# Patent

## Title
Crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same

## Abstract

A crystal of a 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate, or a solvate thereof.

## Background
TECHNICAL FIELD
The present invention relates to a crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing 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 exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).
However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
[Patent Document 1] WO 02/32872
[Patent Document 2] WO 2004/080462
[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
It is an object of the present invention to provide a crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt which has high usability as a medicament and a process for preparing the same.
Means for Solving the Problems
In order to achieve the above object, the present invention provides the followings:

    
    
        <1> A crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, wherein said crystalline compound is the hydrochloride of said compound, the hydrobromide of said compound, the p-toluenesulfonate of said compound, the sulfate of said compound, the methanesulfonate of said compound or the ethanesulfonate of said compound, or the solvate of said salt;
        <2> A crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate or the solvate of said salt;
        <3> A crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate or the solvate of said salt;
        <4> A crystalline form of 4(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate;
        <5> A crystalline form of the hydrate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate;
        <6> A crystalline form of the dimethyl sulfoxide solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate;
        <7> A crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate;
        <8> A crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate;
        <9> A crystalline form of the dimethyl sulfoxide solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate;
        <10> A crystalline form according to <4> (Form A) having diffraction peaks at diffraction angles (2θ±0.2°) of 9.65° and 18.37° in a powder X-ray diffraction;
        <11> A crystalline form according to <4> (Form A) having peaks at chemical shifts of about 162.4 ppm, about 128.0 ppm, about 102.3 ppm and about 9.9 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <11-1> A crystalline form according to <4> (Form A) having a peak at a chemical shift of about 162.4 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <11-2> A crystalline form according to <4> (Form A) having a peak at a chemical shift of about 128.0 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <11-3> A crystalline form according to <4> (Form A) having a peak at a chemical shift of about 102.3 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <11-4> A crystalline form according to <4> (Form A) having a peak at a chemical shift of about 9.9 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <12> A crystalline form according to <4> (Form A) having absorption bands at wavenumbers of 1161±1 cm−1 and 1044±1 cm −1 in an infrared absorption spectrum;
        <12-1> A crystalline form according to <4> (Form A) having an absorption band at a wavenumber of 1161±1 cm−1 in an infrared absorption spectrum;
        <12-2> A crystalline form according to <4> (Form A) having an absorption band at a wavenumber of 1044±1 cm−1 in an infrared absorption spectrum;
        <13> A crystalline form according to <4> (Form B) having diffraction peaks at diffraction angles (2θ±0.2°) of 5.72° and 13.84° in a powder X-ray diffraction;
        <14> A crystalline form according to <4> (Form B) having absorption bands at wavenumbers of 1068±1 cm−1 and 918±1 cm−1 in an infrared absorption spectrum;
        <14-1> A crystalline form according to <4> (Form B) having an absorption band at a wavenumber of 1068±1 cm−1 in an infrared absorption spectrum;
        <14-2> A crystalline form according to <4> (Form B) having an absorption band at a wavenumber of 918±1 cm−1 in an infrared absorption spectrum;
        <15> A crystalline form according to <4> (Form C) having diffraction peaks at diffraction angles (2θ±0.2°) of 14.20° and 17.59° in a powder X-ray diffraction;
        <16> A crystalline form according to <4> (Form C) having peaks at chemical shifts of about 160.2 ppm, about 126.6 ppm, about 105.6 ppm and about 7.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <16-1> A crystalline form according to <4> (Form C) having a peak at a chemical shift of about 160.2 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <16-2> A crystalline form according to <4> (Form C) having a peak at a chemical shift of about 126.6 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <16-3> A crystalline form according to <4> (Form C) having a peak at a chemical shift of about 105.6 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <16-3> A crystalline form according to <4> (Form C) having a peak at a chemical shift of about 7.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum;
        <17> A crystalline form according to <4> (Form C) having absorption bands at wavenumbers of 1324±1 cm−1 and 579±1 cm −1 in an infrared absorption spectrum;
        <17-1> A crystalline form according to <4> (Form C) having an absorption band at a wavenumber of 1324±1 cm−1 in an infrared absorption spectrum;
        <17-2> A crystalline form according to <4> (Form C) having an absorption band at a wavenumber of 579±1 cm−1 in an infrared absorption spectrum;
        <18> A crystalline form according to <5> (Form F) having diffraction peaks at diffraction angles (2θ±0.2°) of 8.02° and 18.14° in a powder X-ray diffraction;
        <19> A crystalline form according to <7> (Form I) having diffraction peaks at diffraction angles (2θ±0.2°) of 9.36° and 12.40° in a powder X-ray diffraction;
        <20> A crystalline form according to <7> (Form I) having absorption bands at wavenumbers of 1750±1 cm−1 and 1224±1 cm−1 in an infrared absorption spectrum;
        <20-1> A crystalline form according to <7> (Form I) having an absorption band at a wavenumber of 1750±1 cm−1 in an infrared absorption spectrum;
        <20-2> A crystalline form according to <7> (Form I) having an absorption band at a wavenumber of 1224±1 cm−1 in an infrared absorption spectrum;
        <21> A crystalline form according to <8> (Form α) having diffraction peaks at diffraction angles (2θ±0.2°) at 15.70° and 17.18° in a powder X-ray diffraction;
        <22> A crystalline form according to <8> (Form α) having absorption bands at wavenumbers of 1320±1 cm−1 and 997±1 cm−1 in an infrared absorption spectrum;
        <22-1> A crystalline form according to <8> (Form α) having an absorption band at a wavenumber of 1320±1 cm−1 in an infrared absorption spectrum;
        <22-2> A crystalline form according to <8> (Form α) having an absorption band at a wavenumber of 997±1 cm−1 in an infrared absorption spectrum;
        <23> A crystalline form according to <8> (Form β) having diffraction peaks at diffraction angles (2θ±0.2°) of 6.48° and 9.58° in a powder X-ray diffraction;
        <24> A crystalline form according to <8> (Form β) having absorption bands at wavenumbers of 1281±1 cm−1 and 985±1 cm−1 in an infrared absorption spectrum;
        <24-1> A crystalline form according to <8> (Form β) having an absorption band at a wavenumber of 1281±1 cm−1 in an infrared absorption spectrum;
        <24-2> A crystalline form according to <8> (Form β) having an absorption band at a wavenumber of 985±1 cm−1 in an infrared absorption spectrum;
        <25> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form A), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a solvent and methanesulfonic acid to dissolve;
        <25-1> A process according to <25>, wherein the solvent is methanol, ethanol or 2-propanol;
        <26> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form A), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve;
        <26-1> A process according to <26>, further comprising a step of adding a poor solvent to the mixture;
        <26-2> A process according to <26-1>, wherein the poor solvent is Methanol or ethanol;
        <27> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form B), comprising a step of drying a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I) to remove acetic acid;
        <28> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of heating a crystalline form of the dimethyl sulfoxide solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate;
        <29> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of mixing a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I) and a solvent;
        <29-1> A process according to <29>, wherein the solvent is methanol, ethanol or 2-propanol;
        <30> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve;
        <30-1> A process according to <30>, further comprising a step of adding a poor solvent to the mixture;
        <30-2> A process according to <30-1>, wherein the poor solvent is 2-propanol;
        <31> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of humidifying a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form B);
        <32> A process for preparing a crystalline form of the hydrate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form F), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve;
        <32-1> A process according to <32>, further comprising a step of adding a poor solvent to the mixture;
        <32-2> A process according to <32-1>, wherein the poor solvent is ethyl acetate or isopropyl acetate;
        <33> A process for preparing a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I), comprising the step of mixing 4(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve;
        <33-1> A process according to <33>, further comprising a step of adding a poor solvent to the mixture;
        <33-2> A process according to <33-1>, wherein the poor solvent is 1-propanol, 1-butanol or tert-butanol;
        <34> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form α), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a solvent and ethanesulfonic acid to dissolve;
        <34-1> A process according to <34>, wherein the solvent is dimethyl sulfoxide;
        <35 > A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form β), comprising a step of mixing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form α) and a solvent;
        <35-1> A process according to <27>, wherein the solvent is methanol, ethanol or 2-propanol;
        <36> A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form β), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and ethanesulfonic acid to dissolve;
        <36-1> A process according to <36>, further comprising a step of adding a poor solvent and water to the mixture;
        <36-2> A process according to <36-1>, wherein the poor solvent is ethanol or 2-propanol;
        <37> A pharmaceutical composition, comprising the crystalline form according to any one of <1> to <24-2>;
        <38> A prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective, comprising the crystalline form according to any one of <1> to <24-2>;
        <39> An angiogenesis inhibitor, comprising the crystalline form according to any one of <1> to <24-2>;
        <40> An anti-tumor agent, comprising the crystalline form according to any one of <1> to <24-2>;
        <41> An anti-tumor agent according to <40>, 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;
        <42> A therapeutic agent for angioma, comprising the crystalline form according to any one of <1> to <24-2>;
        <43> A cancer metastasis inhibitor, comprising the crystalline form according to any one of <1> to <24-2>;
        <44> A therapeutic agent for retinal neovascularization, comprising the crystalline form according to any one of <1> to <24-2>;
        <45> A therapeutic agent for diabetic retinopathy, comprising the crystalline form according to any one of <1> to <24-2>;
        <46> A therapeutic agent for an inflammatory disease, comprising the crystalline form according to any one of <1> to <24-2>;
        <47> A therapeutic agent for an inflammatory disease according to <46>, wherein the inflammatory disease is deformant arthritis, rheumatoid arthritis, psoriasis or delayed hypersensitivity reaction;
        <48> A therapeutic agent for atherosclerosis, comprising the crystalline form according to any one of <1> to <24-2>;
        <49> A method for preventing or treating a disease for which angiogenesis inhibition is effective, comprising administering to a patient, a pharmacologically effective dose of the crystalline form according to any one of <1> to <24-2>;
        <50> Use of the crystalline form according to any one of <1> to <24-2> for the manufacture of a prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective;
        <51> A c-Kit kinase inhibitor, comprising the crystalline form according to any one of <1> to <24-2>;
        <52> An anti-cancer agent for treating a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase, comprising the crystalline form according to any one of <1> to <24-2>;
        <53> An anti-cancer agent 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 tumor, an ovarian cancer, a breast cancer, a brain tumor, neuroblastoma or a colon cancer;
        <54> An anti-cancer agent 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> An anti-cancer agent according to any one of <52> to <54>, which is applied to a patient for which a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase is identified;
        <56> A therapeutic agent for mastocytosis, allergy or asthma, comprising the crystalline form according to any one of <1> to <24-2>;
        <57> A method for treating 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 crystalline form according to any one of <1> to <24-2>;
        <58> A method according to <57>, 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 tumor, an ovarian cancer, a breast cancer, a brain tumor, neuroblastoma or a colon cancer;
        <59> A method according to <57>, 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;
        <60> A method for treating a cancer, comprising the steps of: extracting cancer cells from a patient suffering from 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 <51>;
        <61> A method for treating 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 <51>;
        <62> A method for inhibiting 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 <51>;
        <63> Use of the c-Kit kinase inhibitor according to <51> for the manufacture of an anti-cancer agent for treating a cancer expressing excessive c-Kit kinase or a mutant c-Kit kinase;
        <64> Use according to <63>, 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 tumor, an ovarian cancer, a breast cancer, a brain tumor, neuroblastoma or a colon cancer;
        <65> Use according to <63>, 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; and
        <66> Use of the c-Kit kinase inhibitor according to <51> for the manufacture of a therapeutic agent for mastocytosis, allergy or asthma.
    
    


EFFECT OF THE INVENTION
A crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (hereunder, referred to as “carboxamide”) or the solvate of the salt according to the present invention has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability (BA)), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph illustrating the relation between time and blood concentration in a pharmacokinetic study when a crystalline form of the free form of the carboxamide, a crystalline form of the hydrobromide of the carboxamide, and a crystalline form of the methanesulfonate of the carboxamide (Form A) were administered to beagle dogs.
FIG. 2 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the free form of the carboxamide obtained in Preparation Example 1.
FIG. 3 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the hydrochloride of the carboxamide obtain in Example 1.
FIG. 4 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the hydrobromide of the carboxamide obtained in Example 2.
FIG. 5 is a figure illustrating a powder X-ray diffraction pattern of a crystalline form of the p-toluenesulfonate of the carboxamide obtained in Example 3.
FIG. 6 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the sulfate of the carboxamide obtained in Example 4.
FIG. 7 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the methanesulfonate of the carboxamide (Form A) obtained in Example 5.
FIG. 8 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the methanesulfonate of the carboxamide (B) obtained in Example 6.
FIG. 9 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the methanesulfonate of the carboxamide (Form C) obtained in Example 7.
FIG. 10 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the hydrate of the methanesulfonate of the carboxamide (Form F) obtained in Example 9.
FIG. 11 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the acetic acid solvate for the methanesulfonate of the carboxamide (Form I) obtained in Example 10.
FIG. 12 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the ethanesulfonate of the carboxamide (Form α) obtained in Example 11.
FIG. 13 is a figure illustrating a powder X-ray diffraction pattern for a crystalline form of the ethanesulfonate of the carboxamide (Form β) obtained in Example 12.
FIG. 14 is a figure illustrating a 13C Solid State NMR spectrum for a crystalline form of the methanesulfonate of the carboxamide (Form A) obtained in Example 5.
FIG. 15 is a figure illustrating a 13C Solid State NMR spectrum for a crystalline form of the methanesulfonate of the carboxamide (Form C) obtained in Example 7.
FIG. 16 is a figure illustrating an infrared absorption spectrum for a crystalline form of the methanesulfonate of the carboxamide (Form A) obtained in Example 5.
FIG. 17 is a figure illustrating an infrared absorption spectrum for a crystalline form of the methanesulfonate of the carboxamide
FIG. 18 is a figure illustrating an infrared absorption spectrum for a crystalline form of the methanesulfonate of the carboxamide (Form C) obtained in Example 7.
FIG. 19 is a figure illustrating an infrared absorption spectrum for a crystalline form of the acetic acid solvate of the methanesulfonate of the carboxamide (Form I) obtained in Example 10.
FIG. 20 is a figure illustrating an infrared absorption spectrum for a crystalline form of the ethanesulfonate of the carboxamide (Form α) obtained in Example 11.
FIG. 21 is a figure illustrating an infrared absorption spectrum for a crystalline form of the ethanesulfonate of the carboxamide (Form β) obtained in Example 12.



BEST MODE FOR CARRYING OUT THE INVENTION
Hereunder, the present invention is described in detail.
As examples of the salts of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (hereunder, referred to as “carboxamide”) according to the present invention, methanesulfonate, ethanesulfonate, p-toluenesulfonate, hydrochloride, hydrobromide, sulfate, tartrate and phosphate may be mentioned.
The salt of the carboxamide according to the present invention can be prepared by ordinary methods (for example, by mixing the carboxamide and the corresponding acid at a suitable ratio in the presence or absence of a solvent).
In this connection, in addition to the method described in WO 02/32872, the carboxamide can also be prepared by the method described in Preparation Examples 1 to 3 below.
As examples of the solvate of the salt of the carboxamide according to the present invention, a hydrate, a dimethyl sulfoxide solvate, an acetic acid solvate, and an N,N-dimethylformamide solvate may be mentioned.
In general, since an error within a range of ±0.2° can occur for a diffraction angle (2θ) in powder X-ray diffraction, it is necessary that the above diffraction angle values are understood to also include numerical values within a range of ±0.2° thereof. Therefore, the present invention encompasses crystals for which the diffraction angle matches within an error range of ±0.2° in powder X-ray diffraction, as well as crystals for which the diffraction angle is completely matching in powder X-ray diffraction.
In the present specification, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 9.65° and 18.37°” means “having diffraction peaks at diffraction angles (2θ) of 9.45° to 9.85° and 18.17° to 18.57°”, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 5.72° and 13.84°” means “having diffraction peaks at diffraction angles (2θ) of 5.52° to 5.92° and 13.64° to 14.04°”, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 14.20° and 17.59°” means “having diffraction peaks at diffraction angles (2θ) of 14.00° to 14.40° and 17.39°”, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 8.02° and 18.14°” means “having diffraction peaks at diffraction angles (2θ) of 7.82° to 8.22° and 17.94° to 18.34°”, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 9.36° and 12.40°” means “having diffraction peaks at diffraction angles (2θ) of 9.16° to 9.56° and 12.20° and 12.60°”, the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 15.70° and 17.18°” means “having diffraction peaks at diffraction angles (2θ) of 15.50° to 15.90° and 16.98° to 17.38°”, and the phrase “having diffraction peaks at diffraction angles (2θ±0.2°) of 6.48° and 9.58°” means “having diffraction peaks at diffraction angles (2θ) of 6.28° to 6.68° and 9.38° to 9.78°”.
In the present specification, the phrase “having a peak at a chemical shift of about 162.4 ppm” means “having a peak substantially equivalent to 162.4 ppm when a 13C Solid State Nuclear Magnetic Resonance spectrum (hereinafter abbreviated as ‘a 13C Solid State NMR spectrum’) is measured under normal conditions”, the phrase “having a peak at a chemical shift of about 128.0 ppm” means “having a peak substantially equivalent to 128.0 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”, the phrase “having a peak at a chemical shift of about 102.3 ppm” means “having a peak substantially equivalent to 102.3 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”, and the phrase “having a peak at a chemical shift of about 9.9 ppm” means “having a peak substantially equivalent to 9.9 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”.
In the present specification, the phrase “having a peak at a chemical shift of about 160.2 ppm” means “having a peak substantially equivalent to 160.2 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”, the phrase “having a peak at a chemical shift of about 126.6 ppm” means “having a peak substantially equivalent to 126.6 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”, the phrase “having peak at a chemical shift of about 105.6 ppm” means “having a peak substantially equivalent to 105.6 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”, and the phrase “having a peak at a chemical shift of about 7.8 ppm” means “having a peak substantially equivalent to 7.8 ppm when a 13C Solid State NMR spectrum is measured under normal conditions”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1161±1 cm−1” means “having an absorption band at a wavenumber of 1160 cm−1 to 1162 cm−1”, the phrase “having an absorption band at a wavenumber of 1044±1 cm−1” means “having an absorption band at a wavenumber of 1043 cm−1 to 1045 cm−1”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1068±1 cm−1 ” means “having an absorption band at a wavenumber of 1067 cm−1 to 1069 cm−1”, the phrase “having an absorption band at a wavenumber of 918±1 cm−1 ” means “having an absorption band at a wavenumber of 917 cm−1 to 919 cm−1”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1324±1 cm−1” means “having an absorption band at a wavenumber of 1323 cm−1 to 1325 cm−1”, the phrase “having an absorption band at a wavenumber of 579±1 cm−1” means “having an absorption band at a wavenumber of 578 cm−1 to 580 cm−1”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1750±1 cm−1” means “having an absorption band at a wavenumber of 1749 cm−1 to 1751 cm−1”, the phrase “having an absorption band at a wavenumber of 1224±1 cm−1” means “having an absorption band at a wavenumber of 1223 cm−1 to 1225 cm−1”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1320±1 cm−1” means “having an absorption band at a wavenumber of 1319 cm−1 to 1321 cm−1”, the phrase “having an absorption band at a wavenumber of 997±1 cm−1” means “having an absorption band at a wavenumber of 996 cm−1 to 998 cm−1”.
In the present specification, the phrase “having an absorption band at a wavenumber of 1281±1 cm−1” means “having an absorption band at a wavenumber of 1280 cm−1 to 1282 cm−1”, the phrase “having an absorption band at a wavenumber of 985±1 cm−1” means “having an absorption band at a wavenumber of 984 cm−1 to 986 cm−1”.
[General Process for Preparation]
A process for preparing a crystalline form of the salts of carboxamide or the solvate of the salts according to the present invention is described in detail hereunder.
1. Process for Preparing a Crystalline Form of the Hydrochloride or Hydrobromide
A crystalline form of the hydrochloride or hydrobromide can be prepared by mixing the carboxamide and a solvent to dissolve, and followed by adding thereto hydrochloric acid or hydrobromic acid.
More specifically, for example, after mixing the carboxamide and a solvent and heating the mixture to dissolve the carboxamide, hydrochloric acid or hydrobromic acid is added thereto and the mixture is then cooled slowly to room temperature to give a crystalline form of the hydrochloride or hydrobromide.
As a solvent, an alcohol such as methanol, ethanol, 1-propanol or 2-propanol can be used, and preferably ethanol is used. Where necessary, the alcohol may be used after adding water thereto.
Although the amount of solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold.
The amount of hydrochloric acid or hydrobromic acid used can be 1.0 to 1.5 equivalents relative to the substrate amount, and an equivalent of 1.1 is preferable.
While a heating temperature is not particularly limited, preferably the heating temperature is between 60° C. and reflux temperature, and more preferably reflux temperature.
Slow cooling from the heating temperature to room temperature can be performed in a period between 10 min and 24 hours.
2. Process for Preparing a Crystalline Form of the p-toluenesulfonate or Sulfate
A crystalline form of the sulfate or p-toluenesulfonate can be prepared by mixing the carboxamide, a solvent and sulfuric acid or p-toluenesulfonic acid to dissolve the carboxamide.
More specifically, for example, a crystalline form of the p-toluenesulfonate or sulfate can be prepared by mixing the carboxamide, a solvent and p-toluenesulfonic acid or sulfuric acid, heating the mixture to dissolve the carboxamide, and then slowly cooling the mixture to room temperature.
As a solvent, for example, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide can be used, and dimethyl sulfoxide is preferable.
Although the amount of solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold.
The amount of p-toluenesulfonic acid or sulfuric acid used can be 1.0 to 1.5 equivalents relative to the substrate amount, and an equivalent of 1.2 is preferable.
While a heating temperature is not particularly limited, the heating temperature is preferably between 60° C. and reflux temperature, more preferably between 70 and 100° C., and further preferably 80° C.
Slow cooling from the heating temperature to room temperature can be performed in a period between 10 min and 24 hours.
3. Process for Preparing a Crystalline Form of the Methanesulfonate (Form A)
(Preparation Method 1)
A crystalline form of the methanesulfonate (Form A) can be prepared by mixing the carboxamide, a solvent and methanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the methanesulfonate (Form A) can be prepared, for example, by mixing the carboxamide, a solvent and methanesulfonic acid, and heating the mixture to dissolve the carboxamide, and then slowly cooling the mixture to room temperature.
As a solvent, for example, methanol, ethanol, 2-propanol can be used, and methanol is preferable.
Although the amount of solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold.
The amount of methanesulfonic acid used can be 1.0 to 1.5 equivalents relative to the substrate amount, and an equivalent of 1.2 is preferable.
While a heating temperature is not particularly limited, the heating temperature is preferably between 60° C. and reflux temperature, and more preferably between 70 and 80° C.
Slow cooling from a heating temperature to room temperature can be performed in a period between 1 and 24 hours, and preferably in a period between 3 and 12 hours.
(Preparation Method 2)
A crystalline form of the methanesulfonate (Form A) can be prepared by mixing the carboxamide, acetic acid and methanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the methanesulfonate (Form A) can be prepared, for example, by mixing the carboxamide, acetic acid and methanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent and slowly cooing the mixture to room temperature. Preferably, seed crystals of a crystalline form of the methanesulfonate (Form A) are added when the poor solvent is added.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
The amount of methanesulfonic acid used can be 1.0 to 2.5 equivalents relative to the substrate amount, and an equivalent of 1.4 to 2.2 is preferable.
As a poor solvent, for example, methanol and ethanol can be used, and ethanol is preferred.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 10-fold to 30-fold relative to substrate amount, and more preferably 20-fold. Further, the poor solvent can be added at one time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added the second time is from 1:1 to 3:1, and preferably 3:2.
Although a heating temperature is not particularly limited, preferably the temperature is between 50° C. and reflux temperature, and more preferably 50° C.
Slow cooling from a heating temperature to room temperature can be performed in a period between 10 min and 6 hours, and preferably in a period between 1 and 2 hours.
4. Process for Preparing a Crystalline Form of the Methanesulfonate (Form B)
A crystalline form of the methanesulfonate (Form B) can be prepared by drying a crystalline form of the acetic acid solvate of the methanesulfonate (Form I) by a method such as drying under aeration to remove acetic acid.
5. Process for Preparing a Crystalline form of the Methanesulfonate (Form C)
(Preparation Method 1)
A crystalline form of the methanesulfonate (Form C) can be prepared by heating a crystalline form of the dimethyl sulfoxide solvate of the methanesulfonate and slowly cooling to room temperature.
This preparation method can be carried out in the presence or absence of a solvent.
When using a solvent, examples of a solvent that can be used include ethyl acetate, isopropyl acetate and n-butyl acetate, and n-butyl acetate is preferable.
Although a heating temperature is not particularly limited, preferably the temperature is between 70° C. and reflux temperature, and more preferably reflux temperature.
(Preparation Method 2)
A crystalline form of the methanesulfonate (Form C) can be prepared by mixing a crystalline form of the acetic acid solvate of the methanesulfonate (Form I) and a solvent, and stirring the mixture.
As a solvent, for example, an alcohol such as methanol, ethanol, or 2-propanol can be used, and ethanol is preferable.
Although a stirring temperature is not particularly limited, preferably the temperature is between 20 and 60° C., and more preferably 40° C.
(Preparation Method 3)
A crystalline form of the methanesulfonate (Form C) can be prepared by mixing the carboxamide, acetic acid and methanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the methanesulfonate (Form C) can be prepared, for example, by mixing the carboxamide, acetic acid and methanesulfonic acid, heating the mixture to dissolve the carboxamide, and then adding 2-propanol as a poor solvent and slowly cooling the solution to around 15° C. Preferably, seed crystals of a crystalline form of the methanesulfonate (Form C) are added when the poor solvent is added, and isopropyl acetate is further added to accelerate precipitation.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 5- to 10-fold relative to the substrate amount, and more preferably 7- to 8-fold.
The amount of methanesulfonic acid used can be an equivalent of 1.0 to 1.5 relative to the substrate amount, and an equivalent of 1.2 is preferable.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 2- to 10-fold relative to the substrate amount, and more preferably 4- to 5-fold.
When adding isopropyl acetate, although the amount thereof is not particularly limited, a preferable amount is 2- to 10-fold relative to the substrate amount, and more preferably 5-fold.
Although a heating temperature is not particularly limited, a preferably temperature is 40° C.
Slow cooling from a heating temperature to around 15° C. can be performed in a period between 10 min and 6 hours, and preferably in a period between 1 and 2 hours.
(Preparation Method 4)
A crystalline form of the methanesulfonate (Form C) can be prepared by mixing the carboxamide, acetic acid and methanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the methanesulfonate (Form C) can be prepared, for example, by mixing the carboxamide, acetic acid and methanesulfonic acid, dissolving the carboxamide at room temperature (or around 30° C.), adding 2-propanol as a poor solvent, slowly cooling the mixture to around 15° C., filtering off precipitated crystals, and mixing and stirring the crystals and a solvent. Preferably, seed crystals of a crystalline form of the methanesulfonate (Form C) are added when the poor solvent is added.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
The amount of methanesulfonic acid used can be an equivalent of 1.0 to 2.5 relative to the substrate amount, and an equivalent of 1.8 to 2.2 is preferable.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold.
Slow cooling from room temperature (or around 30° C.) to around 15° C. can be preformed in a period between 10 min and 4 hours, and preferably in a period between 30 min and 2 hours.
As a solvent to be mixed with the crystals which are filtered off, for example, an alcohol such as methanol, ethanol or 2-propanol can be used, and ethanol is preferred.
(Preparation Method 5)
A crystalline form of the methanesulfonate (Form C) can be prepared by humidifying a crystalline form of the methanesulfonate (Form B).
6. Process for Preparing a Crystalline Form the Dimethyl Sulfoxide Solvate of the Methanesulfonate
A crystalline form of the dimethyl sulfoxide solvate of the methanesulfonate can be prepared by mixing the carboxamide, dimethyl sulfoxide and methanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent, and slowly cooling the mixture to around 15° C. Preferably, seed crystals of a crystalline form of the methanesulfonate (Form A) are added when the poor solvent is added.
Although the amount of the dimethyl sulfoxide is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 8- to 10-fold.
The amount of methanesulfonic acid used can be an equivalent of 1.0 to 4.0 relative to the substrate amount, and an equivalent of 1.2 to 3.5 is preferable.
As a poor solvent, for example, ethyl acetate, isopropyl acetate, 1-propanol, 2-propanol can be used, and preferably ethyl acetate or 2-propanol is used.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold. Further, the poor solvent can be added at one time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added th second time is from 1:1 to 1:5, and preferably 1:4.
Although a heating temperature is not particularly limited, preferably the temperature is between 50 and 100° C., and more preferably between 60 and 80° C.
Slow cooling from a heating temperature to around 15° C. can be performed in a period between 10 min and 6 hours, and preferably in a period between 1 and 2 hours.
7. Process for Preparing a Crystalline of the Hydrate of the Methanesulfonate (Form F)
A crystalline form of the hydrate of the methanesulfonate (Form F) can be prepared by mixing the carboxamide, acetic acid and methanesulfonic acid and to dissolve the carboxamide.
More specifically, a crystalline form of the hydrate of the methanesulfonate (Form F) can be prepared, for example, by mixing the carboxamide, acetic acid and methanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent, and then slowly cooling the mixture to room temperature. Preferably, seed crystals of a crystalline of the methanesulfonate (Form A) are added when the poor solvent is added.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
The amount of methanesulfonic acid used can be an equivalent of 1.0 to 2.0 relative to the substrate amount, and an equivalent of 1.3 to 1.6 is preferable.
As a poor solvent, for example, ethyl acetate, isopropyl acetate can be used, and ethyl acetate is preferable.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 10- to 30-fold relative to the substrate amount, and more preferably 20-fold. Further, the poor solvent can be added at one time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added the second time is from 1:1 to 1:5, and a ratio of 1:3 is preferable.
Although a heating temperature is not particularly limited, preferably the temperature is between 40 and 60° C., and more preferably 50° C.
Slow cooling from a heating temperature to room temperature can be performed in a period between 10 min and 6 hours, and preferably in a period between 2 and 4 hours.
8. Process for Preparing a Crystalline Form of the Acetic Acid Solvate of the Methanesulfonate (Form I)
A crystalline form of the acetic acid solvate of the methanesulfonate (Form I) can be prepared by mixing the carboxamide, acetic acid and methanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the acetic acid solvate of the methanesulfonate (Form I) can be prepared, for example, by mixing the carboxamide, acetic acid and methanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent, and slowly cooling the mixture to room temperature. Preferably, seed crystals of a crystalline form of the methanesulfonate (Form C) are added when the poor solvent is added, and isopropyl acetate is further added to accelerate precipitation.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 5- to 10-fold relative to the substrate amount, and more preferably 7- to 8-fold.
The amount of methanesulfonic acid used can be an equivalent of 1.0 to 1.5 relative to the substrate amount, and an equivalent of 1.2 is preferable.
As a poor solvent, for example, 1-propanol, 1-butanol, tert-butanol can be used, and 1-propanol is preferred.
Although the amount of poor solvent is not particularly limited, a preferably amount is 5- to 20-fold relative to the substrate amount, and more preferably 8- to 10-fold. Further, the poor solvent can be added at one time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added the second time is from 1:1 to 1:5, and a ratio of 1:3.5 is preferable.
When adding isopropyl acetate, although the amount thereof is not particularly limited, a preferable amount is 2- to 10-fold relative to the substrate amount, and more preferably 5-fold.
Although a heating temperature is not particularly limited, a preferable temperature is 40° C.
Slow cooling from a heating temperature to room temperature can be performed in a period between 10 min and 6 hours, and preferably in a period between 1 and 2 hours.
9. Process for Preparing a Crystalline Form of the Ethanesulfonate (Form α)
A crystalline form of the ethanesulfonate (Form α) can be prepared by mixing the carboxamide, a solvent and ethanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the ethanesulfonate (Form α) can be prepared, for example, by mixing the carboxamide, a solvent and ethanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent, and then cooling this solution to room temperature.
As a solvent, for example, dimethyl sulfoxide can be used.
Although the amount of solvent is not particularly limited, a preferable amount is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
The amount of ethanesulfonic acid used can be an equivalent of 1.0 to 1.5 relative to the substrate amount, and an equivalent of 1.2 is preferable.
As a poor solvent, for example, ethyl acetate can be used.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
Although a heating temperature is not particularly limited, a preferably temperature is between 50 and 70° C., and more preferably is 60° C.
Cooling from a heating temperature to room temperature can be performed in a period between 5 min and 2 hours, and preferably in a period between 5 min and 1.5 hours.
10. Process for Preparing a Crystalline Form of the Ethanesulfonate (Form β)
(Preparation Method 1)
A crystalline form of the ethanesulfonate (Form β) can be prepared by adding a solvent and water to a crystalline form of the ethanesulfonate (Form α) and stirring the mixture at room temperature.
As a solvent, for example, methanol, ethanol, and 2-propanol can be used, and ethanol is preferable.
Although the amount of solvent is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
Although the amount of water is not particularly limited, a preferable amount is 1/10 to 1⁄2 of the ethanol amount, and more preferably 1⁄6 of the ethanol amount.
(Preparation Method 2)
A crystalline form of the ethanesulfonic (Form β) can be prepared by mixing the carboxamide, acetic acid and ethanesulfonic acid to dissolve the carboxamide.
More specifically, a crystalline form of the ethanesulfonate (Form β) can be prepared, for example, by mixing the carboxamide, acetic acid and ethanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent and water, and cooling this solution to 0° C. Preferably, seed crystals of a crystalline form of the ethanesulfonate (Form β) are added when the poor solvent is added.
Although the amount of acetic acid is not particularly limited, preferably the amount used is 2.5- to 10-fold relative to the substrate amount, and more preferably 5-fold.
The amount of ethanesulfonic acid used can be an equivalent of 1.0 to 1.5 relative to the substrate amount, and an equivalent of 1.2 is preferable.
As a poor solvent, for example, ethanol, and 2-propanol can be used, and 2-propanol is preferable.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 10- to 40-fold relative to the substrate amount, and more preferably 30-fold. Further, the poor solvent can be added at on time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added the second time is from 1:1 to 1:5, and a ratio from 1:1.5 to 1.2 is preferable.
Although the amount of water is not particularly limited, a preferable amount is 1/10 to 1/30 of the poor solvent amount, and more preferably is 1/20 of the poor solvent amount.
Although a heating temperature is not particularly limited, a preferable temperature is between 50 and 70° C., and more preferably 60° C.
Cooling from a heating temperature to 0° C. can be performed in a period between 10 min and 6 hours, and preferably in a period between 2 and 4 hours.
11. Process for Preparing a Crystalline Form of the Dimethyl Sulfoxide Solvate of the Ethanesulfonate
A crystalline form of the dimethyl sulfoxide solvate of the ethanesulfonate can be prepared by mixing the carboxamide, dimethyl sulfoxide and ethanesulfonic acid, heating the mixture to dissolve the carboxamide, adding a poor solvent, and cooling the mixture to 0° C. Preferably, seed crystals of a crystalline form of the ethanesulfonate (Form β) are added when the poor solvent is added.
Although the amount of dimethyl sulfoxide is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold.
The amount of ethanesulfonic acid used can be an equivalent of 1.0 to 1.5 relative to the substrate amount, and an equivalent of 1.2 is preferable.
As a poor solvent, for example, ethyl acetate can be used.
Although the amount of poor solvent is not particularly limited, preferably the amount used is 5- to 20-fold relative to the substrate amount, and more preferably 10-fold. Further, the poor solvent can be added at one time or can be added dividedly 2 to 4 times, and preferably the poor solvent is divided and added 2 times. In this case, the ratio for the amount of solvent added the first time and the amount of solvent added the second time if from 1:1 to 3:1, and a ratio of 3:2 is preferable.
Although a heating temperature is not particularly limited, a preferable temperature is between 50 and 70° C., and more preferably 60° C.
Cooling from a heating temperature to 0° C. can be performed in a period between 10 min and 6 hours, and preferably in a period between 1 and 2 hours.
When the crystals of the present invention are to be used as a medicament, it will normally be mixed with suitable additives for use as a formulation. However, the foregoing description does not limit the use of the crystals of the present invention as medicament in the state of intact products.
Such additives may include excipients, binders, lubricants, disintegrators, coloring agents, taste correctives, emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, buffering agents, antiseptics, antioxidants, stabilizers, absorption accelerators and the like which are commonly used in pharmaceuticals, and they may be added in appropriate combinations as desired.
As examples of such excipients there may be mentioned lactose, white soft sugar, glucose, corn starch, mannitol, sorbitol, starch, alpha starch, dextrin, crystalline cellulose, soft silicic anhydride, aluminum silicate, calcium silicate, magnesium aluminometasilicate, calcium hydrogenphosphate, and the like.
As examples of binders there may be mentioned polyvinyl alcohol, methylcellulose, ethylcellulose, gum Arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, macrogol, and the like.
As examples of lubricants there may be mentioned magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silica, and the like.
As examples of disintegrators, there may be mentioned crystalline cellulose, agar, gelatin, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch, and carboxymethyl starch sodium, and the like.
As coloring agents there may be mentioned those approved for addition to pharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake and the like.
As taste correctives there may be mentioned cocoa powder, menthol, aromatic powders, mentha oil, borneol, powdered cinnamon bark, and the like.
As emulsifiers or surfactants there may be mentioned stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, glycerin monostearate, sucrose fatty acid esters, glycerin fatty acid esters, and the like.
As dissolving aids there may be mentioned polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, nicotinamide, and the like.
As suspending agents there may be mentioned the surfactants referred to above, as well as hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
As isotonizing agents there may be mentioned glucose, sodium chloride, mannitol, sorbitol and the like.
As buffering agents there may be mentioned buffering solutions of phosphate, acetate, carbonate, citrate and the like.
As antiseptics there may be mentioned methylparaben, propylparaben, chlororbutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
As antioxidants there may be mentioned sulfite, ascorbic acid, α-tocopherol, And the like.
The formulation may be in the form of an oral preparation such as a tablet, powder, granule, capsule, syrup, lozenge or inhalant; an external preparation such as a suppository, ointment, eye salve, tape, eye drop, nasal drop, ear drop, pap or lotion; or an injection.
An oral preparation will be formulated using an appropriate combination of additives among those mentioned above. The surface thereof may also be coated if necessary.
An external preparation will be formulated using an appropriate combination of additives among those mentioned above, and particularly excipients, binders, taste correctives, emulsifies, surfactants, dissolving aids, suspending agents, isotonizing agents, antiseptics, antioxidants, stabilizers and absorption accelerators.
An injection will be formulated using an appropriate combination of additives among those mentioned above, and particularly emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, buffering agents, antiseptics, antioxidants, stabilizers and absorption accelerators.
When the crystals of the invention is to be used as a medicament, the dosage thereof will differ depending on the symptoms and age of the patient as well as the form of administration, but it will ordinarily be 100 μg to 10 g per day, administered at once or divided over several times.
The crystals of the present invention are extremely useful as an angiogenesis inhibitor, and are also useful as a prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective, an angiogenesis inhibitor, an anti-tumor agent, a therapeutic agent for angioma, a cancer metastasis inhibitor, a therapeutic agent for retinal neovascularization, a therapeutic agent for diabetic retinopathy, a therapeutic agent for an inflammatory disease, a therapeutic agent for an inflammatory disease selected from the group consisting of deformant arthritis, rheumatoid arthritis, psoriasis and delayed hypersensitivity reaction, and a therapeutic agent for atherosclerosis.
When using the crystals of the present invention as an anti-tumor agent, examples of the tumor include a pancreatic cancer, a gastric cancer, a colon cancer, a breast cancer, a prostrate cancer, a lung cancer, a renal cancer, a brain tumor, a blood cancer or an ovarian cancer, and in particular, a gastric cancer, a colon cancer, a prostrate cancer, a lung cancer or a renal cancer are preferable.
Further, the crystals of the present invention exhibit a strong inhibitory activity for c-Kit kinase, and are useful as an anti-cancer agent for a cancer which has undergone a malignant alteration due to activation of c-Kit kinase (for example, acute myelogenous leukemia, mast cell leukemia, a small cell lung cancer, GIST, a testicular tumor, an ovarian cancer, a breast cancer, a brain tumor, neuroblastoma or a colon cancer). The crystals of the present invention are also useful as a therapeutic agent for a disease such as mastocytosis, allergy or asthma that is considered to be caused by c-Kit kinase.
EXAMPLES
Hereunder, examples are described to facilitate further understanding of the present invention, however, the following examples are not intended to limit the scope of the present invention.
Preparation Example 1
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).
Preparation Example 2
Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)
(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate




To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, 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.

    1H-NMR Spectrum (CDCl3) δ(ppm): 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).

(2) Preparation of 1-(2-chloro-4-hydroxyphenyl)-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) while 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, and the mixture was stirred. The organic layer was then separated off, 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%).

    1H-NMR Spectrum (CDCl3) δ(ppm): 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=8.8 Hz)

(3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide



To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-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, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).
Preparation Example 3
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)
7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).
1H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.
Example 1
A Crystalline Form of the Hydrochloride of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
A suspension of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (854 mg, 2.0 mmol) in ethanol (17 mL) was stirred, and 2 N hydrochloric acid (1.1 mL, 2.2 mmol) was added dropwise to the reaction mixture while refluxing using an oil bath with an external temperature of 100° C. After confirming that the suspension had changed into a solution, the heating of the oil bath was stopped, and the mixture was cooled slowly to room temperature while immersed in the oil bath, followed by stirring overnight. Ethanol (8.6 mL) was added to the reaction mixture, and resultant crystals were filtered off, washed with ethanol (4.3 mL×2), dried under aeration on filter paper (1.5 hours), and then dried (23 hours) with hot air at 70° C. to give the titled crystals (786.1 mg, 85%).
1H-NMR. Spectrum (DMSO-d6) δ(ppm): 0.30-0.50 (2H, m), 0.60-0.70 (2H, m), 2.56 (1H, m), 4.06 (3H, s), 6.86 (1H, d, J=6.4 Hz), 7.29-7.35 (2H, m), 7.60 (1H, d, J=2.8 Hz), 7.64 (1H, s), 7.88 (1H, s), 7.95 (1H, s), 8.07 (1H, s), 8.34 (1H, d, J=9.2 Hz), 8.70 (1H, s), 8.91 (1H, d, J=6.4 Hz).
Example 2
A Crystalline Form of the Hydrobromide of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
A suspension of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (500 mg, 1.17 mmol) in ethanol (10 mL) was stirred, and an aqueous solution of 1 N hydrobromic acid (1.3 mL, 1.3 mmol) was then added dropwise to the reaction mixture while refluxing using an oil bath with an external temperature of 100° C. After water (2.0 mL) was gradually added to the mixture to form a solution, the heating of the oil bath was stopped, and the mixture was cooled slowly to room temperature while immersed in the oil bath, followed by stirring overnight. Precipitated crystals were filtered off, washed with ethanol (2.5 mL×2), dried under aeration on filter paper (15 min), and then dried (22 hours) with hot air at 100° C. to give the titled crystals (483.7 mg, 81%).
1H-NMR Spectrum (DMSO-d6) δ(ppm): 0.40-0.50 (2H, m), 0.60-0.70 (2H, m), 2.58 (1H, m), 4.09 (3H, s), 6.89 (1H, d, J=6.4 Hz), 7.26 (1H, d, J=2.8 Hz), 7.33 (1H, dd, J=2.8, 9.2 Hz), 7.59 (1H, s), 7.62 (1H, d, J=2.8 Hz), 7.90 (1H, s), 7.96 (1H, s), 8.06 (1H, s), 8.36 (1H, d, J=9.2 Hz), 8.72 (1H, s), 8.93 (1H, d, J=6.4 Hz).
Example 3
A Crystalline Form of the p-toluenesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
Dimethyl sulfoxide (1.5 mL) and p-toluenesulfonic acid monohydrate (80 mg, 0.422 mmol) were added to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol) at room temperature. Although a solution was temporarily formed, crystals precipitated immediately. Therefore, dimethyl sulfoxide (2.25 mL) was added to the reaction mixture at 80° C. to dissolve the crystals. The mixture was cooled slowly to room temperature, and stirred for 14 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (177 mg).
1H-NMR Spectrum (400 MHz, DMSO-d6) δ(ppm): 0.39 (2H, m), 0.63 (2H, m), 2.24 (3H, s), 2.54 (1H, m), 4.04 (3H, s), 6.88 (1H, d, J=6.4 Hz), 7.05 (1H, s), 7.07 (1H, s), 7.21 (1H, d, J=2.8 Hz), 7.31 (1H, dd, J=2.6, 9.3 Hz), 7.41 (1H, s), 7.43 (1H, s), 7.59 (1H, d, J=2.8 Hz), 7.86 (1H, s), 7.92 (1H, s), 8.02 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.68 (1H, s), 8.91 (1H, d, J=6.4 Hz)
Example 4
A Crystalline Form of the Sulfate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
Dimethyl sulfoxide (1.5 mL) and sulfuric acid (23 μL, 0.422 mmol) were added to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol) at room temperature. Although a solution was temporarily formed, crystals precipitated immediately. Therefore, dimethyl sulfoxide (2.25 mL) was added to the reaction mixture at 80° C. to dissolve the crystals. The mixture was cooled slowly to room temperature, and stirred for 16 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (174 mg).
1H-NMR Spectrum (400 MHz, DMSO-d6) δ(ppm): 0.39 (2H, m), 0.63 (2H, m), 2.46 (2H, d, J=1.2 Hz), 2.52 (1H, m), 4.04 (3H, s), 6.88 (1H, d, J=5.8 Hz), 7.21 (1H, s), 7.31 (1H, d, J=8.2 Hz), 7.56 (1H, s), 7.59 (1H, s), 7.86 (1H, s), 7.93 (1H, s), 8.02 (1H, s), 8.33 (1H, d, J=8.2 Hz), 8.68 (1H, s), 8.91 (1H, d, J=5.8 Hz)
Example 5
A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)
(Preparation Method 1)
In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).
(Preparation Method 2)
In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).
Example 6
A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)
A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg).
Example 7
A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form C)
(Preparation Method 1)
n-butyl acetate (12 mL) was added to a crystalline form of the dimethyl sulfoxide solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.15 mmol) obtained in Example 8 (Preparation Method 1), and the reaction mixture was stirred at 115° C. for 10 hours and further stirred at room temperature for 1.5 hours Resultant crystals were then filtered off and dried at 60° C. to give the titled crystals (503 mg).
(Preparation Method 2)
Ethanol (6.4 mL) was added to a crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (1.28 g) obtained in Example 10 to dissolve at 40° C., and then the reaction mixture was stirred at the same temperature for 36 hours. Precipitated crystals were filtered off and dried at 50° C. to give the titled crystals (0.87 g).
(Preparation Method 3)
To a mixed solution of acetic acid (14 mL) and methanesulfonic acid (0.37 mL, 5.62 mmol) 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2.00 g, 4.69 mmol) was added to dissolve at 40° C. After confirming the dissolution, 2-propanol (9 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form C) (100 mg) were added in this order to the reaction mixture, and the reaction mixture was stirred for 20 min. Isopropyl acetate (10 mL) was then further added dropwise over 30 min. After the addition of the isopropyl acetate was completed, the reaction mixture was stirred for 1.5 hours, and further stirred at 15° C. for 14 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (2.22 g).
(Preparation Method 4)
To a suspension of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1.28 g, 3 mmol) in acetic acid (12.8 ml) was added methanesulfonic acid (0.408 ml, 6.3 mmol), and the mixture was stirred at room temperature to dissolve. The reaction mixture was heated with a bath at a temperature of 30° C., and 2-propanol (7.7 ml) was added. Seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form C) was added, and 2-propanol was further added 14 times by every amount of 1.28 ml over 44 min. The warm bath was removed, the reaction mixture was stirred for 10 min at room temperature, then for 5 min in a water bath, and for 25 min in a water bath with a small amount of ice (internal temperature: 17.6° C.). Resultant crystals were filtered off and washed with 2-propanol (10 ml). The filtered crystals were stirred in ethanol (6.4 ml) at room temperature for 1 hour. Resultant crystals were filtered off, washed with ethanol (4 ml) and dried at 60° C. to give the titled crystals (1068 mg).
Example 8
A Crystalline Form of the Dimethyl Sulfoxide Solvate of Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
(Preparation Method 1)
Dimethyl sulfoxide (7 mL) was added at room temperature to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.640 mmol) and the mixture was dissolved at 80° C. Methanesulfonic acid (143 μL, 1.97 mmol), ethyl acetate (1.4 mL), and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) were added in this order to the reaction mixture at 60° C., and ethyl acetate (5.6 mL) was further added dropwise over 45 min. 15 min after completion of the addition of the ethyl acetate, the reaction mixture was cooled to room temperature over 1 hour, and stirred at the same temperature for 18 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (746 mg).
(Preparation Method 2)
Dimethyl sulfoxide (6.8 mL) was added at room temperature to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (854 mg, 2 mmol) and the mixture was dissolved at 60° C. Methanesulfonic acid (389 μL, 6 mmol) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) were added in this order to the reaction mixture at the same temperature, and 2-propanol (6.8 mL) was then added dropwise over 30 min. After completion of the addition of the 2-propanol, the reaction mixture was cooled to 15° C. over 2 hours, and then stirred at the same temperature for 30 min. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (1095 mg).
(Preparation Method 3)
Dimethyl sulfoxide (6.8 mL) was added at room temperature to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (854 mg, 2 mmol) and the mixture was dissolved at 62° C. Methanesulfonic acid (454 μL, 7 mmol) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) were added in this order to the reaction mixture at the same temperature, and 2-propanol (13.6 mL) was then added dropwise over 1 hour. After the completion of the addition of the 2-propanol, the reaction mixture was cooled to 15° C. over 2 hours, and then stirred at the same temperature for 30 min. Precipitated crystals were filtered off and dried at 60° C. to obtain the titled crystal (1082 mg).
Example 9
A Crystalline Form of the Hydrate of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form F)
In a mixed solution of acetic acid (1.5 mL) and methanesulfonic acid (31 μL, 0.422 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol) at 50° C. After confirming the dissolution, ethyl acetate (0.6 mL) and a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) obtained in Example 5 (Preparation method 1) were added In this order to the reaction mixture, and ethyl acetate (1.8 mL) was further added dropwise over 2 hours. After the addition of ethyl acetate was completed, the reaction mixture was stirred at 50° C. for 30 min, and then stirred at room temperature for 7.5 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (176 mg).
Example 10
A Crystalline Form of the Acetic Acid Solvate of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I)
In a mixed solution of acetic acid (14 mL) and methanesulfonic acid (0.36 mL, 5.62 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2.00 g, 4.69 mmol) at 40° C. After confirming the dissolution, 1-propanol (4 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form C) (100 mg) were added in this order to the reaction mixture, and 1-propanol (14 mL) and isopropyl acetate (10 mL) were further added dropwise over 1 hour. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour, and then stirred at 25° C. for a further 40 min. Precipitated crystals were filtered off to give the titled crystals (2.61 g).
The 1H-NMR chemical shift values for the methanesulfonate are as follows:
1H-NMR Spectrum (DMSO-d6) δ(ppm): 0.44 (2H, m), 0.67 (2H, m), 2.36 (3H, s), 2.59 (1H, m), 4.09 (3H, s), 6.95 (1H, d, J=7 Hz), 7.25 (1H, d, J=2 Hz), 7.36 (1H, dd, J=3, 9 Hz), 7.63 (1H, d, J=3 Hz), 7.65 (1H, s), 7.88 (1H, brs), 7.95 (1H, brs), 8.06 (1H, s), 8.37 (1H, d, J=9 Hz), 8.73 (1H, s), 8.97 (1H, d, J=7 Hz)
Example 11
A Crystalline Form of the Ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form α)
(Preparation Method 1)
Dimethyl sulfoxide (1.5 mL) and ethanesulfonic acid (34 μL, 0.422 mmol) were added to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol) and the mixture was dissolved at room temperature. Ethyl acetate (1.5 mL) was added dropwise to the reaction mixture at 60° C. over 1.5 hours. 30 min after the addition of ethyl acetate was completed, the reaction mixture was cooled to room temperature over 1.5 hours, and then stirred at room temperature for a further 7 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (176 mg).
(Preparation Method 2)
Ethanol (40 mL) and ethanesulfonic acid (459 μL, 5.622 mmol) were added to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol) at room temperature and the mixture was dissolved at 65° C. The reaction mixture was cooled with a bath at a temperature of 22° C., and seed crystals of a crystalline form of the ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form α) was added. The mixture was stirred for further 7 hours. Precipitated crystals were filtered off and dried at 70° C. to give the titled crystals (1.55 g).
Example 12
A Crystalline Form of the Ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form β)
(Preparation Method 1)
Ethanol (3 mL) and water (0.5 mL) were added to a crystalline form of the ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form α) (198 mg) obtained in Example 11, and the reaction mixture was stirred at room temperature for 3 hours. Crystals were filtered off and dried at 60° C. to give the titled crystals (89 mg).
(Preparation Method 2)
Acetic acid (0.75 mL) and ethanesulfonic acid (34 μL, 0.422 mmol) were added at room temperature to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (150 mg, 0.351 mmol), and the mixture was then dissolved at 60° C. To the reaction mixture were added water (0.225 mL), 2-propanol (2 mL), a crystalline form of the ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form β) obtained in (Preparation method 1) of Example 12, and 2-propanol (2.5 mL) in this order, and the mixture was then cooled to 0° C. over 2.5 hours, and stirred for 30 min. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (139 mg).
Example 13
A Crystalline Form of the Dimethyl Sulfoxide Solvate of the Ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
Dimethyl sulfoxide (4 mL) was added at room temperature to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (400 mg, 0.937 mmol), and the mixture was then dissolved at 60° C. To the reaction mixture were added ethanesulfonic acid (92 μL, 1.124 mmol), ethyl acetate (2.4 mL) and a crystalline form of the ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form β) obtained in (Preparation Method 1) of Example 12 in this order, and the mixture was then stirred at 60° C. for 20 min. After a further addition of ethyl acetate (1.6 mL), the reaction mixture was once heated to 80° C., and then cooled to 0° C. over 1.5 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (523 mg).
The 1H-NMR chemical shift values for the ethanesulfonate are as follows:
1H-NMR Spectrum (DMSO-d6) δ(ppm): 0.43 (2H, m), 0.66 (2H, m), 1.05 (3H, t, J=7.4 Hz), 2.38 (2H, q, J=7.4 Hz), 2.58 (1H, m), 4.08 (3H, s), 6.88 (1H, s), 7.24 (1H, s), 7.34 (1H, d, J=9.0 Hz), 7.60 (1H, s), 7.61 (1H, s), 7.88 (1H, s), 7.94 (1H, s), 8.05 (1H, s), 8.36 (1H, d, J=9.01 Hz), 8.72 (1H, s), 8.92 (1H, s)
Test Example 1
Test for Measuring Dissolution Rate 
[Method]
The dissolution rates of the following crystals were measured under the conditions described below by the rotating disk method (see, J. H. Woods et al., J. Pharm. Soc., 54, 1068 (1955)): a crystalline form of the free carboxamide (obtained in Preparation Example 1), a crystalline form of the hydrochloride of the carboxamide (obtained in Example 1), a crystalline form of the hydrobromide of the carboxamide (obtained in Example 2), a crystalline form of the methanesulfonate (hereunder, referred to as “mesylate”) of the carboxamide (Form A) (obtained in Example 5), a crystalline form of the mesylate of the carboxamide (Form C) (obtained in Example 7) and a crystalline form of the ethanesulfonate (hereunder, referred to as “esylate”) (Form β) (obtained in Example 12). The dissolution rates were calculated based on a range in which linearity was maintained in the relation between concentration and time at the initial stage of dissolution.
(Rotating Disk Method Conditions)


    Solvent: “2nd fluid” (pH 6.8, 500 mL) as described in Japanese Pharmacopoeia 14th Edition, General Tests (disintegration test)
    Temperature: 37° C.
    Disk rotation speed: 50 rpm
    Area of powder contacting with solvent on disk: 1 cm2 
    Sampling amount: approx. 1 mL

(HPLC Conditions)

    Column: Cadenza CD-18 (Imtakt Corporation; inner diameter 4.6 mm, Column length 100 mm, particle size 3 μm)
    Column temperature: 40° C.
    Flow rate: 1.0 mL/min
    Mobile phase:


Solution A: H2O:CH3CN:HClO4=990:10:1 (v/v/v)
Solution B: CH3CN:H2O:HClO4=900:100:1 (v/v/v)
Concentration of solution B: 20%

    Injection amount: 100 μL
    Detection: ultraviolet absorbance photometer (wavelength: 252 nm)
    Temperature of auto sampler: 25° C.

[Results]



Table 1 shows the dissolution rates.









TABLE 1







dissolution rate



(μg/min/cm2)



















free form
0.8



hydrochloride
4.7



hydrobromide
8.7



mesylate (Form A)
11.8



mesylate (Form C)
15.5



esylate (Form β)
18.5










For each crystal of the salts, the dissolution rate increased significantly in comparison to a crystalline form of the free form of the carboxamide. The increase of dissolution rate was particularly remarkable for a crystalline form of the mesylate and a crystalline form of the esylate.
Test Example 2
Study of Pharmacokinetics in Beagle Dogs
[Method]
A crystalline form of the free from of the carboxamide (obtained in Preparation Example 1), a crystalline form of the hydrobromide of the carboxamide (obtained in Example 2) and a crystalline form of the mesylate of the carboxamide (Form A) (obtained in Example 5) were grounded in a mortar, encapsulated in a gelatin capsule, and then administered orally to beagle dogs (n=3). After administration, 10 mL of water was further administered orally. The dose was set such that it was equivalent to 3 mg/kg as a free form, and the beagle dogs were fasted from the day before administration, and fed again 8 hours after the administration.
To calculate bioavailability (BA), a test was conducted using a single intravenous administration. More specifically, a crystalline form of the free from of the carboxamide was dissolved in a solution containing 10% dimethyl sulfoxide, 50% polyethylene glycol 400 and 40% 0.1 M aqueous solution of hydrochloric acid and administered intravenously through cephalic vein of the foreleg.
The plasma concentration of the carboxamide was measured by HPLC-UV method after sampling blood from cephalic vein of the foreleg. Based on the concentration, pharmacokinetic parameters were calculated for each individual by the moment method. Further, based on the calculated parameters, the mean value and standard error thereof were calculated.
[Results]
Table 2 shows the pharmacokinetic parameters, and FIG. 1 shows the relation between time and plasma concentration.











TABLE 2









mesylate



free form
hydrobromide
(Form A)




















time to reach maximum
(hr)
1.17 ± 0.4 
2.67 ± 0.7 
1.67 ± 0.3 


plasma concentration (Tmax)


Maximum plasma
(ng/mL)
53.3 ± 9.9 
480.4 ± 31.4 
397.1 ± 100.1


concentration (Cmax)


plasma concentration after
(ng/mL)
24.0 ± 9.0 
100.5 ± 81.7 
17.1 ± 2.5 


24 hours (C24hr)


AUC0-24hr
(μg hr/mL)
0.6 ± 0.0
4.8 ± 0.2
3.0 ± 0.4


BA
(%)
9.1 ± 0.4
73.5 ± 2.3 
46.2 ± 5.9 









The maximum plasma concentration and BA increased significantly for each crystalline form of the salts in comparison to a crystalline form of the free form.
Test Example 3
Evaluation of Hygroscopicity and Solid Stability 
[Method]
The hygroscopicity and solid stability of a crystalline form of the mesylate of the carboxamide (Form A) (obtained in Example 5), a crystalline form of the mesylate of the carboxamide (Form C) (obtained in Example 7), a crystalline form of the acetic acid solvate of the mesylate of the carboxamide (Form I) (obtained in Example 10) and a crystalline form of the esylate of the carboxamide (Form β) (obtained in Example 12) were measured under the following conditions.
1. Storage Conditions for the Hygroscopicity Test (Period: 1 Week)
a-1. 25° C., relative humidity 75%
b-1. 25° C., relative humidity 93%
2. Storage Conditions for the Solid Stability Test (Period: 2 Weeks)
a-2. −20° C. (well closed)
b-2. 25° C., light irradiation (1000 1×; shading with aluminum foil, well closed)
c-2. 25° C., light irradiation (1000 1×; well closed)
d-2. 40° C., relative humidity 75%
e-2. 60° C. (well closed except the following case: slightly open in the case of a crystalline form of the acetic acid solvate of the mesylate (Form I))
3. Method for Measuring the Impurity Amount by HPLC
After storage, the sample solution was prepared by adding a mixed solvent of water and methanol (3:1) to each crystal at 0.1 mg/mL as final concentration.
Tests were conducted by the HPLC method for these sample solutions under the measurement conditions described below, and the eluted peak areas were measured to determine the total impurity amount by the relative area method (impurities of 0.05% or more were counted).
(Formula for Calculating Total Impurity Amount)


    Individual impurity amount (%)=(the peak area for the individual impurity)×100/{(the peak area for carboxamide)+(sum of the peak areas for impurities)}
    Total impurity amount (%)=sum of individual impurity amounts

(HPLC Measurement Conditions)

    Column: Mightysil RP-18 GP (Kanto Kagaku; inner diameter 4.6 mm, column length 150 mm, particle size 3 μm)
    Column temperature: constant temperature in vicinity of 40° C.
    Flow rate: 1.0 mL/min
    Mobile phase:


Solution A: H2O:CH3CN:HClO4=990:10:1 (v/v/v)
Solution B: CH3CN:H2O:HClO4=900:100:1 (v/v/v)

    Gradient conditions












TABLE 3








concentration of



time (min)
Solution B (%)



















0
5



3
20



15
20



30
100



30.01
5



35
5










    Injection amount: 10 μL
    Detection: ultraviolet absorbance photometer (wavelength: 252 nm)
    Temperature of auto sampler: constant temperature in vicinity of 10° C.

4. Powder X-ray Diffraction



Analysis was carried out according to “X-Ray Powder Diffraction Method” described in Japanese Pharmacopoeia 14th Edition, General Tests (B-614 to 619) under the following measurement conditions.

    Apparatus: RINT-2000 (manufacture by Rigaku Denki K. K.)
    X-ray: CuKα ray
    Monochrometer: curved crystal monochrometer
    Goniometer: vertical goniometer
    Counter: scintillation counter
    Applied voltage: 40 kV
    Charging current: 200 mA
    Scan speed: 5°/min
    Scan axis: 2θ/θ
    Scan range; 2θ+5° to 40°
    Divergent slit: 0.5°
    Scattering slit: 0.5°
    Receiving slit: 0.3 mm

5. Measurement of Water Content



Measurement was carried out according to the Water Determination as described in Japanese Pharmacopoeia 14th Edition, General Tests (B-318 to 331) using 6 to 10 mg of each crystal.
[Results]
The results of hygroscopicity evaluation are shown in Table 4 to Table 7.







TABLE 4







Evaluation of hygroscopicity of a crystalline


form of the mesylate (Form A)











condition
water content (%)
crystal form







initial
0.7
C



a-1
0.6
C



b-1
0.7
C

















TABLE 5







Evaluation of hygroscopicity of a crystalline


form of the mesylate (Form C)











condition
water content (%)
crystal form







initial
0.7
C



a-1
0.6
C



b-1
0.7
C

















TABLE 6







Evaluation of hygroscopicity of a crystalline form


of the acetic acid solvate of the mesylate (Form I)











condition
water content (%)
crystal form







initial
2.9
I



a-1
0.6
C



b-1
0.8
C

















TABLE 7







Evaluation of hygroscopicity of a crystalline form of the esylate (Form β)











condition
water content (%)
crystal form







initial
1.7
β



a-1
1.7
β



b-1
1.4
β










Water content did not change remarkably for a crystalline form of the mesylate (Form A), a crystalline form of the mesylate (Form C) and a crystalline form of the esylate (Form β), and hygroscopicity was not observed. Neither remarkable change in appearance nor crystal transition was observed.
In contrast, with regard to a crystalline form of the acetic acid solvate of the mesylate (Form I), a decrease in water content was observed as well as transition to a crystalline form of the mesylate (Form C).
The results of evaluation of solid stability are shown in Table 8 to Table 11.







TABLE 8







Evaluation of solid stability of a crystalline form


of the mesylate (Form A)












water content



condition
total impurity (%)
(%)
crystal form





initial
4.02
0.3
A


a-2
3.90
0.0
A


b-2
3.95
0.0
A


c-2
4.23
0.1
A


d-2
3.90
0.2
A


e-2
3.97
0.2
A
















TABLE 9







Evaluation of solid stability of a crystalline form


of the mesylate (Form C)












water content



condition
total impurity (%)
(%)
crystal form





initial
2.11
0.7
C


a-2
2.10
0.7
C


b-2
2.09
0.8
C


c-2
2.22
0.7
C


d-2
2.06
0.6
C


e-2
2.18
0.5
C
















TABLE 10







Evaluation of solid stability of a crystalline form


of the acetic acid solvate of the mesylate (Form I)












water content



condition
total impurity (%)
(%)
crystal form





initial
0.62
2.9
I


a-2
0.67
3.1
I


b-2
0.66
3.1
I


c-2
0.87
2.9
I


d-2
0.61
0.9
C


e-2
0.84
0.3
B
















TABLE 11







Evaluation of solid stability of a crystalline form


of the esylate (Form β)












water content



condition
total impurity (%)
(%)
crystal form





initial
0.55
1.7
β


a-2
0.48
2.0
β


b-2
0.46
2.5
β


c-2
0.49
2.1
β


d-2
0.48
2.0
β


e-2
0.51
2.2
β









For a crystalline form of the mesylate (Form A), a crystalline form of the mesylate (Form C) and a crystalline form of the esylate (Form β), neither remarkable changes in water content and appearance nor crystal transition was observed.
In contrast, with regard to a crystalline form of the mesylate (Form I), neither crystal transition nor remarkable changes in total impurity amount, water content and appearance were observed when stored in a well closed container. However, for a sample stored under conditions of 40° c. and relative humidity of 75%, a decrease in water content was observed along with transition to a crystalline form of the mesylate (Form C). Further, for a sample stored at 60° c. in a slightly opened container, a decrease in water content was observed along with transition to a crystalline form of the mesylate (Form B).
Test Example 4
Powder X-ray Diffraction of a Crystalline Form of the Mesylate (Form B) (Obtained in Example 6) with a Treatment of Humidification
[Method]
Powder X-ray diffraction was measured under the measurement conditions similar to those in 4. (powder X-ray diffraction) of Test Example 3. Humidification was carried out using a humidity control unit HUM-1A (manufactured by Rigaku Denki K. K.)), to sequentially adjust relative humidity to 3%, 30%, 50%, 60%, 70%, 75%, 80% and 85% at room temperature.
[Results]
A crystalline form of the mesylate (Form B) remained its state and did not exhibit a crystal transition at a relative humidity from 3% to 70%. However it changed to a mixture of crystalline forms of the mesylate (Form B) and (Form C) at a relative humidity of 75% and 80%, a transition to a crystalline form of the mesylate (Form C) was observed. At a relative humidity of 85%, there was a complete transition to a crystalline form of the mesylate (Form C).
Test Example 5
Temperature-controlled Powder X-ray Diffraction of a Crystalline Form of the Dimethyl Sulfoxide Solvate of the Mesylate (Obtained in Example 8 (Preparation Method 1))
[Method]
Powder X-ray diffraction was conducted under the measurement conditions similar to those in 4. (powder X-ray diffraction) of Test Examples 3. The temperature was increased according to the following conditions.

    Temperature controller: PCT-20 (manufactured by Rigaku Denki K.K.)
    Rate for the increase of the temperature: 2° C./min
    Measurement temperatures: 30° C., 40° C., 60° C., 80° C., 120° C., 140° C., 180° C., 200° C., 205° C., 210° C. and 215° C.

[Results]



While crystal transition was not observed at temperatures from 30° C. to 80° C., at temperatures of 120° C. or more transition to a crystalline form of the mesylate (Form C) was observed.
(Powder X-ray Diffraction Measurement)
Powder X-ray diffraction analysis was carried out for crystals obtained in Preparation Example 1 and Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 and 12 under the following measurement conditions in accordance with “X-Ray Powder Diffraction Method” described in Japanese Pharmacopoeia 14th Edition, General Tests (B-614 to 619).

    Apparatus: RINT-2000 (manufactured by Rigaku Denki K.K.)
    X-ray: CuKα ray
    Monochrometer: curved crystal monochrometer
    Goniometer: vertical goniometer
    Counter: scintillation counter
    Applied voltage: 40 kV
    Charging current: 200 mA
    Scan speed: 5°/min (2°/min with respect to a crystalline form of the free form of the carboxamide obtained in Preparation Example 1, a crystalline form of the hydrochloride obtained in Example 1, a crystalline form of the hydrobromide obtained in Example 2, and a crystalline form of the acetic acid solvate of the mesylate (Form I) obtained in Example 10)
    Scan axis: 2θ/θ
    Scan range: 2θ+5 to 40°
    Divergent slit: 0.5°
    Scattering slit: 0.5°
    Receiving slit: 0.3 mm


The powder X-ray diffraction patterns of the crystals obtained in Preparation Example 1 and Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 and 12 are shown in FIGS. 2 to 13, respectively. The peaks and intensities of the diffraction angles (2θ) for the crystals obtained in Preparation Example 1 and Examples 5, 6, 7, 9, 10, 11 and 12 are listed in Tables 12 to 19, respectively.












TABLE 12





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
7.210
0.165
12.2505
1593
7


2
8.250
0.153
10.7084
4113
18


3
8.930
0.176
9.8944
1680
7


4
9.200
0.141
9.6046
1710
8


5
9.910
0.165
8.9180
3680
16


6
10.430
0.188
8.4746
2220
10


7
10.930
0.153
8.0880
4197
19


8
12.240
0.188
7.2251
1853
8


9
13.720
0.165
6.4489
6133
27


10
15.090
0.165
5.8664
2283
10


11
15.370
0.141
5.7601
2553
11


12
15.700
0.176
5.6398
7390
33


13
16.550
0.188
5.3520
1293
6


14
18.580
0.176
4.7716
9897
44


15
19.230
0.188
4.6117
15977
71


16
19.930
0.165
4.4513
4683
21


17
20.330
0.188
4.3646
13577
60


18
20.970
0.176
4.2328
3610
16


19
22.010
0.176
4.0351
3100
14


20
22.410
0.259
3.9640
5203
23


21
22.970
0.165
3.8686
2593
12


22
23.440
0.188
3.7921
22513
100


23
24.110
0.176
3.6882
5120
23


24
24.540
0.176
3.6245
5353
24


25
24.990
0.188
3.5603
5263
23


26
25.520
0.188
3.4875
1867
8


27
25.790
0.141
3.4516
1370
6


28
26.280
0.188
3.3884
8420
37


29
26.880
0.188
3.3141
4030
18


30
27.400
0.176
3.2524
2080
9


31
27.710
0.176
3.2167
2077
9


32
28.010
0.141
3.1829
1190
5


33
28.560
0.188
3.1228
4867
22


34
28.860
0.165
3.0911
3810
17


35
29.400
0.212
3.0355
2050
9


36
30.490
0.188
2.9294
6207
28


37
30.880
0.247
2.8933
2667
12


38
31.280
0.188
2.8572
1397
6


39
31.760
0.259
2.8151
3050
14


40
32.100
0.176
2.7861
1447
6


41
32.920
0.129
2.7185
1310
6


42
33.120
0.212
2.7026
1697
7


43
33.710
0.141
2.6566
1337
6


44
34.290
0.259
2.6130
1163
5


45
34.640
0.165
2.5874
1223
5


46
34.940
0.188
2.5658
1350
6


47
36.080
0.176
2.4873
1117
5


48
36.730
0.176
2.4448
2140
10


49
37.600
0.235
2.3902
1677
7


50
38.140
0.188
2.3576
1500
7


51
38.600
0.212
2.3306
1200
5


52
39.400
0.271
2.2851
1650
7





















TABLE 13





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
6.540
0.188
13.5039
1954
10


2
9.660
0.141
9.1483
9646
52


3
10.640
0.188
8.3078
2662
14


4
11.380
0.141
7.7692
3025
16


5
12.220
0.212
7.2369
1592
9


6
12.640
0.141
8.9974
1808
10


7
13.100
0.165
6.7527
1917
10


8
14.480
0.141
6.1121
1904
10


9
15.020
0.165
5.8935
1304
7


10
15.420
0.212
5.7415
1600
9


11
16.740
0.165
5.2917
3446
18


12
17.020
0.185
5.2052
1704
9


13
17.300
0.141
5.1216
2129
11


14
17.700
0.165
5.0068
2329
12


15
18.380
0.165
4.8230
3825
20


16
18.880
0.165
4.6964
3479
19


17
19.400
0.235
4.5717
2800
15


18
19.960
0.165
4.4447
4054
22


19
20.340
0.141
4.3625
4133
22


20
20.820
0.235
4.2630
10558
56


21
21.380
0.165
4.1526
5504
29


22
22.180
0.188
4.0046
4988
27


23
22.900
0.165
3.8803
5158
28


24
23.180
0.141
3.8340
9562
51


25
23.420
0.165
3.7953
18721
100


26
24.080
0.141
3.6927
2438
13


27
24.820
0.188
3.5843
3908
21


28
25.480
0.212
3.4929
3183
17


29
25.880
0.212
3.4398
2012
11


30
26.400
0.141
3.3732
2288
12


31
26.740
0.188
3.3311
3568
19


32
27.060
0.141
3.2924
1192
6


33
27.640
0.212
3.2247
2842
15


34
28.320
0.212
3.1488
1812
10


35
28.600
0.141
3.1186
1892
10


36
29.220
0.165
3.0538
1746
9


37
25.680
0.141
3.0075
3154
17


38
29.960
0.188
2.9800
6300
28


39
30.300
0.165
2.9474
1846
10


40
31.800
0.118
2.8117
1412
8


41
32.660
0.212
2.7396
2133
11


42
32.940
0.141
2.7169
1567
8


43
33.360
0.259
2.6837
1312
7


44
35.400
0.141
2.5335
1867
10


45
36.550
0.235
2.4493
1167
6


46
37.240
0.259
2.4125
1412
8


47
38.320
0.165
2.3469
1575
8


48
38.700
0.118
2.3248
1425
8





















TABLE 14





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
5.720
0.141
15.4378
3079
45


2
9.640
0.165
9.1672
2229
33


3
10.140
0.188
8.7163
2788
41


4
10.500
0.235
8.4182
2458
36


5
11.320
0.212
7.8102
4175
61


6
11.480
0.141
7.7017
4042
59


7
13.200
0.118
6.6716
1550
23


8
13.840
0.212
6.3933
3333
49


9
15.280
0.165
5.7938
1862
27


10
15.620
0.188
5.6685
1508
22


11
16.440
0.212
5.3875
1488
22


12
17.060
0.165
5.1931
2154
32


13
17.620
0.259
5.0293
4746
69


14
19.160
0.212
4.6284
6829
100


15
19.800
0.235
4.4802
2896
42


16
20.340
0.282
4.3625
2279
33


17
20.760
0.212
4.2752
2079
30


18
21.460
0.188
4.1373
2558
37


19
22.080
0.259
4.0225
1871
27


20
22.560
0.118
3.9380
2292
34


21
23.140
0.141
3.8406
3012
44


22
23.840
0.306
3.7293
3167
46


23
24.940
0.353
3.5673
3958
58


24
25.780
0.212
3.4629
3571
52


25
26.800
0.118
3.3238
1458
21


26
28.300
0.118
3.1509
2029
30


27
29.900
0.165
2.9859
1683
26


28
31.040
0.118
2.8788
1467
21


29
31.160
0.118
2.8679
1379
20


30
32.760
0.165
2.7314
1429
21


31
33.560
0.118
2.6681
1671
24


32
34.440
0.141
2.6019
1267
19





















TABLE 15





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
6.160
0.141
14.3361
3760
37


2
9.840
0.165
8.9813
3062
31


3
10.160
0.165
8.6992
3238
32


4
10.580
0.141
8.3547
7715
77


5
12.300
0.141
7.1900
1923
19


6
12.540
0.118
7.0530
1783
18


7
12.960
0.141
6.8263
1912
19


8
13.400
0.141
6.6022
1655
16


9
14.220
0.212
6.2233
3978
40


10
14.860
0.188
5.9566
1905
19


11
15.200
0.165
5.8241
3047
30


12
15.960
0.236
5.5485
1383
14


13
16.360
0.212
5.4137
1267
13


14
17.160
0.141
5.1631
1793
18


15
17.600
0.282
5.0350
4173
42


16
19.080
0.165
4.6476
6007
60


17
19.280
0.165
4.5999
5715
57


18
19.960
0.188
4.4447
4740
47


19
20.420
0.165
4.3456
2607
26


20
20.820
0.212
4.2630
3305
33


21
21.280
0.188
4.1719
3210
32


22
21.740
0.235
4.0846
4487
45


23
22.560
0.282
3.9380
3627
36


24
23.140
0.188
3.8406
2402
24


25
23.560
0.188
3.7730
10033
100


26
23.720
0.118
3.7479
6733
67


27
24.020
0.141
3.7018
5015
50


28
24.320
0.259
3.6668
4275
43


29
24.760
0.259
3.5928
2563
26


30
25.540
0.282
3.4848
8082
81


31
26.020
0.141
3.4216
2278
23


32
26.220
0.118
3.3960
1422
14


33
26.980
0.212
3.3020
2438
24


34
27.500
0.165
3.2408
1085
11


35
27.980
0.235
3.1862
1798
18


36
28.400
0.212
3.1401
2785
28


37
28.760
0.141
3.1016
1137
11


38
29.220
0.212
3.0538
1517
15


39
29.500
0.118
3.0254
1727
17


40
29.620
0.165
3.0134
1818
18


41
29.840
0.118
2.9917
1643
16


42
30.640
0.376
2.9154
2390
24


43
31.280
0.259
2.8572
1123
11


44
31.500
0.118
2.8378
1062
11


45
32.440
0.141
2.7576
1100
11


46
33.640
0.118
2.6620
1208
12


47
34.500
0.165
2.5975
1362
14


48
35.040
0.118
2.5587
1297
13


49
36.100
0.188
2.4860
1245
12


50
37.640
0.306
2.3878
1565
16


51
38.940
0.141
2.3110
1427
14


52
39.480
0.118
2.2806
1215
12





















TABLE 16





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
5.700
0.212
15.4919
1821
25


2
6.100
0.188
14.4770
1946
26


3
8.020
0.212
11.0149
4092
56


4
9.640
0.212
9.1672
2379
32


5
10.540
0.165
8.3864
2021
27


6
11.280
0.259
7.8378
3871
53


7
12.680
0.236
6.9764
2129
29


8
14.140
0.259
6.2683
1358
18


9
16.120
0.212
5.4938
1529
21


10
17.200
0.259
5.1512
2258
31


11
18.140
0.235
4.8863
5121
70


12
19.520
0.235
4.5209
3671
50


13
20.240
0.165
4.3838
1921
26


14
20.700
0.329
4.2874
2962
40


15
21.320
0.235
4.1641
1525
21


16
22.120
0.212
4.0153
2558
35


17
22.900
0.282
3.8803
5721
78


18
23.400
0.188
3.7985
4458
61


19
23.740
0.259
3.7448
5092
69


20
24.280
0.259
3.6628
3929
53


21
24.760
0.188
3.5928
1971
27


22
25.060
0.235
3.5505
2164
29


23
25.500
0.282
3.4902
2454
33


24
26.300
0.282
3.3858
2083
28


25
26.960
0.329
3.3044
7362
100


26
28.300
0.212
3.1509
1921
26


27
28.820
0.306
3.0953
1850
25


28
29.480
0.329
3.0274
2371
32


29
29.920
0.165
2.9839
1554
21


30
31.660
0.353
2.8238
1321
18


31
34.840
0.259
2.5730
1700
23


32
36.280
0.329
2.4741
1888
26


33
37.940
0.165
2.3696
1400
19





















TABLE 17





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
9.360
0.188
9.4408
6027
100


2
10.200
0.165
8.6651
2107
35


3
10.460
0.165
8.4503
3292
55


4
12.400
0.165
7.1323
2693
46


5
13.380
0.188
6.6120
1382
23


6
13.880
0.235
6.3749
1450
24


7
14.400
0.165
6.1459
1432
24


8
15.640
0.282
5.6613
3673
61


9
16.840
0.165
5.2605
1560
26


10
17.260
0.118
5.1334
2425
40


11
17.460
0.165
5.0750
4155
69


12
18.860
0.212
4.7014
2442
40


13
19.420
0.212
4.5670
1597
26


14
20.040
0.212
4.4271
2845
47


15
20.760
0.212
4.2752
3693
61


16
21.100
0.212
4.2070
2805
46


17
21.760
0.188
4.0809
6035
100


18
22.660
0.212
3.9208
3982
66


19
23.200
0.188
3.8308
1322
22


20
23.660
0.212
3.7573
4177
69


21
25.180
0.329
3.5338
4802
80


22
25.660
0.188
3.4688
3073
51


23
25.840
0.141
3.4451
2603
43


24
26.480
0.188
3.3632
1992
33


25
26.980
0.236
3.3020
2142
35


26
28.040
0.329
3.1796
2292
38


27
28.480
0.118
3.1314
995
16


28
29.740
0.282
3.0016
1248
21


29
30.360
0.282
2.9417
1915
32


30
31.200
0.188
2.8644
1075
18


31
31.640
0.118
2.8255
960
16


32
32.520
0.141
2.7510
1057
18


33
33.340
0.212
2.6852
1740
29


34
35.120
0.118
2.5531
985
16


35
35.440
0.141
2.5308
953
16


36
35.860
0.165
2.5021
937
16


37
37.360
0.259
2.4050
1443
24


38
39.560
0.141
2.2762
1217
20






















TABLE 18










RELATIVE



PEAK NUMBER
2 θ
HALF WIDTH
d_VALUE
INTENSITY
INTENSITY
PEAK NUMBER





















1
6.000
0.188

14.7180
2058
37


2
9.200
0.447

9.6046
2108
38


3
10.640
0.235

8.3078
5392
96


4
13.480
0.165

6.5632
1862
33


5
13.620
0.165

6.4960
1783
32


6
14.520
0.212

6.0953
1946
35


7
15.700
0.259

5.6398
2775
49


8
17.180
0.282

5.1571
2508
45


9
17.820
0.282

4.9733
2579
46


10
18.380
0.259

4.8230
2571
46


11
19.880
0.306

4.4624
4421
79


12
20.720
0.259

4.2833
2712
48


13
21.460
0.518

4.1373
2692
48


14
22.200
0.259

4.0010
3658
65


15
22.820
0.471

3.8937
5621
100


16
24.160
0.165

3.6807
2438
43


17
24.600
0.282

3.6158
2942
52


18
25.560
0.306

3.4822
4200
75


19
26.200
0.188

3.3985
1667
30


20
26.900
0.353

3.3117
2196
39


21
27.180
0.165

3.2782
1854
33


22
28.220
0.353

3.1597
2212
39


23
29.320
0.353

3.0436
1696
30


24
30.260
0.212

2.9512
1721
31





















TABLE 19





PEAK

HALF


RELATIVE


NUMBER
2 θ
WIDTH
d_VALUE
INTENSITY
INTENSITY




















1
8.480
0.165
13.6288
2662
20


2
9.040
0.141
9.7743
5021
38


3
9.580
0.141
9.2245
10096
76


4
10.600
0.118
8.3390
2671
20


5
12.500
0.141
7.0754
2096
16


6
13.660
0.141
6.4771
1558
12


7
14.640
0.212
6.0456
1712
13


8
15.080
0.141
5.8702
7054
53


9
17.740
0.235
4.9956
2675
20


10
18.140
0.165
4.8863
4188
32


11
19.100
0.141
4.6428
3083
23


12
19.400
0.212
4.5717
6029
45


13
19.700
0.141
4.5027
2796
21


14
20.080
0.141
4.4184
2862
22


15
20.380
0.141
4.3540
3279
25


16
20.660
0.165
4.2956
10933
82


17
20.920
0.141
4.2428
2729
21


18
21.280
0.118
4.1719
2771
21


19
21.520
0.165
4.1259
6142
46


20
21.740
0.141
4.0846
4908
37


21
22.140
0.165
4.0117
3754
28


22
22.680
0.165
3.9174
13275
100


23
23.220
0.165
3.8275
2008
15


24
23.640
0.188
3.7604
6554
49


25
24.260
0.165
3.6657
5350
40


26
24.880
0.165
3.5758
3129
24


27
25.160
0.141
3.5366
2350
18


28
25.320
0.118
3.5146
1879
14


29
26.100
0.165
3.4113
4004
30


30
26.260
0.141
3.3909
3646
27


31
26.740
0.188
3.3311
3650
27


32
27.260
0.188
3.2687
5421
41


33
27.480
0.141
3.2431
3008
23


34
28.360
0.165
3.1444
1767
13


35
28.580
0.141
3.1207
1267
10


36
29.300
0.141
3.0456
1404
11


37
29.560
0.212
3.0194
2117
16


38
30.360
0.212
2.9417
2275
17


39
30.860
0.188
2.8951
2250
17


40
31.860
0.141
2.8065
1392
10


41
32.140
0.118
2.7827
1204
9


42
33.600
0.259
2.6650
1779
13


43
35.360
0.141
2.5363
1800
14


44
35.580
0.141
2.5211
1408
11


45
36.360
0.141
2.4688
1896
14


46
36.740
0.118
2.4442
1650
12


47
37.520
0.235
2.3951
1650
12


48
38.180
0.235
2.3552
1471
11


49
38.900
0.235
2.3133
2033
15


50
39.640
0.118
2.2718
1500
11









(13C Solid State NMR Spectrum Measurement)

13C Solid State NMR spectrum measurement was carried out for crystals obtained in Examples 5 and 7 under the following measurement conditions.

    Apparatus: CMX-300 (Chemagnetics)
    Measurement temperature: room temperature (22° C.)
    Chemical shift reference: poly(dimethylsiloxane) (Internal Standard: 1.56 ppm)
    Measurement nucleus: 13C (75.497791 MHz)
    Relaxation delay: 25 sec
    Pulse sequence: TOSS


The 13C Solid State NMR spectra of the crystals obtained in Examples 5 and 7 are shown in FIG. 14 and FIG. 15, respectively. The chemical shifts of the crystals obtained in Examples 5 and 7 are listed in Tables 20 and 21, respectively.







TABLE 20





mesylate (Form A)


chemical shift (ppm)















169.7


162.4


156.3


147.5


142.3


137.0


130.1


128.0


123.4


120.5


114.6


102.3


98.4


58.8


39.2


23.8


9.9


5.7
















TABLE 21





mesylate (Form C)


chemical shift (ppm)















170.9


166.1


160.2


155.3


148.1


144.6


142.4


136.8


130.3


126.6


122.9


121.4


115.9


105.6


97.0


57.4


39.3


21.9


7.8









(Infrared Absorption Spectrum Measurement)

Infrared absorption spectrum measurement was carried out for crystals obtained in Examples 5, 6, 7, 10, 11 and 12 was carried out according to the ATR method in the infrared absorption spectrum method as described in the Japanese Pharmacopoeia 14th Edition, General Tests by using FT-IR Spectrum-One (manufactured by PerkinElmer Japan Co., Ltd.) 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 5, 6, 7, 10, 11 and 12 are shown in FIGS. 16 to 21, respectively, and wave numbers of the absorption peaks (cm−1) and transmittance (% T) are listed in Tables 22 to 27, respectively.







TABLE 22







MESYLATE (FORM A)










WAVE NUMBER




(cm−1)
% T














3306.50
87.76



3143.87
89.68



2676.03
90.20



2179.21
92.50



1709.03
76.99



1689.20
75.28



1639.51
83.49



1589.27
83.46



1526.06
76.88



1492.40
85.76



1456.75
74.01



1420.18
83.16



1350.26
72.77



1311.98
88.26



1280.50
77.49



1239.62
73.06



1204.43
65.76



1194.13
65.42



1181.63
65.44



1161.34
62.76



1091.07
79.89



1044.40
60.26



985.56
78.02



911.30
76.39



846.45
83.06



827.77
76.51



811.59
76.37



775.98
73.68



756.07
82.42



739.83
85.42



721.85
79.51



697.83
84.41



681.20
81.05



642.73
72.54



595.47
76.50



550.94
56.67



523.19
63.87



458.48
77.37



428.43
84.18



404.39
73.43

















TABLE 23







MESYLATE (FORM B)










WAVE NUMBER




(cm−1)
% T














3403.30
88.90



3288.86
87.65



3148.98
86.30



2500.86
89.65



2071.00
90.59



1975.82
90.44



1676.34
72.60



1654.00
75.28



1610.72
80.67



1585.16
80.02



1549.95
76.15



1492.04
71.57



1474.49
78.84



1447.27
70.65



1418.76
72.95



1385.12
68.18



1349.46
74.29



1281.22
76.13



1259.90
66.26



1238.09
73.20



1216.34
65.61



1187.31
65.81



1147.23
59.40



1086.20
72.28



1068.05
78.63



1051.40
77.11



1034.51
53.11



988.08
74.83



957.18
82.10



917.63
74.99



885.07
76.41



846.37
75.01



824.56
71.62



774.19
68.81



740.35
79.48



717.65
83.13



697.26
75.94



667.94
76.40



648.45
76.93



621.03
80.63



582.94
68.34



553.10
54.69



524.26
52.32



460.20
71.59



445.97
70.23



429.58
74.11



417.86
77.33



404.47
75.14

















TABLE 24







MESYLATE (FORM C)










WAVE NUMBER




(cm−1)
% T














3423.95
95.31



3387.99
94.61



3265.37
94.09



3134.95
93.21



2189.73
96.49



2055.55
96.35



1701.76
86.67



1682.83
77.44



1652.89
90.15



1613.76
88.25



1587.67
89.60



1528.85
75.23



1474.24
89.39



1454.93
79.66



1417.85
85.41



1390.53
79.57



1352.31
83.39



1323.76
82.35



1286.71
83.52



1259.58
78.08



1241.58
83.13



1211.19
71.92



1185.21
72.85



1151.72
68.76



1132.10
77.56



1094.87
80.65



1053.79
88.07



1031.32
69.48



999.13
86.02



957.03
92.45



923.13
91.37



909.07
83.03



885.46
87.22



873.44
88.13



849.08
79.00



823.54
86.89



770.37
80.47



746.03
83.64



720.92
92.81



678.66
86.22



622.21
83.97



599.75
82.04



589.04
82.04



578.57
84.66



553.91
71.59



522.49
56.69



502.44
71.80



456.20
76.23



446.12
77.77



419.73
79.39

















TABLE 25







MESYLATE (FORM I)










WAVE NUMBER




(cm−1)
% T














3397.97
86.39



3319.94
84.81



3177.53
83.45



3096.06
83.80



2159.87
91.01



2032.91
90.61



1749.63
86.77



1724.72
86.69



1683.59
71.59



1641.48
62.67



1605.84
67.15



1585.45
65.70



1557.92
64.45



1505.67
75.91



1474.53
73.63



1453.55
63.44



1416.08
65.42



1396.67
60.87



1350.85
66.67



1284.69
68.19



1260.86
62.02



1223.56
52.48



1201.48
57.53



1186.05
55.01



1146.06
51.51



1091.15
69.64



1057.74
71.52



1030.17
53.75



989.94
65.62



971.08
73.93



909.73
61.10



876.69
74.65



844.04
65.31



798.03
71.63



772.20
68.51



717.29
75.90



686.79
66.91



668.46
68.22



650.21
68.04



601.50
59.64



547.68
44.53



526.55
45.99



482.62
58.93



471.45
60.44



444.14
59.99



423.38
58.76

















TABLE 26







ESYLATE (FORM β)










WAVE NUMBER




(cm−1)
% T














3422.06
93.12



3303.44
89.24



3128.13
92.01



2595.94
92.67



2276.37
95.87



2051.39
95.50



1694.09
72.13



1644.75
84.09



1588.32
83.16



1529.21
65.27



1457.83
69.69



1426.95
85.03



1400.48
72.09



1385.04
83.40



1355.81
74.56



1319.88
77.31



1296.55
77.66



1253.87
64.28



1199.61
71.21



1187.91
69.92



1139.76
64.85



1092.92
83.86



1066.96
88.29



1055.19
86.48



1028.72
62.50



996.79
86.93



931.15
91.11



909.24
84.55



885.60
88.76



872.37
82.05



838.72
77.28



779.73
90.55



741.49
76.67



723.87
81.99



676.10
84.75



599.47
91.23



578.37
80.13



552.44
80.28



537.09
74.86



527.37
71.96



514.22
64.33



476.26
89.39



460.92
87.09



446.30
84.63



429.94
87.20



416.02
78.03

















TABLE 27







ESYLATE (FORM β)










WAVE NUMBER




(cm−1)
% T














3303.18
78.44



3107.11
84.00



3000.63
87.00



2931.74
88.33



2582.21
87.39



2260.15
91.52



2040.56
90.88



1968.01
91.72



1689.52
55.42



1647.24
71.29



1587.52
70.97



1524.38
57.93



1453.72
46.32



1426.27
66.22



1398.05
55.56



1355.93
50.43



1309.97
80.04



1281.20
64.46



1241.00
51.31



1205.77
45.41



1184.19
43.37



1151.28
55.33



1131.31
44.71



1086.08
65.79



1061.38
70.95



1049.91
62.19



1033.17
38.75



985.47
65.92



945.83
78.73



910.85
56.84



892.18
69.98



871.99
76.39



840.95
59.27



830.58
55.72



788.17
78.25



763.00
78.08



741.34
50.54



682.32
67.23



644.25
70.08



612.89
65.29



591.48
61.15



578.14
47.06



551.71
51.97



529.84
43.75



518.10
46.42



468.69
66.48



457.49
62.27



446.73
65.90



430.38
71.60



405.91
50.91










(Preparation of Pharmaceutical Composition)

    1 mg tablet


24 g of a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C) (hereunder, referred to as “Crystalline Form C”) and 192 g of light anhydrous silicic acid (anti-gelation agent; trade name: Aerosil (registered trademark) 200, Nippon Aerosil Co., Ltd.) were mixed using a 20 L super mixer, after which 1236 g of D-mannitol (excipient; Towa Chemical Industry Co., Ltd.), 720 g of crystalline cellulose (excipient; trade name: Avicel PH 101, Asahi Chemical Industry Co., Ltd.) and 72 g of hydroxypropylcellulose (binder; trade name: HPC-L, Nippon Soda Co., Ltd.) were further added and mixed. Thereafter, a suitable amount of anhydrous ethanol was added to produce granulated products containing Crystalline Form C. The granulated products were dried with a shelf dryer (60° C.), and size-controlled using a power mill to produce granules. The obtained granules were mixed in a 20 L tumbler mixer with 120 g of croscarmellose sodium (disintegrator; trade name: Ac-Di-Sol, FMC International Inc.) and 36 g of sodium stearyl fumarate (lubricant; JRS Pharma LP), and the resulting mixture was formed into tablets with a tableting machine to produce tablets having a total weight of 100 mg. These tablets were then coated using a tablet coating machine employing a 10% aqueous solution of opadry yellow (opadry 03F42069 yellow, Colorcon (Japan) Ltd.) as a coating solution, to produce coated tablets having a total weight of 105 mg.
10 mg Tablet
60 g of Crystalline Form C and 192 g of light anhydrous silicic acid (anti-gelation agent; trade name: Aerosil (registered trademark) 200, Nippon Aerosil Co., Ltd.) were mixed using a 20 L super mixer, after which 1200 g of D-mannitol (excipient; Towa Chemical Industry Co., Ltd.), 720 g of crystalline cellulose (excipient; trade name: Avicel PH 101, Asahi Chemical Industry Co., Ltd.) and 72 g of hydroxypropylcellulose (binder; trade name: HPC-L, Nippon Soda Co., Ltd.) were further added and mixed. Thereafter, a suitable amount of anhydrous ethanol was added to produce granulated products containing Crystalline Form C. The granulated products were dried with a shelf dryer (60° C.), and size-controlled using a power mill to produce granules. The obtained granules were mixed in a 20 L tumbler mixer with 120 g of croscarmellose sodium (disintegrator; trade name: Ac-Di-Sol, FMC International Inc.) and 36 g of sodium stearyl fumarate (lubricant; JRS Pharma LP), and the resulting mixture was formed into tablets with a tableting machine to produce tables having a total weight of 400 mg. These tablets were then coated using a tablet coating machine employing a 10% aqueous solution of opadry yellow (opadry 03F42069 yellow, Colorcon (Japan) Ltd.) as a coating solution, to produce coated tablets having a total weight of 411 mg.
100 mg Tablet
31.4 of Crystalline Form C and 4 g of light anhydrous silicic acid (anti-gelation agent; trade name: Aerosil (registered trademark) 200Nippon Aerosil Co., Ltd.) were mixed using a 1 L super mixer, after which 40.1 g of anhydrous dibasic calcium phosphate (excipient; Kyowa Chemical Industry Co., Ltd.), 10 g of low-substituted hydroxypropylcellulose (binder; trade name: L-HPC (LH-21), Shin-Etsu Chemical Co., Ltd.) and 3 g of hydroxypropylcellulose (binder; trade name: HPC-L, Nippon Soda Co., Ltd.) were further added and mixed. Thereafter, a suitable amount of anhydrous ethanol was added thereto to produce granulated products containing Crystalline Form C. The granulated products were dried with a shelf dryer (60° C.), and size-controlled using a power mill to produce granules. The obtained granules were mixed with 10 g of croscarmellose sodium (disintegrator; trade name: Ac-Di-Sol, FMC International Inc.) and 1.5 g of sodium stearyl fumarate (lubricant; JRS Pharma LP), and the resulting mixture was formed into tablets with a tableting machine to produce tablets having a total weight of 400 mg.
INDUSTRIAL APPLICABILITY
The salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the solvate of the salt as well as the crystalline form thereof according to the present invention have excellent characteristics in terms of physical properties and pharmacokinetics, and are extremely useful as an angiogenesis inhibitor or a c-Kit kinase inhibitor.

## Claims

1. A crystalline form (Form A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 9.65° and 18.37° in a powder X-ray diffraction.

2. A crystalline form (Form A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having peaks at chemical shifts of about 162.4 ppm, about 128.0 ppm, about 102.3 ppm and about 9.9 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.

3. A crystalline form (Form A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having absorption bands at wavenumbers of 1161±1 cm−1 and 1044±1 cm−1 in an infrared absorption spectrum.

4. A crystalline form (Form B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 5.72° and 13.84° in a powder X-ray diffraction.

5. A crystalline form (Form B) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having absorption bands at wavenumbers of 1068±1 cm−1 and 918±1 cm−1 in an infrared absorption spectrum.

6. A crystalline form (Form C) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 14.20° and 17.59° in a powder X-ray diffraction.

7. A crystalline form (Form C) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having peaks at chemical shifts of about 160.2 ppm, about 126.6 ppm, about 105.6 ppm and about 7.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.

8. A crystalline form (Form C) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having absorption bands at wavenumbers of 1324±1 cm−1 and 579±1 cm−1 in an infrared absorption spectrum.

9. A crystalline form (Form F) of a hydrate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 8.02° and 18.14° in a powder X-ray diffraction.

10. A crystalline form (Form I) of an acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 9.36° and 12.40° in a powder X-ray diffraction.

11. A crystalline form (Form I) of an acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate having absorption bands at wavenumbers of 1750±1 cm−1 and 1224±1 cm−1 in an infrared absorption spectrum.

12. A crystalline form (Form α) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 15.70° and 17.18° in a powder X-ray diffraction.

13. A crystalline form (Form α) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate having absorption bands at wavenumbers of 1320±1 cm−1 and 997±1 cm−1 in an infrared absorption spectrum.

14. A crystalline form (Form β) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate having diffraction peaks at diffraction angles (2θ±0.2°) of 6.48° and 9.58° in a powder X-ray diffraction.

15. A crystalline form (Form β) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate having absorption bands at wavenumbers of 1281±1 cm−1 and 985±1 cm−1 in an infrared absorption spectrum.

16. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form A), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, methanol and methanesulfonic acid to dissolve.

17. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form A), comprising:
mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve; and
adding ethanol to the mixture.

18. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form B), comprising a step of drying a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I) at 30° C. for 3 hours and at 40° C. for 16 hours to remove acetic acid.

19. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of heating a crystalline form of the dimethyl sulfoxide solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate at 115° C. for 10 hours.

20. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of mixing a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I) and ethanol.

21. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-methoxy-6-quinolinecarboxamide Methanesulfonate (Form C), comprising:
mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve; and
adding 2-propanol to the mixture.

22. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form C), comprising a step of humidifying a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form B).

23. A process for preparing a crystalline form of the hydrate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form F), comprising:
mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve and
adding ethyl acetate to the mixture.

24. A process for preparing a crystalline form of the acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (Form I), comprising:
mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and methanesulfonic acid to dissolve; and
adding 1-propanol to the mixture.

25. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form α), comprising a step of mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, dimethyl sulfoxide and ethanesulfonic acid to dissolve.

26. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form β), comprising a step of mixing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form α) and ethanol.

27. A process for preparing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate (Form β), comprising:
mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid and ethanesulfonic acid to dissolve; and
adding 2-propanol and water to the mixture.

28. A pharmaceutical composition in the form of a tablet, powder, granule, capsule or lozenge, said pharmaceutical composition comprising the crystalline form according to claim 15; and
a pharmaceutically acceptable carrier.