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WO1998039305A1 - Forme cristalline d'un compose de bis 1,2,3-triazole - Google Patents

Forme cristalline d'un compose de bis 1,2,3-triazole Download PDF

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Publication number
WO1998039305A1
WO1998039305A1 PCT/JP1998/000882 JP9800882W WO9839305A1 WO 1998039305 A1 WO1998039305 A1 WO 1998039305A1 JP 9800882 W JP9800882 W JP 9800882W WO 9839305 A1 WO9839305 A1 WO 9839305A1
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Prior art keywords
crystals
compound
mixture
water
added
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PCT/JP1998/000882
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English (en)
Inventor
Yukio Mizuno
Taihei Yamane
Motoki Ikeuchi
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Takeda Chemical Industries, Ltd.
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Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU61197/98A priority Critical patent/AU6119798A/en
Publication of WO1998039305A1 publication Critical patent/WO1998039305A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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

Definitions

  • This invention relates to stabilized crystals of an azole compound useful as therapeutic agent of mycosis [described on for example EP-0567982].
  • an azole compound such as ( 2- [( 1R,2R) -2- (2, 4-difluorophenyl ) -2-hydroxy-l- methyl-3- ( 1H-1 , 2 , 4-triazol-l-yl ) propyl ] -4- [ 4- ( 2 , 2 , 3 , 3- tetrafluoropropoxy)phenyl ] -3- ( 2H, 4H) -1 , 2 , 4-triazolone) (hereinafter simply called Compound A), which has an excellent antifungal activity, is disclosed.
  • an oxirane compound i.e. ( 2R, 3S) -2- ( 2 , 4-difluorophenyl ) -3-methyl- 2-( 1H-1,2 ,4-triazol-l-yl)methyloxirane (hereinafter simply called Compound B) is allowed to react with a triazolone compound, i .e .4- [ 4-( 2 , 2 , 3 , 3- tetrafluoropropoxy)phenyl]-3-(2H, 4H) -1, 2 , 4-triazolone (hereinafter simply called Compound C) for 27 hours at 80°C in the presence of potassium carbonate, allowing the reaction to proceed for further 4 hours at 100 °C, washing the reaction mixture by shaking with water (once), with a IN aqueous solution of sodium hydroxide (three times), with IN HC1 (twice) and a saturated aqueous
  • the quality and yield of the crystalline Compound A, m.p.154-155°C, (Form I crystal) obtained in Working Example 5 of the above-mentioned EP-0659751 vary widely, because the reaction solvent (N,N- dimethylformamide) employed in the process for producing Compound A by subjecting the Compound B and the Compound C to coupling remains in the concentrate after the reaction, thus the maintenance of homogeneous quality being extremely difficult and further refining procedures by many times of recrystallization being inevitable .
  • the present inventors have made an extensive study for establishing a method of producing the said azole Compound A in a highly pure and stable crystalline form, which is useful as the above-described agent for treatment of mycosis, conveniently on an industrially large scale.
  • crystals of higher purity and stability than those so far produced can be obtained by conducting dilution of the said reaction mixture in an organic solvent and shaking the solution three times, followed by crystallization once from a mixture of an organic solvent and a basic aqueous solution.
  • the present inventors have made further diligent investigation to complete the present invention. More specifically, the present invention relates to: (1) Form II crystals having a melting point of 127 °C plus/minus 3°C, of a compound represented by the formula:
  • a pharmaceutical composition which comprises Form II crystals shown in (1) above and pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition described in (4) above which is for the treatment of fungal infections.
  • a method for treating fungal infection which comprises administering an effective amount of Form II crystals shown in (1) above optionally together with a pharmaceutically acceptable carrier, diluent or excipient to a patient suffering from fungal infection.
  • Compound A represented by the formula (I) can be produced by the methods disclosed in, for example, the above-mentioned EP-0567982 and EP- 0659751 or analogous methods thereto.
  • Compound A represented by the formula (I) can be conveniently produced efficiently in a higher purity and yield by the following method.
  • (1) The hydroxyl group of methyl (R)-lactate is protected with 3 , 4 , 5 , 6-tetrahydropyranyl (sometimes abbreviated as THP) group, then the ester group is amidated with morpholine, followed by allowing the resultant to react with a Grignard reagent obtained by allowing l-bromo-2 , -difluorobenzene to react with magnesium in an ether type organic solvent [preferably tetrahydrofuran (THF)] to give ( 2R) -2 ' , 4 ' -difluoro-2- (3,4,5, 6-tetrahydro-2H-pyran-2-yloxy) -propionphenone .
  • THP 6-tetrahydropyranyl
  • Compound B i.e. an oxirane compound
  • Compound C i.e. a triazolone compound
  • Form II crystal of Compound A represented by the formula (I) can be produced by the following processes.
  • Compound B is react with Compound C by the above- described method (concretely stating, the method to be described in the following Working Example); the reaction mixture is diluted in a mixture of an organic solvent and water, which is washed by shaking, then the organic layer was processed with activated charcoal, and the reaction mixture is concentrated, followed by subjecting the resultant to crystallization from a mixture of an organic solvent and a basic aqueous solution and, after processing with activated charcoal, subjecting the resultant to crystallization from a mixture of an organic solvent and water.
  • the solvent for dilution use is made of, usually, a mixture of a hardly water-soluble organic solvent and water in an appropriate ratio.
  • the hardly water-soluble organic solvent include esters such as ethyl acetate, ketones such as methyl ethyl ketone, ethers such as diethyl ether and isopropyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and 1 , 2-dichloroethane .
  • esters such as ethyl acetate, ketones such as methyl ethyl ketone, and halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane, more preferably, esters such as ethyl acetate, and halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane, especially preferably ethyl acetate.
  • volume of the solvent to be employed is as follows: a hardly water-soluble organic solvent of about 50 to about 500 times as much weight as Compound B, preferably about 70 to about 200 times as much, especially preferably about 100 to about 150 times as much, and water of about 5 to about 50 times as much weight as Compound B, preferably about 10 to about 50 times as much.
  • Washing is conducted by using an aqueous saline solution in accordance with a conventional method.
  • Concentration of the aqueous solution of sodium chloride ranges from about 5 to about 50 weight %, preferably about 10 weight %.
  • Volume of the aqueous saline solution to be employed ranges from about 10 to about 50 times by weight relative to Compound B, preferably about 30 times by weight.
  • the processing with activated charcoal is conducted by adding activated charcoal to the organic layer (or the organic solvent in which the reaction mixture is dissolved), or adding the organic layer (or the organic solvent in which the reaction mixture is dissolved) to activated charcoal, and by stirring the whole mixture.
  • Amount of the activated charcoal to be employed ranges from about 0.001 to about 10 times by weight relative to Compound B, preferably from about 0.025 to about 1 times by weight, especially preferably from about 0.05 to about 1 times by weight.
  • Temperatures of the processing with activated charcoal are not higher than the boiling point of the organic solvent employed, preferably about 10 to about 50°C.
  • the processing with activated charcoal after concentration of the reaction mixture can be conducted substantially by the same manner. Removal of the activated charcoal after the processing can be conducted by a per se known method, for example, filtration and centrifugation.
  • Concentration of the organic layer after processing with activated charcoal can be conducted by a per se known method .
  • Examples of the organic solvent capable of dissolving the concentrate mentioned in (1) above and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; ketones such as acetone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1, 3-dimethyl-2-imidazolidinone .
  • alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol
  • ketones such as acetone
  • sulfoxides such as dimethyl sulfoxide
  • nitriles such as acetonitrile
  • amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1, 3-dimethyl-2-imidazolidinone .
  • the organic solvent capable of dissolving the concentrate and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-indazolidinone . More preferably, are mentioned alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol, especially preferably denatured alcohol .
  • the solvents can be used singly or as a mixture of two or more of them in appropriate ratios .
  • the basic aqueous solution of (2) above mention is made of, for example, an aqueous solution of alkali metal hydroxide, alkali metal carbonate or alkali metal hydrogencarbonate, preferably alkali metal hydroxide.
  • alkali metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, and sodium hydroxide is especially preferable.
  • Volume of the organic solvent of (1) to be employed for crystallization ranges from about 5 to about 50 times as much by weight, preferably from about 15 to about 35 times as much by weight relative to Compound B.
  • Concentration of the basic aqueous solution of (2) ranges from about 0.05N to about 3N, preferably from about 0.5N to about 2N.
  • Volume of the basic aqueous solution of (2) ranges from about 10 to about 100 times as much by weight, preferably from about 15 to about 50 times as much by weight relative to Compound B.
  • the mixing ratio of the organic solvent and the basic aqueous solution ranges preferably from about 1 to about 100, more preferably from about 2 to about 20, using the latter in an excess volume to the former. Crystallization is preferably conducted by dissolving the concentrate in an organic solvent and by adding thereto dropwise a basic aqueous solution.
  • the crystallization is conducted at temperatures not higher than about 50 °C, preferably about 10 to about 30°C.
  • Time for the crystallization ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours. Aging of the crystals is conducted by stirring or leaving standing. Temperatures of the aging are not higher than those for crystallization. Time of the aging ranges from about
  • the crystals After being aged, the crystals are collected by a per se known means such as filtration and centrifugation, which are dried under reduced pressure to afford crystals of Compound A as a crude product.
  • the organic solvent which is capable of dissolving crystals of the crude Compound A and soluble in water, include alcohol such as methyl alcohol and ethyl alcohol and denatured alcohol; ketones such as acetone; sulfoxides such as methyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-imidazolidinone .
  • alcohol such as methyl alcohol and ethyl alcohol and denatured alcohol
  • ketones such as acetone
  • sulfoxides such as methyl sulfoxide
  • nitriles such as acetonitrile
  • amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-imidazolidinone .
  • the organic solvent capable of dissolving crystals of the crude Compound A and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; and ketones such as acetone, more preferably alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol, especially preferable one being denatured alcohol .
  • These solvents may optionally be used singly or as a mixture of two or more of them at an appropriate ratio.
  • Volume of the organic solvent to be employed ranges from about 5 to about 50 times by weight, preferably from about 20 to about 35 times by weight, relative to the crystals of crude Compound A.
  • Volume of water to be employed ranges from about 5 to about 100 times by weight, preferably from about 15 to about 50 times by weight, relative to crude Compound A.
  • Volume of water in the mixture of an organic solvent and water, relative to the organic solvent is the same or an excess volume, preferably about 1 to about 10 times, more preferably about 1 to about 2 times .
  • the process for crystallization comprises dissolving the concentrate of the reaction mixture in an organic solvent, processing the solution with activated charcoal, removing the activated charcoal, and adding dropwise, to the solution, a basic aqueous solution to cause crystallization.
  • Temperatures for the crystallization are not higher than about 50 °C, preferably ranging from about 10 to about 30 °C. Time required for the crystallization ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours. Aging of the crystals is conducted by stirring or leaving standing the reaction mixture containing the crystals. Temperatures of the aging are not higher than the crystallization temperature. Time for the aging ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours .
  • the crystals, after being aged, are recovered by conventional means such as filtration and centrifugation, which are then dried under reduced pressure to afford the desired Form II crystals of Compound A.
  • a solvent in which Compound A is soluble is used singly or any mixture of a solvent capable of dissolving Compound A and a solvent in which Compound A is insoluble or hardly soluble can be used.
  • a solvent in which Compound A is soluble use is made of ethers such as diethyl ether and isopropyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; preferably ethers such as diethyl ether and isopropyl ether; especially preferably isopropyl ether.
  • Compound A is insoluble or hardly soluble, use is made of, as the solvent in which Compound A is soluble, alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; ketones such as acetone; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-imidazolidinone, preferably alcohols such as methyl alcohol ethyl alcohol and denatured alcohol; ketones such as acetone; nitriles such as acetonitrile; and esters such as ethyl acetate, more preferably alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol .
  • alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol
  • ketones such as acetone
  • nitriles such as
  • Examples of the solvent, in which Compound A is insoluble or hardly soluble include water and hydrocarbons such as hexane, preferably water.
  • Crystallization temperatures for obtaining preferentially Form II crystals mention is made of those not higher than about 50 °C, preferably those not higher than about 40°C, more preferably those below about 30°C.
  • the lowest limit of crystallization temperatures mention is made of any ones at which the solvent then used does not freeze (for example, not lower than about -10°C, preferably not lower than about 10 °C) .
  • the crystallization temperatures in the method of producing crystals of this invention are in the range from about -10 to about 50 °C, preferably from about -10 to about 40°C, more preferably from about 10 to about 30 °C.
  • Form II crystals of Compound A represented by the formula ( I ) are characterized by having the melting point ranging from about 115 to about 145°C, more concretely 127°C ⁇ about 3°C. In this respect, they are entirely different from Form I crystals (m.p. 154-155°C) disclosed in the afore-mentioned official gazette of EP-0659751. Since melting point of Form II crystals of this invention is lower than that of Form I crystals by about 30 °C, Form I crystals are surmised to be thermodynamically stable, and, as is clear from results of the stability test described later, it was confirmed that Form II crystals were quite unexpectedly excellent in stability as compared with Form I crystals .
  • Form I crystals are of needles under polarizing microscopic observation
  • Form II crystals of Compound A are of prisms which are entirely different from needles (cf. Working Examples to be described later) .
  • Form II crystals of Compound A show completely different spectrum from Form I crystals in powder X-ray diffraction. Namely, Form II crystals have a peak near about 9° diffraction angle in powder X-ray diffraction and have not a peak near 6 to 6.5°, which is a characteristic feature.
  • Form II crystals of Compound A show completely different spectrum from that of Form I crystals in differential thermal analysis as well. Namely, Form II crystals have a characteristic feature of having an endothermic peak near 130 °C, which is not observed in Form I crystals . Accordingly, Form II crystals of Compound A represented by the formula (I) in this invention are novel crystals, which are completely different from Form I crystals disclosed in the official gazette of EP-0659751. Form II crystals of Compound A produced by the present invention can be used as the antifungal agent.
  • the present compound (I) has strong antifungal activity to the genus Candida [e.g. Candida albicans r Candida utilis, Candida graburata, etc.], genus Histoplasma [e.g. Histoplasma capsulatum, etc.], genus Aspergillus [e.g. Aspergillus niger, Aspergillus fumigatus , etc.], genus Cryptococcus [e.g. Cryptococcus neoformans , etc.], genus richophyton [e.g. Trichophyton rubrum. Trichophton mentagrophytes , etc.], genus Microsporum [e.g.
  • Microsporum gypseum, etc.] genus Mallassezia [e.g. Mallassezia furfur, etc.] etc., it can be used for prevention or treatment of fungal infections [e.g. mucosal candidiasis (oral thrush, angular stomatitis, vulvovaginal candidiasis, Candida balanoposthitis and urethritis), dermal candidiasis ( interdigital candidiasis, intertriginous candidiasis, perianal candidiasis, blastomycosis cutis eczematosa, Candida onychia, Candida paronychia, auricular candidiasis, cutaneous lesion of Candida septicaemia, diffuse superficial candidiasis, Candida granuloma, congenital cutaneous candidiasis, candidids), chronic mucocutaneous candidiasis and systemic candidiasis (candidiasis of the respiratory
  • aspergillosis of the respiratory tract allergic aspergillosis, bronchial aspergillosis, aspergilloma, pulmonary aspergillosis (acute invasive pulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis), aspergillary empyema) , disseminated aspergillosis, central nervous system aspergillosis, aspergillary endocarditis, aspergillary myocarditis, aspergillary pericarditis, aspergillary mycetoma, aspergillary otomycosis, aspergillary onychia, aspergillary paronychia, aspergillary keratitis, aspergillary endophthalmitis , cutaneous aspergillosis and nasal-orbital aspergillosis, etc.
  • pulmonary cryptococcosis central nervous system cryptococcosis , cutaneous and mucocutaneous cryptococcosis, osseous cryptococcosis, cryptococcosis of lymphnodes, disseminated cryptococcosis and cryptococcosis of hematopoetic organs, etc.
  • the compound (I) of the present invention can be used as an agricultural antifungal agent.
  • the present Form II crystals When the present Form II crystals are administered to human, it can be administered orally or parenterally in safety as a pharmaceutical composition such as oral administration (e.g. powder, granule, tablet, capsule, etc.), parenteral administration [e.g. injection, external preparation (e.g. nasal administration, percutaneous administration, etc.) and suppository
  • compositions can be prepared by a per se known method which is usually used in the production process.
  • the proportion of the present Form II crystals in the preparation varies depending on the form thereof, and can be in the range usually employed in the antifungal agent. For example, it is about 10 to about 95% by weight in case of the above oral administration and is about 0.001 to about 95% by weight in case of the above parenteral administration.
  • the injection can be prepared by mixing the presnet Form II crystals with dispersants [e.g. Tween 80 (manufactured by Atlas Powder company, U.S.A.), HCO 60 (manufactured by Nikko Chemicals Co.), carboxymethylcellose, sodium aspartate, etc.], preservatives (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.) and isotonic agents (e.g. sodium chloride, glycerin, sorbitol, glucose, etc.) to form an aqueous injection, or by dissolving, suspending or emulsifying into vegetable oils (e.g. olive oil, sesame oil, peanut oil, cotton seed oil, corn oil, etc.), propyleneglycol , etc. to form an oily injection.
  • dispersants e.g. Tween 80 (manufactured by Atlas Powder company, U.S.A.), HCO 60 (man
  • An oral administration preparation can be prepared by adding excipients (e.g. lactose, sucrose, starch, etc.), disintegrators (e.g. starch, calucium carbonate), binders (e.g. starch, arabic gum, carboxymethycellulose, polyvinyl pyrolidone, hydroxypropylcellulose, etc.) and lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.) to the present compound (I), subjecting the mixture to compress molding and optionally masking of taste or coating with a per se known method for the purpose of imparting enteric property or sustained- release property.
  • excipients e.g. lactose, sucrose, starch, etc.
  • disintegrators e.g. starch, calucium carbonate
  • binders e.g. starch, arabic gum, carboxymethycellulose, polyvinyl pyrolidone, hydroxypropylcellulose, etc.
  • hydroxypropylmethylcellulose for example, hydroxypropylmethylcellulose , ethylcellulose , hydroxymethylcellulose , hydroxypropylcellulose , polyoxyethyleneglycol, Tween 80, Pulronick P68, cellulose acetate phtharate, hydroxypropylmethylcellulose phthalate , hydroxymethylcellulose acetate succinate, Oidora kid (manufactured by Rhome Co., West Germany, copolymer of methacrylic acid and acrylic acid) and pigment (e.g. titanium oxide, iron oxide red, etc.) can be used.
  • the Form II crystals of the present invention can be used as a solid, semi-solid or liquid external preparation.
  • the solid external preparation can be prepared by using the present compound (I) as it is, or adding excipients (e.g. glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (e.g. natural gums, cellulose derivatives, acrylic polymer, etc.), etc. to the present Form II crystals, followed by mixing to form a powdered composition.
  • excipients e.g. glycol, mannitol, starch, microcrystalline cellulose, etc.
  • thickeners e.g. natural gums, cellulose derivatives, acrylic polymer, etc.
  • the liquid external preparation it can be prepared by forming into an oily or aqueous suspension in the nearly same manner as in case of the injection.
  • pH adjustors e.g. carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.
  • preservatives e.g. paraoxybenzoates , chlorobutanol, banzalkonium chloride, etc.
  • an ointment containing vaseline, lanoline, etc. as a base, and about 0.1 to about 100 mg of the present Form II crystals can be used for sterilization or disinfection of skin or mucosa.
  • the present Form II crystals can be formed into an oily or aqueous solid, semi-solid or liquid suppository.
  • the oily base include glyceride of higher fatty acid [e.g. cacao butter, witepsols (manufactured by Dynamite Novel Company), etc.], medium fatty acid [e.g. migriolic acid (manufactured by Dynamite Novel Company), etc.] and vegetable oil [e.g.
  • aqueous base examples include polyethylene glycols, propylene glycols, etc. and examples of the aqueous gel base include natural gums, cellulose derivative, vinyl polymer, acrylic polymer, etc.
  • the dose of the present Form II crystals varies depending on the infecting condition and administering route, etc. In case of administering orally to adult (weight 50 kg) patients for the purpose of treating Candidiasis, the dose is about 0.01 to about 100 mg/kg/day, preferably about 0.1 to about 50 mg/kg/day. More preferably, the dose is about 0.5 to about 10 mg/kg/day.
  • the Form II crystals of the present invention is stable and especially solid composition can be stored with stable for a long term.
  • the Form II crystals are stable for a long term if the Form II crystals are packed separately with the other liquid substances, which are capable to combine with each other to give an injectable solution.
  • the pharmaceutical composition of the present invention may contain one or more of known antifungal compound together with Form II crystals of the present invention.
  • Examples of the known antifungal compound include such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, D0870, voriconazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, bifonazole, croconazole, oxiconazole, terconazole, SSY-726, KP-103, Sch-56592, Sch-51048, UR-9746, MFB-1041, UR-9751, UR-9728, UR- 9825, ER-30346, T-8581, BAY-W-9279, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, etc., but are not limited to known antifungal agents .
  • the present Form II crystals When using the present Form II crystals as an agricultural antifungal agent, the present Form II crystals is dissolved or suspended into a suitable liquid carrier (e.g. solvent), or mixed with or adsorbed to a suitable solid carrier (e.g. diluent, bulking agnet, etc.) and, if necessary, emulsifiers, suspension, spreading agents, osmotic agents, wetting agents, mucilages, stabilizers, etc. are added to form an emulsion, hydrate, powder, granule, etc.
  • a suitable liquid carrier e.g. solvent
  • a suitable solid carrier e.g. diluent, bulking agnet, etc.
  • emulsifiers e.g. diluent, bulking agnet, etc.
  • suspension, spreading agents, osmotic agents, wetting agents, mucilages, stabilizers, etc. are added to form an emulsion, hydrate, powder,
  • liquid carrier for example, water, alcohols (e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), aliphatic hydrocarbons (e.g. kerosene, kerosene oil, fuel oil, etc.), aromatic hydrocarbons (e.g. methylene chloride, chloroform, etc.), acid amides (e.g. dimethylformamide, dimethylacetoamide, etc.), esters (e.g. ethyl acetate, butyl acetate, etc.) and nitriles (e.g.
  • alcohols e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, etc.
  • ethers e.g. dioxane, tetrahydrofuran,
  • acetonitrile, propionitrile, etc. can be used, and these liquid carriers can be used alone or in combination thereof at a suitable proportion.
  • the solid carrier for example, vegetable flours (e.g. soy bean flours, tabaco flours, wheat flours, etc.), mineral powders (e.g. kaolin, bentonite, etc.), alumina, sulfur powder, active carbon, etc. can be used, and these solid carriers can be used alone or in combination thereof at a suitable proportion.
  • H-spectrum was measured with Brucker 300 (300 MHz) spectrometer using tetramethylsilane as internal standard. All ⁇ values were shown by ppm. Percent (%) means weight percent unless otherwise specified.
  • symbols have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, tt: triple triplet, m: multiplet, quintet: quintet, septet: septet, br: broad, J: coupling constant
  • DSC 220C type manufactured by SEIKO
  • Powder X-ray diffractometry was conducted by employing a powder X-ray diffractometry apparatus (RU- 200BV type, manufactured by RIGAKU) under the following conditions for the measurement: Tube : Cu
  • Goniometer vertical goniometer monoaxial Sampling width : 0.020°
  • reaction mixture was cooled to -5°C or below, to which was added dropwise a solution of 104.9 g of 4- [ ( 2R) -2- ( 3 , 4 , 5 , 6-tetrahydro- 2H-pyran-2-yloxy)propionyl] morpholine in THF (110 m ) while keeping the temperatures at not higher than 0°C.
  • the mixture was then warmed to about 20°C, which was stirred for 90 minutes at the same temperature range.
  • the reaction mixture was then cooled to -5°C, to which was added dropwise, at temperatures not higher than
  • the activated charcoal was filtered off, which was washed with 23 m ⁇ of ethanol. The filtrate and the washing were combined, to which was added dropwise 64 ml? of water under stirring at room temperature.
  • To the mixture was added, at 25°C, seed crystals of (2R,3S)- 2- ( 2 , -difluorophenyl ) -3-methyl-2- ( 1H-1 , 2 , 4-triazol-l- yl )methyloxirane .
  • the mixture was gradually cooled to cause crystallization, which was stirred for 30 minutes at 15°C.
  • the mixture was cooled to 5°C, to which was then added 210 mi of water over 30 minutes at the same temperature.
  • the mixture was cooled to 5°C and aged for one hour under stirring.
  • Crystals were collected by filtration and washed with 90 mi of a cold mixture of methanol and water (1:3) to give wet crystals. To the wet crystals was added 20 mi of methanol, and the mixture was dissolved at 30 °C. The solution was cooled to 20°C, to which were added seed crystals, followed by stirring for 30 minutes to cause crystallization. The mixture was cooled to 5°C and aged for one hour under stirring. Crystals were collected by filtration and washed with 60 ml?
  • the mixture was left standing at not higher than 5°C to age.
  • the resulting crystals were harvested by filtration and washed with a mixed solution (60 mi ) of methanol-denatured ethanol and distilled water (1:1).
  • the crystals were dried under vacuum at 60°C to give a crude crystals as a white crystals (28.0 g, yield 72.0%).
  • the crude crystals were dissolved in methanol-denatured ethanol (21 iri ) at 50°C.
  • activated charcoal 90 mi
  • the mixture was stirred for 30 minutes at 50°C and the activated charcoal was filtered off.
  • the activated charcoal was washed with methanol-denatured ethanol (6 mi ) and the washings were combined with mother liquor.
  • a fluid granulator (FD-5S, manufactured by Paulek Co.) was charged with 525 g of Compound A, 2696 g of lactose and 630 g of corn starch. Onto the mixture was sprayed, while controlling the air-feeding temperature at about 70°C and controlling the temperature of the mixture at about 40°C, 2520 g of an aqueous solution containing 126 g of hydroxypropyl cellulose. After completion of the spraying, the resultant was dried for 3 minutes .
  • FD-5S manufactured by Paulek Co.
  • Composition per tablet is as follows:
  • the Form II crystals of the present invention are remarkably low in hygroscopicity and are remarkably excellent in stability.
  • Compound A is crystallized as the Form II crystals from reaction mixture containing Compound A chemically synthesized, Compound A can be isolated by a simple and convenient procedure, on an industrially large scale, in a high purity and with a high yield.
  • FIG. 1 shows a photograph of Form II crystals of
  • FIG. 2 shows powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of Form II crystals of Compound A produced in Working Example 1.
  • Transverse axis shows angle of diffraction (2 ⁇ ), and ordinate axis shows peak strength.
  • FIG. 3 shows a photograph of Form I crystals of Compound A produced in Comparative Example 1, under observation by a polarizing microscope.
  • FIG. 4 shows powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of Form I crystals of Compound A produced in Comparative Example 1.
  • Transverse axis shows angle of diffraction (2 ⁇ ), and ordinate axis shows peak strength.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des cristaux de forme II, possédant un point de fusion de l'ordre de 127 °C ± 3 °C, du composé représenté par la formule (I). Ces cristaux présentent une faible hygroscopicité et une excellente stabilité.
PCT/JP1998/000882 1997-03-05 1998-03-04 Forme cristalline d'un compose de bis 1,2,3-triazole WO1998039305A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61197/98A AU6119798A (en) 1997-03-05 1998-03-04 Crystalline form of a bis 1,2,4-triazole compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5057197 1997-03-05
JP9/50571 1997-03-05

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WO1998039305A1 true WO1998039305A1 (fr) 1998-09-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051925A1 (fr) * 2003-11-27 2005-06-09 Ajinomoto Co., Inc. Cristal de derive de phenylalanine et son procede de production
EP2009009A1 (fr) * 2007-06-26 2008-12-31 Palau Pharma, S.A. Composés antifongiques cristallins
EP2049504A2 (fr) * 2006-08-07 2009-04-22 Stiefel Laboratories, Inc. Composés cristallins antifongiques
CN105367556A (zh) * 2015-11-10 2016-03-02 南通诺泰生物医药技术有限公司 一种抗真菌药物中间体(2r,3s)-1-(1,2,4-三氮唑基)-2-二氟代苯基-2,3-环氧丁烷的合成方法

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Publication number Priority date Publication date Assignee Title
EP0567982A1 (fr) * 1992-04-28 1993-11-03 Takeda Chemical Industries, Ltd. Dérivés d'azole, leurs préparation et application
EP0659751A1 (fr) * 1993-12-22 1995-06-28 Takeda Chemical Industries, Ltd. Dérivés d'azoles optiquement actifs, leur préparation et leur application
EP0687672A2 (fr) * 1994-05-31 1995-12-20 Takeda Chemical Industries, Ltd. Préparation de dérivés de triazole optiquements actifs et leurs intermédiaires

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EP0567982A1 (fr) * 1992-04-28 1993-11-03 Takeda Chemical Industries, Ltd. Dérivés d'azole, leurs préparation et application
EP0659751A1 (fr) * 1993-12-22 1995-06-28 Takeda Chemical Industries, Ltd. Dérivés d'azoles optiquement actifs, leur préparation et leur application
EP0687672A2 (fr) * 1994-05-31 1995-12-20 Takeda Chemical Industries, Ltd. Préparation de dérivés de triazole optiquements actifs et leurs intermédiaires

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051925A1 (fr) * 2003-11-27 2005-06-09 Ajinomoto Co., Inc. Cristal de derive de phenylalanine et son procede de production
US7683169B2 (en) 2003-11-27 2010-03-23 Ajinomoto Co., Inc. Crystals of phenylalanine derivatives and production methods thereof
US7951942B2 (en) 2003-11-27 2011-05-31 Ajinomoto Co., Inc. Crystals of phenylalanine derivatives and production methods thereof
EP2049504A2 (fr) * 2006-08-07 2009-04-22 Stiefel Laboratories, Inc. Composés cristallins antifongiques
EP2049504A4 (fr) * 2006-08-07 2010-09-22 Stiefel Laboratories Composés cristallins antifongiques
US7879867B2 (en) 2006-08-07 2011-02-01 Palau Pharma, S.A. Crystalline antifungal compounds
US8258296B2 (en) 2006-08-07 2012-09-04 Palau Pharma, S.A. Crystalline antifungal compounds
EP2009009A1 (fr) * 2007-06-26 2008-12-31 Palau Pharma, S.A. Composés antifongiques cristallins
CN105367556A (zh) * 2015-11-10 2016-03-02 南通诺泰生物医药技术有限公司 一种抗真菌药物中间体(2r,3s)-1-(1,2,4-三氮唑基)-2-二氟代苯基-2,3-环氧丁烷的合成方法

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