CA1151151A - Cephem derivatives and process for their manufacture - Google Patents
Cephem derivatives and process for their manufactureInfo
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- CA1151151A CA1151151A CA000349333A CA349333A CA1151151A CA 1151151 A CA1151151 A CA 1151151A CA 000349333 A CA000349333 A CA 000349333A CA 349333 A CA349333 A CA 349333A CA 1151151 A CA1151151 A CA 1151151A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
-
- 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
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- Cephalosporin Compounds (AREA)
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Abstract
Cephem derivatives and process for their manufacture Abstract of the disclosure:
Cephem compounds of the formula I
I
pharmaceutical preparations having an activity against bac-terial infections and containing these cephem compounds, process for the manufacture of the cephem compounds and of the pharmaceutical preparations and use of the cephem com-pounds for combating bacterial infections.
Cephem compounds of the formula I
I
pharmaceutical preparations having an activity against bac-terial infections and containing these cephem compounds, process for the manufacture of the cephem compounds and of the pharmaceutical preparations and use of the cephem com-pounds for combating bacterial infections.
Description
5~
- 2 - HOE 79/F 087 Subject of the present invention are cephem derivati ves of the formula I
O R1 (O~ :
C- CNH ~ S~
b CH3 O N ~ CH2R
COOH
~--~
wherein n is O or 1, R1 is hydrogen or low-molecular alcoxy and R2 is azido or a radical -SR3, in which R3 is an op-tionally substituted five- or six-membered hetero-cycle, optionally carrying a fused benzene nucleus, or in which R3 is low-molecular alkyl or acyl, the methoximino group being in syn-position, and pharmalogically acceptable salts and esters thereof.
Subject of the present invention further is a process for the manufacture of the cephem compounds of the formula I, which co~prises a) reacting cephem compounds of the formula II
R1 ()n ~ ~ C -CON~ ~
COOH
wherèin n and R1 are as defined above, in the presence of a solvent and a base, with an azide or with compounds of the formula HSR3, in which R3 is as defined above, or ~;
~ : .
. :' , ~, .' :
. . .
5 ~
O R1 (O~ :
C- CNH ~ S~
b CH3 O N ~ CH2R
COOH
~--~
wherein n is O or 1, R1 is hydrogen or low-molecular alcoxy and R2 is azido or a radical -SR3, in which R3 is an op-tionally substituted five- or six-membered hetero-cycle, optionally carrying a fused benzene nucleus, or in which R3 is low-molecular alkyl or acyl, the methoximino group being in syn-position, and pharmalogically acceptable salts and esters thereof.
Subject of the present invention further is a process for the manufacture of the cephem compounds of the formula I, which co~prises a) reacting cephem compounds of the formula II
R1 ()n ~ ~ C -CON~ ~
COOH
wherèin n and R1 are as defined above, in the presence of a solvent and a base, with an azide or with compounds of the formula HSR3, in which R3 is as defined above, or ~;
~ : .
. :' , ~, .' :
. . .
5 ~
- 3 - ~OE 79tF 087 b) reac~ing cephem compounds of the formula III in the form of their salts or esters R1 (~n H2N ~ ~
o~ N ~CH 2R
COOH
wherein n, R1 and R2 are as defined above, with reactive derivatives of 2~ 3-thiazol-4-yl)-2-syn-methoximinoacetic acid and, if desired, in the compounds obtained according to a) or b) c~) converting a salt obtained into the free carboxylic acid and optionally further esterifying the latter or ~) converting a salt obtained directly into an ester or d~ saponifying an ester obtained and optionally convert-ing the carboxylic acid obtained into a salt or ~) subsequently oxidizing a compound of the formula I
wherein n is zero or subsequently reducing a compound of the formula I in which n is 1 and, if desired, further converting the resulting cephem compounds ob-tained according to steps ~,~or ~.
25` If in the compounds of the formula I R1 is low-mole-cular alkoxy, possible examples of this are alkoxy groups with 1 to 4 carbon atoms, such as methoxy, ethoxy, isoprop-oxy or n-butoxy.
Compounds in which R1 is hydrogen or methoxy are preferred.
If R2 is a radical -SR3 and R3 is low-molecular acyl, possible acyl radicals are in particular aliphatic acyl radicals having 1 to 4 carbon atoms, preferably acetyl or propionyl. If R3 is low-molecular alkyl, examples of this are straight-chain or branched alkyl with 1 to 4 carbon atoMs, such as methyl, ethyl, isopropyl or butyl, preferably methyl.
- , .. . ~. ..
. - . ., . ~ . , : . - ~ : .
5~L
o~ N ~CH 2R
COOH
wherein n, R1 and R2 are as defined above, with reactive derivatives of 2~ 3-thiazol-4-yl)-2-syn-methoximinoacetic acid and, if desired, in the compounds obtained according to a) or b) c~) converting a salt obtained into the free carboxylic acid and optionally further esterifying the latter or ~) converting a salt obtained directly into an ester or d~ saponifying an ester obtained and optionally convert-ing the carboxylic acid obtained into a salt or ~) subsequently oxidizing a compound of the formula I
wherein n is zero or subsequently reducing a compound of the formula I in which n is 1 and, if desired, further converting the resulting cephem compounds ob-tained according to steps ~,~or ~.
25` If in the compounds of the formula I R1 is low-mole-cular alkoxy, possible examples of this are alkoxy groups with 1 to 4 carbon atoms, such as methoxy, ethoxy, isoprop-oxy or n-butoxy.
Compounds in which R1 is hydrogen or methoxy are preferred.
If R2 is a radical -SR3 and R3 is low-molecular acyl, possible acyl radicals are in particular aliphatic acyl radicals having 1 to 4 carbon atoms, preferably acetyl or propionyl. If R3 is low-molecular alkyl, examples of this are straight-chain or branched alkyl with 1 to 4 carbon atoMs, such as methyl, ethyl, isopropyl or butyl, preferably methyl.
- , .. . ~. ..
. - . ., . ~ . , : . - ~ : .
5~L
4 - HOE 79/F 087 If R3 is an optionally substituted 5- or 6-membered heterocycle, possible examples thereof are heterocycles that contain from 1 to 4 hetero atoms, such as nitrogen, sulfur and/ or oxygen as ring atoms.
The following fundamental ring systems may be mention-ed as examples of the radical R3:
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxdiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazinyl, pyridazinyl, oxazinyl, imidazolinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzthiazolyl, benzimidazolyl and indolyl.
Preferred ring systems are 5-membered ring systems with 1 to 2 nitrogen atoms and optionally an oxygen atom, such as oxazolyl, preferably oxazol-2~yl, oxadiazolyl, such as 1,3,4-oxadia~olyl, imidazolinyl, preferably imidazolin-2-yl and 6-membered ring systems with 1 to 3, preferably with 1 to 2, in particular with one nitrogen atom and op-tionally a sulfur atom, such as pyridyl, for example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidyl, preferably pyri-mid-2-yl and pyrimid-4-yl, pyrazinyl or pyridazinyl and
The following fundamental ring systems may be mention-ed as examples of the radical R3:
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxdiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazinyl, pyridazinyl, oxazinyl, imidazolinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzthiazolyl, benzimidazolyl and indolyl.
Preferred ring systems are 5-membered ring systems with 1 to 2 nitrogen atoms and optionally an oxygen atom, such as oxazolyl, preferably oxazol-2~yl, oxadiazolyl, such as 1,3,4-oxadia~olyl, imidazolinyl, preferably imidazolin-2-yl and 6-membered ring systems with 1 to 3, preferably with 1 to 2, in particular with one nitrogen atom and op-tionally a sulfur atom, such as pyridyl, for example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidyl, preferably pyri-mid-2-yl and pyrimid-4-yl, pyrazinyl or pyridazinyl and
5-membered ring systems with 1 to 4 nitrogen atoms and op-tionally a sulfur atom, in particular with 1 to 2 nitrogen atoms and one sulfur atom or with 3 or 4 nitrogen atoms, in particular with 3 nitrogen atoms, such as thiazolyl, in particular thiazol-2-yl, thiadiazolyl, in particular 1,3,4~
thiadiazolyl-5-yl and 1,2,4-thiadiazol-5-yl, triazolyl, preferably 4-H-1,2,4-triazol-3-yl and tetrazolyl, preferably lH-tetra~ol-5-yl.
If R is a heterolytic radicalg it can be mono- or polysubstituted, examples of possible substituents being the following: straight--chain or branched, optionally substitut-ed alkyl with 1 to 15 carbon atoms, such as methyl, n-prop-yl, i propyl, n-butyl, undecyl and pentadecyl, preferably those with 1 to 4 carbon atoms, in particular methyl, or hydroxy, amiro, C1 4 alkylamino, C1 4dialkyl-amino, phenyl or heterocyclic radicals,in particular 5- or 6-mem-bered heterocyclic radicals that have 1 to 2 nitrogen atoms and/or one sulfur or oxygen atom in the ring for exam-le pyrid-2-yl, pyrid-3-yl, pyrid-4--yl, thien-2-yl or ~- thien-3-yl.
. .
,:
~s~
If R3 is a heterocyclic radical, preferred hetero-lytic radicals are those being unsubstituted or substituted by amino, thienyl or straight-chain or branched alkyl with 1 to 4 carbon atoms, possible substituents for alkyl being, for example, carboxy, halogen, in particular fluorine. such as methyl, ethyl, isopropyl, n-butyl, carboxymethyl, tri-fluormethyl or pentafluoroethyl.
Examples or pharmacologically acceptable salts of the cephem compounds of the formula I are inorganic and organic salts, in particular the alkali metal and alkaline earth metals salts, preferably the sodium, potassium, magnesium and calcium salts; tertiary or quartenary ammonium salts, such as the triethylammonium or tetraethylammonium salts or the procaine salt. Examples of pharmacologically acceptable esters are in particular easily cleavable esters, such as the acetoxymethyl ester, the pivaloyloxymethyl ester , the 1-acetoxyethyl ester or the phthalide ester.
The cephem compounds of the formula II in accordance with the present invention are the subject of German Offenlegungsschrift 28 22 860.
The cephem compounds of the formula I can be obtained in accordance with the present invention in the following manner:
The cephalosporin derivatives of the formula I are reacted with azides, preferably alkali metal azides, in particular the sodium azide, or with mercapto compounds Or the formula HSR . The reaction is run particularly prefer-ably in aqueous solution or in mixtures of water and of solvents miscible with water, such as acetone, a pH of approximately from 5.5 to 7.5 being adjusted by the addition of bases.
Suitable bases are, for example, alkali metal carbonates, such as sodium bicarbonate or potassium bicarbonate, or mixtures of primary and secondary alkali metal phosphate.
The reaction is run preferably at elevated temperature from approximately 50 to 100C , preferably from 50 to 80~. The reaction time depends on the temperature, at which the reaction is run. 3 The mercapto compounds of the formula HSR l that are known in the literature or obtainable according to proces-ses known in the literature, can be used alternatlvely in the form of their salts, in particular the alkali metal ;- :
. : ~
~15~
thiadiazolyl-5-yl and 1,2,4-thiadiazol-5-yl, triazolyl, preferably 4-H-1,2,4-triazol-3-yl and tetrazolyl, preferably lH-tetra~ol-5-yl.
If R is a heterolytic radicalg it can be mono- or polysubstituted, examples of possible substituents being the following: straight--chain or branched, optionally substitut-ed alkyl with 1 to 15 carbon atoms, such as methyl, n-prop-yl, i propyl, n-butyl, undecyl and pentadecyl, preferably those with 1 to 4 carbon atoms, in particular methyl, or hydroxy, amiro, C1 4 alkylamino, C1 4dialkyl-amino, phenyl or heterocyclic radicals,in particular 5- or 6-mem-bered heterocyclic radicals that have 1 to 2 nitrogen atoms and/or one sulfur or oxygen atom in the ring for exam-le pyrid-2-yl, pyrid-3-yl, pyrid-4--yl, thien-2-yl or ~- thien-3-yl.
. .
,:
~s~
If R3 is a heterocyclic radical, preferred hetero-lytic radicals are those being unsubstituted or substituted by amino, thienyl or straight-chain or branched alkyl with 1 to 4 carbon atoms, possible substituents for alkyl being, for example, carboxy, halogen, in particular fluorine. such as methyl, ethyl, isopropyl, n-butyl, carboxymethyl, tri-fluormethyl or pentafluoroethyl.
Examples or pharmacologically acceptable salts of the cephem compounds of the formula I are inorganic and organic salts, in particular the alkali metal and alkaline earth metals salts, preferably the sodium, potassium, magnesium and calcium salts; tertiary or quartenary ammonium salts, such as the triethylammonium or tetraethylammonium salts or the procaine salt. Examples of pharmacologically acceptable esters are in particular easily cleavable esters, such as the acetoxymethyl ester, the pivaloyloxymethyl ester , the 1-acetoxyethyl ester or the phthalide ester.
The cephem compounds of the formula II in accordance with the present invention are the subject of German Offenlegungsschrift 28 22 860.
The cephem compounds of the formula I can be obtained in accordance with the present invention in the following manner:
The cephalosporin derivatives of the formula I are reacted with azides, preferably alkali metal azides, in particular the sodium azide, or with mercapto compounds Or the formula HSR . The reaction is run particularly prefer-ably in aqueous solution or in mixtures of water and of solvents miscible with water, such as acetone, a pH of approximately from 5.5 to 7.5 being adjusted by the addition of bases.
Suitable bases are, for example, alkali metal carbonates, such as sodium bicarbonate or potassium bicarbonate, or mixtures of primary and secondary alkali metal phosphate.
The reaction is run preferably at elevated temperature from approximately 50 to 100C , preferably from 50 to 80~. The reaction time depends on the temperature, at which the reaction is run. 3 The mercapto compounds of the formula HSR l that are known in the literature or obtainable according to proces-ses known in the literature, can be used alternatlvely in the form of their salts, in particular the alkali metal ;- :
. : ~
~15~
- 6 - HOE 79/F 087 salts, preferably the sodium and potassium salts, provided that these are easier to handle during the manufacture. The compounds of the formula II, too, can be used alternatively in the form of their salts, such as the alkali metal salts, in particular the sodium or potassium salts.
The final products obtained according to the above process variant can be isolated easily according to proces-ses common in laboratory work. For example, the acid deri-vatives Or the formula I are obtainable by precipitating the cephem acids from the reaction solution by adding mineral acids. Suitable mineral acids are in particular dilute acids, such as dilute hydrochloric acid or sulfuric acid.
In this process variant the cephem compounds of the formula I are in most cases obtained as amorphous solids or in crystalline form. Alternatively they can be separated as the free acids by extraction at a pH frorn approximately 2 to 1. Examples of suitable extraction agents are organic solvents immiscible with water, such as halogenated hydro-carbons, for example methylene chloride, esters such asacetic acid ethyl esters or acetic acid n-butyl esters, or ketones, such as methylisobutylketone.
The corresponding cephem acids of the formula I are obtained from the extracts in substance, for example by concentration, or they are converted directly into a form suitable for application, for example into a pharmacologi-cally acceptable salt or ester.
The compounds of the formula I can be obtained alterna-tively according to the invention in the following manner:
Cephem compounds of the formula III in the form of their salts or esters are acylated with a reactive derivative of the 2-(1,3-thiazol-4-yl)-2-syn-methoximino-acetic acid. The cephem compounds of the formula III are known in the lite-rature. The 2-(1,3-thiazol-3-yl)-2-syn-methoximino-acetic acid is the subject of German Offenlegungsschrift 28 22 860. The 2-(1,3-thiazol-4-yl?-2-syn-methoximino-acetic acid is reacted with the cephem compounds of the formula III in known manner, for example by activating the carboxylic acid ~ .
s~
The final products obtained according to the above process variant can be isolated easily according to proces-ses common in laboratory work. For example, the acid deri-vatives Or the formula I are obtainable by precipitating the cephem acids from the reaction solution by adding mineral acids. Suitable mineral acids are in particular dilute acids, such as dilute hydrochloric acid or sulfuric acid.
In this process variant the cephem compounds of the formula I are in most cases obtained as amorphous solids or in crystalline form. Alternatively they can be separated as the free acids by extraction at a pH frorn approximately 2 to 1. Examples of suitable extraction agents are organic solvents immiscible with water, such as halogenated hydro-carbons, for example methylene chloride, esters such asacetic acid ethyl esters or acetic acid n-butyl esters, or ketones, such as methylisobutylketone.
The corresponding cephem acids of the formula I are obtained from the extracts in substance, for example by concentration, or they are converted directly into a form suitable for application, for example into a pharmacologi-cally acceptable salt or ester.
The compounds of the formula I can be obtained alterna-tively according to the invention in the following manner:
Cephem compounds of the formula III in the form of their salts or esters are acylated with a reactive derivative of the 2-(1,3-thiazol-4-yl)-2-syn-methoximino-acetic acid. The cephem compounds of the formula III are known in the lite-rature. The 2-(1,3-thiazol-3-yl)-2-syn-methoximino-acetic acid is the subject of German Offenlegungsschrift 28 22 860. The 2-(1,3-thiazol-4-yl?-2-syn-methoximino-acetic acid is reacted with the cephem compounds of the formula III in known manner, for example by activating the carboxylic acid ~ .
s~
- 7 - HOE 79/F 087 groups by conversion into a group capable of forming an amide, preferably into an active ester, for exarnple the hydroxybenztriazole ester, or by conversion into an acid halide, preferably an aci.d chloride, or by conversion into a symmetrical or asymmetrical anhydride. All of these me-thods are known in the literature.
Activation of the carboxylic acid has to be carried out under reaction conditions as mild as possible, such as are described in the literature for analogous reactions, to prevent any possible flipping over the syn-oxime into the trans-oxime derivative represented by the following formula:
~C----COOE~
~ /
- C~30 Activation should be carried out at a temperature as low as possible in the range from approximately -50 to ~50C, preferably from -20 to ~20C. Suitably rather acid reaction conditions should moreover be avoided.
The cephem carboxylic acids of the formula III can be dissolved in various manner, for example by adding bases or by conversion into silyl esters. The silylation agents may be any common reagents, in particular the trimethylchloro-silane which is used in the presence of a stoichiometrical quantity of a base, or especially preferably the O,N-bis- `
trimethylsilylacetamide which may be used without the addi-tion of a base. For attaining good yields the silylation agent is suitably used in a ratio of approximakely 2 equi-valents of a silyl compound per mol of cephem cornpound of the formula III.
Suitable bases which can be used for dissolving a 35 great number of 7-amino-~ 3-cephem-4-carboxylic acids, are inorganic or organic bases. Thus, tertiary amines, such as triethylamine, N,N-dimethylaniline or N-methylmorpholine, , 5~
have proved partlcularly suitable for the preparation Or ~ solutions in organic solvents.
In general the bases are added in an at least stoi-chiometrical amount, relative to the desired reaction. An excess of base of, for example a~out 20 to 80 ~, can be advantageous.
In the case of compounds of the formula III which are sensitive towards bases, the pH can be kept constant at about 4 to 8, preferably 6 to 7, depending on the reaction course, by continuously adding the base.
The compounds of the formula III can be dissolved in a wide temperature range. However, in the case of derivatives that are sensitive towards bases, it is advisable to choose a temperature range from about O to 15C.
The acylation of the cephem compounds of the formula III with the 2-t1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid can be carried out under variable experimental condi-tions, for example, using various solvents. Examples of suitable solvents are organic solvents, such as halogenated hydrocarbons, for example methylene chloride or chloroform, but also tertiary amines, such as dimethylformamide or ~imethylacetamide.
If cephem esters of the formula III are used, the re-action is carried out in organic solvents, in which most of`
the esters are readily soluble. Examples of such solvents are likewise halogenated hydrocarbons or the tertiary amides.
Examples of suitable esters are compounds of the for~
mula III, in which R4 in the ester group -CooR4 may stand for straight-chain or branched alkyl with 1 to 6 carbon atoms, for example methyl, ethyl, tert.-butyl, isoamyl or hexyl, it being possible for the alkyl group to be further substituted, preferably in ~-position, for example by tri-chloromethyl, acyloxy with 1 to 6 carbon atoms, preferably acetoxy or pivaloyloxy, or by one or two phenyl radicals, it being possible for the latter to be substituted by alk-oxy with 1 to 4 carbon atoms, preferably methoxy, or nitro, .
or R4 may starld for the phthalide group. Examples of the above definitions are the tert.-butyl esters, the trichlo-roethyl esters, the p-methoxybenzyl esters, the benzhydryl esters, the acetoxymethyl esters, the 1-acetoxyethyl esters, the 1-propionyloxypropyl esters, the 1-acetoxy-n-butyl esters, the pivyloyloxymethyl esters or the phthalide esters.
The activated 2-(1t3-thiazol-4-yl)-2 syn-methoximino-acetic acid is added to the cephem derivatives of the for-mula III present in dissolved or suspended state or toesters thereof, in dissolved state or suspended in an inert solvent or in substance.
The reaction temperature depends greatly on the reacti-vity of the activated 2-(1,3-thiazol-4-yl)-2-syn-methoximi-noacetic acid, a temperature interval from approximately -50 to ~50C having proved advantageous, a temperature from approximately -20 to +20C being particularly advantageous.
In order to reach higher yields, the activated acid derivative is used in an at least stoichiometrical amount, excess from approximately 5 to 25 % being possibly advan-tageous~
The final products obtained upon acylation are isolat-ed in known rnanner, for example such as are described here-inbefore for the final products obtained by exchange of the acetoxy group. For example, if the symmetrical anhydride of the 2-(1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid has been used, the side chain acid liberated during the acyla-tion may be separated, for example by extraction or preci-pitation.
The compounds of the formula I wherein n is 1 can beprepared alternatively by oxidizing compounds of the f`ormula I wherein n is 0.
The oxidation of the sulfur in the cephem ring has been described repeatedly. This oxidation may yield ~- and ~-oxides (Cf. E. Flynn, Cephalosporins and Penicillins, Chemistry and Biology, Academic Press, 1972, pages 135 et se~.), depending on the oxidant used.
~ ` .
- 10 - ~OE 79/F 087 For example, if peracetic acid is used in glacial ace-tic acid, there are obtained R-S-oxides. The reaction tem-perature is not critical. It is,however, advisable to carry out oxidation at room temperature, in order to avoid unde-sired sequence reactions, and to add the oxidant in an atleast stoichiometri.cal amount, an excess from 10 to 100 %
being frequently advantageous, as long as the temperature of the reaction is not increased substantially.
The cephem-S-oxides obtained in this way can be iso-lated without difficulty, for example by precipitation, forexample using non-polar organic solvents, followed by filt-ration, or by extraction, for example using n-butanol.
A possibly intended reduction of the S-oxides of the compounds of the formula I can be carried out according to processes known from the literature, for example by treat-ing the oxides with phosphorotrihalides, triphenylphosphine or phosphoropentasulfide.
The cephem compounds of the formula I can be alterna-tively converted into the physiologically acceptable esters of the formula I by subsequent esterification according to processes known from the literature. For example the acet-oxymethyl esters or the pivaloyloxymethyl esters may be ob-tained by reacting the alkali metal salts, preferably the sodium salts, or the ammonium salts, preferably the tri-ethylammonium salts, with the corresponding halogenomethyl-acyl compounds, such as chloromethylacetate, chloromethyl-propionate or pivaloylic acid chloromethyl ester.
A subsequènt esterification of the carboxy group can be dispensed with, as far as the esters, in particular the physiologically acceptable esters, are obtained during the acylation.
The esters directly obtained in the reaction in accor-dance with the present invention, such as the p-methoxyben-zyl esters, the p-nitrophenyl esters, the tert.-butyl esters or the benzhydryl esters, can alternatively be con verted lnto the free carboxylic acids of the ~ormula I in a manner known from the literature, for example by acid cleavage or hydrogenation.
, .. :
The salts are obtainable in known manner by reaction o~ the carboxylic acid with suitable bases.
The cephem derivatives of the formula I are valuable antibiotics which possess a surprisingly powerful action against Gram-positive and Gram-negative bacteria and which have an unexpectedly good action against penicillinase-for-ming Staphylococci.
The co~pounds of the invention can be used as such or in conjunction with the pharmaceutically usual auxiliaries and excipients, such as tragacanth, lactose, talc, solvents etc. in the form of galenical formulations, such as tablets, dragées, capsules, suspensions, solutions et.c., perorally, but preferably parenterally, the active ingredient being ge-nerally contained in an amount from approximately 50 to 1,000 mg, preferably from about 100 to 500 mg, in one indivivual dose.
The solvents used for parental application are those common for therapeutical use, in particular solvents dis-solved in water.
The compounds of the present invention can alternati-vely be combined with other active ingradients. For example other antibiotics, such as those of the series of the peni-cillins, cephalosporins, aminoglycoside antibiotics or com-pounds acting on the symptomatic of bacterial infections, such as antipyretics, antiphlogistics or analgetics, may be applied simultaneously with the compounds of the invention.
The following compounds may be prepared, by way of example, according to the present invention in addition to the cephem derivatives of the formula I, described in the examples:
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(2-ethyl-1,3,4-thiadiazol-5-yl)-thiome-- thyl-3-cephem-~-carboxylic acid 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(2-methyl-1,3,!l-thiadiazol-5-yl)-3-cephern-4-carboxylic acid pivaloyloxymetnyl ester - 12 - HOE 79/F ~87 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid 1-~-oxide 7-/~-syn-Methoximino-2-(1,3-thiazo'-4-yl~-acet~
amido7-3-(2-ethyl 113,4-oxdiazol-5-yl)-thiome-thyl-3-cephem-4-carboxylic acid 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7 3-(6-methoxy-pyridazin-3-yl)-thiomethyl-cephem-4-carboxylic acid 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-azidomethyl-3-cephem-4-carboxylic acid 1~-S-oxide Example 1 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet amido7-3~ thien-2-yl-1,3,4-triazol-5-yl7-thio-methyl-3-cephem-4-carboxylic acid 1.86 g of 2-syn-methoximino-2-(1,3-thia~ol-4-yl)-acetic acid are dissolved in 67 ml of dioxane. After adding 1.35 g of 1-hydroxybenzotriazole and 2.1 g of dicyclohexylcarbo-imide, the reaction mixture is stirred for 1 hour at room temperature. The precipitate of dicyclohexylurea is suc-tion-filtered. Next, a solution of 3.95 g of 7-amino-3 (2-thien-2-yl-1,3,4-triazol-5-yl)-thiomethyl-3-cephem-4~carb-oxylic acid and of 1.7 g of sodium bicarbonate in 50 ml ofwater is added to the filtrate and the mixture is stirred for 4 hours at room temperature. After removing the dioxane in the water jet vacuum, the pH is adjusted to 4 with 2N
hydrochlorid acid. Thus substantially 1-hydroxybenzotriazole precipitates. Upon acidification to pH 2 the title compound precipitates. It is subsequently washed with 50 m] portions of water, acetone and ether and dried in vacuo over phos~
phorus pentoxide.
.
5~
~iese l ~1( ~r~ Rf -value( ~ /Merck,n-butanol:water:acetic acid:
ethanol 10:4:3:3 V/V)= 0.4 NMR (d6-DMSO, 60 MHz) ~= 3.95 ppm tsinglet, 3 H,= N - OCH3) ~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2 - S -3 J= 5.17 ppm (doublet, 1 H, 6 - CH) ~= 5.79 ppm (quartet, 1 H, 7 - CH) ~= 7.1 - 7.6 ppm (multiplet, 3 H, thienyl) ~= 7.94 - 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.66 ppm (doublet, 1 H, -CONH) Example 2 7 ~ yn-Methoximino-?-(1,3-thiazol-4-yl)-acet-~mido7-3-azidomethyl-3-cep~em-4-carboxylic acid The title compound is obtained in analogous manner as in Example 1 by reacting equivalent quantities of 2-syn-meth-oximino-2-(1,3-thiazol-4-yl)-acetic acid as the activated ester with 7-amino-3-azido-methyl-3-cephem-4-carboxylic acid.
Rf-value (carrier material and solvent identical to those in Example 1) =0.3 : NMR (d6-DMSO, 60 MHz) S= 3.92 ppm (singlet, 3 H, - N OCH3) J= 4.17 ppm (AB-spectrum, 2 H, 3 - CH2N3) ~- 5.20 ppm (doublet, 1 H, 6-CH) J= 5.~7 ppm (quartet, 1 H, 7-CH) ~= 7.94 and 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.73 ppm (doublet, 1 H, - CONH - ) .
.
. .
- 14 _ HOE 79/F 087 Example 3 7-/2-syn-Methoximino-2-(1,3-thiazol-4 yl)-acetamido7-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carb-.... _ _ oxylic acid .
4.4 g of 7-J~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are dissolved in 10 ml of 1 N sodium hydroxide solution and in 50 ml of water. After adding 1.75 g of 2-mercapto-1-methyl-1H-tetrazole (sodium salt) dissolved in 25 ml of water, the reaction solution is stirred under nitrogen at 60C for 6 hours. After cooling, the pH is adjusted to 2 with 2N hydrochloric acid while cooling with ice. The precipitated title compound is washed with water and subsequently dried in ~acuo over phosphorus pentoxide.
Rf~value (kieselgel/Merck,n-BuOH:glacial acetic acid:water=
3:1:1 V/V) = 0.60 NMR (d6-DMSO, 60 MHz) ~= 4.0 ppm (singlet, 3 H, - N - OCH3) ~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2- S ) ~= 5.10 ppm (doublet, 1 H, 6-CH) ~- 5.76 ppm (quartet, 1 H, 7-CH) ~= 7.91 and 9.12 ppm (2 doublets, 2 H, thiazolyl) ~- 9.59 ppm (doublet, 1 H, - CONH - ) Example 4 7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-3-(2-methyl-1,3,4-tiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid 4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and 1.3 g of 5-mercapto-2-methyl-1,3,4-thiadiazole are suspended in 75 ml of water.
After carefully adding 20 ml of 1 N sodium hydroxide solu-tion while stirring, the mixture is subsequently heated to 15 - HOE 79/F 0~7 -80C for 2 hours, cooled with ice and acidified to pH 2 with hydrochloric acid. The precipitated title compound is suetion-filtered, thoroughly washed out with water and dried in vacuo over phosphorus pentoxide.
Rf(DC, carrier material and solvent as in Example 3) - 0.60 NMR Sd6-DMSO, 60 MHz) ~- 2.73 ppm ~singlet, 3 H, CH3) 10~= 3.96 ppm ~singlet., 3 H, ~ OCH
= 4.40 ppm (AB-spectrum, 2 H, 3 - CH2S-~
~= 5.2t ppm (doublet, 1 H, - 6 - CH) ~= 5.83 ppm (quartet, 1 H, 7 - CH -) J- 7.94 and 9.20 ppm (3 doublets, 2 H, thiazolyl) ~= 9.66 ppm (doublet, 1 H, - CINH - ) Example 5 7-/~-syn-Methoximino-2-(1,3-thiazo1-4-yl)-acetamido7-3-(1H-1-methyl-2-triflourmethyl-1,3,4-triazol-5-yl)-thio-methYl-3-cephem-4-carboxylic acid 4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-aeetamido7-cephalosporanie aeid are suspended in 50 ml of water and 10 ml of 1 N sodium hydroxide solution are added earefully while stirring. After adding 1.8 g of 5-mercapto 1H-1-methyl-2-trifluoromethyl-1,3,4-triazole, dissolved in 1~5 ml of water and 10 ml of 1 N sodium hydroxide solution, the solution is stirred under nitrogen at 50C for 10 hours. Subsequently its pH is adjusted to 2 while eooling with iee, the precipitated title compound is suction-fil-tered, washed thoroughly with water and dried in vacuo over phosphorus pentoxide.
Rf~value (DC,carrier material and solvent as in Example 1)-9.25 r ~ .
.' ': , ' .
L5~
NMR (d6-DMSO, 60 MHz) = 3.94 ppm (singlet, 3 H, = N ~ OCH3) ~ = 4.12 ppm (AB-spectrum, 2 H, 3-CH2-S~
~ = 5.13 ppm (doublet, 1 H, - 6 - CH) ~= 5.81 ppm (quartet, 1 H, 7 - CH) ~= 7.92 and 9.17 ppm (2 doublets, 2 H~ thiazolyl) ~= 9.68 ppm (doublet, 1 H, - CONH - ) Example 6 7-/2-syn-Methoximino-2-(1~3-thiazol-4-yl)-acetamido7-3-(4~6-diamino-pyrimidin-2-yl)-thiomethyl-3-cephem-4-carb-___ _ _ _ _ .._...._ oxylic acid The title compound is obtained in analogous manner as in Example 3 by reacting equivalent quantities of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and 4,6-diamino-2-mercapto-pyrimidine.
Rf-value (DC-solvent as in Example 1)= 0.24 NMR (d6-DMSO, 60 MHz) ~ = 3.94 ppm (singlet, 3 H, = N - OCH3) d= 5.17 ppm (doublet, 1 H, 6 - CH) ~= 5.79 ppm (quartet, 1 H, 7 - CH) ~= 6.15 ppm (singlet, 1 H, pyrimidine) ~= 6.38 ppm (singlet, 4 H, diamino ) ~= 7.92 and 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.63 ppm (doublet, 1 H, - CONH - ) `' ~ , ,'-, i' ' ' . ., . ' ' ,. .1. ' . ' ,~ , ,' ' .
: - . .. -, . . . ~. , ~ , , E mple 7_ 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-3-(5-carboxymethyl-4-methyl-thiazol-2-yl)-thiometh~1-3-cephem-4-carboxylic acid The title compound is obtained in analogous manner as in Example 3 by reacting equivalent quantities of 7-/~-syn-methoximino-2-(1,3-thiazol-4-yl~-acetamido7-cephalo-sporanic acid and of 5-carboxy-methyl-2-mercapto-4-methyl-thiazole.
Rf-value:(kieselgel/Merck,acetone:glacial acetic acid =
20:1, V/V) _ 0.32 NMR (d6-DMSO, 60 MH~
~= 2.20 ppm (singlet, 3 H, 4-CH3) J= 3.89 ppm (singlet, 3 H, = N - OCH3) ~= 5.10 ppm (doublet, 1 H, 6 - CH) J= 7.88 and 9.10 ppm (2 doublets, 2 H, thiazolyl) ~= 9~58 ppm (doublet, 1 H, - CO - NH - ) Example 8 7-/2-syn-Methoximino-2-(1 3-thiazol-4-yl)-acetamido7-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid To a suspension of 7.4 g of 2-syn-methoxymino-2-(1~3-thiazol-4-yl)-acetic acid in 75 ml of methylene chloride there is added 3.6 ml of dimethylacetamide at -10C with the exclusion of humidity and subsequently at -1QC there is added dropwise 25 ml of a 21.3 ~ phosgene solution in toluene, in 15 minutes. The reaction mixture is stirred for 2 hours, while the 2-syn~methoxymino-2 (1,3-thiazol~4-yl)~
acetic acid chloride is formed. Next, a solution of 13.1 g of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-ce-phem -4-&arboxylic acid in 200 ml of methylene chloride, 10.3 ml of triethylamine and 6.8 g of pyrolidone is added 5~
- 18 - HOE 79/F o87 dropwise at -1~C to the reaction mixture. The reaction mixture is stirred for 2 hours at -5~C. After adding wa-ter to the organic phase, its pH is adjusted to 7. The aqueous phase is separated and its pH is adjusted to 3.5.
The precipitated product is separated and its pH is adjus-ted to 1 with acidification. The title compound precipita-tes as an amorphous solid, which is isolated, washed with water and dried over P205 in a high vacuum. According to the thin layer chromatogram, to NMR and IR, the resulting compound is identical to that obtained in Example 3.
Example 9 7-/2-syn-Methoximino-2-(1,3-thiaz 1-4-yl)-acetamido7-3-(2-methyl-1,3,4-oxdiazol-5-yl)-thiomethyl-3-cephem-4-carb-.
oxylic acid 580 mg of 2-mercapto-5-methyl-1,3,4-oxadiazole are add-ed to a solution of 1,32 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and of 0.75 g of sodium bicarbonate in a mixture of 30 ml of water and of 10 ml of acetone. The reaction mixture is heated to 65C for 6 hours. The acetone is removed in vacuo, the pH
of the aqueous solution is adjusted to 4 with acidification and the excess oxadiazole is removed with ether. The pH of the aqueous phase is adjusted to 1.5 with acidification, with the title compound precipitating in the form of cream-colored crystals, which are washed with water and ether subse~uently and dried in vacuo over phosphorus pentoxide.
Rf-value(kieselgel/Merck, n-BuOH:water:glacial acetic acid:
ethanol 10:4:3:3 V/V) _ 0.34 NMR (CF3COOD, 60 MHz) ~= 2.88 ppm (singlet, 3 H, CH3-oxdiazolyl) ~_ 3.88 ppm (broadened singlet, 2 H, S - CH2) ~= 4.45 ppm (singlet, 3 H, = N - OCH3)~
~= 4.55 ppm (AB, 2 H, 3-CH2-S-)*
* total integration 5 H
.
~= 5.33 ppm (doublet, 1 H, 6-CH) ~= 6.10 ppm (doublet, 1 H, 7-CH) ~= 8.66 ppm (doublet, 1 H, 2. thiazol-H in CF3COOD
thiazol-H in d6-DMSO, 60 MHz : 7.90 and 9.13 (2 doublets, 2 H) Example 10 7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7 3-(benzthiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid 1.32 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are dissolved in 30 ml of water and 10 ml of acetone with 0.75 g of sodium bicarbonate and 0.85 g of 2-mercaptobenzthiazole is added whi.le stirr-ing. The reaction mixture is stirred for 6 hours at 65C,subsequently cooled, acidified to a pH of 1 and extracted several times ~ith methylene chloride. The combined ex-tracts are dried with sodium sulfate and concentrated. The residue is digested with ether, leaving a cream-colored solid, which is isolated, washed with ether and dried over P2O5 in a high vacuum.
Rf-value(DC, carrier material and solvent as in Example 1)=
~.53 NMR: (d6-DMSO, 60 MHz) J= 3.g2 ppm (singlet, 3 H, - NOCH3) ~= 4.53 ppm (AB-spectrum, 2 H, -CH2~S) ~= 5.12 ppm (doublet, 1 H, 6-CH) ~= 5.76 ppm (quartet, 1 H, 7-CH) ~= 7.2 - 8.1 ppm (multiplet, 4 H, benzthiazole and doublet 7.90 1 H, thiazolyl) ~= 9.13 ppm (doublet9 1 H, thiazolyl) ~= 9.65 ppm ~doublet, 1 H, CONH) :
Example 11 7~ syn-Methoximino-2-(1,3-thiazol~4-yl)-acetamido7-3-(6-hydroxy-pyridazin -3-yl)-thiomethyl-3-cephem-4-carboxylic acid 7-/~-syn-methoximino 2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are reacted with 6-hydroxy-3-mercapto-pyridazine in the manner described in Example 10. The title compound is obtained upon extraction with acetic ester and digestion with ether in the form of a beige-colored solid.
4-carboxylic acid ~f-value (kieselgel/Merck, solvent of Example 1~ = 0.35 NMR (d6-DMSO, 60 MHz) J= 3.90 ppm (singlet, 3 H, = NOCH3) ~= 4.50 ppm (AB-spectrum, 2 H, -CH2-S) ~= 5.12 ppm (doublet, 1 H, 6-CH) ~= 5.70 ppm (quartet, 1 H, 7-CH) ~= 6.88 and 7.65 ppm (2 doublets, each 1 H, pyridazinyl) ~= 7.90 and 9.05 ppm (2 doublets, each 1 H, thiazolyl) J. 9 . 45 ppm (doublet, 1 H, CONH) --~.
.....
Activation of the carboxylic acid has to be carried out under reaction conditions as mild as possible, such as are described in the literature for analogous reactions, to prevent any possible flipping over the syn-oxime into the trans-oxime derivative represented by the following formula:
~C----COOE~
~ /
- C~30 Activation should be carried out at a temperature as low as possible in the range from approximately -50 to ~50C, preferably from -20 to ~20C. Suitably rather acid reaction conditions should moreover be avoided.
The cephem carboxylic acids of the formula III can be dissolved in various manner, for example by adding bases or by conversion into silyl esters. The silylation agents may be any common reagents, in particular the trimethylchloro-silane which is used in the presence of a stoichiometrical quantity of a base, or especially preferably the O,N-bis- `
trimethylsilylacetamide which may be used without the addi-tion of a base. For attaining good yields the silylation agent is suitably used in a ratio of approximakely 2 equi-valents of a silyl compound per mol of cephem cornpound of the formula III.
Suitable bases which can be used for dissolving a 35 great number of 7-amino-~ 3-cephem-4-carboxylic acids, are inorganic or organic bases. Thus, tertiary amines, such as triethylamine, N,N-dimethylaniline or N-methylmorpholine, , 5~
have proved partlcularly suitable for the preparation Or ~ solutions in organic solvents.
In general the bases are added in an at least stoi-chiometrical amount, relative to the desired reaction. An excess of base of, for example a~out 20 to 80 ~, can be advantageous.
In the case of compounds of the formula III which are sensitive towards bases, the pH can be kept constant at about 4 to 8, preferably 6 to 7, depending on the reaction course, by continuously adding the base.
The compounds of the formula III can be dissolved in a wide temperature range. However, in the case of derivatives that are sensitive towards bases, it is advisable to choose a temperature range from about O to 15C.
The acylation of the cephem compounds of the formula III with the 2-t1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid can be carried out under variable experimental condi-tions, for example, using various solvents. Examples of suitable solvents are organic solvents, such as halogenated hydrocarbons, for example methylene chloride or chloroform, but also tertiary amines, such as dimethylformamide or ~imethylacetamide.
If cephem esters of the formula III are used, the re-action is carried out in organic solvents, in which most of`
the esters are readily soluble. Examples of such solvents are likewise halogenated hydrocarbons or the tertiary amides.
Examples of suitable esters are compounds of the for~
mula III, in which R4 in the ester group -CooR4 may stand for straight-chain or branched alkyl with 1 to 6 carbon atoms, for example methyl, ethyl, tert.-butyl, isoamyl or hexyl, it being possible for the alkyl group to be further substituted, preferably in ~-position, for example by tri-chloromethyl, acyloxy with 1 to 6 carbon atoms, preferably acetoxy or pivaloyloxy, or by one or two phenyl radicals, it being possible for the latter to be substituted by alk-oxy with 1 to 4 carbon atoms, preferably methoxy, or nitro, .
or R4 may starld for the phthalide group. Examples of the above definitions are the tert.-butyl esters, the trichlo-roethyl esters, the p-methoxybenzyl esters, the benzhydryl esters, the acetoxymethyl esters, the 1-acetoxyethyl esters, the 1-propionyloxypropyl esters, the 1-acetoxy-n-butyl esters, the pivyloyloxymethyl esters or the phthalide esters.
The activated 2-(1t3-thiazol-4-yl)-2 syn-methoximino-acetic acid is added to the cephem derivatives of the for-mula III present in dissolved or suspended state or toesters thereof, in dissolved state or suspended in an inert solvent or in substance.
The reaction temperature depends greatly on the reacti-vity of the activated 2-(1,3-thiazol-4-yl)-2-syn-methoximi-noacetic acid, a temperature interval from approximately -50 to ~50C having proved advantageous, a temperature from approximately -20 to +20C being particularly advantageous.
In order to reach higher yields, the activated acid derivative is used in an at least stoichiometrical amount, excess from approximately 5 to 25 % being possibly advan-tageous~
The final products obtained upon acylation are isolat-ed in known rnanner, for example such as are described here-inbefore for the final products obtained by exchange of the acetoxy group. For example, if the symmetrical anhydride of the 2-(1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid has been used, the side chain acid liberated during the acyla-tion may be separated, for example by extraction or preci-pitation.
The compounds of the formula I wherein n is 1 can beprepared alternatively by oxidizing compounds of the f`ormula I wherein n is 0.
The oxidation of the sulfur in the cephem ring has been described repeatedly. This oxidation may yield ~- and ~-oxides (Cf. E. Flynn, Cephalosporins and Penicillins, Chemistry and Biology, Academic Press, 1972, pages 135 et se~.), depending on the oxidant used.
~ ` .
- 10 - ~OE 79/F 087 For example, if peracetic acid is used in glacial ace-tic acid, there are obtained R-S-oxides. The reaction tem-perature is not critical. It is,however, advisable to carry out oxidation at room temperature, in order to avoid unde-sired sequence reactions, and to add the oxidant in an atleast stoichiometri.cal amount, an excess from 10 to 100 %
being frequently advantageous, as long as the temperature of the reaction is not increased substantially.
The cephem-S-oxides obtained in this way can be iso-lated without difficulty, for example by precipitation, forexample using non-polar organic solvents, followed by filt-ration, or by extraction, for example using n-butanol.
A possibly intended reduction of the S-oxides of the compounds of the formula I can be carried out according to processes known from the literature, for example by treat-ing the oxides with phosphorotrihalides, triphenylphosphine or phosphoropentasulfide.
The cephem compounds of the formula I can be alterna-tively converted into the physiologically acceptable esters of the formula I by subsequent esterification according to processes known from the literature. For example the acet-oxymethyl esters or the pivaloyloxymethyl esters may be ob-tained by reacting the alkali metal salts, preferably the sodium salts, or the ammonium salts, preferably the tri-ethylammonium salts, with the corresponding halogenomethyl-acyl compounds, such as chloromethylacetate, chloromethyl-propionate or pivaloylic acid chloromethyl ester.
A subsequènt esterification of the carboxy group can be dispensed with, as far as the esters, in particular the physiologically acceptable esters, are obtained during the acylation.
The esters directly obtained in the reaction in accor-dance with the present invention, such as the p-methoxyben-zyl esters, the p-nitrophenyl esters, the tert.-butyl esters or the benzhydryl esters, can alternatively be con verted lnto the free carboxylic acids of the ~ormula I in a manner known from the literature, for example by acid cleavage or hydrogenation.
, .. :
The salts are obtainable in known manner by reaction o~ the carboxylic acid with suitable bases.
The cephem derivatives of the formula I are valuable antibiotics which possess a surprisingly powerful action against Gram-positive and Gram-negative bacteria and which have an unexpectedly good action against penicillinase-for-ming Staphylococci.
The co~pounds of the invention can be used as such or in conjunction with the pharmaceutically usual auxiliaries and excipients, such as tragacanth, lactose, talc, solvents etc. in the form of galenical formulations, such as tablets, dragées, capsules, suspensions, solutions et.c., perorally, but preferably parenterally, the active ingredient being ge-nerally contained in an amount from approximately 50 to 1,000 mg, preferably from about 100 to 500 mg, in one indivivual dose.
The solvents used for parental application are those common for therapeutical use, in particular solvents dis-solved in water.
The compounds of the present invention can alternati-vely be combined with other active ingradients. For example other antibiotics, such as those of the series of the peni-cillins, cephalosporins, aminoglycoside antibiotics or com-pounds acting on the symptomatic of bacterial infections, such as antipyretics, antiphlogistics or analgetics, may be applied simultaneously with the compounds of the invention.
The following compounds may be prepared, by way of example, according to the present invention in addition to the cephem derivatives of the formula I, described in the examples:
7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(2-ethyl-1,3,4-thiadiazol-5-yl)-thiome-- thyl-3-cephem-~-carboxylic acid 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(2-methyl-1,3,!l-thiadiazol-5-yl)-3-cephern-4-carboxylic acid pivaloyloxymetnyl ester - 12 - HOE 79/F ~87 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid 1-~-oxide 7-/~-syn-Methoximino-2-(1,3-thiazo'-4-yl~-acet~
amido7-3-(2-ethyl 113,4-oxdiazol-5-yl)-thiome-thyl-3-cephem-4-carboxylic acid 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7 3-(6-methoxy-pyridazin-3-yl)-thiomethyl-cephem-4-carboxylic acid 7-/~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet-amido7-3-azidomethyl-3-cephem-4-carboxylic acid 1~-S-oxide Example 1 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acet amido7-3~ thien-2-yl-1,3,4-triazol-5-yl7-thio-methyl-3-cephem-4-carboxylic acid 1.86 g of 2-syn-methoximino-2-(1,3-thia~ol-4-yl)-acetic acid are dissolved in 67 ml of dioxane. After adding 1.35 g of 1-hydroxybenzotriazole and 2.1 g of dicyclohexylcarbo-imide, the reaction mixture is stirred for 1 hour at room temperature. The precipitate of dicyclohexylurea is suc-tion-filtered. Next, a solution of 3.95 g of 7-amino-3 (2-thien-2-yl-1,3,4-triazol-5-yl)-thiomethyl-3-cephem-4~carb-oxylic acid and of 1.7 g of sodium bicarbonate in 50 ml ofwater is added to the filtrate and the mixture is stirred for 4 hours at room temperature. After removing the dioxane in the water jet vacuum, the pH is adjusted to 4 with 2N
hydrochlorid acid. Thus substantially 1-hydroxybenzotriazole precipitates. Upon acidification to pH 2 the title compound precipitates. It is subsequently washed with 50 m] portions of water, acetone and ether and dried in vacuo over phos~
phorus pentoxide.
.
5~
~iese l ~1( ~r~ Rf -value( ~ /Merck,n-butanol:water:acetic acid:
ethanol 10:4:3:3 V/V)= 0.4 NMR (d6-DMSO, 60 MHz) ~= 3.95 ppm tsinglet, 3 H,= N - OCH3) ~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2 - S -3 J= 5.17 ppm (doublet, 1 H, 6 - CH) ~= 5.79 ppm (quartet, 1 H, 7 - CH) ~= 7.1 - 7.6 ppm (multiplet, 3 H, thienyl) ~= 7.94 - 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.66 ppm (doublet, 1 H, -CONH) Example 2 7 ~ yn-Methoximino-?-(1,3-thiazol-4-yl)-acet-~mido7-3-azidomethyl-3-cep~em-4-carboxylic acid The title compound is obtained in analogous manner as in Example 1 by reacting equivalent quantities of 2-syn-meth-oximino-2-(1,3-thiazol-4-yl)-acetic acid as the activated ester with 7-amino-3-azido-methyl-3-cephem-4-carboxylic acid.
Rf-value (carrier material and solvent identical to those in Example 1) =0.3 : NMR (d6-DMSO, 60 MHz) S= 3.92 ppm (singlet, 3 H, - N OCH3) J= 4.17 ppm (AB-spectrum, 2 H, 3 - CH2N3) ~- 5.20 ppm (doublet, 1 H, 6-CH) J= 5.~7 ppm (quartet, 1 H, 7-CH) ~= 7.94 and 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.73 ppm (doublet, 1 H, - CONH - ) .
.
. .
- 14 _ HOE 79/F 087 Example 3 7-/2-syn-Methoximino-2-(1,3-thiazol-4 yl)-acetamido7-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carb-.... _ _ oxylic acid .
4.4 g of 7-J~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are dissolved in 10 ml of 1 N sodium hydroxide solution and in 50 ml of water. After adding 1.75 g of 2-mercapto-1-methyl-1H-tetrazole (sodium salt) dissolved in 25 ml of water, the reaction solution is stirred under nitrogen at 60C for 6 hours. After cooling, the pH is adjusted to 2 with 2N hydrochloric acid while cooling with ice. The precipitated title compound is washed with water and subsequently dried in ~acuo over phosphorus pentoxide.
Rf~value (kieselgel/Merck,n-BuOH:glacial acetic acid:water=
3:1:1 V/V) = 0.60 NMR (d6-DMSO, 60 MHz) ~= 4.0 ppm (singlet, 3 H, - N - OCH3) ~= 4.25 ppm (AB-spectrum, 2 H, 3 - CH2- S ) ~= 5.10 ppm (doublet, 1 H, 6-CH) ~- 5.76 ppm (quartet, 1 H, 7-CH) ~= 7.91 and 9.12 ppm (2 doublets, 2 H, thiazolyl) ~- 9.59 ppm (doublet, 1 H, - CONH - ) Example 4 7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-3-(2-methyl-1,3,4-tiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid 4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and 1.3 g of 5-mercapto-2-methyl-1,3,4-thiadiazole are suspended in 75 ml of water.
After carefully adding 20 ml of 1 N sodium hydroxide solu-tion while stirring, the mixture is subsequently heated to 15 - HOE 79/F 0~7 -80C for 2 hours, cooled with ice and acidified to pH 2 with hydrochloric acid. The precipitated title compound is suetion-filtered, thoroughly washed out with water and dried in vacuo over phosphorus pentoxide.
Rf(DC, carrier material and solvent as in Example 3) - 0.60 NMR Sd6-DMSO, 60 MHz) ~- 2.73 ppm ~singlet, 3 H, CH3) 10~= 3.96 ppm ~singlet., 3 H, ~ OCH
= 4.40 ppm (AB-spectrum, 2 H, 3 - CH2S-~
~= 5.2t ppm (doublet, 1 H, - 6 - CH) ~= 5.83 ppm (quartet, 1 H, 7 - CH -) J- 7.94 and 9.20 ppm (3 doublets, 2 H, thiazolyl) ~= 9.66 ppm (doublet, 1 H, - CINH - ) Example 5 7-/~-syn-Methoximino-2-(1,3-thiazo1-4-yl)-acetamido7-3-(1H-1-methyl-2-triflourmethyl-1,3,4-triazol-5-yl)-thio-methYl-3-cephem-4-carboxylic acid 4.4 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-aeetamido7-cephalosporanie aeid are suspended in 50 ml of water and 10 ml of 1 N sodium hydroxide solution are added earefully while stirring. After adding 1.8 g of 5-mercapto 1H-1-methyl-2-trifluoromethyl-1,3,4-triazole, dissolved in 1~5 ml of water and 10 ml of 1 N sodium hydroxide solution, the solution is stirred under nitrogen at 50C for 10 hours. Subsequently its pH is adjusted to 2 while eooling with iee, the precipitated title compound is suction-fil-tered, washed thoroughly with water and dried in vacuo over phosphorus pentoxide.
Rf~value (DC,carrier material and solvent as in Example 1)-9.25 r ~ .
.' ': , ' .
L5~
NMR (d6-DMSO, 60 MHz) = 3.94 ppm (singlet, 3 H, = N ~ OCH3) ~ = 4.12 ppm (AB-spectrum, 2 H, 3-CH2-S~
~ = 5.13 ppm (doublet, 1 H, - 6 - CH) ~= 5.81 ppm (quartet, 1 H, 7 - CH) ~= 7.92 and 9.17 ppm (2 doublets, 2 H~ thiazolyl) ~= 9.68 ppm (doublet, 1 H, - CONH - ) Example 6 7-/2-syn-Methoximino-2-(1~3-thiazol-4-yl)-acetamido7-3-(4~6-diamino-pyrimidin-2-yl)-thiomethyl-3-cephem-4-carb-___ _ _ _ _ .._...._ oxylic acid The title compound is obtained in analogous manner as in Example 3 by reacting equivalent quantities of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and 4,6-diamino-2-mercapto-pyrimidine.
Rf-value (DC-solvent as in Example 1)= 0.24 NMR (d6-DMSO, 60 MHz) ~ = 3.94 ppm (singlet, 3 H, = N - OCH3) d= 5.17 ppm (doublet, 1 H, 6 - CH) ~= 5.79 ppm (quartet, 1 H, 7 - CH) ~= 6.15 ppm (singlet, 1 H, pyrimidine) ~= 6.38 ppm (singlet, 4 H, diamino ) ~= 7.92 and 9.17 ppm (2 doublets, 2 H, thiazolyl) ~= 9.63 ppm (doublet, 1 H, - CONH - ) `' ~ , ,'-, i' ' ' . ., . ' ' ,. .1. ' . ' ,~ , ,' ' .
: - . .. -, . . . ~. , ~ , , E mple 7_ 7-~-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7-3-(5-carboxymethyl-4-methyl-thiazol-2-yl)-thiometh~1-3-cephem-4-carboxylic acid The title compound is obtained in analogous manner as in Example 3 by reacting equivalent quantities of 7-/~-syn-methoximino-2-(1,3-thiazol-4-yl~-acetamido7-cephalo-sporanic acid and of 5-carboxy-methyl-2-mercapto-4-methyl-thiazole.
Rf-value:(kieselgel/Merck,acetone:glacial acetic acid =
20:1, V/V) _ 0.32 NMR (d6-DMSO, 60 MH~
~= 2.20 ppm (singlet, 3 H, 4-CH3) J= 3.89 ppm (singlet, 3 H, = N - OCH3) ~= 5.10 ppm (doublet, 1 H, 6 - CH) J= 7.88 and 9.10 ppm (2 doublets, 2 H, thiazolyl) ~= 9~58 ppm (doublet, 1 H, - CO - NH - ) Example 8 7-/2-syn-Methoximino-2-(1 3-thiazol-4-yl)-acetamido7-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid To a suspension of 7.4 g of 2-syn-methoxymino-2-(1~3-thiazol-4-yl)-acetic acid in 75 ml of methylene chloride there is added 3.6 ml of dimethylacetamide at -10C with the exclusion of humidity and subsequently at -1QC there is added dropwise 25 ml of a 21.3 ~ phosgene solution in toluene, in 15 minutes. The reaction mixture is stirred for 2 hours, while the 2-syn~methoxymino-2 (1,3-thiazol~4-yl)~
acetic acid chloride is formed. Next, a solution of 13.1 g of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-ce-phem -4-&arboxylic acid in 200 ml of methylene chloride, 10.3 ml of triethylamine and 6.8 g of pyrolidone is added 5~
- 18 - HOE 79/F o87 dropwise at -1~C to the reaction mixture. The reaction mixture is stirred for 2 hours at -5~C. After adding wa-ter to the organic phase, its pH is adjusted to 7. The aqueous phase is separated and its pH is adjusted to 3.5.
The precipitated product is separated and its pH is adjus-ted to 1 with acidification. The title compound precipita-tes as an amorphous solid, which is isolated, washed with water and dried over P205 in a high vacuum. According to the thin layer chromatogram, to NMR and IR, the resulting compound is identical to that obtained in Example 3.
Example 9 7-/2-syn-Methoximino-2-(1,3-thiaz 1-4-yl)-acetamido7-3-(2-methyl-1,3,4-oxdiazol-5-yl)-thiomethyl-3-cephem-4-carb-.
oxylic acid 580 mg of 2-mercapto-5-methyl-1,3,4-oxadiazole are add-ed to a solution of 1,32 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid and of 0.75 g of sodium bicarbonate in a mixture of 30 ml of water and of 10 ml of acetone. The reaction mixture is heated to 65C for 6 hours. The acetone is removed in vacuo, the pH
of the aqueous solution is adjusted to 4 with acidification and the excess oxadiazole is removed with ether. The pH of the aqueous phase is adjusted to 1.5 with acidification, with the title compound precipitating in the form of cream-colored crystals, which are washed with water and ether subse~uently and dried in vacuo over phosphorus pentoxide.
Rf-value(kieselgel/Merck, n-BuOH:water:glacial acetic acid:
ethanol 10:4:3:3 V/V) _ 0.34 NMR (CF3COOD, 60 MHz) ~= 2.88 ppm (singlet, 3 H, CH3-oxdiazolyl) ~_ 3.88 ppm (broadened singlet, 2 H, S - CH2) ~= 4.45 ppm (singlet, 3 H, = N - OCH3)~
~= 4.55 ppm (AB, 2 H, 3-CH2-S-)*
* total integration 5 H
.
~= 5.33 ppm (doublet, 1 H, 6-CH) ~= 6.10 ppm (doublet, 1 H, 7-CH) ~= 8.66 ppm (doublet, 1 H, 2. thiazol-H in CF3COOD
thiazol-H in d6-DMSO, 60 MHz : 7.90 and 9.13 (2 doublets, 2 H) Example 10 7-/2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido7 3-(benzthiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid 1.32 g of 7-/2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are dissolved in 30 ml of water and 10 ml of acetone with 0.75 g of sodium bicarbonate and 0.85 g of 2-mercaptobenzthiazole is added whi.le stirr-ing. The reaction mixture is stirred for 6 hours at 65C,subsequently cooled, acidified to a pH of 1 and extracted several times ~ith methylene chloride. The combined ex-tracts are dried with sodium sulfate and concentrated. The residue is digested with ether, leaving a cream-colored solid, which is isolated, washed with ether and dried over P2O5 in a high vacuum.
Rf-value(DC, carrier material and solvent as in Example 1)=
~.53 NMR: (d6-DMSO, 60 MHz) J= 3.g2 ppm (singlet, 3 H, - NOCH3) ~= 4.53 ppm (AB-spectrum, 2 H, -CH2~S) ~= 5.12 ppm (doublet, 1 H, 6-CH) ~= 5.76 ppm (quartet, 1 H, 7-CH) ~= 7.2 - 8.1 ppm (multiplet, 4 H, benzthiazole and doublet 7.90 1 H, thiazolyl) ~= 9.13 ppm (doublet9 1 H, thiazolyl) ~= 9.65 ppm ~doublet, 1 H, CONH) :
Example 11 7~ syn-Methoximino-2-(1,3-thiazol~4-yl)-acetamido7-3-(6-hydroxy-pyridazin -3-yl)-thiomethyl-3-cephem-4-carboxylic acid 7-/~-syn-methoximino 2-(1,3-thiazol-4-yl)-acetamido7-cephalosporanic acid are reacted with 6-hydroxy-3-mercapto-pyridazine in the manner described in Example 10. The title compound is obtained upon extraction with acetic ester and digestion with ether in the form of a beige-colored solid.
4-carboxylic acid ~f-value (kieselgel/Merck, solvent of Example 1~ = 0.35 NMR (d6-DMSO, 60 MHz) J= 3.90 ppm (singlet, 3 H, = NOCH3) ~= 4.50 ppm (AB-spectrum, 2 H, -CH2-S) ~= 5.12 ppm (doublet, 1 H, 6-CH) ~= 5.70 ppm (quartet, 1 H, 7-CH) ~= 6.88 and 7.65 ppm (2 doublets, each 1 H, pyridazinyl) ~= 7.90 and 9.05 ppm (2 doublets, each 1 H, thiazolyl) J. 9 . 45 ppm (doublet, 1 H, CONH) --~.
.....
Claims (8)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a cephem compound of the formula I
I
wherein R2 is azido or a radical -SR3, wherein R3 is a 5-membered hetero-cycle with 1 to 4 nitrogen atoms and which may contain a sulfur atom, a 5-membered heterocycle with 1 to 2 nitrogen atoms and an oxygen atom or a 6-membered heterocycle with 1 to 3 nitrogen atoms and which may contain a sulfur atom, and wherein these heterocycles may carry a fused benzene nucleus and may be substituted by alkyl with 1 to 4 carbon atoms, trifluoromethyl, carboxymethyl, hydroxy, amino, alkylamino with 1 to 4 carbon atoms in the alkyl part, dialkylamino with 1 to 4 carbon atoms each in the alkyl part, phenyl or by a 5- or 6-membered heterocycle, containing 1 to 2 nitrogen atoms and which also may contain a sulfur or oxygen atom, and wherein R3 may also be alkyl with 1 to 4 carbon atoms or aliphatic acyl with 1 to 4 carbon atoms, the methoximino group being in syn-position and pharmacologically acceptable salts and esters thereof, in which (a) a cephem compound of the formula II
II
is reacted, in the presence of a solvent and a base, with an azide or with a compound of the formula HSR3, wherein R3 is as defined above, or (b) a cephem compound of the formula III in the form of its salts or esters III
wherein R2 is as defined above, is reacted with a reactive derivative of 2-(1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid and, if desired, in the compunds obtained according to (a) or (b) .alpha.) a salt obtained is converted into the free carboxylic acid and the latter may be further esterified or .beta.) a salt obtained is converted directly into an ester or ?) an ester obtained is saponified to yield a carboxylic acid which may be converted into a salt.
I
wherein R2 is azido or a radical -SR3, wherein R3 is a 5-membered hetero-cycle with 1 to 4 nitrogen atoms and which may contain a sulfur atom, a 5-membered heterocycle with 1 to 2 nitrogen atoms and an oxygen atom or a 6-membered heterocycle with 1 to 3 nitrogen atoms and which may contain a sulfur atom, and wherein these heterocycles may carry a fused benzene nucleus and may be substituted by alkyl with 1 to 4 carbon atoms, trifluoromethyl, carboxymethyl, hydroxy, amino, alkylamino with 1 to 4 carbon atoms in the alkyl part, dialkylamino with 1 to 4 carbon atoms each in the alkyl part, phenyl or by a 5- or 6-membered heterocycle, containing 1 to 2 nitrogen atoms and which also may contain a sulfur or oxygen atom, and wherein R3 may also be alkyl with 1 to 4 carbon atoms or aliphatic acyl with 1 to 4 carbon atoms, the methoximino group being in syn-position and pharmacologically acceptable salts and esters thereof, in which (a) a cephem compound of the formula II
II
is reacted, in the presence of a solvent and a base, with an azide or with a compound of the formula HSR3, wherein R3 is as defined above, or (b) a cephem compound of the formula III in the form of its salts or esters III
wherein R2 is as defined above, is reacted with a reactive derivative of 2-(1,3-thiazol-4-yl)-2-syn-methoximinoacetic acid and, if desired, in the compunds obtained according to (a) or (b) .alpha.) a salt obtained is converted into the free carboxylic acid and the latter may be further esterified or .beta.) a salt obtained is converted directly into an ester or ?) an ester obtained is saponified to yield a carboxylic acid which may be converted into a salt.
2. A process as claimed in claim 1 in which the compounds of the formula II and of the formula HSR3 are used in the form of their salts.
3. A process as claimed 1 in which the preparation is carried out according to reaction (a).
4. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b).
6. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of 7-[2-syn-methoximino-2-(1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid in which 7-[2-syn-methoximino-2-(l,3-thiazol-4-yl)-acetamido]-cephalosporanic acid is reacted in the presence of a base with the sodium salt of 2-mercapto-1-methyl-1H-tetrazole and the resultant product is subsequently isolated.
8. 7-[2-syn-Methoximino-2-(1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792914327 DE2914327A1 (en) | 1979-04-09 | 1979-04-09 | CEPHEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| DEP2914327.9 | 1979-04-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151151A true CA1151151A (en) | 1983-08-02 |
Family
ID=6067880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000349333A Expired CA1151151A (en) | 1979-04-09 | 1980-04-08 | Cephem derivatives and process for their manufacture |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0017238B1 (en) |
| JP (1) | JPS55141490A (en) |
| AT (1) | ATE2793T1 (en) |
| CA (1) | CA1151151A (en) |
| DE (2) | DE2914327A1 (en) |
| ES (2) | ES8200372A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4705784A (en) * | 1983-12-21 | 1987-11-10 | Sumitomo Pharmaceuticals Company, Limited | Cephem compounds |
| US4761409A (en) * | 1984-08-16 | 1988-08-02 | Sumitomo Pharmaceuticals Company, Limited | Cephem derivatives |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE53429B1 (en) * | 1981-08-03 | 1988-11-09 | Fujisawa Pharmaceutical Co | New cephem compounds and processes for preparation thereof |
| US4499088A (en) * | 1983-01-04 | 1985-02-12 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1399086A (en) * | 1971-05-14 | 1975-06-25 | Glaxo Lab Ltd | Cephalosporin compounds |
| DE2822860A1 (en) * | 1978-05-26 | 1979-11-29 | Hoechst Ag | CEPHEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
-
1979
- 1979-04-09 DE DE19792914327 patent/DE2914327A1/en not_active Withdrawn
-
1980
- 1980-04-01 ES ES490163A patent/ES8200372A1/en not_active Expired
- 1980-04-03 EP EP80101800A patent/EP0017238B1/en not_active Expired
- 1980-04-03 AT AT80101800T patent/ATE2793T1/en not_active IP Right Cessation
- 1980-04-03 DE DE8080101800T patent/DE3062318D1/en not_active Expired
- 1980-04-08 CA CA000349333A patent/CA1151151A/en not_active Expired
- 1980-04-09 JP JP4578580A patent/JPS55141490A/en active Pending
- 1980-12-11 ES ES497635A patent/ES8200693A1/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4705784A (en) * | 1983-12-21 | 1987-11-10 | Sumitomo Pharmaceuticals Company, Limited | Cephem compounds |
| US4761409A (en) * | 1984-08-16 | 1988-08-02 | Sumitomo Pharmaceuticals Company, Limited | Cephem derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ES490163A0 (en) | 1981-10-16 |
| ES497635A0 (en) | 1981-11-01 |
| JPS55141490A (en) | 1980-11-05 |
| EP0017238B1 (en) | 1983-03-16 |
| DE2914327A1 (en) | 1980-10-30 |
| ATE2793T1 (en) | 1983-04-15 |
| ES8200693A1 (en) | 1981-11-01 |
| ES8200372A1 (en) | 1981-10-16 |
| EP0017238A1 (en) | 1980-10-15 |
| DE3062318D1 (en) | 1983-04-21 |
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