GB2102423A - Cephalosporin derivatives - Google Patents

Cephalosporin derivatives Download PDF

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GB2102423A
GB2102423A GB08220930A GB8220930A GB2102423A GB 2102423 A GB2102423 A GB 2102423A GB 08220930 A GB08220930 A GB 08220930A GB 8220930 A GB8220930 A GB 8220930A GB 2102423 A GB2102423 A GB 2102423A
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hydrazonocephem
derivatives
tetrazol
methyl
aminothiazol
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Piero Bellani
Giordano Bruno Corsi
Sergio Innocenti
Giampietro Broccali
Umberto Valcavi
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Craf Sud
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Craf Sud
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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
    • C07D277/32—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 hetero atoms or with 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • 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
    • C07D277/32—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 hetero atoms or with 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • 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
    • C07D277/32—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 hetero atoms or with 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel hydrazonocephem derivatives of the general formula:- <IMAGE> wherein R is an acetyloxy or 1-methyl- 1H-tetrazol-5-ylthio radical; and the pharmaceutically-acceptable, non- toxic salts thereof, in the sin and/or anti configuration, have antibacterial activity and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Hydrozono cephem derivatives The present invention provides two hydrazonocephem derivatives, a process for the preparation thereof and pharmaceutical compositions containing them.
The new hydrazonocephem derivatives according to the present invention have the general formula:
wherein R is an acetyloxy or l-methyl-l H-tetrazol-5-yl-thio radical, the wavy line on the amino group indicating that, depending upon the configuration of this group, the compounds of general formula (I) may have the sin and/or anti configuration; and the pharmaceutically-acceptable, non-toxic salts thereof.
The above-mentioned cephem derivatives have a broad-spectrum activity, particularly against gram-negative micro-organisms.
The pharmaceutically-acceptable salts of compounds of general formula (I) include, for example, the sodium and potassium salts and the salts with organic bases.
The compounds of the present invention can be prepared by reacting a 7p-aminocephalosporanic acid in an optionally protected form of the general formula:
wherein R has the same meaning as above, with a hydrazono derivative of the general formula t
in a protected form in an aprotic solvent under anhydrous conditions in the presence of an appropriate condensation agent at a temperature of from -45 to OOC.
The condensation agent can be, for example, ethyl chlorocarbonate, dicyclohexylcarbodiimide or pivaloyl chloride. Among the aprotic solvents, apolar solvents are preferred, such as tetrahydrofuran, dioxan and chlorinated solvents, such as methylene chloride.
The condensation products are isolated in protected form and from them are obtained the hydrazono derivatives (I) in known manner. The compounds (III) can be obtained by condensing 2-(2aminothiazol-4-yl)glycoxylic acid, in the form of a salt or ester and optionally protected on the amino group, with hydrazine, optionally in a protected form, in aqueous solution at ambient temperature and optionally in the presence of a low molecular weight alcohol.
Among the amino-protecting groups, the formyl, chloroacetyl, trityl, tert.-butoxycarbonyl and carbobenzyloxy groups are particularly preferred, while the carboxyl group can be salified with alkali metals or organic bases, for example diethylamine or triethylamine, or esterified with appropriate groups, such as benzhydryl.
The compounds of the present invention possess a broad-spectrum activity, particularly against gram-negative micro-organisms, including many strains of p-lactamase producers. The antibacterial activity has been evaluated in vitro by determining the minimum inhibiting concentration (MIC) on agar medium plates inoculated with standard bacterial suspensions grown overnight at 370C. and diluted in a liquid medium (1/25 v/v) at the moment of use. Under such conditions, the MIC represents the minimum inhibiting concentration (pill.) of the test compounds which is able to inhibit bacteria grown after incubation of the plates for 18 hours at 370C.The experiments were carried out using as a standard for evaluating the activity of the compounds of the present invention, the compound cefazolin, which is known to be one of the best cephalosporins active against gram-negative micro-organisms.
The values obtained are given in the following Table.
TABLE
7ss-[2-(2-aminothiazol-4-yl)- 7ss-[2-(2-aminothiazol-4-yl) 2-hydrazonoacetamldo]-3-[(1- 2-hydrazonoacetamido] methyl-1H-tetrazol-5-yl)- 3-acetoxymethylceph Micro-organisms thiomethyl]ceph-3-em-4- 3-em-4-carboxylic acld Cefazolin carboxylic acid MIC (&gamma;/ml) MIC (&gamma;/ml) MIC (&gamma;/ml) S. aureus Smith 1.56 3.12 0.046 S. aureus ATCC 9144 1.56 3.12 0.038 S. aureus 39/11 FBF * 1.56 3.12 0.36 S. pyogenes ISM 68/231 0.024 0.097 0.028 S. pyogenes ISM 68/241 0.024 0.097 0.028 S. pyogenes ss haem. A 0.39 0.78 0.019 S. pyogenes A5 To 0.024 0.097 0.25 S. pneumoniae Felton UC41 1.56 3.12 0.088 S. Lutea ATCC 9341 0.19 0.39 0.11 S. typhimurlum To 0.097 0.78 1.69 E. coli R TEM * 0.78 1.56 4.68 E. coli 120 < 0.012 0.024 0.42 S. tiphl 6/12 To 0.024 0.097 0.65 S. typhimurium No 0.47 0.78 1.17 S. paratyphl B To 0.097 0.39 1.69 S. dysenterlae HLTC 4837 < 0.012 0.024 0.78 E. cloacae 214* 12.5 12.5 200 A. cloacae E 53* 12.5 12.5 200 N. pneumoniae ATCC 10031 < 0.012 0.024 0.71 N. meningitidls To A < 0.012 < 0.012 0.032 P. aeruginosa ISF 1 > 200 > 200 > 200 P. providence To < 0.012 < 0.012 0.29 S. enteriditis To 0.048 0.39 3.64
GRAM - GRAM + * ss-lactamase producers.
The compounds of the present invention can be mixed with appropriate pharmaceutically acceptable, non-toxic solid or liquid excipients in order to be administered to humans and animals.
These pharmaceutical preparations can also contain other therapeutically-active agents suitable for administration together with the compounds of the present invention.
The following Examples are given for the purpose of illustrating the present invention: EXAMPLE 1 7p-[2-(2-Aminothiazol-4-yl)-2-hydrnzonoaceta mido]-3-[( -methyl-l H-tetrazol-5-yl)-thiomethyl]-ceph- 3-em-4-carboxylic acid.
To a solution of 300 g. 2-(2-tritylaminothiazol-4-yl)-2-hyd roxyiminoethyl acetate in 3 litres dioxane, refluxing at 500 C., a solution of 600 g. sodium metabisulphite in 3 litres water is slowly added, while stirring, then heated under reflux for 9 hours. It is cooled and acidified (Congo Red) with 6N hydrochloric acid, stirred for 30 minutes, then filtered and the solution extracted 3 times with 3 litre amounts of methylene chloride. The organic phase is dried with anhydrous sodium sulphate and then evaporated to dryness in vacuo. The thick yellow oil so obtained is purified over a silica gel column (eluent: hexane/ethyl acetate 6:4 v/v) to give 85 g. 2-(2-tritylaminothiazol-4-yl)-ethyl glyoxylate; m.p.
118-12i0C.
To a solution of 85 g. 2-(2-trieylaminothiazol-4-yl)-ethyl glyoxylate in 90 ml. methanol, stirred at 50 C., is added a solution of sodium hydroxide in methanol, followed by stirring for a further 1.5 hours.
The solid precipitate so obtained is washed on the filter first with 300 ml. methanol and then with 200 ml. diethyl ether, where after it is dried in vacuo to give 52 g. of the sodium salt of 2-(2tritylaminothiazol-4-yl)-glyoxylic acid; m.p. 1 64-i 670C.
To a solution of 35 g. of the sodium salt of 2-(2-tritylaminothiazol-4-yl)-glyoxylic acid and 4 litres of a mixture of ethanol and water (3:1 v/v) is added a freshly prepared solution of 12.7 g. tert. butoxycarbonyihydrazine in 80 ml. N hydrochloric acid and 250 ml. ethanol and the mixture is then stirred for 2 hours, whereafter it is left to stand and the precipitate is filtered off and washed with water; the mother liquors are combined and concentrated to a small volume to give a second precipitate, which is separated off, washed with water and combined with the previous one. It is dried in vacuo to give 30.5 g. of 2-(2-tritylaminothiazol-4-yl)-2-tert.-butoxycarbonylhydrazonoacetic acid; m.p.
169--1710C. (with decomposition).
To a solution of 3.6 g. 2-(2-tritylaminothiazol-4-yl)-2-tert.-butoxyca rbonylhydrazonoacetic acid in 25 ml. methylene chloride is added a solution of 3.5 g. benzhydryl 7p-amino-3-[(1 -methyl-l H-tetrazol 5-yl)-thiomethyl]-ceph-3-em-4-carboxylate in 25 ml. methylene chloride. The mixture is then cooled to OOC. and, while stirring, 1.8 g. dicyclohexylcarbodiimide is added thereto. After stirring for 3 hours at ambient temperature, the precipitate is separated off by filtration, the organic phase is washed first with 1% aqueous solution of tritylamine and then with water, dried with anhydrous sodium sulphate and evaporated to dryness.There are so obtained 5.5 g. (Z) benzhydryl 7P-[2-(2-tritylaminothiazol-4-yl)-2- tert.-butyloxycarbonyl-hydrazonoacetamido]-3-[(1 i-methyl-i H-tetrazol-5-yl)-thiomethyl]-ceph-3-em-4carboxylate. NMR (CDCl3): 1.55 (9H, s) 3.5 (2H, q) 4.0 (3H, s) 4.4 (2H, s) 5.1(1 H, d) 5.75 (1 H, dd) 6.7 (1H, s) 7.05 (1H, s) 7.4 (25H, s)11.4(1 H, d) 12.8(1 H, s).
To a solution of 5 g. (Z) benzhyd ryl 7/3-[2-(2-tritylaminothiazoi-4-yl)-2-tert.-butoxyCarbonyl- hydrazonoaceta mido] -3-[(1 -methyl-l H-tetrazol-5-yl)thio methyl]-ceph-3-em-4-carboxylate in 1 5 ml.
anisole are added 10 ml. trifluoroacetic acid. The mixture is stirred at ambient temperature for 10 minutes, then treated with 250 ml. diethyl ether and the precipitate obtained is filtered off and washed with diethyl ether to give 2.8 g. 7/3-[2-(2-trityla minothiazol-4-yl)-2-hydrazonoacetamido]-3-[( -methyl1 H-tetrazol-5-yl)-thiomethyll-ceph-3-em-4-carboxylic acid which is treated for 2 hours at ambient temperature with 40 ml. of a mixture of formic acid/water (1::1 v/v).The solid so obtained is filtered off, the filtrate is slightly concentrated and adjusted to pH 4.5 with 7.5N ammonium hydroxide to give a solid which is filtered off, first washed with water and then with diethyl ether and thereafter dried in vacuo to give 0.7 g. 7-[2-(2-aminothiazol-4-yl)-2-hyd razonoaceta midoj-3-[( 1 -methyl-1 H-tetrazol-5yl)-thiomethyl]-ceph-3-em-4-carboxylic acid; m.p. 2000C. (with decomposition).
EXAMPLE 2 7p-[2-(2-Aminothiazol-4-yl)-2-hyd razonoaceta midoj-3-acetoxymethylceph-3-em-4-carboxylic acid.
Operating in a manner similar to that described above in Example 1 but using benzhydryl 7p- amino-3-acetoxymethylceph-3-em 4-carboxylate instead of benzhydryl 7p-amino-3-[(i-methyl-1 H tetrazol-5-yl)-thiomethyl]-ceph-3-em-4-carboxylate, there is first obtained 7P-[2-(2-trityla minothiazol- 4-yl)-2-tert.-butoxyCarbonylhydrazonoacetamido]-3-acetoxymethylceph-3-em-4-carboxylic acid, then 7,)-[2-(2-trityla minothiazol-4-yl)-2-hydrazonoacetamido]-3-acetoxymethylceph-3-em-4-carboxylic acid and finally 7ss-[2-(2-aminothiazol-4-yl)-2-hydrazonoacetamido]-3-acetoxymethylceph-3-em-4carboxylic acid; m.p. 90 950C. (with decomposition).
EXAMPLE 3 7,8-[2-(2-Am inothiazol-4-yl)-2-hyd razonoacetamido]-3-[(1 1 -methyl-l H-tetrazol-5-yl)-thiomethyl]-ceph- 3-em-4-carboxylic acid.
A solution of 1.5 g. 2-aminothiazol-4-yl-glyoxylic acid in 50 ml. N,N-dimethylformamide is added at OOC. to a solution of formylacetic anhydride, prepared by adding 25.6 ml. acetic anhydride dropwise to 8.9 ml. formic acid at 0 C. and stirring for 2 hours at 55 OC. The temperature is lowered to ambient temperature and stirring is continued for a further 2 hours. The reaction mixture is concentrated to a small volume, poured into diethyl ether, cooled to OOC. and stirred for 1 hour. The precipitate obtained is filtered off and washed with diethyl ether.The product is triturated with water, filtered and evaporated in vacuo to give 1.6 g. 2-formylaminothiazol-4-yl-glyoxylic acid IR (Nujol) = max 1740, 1 700 cm~1.
4.5 g. 2-Formylaminothiazol-4-yl-glyoxylic acid are suspended in 45 ml. water and dissolved at OOC. by adding 45 ml. N sodium hydroxide solution. To the so obtained solution there is added a solution of formylhydrazine hydrochloride in 45 ml. water. After 1 hour at ambient temperature and 1 hour at 0 C. the product is filtered off, washed with water and dried in vacuo. There are so obtained 3.4 g t-formylhydrazono-(2-formylaminothiazol-4-yl)-acetic acid; IR (Nujol) = max 1 700-1 650 cm~1.
2.42 g. -FormylhydrazonoA24ormylaminothiazoI-4-yl)-acetic acid are suspended in 50 ml.
methylene chloride and dissolved by adding 1.66 ml. triethylamine. The temperature is then lowered to 100 C., 0.956 ml. ethyl chlorocarbonate and 3 drops of 3-dimethylaminopropanol are added thereto and the mixture is stirred for 2 hours. It is then cooled to -400C. and there is added a solution which has been separately prepared by adding 1.1 ml. diethylamine to a suspension of 2.95 g. 7ss-amino-3- 1(1 -methyl-1 H-tetrazol-5-yl)-thiomethyl]-ceph-3-em-4-carboxylic acid in 30 ml. methylene chloride.
After stirring for 2 hours at 200 C. and for 1 hour at ambient temperature, the solution is evaporated to dryness in vacuo and the residue obtained is taken up in 40 ml. methanol at 0 C., the temperature is kept below 1 OOC. and, in the course of 10 minutes, 5 ml. hydrochloric acid are added thereto. When the addition of the hydrochloric acid is finished, the temperature is raised to 250 C. and the solution is stirred for2 hours, then cooled to -50C., diluted with 12 ml. water and slowly adjusted to pH 4 by adding ammonium hydroxide and stirred at 1 00C. for 2 hours. The precipitate is filtered off, washed with water/methanol (1:1 v/v) and then with diethyl ether. After drying, there are thus obtained 2.2 g.
(2-aminothiazol-4-yl)-2-hydrazonoacetamidoj-3-[( 1 -methyl-1 H-tetrazol-5-yl)-thiomethyl]-ceph-3-em4-carboxylic acid, which is identical to the compound obtained in Example 1.
EXAMPLE 4 7ss--[2-(2-Aminothiazol-4-yl)-2-hydrazonoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylic acid.
To an aqueous solution of 3 g. of the sodium salt of 2-aminothiazol-4-yl-glyoxylic acid is added an aqueous solution containing an equimolar amount of hydrazine hydrochloride. After stirring for 1 hour at ambient temperature, the reaction mixture is adjusted to pH 4.5 with hydrochloric acid and the precipitate obtained is filtered off, washed with water and dried in vacuo to give 2.4 g. cr-hydrazono-(2- aminothiazol-4-yl)-acetic acid; IR (Nujol) = max 1 650-1600 cm~'.
0.47 g. &alpha;-Hydrazono-(2-aminothiazol-4-yl)-acetic acid are dissolved in 4.7 ml. of N,Ndimethylformamide. The solution is cooled to 350C. and, after the addition of 0.767 ml.
dimethylaniline and 0.455 ml. chloroacetyl chloride, the temperature is allowed to rise. After 1 hour at ambient temperature, the solution is poured into 20 ml. N hydrochloric acid and stirred for 1 hour; the precipitate is filtered off, washed with water and dried in vacuo to give 0.6 g. N-chloroacetylhydrazono- (2-chloroacetamidothiazol-4-yl)-acetic acid; IR (Nujol) = max 1720, 1680 cm~1.
3.4 g. er-Chloroacetylhydrazono-(2-chloroacetamidothiazol-4-yl)-acetic acid are suspended in 50 ml. methylene chloride and dissolved by the addition of 1.66 ml. trimethylamine. The solution is cooled to-10 C., 0.95 ml. ethyl chlorocarbonate and 3 drops of 3-dimethylaminopropanol are added thereto and the mixture is stirred for 2 hours. It is then cooled to -400C. and added to a solution separately prepared by adding 1.1 ml. diethylamine to a suspension of 2.95 g. 7P-amino-3-[(l -methyl-l H-tetrazol5-yl)-thiomethyl]-ceph-3-em-4-carboxylic acid in 30 ml. methylene chloride. After stirring for 2 hours at -200C. and for 1 hour at ambient temperature, the solution is washed with water acidified to pH 1.5 and then with water until a neutral reaction is obtained.
The organic phase is dried with anhydrous sodium sulphate and evaporate to dryness in vacuo to give a crude oily compound, 1.5 g. of which is dissolved in 10 ml. dimethylformamide and 0.64 ml.
triethylamine, to which 0.35 g. thiourea are added, followed by stirring for 24 hours. The precipitate is filtered off, 100 ml. diethyl ether are added to the mother liquors and the mixture is stirred for 1 hour.
There are obtained by filtration 0.4 g. 7P-[2-(2-aminothiazoI-4-yl)-2-hydrazonoa mido]-3-[( 1 methyl-1 H-tetrazol-5-yl)-thiomethylj-ceph-3-em-4-carboxylic acid, which is identical to the compound obtained in Example 1.
EXAMPLE 5 (E) 7p-[2-(2-Aminothiazol-4-yl)-2-hydrazonoacetamido]-3-[(1 -methyl-1 H-tetrazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylic acid.
To a solution of 0.2 g. 7ss-[2-(2-aminothiazol-4-yl)-2-hhydazonoacetamido]-3-[(1-methyl-1 H tetrazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylic acid, obtained as described in one of the previous Examples, in 10 ml. water and 10 ml. tetrahydrofuran is added a drop of 37% hydrochloric acid. The mixture is stirred at ambient temperature for 4 hours and then evaporated to dryness to give 0.2 g. of the (E) form of 7-[2-(2-a minothiazol-4-yl)-2-hydrazonoaceta midoj-3-t( i-methyl-i H-tetrazol-5-yl) thiomethyl]-ceph-3-em-4-carboxylic acid; m.p. > 200 C.; [a] = -63.60C (c=0.2 in tetrahydrofuran/water 1:1 v/v).

Claims (7)

1. Hydrazonocephem derivatives of the general formula:
wheren Ris an acetyloxy or 1-methyl-1H-tetrazol-5-yl-thio radical; and the pharmaceutically-acceptable, non-toxic salts thereof, in the sin and/or anti configuration.
2. 7-[2-(2-Aminothiazol-4-yl)-2-hyd razonoacetamido]-3-acetoxy-methylceph-3-em-4-carboxylic acid.
3. 7ss-[2-(2-Aminothiazol-4-yl)-2-hydrazonoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-ceph-3-em-4-carboxylic acid.
4. Process for the preparation of hydrazonocephem derivatives according to claim 1, wherein a 7P-amino-cephalosporanic acid derivative of the general formula:
in which R has the same meaning as in claim 1, optionally in a protected form, is reacted in an anhydrous aprotic solvent at a temperature of from -45 to OOC. in the presence of a condensation agent with a hydrazono derivative of the general formula:
in protected form, whereafter the protecting groups are removed to give the desired hydrazonocephem derivative, which, if desired, is subsequently converted into a salt and/or separated into its isomers in known manner.
5. Process according to claim 4 for preparing hydrazonocephem derivatives, substantially as hereinbefore described and exemplified.
6. Hydrazonocephem derivatives, whenever prepared by the process according to claim 4 or 5.
7. Pharmaceutical composition containing at least one compound according to any of claims 1 to 3, in admixture with pharmaceutically acceptable excipients and optionally with at least one known therapeutically-active agent.
GB08220930A 1981-07-21 1982-07-20 Cephalosporin derivatives Expired GB2102423B (en)

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IT8123033A IT1211080B (en) 1981-07-21 1981-07-21 BIOLOGICALLY ACTIVE HYDRAZONOCEFEM.

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GB2102423B GB2102423B (en) 1985-08-14

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ES (1) ES514106A0 (en)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT381702B (en) * 1984-04-10 1986-11-25 Biochemie Gmbh METHOD FOR PRODUCING NEW THIAZOLE DERIVATIVES
EP2105435A1 (en) * 2007-01-10 2009-09-30 Mitsubishi Tanabe Pharma Corporation Hydrazone derivative
EP2308874A1 (en) 2005-12-07 2011-04-13 Basilea Pharmaceutica AG Useful beta-lactamase inhibitors
CN112010821A (en) * 2020-09-29 2020-12-01 山东金城医药化工有限公司 Recovery method of ethyl aminothiazoly loximate

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1208014A (en) * 1967-03-23 1970-10-07 Glaxo Lab Ltd Cephalosporins
GB1208015A (en) * 1967-03-23 1970-10-07 Glaxo Lab Ltd Cephalosporins
DK400074A (en) 1973-10-01 1975-06-09 Ciba Geigy Ag
IT1081809B (en) * 1977-06-07 1985-05-21 Isf Spa HYDRAZE CEPHALOSPORINE
DE2818263A1 (en) * 1978-04-26 1979-11-08 Bayer Ag BETA LACTAMANTIBIOTICS

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT381702B (en) * 1984-04-10 1986-11-25 Biochemie Gmbh METHOD FOR PRODUCING NEW THIAZOLE DERIVATIVES
EP2308874A1 (en) 2005-12-07 2011-04-13 Basilea Pharmaceutica AG Useful beta-lactamase inhibitors
US8901293B2 (en) 2005-12-07 2014-12-02 Basilea Pharmaceutica Ag Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
EP2105435A1 (en) * 2007-01-10 2009-09-30 Mitsubishi Tanabe Pharma Corporation Hydrazone derivative
EP2105435A4 (en) * 2007-01-10 2011-06-15 Mitsubishi Tanabe Pharma Corp Hydrazone derivative
US8314247B2 (en) 2007-01-10 2012-11-20 Mitsubishi Tanabe Pharma Corporation Hydrazone derivative
CN112010821A (en) * 2020-09-29 2020-12-01 山东金城医药化工有限公司 Recovery method of ethyl aminothiazoly loximate

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PT75281A (en) 1982-08-01
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FR2510117A1 (en) 1983-01-28
IT1211080B (en) 1989-09-29
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IT8123033A0 (en) 1981-07-21
DE3227284A1 (en) 1983-02-24

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