EP0000285A1 - 7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carboxylic acid derivatives, processes for their preparation and compositions containing them - Google Patents
7-Acylamino-3-((3-(carboxymethyl) thio-1 H-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carboxylic acid derivatives, processes for their preparation and compositions containing them Download PDFInfo
- Publication number
- EP0000285A1 EP0000285A1 EP78300103A EP78300103A EP0000285A1 EP 0000285 A1 EP0000285 A1 EP 0000285A1 EP 78300103 A EP78300103 A EP 78300103A EP 78300103 A EP78300103 A EP 78300103A EP 0000285 A1 EP0000285 A1 EP 0000285A1
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- EP
- European Patent Office
- Prior art keywords
- triazol
- thio
- compound
- formula
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- This invention relates to cephalosporin compounds having antibacterial activity, to intermediates for preparing them, to compositions containing them, and to processes for their preparation.
- the acyl group R is preferably a group known to be of utility as a substituent on the 7-amino group in the structures of known or prior art cephalosporins or on the 6-amino group in the structures of known or prior art penicillins.
- the 4-carboxylic acid group of the compounds of Formula 1 may be readily esterified by methods well known to the art.
- esters include, for example, simple alkyl and aryl esters as well as esters which are easily cleaved, within the body, to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycylbxymethyl esters and others.
- A is COOH
- this group may be similarly esterified. All such ester derivatives are included within the scope of this invention.
- Also covered in this invention are pharmaceutically- acceptable, non-toxic derivatives of the compounds of Formula 1, e.g.salts; as stated above easily split ester or ther derivatives of either a carboxy or hydroxy function; amide derivatives of an amino group in.a 7-phenylglycyl- amino group, for example the furyl-, pyranyl-, oxolanyl or oxiranyl-carbonyl amides (i.e. Belgian Patent No. 835,295); and solvates such as hydrates, glycolates or alcoholates.
- alkali metal salts such as the sodium or potassium salts (for example using sodium or potassium 2-ethyl hexanoate), ammonium salts, and organic amine salts such as those with procaine or dibenzylethylenediamine.
- cephalosporin modifications can be made by known synthetic procedures such as introduction of an ⁇ -methoxy group at position 7, preferably at the stage of the 7-aminocephalosporanic acid reactants described below (IV), prior to N-acylation.
- Optical isomers are also possible, such as with mandeloyl or phenylglycyl substituents at 7. The D-forms of these subgeneric groups are preferred.
- the compounds of this invention are conveniently prepared by a displacement of the acetoxy group of a known 7-acylaminocephalosporanic acid (II) by [(4,5-dihydro-5-thioxo-lH-1,2,4-triazol-3-yl)thio]acetic acid (III).
- a similar displacement with the above acetic acid can be effected on 7-aminocephalosporanic acid to give 7-amino-3-((3-(carboxymethyl)thio-1H-1,2,4-triazbl-5-yl]-thiomethyl]-3-cephem-4-carboxylic acid (IV) which may then be N-acylated as known to the art as described above.
- Suitable protective groups may be used in either method as is known to the art (see “Protective Groups in Organic Chemistry”, J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxyl protective groups).
- t-butyl (for COOH) or t-butoxycarbonyl (for NH 2 ) groups are easily removed by treatment with trifluoroacetic acid.
- the compound of Formula III which can exist in several tautomeric forms, is a new compound and is part of this invention.
- This invention also includes the alkali metal and ammonium salts of the compound of Formula III.
- the compounds of Formula I have antibacterial activity against both Gram positive and Gram negative bacteria, and minimum inhibitory concentrations (MIC's) in vitro of from 0.2 to greater than 200 ug/ml have been observed.
- MIC's minimum inhibitory concentrations
- Compound A showed an ED 50 in mice of 1.56 against E. coli as well as 1.02 mg/kg against Kleb. pneumo. (s.c.).
- compositions having antibacterial activity which comprise a pharmaceutical carrier containing a compound of Formula I as well as methods of combatting bacterial infections by administering such a composition in a nontoxic amount sufficient to combat such infections are also objects of this invention.
- the administration may be orally or by parenteral injection such as subcutaneously, intramuscularly.or intravenously.
- the injection of suitably prepared sterile solutions or suspensions containing an effective, non-toxic amount of a cephalosporin compound of the invention is the preferred route of administration.
- the compounds of Formula I are preferably formulated adn administered in the same manner as other prior art cephalosporins such as cephazolin of cephalothin.
- the dosage regimen preferably comprises administration, preferably by injection, of an active but non-toxic quantity of a compound of Formula I selected from the dosage unit range of from about 250 mg. to 600 mg. with the total daily dosage regimen being from about 750 mg. to 6 g.
- the precise dosages are dependent upon the age and weight of the subject and on the susceptibility of the infection being treated to each individual. These can be determined by those skilled in the art based on the data disclosed herein compared with that available to the art attained with the known cephalosporins outlined herebefore.
- reaction mixture is purified on an XAD-7 column as described in Example 1 to give a lyophilized product, 7-[ a(Z)-(methoxyimino)-2-furanacetamido]-3-[[3-(carboxymethyl) thio-1H-1,2,-4- triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt.
- This derivative is stirred at 25°C. with 25 ml. of trifluoroacetic acid and 25 ml. of 1,3-dimethoxybenzene for 2 hours. The mixture is evaporated to dryness in vacuo, ethyl acetate is added to the residue and the precipitated salt is collected. This is dissolved in water and treated with Amberlite IR-45 weakly basic ion-exchange resin. The solution is lyophilized to give 7-(D-a-amino-4-hydroxy- phenylacetamido)-3-[[3-carboxymethyl)thio-1H-1,2,4-triazol-5 -yl]thiomethyl]-3-cephem-4-carboxylic acid.
- An injectable pharmaceutical composition is formed by adding sterile saline solution (2 ml.) to 500 mg. of the product of Example 1. This material is injected parenterally four times daily to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.
Abstract
- R' represents hydrogen or an alkali metal salt, have antibacterial activity.
Description
- This invention relates to cephalosporin compounds having antibacterial activity, to intermediates for preparing them, to compositions containing them, and to processes for their preparation.
-
- X is thienyl, furyl, phenyl or phenyl mono-substituted by hydroxy, hydroxymethyl, formamido or ureido:
- A is NH2, OH, COOH, S03H, formyloxy or, when the α-C-hydrogen is absent, methoxyimino:
- Y is cyano, sydnone, pyridone, thienyl, o-aminomethylphenyl, phenyl or tetrazolyl;
- Z is methyl, trifluoromethyl, trifluoroethyl, pyridyl or cyanomethyl; and
- m is zero to two;
- R' is hydrogen or an alkali metal salt such as sodium or potassium.
- The acyl group R is preferably a group known to be of utility as a substituent on the 7-amino group in the structures of known or prior art cephalosporins or on the 6-amino group in the structures of known or prior art penicillins.
- Representative 7-acylamino substituents of the compounds of Formula I are listed below:
- α-hydroxyphenylacetamido
- α-aminophenylacetamido
- α-amino-4-hydroxyphenylacetamido
- trifluoromethylthioacetamido
- 2,2,2-trifluoroethylsulfinylacetamido
- 2,2,2-trifluoroethylthioacetamido
- cyanoacetamido
- α-carboxythienylacetamido
- a-carboxyphenylacetamido
- a-sulfophenylacetamido
- methylsulfonylacetamido
- : cyanomethylthioacetamido
- 3-sydnoneacetamido
- 1-tetrazolylacetamido
- 2-thienylacetamido
- a(Z)-(methoxyimino)-2-furanacetamido
- 4-pyridylthioacetamido
- o-aminomethylphenylacetamido
- It will be recognized that the 4-carboxylic acid group of the compounds of Formula 1 may be readily esterified by methods well known to the art. These esters include, for example, simple alkyl and aryl esters as well as esters which are easily cleaved, within the body, to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycylbxymethyl esters and others. Of course, when A is COOH; this group may be similarly esterified. All such ester derivatives are included within the scope of this invention.
- Also covered in this invention are pharmaceutically- acceptable, non-toxic derivatives of the compounds of Formula 1, e.g.salts; as stated above easily split ester or ther derivatives of either a carboxy or hydroxy function; amide derivatives of an amino group in.a 7-phenylglycyl- amino group, for example the furyl-, pyranyl-, oxolanyl or oxiranyl-carbonyl amides (i.e. Belgian Patent No. 835,295); and solvates such as hydrates, glycolates or alcoholates. As examples of these, one skilled in the art would be able to prepare and use the alkali metal salts such as the sodium or potassium salts (for example using sodium or potassium 2-ethyl hexanoate), ammonium salts, and organic amine salts such as those with procaine or dibenzylethylenediamine.
- Other known cephalosporin modifications can be made by known synthetic procedures such as introduction of an α-methoxy group at position 7, preferably at the stage of the 7-aminocephalosporanic acid reactants described below (IV), prior to N-acylation. Optical isomers are also possible, such as with mandeloyl or phenylglycyl substituents at 7. The D-forms of these subgeneric groups are preferred.
- The compounds of this invention are conveniently prepared by a displacement of the acetoxy group of a known 7-acylaminocephalosporanic acid (II) by [(4,5-dihydro-5-thioxo-lH-1,2,4-triazol-3-yl)thio]acetic acid (III). Alternatively, a similar displacement with the above acetic acid can be effected on 7-aminocephalosporanic acid to give 7-amino-3-((3-(carboxymethyl)thio-1H-1,2,4-triazbl-5-yl]-thiomethyl]-3-cephem-4-carboxylic acid (IV) which may then be N-acylated as known to the art as described above. Suitable protective groups may be used in either method as is known to the art (see "Protective Groups in Organic Chemistry", J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxyl protective groups).
- For example, the t-butyl (for COOH) or t-butoxycarbonyl (for NH2) groups are easily removed by treatment with trifluoroacetic acid.
-
- This invention also includes the alkali metal and ammonium salts of the compound of Formula III.
- The compounds of Formula I have antibacterial activity against both Gram positive and Gram negative bacteria, and minimum inhibitory concentrations (MIC's) in vitro of from 0.2 to greater than 200 ug/ml have been observed. Test results for 7-D-mandelamino-3-[[3-(carboxymethyl)thio-lH-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt, hydrate (A) are:
- Compound A showed an ED50 in mice of 1.56 against E. coli as well as 1.02 mg/kg against Kleb. pneumo. (s.c.).
- These results are superior to those for a related compound, 7-D-mandelamino-3-(2-carboxymethylthio-l,3,4-thiadiazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, sodium salt hydrate which showed an ED50 against E. coli of 6.4 and as well as 4.4 mg/kg against Kleb. pneumo.
- Pharmaceutical compositions having antibacterial activity which comprise a pharmaceutical carrier containing a compound of Formula I as well as methods of combatting bacterial infections by administering such a composition in a nontoxic amount sufficient to combat such infections are also objects of this invention. The administration may be orally or by parenteral injection such as subcutaneously, intramuscularly.or intravenously. The injection of suitably prepared sterile solutions or suspensions containing an effective, non-toxic amount of a cephalosporin compound of the invention is the preferred route of administration.
- The compounds of Formula I are preferably formulated adn administered in the same manner as other prior art cephalosporins such as cephazolin of cephalothin. The dosage regimen preferably comprises administration, preferably by injection, of an active but non-toxic quantity of a compound of Formula I selected from the dosage unit range of from about 250 mg. to 600 mg. with the total daily dosage regimen being from about 750 mg. to 6 g. The precise dosages are dependent upon the age and weight of the subject and on the susceptibility of the infection being treated to each individual. These can be determined by those skilled in the art based on the data disclosed herein compared with that available to the art attained with the known cephalosporins outlined herebefore.
- The following examples illustrate the invention. Temperatures are in degrees Centigrade (°C.) unless otherwise stated.
- To a suspension of 5.48 g. (40 mmol) of 1,2,4-triazolidine-3,5-dithione, monohydrazine salt in 80 ml. of tetrahydrofuran and 80 ml. of dimethylformamide was added a solution of 6.7 (40 mmol) of ethyl bromoacetate in 20 ml. of tetrahydrofuran. The mixture was stirred at room temperature for 1-1/2 hours, and then at 50°C. for 1/2 hour. The solution was filtered and the filtrate was concentrated to 80 ml., diluted with 250 ml. of water and extracted with diethyl ether. The extract was dried (MgSO4) and evaporated to dryness to give a residue which was crystallized from methanol and water to give 5.76 g. (65% yield) of ethyl [(4,5-dihydro-5-thioxo-lH-1,2,4,-triazol-3-yl)thio]acetate, mp 134-6°C.
- A solution of 2.19 g. (10 mmol) of ethyl [4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetate in 50 ml. of 5% sodium hydroxide was heated at reflux for 1 hour. After thorough cooling, the mixture was filtered, and the filtrate was washed with ethyl acetate. The aqueous layer was separated, acidified to pH 1 and extracted with ethyl acetate. The extract was evagporated in vacuo to dryness. The residue was crystallized from chloroform to give 1.43 g. (75% yield) of [(4,5-dihydro-5-thioxo-lH-1,2,4-triazol-3-yl)thio]acetic acid.
- To a solution of 1.16 g. (13.8 mmol) of sodium bicarbonate in 30 ml. of water was added 1.32 g. (6.9 mmol) of [4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetic acid. After C02 gas evolution had ceased, 2.12 g. (5 mmol) of 7-mandelamido-cephalosporanic acid sodium salt was added to the solution. The mixture was heated at 80°C. for 3.5 hours. After cooling, the solution was filtered. The filtrate was applied to an XAD-7 (200 ml.) resin column, eluting with water. The fractions containing product by thin layer chromatography were pooled and evaporated to dryness. The residue was triturated with absolute ethanol and filtered. The filtrate was diluted with isopropanol, and the solid formed was filtered, air-dried, dissolved in de-ionized water and lyophilized to give 1.02 g. (15.6 % yield) of 7-D-mandelamido-3-[[3-(carboxymethyl)thio-1H-1.,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt hydrate, mp 220-230°C. dec. Anal. calculated for C20H17N5O7S3Na2.4H2O = C, 36.75; H, 3.85; N, 10.71. Found: C, 36.47; H, 3.53; N, 10.11. IR-(NUJOL) = 5.65 .
- An aqueous solution (100 ml.) of 4.27 g (0.0096 mol) of 7-[a(Z)-(methoxyimino)-2-furanacetamido]-cephalosporanic acid sodium salt, 1.78 g. (0.0212 mol) of sodium bicarbonate and 2.02 g. (0.0106 mol) of [(4,5-dihydro-5- thioxo-1H-1,2,4-triazol-3-yl)thio]acetic acid is heated at 65°C. for 6 hours during which time the pH is maintained at 7.6-7.8 with dilute sodium bicarbonate. After cooling, the reaction mixture is purified on an XAD-7 column as described in Example 1 to give a lyophilized product, 7-[ a(Z)-(methoxyimino)-2-furanacetamido]-3-[[3-(carboxymethyl) thio-1H-1,2,-4- triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid, disodium salt.
- A mixture of 5.22 g. (10.0 mmol) of 7-(D--t-butoxycarbonylamino-4-hydroxyphenylacetamido)cephalosporanic acid and an excess (15.0 mmol) of [(4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetic acid in 75 ml. of pH 6.4 phosphate buffer solution is treated with sufficient sodium bicarbonate togive a pH of 6.4. The mixture is heated at 70° for 3 hours, cooled, acidified with dilute hydrochloric acid to pH 2 and extracted with ethyl acetate. Removal of the ethyl acetate in vacuo gives the t-boc derivative of the desired compound. This derivative is stirred at 25°C. with 25 ml. of trifluoroacetic acid and 25 ml. of 1,3-dimethoxybenzene for 2 hours. The mixture is evaporated to dryness in vacuo, ethyl acetate is added to the residue and the precipitated salt is collected. This is dissolved in water and treated with Amberlite IR-45 weakly basic ion-exchange resin. The solution is lyophilized to give 7-(D-a-amino-4-hydroxy- phenylacetamido)-3-[[3-carboxymethyl)thio-1H-1,2,4-triazol-5 -yl]thiomethyl]-3-cephem-4-carboxylic acid.
- A mixutre of an excess (12.2 mmol) of [(4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetic acid, 32.5 mmol of sodium bicarbonate and 8.1 mmol of 7-tri- fluoromethylthioacetamidocephalosporanic acid in 50 ml. of water is stirred at 70° for 5 hours. The reaction mixture is cooled and applied to an XAD-2 column and eluted with water and then methanol. The product containing effluent is evaporated to dryness to give a residue which is dissolved in a small amount of water and lyophilized to give 7-trifluoromethylthioacetarnido-3-[[3-(carboxymethyl)thio-lH-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid disodium salt. Substituting 7-(2-thienylacetamido)-cephalosporanic acid gives 7-(2-thienylacetamido)-3-[[3-(carboxymethyl)thio-1H-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid sodium salt.. '
- Stoichiometric quantities of cephalosporanic acids having the individual 7-acylamino substituent listed hereabove may be substituted in Examples 1-3 with variations which will be obvious to those skilled in this art.
- An injectable pharmaceutical composition is formed by adding sterile saline solution (2 ml.) to 500 mg. of the product of Example 1. This material is injected parenterally four times daily to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.
Others together with N-acylation procedures may be found in Cephalosporins and Penicillins, Flynn, Academic Press, 1972; U. S. Patent Nos. 2,721,196 and 3,953,424; Belgian Patent No. 832,725; German Patent Nos. 2,127,285 and 2,406,165.
Claims (7)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US811642 | 1977-06-30 | ||
US05/811,642 US4117124A (en) | 1977-06-30 | 1977-06-30 | 7-Acylamino-3-[[3-(carboxymethyl)thio-1H-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acids |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000285A1 true EP0000285A1 (en) | 1979-01-10 |
EP0000285B1 EP0000285B1 (en) | 1982-02-17 |
Family
ID=25207126
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78300103A Expired EP0000285B1 (en) | 1977-06-30 | 1978-06-29 | 7-acylamino-3-((3-(carboxymethyl) thio-1 h-1,2,4-triazol-5-yl) thiomethyl)-3-cephem-4-carboxylic acid derivatives, processes for their preparation and compositions containing them |
EP80200247A Expired EP0015631B1 (en) | 1977-06-30 | 1978-06-29 | ((4,5-dihydro-5-thioxo-1h-1,2,4-triazol-3-yl)thio)acetic acid and its salts |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP80200247A Expired EP0015631B1 (en) | 1977-06-30 | 1978-06-29 | ((4,5-dihydro-5-thioxo-1h-1,2,4-triazol-3-yl)thio)acetic acid and its salts |
Country Status (4)
Country | Link |
---|---|
US (1) | US4117124A (en) |
EP (2) | EP0000285B1 (en) |
JP (1) | JPS6054958B2 (en) |
DE (2) | DE2861631D1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57133686A (en) * | 1981-02-12 | 1982-08-18 | Sharp Corp | Semiconductor light emitting element and manufacture thereof |
JPS5834986A (en) * | 1981-08-27 | 1983-03-01 | Sharp Corp | Manufacture of light emitting device |
JPH0783884A (en) * | 1993-09-14 | 1995-03-31 | Kenzo Miya | Flaw examination method, flow examination device and flaw examination sensor |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2016082A1 (en) * | 1969-04-04 | 1970-10-08 | Eastman Kodak Co., Rochester, N.Y. (V.St.A.) | Addition compounds of thiourazoles and alpha, beta-unsaturated, organic carbon compounds |
JPS50131981A (en) * | 1974-04-05 | 1975-10-18 | ||
FR2266507A1 (en) * | 1974-04-05 | 1975-10-31 | Yamanouchi Pharma Co Ltd | |
DE2655717A1 (en) * | 1975-12-16 | 1977-06-30 | Erba Carlo Spa | THIADIAZOLYL DERIVATIVES OF 7-ACYLAMIDO-3-CEPHEM-4-CARBONIC ACID, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL AND VETERINAL MEDICINAL PRODUCTS CONTAINING THE SAME |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3615618A (en) * | 1969-04-04 | 1971-10-26 | Eastman Kodak Co | Photographic silver halide compositions comprising thiourazole adducts |
US4018921A (en) * | 1973-08-01 | 1977-04-19 | Smithkline Corporation | Substituted phenylglycylcephalosporins |
US3989694A (en) * | 1974-12-27 | 1976-11-02 | Smithkline Corporation | 7-Acyl-3-(substituted triazolyl thiomethyl)cephalosporins |
US4045438A (en) * | 1975-10-24 | 1977-08-30 | Yeda Research And Development Co. Ltd. | Cephalosporin antibiotics |
-
1977
- 1977-06-30 US US05/811,642 patent/US4117124A/en not_active Expired - Lifetime
-
1978
- 1978-06-26 JP JP53077967A patent/JPS6054958B2/en not_active Expired
- 1978-06-29 DE DE7878300103T patent/DE2861631D1/en not_active Expired
- 1978-06-29 DE DE8080200247T patent/DE2862354D1/en not_active Expired
- 1978-06-29 EP EP78300103A patent/EP0000285B1/en not_active Expired
- 1978-06-29 EP EP80200247A patent/EP0015631B1/en not_active Expired
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2016082A1 (en) * | 1969-04-04 | 1970-10-08 | Eastman Kodak Co., Rochester, N.Y. (V.St.A.) | Addition compounds of thiourazoles and alpha, beta-unsaturated, organic carbon compounds |
JPS50131981A (en) * | 1974-04-05 | 1975-10-18 | ||
FR2266507A1 (en) * | 1974-04-05 | 1975-10-31 | Yamanouchi Pharma Co Ltd | |
DE2655717A1 (en) * | 1975-12-16 | 1977-06-30 | Erba Carlo Spa | THIADIAZOLYL DERIVATIVES OF 7-ACYLAMIDO-3-CEPHEM-4-CARBONIC ACID, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL AND VETERINAL MEDICINAL PRODUCTS CONTAINING THE SAME |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS 85 (1976) 21397e. & JP-A-50 131981 (YAMANOUCHI). * |
Also Published As
Publication number | Publication date |
---|---|
DE2862354D1 (en) | 1984-01-12 |
JPS5412396A (en) | 1979-01-30 |
US4117124A (en) | 1978-09-26 |
JPS6054958B2 (en) | 1985-12-03 |
EP0015631B1 (en) | 1983-12-07 |
DE2861631D1 (en) | 1982-03-25 |
EP0000285B1 (en) | 1982-02-17 |
EP0015631A1 (en) | 1980-09-17 |
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