Abstract:
In the course of developing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide (compound A), there are the multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. For solving these problems, we made examination focusing on the kind of the salt and, as a result, found that 1) benzenesulfonate of compound A does not decompose by light, humidity and other factors in a 1-week preliminary stability test (severe test), and has no problem in its storage stability, 2) a method of selectively producing two kinds of crystal forms of benzenesulfonate of compound A, and that 3) no mineral deposition in the stomach is observed even after a 4-week repeated oral administration.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of U.S. patent application Ser. No. 14/686,577, filed on Apr. 14, 2015, which is a divisional of U.S. patent application Ser. No. 13/384,590, filed on Jan. 17, 2012, which is a U.S. National Stage Application under U.S.C §371 of PCT Application Number PCT/JP2010/062071, filed on Jul. 16, 2010, which claims priority under U.S.C §119 to Japanese Patent Application No. 2009-169130, filed on Jul. 17, 2009, the entire disclosures of which are incorporated by reference herein. 
    
    
     TECHNICAL FIELD 
     The present invention relates to benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide that is highly safe, excellent in storage stability, and useful as a pharmaceutical, a crystal of the same, a crystal polymorph thereof, and production methods thereof. The present invention also relates to a pharmaceutical containing at least one selected from the group consisting of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, a crystal of the same, and a crystal polymorph thereof. 
     BACKGROUND ART 
     Usually, for pharmaceutical products, safety, quality, and stable supply are required, as well as a therapeutic efficacy on diseases. Therefore, for a compound serving as an active ingredient of a pharmaceutical product, little side effect, excellent storage stability of the compound in various conditions (light, temperature, humidity and so on), and ease of process control in a production stage of the pharmaceutical product (ease of handling) and the like are requested, and the compound will be a pharmaceutical product only when all of these requirements are satisfied. 
     On the other hand, U.S. Patent Publication No. 2007/0149574 (PTL 1) describes that 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide exhibits a cell proliferation inhibiting effect in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system, exhibits a tumor proliferation suppressing effect in a test system using a tumor-bearing mouse model, exhibits a paw edema suppressing effect in a test system using a rat adjuvant arthritis model, and exhibits a choroidal neovascularization inhibiting effect in a test system using a rat choroidal neovascularization model, and that, owing to these pharmacologic effects, 2-[[[2-[hydroxyacetyl)amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide is useful as a pharmaceutical, and is especially expected as a prophylactic or therapeutic agent for diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema and the like. PTL 1 also describes that 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide has a property of a light yellow solid. 
     However, PTL 1 lacks concrete description of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, a crystal of the same, a crystal polymorph thereof and production methods thereof, and lacks description and suggestion of a problem that 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide will cause mineral deposition in the stomach when it is orally administered repeatedly. 
     CITATION LIST 
     Patent Literature 
     
         
         PTL 1: U.S. Patent Publication No. 2007/0149574 
       
    
     SUMMARY OF INVENTION 
     Technical Problem 
     In the course of developing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide (hereinafter, also referred to as “compound A”) that is useful as a pharmaceutical, the present inventors found that there were the following multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A or its salt, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. 
     Solution to Problem 
     In light of the above, the present inventors made diligent effort focusing on the kind of the salt in compound A for solving all of the aforementioned problems 1) to 3). 
     As a result, the present inventors found that compound A formed a salt with methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. For examining the storage stability for these salts with compound A, a 1-week preliminary stability test (severe test) was executed. As a result, methanesulfonate of compound A decomposed by light, and p-toluenesulfonate decomposed by humidity, to cause a decrease in purity (decomposition) of about 1% to about 8%, demonstrating that these salts have great problems in storage stability. On the other hand, benzenesulfonate of compound A did not show a decrease in purity (decomposition) by light, humidity and other factors in a similar test, demonstrating that it has very high storage stability. 
     Focusing on the existence of a crystal polymorph of benzenesulfonate of compound A, the present inventors also found that benzenesulfonate of compound A has at least two crystal forms and found a method of producing the two crystal forms selectively. 
     Further, the present inventors found that mineral deposition in the stomach was observed in a rat 1-week repeated oral administration toxicity test (30 mg/kg) of compound A, whereas mineral deposition in the stomach was not observed in a rat 4-week repeated oral administration toxicity test (30 mg/kg) of benzenesulfonate of compound A, and accomplished the present invention. That is, the present invention is as follows. 
     The present invention is benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide. 
     The present invention also provides a method of producing benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the step of adding 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide to an organic solvent solution containing benzenesulfonic acid. 
     The present invention also provides a method of producing benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the step of adding at least either of benzenesulfonic acid and its hydrate to an organic solvent solution containing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide. 
     Here, the organic solvent is preferably a non-protonic polar solvent or cyclic ether. Further, as the non-protonic polar solvent, dimethylsulfoxide or N,N-dimethylformamide is more preferred, and as the cyclic ether, tetrahydrofuran is more preferred. 
     The present invention is a crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide. 
     The present invention also provides a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide having characteristic peaks at 4.4 angstroms, 3.8 angstroms and 2.3 angstroms as a d value of powder X-ray diffraction pattern. 
     The present invention also provides a method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the steps of: adding 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide to a good solvent solution containing benzenesulfonic acid; and sequentially adding a poor solvent to the reaction solution. 
     The present invention also provides a method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the steps of: adding at least either of benzenesulfonic acid and its hydrate to a good solvent solution containing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide; and sequentially adding a poor solvent to the reaction solution. 
     Here, the good solvent is preferably a non-protonic polar solvent, and more preferably dimethylsulfoxide or N,N-dimethylformamide. 
     Here, the poor solvent is preferably a solvent that substantially fails to dissolve benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide at room temperature, and is more preferably water, a lower alkyl alcohol, a lower alkyl ketone or a lower alkyl carboxylic acid ester, and the solvent is further preferably water, ethanol, acetone or ethyl acetate, and particularly preferably ethanol. 
     The present invention also provides a method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the step of adding a poor solvent to a good solvent solution containing benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide. 
     Here, the good solvent is preferably a non-protonic polar solvent, and more preferably dimethylsulfoxide or N,N-dimethylformamide. 
     Here, the poor solvent is preferably a solvent that substantially fails to dissolve benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide at room temperature, and is more preferably water, a lower alkyl alcohol, a lower alkyl ketone or a lower alkyl carboxylic acid ester, and the solvent is particularly preferably water, ethanol, acetone or ethyl acetate. 
     The present invention also provides a method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the steps of: adding and dissolving benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide in a warmed lower alcohol; and sequentially cooling the lower alcohol solution. 
     Here, the lower alcohol is preferably methanol or ethanol. 
     The present invention also provides a so-called β-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide having characteristic peaks at 8.1 angstroms, 6.8 angstroms, 4.1 angstroms and 4.0 angstroms as a d value of powder X-ray diffraction pattern. 
     The present invention also provides a method of producing a so-called β-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the step of adding 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide to a cyclic ether solution containing benzenesulfonic acid. 
     The present invention also provides a method of producing a so-called β-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide, including the step of adding at least either of benzenesulfonic acid and its hydrate to a cyclic ether solution containing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide. 
     Here, the cyclic ether is preferably tetrahydrofuran. 
     The present invention also provides a pharmaceutical containing as an active ingredient, at least one selected from the group consisting of any of the aforementioned benzenesulfonates, a crystal of the same, and a so-called α-form crystal and a so-called β-form crystal thereof. 
     The present invention also provides an oral or parenteral agent containing as an active ingredient, at least one selected from the group consisting of any of the aforementioned benzenesulfonates, a crystal of the same, and a so-called α-form crystal and a so-called β-form crystal thereof. 
     Advantageous Effects of Invention 
     The present invention provides benzenesulfonate of compound A that is highly safe, excellent in storage stability, and useful as a pharmaceutical, a crystal of the same, a crystal polymorph thereof, and production methods thereof. The present invention also provides a pharmaceutical containing at least one selected from the group consisting of benzenesulfonate of compound A, a crystal of the same, and a crystal polymorph thereof. 
    
    
     DESCRIPTION OF EMBODIMENTS 
     In the present invention, “2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl] methyl] thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide” (compound A) means a compound represented by the following chemical structure formula (1). 
     
       
                 
         
             
             
         
      
     
     Compound A can be produced according to, but not limited to, the production method described in U.S. Patent Application Publication No. 2007/0149574 specification. 
     In the present invention, “benzenesulfonate of compound A” means a compound formed by the above chemical structure formula (1) and benzenesulfonic acid. A constituting ratio between compound A and benzenesulfonic acid is preferably 1:1 or 1:2, and is particularly preferably 1:1. Further, when the constituting ratio between compound A and benzenesulfonic acid is 1:1, “benzenesulfonate of compound A” is desirably a compound represented by the following chemical structural formula (2). 
                                
(1) Production Method of Benzenesulfonate of Compound A
 
     Benzenesulfonate of compound A can be produced by: 
     (1a) adding compound A to an organic solvent solution containing benzenesulfonic acid, or 
     (1b) adding at least either of benzenesulfonic acid and its hydrate to an organic solvent solution containing compound A. 
     While the temperature at the time of executing (1a) or (1b) is not particularly limited insofar as salt formation progresses, it is executed preferably under ice cooling or at room temperature, and more preferably at 15 to 30° C. 
     The time of executing (1a) or (1b) is not particularly limited insofar as it is enough to allow progression of salt formation. 
     Further, benzenesulfonate of compound A generated in this operation can be isolated and/or purified by a widely used treatment method and/or purification method, for example, by using techniques such as concentration under reduced pressure, crystallization in water, an organic solvent and the like, filtration, washing, drying under reduced pressure and so on. 
     As the “organic solvent” in (1a) or (1b), any organic solvent capable of dissolving compound A may be used without any limitation, however, a non-protonic polar solvent or cycle ether is preferred. 
     As the “non-protonic polar solvent”, any polar solvent not having a proton-donating ability may be used without any limitation, and for example, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide and the like can be recited. Among these, dimethylsulfoxide or N,N-dimethylformamide is particularly preferred. 
     As the “cyclic ether”, any cyclic ether containing 1 to 6 carbon atom(s) and one or two oxygen atom(s) may be used without any limitation, and for example, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, [1,4]dioxane, oxepane, oxocane and the like are recited. Among these, tetrahydrofuran is particularly preferred. 
     (2) Production Method of so-Called α-Form Crystal of Benzenesulfonate of Compound A 
     A so-called α-form crystal of benzenesulfonate of compound A can be produced by: 
     (2a) adding compound A to a good solvent solution containing benzenesulfonic acid, followed by adding a poor solvent to the reaction solution, or 
     (2b) adding at least either of benzenesulfonic acid and its hydrate to a good solvent solution containing compound A, followed by adding a poor solvent to the reaction solution, or 
     (2c) adding a poor solvent to a good solvent solution containing benzenesulfonate of compound A, or 
     (2d) adding and dissolving benzenesulfonate of compound A in a warmed lower alcohol, followed by cooling the lower alcohol solution. 
     While the temperature at the time of executing (2a) or (2b) is not particularly limited insofar as salt formation progresses, it is executed preferably under ice cooling or at room temperature, and more preferably at 15 to 30° C. 
     While the temperature during and after the addition of the poor solvent in executing (2a), (2b) or (2c) is not particularly limited insofar as crystallization progresses, it is executed preferably at room temperature, and more preferably at 15 to 30° C. 
     While the warming in executing (2d) is not particularly limited insofar as it is such a degree of warming that allows (complete) dissolution of benzenesulfonate of compound A in a lower alcohol, the warming temperature is preferably 40 to 70° C., and more preferably 45 to 65° C. 
     While the cooling after the warming may be conducted at any temperature without any limitation insofar as crystallization progresses, it is preferably executed under ice cooling or at room temperature (allowing to cool), and more preferably at 15 to 30° C. 
     The reaction time in executing (2a) or (2b) is not particularly limited insofar as it is enough for the reaction to progress. 
     While the crystallization time after the addition of the poor solvent in executing (2a), (2b), (2c) or (2d) is not particularly limited insofar as crystallization progresses, it is executed preferably for 0.25 hours to 48 hours, and more preferably 3 hours to 24 hours. 
     Further, a so-called α-form crystal of benzenesulfonate of compound A generated in the reaction or the like can be isolated and/or purified by a widely used treatment method and/or purification method, for example, by using techniques such as concentration under reduced pressure, crystallization in water, an organic solvent and the like, filtration, washing, drying under reduced pressure and so on. 
     The “good solvent” in (2a), (2b) or (2c) means “an organic solvent capable of dissolving benzenesulfonate of compound A”, and preferably, a non-protonic polar solvent is recited, and particularly preferably, dimethylsulfoxide or N,N-dimethylformamide is recited. 
     Here, the “non-protonic polar solvent” is not particularly limited insofar as it is a polar solvent not having a proton donating ability, and for example, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoramide is recited, and among these, dimethylsulfoxide or N,N-dimethylformamide is preferred. 
     The “poor solvent” means a “solvent substantially not dissolving benzenesulfonate of compound A at room temperature”, and for example, water, a lower alcohol, a lower alkyl ketone or a lower alkyl carboxylic acid ester is recited, and among these, a lower alcohol is preferred. 
     Here, the “lower alcohol” means an alcohol having 1 to 6 carbon atom(s), and for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol is recited, and among these methanol or ethanol is preferred. 
     The “lower alkyl ketone” means an alkyl ketone having 1 to 13, preferably 1 to 7 carbon atom(s), and for example, acetone, methylethylketone or diethylketone is recited, and among these acetone is preferred. The “lower alkyl carboxylic acid ester” means an alkyl carboxylic acid ester having 1 to 13, preferably 1 to 7 carbon atom(s), and for example, ethyl acetate, methyl acetate or isopropyl acetate is recited, and among these ethyl acetate is preferred. 
     As to the ratio between the “good solvent” and the “poor solvent”, the ratio of the good solvent and the poor solvent may be appropriately selected within the range of 10:1 to 1:10 depending on the kinds of the good solvent and the poor solvent. For example, when the good solvent is dimethylsulfoxide and the poor solvent is water, the ratio of these is preferably in the range of 3:1 to 1:1, and more preferably in the range of 2:1. When the good solvent is dimethylsulfoxide and the poor solvent is ethanol, the ratio of these is preferably in the range of 1:3 to 1:7, more preferably in the range of 1:4 to 1:6, and particularly preferably 1:5. When the good solvent is dimethylsulfoxide and the poor solvent is acetone, the ratio of these is preferably in the range of 1:3 to 1:7, more preferably in the range of 1:4 to 1:6, and particularly preferably 1:5. When the good solvent is dimethylsulfoxide and the poor solvent is ethyl acetate, the ratio of these is preferably in the range of 1:2 to 1:6, more preferably in the range of 1:3 to 1:5, and particularly preferably 1:4. 
     In (2d), the “lower alcohol” means an alcohol having 1 to 6 carbon atom(s), and for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol is recited, and among these methanol or ethanol is preferred. 
     (3) Production Method of a so-Called β-Form Crystal of Benzenesulfonate of Compound A 
     A so-called β-form crystal of benzenesulfonate of compound A can be produced by: 
     (3a) adding compound A to a cyclic ether solution containing benzenesulfonic acid, or 
     (3b) adding at least either of benzenesulfonic acid and its hydrate to a cyclic ether solution containing compound A. 
     While the temperature at the time of executing (3a) or (3b) is not particularly limited insofar as salt formation progresses, it is executed preferably under ice cooling or at room temperature, and more preferably at 15 to 30° C. 
     The reaction time in executing (3a) or (3b) is not particularly limited insofar as it is enough for the reaction to progress. 
     Further, a so-called β-form crystal of benzenesulfonate of compound A generated in the reaction or the like can be isolated and/or purified by a widely used treatment method and/or purification method, for example, by using techniques such as concentration under reduced pressure, crystallization in water, an organic solvent and the like, filtration, washing, drying under reduced pressure and so on. 
     The “cyclic ether” in (3a) or (3b) is not particularly limited insofar as it is a cyclic ether capable of dissolving compound A and being a poor solvent with respect to benzenesulfonate of compound A, and cyclic ethers containing 2 to 6 carbon atom(s) and one or two oxygen atom(s) are recited. Preferably, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, [1,4]dioxane, oxepane, oxocane or the like are recited, and particularly preferably, tetrahydrofuran is recited. 
     While two forms of crystals called an α-form and a β-form exist as crystals of benzenesulfonate of compound A, crystal polymorphs other than these, if exist, are also involved in crystals of benzenesulfonate of compound A of the present invention. 
     In the following, benzenesulfonate of compound A, a crystal of the same and a crystal polymorph thereof (including a so-called α-form crystal and a so-called β-form crystal) are also referred to as a “present compound”. 
     While the present compound can absorb water and have adsorbed water, or become a hydrate when it is left still in atmospheric air or recrystallized, such a hydrate is also involved in the present invention. 
     Since the present compound exhibits a cell proliferation inhibiting effect in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system, exhibits a tumor proliferation suppressing effect in a test system using a tumor-bearing mouse model, exhibits a paw edema suppressing effect in a test system using a rat adjuvant arthritis model, and exhibits a choroidal neovascularization inhibiting effect in a test system using a rat choroidal neovascularization model, it is useful as a pharmaceutical, and is especially useful as a prophylactic or therapeutic agent for diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema and the like. The pharmaceutical is for use in a warm-blooded animal, and preferably for a human being. 
     When the present compound is used as a prophylactic or therapeutic drug for the aforementioned diseases, the present compound can be administered either orally or parenterally. As a dosage form, tablet, capsule, granule and powder are recited as oral agents, and injection, eye drop, nasal drop, transdermally absorbable agent, aerosol (including “inhalant”) and the like are recited as parenteral agents, and they may be formulated using widely used techniques. 
     For example, oral agents such as tablet, capsule, granule and powder can be prepared while using excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate and calcium hydrogen phosphate, lubricants such as stearic acid, magnesium stearate and talc, binders such as starch, hydroxypropyl cellulose, hypromellose and polyvinyl pyrrolidone, disintegrants such as carboxymethyl cellulose, low substitution degree hydroxypropyl cellulose and calcium citrate, coating agents such as hypromellose, hydroxymethyl cellulose, macrogol and silicone resin, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, flavoring agents such as sweetener, acidulant and flavor, and the like as necessary. 
     Further, parenteral agents such as injection and eye drop can be prepared while using isotonizing agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol and mannitol, buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium acetate, citric acid, glacial acetic acid and trometamol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate and polyoxyethylene hydrogenated castor oil, stabilizing agents such as sodium citrate and sodium edetate, preservatives such as benzalkonium chloride, paraben, benzethonium chloride, paraoxybenzoic acid ester, sodium benzoate and chlorobutanol, pH modifiers such as hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate and sodium hydrogen carbonate, soothing agents such as benzyl alcohol, thickening agents such as hypromellose, and the like as necessary. 
     A dosage of the present compound can be appropriately selected and used according to the symptom, age, dosage form and the like. For example, an oral agent may be typically administered in a dosage of 0.01 to 1000 mg, preferably 1 to 100 mg per day by a single dose or in several doses. An eye drop can be typically administered in a concentration of 0.0001 to 10% (w/v), preferably 0.01 to 5% (w/v) by a single dose or in several doses. 
     Hereinafter, production examples of the present compound, a storage stability test and a result of the same, a side effect verification test and a result of the same, and formulation examples will be described, however, it is to be noted that these examples are given for better understanding of the present invention and not for limiting the scope of the present invention. Hereinafter, “ 1 H-NMR” means “proton nuclear magnetic resonance”, “PXRD” means “powder X-ray diffraction”, “DSC” means “differential scanning calorimeter measurement”, “TGA” means “thermogravimetric apparatus”, and “RH” means “relative humidity”. 
     PRODUCTION EXAMPLES 
     Example 1 
     Production Method of Benzenesulfonate of Compound A 
     To compound A (200 mg) was added tetrahydrofuran (2 mL) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (85 mg) was added at the same temperature. After end of salt formation, the solvent was distilled off under reduced pressure. To the concentrated residue was added ethyl acetate, and the precipitated solid was collected by filtration, and dried under reduced pressure to obtain benzenesulfonate of compound A in white (171 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ) 
     δ 4.02 (s, 2H), 4.44 (s, 2H), 7.17 (dd, J=4.9, 1.5 Hz, 1H), 7.28-7.38 (m, 5H), 7.58-7.60 (m, 2H), 7.71 (d, J=1.2 Hz, 1H), 7.80-7.82 (m, 2H), 7.99 (dd, J=7.6, 1.8 Hz, 1H), 8.20 (d, J=5.2 Hz, 2H), 8.60 (dd, J=4.9, 1.8 Hz, 1H), 10.66 (s, 1H) 
     Example 2 
     Production Method 1 of Benzenesulfonate of Compound A (α Crystal) (Ethyl Acetate/DMSO) 
     To compound A (503 mg) was added dimethylsulfoxide (2.0 mL) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (207 mg) was added at the same temperature, and stirred for another 1.25 hours. Sequentially, ethyl acetate (15 mL) was added, and stirred for another 3.5 hours. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (510 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.05 (s, 2H), 4.47 (s, 2H), 7.28-7.38 (m, 7H), 7.58-7.60 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.01 (dd, J=7.6, 1.8 Hz, 1H), 8.16 (s, 1H), 8.24 (d, J=5.5 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.08 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 1                       Peak   Angle           Angstrom   2θ°                           d = 4.4627   19.878           d = 4.3709   20.300           d = 3.8408   23.139           d = 2.3377   38.477                        
TGA:
 
Endothermic peak: 206.2° C.
 
     Example 3 
     Production Method 2 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO) 
     To compound A (505 mg) was added dimethylsulfoxide (2.0 mL) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (200 mg) was added at the same temperature, and stirred for another 1.25 hours. Sequentially, ethanol (10 mL) was added, and stirred for another 2.5 hours. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (482 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.07 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.58-7.60 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.8 Hz, 1H), 8.15 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.32 (bs, 1H), 10.67 (s, 1H) 
     PXRD: 
                                 TABLE 2                       Peak   Angle           Angstrom   2θ°                           d = 4.4670   19.859           d = 4.3711   20.300           d = 3.8438   23.120           d = 2.3377   38.478                        
TGA:
 
Endothermic peak: 207.7° C.
 
     Example 4 
     Production Method 3 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO) 
     To benzenesulfonic acid monohydrate (388 g) was added dimethylsulfoxide (1650 g) at room temperature (internal temperature 28° C.). Sequentially, compound A (750 g) was added at the same temperature. After stirring for 2.0 hours at room temperature, the solution was filtered. Sequentially, to the filtrate was added ethanol (5938 g) and stirred for 2.0 hours at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (820 g). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.58-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.8, 1.8 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.59 (dd, J=5.0, 1.8 Hz, 1H), 10.40 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4579 
                 19.900 
               
               
                   
                 d = 4.3624 
                 20.340 
               
               
                   
                 d = 3.8405 
                 23.141 
               
               
                   
                 d = 2.3364 
                 38.500 
               
               
                   
                   
               
             
          
         
       
     
     Example 5 
     Production Method 4 of Benzenesulfonate of Compound A (α Crystal) (Methanol, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (99 mg) was added methanol (3 mL), and then stirred at an external temperature of 65° C. for 4 minutes. After confirming dissolution, the reaction was left still overnight at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (50 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ) 
     δ 4.12 (s, 2H), 4.52 (s, 2H), 7.30 (dd, J=4.6, 1.5 Hz, 1H), 7.31-7.34 (m, 4H), 7.38 (d, J=8.6 Hz, 2H), 7.47 (d, J=5.8 Hz, 1H), 7.60-7.62 (m, 2H), 7.81-7.83 (m, 2H), 8.05 (dd, J=7.6, 1.5 Hz, 1H), 8.12 (s, 1H), 10.68 (s, 1H), 10.83 (s, 1H) 
     Example 6 
     Production Method 5 of Benzenesulfonate of Compound A (α Crystal) (Ethanol, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (99 mg) was added ethanol (5 mL), and then stirred at an external temperature of 85° C. for 3 minutes. After confirming dissolution, the reaction was left still overnight at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (66 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ) 
     δ 4.11 (s, 2H), 4.52 (s, 2H), 7.30 (dd, J=4.6, 2.4 Hz, 1H), 7.31-7.34 (m, 4H), 7.38 (d, J=8.6 Hz, 2H), 7.44 (s, 1H), 7.60-7.61 (m, 2H), 7.81-7.83 (m, 2H), 8.05 (d, J=7.6 Hz, 1H), 8.12 (s, 1H), 10.67 (s, 1H), 10.83 (bs, 1H) 
     Example 7 
     Production Method 6 of Benzenesulfonate of Compound A (α Crystal) (Ethyl Acetate/DMSO, Leaving Still at Room Temperature)&gt; 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 11 minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added. After leaving still overnight at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (619 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.07 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.58 (dd, J=4.9, 1.8 Hz, 1H), 10.35 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 4                       Peak   Angle           Angstrom   2θ°                           d = 4.4665   19.861           d = 4.3670   20.319           d = 3.8408   23.138           d = 2.3399   38.440                        
TGA:
 
Endothermic peak: 207.2° C.
 
     Example 8 
     Production Method 7 of Benzenesulfonate of Compound A (α Crystal) (Ethyl Acetate/DMSO, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 6 minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added. After stirring for 4.5 hours at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (701 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.39 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 5                       Peak   Angle           Angstrom   2θ°                           d = 4.4627   19.879           d = 4.3673   20.318           d = 3.8437   23.121           d = 2.3366   38.495                        
TGA:
 
Endothermic peak: 209.2° C.
 
     Example 9 
     Production Method 8 of Benzenesulfonate of Compound A (α Crystal) (Ethyl Acetate/DMSO, Leaving Still Under Ice Cooling) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 6 minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added. After leaving still overnight under ice cooling (internal temperature 5° C.), the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (227 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.30-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.02 (d, J=6.4 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.59 (m, 1H), 10.36 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 6                       Peak   Angle           Angstrom   2θ°                           d = 4.4670   19.859           d = 4.3664   20.321           d = 3.8409   23.138           d = 2.3375   38.480                        
TGA:
 
Endothermic peak: 207.1° C.
 
     Example 10 
     Production Method 9 of Benzenesulfonate of Compound A (α Crystal) (Acetone/DMSO, Stirring at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After confirming dissolution, acetone (7.0 mL) was added. After stirring for 5.0 hours at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (629 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.8 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.39 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 7 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4628 
                 19.878 
               
               
                   
                 d = 4.3746 
                 20.283 
               
               
                   
                 d = 3.8378 
                 23.157 
               
               
                   
                 d = 2.3376 
                 38.480 
               
               
                   
                   
               
             
          
         
       
     
     Example 11 
     Production Method 10 of Benzenesulfonate of Compound A (α Crystal) (Acetone/DMSO, Leaving Still Under Ice Cooling) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After confirming dissolution, acetone (7.0 mL) was added. After leaving still overnight under ice cooling (internal temperature 5° C.), the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (224 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=8.9 Hz, 2H), 8.03 (dd, J=7.6, 1.5 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.37 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 8 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4712 
                 19.840 
               
               
                   
                 d = 4.3709 
                 20.300 
               
               
                   
                 d = 3.8472 
                 23.100 
               
               
                   
                 d = 2.3399 
                 38.440 
               
               
                   
                   
               
             
          
         
       
     
     Example 12 
     Production Method 11 of Benzenesulfonate of Compound A (α Crystal) (Water/DMSO, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 6 minutes. After confirming dissolution, water (0.8 mL) was added. After leaving still for 1 hour at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (928 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.5 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.36 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 9                       Peak   Angle           Angstrom   2θ°                           d = 4.4673   19.858           d = 4.3710   20.300           d = 3.8469   23.101           d = 2.3376   38.479                        
TGA:
 
Endothermic peak: 205.5° C.
 
     Example 13 
     Production Method 12 of Benzenesulfonate of Compound A (α Crystal) (Water/DMSO, Stirring at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After confirming dissolution, water (0.8 mL) was added. After stirring for 0.5 hours at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (910 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.8 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.40 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 10 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4662 
                 19.863 
               
               
                   
                 d = 4.3672 
                 20.318 
               
               
                   
                 d = 3.8439 
                 23.120 
               
               
                   
                 d = 2.3376 
                 38.479 
               
               
                   
                   
               
             
          
         
       
     
     Example 14 
     Production Method 13 of Benzenesulfonate of Compound A (α Crystal) (Water/DMSO, Leaving Still Under Ice Cooling) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (1.5 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After confirming dissolution, water (0.8 mL) was added. After leaving still overnight under ice cooling (internal temperature 7° C.), the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (927 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=8.9 Hz, 2H), 8.03 (dd, J=7.6, 1.5 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.41 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 11 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4628 
                 19.878 
               
               
                   
                 d = 4.3710 
                 20.300 
               
               
                   
                 d = 3.8407 
                 23.139 
               
               
                   
                 d = 2.3366 
                 38.496 
               
               
                   
                   
               
             
          
         
       
     
     Example 15 
     Production Method 14 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) were added dimethylsulfoxide (2.7 mL) and ethanol (6.0 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After leaving still overnight at room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (104 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.8 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=6.1 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.39 (bs, 1H), 10.66 (s, 1H) 
     TGA: 
     Endothermic peak: 210.1° C. 
     Example 16 
     Production Method 15 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO, Stirring at Room Temperature) 
     To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide (2.5 mL), and then stirred at an internal temperature of 50° C. for 5 minutes. After confirming dissolution, ethanol (3.0 mL) was added. After stirring at room temperature for 5.0 hours, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (71 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.5 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.40 (bs, 1H), 10.66 (s, 1H) 
     TGA: 
     Endothermic peak: 210.7° C. 
     Example 17 
     Production Method 16 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO, Leaving Still Under Ice Cooling) 
     To benzenesulfonate of compound A (1.0 g) were added dimethylsulfoxide (3.3 mL) and ethanol (6.0 mL), and then stirred at an internal temperature of 50° C. for 15 minutes. After leaving still overnight under ice cooling (internal temperature 4° C.), the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (301 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.29-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.59 (dd, J=4.9, 1.8 Hz, 1H), 10.37 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 12 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4665 
                 19.861 
               
               
                   
                 d = 4.3709 
                 20.301 
               
               
                   
                 d = 3.8438 
                 23.120 
               
               
                   
                 d = 2.3398 
                 38.441 
               
               
                   
                   
               
             
          
         
       
     
     Example 18 
     Production Method 17 of Benzenesulfonate of Compound A (α Crystal) (Ethanol/DMSO, Leaving Still at Room Temperature) 
     To benzenesulfonate of compound A (4.0 g) was added dimethylsulfoxide (9.0 mL), and then stirred at room temperature (internal temperature 25° C.) for 6 minutes. After confirming dissolution, ethanol (45 mL) was added. After stirring at room temperature for 1.0 hour, the precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (3.3 g). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.08 (s, 2H), 4.49 (s, 2H), 7.30-7.39 (m, 7H), 7.59-7.61 (m, 2H), 7.81 (d, J=9.2 Hz, 2H), 8.03 (dd, J=7.6, 1.5 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.40 (bs, 1H), 10.67 (s, 1H) 
     PXRD: 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 13 
               
               
                   
                   
               
               
                   
                 Peak 
                 Angle 
               
               
                   
                 Angstrom 
                 2θ° 
               
               
                   
                   
               
             
             
               
                   
                 d = 4.4705 
                 19.843 
               
               
                   
                 d = 4.3709 
                 20.300 
               
               
                   
                 d = 3.8499 
                 23.083 
               
               
                   
                 d = 2.3399 
                 38.440 
               
               
                   
                   
               
             
          
         
       
     
     Example 19 
     Production Method of Benzenesulfonate of Compound A (β Crystal) 
     To compound A (507 mg) was added tetrahydrofuran (5.0 mL) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (202 mg) was added at the same temperature, and stirred for another 1.5 hours. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain benzenesulfonate of compound A in white (591 mg). 
       1 H-NMR (500 MHz, DMSO-d 6 ): 
     δ 4.05 (s, 2H), 4.47 (s, 2H), 7.27-7.38 (m, 7H), 7.58-7.60 (m, 2H), 7.80 (d, J=9.2 Hz, 2H), 8.02 (dd, J=7.6, 1.8 Hz, 1H), 8.16 (s, 1H), 8.24 (d, J=5.5 Hz, 1H), 8.59 (dd, J=4.9, 1.5 Hz, 1H), 10.05 (bs, 1H), 10.66 (s, 1H) 
     PXRD: 
                                 TABLE 14                       Peak   Angle           Angstrom   2θ°                           d = 8.0767   10.945           d = 6.8137   12.982           d = 4.2876   20.699           d = 4.1260   21.519           d = 3.9623   22.420                        
TGA:
 
Endothermic peak: 205.5° C.
 
     In the analysis of PXRD in the foregoing [Production examples], copper radiation (40 kV/40 mA) was used as a radiation source, and measurement was conducted with the following scanning parameters: scan axis: 2θ/θ, range: 2.500-40.000°, scanning mode: continuous, sampling width: 0.020°, and scan speed: 4.000°/min. 
     As to the TGA analysis, about 5 mg of a sample was used, and each sample was scanned at 25.0 to 300.0° C. at a rate of 10.00° C./minute. At this time, a nitrogen gas was made to constantly flow in a crucible at a flow rate of 150.0 mL/minute. 
     &lt;Storage Stability Tests for Benzenesulfonate, Methanesulfonate and p-Toluenesulfonate of Compound A (1-Week Preliminary Stability Test)&gt; 
     (Test Method) 
     For benzenesulfonate, methanesulfonate and p-toluenesulfonate of compound A, after storing under the conditions of 40° C. 75% RH, 60° C. or light (1000 lux/hr), the content of each salt of compound A was measured by HPLC. The percentage of change, relative to the content before storage of 100%, was calculated. 
     (Test Result) 
                                         TABLE 15                       Storage    Benzene-    Methane-   p-toluene-           condition    sulfonate   sulfonate   sulfonate                           40° C. 75% RH/1 week    100.0%   99.8%   92.3%           60° C./1 week   100.0%   99.9%   99.3%           1000 lux/hr, 1 week   100.0%   99.1%   99.8%                        
&lt;Side Effect Verification Test (Rat 1-Week Repeated Oral Administration Toxicity Test of Compound A (Free Body) and Rat 4-Week Repeated Oral Administration Toxicity Test of Benzenesulfonate of Compound A)&gt;
 
1) Rat 1-week repeated oral administration toxicity test of compound A (free body) (Test and observation method)
 
i) To Crl:CD (SD) rat was orally administered compound A (10 mL/kg (body weight), 30 mL/kg (body weight)) suspended in a 1% methylcellulose liquid once a day for 7 days.
 
ii) After completion of the administration, the rat was exsanguinated to death under ether anesthesia, then the stomach was removed, fixed in a 10% neutral buffered formalin aqueous solution, and then stained with hematoxylin-eosin to prepare a specimen, and the change in the stomach was observed histopathologically.
 
2) Rat 4-week repeated oral administration toxicity test of benzenesulfonate of compound A
 
(Test and Observation Method)
 
i) To Crl:CD (SD) rat was orally administered benzenesulfonate of compound A (10 mL/kg (body weight), 30 mL/kg (body weight)) suspended in a 1% methylcellulose liquid once a day for 4 weeks.
 
ii) After completion of the administration, the rat was exsanguinated to death under ether anesthesia, then the stomach was removed, fixed in a 10% neutral buffered formalin aqueous solution, and then stained with hematoxylin-eosin to prepare a specimen, and the change in the stomach was observed histopathologically.
 
(Test Result)
 
     In contrast to compound A for which mineral deposition in the stomach was observed after 1-week repeated oral administration, mineral deposition in the stomach was not observed even after 4-week repeated oral administration for benzenesulfonate of compound A. 
     FORMULATION EXAMPLES 
     Representative formulation examples of the present compound will be shown below. 
     Prescription Example 1 
     Tablet (in 100 mg) 
     
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Present compound 
                 1 
                 mg 
               
               
                   
                 Lactose 
                 66.4 
                 mg 
               
               
                   
                 Corn starch 
                 20 
                 mg 
               
               
                   
                 Carboxymethyl cellulose calcium 
                 6 
                 mg 
               
               
                   
                 Hydroxypropyl cellulose 
                 4 
                 mg 
               
               
                   
                 Magnesium stearate 
                 0.6 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
     By appropriately varying the kind and/or the amount of the present compound and/or the additives, a desired tablet can be obtained. Such a tablet can be coated with a coating agent (for example, normal coating agents such as hypromellose, macrogol and silicone resin) to obtain an intended coated tablet. 
     Prescription Example 2 
     Capsule (in 150 mg)) 
     
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Present compound 
                  5 mg 
               
               
                   
                 Lactose 
                 145 mg 
               
               
                   
                   
               
             
          
         
       
     
     By appropriately varying the mixing ratio of the present compound and lactose, a desired capsule can be obtained. 
     Prescription Example 3 
     Eye Drop (in 100 mL)) 
     
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Present compound 
                 100 mg 
               
               
                   
                 Sodium chloride 
                 900 mg 
               
               
                   
                 Polysorbate 80 
                 200 mg 
               
               
                   
                 Benzalkonium chloride 
                  5 mg 
               
               
                   
                 Sodium hydroxide 
                 quantum libet 
               
               
                   
                 Hydrochloric acid 
                 quantum libet 
               
               
                   
                 Sterilized purified water 
                 quantum libet 
               
               
                   
                   
               
             
          
         
       
     
     By appropriately varying the kind and/or the amount of the present compound and/or the additives, a desired eye drop can be obtained. 
     INDUSTRIAL APPLICABILITY 
     The present invention provides benzenesulfonate of compound A that is highly safe, excellent in storage stability, and useful as a pharmaceutical, a crystal of the same, a crystal polymorph thereof, and production methods thereof. The present invention also provides a pharmaceutical containing at least one selected from the group consisting of benzenesulfonate of compound A, a crystal of the same, and a crystal polymorph thereof.