CA1099257A - Cephalosporin derivatives - Google Patents
Cephalosporin derivativesInfo
- Publication number
- CA1099257A CA1099257A CA340,052A CA340052A CA1099257A CA 1099257 A CA1099257 A CA 1099257A CA 340052 A CA340052 A CA 340052A CA 1099257 A CA1099257 A CA 1099257A
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- CA
- Canada
- Prior art keywords
- amino
- cephem
- carboxylic acid
- thiomethyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
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- 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
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- Cephalosporin Compounds (AREA)
Abstract
Abstract of the Disclosure A compound of the formula:
wherein W represents a halogen and Y represents an acetoxy group or a group of formula -SR3 (where R3 is a nitrogen-containing heterocyclic group), or a salt thereof, is found to be a useful intermediate for the cephem compounds of the formula:
wherein W represents a halogen and Y represents an acetoxy group or a group of formula -SR3 (where R3 is a nitrogen-containing heterocyclic group), or a salt thereof, is found to be a useful intermediate for the cephem compounds of the formula:
Description
5~7 This .invention relates to novel cephalosporin deriva-tives having novel 7-acyl groups and preparations thereo~.
More particularly, this invention r~lates to 7-(4-halogeno-3-~xobutyrylamido)cephalosporin derivatives of the formula:
WCEI2COCH2CONH ~ S ~ [VI ]
o ~LCH2Y
COOH
wherein W is a halogen and Y is an acetoxy group or a grou~ of Pormula SR (where R3 is a n~trogen-containing heterocyclic group), or a salt thereof and also relates to processes for producing the same.
Heretofore~ studies on synthetic cephalosporin derivatives have been directed to the conversion of 7-aminocephalosporanic acid to various acyl derivatives at the 7-position or to derivatives at the 3-acetoxy group in order to synthesize compounds having either a broad antibacterial spectrum or a specific antibacterial spectxum. However, these well-known cephalosporin derivatives are not yet satisfactory in antimicrobi.al activities against a wide variety of microorganisms. Hence, a compound has been sought after which has a broad or antimicrobial spectrum and is effective even at a lower concentration.
It has now been found that novel cephalosporin deri~a-tives represented by the above formula [VI] are useful inter-mediates for the production of 7-[2-(2-exo-substituted-4-thiazolin-4-yl)acetamido]cephalosporin derivatives of the formula:
~t,~
x~s N ~il -- CH2coHN ~
R~ N~L C~ 2 Y [ I ]
COOH
wherein Rl is a hydrogen atom or an alkyl group; X is oxygen or a sulfur atom or a group of formula NR2 (where R2 is hydrogen or an alkvl gr~up, and in the case of an alkyl group, it may ~orm a ring joined ~ith Rl), Y hasthe same meaning as defined above, or a pharmaceutically acceptable salt thereof, ~ich have broader antimicro~ial spectra as compared with those of known cephalo-sporins. For example, the cephalosporin deriva-tives ~I~ are desirable cephalosporin antibiotics, having a strong and broad an_imicrobial spectrum especiaLly against such gram-negative bacterla as Escherichia coli, Klebs_ella pneumoniae, Proteus vulgaris and Pro_teus morganl , showing greater in-hibitory activlty in comparison wlth known cephalosporins.
` Referring, now, to the above formula [VI], Y stands :Eor an-acetc~ygroup or a group denoted by formula -SR3. R3 stands for a nltrogen-containing heterocyclic group containing not less than one nitrogen whlch may be in the oxide form or, in addition to nitrogen or nitrogens, such others as oxygen or/and sulfur. The nitrogen-containing heterocyclic group desirably has one to:four hetero atoms in its heterocyclic ring and the ring maybe a 5 or 6 membered one. As such nitrogen-containing heterocyclic group, there may be mentioned, among others, pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N- `~
oxido-pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4~thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiaæolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl~
9~9~
lH-tetrazolyl, 2H-tetrazolyl and others. Each of these nitrogen-containing heterocyclic groupS may be further sub-stituted and, as the substituents, there may be mentioned monovalent groups, for example, lower alkyls such as methyl, ethyl, trifluoromethyl~ etc., lower alkoxyls such as methoxy, ethoxy, etc., halogens such as chlorine, bromine, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl groups, etc. or a substituted lower alkyl group, a substituted mercapto group, or a mono- or di-substituted amino group, etc. The substituents in the substituted lower alky] group may be hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl,~alkoxycarbonyl, mono-, di- or tri-lower alkylamino, mono- or dl-lower alkyl-carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, morpholino-carbonyl groups, etc., wherein the acyloxy group is exemplified by acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy, phenylacetoxy, etc., the alkoxy group by methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, etc. r and others are the same meaning as hereir.-before described. The substituent of the substituted mercapto group may be a lower alkyl group or a substituted lower alkyl group above mentioned. The substituents of the mono- or-di-substituted amino group may be alower alkyl group, an alkoxy-carbonyl, an acyl, carbamoyl, a lower alk~lcarbamoyl,oor a substituted lower alkyl group mentioned above.
Specifically, use may be made of, for example, a substituted lower alkyl group such as carboxymethyl, carbamoyl-methyl, an N-lower alkylcarbamoylmethyl (e.g. N,N-dimethyl-carbamoylmethyl), a hydroxy-lower alkyl (e.g. hydroxymethyl, 2-hydroxyethyl), an acyloxy-lower alkyl (e.g. acetoxymethyl,
More particularly, this invention r~lates to 7-(4-halogeno-3-~xobutyrylamido)cephalosporin derivatives of the formula:
WCEI2COCH2CONH ~ S ~ [VI ]
o ~LCH2Y
COOH
wherein W is a halogen and Y is an acetoxy group or a grou~ of Pormula SR (where R3 is a n~trogen-containing heterocyclic group), or a salt thereof and also relates to processes for producing the same.
Heretofore~ studies on synthetic cephalosporin derivatives have been directed to the conversion of 7-aminocephalosporanic acid to various acyl derivatives at the 7-position or to derivatives at the 3-acetoxy group in order to synthesize compounds having either a broad antibacterial spectrum or a specific antibacterial spectxum. However, these well-known cephalosporin derivatives are not yet satisfactory in antimicrobi.al activities against a wide variety of microorganisms. Hence, a compound has been sought after which has a broad or antimicrobial spectrum and is effective even at a lower concentration.
It has now been found that novel cephalosporin deri~a-tives represented by the above formula [VI] are useful inter-mediates for the production of 7-[2-(2-exo-substituted-4-thiazolin-4-yl)acetamido]cephalosporin derivatives of the formula:
~t,~
x~s N ~il -- CH2coHN ~
R~ N~L C~ 2 Y [ I ]
COOH
wherein Rl is a hydrogen atom or an alkyl group; X is oxygen or a sulfur atom or a group of formula NR2 (where R2 is hydrogen or an alkvl gr~up, and in the case of an alkyl group, it may ~orm a ring joined ~ith Rl), Y hasthe same meaning as defined above, or a pharmaceutically acceptable salt thereof, ~ich have broader antimicro~ial spectra as compared with those of known cephalo-sporins. For example, the cephalosporin deriva-tives ~I~ are desirable cephalosporin antibiotics, having a strong and broad an_imicrobial spectrum especiaLly against such gram-negative bacterla as Escherichia coli, Klebs_ella pneumoniae, Proteus vulgaris and Pro_teus morganl , showing greater in-hibitory activlty in comparison wlth known cephalosporins.
` Referring, now, to the above formula [VI], Y stands :Eor an-acetc~ygroup or a group denoted by formula -SR3. R3 stands for a nltrogen-containing heterocyclic group containing not less than one nitrogen whlch may be in the oxide form or, in addition to nitrogen or nitrogens, such others as oxygen or/and sulfur. The nitrogen-containing heterocyclic group desirably has one to:four hetero atoms in its heterocyclic ring and the ring maybe a 5 or 6 membered one. As such nitrogen-containing heterocyclic group, there may be mentioned, among others, pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N- `~
oxido-pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4~thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiaæolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl~
9~9~
lH-tetrazolyl, 2H-tetrazolyl and others. Each of these nitrogen-containing heterocyclic groupS may be further sub-stituted and, as the substituents, there may be mentioned monovalent groups, for example, lower alkyls such as methyl, ethyl, trifluoromethyl~ etc., lower alkoxyls such as methoxy, ethoxy, etc., halogens such as chlorine, bromine, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl groups, etc. or a substituted lower alkyl group, a substituted mercapto group, or a mono- or di-substituted amino group, etc. The substituents in the substituted lower alky] group may be hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl,~alkoxycarbonyl, mono-, di- or tri-lower alkylamino, mono- or dl-lower alkyl-carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, morpholino-carbonyl groups, etc., wherein the acyloxy group is exemplified by acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy, phenylacetoxy, etc., the alkoxy group by methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, etc. r and others are the same meaning as hereir.-before described. The substituent of the substituted mercapto group may be a lower alkyl group or a substituted lower alkyl group above mentioned. The substituents of the mono- or-di-substituted amino group may be alower alkyl group, an alkoxy-carbonyl, an acyl, carbamoyl, a lower alk~lcarbamoyl,oor a substituted lower alkyl group mentioned above.
Specifically, use may be made of, for example, a substituted lower alkyl group such as carboxymethyl, carbamoyl-methyl, an N-lower alkylcarbamoylmethyl (e.g. N,N-dimethyl-carbamoylmethyl), a hydroxy-lower alkyl (e.g. hydroxymethyl, 2-hydroxyethyl), an acyloxy-lower alkyl (e.g. acetoxymethyl,
2-acetoxyethyl), an alkoxycarbonylmethyl (e.g. methoxycarbonyl-methyl, hexyloxycarbonylmethyl, octyloxycarbonylmethyl), methyl-thiomethyl, methylsulfonylmethyl, an N-lower alkylamino-lower alkyl te.g. N,N-dimethylaminomethyl, N,N-dimeth~ylaminoethyl, N,N,N-trimethylammoniumethyl), morpholinomethyl, etc., mono-or dl-substituted amino groups such as a lower alkylamino ~e~g. methylamino), a sulfo-lower alkylamino ~e.g. 2-sulfo-ethylamino), a hydroxy-lower alkylamino (e.g., hydroxyethyl-amino), a lower alkylamino-lower alkylamino (e.g. 2-dimethyl-amino-ethylamino, 2-trimethylammoniumethylamino), an acylamino (e.g~ acetylamino), 2-dimethylaminoacetylamino, 2-trimethyl-ammonium-acetylamino, a lower alkoxycarbonylamino (e.g.
methoxycacbonylamino), etc., a substituted mercapto group such as methylthio, 2-hydroxyethylthio, a 2-acyloxyethylthio (e.g.
2-acetoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxy-ethylthio), carboxymethylthio, an alkoxycarbonylmethylthio (e.g. methoxycarbonylmethylthio, hexyloxycarbonylmethylthio~, carbamoylmethylthio, an N-lower alkylcarbamoylmethylthio (e.g.
N,N-dlmethylcarbamoylméthylthio), acetylmethylthio, an N-lower alkylamino-lower alkylthio (e.g. 2-N,N-dimethylamino-ethylthio, 2-N,N,N-trimethylammonium-ethylthio), morpholinocarbonylmethyl-thio, 2-sulfoethylthio, etc.
The 7-(4-halogeno-3-oxobutyrylamido)cephalosporin derivatives ~q]of this invention may be used with its 4-carboxyl group being free or after being made into a salt with a nontoxic cation such as sodium, potassium or the like; a basic amino acid such as arginine, ornithine, lysine, histidine or the like;
or a polyhydroxyalkylamine such as N-methylglucamine, diethanol-amine, triethanolamine, tris-hydroxymethylaminomethane or the like. The compounds [I] may also be used after it has been converted to an ester derivative by esterification of its 4- !
carboxyl group, said ester derivatives being conducive to, for instance, an increased blood level or/and a longer duration of activity. As the ester residues of use for this purpose~ there ~ 57 may be m~ntioned, for example, alkoxylmethyl and ~-alkox~ethyl and other ~-alkoxy~subs~ituted methyl groups, e.g. methoxy-methyl, ethoxymethyl, isopropoxymethyl, ~-methoxyethyl, ~-ethoxyethyl, etc ; alkylthio~e~hyl groups, e.g. methylthio-methyl, ethylthiomethyl, isopropylthiomethyl, etc.; and acyloxy-methyl and a-acyloxy-~-substituted methyl groups, e.g.
pivaloyloxymethyl, ~-acetoxybutyl, etc.
The present invention, in a broad aspect, resides in a process for producing a compound o~ the formula:
WcH2cocH2coNE~F~s ~
N ~ CH2Y
COOH
wherein W is a halogen atom and Y represents acetoxy or a group of formula -SR3 (where R3 is a nitrogen-containing heterocyclic group), or a salt or ester thereof, which comprises reacting a compound o the formula:
O N ~ CH2Y
COOH
wherein Y is the same meanIng as defined above, or a salt or ester thexeof, with a compound of the formula:
wherein ~ is the same meaning as defined above.
In another broad aspect, this invention resides in a compound of the formula WCH~COCH2CONH ~ ~ S
~CH2Y [
~ ~ - 6 - .
..., .~si~, ;7 wherein W is a halogen atom and Y represents acetoxy or a group of formula - SR (where R3 is a nitrogen-containing heterocyclic group), or a salt thereof.
The cephalosporin derivatives [VI] of the present invention may be allowed to react with a compound of the formula:
NH
NH2-C-SH [VII]
or a salt thereof, to obtain a compound of the formula [II]
NH
NH2-c-sc~2coc~l2coNH ~ [II]
~O ~ N ~ CH2Y
~ COOH
wherein the symbol has the same meaning as above, or a salt or an ester thereof, whlch is subjected to a ~ closure re-action with elimination of water, to obtain cephalosporin derivatives of the formula [I].
The 3-nitrogen-containing heterocyclic thiomethyl compounds [VI] and [XII] are prepared by the reaction formulated below;
.
NH ~ S j ~XII]
o~ N~o~L 2 COOH
;
i WCH2COCH2COW [XIV]
WCH2COCH2CONH ~ ~S
o~N~ CH2Y [VI~
COOH
` ~L@~257 The amino compounds [XII] may be prepared by de-acylating the reaction product of cephalosporin C and a nitrogen-containing heterocyclic thiol of the formula [X];
R3SH wherein R3 ha~ the same meaning as above, or its salt, or by reacting 7-protected aminocephalosporanic acid with a nitrogen-containing heterocyclic thiol [X] and removing the protecting group from the reaction product with the nomenclature of similar compounds adopted by Chemical Abstracts. The tautomeric isomers, however, are all included within the scope of this invention.
The typical examples of 7-(4-halogeno-3-oxobutyrylamido) cephalosporin derivatives ~1] thus obtained are 7-(4-chloro or bromo-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
methoxycacbonylamino), etc., a substituted mercapto group such as methylthio, 2-hydroxyethylthio, a 2-acyloxyethylthio (e.g.
2-acetoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxy-ethylthio), carboxymethylthio, an alkoxycarbonylmethylthio (e.g. methoxycarbonylmethylthio, hexyloxycarbonylmethylthio~, carbamoylmethylthio, an N-lower alkylcarbamoylmethylthio (e.g.
N,N-dlmethylcarbamoylméthylthio), acetylmethylthio, an N-lower alkylamino-lower alkylthio (e.g. 2-N,N-dimethylamino-ethylthio, 2-N,N,N-trimethylammonium-ethylthio), morpholinocarbonylmethyl-thio, 2-sulfoethylthio, etc.
The 7-(4-halogeno-3-oxobutyrylamido)cephalosporin derivatives ~q]of this invention may be used with its 4-carboxyl group being free or after being made into a salt with a nontoxic cation such as sodium, potassium or the like; a basic amino acid such as arginine, ornithine, lysine, histidine or the like;
or a polyhydroxyalkylamine such as N-methylglucamine, diethanol-amine, triethanolamine, tris-hydroxymethylaminomethane or the like. The compounds [I] may also be used after it has been converted to an ester derivative by esterification of its 4- !
carboxyl group, said ester derivatives being conducive to, for instance, an increased blood level or/and a longer duration of activity. As the ester residues of use for this purpose~ there ~ 57 may be m~ntioned, for example, alkoxylmethyl and ~-alkox~ethyl and other ~-alkoxy~subs~ituted methyl groups, e.g. methoxy-methyl, ethoxymethyl, isopropoxymethyl, ~-methoxyethyl, ~-ethoxyethyl, etc ; alkylthio~e~hyl groups, e.g. methylthio-methyl, ethylthiomethyl, isopropylthiomethyl, etc.; and acyloxy-methyl and a-acyloxy-~-substituted methyl groups, e.g.
pivaloyloxymethyl, ~-acetoxybutyl, etc.
The present invention, in a broad aspect, resides in a process for producing a compound o~ the formula:
WcH2cocH2coNE~F~s ~
N ~ CH2Y
COOH
wherein W is a halogen atom and Y represents acetoxy or a group of formula -SR3 (where R3 is a nitrogen-containing heterocyclic group), or a salt or ester thereof, which comprises reacting a compound o the formula:
O N ~ CH2Y
COOH
wherein Y is the same meanIng as defined above, or a salt or ester thexeof, with a compound of the formula:
wherein ~ is the same meaning as defined above.
In another broad aspect, this invention resides in a compound of the formula WCH~COCH2CONH ~ ~ S
~CH2Y [
~ ~ - 6 - .
..., .~si~, ;7 wherein W is a halogen atom and Y represents acetoxy or a group of formula - SR (where R3 is a nitrogen-containing heterocyclic group), or a salt thereof.
The cephalosporin derivatives [VI] of the present invention may be allowed to react with a compound of the formula:
NH
NH2-C-SH [VII]
or a salt thereof, to obtain a compound of the formula [II]
NH
NH2-c-sc~2coc~l2coNH ~ [II]
~O ~ N ~ CH2Y
~ COOH
wherein the symbol has the same meaning as above, or a salt or an ester thereof, whlch is subjected to a ~ closure re-action with elimination of water, to obtain cephalosporin derivatives of the formula [I].
The 3-nitrogen-containing heterocyclic thiomethyl compounds [VI] and [XII] are prepared by the reaction formulated below;
.
NH ~ S j ~XII]
o~ N~o~L 2 COOH
;
i WCH2COCH2COW [XIV]
WCH2COCH2CONH ~ ~S
o~N~ CH2Y [VI~
COOH
` ~L@~257 The amino compounds [XII] may be prepared by de-acylating the reaction product of cephalosporin C and a nitrogen-containing heterocyclic thiol of the formula [X];
R3SH wherein R3 ha~ the same meaning as above, or its salt, or by reacting 7-protected aminocephalosporanic acid with a nitrogen-containing heterocyclic thiol [X] and removing the protecting group from the reaction product with the nomenclature of similar compounds adopted by Chemical Abstracts. The tautomeric isomers, however, are all included within the scope of this invention.
The typical examples of 7-(4-halogeno-3-oxobutyrylamido) cephalosporin derivatives ~1] thus obtained are 7-(4-chloro or bromo-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-oxobutyryl-amido)-3-(l~methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3 oxobutyrylamido)-3-(1-ethyltetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or I bromo-3-oxobutyrylam.ido)-3-(2-methyl-1,3,4-thiadiazol-~-yl)-thiomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-oxobutyrylamido -3-[2-(2-hydroxyethyl-thio)-1,3,4~thiadiazol-5-yl]t~iomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-oxobutyrylamido)-3-12-(N,N-di-methylcarbamoylmethyl)-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, 7 (4-chloro or bromo-3-oxobutyryl-amido)-3-[2-(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl]thio-methyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-oxobutyrylamido)-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, 7-(4 chloro or bromo-3-oxobutyrylamido)-3-(2-carbamoylmethyl-1,3,4~thi.adiazol-5-yl~thiomethyl-3-cephem-4-carboxylic acid, 7 (4-chloro or bromo-3-oxobutyrylamido)-3-(2 carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carhoxylic acid.
, ~ ~
i7 The present invention is illustrated in further detail below with reference to examples, but it is to be understood that the examples are solely for the purpose of illustration and not to be construed as limitations of the invention, and that many variations may be resorted to with-out departing from the spirit and scope of the invention~
In this specification, "g", "mg.", "kg.", "ml.", "cm.", "ppm", "H2", "MHz", "mol", "m mol", "mcg"~ "Calcd.", "DMSO", "nm"
and "decomp." are abbreviations of "gram", "milligram", "kilogram", "milliliter", "centimeter", "part per million", "Herz"j "mega Herz"~ "Mole", "milli-Mole", "microgram", "Calculated", "dimethylsulfoxide", "Nano meter", and "decom-posed", respectively. Resins named 'Amberlite"* are products manufactured by Rohm & Haas Co. in U.S.A. All the temperatures are uncorrected and the percentages are all on the weight basis except specifically defined. The NMR spectra given therein were measured using a Varian Model HA 100 (100 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as the in-ternal reference and all ~ values are in ppm. The sy~bol s ~0 stands for a singlet, d a doublet, t a triplet, q a quartet, _ a multiplet, and J a coupling constant.
Reference ExamDle 1 Production of sodium 7-[2-(2-aminothiazol-4-yl) acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate In a mixture of 53 mQ. of water and 26.4 mQ. of tetrahydrofuran are dissolved 0.442 g. of thiourea and 0.889 g.
of sodium hydrogen carbonate. Then, 2.3 g. of 7-(4-bromo-3-* Trade~ark g 9~i~57 oxobutyrylamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid iS
gradually added and dissolved. The mixture is stirred at room temperature for 30 minutes, af~er which time it is concentrated under reduced pressure to remove the tetrahydrofuran and further to a final volume of 20 mQ. The residue is chromatographed on a column of polystyrene r sin (~erlite X~2"*) and developed with water. The fractions containing the desired product (with good absorption of ultraviolet light at 254 m~) are pooled and freeze-dried. The procedure gives the above-indicated compound.
Yield 1.305 g. (52.6 %) IR(cm , KBr): 1767 UV~ max( in water): 256 nm(1.35 x 104) NMR(~ in D2O): 2.15 (s, CH3CO), 3.39 & 3.69(ABq, J18Hz, 2-CH2), 3.62(s, CH2CO), 4.75 & 4.94(ABq, J13Hz, 3-CH2), 5.15(d, J5Hz, 6-H), 5.71(d, JSHz, 7-H), 6.52(s, thiazole 5-H) Elemental analysis: Calcd. for C15H15N4O6S2Na 2H2O:
C, 38.29; H, 4.07; N, 11.91 Found: C, 38.41; H, 3.90; N, 11.72 Antibacterial spectra -(mcg/mQ., agar diluti-on m~thod) , Strain of Product microorganism of this Cephalor~dine Cephazolin example . . ~
S. aureus 209P <0.78 0.05 0.1 S. aureus 1840 1.56 0.39 1.56 E. coli NIHJ JC-21.56 6.25 1.56 K. pneumoniae DT<0.78 3.125 1.56 P. vulgaris Eb-57~0.78 ~100 50 .. _ _ ............. _ . ... _ _ ._ _ *,Trademark `~ 25~
Reference Example 2 Production of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid III a mixture of 80 mQ. of water and 40 mQ. of tetrahydrofuran are dissolved 0.602 g. of thiourea and 0.664 g.
of sodium hydrogen carbonate. Then, 3.085 g. of 7-(4-chloro-3-oxobutyrylamido)-3-acetoxymethyl-3~cephem-4-carboxylic acid is gradually added and dissolved. The mixture is stirred at room temperature for 1 hour, after which time the te-trahydro-furan is dlstilled off under reduced pressure. The residue is allowed to stand at room temperature and the resulting crystals are recovered by filtration. The filtrate is further eoncentrated and allowed to stand, whereupon an additional crop of crys-tals is obtained. These crystals are recovered and combined with those previously harvested. The described proeedure gives 2.703 g. (83%) of the above-indicated compound.
IR(cm , KBr): 1776 UV~ max(- in water): 256 nm(l.35 x 104) NMR(~ in d6-DMSO): 2.01(s, CH3CO), 3.38(s, CH2CO), 3.40 & 3.63(ABq, J18Hz, 2-CH2), 4.68 & 4.98 (ABq, J13Hz, 3-CH2), 5.06(d, J5Hz, 6-H), 5.68(dd, J5 & 8Hz, 7-H), 6.23(s, thiazole 5-H), 6.90(broad s, NH2), 8.82(d, J8Hz, CONH), 9.20(broad s, COOH).
Referenee Example 3 Production of sodium 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate In a mixture of 10 mQ. of water and 10 mQ. of tetrahydrofuran are dissolved 0.076 g. of thiourea and 0.084 g.
of sodium hydrogen carbonate. Then, 0.447 g. of powdery ;7 7-(4-chloro-3-oxobutyrylamido~-3-~1-methyltetrazol-5-yl)thio-methyl-3-cephem-4-car~oxylic acid is added and dissolved. The reaction mixture iS allowed to stand at room temperature overnight, after which it is concentrated under reduced pressure to remove the tetrahydrofuran. To t~e residue is added 0.16 g.
of sodium hydrogen carbonate and the resultant mixture is chromatographed on a column of polystyrene resin ("Amberlite ~21'*3 and developed with water~ The fractions containing the desired product axe pooled and freeze-dried. The procedure gives the above indicated compound. Yield 0.182 g.
IR(cm 1, KBr): 1763 w~ max( in water): 260 nm(1.48 x 104) NMR~ in D20): 3.48 & 3.81(ABq, J17~z, 2-CH2), 3.63(s, CH2CO), 4.06(s, tetrazolyl 1-CH3), 4.09 &
, ~ ~
i7 The present invention is illustrated in further detail below with reference to examples, but it is to be understood that the examples are solely for the purpose of illustration and not to be construed as limitations of the invention, and that many variations may be resorted to with-out departing from the spirit and scope of the invention~
In this specification, "g", "mg.", "kg.", "ml.", "cm.", "ppm", "H2", "MHz", "mol", "m mol", "mcg"~ "Calcd.", "DMSO", "nm"
and "decomp." are abbreviations of "gram", "milligram", "kilogram", "milliliter", "centimeter", "part per million", "Herz"j "mega Herz"~ "Mole", "milli-Mole", "microgram", "Calculated", "dimethylsulfoxide", "Nano meter", and "decom-posed", respectively. Resins named 'Amberlite"* are products manufactured by Rohm & Haas Co. in U.S.A. All the temperatures are uncorrected and the percentages are all on the weight basis except specifically defined. The NMR spectra given therein were measured using a Varian Model HA 100 (100 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as the in-ternal reference and all ~ values are in ppm. The sy~bol s ~0 stands for a singlet, d a doublet, t a triplet, q a quartet, _ a multiplet, and J a coupling constant.
Reference ExamDle 1 Production of sodium 7-[2-(2-aminothiazol-4-yl) acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate In a mixture of 53 mQ. of water and 26.4 mQ. of tetrahydrofuran are dissolved 0.442 g. of thiourea and 0.889 g.
of sodium hydrogen carbonate. Then, 2.3 g. of 7-(4-bromo-3-* Trade~ark g 9~i~57 oxobutyrylamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid iS
gradually added and dissolved. The mixture is stirred at room temperature for 30 minutes, af~er which time it is concentrated under reduced pressure to remove the tetrahydrofuran and further to a final volume of 20 mQ. The residue is chromatographed on a column of polystyrene r sin (~erlite X~2"*) and developed with water. The fractions containing the desired product (with good absorption of ultraviolet light at 254 m~) are pooled and freeze-dried. The procedure gives the above-indicated compound.
Yield 1.305 g. (52.6 %) IR(cm , KBr): 1767 UV~ max( in water): 256 nm(1.35 x 104) NMR(~ in D2O): 2.15 (s, CH3CO), 3.39 & 3.69(ABq, J18Hz, 2-CH2), 3.62(s, CH2CO), 4.75 & 4.94(ABq, J13Hz, 3-CH2), 5.15(d, J5Hz, 6-H), 5.71(d, JSHz, 7-H), 6.52(s, thiazole 5-H) Elemental analysis: Calcd. for C15H15N4O6S2Na 2H2O:
C, 38.29; H, 4.07; N, 11.91 Found: C, 38.41; H, 3.90; N, 11.72 Antibacterial spectra -(mcg/mQ., agar diluti-on m~thod) , Strain of Product microorganism of this Cephalor~dine Cephazolin example . . ~
S. aureus 209P <0.78 0.05 0.1 S. aureus 1840 1.56 0.39 1.56 E. coli NIHJ JC-21.56 6.25 1.56 K. pneumoniae DT<0.78 3.125 1.56 P. vulgaris Eb-57~0.78 ~100 50 .. _ _ ............. _ . ... _ _ ._ _ *,Trademark `~ 25~
Reference Example 2 Production of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid III a mixture of 80 mQ. of water and 40 mQ. of tetrahydrofuran are dissolved 0.602 g. of thiourea and 0.664 g.
of sodium hydrogen carbonate. Then, 3.085 g. of 7-(4-chloro-3-oxobutyrylamido)-3-acetoxymethyl-3~cephem-4-carboxylic acid is gradually added and dissolved. The mixture is stirred at room temperature for 1 hour, after which time the te-trahydro-furan is dlstilled off under reduced pressure. The residue is allowed to stand at room temperature and the resulting crystals are recovered by filtration. The filtrate is further eoncentrated and allowed to stand, whereupon an additional crop of crys-tals is obtained. These crystals are recovered and combined with those previously harvested. The described proeedure gives 2.703 g. (83%) of the above-indicated compound.
IR(cm , KBr): 1776 UV~ max(- in water): 256 nm(l.35 x 104) NMR(~ in d6-DMSO): 2.01(s, CH3CO), 3.38(s, CH2CO), 3.40 & 3.63(ABq, J18Hz, 2-CH2), 4.68 & 4.98 (ABq, J13Hz, 3-CH2), 5.06(d, J5Hz, 6-H), 5.68(dd, J5 & 8Hz, 7-H), 6.23(s, thiazole 5-H), 6.90(broad s, NH2), 8.82(d, J8Hz, CONH), 9.20(broad s, COOH).
Referenee Example 3 Production of sodium 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate In a mixture of 10 mQ. of water and 10 mQ. of tetrahydrofuran are dissolved 0.076 g. of thiourea and 0.084 g.
of sodium hydrogen carbonate. Then, 0.447 g. of powdery ;7 7-(4-chloro-3-oxobutyrylamido~-3-~1-methyltetrazol-5-yl)thio-methyl-3-cephem-4-car~oxylic acid is added and dissolved. The reaction mixture iS allowed to stand at room temperature overnight, after which it is concentrated under reduced pressure to remove the tetrahydrofuran. To t~e residue is added 0.16 g.
of sodium hydrogen carbonate and the resultant mixture is chromatographed on a column of polystyrene resin ("Amberlite ~21'*3 and developed with water~ The fractions containing the desired product axe pooled and freeze-dried. The procedure gives the above indicated compound. Yield 0.182 g.
IR(cm 1, KBr): 1763 w~ max( in water): 260 nm(1.48 x 104) NMR~ in D20): 3.48 & 3.81(ABq, J17~z, 2-CH2), 3.63(s, CH2CO), 4.06(s, tetrazolyl 1-CH3), 4.09 &
4.37td, J14Hz, 3-CH2), 5.13(d, J5Hz, 6-H),
5.68(d, J5Hz, 7-H), 6.52(s, thiazole 5-H) Elemental analysis: Calcd. fox C16H15N8O4S3 2.5H2O
C, 33.54; H, 3.76i N, 20.92 Found : C, 33.80; H, 3.33; M, 19.86 Antibacterial spectra ~mcg/mQ., agar dilution method) - -.
Strain of Product microorganism - of this Cephaloridine Cephazolin example .. . . . . . _ . . . . . _ S. aureus 209P 0.39 0.05 0.1 S. aureus 1840 0.78 0.39 1.56 E. coli NIHJ JC-2 0.39 6.25 1.56 E. c _ 0-111 0.2 3.125 1.56 K. pneumoniae DT ~0.1 3.125 1.56 P. vulgaris Eb 58 0.39 12.5 6.25 P. morganii Eb 53 3.125 >100 100 .. ....... ..
* Trademark Reference Example 4 Production of sodium 7-12-(2-aminothiazol-4-yl)-acetamido]-3-(5-methyl-1,3~4-thiadiazol-2-yl)thiomethyl-3 cephem-4-carboxylate In a mixture o~ 10 m~. of water and 10 m~O of tetrahydrofuran are dissolved 0.076 g. of thiourea and 0.084 g. of sodium hydrogen carbonate. Then, 0.463 g. of 7-(4-chloro-3-oxobutyrylamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid is added and dissolved. The mixture is allowed to stand at room temperature ~vernightr after which it is concentrated under reduced pres-sure to remove the tetrahydrofuran. To the residue is added 0.16 g. of sodium hydrogen carbonate and the mixture is chromatographed on a column of polystyrene resin (Amberlite XAD-2) and developed with water. The fractions containing the desired product are pooled and freeze-dried.
IR(cm , KBr): 1763 NMR(~ in D2O): 2.76(s, thiadiazole 5-CH3), 3.42 & 3.79 tABq, J18Hz, 2-CH2), 3.62(s, CH2CO), 4.02 &
4.51(ABq, J14Hz, 3-CH2), 5.11 (d, J5Hz, 6-H), 5.68(d, J5Hz, 7-H), 6.50(s, thiazole 5-H) Elemental analysis: Calcd. for Cl6Hl5N6o4s4Na-2.5H2o C, 34.84; H, 3.65; N, 15.23 Found : C, 34.87; H, 3.47; N, 14.82 Elemental analysis: Calcd. for Cl7Hl9N~o6s2Na-l.5H2o C, 41.71; H, 4.53; N, 11.45;
Found : C, 42.08; H, 4.98; N, 11.47 Example 1 The compounds listed in Tables 1 to 4 are prepared by one or more of the following Methods 1 to 2.
2~ii7 Method l (l) In 40 mQ . of water are dissolved 10.7 g. (7.30 m mol) of 7-acetoacetamido~3-acetoxymethyl-3-cephem-4-carboxylic acid, 30 m mol of a nitrogen-containing heterocyclic thiol and 5.04 g. (60 m mol) of sodium hydrogen carbona~e and the solution is adjusted at pH 7.0 with a lO ~ aqueous solution of sodium hydroxide, followed by stirring for 4 hours at 60 - 65C.
After cooling, 2.31 g. (33 m mol) of hydroxylamine hydrochloride is added to the reaction mixture and the mixture is adjusted to pH 3.6 by adding N-hydrochloric acid, followed by standing at room temperature for overnight. The precipitated crystals of a 7~amino-3-(nitrogen-containing heterocyclic)-~hiomethyl-3-cephem-4-carboxylic acid are collected by filtration, washed with acetone and dried.
(2) A solution of 1.03 g. (13 m mol) of diketene in 5 mQ.
of methylene chloride is previously chilled to -30C and a solution of 1.05 g (15 m mol) of chlorine in lO mQ. of carbon tetrachloride or a solution of 2.24 g. (14 m mol) of bromine in 5 mQ. of methylene chloride is added dropwise thereto.
Meanwhile, 10 m mol of a 7-amino-3-(nitrogen-containing heter-ocyclic)thiomethyl-3-cephem-4-carboxylic acid and 2.02 g.
(20 m mol) of triethylamine are dissolved in 20 mQ. of methylene chloride and the solution is chilled to -20~C. To this solution is dropped rapidly the above-prepared reaction mixture. The temperature rises in most cases to the neighborhood of 0C
caused by the exothermic reaction~ After the exothermic reaction is subsided, the temperature is gradually increased to room temperature. After stirring for 15 minutes, the reaction solu-tion is added to a mixture of 150 mQ. of e-thyl acetate and lO0 mQ. of a lO % aqueous solution of phosphoric acid under vigorous stirring. The organic layer is separated, washed with - 14 ~
~g~;~57 water and dried, followed by the evaporation of the solvent.
To the residue is added ether and the mixture is allowed to stand. The resulta~t preeipitate of a 7-(4-chloro or bromo-3-oxobutyrylamido)-3-(nitrogen-eontalning heterocyelic)thio-methyl-3-eephem-4-earboxylie acid is recovered by filtration as powder.
Method 2 (1) A solution of 60 g. (0.2 mol) of 7-formamido-3-aeetoxymethyl-3-eephem-4-carboxylie aeid, 0.2 mol of a nitrogen-eontaining heterocyelic thiol and 33.6 g. (0.4 mol) of sodium hydroger, earbonate dissolved in 200 mQ. of water is adjusted to pH 7.0 by adding a 10 % aqueous solution of sodium hydroxide and stirred for 4-5 hours at 60-65C, followed by addition of 500 mQ. of methanol. The mixture is eooled down with ice and 80 g. of concentrated sulfurie aeid is added thereto under stirring and keeping the temperature not exceeding 30C, followed by standing in ice-room overnight. The reaetion mixture is diluted with 1000 mQ. of water and the mixed solu-tion is shaken with ethyl aeetate (2 x 400 mQ.). The combined aqueous layer is subjeeted to the filtration under suction to remove undissolved materials and the filtrate is adjusted to pH 3.8 by adding eoncentrated aqueous ammonia, followed by standing at 0C for 3 hours. The preeipitated erystals are eolleeted by filtration and washed with cold water (100 mQ.) and then aeetone (300 mQ.), followed by drying to give 7-amino-3-(nitrogen-eontaining heteroeyclie)thiomethyl-3-eephem-~-earboxylie acid.
(2) The material obtained in above (1) is treated in the similar manner as (2) of Method 1 to obtain 7-(4-ehloro or bromo-3-oxobutyrylamido)-3-(nitrogen-eontaining heterocyclic)-thiomethyl-3-eephem-4-carboxylic acid.
1 5 ~`r ~i7 Table 1 WcH2cocH2coNH ~ S ~ N N
N ~ CH2S ~ S ~ R
COOM
Compound No. I- R5 Method No.
_. I
¦ -NH2 H 2 I _ .. l __ ~ 1 2 2 H , H 2 ,, .
-NHCOCH2N(CH3)2
C, 33.54; H, 3.76i N, 20.92 Found : C, 33.80; H, 3.33; M, 19.86 Antibacterial spectra ~mcg/mQ., agar dilution method) - -.
Strain of Product microorganism - of this Cephaloridine Cephazolin example .. . . . . . _ . . . . . _ S. aureus 209P 0.39 0.05 0.1 S. aureus 1840 0.78 0.39 1.56 E. coli NIHJ JC-2 0.39 6.25 1.56 E. c _ 0-111 0.2 3.125 1.56 K. pneumoniae DT ~0.1 3.125 1.56 P. vulgaris Eb 58 0.39 12.5 6.25 P. morganii Eb 53 3.125 >100 100 .. ....... ..
* Trademark Reference Example 4 Production of sodium 7-12-(2-aminothiazol-4-yl)-acetamido]-3-(5-methyl-1,3~4-thiadiazol-2-yl)thiomethyl-3 cephem-4-carboxylate In a mixture o~ 10 m~. of water and 10 m~O of tetrahydrofuran are dissolved 0.076 g. of thiourea and 0.084 g. of sodium hydrogen carbonate. Then, 0.463 g. of 7-(4-chloro-3-oxobutyrylamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid is added and dissolved. The mixture is allowed to stand at room temperature ~vernightr after which it is concentrated under reduced pres-sure to remove the tetrahydrofuran. To the residue is added 0.16 g. of sodium hydrogen carbonate and the mixture is chromatographed on a column of polystyrene resin (Amberlite XAD-2) and developed with water. The fractions containing the desired product are pooled and freeze-dried.
IR(cm , KBr): 1763 NMR(~ in D2O): 2.76(s, thiadiazole 5-CH3), 3.42 & 3.79 tABq, J18Hz, 2-CH2), 3.62(s, CH2CO), 4.02 &
4.51(ABq, J14Hz, 3-CH2), 5.11 (d, J5Hz, 6-H), 5.68(d, J5Hz, 7-H), 6.50(s, thiazole 5-H) Elemental analysis: Calcd. for Cl6Hl5N6o4s4Na-2.5H2o C, 34.84; H, 3.65; N, 15.23 Found : C, 34.87; H, 3.47; N, 14.82 Elemental analysis: Calcd. for Cl7Hl9N~o6s2Na-l.5H2o C, 41.71; H, 4.53; N, 11.45;
Found : C, 42.08; H, 4.98; N, 11.47 Example 1 The compounds listed in Tables 1 to 4 are prepared by one or more of the following Methods 1 to 2.
2~ii7 Method l (l) In 40 mQ . of water are dissolved 10.7 g. (7.30 m mol) of 7-acetoacetamido~3-acetoxymethyl-3-cephem-4-carboxylic acid, 30 m mol of a nitrogen-containing heterocyclic thiol and 5.04 g. (60 m mol) of sodium hydrogen carbona~e and the solution is adjusted at pH 7.0 with a lO ~ aqueous solution of sodium hydroxide, followed by stirring for 4 hours at 60 - 65C.
After cooling, 2.31 g. (33 m mol) of hydroxylamine hydrochloride is added to the reaction mixture and the mixture is adjusted to pH 3.6 by adding N-hydrochloric acid, followed by standing at room temperature for overnight. The precipitated crystals of a 7~amino-3-(nitrogen-containing heterocyclic)-~hiomethyl-3-cephem-4-carboxylic acid are collected by filtration, washed with acetone and dried.
(2) A solution of 1.03 g. (13 m mol) of diketene in 5 mQ.
of methylene chloride is previously chilled to -30C and a solution of 1.05 g (15 m mol) of chlorine in lO mQ. of carbon tetrachloride or a solution of 2.24 g. (14 m mol) of bromine in 5 mQ. of methylene chloride is added dropwise thereto.
Meanwhile, 10 m mol of a 7-amino-3-(nitrogen-containing heter-ocyclic)thiomethyl-3-cephem-4-carboxylic acid and 2.02 g.
(20 m mol) of triethylamine are dissolved in 20 mQ. of methylene chloride and the solution is chilled to -20~C. To this solution is dropped rapidly the above-prepared reaction mixture. The temperature rises in most cases to the neighborhood of 0C
caused by the exothermic reaction~ After the exothermic reaction is subsided, the temperature is gradually increased to room temperature. After stirring for 15 minutes, the reaction solu-tion is added to a mixture of 150 mQ. of e-thyl acetate and lO0 mQ. of a lO % aqueous solution of phosphoric acid under vigorous stirring. The organic layer is separated, washed with - 14 ~
~g~;~57 water and dried, followed by the evaporation of the solvent.
To the residue is added ether and the mixture is allowed to stand. The resulta~t preeipitate of a 7-(4-chloro or bromo-3-oxobutyrylamido)-3-(nitrogen-eontalning heterocyelic)thio-methyl-3-eephem-4-earboxylie acid is recovered by filtration as powder.
Method 2 (1) A solution of 60 g. (0.2 mol) of 7-formamido-3-aeetoxymethyl-3-eephem-4-carboxylie aeid, 0.2 mol of a nitrogen-eontaining heterocyelic thiol and 33.6 g. (0.4 mol) of sodium hydroger, earbonate dissolved in 200 mQ. of water is adjusted to pH 7.0 by adding a 10 % aqueous solution of sodium hydroxide and stirred for 4-5 hours at 60-65C, followed by addition of 500 mQ. of methanol. The mixture is eooled down with ice and 80 g. of concentrated sulfurie aeid is added thereto under stirring and keeping the temperature not exceeding 30C, followed by standing in ice-room overnight. The reaetion mixture is diluted with 1000 mQ. of water and the mixed solu-tion is shaken with ethyl aeetate (2 x 400 mQ.). The combined aqueous layer is subjeeted to the filtration under suction to remove undissolved materials and the filtrate is adjusted to pH 3.8 by adding eoncentrated aqueous ammonia, followed by standing at 0C for 3 hours. The preeipitated erystals are eolleeted by filtration and washed with cold water (100 mQ.) and then aeetone (300 mQ.), followed by drying to give 7-amino-3-(nitrogen-eontaining heteroeyclie)thiomethyl-3-eephem-~-earboxylie acid.
(2) The material obtained in above (1) is treated in the similar manner as (2) of Method 1 to obtain 7-(4-ehloro or bromo-3-oxobutyrylamido)-3-(nitrogen-eontaining heterocyclic)-thiomethyl-3-eephem-4-carboxylic acid.
1 5 ~`r ~i7 Table 1 WcH2cocH2coNH ~ S ~ N N
N ~ CH2S ~ S ~ R
COOM
Compound No. I- R5 Method No.
_. I
¦ -NH2 H 2 I _ .. l __ ~ 1 2 2 H , H 2 ,, .
-NHCOCH2N(CH3)2
6 -CH2CON(CH3)2 2 . .. .. _ ' , .
7 2 2 (CH3)2 2 , . I
...
...
8 -SCH2COOC2H5 2 ~ 1 1 '
9 -SCH2CON O H
_ ____ _ -SCH2COOH H ~
. __ . . .. _ ~
Compound No. R M l~let~od ~o.
_ . ~. _ _~ . -~
~ . -12 ~NHCH2CH2OH . H 2 .__ _ . _ 1 3 -NHCH 2 C H 2 N ( CH 3 ) 2 H 2 . __ . . . , . I
_ . _ .
/ \ I 1 19 , -CH2CON f H 1 2 -SCH2CON (CH3) 2 2 i7 Table 2 . _ .. . . ~ .. _ Compound No. R M M~thod No.
__ _ _. _........ _ 21 -CH2CH2N(CH3)2 H 2 ..
.
Table 3 . _ . .
WCH2COCH2CONH I S~ ~ R7 o N ~L CH 2 S 1~ S ~i~
COOM
. .. ... _ .. ~
Compound No ~7 I M
. ~thod No .~ _ _ _ _ 23 -C~COO~ ~ 1 .
Table 4 WC~2COCH2CO~ f S~
N ~ CH2SR
. COOM
;~ Compound No.¦ R __ _ M ~e~xlNo.
N
3;~7 Example 2 Preparatlon of 7-(4 chloro-3-oxobutyrylamido)-3-acetoxymethyl-3-cephem-4~carboxylic acid.
A solution of 4.4 g. of diketene in lO ml. of methylene chloride is previously chilled to -35~C and 3.92 g.
of chlorine is passed into the solution. The reaction mixture is stirred for 15 minutes. Meanwhile, 10.9 g. of 7-amino-cephalosporanic acid and 8.1 g. of triethylamine are dis-solved in 100 ml. of methylene chloride and the solution is chilled to -30C. To this solution is added the above-pre-pared reaction mixture under stirring and coollng so that the temperature will not rise beyond -30C. Then, the temperature of the mixture is gradually increased to room temperature over a period of one hour, after which the solvent is distilled off under reduced pressure. To the residue is added 100 ml.
of ethyl acetate and the mixture is shaken vigorously with 100 ml. of a 10% aqueous solution of phosphoric acid. The water layer is taken, saturated with sodium chloride and extracted three times with ethyl ace-tate. The ethyl acetate layers are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated and concentrated under reduced pressure to a final volume of 20 ml. The concentrate is allowed to stand in the cold and the resultant crystals are recovered by filtration. The described procedure gives the above-indicated compound.
Yield 6.3 g. Melting point: 135-140C (decomp.) IR(cm , KBr): 1790, 1750, 1655 r NMR(~ in d6-DMSO): 2.00(s,COCH3), 3.41 & 3.64(ABq, J18Hz, 2-CH2), 3.56(s,COCH2CO), 4.50(s,ClCH2-), 4.67 & 5.00 (ABq, J13Hz, 3-CH2), 5-07(d, J4.5Hz 6-H), 5.66(dd, J4.5 & 8Hz, 7-H), 9.04(d, J8Hz, CONH) .
Elemental analysis: Calcd. for C14H15ClN2O7S :
C, 43.03; H, 3.87, N, 7.17 Found : C, 43.01; H, 3.89; N, 7.18 Example 3 .
Preparation of 7-(4-bromo-3-oxobutyrylamido)-3-acetoxymethyl-3-cephem 4-carboxylic acid.
~ solution of 3.4 g. of diketene in 10 ml. of methylene chloride is previously chilled to -30C and a solution of 6.4 g. of bromine in 10 ml. of methylene chloride is added dropwise. Meanwhile, 10.9 g. of 7-aminocephalosporanic acid and 8.1 g. of triethylamine are dissolved in 100 ml. of methylene chloride and the solution is chilled to -30C. To this solution is added the above-prepared reaction mixture under stirring and cooling so that the temperature of the mixture will not exceed -30~C.
The temperature is gradually increased to room temperature over a period of one hour, after which the solvent is distilled off under reduced pressure. To the residue is added 100 ml. of ethyl acetate and the mixture is shaken vigorously with 100 ml. of a 10% aqueous solution of phos phoric acid. The water layer is taken, saturated with sodium chloride and extracted twice with ethyl acetate. The ethyl acetate layers are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated, treated with activated carbon and concentrated to dryness under reduced pressure. To the residue is added ether and the mixture is allowed to stand.
The resultant crystals are recovered by Eiltration under suction. The procedure gives the above-indica-ted com-pound. This product includes a quarter of a mole of e-thyl acetate as the solvent of crystallization. Yield 8 grams.
IR(cm , KBr): 1780, 1735, 1650 NMR(~ in d6-DMSO): 2.O1~s,CH3CO), 3.54(m,2-CH2), 3.62(s,COCH2CO)~ 4.37(s,BrCH2CO), 4.67 & 5.01 (ABq, Jl4Hz, 3-CH2), 5.08(d, J4Hz, 6-H), 5.66(dd, J4 & 8Hz, 7-H), 9.04(d, J8Hz, CONH) Elemental analysis: Calcd- for C14H15BrN2O7S 1/4 C4H~O2:
C, 39.40; H, 3.75; N, 6.13;
Found : C, 39.20; H, 3.63; N, 6.09
_ ____ _ -SCH2COOH H ~
. __ . . .. _ ~
Compound No. R M l~let~od ~o.
_ . ~. _ _~ . -~
~ . -12 ~NHCH2CH2OH . H 2 .__ _ . _ 1 3 -NHCH 2 C H 2 N ( CH 3 ) 2 H 2 . __ . . . , . I
_ . _ .
/ \ I 1 19 , -CH2CON f H 1 2 -SCH2CON (CH3) 2 2 i7 Table 2 . _ .. . . ~ .. _ Compound No. R M M~thod No.
__ _ _. _........ _ 21 -CH2CH2N(CH3)2 H 2 ..
.
Table 3 . _ . .
WCH2COCH2CONH I S~ ~ R7 o N ~L CH 2 S 1~ S ~i~
COOM
. .. ... _ .. ~
Compound No ~7 I M
. ~thod No .~ _ _ _ _ 23 -C~COO~ ~ 1 .
Table 4 WC~2COCH2CO~ f S~
N ~ CH2SR
. COOM
;~ Compound No.¦ R __ _ M ~e~xlNo.
N
3;~7 Example 2 Preparatlon of 7-(4 chloro-3-oxobutyrylamido)-3-acetoxymethyl-3-cephem-4~carboxylic acid.
A solution of 4.4 g. of diketene in lO ml. of methylene chloride is previously chilled to -35~C and 3.92 g.
of chlorine is passed into the solution. The reaction mixture is stirred for 15 minutes. Meanwhile, 10.9 g. of 7-amino-cephalosporanic acid and 8.1 g. of triethylamine are dis-solved in 100 ml. of methylene chloride and the solution is chilled to -30C. To this solution is added the above-pre-pared reaction mixture under stirring and coollng so that the temperature will not rise beyond -30C. Then, the temperature of the mixture is gradually increased to room temperature over a period of one hour, after which the solvent is distilled off under reduced pressure. To the residue is added 100 ml.
of ethyl acetate and the mixture is shaken vigorously with 100 ml. of a 10% aqueous solution of phosphoric acid. The water layer is taken, saturated with sodium chloride and extracted three times with ethyl ace-tate. The ethyl acetate layers are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated and concentrated under reduced pressure to a final volume of 20 ml. The concentrate is allowed to stand in the cold and the resultant crystals are recovered by filtration. The described procedure gives the above-indicated compound.
Yield 6.3 g. Melting point: 135-140C (decomp.) IR(cm , KBr): 1790, 1750, 1655 r NMR(~ in d6-DMSO): 2.00(s,COCH3), 3.41 & 3.64(ABq, J18Hz, 2-CH2), 3.56(s,COCH2CO), 4.50(s,ClCH2-), 4.67 & 5.00 (ABq, J13Hz, 3-CH2), 5-07(d, J4.5Hz 6-H), 5.66(dd, J4.5 & 8Hz, 7-H), 9.04(d, J8Hz, CONH) .
Elemental analysis: Calcd. for C14H15ClN2O7S :
C, 43.03; H, 3.87, N, 7.17 Found : C, 43.01; H, 3.89; N, 7.18 Example 3 .
Preparation of 7-(4-bromo-3-oxobutyrylamido)-3-acetoxymethyl-3-cephem 4-carboxylic acid.
~ solution of 3.4 g. of diketene in 10 ml. of methylene chloride is previously chilled to -30C and a solution of 6.4 g. of bromine in 10 ml. of methylene chloride is added dropwise. Meanwhile, 10.9 g. of 7-aminocephalosporanic acid and 8.1 g. of triethylamine are dissolved in 100 ml. of methylene chloride and the solution is chilled to -30C. To this solution is added the above-prepared reaction mixture under stirring and cooling so that the temperature of the mixture will not exceed -30~C.
The temperature is gradually increased to room temperature over a period of one hour, after which the solvent is distilled off under reduced pressure. To the residue is added 100 ml. of ethyl acetate and the mixture is shaken vigorously with 100 ml. of a 10% aqueous solution of phos phoric acid. The water layer is taken, saturated with sodium chloride and extracted twice with ethyl acetate. The ethyl acetate layers are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated, treated with activated carbon and concentrated to dryness under reduced pressure. To the residue is added ether and the mixture is allowed to stand.
The resultant crystals are recovered by Eiltration under suction. The procedure gives the above-indica-ted com-pound. This product includes a quarter of a mole of e-thyl acetate as the solvent of crystallization. Yield 8 grams.
IR(cm , KBr): 1780, 1735, 1650 NMR(~ in d6-DMSO): 2.O1~s,CH3CO), 3.54(m,2-CH2), 3.62(s,COCH2CO)~ 4.37(s,BrCH2CO), 4.67 & 5.01 (ABq, Jl4Hz, 3-CH2), 5.08(d, J4Hz, 6-H), 5.66(dd, J4 & 8Hz, 7-H), 9.04(d, J8Hz, CONH) Elemental analysis: Calcd- for C14H15BrN2O7S 1/4 C4H~O2:
C, 39.40; H, 3.75; N, 6.13;
Found : C, 39.20; H, 3.63; N, 6.09
Claims (78)
1. A process for producing a compound of the formula:
wherein W is a halogen atom and Y represents acetoxy or a group of the formula -SR3, where R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or more other hetero atoms selected from the group consisting of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group, or a halogen atom; or a salt or ester thereof, which comprises reacting a compound of the formula;
wherein Y has the same meaning as defined above, or a salt or ester thereof, with a compound of the formula;
wherein W has the same meaning as defined above.
wherein W is a halogen atom and Y represents acetoxy or a group of the formula -SR3, where R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or more other hetero atoms selected from the group consisting of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group, or a halogen atom; or a salt or ester thereof, which comprises reacting a compound of the formula;
wherein Y has the same meaning as defined above, or a salt or ester thereof, with a compound of the formula;
wherein W has the same meaning as defined above.
2. A compound of the formula.
wherein W is a halogen and Y represents acetoxy or a group of formula -SR3 where R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or more other hetero atoms selected from the group consisting of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-.or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-di - or tri-(lower alkyl) amino, mono- or di-(lower alkyl) car-bamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-linocarbonyl group, or a halogen atom; or a salt or ester there-of, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
wherein W is a halogen and Y represents acetoxy or a group of formula -SR3 where R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or more other hetero atoms selected from the group consisting of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-.or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-di - or tri-(lower alkyl) amino, mono- or di-(lower alkyl) car-bamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-linocarbonyl group, or a halogen atom; or a salt or ester there-of, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
3. A process as claimed in Claim 1, wherein the halo-gen is chlorine or bromine.
4. A process as claimed in Claim 3, wherein Y repre-sents an acetoxy group.
5. A process as claimed in Claim 3, wherein Y repre-sents a group of formula -SR3, where R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or more other hetero atoms selected from the group consist-ing of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino;
mercapto; hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, car-boxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl) amino, mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, car-boxyl, sulfo, carbamoyl, mono-, di-or -tri-(lower alkyl) amino, mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)-carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-linocarbonyl group, or a halogen atom.
mercapto; hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, car-boxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl) amino, mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, car-boxyl, sulfo, carbamoyl, mono-, di-or -tri-(lower alkyl) amino, mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)-carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-linocarbonyl group, or a halogen atom.
6. A process as claimed in Claim 5, wherein the ring is selected from pyridyl, N-oxide-pyridyl, pyrimidyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, diazolyl, triazolyl and tetra-zolyl.
7. A process as claimed in Claim 5, wherein the ring contains oxygen.
8. A process as claimed in Claim 7, wherein the ring is oxadiazolyl.
9. A process as claimed in Claim 5, wherein the ring contains sulfur.
10. A process as claimed in Claim 9, wherein the ring is thiazolyl or thiadiazolyl.
11. A process as claimed in Claim 5, wherein the sub-stituent of the substituted lower alkyl group is a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-di- or tri- lower alkylamino, mono-, or di- lower alkylcarbamoyl, alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholino-carbonyl group.
12. A process as claimed in Claim 5, wherein the sub-stituent of the substituted mercapto group is a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri- lower alkylamino, mono- or di- tri- lower alkyl-carbamoyl, alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group.
13. A process as claimed in claim 5, wherein the sub-stituent of the substituted amino group is a lower alkyl group, an alkoxycarbonyl, an acyl, carbamoyl, a lower alkylcarbamoyl, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri- lower alkylamino, mono-, or di- lower alkylcarbamoyl, alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group.
14. A process as claimed in Claim 5, wherein the ring is triazolyl.
15. A process as claimed in Claim 5, wherein the ring is tetrazolyl.
16. A process according to Claim 4 wherein 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW whereln W is bromine or chlorine; thereby to produce 7-(4-bromo or chloro-3-oxo-butyryla-mido)-3-acetoxymethyl-3-cephem-4-carboxylic acid.
17. A process according to Claim 15 wherein 7-amino-3-[1-(2-N,N-dimethylaminoethyl) tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to pro-duce 7-(4-bromo or chloro-3-oxybutyrylamido)-3-[1-(2-N,N- di-methylaminoethyl)tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
18. A process according to Claim 15 wherein 7-amino-3-(1-carbamoylmethyl tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to pro-duce 7-(4-bromo or chloro-3 oxobutyrylamido)-3-(1-carbamoylmethyl tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
19. A process according to Claim 15 wherein 7-amino-3-(l-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
20. A process as claimed in Claim 5, wherein the ring is thiazolyl.
21. A process according to Claim 20 wherein 7-amino-3-(4-carboxylmethyl-1,3 thiazol-2-yl)-thiomethyl-3-cephem-4-car-boxylic acid is reacted with a compound of the formula WCH2COCH2 COW wherein W is Br or C1, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-carboxyl-methyl-1,3-thiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid.
22. A process as claimed in Claim 5 wherein the ring is thiadiazolyl.
23 A process according to Claim 22 wherein 7-amino-3 (2-amino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is Br or Cl, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-amino-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid.
24. A process according to Claim 22 wherein 7-amino-3-[2-(hydroxyl-ethylthio)-1,3,4-thiadiazol-5-yl[ thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-[2-hydroxyl-ethylthio)-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
25. A process according to Claim 22 wherein 7-amino-3-[3-(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem 4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine thereby to produce 7-(4-bromo or chloro-3-oxobutyryl-amido)-3-[2-(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid.
26. A process according to Claim 22 wherein 7-amino-3-[2-(N,N-dimethylaminomethylcarbonyl)amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3- oxobutyrylamido)-3-[2-(N,N-dimethylaminomethylcarbonyl) amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
27. A process according to Claim 22, wherein 7-amino-3-[2-(N,N-dimethylaminocarbonyl)methyl-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyryl-amido-3-[2-(N,N-dimethylaminocarbonyl)methyl-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
28. A process according to Claim 22 wherein 7-amino-3-[2-(2-N,N-dimethylaminoethyl)thio-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-[2-(2-N,N-dimethylaminoethyl)thio-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
29. A process according to Claim 22 wherein 7-amino-3-(2-carboxylmethyl -thio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCHCOCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carboxyl-methylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
30. A process according to Claim 22 wherein 7-amino-3-(2-ethoxycarbonylmethyl-thio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem,4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic ac:
31. A process according to Claim 22 wherein 7-amino-3-(2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxybutyrylamido)-3-(2-carbamoyl-methylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
32. A process according to Claim 22 wherein 7-amino-3-[2-(2-hydroxyethyl)amino-1,3,4-thiadiazol-5-yl]thio-methyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine thereby to produce 7-4-bromo or chloro-3-oxybutyrylamido)-3-[2-2-hydro-xyethyl) amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-car-boxylic acid.
33. A process according to Claim 22 wherein 7-amino-3-[2-(2-N,N-dimethylaminoethyl)amino-1,3,4-thiadiazol-5-yl]thio-methyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW, thereby to produce 7-(4-bromo or chloro-3-oxybutyrylamido-3-[2-(2-N,N-dimethylamino-ethyl)amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
34. A process according to Claim 22 wherein 7-amino-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2 COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
35. A process according to Claim 22 wherein 7-amino-3-(2-carbamoylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2 COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carbamoylmethyl-1, 3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
36. A process according to Claim 22 wherein 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW
wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
37. A process according to Claim 22 wherein 7-amino-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW
wherein W is bromine or chlorine,, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid.
wherein W is bromine or chlorine,, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid.
38. A process according to Claim 22 wherein 7-amino-3-(2-methylthiomethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3 oxobutyrylamido)-3-(2-methyl-thiomethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
39. A process according to Claim 22 wherein 7-amino-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
40. A compound according to Claim 2 wherein the halogen is chlorine or bromine, whenever prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.
41. A compound according to Claim 2 wherein the halogen is chlorine or bromine and Y represents an acetoxy group, whenever prepared by the process of Claim 4 or an obvious chemical equivalent thereof.
42. A compound of the formula wherein W is chlorine or bromine and Y represents a group of formula -SR3 wherein R3 is a 5 or 6 membered ring containing one to four nitrogens as hetero atoms which may be in oxide form or, in addition to the nitrogen atom or atoms, one or-more other hetero atoms selected from the group consisting-of oxygen and sulfur, said ring being optionally substituted with one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower aikyl)amino, mono-, di or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkyithio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alliyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group, or a halogen atom; whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower aikyl)amino, mono-, di or tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto group substituted with a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower alkyl)carbamoyl, alkoxy, alkyithio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino group substituted with a lower alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono- or di-(lower alliyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group, or a halogen atom; whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
43. A compound according to Claim 42, wherein the ring is selected from pyridyl, N-oxide pyridyl, pyrimidyl, pyridazinyl, N-oxide pyridazinyl, pyrazolyl, diazolyl, triazolyl and tetrazolyl, whenever prepared by the process of Claim 6 or an obvious chemical equivalent thereof.
44. A compound according to Claim 42, wherein the ring contains oxygen, whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.
45. A compound according to Claim 42, wherein the ring is oxadiazolyl, whenever prepared by the process of Claim 8 or an obvious chemical equivalent thereof.
46. A compound according to Claim 42, wherein the ring contains sulfur, whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.
47. A compound according to Claim 42, wherein the ring is thiazolyl or thiadiazolyl, whenever prepared by the process of Claim 10 or an obvious chemical equivalent thereof.
48. A compound according to Claim 42, wherein the substituent of the substituted lower alyl group is a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-di- or tri- lower alkylamino, mono-, or di- lower alkylcarbamoyl, alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl group, whenever prepared by the process of Claim 11 or an obvious chemical equivalent thereof.
49. A compound according to Claim 42, wherein the substituent of the substituted mercapto group is a lower alkyl group or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di or tri-lower alkylamino, mono- or di- tri- lower alkylcarbamoyl, alkoxyl, alkylthiol alkylsulfonyl, acyloxy, or morpholinocarbonyl group, whenever prepared by the process of Claim 12 or an obvious chemical equivalent thereof.
50. A compound according to claim 42, wherein the substitute of the substituted amino group is a lower alkyl group, an alkoxycarbonyl, an acyl, carbamoyl, a lower alkylcarbamoyl, or a lower alkyl group substituted with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri-lower alkylamino, mono-, or di- lower alkylcarbamoyl, alkoxyl, alkylthio, alkyl-sulfonyl, acyloxy, or morpholinocarbonyl group, whenever prepared or produced by the process of claim 13 or by an obvious chemical equivalent thereof.
51. A compound according to claim 42, wherein the ring is triazolyl, whenever prepared or produced by the process of claim 14 or by an obvious chemical equivalent thereof.
52. A compound according to claim 42, wherein the ring is tetrazolyl, whenever prepared or produced by the process of claim 15 or by an obvious chemical equivalent thereof.
53. The compound, 7-(4-bromo or chloro-3-oxobutyrylamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 16 or by an obvious chemical equivalent thereof.
54. The compound, 7-(4-bromo or chloro-3-oxobutyryl amido)-3-[1-(2 N, N-dimethylaminoethyl)tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 17 or by an obvious chemical equivalent thereof.
55. The compound, 7-(4-bromo or chloro-3-oxobutyryl amido)-3-(1-carbamoylmethyltetrazol-5-yl)thio-methyl-3 cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 18 or by an obvious chemical equivalent thereof.
56. The compound, 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid whenever prepared or produced by the process of claim 19 or by an obvious chemical equivalent thereof.
57. A compound according to claim 42 wherein the ring is thiazolyl, whenever prepared or produced by the process of claim 20 or by an obvious chemical equivalent thereof.
58. The compound 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(4-carboxylmethyl-1, 3-thlazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 21 or by an obvious chemical equivalent thereof.
59. A compound according to claim 42 wherein the ring is thiadiazolyl, whenever prepared or produced by the process of claim 22 or by an obvious chemical equivalent thereof.
60. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-amino-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 23 or by an obvious chemical equivalent thereof.
61. The compound 7-(4-bromo or chloro-3 oxo-butyrylamido)-3-[2-(hydroxyethylthio)-1, 3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 24 or by an obvious chemical equivalent thereof.
62. The compound 7-(4-bromo or chloro-3-oxobutyrylamido)-3[[2-(2-acetoxyethylthio)-1, 3, 4-thia-diazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 25 or by an obvious chemical equivalent thereof.
63. The compound 7- (4-bromo or chloro-3-oxobutyrylamido)-2-[2-(N, N-di-methylaminomethylcarbonyl)amino-1, 3, 4-thiadiazol-5-yl]
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 26 or by an obvious chemical equivalent thereof.
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 26 or by an obvious chemical equivalent thereof.
64. The compound 7-(4-bromo or chloro-3-oxobutyryl-amido)-3-[2-(N, N-dimethylaminocarbonyl)methyl-1, 3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 27 or by an obvious chemical equivalent thereof.
65. The compound 7-(4-bromo or chloro-3-oxobutyrylamido)-3-[2-(2-N, N-dimethylaminoethyl)thio-1, 3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 28 or by an obvious chemical equivalent thereof.
66. The compound 7-(4-bromo or chloro-3 oxobutyrylamido)-3-(2-carboxylmethylthio-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 29 or by an obvious chemical equivalent thereof.
67. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-ethoxycarbonylmethylthio-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 30 or by an obvious chemical equivalent thereof.
68. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-carbamoylmethylthio-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 31 or by an obvious chemical equivalent thereof.
69. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-[2-(2-hydroxyethyl)amino-1, 3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 32 or by an obvious chemical equivalent thereof.
70. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-[2-(2-N, N-dimethylaminoethyl)amino-1, 3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 33 or by an obvious chemical equivalent thereof.
71. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-carboxymethyl-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 34 or by an obvious chemical equivalent thereof.
72. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-carbamoylmethyl-1, 3, 4-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 35 or by an obvious chemical equivalent thereof.
73. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-methyl-1, 3, 4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 36 or by an obvious chemical equivalent thereof.
74. The compound 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(1, 3, 4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 37 or by an obvious chemical equivalent thereof.
75. The compound 7-(4-bromo or chloro-3-oxo-butyrylamido)-3-(2-methylthiomethyl-1, 3, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or produced by the process of claim 38 or by an obvious chemical equivalent thereof.
76 . The compound 7-(4-bromo or chloro-3-oxobutyryl-amido)-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, whenever prepared by the process of Claim 39 or by an obvious chemical equivalent thereof.
77. A process according to Claim 22 wherein 7-amino-3-(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid, is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3 cephem-4-carboxylic acid.
78. The compound 7-(4-bromo or chloro-3-oxobutyryl-amido)-3-(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid; whenever prepared by the process of Claim 77 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA340,052A CA1099257A (en) | 1973-12-25 | 1979-11-16 | Cephalosporin derivatives |
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP741521A JPS57873B2 (en) | 1973-12-25 | 1973-12-25 | |
| JP1521/74 | 1973-12-25 | ||
| JP49020752A JPS50111093A (en) | 1974-02-20 | 1974-02-20 | |
| JP20752/74 | 1974-02-20 | ||
| JP42574/74 | 1974-04-15 | ||
| JP4257474A JPS57874B2 (en) | 1974-04-15 | 1974-04-15 | |
| JP8262374A JPS5652908B2 (en) | 1974-07-17 | 1974-07-17 | |
| JP82623/74 | 1974-07-17 | ||
| JP13138174A JPS5512913B2 (en) | 1974-11-13 | 1974-11-13 | |
| JP131381/74 | 1974-11-13 | ||
| KR7500661A KR800001569B1 (en) | 1973-12-25 | 1975-03-29 | Process for preparing cephalosporin derivatives |
| CA340,052A CA1099257A (en) | 1973-12-25 | 1979-11-16 | Cephalosporin derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1099257A true CA1099257A (en) | 1981-04-14 |
Family
ID=27560898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA340,052A Expired CA1099257A (en) | 1973-12-25 | 1979-11-16 | Cephalosporin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1099257A (en) |
-
1979
- 1979-11-16 CA CA340,052A patent/CA1099257A/en not_active Expired
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