WO2001090086A1 - Polymorphe de 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole - Google Patents

Polymorphe de 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole Download PDF

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WO2001090086A1
WO2001090086A1 PCT/JP2001/004343 JP0104343W WO0190086A1 WO 2001090086 A1 WO2001090086 A1 WO 2001090086A1 JP 0104343 W JP0104343 W JP 0104343W WO 0190086 A1 WO0190086 A1 WO 0190086A1
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cyclohexyl
aminosulfonyl
fluorophenyl
methyloxazole
polymorph
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PCT/JP2001/004343
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English (en)
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Katsuyoshi Hara
Hideto Uehara
Hiromasa Hashimoto
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Japan Tobacco Inc.
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Priority to AU2001260610A priority Critical patent/AU2001260610A1/en
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
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Definitions

  • the present invention relates to novel polymorphs of 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole (general name: tiracoxib) , an excellent selective inhibitor of cyclooxygenase-2, the method for the production of them and thepharmaceutical compositions comprising themas the effective ingredient .
  • Japanese Patent No.2636819 discloses a specific crystal form of the present compound, 5- (4-aminosulfonyl-3- fluorophenyl)-4-cyclohexyl-2-methyloxazole, there is no disclosure concerning the presence of different crystal forms of the compound, relationshipbetween those different polymorphs , or the method how to maintain the quality of the product , which are crucial for industrial production of the compound.
  • celecoxib an inhibitor of cyclooxygenase-2 , is effective against rheumatoid arthritis and arthritis deformans .
  • celecoxib an inhibitor of cyclooxygenase-2, is effective against familial adenomatous polyposis .
  • the present invention relates to novel polymorphs of 5- ( 4-aminosulfonyl-3-fluorophenyl) -4-cyclohexy1-2- methyloxazole as defined in the following items (1) to (20), the production method of the polymorphs and the pharmaceutical compositions comprising the novel polymorphs as active ingredient .
  • the present invention relates to: (1) A substantially pure polymorph of 5-(4-aminosulfonyl-3- fluorophenyl) -4-cyclohexyl-2-methyloxazole having the structure of formula (I);
  • a pharmaceutical composition comprising as an active ingredient the polymorph of 5- (4-aminosulfonyl-3- fluorophenyl) -4-cyclohexyl-2-methyloxazole described in (1) .
  • a pharmaceutical composition comprising as an active ingredient the polymorph of 5- (4-aminosulfonyl-3- fluorophenyl) -4-cyclohexyl-2-methyloxazoledescribedinanyof (2) to (4).
  • a pharmaceutical composition comprising as an active ingredient the polymorph of 5- (4-aminosulfonyl-3- fluorophenyl) -4-cyclohexyl-2-methyloxazoledescribedinanyof (5) to (7).
  • a prophylactic and/or therapeutic agent for the treatment of a disease caused by cyclooxygenase-2 comprising as an active ingredient the polymorph of 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole described in (1).
  • a prophylactic and/or therapeutic agent for the treatment of a disease caused by cyclooxygenase-2 comprising as an active ingredient the polymorph of 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole described in any of ( 2 ) to ( 4 ) .
  • a prophylactic and/or therapeutic agent for the treatment of a disease caused by cyclooxygenase-2 comprising as an active ingredient the polymorph of 5- (4-aminosulfonyl- 3-fluorophenyl) -4-cyclohexyl-2-methyloxazole described in any of (5) to (7).
  • a further object of the present invention is to provide pharmaceutical composition which is consist of pharmacologically effective amount of the polymorph said above and other ingredients such as fillers which are pharmacologically allowable.
  • the novel polymorphs of the compound of the present invention are useful not only as antipyretics , analgesics , and the anti-inflammatory agents, but they are useful as the agents for treating such diseases and syndromes as arthritis including rheumatoid arthritis, spondyloarthropathies, gouty arthritis , osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; gout or ankylosing spondylitis; asthma; bronchitis; menstrual cramps; dysmenorrhea; premature labor; tenositis; myositis; bursitis; synovitis; hepatopathy including hepatitis; skin-related diseases including such as psoriasis, eczema, burns anddermatitis;
  • the compounds of the present invention are used for the treatment of arthritis including rheumatoid arthritis, spondyloarthropathies , gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; gout an ankylosing spondylitis; asthma; bronchitis; menstrual cramps; dysmenorrhea; premature labor; myositis; bursitis; synovitis; skin-related diseases including such as psoriasis, eczema, burns and dermatitis; post-operative inflammation after ophthalmic surgery such as cataract surgery and refractive surgery; gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis; familial adenomatous polyposis; cancers suchas colorectal cancer, breast cancer, lung cancer, prostatic cancer, bladder cancer, cervical cancer, cancer of the uterine cervix
  • arthritis including rheumatoid arthritis, spondyloarthropathies , gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; gout; asthma; bronchitis; dysmenorrhea; skin-relateddiseases including suchas psoriasis, eczema, burns and dermatitis; gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis; familial adenomatous polyposis; cancers such as colorectal cancer, breast cancer, lung cancer, prostatic cancer, bladder cancer, cervical cancer, cancer of the uterine cervix and skin cancer, as well as metastases of those cancers; cellular neoplastic transformations and metastatic tumor growth; tumor angiogenesis; migraine headaches; aplastic anemia; gingivitis; ophthalmic diseases
  • the polymorphs of the present invention may usually be mixed, according to the method known in itself, with pharmacologically allowable carriers, fillers, diluents, disintegrants, stabilizers, preservatives, buffering agents, emulsifying agents, aromatics, colorings, sweeteners, viscid agents , flavoringagents , andotheradditives , concrete examples thereof being water, vegetable oils, alcohols such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatine, carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin, vaseline and so on, and then formed into tablets, pills, powders, granules, suppositories, injecting drugs, eye-lotions, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions and syrups and so on, appropriate for administration per os or parenterally
  • pharmacologically allowable carriers
  • the administration dose may vary depending on the kind of disease and the severity of the disease, compounds to be administered, route of administration, age, sex and body weight of each patient.
  • the dose may be selected, in general, preferably from the range of about 0.1 to lOOOmg, and more preferably from the range of about lmg to 300mg, and the most preferably from the range of about 5mg to 200mg for an adult per day.
  • the compounds of the present invention can be used as medicines not only for human use, but for veterinary use.
  • the polymorph of the present invention can be produced by the methods of crystallization described below. However, it will be apparent that the production method is not restricted to the ones described here.
  • the compound 5- (4-aminosulfonyl-3-fluorophenyl) -4- cyclohexyl-2-methyloxazole itself may be produced according to the method described in the specification of Japanese Patent No. 2636819 and/or of Japanese Patent Application No.1998-249621.
  • This polymorph can be produced by crystallizing 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole either frommixed solvents of methanol-water, ethanol-water and isopropyl alcohol-water or from solvents such as toluene, xylene and water, which have only limited solubility for the objective compound, at the temperature of about 50°C or higher, and more preferably at about 60°C or higher, but below the boiling point of the solvent or solvent mixtures used.
  • the crystallization process may include the operation of crystal growth.
  • This polymorph can be produced by crystallizing 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole either from organic solvents such as acetone, ethanol, ethyl acetate, methyl ethyl ketone, water or the mixtures thereof, at the temperature of about 50°C or lower, and more preferably at about 40°C or lower, and above the melting point of the solvent or solvent mixtures used.
  • organic solvents such as acetone, ethanol, ethyl acetate, methyl ethyl ketone, water or the mixtures thereof
  • FIG. 1 shows the results of the differential scanning calorimetry (DSC) measurement of the polymorph of 5- (4- aminosul onyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole (Form A) .
  • FIG. 2 shows the results of the differential scanning calorimetry (DSC) measurement of the polymorph of 5- (4- aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyloxazole (Form B) .
  • FIG. 3 shows the infrared absorption spectrum of the polymorph of 5- ( 4-aminosulfonyl-3-fluorophenyl) -4- cyclohexyl-2-methyloxazole (Form A) in potassium bromide.
  • FIG. 4 shows the infrared absorption spectrum of the polymorph of 5- (4-aminosulfonyl-3-fluorophenyl) -4- cyclohexyl-2-methyloxazole (Form B) in potassium bromide.
  • FIG. 5 shows the X-ray powder diffraction pattern of the polymorph of 5- (4-aminosulfonyl-3-fluorophenyl) -4- cyclohexyl-2-methyloxazole (Form A) .
  • FIG. 6 shows the X-ray powder diffraction pattern of the polymorph of 5- (4-aminosulfonyl-3-fluorophenyl) -4- cyclohexyl-2-methyloxazole (Form B) .
  • the active charcoal was then removed by filtration under pressure, and the dissolving flask and the filtering apparatus used were rinsed with methanol (425 ml) , and the washings was combined with the main filtrate.
  • the combined filtrate and washings was then poured into pure water (5100 ml) prepared in a separate vessel, and the resulting mixture was heated up to 80 * 0 and stirred at the same temperature for two hours, followed by cooling to 20°C (inner temperature) and stirring at the same temperature for one hour. Then, the resulting mixture was filtered, and crystals obtained were washed with pure water ( 1700 ml) and dried in vacuo giving the titled compound as white crystals (810.0 g, in a yield of 95%) .
  • the combined filtrate and washings were then poured into pure water (525 ml) prepared in a separate vessel, and the resulting mixture was heated up to 75°C (inner temperature) or higherandstirred at the same temperature for twohours , followed by cooling to 20°C (inner temperature) and stirring at the same temperature for one hour. Then, the resulting mixture was filtered, and crystals obtained were washed with pure water (40 ml) anddried in vacuogivingthe titledcompoundaswhite crystals (48.1 g, yield: 96%).
  • Rate of scanning 4° /minute Step of scanning: 0.02°
  • Samples of the polymorphs of the present invention were stored in an atmosphere of temperature, 60°C, and humidity, 75%, for two weeks , and the appearances of the samples were compared with those of the untreated ones. The comparison was made by observing the samples in beakers placed on a white paper. The results are shown in Table 4.
  • Samples of the polymorphs of the present invention were stored in an atmosphere of temperature, 60°C , and humidity, 75%, for two weeks.
  • the purity of the samples was measured before and after the storage using a liquid chromatograph as follows .
  • Each 0.04 g of the polymorph was weighed accurately, dissolved in the mobile phase A solution, and the total volume of the solution was adjusted to accurately to 20 ml to give the sample solution.
  • Precisely 1 ml of this solution was diluted with the mobile phase A solution to 100 ml accurately, to give the standard solution (1 %) .
  • Each 50 l of the sample and the standard solutions was analyzed according to the Liquid ChromatographyMethod in the General Test Methods of the Japanese Pharmacopoeia, under the conditions described below.
  • the peak areaof eachpeak was determinedbyusingan automated integration method and the content of each impurity ( %) and the total content of the impurities (%) were calculated.
  • the results are shown in Table 4. [Value 1 ]
  • the total impurity (%) X 100
  • Detector a ultra-violet spectrometer (wave lengths used for the measurement: 220 nm and 290 nm)
  • Column a stainless steel tube of 4.6 mm in diameter and 15 cm in length, packed with a silica gel for chromatographic use of 5/im in size on which octade ⁇ yl groups are bonded chemicall .
  • Mobile phase The mobile phase A and B solutions were used according to the time-program as shown in Table 3.
  • Detector sensitivity The sensitivity was adjusted so that the peak height of the peak due to polymorph will be 30 to 50 % of the full scale, when 50 Zl of the standard solution was applied.
  • Samples of the polymorphs of the present invention were stored in an atmosphere of the temperature, 60°C , and the humidity, 75%, for two weeks. The samples before and after the storage were quantitatively determined by means of liquid chromatography as follows .
  • Detector a ultra-violet spectrometer (wave lengths used for the measurement: 220 nm)
  • Standard solutions which contain 2, 4, 6, 8, and 10 Ml of the polymorph of the present invention, respectively, were prepared by precisely weighing 25 mg of the polymorph of the present invention, dissolving it in the mobile phase, adjusting the volume to 50 ml, and diluting the resulting solution with the mobile phase. By using these solutions, a standard calibration curve was made. (Preparation of the sample solutions)
  • the polymorph of the present invention was ground in a mortar, and 10 mg of it was weighed precisely and transferred into a 50-ml centrifuge tube, followed by addition of 20 ml of distilled water. The mixture was then stirred at 25°C for 3 hours. After stirring, the solution was filtered. The first 12 ml of the filtratewas discarded and the next 5ml of the filtrate was taken, transferred to a 10 ml flask and diluted with acetonitrile to a volume of 10 ml.
  • Detector a ultra-violet spectrometer (wave lengths used for the measurement: 220 nm)
  • Column a stainless steel tube of 4.6 mm in diameter and 15 cm in length, packed with a silica gel for chromatographic use of 5 M m in size on which octadecyl groups are bonded chemically.
  • Tumor cell growth suppression action of the compounds of the present invention can be confirmedwith NSCLC cells as object by the ordinary MTT
  • the test results showed that the compounds of the present invention have an excellent cell growth suppression action.
  • Subcutaneous transplantation-natural metastasis model (LNM35 ) mice are prepared by transplanting sub ⁇ utaneously human lung cancer cell line in SCID mice. The mice are divided into two groups; one is treated with the compound of the present invention and the other not . After tens of days , the tumor size at the transplanted site and the presence or absence of lymphatic metastasis in the treated group are compared with those in the untreated one to assess the lung cancer suppression action of the compound.
  • the test results showed that the compounds of the present invention have an excellent lung cancer growth suppression action.
  • NNK [4- (methylnitrosoamino) -1- (3-pyridyl) -1- butanone] -inducedlung cancer developingmodelmice areprepared by using A/J mice. The mice are divided into two groups; one is treated with the compound of the present invention and the other not . The presence or absence of development of lung cancer in the treated group is compared with that of the untreated one with respect to time after NNK has been given, to assess the lung cancer development suppression action of the compound. The test results showed that the compounds of the present invention have an excellent lung cancer development suppression action.
  • NMBA-induced esophagus cancer development model rats are preparedbyusing F344 rats .
  • the rats are divided into two groups ; one is treated with the compound of the present invention and the other not .
  • the number and volume of tumors in the treated group are compared with those in the untreated one to assess the esophagus cancer suppression action of the compound.
  • test results showed that the compounds of the present inventionhave an excellent esophagus cancer suppression action.
  • DMH (dimethylhydrazine) -induced large intestine tumor generation model rats are prepared by using Fischer strain of rats. The rats are divided into two groups; one is treated with the compounds of the present invention and the other not . After a given period of time from the start of administration of the compound, thenumberofAFCformedin the treatedgroupis compared with that in the untreated one to assess the large intestine ACF generation suppression action.
  • test results showed that the compounds of the present invention have an excellent large intestine ACF generation suppression action.
  • a large intestine tumor cell line is transplanted in the back of Balb/c mice.
  • the mice are divided into two groups; one is treated with the compounds of the present invention and the other not.
  • the size of the tumor at the transplanted site in the treated group is measured with respect of time and compared with that in the untreated one to assess the large intestine cancer suppression action of the compounds.
  • Lungmetastasis model mice are prepared by injecting tumor cells via tail vein. The mice are divided into two groups; one is treated with the compound of the present invention and the other not . After a given period of time after the tumor cells have been injected, the number of lung metastasis in the treated group is compared with that in the untreated one to assess the lung metastasis suppression action of the compound. The test results showed that the compounds of the present invention have an excellent lung metastasis suppression action.
  • liver metastasismodelmice arepreparedbyinjecting tumor cells into pancreas of mice .
  • Themice are divided into two groups; one is treated with the compound of the present invention and the other not .
  • the number of liver metastasis in the treated group is comparedwith that in the untreated one to assess the liver metastasis suppression action of the compound.
  • Experimental Example 17 Bone Metastasis Suppression Action
  • Cells of a mouse breast cancer cell line and mouse bone marrow cells are co-incubated in the presence and absence of the compound of the present invention. After a given period of time, the number of osteoclast cells in the treated culture is compared with that in the untreated one to assess the bone metastasis suppression action. The test results showed that the compounds of the present invention have an excellent bone metastasis suppression action.
  • Experimental Example 18 Neurite Elongation Promotion Action NG cells in which cyclooxygenase 2 is expressed by means of the cyclooxygenase expression vector are incubated in the presence and absence of the compound of the present invention.
  • the length of the neurites of the treated and untreated cells is determinedunderamicroscopewithrespect of time andcompared to assess the neurite elongation promotion action of the compound.
  • test results described above clearly show that the polymorphs of the present invention have superior stability, and that they will keep their quality and pharmacological effectiveness under various environmental conditions encountered during distribution and storage. Furthermore, the compounds of the present invention have excellent therapeutic effects against various diseases in which cyclooxygenase 2 is involved.

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Abstract

L'invention concerne de nouveaux polymorphes de 5-(4-aminosulfonyl-3-fluorophényl)-4-cyclohéxyl-2-méthyloxazole possédant d'excellentes caractéristiques de stabilité à la chaleur et à la conservation. Polymorphe de 5-(4-aminosulfonyl-3-fluorophényl)-4-cyclohéxyl-2-méthyloxazole représenté par la formule (I) dans laquelle Me représente un groupe méthyle.
PCT/JP2001/004343 2000-05-26 2001-05-23 Polymorphe de 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole WO2001090086A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001260610A AU2001260610A1 (en) 2000-05-26 2001-05-23 A polymorph of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxaz ole

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2000-156961 2000-05-26
JP2000156961 2000-05-26
JP2000303045 2000-10-03
JP2000-303045 2000-10-03
JP2001-121703 2001-04-19
JP2001121703A JP2002179657A (ja) 2000-05-26 2001-04-19 ５−（４−アミノスルホニル−３−フルオロフェニル）−４−シクロヘキシル−２−メチルオキサゾールの結晶多形

Publications (1)

Publication Number Publication Date
WO2001090086A1 true WO2001090086A1 (fr) 2001-11-29

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PCT/JP2001/004343 WO2001090086A1 (fr) 2000-05-26 2001-05-23 Polymorphe de 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole

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JP (1) JP2002179657A (fr)
KR (1) KR20030003751A (fr)
AU (1) AU2001260610A1 (fr)
PE (1) PE20011312A1 (fr)
WO (1) WO2001090086A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014352A2 (fr) * 2002-08-07 2004-02-19 Pharmacia Corporation Methodes de traitement de troubles dont la mediation est assuree par l'anhydrase carbonique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996019463A1 (fr) * 1994-12-20 1996-06-27 Japan Tobacco Inc. Composes heteroatomiques d'oxazole et leur emploi

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996019463A1 (fr) * 1994-12-20 1996-06-27 Japan Tobacco Inc. Composes heteroatomiques d'oxazole et leur emploi

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014352A2 (fr) * 2002-08-07 2004-02-19 Pharmacia Corporation Methodes de traitement de troubles dont la mediation est assuree par l'anhydrase carbonique
WO2004014352A3 (fr) * 2002-08-07 2004-09-10 Pharmacia Corp Methodes de traitement de troubles dont la mediation est assuree par l'anhydrase carbonique

Also Published As

Publication number Publication date
PE20011312A1 (es) 2002-01-02
JP2002179657A (ja) 2002-06-26
KR20030003751A (ko) 2003-01-10
AU2001260610A1 (en) 2001-12-03

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