selected from hydroxy and halogen; c") C2-C6 alkenyl, optionally substituted by one or more substituents chosen from hydroxy and halogen;
wherein m is zero or an integer of 1 to 3 and R2 and R3 are as defined above; or e") -S-(CH2)rn-COOR1; -(CH2)rn-COOR1; -CH=CH-COOR1; -(CH2)rn-SO3H; (CH2)rnCN,
wherein m, R1, R2 and R3 are as defined above.
T is a free or esterified carboxy group.
The present invention also includes within its scope the pharmaceutically and veterinarily acceptable salts of the compounds of formula (1) as well all the possible isomers, e.g. syn- and antiisomers, cis- and trans-isomers and optical isomers and their mixtures, the metabolites provided with antibacterical activity and the metalbolic precursors of the compounds of formula (I).
In the formulae of the invention the wavy line ( ç ) means that the oxyimino group may be both in the syn- and in the anti-configuration. As already said, both the single syn and anti-isomers and their mixtures are included in the scope of the invention.
The chain linked to the carbon atom in the 7-position is always a 7,1chain.
The alkyl, alkenyl, alkoxy and aliphatic groups may be branched or straight chain groups.
Carboxy-, amino- and hydroxy-protecting groups can be protecting groups usually employed in the chemistry of peptides for these groups.
Examples of carboxy-protecting groups are tert-butyl, benzhydryl, p-methoxy benzyl, p-nitrobenzyl, trityl and trialkylsilyl.
Examples of amino-protecting groups are formyl, an optionally halo- substituted C1-C8 aliphatic acyl, preferably chloroacetyl or dichloroacetyl, tert-butoxy carbonyl, p-nitrobenzyloxy-carbonyl or trityl.
Examples of hydroxy-protecting groups are formyl, acetyl, chloroacetyl, dichloroacetyl, trifl uoroacetyl, tetrahydropyranyl, trityl, or silyl, especially trimethylsilyl or dimethyl-tert.butyl silyl.
A C1-C6 alkyl group is preferably C1-C4 alkyl, in particular methyl, ethyl, propyl or isopropyl.
A C2-C6 alkenyl group is preferably C2-C4 alkenyl, in particular vinyl or allyl.
A C1-C6-alkoxy group is preferably C1-C6-alkoxy group is preferably C1-C3 alkoxy, in particular methoxy or ethoxy.
(The term "in particular whenever used herein is a non-limiting indication of preference).
A halogen atom is preferably fluorine, chlorine or bromine, more preferably chlorine.
A C1-C6 alkyl substituted by halogen is preferably a trihalo-C1-C6-alkyl group, in particular trifluoromethyl.
AC-C6 aliphatic acyl group is preferably C2-C3 alkanoyl, more preferably acetyl.
When A represents a C1-C6 branched or straight chain saturated hydrocarbon radical this is preferably C1-C3 alkylene, in particular methylene.
When A represents a C2-C6 branched or straight chain unsaturated aliphatic hydrocarbon radical this is preferably C2-C6-alkenylene, in particular vinylene or allylene, or C2-C6 alkynylene, in particular propargylene, but vinylene is the best, most preferred, meaning.
When Y represents a group -S-Het wherein Het is a pentatomic or hexatomic heteromonocyclic radical as defined above this is preferably thiazolyl, thiadiazolyl, isoxazolyl, imidazolyl, tetrazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyi, pyrazinyl, triazinyl or triazolyl.
When Y is a group -5-Het wherein Het represents a heterobicyclic radical as defined above, this is preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl ring condensed either with a pentatomic ring chosen from tetrazole, triazole, thiadiazole, oxadiazole, thiazole, imidazole, pyrazole, oxazole, isoxazole, furan, thiophene, pyrrole, or with a hexatomic ring chosen from pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyran, thiopyran, oxazine, thiazine.
When R is a branched or straight chain saturated C1-C6 aliphatic hydrocarbon group is is preferably C1-C3 alkyl, namely methyl, ethyl, n-propyl or isopropyl, either unsubstituted or substituted by carboxy, cyano or carbamoyl.
When R is a branched or straight chain unsaturated C2-C6 aliphatic hydrocarbon group this is preferably C2-C4 alkenyl, in particular vinyl or allyl or C3-C4 alkynyl, in particular propargyl, either unsubstituted or substituted by carboxy, cyano or carbamoyl.
When T is an esterified carboxy group it is preferably a group of formula -COOM1, wherein M1 is one of the radicals
wherein R4 is hydrogen or C1-C6 alkyl; Q is -0-or -NH-; R5 is an alkyl group, e.g. C1-C6 alkyl, or a basic group, in particular an alkyl, e.g. C1-C6 alkyl, or aralkyl, e.g. benzyl, group substituted by at least an amino group, which in turn, may be unsubstituted or substituted, e.g. R6 may be alkyl-NH-CH3, aralkyl-NH-CH3,
or -CH2NH2;; R8 is an alkyl group, in particular a C1-C6 alkyl group, e.g. methyl, propyl, isopropyl, an aryl group, in particular phenyl, a cycloalkyl group, in particular cyclopentyl, cyclohexyl and cycloheptyl, a heteromonocyclic ring, e.g. pyridyl, a bicyclic ring, e.g. indanyl, an aralkyl group, e.g. benzyl.
The pharmaceutically and veterinarily acceptable salts of the compounds of formula (I) are those either with inorganic acids,such as hydrochloric acid, sulphuric acid, or with organic acids, such as citric, tartaric, malic, maleic, mandelic, fumaric and methanesulphonic acid, or with inorganic bases such as sodium, potassium, calcium or aluminium hydroxides and alkaline or alkaline-earth carbonates or bicarbonates, or with organic bases, such as organic amines, e.g., lysine, triethylamine, procaine, dibenzylamine, N-benzyl-,1-phenethylamine, N-benzyl-ss-phenethylamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N-ethyl-piperidine, diethanolamine, N-methyl-glucamine, tris-hydroxymethyl aminomethane and the like.Also the internal salts, e.g. zwitterions, are included in the scope of this invention.
As stated above the present invention includes within its scope all the possible isomers, e.g. syn and anti-isomers or cis and trans isomers or their mixtures; when, e.g., two groups -CH=CH- are present in the compounds of formula (I), the invention includes within its scope either the cis,cis- or trans,trans- or cis,trans- or trans,cis-isomers or their mixtures.
The compounds of formula (I) containing one or more protecting groups are also included in the scope of the present invention.
Preferred compounds of the invention are the compounds of formula (I) wherein: Z is -CN; -CONH2 or-COOR1, in which R1 is as defined above; A is -CH2- or -CH=CH-; A1 A1 is a bond, -CH2-or-CH=CH-; isabond,-CH2-or-C H=CH-; R is hydrogen; C1-C6 alkyl; C2-C4 alkenyl;.
-CH=CH-COOH;-(CH2)-COOH,-(CH2)-CN or-(CH2)-C0NH2, wherein n is 1,2 or 3; Y is --OO-COCH, or -5-Het,, wherein Het is: a"') a tetrazolyl radical, unsubstituted or substituted by one or more substituents chosen from C1-C3 alkyl; C2-C4 alkenyl;(CH2)COOR1,-CH=CH-COOR1, (CH2)nSO3H,(CH2)nCN,
wherein n, R, R2 and R3 are as defined above; or b"') a thiadiazolyl radical, unsubstituted or substituted by one or more substituents chosen from C1-C4 alkyl;C2C4 alkenyl;-SH;-SCH3;-S-CH2COOH;(CH2)COOH,
wherein m, R2 and R3 are as defined above; or c"') a heterobicyclic radical selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl each optionally substituted by one or more substituents, chosen from -OH; -SH; C1-C3 alkyl; C2-C4 alkenyl;(CH2)COOR-CH=CH-COOR, -S-CH2-CUOH,
wherein n, R, R2 and R3 are as defined above; especially the Het radicals in any of compounds 1-32 hereinafter; and the pharmaceutically and veterinarily acceptable salts thereof.
A preferred class of the compounds of the invention are the syn isomers of the compounds of the formula (I).
Specific examples of compounds of the invention are the following: 1) 7-[(ss-cyanomethylthio)-(&alpha;-methoxy-imino-)propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 2) 7-[(ss-carboxymethylthio)-(ct-methoxy-imino)-propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 3) 7-[(,1-cyanomethylthio)-(a-methoxy-imino)-propionamido]-3-[( 1-methyl-i ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 4) 7-[(ss-cyanomethylthio)-(&alpha;-methoxy-imino)-propionamido]-3-[(tetrazolo[1,5-b]-pyridazin-6-yl)- thiomethyl]-3-cephem-4-ca rboxylic acid (syn-isomer); 5) 7-[(,B-carboxymethyithio)-(-methoxy-imino)propiona mido]-3-[( 1 -methyl-1 ,2,3,4-tetrazol-5-yl) thiomethyl]3-cephem-4-carboxylic acid (syn-isomer); 6) 7[(ss-carboxymethylthio)(&alpha;-amethoxyimino)propionamido]-3-[(8-amino-tetrazolo[1 ,5-b] pyridazin-6-yl)-thiomethyl)-3-cephem-4-carboxylic acid (syn-isomer); 7) 7-[(ss-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)propionamido]-3-acétoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 8) 7[(ss-(Z)carboxyviny-thio)(amethoxyimino)propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 9) 7-[(ss-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-propionamido-3-[(1-methyl-1 ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 10) 7-[(,1-(Z)-carboxyvinylene-thio)-(a-methoxy-im ino)-propionamido]-3-[( 1 -methyl- 1 ,2,3,4-tetrazol 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 11) 7[(ss-(Z)carboxyvinylenethio)(&alpha;-methoxy-imino)propionamido]-3-[(8-amino-tetrnzoIo-[1 ,5-b]- pyridazin-6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (syn-isomer); 12) 7-[(&alpha;-cyano-methylthio)-&alpha;-(methoxy-imino)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer); 1 3) 7-[(a-cyano-methyIthio)--(methoxy-imino)-aceta mido]-3-[( 1 -methyl-1 ,2,3,4-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 14) 7-[(a-cyano-methylthio)--(methoxy-imino)-acetam ido]-3-[(8-amino-tetrazolo[ 1 ,5-b]-pyridazin 6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (syn-isomer); 1 5) 7-[(c'-carboxy-methyl-thio)-(-methoxy-im ino)-aceta mido]-3-acetoxymethyl-3-cephem-4 carboxylic acid (syn-isomer); 1 6) 7-[(a!-carboxy-methyi-thio)-(sg-methoxy-imino)-acetamido]-3-[( -methyl-l ,2,3,4-tetrazol-5-yI )- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 17) 7-[(,z-carboxy-methyl-thio)-(ar-methoxy-imino)-acetamido]-3-Ltetrazolo-[1 ,5-b]-pyridazin-6-yl)- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 1 8) 7-[(a-carboxy-methyl-thio)-(cz-methoxy-im ino)-aceta mido]-3-[8-am ino-[1 ,5-b]-pyridazin-6-yl) thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 1 9) 7-[(cE-(Z)-cyanovinylene-thio)-(zz-methoxyimino)-acetam ido]-3-acetoxymethyl-3-cephem-4 carboxylic acid (syn-isomer); 20) 7-[(&alpha;-(Z)-cyanovinylene-thio)-(-methoxyimino)-acetamido]-3-[( 1-methyl-i 2,3 ,4-tetrazol-5-yI )- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 21) 7-[(a-(Z)-carboxyvinylene-thio)-(a-methoxy-im ino)-acetamido]-3-acetoxymethyl-3-cephem-4 carboxylic acid; 22) 7-[(eE-(Z)-carboxyVinylene-thio)-(-methoxy-imino)-acetamido]-3-[( 1 -methyl-l ,2,3,4-tetrazol-5 yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 23) 7-[ss-cyanomethyl-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-acetoxy-methyi-3-cephem- 4-carboxylic acid (syn-isomer); 24) 7-[,1-cyanomethyl-thio-(Z)-vinylene-a-methoxy-im ino-aceta mido]-3-[( l-methyl-l ,2,3,4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 25) 7-[,1-carboxymethyI-thio-(Z)-vinylene--methoxy-im ino-acetamido]-3-acetoxy-methyl-3-cephem 4-carboxylic acid (syn-isomer); 26) 7-[ss-carboxymethyl-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[( -methyl-1,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 27) 7-[ss-carboxymethyl-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[(8-amino-tetrazolo] 1 5- b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 28) 7-[(,1-(Z)-cya novinylene-thio)-(Z)-vinylene-an-methoxy-im ino-acetamido]-3-acetoxymethyl-3 cephem-4-carboxylic acid (syn-isomer); 29) 7-[(,1-(Z)-cyanovinylene-thio)-(Z)-vinylene-a-methoxy-im ino-aceta mido]-3-[( 1-methyl-i ,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 30) 7-[(,1-(Z)-carboxyvinylene-thio)-(Z)-vinylene-a-methoxy-im ino-aceta m ido]-3-acetoxymethyl-3 cephem-4-carboxylic acid (syn-isomer); 31) 7-[(ss-(Z)-carboxyvinylene-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[( 1-methyl- 1 ,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 32) 7-[(ss-(Z)-carboxyvinylene-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[(8-amino- tetrazolo[1 S-b] pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer), as well as the pharmaceutically or veterinarily acceptable salts thereof.
The structural formulae of the above numbered compounds are shown in the following table.
Compound No. Z A A1 R Y 1 NC- -OH2- -CH,- -CH, -O-COCH, 2 HOOC- -OH2- CH2 OH3 -O-COCH3 NN 3 NC- -OH2- -OH2 OH3 N-'C::H3 3 NC- -CH,- -CH,- 3 4 NC- -OH2- -CH,- CH3 -Si\N OH3 5 HOOC- -OH2- -CH2 OH3 -stN,Ncg3 %CH3 6 HOOC- -OH2- -OH2- f 6 HOOC CH2 CH2 CH3 - > ig* 7 N -CH=CH- -OH2- CH2 -OoCOCH3 8 HOOCH -CH=CH-- -OH2- CH3 -NCOCH3 9 N -CH=CH- -OH2- CH2 H3 10 HOOC- -CH=CH- -OH2- CH 3 N ZPI2 dl 11 HOOC- -CHICH- CH2 OH3 ~SQ ,NN -ococii 12 NC- -OH2- bond CH3 -O-COCN3 N-N 13 NC- -OH2- bond CH3 CH3 NH2 14 NC- -OH2- bond CH3 15 HOOC- -OH2- bond CH3 -O-COCH3 16 HOOC- -OH2- bond -OH3 cii3 17 HOOC- -OH2- bond -OH3 18 HOOC -OH2- bond CH3 iNsNN 19 NC- -CH=CH- bond -OH2 -NCOCH3
Oompound Compound No. Z A A, R Y NN 20 NO- -CH--CH- bond -cH3 -StN4g3 21 HOOC- -CH=CH- bond -OH3 -o-cocH, 22 HOOC- -CH=CH- bond -OH3 ~ AN,Ncg3 NH3 23 NC- -CH2- -CH=CH- -OH3 OCOCH 24 NC- -OH2- -OH=OH- -OH3 CH3 25 HOOC- -CH2- -CH=OH- -OH2 W LCOCH3 N-N 26 HOOC- -OH2- -OH=OH- -OH3 NH3 27 HOOC- -CH2- -CH=CH- -0-H3 28 NC- -CH=CH- -CH=CH- -OH2 OOCH3 29 NO- -CH=CH- -CH=CH- -OH3 - 1NI7,NI CR 3 30 HOOC- -CH=CH- -CH=CH- -OH3 O-CoCH --3 31 HOOC- -CH=CH- -CH=CH 32 FOOT~ -CH=CH- -CH=CH-- -CH,
The compounds of the invention are prepared by a process comprising: a) reacting a compound of formula (II)
where Y and T are as defined above, and E is amino or a group-N=C=# wherein Ct) is oxygen or sulphur, or a reactive derivative thereof, with a compound of formula (III)
where Z, A, A1 and R are as defined above, or with the reactive derivative thereof and if desired removing the protecting groups where present; or b) reacting a compound of formula (IV)
where A1, R, T and Y are as defined above and Xis halogen, or a salt thereof, with a compound of formula (V) Z-A-SH (V) where Z and A are as defined above, or with a reactive derivative thereof and if desired removing the protecting groups where present; or c) reacting a compound of formula (VI)
where Z, A, A,, T and Rare as defined above, or a salt thereof, with a compound of formula (VII) H-S-H et (Vll) where Het is as defined above, or with a reactive derivative thereof; and if desired removing the protecting groups where present; or d) reacting a compound of formula (VIII)
where Z, A, A1,T and Y are as defined above, or a salt thereof, with a compound of formula (IX) H2N-O-R (IX) where R is as defined above, or a salt thereof and, if desired, removing the protecting groups, where present, and, if desired, converting a compound of formula (I) into a pharmaceutically or veterinarily acceptable salt and/or, if desired, obtaining a free compound from a salt and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof and/or, if desired, resolving a mixture of isomers into the single isomers.
In the compounds having the formulae from (II) to (IX), the free carboxy and/or amino and/or hydroxy groups possibly present may be protected if necessary, in a conventional way before the reactions a) to d) take place. Examples of protecting groups are those ones usually employed in the synthesis of peptides, for example the protecting groups reported above. At the end of the reaction the protecting groups, if desired, may be removed in a conventional way.
The carboxy-protecting groups may be removed, for example, by mild hydrolysis or by catalytic hydrogenation, for example, with Pd/C at room pressure.
The amino-protecting groups, if desired may be removed in a known manner too; for example the monochloro-acetyl group may be removed by treatment with thiourea; the formyl and trifluoroacetyl groups may be removed with potassium carbonate in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid.
The hydroxy-protecting groups if desired may be removed in a known analogous way.
Since, however, compounds of formula (I) containing the said protecting groups are included in the present invention, removal of the protecting groups is not an essential process step.
The starting materials used in each of the above mentioned processes (a) to (d) when one or more asymmetric carbon atom are present, may be either optically active or racemic compounds.
Moreover, the starting materials, when e.g., a group -CH=CH- is present, may be either the cisisomers or the trans-isomers; when there are, e.g., two -CH=CH- groups, the starting materials may be either the cis,cis-isomers, or the trans,trans-isomers or the cis,trans-isomers or the trans,cis-isomers.
The starting materials may also be syn- or anti-isomers and their mixtures.
A reactive derivative of the compounds of formula (II) may be, for example, an amine salt, a silyl ester or a metal salt when X is carboxy.
A reactive derivative of the compounds of formula (Ill) may be, for example, an acyl halide, an an hydroxide or a mixed anhydride, an amide, an azide, a reactive ester or a salt, for instance, the salts formed with alkali or alkaline-earth metals, ammonia or an organic base.
A reactive ester may be, for example, p-nitrobenzyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl-ester, N-hydroxy succinimide ester and N-hydroxyphthalimide ester.
The reaction between a compound of formula (II) or a reactive derivative thereof and a compound of formula (lli) or a reactive derivative thereof may be performed either at room temperature or under cooling, preferably from about -500C to about +400 C, in a suitable solvent, e.g. acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, 1 ,2-dichloro-ethane or in a mixture of water and a solvent miscible with water, e.g. acetone, dioxane or dimethylformamide, and, if necessary, in the presence of a base, such as, for example, sodium bicarbonate, potassium bicarbonate or a trialkylamine, or in the presence of another acid acceptor, such as an alkylene oxide, e.g., propylene oxide.
When the compound of formula (III) is reacted with the compound of formula (II) wherein E is amino, as a free acid or as a salt, it is desirable that the reaction is performed in the presence of a condensing agent, such as, for instance, N,N'-dicyclohexyl-carbodiimide, or in the presence of an appropriate carbonyl derivative such as, for example, carbonyl diimidazole in an anhydrous solvent preferably selected from the group consisting of methylene chloride, acetonitrile, dimethylformamide.
A salt of a compound of formula (IV) is preferably a salt of a compound of formula (IV) where T is a free -COOH, for example, an alkali metal in particular sodium or potassium salt.
A reactive derivative of a compound of formula (V) is preferably a salt, in particular an alkali metal, e.g. sodium or potassium, salt.
The reactive derivative of a compound of formula (V) is preferably a salt, in particular an alkali metal, e.g. sodium or potassium.
The reaction of a compound of formula (IV), our a salt thereof, with a compound of formula (V), or a reactive derivative therof, for example a salt, is preferably carried out at temperatures ranging from about 3000 to about +900 C, preferably at room temperature in the presence of an inorganic or organic base, such as, for instance, sodium or potassium hydroxides, sodium carbonate and triethylamine, in a suitable solvent which may be, for instance, acetone, chloroform, methanol, ethanol, methylene chloride, dimethylformamide, dioxane or water.
When in the compound of formula (V) the -SH group is not salified, it is preferable to carry out the reaction in the presence of a base, such as, for example, an alkali metal carbonate, an alkali metal hydroxide or triethylamine.
The reaction between a compound of formula (VI), or a salt thereof, and a compound of formula (all), or a reactive derivative thereof, for example, an alkali metal salt, may be carried out in water or in a mixture of water and an organic solvent such as acetone, ethanol, dioxane and tetrahydrofuran. The reaction temperature is preferably from about 50C to about 950C and the pH from about 4.5 to about 7.5. If preferred, a buffer is used such as, for example, sodium phosphate or acetate. In the compound of formula (VI) the salifying agent for the carboxy group is preferably an alkali or alkaline-earth metal hydroxide.
In a different way, the same reaction may be performed without any base and in a strictly anhydrous solvent, at temperatures ranging from about 500C to about 1200C, and for reaction times ranging from a few hours to a few days. The preferred solvent is acetonitrile and an inert atmosphere (e.g. nitrogen) may be advisable in order to prevent the oxidation of the heterocyclic thiol (VII).
The reaction between a compound of formula (VIII), or a salt thereof, e.g. an alkali or alkaline-earth metal salt, and a compound of formula (IX) or a salt thereof, e.g., the hydrochloride, is preferably performed in aqueous solvents or in a solvent mixable with water, e.g. acetone, dioxane, tetrahydrofuran, dimethylformamide, at a temperature ranging from about 50C to about 900C, preferably from 250Cto 550the pH ranging preferably from 4 to 7.5.
The optional salification of the compounds of formula (I) as well as the optional conversion of a salt into a free compound, may be carried out according to conventional methods, i.e. methods already known in organic chemistry.
As stated above, a compound of formula (I) or a salt thereof, may be converted into another compound of formula (I) or a salt thereof; also these optional conversions may be performed by conventional methods. Thus, for example, an optional conversion may be the esterification of a compound of formula (I), wherein T is carboxy, which may be carried out by reacting the compound of formula (I), wherein the carboxy group is free or salified, for example in the form of a sodium, potassium, calcium or triethylammonium salt, with the suitable halide, in an organic solvent, such as acetone, tetrahydrofurane, chloroform, methylene chloride, dimethylformamide, dimethylsulphoxide, or in a mixture of water and an organic solvent, e.g. dioxane and acetone; the reaction temperature ranges from about 2000 to about +800C. Furthermore a compound of formula (I), wherein T is an esterified carboxy group, may be saponified using, for example, an inorganic acid, such as hydrochloric acid or an inorganic basis, such as sodium or potassium hydroxide, as it is known in organic chemistry.
Also the optional resolution of a mixture of isomers into the single isomers may be carried out by conventional methods such as, for example, fractionated crystallization and chromatography.
Thus, racemic compounds may be resolved into the optical antipodes, for example, by resolution, e.g. by means of fractionated crystallization of mixtures of diastereoisomeric salts, and, if desired, liberating the optical antipodes from the salts. What specified above for the reactions a) to d) as regards protection and de-protection of carboxy-, amino- and hydroxy-groups apply also to the herebelow reported reactions concerning the preparation of intermediate compounds, that is carboxy-, amino- and hydroxy-groups, if present, may be protected before the reactions take place and, at the end of the reactions, carboxy-, amino- and hydroxy protecting groups, if desired, may be removed.
Both protection and de-protection may be carried out by following conventional ways, for example those reported above.
The compounds of formula (II) where E is amino and is --OO-COCH, are known.
The compound of formula (II), wherein E is amino, and Y is -5-Het, may be prepared, for example, by reacting 7-amino-cephalosporanic acid or a salt thereof e.g. on alkali or alkaline-earth metal salt with the compound of formula (VII), using reaction conditions well known in literature, e.g.
those indicated above for the reaction between a compound (Vl) and a compound (VII).
The compound of formula (Il), wherein E is-N=C=Ct) may be prepared, e.g. by reacting a compound of formula (II), wherein E is amino, with phosgene or thiophosgene, in the presence of a hydrochloric acid acceptor, using known methods.
The compounds of formula (III) may be prepared according to one of the following methods: 1 ) by reacting a glyoxylic acid derivative of formula (X)
where Z, A and A1 are as defined above, or an ester thereof e.g. a C1-C6 alkyl ester, with a compound of formula (IX), using reaction conditions similar to those described for the preparation of the compounds (I) from the compounds (VII I) and IX); or 2) by reacting a compound of formula (III), wherein R is hydrogen, with an alkylating agent of formula (XI) R--X, (Xl) where R is as defined above, except hydrogen or hydroxy-protecting group, and X, is halogen, preferably iodine, bromine or chlorine, or the residue of a reactive ester of an alcohol, e.g. mesyloxy or tosyloxy; the reaction between the compound of formula (III), wherein R is hydrogen, and the compound of formula (Xl) may be carried out, preferably in an apolar aprotic solvent such as DMSO, THF, acetone, etc. or in an alcohol at temperatures ranging from about50 C to about +900C, optionally in the presence of 0-2 equivalents of a base e.g. an alkali metal hydride such as NaH or KH, an alkoxide, such as OH 3ONa, t BuOK, a terziary amine such as triethylamine, or an alkali metal carbonate, such as K2CO3;; or 3) by reacting a compound of formula (XII)
wherein A, and R are as defined above and the carboxy group may be free or protected in usual manner, with a compound of formula (XIII) Z-A-X1 (oil) where Z, X, and A are as defined above; this reaction may be performed either in an aqueous medium and in the presence of an inorganic base or in an organic solvent, preferably in an anhydrous organic solvent, for example, methylene chloride, chloroform, dioxane, in the presence of an organic base; the reaction temperatures range from about -200C to about +500C; or 4) by reacting a compound of formula (V) with a compound of formula (XIV)
where A,, Rand X are as defined above or a salt or an ester thereof, using reaction conditions similar to those described for the reaction between a compound of formula (V) and a compound of formula (IV) to give a compound of formula (I); or 5) by reacting a compound of formula (XII) with a compound of formula (XV) Z-C=-CH (XV) where Z is as defined above, so obtaining a compound of formula (III), wherein A is-CH=CH- (cis or trans).The reaction between the compound of formula (XII) and the compound of formula (XV) may be carried out preferably in a protic solvent, e.g., water or a lower aliphatic alcohol, e.g., ethanol, in the presence of 0-1 equivalent of a base such as, for example, triethylamine, an alkali metal bicarbonate, or carbonate or an alkali metal hydroxide, at temperatures ranging from about --200C to about +20oC; or 6) by reacting a compound of formula (V) with a compound of formula (XVI)
or a salt or an ester thereof, where R is as defined above, so obtaining, after hydrolysis of the possible ester group, a compound of formula (III) wherein A is-CH=CH-.
The reaction may be carried out in a suitable solvent, e.g. water or water and ethyl alcohol, at temperatures ranging from about --1 OOC to about +300C. The compound of formula (IV) may be prepared according to one of the following methods: 1 ') by reacting a compound of formula (II) with an acid of formula (XIV), or a reactive derivative thereof, using reaction conditions similar to those described for the reaction between the compound of formula (II) and an acid of formula (Ill), our a reactive derivative thereof, to give a compound of formula (I) or 2') by reacting a compound of formula (XVII)
where X, Ar, T and Y are as defined above, or a salt thereof, with a nitrosating agent to give compounds of formula (IV), where R is hydrogen. As nitrosating agent the nitrous acid may be used, prepared, for example, in situ from an alkaline nitrite and an acid such as HCI or CH2COOH, or an ester of the nitrous acid, such as, for example, amyl nitrite or even nitrosyl chloride.
The nitrosation reaction may be generally carried out in an organic solvent, such as, tetrahydrofurane, acetonitrile, dioxane, or in water, or in acetic acid, or in a mixture of these solvents.
The reaction may be accelerated by the presence of an acid, generally hydrochloric acid or acetic acid in the amount of one mole or more for each mole of the compound (XVII); the temperature ranges from --200C to +500C and generally it is near the room temperature.
Furthermore, a compound of formula (it), wherein R is hydrogen may be converted into a compound of formula (IV), wherein R has the general values above described and wherein the carboxy group is in protected form, by reaction with an appropriate diazoalkane, preferably in an inert solvent, such as, e.g. ethyl ether, or by alkylation with a compound of formula (Xl), using the same conditions already described for the reaction between a compound of formula (II[), wherein R is hydrogen, and a compound of formula (XI).
The compounds of formula (V) are known or may be obtained by known methods.
The compounds of formula (VI) may be prepared according to the methods described for the preparation of the compounds of formula (I) at the paragraphs a), b), and d), by replacing in each of these methods the compound of formula (II) with the compound of formula (XVIII),
where E and T are as defined above, or a salt thereof, and using analogous reaction conditions.
The compounds of formula (VII) are known compounds or may be obtained by known methods.
The compound of formula (VIII) may be obtained according to one of the following methods: 1 "') by reacting a compound of formula (II) with an acid of formula (X), or a reactive derivative thereof, using the reaction conditions similar to those described for the reaction between the compound of formula (II) and an acid of formula (III) to give compounds of formula (I); or 2"') by reacting a compound of formula (V) with a compound of formula (XIX)
where X, Aa, T and Y are as defined above, or a salt thereof, using reaction conditions analogous to those described for the preparation of the compounds of formula (I) starting from compounds of formula (V) and compounds of formula (IV).
The compounds of formula (IX) are known or may be obtained by known methods.
The compounds of formula (X) may be prepared according to one of the following methods: 1 Iv) by reacting a compound of formula (XIII) with a compound of formula (XX)
where A1 is as defined above, or an ester thereof, and, possibly, by hydrolyzing the obtained ester, using reaction conditions similar to those already described for the reaction between the compounds of formula (XII) and the compounds of formula (XIII) to give compounds of formula (III), or 2lV) by reacting a compound of formula (V) with a compound of formula (XXI)
where X and A, are as defined above, or with an ester thereof, and, possibly, by hydrolyzing the obtained ester, using reaction conditions analogous to those described for the preparation of compounds of formula (I) starting from compounds of formula (V) and compounds of formula (IV); or 31V) by reacting a compound of formula (XX) with a compound of formula (XV), so obtaining a compound of formula (X), wherein A is -OH-OH- (cis or trans), using the same reaction conditions described for the preparation of compounds of formula (III) starting from compounds of formula (VII) and compounds of formula (XV).
The compounds of formula (XVII) may be obtained by reacting a compound of formula (II) with an acid of formula (XXI I) X-A1-CH2-COOH (XXII) where X and A1 are as defined above, or with a reactive derivative thereof, using reaction conditions analogous to those described for the preparation of compounds of formula (I) starting from compounds of formula (II) and compounds of formula (III).
The compounds of formula (XIX) may be obtained by reacting a compound of formula (Il) with a compound of formula (XXI), or a reactive derivative thereof, using reaction conditions similar to those described for the reaction between the compound of formula (II) and an acid of formula (III), or a reactive derivative thereof, to give compounds of formula (I).
The compounds of formula (Xl), (XIII), (XV), (XVIII) and (XXII), are known compounds or may be prepared by known methods.
Also the compounds of formula (XII), (XIV) and (XVI) may be prepared by chemical methods well known in literature, for example, by reaction of the corresponding -oxo-acids with a hydroxy or alkoxyamine or, sometimes, by nitrosation of the corresponding monosubstituted acetic acids or, preferably, esters, and in this case hydrolysing the obtained esters.
When the starting materials of formula (III) (IV), (VI), (XIV) and (XVI), are syn-isomers, the reaction products are syn-isomers too and vice versa. In some cases a little amount of the anti-isomers might be obtained together with the syn-isomer. The separation of the isomers may be performed by known methods, e.g. by fractional crystallization or by chromatography as stated above.
The compounds of the present invention have a high antibacterial activity both in animals and in humans against Gram-Positive and Gram-negative bacteria normally susceptible to cephalosporins such as staphylococci, streptococci, diplococci, Klebsiella, Escherichia coli, Proteus mirabilis, Salmonella, Shigella, Haemophilus and Neisseria. The compounds of the invention show also a high activity against the strong beta-lactamase producer micro-organisms, for example, Kiebsiella aerogenes 1082 E, Escherichia coli Tem, Enterobacter cloacae P99, and indole-positive Proteus and the like, as well as against Pseudomonas aeruginosa strains, which are normally resistant to most cephalosporins.
Owing to their high antibacterial activity either in animals or in humans against both Grampositive and Gram-negative bacteria the compounds of the present invention are useful in the treatment of the infections caused by said microorganisms, such as respiratory tract infections, for example, bronchitics, bronchopneumonia, pleurisy; hepatobiliary and abdominal infections, for example, septicemia, urinary tract infections, for example, pyelonephritis, cystitis, obstetrical and gynecological infections, for instance, cervicitis, endometritis; ear, nose and throat infections, for instance, otitis, sinusitis, parotitis.
The toxicity of the compounds of the invention is quite negligible and therefore they can be safely used in therapy. For example, the approximate acute toxicity in the mouse determined with single intravenous administrations of increasing doses and measured on the seventh day of treatment is greater than 2000 mg/kg.
The compounds of the invention may be administered either to humans or to animals, in a variety of dosage forms, e.g. orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally, e.g. intravenously or intramuscularly (as solutions or suspensions), with intravenous administration being preferred in emergency situation; by inhaiation in the form of aerosols or solutions for nebulizers; intravaginally in the form, e.g. of bougies or topically in the form of lotions, creams and ointments.
The invention includes pharmaceutical and veterinary compositions comprising a compound of the invention, in association with a pharmaceutically or veterinarily acceptable excipient e.g. a diluent or carrier. These pharmaceutical or veterinary compositions may be prepared in a conventional way by employing the conventional carriers or diluents used for the other cephalosporins. Conventional carriers or diluents are, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like.
Daily doses in the range of about 1 to about 100 mg per Kg of body weight may be used, in various animal species; the exact dose depending on the age, weight and condition of the subject to be treated and on the frequency and route of administration. A preferred way of administration of the compounds of the invention is the parenteral one: in this case the compounds may be administered, for example to adult humans, in an amount ranging from about 100 mg to about 200 mg pro-dose, preferably about 1 50 mg pro-dose, 1-4 times a day, dissolved in a suitable solvent, such as, for example sterile water or lidocaine hydrochloride solution for intramuscular injections, and sterile water, physiological saline solution, dextrose solution or the conventional intravenous fluids or electrolytes, for intravenous injections.
Furthermore, the compounds of the invention may be used as anti-bacterial agents in a prophylactic manner, e.g. in cleaning or as surface disinfecting compositions, for example, at a concentration of about 0.2 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert, dry or aqueous carriers for application by washing or spraying. They are also useful as a nutritional supplement in animal feeds.
The I.R. spectra were determined in a solid phase or in NujolR on a Perkin Elmer 125 spectrophotometer.
N.M.R. spectra were determined with a Perkin Elmer R-24 B (60 MHZ) in DMSO (dimethylsulphoxide), CD3COCD3, CC14, or CDCI3 with (CH3)4Si as internal standard.
As the solvents are in some cases retained, the assessment of melting points of the compounds was somewhat difficult. In these cases the physico-chemical constant is followed by the word "dec", namely decomposition.
The following examples illustrate but do not limit the present invention.
PREPARATION 1 p-mercapto--methoxy-imino-propionic acid A solution of O-methyl-hydroxylamine hydrochloride (1.71 g; 0.0205 M) in water (20 ml) was added, under stirring, in 30 minutes at about 10 C, to a solution of /3-mercapto-pyruvic acid sodium salt (3.56 g; 0.02 M) (Synthetized according to Biochem. Biophys. Acts. 121, 159 (1966). NaHCO3 (1.7 g) was added at the same time so as to maintain the pH between 4 and 5. The mixture was then stirred for 3 hours at room temperature, allowed to stand overnight, then acidified with 2 N aqueous HCI (10 ml) and extracted with ethyl acetate (3 x 50 ml). The organic extract was washed with 25% aqueous NaCI solution (2 x 25 ml), the separated organic phase was dried (Na2SO4), then evaporated to dryness under vacuum.The obtained residue was crystallized from cyclohexane (100 ml), so obtaining ,1-mercapto-n- methoxy-imino propionic acid (Yield 90%; m.p.82.5-4 C).
Elemental analysis: found: C 32.30; H 4.73; N 9.29; S 21.46 calculated for C4H7NO2S: C 32.20; H 4.73; N 9.39; S 21.50
1050 cm-l =N-OCH2) N.M.R. (acetone-d6): 2.3 (1H,t,-SH) [S p.p.m.] 3.44 (2H, d, S-OH2-) 4.05 (3H, s, -OCH2) 8.85 (1H, br-s,-COOH) PREPARATION 2 ,1-cyanomethyl-thio-a-methoxy-imino-propionic acid A solution of ss-mercapto-&alpha;-methoxy-imino-propionic acid (13.5 g; 0.09 M) in ethanol (50 ml), was added under stirring to a solution of 85% KOH (12.0 g; 0.18 M) in ethanol (250 ml), in about 15 minutes at 10--1 5"C. A solution of chloroacetonitrile (7.1 g; 0.093 M) in ethanol (50 ml) was dropped, in 60 minutes into the solution above obtained.
The rection mixture was stirred for 18 hours at room temperature; the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water (100 ml) and the aqueous solution was extracted with ethyl ether (3 x 50 ml). The ethereal extracts were discarded and the aqueous solution was acidified with 20% HCI. The white precipitate so obtained was extracted with ethyl ether (3 x 100 ml).
The ether was washed with 25% aqueous NaCI solution (2 x 50 ml); the ethereal phase was separated, dried (NaSO4) and evaporated to dryness under vacuum. The obtained residue was crystallized from benzol (150 ml), to give ss-cyanomethyl-thio-&alpha;-methoxy-imino-propionic acid. (Yield 90%; m.p. 63--650C).
Elemental analysis: found: C37.95; H4.26; N 14.64; S 17.12 calculated for C6H8N2O3S: C 38.29; H 4.28; N 14.89; S 17.03 l.R. (KBr); U 2250 cm-l (-C-N)
1050 cm-' (=N-OCH3) N.M.R. (acetone-d6): 3.6 (2H, s, -SCH2CN)
4.07 (3H, s, =N-OCH3) 8.0 (1 H, br, -s, -COOH) PREPARATION 3 ss-tert-butoxy-carbonyl-methyl-thio-&alpha;-methoxy-imino-propionic acid A solution of tert-butyl-chloroacetate (4.65 g; 0.031 M) in ethanol (20 ml) was dropped, under stirring at 5100C, in 60 minutes into a solution of the ss-mercapto-&alpha;-methoxy-imino-propionic acid potassium salt (0.03 M) in ethanol (100 ml), obtained as reported in the previous preparation 2. The mixture was stirred for 18 hours at room temperature, then evaporated to dryness under vacuum; the residue was dissolved in water (50 ml).The aqueous solution was extracted with ethyl ether (2 x 50 ml) and the ethereal layer was discarded, and the aqueous solution was acidified with 3 N aqueous HCI (10 ml); the obtained oil was extracted with ethyl acetate (3 x 100ml). The organic phase was washed with water (2 x 50 ml), dried (Na2SO4) and evaporated to dryness under vacuum. The oily residue solidified; the obtained mass was crystallized from cyclohexane (100 ml), to give p-tert-butoxy- carbonyl-methyl-thio-o:-methoxy-imino-propionic acid (Yield 85%; m.p. 55-7 C).
Elemental analysis: found: C 45.55; H 6.49; N 5.32; S 12.39 calculatedforC10H'7NO5S: C45.61; H 6.51; N 5.32; S 12.17
1375 cm-' [-C(CH2)2] 1170-1160 cm-l (C--OO-C ester) 1050 cm-1 (=N-OCH2)
N.M.R. (acetone-d6): 1.45 (9H, s, tert-butyl) [s p.p.m.] 3.2 (2H, s, S-CH2-COO)
3.95 3H, s, =N-OCH3) 8.78 (1 H, br-s, -COOH) PREPARATION 4 ss-(Z)-tert-butoxy-carbonylvinylene-thio-&alpha;-methoxy-imino-propionic acid To a stirred solution of the ss-mercapto-&alpha;-methoxy-imino-propionic acid potassium salt (0.03 M) in a mixture of water (25 ml) and 95% ethanol (15 ml) maintained at 200C, a solution of tert-butyl propiolate (0.03 M1 in ethanol (15 ml) was added quickly.
The mixture was stirred for 20 hours at 200 C, the ethanol was evaporated under vacuum; the aqueous solution was acidified with 3 N aqueous HCI (10 ml); the obtained oil was extracted with ethyl ether (3 x 100 ml). The organic phase was washed with water (3 x 50 ml), dried (Na2SO4) and evaporated to dryness under vacuum.
The oily residue solidified, the obtained mass was crystallized from iso-propylether (75 ml) to give ss-(Z)-tert-butoxy-carbonylvinylene-thio-&alpha;-methoxy-imino-propionic acid (Yield 91%; m.p. 127-9 C).
Elemental analysis: found: C48.20; H 6.26; N 5.04; S 11.79 calculated for C,1H17NO5S: C, 47.98; H 6.22; N 5.09; S 11.64
1375 cm-1 [-C(CH3)2] 1050 cm-1 (=N-OCH3) N.M.R. (acetone-d6): 1.43 (9H, s, tert-butyl) [8 p.p.m.] 3.75 (2H, s, -SCH2-COO) 4.02 (3H, s,=N-OCH3) 5.65 (1 H, d, =CH-COO) 7.27 (1H,d,=CH-S) 9.3 (1 H, br-s, -COOH) PREPARATION 5 Tert-butoxycarbonyl methyl-thio-a-methoxy-imino-acetic acid Step A 3.5 g (0.05 M) of hydroxylamine hydrochloride were dissolved in water (25 ml) and the pH of the solution was brought to 5-5.5 by adding solid NaHCO3 (3.8 g).To this solution, cooled at 05C, C, was added, under stirring, n-butyl glyoxylate (6.5 g) dissolved in 95% ethanol (25 ml). The reaction mixture was stirred for 3 hours at 5-10 C and afterwards for 1 hour at room temperature.
The ethanol was evaporated under vacuum; the aqueous phase was extracted with ethyl ether (3 x 80 ml). The combined organic extracts were washed with 50 ml of saturated NaCI solution, dried (Na2SO4) and evaporated to dryness in vacuo, so obtaining n-butyl-a-hydroxy-imino acetate (7.25 g; yield 96.5%).
Elemental analysis: found: C 50.00; H 7.72; N 9.57 calculated for C6H11NO3: C 49.64; H 7.64; N 9.65
950 cm- (=NOH) N.M.R. (acetone-d6): 0.5-1.5 (7H, m -CH2CH2CH3) [ p.p.m.] 4.05 (2H, t, -O-CH2-)
Step B A stream of dry chlorine was bubbled through a solution of n-butyl-a-hydroxy-imino acetate (7 g; 0.04 M) in anhydrous ethyl ether (100 ml), cooled at -60 C, until about 7 g of chlorine was absorbed.
Afterwards the temperature of the solution was allowed to rise to 200C and the reaction mixture was stirred for 30 minutes at this temperature.
The ethyl ether was evaporated in vacuo so obtaining n-butyl-a-chloro-a-hydroxy-imino acetate (8.55 g) as oily residue.
Elemental analysis: found: C 40.23; H 5.70; N 7.82; Cl 19.52 calculatedforC6H10ClNO3: C 40.1 1; H 5.61; N 7.79; Cl 19.73 N.M.R. (acetone-d6): 0.5-1.5 (7H, m,-CH2CH2CH2) [S p.p.m.] 4.05 (2H, t, -0-OH2-) Step C To an ice-cooled solution of n-butyl-ct-chloro--hydroxy-imino-acetat (6.3 g; 0.035 M) and tertbutyl thioglycolate (5.18 g; 0.035 M) in anhydrous tetrahydrofuran (THF) (50 ml) a solution of triethylamine (4.9 ml) in anhydrous THF (10 ml) was added dropwise under stirring. After the addition the reaction mixture was stirred overnight at room temperature and then evaporated to dryness in vacuo.
The oily residue was taken up with 50 ml of ethyl ether and 50 ml of water. The organic phase was separated, the aqueous phase was extracted with ethyl ether (2 x 50 ml); the combined organic extracts were washed with saturated NaCI solution, dried (Na2SO4), and evaporated to dryness in vacuo so obtaining the n-butyl ester of tert-butoxy carbonyl methyl-thio-cr-hydroxy-imino acetic acid (10.2 g; yield 85%) as oil.
Elemental analysis: found: C49.23; H7.16; N4.71; S 11.20 calculated for C12H21N05S: C 49.47; H 7.26; N 4.80; S 11.00 N.M.R. (CCI4): 0.5-1.5 (7H, m, -CH2CH2CH3) [# p.p.m.] 1.3 (9H, s, -tert-butyl) 3.6 (2H, s,-SCH2-) 4.05 (2H t -0-OH2-) 10.5 (1H,s,=NOH) Step D To an ice-cold solution of the compound described in Step C (2.3 g; 0.0079 M) in anhydrous THF (35 ml) was added anhydrous K2CO3 (1.09 g; 0.0079 M) and then a solution of dimethylsulphate (0.75 ml; 0.0079 M) in anhydrous THF (5 ml).The mixture was stirred overnight at room temperature; the undissolved matter was filtered off, the filtrate was evaporated to dryness in vacuo, the residue was taken up with 50 ml of water and 100 ml of ethyl ether. The organic layer was separated, the aqueous phase was extracted with ethyl ether (2 x 100 ml).
The combined organic extracts were washed with saturated NaCI solution (2 x 50 ml), dried (Na2SO4) and evaporated to dryness in vacuo, obtaining an oily residue, which was purified by column chromatography of silica gel using OH2Cl2-EtOAc (150:20) as eluentto give the n-butyl ester of tert butoxycarbonylmethylthio-o:-methoxyimino-acetic acid (1.5 g); yield 62%).
Elemental analysis: found: C 50.82; H 7.41; N 4.38; S 10.83 calculated for C,3H23NO5S: C 51.12; H 7.59; N 4.58; S 10.49 N.M.R. (CCI4): 0.8-1.8 (7H, m,-CH2CH2CH2) [d p.p.m.] 1.3 (9H, s, tert-butyl) 3.6 (2H,s,-SCH2-) 4.0 (3H, s, =NOCH3) 4.0.5 (2H, t, -OCH2-) Step E To a solution of the diester described in Step D (1.3 g; 4.25 mM) in 50% EtOH (50 ml); K2CO3 (4.25 g) was added and the mixture was stirred at 650C for 1 hour. (T.L.C. indicated complete reaction).
The ethanol was removed under vacuum, the aqueous phase was stratified with ethyl ether (50 ml) and acidified with 1 N HCi (8.5 ml) under cooling.
The organic layer was separated, the aqueous phase was extracted with ethyl ether (3 x 50 ml); the combined organic extracted were washed with saturated NaCI solution, dried (Na2SO4) and evaporated to dryness under vacuum to give the title compound as an oily residue, which was used for the next step without further purification.
PREPARATION 6 Tert-butoxycarbonyl-methyl-thio-(Z)-vinylene-a-methoxyimino acetic acid Step A To a stirred solution of 2-hydroxy-3-butynoic acid butyl ester (4.8 g; 0.03 M) (prepared according to Bull. Soc. Chim. France 6,22106 (1967) in chloroform (200 ml), manganese dioxide (25 g) was added in several portions in 1 5 minutes at room temperature. After addition stirring for 5 minutes at room temperature, manganese dioxide was filtered off and the filtrate was evaporated in vacuo at room temperature, to give 2-oxo-3-butynoic acid butyl ester (65%) as oily residue, which was used for the next step without further purification.
I.R. (neat); v 3270 cam~' (=0-H) 2090 cm-' (0=0-H) 1740 cm-' (C=O ester) 1690 cam~' (C=O, &alpha;,ss unsatd. Keto-group) N.M.R. (CCI4): 1.0-2.0 (7H, m, CH2CH2CH3) [8 p.p.mJ 3.8 (1 H, s, H-C=) 4.1 (2H, t, OCH2) Step B To a solution of the above prepared oxo-ester in 95% ethanol (20 ml) a solution of O-methylhydroxylamine hydrochloride (2.0 g; 0.025 Mole) in water (20 ml) (previously treated with NaHCO3 until pH 5.0) was added slowly.
After stirring overnight at room temperature, 100 ml of water were added and then the mixture was extracted three times with ethyl acetate.
The organic layers were dried (Na2SO4) and evaporated to dryness in vacuo.
The oily residue was chromatographed on silica gel eluting with petroleum ether-ethylether (2:1).
After evaporation 2-methoxyimino-3-butynoic acid butyl ester (60%) was obtained.
T.L.C.: (petroleum ether:ethyl ether = 1:1) Rf = 0.6 Elemental analysis: found: C 58.78; H 7.20; N 7.55 calculated for CgH13NO3: C 59.00; H 7.15; N 7.65 I.R. (Neat): v 3260 cm- (=0-H) 2820 cm- (0-OH3) 2105 cm~ (0=0-H) 1730 cm- (C=O ester) 1055 cm-' (=N-O-CH3, oxime) N.M.R. (CCL4): 0.8-2.00 (7H, m, CH2CH2CH3) [#p.p.m.] 3.6 (1H,s,-C#C-H) 4.2 (2H, t, OCH2) Step C To a stirred solution of 2-methoxyimino-3-butynoic acid butyl ester (1 g; 5.5 mM) in EtOH (1 5 ml) and water (4 ml) a solution of tert-butyl thioglycolate (0.8 g; 5.4 mM) in EtOH (2 ml) was added.
After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (100 ml) and extracted three times with ethyl ether. The combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo.
The crude oil was purified by column chromatography on silica gel using petroleum etherethylether(95:5) as eluentto give 1.5 g (87%) of tert-butoxycarbonyl-methyl-thio-(Z)-vinylene-&alpha;- methoxyimino acetic acid butyl ester as a colourless oil.
T.L.C.: (petroleum ether:ethyl ether = 95:5) Rf = 0.3 I.R. (neat); v (--C=O esters) 17201730 cm-' (=NOCH3 oxime) 1060 cm-' N.M.R. (CCI4) [8 p.p.m.] 1.0-2.0 (7H, m, CH2CH2CH3) 1.4 (9H,s,tert-butyl) 3.1 (2H, s, s.CH2-CO0-) 3.9 (3H, s, =N-OCH3) 4.05 (2H, t, -COOCH2-) 6.05 (1 H, d, -CH=) JCH=CH(CIS) 11 Hz 6.45 (1H,d,S-CH=) Step D To a solution of the diester described in Step C (0.4 g; 1.25 mM) in 50% EtOH (8 ml), K2CO3 (0.2 g; 1.45 mM) was added. The mixture was stirred at 65 C for 90 minutes.After cooling to room temperature, the reaction mixture was diluted with 50 ml of water and then extracted three times with ethylether. The organic layers were discarded; the aqueous layer was acidified with 1 N HCI to pH 2.0 under cooling. The product was extracted with ethylether (3 x 50 ml), dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound (0.25 g; 76.9%), which was used without further purification.
1050 cm-' (=N--OCH3) N.M.R. (CDCI3): 1.4 (9H, s, tert-butyl) [# p.p.m.] 3.2 (2H, 5, -SOH2-) 4.00 (3H, s, =NOCH3) 6.15 (1H,d,-OH=) 6.65 (1H, d, --SS-CH=) J,,,,,I,,, = 11 Hz N7.5-8.5 ( 1 H, br-s, -OOOH) EXAMPLE 1 7-[(ss-cyanomethyl-thio)-(&alpha;-methoxy-imino)-propiona mido]-3-acetoxy-methyl-3-cephem-4-carboxylic acid (Syn-isomer) (compound 1) Step A Triethylamine (1.4 ml) was added to a stirred solution of ss-cyanomethyl-thio-&alpha;-methoxy-imino- propionic acid (1.88 g; 10 mM) in anhydrous CH2CI2 (25 ml). The mixture was cooled to OOC, then PCI5 (2.08 g; 10 mM), at once, was added.Afterwards the solution was stirred for one hour at room temperature. The solvent and the formed POCl3 were evaporated under vacuum at 25-30 C; the residue was taken up twice with anhydrous benzene. This was removed under vacuum and the residue was taken up with CH2CI2, so obtaining ss-cyanomethyl-thio-&alpha;-methoxy-imino-propionyl chloride as crude product.
Step B The solution of the compound obtained in Step A in CH2CI2 2was dropped into a solution of 7- aminocephalosporanic acid t-butyl ester (3.28 g; 10 mM) in an hydros CH2CI2 (25 ml) containing N,Ndiethylaniline (1.6 ml; 10 mM) cooled at 0 C. The solution was stirred for 2 hour at OOC and then 1 5 minutes at room temperature. The mixture was washed with 4% HCI, with H2O, then with an aqueous solution of sodium bicarbonate and then again with water.The organic phase was dried over anhydrous CaCl2, and evaporated to dryness, thus obtaining 4.5 g of a slimy oil which was purified by column chromatography (SiO2, 400 g); mobile phase: ethylacetate:cyclohexane = 1:1, to give 3.2 g of chromatographically uniform 7-[(ss-cyanomethyl-thio)-(&alpha;-methoxy-imino)-propiona mido]-3 acetoxymethyl-3-cephem-4-carboxylic acid tert-butylester.
N.M.R. (CDCI3): 1.54 (9H,s,t-C4H9 [8 p.p.m.] 2.07 (3H, s, OCOCH2) 3.35 (2H, s, -SCH2-) 3.48 (2H, d.d., 2-OH2) 3.72 (2H, s, NO-CH2S) 4.05 (3H, s,=NOCH,) 4.93 (2H, d.d., 3-OH2) 5.03 (1H,d.,6-H) 5.83 (1 H, d.d., 7-H) 7.39 (1 H, d., CONH) Step C Trifluoroacetic acid (20 ml) was added to the solution of the tert-butylester obtained in Step B (1 g, about 2 mM) in CH2CI2 (2 ml) and anisole (5 ml). The mixture was stirred in a stoppered flask for 2 hours at room temperature, then evaporated under vacuum; the residue was taken up twice with benzene and the benzene then removed.The residue was kept under vacuum for 2 hours (0.01 mmHg), then dissolved in ethyl acetate, and finally extracted with a saturated aqueous solution of NaHC03. The aqueous phase was washed twice with ethyl ether, then stratified with ethyl ether and brought to about pH 2 with 8% HCI. The mixture was shaken.
The organic phase was separated and the aqueous phase was extracted again with ethyl ether.
The combined organic phases were washed with water, dried (Na2SO4) and evaporated to dryness; so obtaining 7-[(/3-cyanomethyl-thio)-(-methoxy-imino)-propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (0.75 g; m.p. 650C dec).
Elemental analysis: Found: C43,32; H4.15; N 12.41; S 14.32 CalculatedforC,6H,8N407S2: C43.43; H4.10; N 12.60; S 14.49 I.R. (KBr): v 2,250 cam~' (-C=N)
1,050cm-1 (-N-OCH3) N.M.R. (acetone-d6): 2.01 (3H, s, OCOCH2) [6 p.p.m.] 3.65 (4H, s + d.d., 2-OH2 + -SCH2-) 3.70 2H, s, OH2-S) 4.01 (3H, s, =NOTCH3) 4.91 (2H,d.d.,3-OH2) 5.14 (1 H, d., 6-H) 5.81 (1H,d.d.,7-H) 7.95 (1H,d..CONH) EXAMPLE 2 Using the method reported in example 1 also the following compounds were obtained:: 7-[(ss-cyanomethyl-thio)-(&alpha;-methoxy-imino-propionamido)]-3-[( -methyl-l ,2,3,4-tetrazol-5-yi)- thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 3); 7-[(ss-cyanomethyl-thio)-(-methoxy-imino-prnpionamido)]-3-[(tetrnzolo-[1 ,5-b]-pyridazin-6-yl)thiomethyl]3-cephem-4-carboxylic acid (Syn-isomer) (compound 4); 7-[(,1-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-propionamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid (syn-isomer) (compound 7); 7-[(ss-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-propionamido]-3-[( 1 -methyl- 1 ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 2); 7-[(a-cya nomethyl-thio)--(methoxy-imino-aceta m ido)]-3-acetoxy methyl-3-cephem-4carboxylic acid (Syn-isomer) (compound 12);; 7-[(a-cyanomethyl-thio)-a-(methoxy-imino-acetamido)J-3-( 1 -methyl- 1 ,2,3,4-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 1 3); 7-[(&alpha;-cyanomethyl-thio)-&alpha;-(methoxy-imino-acetamido]-3-[(8-amino-tetrazolo-[1 ,5-b]-pyridazin6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 14); 7-[(&alpha;-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-acetamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid (Syn-isomer) (compound 19); 7-[(&alpha;-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-acetamido]-3-[( 1 -methyl- 1 ,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 20); ; 7-[ss-cyanomethyl-thio-(Z)-vinylene-(-methoxy-imino)-acetamido)]-3-acetoxy-methyl-3-cephem- 4-carboxylic acid (Syn-isomer) (compound 23); 7-[,1-cyanomethyl-thio-(Z)-vinyl ene-(a-methoxy-imino)-aceta mido]-3-[( 1-methyl- 1 ,2,3 4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 24); 7-[(ss-(Z)-cyanovinylene-thio)-(Z)-vinylene-(&alpha;-methoxy-imino)-acetamido]-3-acetoxymethyl-3- cephem-4-carboxylic acid (Syn-isomer) (compound 28); 7-[(ss-(Z)-cyanovinylene-(thio)-(Z)-vinylene-(&alpha;-methoxy-imino)-acetamido]-3-[(1-methyl-1,2,3,4- 1-methyl-I 2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 29).
EXAMPLE 3 7-[(ss-carboxymethyl-thio)-(&alpha;-methoxy-imino)-propionamido]-3-acetoxy-methyl-3-cephem-4-carboxylic acid (Syn-isomer) (compound 2) Step A Triethylamine (0.704 ml; 5 mM) was added to a solution of ss-tert-butoxy-carbonylmethyl-thio-&alpha;- methoxy-imino propionic acid (1.32 g; 5 mM) in anhydrous CH2CI2 (20 ml) and then, at OcO, PCI5 (1.04 g; 5 mM) was added. After stirring for an hour at room temperature, the mixture was evaporated to dryness under low pressure; the residue was taken up twice with anhydrous benzene, removing the benzene after each addition; the organic residue so obtained was dissolved in anhydrous CH2CI2 (15 ml) and used as such at once for the following step B.
Step B The solution of the ,l-tert-butoxycarbonyl-methyl-thio-a-methoxy-imino-propionyl chloride in CH2CI2, obtained in step A, was dropped, under stirring at 0 C, into a solution of 7aminocephalosporanic acid tert-butyl ester (1.64 g; 5 mM) in anhydrous CH2CI2 (25 ml) containing N,Ndimethylaniline (0.8 ml; 5 mM). After stirring for an hour at OCO, the solvent was evaporated, the residue was taken up with ethyl acetate, the solution was washed with 4% HCI, then with a saturated solution of NaHCO2, and finally with water. The organic phase was dried (Na2SO4) and evaporated to dryness.The crude product so obtained was purified by column chromatography (mobile phase: ethyl acetate/cyclohexane = 1/1); thus 2.1 g were obtained of chromatographically uniform 7-[(,B- carboxymethylthio)-(-methoxy-imino)-propionamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid bis-tert-butyl ester N.M.R. (DMSO-d6): 1.42 (9H, s, t-Bu) [3 p.p.m.] 1.48 (9H, s, t-Bu) 2.05 (3H, s, OCOCH3) 3.28 (2H, s, OH2-S) N3.6 (4H, s + d.d., SCH2 +2-OH2) 3.99 (3H, s, =NOCH3) 4.8 (2H, d.d., 3CH2) 5.15 (1H,d.,6-H) 5.72 (1H,d.d., 7-H) 8.79 (1H,d.,CONH) Step C Anisole (1 ml) and then trifluoroacetic acid (15 ml) were added to a solution of the double tertbutyl ester (1.72 g; 3 mM) obtained in Step B, in 5 ml of anhydrous CH2CI2. The mixture was stirred for an hour at room temperature in a stopped vessel. The solvents were evaporated under low pressure; the residue was taken up several times with benzene and the benzene removed every time in order to eliminate complete the trifluoroacetic acid.The residue was then taken up witif ethyl acetate; this was extracted with an aqueous solution of sodium bicarbonate (1 g NaHCO3 in 25 ml H2O). The aqueous phase was washed with ethyl acetate, stratified with ethyl ether (50 ml) and then acidified with 8% HCI to pH 4. The ethyl ether was discarded and the operation was repeated, acidifying to pH 2.4.
The ethyl ether was discarded again, the aqueous phase was stratified with ethyl acetate and further acidified. The organic layer was separated, washed with water (2 x 25 ml), then evaporated to dryness under low pressure, to give 7-[(p-carboxymethyl thio)-(&alpha;-methoximino)-propionamido]-3- acetoxymethyl-3-cephem-4-carboxylic acid as a pale yellow powder (g 0.94; m.p. N90OC (dec.)).
Elemental analysis: Found: C41.58; H4.23; N 9.02; S 13.77 Calculated for C16H1N3O9S2: C41.64; H4.15; N 9.10; S 13.89
1050 cm-l (=N-00H3) N.M.R. (DMSO-d6) 2.04 (3H, s, OCOCH3) [8 p.p.m.] 3.32 (2H, s,-SOH2-) N3.6 (4H, s + d.d., 0H2-S + 2-OH2) 4.0 (3H, s, =NOCH3) 4.89 (2H, d.d., 3-OH2) 5.18 (1H,d., 6-H) 5.73 (1H,d.d., 7-H) 8.79 (1H,d.,CONH) EXAMPLE 4 Using the method reported in example 3 also the following compounds were obtained:: 7-[(ss-carboxy-methyl-thio)-(-methoxy-imino) propionam ido]-3-[( 1 -methyl-1 ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 5); Elemental analysis: Found: C36.91; H3.81; N 18.72; S 18.32 Calculated for C,6H19N707S3: C 37.13; H 3.70; N 18.94; S 18.58
7-[(,1-carboxymethyl-thio)-(a-methoxy-imino)-prnpionamido]-3-[(8-amino-tetrazolo[ 1,5-b]- pyridazi n-6-yl )-thiomethyl]-3-cephem-4-ca rboxylic acid (Syn-isomer) (compound 6).
EXAMPLE 5 7-[(ss-(Z)-carboxyvinylene-thio)-(&alpha;-methoxy-imino)-propionamido]-3-[( methyl 1 ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 1 0) Step A Triethylamine (1.4 ml; 10 mM) was added to a solution of ss-(Z)-tert-butoxy-carbonylvinylene-thio- a-methoxy-imino-propionic acid (2.73 g; 10 mM) in an hydros CH2CI2 (25 ml) and then, at 0 C, PCI5 (2.08 g; 10 mM) was added.
After stirring for 30 minutes at OOC and for additional 30 minutes at room temperature, the solvent and the formed POCI3 were removed under vacuum at 25o30oO; the residue was taken up twice with anhydrous benzene, evaporated again in order to remove any traces of phosphorus oxychloride and taken up with 50 ml of anhydrous acetone. Triethylamine hydrochloride was then removed by filtration.
The acetone solution of ,1-(Z)-tert-butoxyca rbonyl-vinylene-thio-a-methoxyimino propionyl chloride thus obtained was dropped into a vigorously stirred, ice-cooled solution of 7-amino-3-[( 1 - methyl-1 ,Z,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (4.05 g), and NaHCO3 (2.52 g) in 50% acetone (80 ml). The reaction mixture was stirred for 1 hour at 0 5 C and for 1 hour at room temperature. The acetone was removed under vacuum, the aqueous phase was washed with ethyl acetate, stratified with fresh ethyl acetate, acidified with 2 N HCI.
The organic layer was separated, the aqueous phase was extracted three times with ethyl acetate; the combined organic extracts were washed with water, dried (Na2SO4) and evaporated to dryness under vacuum.
To the crude product so obtained, dissolved in acetonitrile (30 ml), a solution of diphenyldiazomethane (1 g) in acetonitrile (15 ml) was added, and the mixture was stirred for 1 hour at room temperature. After quenching with 0.5 ml of glacial acetic acid, the reaction mixture was evaporated to dryness under vacuum. The residue was purified by column chromatography using EtOH:cyclohexane (70:100) as eluent Treatment of the benzhydryl ester with trifluoroacetic acid-anisole followed by sodium-2-ethyl hexanoate gave crude sodium salt as a precipitate, which was collected by filtration, washed with ethanol and dried under vacuum to give the sodium salt of the title compound.
Elemental analysis: Found: C39.71; H3.52; N8.25 S 12.01 Na 8.51 Calculated for C17H17N7S2O9No2:C39.45; K3.31; N8.12; S12.39; Na8.88 Calculated for C17H17N7S2O9No2: N.M.R. (DMSO-d6): 2.1 (3H,s,-OCOCH2) [8 p.p.m.] 3.48 (2H, d.d., 2-OH2) 3.79 (2H, s,-S-CH2-) 4.09 (3H, s, =NOCH3) 4.91 (2H, d.d., 3-OH2) 5.1 (1H,d,6-H) 5.64 (1H,d.d.,7-H) 5.88 (1H,d,-OH=) 7.37 (1H, d, =CH-) JCH=CH(cis)=10HZ = 1 0 HZ 8.65 (1H,d,-O0NH) EXAMPLE 6 Using the method reported in example 5 also the following compounds were obtained:: 7 [(,B-(Z)-carboxyvinylene-thio)-(cg-methoxy-imino)-propiona mido]-3-[ 1-methyl- 1 2,3 4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 10); 7-[(ss-(Z)-carboxyvinylene-thio)-(&alpha;-methoxy-imino)-propionamido]-3-[(8-am ino-tetrazolo-[1 ,5-b]pyridazin-6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 11); 7-[(3-(Z)-carboxyvinylene-thio)-((&alpha;-methoxy-imino)propionamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid (syn-isomer) (compound 8).
EXAMPLE 7 7-[(&alpha;-carboxymethylthio)-(&alpha;-methoxy-imino)-acetamido]-3-[( 1 -methyl)-1 ,2,3,4-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxyiic acid (Syn-isomer) (compound 16) To a stirred solution of (,z-tert-butoxycarbonyl-methyl-thio)-(a-methoxyimino) acetic acid (1 g; 4 mM) in anhydrous CH2Ci2 (25 ml), cooled at 0 C, a solution of N,N'-dicyclohexylcarbodiimide (0.44 g) in anhydrous CH2CI2 (5 ml) was added dropwise in 15 minutes.
The mixture was stirred for 2 hour at O5 C OC and then for 2 hour at room temperature. After cooling at -20 C a solution of 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4- carboxylic acid tert-butyl ester (0.81 g; 2.16 mM) in anhydrous CH2Cl2 (25 ml) was addled dropwise in 10 minutes. After stirring for 2 hour at -20 C and overnight at room temperature, the undissolved matter was filtered off, the filtrate was evaporated to dryness under vacuum.
The crude product so obtained was purified by column chromatography (SiO2, 300 g) using CH2CI2:Ethyl acetate (1 50:10) as eluent.
After evaporation of the collected fractions the butylester of the title compound was obtained.
500 mg of the double tert-butylester were stirred for 2 hours at OO with trifluoroacetic acid (1 5 ml).
After evaporating the trifluoroacetic acid under vacuum the residue was taken up several times with benzene and the benzene removed every time under vacuum in order to eliminate completely the trifluoroacetic acid. The residue was taken up with ethyl acetate; this was extracted with an aqueous solution of sodium bicarbonate, the aqueous phase was washed with ethyl acetate, stratified with ethyl acetate (50 ml) and then acidified with 8% HCI.
The organic layer was separated, washed with water, dried (Na2SO4) and evaporated to dryness under vacuum. The residue was dissolved in a small amount of acetone, ethyl ether was then added to give the title compound.
Elemental analysis: Found: C35.91; H, 3.65; N 19.11; S 18.81 Calculated for C15H17N7O7S2: C35.77; H 3.40; N 19.47; S 19.10
N.M.R. (DMSO-d6): 3.65 (2H, q, 2-OH2-) [6 p.p.m.] 3.95 (3H, s, -NCH3) 4.05 (3H, s, =NOTCH3) 4.1 (2H, s, -CH2-S-) 4.25 (2H, q, 3-OH2-) 5.0 (1H,d,6-H) 5.8 (1H,d.d., 7-H) 9.5 (1H,d,-CONH) EXAMPLE 8 Using the same method reported in example 7: 7-[,1-carboxymethyl-thio (Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[( -methyl-1,2,3,4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 26) was obtained.
Elemental analysis: Found: C 38.45; H 3.70; N 18.40; S 10.03 Calculated for C17H19N70703: C 38.55; H 3.62; N 18.52; S 18.16
1050cm- (=NOCH3) N.M.R.(CDCI3): 3.2 (2H,s,-CH2-S-COO) [# p.p.m.] 3.6 (2H, s, 2-OH2-) 3.8 (3H,s,-NCH3) 3.95 (3H, s, NOCH3) 4.30 (2H,s,3-CH2) 4.95 (1H,d,6-H) 5.75 (1H,d.d.,7-H) 6.1 (1H,d,=CH) 6.65 (1H,d,-S-CH=) JCH=CH(cis) = 10 HZ 7.25 (1H,d,-CONH) EXAMPLE 9 Using the method reported in example 7 also the following compounds were obtained: 1) ) carboxylic acid (Syn-isomer) (compound 15) Elemental analysis: Found: C40.11; H3.91; N9.17;S14.15 Calculated for O16H17N309S2: C40.26; H 3.82; N 9.39; S 14.33
N.M.R. (acetone-d6): 2.1 (3H, s,-0-OOCH3) [8 p.p.m.] 3.6 (2H, d, 2-OH2) 4.0 (3H, s, =N-OCH2) 4.05 (2H, s,-S-CH2) 5.0 (2H, d.d., 3-OH2) 5.25 (1H,d,6-H) 5.8 (1H,d.d.,7-H) 8.2 (1H,d,-CONH-) 7-[(-carboxy-methyl-thio)-(-methoxyimino)-acetamido]-3-[tetrazolo-[1,5-b]-pyridazin-6-yl)- thio-methyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 17) 7-[(&alpha;-carboxy-methyl-thio)-(&alpha;;-methoxy-im ino)-acetamidoj-3-[8-a mino-[1,5-b]-pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 18) 7-[('z-carboxy-methyl-thio)-(Z)-vinylene-a'-methoxy-imino-aceta mido]-3-acetoxy-methyl-3cephem-4-carboxylic acid (Syn-isomer) (compound 25) 7-[(&alpha;-(Z)-carboxyvinylene-thio)-(&alpha;-methoxy-imino)-acetamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid (Syn-isomer) (compound 21) 7-[(eg-(Z)-carboxyVinylene-thio)-(cg-methoxy-imino)-acetamido]-3-[(1 1-methyl-l 1 ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 22) 7-[(ss-carboxymethyl-thio)-(Z)-vinylene-&alpha;;-methoxyimino-acetamido]-3-[( 1 -methyl-l 1,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 26) 7-[(p-(Z)-carboxyVinylene-thio)-(Z)-vinylene-cg-methoxy-imino-acetamido]-3-acetoxy-methyl-3- cephem-4-carboxylic acid (Syn-isomer) (compound 30) 7-[(ss-(Z)-carboxyvinylene-thio)-(Z)-vinylene-&alpha;-methoxy-imino-acetam ido]-3-[( 1 -methyl-l 1,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 31) 7-[(ss-(Z)-carboxyvinylene-thio)-(Z)-vinylene-&alpha;-methoxyimino-acetamido]-3-[8-amino-tetrazolo- [1,5-b]-pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 32).
EXAMPLE 10 7-[(,1-carboxymethyl-thio)-(a-methoxy-imino)-propionam ido]-3-[(1 1-methyl- 1 ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (Syn-isomer) (compound 5) To a mixture of 7-[(ss-carboxymethyl-thio)-(&alpha;-methoxyimino)-propionamido]-3-acetoxymethyl-3- cephem-4-carboxyiic acid (syn-isomer) (prepared as described in Example 3) (120 mg) and l-methyl-5- mercapto-1 ,2,3,4-tetrazole sodium salt di-hydrate (30 mg) in distilled water (7.5 ml), NaHCO3 was added in small portions, under stirring, until a clear solution was obtained and a pH value of 6.5-7 was reached.This solution was heated for 6.5 hours in an oil bath at 67aC. After cooling at 5 C, a few drops of 8% HCI were carefully added under stirring, the precipitate was collected, washed with acetone and dried, thus giving 65 mg of the title compound, which was identical to that described in Example 4.
By proceeding analogously also the compounds nO 3, 4, 6, 10, 11, 13,14, 1 6, 17, 18, 20, 22, 24, 26, 27, 29, 31 and 32 of the table were prepared.
EXAMPLE 11 To an aqueous suspension of 7-[(&alpha;-carboxymethylthio)-(&alpha;-methoxy-imino)-acetamido]-3-[(1- methyl-1,2t3t4-tetrawl-5-yl)-thiomethyll-3-cephem-4-carboxygic acid (1.5 g) in water (50 ml) two equivalents of NaHCO3 were added, thus giving a complete solution of the compound. This solution was then lyophilized, to give the disodium salt of the above-mentioned acid.
Preparation of pharmaceutical compositions EXAMPLE 12 Injectable pharmaceutical compositions were prepared by dissolving 100-500 mg of the disodium salt of 7-[(a-carboxymethylthio)-(t-methoxy-im ino)-acetamido]-3-[( 1 -methyl-1 ,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid in sterile water or sterile normal saline solution (1-2 ml).

Claims (6)

1. Compounds having the general formula (I)
wherein: Z is -ON; -OONH2 or -C00R1,where in R is hydrogen, C,--C, alkyl or a carboxy protecting group; A, is a bond or has any of the meanings given below for A; in which case it can be the same as A or different therefrom; A is a branched or straight chain C,--C, saturated or C2C6 unsaturated aliphatic hydrocarbon radical, which may be unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, amino, -COR', where R' is hydrogen or C,C6 alkyl, or -COOR1,w wherein R, is as defined above; R is hydrogen; a hydroxy protecting group or a branched or straight chain C,C6 saturated or C2C6 unsaturated aliphatic hydrocarbon group, which may be unsubstituted or substituted by one or more substituents selected from a) hydroxy; b) cyano; c) CC6 alkyl;
wherein each of R2 and R3, which may be the same or different, is hydrogen, C1-C6 alkyl, C1-C6 aliphatic acyl or one of R2 and R3 is hydrogen and the other is an amino protecting group; and e) --COOR,, wherein R, is as defined above; Y is -O-COCH3 or -S-Het, wherein Het is a') a pentatomic or hexatomic heteromonocyclic radical containing at least a double bond and at least a heteroatom chosen from N, S and 0; or b') a heterobicyclic radical formed by a hexatomic heteromonocyclic ring, containing 1 to 3 nitrogen atoms, condensed with either a pentatomic or a hexatomic heteromonocyclic ring; the heteromonocyclic and the heterobicyclic radicals defined above at points a') and b') being unsubstituted or substituted by one or more substituents selected from a") hydroxy; halogen; C,C6 alkoxy, -SR' or-COR' wherein R' is as defined above; b") C,C6 alkyl, optionally substituted by one or more substituents selected from hydroxy and halogen; c") C2C6 alkenyl, optionally substituted by one or more substituents chosen from hydroxy and halogen;
wherein m is zero or an integer of 1 to 3 and R2 and R2 are as defined above; or e")-S-(CH2)m-COOR1;-(CH2)m-COOR1;-CH=OH-COOR1;-(CH2)m-SO3H; -(CH2)m-CN.
wherein m, Ra, R2 and R3 are as defined above, and T is a free or esterified carboxy group; as well as the pharmaceutically and veterinarily acceptable salts thereof.
2 A compound selected from the group consisting of: 7-[(,B-cya nomethylthio)-(a-methoxy-im ino-)propiona mido]-3-acetoxymethyl-3-cephem-4carboxylic acid (syn-isomer); 7-[(ss-carboxymethylthio)-(&alpha;-methoxy-imino)-propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 7-[(,1-cyanomethylthio)-(a-methoxy-imino-prnpiona mido)]-3-[(1 -methyl-1,2,3,4-tetrazol-5-yl)- thiomethylj-3-cephem-4-carboxylic acid (syn-isomer); 7-[(,1-cyanomethylthio)-(a-methoxy-imino-prnpiona mido)]-3-[(tetrazolo[1,5-b]-pyridazin-6-yl)- thiomethyl]-3-cephem-4-ca rboxylic acid (syn-isomer); 7-[(ss-carboxymethylthio)-(&alpha;;-methoxy-imino)propionamido]-3-[( 1-methyl- 1 ,2,3,4-tetrazol-5-yl )- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(,1-arboxymethylthio)-(a-methoxy-imino)prnpionamidoj-3-[(8-amino-tetrazolo[1 S-b]- pyridazin-6-yl)-thiomethyl)-3-cephem-4-carboxylic acid (syn-isomer); 7-[(p-(Z)-cyanovinylene-thio)-(cg-methoxy-imino)propionamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 7-[(,1-(Z)-carboxyvinylene-thio)-(a-methoxy-im ino)propiona mido]-3-acetoxymethyl-3-cephem-4carboxylic acid (syn-isomer); 7-[(ss-(Z)-cyanovinylene-thio)-(&alpha;-methoxy-imino)-propionamido]-3-[( 1 -methyl-1 ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer);; 7-[(,1-(Z)-carboxyvinylene-thio)-(a-methoxy-im ino)-propionam ido]-3-[( 1-methyl-I ,2,3 ,4-tetrazol- 5-yl)-th iomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(,14Z)-carboxyvinylene-thio)-(-methoxy-imino)prnpionamido]-3-[(8-aminoAetrnzolo-[ 1 S-b]- pyridazin-6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(&alpha;-cyano-methylthio)-&alpha;-(methoxy-imino)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer); 7-[(-cyano-methylthio)-a::-(methoxy-imino)-aceta mido]-3-[(1 1-methyl-1,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(&alpha;-cyano-methylthio)-&alpha;-(methoxy-im ino)-acetamido]-3-[(8-am ino-tetrazolo[1,5-b]-pyridazin6-yl)-thiomethyl)]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(&alpha;-carboxy-methyl-thio)-(&alpha;-methoxy-imino)-acetamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 7-[(a-ca rboxy-methyl-thio)-(a-methoxy-im ino)-acetamido]-3-[(1 -methyl- ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(&alpha;-carboxy-methyl-thio)-(&alpha;-methoxy-imino)-acetamido]-3-[-tetrazolo-[1,5-b]-pyridazin-6-yl)- thiomethyl]-3-cephem-4-ca rboxylic acid (syn-isomer); 7-[(&alpha;;-carboxy-methyl-thio)-(&alpha;-methoxy-imino)-acetamido]-3-[8-amino-[1,5-b]-pyridazin-6-yl)- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(&alpha;-(Z)-cyanovinylene-thio)-(&alpha;-methoxyimino)-acetamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid (syn-isomer); 7-[(&alpha;-(Z)-cyanovinylene-thio)-(&alpha;-methoxyimino)-acetamido]-3-[( 1-methyl- 1 ,2,3,4-tetrazol-5-yl )- thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(-(Z)-ca rboxyvinylene-thio)-(a-methoxy-im ino)-acetamido]-3-acetoxymethyl-3-cephem-4carboxylic acid; 7-[(&alpha;-(Z)-carboxyvinylene-thio)-(&alpha;-methoxy-imino)-acetamido]-3-[( -methyl- ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer);; 7-[ss-cyanomethyl-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-acetoxy-methyl-3-cephem- 4-carboxylic acid (syn-isomer); 7-[ss-cyanomethyl-thio-(Z)-vinylene-cr-methoxy-i mino-aceta m ido]-3-[( i-methyl- 1 ,2,3,4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[,B-carboxymethyl-thio-(Z)-vinylene-c-methoxy-im ino-aceta m ido]-3-acetoxy-methyl-3-cephem4-carboxylic acid (syn-isomer); 7-[ss-carboxymethyl-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[( 1-methyl-1,2,3,4- tetrazol-5-yl)-th iomethyl]-3-cephem-4-carboxylic acid (syn-isomer); ; 7-[,1-carboxymethyl-thio-(Z)-vinyIene--methoxy-im ino-aceta mido]-3-[(8-amino-tetrazolo[1,5 b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(p-(Z)-cyanovinyiene-thio)-(Z)-vinyiene-cr-methoxy-im ino-aceta m ido]-3-acetoxymethyl-3cephem-4-carboxylic acid (syn-isomer); 7-[(A-(Z)-cyanovinylene-thio)-(Z)-vinylene-a!-methoxy-im ino-acetamido]-3-[( 1-methyl-1 1,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(ss-(Z)-carboxyvinylene-thio)-(Z)-vinylene-&alpha;-methoxy-im ino-aceta mido]-3-acetoxymethyl-3cephem-4-carboxylic acid (syn-isomer); 7-[(ss-(Z)-carboxyvinylene-thio-(Z)-vinylene-&alpha;;-methoxy-imino-acetamido]-3-[(1 1-methyl-1,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer); 7-[(ss-(Z)-carboxyvinylene-thio-(Z)-vinylene-&alpha;-methoxy-imino-acetamido]-3-[(8-amino- tetrazolo[ 1 ,5-b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer), as well as the pharmaceutically or veterinarily acceptable salts thereof.
3. A process for the preparation of a compound according to any one of the preceding claims, the process comprising: a) reacting a compound of formula (II)
where Y and Tare as defined in claim 1, and E is amino or a group --N=C=, wherein Ct) is oxygen or sulphur, or a reactive derivative thereof, with a compound of formula (III)
where Z, A, A, and Rare as defined in claim 1, or with the reactive derivative thereof and if desired removing the protecting groups where present; or b) reacting a compound of formula (IV)
where A1, R, T and Y are as defined in claim 1, and X is halogen, or a salt thereof, with a compound of formula (III) Z-A-SH (V) where Z and A are as defined in claim 1, or with a reactive derivative thereof and if desired removing the protecting groups where present; or c) reacting a compound of formula (Vl)
where Z, A, A,, T and R are as defined in claim 1, or a salt thereof, with a compound of formula (VII) H-S-Het (Vll) where Het is as defined in claim 1, or with a reactive derivative thereof; and if desired removing the protecting groups where present; or d) reacting a compound of formula (VIII)
where Z, A, A,, T and Y are as defined in claim 1, or a salt thereof, with a compound of formula (IX) H2N-O-R (IX) where R is as defined above, or a salt thereof and, if desired, removing the protecting groups, where present, and, if desired, converting a compound of formula (I) into a pharmaceutically or veterinarily acceptable salt and/or, if desired, obtaining a free compound from a salt and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof and/or, if desired, resolving a mixture of isomers into the single isomers.
4. A process according to claim 3 substantially as described in any one of the foregoing Examples.
5. A compound of formula (I) as defined in claim 1 when prepared by a process according to claim 3 or4.
6. A pharmaceutical or veterinary composition comprising a compound as claimed in any one of the claims 1 to 3 and 5, and a pharmaceutically or veterinarily acceptable carrier and/or diluent.
GB8016252A 1980-05-16 1980-05-16 Substituted 7-(a-oxy-imino-acetamido)-cephalosporins and process for their preparation Expired GB2076803B (en)

Priority Applications (4)

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GB8016252A GB2076803B (en) 1980-05-16 1980-05-16 Substituted 7-(a-oxy-imino-acetamido)-cephalosporins and process for their preparation
DE19813115935 DE3115935A1 (en) 1980-05-16 1981-04-22 SUBSTITUTED 7 - ((ALPHA) -OXYIMINO-ACETAMIDO) -CEPHALOSPORINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL OR VETERINE MEDICAL CONTAINERS THEREOF
BE0/204795A BE888815A (en) 1980-05-16 1981-05-15 7- (ALPHA-OXY-IMINO-ACETAMIDO)-SUBSTITUTED CEPHALOSPORINS AND THEIR PREPARATION
JP7237981A JPS5716890A (en) 1980-05-16 1981-05-15 Substituted 7-(alpha-oxy-imino-acetoamido)- cephalosporin,manufacture and antibacterial medicine and veterinary drug composition containing it

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2186875A (en) * 1983-10-31 1987-08-26 Fujisawa Pharmaceutical Co New cephem compounds and processes for preparation thereof
WO1999029700A2 (en) * 1997-12-05 1999-06-17 Novartis Ag Cyclohexadiene-derivatives as pesticides
US6608196B2 (en) 2001-05-03 2003-08-19 Galileo Pharmaceuticals, Inc. Process for solid supported synthesis of pyruvate-derived compounds
EP1392639A1 (en) * 2001-05-03 2004-03-03 Galileo Laboratories, Inc. Pyruvate derivatives

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59193889A (en) * 1983-04-18 1984-11-02 Asahi Chem Ind Co Ltd Cephalosporin compound
US10487050B2 (en) 2014-08-29 2019-11-26 Basf Se Oxime sulfonate derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1075277B (en) * 1977-02-11 1985-04-22 Erba Carlo Spa UNSATURATED AND EPOXY DERIVATIVES OF ACIO 7-ACYLAMIDE-3-CEFEM-4-CARBOXYL AND PROCEDURE FOR THEIR PREPARATION
GB1478055A (en) * 1973-07-27 1977-06-29 Erba Carlo Spa Cephalosporin compounds

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2186875A (en) * 1983-10-31 1987-08-26 Fujisawa Pharmaceutical Co New cephem compounds and processes for preparation thereof
WO1999029700A2 (en) * 1997-12-05 1999-06-17 Novartis Ag Cyclohexadiene-derivatives as pesticides
WO1999029700A3 (en) * 1997-12-05 1999-08-26 Novartis Ag Cyclohexadiene-derivatives as pesticides
US6310096B1 (en) 1997-12-05 2001-10-30 Bayer Aktiengesellschaft Cyclohexadiene-derivatives as pesticides
US6608196B2 (en) 2001-05-03 2003-08-19 Galileo Pharmaceuticals, Inc. Process for solid supported synthesis of pyruvate-derived compounds
EP1392639A1 (en) * 2001-05-03 2004-03-03 Galileo Laboratories, Inc. Pyruvate derivatives
US6900218B2 (en) 2001-05-03 2005-05-31 Galileo Pharmaceuticals, Inc. Pyruvate derivatives
EP1392639A4 (en) * 2001-05-03 2006-01-25 Galileo Lab Inc Pyruvate derivatives

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BE888815A (en) 1981-11-16
GB2076803B (en) 1984-02-08
DE3115935A1 (en) 1982-02-25

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