WO1996007659A1 - Nouveau cristal de compose de cephalosporine - Google Patents

Nouveau cristal de compose de cephalosporine Download PDF

Info

Publication number
WO1996007659A1
WO1996007659A1 PCT/JP1995/001769 JP9501769W WO9607659A1 WO 1996007659 A1 WO1996007659 A1 WO 1996007659A1 JP 9501769 W JP9501769 W JP 9501769W WO 9607659 A1 WO9607659 A1 WO 9607659A1
Authority
WO
WIPO (PCT)
Prior art keywords
inole
salt
acid
crystal
water
Prior art date
Application number
PCT/JP1995/001769
Other languages
English (en)
Japanese (ja)
Inventor
Kohji Kawabata
Takeshi Terasawa
Ayako Ohki
Fumiyuki Shirai
Hirofumi Yamamoto
Ryoichi Kawakami
Chiaki Hamaguchi
Original Assignee
Fujisawa 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
Priority claimed from ZA946888A external-priority patent/ZA946888B/xx
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU33989/95A priority Critical patent/AU3398995A/en
Priority to EP95930705A priority patent/EP0780393A4/fr
Publication of WO1996007659A1 publication Critical patent/WO1996007659A1/fr
Priority to US09/906,704 priority patent/US20010056089A1/en

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

Definitions

  • the present invention has the following chemical formula:
  • Compound (I) or a salt thereof is a cephalosporin antibiotic having extremely strong antibacterial activity. Due to its strong antibacterial activity and high urinary excretion rate in animals, oral or It is a compound that is expected to be a fosporin. However, the amorphous compound (I) or a salt thereof is physically and chemically unstable, and the compound (I) or a salt thereof can be obtained as a crystal. Due to the difficulty, it could not be developed as a pharmaceutical until then. Disclosure of the invention
  • the present inventors have conducted intensive studies and succeeded in obtaining the compound (I) or a salt thereof as a crystal, and this crystal has been obtained in the amorphous form. As a result, they have found that they are remarkably more stable to heat, light, and the like, and have excellent physical, chemical, and pharmaceutical properties, and completed the present invention.
  • the crystal of the solvate of the compound (I) or a salt thereof is a solvent in which the solvent is included as a part of the crystal lattice of the crystal of the compound (I) or a salt thereof.
  • the solvent may be included in the crystal lattice of the crystal of the compound (I) or a salt thereof, or may be attached thereto. Any combination of these may be used.
  • the solvent contained in the solvate crystals is harmful to the human body
  • the solvent is not particularly limited as long as it does not affect the solvent.
  • lower alcohols and acetates such as ethynoleanol and isopropyl alcohol
  • organic solvents such as lower alkyl ketones such as methyl ethyl ketone, and these solvents may be used alone or in combination.
  • the solvent is a hydrate in which the solvent is water only, or water and an organic solvent, particularly preferably water and ethyl alcohol monopropyl propylene alcohol. And solvates composed of water and lower alcohols.
  • the crystals of the compound (I) or a salt thereof of the present invention are not particularly limited with respect to the crystal form, but the solvent is a compound (I) or a crystal structure of the salt thereof. And crystals in which these solvents are included in the crystal structure of the compound (I) or a salt thereof.
  • the crystal of the solvate includes the inclusion-type crystal and the crystal to which a part of the solvent is attached, as well as the present invention.
  • the ratio of the amount of the solvent contained in the crystal of the solvate to one molecule of the compound (I) or one salt thereof is not particularly limited, but may be one molecule of the compound (I) or one molecule thereof.
  • the solvent contains water and an organic solvent
  • the number of water molecules is from 0.1 to 6 molecules, preferably from 0 to 1 molecule of compound (I) or a salt thereof.
  • the number of organic solvents is preferably from 0.1 to 2 molecules, preferably from 1 to 4 molecules.
  • the water molecule is Two to three molecules and 0.1 to two molecules of organic solvent.
  • the solvent is water alone, the number of water molecules is 1 to 6 molecules, preferably 1 to 4 molecules per compound (I) or one molecule of the salt thereof.
  • two to three molecules are particularly preferred, and the present inventors further analyzed the powder X-ray pattern of the crystal of compound (I).
  • the diffraction angles in the powder X-ray diffraction pattern were around 7.5 ′, 11.3 ′, 19.5 °, 21.3 ′, 24.5 °, It was found that crystals showing peaks around 25.9 ° and 29.0 ° were preferable. If the characteristics of the X-ray diffraction pattern are those described above or those similar thereto, they are included in the scope of the present invention.
  • the salt of compound (I) is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes a salt with a base or an acid addition salt, for example, an inorganic base salt [Alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.) ), Organic base salts [eg, trimethylammine salt, triethylammine salt, pyrimidine salt, picolimium salt) Salts, dicyclohexyl oleamine salts, N, N'-dibenzylidylenediamine salts, etc.), organic acid salts [for example, formate, acetate, trifluorene] B Acetate, maleate, tartrate, methansulfonate, benzenesulfonate, tonolenesulfo Salt, etc.], an inorganic acid salt [E.g., hydrochloride, hydrobromide, sulfate,
  • the amorphous compound (I) or a salt thereof can be produced, for example, according to Production Examples 1 to 21 of this specification.
  • the compound (I) obtained by the production method or a salt thereof can be used in the following method for producing a crystal.
  • Crystals of compound (I) or a salt thereof precipitate crystals under acidic conditions by cooling a solution containing compound (I) or a salt thereof, at room temperature or under heating. This makes it possible to manufacture.
  • Preferred examples of the solution containing the compound (I) or a salt thereof include, for example, an aqueous solution of the metal salt of the compound (I) or the salt thereof, or water and an organic solvent.
  • Preferred organic solvents used in this solution include lower alcohols such as ethyl alcohol and isoprovir alcohol, and lower alcohols. Lower alkyl ketones such as seton and methyl ethyl ketone are exemplified.
  • a solution containing the compound (I) or a salt thereof may be mixed with activated carbon, a nonionic adsorbent resin, alumina, or acid oxidized aluminum, if desired.
  • the acid is added by cooling, at room temperature or under heating.
  • the compound (I) or a salt thereof can be produced by making the mixture acidic and further performing an operation such as shrinkage as required.
  • the amount of the acid to be added is preferably such that the pH value of the solution is from 1 to 5.
  • the kind of acid is not particularly limited, and hydrochloric acid or the like can be used.
  • the crystals of a solvate containing an organic solvent may be subjected to elimination of the organic solvent, if desired. You can also.
  • the separation of the organic solvent may break the crystal structure by the usual vacuum drying method. Therefore, the supercritical gas extraction method using carbon dioxide gas or the like (see Japanese Patent Laid-Open Publication No. Hei 11-238589) or humid air may be used.
  • the organic solvent can be efficiently separated by the ventilation drying method or the like used.
  • the ventilation drying method using humid air pass the humid air or nitrogen with a humidity of 20% or more, preferably 30% or more through the sample, and remove the organic solvent according to the usual method. be able to . At this time, the moisture contained in the crystal can be controlled by the humidity.
  • the crystals of the compound (I) or a salt thereof obtained in this way are allowed to stand in an atmosphere of an organic solvent, so that the organic solvent contained in the crystals can be converted to another organic solvent. It can be replaced or the amount of organic solvent contained in the crystal can be increased. In addition, the moisture content of the crystal can be increased or decreased by leaving it in the air with different humidity.
  • Compound (I) or a compound (I) in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for administration and topical administration It is used in the form of a conventional pharmaceutical preparation containing the salt as an active ingredient.
  • the pharmaceutical preparation may be in the form of a solid, such as tablets, granules, powders, capsules, or in the form of a liquid, such as a suspension or the like.
  • L-sugar citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, tanolek, gelatin, agar It may contain commonly used additives such as lactocin, peanut oil, olive oil, cocoa butter, ethyl alcohol, and the like.
  • the dose of the crystal of compound (I) or a salt thereof varies depending on the age, condition, type of disease, type of crystal used, etc. of the patient, but generally, The daily dose may range from about ling to about 4000 mg / person or more.
  • the crystals of the compound (I) or a salt thereof according to the present invention are administered in a unit dose, and in the case of oral administration, tablets, granules, tablets containing about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1 OOOmg, It can be used as a powder or capsule for the treatment of pathogenic bacterial infections.
  • a male male rat of JCL (6-7 weeks old) was used.
  • the test compound became turbid in a 0.5% methylcellulose solution. Rats were fasted overnight before administration of ZOmgZ kg.
  • a urine sample collected from urine within 0 to 6 hours and 6 to 24 hours is used as a test organism, Bacillus subti 1 is ATCC 6633, as a test medium.
  • Sodium citrate agar medium (0.8% sodium citrate, 0.5% polypeptone, 0.3% beef strain) And 1.0% agar) were measured by the disk-plate diffusion method.
  • FAB-MASS fast atom bombardment mass spectrometry
  • FIG. 1 is a powder X-ray diffraction diagram of the crystals obtained in Example 4.
  • FIG. 2 is a powder X-ray diffraction diagram of the crystals obtained in Example 5.
  • FIG. 3 is a powder X-ray diffraction diagram of the crystals obtained in Example 6.
  • FIG. 4 is a powder X-ray diffraction diagram of the crystals obtained in Example 7.
  • FIG. 5 is a powder X-ray diffraction diagram of the crystals obtained in Example 8 (1).
  • FIG. 6 is a powder X-ray diffraction diagram of the crystals obtained in Example 9.
  • reaction solution After stirring the reaction solution at 80'C for 2 hours, it is added to a mixture of dilute aqueous sodium hydrogen carbonate solution and ethyl acetate. After separating the organic layer, wash with brine and dry with magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel chromatography.
  • suspension A Suspension of 4-chloromethyl-1-1-tritylpyrazole (198.3 g) in acetone (3.0 liters) and heating to 50 t for dissolution Let me do it. Add sodium iodide (165.6 g) at room temperature and stir for 1 hour at the same temperature. The reaction solution is poured into a mixture of water (3.0 liters) and ethyl acetate (3.0 liters), the organic layer is separated, and dried over magnesium sulfate. . The solvent is distilled off under reduced pressure, and the residue obtained is suspended in DMF (400 liters).
  • Example 4 The crystals obtained in Example 4 were air-dried at 35'C for 2 days using humid air having a humidity of 35 to 50% to remove the solvent, and then dried under reduced pressure to obtain 7? — [2— (2—Amino Chia Zonore 1 4 1 Nore) 1 2 — (Z) 1 (Hydroxymino) Acetamido] 1 3 — [(Pyra Zonore 1 4 ) [Methylthio] 13-sephemo-4 A monohydrate crystal of a hydrate containing 2.5 molecules of water (16.5 g) was obtained. This crystal showed the powder X-ray diffraction diagram of FIG.
  • Example 8 When the crystals obtained in Example 8 were added as seed crystals, crystallization gradually occurred. Further, the mixture is stirred for 10 hours with 1 N hydrochloric acid to maintain the pH at 3.8 to 4.3. The resulting precipitate is collected, washed with water (200 ml) and acetone (100 ml), dried under reduced pressure, and dried under reduced pressure. ) 1 2 — (Z) 1 (Hydroxymino) Acetamido] 1 3 — [(Villa ⁇ 1 ⁇ 1) 4) Mechinorecho] 1 3- ⁇ Moon 4 — A crystal containing water (2.2 molecules) of carboxylic acid and acetate (0.37 molecules) was obtained. This crystal had the powder X-ray diffraction pattern shown in FIG.
  • Example 6 The crystals obtained in Example 6 were dried for 1 day using a vibrating fluidized bed drier made by Chuo Kakoki Co., Ltd. while maintaining the internal humidity at 35% to 50% and the temperature at 35. , And dried under reduced pressure. 75 1 [2 — (2-Aminozone 1-4- ⁇ ⁇ ) 1 2-(Z)-(Hydroxymino) acetamide] One three —
  • Example 8 (1) The crystal obtained in Example 8 (1) was filled in a cylindrical vessel having a filter plate at the bottom and having a capacity of about 200 ml, the outside temperature of the vessel and the fluid inlet temperature were set to about 40 ° C, and the pressure in the vessel was reduced to about 40 ° C. While adjusting to 200, flow carbon dioxide downward from the top of the container through the powder layer for 1 hour, and then add water from the supply port to extract isopropanol real alcohol.
  • Example 8 Water and isopro obtained by the same method as (1) 7-[2-(2-aminoazone 1-4-inore) 1 2-(Z) 1-(hydroxyimino) acetami C) — 3 — [(pyrazole-41-yl) methyno-rethiol] 1- 3 — C-fume 4-force Crystal of sulfonic acid (water: 2.4 molecules, isopropyranol) (Call: 0.57 molecules) was left in the isopropyl alcohol vapor atmosphere for 48 hours. As a result, 1.8 molecules each of water and isopropyl alcohol were added.
  • Example 12 Including water and isopropanol obtained by the same method as in Example 8 (1) 7 9 — [2- (2-aminothiazolone 1-4) 1 2 — (Z) 1 (Hydroxy imino) Acetamido] 1 3 — [(Pyrazone 1 4-inole) Meinorochio] 1 3 — SEFM ⁇ 4 Crystals of oleonic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau cristal d'acide 7β-[2-(2-aminothiazol-4-yl)-2-Z-(hydroxyimino)acétamido]-3-[(pyrazol-4-yl)-méthylthio]-3-céphem-4-carboxylique ou sel de cet acide. Ce composé est un antibiotique céphalosporine exerçant une activité antibactérienne puissante et présentant des propriétés remarquables sur les plans physique, chimique et pharmaceutique.
PCT/JP1995/001769 1994-09-07 1995-09-06 Nouveau cristal de compose de cephalosporine WO1996007659A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU33989/95A AU3398995A (en) 1994-09-07 1995-09-06 Novel crystal of cephalosporin compound
EP95930705A EP0780393A4 (fr) 1994-09-07 1995-09-06 Nouveau cristal de compose de cephalosporine
US09/906,704 US20010056089A1 (en) 1994-09-07 2001-07-18 Novel crystal of cephalosporin compound

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
ZA946888A ZA946888B (en) 1993-09-09 1994-09-07 New cephem compounds
ZA946888 1994-09-07
US39274095A 1995-03-07 1995-03-07
US40077095A 1995-03-08 1995-03-08
US08/400,770 1995-03-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US08/793,601 Continuation US20010007903A1 (en) 1994-09-07 1995-09-06 Novel crystal of cephalosporin compound

Publications (1)

Publication Number Publication Date
WO1996007659A1 true WO1996007659A1 (fr) 1996-03-14

Family

ID=27410043

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001769 WO1996007659A1 (fr) 1994-09-07 1995-09-06 Nouveau cristal de compose de cephalosporine

Country Status (1)

Country Link
WO (1) WO1996007659A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09507283A (ja) * 1993-10-22 1997-07-22 アセプティック コントロールス インヴェストメント カンパニー サテライト弁座を有する弁室壁

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09507283A (ja) * 1993-10-22 1997-07-22 アセプティック コントロールス インヴェストメント カンパニー サテライト弁座を有する弁室壁

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0780393A4 *

Similar Documents

Publication Publication Date Title
KR100245938B1 (ko) 트리아졸릴티오메틸티오 세팔로스포린 염산염, 그의 결정성 수화물 및 이들의 제조방법
JP5748954B2 (ja) チアゾリジンジオン化合物の結晶およびその製造方法
US8614331B2 (en) Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium
JP5844508B2 (ja) メシル酸イマチニブのｆ結晶形
JP2007523896A (ja) アスコマイシンの結晶形態とその調製方法
WO2006104141A1 (fr) Dérivé de 3-propénylcéphème
JP2008506784A (ja) 結晶形ミコフェノール酸・ナトリウム
JP2009173685A (ja) 非結晶性及び結晶性ロサルタン・カリウム、及びそれらの調製方法
US20050209211A1 (en) Trihemihydrate, anhydrate and novel hydrate forms of Cefdinir
WO2018184185A1 (fr) Cristal de sel d'addition d'ozanimod, procédé de préparation, composition pharmaceutique, et utilisations
JP2006514108A (ja) パントプラゾールナトリウムの固体状態、それらの調製方法、及び公知のパントプラゾールナトリウム水和物の調製方法
US20060029674A1 (en) Stable amorphous Cefdinir
JP2007532579A (ja) 安定な非晶質セフジニル
JP2023535447A (ja) ベルモスジル及びベルモスジル塩の固体形態
EP2093225A1 (fr) Procédé de préparation de la forme ß de l'hydrobromide d'élétriptan crystallin
JP2641745B2 (ja) 結晶性β−ラクタム水和物
CN117362305A (zh) 9-ing-41的固体形式
JP2723088B2 (ja) セファロスポリン化合物の新規な結晶
WO2023160405A1 (fr) FORME POLYMORPHE DE SEL DISODIQUE DE β-NICOTINAMIDE MONONUCLÉOTIDE RÉDUIT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
JPH0741484A (ja) セフェム化合物及び抗菌剤
WO2013174035A1 (fr) Procédé de préparation d'une forme cristalline anhydre i du phosphate de sitagliptine
WO1996007659A1 (fr) Nouveau cristal de compose de cephalosporine
JPH10195076A (ja) 結晶形態のカルバペネム化合物
TW201008935A (en) Crystalline forms of thiazolidinedione compound and its manufacturing method
WO2006121151A1 (fr) Cristal de compose 1-methylcarbapenem

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN FI HU MX NO NZ RU US US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2199253

Country of ref document: CA

Ref country code: CA

Ref document number: 2199253

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1995930705

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 08793601

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1995930705

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1995930705

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995930705

Country of ref document: EP