MXPA06008747A - Prodrug comprising 5-aminosalicylate glycoside - Google Patents

Abstract

It is intended to provide a remedy for ulcerative colitis by which 5-aminosalicylic acid (5-ASA) useful as a remedy for ulcerative colitis can be efficiently delivered to the affected site (i.e., the large intestine) with little absorption or metabolism in the stomach or the upper part of the small intestine and which is highly safe and can be administered over a long time. Namely, 5-ASA carrying D-galactose introduced thereinto which is represented by the following general formula [1]. [1]This compound can efficiently get to the function site (i.e., the large intestine). Then the intestinal flora decomposes it to thereby form 5-ASA which is the active ingredient in the large intestine.

Description

wo m sm AI LT, LU, LV, M ?, MD, MG, MK, MN, MW, MX, MZ, N ?, IB, 1S, IT, LT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), NI, NO, NZ, OM, PG, PH, PL, PT, RO, KÍJ, SC, SD, SE, OA ?? (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, G .ML, SB, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, MR , E, SN.TD.TG). UZ, VC, VN, YU, ZA, ZM, ZW. (8) Xf? O @ »% S K ^: l ^? É ^ # J¿btí '^^ & d5 - t ^ -y9: - ^ (5-ASA)% f :? PROFARMACO COMPRISING GLICOSIDE OF 5-AMINOOSE ICILATE FIELD OF THE INVENTION The present invention relates to 5-amino-2- (β-D-galactopyranosyloxy) benzoic acid (hereinafter referred to as "compound [1]") represented by the following general formula [1] or acid 5-amino-2- (cc-D-galactopyranosyloxy) benzoic acid (hereinafter referred to as "compound [2]") represented by the following general formula [2] or a pharmaceutically acceptable salt thereof. [Chemistry 1] Furthermore, the present invention relates to a pharmaceutical composition comprising as an active ingredient the compound [1] or the compound [2] or a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a therapeutic agent for ulcerative colitis which comprises as an active ingredient the compound [1], the compound [2] or acid -amino-2- (β-D-glucopyranosyloxy) benzoic acid (hereinafter referred to as "compound [3]") represented by the following Ref. 174427 general formula [3] or a pharmaceutically acceptable salt thereof. [Chemistry 2] [3J1 BACKGROUND OF THE INVENTION 5-aminosalicylic acid (hereinafter referred to as "5-ASA") has a free radical reducing action (DPPHL), a hydrogen peroxide scavenging action, a hypochlorite ion scavenging action, inhibitory action On lipid peroxidation and B4 leukotriene biosynthesis, therefore, it is useful as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD) generically called inflammatory bowel diseases (IBD), which are refractory inflammatory diseases in nature that require long-lived treatment while alternating between remission and exacerbation (see, for example, document 1 which is not patent). However, it is known that 5-ASA administered orally per se is rapidly and completely absorbed in the upper part of the small intestine, and a small amount of 5-ASA, which has its effect by local action in the inflammatory site, is supplied near the large intestine of the affected site (see, for example, document 3 which is not patent), In view of this, to supply 5-ASA to the large intestine of the site of action, the system has been studied of drug delivery (hereinafter referred to as "DDS") of 5-ASA and 5-ASA prodrugs (see, for example, documents 1, 2 and 4 which are not patents). There is a DDS preparation of 5-ASA, trade name: Pentasa (registered trademark), manufactured by Nisshin Kyorin Pharmaceutical Co., Ltd., which is formulated for gradual release of 5-ASA in the area from the small intestine to the intestine thickness when coating 5-ASA with a porous film of ethylcellulose (see, for example, documents 1 and 2 which are not patent). However, it is known that a considerable amount of 5-ASA is transferred to the plasma after a single oral administration of Pentasa to healthy adults at a dose of 1000 mg as 5-ASA in the fasted state, although the concentration in the plasma of the unchanged drug is reduced to a level of one-fourteenth to the lowest (Cma = 1448.6 ± 586.4 ng / ml) compared to the case where there is a single oral administration of 5-ASA per se (see, for example, document 5 that is not patent). In addition, as a prodrug of 5-ASA, there is salazosulfapyridine (hereinafter referred to as "SASP") (trade name: Salazopyrin (registered trademark), manufactured by Pfizer Inc.), in which an amino group of 5-ASA is azotized (see, for example, document 3 that is not patent). The compound is metabolized to 5-ASA by the intestinal bacteria that exist in the large intestine and has an azo-reduction enzyme. Although the effectiveness of SASP for ulcerative colitis has been established, there is a problem that side effects such as drug hypersensitivity, male infertility, nausea and headache are caused by sulfapyridine (SP) which is formed after the degradation of SASP. by intestinal bacteria (see, for example, document 3 which is not patent). In addition, as other prodrugs, methyl 5-amino-2- (β-D-glucopyranosyloxy) enzoate and methyl 2-acetoxy-5- (β-D-glucopyranosylamino) benzoate which are 5-aminosalicylate glucose glycosides are known. of methyl that have high solubility in water (see, for example, documents 6 and 7 that are not patent). Although the safety of the compounds has been established, their therapeutic effects on ulcerative colitis have not been investigated at all. In addition, apart from 5-ASA, as a prodrug of steroidal compound useful as a therapeutic agent for ulcerative colitis, a glycoside of dexamethasone or prednisolone with glucose or the like has been reported (see, for example, example, patent document 1). An object of the compound is to give a specific drug supply to the large intestine. However, it has been reported that after intragastric administration to rats, only 60% of a glucose derivative of dexamethasone is delivered to the caecum and only 15% or less of a prednisolone glucose derivative is delivered to the caecum. As described above, currently, there are no known therapeutic agents for ulcerative colitis that are safe, can be administered in the long term, and are capable of efficiently delivering useful 5-ASA as a therapeutic agent for ulcerative colitis to the large intestine of the affected site. without it being absorbed or metabolized in the stomach or upper part of the small intestine. [Patent Document 1] JP-B-60-501105 [Document 1 which is not patent] Folia Pharmacol.

Jpn. 104, pp. 447-457 (1994) [Document 2 which is not patent] Folia Pharmacol. Jpn. 104, pp. 303-311 (1994) [Document 3 that is not patent] Scandinavian Journal of Gastroenterology, 23, pp. 107-112 (1988) [Document 4 which is not patent] Advanced Drug Delivery Reviews, 7, pp. 149-199 (1991) [Document 5 that is not patent] Ya uri To Chiryo, 22 (Suppl 10), pp. S2467-S2495 (1994) [Document 6 that is not patent] Magyar Kemiai Folyoirat, 97 (4), pp. 143-148 (1991) [Document 7 which is not patent] Archiv der Pharmazie An International Journal Pharmaceutical and Medicinal Chemistry, 332 (9), pp. 321-326 (1999) BRIEF DESCRIPTION OF THE INVENTION Problems to be solved by the invention An object of the present invention is to provide a therapeutic agent for ulcerative colitis that allows 5-ASA useful as a therapeutic agent for ulcerative colitis to be efficiently delivered to the patient. Large intestine of the affected site almost without being absorbed or metabolized in the stomach or upper part of the small intestine and to be administered safely in the long term. Means for solving the problems As a result of extensive studies, the inventors of the present have found a compound with which the aforementioned object can be achieved, thereby completing the present invention. The present invention may include a compound [1] or a compound [2] or a pharmaceutically acceptable salt thereof. In addition, the present invention may include a pharmaceutical composition comprising a compound [1] or a compound [2] or a pharmaceutically acceptable salt thereof as the active ingredient, and in addition, a therapeutic agent for ulcerative colitis comprising a compound [1], a compound [2] or a compound [3] (for purposes of convenience, hereinafter collectively referred to as the "compound of the present invention") or a pharmaceutically acceptable salt of the same as an active ingredient. Because the compound of the present invention is metabolized to 5-ASA by the intestinal bacterial flora in the large intestine, systemic side effects can be reduced and a relatively long-term administration at a relatively high dose has become possible when using the compound of the present invention. The definition of the term used in the present description is as follows. "Ulcerative colitis" is a nonspecific erosive inflammation of the large intestine of unknown cause, which mainly attacks the mucosa and often forms erosions and ulcers. Hereinafter, the present invention will be described in detail. The compound of the present invention can be produced according to, for example, the following method from an unknown compound or an intermediate that can be easily prepared. In the production of the compound of the present invention, when a starting material has a substituent that affects a reaction, it is general that the The reaction is carried out after the starting material is protected with an appropriate protecting group by a method known in advance. The protective group can be removed by a known method after the reaction. Production method 1 [Chemistry 3) 1. i 18] (In the formula, R 1 represents straight chain alkyl or branched chain having 1 to 6 carbon atoms, R 2 represents D-glucopyranosyl or D-galactopyranosyl (each hydroxyl group of R 2 can be protected with a protecting group such as acetyl), and X represents a halogen atom such as fluorine, chlorine, bromine and iodine.). Step 1 This step is esterification of a known compound [4] and can be carried out by a known method (see document 7 which is not patent). The reaction temperature is suitably in the range of 20 ° C to 200 ° C. In general, a reaction solvent varies according to the type of ester carboxylic to be produced, but examples thereof may include alcohols such as methanol and ethanol. Examples of an acid may include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction time varies according to the type of starting material to be used or the reaction temperature, but is suitably in the range of 1 hour to 72 hours in general. Step 2 This step is condensation of a compound [5] with a compound obtained by hydrogenation of glucose or galactose in the anomeric position, and can be carried out by a method known per se (see document 7 which is not patent). This reaction proceeds by inversion of the configuration in the presence of a catalyst. Examples of the catalyst for this reaction may include silver oxide (I), mercury (II) oxide and AgOCOR3 (R3 represents straight chain alkyl or branched chain having 1 to 6 carbon atoms). In general, a reaction solvent is not particularly limited as long as it is not involved in the reaction, and examples thereof may include quinoline. The reaction temperature is suitably in the range of 0 ° C to 100 ° C. The reaction time varies according to the type of starting material to be used, the reaction temperature, etc., but is suitably in the range of 1 hour to 72 hours in general. In addition, if desired, a protective group for each Hydroxyl group of R2 of a compound produced [6] can be removed by a known method. In addition, although the compound [9], which is a starting compound, is commercially available, it can also be produced, for example, by the following method. This reaction is a halogenation reaction in the anomeric position of a sugar such as glucose or galactose, and can be carried out by a method known per se. Examples of the halogenating agent may generally include a solution of hydrogen bromide in acetic acid, phosphorus oxybromide, phosphorus oxychloride and the like. In general, a reaction solvent is not particularly limited as long as it is not involved in the reaction, and examples thereof may include halogenated solvents such as methylene chloride, chloroform and 1,2-dichloroethane. The reaction temperature is suitably in the range of 0 ° C to 1.00 ° C. The reaction time varies according to the type of starting material to be used or the reaction temperature, but is suitably in the range of 1 hour to 72 hours in general. Step 3 This step is hydrogenating the compound [6} , and can be carried out by a method known per se (see: document 7 that is not patent). This reaction can be carried out, for example, in the presence of a metal catalyst in a suitable solvent, generally under an atmosphere of nitrogen from 1 to 1.0 atm. and at 0 ° C to 1.00 ° C. Examples of the metal catalyst may generally include palladium on carbon, palladium black, platinum dioxide, platinum on carbon, and the like. The reaction solvent is not particularly limited as long as it is not involved in the reaction, and examples thereof may include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, amides such as N, N.- dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene, toluene and the reaction time varies according to the type of starting material to be used or the reaction temperature, but is suitably in the range of 1 hour to 48 hours in general. Further, if desired, a protecting group for each hydroxyl group of R2 of a produced compound [7] can be removed by a known method. Step 4 This step is hydrolysis of a carboxylic ester of the compound [7], and can be carried out by a method known per se. The reaction temperature is suitably in the range of 0 ° C to 100 ° C. A reaction solvent is not particularly limited as long as it is not involved in the reaction, and examples thereof may include alcohols such as methanol and ethanol. Examples of a base may include inorganic bases such as sodium hydroxide and hydroxide of potassium. The reaction time varies according to the type of starting material to be used or the reaction temperature, but is suitably in the range of 1 hour to 72 hours in general. In addition, as another method of production of the compound [6], the following method can be exemplified. Production method 2 [Chemistry 4] i. BJ (In the formula, R1 and R2 have the same meaning as described above X1 represents a halogen atom such as fluorine, chlorine, bromine or iodine.) Step 1 This step is esterification of a known compound [10] and can be carried out by a known method (see document 7 which is not patent). The reaction temperature is suitably in the range of 20 ° C to 200 ° C. In general, a reaction solvent varies according to the type of carboxylic ester to be produced, and examples thereof may include alcohols such as methanol and ethanol. Examples of an acid may include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction time varies according to the type of starting material to be used or the reaction temperature, but is suitably in the range of 1 hour to 72 hours in general. Step 2 This step is condensation of a compound [11] with a glucose or galactose derivative [12], and can be carried out by a method known per se. Examples of a condensing agent for this reaction may include bases. In this reaction, because the configuration of the anomeric position can not be controlled, it is necessary to separate and purify a single diastereomer by using chromatography on silica gel or the like. By this separation process, both compounds (form a and form f3) can be obtained for the configuration of the anomeric position. Examples of the base to be used in this reaction may include 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0 ] -7-undecene In general, a reaction solvent is not particularly limited as long as it is not involved in the reaction, and examples thereof may include acetonitrile and dimethyl sulfoxide. The reaction temperature is suitably in the range of 0 ° C to 100 ° C. The reaction time varies according to the type of starting material to be used, the reaction temperature, etc., but is suitably in the range of 1 hour to 72 hours in general. In addition, if desired, a protective group for each Hydroxyl group of R2 of a compound produced [6] can be removed by a known method. The compound of the present invention produced in this manner can be separated and purified by a method known per se such as concentration, solvent conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation or chromatography. The compound of the present invention can be used as a medicament such as, and can also be converted to a pharmaceutically acceptable salt by a known method. The "salt" of the compound of the present invention can include a pharmaceutically acceptable salt, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid, salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphor sulfonic acid, alkali metal or alkaline earth metal salts such as sodium, potassium and calcium. The hydrochloride salt is preferable. A hydrochloride salt of the compound of the present invention can be obtained by treating the compound of the present invention with an alcohol solution of hydrogen chloride or a solution of diethyl ether, the same and then get a crystal deposited by filtration, or when a crystal is not deposited, concentrate the solution to deposit a crystal and obtain the crystal, for example, by filtration. As shown in the test examples described below, the compound of the present invention has an excellent characteristic feature that is hardly transferid to plasma, which is not possessed by currently available 5-ASA-related pharmaceutical products, and allows 5- ASA, which is an active ingredient, is efficiently supplied widely, to the affected sites, ie, the caecum and along the large intestine over the proximal colon, distal colon and rectum after oral administration. Therefore, the compound of the present invention is useful as a therapeutic agent for ulcerative colitis that is safe and can be administered in the long term. In particular, the compound [1] has a prominent effect. In a rat model with trinitrobenzenesulfonic acid-induced colitis (TNBS), as shown in the test examples described below, the compound [1] of the present invention significantly suppresses the damage rating and the weight of the large intestine and It is shown to be an excellent therapeutic agent for ulcerative colitis.

In the event that the compound of the present invention is administered as a medicine, the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to mammals including humans, as such or as a pharmaceutical composition containing the compound in a non-toxic and pharmaceutically acceptable active vehicle in an amount of, for example, 0.1% to 99.5%, preferably 0.5% to 90%. The pharmaceutically acceptable carrier can include diluents and fillers in solid, semisolid or liquid form, and other formulation aids, and at least one of them is used. The pharmaceutical composition is preferably administered in a dosage form. The pharmaceutical composition can be administered orally or parenterally (e.g., transrectal administration, etc.). Of course, it is administered in the dosage form suitable for these administration methods. For example, oral administration is preferred. The dose of the compound of the present invention can be preferably adjusted in view of conditions of a patient such as age, body weight, character and severity of the disease, as well as the route of administration, but usually is in the range of 10 mg / adult at 10 g / adult, preferably 1 g to 4 g / adult per day in the case of oral administration as an effective amount of compound of the present invention or a pharmaceutically acceptable salt thereof. In some cases, a lower dose may be required than the previous interval may be sufficient or a higher dose than the previous interval. Usually, the daily dose may be administered once a day or several times when divided into portions. Oral administration can be carried out in a solid or liquid unit dosage form, such as a, a particle, a powder, a tablet, a sugar-coated tablet, a capsule, a granule, a suspension, a liquid, a syrup, a drop, a sublingual tablet, or other dosage forms. The particle can be produced by spraying the compound of the present invention or a pharmaceutically acceptable salt thereof into a suitable particle size. The powder can be produced by spraying the compound of the present invention or a pharmaceutically acceptable salt thereof into a suitable particle size and subsequently by mixing it with a pharmaceutical carrier, such as an edible carbohydrate such as starch or mannitol and others. Those that can be mixed, if necessary, are flavors, preservatives, dispersants, colorants, fragrances or the like. The capsule can be produced by filling a capsule shell such as gelatin capsule with the particle or powder that has been sprayed as before or granulated as described in the tablet section. A lubricant or a fluidizer, eg, colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol may be added to the powder and the filling operation may then be conducted. When a disintegrant or a solubilizer is added, e.g., carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose having a low degree of substitution, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, or sodium carbonate, the effectiveness of the medicine when the capsule is taken can be improved. The tablet can be produced by preparing a powder mixture together with an excipient, by granulating or cutting it, by adding a disintegrant or a lubricant thereto, and then compacting it into a tablet. The powder mixture can be produced by mixing an appropriately pulverized material with the above diluent or a base and, if necessary, a binder (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone or polyvinyl alcohol), a dissolution retarder (e.g., paraffin), a re-absorbent (e.g., a quaternary salt), or an adsorbent, (e.g., bentonite, kaolin, dicalcium phosphate) can be used in combination. The powder mixture can first be moistened with such a binder as syrup, starch glue, gum arabic, a cellulose solution, and a polymer solution, followed by mixing with stirring, and then by drying and grinding. Instead of the process for granulating the powder as described above, after it is subjected to a tablet compactor machine, the resulting pieces in an incomplete form can be ground to form granules. It is possible to prevent the granules thus formed from being bound in another way by adding stearic acid, a stearate salt, talc, mineral oil, or the other substance as a lubricant. The mixture thus lubricated can then be formed into tablets. The uncoated tablets thus produced can be subjected to film coating or sugar coating. Moreover, the compound of the present invention or a pharmaceutically acceptable salt thereof can be directly compacted into tablets after mixing with a fluid inactive vehicle without the steps of granulation and chunk formation as described above. A transparent or translucent protective film in the form of a lacquer sealing film, a film of a sugar or polymer material, a gloss film composed of wax may also be used. The other forms of oral administration, such as a solution, a syrup and an elixir can be formulated as an oral dosage form so that a certain amount thereof can contain a certain amount of a medicine. The syrup may be produced by dissolving the compound of the present invention or a pharmaceutically acceptable salt thereof in an appropriate flavored aqueous solution; although the elixir can be produced when using a non-toxic alcoholic vehicle. If necessary, a unit dose formulation for oral administration can be encapsulated. An extended working time and sustained release of the active ingredient can also be achieved by coating the formulation or embedding them in a polymer, wax, or the like. In parenteral administration, a suppository, or the like, can be used. Transrectal administration can be achieved with the use of a suppository produced by dissolving or suspending the compound of the present invention or a pharmaceutically acceptable salt thereof in a water-soluble or water-insoluble solid of low melting point, such as polyethylene glycol, cocoa butter, a semi-synthesized oil and fat (e.g., itepsol / registered trademark), a higher ester (e.g., myristyl palmitate), or a mixture thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the concentration change in the plasma of 5-ASA. The vertical axis represents the concentration in the plasma of 5-ASA (ng / ml) in rat and the horizontal axis represents the time (hour). Black circles, diamonds White, white triangles, and white circles represent the change in concentration of 5-ASA after administration of compound [1], compound [2], compound [3] and Pentase (registered trademark), respectively. Figure 2 shows the change of the amount of 5-ASA in the contents of the caecum. The vertical axis represents the amount of 5-ASA (% of dose) present in the contents in the caecum of the rat and the horizontal axis represents the time (hour). The black circles, the white circles and the black triangles represent the change in the amount of 5-ASA after the administration of the compound [1], Pentasa (registered trademark) and 5-ASA, respectively. Figure 3 shows the change in the amount of 5-ASA in the proximal colonic contents. The vertical axis represents the amount of 5-ASA (% dose) present in the rat proximal colonic contents and the horizontal axis represents the time (hour). The black circles, the white circles, and the black triangles represent the change in the amount of 5-ASA after the administration of the compound [1], Pentasa (registered trademark) and 5-ASA, respectively. Figure 4 shows the change in the amount of 5-ASA in the distal colonic contents. The vertical axis represents the amount of 5-ASA (% dose) present in the rat distal colonic contents and the horizontal axis represents the time (hour). Black circles, circles Whites and black triangles represent the change in the amount of 5-ASA after administration of the compound [1], Pentasa (registered trademark) and 5-ASA, respectively. Figure 5 shows the change in the amount of 5-ASA in the rectal contents. The vertical axis represents the amount of 5-ASA (% dose) present in the rat rectal contents and the horizontal axis represents the time (hour). The black circles, the white circles and the black triangles represent the change in the amount of 5-ASA after the administration of the compound [1], Pentasa (registered trademark) and 5-ASA, respectively. Figure 6 shows the change in the concentration of 5-ASA in the colonic tissue. The vertical axis represents the concentration of 5-ASA (μg / g) present in 1 g of rat colon and the horizontal axis represents the time (hour). The white rhombuses, and the white circles represent the change in the concentration of 5-ASA represent the change in the concentration of 5-ASA after the administration of the compound [2], and Pentasa (registered trademark), respectively. Figure 7 shows the change in the concentration of -ASA in the rectal tissue. The vertical axis represents the concentration of 5-ASA (μg / g) present in 1 g of the rectum of the rat and the horizontal axis represents the time (hour). The white rhombuses, and the white circles represent the change in the concentration of 5-ASA after the administration of the compound [2], and Pentasa (registered trademark), respectively. Figure 8 shows the therapeutic effects of Pentase (trademark) and compound [1] on TNBS-induced colitis in rats by damage score. The vertical axis represents the damage rating and the horizontal axis represents the dose of each test drug (mg / g / one time). Figure 9 shows the effects of Pentase (trademark) and compound [I] on TNBS-induced colitis in rats against an increase in the wet tissue weight that accompanies the onset of colitis. The vertical axis represents the wet weight of the large intestine (g) and the horizontal axis represents the dose of each test drug (mg / kg / one time). DETAILED DESCRIPTION OF THE INVENTION The present invention will be further illustrated in detail below with reference to examples, test examples and formulation examples, but the present invention is not limited thereto. Example 1 5-Amino-2- (β-D-galactopyranosyloxy) benzoic acid Step 1: 5-Nitrosalicylate methyl To a solution of 30 g of 5-nitrosalicylic acid in 500 ml of anhydrous methanol, concentrated sulfuric acid was added dropwise, and the mixture was heated to reflux for 2 days. The reaction solution was concentrated under reduced pressure and diluted with 500 ml of ethyl acetate, and 500 ml of water was added thereto. Then, a saturated solution of sodium bicarbonate was added slowly to it, under cooling with ice to make the alkaline solution (pH = 9). The deposited yellow precipitate was filtered, and the aqueous layer of the filtrate was subjected to extraction with ethyl acetate. The combined organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate and then filtered. Then, the solvent was concentrated, whereby 31.26 g of methyl 5-nitrosalicylate was obtained. Step 2-1; 2 ', 3', 4 ', 6'-tetra-O-acetyl-aD-galactopyranosyl bromide A solution of 65 g of 1', 2 ', 3', 4 ', 6' -penta-O-acetyl- β-D-galactopyranose in 500 ml of methylene chloride was cooled with ice, and 177.5 g of 30% solution of hydrogen bromide / acetic acid was added dropwise thereto. The reaction mixture was stirred at room temperature for 14 hours, and then emptied into a saturated solution of sodium bicarbonate containing ice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and then filtered. Then, the solvent was concentrated, whereby 68.7 g of 2 ', 3', 4 ', 6'-tetra-O-acetyl-α-D-galactopyranosyl bromide was obtained.

Step 2-2: Methyl 5-nitro-2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-galactopyranosyloxy) benzoate To a solution of 30.55 g of 5-nitrosalicylate from methyl obtained in step 1 and 63.7 g of 5. 2 ', 3', 4 ', 6' -tetra-O-acetyl-aD-galactopyranosyl bromide obtained in step 2-1 in 250 ml of quinoline was added 35.92 g of silver oxide, and the mixture was stirred at room temperature for 62 hours under dark condition. The reaction mixture was diluted with 1000 ml of ethyl acetate, and then celite filtration was carried out. After the ethyl acetate layer was washed twice with 1000 ml of 2N hydrochloric acid, the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a saturated solution of sodium bicarbonate, water, and saturated brine, and dried over sodium sulfate, and then filtered. Then, the solvent was concentrated, whereby 71.7 g of methyl 5-nitro-2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-galactopyranosyloxy) benzoate was obtained. Step 2-3: 0-methyl 5-nitro-2- (β-D-galactopyranosyloxy) -benzoate A solution in methanol containing 10.55 g of 5-nitro-2- (2 ', 3', 4 ', 6' methyl-tetra-O-acetyl-β-D-galactopyrano-siloxy) benzoate obtained in step 2-2 was stirred at 60 ° C, and sodium methoxide was added thereto. After the mixture was stirred for 30 minutes, the reaction mixture it was neutralized with 5.0 g of Amberlite IRC-50. After the filtration was carried out, the organic layer was concentrated, whereby 4.90 g of methyl 5-nitro-2- (β-D-galactopyranosyloxy) benzoate was obtained. 5. Step 3: Methyl 5-amino-2- (β-D-galactopyranosyloxy) benzoate To a solution of 4.90 g of methyl 5-nitro-2- (β-D-galactopyranosyloxy) benzoate obtained in step 2 3 in 100 ml of methanol, 0.49 g of 10% palladium on charcoal was added, and a catalytic reduction was carried out at 0 room temperature under a nitrogen atmosphere of 1 atm. After 20 hours, the reaction solution was filtered to remove the catalyst, and the organic layer was concentrated, whereby 4.18 g of methyl 5-amino-2- (β-D-galactopyranosyloxy) benzoate was obtained. Step 4: 5-Amino-2- (β-D-galactopyranosyloxy) -benzoic acid To a suspension of 4.18 g of methyl 5-amino-2- (β-D-galactopyranosyloxy) benzoate obtained in step 2-4 in 120 ml of anhydrous methanol, 12.7 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise. The mixture was stirred while heating to reflux for 16 hours. The reaction solution was concentrated under reduced pressure as such, and the residue was diluted with distilled water. Then, the solution was neutralized with 6.4 ml of 2N hydrochloric acid. The mixture was concentrated, whereby 3.41 g of the objective compound was obtained.

Colorless powder MS (El): m / z = 338 [M + Na] + Rotation: [a] D20 = -19.84 (C = 1.28, H20) Elemental analysis values (such as C? 3H1N08) Calculated (%): C : 49.52, H: 5.43, N: 4.44 Found (%): C: 49.12, H: 5.37, N: 4.38 XH NMR (D20): 3.74 to 4.01 (m, 6H, H-2 to 6), 5.04 (d , ÍH, Jl, 2 = 7.4 Hz, Hl), 7.30 to 7.39 (m, 3H, Ph) Example 2 5-Amino-2- (aD-galactopyranosyloxy) benzoic acid Step 1: Methyl 2-fluoro-5-nitrobenzoate A solution containing 12.0 g of 2-fluoro-5-nitrobenzoic acid, 60 ml of anhydrous tetrahydrofuran and 60 ml of dimethylformamide was cooled with ice, and 9.05 g of oxalyl chloride was added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. To the reaction solution, 30 ml of anhydrous tetrahydrofuran and 30 ml of a methanol solution were added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and diluted with 240 ml of ethyl acetate. Then, the diluted solution was washed with a 5% aqueous solution of sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. and then it leaked. Then, the solvent was concentrated, and to the concentrated residue, 24 ml of isopropyl ether was added to dissolve the residue. Then, the solution was cooled to 5 ° C to deposit a crystal. The deposited crystal was filtered under reduced pressure and dried at room temperature under reduced pressure, whereby 10.5 g of methyl 2-fluoro-5-nitrobenzoate was obtained. Step 2 Methyl 5-nitro-2- (2 ', 3', 4 ', 6' tetra-o-acetyl-aD-galactopyranosyloxy) benzoate To a solution of 7.13 g of methyl 2-fluoro-5-nitrobenzoate obtained in step 1 and 12.50 g of 2 ', 3', 4 ', 6'-tetra-O-acetyl-D-galactopyranose in 70 ml of acetonitrile, 4.95 9 of DBU was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with 300 ml of ethyl acetate, washed with 150 ml of 1 N hydrochloric acid, 150 ml of 5% aqueous sodium bicarbonate solution and 150 ml of saturated brine, and dried over anhydrous magnesium sulfate and then filtered. Then, the solvent was concentrated. The concentrate was purified with a column chromatograph (Wako gel (trademark) C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), n-hexane: ethyl acetate = 4 to 1.5), resulting in 7.51 g of methyl 5-nitro-2- (2 ', 3', 4 ', 6'-tetra-o-acetyl-aD-galacto-pyranosyloxy) benzoate and 7.92 g of 5-nitro-2- (2', 3 ',', 6 • -tetra-O-acetyl-ß-D- galactopyranosiloxy) methyl benzoate. Step 3-1: Methyl 5-amino-2- (2 ', 3', 4 ', 6' -tetra-O-acetyl-aD-galactopyranosyloxy) benzoate To a solution of 7.00 g of 5-nitro-2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-aD-galactopyranosyloxy) methyl benzoate obtained in step 2-1 in 210 ml of methanol, 0.70 g of 10% palladium on charcoal was added, and a catalytic reduction was carried out at room temperature under a nitrogen atmosphere of 1 atm. After 18 hours, the reaction solution was filtered to remove the catalyst, and the organic layer was concentrated. The concentrate was purified with a column chromatograph (Wako gel (trademark) C-200 (manufactured by Wako Puré Chemical Industries, Ltd.), n-hexane: ethyl acetate = 3: 1 to 3: 2), so that 5.73 g of methyl 5-amino-2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-aD-galactopyranosyloxy) benzoate was obtained. Step 3-2: Methyl 5-amino-2- (α-D-galactopyranosyloxy) benzoate To 5.52 g of methyl 5-amino-2- (2 3 A 4 6 '-tetra-O-acetyl-aD-galactopyranosyloxy) benzoate obtained in step 3-1 in 110 ml of anhydrous tetrahydrofuran and anhydrous methanol (1: 1), 307 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was purified with a column chromatograph (Wako gel (registered trademark) C-200 (manufactured by Wako Puré Chemical Industries, Ltd.), chloroform: methanol = 10: 1 to 5: 1) ,. whereby 2.11 g of methyl 5-amino-2- (α-D-galactopyranosyloxy) benzoate was obtained. Step 4: 5-Amino-2- (aD-galactopyranosyloxy) -benzoic acid A suspension of 2.00 g of methyl 5-amino-2- (aD-galactopyranosyloxy) benzoate obtained in step 3-2 in 40 ml of water, 6.07 ml of 1N aqueous solution of sodium hydroxide was added dropwise, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was filtered to remove insoluble substances, and the filtrate was neutralized by adding 6.07 ml of 1 N hydrochloric acid thereto. The reaction solution was concentrated under reduced pressure, whereby 1.34 g of the objective compound was obtained. Light yellow powder MS (FAB): m / z = 316 [M + 1] + Rotation: [a] D20 = 79.37 (C = 1.28, H20) Elemental analysis value (as C? 3H17N08, 0.8H20) Calculated (% ): C: 41.36, H: 5.69, N: 4.25 Found (%): C: 47.20, H: 5.48, N: 4.22 XH NMR (D20): 3.70 to 4.10 (m, 6H, H-2 to 6), 5.76 (d, ÍH, Jl, 2 = 3.6 Hz, Hl), 7.37 to 7.40 (m, 3H, Ph) Reference Example 1 5-Amino-2- (β-D-glucopyranonsiloxy) benzoic acid Step 1: 5-Methyl Nitrosalicylate La synthesis was carried out with the use of it method as in step 1 of example 1. Step 2 5-Nitro-2- (2 ', 3', 4 ', 6' -tetra-O-acetyl-β-D-glucopyranosyloxy) methyl benzoate To one solution of 6.0 g of methyl 5-nitrosalicylate obtained in step 1 and 18.8 g of 2 ', 3', 4 6'-tetra-O-acetyl-aD-glucopyranosyl bromide in 60 ml of quinoline, 10.5 g of silver oxide, and the mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was diluted with 300 ml of ethyl acetate, and then celite filtration was carried out. After the ethyl acetate layer was washed twice with 2 ml of 2N hydrochloric acid, the aqueous layer was extracted twice with 300 ml of ethyl acetate. The combined organic layer was washed with a saturated solution of sodium bicarbonate, water and saturated brine, and dried over sodium sulfate, and then filtered. Then, the solvent was concentrated, whereby 15.63 g of methyl 5-nitro-2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-glucopyranosyloxy) -benzoate was obtained. . Step 3-1: Methyl 5-amino-2- (2 ', 3', 4 '6' tetra-O-acetyl-β-D-glucopyranosyloxy) benzoate To a suspension of 12.0 g of 5-nitro-2- (2 ', 3', 4 ', 6' -tetra-O-acetyl-β-D-glucopyranosyloxy) methyl benzoate obtained in step 2 in 400 ml of methanol, 2.4 g of 10% palladium on carbon was added , and a Catalytic reduction at 30 ° C under a nitrogen atmosphere of 3 atm. After 3 hours, celite filtration of the reaction solution was carried out. The solvent was concentrated, whereby 11.2 g of methyl 5-amino-2- (2 ', 3', 4 ', 6'-tetra-O-, acetyl-β-D-glucopyranosyloxy) benzoate was obtained. Step 3-2: Methyl 5-amino-2- (β-D-glucopyranosyloxy) benzoate To 16 ml of a solution of anhydrous tetrahydrofuran and methanol (1: 1) containing 0.68 g of 5-amino-2- (2 ', 3', 4 ', 6' .- tetra-O-acetyl-β-D-glucopyranosyloxy) methyl benzoate obtained in step 3-1, 37.8 mg of potassium carbonate was added, and the mixture was stirred for the night at room temperature. To the reaction solution, 0.14 ml of a 4 N solution of hydrogen chloride / ethyl acetate was added dropwise, and the solvent was concentrated as such. The resulting crude product was purified by column chromatography on silica gel (Wako gel (trademark) C-200 (manufactured by Wako Puré Chemical Industries, Ltd.), methylene chloride: methanol = 10: 1 to 8: 1 a 5: 1), whereby 332 mg of methyl 5- amino-2- (β-D-glucopyranosyloxy) benzoate was obtained. Step 4: 5-Amino-2- (β-D-glucopyranosyloxy) -benzoic acid To a suspension of 100 mg of methyl 5-amino-2- (β-D-glucopyranosyloxy) benzoate obtained in step 3-2 in 3 ml of methanol, 0.3 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise, and the mixture was stirred at 50 ° C. After 5 hours, the temperature was returned to room temperature, and the solvent was distilled under reduced pressure. The resulting oily residue was dissolved in 1 ml of water, and 0.3 ml of 1 N hydrochloric acid was added dropwise thereto while stirring and cooled on ice. This solution was concentrated to about 1/3 of the initial volume, and the deposited material was obtained by filtration, whereby 93 mg of the target compound was obtained. Elemental analysis values (such as C? 3H? 7N08, 0.2H20) Calculated (%): C: 48.97, H: 5.50, N: 4.39 Found (%): C: 48.80, H: 5.35, N: 4.31 'Example of Test 1 Measurement of plasma concentration of 5-ASA To SD male rats of 7 weeks of age, 5-ASA was administered intravenously as a test drug, and compound [1], compound [2], the compound [3] or Pentase (registered trademark) was administered orally at a dose of 50 mg / kg as5-ASA. The concentration in the plasma of 5-ASA was measured by high performance liquid chromatography (HPLC, for its acronym in English). For Pentasa (registered trademark), granules obtained by spraying the Pentasa tablet (registered trademark) were used. The results are shown in Table 1.

Table 1 Pharmacokinetic parameter values based on plasma levels of 5-ASA in rats n = 2 to 3 1) (AUC after oral administration of each test compound / AUC after intravenous administration of 5-ASA) x (amount administered intravenously of 5-ASA / orally administered amount of each test compound) x 100 The above results show that 5-ASA was detected in the plasma at a relatively high concentration after oral administration of Pentase (trademark) (see Figure 1), and therefore 5-ASA is released from a portion of the Pentasa. administered in the upper part of the small intestine as the site of absorption. On the other hand, the concentration in plasma of 5-ASA after oral administration of compound [1], compound [2] and compound [3], each of which is a -ASA glycoside remained low compared to those of Pentasa (registered trademark) (see Figure 1). In addition, when the compound (1) or the compound (2) was administered, the plasma concentrations of 5-ASA remained low compared to the case where the compound [3] was administered, and a small amount of 5-ASA (see Figure 1). The bioavailability values of 5-ASA (see Table 1) after oral administration of compound [1], compound [2], compound [3] and Pentase (registered trademark) were calculated to be 2, 0.8, 6 and 15%, respectively. Namely, it was found that compound [1], compound [2] and compound [3] had lower absorption rate of the gastrointestinal tract compared to Pentase. In particular, it was found that compound [1] and compound [2] had remarkably low bioavailability values. The likely reason for this is that the compound [1] and the compound [2] are not easily hydrolyzed in the stomach and small intestine compared to the compound [3] and do not produce 5-ASA in the stomach and the upper part of the small intestine. Test Example 2 Change in the concentration of 5-ASA in the contents of the gastrointestinal tract To male SD rats of 7 weeks of age, administered orally the compound [1], Pentasa (registered trademark) and 5-ASA at a dose of 50 mg / kg as 5-ASA, and those contained in the cecum, the proximal colon, the distal colon and the rectum were homogenized and centrifuged. Then, the amount of 5-ASA in the respective sites of the large intestine was measured by high performance liquid chromatography (HPLC). For Pentasa (registered trademark), granules obtained by spraying the Pentasa tablet (registered trademark) were used. The results are shown in Figure 2 to Figure 5. The amount of 5-ASA in the respective sites of the large intestine showed the highest value when the compound [1] was administered (see Figures 2, 3, 4 and 5). ). In addition, the compound [2] and Pentase (registered trademark) were administered orally at a dose of 50 rog / kg as 5-ASA, and the colon and rectum were homogenized and centrifuged. Then, the concentrations of 5-ASA in colonic tissue and rectal tissue were measured by high performance liquid chromatography (HPLC). For Pentasa (registered trademark), granules were obtained by spraying the Pentasa tablet (registered trademark). The results are shown in figure 6 and figure 7. Also in the case of compound (2), the Concentrations of 5-ASA in colonic tissue and rectal tissue were higher compared to Pentase (registered trademark) (see figures 6 and 7). In test compound 1, it has been confirmed that compound [1] and compound [2] do not easily hydrolyze in the stomach and small intestine, they do not produce 5-ASA in the stomach and upper part of the small intestine, and they are low in absorption speed of the gastrointestinal tract. From the results of test example 2, it was revealed that compound [1] and compound [2] are delivered to the large intestine of the affected site and are metabolized to 5-ASA by intestinal bacteria. In particular, for the compound [1], 5-ASA that is effective for ulcerative colitis was detected at high concentrations in the respective sites of the large intestine. Test Example 3 Investigation of the effect of compound [1] on trinitrobenzenesulfonic acid (hereinafter referred to as "TNBS-induced" colitis in rats A female SD rat that was left fasted for 24 hours, an aqueous solution of TNBS / 50% ethanol (30 mg / 0.25 ml / rat) was administered to the colon 8 cm from the anus with the use of a probe for oral administration under anesthesia with pentobarbital to induce colitis. 3 days after administration of TNBS, the colon was excised, and the wet weight of the colon 8 cm long from the anus was weighed. The degree of onset of colitis was graded according to the method of Wallace et al. (Gastroenterology 96, 29-36 (1989)). As the test compounds, Pentase (registered trademark) at doses of 30 mg / kg and 100 mg / kg and compound [1] at doses of 61.8 mg / kg and 205.9 mg / kg (correspondingly to 30 mg / kg and 100 mg / kg in terms of 5-ASA) were administered orally twice a day (the day of administration of TNBS, once 4 hours before the administration of TNBS). Pentasa (registered trademark) was administered as granules obtained by spraying Peptasa tablet (registered trademark). The results are shown in Figure 8 and Figure 9. Compound [1] significantly reduced the damage rating at a dose of 61.8 mg / kg (correspondingly to 30 mg / kg as 5-ASA), and inhibited the increase of the colon wet weight significantly at a dose of 205.9 mg / kg (corresponding to 100 mg / kg as 5-ASA), (see figures 8 and 9). On the other hand, Pentasa (registered trademark) showed no obvious effect on the damage score or on the increase of the wet weight of the colon. Formulation Example 1 Powdered drug (preparation for internal use) In one preparation (700 mg) Compound [1] 500 mg Corn starch 127 mg Crystalline cellulose 35 mg Polyvinyl alcohol 35 mg Magnesium stearate 3 mg 250 g of the compound [1], 63.5 9 of corn starch and 17. 5 g of crystalline cellulose were fed to a fluid bed granulator / dryer, and 175 ml of 10% aqueous solution of polyvinyl alcohol was sprayed for granulation. Then, magnesium stearate (0.4% (w / w)) was added thereto, whereby a powder drug containing 500 mg of this compound in 700 mg was obtained. Formulation Example 2 Tablet (preparation for internal use) In one preparation (600 mg) Compound [1] 400 mg Corn starch 153 mg Crystalline cellulose 42 mg Magnesium stearate 5 mg A powder mixture of 400 g of the compound [1] , 153 g of corn starch and 42 g of crystalline cellulose were compressed with a dry granulator and pulverized into granules. Then, magnesium stearate (0.8% (w / w)) was added thereto, and the mixture was formed into a tablet weighing 600 mg and having a diameter of 11 mm, whereby a tablet containing 400 mg of this compound.

Formulation Example 3 Capsule (preparation for internal use) In a preparation (500 mg) Compound [1] 250 mg, Anhydrous calcium acid phosphate 222.5 mg Croscarmellose sodium 25 mg Magnesium stearate 2.5 mg A powder mixture of 250 g compound [1], 222.5 g of anhydrous calcium acid phosphate and 25 g of croscarmellose sodium were compressed with a "dry" granulator and pulverized into granules, then magnesium stearate (0.5% (w / w)) was added. to it, and a hard capsule No. 0 was filled with 500 mg of the mixture, whereby a capsule containing 250 mg of this compound was obtained Formulation Example 4 Cylindrical granule (preparation for internal use) In a preparation (1000 mg) Compound [1] 750 mg Corn starch 170 mg Crystalline cellulose 50 mg Polyvinyl alcohol 30 mg 375 g of the compound [1], 85 g of corn starch and 25 g of crystalline cellulose were fed to a kneader, and 125 ml of 12% aqueous solution of alcohol p Olivinil was added to it and the mixture was kneaded. After, the material The kneading was extruded with a pellet extrusion molding machine equipped with a screen having 0.7 mm diameter openings. The extruded material was dried and sized, whereby a granule containing 750 mg of this compound in 1000 mg was obtained. Formulation Example 5 Spherical coated granule (preparation for internal use) In one preparation (1000 mg) Sugar sphere 200 mg Compound [1] 500 mg Corn starch 170 mg Low-substituted hydroxypropyl cellulose 40 mg Hydroxypropylcellulose 50 mg Hydroxypropylmethylcellulose 30 mg Propylene glycol 6 mg Titanium oxide 4 mg 200 g of sugar sphere (24 to 32 mesh) was fed to a centrifugal fluidized coating granulation machine, and while an 8% aqueous solution of hydroxypropylcellulose (50% ethanol) was sprayed, a powder mixture of 500 9 of compound [1], 170 g of corn starch and 40 g of low-substituted hydroxypropylcellulose was added gradually to the same for granulation, and the resulting granule was dried to obtain approximately 900 g of spherical granule base.

Then, 400 g of this spherical granule base was fed to a fluid bed granulator / dryer, and 250 ml of an aqueous solution containing 12.5 g of hydroxypropylmethylcellulose, 2.5 g of propylene glycol and 1.7 g of titanium oxide was sprayed, so that a coated granule containing 500 mg of this compound in 1000 mg was obtained. Industrial Applicability The compound of the present invention has a characteristic feature that allows 5-ASA useful as a therapeutic agent for ulcerative colitis to be efficiently delivered to the large intestine as the site of action and does not allow 5-ASA to be transferred to the plasma. In other words, it can reduce systemic side effects and can also increase the dose until a maximum therapeutic effect is obtained. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (3)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. 5-amino-2- (β-D-galactopyranosyloxy) -benzoic acid or 5-amino-2- (α-D-galactopyranosyloxy) benzoic acid or a pharmaceutically acceptable salt thereof.
2. 2. A pharmaceutical composition characterized in that it comprises as an active ingredient 5-amino-2- (β-D-galactopyranosyloxy) benzoic acid or 5-amino-2- (α-D-galactopyranosyloxy) benzoic acid or a pharmaceutically acceptable salt thereof.
3. 3. A therapeutic agent for ulcerative colitis characterized in that it comprises as an active ingredient acid 5-amino-2- (β-D-galactopyranosyloxy) benzoic acid, 5-amino-2- (aD-galactopyranosyloxy) benzoic acid or 5-amino-2- (β-D-glucopyranosyloxy) benzoic acid or a pharmaceutically acceptable salt of the same.