EP0000005B1 - Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques - Google Patents

Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques Download PDF

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Publication number
EP0000005B1
EP0000005B1 EP78100078A EP78100078A EP0000005B1 EP 0000005 B1 EP0000005 B1 EP 0000005B1 EP 78100078 A EP78100078 A EP 78100078A EP 78100078 A EP78100078 A EP 78100078A EP 0000005 B1 EP0000005 B1 EP 0000005B1
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salts
formula
compounds
methyl
hydrates
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EP0000005A1 (fr
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Marc Dr. Montavon
Roland Dr. Reiner
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to new acyl derivatives of the general formula in which R is furyl, thienyl or phenyl which is optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 is lower alkyl or aminocarbonylmethyl and X is a group of the formulas in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is lower alkyl, carboxymethyl or sulfomethyl, and salts of these compounds and hydrates of these salts.
  • salts of the compounds of formula 1 are alkali metal salts such as the sodium and potassium salt; the ammonium salt; Alkaline earth metal salts such as the calcium salt; Salts with organic bases, such as salts with amines, e.g. Salts with N-ethyl-piperidine, procaine, dibenzylamine, N, N'-dibenzyl-ethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as e.g. Salts with arginine or lysine.
  • the salts can be mono-salts or also disalts.
  • the second salt formation takes place on the tautomeric enol form of the triazine residue b, which has an acid character.
  • the compounds of formula I also form addition salts with organic or inorganic acids.
  • such salts are hydrohalides, for example hydrochlorides, hydrobromides; Hydroiodides, as well as other minor acid salts, such as sulfates, nitrates, phosphates and the like, alkyl and mono-aryl sulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like, and also other organic acid salts, such as acetates, tartrates, maleates, citrates, benzoates, salic , Abscorbate and the like
  • the salts of the compounds of formula I can be hydrated.
  • the hydration can take place in the course of the production process or can occur gradually as a result of hygroscopic properties of an initially anhydrous salt of a compound of the formula I.
  • lower alkyl groups are either straight chain or branched and can contain up to 7 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-heptyl, lower alkoxy groups have an analogous meaning.
  • Halogen represents all four halogens, i.e. Fluorine, chlorine, bromine and iodine; chlorine and bromine are preferred.
  • Preferred R groups are furyl, thienyl and phenyl, especially furyl. Methyl is preferred as R 1 .
  • Preferred X groups are group (c) and groups (a) and (b), in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is methyl. Particularly preferred X groups are the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl and the 1,4,5,6-tetrahydro-4-methyl - 5,6-dioxo-as-triazin-3-yl group.
  • Preferred compounds are (7R) - 7 - [2 - (2 - furyl) - 2 - (methoxyimino) acetamido] - 3 - / [(1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl) thio] methyl / - 3 - cephem - 4 - carboxylic acid and its salts and the hydrates of these salts.
  • the compounds of the formula I and their salts or hydrates of the salts can be in the synisomeric form or in the anti-isomeric form or as mixtures of these two forms.
  • the syn-isomeric form or mixtures in which the syn-isomeric form predominates is preferred.
  • the carboxy groups present in the starting compounds of formulas II and IV can optionally be protected, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. the trimethylsilyl ester.
  • the carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.
  • Suitable reactive functional derivatives of acids of the formula III are e.g. Halides, i.e. Chlorides, bromides and fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxy succinimide esters, and amides, e.g. Imidazolides.
  • Halogens e.g. Chlorine, bromine or iodine
  • acyloxy residues e.g. lower alkanoyl radicals, such as acetoxy, lower alkyl or arylsulfonyloxy radicals, such as mesyloxy or tosyloxy, or the azidorest in question.
  • a free acid of formula III can be condensed with one of the esters corresponding to formula II by means of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the ester group is split off .
  • carbodiimides can be as Condensing agents also use oxazolium salts, for example N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
  • an acid halide preferably the chloride of an acid of the formula III
  • the reaction is preferably carried out in the presence of an acid binding agent, e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylated amine, such as triethylamine.
  • an acid binding agent e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylated amine, such as triethylamine.
  • Water is preferably used as the solvent; but it can also be in an aprotic organic solvent such as e.g. Dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamide can be worked.
  • reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be advantageously carried out at temperatures between about -40 ° C and room temperature, for example at about 0-10 o C, take place.
  • reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitably at about 60 ° C, in a polar solvent, for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • a polar solvent for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • the protective group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. If the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), this salt-forming protective group can be split off by treatment with acid.
  • the acid can be e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
  • the 7-amino compounds of the formula 11 used as starting products can be started from a compound of the formula in which Y represents a leaving group and the carboxy group can be in protected form, are prepared with a thiol of the formula V.
  • the reaction can be carried out under the same conditions as those of the starting compounds IV and V.
  • syn / anti mixture of a compound of the formula I obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
  • 2,275,215 and 2,280,381 cephalosporin derivatives which can carry a substituted thiomethyl radical of the present type ⁇ CH 2 ⁇ S ⁇ X in the 3-position. It has now been found that the new cephalosporin derivatives of the formula I and their salts and the hydrates of these salts, in which the substituents mentioned in positions 7 and 3 are present simultaneously for the first time, have valuable antibiotic, in particular bactericidal activity.
  • ß-lactamase-forming staphylococci and various ß-lactamase-forming gram-negative bacteria, such as, for example, Haemophilus influenzae, Escherichia coli, Proteus and Klebsiella species.
  • the compounds of formula I can be used for the treatment and prophylaxis of infectious diseases.
  • a daily dose of approximately 1 g to approximately 4 g is suitable for the adult.
  • the parenteral administration of the compounds according to the invention is particularly preferred.
  • mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis.
  • the test substance is applied subcutaneously one hour after the infection.
  • the number of surviving animals is determined on the 4th day.
  • Different doses are applied and the dose at which 50% of the test animals survived (CD sa , mg / kg) is determined by interpolation.
  • compositions can contain the compounds of formula I, their salts or hydrated forms of these salts, possibly in a mixture with another therapeutically valuable substance. They are expediently mixed with a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as e.g. with water, gum arabic.
  • the pharmaceutical preparations are preferably in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (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)
  • Saccharide Compounds (AREA)

Claims (17)

1. Les dérivés de céphalosporine de formule générale
Figure imgb0031
où R représente un furyle, un thiényle ou un phényle éventuellement substitué par un halogène, un hydroxy, un alcoxy inférieur ou un alcoyle inférieur, R, représente un alcoyle inférieur ou un amino- carbonylméthyle et X un groupe de formules
Figure imgb0032
où l'un des deux radicaux R2 et R3 ou R4 et Rs représente un hydrogène et l'autre un alcoyle inférieur, un carboxyméthyle ou un sulfométhyle, ainsi que les sels de ces composés et les hydrates de ces sels.
2. Les dérivés selon la revendication 1, caractérisés en ce que R représente un furyle, ainsi que les sels de ces composés et les hydrates de ces sels.
3. Les dérivés selon la revendication 1 ou 2, caractérisés en ce que R, représente le méthyle, ainsi que les sels de ces composés et les hydrates de ces sels.
4. Les dérivés selon l'une des revendications 1-3, caractérisés en ce que X représente le groupe (c) ou l'un des groupes (a) et (b), dans lesquels l'un des radicaux R2 et R3 ou R4 et R5 représente un hydrogène et l'autre le méthyle, ainsi que les sels de ces composés et les hydrates de ces sels.
5. Les dérivés selon la revendication 4, caractérisés en ce que X représente le groupe 1,2,5,6 - tétrahydro - 2 - méthyl - 5,6 - dioxo - as - triazin - 3 - yle, ainsi que les sels de ces composés et les hydrates de ces sels.
6. Les dérivés selon la revendication 4, caractérisés en ce que X représente le groupe 1,4,5,6 - tétrahydro - 4 - méthyl - 5,6 - dioxo - as - triazin - 3 - yle, ainsi que les sels de ces composés et les hydrates de ces sels.
7. L'acide (7R) - 7 - [2 - (2 - furyl) - 2 - (méthoxyimino) - acétamido] - 3 - /[1,2,5,6 - tétrahydro - 2 - méthyl - 5,6 - dioxo - as - triazin - 3 - yl)thio] - methyl/ - 3 - céphem - 4 - carboxylique, ainsi que les sels de ce composé et les hydrates de ces sels.
8. Procédé pour la préparation de dérivés de céphalosporine de formule générale
Figure imgb0033
où R représente un furyle, un thiényle ou un phényle éventuellement substitué par un halogène, un hydroxy, un alcoxy inférieur ou un alcoyle inférieur, R, représente un alcoyle inférieur ou un aminocarbonyl-méthyle et X un groupe de formules
Figure imgb0034
où l'un des deux radicaux R2 et R3 ou R4 et R5 représente un hydrogène et l'autre un alcoyle inférieur, un carboxyméthyle ou un sulfométhyle, ainsi que les sels de ces composés et les hydrates de ces sels, caractérisé en ce que
a) on fait réagir un composé de formule générale
Figure imgb0035
où X a la signification donnée dans la formule I et où le groupe carboxy peut se présenter sous forme protégée, avec un acide de formule générale
Figure imgb0036
où R et R, ont la signification donnée dans la formule I, ou avec un dérivé fonctionnel réactif de cet acide et on sépare le groupe protecteur éventuellement présent, ou
b) on fait réagir un composé de formule générale
Figure imgb0037
 où R et R1 ont la signification donnée dans la formule I, Y représente un groupe détachable et où le groupe carboxy peut se présenter sous forme protégée, avec un thiol de formule générale
Figure imgb0038
où X a la signification donnée dans la formule I , et on sépare le groupe protecteur éventuellement présent, après quoi on transforme, le cas échéant, le produit réactionnel en un sel ou en un hydrate de ce sel.
9. Un procédé selon la revendication 8, caractérisé en ce que l'on part d'un produit de départ de formule II et d'un acide de formule III ou d'un dérivé fonctionnel réactif d'un tel acide.
10. Un procédé selon la revendication 9, caractérisé en ce que l'on fait réagir le chlorure d'un acide de formule III avec un produit de départ de formule Il dans un alcali aqueux.
11. Un procédé selon l'une des revendications 8-10 de préparation de composés de formule I, où R représente un furyle, ainsi que de leurs sels ou des hydrates de ces sels, caractérisé en ce que l'on utilise des produits de départ substitués correspondants.
12. Un procédé selon l'une des revendications 8-11 de préparation de composés de formule I, où R1 représente un méthyle, ainsi que de leurs sels ou des hydrates de ces sels, caractérisé en ce qu'on utilise des produits de départ substitués correspondants.
13. Un procédé selon l'une des revendications 8-12 de préparation de composés de formule I, où X représente le groupe (c) ou un des groupes (a) et (b), dans lesquels l'un des deux radicaux R2 et R3 ou R4 et R5 représente un hydrogène ou l'autre un méthyle, ainsi que de leurs sels ou des hydrates de ces sels, caractérisé en ce que l'on utilise des composés de départ substitués correspondants.
14. Un procédé selon la revendication 13 de préparation de composés de formule I, où X représente un groupe 1,2,5,6-tétrahydro-2-méthyl-5,6-dioxo-as-triazin-3-yle, ainsi que de leurs sels ou des hydrates de ces sels, caractérisé en ce que l'on utilise des produits de départ substitués correspondants.
15. Un procédé selon la revendication 13 de préparation de composés de formule I, où X représente le groupe 1,4,5,6-tétrahydro-4-méthyl-5,6-dioxo-as-triazin-3-yle, ainsi que de leurs sels ou des hydrates de ces sels, caractérisé en ce que l'on utilise des produits de départ substitués correspondants.
16. Un procédé selon la revendication 14 de préparation de l'acide (7R) - 7 - [2 - (2 - furyl) - 2 - (méthoxyimino) - acétamido] - 3 - /[(1,2,5,6 - tétrahydro - 2 - méthyl - 5,6 - dioxo - as - triazin - 3 - yl)thio] - méthyl/ - 3 - céphem - 4 - carboxylique, ainsi que de ses sels ou des hydrates de ces sels, caractérisé en ce que l'on utilise des composés de départ substitués correspondants.
17. Préparations pharmaceutiques, caractérisées en ce qu'elles contiennent un composé de formule générale
Figure imgb0039
où R représente un furyle, un thiényle ou un phényle éventuellement substitué par un halogène, un hydroxy, un alcoxy inférieur ou un alcoyle inférieur, R1 représente un alcoyle inférieur ou un amino- carbonylméthyle et X un groupe de formules
Figure imgb0040
où l'un des deux radicaux R2 et R3 ou R4 et R5 représente un hydrogène et l'autre un alcoyle inférieur, un carboxyméthyle ou un sulfométhyle, ou un sel pharmaceutiquement compatible de ce composé ou un hydrate d'un tel sel.
EP78100078A 1977-06-03 1978-06-01 Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques Expired EP0000005B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
LU77485 1977-06-03
LU77485 1977-06-03
CH3142/78 1978-03-22
CH314278 1978-03-22

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EP0000005A1 EP0000005A1 (fr) 1978-12-20
EP0000005B1 true EP0000005B1 (fr) 1980-10-29

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EP (1) EP0000005B1 (fr)
JP (1) JPS5412394A (fr)
AR (1) AR225134A1 (fr)
AT (2) AT362501B (fr)
AU (1) AU518648B2 (fr)
BR (1) BR7803565A (fr)
CA (1) CA1114808A (fr)
CU (1) CU21118A (fr)
DE (2) DE2860248D1 (fr)
DK (1) DK246878A (fr)
ES (2) ES470442A1 (fr)
FI (1) FI781754A7 (fr)
FR (1) FR2393000A1 (fr)
GB (1) GB1599232A (fr)
GR (1) GR73554B (fr)
HU (1) HU182498B (fr)
IE (1) IE46903B1 (fr)
IL (1) IL54803A (fr)
IT (1) IT1098306B (fr)
MC (1) MC1195A1 (fr)
NL (1) NL7805715A (fr)
NO (1) NO781934L (fr)
NZ (1) NZ187392A (fr)
PH (1) PH14653A (fr)
PT (1) PT68134A (fr)
SE (1) SE7806465L (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4200745A (en) * 1977-12-20 1980-04-29 Eli Lilly And Company 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins
FR2432521A1 (fr) * 1978-03-31 1980-02-29 Roussel Uclaf Nouvelles oximes o-substituees derivees de l'acide 7-amino thiazolyl acetamido cephalosporanique, leur procede de preparation et leur application comme medicaments
MC1259A1 (fr) * 1978-05-30 1980-01-14 Hoffmann La Roche Derives acyles
NO782998L (no) * 1978-07-19 1980-01-22 Hoffmann La Roche Cephalosporinestere og -etere.
US4472574A (en) * 1981-05-22 1984-09-18 Hoffman-La Roche Inc. Process for the manufacture of a cephem carboxylic acid derivative
US4698338A (en) * 1986-02-19 1987-10-06 Eli Lilly And Company 7[2-(2-aminothiazol-4-yl)-2-benzyloximino]acetamido-3[4-alkyl-5-oxo-6-hydroxy-3,4-dihydro-1,2,4-triazin-3-yl]thiomethyl cephalosporins

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1399086A (en) * 1971-05-14 1975-06-25 Glaxo Lab Ltd Cephalosporin compounds
CH609989A5 (en) * 1974-06-21 1979-03-30 Hoffmann La Roche Process for the preparation of acyl derivatives
CA1100129A (fr) * 1974-08-02 1981-04-28 William H.W. Lunn Traduction non-disponible
GB1555471A (en) * 1975-06-19 1979-11-14 Glaxo Lab Ltd 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof
GB1576625A (en) * 1976-04-12 1980-10-08 Fujisawa Pharmaceutical Co Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof
GB1596278A (en) * 1976-11-30 1981-08-26 Glaxo Operations Ltd 7-(-oxyimino-acetamino)cephalosporin derivatives

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PT68134A (en) 1978-07-01
FI781754A7 (fi) 1978-12-04
AT362501B (de) 1981-05-25
HU182498B (en) 1984-01-30
IE46903B1 (en) 1983-11-02
AT365197B (de) 1981-12-28
ATA345980A (de) 1981-05-15
IL54803A0 (en) 1978-07-31
NL7805715A (nl) 1978-12-05
DE2860248D1 (en) 1981-01-29
IE781056L (en) 1978-12-03
ES470442A1 (es) 1979-10-01
GR73554B (fr) 1984-03-14
CA1114808A (fr) 1981-12-22
CU21118A (es) 1983-04-06
AR225134A1 (es) 1982-02-26
NZ187392A (en) 1984-05-31
JPS5412394A (en) 1979-01-30
AU518648B2 (en) 1981-10-15
FR2393000A1 (fr) 1978-12-29
DE2824065A1 (de) 1978-12-14
DK246878A (da) 1978-12-04
GB1599232A (en) 1981-09-30
IT1098306B (it) 1985-09-07
FR2393000B1 (fr) 1982-10-29
SE7806465L (sv) 1978-12-04
BR7803565A (pt) 1979-02-20
ES478115A1 (es) 1979-06-01
IT7824165A0 (it) 1978-06-02
IL54803A (en) 1982-01-31
NO781934L (no) 1978-12-05
MC1195A1 (fr) 1979-02-23
ATA403578A (de) 1980-10-15
AU3658878A (en) 1979-12-06
PH14653A (en) 1981-10-14
EP0000005A1 (fr) 1978-12-20

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