Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-28
2003-08-19
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S273700
Reexamination Certificate
active
06608092
ABSTRACT:
This application is a 371 of PCT/JP00/04279 filed Jun. 29, 2000.
TECHNICAL FIELD
The present invention relates to crystals of a benzimidazole compound that possesses an antiulcer action.
BACKGROUND ART
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof, which possess an antiulcer activity, has been described in JP 61-50978 A and the like.
DISCLOSURE OF THE INVENTION
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole possesses a chiral sulfur within the molecule, and two kinds of optical isomers thereof exist. As a result of intensive investigations, the present inventors have succeeded in the optical resolution and crystallization of the (S) isomer of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and have found for the first time that the crystals are satisfactory enough for drugs, thereby having completed the present invention on the basis of these findings.
In other words, the present invention relates to
(1) crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof,
(2) crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,
(3) the crystals as described in the above (2) which possess a pattern of the powder X-ray diffraction whose characteristic peaks appear at the lattice spacing (d) of the powder X-ray diffraction of 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11 angstrom (Å),
(4) a pharmaceutical composition comprising the crystals as described in the above (1) and the like.
As for the“salt” of “(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof”, a physiologically acceptable salt is preferred, which is exemplified by a metal salt, a salt with an organic base, a salt with a basic amino acid or the like.
Examples of a metal salt include an alkaline metal salt such as sodium salt, potassium salt, etc., an alkaline earth metal salt such as calcium salt, magnesium salt, barium salt, etc., and the like. A salt with an organic base is exemplified by a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine or the like. A salt with a basic amino acid is exemplified by a salt with arginine, lysine or the like.
Crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof may be a hydrate or a non-hydrate.
Said “hydrate” is exemplified by a 0.5 to 5.0 hydrate. Among them, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate, or 2.5 hydrate is preferable. Particularly preferred is 1.5 hydrate.
Crystals of (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof can be obtained by subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof to optical resolution or by subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole or a salt thereof to asymmetric oxidation to obtain the (S)-isomer, followed by crystallization.
Examples of a method used for the optical resolution include a per se known method such as a fractional recrystallization method, a chiral column method, a diastereomer method and the like. As asymmetric oxidation, a per se known method is used.
The “fractional recrystallization method” is exemplified by a method, in which the racemate is treated with an optically active compound [e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form the salts, followed by separation by a fractional recrystallization or the like, and, optionally, by subjecting the resultant to a neutralization step to obtain the optical isomer in the free form.
The “chiral column method” is exemplified by a method, in which the racemate or a salt thereof is applied to a column for separation of optical isomers (a chiral column). In the case of liquid chromatography, for instance, there is exemplified a method, in which the racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Toso Corporation), CHIRAL series manufactured by Daicel Company or the like, which is eluted with water, a buffer solution (e.g., a phosphate buffer solution), an organic solvent (e.g., hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate the optical isomers. In the case of gas chromatography, for instance, a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by G-L Sciences Inc.) or the like is exemplified.
The “diastereomer method” is exemplified by a method, in which the racemate is allowed to react with an optically active reagent (preferably, to react with the optically active reagent at position 1 of the benzimidazole group) to obtain a mixture of the diastereomers, followed by treatment with a conventional separation means (e.g., fractional recrystallization, chromatography method, etc.) to obtain one of the diastereomers, which is then subjected to a chemical reaction (e.g., acid hydrolysis reaction, basic hydrolysis reaction, hydrogenolysis reaction, etc.) to cleave the moiety of the optically active reagent, thereby obtaining the objective optical isomer. Examples of said “optically active reagent” include optically active organic acids such as MTPA [&agr;-methoxy-&agr;-(trifluoromethyl)phenylacetic acid], (−)-menthoxyacetic acid and the like; optically active alkoxymethyl halides such as (1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane, and the like.
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof is produced according to the method described in JP 61-50978 A, U.S. Pat. No. 4,628,098 or the like, or a modified method thereof.
Examples of the method for crystallization include a per se known method such as crystallization from a solution, crystallization from a vapor, and crystallization from a melt.
Examples of the method for said “crystallization from a solution” include a concentration method, a slow cooling method, a reaction method (diffusion method or electrolysis method), a hydrothermal formation method, a fluxing agent method and the like. Examples of the solvent to be used include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrites (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents are used alone or in combination of two or more thereof in an adequate ratio (for example, 1:1 to 1:100).
Examples of the method for said “crystallization from a vapor” include an evaporation method (a sealed tube method or an air stream method), a vapor phase reaction method, a chemical transportation method or the like.
Examples of the method for said “crystallization from a melt” include a normal freezing method (pulling-up method, temperature gradient method or Bridgman method), a zone melting method (zone leveling method or float zone me
Aoki Isao
Fujishima Akira
Kamiyama Keiji
Fan Jane
Takeda Chemical Industries Ltd.
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