WO1988010262A1 - Compose cristallin de cephalosporine - Google Patents

Compose cristallin de cephalosporine Download PDF

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Publication number
WO1988010262A1
WO1988010262A1 PCT/JP1987/000416 JP8700416W WO8810262A1 WO 1988010262 A1 WO1988010262 A1 WO 1988010262A1 JP 8700416 W JP8700416 W JP 8700416W WO 8810262 A1 WO8810262 A1 WO 8810262A1
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WIPO (PCT)
Prior art keywords
added
methyl
water
compound
solution
Prior art date
Application number
PCT/JP1987/000416
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English (en)
Japanese (ja)
Inventor
Susumu Nakagawa
Ryosuke Ushijima
Fumio Nakano
Koji Yamada
Eiichi Mano
Original Assignee
Banyu Pharmaceutical Co., Ltd.
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 Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to PCT/JP1987/000416 priority Critical patent/WO1988010262A1/fr
Publication of WO1988010262A1 publication Critical patent/WO1988010262A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—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, cefaclor, or cephalexine

Definitions

  • the present invention relates to a cephalosporin compound useful as a therapeutic agent for bacterial infections in the field of medicine, and more particularly, to crystalline (6R, 7R) -7-[(Z) -2- (2-aminothiazole-4) -Yl)-2- (1-carboxy-1-methylethoxyimino) acetamide]-3- (5: 6-dihydroxy-2-methyl-2-isoindolindium) methyl-3-cefem-4 -Power This is related to ruboxylate hydrate.
  • the present inventors have proposed (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-force ruvoxy-1-methylethoxyimino) acetoamido. -]-3- (5,6-Dihydroxy-2-methyl-2-isoindolindium) methyl-3-cef-4-carboxylate
  • the present invention has been completed by finding that a crystalline hydrate of the compound is superior in stability to an amorphous powder.
  • the present invention relates to a stable crystalline (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide. De] -3- (5,6-dihydroxy-2-methyl-2-isoindolinidium) methyl-3-cephem-4-hydroxylboxyl hydrate.
  • the crystalline hydrate of the compound [I], which is the target compound of the present invention, comprises a free form of the compound [I], a solvate thereof, a base addition salt thereof or an acid addition salt thereof formed of water or a hydrophilic organic compound.
  • the solvent can be produced by adding a base, if necessary, and dissolving, and then adding an acid to adjust the solvent to 3-5.
  • the compound [I], a solvate thereof, an acid addition salt or a base addition salt thereof, which is a raw material of the present invention may be prepared according to the method described in Reference Examples below and a method similar thereto. It is manufactured by the method.
  • the solvates thereof include, for example, crude hydrates, methanol hydrates, and acetone hydrates
  • the base addition salts thereof include, for example, sodium salts and potassium salts.
  • the acid addition salt examples include a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and a salt with an organic acid such as acetic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid.
  • the raw material according to the present invention is suspended in water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetonitrile, acetone or a mixed solvent thereof at ice or at room temperature, and if necessary, for example, sodium hydroxide.
  • a base such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or sodium bicarbonate, preferably sodium hydroxide or potassium hydroxide, is added, and the mixture is dissolved at pH 5.5 to 7.0. Then, slowly add an acid such as hydrochloric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid to 0-.
  • the hydrate of compound [I], which is the target compound of the present invention includes hydrates containing 4 to 10 molecules of water molecules.
  • hydrates containing 4 to 10 molecules of water molecules For example, tetrahydrate, pentahydrate of compound [I] , Hexahydrate, hemihydrate or octahydrate.
  • the target compound of the present invention can also be produced by the following method. That is, a free form of compound [I], a solvate thereof, a base addition salt or an acid addition salt thereof are added to a base and an antioxidant as necessary, and dissolved in water. After purifying by chromatography using an activated carbon treatment and / or a water-insoluble carrier having a hydrophobic group according to the concentration of the compound [I], the fraction containing the compound [I] is concentrated under reduced pressure, if necessary, and then acidified. The target compound of the present invention is crystallized by adjusting the pH to 3 to 5, or after purification by the chromatography, the fraction containing the compound [I] is concentrated, and adjusted to 0.5 to 2.0 with an acid.
  • the fraction containing compound [I] is concentrated under reduced pressure if necessary, and if necessary, is adjusted to ⁇ 3 to 5 to prepare the target compound of the present invention. Can be crystallized.
  • known antioxidants such as sodium hydrogen sulfite, sodium sulfite, L-ascorbic acid or hydroquinone can be used as the antioxidant.
  • the water-insoluble carrier having a hydrophobic group include porous polymers such as Diaion HP-20®, Diaion HP-21, Diaion SP-206® or Diaion SP 207® (Mitsubishi Chemical).
  • One example is a chemically bonded type gel such as ODS.
  • the elution layer used in the chromatography using these carriers is water or an alkali metal phosphate buffer having a pH of 4 to 7 or a hydrophilic solvent such as 80% methanol, ethanol, tetrahydrofuran or acetone. An aqueous solution containing an organic solvent is fisted. Further, the above-mentioned antioxidant may be added to the eluent.
  • the target compound of the present invention when used as a medicine, it can be used as the following thorns.
  • the compounds of the present invention can be mixed with solid or liquid excipients and used in the form of pharmaceutical preparations suitable for oral administration, parenteral administration or external administration.
  • Pharmaceutical preparations include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules or granules, and external preparations such as ointments and suppositories.
  • Previous The preparations described above may contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents or emulsifiers. For example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like are used as the base.
  • a dissolving solution such as distilled water for injection, physiological saline or Ringer's solution, and a preservative such as methyl paraoxybenzoate or propyl paraoxybenzoate are used.
  • Liquids such as syrups and emulsions include sorbitol syrup, methylcellulose, darcos, sucrose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, edible oil, tonsil oil, coconut ash, oily esters
  • sorbitan monooleate propylene glycol, glycerin, ethyl alcohol or water, emulsifiers such as gum arabic, gelatin or lecithin, and surfactants such as twin or span are used.
  • lactose sucrose, corn starch, calcium phosphate, magnesium stearate, talc, caic acid, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol or sodium lauryl sulfate are used.
  • base of the ointment or suppository for example, cocoa butter, glycerides, polyethylene glycols, white cellulose, or the like is used. If necessary, a surfactant or an absorption enhancer may be used.
  • the target compound of the present invention can be used for the treatment and prevention of bacterial infections such as respiratory tract infections, urinary tract infections, gynecological infections, purulent diseases or surgical infections.
  • the dose of the target compound of the present invention varies depending on the age and symptoms of the patient, but it is usually used in the range of 135 mg / kg per day, and should be administered in 5 to 35 mg / kg per day in 2 to 4 divided doses. Is preferred.
  • the present invention will be described specifically with reference to Experimental Examples, Examples, and Reference Examples, but the present invention is not limited thereto. Experimental example Stability test
  • the crystalline powder of the compound [I] hydrate and the amorphous powder of the compound [I] prepared by the method of the present invention, that is, the method of Example 1, were stored in a vial at 25 ° C. fe.
  • the residual ratio was measured by high performance liquid chromatography (HP IX). The results are shown in the table below.
  • the compound of the present invention is extremely excellent in storage stability and the content reduction rate is low as compared with the amorphous powder. Therefore, the compound of the present invention is more suitable for use as a therapeutic agent for bacterial infection.
  • Reference example 1
  • the reaction solution was poured into a mixture of 2.5fi of ethyl acetate, 1.7J2 of water and 150ra £ of 203 ⁇ 4 sodium thiosulfate. After separation, the organic layer was washed with a mixture of 0.9J2 of water and 100 of saturated saline, and then 400m of saturated saline. Washed for £. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methylene chloride (210 mfi), and nucyl iodide (220 ml, 3.5 mol) was added, and the mixture was allowed to stand at room temperature for one hour.
  • methylene chloride 210 mfi
  • nucyl iodide 220 ml, 3.5 mol
  • reaction solution was cooled to -10 ° C or less, and P-methoxybenzyl (6R, 7R) -7-amino-3-chloromethyl-3-sephae was added.
  • 52-4-carboxylate 'hydrochloride (526.9 g) (1.3 mol) was added, and triethylamine 453.3 ml (3.25 mol) was added dropwise at ⁇ 5 ° C. or lower over 30 minutes.
  • 3.9 ⁇ of cold water was added, the organic layer was separated, and washed with a mixed solution of 910 mL of saturated aqueous sodium hydrogen carbonate and water 3J2, and then with saturated saline 3J2.
  • the reaction solution was added to a mixture of ethyl acetate 16 ⁇ cooled to 5 ° C or less, water and concentrated hydrochloric acid (215 mL), the organic layer was separated, washed with water (7.8fi), dried over anhydrous magnesium sulfate, and then dried under reduced pressure. And concentrated to dryness.
  • the residue was dissolved in methylene chloride, 780 ml of anisol, 2.8 ⁇ of acetic acid and 780 ⁇ of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 20 hours.
  • the reaction solution was added with stirring to 39 ° C. of acetone cooled to 5 ° C. or lower, and stirred at the same temperature for 1 hour.
  • the concentrate was added with trifluoroacetic acid (8.8 8.), and then subjected to reverse phase chromatography (0DS, 380 ml £) to elute with water, 1.5% tetrahydrofuran aqueous solution and 2.5 tetrahydrofuran aqueous solution.
  • the brush containing the target substance was collected, concentrated under reduced pressure until some insolubles began to precipitate, seeded, and left at room temperature for 40 minutes. The solution was further concentrated under reduced pressure to about 80 ⁇ and left overnight at 5 ° C.
  • Moisture content (Test method for loss on drying): 11.5%
  • the column labeled 2 ⁇ shows the diffraction angle
  • the column labeled with shows the interplanar spacings
  • the column labeled I / Imax shows the relative intensities.
  • the concentrate was subjected to HP-20 (3.2 J2) column chromatography, and eluted sequentially with water, a 303 ⁇ 4 aqueous solution of methanol, a 353 ⁇ 4 aqueous solution of methanol, and a 50% aqueous solution of ethanol.
  • the fractions containing the desired product were collected, adjusted to ⁇ 4.8 with sodium hydroxide, and concentrated under reduced pressure. Crystals precipitated during the concentration, but were concentrated to about 1 J2.
  • 80 mL of 6N phosphoric acid was slowly dropped into the concentrated solution at 20 to 22 ° C to adjust the pH to 4.4, followed by stirring at 5 ° C.
  • the precipitated crystals were collected by filtration, washed twice with 70 ml of cold water, sequentially with ethanol 100 and acetone 100, and air-dried at room temperature for 5 hours to obtain 141.9 g (yield 60%) of the title compound.
  • the fractions containing the target compound were collected, concentrated under reduced pressure until some insolubles began to precipitate, seeded, allowed to stand at room temperature for 40 minutes, further concentrated under reduced pressure to about 200, and left overnight at 5 ° C.
  • the precipitated crystals were collected by filtration, washed successively with 50 ml of cold water, 50 ethanol and 50 acetone, and air-dried at room temperature for 7 hours to obtain 31.3 g (yield: 82.8%) of the title compound.
  • the precipitated crystals were collected by filtration, washed successively with 240 ml of cold water, 300 ml of ethanol and 300 ml of acetone, and air-dried at room temperature for 5 hours to obtain 454.6 g (yield: 83%) of the title compound.
  • Example 4 300 g of the hydrate crystal obtained in Example 4 (content by HPLC method: 89) was suspended in 2 fi of water, cooled to about 5 ° C, and 425 mL of 1N sodium hydroxide was gradually added to adjust the pH to 6.2. It was adjusted. The insoluble material was removed by filtration, 500 mL of water was added to the filtrate, and then 6N phosphoric acid 70 was added dropwise to adjust the pH to 4.85 and raise the temperature of the solution to 17 to 20 ° C. After stirring this solution for a while to precipitate crystals, add 140 ⁇ of phosphoric acid dropwise, hold it at ⁇ 4.6 or more, finally adjust it to ⁇ 4.7, and stir at 17-20 ° C for 3 hours did.
  • Example 4 7.0 g of the hydrate crystals (content 89% according to the HPLC method) obtained in Example 4 were suspended in 11 £ of water 50], cooled to about 5 ° C, and 9. lm £ of sodium hydroxide IN was added. PH was adjusted to 6.3. The insoluble material was removed by filtration, 10 mL of water was added to the filtrate, and 9.3 mL of 1N hydrochloric acid was added to adjust the pH to 4.0, and the temperature of the solution was adjusted to 17 to 20 ° C.
  • Example 4 1.0 g of the hydrate crystal obtained in Example 4 (content by HPLC method: 89%) was suspended in 15 ml of water, cooled to about 5 ° C, and 1.3 ml of 1N sodium hydroxide was added thereto. Adjusted to .0. The insoluble material was removed by filtration, 3.7 mL of water was added to the filtrate, and the mixture was diluted with 30 trifluoroacetic acid aqueous solution. 0.25 ⁇ 5 was added to adjust to pli4.2, and the temperature of the solution was raised to 17 to 20 ° C. A seed crystal of the title compound was added thereto, and the mixture was stirred at 17 to 20 ° C for 3.5 hours.
  • a seed crystal of the title compound was added thereto, and the mixture was stirred for a while to precipitate crystals.After that, 0.47 ⁇ of 6N phosphoric acid was added dropwise, and the pH was maintained at 4.6 or higher. Stir at 20 ° C for 3 hours fe. The precipitated crystals are collected by filtration, washed twice with water ( ⁇ ), and then with a 50% aqueous ethanol solution ( ⁇ ). ° /.
  • Moisture content (Test method for loss on drying): 19.0% Potential for industrial use

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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

Hydrate cristallin stable de (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-méthyléthoxyimino)-acétamido]-3-(5,6-dihydroxy-2-méthyl-2-isoindolinium)-méthyl-3-céphem-4-carboxylate, utile en tant qu'agent de traitement de maladies provoquées par des infections bactériennes.
PCT/JP1987/000416 1987-06-25 1987-06-25 Compose cristallin de cephalosporine WO1988010262A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1987/000416 WO1988010262A1 (fr) 1987-06-25 1987-06-25 Compose cristallin de cephalosporine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1987/000416 WO1988010262A1 (fr) 1987-06-25 1987-06-25 Compose cristallin de cephalosporine

Publications (1)

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WO1988010262A1 true WO1988010262A1 (fr) 1988-12-29

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PCT/JP1987/000416 WO1988010262A1 (fr) 1987-06-25 1987-06-25 Compose cristallin de cephalosporine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100512870B1 (ko) * 2002-10-15 2005-09-07 주식회사 엔지켐 7α-메톡시세팔로스포린 유도체 나트륨염 7수화물의제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5657791A (en) * 1979-10-02 1981-05-20 Glaxo Group Ltd Improvement for cephalosporin antibiotic
JPS61263985A (ja) * 1985-05-16 1986-11-21 Teijin Ltd セフアロスポリン誘導体
JPS61267587A (ja) * 1984-12-27 1986-11-27 Banyu Pharmaceut Co Ltd 新規セファロスポリン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5657791A (en) * 1979-10-02 1981-05-20 Glaxo Group Ltd Improvement for cephalosporin antibiotic
JPS61267587A (ja) * 1984-12-27 1986-11-27 Banyu Pharmaceut Co Ltd 新規セファロスポリン誘導体
JPS61263985A (ja) * 1985-05-16 1986-11-21 Teijin Ltd セフアロスポリン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100512870B1 (ko) * 2002-10-15 2005-09-07 주식회사 엔지켐 7α-메톡시세팔로스포린 유도체 나트륨염 7수화물의제조방법

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