EP0528985A1 - Esters de cephalosporine utiles en tant qu'antibiotiques - Google Patents

Esters de cephalosporine utiles en tant qu'antibiotiques

Info

Publication number
EP0528985A1
EP0528985A1 EP91911052A EP91911052A EP0528985A1 EP 0528985 A1 EP0528985 A1 EP 0528985A1 EP 91911052 A EP91911052 A EP 91911052A EP 91911052 A EP91911052 A EP 91911052A EP 0528985 A1 EP0528985 A1 EP 0528985A1
Authority
EP
European Patent Office
Prior art keywords
compound
disulfide
desfuroylceftiofur
methyl
ester
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.)
Withdrawn
Application number
EP91911052A
Other languages
German (de)
English (en)
Inventor
Terry J. Gilbertson
Catherine L. Gatchell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0528985A1 publication Critical patent/EP0528985A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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 new cephalosporin esters, which compounds are useful as antibiotics, primarily for treating valuable warm-blooded animals to resist, ward off or combat pathogenic infections caused by bacteria susceptible to these cephalosporin compounds.
  • cephalosporin antibiotic ceftiofur named as 7-[2-(amino-1,3-thiazol-4-yl)-2- (methoxyimino)acetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid, its alkali metal, alkaline earth metal and amine salts of the carboxylic acid group and easily hydrolyzable ester groups thereof are described and claimed in Labeeuw et al U.S. Patent No. 4,464,367.
  • a hydrohalide salt of ceftiofur is described and claimed in Amin et al. U.S. Patent No. 4,902,683.
  • Desacetyl cefotaxime, 7-[2-(2-amino-1,3-thiazo l-4-yl)-(syn)-2-methoxyiminoacetamido]-3- hydroxymethylceph-3-em-4-ca ⁇ boxylic acid, is disclosed in a publication entitled "Disposition of Cefotaxime in Rat, Dog and Man" by C. M. Macdonald, et al in Arzneistoffmaschine Drug Research, 34 (Il), No. 12 (1984), pp. 1719 to 1723.
  • the present invention particularly provides: A compound of the formula I
  • n is one to five, inclusive.
  • C i -C j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C 1 -C 4 alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof.
  • the compound of Formula I is useful as an active antibiotic drug compound in pharmaceutical dosage forms for treating valuable warm-blooded animals or humans.
  • this compound will be especially useful as a veterinary antibiotic drug to treat valuable warm-blooded animals such as cattle, horses, sheep, monkeys, goats, dogs, cats and the like to fight the effects of bacterial infections caused by organisms such as Pasteurella hemolytica, P.multocida, Haemophilus pleuropneumoniae, H.somnus, Escherichia coli, Salmonella spp., Staphylococcus aureus, Streptococcus agalactiae, Strep, bovis, Strep, dysgalactiae, Strep, faecatis, Strep, uberis, Salmonella typhimurium, E.coli, Staphyloccus aureus, and the like, some of which are commonly associated with infections referred to as "shipping fever" in animals.
  • Chart A illustrates the preparation of the esters of the present invention.
  • Chart B describes the preparation of the R 1 -desfuroyl ceftiofur disulfide sodium salt which is used as the starting material for Chart A.
  • the compounds of the present invention have the advantage of increased oral bioavailability over other cephalosporin compounds.
  • these compounds are more orally bioavailable than the known cephalosporin antiobiotic ceftiofur.
  • the compounds of the present invention are preferably orally administered in the form of, for example, tablets, capsules and soluble powders. Such means of administration would be readily known and available to one of ordinary skill in the art.
  • the compounds of this invention are administered in accordance with the preceding description to provide from about 1 mg to about 500 mg of me compound per dose.
  • An effective amount of the compound provided per dose is that amount sufficient to obtain antibiotic effects within me aforesaid non-toxic range.
  • an effective amount of the compound is provided to a recipient within a range from about 0.2 mg/kg to about 100 mg/kg of body weight of the recipient.
  • Preferred dosages for most applications are 0.2 mg/kg to 10.0 mg/kg of body weight of the compound depending upon the animal being treated.
  • concentration of the compound may be 1%-20%, preferably 5%-10% in a carrier, such as a pharmaceutical cream base.
  • the compounds of the present invention are useful for obtaining antibiotic effects in mammals, for example, valuable warm-blooded animals such as dogs, cats, horses, and other commercially valuable animals, by administering to the mammals an effective, non-toxic amount of the compounds of the present invention.
  • the sodium salt is dissolved in dimethylformamide (10ml) and cooled to -5°C.
  • Iodoalkyloxy acylate or alkyl-iodoalkyl carbonate (2.44mmol) is added with stirring, and die mixture is stirred at RT for 30 minutes. It is poured into a mixture of ethyl acetate (50ml) and ice cold H 2 O (40ml) and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (40ml). The combined ethyl acetate layer is washed with ice cold H 2 O (3x40ml) and dried over magnesium sulfate.
  • a solution of iodomethyl acetate (0.2 g) in dimethylformamide (0.5 ml) is added slowly with stirring, and the mixture is stirred at room temperature for 30 minutes.
  • the mixture is poured into a mixture of ethyl acetate (25 ml) and chilled water (10 ml) and the organic layer is separated.
  • the aqueous layer is extracted with ethyl acetate (2 x 15 ml).
  • the combined organic layer is washed with chilled water (3 x 15 ml) and saturated sodium chloride solution (15 ml) and dried over sodium sulfate.
  • the organic layer is evaporated in vacuo to get a brown viscous oil.
  • HPLC of the product shows no peak in 1:1 methanohwater.
  • 4-Methoxphenyl-desfuroylceftiofur disulfide sodium (474 mg) is dissolved in dimethylformamide (3.0 ml) and cooled to -10 to -20°C.
  • a solution of iodomemyl acetate (0.2 g) in dimethylformamide (0.5 ml) is added slowly with stirring, and the mixture is stirred at room temperature for 30 minutes.
  • the mixture is poured into a mixture of ethyl acetate (25 ml) and chilled water (10 ml), and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2 x 15 ml).
  • the combined organic layer is washed with chilled water (3 x 15 ml) and saturated sodium chloride solution (15 ml), and dried over sodium sulfate.
  • the organic layer is concentrated in vacuo to get a brown solid. It is dissolved in methylene chloride and loaded onto 8 g silica gel column and eluted with 1:1 methylene chloride: ethyl acetate. Those fractions containing pure product are combined and concentrated in vacuo to get a yellow viscous oil. It is crystallized from ethyl acetate-ethyl ether to give 106 mg of an off-white solid.
  • HPLC of the product shows a small broad peak at about 20 minutes in 1 : 1 methanol:water.
  • the aqueous layer is extracted with ethyl acetate (2 x 15 ml).
  • the combined organic layer is washed with chilled water (3 x 15 ml) and saturated sodium chloride solution (15 ml), and dried over sodium sulfate.
  • the organic layer is concentrated in vacuo to get a brown solid. It is dissolved in methylene chloride and loaded onto 10 g silica gel column and eluted with 1:1 methylene chloride: ethyl acetate. Those fractions containing pure product are combined and concentrated in vacuo to get a yellow solid. It is recrystallized from ethyl acetate-ethyl ether to give 99 mg of an off-white solid.
  • Methyl-desfuroylceftiofur disulfide sodium (0.50 g) is dissolved in dimethylformamide (3.7 ml) and cooled to -10 to -20°C.
  • a solution of iodometiiyl acetate (0.25 g) in dimethylformamide (1.0 ml) is added slowly with stirring, and the mixture is stirred for another 10 minutes.
  • the mixture is poured into a mixture of ethyl acetate (30 ml) and chilled water (15 ml) and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2 x 20 ml).
  • the combined organic layer is washed with chilled water (3 x 20 ml) and saturated sodium chloride solution (20 ml) and dried over sodium sulfate.
  • the organic layer is evaporated in vacuo to get a light yellow solid. It is dissolved in methylene chloride and loaded onto 6 g silica gel column and eluted with 1:1 methylene chloride: ethyl acetate. Those fractions containing pure product are combined and concentrated in vacuo to get a light yellow solid. It is recrystallized from methanol-ethyl acetateethyl ether to give 92 mg of a white solid.
  • HPLC of the sample shows a single peak in 1:1 methanol: water.
  • mice 12-14 g weanling female mice 21-25 days old Crl:CD-1 (ICR) BR Swiss mice are used.
  • bacteria Pasteurella hemolytica or Salmonella typhimurium are mixed with 2% brewer's yeast (as adjuvant for infection) and administered intraperitioneally at approximately 100 LD50 doses.
  • Antibiotics (0.1 ml) are administered per os into the stomach, using a 22G oral dosing needle, immediately after and at post-challenge exposure hours 24 and 48. Groups of 6 to ten mice are injected at each dosage level of antibiotic and at least 5, 2-fold serial dilutions of antibiotic are used for a single determination.
  • Measurement of antibiotic effectiveness is calculated on post-challenge exposure day 6 and is reported as the ED50, the amount of antibiotic in milligrams per kilogram per day required to protect 50% of infected mice. This value is estimated by the statistical method of probit analysis. As mentioned, in all experiments the challenge-exposure dose is approximately 100 times the LD50. The LD50 for the bacteria is titrated for each experiment. Also, in each experiment, a nontreated, saline-dosed group is used to prove the lethality of the 100 LD50 dose.
  • test compounds are dissolved in 95% ethanol and diluted in sterile vehicle 122 (0.25% methyl cellulose) to a final concentration of 10% ethanol before final dilutions for the test in vehicle 122.
  • sterile vehicle 122 0.25% methyl cellulose
  • Ceftiofur sodium (25.0g) is dissolved in 500ml H 2 O and the pH of this solution, which is around 5, is adjusted to 9 with ammonium hydroxide. Then a solution of dithioerythritol (10.1g) in 250ml H 2 O is added and the white mixture is stirred at RT for 1 hr. The mixture is brought to between pH 3.0-3.5 with 85% phosphoric acid resulting in the precipitation of white solids. The solids are filtered and washed with H 2 O. After drying the solids in vacuo in a dessicator , the yield of the title product is about 16g.
  • Ceftiofur sodium of Preparation 2 (5.00g) is dissolved in 100ml H 2 O, and me pH of this solution is adjusted to 9 with NH 4 OH. Then a solution of dithioerythritol (2.25g) in 5ml H 2 O is added resulting in a cloudy solution, and the mixture is stirred at RT for 1 hr. MeOH (140ml) is added to the mixture to make it clear, then methyl methanetiiiolsulfonate (2.65g) in MeOH (30ml) is added slowly to the mixture causing the mixture to become opaque. The mixture is stirred at RT for 1 hr. The liquid is decanted into another flask to leave behind an orange viscous material.
  • the decanted MeOH is evaporated in vacuo to precipitate yellow viscous semi-solid material sticking to the sides of the flask. After discarding the remaining H 2 O in the flask, the residue in the flask is dissolved in a minimal volume of MeOH, then enough ice H 2 O is added to precipitate off-white solid clumps in white liquid. The liquid is discarded, and the solid is washed with ice H 2 O and dried in vacuo in a dessicator to give 4.65g of off-white crystals.
  • Methyl-desfuroylceftiofur disulfide of Preparation 3 (4.65g) is dissolved in tetrahydrofuran (10ml) and cooled to O°C.
  • Sodium 2-ethylhexanoate in tetrahydrofuran solution (14ml, 1.6g) is added causing the precipitation of a white solid. It is filtered and washed with acetone to give 2.91g of the title product.
  • the sodium salt of Preparation 4 (1.00g) is dissolved in dimethylformamide (10ml) and cooled to -5°C.
  • 1-Iodomethyl propionate (0.55g) is added with stirring, and the mixture is stirred at RT for 30 minutes. It is poured into a mixture of ethyl acetate (50ml) and ice cold H 2 O (40ml) and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (40ml). The combined ethyl acetate layer is washed with cold H 2 O (3x40ml) and dried over magnesium sulfate. The organic layer is concentrated in vacuo to get a light yellow solid.

Landscapes

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

Abstract

Esters de céphalosporine de la formule (I), dans laquelle R1 représente un groupe disulfure, et R2 représente le groupe de terminaison des esters. Ces composés sont utiles en tant qu'antibiotiques utilisés dans le traitement d'animaux à sang chaud afin de combattre les infections bactériennes pathogènes provoquant des maladies telles que la "pasteurellose du bétail" bien connue.
EP91911052A 1990-05-17 1991-05-15 Esters de cephalosporine utiles en tant qu'antibiotiques Withdrawn EP0528985A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52475690A 1990-05-17 1990-05-17
US524756 1990-05-17

Publications (1)

Publication Number Publication Date
EP0528985A1 true EP0528985A1 (fr) 1993-03-03

Family

ID=24090555

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91911052A Withdrawn EP0528985A1 (fr) 1990-05-17 1991-05-15 Esters de cephalosporine utiles en tant qu'antibiotiques

Country Status (4)

Country Link
EP (1) EP0528985A1 (fr)
JP (1) JPH05507485A (fr)
AU (1) AU7977591A (fr)
WO (1) WO1991017996A1 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3887691T2 (de) * 1987-11-10 1994-06-09 Upjohn Co Cephalosporin-antibiotika.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9117996A1 *

Also Published As

Publication number Publication date
JPH05507485A (ja) 1993-10-28
AU7977591A (en) 1991-12-10
WO1991017996A1 (fr) 1991-11-28

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