CA1141373A - Acyl derivatives - Google Patents
Acyl derivativesInfo
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- CA1141373A CA1141373A CA000328630A CA328630A CA1141373A CA 1141373 A CA1141373 A CA 1141373A CA 000328630 A CA000328630 A CA 000328630A CA 328630 A CA328630 A CA 328630A CA 1141373 A CA1141373 A CA 1141373A
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
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- Animal Behavior & Ethology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Cephalosporin Compounds (AREA)
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Abstract
ABSTRACT
This invention is concerned with the manufacture of an acyl deri-vative of the general formula
This invention is concerned with the manufacture of an acyl deri-vative of the general formula
Description
~41373 The present invention relates to acyl derivatives. More particularly, the invention is concerned with cephalosporin derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same. The invention is further concerned with the use of said cephalosporin derivatives.
The cephalosporin derivatives provided by the present invention are H H
a compound of the general formula CH30N - C - CONH - ~ ~ I
H2N ~3 0 N CH2 - S X
COOH
, wherein X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the corresponding tautomeric form thereof, the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, as well as readily hydrolysable ester/ethers and pharmaceutically acceptable salts of this compound and hydrates of the compound of formula I or of its esters/ethers and salts.
As readily hydrolysable esters of the compound of formula I there are to be understood compounds corresponding to formula I in which the carboxy gTOUp is present in the form of a readily hydrolysable ester group. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxyalkyl esters (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and l-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the phthalidyl and thiophthalidylester), the lower alkoxymethyl esters (e.g. the methoxymethyl ester) and the lower alkanoylaminomethyl esters ~e.g. the acetamidomethyl ester).
f~ i ~,' ~
Other esters (e.g. the benzyl and cyanomethyl esters) can also be used.
As readily hydrolysable ethers of the compounds of formula I there are to be understood compounds corresponding to formula I wherein X represents the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group in which the enolic OH group is present in the form of a readily hydrolysable ether group.
Possible ether groups are thesame ether groups which have already been mentioned earlier in connection with the readily hydrolysable ester groups. Examples of such ethers are the lower alkanoyloxyalkyl ethers (e.g. the acetoxymethyl, pivaloyloxymethyl,l-acetoxyethyl and l-pivaloyloxyethyl ether), the lower alkoxycarbonyloxyalkyl ethers (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ether), the lactonyl ethers (e.g. the phthalidyl and thiophthalidyl ether), the lower alkoxymethyl ethers (e.g. the methoxymethyl ether) and the lower alkanoylaminomethyl ethers (e.g. the acetamidomethyl ether).
Examples of salts of the compound of formula I are alkali metal salts such as the sodium salt and the potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylethylenediamine, alkylamines or dialkylamines), and salts with amino acids (e.g. salts with arginine or lysine). The salts can be mono-salts or di-salts. The second salt formation can occur in compounds with the hydroxy moiety of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.
The compound of formula I also forms acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates and phosphates, alkylsulphonates and monoarylsulphonates such as ~i41373 ethanesulphonstes, toluenesulphonates and benzenesulphonates and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
The compound of formula I and its salts and readily hydrolysable esters/ethers can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.
The cephalosporin derivatives provided by the present invention can exist in the syn-isomeric form or in the anti-isomeric form N ~ C - CONH
or as mixtures of these two forms. The syn-isomeric form is preferred, as are mixtures in which the syn-isomeric form predominates.
Preferred cephalosporin derivatives provided by the present invention are:
(6R,7~)-7-~2-(2-Amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[~2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl~-8-oxo-5-thia-l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid and salts thereof as well as the corresponding hydrates.
According to the process provided by the present invention, the ~ ' ,. . . i ~1373 cephalosporin derivatives aforesaid are manufactured by (a) cleaving off the protecting group R (and, if desired, also a carboxy protecting group which may be present) in a compound of the general formula H H
~ II
~ N~LCH2--S X
RHN
S COOH
, wherein X has the significance given earlier, R represents a cleavable pro-tecting group and the carboxy group can be present in protected form, (b) for the manufacture of a readily hydrolysable ester/ether of the compound of formula I, subjecting same to a corresponding esterification or etherification, or (c) for the manufacture of salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a salt or hydrate or into a hydrate of said salt.
If desired, the carboxy group present in the starting materials of formula II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester). The carboxy group can also be protected in the form of one of the aforementioned readily hydrolysable esters. Furthermore, the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Possible protecting groups denoted by R are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the tert.
butoxycarbonyl or trityl group) or by basic hydrolysis (e.g. the trifluoroacetyl group). Preferred protecting groups denoted by R are the chloroacetyl, bromo-acetyl and iodoacetyl groups, especially the chloroacetyl group. These last-li~l373 mentioned protecting groups can be cleaved off by treatment with thiourea.
The starting materials of formula II hereinbefore can be prepared, for example, by N-acylating a corresponding 7-amino compound, namely by reacting a compound of the general formula ~, ~7 ~ H
H2N~9`~
COO~
, wherein X has the significance given earlier and the carboxy group and/or the amino group can be present in protected form, with an acid of the general formula CH30N===C C00 ,7~ IV
RHN S
, wherein R has the significance given earlier, or with a reactive functional derivative of this acid and, if desired, cleaving off a carboxy protecting group which may be present.
If desired, the carboxy group present in the 7-amino compounds of formula III can be protected in the same manner as mentioned hereinbefore in connection with the starting materials of formula II. The amino group in the compounds of formula III can be protected, or example, by a silyl protecting group such as the trimethylsilyl group.
~ ~373 ,~
Examples of reactive functional derivatives of acids of formula IV are halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccin-S imide esters) and amides (e.g. imidazolides).
The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula IV can be reacted with an aforementioned ester of a compound of formula III in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethyl-formamide and subsequently the ester group can be clea~ed lS off. Oxazolium salts (e.g. N-ethyl-5-phenyl-isoxazolium 3'-sulphonate) can be used in place of carbodiimides in the foregoing reaction.
According to another embodiment, a salt of an acid of formula III (e.g. a trialkylammonium salt such as the tri-ethylammonium salt) is reacted with a reactive functionalderivative of an acid of formula IV as mentioned earlier in an inert solvent (e.g. one of the aforementioned solvents).
According to a further embodiment, an acid halide, preferably tne chloride, of an acid of formula IV is reacted with an amine of formula III. The reaction is prefera~ly carried out in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethyl sulphoxide or hexamethyl-phosphoric acid triamide. When a silylated compound of formula III is used, the reaction is carried out in an anhydrous medium.
The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof can conveniently be carried out at a temperature be~ween about -40 C and room temperature, for example at about 0-10C.
In accordance with embodiment (a) of the process provided by the present invention, the amino protecting group denoted by R in a compound of formula II is cleaved off. Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly elevated or slightly reduced temperature, for example a temperature in the range of about 0 C to +40 C.
Protecting groups which are cleavable under alkaline conditions are generally hydrolysed with a dilute aqueous alkali metal hydroxide solution at 0 C to 30 C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off by means of thiourea in an acid, neutral or alkaline medium at about 0-~0C. Hydrogenolytic cleavage (e.g.cleavage of the benzyl group) is unsuitable in this case, since the oxime group is reduced to the -,~
...,~,, ~....
amino group during the hydrogenolysis.
After carrying out embodiment ~a) of the process, a carboxy protecting group present in the resulting product can be cleaved off if desired. When the protecting group is a silyl group (silyl ester), this group can be cleaved ~ 4 11'~1373 off especially readily by treatment with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase at about 20 - 40C. ~hen the carboxy group is protected by salt formation ~e.g.
with triethylamine), then the cleavage of this salt-forming protecting group can be carried out by treatment with an acid. Acids which can be used for this purpose are, for example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.
The carboxy protecting group can be cleaved off in the same manner as just described also prior to the cleavage of the protecting group denoted by R.
In order to manufacture a readily hydrolysable ester of the carboxylic acid of formula I in accordance with embodiment (b) of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine (e.g. triethylamine). The 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group with its enolic function is etherified with the formation of a corresponding readily hydrolysable ether. (The so-obtained, simultaneously esterified and etherified products are herein referred to as "readily hydrolysable esters/ethers"). In this case there is preferably used an excess of the corresponding halide. The esterification/etherification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethyl-phosphoric acid triamide, dimethyl sulphoxide or, especially, dimethylformamide.
The reaction is preferably carried out at a temperature in the range of about 0 - 40 C.
11~13`73 The manufacture of the salts and hydrates of the compound of formula I or the hydrates of said salts in accordance with embodiment (c) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). When a second equivalent of base is used, salt formation also takes place on the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), whereby a di-salt is formed. The temperature at which the salt formation is carried out is not critical, The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of O C to + 50C.
The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially _ 11 -` ` 11'~1373 ,~
,~,~
anhydrous product. For the controlled ~anufacture of a hydrate, a comple`tely or partially anhydrous carboxy7ic acid of formula I or ester, ether or salt thereof can be exposed to a moist atmosphere, e.g. at about ~10C to ~40C.
The 7-amino compounds of formula III hereinbefore can be prepared by reacting a compound of the general for~ula H H
H2N~L-CHz--Y VIl COO H
, wherein Y represents a leaving atom or group, with a thiol of the general formula HS - X VI
wherein X has the significance given earlier.
Examples of leaving atoms and groups denoted by Y in a compound of formula V are halogen atoms (e.g. a chlorine, bromine or iodine atom), acyloxy groups (e.g. lower alkanoyloxy groups such as the acetoxy group), lower alkyl-sulphonyloxy or arylsulphonyloxy groups (e.g. the mesyloxy or tosyloxy groups) and the azido group.
The reaction of a compound of formula V with a thiol of formula VI can be carried out in a manner known per se;
11 ~1373 , ~
for example, at a temperature between about 40C and 80C, conveniently at about 60C, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.
, 3~..i il4i373 A syn/anti mixture of the compound of formula I which may be obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters/ethers and salts and the hydrates of same have antibiotic, especially bactericidal, activity. They possessa broad spectrum of activity against gram-positive and gram-negative microorganisms, including B-lactamase-forming Staphylococci and various B-lactamase-forming gram-negative bacteria such as, for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens and Proteus and Klebsiella species.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters/ethers and salts and the hydrates of same can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of about 0.1 g to about 2 g is envisaged for adults. The parenteral administration of the compounds provided by the present invention is especially preferred.
In order to demonstrate the antimicrobial activity of the compounds provided by the present invention, the following representatives were tested:
il ~i373 Compound A: (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z--methoxyimino)acetamido3-3-/ [(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio3-methyl 7-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
The cephalosporin derivatives provided by the present invention are H H
a compound of the general formula CH30N - C - CONH - ~ ~ I
H2N ~3 0 N CH2 - S X
COOH
, wherein X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the corresponding tautomeric form thereof, the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, as well as readily hydrolysable ester/ethers and pharmaceutically acceptable salts of this compound and hydrates of the compound of formula I or of its esters/ethers and salts.
As readily hydrolysable esters of the compound of formula I there are to be understood compounds corresponding to formula I in which the carboxy gTOUp is present in the form of a readily hydrolysable ester group. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxyalkyl esters (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and l-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the phthalidyl and thiophthalidylester), the lower alkoxymethyl esters (e.g. the methoxymethyl ester) and the lower alkanoylaminomethyl esters ~e.g. the acetamidomethyl ester).
f~ i ~,' ~
Other esters (e.g. the benzyl and cyanomethyl esters) can also be used.
As readily hydrolysable ethers of the compounds of formula I there are to be understood compounds corresponding to formula I wherein X represents the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group in which the enolic OH group is present in the form of a readily hydrolysable ether group.
Possible ether groups are thesame ether groups which have already been mentioned earlier in connection with the readily hydrolysable ester groups. Examples of such ethers are the lower alkanoyloxyalkyl ethers (e.g. the acetoxymethyl, pivaloyloxymethyl,l-acetoxyethyl and l-pivaloyloxyethyl ether), the lower alkoxycarbonyloxyalkyl ethers (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ether), the lactonyl ethers (e.g. the phthalidyl and thiophthalidyl ether), the lower alkoxymethyl ethers (e.g. the methoxymethyl ether) and the lower alkanoylaminomethyl ethers (e.g. the acetamidomethyl ether).
Examples of salts of the compound of formula I are alkali metal salts such as the sodium salt and the potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylethylenediamine, alkylamines or dialkylamines), and salts with amino acids (e.g. salts with arginine or lysine). The salts can be mono-salts or di-salts. The second salt formation can occur in compounds with the hydroxy moiety of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.
The compound of formula I also forms acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates and phosphates, alkylsulphonates and monoarylsulphonates such as ~i41373 ethanesulphonstes, toluenesulphonates and benzenesulphonates and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
The compound of formula I and its salts and readily hydrolysable esters/ethers can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.
The cephalosporin derivatives provided by the present invention can exist in the syn-isomeric form or in the anti-isomeric form N ~ C - CONH
or as mixtures of these two forms. The syn-isomeric form is preferred, as are mixtures in which the syn-isomeric form predominates.
Preferred cephalosporin derivatives provided by the present invention are:
(6R,7~)-7-~2-(2-Amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[~2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl~-8-oxo-5-thia-l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid and salts thereof as well as the corresponding hydrates.
According to the process provided by the present invention, the ~ ' ,. . . i ~1373 cephalosporin derivatives aforesaid are manufactured by (a) cleaving off the protecting group R (and, if desired, also a carboxy protecting group which may be present) in a compound of the general formula H H
~ II
~ N~LCH2--S X
RHN
S COOH
, wherein X has the significance given earlier, R represents a cleavable pro-tecting group and the carboxy group can be present in protected form, (b) for the manufacture of a readily hydrolysable ester/ether of the compound of formula I, subjecting same to a corresponding esterification or etherification, or (c) for the manufacture of salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a salt or hydrate or into a hydrate of said salt.
If desired, the carboxy group present in the starting materials of formula II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester). The carboxy group can also be protected in the form of one of the aforementioned readily hydrolysable esters. Furthermore, the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Possible protecting groups denoted by R are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the tert.
butoxycarbonyl or trityl group) or by basic hydrolysis (e.g. the trifluoroacetyl group). Preferred protecting groups denoted by R are the chloroacetyl, bromo-acetyl and iodoacetyl groups, especially the chloroacetyl group. These last-li~l373 mentioned protecting groups can be cleaved off by treatment with thiourea.
The starting materials of formula II hereinbefore can be prepared, for example, by N-acylating a corresponding 7-amino compound, namely by reacting a compound of the general formula ~, ~7 ~ H
H2N~9`~
COO~
, wherein X has the significance given earlier and the carboxy group and/or the amino group can be present in protected form, with an acid of the general formula CH30N===C C00 ,7~ IV
RHN S
, wherein R has the significance given earlier, or with a reactive functional derivative of this acid and, if desired, cleaving off a carboxy protecting group which may be present.
If desired, the carboxy group present in the 7-amino compounds of formula III can be protected in the same manner as mentioned hereinbefore in connection with the starting materials of formula II. The amino group in the compounds of formula III can be protected, or example, by a silyl protecting group such as the trimethylsilyl group.
~ ~373 ,~
Examples of reactive functional derivatives of acids of formula IV are halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccin-S imide esters) and amides (e.g. imidazolides).
The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula IV can be reacted with an aforementioned ester of a compound of formula III in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethyl-formamide and subsequently the ester group can be clea~ed lS off. Oxazolium salts (e.g. N-ethyl-5-phenyl-isoxazolium 3'-sulphonate) can be used in place of carbodiimides in the foregoing reaction.
According to another embodiment, a salt of an acid of formula III (e.g. a trialkylammonium salt such as the tri-ethylammonium salt) is reacted with a reactive functionalderivative of an acid of formula IV as mentioned earlier in an inert solvent (e.g. one of the aforementioned solvents).
According to a further embodiment, an acid halide, preferably tne chloride, of an acid of formula IV is reacted with an amine of formula III. The reaction is prefera~ly carried out in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethyl sulphoxide or hexamethyl-phosphoric acid triamide. When a silylated compound of formula III is used, the reaction is carried out in an anhydrous medium.
The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof can conveniently be carried out at a temperature be~ween about -40 C and room temperature, for example at about 0-10C.
In accordance with embodiment (a) of the process provided by the present invention, the amino protecting group denoted by R in a compound of formula II is cleaved off. Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly elevated or slightly reduced temperature, for example a temperature in the range of about 0 C to +40 C.
Protecting groups which are cleavable under alkaline conditions are generally hydrolysed with a dilute aqueous alkali metal hydroxide solution at 0 C to 30 C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off by means of thiourea in an acid, neutral or alkaline medium at about 0-~0C. Hydrogenolytic cleavage (e.g.cleavage of the benzyl group) is unsuitable in this case, since the oxime group is reduced to the -,~
...,~,, ~....
amino group during the hydrogenolysis.
After carrying out embodiment ~a) of the process, a carboxy protecting group present in the resulting product can be cleaved off if desired. When the protecting group is a silyl group (silyl ester), this group can be cleaved ~ 4 11'~1373 off especially readily by treatment with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase at about 20 - 40C. ~hen the carboxy group is protected by salt formation ~e.g.
with triethylamine), then the cleavage of this salt-forming protecting group can be carried out by treatment with an acid. Acids which can be used for this purpose are, for example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.
The carboxy protecting group can be cleaved off in the same manner as just described also prior to the cleavage of the protecting group denoted by R.
In order to manufacture a readily hydrolysable ester of the carboxylic acid of formula I in accordance with embodiment (b) of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine (e.g. triethylamine). The 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group with its enolic function is etherified with the formation of a corresponding readily hydrolysable ether. (The so-obtained, simultaneously esterified and etherified products are herein referred to as "readily hydrolysable esters/ethers"). In this case there is preferably used an excess of the corresponding halide. The esterification/etherification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethyl-phosphoric acid triamide, dimethyl sulphoxide or, especially, dimethylformamide.
The reaction is preferably carried out at a temperature in the range of about 0 - 40 C.
11~13`73 The manufacture of the salts and hydrates of the compound of formula I or the hydrates of said salts in accordance with embodiment (c) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). When a second equivalent of base is used, salt formation also takes place on the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), whereby a di-salt is formed. The temperature at which the salt formation is carried out is not critical, The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of O C to + 50C.
The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially _ 11 -` ` 11'~1373 ,~
,~,~
anhydrous product. For the controlled ~anufacture of a hydrate, a comple`tely or partially anhydrous carboxy7ic acid of formula I or ester, ether or salt thereof can be exposed to a moist atmosphere, e.g. at about ~10C to ~40C.
The 7-amino compounds of formula III hereinbefore can be prepared by reacting a compound of the general for~ula H H
H2N~L-CHz--Y VIl COO H
, wherein Y represents a leaving atom or group, with a thiol of the general formula HS - X VI
wherein X has the significance given earlier.
Examples of leaving atoms and groups denoted by Y in a compound of formula V are halogen atoms (e.g. a chlorine, bromine or iodine atom), acyloxy groups (e.g. lower alkanoyloxy groups such as the acetoxy group), lower alkyl-sulphonyloxy or arylsulphonyloxy groups (e.g. the mesyloxy or tosyloxy groups) and the azido group.
The reaction of a compound of formula V with a thiol of formula VI can be carried out in a manner known per se;
11 ~1373 , ~
for example, at a temperature between about 40C and 80C, conveniently at about 60C, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.
, 3~..i il4i373 A syn/anti mixture of the compound of formula I which may be obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters/ethers and salts and the hydrates of same have antibiotic, especially bactericidal, activity. They possessa broad spectrum of activity against gram-positive and gram-negative microorganisms, including B-lactamase-forming Staphylococci and various B-lactamase-forming gram-negative bacteria such as, for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens and Proteus and Klebsiella species.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters/ethers and salts and the hydrates of same can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of about 0.1 g to about 2 g is envisaged for adults. The parenteral administration of the compounds provided by the present invention is especially preferred.
In order to demonstrate the antimicrobial activity of the compounds provided by the present invention, the following representatives were tested:
il ~i373 Compound A: (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z--methoxyimino)acetamido3-3-/ [(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio3-methyl 7-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylic acid.
Compound B: (6R,7R)-7-~ 2-[2-(2-Chloroacetamido)-4-thia-zolyl}-2-(Z-methoxyimino)acetamido_7-3--/ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]methyl_7-8-oxo-5-thia-1--azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Activity in vitro: Minimum inhibitory concentration (~g/ml) .., _ 11~1373 i`` j~.
_ A ¦ B
Haemophilus influenzae strain 1 0.08 1.2 strain 2 0.005 0.3 strain 3 0.005 0.16 5strain 4 0.005 0.16 strain 5 0.0025 0.08 strain 6 0.0025 0.16 strain 7 0.0025 0.16 Klebsiella pneumoniae 1.2 10 10Escherichia coli strain 1 0.02 0.16 strain 2 0.6 5 Proteus mirabilis strain 1 ~0.01 0.08 strain 2 <0.01 0.16 Proteus vulgaris ~0.01 0.16 15Proteus rettgeri <0.01 0.16 Staphylococcus aureus st~ain ATCC 6538 2.5 2.5 Penicillin-resistant strain 2.5 5 Pseudomonas aeruginosa strain 1 0.3 1.2 strain 2 10 >80 20strain 3 2.5 40 strain 4 5 80 strain 5 5 80 strain 6 10 80 strain 7 5 80 - . .
25 Serratia marcescens 0.08 2.;
l373 I /
,~g _ Activity in vivo Groups of 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. The test sub-stance is administered subcutaneously in physiological S sodium chloride solution three times, i.e. 1 hour, 2.5 hours and 4 hours, after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which S0~ of the test animals survive (CD50, mg/~g) is determined by interpolation.
¦ Test substance ¦ A ¦ B
.
CD50, mg/kg <0 005 0.16 Toxicity Test substance LD50, mg/kg i.v. 250-500 250-500 1~ s.c. ~4000 2000-4000 p.o. >5000 >S000 The cephalosporin derivatives provided by the present invention can be used as medicaments, for example in the form of pharmaceutical preparations which contain them in association with a compatible carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable li~l373 1~
oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, dragées, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions).
~S The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. The pharmaceutical preparations can also contain other therapeutically valuable substances. The compounds of formula I and their salts and hydrates are especially suitable for parenteral admini-stration and for this purpose they are preferably made up in the form of lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution. The readily hydrolysable esters and readily hydrolysable ethers of the compounds of formula I
and their salts or hydrates are also suitable for enteral administration.
ll~i3'~
The following Examples illustrate ~he process provided by the present invention:
Example 1 Manufacture of the disodium salt of (6R,7R)-7-[2-(2--amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-L [(2,5--dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl 7-8-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2--carboxylic acid.
15.3 g of (6R,7R)-7-/ 2-[2-(2-chloroacetamido)-4--thiazolyl]-2-(Z-methoxyimino)acetamido 7-3-/ ~(2,5-dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_7-8--oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid (fraction I, see hereinafter) are suspended in 150 ml of water together with 5 g of thiourea. While gassing well with nitrogen and stirring ~horoughly the pH is adjusted to 6.8-7.0 with saturated sodium hydrogen carbonate solution, there being obtained an orange coloured solution. The pH
of the solution is kept constant at 6.8 for 6 hours by adding sodium hydrogen carbonate solution by means of an autotitrator. Thereafter, a further 2.5 g of thiourea are added and the solution is stirred for a further 3 hours, the p~ being kept at 6.8 by adding saturated sodium hydrogen carbonate solution. Thereafter, the red so}~tion is stored overnight in a refrigerator, whereby it becomes darker.
The pH of this solution is adjusted to 2.0-2.5 by adding 100~ formic acid, wnereby the substance separa~es out. The precipitate is filtered off under suction and washed with 100 ml of 10~ formic acid. The mother liquor is discarded.
The brownish material on the suction filter is susper.ded in 200 ml of water and the pH is adjusted to 7 with triethyl-amine, a brown solution being obtained. This solution is stirred with 2 g of active carbon for 30 minutes, the carbon is filtered off and the filtrate, which is still brown, is adjusted to pH 3.5 with 100% formic acid while stirring well. The substance which thereby precipitates out is filtered off under suction, washed with 50 ml of 10~ formic acid and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 100% formic acid, whereby the substance precipitates out. This precipitate is filtered off under suction, washed with ice-water and dried. For conversion into the disodium salt, the cephalosporin acid obtained is suspended in a mixture of 40 ml of acetone and 40 ml of water and treated with 20 ml of a 2-N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate. 50 ml of acetone are added to the thus-obtained orange coloured solution, whereby there separates out a brown resin which is separated off by filtration. The yellow filtrate is stirred for 3Q minutes, whereby the disodium salt crystal-lises. The mixture is treated portionwise with 50 ml of acetone and stored overnight in a refrigerator. The crystallisate is filtered off under suction, washed succes-sively with an acetone/water mixture (85:15), pure acetone and low-boiling petroleum ether and dried overnight at 40C
\
,~
in vacuo. The title substance is obtained in the form of beige crystals; [320 = -144 (c = 0.5 in water). The nuclear magnetic reson&nce spectrum and the microanalysis correspond to the structure indicated.
The (6R,7R)-7-/ 2- ~2-(2-chioroacetamido)-4-thiazolyl]--2-(Z-methoxyimino)acetamido_ 7- 3-/ ~(2,5-dihydro-6-hydroxy--2-methyl-5-oxo-as-triazin-3-yl)thio~methyl_/-8-oxo-5-thia--l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows:
22.24 g of 2- (2-chloroacetamido-thiazol-4-yl)-2-(Z--methoxyimino)-acetic acid are suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine are added to this suspension, a light brown solution being obtained.
This solution is cooled to 0-5C and treated with 16.72 g for 5 minutes of phosphorus pentachloride. The mixture is stirred/at 0-5C and for 20 minutes without cooling. me resulting yellow solution is evaporated at 35C in vacuo. The evaporation residue is sha3~en twice with n-heptane and the latter is decanted off. The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethyl-amine hydrochloride is filtered off. The yellow filtrate contains the acid chloride.
22 g of (7R)-7-amino-3-desacetoxy-3-~(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalo-- 25 sporanic acid are suspended in a mixture of 300 ml of water li~l373 ~ ~, -- 2~ --and 150 ml of tetrahydrofuran. 2-N sodium hydroxide is added dropwise to the suspension with the aid of an auto-titrator while gassing well with nitrogen until a brown-red solutiGn having a pH of 8 is obtained. This solution is cooled to 0-5C and treated dropwise during 15 minutes with the solution of the acid chloride in tetrahydrofuran prepared as described in the preceding paragraph. There-after, the mixture i5 stirred at 25C for 2.5 hours. The pH of the mixture is held constant at 8 by adding 2-N sodium hydroxide. The almost blac~ solution is freed from tetra-hydrofuran at 40C in vacuo. 100 ml of 2-N sulphuric acid are now added. The substance which thereby precipitates out is filtered off under suction, washed with water and filtered off well under suction. The moist brown material ~5 on the suction filter is dissolved in 1.5 l.tres of acetone.
The dark solution is filtered off through Hyflo from a small amount of dark undissolved material, treated with carbon, stirred for 30 minutes and again filtered through ~yflo.
The orange-red filtrate is dried over sodium sulphate, con-centrated in vacuo and evaporated with ethyl acetate. Ablack resin thereby precipitates out. This resin is fil-tered off and discarded. The 2-phase filtrate which still contains water is subjected to azeotropic distillation three times with benzene at 40C in vacuo. The su~stance whi-h thereby precipitates out is filtered off under suction and dried at 40C in vacuo. This substance is stirred up twice with 1 litre of acetone each time, there remaining a brown resin which is discarded. The com~ined orange coloured .~ ~
`Trc~de~Q~y~c ~ ;~
acetone extracts are concentrated to ca 150 ml at 40C in vacuo, a ~rown resin being filtered off and discarded. The filtrate is treated with l litre of ethyl acetate and con-centrated at 40C in vacuo. The substance which thereby precipitates out is filtered off under suction, washed with ethyl acetate and then with ether ~(6R,7R)-7-/ 2-~2-(2--chloroacetamido)-4-thiazolyl]-2-(Z-methoxyimino)acetamido_/-
Compound B: (6R,7R)-7-~ 2-[2-(2-Chloroacetamido)-4-thia-zolyl}-2-(Z-methoxyimino)acetamido_7-3--/ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]methyl_7-8-oxo-5-thia-1--azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Activity in vitro: Minimum inhibitory concentration (~g/ml) .., _ 11~1373 i`` j~.
_ A ¦ B
Haemophilus influenzae strain 1 0.08 1.2 strain 2 0.005 0.3 strain 3 0.005 0.16 5strain 4 0.005 0.16 strain 5 0.0025 0.08 strain 6 0.0025 0.16 strain 7 0.0025 0.16 Klebsiella pneumoniae 1.2 10 10Escherichia coli strain 1 0.02 0.16 strain 2 0.6 5 Proteus mirabilis strain 1 ~0.01 0.08 strain 2 <0.01 0.16 Proteus vulgaris ~0.01 0.16 15Proteus rettgeri <0.01 0.16 Staphylococcus aureus st~ain ATCC 6538 2.5 2.5 Penicillin-resistant strain 2.5 5 Pseudomonas aeruginosa strain 1 0.3 1.2 strain 2 10 >80 20strain 3 2.5 40 strain 4 5 80 strain 5 5 80 strain 6 10 80 strain 7 5 80 - . .
25 Serratia marcescens 0.08 2.;
l373 I /
,~g _ Activity in vivo Groups of 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. The test sub-stance is administered subcutaneously in physiological S sodium chloride solution three times, i.e. 1 hour, 2.5 hours and 4 hours, after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which S0~ of the test animals survive (CD50, mg/~g) is determined by interpolation.
¦ Test substance ¦ A ¦ B
.
CD50, mg/kg <0 005 0.16 Toxicity Test substance LD50, mg/kg i.v. 250-500 250-500 1~ s.c. ~4000 2000-4000 p.o. >5000 >S000 The cephalosporin derivatives provided by the present invention can be used as medicaments, for example in the form of pharmaceutical preparations which contain them in association with a compatible carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable li~l373 1~
oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, dragées, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions).
~S The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. The pharmaceutical preparations can also contain other therapeutically valuable substances. The compounds of formula I and their salts and hydrates are especially suitable for parenteral admini-stration and for this purpose they are preferably made up in the form of lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution. The readily hydrolysable esters and readily hydrolysable ethers of the compounds of formula I
and their salts or hydrates are also suitable for enteral administration.
ll~i3'~
The following Examples illustrate ~he process provided by the present invention:
Example 1 Manufacture of the disodium salt of (6R,7R)-7-[2-(2--amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-L [(2,5--dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl 7-8-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2--carboxylic acid.
15.3 g of (6R,7R)-7-/ 2-[2-(2-chloroacetamido)-4--thiazolyl]-2-(Z-methoxyimino)acetamido 7-3-/ ~(2,5-dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_7-8--oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid (fraction I, see hereinafter) are suspended in 150 ml of water together with 5 g of thiourea. While gassing well with nitrogen and stirring ~horoughly the pH is adjusted to 6.8-7.0 with saturated sodium hydrogen carbonate solution, there being obtained an orange coloured solution. The pH
of the solution is kept constant at 6.8 for 6 hours by adding sodium hydrogen carbonate solution by means of an autotitrator. Thereafter, a further 2.5 g of thiourea are added and the solution is stirred for a further 3 hours, the p~ being kept at 6.8 by adding saturated sodium hydrogen carbonate solution. Thereafter, the red so}~tion is stored overnight in a refrigerator, whereby it becomes darker.
The pH of this solution is adjusted to 2.0-2.5 by adding 100~ formic acid, wnereby the substance separa~es out. The precipitate is filtered off under suction and washed with 100 ml of 10~ formic acid. The mother liquor is discarded.
The brownish material on the suction filter is susper.ded in 200 ml of water and the pH is adjusted to 7 with triethyl-amine, a brown solution being obtained. This solution is stirred with 2 g of active carbon for 30 minutes, the carbon is filtered off and the filtrate, which is still brown, is adjusted to pH 3.5 with 100% formic acid while stirring well. The substance which thereby precipitates out is filtered off under suction, washed with 50 ml of 10~ formic acid and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 100% formic acid, whereby the substance precipitates out. This precipitate is filtered off under suction, washed with ice-water and dried. For conversion into the disodium salt, the cephalosporin acid obtained is suspended in a mixture of 40 ml of acetone and 40 ml of water and treated with 20 ml of a 2-N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate. 50 ml of acetone are added to the thus-obtained orange coloured solution, whereby there separates out a brown resin which is separated off by filtration. The yellow filtrate is stirred for 3Q minutes, whereby the disodium salt crystal-lises. The mixture is treated portionwise with 50 ml of acetone and stored overnight in a refrigerator. The crystallisate is filtered off under suction, washed succes-sively with an acetone/water mixture (85:15), pure acetone and low-boiling petroleum ether and dried overnight at 40C
\
,~
in vacuo. The title substance is obtained in the form of beige crystals; [320 = -144 (c = 0.5 in water). The nuclear magnetic reson&nce spectrum and the microanalysis correspond to the structure indicated.
The (6R,7R)-7-/ 2- ~2-(2-chioroacetamido)-4-thiazolyl]--2-(Z-methoxyimino)acetamido_ 7- 3-/ ~(2,5-dihydro-6-hydroxy--2-methyl-5-oxo-as-triazin-3-yl)thio~methyl_/-8-oxo-5-thia--l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows:
22.24 g of 2- (2-chloroacetamido-thiazol-4-yl)-2-(Z--methoxyimino)-acetic acid are suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine are added to this suspension, a light brown solution being obtained.
This solution is cooled to 0-5C and treated with 16.72 g for 5 minutes of phosphorus pentachloride. The mixture is stirred/at 0-5C and for 20 minutes without cooling. me resulting yellow solution is evaporated at 35C in vacuo. The evaporation residue is sha3~en twice with n-heptane and the latter is decanted off. The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethyl-amine hydrochloride is filtered off. The yellow filtrate contains the acid chloride.
22 g of (7R)-7-amino-3-desacetoxy-3-~(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalo-- 25 sporanic acid are suspended in a mixture of 300 ml of water li~l373 ~ ~, -- 2~ --and 150 ml of tetrahydrofuran. 2-N sodium hydroxide is added dropwise to the suspension with the aid of an auto-titrator while gassing well with nitrogen until a brown-red solutiGn having a pH of 8 is obtained. This solution is cooled to 0-5C and treated dropwise during 15 minutes with the solution of the acid chloride in tetrahydrofuran prepared as described in the preceding paragraph. There-after, the mixture i5 stirred at 25C for 2.5 hours. The pH of the mixture is held constant at 8 by adding 2-N sodium hydroxide. The almost blac~ solution is freed from tetra-hydrofuran at 40C in vacuo. 100 ml of 2-N sulphuric acid are now added. The substance which thereby precipitates out is filtered off under suction, washed with water and filtered off well under suction. The moist brown material ~5 on the suction filter is dissolved in 1.5 l.tres of acetone.
The dark solution is filtered off through Hyflo from a small amount of dark undissolved material, treated with carbon, stirred for 30 minutes and again filtered through ~yflo.
The orange-red filtrate is dried over sodium sulphate, con-centrated in vacuo and evaporated with ethyl acetate. Ablack resin thereby precipitates out. This resin is fil-tered off and discarded. The 2-phase filtrate which still contains water is subjected to azeotropic distillation three times with benzene at 40C in vacuo. The su~stance whi-h thereby precipitates out is filtered off under suction and dried at 40C in vacuo. This substance is stirred up twice with 1 litre of acetone each time, there remaining a brown resin which is discarded. The com~ined orange coloured .~ ~
`Trc~de~Q~y~c ~ ;~
acetone extracts are concentrated to ca 150 ml at 40C in vacuo, a ~rown resin being filtered off and discarded. The filtrate is treated with l litre of ethyl acetate and con-centrated at 40C in vacuo. The substance which thereby precipitates out is filtered off under suction, washed with ethyl acetate and then with ether ~(6R,7R)-7-/ 2-~2-(2--chloroacetamido)-4-thiazolyl]-2-(Z-methoxyimino)acetamido_/-
-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3--yl)thio]methyl_7-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene--2-carboxylic acid, fraction I; a beige, amorphous acid].
This fraction I can be used directly for the manufacture of the desired cephalosporin derivative.
The ethyl acetate mother liquor is concentrated extensively at 40C in vacuo, diluted with ether and the precipitated substance is filtered off under suction [~6R, 7R)-7-L 2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(Z-methoxy-imino)acetamido_7-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, fraction II; a light beige amorphous acid, somewhat purer than fraction I
according to thin-layer chromatography~.
For the manufacture of the disodium salt, 3.5 g of the acid (fraction I~) are dissolved in a mixture of 20 ml of acetone and ll ml of water. The solution is treated with 7 ml o~ a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate, whereby the disodium salt crystallises. A further 25 ml of acetone are now added portionwise and the mixture is stored in a deep-freeze cabinet for 2 hours. Thereafter, the crystallisate is filtered off under suction, washed successively with 25 ml of an ice-cold acetone/water mixture (80:20), pure acetone and low-boiling petroleum ether and dried overnight at 40C in a high vacuum. There is obtained the disodium salt of ~6R,7R)-7- ~2-[2-(2-chloroacetamido)-4-thiazolyl3 -2-(Z-methoxyimino)acetamido~ -3- ~ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio~ methyl~ -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of light yellow crystals; ~ D0 = -142.7 lc = 1 in water).
The nuclear magnetic resonance spectrum and the micro-analysis correspond to the structure indicated.
" 7 -- 3~ --Example 3 Manufacture of methylene-(6R,7R)-7-[2-(2-amino-4--thiazolyl)-2-(Z-methoxyimino)acetamido]-3-{/ [2,5-dihydro--2-methyl-5-oxo-6-[(pivaloyloxy)methoxyl-as-triazin-3-yl]--thio_7methyl}-8-oxo-5-thia-1-azabicyclot4.2.0~oct-2-ene-2--carboxylate pivalate.
1.85 g of the cephalosporin disodium salt manufactured as described in Example 1 are suspended in 50 ml of dimethyl-formamide and treated with 1.35 g of pivaloyloxymethyl iodide at 0-5C while gassing with nitrogen. The mixture is stirred at 0-5C for 30 minutes and thereafter poured into ~00 ml of ethyl acetate. The mixture is washed three times with water, twice with 5% sodium hydrogen carbonate solution and finally again with water. The solution is dried over sodium sulphate and extensively concentrated at 35C in vacuo. The title substance precipitates out in amorphous form after adding ether. This substance is filtered off under suction, washed with ether and low--boiling petroleum ether and dried at 25C overnight in a high vacuum. The title substance is obtained in the form of a beige amorphous powder. The nuclear magnetic resonance spectrum and the microanalysis are in agreement with the structure indicated.
The following Examples illustrate pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention:
11 ~1373 ~, Example A
Manufacture of dry ampoules for intramuscular administration:
A lyophilisate of 1 g of the disodium salt of (6R,7R)--7-[2-~2-amino-4-thiazolyl)-2-(Z-meLhoxyimino)acetamido~-3--/ [(2~5-dihydro-6-hydroxy-2-m~thyl-5-oxo-as-triazin-3-yl)-thio]methyl_/-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2--carboxylic acid is prepared in the usual manner and filled into an ampoule. Prior to the administration, the 10 lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.
Example B
Interloc~ing gelatin capsules each containing the following ingredients are manufacture~ in the usual manner:
Methylene-(6R,7R)-7-[2-(2-amino-4--thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-{/ ~2,5-dihydro-2--methyl-5-oxo-6-[(pivaloyloxy)-methoxy]-as-triazin-3-yl]thio 7-methyl}-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate pivalate 500 mg Luviskol (water-soluble poly-vinylpyrrolidone) 20 mg Mannitol 20 ms Talc 15 mg Magnesium stearate 2 mg 557 .~g
This fraction I can be used directly for the manufacture of the desired cephalosporin derivative.
The ethyl acetate mother liquor is concentrated extensively at 40C in vacuo, diluted with ether and the precipitated substance is filtered off under suction [~6R, 7R)-7-L 2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(Z-methoxy-imino)acetamido_7-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, fraction II; a light beige amorphous acid, somewhat purer than fraction I
according to thin-layer chromatography~.
For the manufacture of the disodium salt, 3.5 g of the acid (fraction I~) are dissolved in a mixture of 20 ml of acetone and ll ml of water. The solution is treated with 7 ml o~ a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate, whereby the disodium salt crystallises. A further 25 ml of acetone are now added portionwise and the mixture is stored in a deep-freeze cabinet for 2 hours. Thereafter, the crystallisate is filtered off under suction, washed successively with 25 ml of an ice-cold acetone/water mixture (80:20), pure acetone and low-boiling petroleum ether and dried overnight at 40C in a high vacuum. There is obtained the disodium salt of ~6R,7R)-7- ~2-[2-(2-chloroacetamido)-4-thiazolyl3 -2-(Z-methoxyimino)acetamido~ -3- ~ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio~ methyl~ -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of light yellow crystals; ~ D0 = -142.7 lc = 1 in water).
The nuclear magnetic resonance spectrum and the micro-analysis correspond to the structure indicated.
" 7 -- 3~ --Example 3 Manufacture of methylene-(6R,7R)-7-[2-(2-amino-4--thiazolyl)-2-(Z-methoxyimino)acetamido]-3-{/ [2,5-dihydro--2-methyl-5-oxo-6-[(pivaloyloxy)methoxyl-as-triazin-3-yl]--thio_7methyl}-8-oxo-5-thia-1-azabicyclot4.2.0~oct-2-ene-2--carboxylate pivalate.
1.85 g of the cephalosporin disodium salt manufactured as described in Example 1 are suspended in 50 ml of dimethyl-formamide and treated with 1.35 g of pivaloyloxymethyl iodide at 0-5C while gassing with nitrogen. The mixture is stirred at 0-5C for 30 minutes and thereafter poured into ~00 ml of ethyl acetate. The mixture is washed three times with water, twice with 5% sodium hydrogen carbonate solution and finally again with water. The solution is dried over sodium sulphate and extensively concentrated at 35C in vacuo. The title substance precipitates out in amorphous form after adding ether. This substance is filtered off under suction, washed with ether and low--boiling petroleum ether and dried at 25C overnight in a high vacuum. The title substance is obtained in the form of a beige amorphous powder. The nuclear magnetic resonance spectrum and the microanalysis are in agreement with the structure indicated.
The following Examples illustrate pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention:
11 ~1373 ~, Example A
Manufacture of dry ampoules for intramuscular administration:
A lyophilisate of 1 g of the disodium salt of (6R,7R)--7-[2-~2-amino-4-thiazolyl)-2-(Z-meLhoxyimino)acetamido~-3--/ [(2~5-dihydro-6-hydroxy-2-m~thyl-5-oxo-as-triazin-3-yl)-thio]methyl_/-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2--carboxylic acid is prepared in the usual manner and filled into an ampoule. Prior to the administration, the 10 lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.
Example B
Interloc~ing gelatin capsules each containing the following ingredients are manufacture~ in the usual manner:
Methylene-(6R,7R)-7-[2-(2-amino-4--thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-{/ ~2,5-dihydro-2--methyl-5-oxo-6-[(pivaloyloxy)-methoxy]-as-triazin-3-yl]thio 7-methyl}-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate pivalate 500 mg Luviskol (water-soluble poly-vinylpyrrolidone) 20 mg Mannitol 20 ms Talc 15 mg Magnesium stearate 2 mg 557 .~g
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a compound of the general formula I
, in which X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, or the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, as well as readily hydrolysable esters/ethers and pharmaceutically acceptable salts of this compound and hydrates of the compound of formula I and of its esters/ethers and salts, which process comprises a) cleaving off the protecting group R (and, if desired, also a carboxy protecting group which may be present) in a compound of the general formula , wherein X has the significance given above, R represents a cleavable protecting group and the carboxy group can be present in protected from, by acid or alkaline hydrolysis, a chloroacetyl, bromoacetyl or iodoacetyl group R being cleaved off by treatment with thiourea, or b) for the manufacture of a readily hydrolysable ester/ether of the compound of formula I, subjecting same to a corresponding esterification or etherification by treatment with a halide containing the ester/ether group, or c) for the manufacture of pharmaceutically acceptable salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a pharmaceutically acceptable salt or hydrate or into a hydrate of said salts.
, in which X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, or the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, as well as readily hydrolysable esters/ethers and pharmaceutically acceptable salts of this compound and hydrates of the compound of formula I and of its esters/ethers and salts, which process comprises a) cleaving off the protecting group R (and, if desired, also a carboxy protecting group which may be present) in a compound of the general formula , wherein X has the significance given above, R represents a cleavable protecting group and the carboxy group can be present in protected from, by acid or alkaline hydrolysis, a chloroacetyl, bromoacetyl or iodoacetyl group R being cleaved off by treatment with thiourea, or b) for the manufacture of a readily hydrolysable ester/ether of the compound of formula I, subjecting same to a corresponding esterification or etherification by treatment with a halide containing the ester/ether group, or c) for the manufacture of pharmaceutically acceptable salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a pharmaceutically acceptable salt or hydrate or into a hydrate of said salts.
2. A process according to claim 1, wherein the compound of formula II in which R represents chloroacetyl is treated with thiourea.
3. A process according to claim 1 , wherein a compound in the syn-isomeric form or a mixture in which the syn-isomeric form predominates is manufactured.
4. A process according to claim 1 or 2, wherein a compound of formula I
given in claim 1, in which X represents the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, or a salt of this compound or a hydrate of this compound or salt thereof is manufactured, which comprises utilising a starting compound of formula II, in which X has the appropriate meaning.
given in claim 1, in which X represents the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, or a salt of this compound or a hydrate of this compound or salt thereof is manufactured, which comprises utilising a starting compound of formula II, in which X has the appropriate meaning.
5. A process according to claim 1, wherein (6R, 7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxy imino)-acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a salt of this compound or a hydrate of this compound or salt thereof is manufactured, which comprises utilising a starting compound of formula II, in which X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.
6. Process according to claim 5, wherein a starting compound of formula II, wherein R represents chloroacetyl, is treated with thiourea.
7. A process according to claim 1 for the manufacture of readily hydrolys-able esters/ethers of the compound of formula I set forth in claim 1 as well as salts of these esters/ethers and hydrates of these esters/ethers and salts, which process comprises esterifying/etherifying a carboxylic acid of formula I with a halide containing the ester group and, if desired, converting the obtained ester into a salt or a hydrate or a hydrate of such a salt.
8. A process according to claim 7 for the manufacture of pivaloyloxymethyl esters/ethers of the compound of formula I set forth in claim 1 as well as phar-maceutically acceptable salts of these esters/ethers and hydrates of these esters/
ethers and salts, which process comprises reacting the carboxylic acid of formula I with a pivaloyloxymethyl halide, and, if desired, converting the obtained ester/ether into a pharmaceutically acceptable salt or a hydrate or a hydrate of such a salt.
ethers and salts, which process comprises reacting the carboxylic acid of formula I with a pivaloyloxymethyl halide, and, if desired, converting the obtained ester/ether into a pharmaceutically acceptable salt or a hydrate or a hydrate of such a salt.
9. Process according to claim 8, wherein as pivaloyloxymethyl halide the iodide is used.
10. Process according to claim 1 for the manufacture of methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-{[[2,5-dihydro-2-methyl-5-oxo-6-[(pivaloyloxy)methoxy]-as-triazin-3-yl]thio methyl3-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as pharmaceutically acceptable salts of this compound and hydrates of this compound and salts, which process comprises reacting (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-{[2,5-dihydro-2-methyl-5-oxo-6-hydroxy-as-triazin-3-yl]thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid with a pivaloyloxy-methyl halide and, if desired, converting the obtained ester into a pharmaceuti-cally acceptable salt or a hydrate or a hydrate of such a salt.
11. Process according to claim 10, wherein as pivaloyloxymethyl halide the iodide is used and the carboxylic acid is in the form of the disodium salt.
12. A compound of the formula I as defined in claim 1 or a readily hydrolysable ester/ether or pharmaceutically acceptable salt of such a compound or a hydrate of a compound of formula I or of an ester/ether or salt thereof, when manufactured by the process of claim 1 or 2 or by an obvious chemical equivalent thereof.
13. A compound of formula I as defined in claim 1 or a readily hydrolysable ester/ether or pharmaceutically acceptable salt of such a compound or a hydrate of compound I or of an ester/ether or salt thereof which is in the syn-isomeric form or in the form of a mixture in which the syn-isomeric form predominates, when manufactured by the process of claim 3 or by an obvious chemical equivalent thereof.
14. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts, when manufactured by the process of claim 5 or by an obvious chemical equivalent thereof.
15. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts, when manufactured by the process of claim 6 or by an obvious chemical equivalent thereof.
16. Methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino) acetamido]-3-{[[2,5-dihydro-2-methyl-5-oxo-6-[(pivaloyloxy)methoxy]-as-triazin-3-yl]thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as pharmaceutically acceptable salts thereof and hydrates of this compound and its salts, whenever manufactured by the process of claim 10 or by an obvious chemical equivalent thereof.
17. Methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino) acetamido]-3-{[[2,5-dihydro-2-methyl-5-oxo-6-[(pivaloyloxy) methoxy]-as-triazin-3-yl]thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2Ø]oct-2-ene-2-carboxylate pivalate, whenever manufactured by the process of claim 11, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH588278A CH641468A5 (en) | 1978-05-30 | 1978-05-30 | CEPHEM DERIVATIVES. |
| CH5882/78 | 1978-05-30 | ||
| CH224879 | 1979-03-08 | ||
| CH2248/79 | 1979-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1141373A true CA1141373A (en) | 1983-02-15 |
Family
ID=25689901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000328630A Expired CA1141373A (en) | 1978-05-30 | 1979-05-29 | Acyl derivatives |
Country Status (40)
| Country | Link |
|---|---|
| EP (2) | EP0005830B1 (en) |
| JP (2) | JPS54157596A (en) |
| AT (3) | AT367764B (en) |
| BG (1) | BG50163A3 (en) |
| BR (1) | BR7903368A (en) |
| CA (1) | CA1141373A (en) |
| CS (1) | CS219254B2 (en) |
| CU (1) | CU35088A (en) |
| CY (1) | CY1182A (en) |
| DD (1) | DD143911A5 (en) |
| DE (4) | DE2963720D1 (en) |
| DK (1) | DK149282C (en) |
| EG (1) | EG14153A (en) |
| ES (2) | ES480990A1 (en) |
| FI (1) | FI65434C (en) |
| FR (2) | FR2427337A1 (en) |
| GB (2) | GB2022090B (en) |
| GR (1) | GR72242B (en) |
| HK (1) | HK31383A (en) |
| HU (1) | HU183089B (en) |
| IE (1) | IE49047B1 (en) |
| IL (1) | IL57392A (en) |
| IS (1) | IS1203B6 (en) |
| IT (1) | IT1121517B (en) |
| KE (1) | KE3268A (en) |
| LU (1) | LU81325A1 (en) |
| MC (1) | MC1259A1 (en) |
| MT (1) | MTP845B (en) |
| MY (1) | MY8400127A (en) |
| NL (1) | NL7904083A (en) |
| NO (1) | NO159797C (en) |
| NZ (1) | NZ190532A (en) |
| OA (1) | OA06263A (en) |
| PH (1) | PH15148A (en) |
| PL (1) | PL122458B1 (en) |
| PT (1) | PT69698A (en) |
| RO (1) | RO77560A (en) |
| SE (1) | SE437522B (en) |
| SG (1) | SG10483G (en) |
| YU (3) | YU42485B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI67385C (en) * | 1979-11-21 | 1985-03-11 | Hoffmann La Roche | PROCEDURE FOR FRAMSTATION OF AV (6R 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (Z-METHOXYIMINO) ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES |
| US4349672A (en) * | 1979-11-29 | 1982-09-14 | Hoffmann-La Roche Inc. | Cephalosporin derivatives |
| CA1177823A (en) * | 1980-03-25 | 1984-11-13 | Andre Furlenmeier | Cephalosporin derivatives |
| CA1154009A (en) * | 1980-03-25 | 1983-09-20 | Roland Reiner | Cephalosporin derivatives |
| GR75711B (en) * | 1980-06-30 | 1984-08-02 | Sanofi Sa | |
| US4308267A (en) | 1980-07-03 | 1981-12-29 | Smithkline Corporation | 7-[2-Alkoxyimino-2-(amino-thiazole)acetamido]-3-[1-(sulfaminoalkly)tetrazolthiomethyl]cephalosporins |
| DK379581A (en) * | 1980-10-06 | 1982-04-07 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF ACYL DERIVATIVES |
| FR2494278A1 (en) * | 1980-11-20 | 1982-05-21 | Rhone Poulenc Ind | NEW DERIVATIVES OF CEPHALOSPORIN, THEIR PREPARATIONS AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| EP0058250A3 (en) * | 1981-02-17 | 1983-08-17 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Cephalosporin derivatives, their preparation and pharmaceutical compositions containing them |
| EP0185220A3 (en) * | 1984-12-19 | 1987-09-02 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Intermediates for the preparation of cephalosporins |
| CA1296012C (en) | 1986-03-19 | 1992-02-18 | Susumu Nakagawa | 6,7-dihydroxy-isoquinoline derivatives |
| RU2021274C1 (en) | 1991-05-17 | 1994-10-15 | Польска Акадэмия Наук Институт Хэмии Органичнэй | Process for preparing aminothiazolyl cephalosporin derivatives |
| KR950014571B1 (en) * | 1991-11-18 | 1995-12-08 | 제일제당주식회사 | Process for the preparation of cephem derivatives |
| AT398764B (en) * | 1992-01-28 | 1995-01-25 | Lek Tovarna Farmacevtskih | METHOD FOR PRODUCING CEFTRIAXONDINATRIUM SALZHEMIHEPTAHYDRATE |
| AT399877B (en) * | 1992-02-20 | 1995-08-25 | Biochemie Gmbh | NEW METHOD FOR PRODUCING CEFTRIAXONE |
| KR100197788B1 (en) * | 1995-06-30 | 1999-06-15 | 김충환 | Processes for manufacturing cephem derivatives |
| DE102011117421A1 (en) | 2011-11-02 | 2013-05-02 | Hans-Peter Gabel | Pharmaceutical composition useful for treating Lyme disease, comprises mixture of active substances including ceftriaxone and cefotaxime |
| RU2504548C1 (en) * | 2012-09-28 | 2014-01-20 | Федеральное Государственное Автономное Образовательное Учреждение Высшего Профессионального Образования "Сибирский Федеральный Университет" (Сфу) | DERIVATIVE OF β-LACTAM CEFTRIAXONE ANTIBIOTIC |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH609989A5 (en) * | 1974-06-21 | 1979-03-30 | Hoffmann La Roche | Process for the preparation of acyl derivatives |
| CA1100129A (en) * | 1974-08-02 | 1981-04-28 | William H.W. Lunn | Cephalosporin compounds |
| FR2345153A1 (en) * | 1976-03-25 | 1977-10-21 | Roussel Uclaf | NEW ALCOYLOXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| DK162391C (en) | 1976-04-12 | 1992-03-09 | Fujisawa Pharmaceutical Co | ANALOGY PROCEDURE FOR PREPARING SYN-ISOMERS OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS |
| GR63088B (en) * | 1976-04-14 | 1979-08-09 | Takeda Chemical Industries Ltd | Preparation process of novel cephalosporins |
| JPS5329936A (en) * | 1976-08-31 | 1978-03-20 | Takeda Chem Ind Ltd | Antibiotic composition |
| GB1599232A (en) * | 1977-06-03 | 1981-09-30 | Hoffmann La Roche | 7-(2-oximinoacetamido)-cephalosporin derivatives |
| US4200745A (en) * | 1977-12-20 | 1980-04-29 | Eli Lilly And Company | 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins |
-
1979
- 1979-04-25 MC MC791376A patent/MC1259A1/en unknown
- 1979-05-09 MT MT845A patent/MTP845B/en unknown
- 1979-05-14 EG EG280/79A patent/EG14153A/en active
- 1979-05-23 NZ NZ190532A patent/NZ190532A/en unknown
- 1979-05-23 NL NL7904083A patent/NL7904083A/en not_active Application Discontinuation
- 1979-05-24 IL IL57392A patent/IL57392A/en unknown
- 1979-05-24 PH PH22556A patent/PH15148A/en unknown
- 1979-05-25 BG BG043718A patent/BG50163A3/en unknown
- 1979-05-25 FR FR7913369A patent/FR2427337A1/en not_active Withdrawn
- 1979-05-25 YU YU1233/79A patent/YU42485B/en unknown
- 1979-05-28 DD DD79213189A patent/DD143911A5/en not_active IP Right Cessation
- 1979-05-28 LU LU81325A patent/LU81325A1/en unknown
- 1979-05-28 JP JP6511179A patent/JPS54157596A/en active Granted
- 1979-05-28 HU HU79HO2154A patent/HU183089B/en unknown
- 1979-05-28 FI FI791703A patent/FI65434C/en not_active IP Right Cessation
- 1979-05-28 GR GR59190A patent/GR72242B/el unknown
- 1979-05-28 IS IS2490A patent/IS1203B6/en unknown
- 1979-05-28 CU CU7935088A patent/CU35088A/en unknown
- 1979-05-28 IT IT23049/79A patent/IT1121517B/en active
- 1979-05-29 NO NO791776A patent/NO159797C/en unknown
- 1979-05-29 GB GB7918655A patent/GB2022090B/en not_active Expired
- 1979-05-29 CA CA000328630A patent/CA1141373A/en not_active Expired
- 1979-05-29 CY CY1182A patent/CY1182A/en unknown
- 1979-05-29 AT AT0390479A patent/AT367764B/en not_active IP Right Cessation
- 1979-05-29 BR BR7903368A patent/BR7903368A/en unknown
- 1979-05-29 ES ES480990A patent/ES480990A1/en not_active Expired
- 1979-05-29 OA OA56816A patent/OA06263A/en unknown
- 1979-05-29 DK DK222679A patent/DK149282C/en not_active IP Right Cessation
- 1979-05-29 GB GB8202226A patent/GB2099418B/en not_active Expired
- 1979-05-29 PT PT69698A patent/PT69698A/en unknown
- 1979-05-29 SE SE7904682A patent/SE437522B/en unknown
- 1979-05-29 CS CS793700A patent/CS219254B2/en unknown
- 1979-05-30 EP EP79101657A patent/EP0005830B1/en not_active Expired
- 1979-05-30 AT AT79101657T patent/ATE1586T1/en active
- 1979-05-30 EP EP81106777A patent/EP0045525B1/en not_active Expired
- 1979-05-30 DE DE7979101657T patent/DE2963720D1/en not_active Expired
- 1979-05-30 DE DE8181106777T patent/DE2966946D1/en not_active Expired
- 1979-05-30 DE DE2922036A patent/DE2922036C2/en not_active Expired
- 1979-05-30 PL PL1979215972A patent/PL122458B1/en unknown
- 1979-05-30 DE DE2954159A patent/DE2954159C2/en not_active Expired
- 1979-05-30 RO RO7997683A patent/RO77560A/en unknown
- 1979-05-30 AT AT81106777T patent/ATE7229T1/en active
- 1979-08-08 IE IE1041/79A patent/IE49047B1/en not_active IP Right Cessation
-
1980
- 1980-02-16 ES ES488687A patent/ES8101606A1/en not_active Expired
-
1982
- 1982-05-11 FR FR8208153A patent/FR2509312A1/en active Granted
-
1983
- 1983-03-14 SG SG104/83A patent/SG10483G/en unknown
- 1983-03-29 KE KE3268A patent/KE3268A/en unknown
- 1983-08-25 HK HK313/83A patent/HK31383A/en not_active IP Right Cessation
-
1984
- 1984-06-21 JP JP59126533A patent/JPS6016994A/en active Granted
- 1984-12-30 MY MY127/84A patent/MY8400127A/en unknown
-
1985
- 1985-05-06 YU YU745/85A patent/YU45257B/en unknown
- 1985-05-06 YU YU744/85A patent/YU45256B/en unknown
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