HK1023125B - Crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide - Google Patents

Description

Crystalline forms of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide

Scope of the invention

The present invention relates to the field of anti-inflammatory drugs, and more specifically to crystalline forms of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide, methods of making the crystalline forms, pharmaceutical compositions and methods of treating cyclooxygenase-2 (COX-2) related diseases, including inflammation.

Background

Prostaglandins play an important role in inflammatory processes, inhibiting the production of prostaglandins, in particular PGG₂、PGH₂And PGE₂Has been a common indicator of the discovery of anti-inflammatory drugs. However, common non-steroidal anti-inflammatory drugs (NSAIDs) are active in reducing prostaglandin-induced pain and swelling associated with inflammatory processes, as well as in affecting other prostaglandin regulatory processes not associated with inflammatory processes. Thus, the use of large doses of the most common NSAIDs can produce serious side effects, including life-threatening ulcers, which limit their therapeutic effectiveness. The use of corticosteroids instead of NSAIDs will have even more serious side effects, especially over long periods of use.

Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes, including Cyclooxygenase (COX), in the human eicosatetraenoic acid/prostaglandin pathway. The recently discovered inducible enzymes associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provide a viable inhibitor that is more effective in reducing inflammation and produces fewer of the serious side effects associated with inhibition of cyclooxygenase-1 (COX-1).

A group of substituted isoxazole compounds is described in U.S. Pat. No. 5633272 to Talley et al and in International application WO 96/25405. The compounds are useful for the treatment of inflammation and inflammation-related disorders. 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamides exhibit potential as inhibitors that selectively inhibit COX-2 over COX-1.

For all pharmaceutical compounds and compositions, the chemical and physical stability of the pharmaceutical compounds is important during the commercial development of the drug. Such stability includes stability at room temperature, especially under humid and storage conditions. Improving stability under different storage conditions requires predicting the various possible storage conditions of a drug product over the life of the commercial product, and a stable drug may avoid the use of special storage conditions and frequent replacement of inventory. The pharmaceutical compounds must also be stable during the manufacturing process. Drug pulverization is often required in production to obtain a drug material having a uniform particle size and surface area, and unstable materials often produce polymorphic changes. Thus, any modification that enhances the stability profile of a drug substance can provide significant benefits over less stable substances.

It has now been found that 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide can be prepared in different crystalline forms. The earlier crystalline material (form a) was unstable after mechanical crushing (milling) and was unstable to heat. The recently determined form (form B) is more stable and has improved physical properties.

Brief description of the drawings

FIG. 1 shows a Differential Scanning Calorimetry (DSC) profile of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide crystalline form A.

FIG. 2 shows a Differential Scanning Calorimetry (DSC) profile of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide crystalline form B.

FIG. 3a shows an infrared spectrum of crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide.

FIG. 3b shows an IR spectrum of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide crystalline form A.

FIG. 4 shows the X-ray diffraction pattern of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide crystalline form A.

FIG. 5 shows the X-ray diffraction pattern of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide crystalline form B.

Detailed description of the invention

It has been found that 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide can be made into the crystalline form designated "form B". Form B can be identified by the following method.

Melting Point

Melting points were determined using a Thomas Hoover melting point apparatus or using a Mettler FP 900 Thermosystem melting point apparatus. The melting range was determined by Differential scanning calorimetry using a TA Instruments Differential scanning calorimeter (Model 2100 controller, Model 912 dual calorimeter). Samples (1-2mg) were placed in open aluminum pans and heated at 10 deg.C/min.

Form A exhibited an initial melt at 160.2 ℃ and an exotherm (imbedded exotherm) was inserted at 170.9 ℃ due to crystallographic rearrangement (see FIG. 1). Form B exhibited an initial melt at 170.9 deg.C (peak at 172.5 deg.C). An example of DSC of form B is shown in figure 2.

Infrared spectroscopy

The infrared spectra were obtained with a Nicolet DRIFT (diffuse reflectance Infrared Fourier transform) Magna System 500 spectrophotometer. A Spectra-Tech Collector system and a 3mm sample cell were used. The samples were analyzed with KBr (2%) and ranged from 400 to 4000cm^-1And (6) scanning. Fig. 3a is an example of an infrared absorption spectrum of form B, and fig. 3B is an example of form a. The Y axis represents the value represented by Kubella-MuCorrected reflectance in nk units.

The characteristic absorptions of the infrared spectrum of form B are at about 3377, 1170, 1151, 925, 844, 745, 729 and 534cm^-1Unlike the absorption observed for form a profile. Part of characteristic absorption of infrared spectrum of the crystal form A is about 723cm^-1Unlike the absorption observed for form B profile. The infrared spectrum of the crystal form B of the invention is basically the same as that shown in figure 3 a.

Powder X-ray diffraction

Analysis was performed with a Siemens 5000 powder diffractometer. The raw data was measured at 2-50, 0.020 intervals for 2 seconds 2 theta values.

Table 1 lists the important parameters for form B in terms of 2 θ values and intensities of the major peaks. Fig. 4 is an example of an X-ray diffraction pattern of form a, and fig. 5 is an example of an X-ray diffraction pattern of form B. Important differences between form a and form B are evident at 12.221, 15.447, 17.081, 19.798 and 23.861.

TABLE 1

Peak index angle-2 theta (degree) D interval peak Cps I/I_max(％)

1 12.221 7.2361 502.38 63.29

2 13.693 6.4617 38.03 4.79

3 14.227 6.2203 51.46 6.48

4 15.447 5.7314 599.94 75.58

5 15.801 5.6039 793.79 100.00

6 16.678 5.3110 239.95 30.23

7 17.081 5.1868 331.31 41.74

8 18.165 4.8796 270.21 34.04

9 19.066 4.6510 73.16 9.22

10 19.400 4.5717 200.13 25.21

11 19.798 4.4807 789.23 99.43

12 20.578 4.3126 209.43 26.38

13 22.008 4.3054 691.33 87.09

14 22.540 3.9414 71.87 9.05

15 22.975 3.8678 137.23 17.29

16 23.580 3.7699 394.27 49.67

17 23.861 3.7261 602.27 75.87

18 24.553 3.6226 397.23 50.04

19 25.206 3.5302 192.44 24.24

20 25.560 3.4822 77.74 9.79

21 25.940 3.4320 31.47 3.96

22 26.200 3.3985 20.87 2.63

23 27.295 3.2646 151.54 19.09

24 28.595 3.1191 207.74 26.17

25 29.124 3.0636 161.44 20.34

26 29.656 3.0099 73.94 9.32

Form B is prepared by recrystallization of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide with a suitable solvent. To prepare form B, 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide is dissolved in a volume of solvent and cooled until crystals form. Preferably, the compound is added to the solvent at a temperature of at least about 25 ℃. More preferably the temperature of the solvent is between 30 ℃ and the boiling point of the solvent. Even more preferably, the temperature ranges from about 65 ℃ to about 75 ℃.

Alternatively, a hot solvent is added to the compound and the mixture is cooled until crystals form. Preferably the temperature of the solvent is at least 25 ℃. More preferably, the temperature of the solvent is in the range of about 50-80 deg.C. Even more preferred is a temperature range of about 65-75 deg.c.

Preferably, the compound is mixed with a solvent in an amount of 3 times or more the weight of the compound. More preferably, the ratio of solvent to compound is from about 7 to about 10 times.

The solution is preferably cooled slowly until form B precipitates. More preferably, the solution is cooled at a rate of less than about 0.5 deg.C/minute. Even more preferably, the solution is cooled at a rate of about 0.3 deg.C/minute or slower.

Suitable solvents are those which dissolve the compound and any impurities at elevated temperature, but preferably precipitate form B upon cooling, or a mixture of solvents. Suitable solvents are selected from the group consisting of alcohols, methyl tert-butyl ether, methyl ethyl ketone and combinations of solvents selected from the group consisting of ethanol, methyl tert-butyl ether, acetonitrile, water, acetone, tetrahydrofuran and methyl ethyl ketone. Alcohols or aqueous alcohols are preferred. More preferred solvents are selected from the group consisting of methanol, aqueous methanol, ethanol, aqueous ethanol, isopropanol, and aqueous isopropanol. Even more preferred are aqueous methanol, ethanol 3A, aqueous ethanol and isopropanol/methanol mixtures.

Or dissolving the compound in a solvent and adding a co-solvent to facilitate crystallization of the desired crystalline form.

The crystalline form B formed is isolated from the solvent, for example by filtration or centrifugation. Preferably, the crystals are dried and more preferably dried at a temperature in the range of from about 30 ℃ to about 100 ℃. Even more preferably, the crystals are dried under vacuum.

Additionally, form B is prepared by heating at a sufficient temperature to convert form a to form B. Preferably form a is heated at a temperature in the range of from 50 ℃ to about 140 ℃.

Preparation of

The following examples contain detailed methods for preparing form B. These details are within the scope and are intended to be exemplary of the invention. The detailed description provided is for illustrative purposes only and does not limit the scope of the invention. All parts are parts by weight and temperatures are in degrees Celsius, unless otherwise indicated.

4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide was prepared by the following method, in which ethanol 3A was aqueous ethanol (5% water) denatured with methanol.

Example 1

Step 1. preparation of deoxybenzoinoxime

In a 5 l flask equipped with mechanical stirring, reflux condenser and thermometer, sodium acetate trihydrate (152.5g, 1.12 moles, 1.1 equivalents) was added to deoxybenzoin (200g, 1.02 moles) and dissolved with ethanol (3A, 0.8 l) and water (0.24 l). The solution was stirred and heated to 70 + -1 deg.C. In another 500ML flask, water (0.1 l) was added to hydroxylamine hydrochloride (78.0g, 1.12 moles, 1.1 equivalents) with stirring. The hydroxylamine hydrochloride solution was transferred to the deoxybenzoin solution while the reaction mixture was maintained at about 70 ℃. The mixture was heated to boiling (about 84 ℃) and maintained at this temperature for 40 minutes. Over the course of two hours, the mixture was cooled to 40 ℃ and water (10.5 l) was added to the reaction mixture. The reaction mixture was cooled to 20 ℃ for a further 1 hour with stirring. The pure oxime crystals formed were separated by filtration (Buchner funnel, Whatman filter paper No. 1) using a vacuum chamber (housevacunum), washed with a mixture of 50ml 3A ethanol and 100ml water and with water (1 l). The solid was dried under vacuum for 2 hours and dried under vacuum chamber at 55 ℃ for 12 hours. Pure deoxybenzoinoxime (213.2g, 99%) was obtained.

Step 2.5-hydroxy-5-methyl-3, 4-diphenylisoxazoline (isoxazoline) preparation

Deoxybenzoin (step 1) was dissolved in anhydrous THF (565ml) under nitrogen. The solution was cooled to-20 ℃. The solution was treated with lithium diisopropylamide (2M, 800ml, 1.60mol) while the reaction temperature was warmed to 10-15 ℃. The reaction mixture cooled to-10 ℃ to-20 ℃ and anhydrous ethyl acetate (218ml) were added to the solution while the reaction temperature was raised to the maximum of 25 ℃ and maintained at 25 ℃ for 30 minutes. The reaction mixture was cooled to about 0 ℃. Water was added to the quench flask and cooled to 0-5 ℃. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25 ℃. The quenched mixture was cooled to 0-5 ℃. Hydrochloric acid (12M) was added to the mixture and the temperature was maintained below 25 ℃ during the addition by controlling the rate of addition and stirring until all the solids were dissolved (about 5 minutes). The pH of the stirred mixture was determined to be pH 3-4. The layers were separated and the organic layer was removed. Heptane was added to the organic layer with stirring. The organic layer was distilled until the flask temperature reached 90-91 ℃. The solution was cooled to 5 ℃ and filtered. The solid was washed twice with 300ml ethyl acetate-heptane (20/80) and cooled to 5 ℃. The solid product was dried on the funnel for several hours and then dried over the weekend at room temperature under vacuum with a nitrogen stream to give isoxazoline (108.75g, 57.7%)

Step 3.4- [ (5-methyl-3-phenyl) -4-isoxazolyl]Preparation of benzenesulfonamides

5-hydroxy-5-methyl-3, 4-diphenylisoxazoline (step 2) (142g, 0.56mol) was dissolved in dichloromethane (568ml) in a 3 liter round bottom flask equipped with a heating mantle, mechanical stirrer, water condenser, J-KEM temperature controller and thermocouple to form a slurry. The slurry was stirred and cooled to < 10 ℃. Chlorosulfonic acid (335ml, 586.3g, 5.04mol) was added to the slurry and the flask temperature was kept below 20 ℃ by controlled addition. The mixture was heated to reflux (about 40 ℃) for 5 hours and then cooled to 0-5 ℃. The cooled reaction solution was slowly transferred to a 3 liter three neck round bottom flask (with mechanical stirrer and thermocouple) containing water (1000ml) pre-cooled to 0-5 ℃, using vigorous stirring and maintaining the flask temperature below 10 ℃. The mixture was stirred for an additional 5 minutes. The layers were separated. In another 3 liter flask (mechanical stirring, external ice/salt bath, thermocouple) 28% ammonium hydroxide was cooled to 0-5 ℃. The dichloromethane solution was transferred to a stirred ammonium hydroxide solution, maintaining the temperature below 10 ℃. The mixture was stirred at room temperature for 60 minutes. The resulting slurry was filtered and the solid was washed with water (200ml) and dried to give 4- [ (5-methyl-3-phenyl) -4-isoxazolyl ] benzenesulfonamide as a white solid (94.3g, 53.5%).

Step 4.4- [ (5-methyl-3-phenyl) -4-isoxazolyl]Recrystallization of benzenesulfonamides

The product of step 3, 4- [ (5-methyl-3-phenyl) -4-isoxazolyl ] benzenesulfonamide, was dissolved in 300ml of boiling methyl ethyl ketone (2-butanone) and diluted with 10% aqueous isopropanol [300ml, (270ml of anhydrous isopropanol and 30ml of water) ]. The material was cooled to room temperature and then crystallized. The crystals were isolated by filtration and dried in a vacuum oven (10mmHg, 100 ℃) to give pure form B (112.95 g; 65%): mp172-173 ℃.

Example 2

5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide (example 1, step 3) (3g) was combined with 80% ethanol 3A/20% water (9ml) and heated until the solid dissolved. The flask was cooled and held for 1 hour with a tap water bath, and a precipitate formed. The solid was filtered off and washed with ethanol 3A. The material was heated to dryness under vacuum (50-60 ℃, 20 Hg). The material formed was identified as form B.

Example 3

5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide (example 1, step 3) (10g) was combined with ethanol 3A (100ml) and heated until the solid dissolved (ca. 70 ℃). The flask was cooled to 20-25 ℃ over 1.5 hours and held for 30 minutes to form a precipitate. The solid (Whatman #1 filter paper) was filtered off and washed with water. The material was heated to dryness under vacuum (90 ℃, 50-100 mmHg). The material formed was identified as form B.

Example 4

5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide (example 1, step 3) (9.8g), methanol (73.5ml) and water (24.5ml) were combined and heated to 65-70 ℃. The solution was held for about 10 minutes and filtered while heating to remove any particulate matter. The solution was slowly cooled to 50 ℃ (about 0.3 ℃/min) and held at 50 ℃ for 1 hour (crystals formed during the hold period). The solution was further cooled to 5 ℃ (about 0.3 ℃/min) and held at 5 ℃ for 1 hour. The product was isolated by filtration and washed with 10ml of cold methanol/water (75/25). The product was dried at 95-100 ℃ for 4 hours to give 8.55g of form B.

Example 5

Methanol/isopropanol (80/20, 120ml) was added to 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide (example 1, step 3) (25g) and heated to about 68 ℃. The solution was held for about 15 minutes and filtered through a glass filter funnel while heating to remove any particulate matter. The solution was slowly cooled to 5 ℃ for more than 3.3 hours (about 0.3 ℃/min) and held at 5 ℃ for 2 hours. The product was isolated by filtration and washed with 10ml of cold methanol/isopropanol (80/20). The product was dried at 95-100 ℃ for 3 hours to give 11g of form B.

Comparative example 6

5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide (example 1, step 3) (10g) was mixed with 20ml of water: methanol (25: 75) and heated until the solid dissolved. The flask containing the solution was placed in ice and the mixture was rapidly cooled to < 10 ℃ without observed crystallization on cooling. A small amount of crystal formation was observed at the bottom of the flask, followed by rapid crystal formation. Left to stand for about 10 minutes. The solid was filtered off and washed with 75% aqueous methanol. The material was heated to dryness under vacuum/nitrogen (50-60 ℃, 20 Hg). The material formed was identified as form a.

The invention also includes methods of treating or preventing cyclooxygenase-2 related disorders such as inflammation, said methods comprising treating a patient suffering from or susceptible to inflammation or the disorder with a therapeutically effective amount of crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide.

Crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide will be useful in, but not limited to, the treatment of inflammation and in the treatment of other cyclooxygenase-2 mediated diseases, for example, the treatment of pain and headache as an analgesic or fever as an antipyretic. For example, form B is useful for treating arthritis, including (but not limited to) rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. Form B may be used for the treatment of asthma, bronchitis, dysmenorrhea, premature labor (preterm labor), tendonitis. Bursitis, liver diseases including hepatitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis, and treatment of post-operative inflammation including ophthalmic surgery such as cataract surgery and refractive surgery. Form B may also be useful in the treatment of gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Form B may be used for the prevention or treatment of cancer, such as colorectal and breast cancer, lung cancer, prostate cancer, bladder cancer, cervical cancer and skin cancer. Form B is useful for treating glaucoma, vascular proliferation, and retinopathy. Form B may be used to treat inflammatory diseases such as vascular disease including atherosclerosis, migraine, adventitious arteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction disease (neuromuscular junction disease) including myasthenia gravis, White matter (White matter) disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis (polymyositis), gingivitis, nephritis, allergy, post-traumatic swelling, myocardial ischemia, and the like. Form B is also useful for treating ophthalmic diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute injury of ocular tissue. Form B may also be used to treat pulmonary inflammation, such as conditions associated with viral infections and cystic fibrosis. Form B may also be useful in the treatment of certain central nervous system disorders, such as cortical dementias (cortical dementias) including Alzheimer's disease, and central nervous system damage caused by stroke, ischemia, seizures, and injury. Form B is useful as an anti-inflammatory agent, such as for the treatment of arthritis, and has the advantage of low adverse side effects. Form B may also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, osteoporosis and in inhibiting bone resorption. Form B may also be used to treat pain, but is not limited to post-operative pain, dental pain, muscle pain, and pain caused by cancer. Form B is useful in the prevention of cardiovascular diseases such as atherosclerosis, liver diseases and dementia such as Alzheimer's disease.

In addition to use in human therapy, the crystalline forms may also be used in veterinary therapy of companion animals (companion animals), exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

The crystalline modification B of the invention can also be administered in a manner co-therapy, partly or totally replacing other conventional anti-inflammatory drugs, with drugs such as steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB₄Receptor antagonists and LTA₄The hydrolase inhibitor is administered together.

Suitable LTA₄Hydrolase inhibitors include RP-64966, (S, S) -3-amino-4- (4-benzyloxyphenyl) -2-hydroxybutyric acid benzyl ester (Scripps Res. Inst), N- (2(R) - (cyclohexylmethyl) -3- (hydroxycarbamoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl) heptanoic acid (Rhone-Poulenc Rorer), and lithium 3- (3- (1E, 3E-tetradecadienyl) -2-oxiranyl) benzoate (Searle).

Suitable LTB₄Receptor antagonists include, for example, EBselen, linazolast, ontazolast, Bayer Bay-x-1005, CGS-25019C, compound ETH-615 of Leo Denmark, compound MAFP of Merck, TMK-688 of Terumo, compound T-0757 of Tanabe, compound LY-213024 of Lilly, LY-210073, LY223982, LY233469 and LY255283, LY-293111, 264086 and 292728, compound ONO-LB457, ONO-4057 and ONO-LB-448, compound S-2474 of Shionogi, calcerol, compound of Lilly, compound SC-53228, SC-41930, SC-50605 and SC-51146, compound BPC15 of Warner Lambert, compound of Smith beer and compound 209247 of Smhnkine Benham&Compound SKF-104493 of F. Preferred LTB₄The receptor antagonist is selected from the group consisting of calcerol, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688.

Suitable 5-LO inhibitors include, Abbott's compounds A-76745, 78773 and ABT 761, Bayer Bay-x-1005, Cytomed CMI-392, Eisai's E-3040, Scotia Pharmaceutica's EF-40, Fujirebio's F-1322, Merckle's ML-3000, Purdue Frederick's PF-5901, 3M Pharmaceuticals ' R-840, rilopirox, flobufen, linalast, lonapolene, malapropacal, ontasolast, teidap, zileuton, pranlukast, tepoxalin, rilopirox, flazalatine hydrochloride, enam phosphate and bunaprost.

The crystalline forms of the invention may also be treated in combination with opioids and other analgesics, which include narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., non-addictive) analgesics, monoamine uptake inhibitors, adenosine modulators, cannabinoid (cannabinoid) derivatives, substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers. More preferably, the compound used in combination is selected from morphine, dolantin, codeine, octopamine, buprenorphine, cyclobutyloxymorphone, dezocine, azone  phenol, dihydrocodeinone, oxycodone, methadone, tramadol [ (+) enantiomer ], DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene naphthalenesulfonate, cyclobutyloxymorphone, E-4018, oxymorphol, mifeprtanil, amitriptyline, DuP 631, tramadol [ (-) enantiomer ], GP-531, adecine, AKI-1, AKI-2, GP-363, GP-69, 4030W92, tramadol racemate, Dynorphine A, E-328, AXC 3742, SNX-129111, SNL-16836, ADCT-363, and their pharmaceutically acceptable salts, CP-999994 and CP-99994.

The invention includes pharmaceutical compositions comprising a therapeutically effective amount of crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide in admixture with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The invention also includes a group of pharmaceutical compositions comprising crystalline form B in admixture with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. Form B of the present invention may be administered by any suitable route, preferably in a pharmaceutical composition suitable for such route of administration and in a dosage to achieve a therapeutic effect. For example, the active form B and compositions are administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or liquid preparations. The pharmaceutical compositions are preferably prepared in dosage unit form containing a specific amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection of the composition, wherein, for example, physiological saline, dextrose or water may be used as suitable carriers.

The amount of therapeutically active compound to be administered and the dosage regimen for treating a disease with the compounds and/or compositions of the present invention will vary widely depending upon a variety of factors including the age, weight, sex and condition of the patient and the severity of the disease, the route and frequency of administration and the particular compound employed. The pharmaceutical composition contains the active ingredient in the range of about 0.1-2000mg, preferably about 0.5-500mg and most preferably between 1-100 mg. Suitable daily dosages are from about 0.01 to 100mg/kg body weight, preferably from about 0.5 to about 20mg/kg body weight and most preferably from about 0.1 to 10mg/kg body weight. The daily dose may be administered from 1 to 4 times daily.

In the case of psoriasis and other skin disorders, it is preferred to use a topical formulation of form B applied to the affected area 2-4 times daily.

For inflammation of the eye or other external tissues such as the mouth and skin, the preferred formulations used are topical ointments or creams or suppositories which contain the active ingredient in a total amount such as 0.075-30% (w/w), preferably 0.2-20% (w/w) and most preferably 0.4-15% (w/w). When in an ointment formulation, the active ingredient may be employed in a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream base using an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least 30% (w/w) of a polyol such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The desired topical formulations include compounds that increase the absorption or penetration of the active ingredient into the skin or other affected area. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

Form B may also be administered by a transdermal device. Topical administration is preferably carried out using a depot (reservoir) and a patch of porous membrane or with a solid matrix. In both cases, the active agent is continuously delivered from the reservoir or microcapsule through a membrane to an active agent permeable adhesive which is in contact with the skin or mucosa of the patient. Where the active agent is absorbed through the skin, the amount administered to the patient can be controlled and predetermined. In the case of microcapsules, their encapsulating capsules also have a membrane action.

The oil phase of the emulsions of the invention may be prepared in known manner from known ingredients. When the phase comprises only emulsifiers, it contains at least one emulsifier fat or oil or a mixture of both fat and oil. Preferably, a hydrophilic emulsifier is used as a stabilizer together with a lipophilic emulsifier. It also preferably contains fats and oils. Emulsifiers (with or without stabilizers) constitute the so-called emulsifying wax and this wax, together with fats and oils, constitutes the so-called emulsifying ointment base, forming the oily dispersed phase of the cream. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include tween 60, span 80, cetostearyl, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.

The choice of the appropriate oil or fat of the formulation is based on the desired emollient properties, since in pharmaceutical emulsions the solubility of the active compound in most oils used is very low. Thus, the cream should preferably be a washable product that is grease-free, non-pigmented and of suitable consistency to avoid leakage from a tube or other container. Straight or branched chain mono-or di-alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut oil fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or incorporation of branched chain esters may be used. These may be used alone or in combination depending on the desired properties. In addition, high-melting lipids such as white soft paraffin (white soft paraffin) and/or liquid paraffin or other mineral oils may be used.

Suitable formulations for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent suitable for the active ingredient. Preferred concentrations of the anti-inflammatory active ingredient in such formulations are from 0.5 to 20%, more preferably from 0.5 to 10% and especially preferably about 1.5% (w/w).

For therapeutic purposes, form B is often mixed with one or more suitable excipients to suit the intended route of administration. For oral (peros) administration, the compounds may be mixed with lactose, sucrose, starch, cellulose alkanoates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then made into tablets or capsules for ease of administration. Such capsules or tablets may be controlled release formulations when the active compound is dispersed in hydroxypropylmethylcellulose. Formulations for parenteral administration may be aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solution preparations and suspension preparations may be prepared from sterile powders or granules, together with one or more of the carriers or diluents mentioned in the preparations for oral administration. Dissolving the crystal form B in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers. Other adjuvants and administration forms are well known in the pharmaceutical art.

All references mentioned are incorporated herein by reference.

While the invention has been described with reference to specific embodiments, these embodiments are not intended to be limiting.

Claims (13)

1. Crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide having a melting point of about 170-174 ℃.
2. 2. Form B crystal of claim 1 having the following IR spectrum peaks: 1170. 925, 844 and 729cm^-1。
3. 3. Form B crystal of claim 1 having no 723cm in IR spectrum^-1Processing the characteristic peak.
4. 4. The crystalline form B of claim 1 having an X-ray diffraction pattern as shown in figure 5.
5. 5. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier, adjuvant or diluent.
6. 6. Use of crystalline form B of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of cyclooxygenase-2 related diseases.
7. 7. The use of claim 6, wherein the medicament is for the treatment of inflammation.
8. 8. The use of claim 6, wherein the medicament is for the treatment of arthritis.
9. 9. The use of claim 6, wherein the medicament is for the treatment of pain.
10. 10. The use of claim 6, wherein the medicament is for the treatment of fever.
11. 11. A process for preparing crystalline form B of claim 1 comprising recrystallizing 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide using an alcohol-based solvent system.
12. 12. The method of claim 11, wherein the solvent system comprises one or more solvents selected from the group consisting of methanol, isopropanol, aqueous methanol, and aqueous ethanol.
13. 13. The process of claim 11, wherein said form B crystals are recrystallized from a mixture of isopropanol and methanol.