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    • 专利摘要:
    (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole of the present invention or Novel crystals of salts are useful as good antitumor agents.
    公开号:KR20030068592A
    申请号:KR10-2003-7009783
    申请日:2000-06-15
    公开日:2003-08-21
    发明作者:후지시마아끼라；아오끼이사오；가미야마게이지
    申请人:다케다 야쿠힌 고교 가부시키가이샤；
    IPC主号:
    专利说明:

    Benzimidazole Compound Crystals {BENZIMIDAZOLE COMPOUND CRYSTAL}
    [1] The present invention relates to benzimidazole compound crystals exhibiting anti-ulcer action.
    [2] 2-[[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl]-having anti-ulcer action in JP-A-61-50978, etc. 1H-benzimidazole or salts thereof have been reported.
    [3] There is a need for more stable and better absorbable antiulcer agents.
    [4] 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole with chiral sulfur in its molecular structure There is a kind of optical isomer. As a result of the intensive studies, the inventors optically resolved 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H. Successfully crystallized the (R) isomer of benzimidazole and found for the first time that this crystal was satisfactory as a medicament, and further research based on this finding has completed the present invention.
    [5] Accordingly, the present invention relates to the following:
    [6] [1] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or its Determination of salts;
    [7] [2] Crystal of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole ;
    [8] [3] The X-ray powder diffraction analysis pattern according to the above [2], wherein the pattern has a characteristic peak in the interplanar space (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and 3.11 Å. decision;
    [9] [4] a pharmaceutical composition containing the crystal according to the above [1];
    [10] [5] the pharmaceutical composition according to the above [4], for treating or preventing a gastrointestinal ulcer;
    [11] [6] A method of treating or preventing a gastrointestinal ulcer in a mammal, comprising administering to the mammal in need thereof an effective amount of the crystals according to [1], together with a pharmaceutically acceptable excipient, carrier or diluent;
    [12] [7] Use of the crystal according to the above [1], used for the manufacture of a pharmaceutical composition for the treatment or prevention of gastrointestinal ulcers and the like.
    [13] "(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1 H-benzimidazole or salt thereof" "Salt" includes, for example, metal salts, salts with organic bases, salts with basic amino acids and the like. Preferred are physiologically acceptable salts.
    [14] Metal salts include, for example, alkali metal salts such as sodium salts and potassium salts; And alkaline earth metal salts such as calcium salts, magnesium salts and barium salts. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. . Salts with basic amino acids include, for example, salts with arginine, lysine, and the like.
    [15] Crystals of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1 H-benzimidazole or salt thereof It may or may not be a hydrate.
    [16] The "hydrate" includes from 0.5 hydrate to 5.0 hydrate.
    [17] Of these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate are preferred. More preferably 1.5 hydrate.
    [18] Crystals of (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1 H-benzimidazole or salt thereof Optically dividing 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or salt thereof or 2 Asymmetric oxidation of [[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole to give the (R) -isomer It can then be prepared by crystallizing the resulting isomers.
    [19] Optical splitting methods include methods known to those skilled in the art, such as fractional recrystallization methods, chiral column methods, diastereomer methods, and the like. Asymmetric oxidation includes methods known to those skilled in the art.
    [20] A "fractional recrystallization method" refers to racemates and optically active compounds [eg, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1 -Phenethylamine, (-)-1-phenethylamine, cinconine, (-)-cinconidine, burucine, etc.] to form a salt, and the salt is separated by a fractional recrystallization method or the like, If any, includes a method of performing a neutralization method to obtain a glass optical isomer.
    [21] The “chiral column method” includes a method of applying a racemate or salt thereof to a column (chiral column) for optical isomer separation. In the case of liquid chromatography, for example, the optical isomer adds racemate to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or DAICEL CHIRAL series (manufactured by Daicel Corporation), Racemates in organic solvents (e.g., hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.), or mixtures of these solvents. Separated by expanding. In the case of gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science) is used to separate the optical isomers.
    [22] The "diastereomer method" reacts a racemate with an optically active reagent (preferably, the optically active reagent is reacted at the 1-position of the benzimidazole group) to obtain a diastereomer mixture, and then usually Separation means (e.g., fractional recrystallization, chromatography, etc.) to obtain either diastereomer, followed by a chemical reaction (e.g., hydrolysis, base hydrolysis, hydrogenolysis, And the like) to cleave the optically active reagent moiety, thereby obtaining the desired optical isomer. The "optically active reagent" is, for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid. ] And optically active organic acids such as (-)-methoxyacetic acid; And optically active alkoxymethyl halides such as (1R-endo) -2- (chloromethoxy) -1,3,3-trimethylbicyclo [2.2.1] heptane, and the like.
    [23] 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or salt thereof is JP-A-61 -50978 and USP 4,628,098 and the like, or by a method similar thereto.
    [24] Crystallization methods include, for example, methods known in the art, crystallization from solutions, crystallization from steam, and crystallization from molten form.
    [25] The "crystallization from solution" method includes, for example, a concentration method, a slowly cooling method, a reaction method (diffusion method, electrolysis method), hydrothermal growth method, fusing agent method, and the like. Solvents used are, for example, aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg dichloromethane, chloroform, etc.), saturated hydrocarbons (eg hexane, heptane, Cyclohexane, etc.), ethers (eg diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrile (eg acetonitrile, etc.), ketones (eg acetone , Etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acidamides (eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols ( For example, methanol, ethanol, isopropyl alcohol, etc.), water, etc. are included. These solvents may be used alone or in a mixture of two or more kinds in suitable ratios (for example, 1: 1 to 1: 100).
    [26] "Crystalization from steam" methods include, for example, gasification methods (sealed tube methods, gas flow methods), gas phase reaction methods, chemical transport methods, and the like.
    [27] The "crystallization from molten form" method is for example a general cooling method (pulling-up method, temperature gradient method, Brigman method), zone melting method (zone leveling method, float Float zone method, special growth method (VLS method, liquid phase epitaxy method), and the like.
    [28] In order to analyze the obtained crystals, X-ray diffraction crystal analysis is generally used. In addition, crystal orientation can also be measured by mechanical methods, optical methods, and the like.
    [29] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole thus obtained or Determination of salts thereof (hereinafter also referred to as "crystal of the present invention") exhibits excellent anti-ulcer action, gastric acid secretion-inhibitory action, mucosal protective action, anti- Helicobacter pylori action, and the like. It is useful as a medicine because of its low toxicity. Moreover, as the (R) -isomer crystallizes, not only its stability is improved but also the handling is easy, it can be prepared as a solid pharmaceutical composition having good reproducibility. In addition, when administered orally, the crystals of the present invention are more absorbable and exhibit faster action than racemates. In addition, when administered, the crystals of the present invention exhibit higher Cmax (maximum blood concentration) and greater AUC (area under the concentration-time curve) than racemates and in part due to increased protein-binding ratio It is not easier to paint and therefore exhibits a long duration of action. The crystals of the present invention are therefore useful as medicaments with low dosages and low prevalence of adverse reactions.
    [30] Crystals of the present invention may include gastrointestinal ulcers (eg, gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, etc.), gastritis, reflux esophagitis, non-ulcer dyspepsia (NUD) Benign indigestion), treatment and prevention of gastric cancer and gastric MALT lymphoma; Eradication of Helicobacter pylori ; Inhibition of upper gastrointestinal bleeding due to digestive ulcers, acute stress ulcers and hemorrhagic gastritis; Suppressing upper gastrointestinal bleeding due to invasive stress (stress from major surgery requiring postoperative critical care, and from cerebrovascular disease, head trauma, multiple organ failure and external burns requiring critical care); Treatment and prevention of cancer caused by nonsteroidal anti-inflammatory agents; Treatment and prevention of hyperacidity and ulcers caused by postoperative stress; It is useful for mammals (eg, humans, monkeys, sheep, cattle, horses, dogs, cats, rabbits, mice, mice, etc.) for pre-anesthesia dosing and the like.
    [31] Since the crystals of the present invention have low toxicity, in the form of pharmaceutical compositions, for example tablets (including dragees and encapsulated tablets), either as such or in combination with pharmacologically acceptable carriers, according to conventional known methods. Orally or parenterally (eg, topically, rectally and intravenously) in the form of powders, granules, capsules (including soft capsules), oral disintegrating tablets, solutions, injections, suppositories, sustained release preparations and patches. Can be.
    [32] The crystal content of the present invention in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight based on the total composition. The dosage varies depending on the subject to be administered, the route of administration, the target disease, and the like, and when administered orally as an antiulcer agent to, for example, an adult (60 kg), from about 0.5 to 1,500 mg / day based on the active ingredient, preferably About 5 to 150 mg / day is common. The crystals of the present invention are administered once a day or divided into two to three times a day.
    [33] Pharmaceutically acceptable carriers that can be used to prepare the pharmaceutical compositions of the invention include excipients, lubricants, binders, disintegrants, water soluble polymers and basic inorganic salts for solid preparations; And various organic or inorganic carrier materials commonly used as pharmaceutical materials, including solvents, dissolution aids, suspending agents, isotonic agents, buffers, and soothing agents for liquid formulations. Other conventional pharmaceutical additives such as preservatives, antioxidants, colorants, sweeteners, souring agents, foaming agents and flavoring agents may also be used as needed.
    [34] Such “excipients” include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, hard silicic anhydride and titanium dioxide.
    [35] Such "lubricants" include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycols, talc and stearic acid.
    [36] Such "binders" include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, α-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low substituted hydroxypropyl cellulose. Include.
    [37] Such "disintegrants" are the so-called super-disintegrants (3) carboxymethyl starch sodium (1) crosslinked povidones, (2) crosslinked carmellose sodium (FMC-Asahi Chemical) and carmelose calcium (Kotoku Yakching). For example, Matsuni Chemical Co., Ltd., (4) low-substituted hydroxypropyl cellulose (for example, Shin-Etsu Chemical Co., Ltd.), (5) corn starch, etc. are included. The “crosslinked povidone” can be any crosslinked polymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer Colidon CL (manufactured by BASF Corporation), Polyplasdon XL (manufactured by ISP), Polyplasdon XL-10 (manufactured by ISP) and Polyplasdon INF-10 (manufactured by ISP) are exemplified.
    [38] Such “water soluble polymers” are for example ethanol soluble water soluble polymers [eg cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone] and ethanol insoluble water soluble polymers [eg, Cellulose derivatives such as hydroxypropylmethyl cellulose (hereafter also referred to as HPMC), methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar rubber.
    [39] Such “basic inorganic salts” include, for example, basic inorganic salts of sodium, potassium, magnesium and / or calcium. Basic inorganic salts of magnesium and / or calcium are preferred. Basic inorganic salts of magnesium are more preferred. Examples of such basic inorganic salts of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like. Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate and the like. Such basic inorganic salts of magnesium are, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 (OH) 16 CO 3 · 4H 2 O], alumina hydroxide magnesium and the like. Among these, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like are preferable. Basic inorganic salts of such calcium include precipitated calcium carbonate, calcium hydroxide and the like.
    [40] Such “solvents” include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and olive oil.
    [41] Such "dissolution aids" include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
    [42] Such “suspending agents” include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearate; And hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
    [43] Such "extinguishing agents" include, for example, glucose, D-sorbitol, sodium chloride, glycerol and D-mannitol.
    [44] Such "buffers" include, for example, buffer solutions such as phosphate, acetate, carbonate, citrate and the like.
    [45] Such "emollients" include, for example, benzyl alcohol.
    [46] Such "preservatives" include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
    [47] Such "antioxidants" include, for example, sulfites, ascorbic acid and α-tocopherol.
    [48] Such "colorants" include, for example, food colorants such as Food Color Yellow No. 5, Food Color Red 2 and Food Color Blue 2; And food lake collars and red oxides.
    [49] Such “sweetening agents” include, for example, saccharin sodium, dipotassium glycyrrhetitin, aspartame, stevia and taumartin.
    [50] Such "powders" include, for example, citric acid (citric acid anhydride), tartaric acid and malic acid.
    [51] Such “foaming agents” include, for example, sodium bicarbonate.
    [52] Such “flavours” can be synthetic or naturally occurring and include, for example, lemons, limes, oranges, menthol and strawberries.
    [53] The crystals of the present invention are compression-molded according to conventional known methods, for example in the presence of excipients, disintegrants, binders, lubricants and the like, and then, if necessary, for the purpose of taste masking, enteric or sustained release. It can be prepared as a preparation for oral administration by coating in a known manner. For enteric preparations, an intermediate layer can be provided by conventional known methods between the enteric layer and the drug containing layer for the purpose of separating the two layers.
    [54] Useful methods for the preparation of the crystals of the present invention as oral disintegrating tablets include, for example, coating the cores containing crystalline cellulose and lactose with the crystals and basic inorganic salts of the present invention and with a coating layer containing a water soluble polymer. Further coating to obtain a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, further coated with an enteric coating layer containing polyethylene glycol, and then with mannitol Further coating to obtain fine granules, which are mixed with additives and shaped. The above-mentioned "enteric coating layers" are, for example, aqueous enteric polymeric materials such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers [eg Eudragit L30D- 55 (trade name; manufactured by Rohm), Colicoat MAE30DP (trade name: manufactured by BASF), Polykid PA30 (trade name: manufactured by Sanyo Chemical)], carboxymethylethyl cellulose and shellac; Sustained-release substances such as methacrylic acid polymers (eg, Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.); Water-soluble polymers; Plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin and castor oil; And mixtures thereof. The above-mentioned "additives" include, for example, water-soluble sugar alcohols (eg, sorbitol, mannitol, watertitol, reduced starch saccharides, xylitol, reduced paratinose, erythritol, etc.), crystalline cellulose [eg, Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose-carmellose sodium), low-substituted hydroxypropyl cellulose [e.g., LH-22, LH-32 , LH-23, LH-33 (Shin-S Chemicals) and mixtures thereof; binders, powders, foaming agents, sweetening agents, flavoring agents, lubricants, colorants, stabilizers, excipients, disintegrating agents and the like can also be used.
    [55] Crystals of the invention can be used in combination with one to three other active ingredients.
    [56] Such “other active ingredients” include, for example, anti- Helicobacter pylori agonists, imidazole compounds, bismuth salts, quinolone compounds and the like. Among these substances, anti-helicobacter pyrroli agonists, imidazole compounds and the like are preferred. Such “anti-helicobacter pyrrole agonists” include, for example, antibiotics penicillin (eg, amokycillin, benzylpenicillin, piperacillin, meslynamin, etc.), antibiotic cefem (eg, sepicsim, cepha) Chlor, etc.), antibiotic macrolides (eg, erythromycin, clarithromycin, etc.), antibiotic tetracyclines (eg, tetracycline, minocycline, streptomycin, etc.), antibiotic aminoglycosides (eg, Gentamicin, amikacin, and the like), imipenem, and the like. Among these substances, antibiotic penicillin, antibiotic macrolide, and the like are preferable. Such “imidazole compounds” include, for example, metronidazole, myconazole, and the like. Such “bismuth salts” include, for example, bismuth acetate, bismuth citrate, and the like. Such “quinolone compounds” include, for example, offloxacin, cifloxacin, and the like.
    [57] Such “other active ingredients” and the crystals of the invention are prepared as a single pharmaceutical composition (eg, tablets, powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained release agents, etc.) according to conventional methods. It can be used in combination as a mixture, can also be prepared as a separate preparation, and can be administered to the same patient at the same time or at time intervals.
    [58] [Best style to carry out invention]
    [59] Hereinafter, the present invention will be described in more detail with the following reference examples, examples and experimental examples, but this does not limit the scope of the present invention.
    [60] In the following Reference Examples and Examples, the term "room temperature" refers to about 15 to 30 ° C.
    [61] Melting point is measured using a Micro Melting Point Apparatus (manufactured by Yanagimoto Seisakusho), and represents an uncorrected value.
    [62] 1 H-NMR spectra were measured with CDCl 3 as solvent using Varian Gemini-200; Data are expressed as chemical shift δ (ppm) from internal standard tetramethylsilane.
    [63] IR is measured using the SHIMADZU FTIR-8200.
    [64] UV is measured using a HITACHI U-3200 spectrophotometer.
    [65] Luminous intensity [α] D is measured at 20 ° C using DIP-370 digital polarimeter (manufactured by JASCO).
    [66] Optical purity was determined using HPLC using a chiral column (column: CHIRALCEL OD 4.6 mm dia.x250 mm, temperature: about 20 ° C., mobile phase; hexane / 2-propanol = 80/20 or hexane / 2-propanol = 85/15, flow rate: 1.0 ml / min, detection wavelength: 285 nm).
    [67] Crystalline X-ray diffraction data for measuring the absolute structure of sulfoxides were determined using Cu-Kxα Obtained by means of a four-circle diffractometer (RIGAKU AFC5R) using a line. After measuring the initial phase directly by method, the microcrystals are analyzed using SHELXL-93. X-ray powder diffraction was performed by the X-ray powder diffractometer Rigaku RINT2500 (ultraX18) No. Measure using PX-3.
    [68] Other symbols used herein have the following definitions:
    [69] s: single line
    [70] d: doublet
    [71] t: triplet
    [72] q: quartet
    [73] m: polyline
    [74] bs: wide single line
    [75] J: binding constant
    [76] Example
    [77] Reference Example 1
    [78] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (R (+) Isolation of lansoprazole)
    [79] 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (lansoprazole) (racemate) ( 3.98 g) was dissolved in mobile phase (330 ml) and acetonitrile (37 ml) and then HPLC (column: CHIRALCEL OD 20 mm dia.x 250 mm, temperature: 30 ° C., mobile phase: hexane / 2-propanol / ethanol = 255/35/10, flow rate: 16 ml / min, detection wavelength: 285 nm, 1 shot: 20-25 mg). Mix and concentrate a fraction of the optical isomer of short residence time; The individual lots were mixed, dissolved in ethanol and filtered through a 0.45 μm filter; After addition of hexane, the filtrate is evaporated again to dryness to give R (+)-lansoprazole (1.6 g, optical purity> 97.6% ee) as an amorphous material.
    [80] The amorphous material obtained is fractionated and isolated in the same manner as described above to give R (+)-lansoprazole (1.37 g, optical purity> 99.9% ee) as an amorphous material.
    [81] [α] D = + 174.3 ° (c = 0.994%, CHCl 3 )
    [82] Reference Example 2
    [83] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (R (+) Isolation of lansoprazole)
    [84] Lansoprazole (racemate) (34.2 g) was dissolved in hexane (1,140 ml) containing 2-propanol (1,710 ml) and triethylamine (0.2%) and HPLC (Column: CHIRALCEL OD 50 mm dia.x 500 mm) , Temperature: room temperature, mobile phase: hexane / 2-propanol = 85/15, flow rate: 60 ml / min, detection wavelength: 285 nm, 1 shot: about 300 mg), and isolate each optical isomer. Mix and concentrate a fraction of the optical isomer of short residence time; Each lot is mixed and dissolved in ethanol (250 ml); After addition of triethylamine (3 ml), the solution is filtered through a 0.45 μm filter. After the filtrate was concentrated, hexane was added and the filtrate was evaporated to dryness again to give R (+)-lansoprazole (9.31 g, optical purity 98.3% ee) as an amorphous material.
    [85] Example 1
    [86] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (R (+) Lansoprazole)
    [87] Amorphous R (+)-lansoprazole (100 mg) obtained in Reference Example 1 was dissolved in acetonitrile (1 ml), which was slowly evaporated at room temperature in a nitrogen stream. After the crystals start to form, diethyl ether (1.5 ml) is added and the vessel is capped and left at room temperature.
    [88] The crystal thus formed was subjected to X-ray structural analysis, and the absolute arrangement of sulfoxide was found to be R-array by the method using Flack parameter. The remaining portion of the crystals is collected by filtration, washed twice with diethyl ether (1 ml) and dried under reduced pressure to give crystals of R (+)-lansoprazole (38 mg).
    [89]
    [90]
    [91] Example 2
    [92] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (R (+) Lansoprazole)
    [93] Amorphous (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benz obtained in Reference Example 2 Imidazole (9.17 g) is dissolved in acetone (20 ml) and water (15 ml) is added with gentle heating. After the solution is left at room temperature overnight, water (20 ml) is added, followed by ultrasound. After collecting by filtration, the solid is washed with water (30 ml, 20 ml), then with diisopropyl ether (20 ml) and then dried under reduced pressure to give a solid (9.10 g). The obtained solid (9.00 g) is dissolved in acetone (30 ml) and the solution is filtered, then diisopropyl ether (50 ml) is added to the filtrate. Crystal seeds are added and the mixture is left at room temperature overnight. The precipitated crystals are collected by filtration, washed three times with diisopropyl ether (10 ml), and dried under reduced pressure to give crystals (7.85 g). The obtained crystals (7.80 g) are dissolved in acetone (22.5 ml) and water (30 ml) under heating, and the solution is left at room temperature for 1 hour. The precipitated solid is collected by filtration, washed with acetone-water (1: 4) (15 ml) and dried under reduced pressure to give a solid (3.88 g). The solid obtained (3.88 g) is dissolved in acetone (4 ml) under heating and diisopropyl ether (14 ml) is added. This solution is left at room temperature for 30 minutes. The precipitated crystals are collected by filtration and washed twice with diisopropyl ether (6 ml) and then dried under reduced pressure to give crystals of R (+)-lansoprazole (3.40 g, optical purity 99.8% ee).
    [94]
    [95]
    [96] Example 3
    [97] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole (R (+) Lansoprazole) 1.5 hydrates crystals
    [98] Amorphous (R) -2-[[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H as obtained in Reference Example 1 Benzimidazole (100 mg) is dissolved in ethanol (0.15 ml) and water (0.15 ml) is added. After seeding, the solution is left to stand at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed twice with water (2 ml), and dried under reduced pressure to give (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) 2-Pyridinyl] methyl] sulfinyl] -1 H-benzimidazole (R (+)-lansoprazole) 1.5 hydrate (96 mg) is obtained.
    [99] Melting Point: 76.0-80.0 ℃
    [100] Elemental analysis
    [101] Calculated: C: 48.48, H: 4.32, N: 10.60, S: 8.09, F: 14.38, O: 14.13.
    [102] Found: C: 48.52, H: 4.44, N: 10.49
    [103]
    [104] Experimental Example 1
    [105] Inhibitory Effect on Gastric Mucosal Injury Caused by Water Immersion Constraints
    [106] Male SD rats (7 weeks old, weight 230-250 g) are allowed to fast for 24 hours, then raised in restraint cages and submerged under the examination method in a standing position in a water chamber at a constant temperature of 23 ° C. for stress. After 5 hours, mice are removed from the cage and lethal using gaseous carbon dioxide, and their stomachs are dissected. After a short cut to the lower part of the esophagus, a 1% formalin solution (10 ml) is injected up through the duodenum, which is then occluded and then the stomach is immersed in the same solution. After 10 minutes, the incision is made along the larger curvature and the length (mm) of each mucosal injury is measured under a stereoscopic microscope. The total sum of the damage lengths of each stomach is taken as the gastric mucosal injury index.
    [107] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H- as obtained in Example 2 Crystals of benzimidazole (R (+)-lansoprazole) are suspended in 0.5% methyl cellulose (pH 9.5) containing 0.05 M NaHCO 3 and administered orally (dose 2 ml / kg) 30 minutes before stress. Each treatment group consists of 9 animals. Control group (solvent dose group) and drug dose group are compared by Steel's test.
    [108] The results are shown in Table 4.
    [109] SampleDose (mg / kg)Gastric mucosal damage index (㎜)Inhibition Rate (%) contrast-10.9 ± 1.9- (R) -lansoprazole crystals30.2 ± 0.2 * 98.0
    [110] Each value for gastric mucosal injury index is the mean ± standard error for 9 dogs in each group.
    [111] * p <0.01 (test of steel against control)
    [112] Experimental Example 2
    [113] Crystals of R (+)-lansoprazole as obtained in Example 2 (about 5 mg) and amorphous R (+)-lansoprazole (about 5 mg) as obtained in Reference Example 1 were respectively placed in a colorless glass bottle, Their stability is tested during storage at 60 ° C. (plugs are removed). 25 ml of the sample solution (concentration: about 0.2 mg / ml) were analyzed under the HPLC conditions shown below after completion of preservation in the mobile phase, together with the standard solution prepared using the initial lot, and R (+)-lansoprazole content %) Is calculated from the peak area obtained. The results are shown in Table 5 below.
    [114] HPLC analysis conditions
    [115] Detection wavelength: UV 275 nm
    [116] Column: YMC Pro C18, 4.6 x 150 mm
    [117] Mobile phase: Phosphoric acid was added to water / acetonitrile / trie to pH 7.
    [118] Fluid prepared by addition to thylamine (63: 37: 1).
    [119] Flow rate: 1.0 ml / min
    [120] Column temperature: 40 ℃
    [121] Sample injection volume: 10 μl
    [122] R (+)-lansoprazole crystals and amorphous stability SampleRetention periodTechnologyContent (residual%) decision1 week 2 weeks 4 weeksLight Brown97.093.891.7 Amorphous1 week 2 weeksBrown black brown70.857.5
    [123] When the sample was stored at 60 ° C. (exposure), the crystals of Example 2 were maintained at greater than 90% by 4 weeks, whereas the amorphous form of Reference Example 1 was 70.8% after 1 week and 57.5% after 2 weeks. A decrease was seen. These results demonstrate that the crystals of R (+)-lansoprazole are more stable than amorphous and are more preferably used in medical applications.
    [124] The crystal of the present invention is useful as a medicament because it has excellent anti-ulcer action, gastric acid secretion-inhibiting action, mucosal protective action, anti-helicobacter pyrroli action and the like and also has low toxicity. Furthermore, by crystallizing the (R) -isomer, not only the stability thereof is improved but also the handling becomes easy, a solid pharmaceutical composition having good reproducibility can be produced. In addition, when administered orally, the crystals of the present invention are more absorbable and exhibit faster action than racemates. In addition, when administered, the crystals of the present invention exhibit higher Cmax and greater AUC than racemates and, due to the increased protein-binding ratio, make partial metabolism easier, thus prolonged duration of action Indicates. The crystals of the present invention are therefore useful as medicaments with low dosages and low prevalence of adverse reactions.
    权利要求:
    Claims (2)
    [1" claim-type="Currently amended] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole or a salt thereof.
    [2" claim-type="Currently amended] (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1 H-benzimidazole.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-06-17|Priority to JP17150999
    1999-06-17|Priority to JPJP-P-1999-00171509
    2000-06-15|Application filed by 다케다 야쿠힌 고교 가부시키가이샤
    2000-06-15|Priority to PCT/JP2000/003880
    2003-08-21|Publication of KR20030068592A
    2005-09-13|Application granted
    2005-09-13|Publication of KR100514204B1
    2009-01-02|First worldwide family litigation filed
    优先权:
    申请号 | 申请日 | 专利标题
    JP17150999|1999-06-17|
    JPJP-P-1999-00171509|1999-06-17|
    PCT/JP2000/003880|WO2000078745A2|1999-06-17|2000-06-15|Crystalline form of -2-[[[3-methyl- 4--2- pyridinyl] methyl] sulfinyl] -1h-benzimidazole|
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