Patent Publication Number: US-2007117842-A1

Title: Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same

Description:
TECHNICAL FIELD OF THE INVENTION  
      The present invention relates to a polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide and a process for the preparation of the same.  
     BACKGROUND ART  
      4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to show an excellent angiogenesis inhibitory action (WO 02/32872). 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide is also known to show a strong c-Kit kinase inhibitory action (95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004).  
     DISCLOSURE OF THE INVENTION  
      However, for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, there has been needed crystals of the compound expected to be more excellent in physical properties and stability than those obtained by conventional preparation processes, and a process to prepare the crystals easily and with a high purity.  
      Thus, an object of the present invention is to provide crystals of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide and a process for the preparation of the crystals.  
      In order to achieve the above object, the present invention provides polymorphs (1) to (10) below.  
      (1): A polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 15.75° in a powder X-ray diffraction.  
      (2): The polymorph (A) according to (1), wherein the polymorph further has diffraction peaks at diffraction angles (2θ±0.2°) of 9.98° and 11.01°in a powder X-ray diffraction.  
      (3): A polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having an absorption band at a wavenumber of 3452.3±2.5 cm −1  in an infrared absorption spectrum in potassium bromide.  
      (4): The polymorph (A) according to (1) or (2), wherein the polymorph has an absorption band at a wavenumber of 3452.3±2.5 cm −1  in an infrared absorption spectrum in potassium bromide.  
      (5): The polymorph (A) according to (3) or (4), wherein the polymorph further has an absorption band at a wavenumber of 1712.2±1.0 cm −1 .  
      (6): A polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 21.75° in a powder X-ray diffraction.  
      (7): The polymorph (B) according to (6), wherein the polymorph further has diffraction peaks at diffraction angles (2θ±0.2°) of 12.43° and 16.56° in a powder X-ray diffraction.  
      (8): A polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having an absorption band at a wavenumber of 1557.6±1.0 cm −1  in an infrared absorption spectrum in potassium bromide.  
      (9): The polymorph (B) according to (6) or (7), wherein the polymorph has an absorption band at a wavenumber of 1557.6±1.0 cm −1  in an infrared absorption spectrum in potassium bromide.  
      (10): The polymorph (B) according to (8) or (9), wherein the polymorph further has an absorption band at a wavenumber of 1464.4±1.0 cm −1  .  
      The present invention also provides processes (11) to (28) for preparing a polymorph below.  
      (11): A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (1) to (5), comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which may be in the form of a crystal or not, in a good organic solvent, followed by rapid admixing with a poor solvent.  
      (12): A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (1) to (5), comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent with stirring, followed by admixing with a poor solvent in such a way that the resultant crystals precipitate when the stirring is stopped.  
      (13): A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (1) to (5), comprising a step of reacting 7-methoxy-4-chloro-quinoline-6-carboxamide with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea in the presence of a base in a good organic solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, followed by rapid admixing with a poor solvent.  
      (14): The process for the preparation according to any one of (11) to (13), wherein the poor solvent is admixed rapidly within 10 minutes.  
      (15): A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (6) to (10), comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which may be in the form of a salt or not, in a good organic solvent, followed by slow admixing with a poor solvent.  
      (16): A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (6) to (10), comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent with stirring, followed by admixing with a poor solvent in such a way that the resultant crystals diffuse when the stirring is stopped.  
      (17): A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (6) to (10), comprising a step of reacting 7-methoxy-4-chloro-quinoline-6-carboxamide with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea in the presence of a base in a good organic solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, followed by slow admixing with a poor solvent.  
      (18): The process for the preparation according to any one of (15) to (17), wherein the poor solvent is admixed slowly in 1 hour or more.  
      (19): A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (6) to (10), comprising a step of heating a polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 15.75° in a powder X-ray diffraction, in suspension in a mixed solvent of a good organic solvent for the polymorph and a poor solvent for the polymorph.  
      (20): The process for the preparation according to (19), wherein the polymorph (A) is a polymorph further having diffraction peaks at diffraction angles (2θ±0.2°) of 9.98° and 11.01° in a powder X-ray diffraction.  
      (21): A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to any one of (6) to (10), comprising a step of heating a polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having an absorption band at a wavenumber of 3452.3±2.5 cm −1  in an infrared absorption spectrum in potassium bromide, in suspension in a mixed solvent of a good organic solvent for the polymorph and a poor solvent for the polymorph.  
      (22): The process for the preparation according to (19) or (20), wherein the polymorph (A) is a polymorph having an absorption band at a wavenumber of 3452.3±2.5 cm −1  in an infrared absorption spectrum in potassium bromide.  
      (23): The process for the preparation according to (21) or (22), wherein the polymorph (A) is a polymorph further having an absorption band at a wavenumber of 1712.2±1.0 cm −1 .  
      (24): The process for the preparation according to any one of (11) to (23), wherein the good organic solvent is dimethylsulfoxide, dimethylimidazolidinone, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, acetic acid, sulforane, or a mixed solvent of at least two of the foregoing.  
      (25): The process for the preparation according to any one of (11) to (23), wherein the poor solvent is water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol, or a mixed solvent of at least two of the foregoing.  
      (26): The process for the preparation according to (13), (14), (17) or (18), wherein the base is potassium t-butoxide, cesium carbonate or potassium carbonate.  
      The present invention also provides the followings.  
      (27): A prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (28): An angiogenesis inhibitor, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (29): An anti-tumor agent, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (30): The anti-tumor agent according to (29), wherein the tumor is a pancreatic cancer, a gastric cancer, a colon cancer, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a brain tumor, a blood cancer or an ovarian cancer.  
      (31): A therapeutic agent for angioma, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (32): A cancer metastasis inhibitor, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (33): A therapeutic agent for retinal neovascularization, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (34): A therapeutic agent for diabetic retinopathy, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (35): A therapeutic agent for an inflammatory disease, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (36): The therapeutic agent for an inflammatory disease according to (35), wherein the inflammatory disease is deformant arthritis, rheumatoid arthritis, psoriasis or delayed hypersensitivity reaction.  
      (37): A therapeutic agent for atherosclerosis, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (38): A prophylactic or therapeutic method for a disease for which angiogenesis inhibition is effective, comprising administering to a patient, a pharmacologically effective dose of the polymorph according to any one of (1) to (10).  
      (39): Use of the polymorph according to any one of (1) to (10) for the manufacture of a prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective.  
      The present invention also provides the followings.  
      (40): A c-Kit kinase inhibitor comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (41): An anti-cancer agent for treating a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (42): The anti-cancer agent according to (41), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, mast cell leukemia, a small cell lung cancer, GIST, a testicular cancer, an ovarian cancer, a breast cancer, a brain cancer, neuroblastoma or a colorectal cancer.  
      (43): The anti-cancer agent according to (41), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, a small cell lung cancer or GIST.  
      (44): The anti-cancer agent according to (41), which is applied to a patient for which a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is identified.  
      (45): A therapeutic agent for mastocytosis, allergy or asthma, comprising as an active ingredient, the polymorph according to any one of (1) to (10).  
      (46): A therapeutic method for a cancer, comprising administering to a patient suffering from a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase, a pharmacologically effective dose of the polymorph according to any one of (1) to (10).  
      (47): The method according to (46), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, mast cell leukemia, a small cell lung cancer, GIST, a testicular cancer, an ovarian cancer, a breast cancer, a brain cancer, neuroblastoma or a colorectal cancer.  
      (48): The method according to (46), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, a small cell lung cancer or GIST.  
      (49): A therapeutic method for a cancer, comprising the steps of: extracting cancer cells from a patient suffering from a cancer; confirming that the cancer cells are expressing excessive c-Kit kinase or a mutant c-Kit kinase; and  
      administering to the patient a pharmacologically effective dose of the c-Kit kinase inhibitor according to (40).  
      (50): A therapeutic method for mastocytosis, allergy or asthma, comprising administering to a patient suffering from the disease, a pharmacologically effective dose of the c-Kit kinase inhibitor according to (40).  
      (51): A method for inhibiting the c-Kit kinase activity, comprising applying to a cell expressing excessive c-Kit kinase or a mutant c-Kit kinase, a pharmacologically effective dose of the c-Kit kinase inhibitor according to (40).  
      (52): Use of the c-Kit kinase inhibitor according to (40) for the manufacture of an anti-cancer agent for treating a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase.  
      (53): The use according to (52), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, mast cell leukemia, a small cell lung cancer, GIST, a testicular cancer, an ovarian cancer, a breast cancer, a brain cancer, neuroblastoma or a colorectal cancer.  
      (54): The use according to (52), wherein the cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is acute myelogenous leukemia, a small cell lung cancer or GIST.  
      (55): Use of the c-Kit kinase inhibitor according to (40) for the manufacture of a therapeutic agent for mastocytosis, allergy or asthma.  
      The polymorph (A) according to the invention has such an advantage that filtration is easy after crystallization.  
      Also, the polymorph (B) according to the invention can be advantageously used to prepare 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide with a high purity.  
      Further, the polymorph (A) has a property that it undergoes crystal transition to the polymorph (B) by suspending the polymorph (A) in a solvent, and the polymorph (B) has an advantage that it can be obtained stably in a production process. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 1a.  
       FIG. 2  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 1b.  
       FIG. 3  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 1c.  
       FIG. 4  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 2a.  
       FIG. 5  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 2b.  
       FIG. 6  is a figure illustrating a powder X-ray diffraction pattern of the crystals obtained in Example 2c.  
       FIG. 7  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 1a.  
       FIG. 8  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 1b.  
       FIG. 9  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 1c.  
       FIG. 10  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 2a.  
       FIG. 11  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 2b.  
       FIG. 12  is a figure illustrating an infrared absorption spectrum of the crystals obtained in Example 2c.  
       FIG. 13  is a figure showing the results of hygroscopicity of the crystals obtained in Example 1d by microbalance method.  
       FIG. 14  is a figure showing the results of hygroscopicity of the crystals obtained in Example 2d by microbalance method.  
       FIG. 15  is a figure showing the results of immunoblot of phosphorylated c-Kit kinase by SCF stimulation.  
       FIG. 16  is a graph showing the relationship between the number of days elapsed after transplantation and tumor volume when H526 was transplanted to a nude mouse.  
       FIG. 17  is a figure showing the results of the immunoblot of phosphorylated c-Kit kinase, c-Kit kinase and β-actin when H526 was transplanted to a nude mouse. 
    
    
     BEST MODE FOR CARRYING OUT THE INVENTION  
      The polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide of the invention can be produced, for example, by the following method.  
      4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide is dissolved in a suitable dissolvable organic solvent (such as dimethylsulfoxide, dimethylimidazolidine, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, acetic acid or sulforane), followed by rapid (for example, within 10 minutes) admixing with an undissolvable solvent (such as water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol, or a mixed solvent thereof) to produce the polymorph (A). The crystals may appear when the undissolvable solvent is admixed rapidly, and the crystals precipitate in the solvent when the stirring is stopped.  
      Alternatively, the polymorph (A) can be also obtained by reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea with 7-methoxy-4-chloro-quinoline-6-carboxamide in an organic solvent (such as dimethylsulfoxide (DMSO), dimethylimidazolidinone, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, or sulforane) in the presence of a base (such as potassium t-butoxide, cesium carbonate, or potassium carbonate), followed by rapid (for example, within 10 minutes) admixing with an undissolvable solvent (such as water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol or a mixed solvent thereof).  
      More specifically, for example, to a mixture of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, 7-methoxy-4-chloro-quinoline-6-carboxamide (1 equivalent or more relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea) and potassium t-butoxide (1 equivalent or more relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea), is added 5- to 10-fold volume of DMSO relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea at room temperature, followed by heating to react at 55-75° C. with stirring for 20 hours or more. To the mixture is added 15-fold volume of an undissolvable solvent (20-50% acetone-water or 20-50% 2-propanol-water) relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea with heating and stirring at 60-65° C. within 8 minutes, then the crystals can appear. Preferably, seed crystals are added when the undissolvable solvent is added in order to allow the crystals to appear. The reaction mixture in which the crystals appeared is stirred at room temperature to 40° C. for 3 hours or more, and the crystals are filtered off to give the polymorph (A).  
      The polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide of the invention can be produced, for example, by the following method.  
      4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide can be dissolved in a suitable dissolvable organic solvent (such as DMSO, dimethylimidazolidine, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, acetic acid, or sulforane), followed by slow (for example, for 1 hour or more) admixing with an undissolvable solvent (such as water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol, or a mixed solvent thereof) to produce the polymorph (B). The crystals may appear when the undissolvable solvent is mixed slowly, and the crystals diffuse in the whole solvent when the stirring is stopped.  
      More specifically, for example, to 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide is added 4- to 5-fold volume of a dissolvable solvent (DMSO or 1-methyl-2-pyrrolidinone) relative to 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, followed by heating and stirring at 80° C. or more to dissolve the compound. To the reaction mixture is added 10- to 20-fold volume of an undissolvable solvent (isopropyl acetate, ethyl acetate, methanol, or isopropanol) relative to 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide over 30 minutes or more with heating and stirring at 65-85° C., then the crystals can appear. Preferably, seed crystals are added when the undissolvable solvent is added in order to allow the crystals to appear. The reaction mixture in which the crystals appeared is heated and stirred at 70° C. or higher for 30 minutes or more and further stirred at room temperature, and the crystals are filtered off to give the polymorph (B).  
      The polymorph (B) can be also produced by heating and suspending the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a mixed solvent of a dissolvable solvent and an undissolvable solvent.  
      Alternatively, the polymorph (B) can be also obtained by reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea with 7-methoxy-4-chloro-quinoline-6-carboxamide in an organic solvent (such as DMSO, dimethylimidazolidinone, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, or sulforane) in the presence of a base (such as potassium t-butoxide, cesium carbonate, or potassium carbonate), followed by slow (for example, for 30 minutes or more) admixing with an undissolvable solvent (such as water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol, or a mixed solvent thereof).  
      More specifically, for example, to a mixture of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, 7-methoxy-4-chloro-quinoline-6-carboxamide (1 equivalent or more relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea) and potassium t-butoxide (1 equivalent or more relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea), is added 5- to 10-fold volume of DMSO relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea at room temperature, followed by heating to react at 55-75° C. with stirring for 20 hours or more. To the mixture is added 15-fold volume of an undissolvable solvent (33% acetone-water) relative to 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea with heating and stirring at 60-65° C. for 2 hours or more, and the crystals can appear. The reaction mixture in which the crystals appeared is heated and stirred at 40° C. for 3 hours or more, and the crystals are filtered off to give the polymorph (B).  
      The dosage of a medicine according to the invention will differ depending on the severity of symptoms, patient age, gender and weight, administration form and type of disease, but administration may usually be from 100 μg to 10 g per day for adults, either at once or in divided doses.  
      There are no particular restrictions on the form of administration of a medicine according to the invention, and it may usually be administered orally or parenterally by conventional methods.  
      Common excipients, binders, glossy agents, coloring agents, taste correctors and the like, and if necessary stabilizers, emulsifiers, absorption promoters, surfactants and the like, may also be used for formulation, with inclusion of components ordinarily used as starting materials for formulation of pharmaceutical preparations by common methods.  
      Examples of such components which may be used include animal and vegetable oils (soybean oil, beef tallow, synthetic glycerides, etc.), hydrocarbons (liquid paraffin, squalane, solid paraffin, etc.), ester oils (octyldodecyl myristate, isopropyl myristate, etc.), higher alcohols (cetostearyl alcohol, behenyl alcohol, etc.), silicone resins, silicone oils, surfactants (polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylenepolyoxypropylene block copolymer, etc.), water-soluble polymers (hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone, methyl cellulose, etc.), alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propyleneglycol, dipropyleneglycol, sorbitol, etc.), sugars (glucose, sucrose, etc.), inorganic powders (silicic anhydride, aluminium magnesium silicate, aluminium silicate, etc.), purified water and the like. For pH adjustment there may be used inorganic acids (hydrochloric acid, phosphoric acid, etc.), alkali metal salts of inorganic acids (sodium phosphate, etc.), inorganic bases (sodium hydroxide, etc.), organic acids (lower fatty acids, citric acid, lactic acid, etc.), alkali metal salts of organic acids (sodium citrate, sodium lactate, etc.), and organic bases (arginine, ethanolamine, etc.). If necessary, preservatives, antioxidants and the like may also be added.  
     EXAMPLES  
      The present invention will be explained through the following examples, but these examples are in no way limitative on the invention.  
     Preparation Example 1  
     Preparation of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea  
     a) Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate  
     
       
         
         
             
             
         
       
     
      To a suspension of 4-amino-3-chlorophenol (23.7 g) suspended in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chlorocarbonate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 minutes, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred, and the organic phase was separated off. The organic phase was washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.  
       1 H-NMR (CDCl 3 ): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s).  
     b) 1-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea  
     
       
         
         
             
             
         
       
     
      To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) with cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, the mixture was stirred, and the organic phase was separated off. The organic phase was washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).  
       1 H-NMR (CDCl 3 ): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8H).  
     Preparation Example 2  
     Preparation of 7-methoxy-4-chloro-quinoline-6-carboxamide  
     a) 4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-ylidenemethyl)-amino]-2-methoxybenzoic acid ethyl ester  
     
       
         
         
             
             
         
       
     
      To a suspension of 4-amino-2-methoxybenzoic acid ethyl ester (CAS NO. 14814-06-3) (3.00 g) suspended in 2-propanol (15 mL) were added Meldrum&#39;s acid (2.44 g: 1.1 equivalent weight) and ethyl orthoformate (7.5 mL), followed by heating at 85° C. for 1 hour. The resultant precipitates were filtered off and washed with MTBE (methyl-tert-butylether) to give 4.92 g of titled compound (yield: 81%).  
       1 H-NMR (DMSO-d 6 ): 1.26 (3H, t, J=7.0 Hz), 1.60 (6H, s), 3.85 (3H, s), 4.20 (2H, q, J=7.0 Hz), 7.15 (1H, br d, J=8.4 Hz), 7.38 (1H, s), 7.69 (1H, d, J=8.4 Hz), 8.63 (1H, s).  
     b) 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid ethyl ester  
     
       
         
         
             
             
         
       
     
      4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-ylidenemethyl)-amino]-2-methoxybenzoic acid ethyl ester (3.55 g) was suspended in Dawtherm (10.7 mL), and the suspension was heated in an oil bath at 200° C. for 50 minutes. After allowed to stand at room temperature, MTBE (10 mL) was added thereto, then the resultant precipitates were filtered off and dried under vacuum to give 1.56 g of the titled compound (yield: 63%).  
       1 H-NMR (DMSO-d 6 ): 1.29 (3H, t, J=7.2 Hz), 3.87 (3H, s), 4.25 (2H, q, J=7.2 Hz), 5.79 (1H, d, J=7.4 Hz), 7.01 (1H, s), 7.84 (1H, d, J=7.4 Hz), 8.38 (1H, s), 11.77 (1H, br s).  
     c) 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid  
     
       
         
         
             
             
         
       
     
      To a solution of 7-methoxy-4-oxo-1,4-dihydroquinone-6-carboxylic acid ethyl ester (120 mg) dissolved in ethanol (1 mL) was added a 25% aqueous sodium hydroxide solution (0.2 mL), and the stirring was continued at 65° C. for 1 hour. 6N-HCl (0.5 mL) was added thereto, then the resultant precipitates were filtered off, washed with water, and dried under vacuum to give 100 mg of the titled compound (yield: 94%).  
       1 H-NMR (DMSO-d 6 ): 4.87 (3H, s), 6.14 (1H, d, J=7.4 Hz), 7.04 (1H, s), 7.98 (1H, d, J=6.0 Hz), 8.40 (1H, s).  
     d) 7-methoxy-4-chloro-quinoline-6-carboxamide  
     
       
         
         
             
             
         
       
     
      To 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (2.0 g) were added thionyl chloride (10 mL) and a small amount of N,N-dimethylformamide, and the mixture was heated under reflux for 2 hours. The mixture was concentrated under vacuum, followed by azeotropic distillation twice with toluene to give 7-methoxy-4-chloro-quinoline-6-carbonyl chloride (2.7 g).  
      Subsequently, 7-methoxy-4-chloro-quinoline-6-carbonyl chloride (2.7 g) thus obtained was dissolved in tetrahydrofuran (150 mL), and the solution was cooled to 0° C. 30% aqueous ammonia (5 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water was added thereto, and the resultant mixture was extracted three times with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, and dried under vacuum to give the titled compound (1.35 g).  
       1 H-NMR (DMSO-d 6 ): 4.03 (3H, s), 7.56-7.66 (2H, m), 7.79 (1H, brs), 7.88 (1H, brs), 8.46-8.49 (1H, m), 8.78-8.82 (1H, m).  
     Preparation Example 3  
     Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide  
     
       
         
         
             
             
         
       
     
      To DMSO (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resultant solid was then filtered off to give 1.56 g of the titled compound (yield: 88%).  
       1 H-NMR (d 6 -DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz).  
     Example 1a  
     Preparation of polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide  
      Firstly, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea was obtained in a similar manner as Preparation Example 1, and 7-methoxy-4-chloro-quinoline-6-carboxamide was obtained in a similar manner as Preparation Example 2.  
      Then, to a mixture of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (114.9 g), 7-methoxy-4-chloro-quinoline-6-carboxamide (80.0 g) and potassium t-butoxide (56.9 g) was added DMSO (800 mL) at room temperature, and the mixture was heated and stirred at 55° C. for 20 hours and, then further at 60° C. for 4 hours. To the reaction mixture, 33% (v/v) acetone-water (165 mL) was added in 1 minute at 60° C. with stirring. Additional 33% (v/v) acetone water (1035 mL) was added dropwise over 7 minutes to allow the crystals to appear, followed by stirring at 40° C. for 19 hours. The crystals were filtered off, washed with 33% (v/v) acetone-water and acetone, and dried to give 131.9 g of yellowish brown granular crystal (the polymorph (A)).  
     Examples 1b, 1c and 1d  
      The polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was obtained in a similar manner as Example 1a.  
     Example 2a  
     Preparation of polymorph (B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide  
      Firstly, 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea was obtained in a similar manner as Preparation Example 1, and 7-methoxy-4-chloro-quinoline-6-carboxamide was obtained in a similar manner as Preparation Example 2.  
      Secondly, to a mixture of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (11.49 g), 7-methoxy-4-chloroquinoline-6-carboxamide (8.00 g) and potassium t-butoxide (5.69 g) was added DMSO (80 mL) at room temperature, and the mixture was heated and stirred at 60° C. for 25 hours. The reaction mixture was divided into four equal parts. To an aliquot was added dropwise 33% (v/v) acetone-water (10 mL) over 3 hours at 60° C. with stirring to allow the crystals to appear. Additional 33% (v/v) acetone-water (20 mL) was added dropwise over 1 hour, and the stirring was continued at 40° C. for 5 hours. The resultant crystals were filtered off, washed with 33% (v/v) acetone-water and acetone, and dried to give 3.22 g of white fibrous crystals (the polymorph (B)).  
     Examples 2b, 2c and 2d  
      A polymorph (B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was obtained in a similar manner as Example 2a.  
     Example 3  
     Preparation of polymorph (B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide  
      Firstly, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was obtained in a similar manner as Preparation Example 3.  
      Secondly, the resultant 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (42.7 g) was added to 1,3-dimethyl-2-imidazolidinone (425 mL) to dissolve at 84° C., and then isopropyl acetate (1000 mL) was added over 20 minutes. After stirring at 80° C. for 30 minutes and further at room temperature for 6 hours, the crystals were filtered off to give 41.1 g of the polymorph (B).  
     Example 4  
     Crystal Transition from the Polymorph (A) to the Polymorph (B)  
      To a mixed solvent of DMSO (1.7 mL) and 33% (v/v) acetone water (0.17, 0.34, 0.51 or 0.85 mL) was added 300 mg of the polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, and the mixture was heated and stirred at 60° C. for 3 hours, during which 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide did not dissolve and remained in suspension.  
      These suspensions were filtered to collect 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (184 to 266 mg). Evaluation of the forms of the resultant crystals demonstrated that crystal transition to the polymorph (B) occurred in every case.  
      In this connection, when 300 mg of the polymorph (A) was dissolved in DMSO (1.7 mL) followed by heating and stirring at 60° C. for 3 hours without adding 33% acetone-water, most of the polymorph (A) dissolved.  
     Comparative Example 1  
     Crystal Transition from the Polymorph (B) to the Polymorph (A)  
      To a mixed solvent of DMSO (1.7 mL) and 33% (v/v) acetone-water (0.17, 0.34, 0.51 or 0.85 mL), was added 300 mg of the polymorph (B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, and the mixture was heated and stirred at 60° C. for 3 hours, during which the 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide did not dissolve and remained in suspension.  
      These suspensions were filtered to collect 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (141 to 256 mg). Evaluation of the forms of the resultant crystals demonstrated that all of them remained the polymorph (B) to reveal that the transition from the polymorph (B) to the polymorph (A) does not occur under the aforementioned conditions.  
      In this connection, when 300 mg of the polymorph (B) was dissolved in DMSO (1.7 mL) followed by heating and stirring at 60° C. for 3 hours without adding 33% acetone-water, most of the polymorph (B) dissolved.  
      (Powder X-ray Diffraction Measurement)  
      Powder X-ray diffraction analysis of the crystals obtained in respective Examples was carried out according to the powder X-ray diffraction method as described in the Japanese Pharmacopoeia, General Tests under the following measurement conditions using about 100 mg of sample.  
      Apparatus: Geiger Flex RAD-3C manufactured by Rigaku Denki KK  
      X-ray: CuKα ray  
      Counter: Scintillation counter  
      Filter: monochromatic  
      Goniometer: horizontal goniometer  
      Applied Voltage: 40 kV  
      Charging current: 20 mA  
      Scan speed: 3°/min  
      Scan axis: 2θ 
      Scan range: 2θ=5-30° 
      Divergent slit: 1° 
      Scattering slit: 1° 
      Receiving slit: 0.15 mm  
      The powder X-ray diffraction patterns of the crystals obtained in Examples 1a-1c and 2a-2c are shown in  FIG. 1-6 , and peaks of the Diffraction angles (2θ) and intensities are shown in Tables 1-6. Further, the peaks of the diffraction angles (2θ) in respective Examples and the average values of the peaks are listed in Table 7.  
               TABLE 1                          SAMPLE: EXAMPLE 1a                                     PEAK       HALF           RELATIVE       NUMBER   2θ   WIDTH   D-VALUE   INTENSITY   INTENSITY                                             1   8.280   *****   10.6696   290   5       2   9.960   *****   8.8734   385   6       3   11.000   *****   8.0367   445   7       4   13.760   *****   6.4302   582   10       5   15.700   *****   6.6398   872   14       6   18.600   *****   4.7665   1860   31       7   19.260   *****   4.6046   3182   53       8   19.960   *****   4.4447   678   11       9   20.380   *****   4.3540   1642   27       10   21.020   *****   4.2229   552   9       11   22.060   *****   4.0261   398   7       12   22.420   *****   3.9622   800   13       13   23.480   *****   3.7857   6032   100       14   24.160   *****   3.6807   1432   24       15   24.580   *****   3.6187   1170   19       16   25.000   *****   3.5589   738   12       17   26.300   *****   3.3858   1528   26       18   26.940   *****   3.3068   705   12       19   28.600   *****   3.1186   772   13       20   28.900   *****   3.0869   628   10                  
 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 1b 
               
            
           
           
               
               
               
               
               
               
            
               
                 PEAK 
                   
                 HALF 
                   
                   
                 RELATIVE 
               
               
                 NUMBER 
                 2θ 
                 WIDTH 
                 D-VALUE 
                 INTENSITY 
                 INTENSITY 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 8.320 
                 ***** 
                 10.6184 
                 322 
                 6 
               
               
                 2 
                 10.000 
                 ***** 
                 8.8380 
                 418 
                 8 
               
               
                 3 
                 11.000 
                 ***** 
                 8.0367 
                 458 
                 8 
               
               
                 4 
                 13.800 
                 ***** 
                 6.4117 
                 792 
                 14 
               
               
                 5 
                 15.780 
                 ***** 
                 5.6114 
                 1095 
                 20 
               
               
                 6 
                 18.660 
                 ***** 
                 4.7513 
                 1822 
                 33 
               
               
                 7 
                 19.360 
                 ***** 
                 4.5810 
                 2932 
                 53 
               
               
                 8 
                 20.000 
                 ***** 
                 4.4359 
                 808 
                 15 
               
               
                 9 
                 20.420 
                 ***** 
                 4.3456 
                 1932 
                 35 
               
               
                 10 
                 21.040 
                 ***** 
                 4.2189 
                 558 
                 10 
               
               
                 11 
                 22.100 
                 ***** 
                 4.0189 
                 480 
                 9 
               
               
                 12 
                 22.480 
                 ***** 
                 3.9518 
                 820 
                 15 
               
               
                 13 
                 23.540 
                 ***** 
                 3.7762 
                 5522 
                 100 
               
               
                 14 
                 24.220 
                 ***** 
                 3.6717 
                 1185 
                 21 
               
               
                 15 
                 24.640 
                 ***** 
                 3.6100 
                 1062 
                 19 
               
               
                 16 
                 25.060 
                 ***** 
                 3.5505 
                 745 
                 13 
               
               
                 17 
                 26.340 
                 ***** 
                 3.3808 
                 1502 
                 27 
               
               
                 18 
                 26.980 
                 ***** 
                 3.3020 
                 780 
                 14 
               
               
                 19 
                 28.640 
                 ***** 
                 3.1143 
                 810 
                 15 
               
               
                 20 
                 28.980 
                 ***** 
                 3.0785 
                 525 
                 10 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 1c 
               
            
           
           
               
               
               
               
               
               
            
               
                 PEAK 
                   
                 HALF 
                   
                   
                 RELATIVE 
               
               
                 NUMBER 
                 2θ 
                 WIDTH 
                 D-VALUE 
                 INTENSITY 
                 INTENSITY 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 8.360 
                 ***** 
                 10.5677 
                 425 
                 14 
               
               
                 2 
                 9.980 
                 ***** 
                 8.8556 
                 292 
                 10 
               
               
                 3 
                 11.040 
                 ***** 
                 8.0076 
                 650 
                 21 
               
               
                 4 
                 13.820 
                 ***** 
                 6.4025 
                 1318 
                 43 
               
               
                 5 
                 15.780 
                 ***** 
                 5.6114 
                 995 
                 32 
               
               
                 6 
                 18.700 
                 ***** 
                 4.7412 
                 1150 
                 37 
               
               
                 7 
                 19.380 
                 ***** 
                 4.5764 
                 3075 
                 100 
               
               
                 8 
                 20.020 
                 ***** 
                 4.4315 
                 738 
                 24 
               
               
                 9 
                 20.480 
                 ***** 
                 4.3330 
                 2658 
                 86 
               
               
                 10 
                 21.120 
                 ***** 
                 4.2031 
                 782 
                 25 
               
               
                 11 
                 22.120 
                 ***** 
                 4.0153 
                 528 
                 17 
               
               
                 12 
                 22.520 
                 ***** 
                 3.9449 
                 1048 
                 34 
               
               
                 13 
                 23.580 
                 ***** 
                 3.7699 
                 2492 
                 81 
               
               
                 14 
                 24.280 
                 ***** 
                 3.6628 
                 718 
                 23 
               
               
                 15 
                 24.700 
                 ***** 
                 3.6014 
                 595 
                 19 
               
               
                 16 
                 25.140 
                 ***** 
                 3.5394 
                 940 
                 31 
               
               
                 17 
                 26.420 
                 ***** 
                 3.3707 
                 1215 
                 40 
               
               
                 18 
                 27.040 
                 ***** 
                 3.2948 
                 582 
                 19 
               
               
                 19 
                 28.680 
                 ***** 
                 3.1100 
                 710 
                 23 
               
               
                 20 
                 29.020 
                 ***** 
                 3.0744 
                 740 
                 24 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2a 
               
            
           
           
               
               
               
               
               
               
            
               
                 PEAK 
                   
                 HALF 
                   
                   
                 RELATIVE 
               
               
                 NUMBER 
                 2θ 
                 WIDTH 
                 D-VALUE 
                 INTENSITY 
                 INTENSITY 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 8.400 
                 ***** 
                 10.5175 
                 142 
                 5 
               
               
                 2 
                 10.520 
                 ***** 
                 8.4023 
                 362 
                 14 
               
               
                 3 
                 12.480 
                 ***** 
                 7.0867 
                 2390 
                 92 
               
               
                 4 
                 14.120 
                 ***** 
                 6.2671 
                 282 
                 11 
               
               
                 5 
                 16.620 
                 ***** 
                 5.3296 
                 2600 
                 100 
               
               
                 6 
                 17.340 
                 ***** 
                 5.1099 
                 262 
                 10 
               
               
                 7 
                 19.160 
                 ***** 
                 4.6284 
                 572 
                 22 
               
               
                 8 
                 21.000 
                 ***** 
                 4.2268 
                 295 
                 11 
               
               
                 9 
                 21.840 
                 ***** 
                 4.0661 
                 612 
                 24 
               
               
                 10 
                 23.640 
                 ***** 
                 3.7604 
                 440 
                 17 
               
               
                 11 
                 26.760 
                 ***** 
                 3.3287 
                 1112 
                 43 
               
               
                 12 
                 29.180 
                 ***** 
                 3.0579 
                 1340 
                 52 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2b 
               
            
           
           
               
               
               
               
               
               
            
               
                 PEAK 
                   
                 HALF 
                   
                   
                 RELATIVE 
               
               
                 NUMBER 
                 2θ 
                 WIDTH 
                 D-VALUE 
                 INTENSITY 
                 INTENSITY 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 8.300 
                 ***** 
                 10.6440 
                 228 
                 6 
               
               
                 2 
                 10.320 
                 ***** 
                 8.5646 
                 510 
                 11 
               
               
                 3 
                 12.400 
                 ***** 
                 7.1323 
                 4600 
                 100 
               
               
                 4 
                 13.980 
                 ***** 
                 6.3295 
                 388 
                 8 
               
               
                 5 
                 16.520 
                 ***** 
                 5.3616 
                 4555 
                 99 
               
               
                 6 
                 17.280 
                 ***** 
                 5.1275 
                 410 
                 9 
               
               
                 7 
                 19.040 
                 ***** 
                 4.6573 
                 852 
                 19 
               
               
                 8 
                 20.940 
                 ***** 
                 4.2388 
                 432 
                 9 
               
               
                 9 
                 21.700 
                 ***** 
                 4.0920 
                 1050 
                 23 
               
               
                 10 
                 23.540 
                 ***** 
                 3.7762 
                 585 
                 13 
               
               
                 11 
                 26.640 
                 ***** 
                 3.3434 
                 1592 
                 35 
               
               
                 12 
                 29.140 
                 ***** 
                 3.0620 
                 1785 
                 39 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2c 
               
            
           
           
               
               
               
               
               
               
            
               
                 PEAK 
                   
                 HALF 
                   
                   
                 RELATIVE 
               
               
                 NUMBER 
                 2θ 
                 WIDTH 
                 D-VALUE 
                 INTENSITY 
                 INTENSITY 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 8.320 
                 ***** 
                 10.6184 
                 240 
                 6 
               
               
                 2 
                 10.400 
                 ***** 
                 8.4989 
                 722 
                 19 
               
               
                 3 
                 12.420 
                 ***** 
                 7.1208 
                 3788 
                 100 
               
               
                 4 
                 14.000 
                 ***** 
                 6.3205 
                 492 
                 13 
               
               
                 5 
                 16.540 
                 ***** 
                 5.3552 
                 3642 
                 96 
               
               
                 6 
                 17.300 
                 ***** 
                 5.1216 
                 465 
                 12 
               
               
                 7 
                 19.100 
                 ***** 
                 4.6428 
                 1052 
                 28 
               
               
                 8 
                 20.900 
                 ***** 
                 4.2468 
                 318 
                 8 
               
               
                 9 
                 21.720 
                 ***** 
                 4.0883 
                 1078 
                 28 
               
               
                 10 
                 23.520 
                 ***** 
                 3.7794 
                 405 
                 11 
               
               
                 11 
                 26.700 
                 ***** 
                 3.3360 
                 1628 
                 43 
               
               
                 12 
                 29.100 
                 ***** 
                 3.0661 
                 1608 
                 42 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                   
               
               
                 Polymorph (A), 
                 Polymorph (B), 
               
               
                 diffraction angle 
                 diffraction angle 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Ex. 1a 
                 Ex. 1b 
                 Ex. 1c 
                 Ave. 
                 Ex. 2a 
                 Ex. 2b 
                 Ex. 2c 
                 Ave. 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 8.28 
                 8.32 
                 8.36 
                 8.32 
                 8.40 
                 8.30 
                 8.32 
                 8.34 
               
               
                 9.96 
                 10.00 
                 9.98 
                 9.98 
                 10.52 
                 10.32 
                 10.40 
                 10.41 
               
               
                 11.00 
                 11.00 
                 11.04 
                 11.01 
                 12.48 
                 12.40 
                 12.42 
                 12.43 
               
               
                 13.76 
                 13.80 
                 13.82 
                 13.79 
                 14.12 
                 13.98 
                 14.00 
                 14.03 
               
               
                 15.70 
                 15.78 
                 15.78 
                 15.75 
                 16.62 
                 16.52 
                 16.54 
                 16.56 
               
               
                 18.60 
                 18.66 
                 18.70 
                 18.65 
                 17.34 
                 17.28 
                 17.30 
                 17.31 
               
               
                 19.26 
                 19.36 
                 19.38 
                 19.33 
                 19.16 
                 19.04 
                 19.10 
                 19.10 
               
               
                 19.96 
                 20.00 
                 20.02 
                 19.99 
                 21.00 
                 20.94 
                 20.90 
                 20.95 
               
               
                 20.38 
                 20.42 
                 20.48 
                 20.43 
                 21.84 
                 21.70 
                 21.72 
                 21.75 
               
               
                 21.02 
                 21.04 
                 21.12 
                 21.06 
                 23.64 
                 23.54 
                 23.52 
                 23.57 
               
               
                 22.06 
                 22.10 
                 22.12 
                 22.09 
                 26.76 
                 26.64 
                 26.70 
                 26.70 
               
               
                 22.42 
                 22.48 
                 22.52 
                 22.47 
                 29.18 
                 29.14 
                 29.10 
                 29.14 
               
               
                 23.48 
                 23.54 
                 23.58 
                 23.53 
               
               
                 24.16 
                 24.22 
                 24.28 
                 24.22 
               
               
                 24.58 
                 24.64 
                 24.70 
                 24.64 
               
               
                 25.00 
                 25.06 
                 25.14 
                 25.07 
               
               
                 26.30 
                 26.34 
                 26.42 
                 26.35 
               
               
                 26.94 
                 26.98 
                 27.04 
                 27.99 
               
               
                 28.60 
                 28.64 
                 28.68 
                 28.64 
               
               
                 28.90 
                 28.98 
                 29.02 
                 28.97 
               
               
                   
               
            
           
         
       
     
      (Infrared Absorption Spectrum Measurement)  
      Infrared absorption spectrum measurement of the crystals obtained in respective Examples was carried out according to the potassium bromide tablet method in the infrared absorption spectrum measurement method as described in the Japanese Pharmacopoeia, General Tests by using FT/1R-620 (JASCO Corporation) with a measurement range of 4000-400 cm −1  and a resolution of 4 cm −1 .  
      The infrared absorption spectra of the crystals obtained in Examples 1a-1c and 2a-2c are shown in  FIG. 7-12 , respectively, and wave numbers of the absorption peaks and transmittance (% T) are shown in Tables 8-13, respectively. Further, the peaks of characteristic absorptions in respective Examples and the average values of respective peaks are listed in Table 14.  
               TABLE 8                          SAMPLE: EXAMPLE 1a                                                                 WAVE           WAVE           WAVE           WAVE           PEAK   NUMBER       PEAK   NUMBER       PEAK   NUMBER       PEAK   NUMBER       NUMBER   (cm −1 )   % T   NUMBER   (cm −1 )   % T   NUMBER   (cm −1 )   % T   NUMBER   (cm −1 )   % T                                                                     1   3931.18   45.9000   2   3902.25   44.2482   3   3882.97   45.5739   4   3870.43   45.0296       5   3853.08   43.8748   6   3839.58   44.4297   7   3820.29   45.3034   8   3801.01   46.0442       9   3749.90   44.2226   10   3735.44   43.9472   11   3723.87   46.3443   12   3711.33   46.0532       13   3690.12   46.1108   14   3674.69   44.0923   15   3648.66   43.7544   16   3629.37   44.6435       17   3617.80   44.4673   18   3586.95   43.2537   19   3566.70   41.4440   20   3451.96   22.3589       21   3352.64   18.1744   22   3195.47   31.8660   23   3003.59   40.9804   24   2941.88   45.5361       25   2361.41   49.8472   26   1908.22   59.1594   27   1868.68   59.3052   28   1844.58   58.8413       29   1792.51   58.7186   30   1771.30   57.8139   31   1712.48   25.6521   32   1698.02   36.3550       33   1664.27   8.0307   34   1624.73   26.2601   35   1583.27   16.5974   36   1523.49   7.8357       37   1488.78   27.5722   38   1474.31   23.5677   39   1447.31   18.5404   40   1422.24   25.7948       41   1396.21   20.3006   42   1373.07   19.2443   43   1343.18   22.5631   44   1292.07   20.8167       45   1251.58   23.4114   46   1232.29   17.1507   47   1186.97   14.2968   48   1164.79   25.7644       49   1140.69   33.1056   50   1127.19   31.5090   51   1063.55   32.8054   52   1015.34   44.9572       53   992.20   31.8739   54   909.27   27.5640   55   872.63   33.5440   56   857.20   34.3007       57   831.17   40.4874   58   790.67   44.8201   59   760.78   47.4970   60   737.64   47.7491       61   682.68   38.0041   62   645.07   36.1694   63   611.32   39.9503   64   592.04   37.6119       65   544.79   33.3718   66   471.51   39.3295   67   443.55   40.0536                  
 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 1b 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
               
               
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
               
               
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 3903.22 
                 62.7887 
                 2 
                 3854.04 
                 62.6193 
                 3 
                 3839.58 
                 63.0859 
                 4 
                 3749.90 
                 63.5221 
               
               
                 5 
                 3735.44 
                 63.3653 
                 6 
                 3711.33 
                 64.2147 
                 7 
                 3674.69 
                 60.8349 
                 8 
                 3648.66 
                 61.1385 
               
               
                 9 
                 3452.92 
                 23.9773 
                 10 
                 3352.64 
                 17.4978 
                 11 
                 3196.43 
                 36.6064 
                 12 
                 3004.55 
                 51.2164 
               
               
                 13 
                 2941.88 
                 57.8045 
                 14 
                 1908.22 
                 70.2357 
                 15 
                 1711.51 
                 29.3651 
                 16 
                 1664.27 
                 5.3748 
               
               
                 17 
                 1624.73 
                 29.4227 
                 18 
                 1584.24 
                 15.5256 
                 19 
                 1524.45 
                 6.6503 
                 20 
                 1475.28 
                 27.7752 
               
               
                 21 
                 1447.31 
                 19.1425 
                 22 
                 1422.24 
                 30.1585 
                 23 
                 1398.21 
                 22.5288 
                 24 
                 1374.03 
                 21.2650 
               
               
                 25 
                 1344.14 
                 25.0454 
                 26 
                 1292.07 
                 21.9457 
                 27 
                 1251.58 
                 25.5724 
                 28 
                 1232.29 
                 17.8466 
               
               
                 29 
                 1186.97 
                 14.1035 
                 30 
                 1165.76 
                 32.8256 
                 31 
                 1140.69 
                 43.4429 
                 32 
                 1128.15 
                 40.7376 
               
               
                 33 
                 1064.51 
                 41.2862 
                 34 
                 1015.34 
                 58.2909 
                 35 
                 992.20 
                 39.1965 
                 36 
                 910.24 
                 32.5256 
               
               
                 37 
                 872.63 
                 43.5868 
                 38 
                 858.17 
                 43.7942 
                 39 
                 832.13 
                 53.1289 
                 40 
                 812.85 
                 58.7989 
               
               
                 41 
                 791.64 
                 58.2784 
                 42 
                 761.74 
                 61.1435 
                 43 
                 737.64 
                 61.4664 
                 44 
                 683.64 
                 49.1766 
               
               
                 45 
                 646.04 
                 47.2793 
                 46 
                 611.32 
                 52.9664 
                 47 
                 592.04 
                 50.1626 
                 48 
                 545.76 
                 45.2944 
               
               
                 49 
                 472.47 
                 55.7279 
                 50 
                 443.55 
                 58.3037 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 1c 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
               
               
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
               
               
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 3902.25 
                 50.3617 
                 2 
                 3854.04 
                 50.1553 
                 3 
                 3839.58 
                 50.6571 
                 4 
                 3801.97 
                 51.7857 
               
               
                 5 
                 3749.90 
                 50.9984 
                 6 
                 3735.44 
                 50.8468 
                 7 
                 3711.33 
                 52.1525 
                 8 
                 3699.16 
                 52.0424 
               
               
                 9 
                 3673.73 
                 49.5143 
                 10 
                 3648.66 
                 49.7618 
                 11 
                 3629.37 
                 50.0407 
                 12 
                 3451.96 
                 24.3465 
               
               
                 13 
                 3350.71 
                 18.5556 
                 14 
                 3190.65 
                 32.4426 
                 15 
                 2983.34 
                 42.7174 
                 16 
                 1844.58 
                 69.0444 
               
               
                 17 
                 1772.26 
                 69.6456 
                 18 
                 1712.48 
                 31.6257 
                 19 
                 1684.27 
                 7.4802 
                 20 
                 1625.70 
                 28.1570 
               
               
                 21 
                 1585.20 
                 18.8340 
                 22 
                 1560.13 
                 25.9825 
                 23 
                 1523.49 
                 10.4464 
                 24 
                 1474.31 
                 26.1905 
               
               
                 25 
                 1447.31 
                 21.5116 
                 26 
                 1422.24 
                 30.2226 
                 27 
                 1396.21 
                 22.3728 
                 28 
                 1373.07 
                 21.8362 
               
               
                 29 
                 1344.14 
                 25.2179 
                 30 
                 1292.07 
                 23.7257 
                 31 
                 1251.58 
                 25.5881 
                 32 
                 1231.33 
                 18.8437 
               
               
                 33 
                 1186.97 
                 16.8881 
                 34 
                 1164.79 
                 28.9811 
                 35 
                 1139.72 
                 35.6581 
                 36 
                 1127.19 
                 34.1104 
               
               
                 37 
                 1063.55 
                 35.7793 
                 38 
                 1014.37 
                 49.3645 
                 39 
                 992.20 
                 36.2202 
                 40 
                 909.27 
                 32.4686 
               
               
                 41 
                 872.63 
                 38.5241 
                 42 
                 857.20 
                 36.1720 
                 43 
                 831.17 
                 44.3965 
                 44 
                 790.67 
                 49.3395 
               
               
                 45 
                 760.78 
                 53.9713 
                 46 
                 737.64 
                 54.8796 
                 47 
                 683.64 
                 43.5492 
                 48 
                 645.07 
                 42.0847 
               
               
                 49 
                 610.36 
                 46.1061 
                 50 
                 592.04 
                 44.2588 
                 51 
                 543.83 
                 39.1675 
                 52 
                 471.51 
                 48.7501 
               
               
                 53 
                 442.58 
                 51.2933 
                 54 
                 403.05 
                 62.2511 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2a 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
               
               
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
               
               
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 3947.57 
                 64.6510 
                 2 
                 3931.18 
                 64.2965 
                 3 
                 3902.25 
                 62.1879 
                 4 
                 3882.00 
                 63.6113 
               
               
                 5 
                 3870.43 
                 62.8534 
                 6 
                 3853.08 
                 61.1682 
                 7 
                 3839.58 
                 61.9789 
                 8 
                 3820.29 
                 62.9568 
               
               
                 9 
                 3801.01 
                 63.7021 
                 10 
                 3779.80 
                 65.4009 
                 11 
                 3749.90 
                 61.2031 
                 12 
                 3735.44 
                 60.7760 
               
               
                 13 
                 3723.87 
                 63.7629 
                 14 
                 3711.33 
                 62.9799 
                 15 
                 3689.18 
                 62.7534 
                 16 
                 3675.86 
                 61.5792 
               
               
                 17 
                 3648.66 
                 58.7798 
                 18 
                 3629.37 
                 59.1510 
                 19 
                 3586.95 
                 55.1412 
                 20 
                 3565.74 
                 51.9090 
               
               
                 21 
                 3339.14 
                 8.8546 
                 22 
                 3184.86 
                 24.4703 
                 23 
                 3099.05 
                 49.6037 
                 24 
                 3007.44 
                 54.1278 
               
               
                 25 
                 2979.48 
                 47.8851 
                 26 
                 2839.67 
                 62.5062 
                 27 
                 2377.80 
                 67.4773 
                 28 
                 2345.98 
                 68.3580 
               
               
                 29 
                 2311.27 
                 67.7863 
                 30 
                 1943.89 
                 67.1878 
                 31 
                 1868.68 
                 67.0682 
                 32 
                 1844.58 
                 66.9751 
               
               
                 33 
                 1828.19 
                 67.1858 
                 34 
                 1792.51 
                 65.1319 
                 35 
                 1771.30 
                 64.4117 
                 36 
                 1732.73 
                 60.9836 
               
               
                 37 
                 1662.34 
                 0.9623 
                 38 
                 1634.38 
                 12.8838 
                 39 
                 1591.95 
                 12.0549 
                 40 
                 1558.20 
                 7.5272 
               
               
                 41 
                 1524.45 
                 22.1174 
                 42 
                 1464.67 
                 8.5881 
                 43 
                 1429.96 
                 32.0119 
                 44 
                 1388.50 
                 23.6552 
               
               
                 45 
                 1370.18 
                 19.5405 
                 46 
                 1350.89 
                 13.8898 
                 47 
                 1296.89 
                 21.5407 
                 48 
                 1281.47 
                 24.8695 
               
               
                 49 
                 1255.43 
                 18.0553 
                 50 
                 1228.43 
                 10.5935 
                 51 
                 1193.72 
                 14.5053 
                 52 
                 1167.69 
                 43.1354 
               
               
                 53 
                 1127.19 
                 40.0860 
                 54 
                 1060.66 
                 38.5032 
                 55 
                 1042.34 
                 46.3845 
                 56 
                 997.02 
                 36.5950 
               
               
                 57 
                 916.02 
                 30.8092 
                 58 
                 874.56 
                 55.0132 
                 59 
                 850.45 
                 33.7215 
                 60 
                 819.60 
                 43.2136 
               
               
                 61 
                 792.60 
                 52.1763 
                 62 
                 752.10 
                 49.4830 
                 63 
                 728.00 
                 50.7867 
                 64 
                 686.53 
                 38.6977 
               
               
                 65 
                 647.96 
                 42.1516 
                 66 
                 626.75 
                 39.6482 
                 67 
                 594.93 
                 45.6731 
                 68 
                 579.50 
                 45.4091 
               
               
                 69 
                 565.04 
                 42.9857 
                 70 
                 474.40 
                 51.0301 
                 71 
                 455.12 
                 50.0223 
                 72 
                 417.51 
                 52.0934 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2b 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
               
               
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
               
               
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 3947.57 
                 66.9343 
                 2 
                 3931.18 
                 66.5212 
                 3 
                 3902.25 
                 63.8862 
                 4 
                 3882.00 
                 65.5681 
               
               
                 5 
                 3870.43 
                 64.6510 
                 6 
                 3853.08 
                 62.8065 
                 7 
                 3838.61 
                 63.5944 
                 8 
                 3820.29 
                 64.5792 
               
               
                 9 
                 3801.01 
                 85.3683 
                 10 
                 3780.76 
                 67.5582 
                 11 
                 3749.90 
                 62.4268 
                 12 
                 3735.44 
                 62.1397 
               
               
                 13 
                 3723.87 
                 65.4550 
                 14 
                 3711.33 
                 64.5822 
                 15 
                 3689.16 
                 64.4015 
                 16 
                 3674.89 
                 63.0108 
               
               
                 17 
                 3648.66 
                 59.9574 
                 18 
                 3628.41 
                 60.6478 
                 19 
                 3610.09 
                 59.7570 
                 20 
                 3586.95 
                 57.2073 
               
               
                 21 
                 3565.74 
                 54.0188 
                 22 
                 3339.14 
                 17.3207 
                 23 
                 3185.83 
                 35.9208 
                 24 
                 3008.41 
                 59.6548 
               
               
                 25 
                 2979.48 
                 56.3115 
                 26 
                 2839.67 
                 66.1140 
                 27 
                 2376.84 
                 68.7358 
                 28 
                 2345.98 
                 69.5194 
               
               
                 29 
                 2310.30 
                 68.8212 
                 30 
                 1942.93 
                 68.4156 
                 31 
                 1920.75 
                 68.6540 
                 32 
                 1868.68 
                 67.5680 
               
               
                 33 
                 1844.58 
                 67.4810 
                 34 
                 1828.19 
                 67.7038 
                 35 
                 1792.51 
                 65.9869 
                 36 
                 1771.30 
                 65.1128 
               
               
                 37 
                 1748.16 
                 63.1139 
                 38 
                 1732.73 
                 62.3721 
                 39 
                 1662.34 
                 3.5651 
                 40 
                 1835.34 
                 23.1958 
               
               
                 41 
                 1591.95 
                 21.1624 
                 42 
                 1557.24 
                 15.0986 
                 43 
                 1524.45 
                 27.1589 
                 44 
                 1464.67 
                 18.1794 
               
               
                 45 
                 1428.99 
                 40.2445 
                 46 
                 1395.25 
                 33.3128 
                 47 
                 1371.14 
                 28.8236 
                 48 
                 1349.93 
                 24.3173 
               
               
                 49 
                 1295.93 
                 30.3197 
                 50 
                 1281.47 
                 34.4593 
                 51 
                 1255.43 
                 27.4197 
                 52 
                 1229.40 
                 19.3922 
               
               
                 53 
                 1193.72 
                 22.4587 
                 54 
                 1167.69 
                 49.9615 
                 55 
                 1127.19 
                 48.2969 
                 56 
                 1061.62 
                 46.7331 
               
               
                 57 
                 1042.34 
                 53.3130 
                 58 
                 997.02 
                 45.1946 
                 59 
                 916.02 
                 39.5083 
                 60 
                 874.56 
                 58.2522 
               
               
                 61 
                 851.42 
                 43.2948 
                 62 
                 819.80 
                 50.6987 
                 63 
                 792.60 
                 56.7426 
                 64 
                 752.10 
                 54.6364 
               
               
                 65 
                 686.53 
                 44.8873 
                 66 
                 627.72 
                 46.8548 
                 67 
                 579.50 
                 49.8957 
                 68 
                 565.04 
                 48.7841 
               
               
                 69 
                 474.40 
                 53.2674 
                 70 
                 455.12 
                 53.3351 
                 71 
                 418.48 
                 55.7359 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                   
               
               
                 SAMPLE: EXAMPLE 2c 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
                   
                 WAVE 
                   
               
               
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
                   
                 PEAK 
                 NUMBER 
               
               
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
                 NUMBER 
                 (cm −1 ) 
                 % T 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 3947.57 
                 56.7484 
                 2 
                 3931.18 
                 56.2460 
                 3 
                 3902.25, 
                 53.0225 
                 4 
                 3882.00 
                 55.0310 
               
               
                 5 
                 3870.43 
                 53.9317 
                 6 
                 3853.08 
                 51.7187 
                 7 
                 3838.61 
                 52.6328 
                 8 
                 3820.29 
                 53.8496 
               
               
                 9 
                 3801.01 
                 54.8032 
                 10 
                 3780.76 
                 57.6637 
                 11 
                 3748.94 
                 51.2303 
                 12 
                 3735.44 
                 50.9972 
               
               
                 13 
                 3723.87 
                 55.0212 
                 14 
                 3711.33 
                 54.1190 
                 15 
                 3689.16 
                 53.9965 
                 16 
                 3674.69 
                 52.5972 
               
               
                 17 
                 3648.66 
                 49.5453 
                 18 
                 3628.41 
                 51.0640 
                 19 
                 3616.84 
                 50.4203 
                 20 
                 3586.95 
                 48.5140 
               
               
                 21 
                 3565.74 
                 45.5294 
                 22 
                 3545.49 
                 45.9023 
                 23 
                 3524.27 
                 44.3791 
                 24 
                 3339.14 
                 8.6318 
               
               
                 25 
                 3184.86 
                 23.5096 
                 26 
                 3099.05 
                 46.2331 
                 27 
                 3007.44 
                 50.4299 
                 28 
                 2979.48 
                 44.8418 
               
               
                 29 
                 2839.67 
                 57.4731 
                 30 
                 2376.84 
                 61.3115 
                 31 
                 2345.98 
                 62.1115 
                 32 
                 2310.30 
                 61.2994 
               
               
                 33 
                 1991.14 
                 62.1221 
                 34 
                 1942.93 
                 61.1286 
                 35 
                 1920.75 
                 61.6056 
                 36 
                 1868.68 
                 60.1388 
               
               
                 37 
                 1844.58 
                 60.0459 
                 38 
                 1828.19 
                 60.3761 
                 39 
                 1792.51 
                 58.1187 
                 40 
                 1771.30 
                 57.1056 
               
               
                 41 
                 1748.16 
                 54.6730 
                 42 
                 1732.73 
                 53.9627 
                 43 
                 1662.34 
                 1.0762 
                 44 
                 1635.34 
                 12.8451 
               
               
                 45 
                 1591.95 
                 12.0388 
                 46 
                 1557.24 
                 6.5300 
                 47 
                 1523.49 
                 20.4790 
                 48 
                 1463.71 
                 8.5892 
               
               
                 49 
                 1429.96 
                 30.2743 
                 50 
                 1388.50 
                 22.7410 
                 51 
                 1370.18 
                 19.2561 
                 52 
                 1349.93 
                 13.4266 
               
               
                 53 
                 1296.89 
                 20.8356 
                 54 
                 1281.47 
                 23.4625 
                 55 
                 1255.43 
                 17.1433 
                 56 
                 1226.43 
                 10.3828 
               
               
                 57 
                 1193.72 
                 13.9089 
                 58 
                 1167.69 
                 39.8446 
                 59 
                 1128.15 
                 37.4359 
                 60 
                 1064.51 
                 35.9921 
               
               
                 61 
                 1042.34 
                 42.9687 
                 62 
                 997.02 
                 33.7870 
                 63 
                 916.02 
                 28.8189 
                 64 
                 874.56 
                 49.6391 
               
               
                 65 
                 850.45 
                 31.1042 
                 66 
                 819.60 
                 39.4562 
                 67 
                 792.60 
                 46.6446 
                 68 
                 752.10 
                 44.1803 
               
               
                 69 
                 728.00 
                 44.6814 
                 70 
                 686.53 
                 32.5322 
                 71 
                 648.93 
                 38.0168 
                 72 
                 627.72 
                 35.8481 
               
               
                 73 
                 594.93 
                 40.6210 
                 74 
                 579.50 
                 40.0418 
                 75 
                 565.04 
                 38.4537 
                 76 
                 518.76 
                 43.5653 
               
               
                 77 
                 474.40 
                 44.1801 
                 78 
                 455.12 
                 43.1782 
                 79 
                 420.41 
                 45.1423 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                   
               
               
                 Polymorph (A), wave number (cm −1 ) 
                 Polymorph (B), wave number (cm −1 ) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Ex. 1a 
                 Ex. 1b 
                 Ex. 1c 
                 Ave. 
                 Ex. 2a 
                 Ex. 2b 
                 Ex. 2c 
                 Ave. 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 3451.96 
                 3452.92 
                 3451.96 
                 3452.28 
                 1558.20 
                 1557.24 
                 1557.24 
                 1557.56 
               
               
                 1712.48 
                 1711.51 
                 1712.48 
                 1712.16 
                 1464.67 
                 1464.67 
                 1463.71 
                 1464.35 
               
               
                   
               
            
           
         
       
     
      (Purity Test of the Polymorph (A))  
      In Example 1a, the purities of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide anterior and posterior to crystallization were measured according to the following method.  
      In Example 1a, a portion of the reaction mixture after being heated and stirred at 55° C. for 20 hours and further at 60° C. for 4 hours was collected, and it was subjected to HPLC as a sample anterior to crystallization. On the other hand, the polymorph (A) obtained in Example 1a was subjected to HPLC as a sample posterior to crystallization.  
      The conditions of HPLC were as follows.  
      Column: ODS column (Mightysil RP-18 GP, Kanto Kagaku KK; inner diameter 4.6 mm, column length 150 mm, particle size 3 μm)  
      Column temperature: 40° C. (using a column oven)  
      Mobile phase:  
      Solution A H 2 O:CH 3 CN:HClO 4 *=990:10:1 (v/v/v)  
      Solution B H 2 O:CH 3 CN:HClO 4 *=100:900:1 (v/v/v)  
      (*: 70% aqueous solution)  
      Eluted by the linear gradient shown in Table 15 
                           TABLE 15                                   time (minute)   B conc. (%)                                                    0   5           3   20           15   20           30   100                      
 
 Flow rate: 1.0 mL/min 
 
 Detection: UV detector (wavelength: 252 nm) 
 
      The contents (the ratio of peak areas) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides and impurities in the samples anterior and posterior to crystallization to the polymorph (A) are shown in Table 16.  
                                   TABLE 16                                   substance   P   Q   R                          anterior   1.26   3.65   92.4           posterior   0.49   not   97.6                      
 
      In Tables 16 and 17, P represents 7-methoxy-4-chloro-quinoline-6-carboxamide, Q represents 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, and R represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.  
      4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was 92.4% in purity anterior to crystallization, but 97.6% in purity posterior to crystallization to the polymorph (A), indicating that the crystallization improved the purity.  
      (Purity Test of the Polymorph (B))  
      In Example 2a, the purities of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide anterior and posterior to crystallization were measured according to the following method.  
      In Example 2a, a portion of the reaction mixture after being heated and stirred at 60° C. for 25 hours was collected, and it was subjected to HPLC as a sample anterior to crystallization. On the other hand, the polymorph (B) obtained in Example 2a was subjected to HPLC as a sample posterior to crystallization. The conditions of HPLC were the same as those above-described in the purity test for the polymorph (A).  
      The contents (the ratio of peak areas) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides and impurities in the samples anterior and posterior to crystallization to the polymorph (B) are shown in Table 17.  
                                   TABLE 17                                   substance   P   Q   R                          anterior   0.46   3.48   92.2           posterior   0.05   not   98.1                      
 
      4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was 92.2% in purity anterior to crystallization, but 98.1% in purity posterior to crystallization to the polymorph (B), indicating that the crystallization improved the purity. Also, the purity was higher compared with that of the polymorph (A), that is, 97.6%. This revealed that the crystallization operation to the polymorph (B) was superior to that to the polymorph (A) in the efficiency of removing the impurities.  
      (Hygroscopicity Test by a Desiccator Method)  
      The hygroscopicities of the crystals obtained in Examples 1d and 2d were evaluated by a desiccator method. The crystals were stored for 1 week under the conditions as shown in Table 18, and then appearance observation, powder X-ray diffraction measurement, and water content measurement were carried out. Weighing bottles (in opened caps) were used for containers, and MIR-552 (Sanyo) was used for a storage apparatus.  
                           TABLE 18                       condition   temperature   relative humidity   desiccator                  A   25° C.   75%   NaCl                   saturated       B   25° C.   93%   KNO 3                     saturated                  
 
      The powder X-ray diffraction analysis was carried out under the following conditions.  
      Apparatus: RINT2000 manufactured by Rigaku Denki KK  
      Sample holder: glass holder (diameter 10 mm)  
      Target: Cu  
      Detector: Scintillation counter  
      Tube voltage: 40 kV  
      Tube current: 200 mA  
      Slit: DS ½°, RS 0.3 mm, SS ½° 
      Scan speed: 2°/min  
      Step/sampling: 0.02° 
      Scan range: 5-40° 
      Goniometer: Vertical goniometer  
      Filter: not used  
      The water content was measured (by the Karl Fischer method) by using the following apparatus and reagents.  
      Apparatus: Moisture meter CA-06 (Mitsubishi Chemical)  
      Reagents:  
      Lactose monohydrate NF (Mallinckrodt)  
      Karl Fischer reagents:  
      Anode solution/Aquamicron AX (Mitsubishi Chemical)  
      Cathode solution/Aquamicron CXU (Mitsubishi Chemical)  
      The results of evaluating the hygroscopicities of the crystals obtained in Examples 1d and 2d are listed in Tables 19 and 20, respectively.  
                           TABLE 19                               water content   powder X-ray       condition   appearance   (wt %)   diffraction pattern                  prior to storage   light brown   1.0   A           powder       A   light brown   1.0   A           powder       B   light brown   1.2   A           powder                  
 
     
       
         
           
               
               
               
               
             
               
                 TABLE 20 
               
               
                   
               
               
                   
               
               
                   
                   
                 water content 
                 powder X-ray 
               
               
                 condition 
                 appearance 
                 (wt %) 
                 diffraction pattern 
               
               
                   
               
             
            
               
                 prior to storage 
                 pale brownish 
                 0.5 
                 B 
               
               
                   
                 white powder 
               
               
                 A 
                 pale brownish 
                 0.5 
                 B 
               
               
                   
                 white powder 
               
               
                 B 
                 pale brownish 
                 0.5 
                 B 
               
               
                   
                 white powder 
               
               
                   
               
            
           
         
       
     
      As is evident from the results shown in Tables 19 and 20, both of the crystals obtained in Examples 1d and 2d had no perceivable hygroscopicitiy and no perceivable crystal transition.  
      (Hygroscopicity Test by Microbalance Method)  
      The higroscopicities of the crystals obtained in Examples 1d and 2d were evaluated by microbalance method. An apparatus and conditions employed were as follows.  
      Apparatus: Integrated microbalance system MB 300W (VTI Co.)  
      Temperature: 25° C.  
      Relative humidity step: 5 to 95 by 5  
      Equilibrium Criteria: 0.0050 wt % (5 minutes)  
      Maximum equilibrium time: 120 minutes  
      Initial dry: on  
      The results of measuring the higroscopicities of the crystals obtained in Examples 1d and 2d by microbalance method are shown in  FIGS. 13 and 14 , respectively. As is seen from the results shown in these figures, within the range of 5-95% of relative humidity, the polymorph (A) gave a weight change of 1% and the polymorph (B) gave that of 1.5%. Both of the polymorphs, therefore, had no perceivable hygroscopisity.  
      (Solid Stability Test)  
      The solid stabilities of the crystal obtained in Examples 1d and 2d were evaluated. The crystals were stored for 1 month under the conditions as shown in Table 21, and then appearance observation, water content measurement (by the Karl Fischer method), purity test and residual ratio (percent) measurement by HPLC, and powder X-ray diffraction measurement were carried out. The water content measurement and the powder X-ray diffraction measurement were carried out by the same method as described in the hygroscopicity test by the dessiccator method. Further, the purity test and the residual ratio (percent) measurement by HPLC were carried out by the same method as described above, except for the condition that the column temperature was 35° C. In this connection, the residual ratio (percent) (measurement by HPLC) was defined as stated bellow by using the crystal stored under the condition C as the standard and its solution as the standard solution. 
 
Remaining percent (%)=[(Peak area of the sample solution)×(Weighed amount of the standard: in terms of a dehydrate (mg))]×100/[(Peak area of the standard solution)×(Weighed amount of the sample: in terms of a dehydrate (mg))]
 
                               TABLE 21                           temperature           storage       condition   etc.   container   cap   apparatus                  C   −20° C.   brown screw vial   closed   PU-1F* 1         D   25° C., 1000lx   shading with   closed   LT-120* 2                 aluminum foil,               quartz tube       E   25° C., 1000lx   quartz tube   closed   LT-120* 2         F   40° C., 75% RH   brown screw vial   open   LH21-       G   60° C.   brown screw vial   closed   DN-61* 3                   * 1 Tabai Espec KK            * 2 Nagano Science KK            * 3 Yamato Science KK             
 
      The results of evaluating solid stabilities of the crystals obtained in Examples 1d and 2d are listed in Tables 22 and 23, respectively.  
                                   TABLE 22                                           powder               water       remaining   X-ray               content   impurity   percent   diffraction       condition   appearance   (wt %)   (%)   (%)   pattern                  prior to   light brown   1.0   2.71   —   A       storage   powder       C   light brown   1.0   2.66   (100)      A           powder       D   light brown   0.7   2.67   103.3   A           powder       E   light brown   0.8   2.68   104.3   A           powder       F   light brown   1.2   2.65   102.3   A           powder       G   light brown   0.5   2.65   104.4   A           powder                  
 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 23 
               
               
                   
               
               
                   
               
               
                   
                   
                   
                   
                   
                 powder 
               
               
                   
                   
                 water 
                   
                 remaining 
                 X-ray 
               
               
                   
                   
                 content 
                 impurity 
                 percent 
                 diffraction 
               
               
                 condition 
                 appearance 
                 (wt %) 
                 (%) 
                 (%) 
                 pattern 
               
               
                   
               
             
            
               
                 prior to 
                 pale brownish 
                 0.5 
                 1.53 
                 — 
                 B 
               
               
                 storage 
                 white powder 
               
               
                 C 
                 pale brownish 
                 0.4 
                 1.55 
                 (100)    
                 B 
               
               
                   
                 white powder 
               
               
                 D 
                 pale brownish 
                 0.3 
                 1.54 
                 101.8 
                 B 
               
               
                   
                 white powder 
               
               
                 E 
                 pale brownish 
                 0.3 
                 1.55 
                 100.5 
                 B 
               
               
                   
                 white powder 
               
               
                 F 
                 pale brownish 
                 0.4 
                 1.54 
                 100.4 
                 B 
               
               
                   
                 white powder 
               
               
                 G 
                 pale brownish 
                 0.5 
                 1.53 
                 101.3 
                 B 
               
               
                   
                 white powder 
               
               
                   
               
            
           
         
       
     
      As is evident from the results shown in Tables 22-23, no change was observed in the polymorphs (A) and (B) under any storage conditions.  
      (Solubility Test)  
      The solubilities (pH 3) of the crystals obtained in Examples 1d and 2d were evaluated by the following method. About 3 mg of the crystals obtained in Examples 1d and 2d were weighed and each of them was put in a 10 mL screw-capped transparent test tube. 5 mL of a buffer solution (Britton Robinson buffer, pH 3.091, ionic strength I=0.3) was added to each of the test tubes to prepare the test solutions.  
      The test tubes were wrapped with aluminum foil to shield from light, and shaken by a shaker (MS-1 Iuchi Seieido) in the following conditions.  
      Temperature: 25-26° C. (a temperature in a laboratory)  
      Shaking frequency: 150 times/minute  
      Shaking time: 3 hours and 5 hours  
      Respective sample solutions after shaking were filtered (0.2 μM, Sample LCR13-LG, Millipore Co.), and each 1 mL of the initial filtrate was discarded. Each of accurately pipetted 1 mL of the filtrates was put in a 10 mL test tube, to which accurately pipetted 1 mL of a mixed solution of water/acetonitrile (1:1 (v/v)) was added to prepare a solution for the HPLC analysis.  
      The HPLC conditions were as follows.  
      Column: ODS column (Mightysil RP-18GP; inner diameter 4.6 mm, column length 150 mm, particle size 3 μm, manufactured by Kanto Kagaku KK)  
      Column temperature: 35° C.  
      Mobile phase:  
      Solution A H 2 O:CH 3 CN:HClO 4 *=990:10:1 (v/v/v)  
      Solution B H 2 O:CH 3 CN:HClO 4 *=100:900:1 (v/v/v)  
      (*: 70% aqueous solution)  
      Isocratic elution by B=20%  
      Flow rate: 1.0 mL/min  
      Detection: UV detector (wavelength: 252 nm)  
      A standard solution for the HPLC analysis were prepared as follows. About 10 mg of the crystals obtained in Example 2d was accurately weighed, to which a mixed solution of water/acetonitrile/ammonium acetate (100:100:0.1, v/v/w) was added to give accurate 100 mL to prepare a stock standard solution. Accurately pipetted 5 mL of the stock control solution was added with a mixed solution of water/acetonitrile/ammonium acetate (100:100:0.1, v/v/w) to give accurate 25 mL to prepare the standard solution for the HPLC analysis. Regarding a blank solution, a mixed solution of water/acetonitrile/ammonium acetate (100:100:0.1, v/v/w) was used.  
      The standard solution and respective filtrates were analyzed by HPLC to measure concentrations (mg/mL) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide in respective filtrates according to the following equation. 
 
Concentration (mg/mL)=(Concentration in the standard solution, mg/mL)×[(Peak area in each filtrate)×2/(Peak area in the standard solution)]
 
      The respective results of the solubility test for the crystals obtained in Examples 1d and 2d are listed in Table 24. The pH of the respective filtrates are listed in Table 25. As is evident from the results, there was no significant difference in the solubility at pH 3 between the polymorphs (A) and (B).  
                       TABLE 24                       shaking time   Example 1d   Example 2d                  3 hours   7.7 × 10 −2     6.2 × 10 −2         5 hours   7.1 × 10 −2     5.4 × 10 −2                   (mg/mL)             
 
     
       
         
           
               
               
               
             
               
                 TABLE 25 
               
               
                   
               
               
                   
               
               
                 shaking time 
                 Example 1d 
                 Example 2d 
               
               
                   
               
             
            
               
                 3 hours 
                 3.123 
                 3.109 
               
               
                 5 hours 
                 3.107 
                 3.106 
               
               
                   
               
            
           
         
       
     
      c-Kit kinase inhibition by 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was tested in the following Test Example 1 to 4.  
     Test Example 1  
     Effect on Cell Proliferation Stimulated by SCF  
      4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was tested for their effects on the proliferation of the small cell lung cancer cell line H-526 expressing c-Kit kinase (purchased from ATCC: CRL-5811).  
      4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was prepared similarly to the method described in Preparation Examples 1 to 3.  
      H-526 cells were cultured in a 5% CO 2  incubator (37° c.) using an RPMI1640 medium (Nissui Pharmaceutical Co., Ltd.) containing 10% FCS (purchased from Cell Culture Technologies). After culturing, H-526 cells were washed with PBS three times and were suspended in an RPMI1640 medium containing 0.1% BSA (Sigma Corporation) (hereinafter abbreviated as “BSA-RPMI1640”) at 1.0×10 5  cells/ml. Each 50 μl of this cell suspension was inoculated to each well of a round bottom 96-well plate, and the suspension was cultured in a 5% CO 2  incubator (37° c.) overnight. After culturing overnight, 50 μl of BSA-RPMI1640 containing 200 ng/ml SCF (R&amp;D Co., Ltd.) and 100 μl of BSA-RPMI1640 containing a diluted test substance (4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide) were added to each well.  
      On the 7th day after addition of the test substance, 20 μl of Cell Counting Kit-8 (Dojin Laboratories) was added to the well and was cultured in a 5% CO 2  incubator (37° c.) for about 2 hours. After color development, the absorbance of each well was determined using a MTP-32 plate reader (Colona Electric Co., Ltd.) at a measuring wavelength of 450 nm and at a reference wavelength of 660 nm. The absorbance of each well was subtracted by the absorbance of the well without addition of SCF, and then the ratio of the absorbance of the well with addition of the test substance to the ratio of the absorbance of the well without addition of the test substance was determined. This ratio was used to calculate the concentration of the test substance required for 50% inhibition of the cell proliferation (IC 50 ).  
      Consequently, IC 50  of 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was 9.46 nM. The compound inhibited the cell proliferation stimulated by SCF, and was considered to possess c-Kit kinase inhibitory activity. The IC 50  of the compound KRN633, which is described in Kazuo Kubo et al., 22nd Symposium on Medicinal Chemistry, Abstracts, pp. 275-277, 2P-320, 2002, proved to be 301 nM and the compound showed only weak activity as compared to 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. STI571 known as a c-Kit kinase inhibitor showed IC 50  of 190 nM.  
     Example 2  
     Effect on c-Kit Kinase Phosphorylation by SCF Stimulation)  
      4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide was tested for its effect on the phosphorylation of the c-Kit kinase molecule by SCF stimulation in the small cell lung cancer cell line H-526 expressing c-Kit kinase.  
      H-526 cells were cultured in a 5% CO 2  incubator (37° c.) using an RPMI1640 medium containing 10% FCS. After culturing, H-526 cells were washed with PBS three times and were suspended in a BSA-RPMI1640 medium at 5.0×10 5  cells/ml. Each 1 ml of this cell suspension was inoculated to the well of a 24-well plate and the suspension was cultured in a 5% CO 2  incubator (37° c.) for 6 hours. After 6-hours culturing, 1 ml of BSA-RPMI1640 containing a diluted test substance (4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide) was added to each well and culturing was carried out in a 5% CO 2  incubator (37° c.) for 1 hour. Additional culturing was then carried out in a 5% CO 2  incubator (37° c.) for 5 minutes after the addition of 10 μl of SCF (10 μg/ml, R&amp;D Corporation). After 5-minutes culturing, the cells were washed with PBS and 100 μl of SDS sample loading buffer was added to the cells to prepare a cell lysate sample. After the sample was heat-treated at 94° c. for 10 minutes, it was cryopreserved at −20° c.  
      The cell lysate sample, 20 μl, was then electrophoresed on a 4-20% gradient polyacrylamide gel (Daiichi Pure Chemicals Co., Ltd.). After electrophoresis, the sample was transferred to a PVDF membrane (Amersham Pharmacia Biotech Inc.) for 3 hours. The transferred membrane was subjected to immunoblot using a phospho-c-kit (Tyr719) antibody (Cell Signaling Technology Inc.) as a primary antibody and an anti-rabbit IgG, HRP-linked antibody (Cell Signaling Technology Inc.) as a secondary antibody. After the membrane was washed, it was developed with a Super Signal (Pierce Biotechnology, Inc.).  
      As the results are shown in  FIG. 15 , c-Kit kinase was not phosphorylated (the farthest left lane) in the absence of SCF, and the addition of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (“compound 1” in figures) suppressed the c-Kit kinase phosphorylation that would take place in the presence of SCF in a concentration-dependent manner. The phosphorylation inhibitory activity of STI571, which is known as a c-Kit kinase inhibitor, was approximately one tenth of that of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.  
     Example 3  
     Effect on Growth of H-526 Tumor Transplanted to Nude Mice  
      H-526 cells were cultured in a 5% CO 2  incubator (37° c.) using an RPMI1640 medium containing 10% FCS. After the culture medium was collected, H-526 cells were washed with PBS twice and were suspended in PBS at 5.0×10 7  cells/ml. This cell suspension (0.1 ml) was transplanted to the subcutaneous parts of the right flank of 6-week female Balb/c nu/nu mice (purchased from Charles River Laboratories, Inc.). After transplantation, administration of a test substance (4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide) was started at the point the tumor volume reached approximately 150 mm 3 , and thus, oral administration was conducted twice daily for a period of 14 days. The test substance was suspended in a 0.5% methylcellulose solution (Wako Pure Chemical Industries Co., Ltd.) so as to give a dose of 0.1 ml/10 g body weight.  
      The tumor volume was measured with a caliper twice weekly during the administration period. The long and short diameters of the tumor were measured with a caliper and the tumor volume was calculated according to the equation: ½×long diameter×short diameter×short diameter. Here, the experiment was conducted in a vehicle control group of 10 animals (solvent-administered group) as well as in a test substance administered group of 5 animals.  
      As the results are shown in  FIG. 16 , 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide suppressed the growth of the nude mouse transplanted H-526 tumor in a dose-dependent manner. On the other hand, STI571 known as a c-Kit kinase inhibitor showed little anti-tumor effect when administered even at 160 mg/kg.  
     Example 4  
     Effect on c-Kit Kinase Phosphorylation in H-526 Tumor Transplanted to Nude Mice  
      0.1 ml of a H-526 cell suspension prepared at a concentration of 5.0×10 7  cells/ml, was transplanted to the subcutaneous parts of the right latus of 6-week female Balb/c nu/nu mice (purchased from Charles River Laboratories, Inc.). The animals were then divided into a vehicle control group (solvent-administered group) and a test substance (4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide) administered group at the point the tumor volume reached 300-1000 mm 3 : the test substance was administered to the latter group. The extracted tumor was placed in a cell lysate buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mm MgCl 2 , 1 mM EDTA, 100 mM NaF, 1 mM PMSF, 10 μg/ml aprotinin, 50 μg/ml leupeptin, 1 μg/ml peptatin A, 1 mM Na 3 VO 4 , 25 mM , βglycerophosphate, and phosphatase inhibitor cocktail 11) and homogenized. After centrifugation, the supernatant was protein quantified, and a 3×SDS sample loading buffer was added to prepare a cell lysate sample. Subsequently, the cell lysate was heat-treated at 94° c. for 10 minutes and cryopreserved at −20° c.  
      The cell lysate sample which was equivalent to 30 μg of protein was electrophoresed on a 4-20% gradient polyacrylamide gel (Daiichi Pure Chemicals Co., Ltd.). After electrophoresis, the sample was transferred to a PVDF membrane (Amersham Pharmacia Biotech Inc.) for 3 hours. In order to assay phosphorylated c-Kit, c-Kit and β-actin, immunoblot was performed using a phospho-c-kit (Tyr719) antibody (Cell Signaling Technologies, Inc.), an anti c-Kit antibody (Cell Signaling Technologies, Inc.) and an anti β-actin antibody (Sigma) as a primary antibody and an anti-rabbit IgG, HRP-linked antibody (Cell Signaling Technologies, Inc.) as a secondary antibody. After the membrane was washed, it was developed with a Super Signal (Pierce Biotechnology, Inc.).  
      As the results are shown in  FIG. 17 , 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide reduced phosphorylated c-Kit in tumor tissue when administered at 30 or 100 mg/kg, but c-Kit and β-actin remained unchanged. While 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide completely inhibited phosphorylation when administered at 30 or 100 mg/kg, STI571 known as a c-Kit kinase inhibitor partially inhibited phosphorylation when administered even at 160 mg/kg.  
      These results demonstrated that 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide inhibits phosphorylation of c-Kit in vivo, and it was confirmed that 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide inhibits activity of c-Kit kinase and shows anti-tumor activity.  
     INDUSTRIAL APPLICABILITY  
      As described above, the present invention can provide novel crystals of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (polymorph (A) and (B)) and a process for the preparation of the same.