TW200304809A - Composition for treating osteoarthritis - Google Patents

Abstract

The present invention relates to a medicine for therapeutic or prophylactic treating arthrosis deformans and/or chronic articular rheumatism, which comprises, as the active component, a compound of the formula (I), or the optically active substance, the prodrug, or the pharmaceutically acceptable salt or the solvate thereof.

Description

200304809 发明 Description of the invention (The description of the invention should state: the technology to which the invention belongs is the ethmazol, the prior technology, the content, the embodiment, and the simple description of the invention.) TECHNICAL FIELD For related deformity arthritis and / or therapeutic and preventive agents. Prior art The development of conditions such as deformable arthritis and chronic rheumatoid arthritis is closely related to defects in the structure and function of joint cartilage. For the maintenance of articular cartilage structure and handles, the extracellular matrix that produces chondrocytes plays an important role. The main components of the extracellular matrix constituting the cartilage of Guan I 卩 are n-type collagen and proteoglycan ', of which approximately 90% of the proteoglycans present in the cartilage are non-polysaccharides (aglycan). Type II collagen is necessary for maintaining cartilage structure and tensile strength, and non-glycan is necessary for maintaining moisture and elasticity. Therefore, its decomposition is one of the reasons for the development of deformed arthritis. Traditionally, non-steroidal anti-inflammatory drugs (NS AIDs) have been used in the treatment of 'deformed arthritis and chronic rheumatoid arthritis. However, because NS AIDs such as Ac et ami nophene and the like act to inhibit the synthesis of prostaglandins and hormones that cause pain and swelling, N S A I D s cannot directly prevent the destruction of cartilage.

It is a type II collagen that is the main component of the extracellular matrix fibrils of the cartilage. The collagen is composed of tightly wound triple helixes. Matrix metalloproteinases (MMPs) that break down type II collagen are known as MMP-1 (collagenase-1), MMP-8 (collagenase-2), and MMP-13 (collagenase-3). Among these three, In particular, MMP-13 (collagenase-3) (non-patent literature 丨) is found almost exclusively in cartilage. This enzyme shows an advantage in the decomposition of type 11 collagen, and an increase in its amount affects the existence of human bone and joint cartilage 200304809 (Non-Patent Document 2). However, it has not been confirmed whether MMP inhibitors are effective in treating diseases such as deformed arthritis and chronic rheumatoid arthritis. Sulfonamide derivatives having an inhibitory effect on M MP can be found in Patent Documents 1 to 8 and the like below. (Patent Document 1) International Publication No. 9 7/2 7 1 74 (Patent Document 2) International Publication No. 9 9/04 7 8 0 (Patent Document 3) International Publication No. 00/6 3 1 94 (Patent Document 4) International Publication No. 00/1 5 2 1 3 (Patent Document 5) International Publication No. 0/1/8 3 4 3 No. 1 (Patent Document 6) International Publication No. 0/1/8 3 4 6 Publication No. 1 (Patent Document 7) International Publication No. 0/1/8 3 4 6 3 (Patent Literature 8) International Publication No. 0/8/3 3 4 6 4 (Non-Patent Literature 1) JM Freije et al. , J. Biol. Chem, 1994, Vol. 269, p. 16766-16773 (Non-Patent Document 2) 200304809

Peter G. Mitchell et al., J. Clin. Invest., 1996, Vol. 96, p. 761-768 Summary of the Invention There is an urgent need to develop therapeutic and preventive agents for deformity arthritis and / or chronic rheumatoid arthritis. In view of this, as a result of intensive research, the present inventors have discovered a novel sulfonamide derivative, which is an excellent therapeutic and preventive agent for deformable arthritis and / or chronic rheumatoid arthritis. The present invention is: I) a compound having an optically active substance, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient for the treatment of deformed arthritis and / or chronic rheumatoid arthritis Or preventive.

COOH Me〇 一 <

MeS

Specifically, it is related to II) to IV). π) The following compounds (V) and (VI)

(V) (VI) 200304809 III) A medicine for treating deformed arthritis and / or chronic rheumatoid arthritis, which uses a compound of I) ~ π). IV) A treatment method to alleviate the effects of mammals due to deformity arthritis, comprising administering a therapeutically effective amount of the compound of I) to 11) to a mammal. In this specification, "deformed arthritis" refers to arthritis characterized by the deterioration of articular cartilage. Specifically, the articular cartilage is softened, abraded, and thinned, and the marginal part accompanied by ivoryization of the subchondral bone forms bone spurs, pain, and functional disorders. 0 In this manual, "chronic rheumatoid arthritis" is a systemic disease, and arthritis is the main clinical symptom. Most joints suffer from arthritis, especially the soft and soft tissue of the joints in the joints of hands and feet. A disease in which cartilage is surrounded by synovial tissue, which erodes soft bodies. Most of the cells experience various symptoms, and gradually deteriorate into chronic diseases such as deformation and disability. The therapeutic effects of compounds (I) to (VI) on deformable arthritis were measured by the following methods. Use guinea pigs, rats, or rabbits by the Meacock method (J. Exp.

Path. 7 1: 2 7 9-2 9 3, 1 9 0 0), the right knee joint half plate and the medial collateral ligament were excised to create a guinea pig, rat, or rabbit deformable knee arthritis model. From the next day after the operation, 0.5% methyl cellulose solution solvent or 30 mg / kg of compound was administered orally once daily for 10 days to 6 weeks. On the day after the last day of administration, the distal femur and the proximal tibia were collected. After the articular cartilage surface was stained with indi a ink, the cartilage surface was photographed electronically. In addition, the tissues were fixed with a 10% neutral buffered formalin solution, and delimed with deashing solution B (trade name, manufactured by Wako Pure Chemical Industries, Ltd.), and then H.E. stained specimens and saffron red stained specimens were prepared. Evaluate the progress of the disease by using the knee joint photography 200304809 image 〇 A lesion, or Η. E. stained specimens and saffron red 〇 stained specimens were evaluated under the microscope according to the evaluation method of the Mankin method. Embodiments The compounds used in the present invention can be synthesized according to the methods described in WO 9 7/2 7 1 7 4 (Methods A to F), WO 00/63194 and WO 01/83463. The "solvate" of the compound used in the present invention is an organic solvent-containing solvate, hydrate, or the like. Any number of water molecules can be coordinated when forming a hydrate. The pharmaceutically acceptable salts of the compounds used in the present invention contain alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium salts, salts of organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrogen Bromic acid, phosphoric acid, sulfuric acid, etc.), and salts of organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). This salt can be prepared according to conventional methods. The compounds of the present invention are not limited to isomers, and may contain all possible isomers and racemic isomers. Prodrugs are compounds of the present invention which contain derivatives of the compounds of the present invention that are chemically and metabolically degradable, and are hydrolyzed to give pharmacologically active compounds under physiological conditions in vivo. The selection and preparation of appropriate prodrug derivatives can be found in Design of Prodrugs, Elsevier Amsterdam 1985. When the compound of the present invention contains a carboxyl group, an acidic compound is reacted with an appropriate alcohol to obtain an ester derivative, particularly an alkoxycarbonyl group which may have a substituent, or an acidic compound is reacted with an appropriate amine to obtain an amidine derivative. Substituted alkylamine carbonyl prodrugs. Esters-10- 200304809 Prodrugs are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholine ethyl, N, N-diethylhydroxyl Acetaminophen and the like. When the compound of the present invention contains a hydroxyl group, the hydroxyl group-containing compound can be reacted with a suitable halogen halide or a suitable acid anhydride to prepare a prodrug of a halogenated oxygen derivative. The oxygen prodrug is preferably -OCOC2H5, -OCO (t-Bu), -OCOC15H31, -OCO (m-COONa-Ph), -OCOCH2CH2COONa, -OCOCH (NH2) CH3, -OCOCH2N (CH3) 2 and the like. When the compound of the present invention contains an amine group, the amine group-containing compound can be reacted with a suitable sulfonium halide or a suitable acid anhydride to prepare a prodrug of a fluorene derivative.宜 The amine prodrug is preferably -NHCO (CH2) 20CH3 '-NHCOCH (NH2) CH3 and the like. When the compound of the present invention is administered to treat the above-mentioned diseases, it can be administered orally by powder, granules, tablets, capsules, nine doses, liquids, or the like, or by injection (intra-articular, intravenous), suppository, or percutaneous absorption. Parenteral administration. If necessary, an effective amount of the compound can be mixed with appropriate excipients, binding agents, wetting agents, dispersing agents, lubricants and other pharmaceutical additives to obtain pharmaceutical preparations. When used as an injection, it is prepared by sterilization with an appropriate carrier. Particularly preferred are oral preparations, injections (intra-articular, intravenous), and patches. The dosage may depend on the condition of the disease, the route of administration, the age of the disease, or the weight. Generally, the dosage for adults is ο. 1 ~ 100 mg / kg / day, preferably 1 ~ 20 mg / kg / day. . The compound used in the present invention has excellent oral absorption, low metabolic enzyme inhibition, does not cause chromosomal abnormalities, and has low toxicity, and is particularly suitable for use as medicine. Examples The present invention is described in more detail by way of examples and test examples below, but the scope of the present invention is not limited thereto. 200304809 The following abbreviations are used in the examples. Me: methyl Et: ethyl tBu: third butyl Compound (I) to compound (VI) can be synthesized by the following method. Example 1 Synthesis of Compound (I) HCI Η2ΝΓ 'CO ^ Bu + 丨 Project 1

C02xBu 3

1

Raw material, 4-phenoxybenzenesulfonyl chloride (2) can be based on Suter, C. Μ · Studies in the Diphenyl Ether Series. II. Preparation and Structure of Some Sulfonic Acids and Related Derivatives. J. Am.

Chem. Soc. 1931, 53, 1112-1116. Dichloromethane compound containing D-valine tert-butyl ester hydrochloride (1) (4.72 g, 22.51 mmol) and phenoxybenzenesulfonyl chloride (2) (6.37 g, 23.64 mmol) (150 ml), and N-formoline (6 · 9 ml, 5 6.2 8 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice-2 mol / l hydrochloric acid 'and extracted with ethyl acetate. The organic layer was washed successively with a saturated ammonium carbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 50/1), and the eluate was collected and crystallized from ethyl acetate / hexane to obtain a melting point of 1 39-1 40 t. The target compound (3) (8.13 g, Yield: 891%). -12- 200304809 IR (KBr, v max cm.1) 3302, 1731, 1369, 1342, 1161 lU NMR (CDCls, δ ppm): 0.85 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 1.28 '(s, 9H), 2.05 (m, 1H), 3.62 (dd, c / = 4.2, 9.6 Hz, 1H), 5.08 (d, J = 9.6 Hz, 1H) 6.97-7.05 (m, 2H), 7.18-7.28 (m, 4H), 7.40 (m, 1H), 7.75-7.81 (m, 2H) [a] D-44.4 ± 0.8. (E = 1.008, CHC13, 24 0C) Elemental analysis (C21H27N05S) Calculate 値: C; 62.20, H; 6.71, N; 3.45, S; 7.91 Experiment 値: C; 62.18, H; 6.68, N; 3.51, S; 7.90 In the second step, a solution of compound (3) (3.23 g, 9.41 mmol) in dichloromethane (36 ml) was added with trifluoroacetic acid (36 ml) at room temperature and stirred for 3 hours. The reaction was concentrated under reduced pressure, and the residue was crystallized from diethyl ether / hexane to obtain the target compound (4) (2.62 g, yield 97.7%) with a melting point of 137-138 ° C. IR (KBr; v max cm1) 3154, 1728, 1375, 1160 XH NMR (CDCls, δ ppm): 0.89 (d, J = 7.0 Hz, 3H), 0.98 (d, e / = 6.8 Hz, 3H) , 2.12 (m, 1H), 3.β0 (dd, J = 4.6, 9.6 Hz, 1H), 5.17 (d, J = 9.6 Hz, 1H), 6.95-7.08 (m, 4H), 7.13-7.45 (m , 3H), 7.70-7.85 (m, 2H) [a] D-3.7 ± 0.4 ° (c = 1.006, DMSO, 24.5 ° C) Elemental analysis (C17HlsNO5S-0.2H2O) Calculate 値: C; 57.84, Η; 5 · 54, N; 3.97, S; 9.08 Experiment 値: C; 57.80, H; 5.44, N; 4.11, S; 8.95 The third project will contain compound (4) (300 mg, 0.8 54 mmol) A solution of dichloromethane (10 ml) in ice was added early acid chloride (0.37 pen liters, 4.27 millitorles) and 1 drop of dimethylformamide under ice cooling, and the mixture was stirred at room temperature. 1 hour. Concentrated under reduced pressure to obtain crude sulfonium chloride of compound (4). A mixed solution of tetrahydrofuran (10 ml) and water (10 ml) containing hydroxyammonium chloride (59 3 mg, 8. 5 4 -13- 200304809 in ice mol),

Add sodium bicarbonate (86.61 mg, 10 · 25 mmol) under cooling, add the above-mentioned hafnium chloride and stir for 1 hour under half J. Add to ice-2. Add the organic layer to bicarbonate The sodium aqueous solution was concentrated under pressure. The residue was concentrated under reduced pressure in a silica m column to obtain a melting point, and the total chloride 5 was added to ice and sodium hydrogen water.

以 To obtain the target compound (I) of U 1 4 9-1 5 1 ° c (2 88 mg, yield 93%). ❿ IR (KBr, v max cm · 1) 3268, 1634, 1584, 1356, 1157 Ή NMR (DMS〇- 'δ ppm): 0.76 (d " / = 6.6 Hz, 6H), 1.77 (m, 1H), 3.26 (m, 1H), 7.00-7.18 (m, 4H), 7.23 (m, 1H), 7.37-7.53 (m, 2H), 7.70-7.81 (m; 2H), 8.88 (br s, 1H) [a ] D-11.2 ± 0.7 ° (c = 0.705, DMSO, 25 ° C) Elemental analysis (C17H2〇N2〇5S) Calculate 値: C; 56.03, H; 5.53, Ν; 7.69, S; 8.80 Experiment 値: C; 55.83, H; 5.62, N; 7.93, S; 8.65 Synthesis of Compound (II) in Example 2 ·

In the first project, compound (5) (50 0 -14- 200304809 mg, 1.24 mmol) and 4-methoxyphenylboronic acid (6) will be synthesized according to the method described in W 0 9 7/2 7 1 7 4 (226 mg, 1.49 mmol) of a mixed solution of diethylene glycol dimethyl ether (3.7 ml) and ethanol (0.8 ml), and a 2 N sodium carbonate solution (1.6 ml) was added at room temperature. , Fully degassing and replacing argon. Add triphenylphosphine palladium (148 mg, 0.12 mmol), fully degas and replace the argon, and stir at 90 ° C for 2 hours. The reaction solution was cooled at room temperature, poured into ice-2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purify by silica gel column chromatography (ethyl acetate / Zhengjiyuan / chloroform / methanol == 1/3/3), collect the eluate and crystallize from acetone / Zhengjiyuan to obtain compound (7) (3 2 3 mg, yield 6 0%), melting point 1 3 4-1 3 6 ° C. Ή NMR (CDC13) δ 3.02-3.16 (in, 2H), 3.57 (S, 3H), 3.85 (s, 3H), 4.33 (m, 1H), 5.17 (d, e / = 9.0Hz, 1H), 6.94 (d,, / = 8.7Hz, 2H), 7.07 (d, c / = 4.2Hz, 1H), 7.06-7.16 (m, 2H), 7.17 ^ 7.30 (m, 3H), 7.43 (d, c / = 4.2Hz, 1H), 7.49 (d, J = 8.7Hz, 2H) Elemental analysis (C21H21N05S2) Calculate 値: C; 58.45, H; 4.91, N; 3.25, S; 14.86 Experiment 値: C; 58.43, H ; 4.89, N; 3.32, S; 14.87 In the second project, a solution of compound methylene sulfoxide (6 ml) containing compound (7) (300 mg, 0.7 mmol) was added at room temperature to imol / liter of hydrogen. Aqueous sodium oxide solution (2.1 ml) was stirred at room temperature for 18 hours. Add to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Crystallization with acetone / water yielded the target compound (11) with a melting point of 6 to 6 5 t (260 mg, yield 89%). 200304809 IR (KBr, v max cm · 1) 3309, 1738, 1606, 1352, 1178, 1165 Ή NMR (DMSO-tf6; δ ppm): 2.75 (dd, J = 9.6, 13.8 Hz; 2H); 2.99 (dd ; J = 5.7; 13.8 Hz, 2H), 3.81 (s, 3H), 3.94 (m; 1H)? 7.02 (d, ^ = 8.7Hz, 2H); 7.07-7.32 (m, 5H), 7.59 (d, J = 9.0 Hz, 1H)? 12.85 (br s, 1H) [a] D + 4.1 ± 0.9- (c = 0.513, DMSO; 24 ° C) Elemental analysis (C20H19N5S2) Calculate 値: C; 57.54, H 4.59, Ν; 3.35, S; 15.36 Experiment 値: C; 57.55, Η; 4.50, N; 3.45, S; 15.19 Example 3 Synthesis of Compound (111)

Project 1 HCI H2N ^ C02Me

S02CI 8 9

The second project

MeS

The third project

Dichloromethane containing methyl D-valinate hydrochloride (8) (1.0 g, 5.97 mmol) and 4-iodobenzenesulfonyl chloride (9) (1.99 g, 6.57 mmol) (10 ml) of the solution, and N-formoline (1.64 ml, 1 4.9 mmol) was added under ice cooling. 'Stir overnight at room temperature. Pour to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1). The eluate was collected and crystallized from ethyl acetate-16-200304809 ester / hexane to obtain a melting point of 7 9-80 ° C. (10) (2.12 g 'yield 89.4%). IR (KBr, v max cm · 1) 3418, 3269, 1738, 1714, 1452, 1433, 1343, 1330, 1278, 1166, 1141, 1089, 1053, 1006 Ή NMR (CDC13, δ ppm): 0.87 (d, 6.9 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 2.04 (m, 1H), 3.49 (s, 3H), 3.74 (dd, J = 5Λ, 10.5 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 7.51-7.57 (m, 2H), 7.83-7.89 (m; 2H) [a] D-29.5 ± 0.7. (E = 1.009, CHC13, 22 0C) Elemental analysis (C12H16IN04S) φ Calculate 値: C; 36.28, H; 4.06, I; 31.95, N; 3.53, S; 8.07 Experimental 値: C; 36.23, H; 3.77, 1 : 31.68, N; 3.44, S; 8.06 In the second process, the compound (10) (5.0 g, 12.6 mmol) and 4-methylthiophenylboronic acid (1 1) (2.62 g, 15.1 mmol) Mol) diethylene glycol dimethyl ether (50 ml) and ethanol (13 ml) mixed solution, add 2M sodium carbonate solution (25.2 ml) at room temperature, fully degas and replace argon. Add triphenylphosphine palladium (1.46 g, 1.26 mmol), and then fully degas to replace the argon, and stir at 90 ° C for 2 hours. The reaction solution was cooled at room temperature, poured into ice-2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1 0/1). The eluate was collected and crystallized from ethyl acetate / ether to obtain the target compound (1 2) with a melting point of 1 7 3-1 5 ° C ( 2 · 7 9 g, yield 5 6.3%) 〇-17- 200304809 IR (KBr, v max cm · 1) 3284, 1735, 1342, 1165 Ή NMR (CDC13j δ ppm): 0.89 (d, J = 6.9 Hz , 3H), 0.97 (d, J = 7.2 Hz, 3H), 2.04 (m, 1H), 2.53 (s, 3H), 3.43 (s, 3H), 3.78 (dd, 5.4, 10.2 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 7.31-7.38 (m, 2H), 7.50-7.57 (m; 2H), 7.65-7.72 (m; 2H), 7.84-7.91 (m; 2H) (a) D + 10.4 ± 1.0 ° (c = 0.502, DMSO, 25 ° C) Elemental analysis (c19h23n〇4s2) Calculate 値: c; 57.99, Η; 5.89, N; 3.56, S; 16.30 Experiment 値: C; 58.08, H; 5.71, N; 3.57, S; 16.12

In the third process, a solution of compound M12® (296 ml) containing compound (12) (12.9 g, 32.8 mmol) was added at room temperature to a 1 mole / liter sodium hydroxide solution (98.5 ml). Stir at 0 ° C for 24 hours. The reaction solution was cooled at room temperature, and the precipitated sodium salt was collected by filtration, washed with ethyl acetate, poured into ice-2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from acetone / water to obtain the target compound (111) (11. 6 g, yield 9 3 · 2%) at a melting point of 2 05-2 0 ° C. IR (KBr, v max cm * 1) 3419, 3328, 1743, 1322, 1166, 1122, 1106, 1091 Ή NMR (DMSO-rf6, δ ppm): 0.81 (d, 6.9 Hz, 3H), 0.84 (d, 6.9 Hz, 3H), 1.95 (m, 1H), 2.53 (s, 3H), 3.55 (m, 1H), 7.34-7.43 (m, 2H); 7.67-7.74 (m, 2H), 7.79-7.88 (m , 4H), 8.05 (d, 9.6 Hz, 1H), 12.52 (br s, 1H) [a] D-9.4 ± 1.0 ° (c = 0.509, DMSO, 25 ° C) Elemental analysis (c18h21n〇4s2) Calculate 値: C; 56.97, H; 5.58, N; 3.69, S; 16.90. Experiment 値: C; 56.75, H; 5.53, N; 3.73, S; 16.95 -18- r200304809 Example 4 Synthesis of Compound (IV) HCI H2N ^ C02Me 8

NC-^^-S02CI 13 Project 1

NC, C02Me 2nd project nh2oh-hci

Ό02Μθ 15 The third project

Et-H〇 ^ COCI 16

Tetrahydrofuran (40 ml) containing D-valine methyl ester hydrochloride (8) (2.2 g, 13.1 mmol) and 4-cyanobenzenesulfonyl chloride (13) (2.4 g, 11.9 mmol) The solution was added with N-methylmorpholine (3.9 ml, 35.5 mmol) and stirred at room temperature for 1.5 hours. Inject to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane to obtain compound (1 4) (3.12 g, yield 88. 4 ° / 〇). Melting point 5 4-5 7 ° C. IR (KBr, v max cm · 1) 3292, 2974, 2231, 1732, 1709, 1469, 1446, 1348, 1173, 833 Ή NMR (CDCls, δ ppm): 0.87 (d; J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 2.09 (m, 1H), 3.51 (s, 3H), 3.80 (dd, J = 5.0, 10.2 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H ), 7.80 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.8 Hz? 2H) [a] D + 4.7 ± 0.9. (E = 0.506, DMS〇, 23 ° C) Elemental analysis (C13HieN204S) Calculate 値: C; 52.69, Η; 5.44, Ν; 9.45, S; 10.82 Experiment 値: C; 52.80, H; 5.34, Ν; 9.52, S; 10.55 200304809 The second project will contain the compound (1 4) (3.24 g, 10.9 mmol) and hydroxylammonium chloride (0.91 g, 13.1 mmol) Ear) of ethanol (100 ml), triethylamine (1.83 ml, 13 -1 mmol) was added at room temperature, and heated under reflux for 1.5 hours. The ethanol was distilled off under reduced pressure, water (50 ml) was added, and extraction was performed with ethyl acetate (50 ml X 3). The organic layer was washed with water (50 ml × 1), dried over anhydrous sodium sulfate 'and concentrated under reduced pressure. The residue was crystallized from diethyl ether / n-hexane to obtain the compound (15) (3.4 g, yield 94. 4%). Melting point 1 3 0-1 3 1 ° C. IR (KBr, v max cm · 1) 3485, 2960, 1722, 1651, 1335, 1165, 1090, 606 Ή NMR (CDCls, δ ppm): 0.87 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 2.04 (m, 1H), 3.46 (s, 3H), 3.77 (dd, J = 5.0, 10.2 Hz, 1H), 5.04 (br s, 2H), 5.44 (d, J = 10.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H) (a) D + 8.8 ± 1.0 ° (c = 0.503, DMSO, 23 ° C) element Analysis (C13H19N305S) Calculate 値: C; 47.40, H; 5.81, N; 12.76, S; 9.73 Experiment 値: C; 47.60, H; 5.76, N; 12.47, S; 9.76 The third project will contain compounds (1 5) (5.0 g, 15 · 2 mmol) diethylene glycol dimethyl · (100 ml) solution, add pyridine (3.7 ml, 45.7 mmol) under ice cooling, and then add 4- Ethyl benzamidine chloride (6) (2.3 ml, 15.2 mmol) was stirred at room temperature for 45 minutes, and then stirred at 110 ° C. for 20 hours. The reaction solution was added to water and the precipitated crystals were collected by filtration, dissolved in ice-2 mol / l hydrochloric acid, and extracted with ethyl acetate / tetrahydrofuran. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 1 0/1), and the eluate was collected and crystallized from acetone / n-hexane-20-200304809 to obtain compound (17) (3.99 g, yield). 5 4.8%). Melting point 1 7 4-1 7 5 ° c. Ή NMR (CDCW6, δ ρριι): 〇89 (d, j = 6 9 Hz, 3H), 〇98 (d, j = 6 6 Hz, 3H), 1.30 (t, J = 7.5 Hz? 3H), 2 .〇7 (m > iH), 2.76 (q, J = 7.5 Hz, 2H); 3.46 (s, 3H), 3.81 (dd, J = 5.1, 10.2 Hz, 1H), 5.20 (d, J = 10.2 Hz , 1H), 7.40 (d, J = 8.4 HZ, 2H), 7.97 (d, J = 8.7 Hz, 2H), 8.13 (d, J = g. 4 Hz, 2H), 8.31 (d, J = 8.7 Hz, 2H) Elemental analysis (C22H25N305S) Calculate plutonium: C; 59.58, plutonium; 5.68, N; 9.48, S; 7.23 pass plutonium: C; 59.34, H; 5.50, N; 9.62, S; 7.47 Step 4: Add a solution of compound (17) (357 mg, 0.8 mmol) in dimethylarsin (10 ml) at room temperature and add 1 mol / L NaOH aqueous solution (2.4 ml '2.4 mmol) ), And stirred at room temperature for 1 4.5 hours. The reaction solution was poured into ice-2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from acetone / n-hexane to obtain the target compound (IV) (283 mg, yield 81.8%). Melting point is 181-183 ° C. IR (KBr, v max cm · 1) 3286, 2968, 1714, 1616, 1408, 1350, 1167, 1136, 752 Ή NMR (DMS〇.if6, δ ppm): 0.81 (d, J = 6.6 Hz, 3H) , 0.85 (d, J = 7.0 Hz, 3H), 1.24 (t, J = 7.8 Hz? 3H), 1.97 (m, 1H), 2.75 (q, J = 7.4 Hz, 2H), 3.59 (m, 1H) , 7.53 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H)? 8.13 (d, J = 8.0 Hz, 2H)? 8.26 (d, J = 8.8 Hz, 2H), 12.64 (br s, 1H) [a] D-10.0 ± l.〇 ° {c = 0.508, DMSO, 25 ° C) Elemental analysis (C21H23N3〇5S-0.3H2O), Calculate 値: C; 58.00, Η; 5. · 47, Ν; 9.66, S; 7.37 Experiment 値: C; 58.03, Η; 5.45, N; 9.63, S; 7.44 Example 5 Synthesis of Compound (V) 200304809

18 Project 1

19 H〇2C- < ^^ ~ S ~ N ^ C02Me 〇 2nd project OH 20

A solution of p-chlorobenzyl bromide (18) (4.9 g '21.0 mmol) in chloroform (5 ml) was added to hexamethylenetetramine (3.2 g' 22.8 mmol) and stirred at room temperature. 2 hours. The crystals were collected by filtration, dissolved in ethanol (64 ml) and concentrated hydrochloric acid (6 ml), and stirred for 6 4 hours. The crystals were collected by filtration, washed with water, ethanol, and dried to obtain compound (19) (2.15 g, yield 55.7%). Melting point 190 ~. C (decomposition).

Ή NMR (DMS0-d6; δ ppm): 4.59 (s; 2H), 7.68 (d, J = 8.8 Hz, 2H); 8.05 (d, J = 8.8 Hz, 2H), 8.51 (br s, 3H) element Analysis (C8H9NOCl2-0.04HBr) Calculate 値: C; 45.91, Η; 4.35, Ν; 6.69, Cl; 33.88, 53 Experiment 値: C; 45.93, H; 4.25, N; 6.80, Cl; 33.62, 46 In the second project, an anhydrous tetrahydrofuran (1 (ml)) solution containing the compound (20) (0.5 g, 1.59 mmol) synthesized according to the method described in WO 01/83463 was added. (0.166 ml, 1.90 mmol) and dimethylformamide (5 μ1), and stirred at room temperature for 3.5 hours. The compound (9) (0.39 g, 1.89 mmol-22-200304809 mole) and N-formoline (0.52 ml, 4.73 mmol) were added and stirred at room temperature for 64 hours. Inject to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Wash with ethyl acetate / n-hexane = W2 to obtain compound (21) (0.51 g, yield 69.1%). ! H NMR (CDC13, δ ppm): 0.88 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 2.07 (m, 1H), 3.48 (s, 3H), 3.80 ( dd, J = 5.1, 9.9 Hz, 1H), 4.94 (d, J = 4.2 Hz, 2H), 5.26 (d, J = 9.9 Hz, 1H), 7.32 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.90-8.10 (m,

In the third process, a solution of compound (2 1) (0.5 1 g, 1.0 8 mmol) in tetrahydrofuran (5 ml) was added, and Borsch reagent (0.44 g, 1.08 mmol) was added. , Stir at 70 ° C for 4 hours. Inject to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 3/1). The eluate was collected and crystallized from ethyl acetate / n-hexane to obtain a compound.

(22) (0.33 g, yield 66.2%). Melting point 190-192 ° C. IR (KBr, V max cm 1) 3282, 3086, 1736, 1479, 1429, 1348, 1171 Ή NMR (CDC136 ppm): 0.89 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 2.07 (m, 1H), 3.47 (s, 3H), 3.81 (dd, J = 5.4, 10.2 Hz, 1H), 5.18 (d, J = 10.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H) [cx] D + 6.2 ± 0 · 9ο (c = 0.501, DMS〇, 27 0C) Elemental analysis (C21H21N204S2) Calculate 値: C; 54.24, H; 4.55, N; 6.02, S; 13.79, Cl; 7.62 Experiment 値: C; 54.15, H; 4.44, N; 6.07, S; 13.69, Cl; 7.43 -23- 200304809 In the 4th project, the dimethyl sub mill (5.4 ml) containing compound (22) (0.28 g, 0.60 mmol) Solution 'was added with 1 mol / L Na a solution (1.79 ml, 179 mmol) at room temperature, and stirred for 17 hours. Inject to ice _ 2 mol / L hydrochloric acid, and take it with ethyl acetate. The organic layer was sequentially washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate / n-hexane to obtain the object compound (V) (0.23 g 'yield 86.4%). Melting point 222-224 ° C. IR (KBr, v max cm · 1) 3228, 1710, 1483, 1427, 1352, 1163, 1140, 1093, 611 lU NMR (DMSO-de, δ ppm): 0.82 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 1.97 (m, lH), 3.58 (m, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.91 (d7 J = 8.5 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 8.2 Hz, 1H), 8.46 (s, 1H) (a) D-13.1 ± 1.1 ° (c = 0.505, DMSO, 27 ° C) Elemental analysis (c20h19n2o4s2ci) Calculate 値: C; 53.27, Η; 4.25, Ν; 6.21 'S; 14.22, Cl; 7.86, N; 6.33, S ; 13.95, Cl; 7.62 Experiment 値: C; 53.03, Η; 4.27, Synthesis of Compound (VI) of Example 6

Example 6 first process

The second project

-24- 200304809 The first project will be a solution of anhydrous tetrahydrofuran (10 ml) containing the compound (20) (0.5 g, 1.59 mmol) synthesized according to the method described in W 〇〇1 / 8 3 4 6 3 ' Add chloramphicol (0.166 ml '1.90 mmol) and dimethylformamide (5 μΐ) under nitrogen, and stir at room temperature for 3 hours. Add 2-amino-4'-methoxyacetamidine hydrochloride (2 3) (0.38 g, 1.90 mmol) and N-formoline (0.52 ml, 4.73 mmol) at room temperature Stir for 19 hours. Inject to ice-2 mol / L hydrochloric acid 'and extract with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with ethyl acetate / n-hexane = 1/2 to obtain compound (24) (0.6 g, yield 82.2 ° / °). Melting point 185-187 ° C. Ή NMR (CDC13, δ ppm): 0.88 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 2.07 (xn; 1H), 3.48 (s, 3H), 3.80 (dd , J = 4.8, 9.9 Hz, 1H), 3.91 (s, 3H), 4.91 (d, J = 3.6 Hz, 2H), 5.25 (d, J = 9.9 Hz, 1H), 7.01 (d, J = 8.4 Hz , 2H), 7.43 (m, 1H), 7.89-8.10 (m, 6H) In the second project, a solution of compound (24) (0.6 g, 1.30 mmol) in anhydrous tetrahydrofuran (5 ml) was added to Borsch reagent (0.53 g, 1.30 mmol), and stirred at 70 ° C for 2.5 hours. Inject to ice-2 mol / L hydrochloric acid and extract with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 7/1 1). The eluate was collected and crystallized from acetone / n-hexane to obtain compound (25) (0.44 g, yield 72.6%). Melting point 190 ° C. 200304809 IR (KBr, v max cm1) 3282, 2968, 1736, 1487, 1431, 1257, 1169, 827, 629 Ή NMR (CDC136 ppm): 0.89 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 2.06 (m, 1H), 3.47 (s, 3H), 3.78 (dd, J = 5.1; 10.2 Hz, 1H), 3.86 (s? 3H); 5.17 (d, J = 10.2 Hz , 1H); 6.97 (d, J = 8.7 Hz, 2H); 7.54 (d; J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H); 7.97 (s, 1H), 8.07 (d , J = 8.7 Hz, 2H) [a] D + 6.8 ± 0.9. (D500, DMSO, 25 ° C) Elemental analysis (C22H24N205S2) Calculate 値: C; 57.37, H; 5.25, N; 6.08, S; l: 3.92 Experimental 値 · C; 57.22, H; 5.14, N; 6.07, S; 13.85 In the third project, a solution of compound (25) (0.38 g, 0.83 mmol) in dimethyl arylene (7.5 ml) was added, and 1 mol / L of NaOH solution (2.49 ml, 2.49) was added at room temperature. Millimoles), heating and stirring at 6 (TC for 19.5 hours. Inject to ice -2 Moore / L hydrochloric acid, extract with ethyl acetate. Wash the organic layer with water in order, and dry under anhydrous sodium sulfate. It was then concentrated under reduced pressure. The residue was crystallized from ethyl acetate / n-hexane to obtain the target compound (VI) (0.36 g, yield 97.2%). Melting point 1 8 8-1 90 ° C. Ή NMR (DMSO-de, δ ppm ): 0.82 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 1.96 (m, 1H), 3.57 (dd, J = 6.1, 8.2 Hz, 1H), 3.82 (s , 3H), 7.06 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 8.17 (d, J = 9.2 Hz, 2H ), 8.30 (s, iH) Test Example 1 Preparation method of MMP-13 M MP-13 is made of cancer cells SW 1 3 5 3 derived from human cartilage that stimulates IL-1 and TN F. RT-PCR was used Amplify Composition (1G4Tyr ~ 2 6 7 Gly). The product was selected and cloned into the E. coli expression vector pTrc99AHE '200304809. The cleavage site has been treated with phosphorylase to obtain the H is-tag. IPTG (isopropyl-β-D) was used. -Thiogalactopyranoside) induced by the insoluble partition. The insoluble partition is separated from Μ Μ Ρ-1 3 is dissolved with a denaturant (6 Μ urea) according to conventional methods, and purified by metal chromatography (nickel chelate Sepharose ). The denaturing agent (6 M urea) is removed by dialysis, and the enzyme is refolded at the same time to obtain the activated M MP-1. Test Example 2 The method of measuring the enzyme inhibitory activity of M MP-13 is that the enzyme activity of MMP can be According to the method of C. Graham Knight, Frances Willenbrock and Gillian Murphy: A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases: FEBS LETT., 296, (1992), 263-266. Matrix: MOCAc-Pro-Leu-Gly-Leu-A2Pr (DNP) -Ala-Arg-NH2 (Osaka Peptide Research Institute, Osaka, Japan) can be used. The analysis of inhibitors is based on the analysis of 1 compound (inhibitor). (A) Matrix (synthetic matrix), enzyme (μM Ps), inhibitor (B) matrix (synthetic matrix), inhibitor (C) matrix (synthetic matrix), enzyme (mMPs) (D) matrix (synthetic matrix) ) The fluorescence intensity was measured and the inhibition (%) was determined by the following formula. Inhibition (° / 〇) = {1- (A-B) / (C-D)} × 100 I C 50 is the inhibition (%), which is 50 ° /. Of the concentration. The data for measuring the 'sulfonamide' based on this is shown below. -27- 200304809 Table 1 Compound No. MMP-1 3 (105 μM) (I) 0.0000833 (II) 0.0079 (III) 0.0104 (IV) _ 0.0097 (V) 0.00551 (VI) 0.00116

Test Example 3 For guinea pigs (1 2 divisions), the right knee osteoarthritis was divided by N mg / kg i \ to the most. The method of measuring the surface electronic software (W i η injury collar according to this test method to determine the disease inhibition effect of compounds in the inflammatory mode of M 1 Sheng IS 10) Zhou Dazhi female Hartley guinea pigs (the method of Charles River male leacock (J Exp. Path 71: 279, 1990), cutting the joint meniscus and the medial lateral collateral ligament, causing deformation in guinea pigs. 0.5% methylcellulose solution or 30 daggers once a day after surgery, Continuous oral administration of 10 days. The next day, the surface of the distal femur of the right thigh and the proximal tibia of the tibia were stained with indiaink (manufactured by Kuretake Co., Ltd.), and cartilage was photographed. The entire area of the medial part of the tibia and staining The area is measured by image analysis Roof (manufactured by MITANI CORPORATION). Domain (%) = staining area / full area x 100. The data of sulfonamide derivatives are listed below. ° ° -28- 200304809 Table 2 Compound No. Carrier ⑴ (Π) (III) (IV) (V) (VI) Level 値 値 (%) 26.0 ± 3.1 15.2 ± 6.5 20.7 ± 2.9 15.8 ± 2.6 8.6 ± 3.6 15.2 ± 4.5 6.2 ± 3.7 Test Example 4 Compound disease inhibitory effect method 12 A female NZW rabbit of the week (Beishan Lapez company), using the method of Me acock (J. Exp · Path. 71: 2 7 9-2 9 3, 1 9 0 0), removed the right knee joint meniscus and Medial lateral collateral ligament, which may cause deformed knee arthritis in rabbits. 0.5% methylcellulose solution or 30 mg / kg compound is administered twice daily for 6 weeks after surgery. The day after the last day of administration, the right femur distal part and the tibia proximal part were collected. The articular cartilage surface was stained with India ink (manufactured by Kuretake Co., Ltd.), and the cartilage surface was photographed electronically. Then the tissue was taken at 10% The neutral buffer solution was fixed, and the ashing solution B (trade name, manufactured by Wako Pure Chemical Industries, Ltd.) was ashed, and then H. E. stained specimens and saffron red stained specimens were prepared. Photographs were taken on the surface of the knee joint The degree of progression of OA lesions was evaluated by grading, or η.E. stained transcripts and saffron red 0 stained specimens were evaluated under a microscope by the Mankin method. Using this measurement, the sulfonamide derivative (I) ~ ( VI) Effective treatment of deformity arthritis. Test example 5 Compound disease inhibitory effect method Female SD rats (Japanese C 1 ea company) of 12 weeks old were prepared by μ eac ock method (J. Exp · Path. 7 1: 2 7 9-2 9 3,1 990), the meniscus and medial collateral ligament of the right knee joint were excised, resulting in a deformed knee arthritis model in rats. -29- 200304809 The 0.5% methylcellulose solution or 30 mg / k g of the compound was administered twice a day starting from the next day after the operation and continuously administered orally for 6 weeks. — The day after the last day of administration, the distal femur and the proximal tibial part of the right femur were taken. The articular cartilage surface was stained with i n d i a i n k (manufactured by Kuretake Co., Ltd.), and the cartilage surface was electronically photographed—). Then, the tissue was fixed with a 10% neutral buffered solution in Fulin, and was delimed with a deashing solution B (trade name, manufactured by Wako Pure Chemical Industries, Ltd.). After deliming, Η · Ε · stained specimens and crocus red stained specimens were prepared . The knee joint surface photography was used to evaluate the degree of grading of 0A lesions, or the Η · Ε · stained specimen and saffron red 0 stained specimen were examined under a microscope.

Mankin method evaluation. Using this measurement, it was shown that the sulfonamide derivatives (I) to (V I) are effective in treating deformity arthritis. Preparation Example Preparation Example 1 Granules containing the following ingredients were prepared. Ingredients should be active ingredients 10 mg lactose 700 mg corn flour 2 74 mg HPC-L 16 mg 1 000 mg Pass the active ingredient and lactose through 60 sieve openings. Pass the corn flour through a 120 mesh opening. This was mixed in a V-type mixer. After mixing, add HP C-L solution (low-viscosity hydroxypropyl cellulose), knead and pull (extruded and granulated, pore size 0.5 ~ 1 mm), and then dry at -30-200304809. The obtained dried granules are shaken and sieved (12/60 mesh) to obtain granules. Formulation Example 2 A powder for filling capsules containing the following ingredients was prepared. Active ingredient 10 mg lactose 79 mg corn powder 10 mg magnesium stearate 1 mg 100 mg The active ingredient and lactose are passed through 60 sieve openings. Pass the corn flour through a 120 mesh opening. This and magnesium stearate were mixed in a V-type mixer. Fill 100 mg to 10 hard capsules with 10 times powder. Formulation Example 3 Granules for filling capsules containing the following ingredients were prepared. Ingredients Active Ingredients 15 mg lactose 90 mg corn flour 42 mg HPC-L 3 mg 1 50 mg Pass the active ingredient and lactose through 60 sieve openings. Pass the corn flour through a 120 mesh opening. After mixing, add the HP C-L solution, knead it, pull it, and dry it. The obtained dried granules were filled into a hard capsule No. 4 with 150 mg. -3 1- 200304809 Preparation Example 4 Preparation of hard capsule active ingredient starch (dry) using the following ingredients Magnesium stearate (milligram 2 5 0 200 10 / capsule) Total Formulation Example 5 Preparation of capsules containing 80 mg of active ingredient Active ingredient starch Microcrystalline cellulose Magnesium stearate 460 mg 80 mg 59 mg 59 mg 2 mg Total 200 mg The active ingredient, starch, cellulose and magnesium stearate are mixed, the sieve opening is filled with 200 Milligrams to hard capsules. Formulation Example 6 A lozenge containing the following ingredients was prepared. Ingredients Active Ingredients Lactose Microcrystalline Cellulose CMC-Na Magnesium Stearate Pass U.S. 4 5 10 mg 90 mg 30 mg 15 mg 5 mg 1 50 mg-32- 200304809 Cellulose and CMC-Na (carboxymethylcellulose sodium salt) are mixed through 60 mesh sieve. The powder was not mixed with magnesium stearate and used to make tablets. The tablets were taken to obtain 150 mg of tablets. Formulation Example 7 A lozenge containing the following ingredients was prepared. Dosage (mg / tablet) Active ingredient 250 cellulose (microcrystalline) 400 silicon dioxide 10 magnesium stearate 5 total 6 6 5 millimeters Mix the ingredients and compress into 6 65 mg tablets. Agent Example 8 A lozenge containing 60 mg of active ingredient was prepared. Active ingredients 60 mg starch powder 45 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone (10% solution in water) 4 mg sodium carboxylate starch 4.5 mg magnesium stearate 0.5 mg talc 1 mg

Total 150 mg Pass the active ingredients, starch, and cellulose through a U.S. 45 mesh and mix. The obtained powder was mixed with a solution containing polyvinylpyrrolidone, and the mixture -33- 200304809 was passed through a U.S. 14 mesh. The resulting granules were dried at 50 ° C and passed through a U.S. No. 18 sieve. Pass through a U.S. 60 mesh sieve, 1 add sodium carboxymethyl starch starch stearate and talc, mix, and compress with a tableting machine to obtain 150 mg lozenges < Formulation Example 9 Prepare an aerosol containing the following ingredients Solution 0 weight active ingredient 0: 2 5 ethanol 2 5 .75 propellant 22 chlorodifluoro 1 methane) 74 total 100.00 mix active ingredient with ethanol, add propellant 2 2 to this mixture, at -3 0 ° C Cool and remove the charging device. Add the required amount to the stainless steel container. The insufficient amount is diluted with propellant. Place the valve in a container. Formulation Example 10 A suppository containing 225 mg of an active ingredient was prepared. Active ingredient 2 2 5 mg Saturated fatty acid triglyceride_2 0 0 0 mg Total 222 5 mg The active ingredient is passed through a U.S. 60 sieve, melted at low temperature and dissolved in saturated fatty acid triglyceride. The resulting mixture was added to a 2 g form and cooled. Formulation Example M A solution containing 50 mg of the active ingredient was prepared. -34- 200304809 Active ingredient 50 mg sodium carboxymethyl cellulose 50 mg syrup 1.25 ml benzoic acid 0.1 ml flavor q. V. Pigment q. V. Add pure water 5 m 1 in total and pass the active ingredient through U. S. 4 No. 5 sieve, mixed with sodium carboxymethyl cellulose and syrup to obtain a matrix solution. Add benzoic acid solution, perfume and perfume solution to dilute and stir. Add water to the required volume. Preparation Example 12 A preparation for intravenous use was prepared. Active ingredient 100 mg physiological saline 1000ml The above ingredients are generally administered to a patient intravenously at a rate of lmin / ml. Formulation Example 1 3 A freeze-dried formulation (1 vial) was prepared. Active ingredients 1 2 7 mg Sodium citrate 2 hydrate 36 6 Mannitol 1 800 mg The active ingredients in the above ingredients are dissolved in water at an injection concentration of 10 mg / g. The first freezing step was performed at-40 ° C for 3 hours, heat-treated at -10 ° C for 10 hours, and then frozen at -40 t for 3 hours. It was dried for the first time at (TC, 10 Pa for 60 hours, and then at 60 ° C, 4 Pa for 5 hours for the second time. The frozen 200304809 dried preparation was obtained. Industrial application The sulfonic acid of the present invention Amidine derivatives can be used as therapeutic and preventive agents for deformity arthritis and / or chronic rheumatoid arthritis.

-36-

Claims (1)

200304809 Patent application scope 1. A therapeutic and preventive agent for deformable arthritis and / or chronic rheumatoid arthritis, which contains a compound selected from the group consisting of a compound of the following formula, an optically active substance, a prodrug thereof, or a pharmaceutically acceptable salt thereof. , Or its solvate as the active ingredient: 2. A method for preparing a medicine for deformable arthritis and / or chronic rheumatoid arthritis, using the compound shown in item 1 of the scope of patent application. 3. A method of treatment to alleviate the effects of mammals due to deformity arthritis, comprising administering to a mammal a therapeutically effective amount of a compound as shown in item 1 of the scope of the patent application. 200304809 Lu, (a), the designated representative of the case is: Figure _ (b), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that can best show the characteristics of the invention = (I)