[go: up one dir, main page]

WO2013103004A1 - Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide - Google Patents

Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide Download PDF

Info

Publication number
WO2013103004A1
WO2013103004A1 PCT/JP2012/050063 JP2012050063W WO2013103004A1 WO 2013103004 A1 WO2013103004 A1 WO 2013103004A1 JP 2012050063 W JP2012050063 W JP 2012050063W WO 2013103004 A1 WO2013103004 A1 WO 2013103004A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
methylsulfonyl
methoxyphenyl
propyl
crystals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2012/050063
Other languages
French (fr)
Japanese (ja)
Inventor
哲央 山口
孝征 石毛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Pharma Corp
Original Assignee
Mitsubishi Tanabe Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Tanabe Pharma Corp filed Critical Mitsubishi Tanabe Pharma Corp
Priority to PCT/JP2012/050063 priority Critical patent/WO2013103004A1/en
Publication of WO2013103004A1 publication Critical patent/WO2013103004A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present invention provides (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3 having an I Kur blocking action useful for the prevention or treatment of atrial fibrillation and the like. It relates to a novel crystalline form of-(methylsulfonyl) propyl] but-2-enamide, a process for its preparation, a pharmaceutical composition thereof and a pharmaceutical use thereof.
  • the phenomenon of obtaining two or more crystal forms in the same compound is called polymorphism, and the individual crystal forms are called crystal polymorphs.
  • Different crystal forms usually have different physicochemical properties such as density, melting point, solubility and stability. Therefore, it is useful to study the polymorphism of a compound that can be a pharmaceutical and obtain a single crystal with excellent physicochemical properties.
  • Patent Document 1 discloses a compound having an I Kur blocking action useful for the prevention or treatment of atrial fibrillation and the like, which is represented by the following formula (2E) -3- (1H- Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide (hereinafter also referred to as compound (I)) is described.
  • compound (I) hereinafter also referred to as compound (I)
  • Patent Document 1 has no specific description or suggestion regarding the solid state, physicochemical properties, and polymorphism of Compound (I).
  • the present invention relates to a novel crystalline form of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide
  • the purpose is to provide.
  • the present inventors have found that the compound (I) has various crystal forms.
  • the compound (I) was found to contain A-form crystals, B-form crystals, C-form crystals, D-form crystals and E-form crystals.
  • the C-type crystal and the E-type crystal are crystal forms having good storage stability, and among them, the E-type crystal is a stable crystal, and the C-type crystal is a crystal having good solubility. It has also been found that C-type crystals and E-type crystals can be made separately.
  • the gist of the present invention is as follows. 1. Crystal of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide. 2. In the powder X-ray diffraction spectrum, peaks at diffraction angles represented by 2 ⁇ of 6.2 ° ⁇ 0.2 ° and 10.5 ° ⁇ 0.2 ° are shown as (2E) -3- (1H-indazole-3 Form C crystals of -yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide. 3.
  • (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide shows a peak at 0.2 ° C crystal. 5.
  • the (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] powder X-ray diffraction spectrum has the pattern shown in FIG. C-form crystal of but-2-enamide. 6).
  • a pharmaceutical comprising the crystal according to any one of 1 to 13 above.
  • a pharmaceutical composition comprising the crystal according to any one of 1 to 13 above and a pharmacologically acceptable carrier.
  • An I Kur blocking agent comprising the crystal according to any one of 1 to 13 as an active ingredient.
  • a preventive or therapeutic agent for cardiac arrhythmia comprising the crystal according to any one of 1 to 13 as an active ingredient.
  • 18. 14 A preventive or therapeutic agent for atrial fibrillation comprising the crystal according to any one of 1 to 13 as an active ingredient.
  • the good solvent is a solvent selected from acetone, methanol, tetrahydrofuran, acetonitrile, benzyl alcohol, formamide, chloroform, ethyl acetate, ethanol, 2-butanol, 1,4-dioxane and cyclohexanone, and the poor solvent is hexane, heptane, toluene and 23.
  • the production method according to 22 above which is a solvent selected from water.
  • the C-type crystal and E-type crystal of the present invention can be produced using a pharmacologically and / or biologically acceptable solvent that is safe for the human body. Therefore, it is very useful as an active ingredient of a drug substance or drug.
  • the E-type crystal is a crystal that exists very stably in a wide temperature range including room temperature, and has excellent stability during storage.
  • C-type crystals satisfy a certain storage stability and are particularly good in solubility.
  • the stability during storage means that the crystalline form is maintained even when stored for a short time (about 1 week) or for a long time (about 3 months) at a certain temperature (for example, room temperature to 60 ° C.) and normal pressure. Change, increase in the amount of related substances, etc., or very little.
  • Form C crystals of the present invention are characterized by one or more of the following: (a) having the powder X-ray diffraction pattern shown in FIG. 1 and / or the differential scanning calorimetry (DSC) curve shown in FIG. Is preferred. (B) The characteristic peaks in the powder X-ray diffraction pattern are 6.2 ° ⁇ 0.2 °, 10.5 ° ⁇ 0.2 °, 12.3 ° ⁇ 0.2 as diffraction angles represented by 2 ⁇ . And 16.4 ° ⁇ 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 108 to 112 ° C., particularly 111 ° C.
  • the C-form crystal of the present invention can be obtained by adding water to compound (I) and then stirring to crystallize. In the crystallization method, C-type crystals can be added as seed crystals.
  • the C-form crystal of the present invention comprises compound (I) in a good solvent [ketone (eg, acetone, cyclohexanone), ester (eg, ethyl acetate), alcohol (eg, methanol, ethanol, isopropanol, 2-butanol), Examples include ethers (for example, tetrahydrofuran, 1,4-dioxane), nitriles (for example, acetonitrile), amides (for example, formamide), halogenated hydrocarbons (for example, chloroform), and mixed solvents of these solvents.
  • ketone eg, acetone, cyclohexanone
  • ester eg, ethyl acetate
  • alcohol eg, methanol,
  • a good solvent solution of compound (I) as a raw material can be crystallized by adding it to an aqueous suspension of seed crystals, and compound (I) as a raw material can be crystallized with good reproducibility.
  • C-type crystals can be obtained. Crystallization of the C-form crystal is usually performed at 0 ° C. to the reflux temperature of the solvent, preferably at room temperature.
  • the starting compound (I) may be a solvate or hydrate of compound (I), or only crystals other than C-type crystals. Instead, it may be a powder, amorphous or oily substance.
  • the stirring time is, for example, 1 hour to 1 week, and is arbitrarily selected depending on the type of solvent used, temperature, and the like.
  • the precipitated C-form crystals are dried at 5 to 50 ° C. after filtering the solution or separating from the solvent by centrifugation or the like. Moreover, you may dry under reduced pressure as needed.
  • the C-type crystal of the present invention exists as 0.2 to 0.6 hydrate at normal temperature and 10 to 95% relative humidity, and exists as about 0.2 hydrate at 10% relative humidity.
  • Form E crystals of the present invention are characterized by one or more of the following: (a) having a powder X-ray diffraction pattern shown in FIG. 3 and / or a differential scanning calorimetry (DSC) curve shown in FIG. Is preferred. (B) The characteristic peaks in the powder X-ray diffraction pattern are 10.2 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 15.2 ° ⁇ 0.2 as diffraction angles represented by 2 ⁇ . And 15.6 ° ⁇ 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 160 to 163 ° C., particularly 162 ° C.
  • compound (I) is compounded with a good solvent (synonymous with the good solvent, preferably methanol, ethanol, ethyl acetate, more preferably ethyl acetate) and a poor solvent [aromatic hydrocarbon (for example, , Benzene, toluene), hydrocarbon (for example, hexane, heptane), water, and a mixed solvent of these solvents, preferably hexane, heptane, toluene, water, more preferably hexane] in a mixed solvent. And obtained by crystallization. Crystallization of the E-form crystal is usually carried out from 0 ° C.
  • E-type crystals can be added as seed crystals.
  • Compound (I) as a raw material may be a solvate or hydrate of compound (I), and may be not only crystals other than E-form crystals but also powders, amorphous or oily substances. .
  • the mixing ratio of the mixed solvent of the good solvent and the poor solvent is arbitrarily selected depending on the raw material and the solvent to be used.
  • the stirring time is, for example, 1 hour to 1 week, and is arbitrarily selected depending on the type of solvent used, temperature, and the like.
  • the precipitated E-form crystals are dried at room temperature to 50 ° C. after filtering the solution or separating from the solvent by centrifugation or the like. Moreover, you may dry under reduced pressure as needed.
  • Compound (I) includes A-type crystals, B-type crystals, and D-type crystals.
  • the form A crystal of compound (I) is a mixture of two kinds of crystals including a form C crystal and a form D crystal.
  • Form A crystals of compound (I) are characterized by one or more of the following: (a) powder X-ray diffraction pattern shown in FIG. 5 and / or differential scanning calorimetry (DSC) curve shown in FIG. It is preferable to have.
  • DSC differential scanning calorimetry
  • the melting point (extrapolated onset temperature) by DSC is 105 to 107 ° C. derived from the D-form crystal, particularly 106 ° C. An endothermic peak derived from C-type crystals may be observed at 108 to 112 ° C.
  • the characteristic peak in the powder X-ray diffraction pattern can include 6.6 ° ⁇ 0.2 ° derived from the D-form crystal as the diffraction angle represented by 2 ⁇ , and the characteristic peak of the C-form crystal.
  • Form A crystals of compound (I) can be obtained by stirring and crystallizing compound (I) from a mixed solvent of a good solvent (preferably ethyl acetate) and a poor solvent (preferably hexane).
  • Form B crystals of compound (I) are characterized by one or more of the following: (a) powder X-ray diffraction pattern shown in FIG. 7 and / or differential scanning calorimetry (DSC) curve shown in FIG. It is preferable to have. (B) The characteristic peaks in the powder X-ray diffraction pattern are 4.8 ° ⁇ 0.2 °, 9.6 ° ⁇ 0.2 °, and 14.4 ° ⁇ 0.2 as diffraction angles represented by 2 ⁇ . And 17.1 ° ⁇ 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 114 to 117 ° C., and particularly 116 ° C. can be mentioned.
  • Form B crystals of compound (I) can be obtained by stirring and crystallizing compound (I) in a mixed solvent of a good solvent (preferably ethyl acetate) and a poor solvent (preferably hexane).
  • the crystal form of the compound (I) is preferably C-form crystal or E-form crystal, and particularly preferably E-form crystal.
  • the C-form crystal and the E-form crystal of compound (I) can be obtained as a single crystal form.
  • the obtained compound (I) may become a mixture.
  • the mixture means a mixture containing 1% or more of one or more other crystal forms, and the mixing ratio in the mixture may be arbitrary.
  • a single crystal form is preferred.
  • crystal form of the present invention particularly C-form crystal and E-form crystal (preferably E-form crystal) are stable crystals, so that mass synthesis is possible, and preparation of tablets and the like is easy. As such, it itself is useful as a drug substance. Moreover, even the mixture of crystal forms of the present invention can be used as an active pharmaceutical ingredient.
  • the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and C-form crystals or E-form crystals.
  • the present invention also provides a preventive or therapeutic agent for arrhythmia, particularly atrial fibrillation based on an I Kur blocking action, which comprises C-form crystals or E-form crystals.
  • the pharmaceutical composition containing the C-form crystal or E-form crystal of the present invention can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the active ingredient compound and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), A lubricant (magnesium stearate, talc, polyethylene glycol, silica), a disintegrant (potato starch), a wetting agent (sodium lauryl sulfate) and the like can be mentioned.
  • the pharmaceutical composition containing the C-form crystal or E-form crystal of the present invention can be administered orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation.
  • Examples of pharmaceutical preparations suitable for oral administration include solid preparations such as tablets, granules, capsules and powders, or solution preparations, suspension preparations, emulsion preparations and the like.
  • Pharmaceutical formulations suitable for parenteral administration include, for example, suppositories, injections, drops, and inhalation formulations.
  • the pharmaceutical composition of the present specification is about 0.003 mg / kg to about 100 mg / kg body weight (preferably about 0.01 mg / kg body weight) of active ingredient per dosage unit, for example, tablet, capsule, powder, injection, suppository.
  • Kg to about 30 mg / kg, more preferably about 0.05 mg / kg to about 10 mg / kg
  • the dose may be appropriately increased or decreased depending on the administration method, patient condition, disease severity, and the like.
  • Mobile phase A; water / trifluoroacetic acid (2000: 1), B; acetonitrile / trifluoroacetic acid (2000: 1)
  • Concentration gradient control Mixer dose 0.5 mL
  • Flow rate 1.0 mL / min
  • Injection volume 1 ⁇ L
  • Equipment High-performance liquid chromatograph Class-VP system (Shimadzu Corporation)
  • Column temperature constant temperature around 40 ° C.
  • Example 1 (2E) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide C-form crystals described in WO2009 / 041559 1 mL of water was added to 300 mg of compound (I) synthesized according to the prepared method, and the mixture was stirred at room temperature for 2 days. The solid was filtered, washed with 10 mL of water, and air-dried at room temperature for 3 days to obtain 320 mg of C-form crystals.
  • the physical properties of the C-type crystals were as follows.
  • Powder X-ray diffraction spectrum Differential scanning calorimetry: The sample was filled in a 40 ⁇ L standard aluminum pan and measured. As a result, the melting point (extrapolated onset temperature) was found around 108 ° C. (Alternative method) An E-form crystal (1.00 g) of compound (I) synthesized according to the method described in WO2009 / 041559 was dissolved in 12 mL of acetone under reflux to obtain an acetone solution. To 100 mL of water, 0.01 g of C-form crystals were added and stirred to obtain a suspension. An acetone solution was gradually added dropwise to the suspension while stirring. The solid was filtered and dried under reduced pressure at 40 ° C. for 2 hours to obtain 0.96 g of C-form crystals. In addition, the obtained C-type crystal was in agreement with the above-mentioned powder X-ray diffraction spectrum. A melting point was observed around 111 ° C.
  • Example 2 E-type crystals of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide described in WO2009 / 041559
  • 600 mL of ethyl acetate was added, and the mixture was heated to reflux for 1 hour with stirring. Cooled to room temperature with stirring for 4 hours. The solid was filtered and dried under reduced pressure at 40 ° C. for 3 hours and at room temperature for 16 hours to obtain 53.83 g of E-type crystals.
  • the physical properties of the E type crystal were as follows.
  • Powder X-ray diffraction spectrum Differential scanning calorimetry (DSC): The measurement was performed under the same conditions as in the differential scanning calorimetry described in Example 1. As a result, the melting point (extrapolated onset temperature) was found around 162 ° C. (Alternative method) 108 mL of ethyl acetate was added to 11.00 g of compound (I) synthesized according to the method described in WO2009 / 041559, and the mixture was stirred at 80 ° C. for 1 hour. 36 mL of n-hexane was added with stirring while hot, and then cooled to room temperature with stirring for 40 minutes. The solid was filtered and dried under reduced pressure at 50 ° C. to obtain 10.31 g of E-form crystals. The obtained E-form crystal was consistent with the aforementioned powder X-ray diffraction spectrum.
  • DSC Differential scanning calorimetry
  • Pharmacological Test Example 1 Effect on Atrial Effective Refractory Period (ERP) in Anesthetized Dogs (1) Surgery Intravenous pentobarbital sodium administration (introduction: 30 mg / kg, sustained: 5 mg / kg /) using a bisexual hybrid dog hr), the cannula was inserted into the airway, and artificial respiration (15 cc / kg / stroke, 20 cycles / min) was performed. Catheters for continuous anesthesia and sample administration were inserted into the bilateral forearm mesenteric veins, respectively. A catheter was inserted into the left femoral vein and the fluid replacement was continuously administered (0.5 ml / min).
  • ERP Atrial Effective Refractory Period
  • the presence or absence of atrial excitement was determined from the atrial electrogram.
  • ERP ms
  • the compound was administered intravenously.
  • ERP was measured after a certain time from compound administration.
  • the ERP after the start of drug administration was compared with the ERP before the drug administration, and the rate of change (%) was calculated.
  • Compound (I) exhibited an ERP prolongation effect of 10% or more when administered at 30 ⁇ g / kg / min.
  • Test Example 1 Solubility Measurement 2 mL of water was added to C-form crystals and E-form crystals (each about 5 mg), shaken at 37 ° C. and 100 rpm for about 21 hours, and then centrifuged (3000 rpm, 10 min, 37 ° C.). )did. The supernatant was filtered, and 500 ⁇ L of acetonitrile was added to 500 ⁇ L of the filtrate and mixed to prepare a sample solution. 500 ⁇ L of water was added to 500 ⁇ L of an E-form crystal acetonitrile solution (0.02 mg / ml) and mixed to obtain a standard solution.
  • Test Example 2 Moisture adsorption measurement C-type crystals and E-type crystals (each about 5 mg) were placed in a quartz cell, and the weight at the start of measurement was measured using a DVS-1 type moisture adsorption device (Surface Measurement Systems Limited). . At 25 ° C., the weight change when the humidity was changed stepwise (relative humidity 0% RH to 95% RH) was recorded over time, and the equilibrium weight at each humidity was determined. The weight change rate and hydration number at each humidity were determined based on the anhydride converted from the amount of water at the time of drying (0% RH) or at the start. As a result, as shown in FIG.
  • the C-type crystal absorbed about 1.6% at a relative humidity of about 70% and increased its weight by absorbing about 1.9% at a relative humidity of about 95%.
  • the E-form crystal absorbed about 0.3% at a relative humidity of about 70%, and increased its weight by absorbing about 1.2% at a relative humidity of about 95%. It was confirmed that C-type crystals and E-type crystals have physical properties suitable as drug substances for pharmaceuticals. In addition, it was confirmed that the C-type crystal has a hydration stage and is 0.2 to 0.6 hydrate at room temperature and a relative humidity of 10 to 95%.
  • Test Example 3 Stability test A-form crystal, B-form crystal, C-form crystal and E-form crystal were stored under the conditions of Table 5, and the total amount of increased related substances and the presence or absence of changes in the crystal form were confirmed. .
  • related substances increased in the A-form crystal.
  • C-type crystals after 1 week of storage at 60 ° C. and 75% RH.
  • B-form crystals increased in related substances.
  • no increase in the related substance was observed in the E-type crystal, a slight increase in the related substance was confirmed in the C-type crystal.
  • Test Example 4 Light Stability Test C-type crystals and E-type crystals were exposed to light using a D65 fluorescent lamp for 2 weeks at a total illumination of 1.2 million lux ⁇ hr and a total ultraviolet radiation energy of 200 W ⁇ h / m 2 or more. The presence or absence of an increase in related substances and a change in crystal form after storage was confirmed. As a result, as shown in Table 6, it was confirmed that the E-type crystal was more stable.
  • Test Example 5 Stability of Form A and Form B Crystals in Water 1 mL of water was added to about 10 mg of Form A crystals, covered, and stirred at room temperature for about 20 hours.
  • Test Example 6 Confirmation of stable form at room temperature About 10 mg each of sample 1 and sample 2 are placed in the same container, 1 mL of toluene or 1 mL of water and 0.05 mL of methanol are added, and the lid is covered for 3 days at room temperature. And stirred. Thereafter, the suspension was collected by filtration, and the crystal form was confirmed by powder X-ray diffraction. As a result, E-type crystals were obtained under all conditions as shown in Table 7. Therefore, among the A-form crystals, B-form crystals, C-form crystals, and E-form crystals, the E-form crystals were stable at room temperature.
  • Novel crystal forms of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide, especially C form The crystal satisfies a certain storage stability and is excellent in solubility, and the E-form crystal is a crystal that exists very stably in a wide temperature range including room temperature, and is excellent in storage stability and light stability. Useful as an active pharmaceutical ingredient.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a novel crystal form of (2E)-3-(1H-indazol-3-yl)-N-(3-methoxyphenyl)-N-[3-(methylsulfonyl)propyl]but-2-enamide. The novel crystal form of (2E)-3-(1H-indazol-3-yl)-N-(3-methoxyphenyl)-N-[3-(methylsulfonyl)propyl]but-2-enamide has excellent stability and other such properties, and is therefore useful as a pharmaceutical drug.

Description

（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの結晶形Crystalline form of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide

　本発明は、心房細動などの予防または治療に有用なＩＫｕｒ遮断作用を有する（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの新規な結晶形、その製造方法、その医薬組成物およびその医薬用途に関する。 The present invention provides (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3 having an I Kur blocking action useful for the prevention or treatment of atrial fibrillation and the like. It relates to a novel crystalline form of-(methylsulfonyl) propyl] but-2-enamide, a process for its preparation, a pharmaceutical composition thereof and a pharmaceutical use thereof.

　同一の化合物において２種以上の結晶形が得られる現象はポリモルフィズム（polymorphism）と呼ばれ、個々の結晶形は互いに結晶多形と呼ばれている。結晶形が異なると、通常、密度、融点、溶解度、安定性などの物理化学的性質が異なる場合がある。
　したがって、医薬品になりうる化合物のポリモルフィズムを検討し、優れた物理化学的性質の単一結晶を獲得することは有用である。しかしながら、単一結晶を見い出すこと、及び供給する方法を発見することは容易ではなく、また、医薬品になりうる化合物の結晶が医薬品として望ましい物理化学的性質を持つかは、発見した単一結晶の性質を確認しなければ分からず、鋭意検討を必要とする。 The phenomenon of obtaining two or more crystal forms in the same compound is called polymorphism, and the individual crystal forms are called crystal polymorphs. Different crystal forms usually have different physicochemical properties such as density, melting point, solubility and stability.
Therefore, it is useful to study the polymorphism of a compound that can be a pharmaceutical and obtain a single crystal with excellent physicochemical properties. However, it is not easy to find a single crystal and to find a method for supplying it, and whether a crystal of a compound that can be a pharmaceutical has desirable physicochemical properties as a pharmaceutical has been found. If the nature is not confirmed, it will not be known, and intensive study is required.

　一方、特許文献１には、心房細動などの予防または治療に有用なＩＫｕｒ遮断作用を有する化合物が開示されており、当該文献には下式で示される（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミド（以下、化合物（Ｉ）ともいう）が記載されている。

Figure JPOXMLDOC01-appb-C000001
　しかしながら、特許文献１には、化合物（Ｉ）の固体状態、物理化学的性質、及びポリモルフィズムに関する具体的な記載はなく、示唆もされていない。 On the other hand, Patent Document 1 discloses a compound having an I Kur blocking action useful for the prevention or treatment of atrial fibrillation and the like, which is represented by the following formula (2E) -3- (1H- Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide (hereinafter also referred to as compound (I)) is described.
Figure JPOXMLDOC01-appb-C000001
 However, Patent Document 1 has no specific description or suggestion regarding the solid state, physicochemical properties, and polymorphism of Compound (I).

国際公開ＷＯ２００９／０４１５５９パンフレットInternational Publication WO2009 / 041559 Pamphlet

　本発明は、（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの新規な結晶形を提供することを目的とする。 The present invention relates to a novel crystalline form of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide The purpose is to provide.

　本発明者等は、化合物（Ｉ）について種々検討した結果、化合物（Ｉ）には種々の結晶形が存在するという知見を得た。そして化合物（Ｉ）にはＡ形結晶、Ｂ形結晶、Ｃ形結晶、Ｄ形結晶およびＥ形結晶が存在することを見い出した。そのうちＣ形結晶及びＥ形結晶は保存安定性が良好な結晶形であり、その中でＥ形結晶は安定な結晶であり、Ｃ形結晶は溶解性の良好な結晶であることを見い出した。また、Ｃ形結晶、Ｅ形結晶は作り分けることが可能であることを見い出した。 As a result of various studies on the compound (I), the present inventors have found that the compound (I) has various crystal forms. The compound (I) was found to contain A-form crystals, B-form crystals, C-form crystals, D-form crystals and E-form crystals. Among them, the C-type crystal and the E-type crystal are crystal forms having good storage stability, and among them, the E-type crystal is a stable crystal, and the C-type crystal is a crystal having good solubility. It has also been found that C-type crystals and E-type crystals can be made separately.

　即ち、本発明の要旨は以下の通りである。
１．（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの結晶。
２．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°および１０．５°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。
３．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°、１０．５°±０．２°および１６．４°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。
４．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°、１０．５°±０．２°、１２．３°±０．２°および１６．４°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。
５．粉末Ｘ線回折スペクトルが図１に示すパターンを有する、（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。
６．示差走査熱量測定による融点が１０８～１１２℃である（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。
７．示差走査熱量測定による融点が１０８～１１２℃である前記２～５のいずれかに記載のＣ形結晶。 That is, the gist of the present invention is as follows.
1. Crystal of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide.
2. In the powder X-ray diffraction spectrum, peaks at diffraction angles represented by 2θ of 6.2 ° ± 0.2 ° and 10.5 ° ± 0.2 ° are shown as (2E) -3- (1H-indazole-3 Form C crystals of -yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide.
3. In the powder X-ray diffraction spectrum, peaks are shown at 6.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, and 16.4 ° ± 0.2 ° as diffraction angles represented by 2θ (2E ) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide C-form crystals.
4). In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 6.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, and 16.4 ° ±. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide shows a peak at 0.2 ° C crystal.
5. The (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] powder X-ray diffraction spectrum has the pattern shown in FIG. C-form crystal of but-2-enamide.
6). (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] butene having a melting point of 108 to 112 ° C. by differential scanning calorimetry -2-Cenamide C crystal.
7). 6. The C-type crystal as described in any one of 2 to 5 above, which has a melting point of 108 to 112 ° C. by differential scanning calorimetry.

８．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°および１１．０°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。
９．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°、１１．０°±０．２°および１５．２°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。
１０．粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°、１１．０°±０．２°、１５．２°±０．２°および１５．６°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。
１１．粉末Ｘ線回折スペクトルが図３に示すパターンを有する、（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。
１２．示差走査熱量測定による融点が１６０～１６３℃である（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。
１３．示差走査熱量測定による融点が１６０～１６３℃である前記８～１１のいずれかに記載のＥ形結晶。 8). In the powder X-ray diffraction spectrum, peaks at diffraction angles represented by 2θ of 10.2 ° ± 0.2 ° and 11.0 ° ± 0.2 ° are shown (2E) -3- (1H-indazole-3 E-form crystals of -yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide.
9. In the powder X-ray diffraction spectrum, peaks are shown at 10.2 ° ± 0.2 °, 11.0 ° ± 0.2 °, and 15.2 ° ± 0.2 ° as diffraction angles represented by 2θ (2E ) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide crystals.
10. In the powder X-ray diffraction spectrum, diffraction angles represented by 2θ are 10.2 ° ± 0.2 °, 11.0 ° ± 0.2 °, 15.2 ° ± 0.2 °, and 15.6 ° ±. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide shows a peak at 0.2 ° E crystal.
11. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl], whose powder X-ray diffraction spectrum has the pattern shown in FIG. E-form crystal of but-2-enamide.
12 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] butene having a melting point of 160 to 163 ° C. by differential scanning calorimetry E-form of -2-enamide.
13. 12. The E-type crystal as described in any one of 8 to 11 above, having a melting point of 160 to 163 ° C. as determined by differential scanning calorimetry.

１４．前記１～１３のいずれかに記載の結晶を含有する医薬。
１５．前記１～１３のいずれかに記載の結晶および薬理的に許容しうる担体を含有する医薬組成物。
１６．前記１～１３のいずれかに記載の結晶を有効成分として含有するＩＫｕｒ遮断薬。
１７．前記１～１３のいずれかに記載の結晶を有効成分として含有する心不整脈の予防または治療剤。
１８．前記１～１３のいずれかに記載の結晶を有効成分として含有する心房細動の予防または治療剤。 14 A pharmaceutical comprising the crystal according to any one of 1 to 13 above.
15. 14. A pharmaceutical composition comprising the crystal according to any one of 1 to 13 above and a pharmacologically acceptable carrier.
16. 14. An I Kur blocking agent comprising the crystal according to any one of 1 to 13 as an active ingredient.
17. A preventive or therapeutic agent for cardiac arrhythmia comprising the crystal according to any one of 1 to 13 as an active ingredient.
18. 14. A preventive or therapeutic agent for atrial fibrillation comprising the crystal according to any one of 1 to 13 as an active ingredient.

１９．（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドに水を加えた後、攪拌して結晶化させ、乾燥させることを特徴とする前記２に記載のＣ形結晶の製造方法。
２０．（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドを良溶媒および水の混合溶媒中、種晶の存在下で攪拌して結晶化させ、乾燥させることを特徴とする前記２に記載のＣ形結晶の製造方法。
２１．良溶媒がアセトンである前記２０に記載の製造方法。
２２．（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドを良溶媒中または良溶媒および貧溶媒の混合溶媒中で撹拌して結晶化させ、乾燥させることを特徴とする前記８に記載のＥ形結晶の製造方法。
２３．良溶媒がアセトン、メタノール、テトラヒドロフラン、アセトニトリル、ベンジルアルコール、ホルムアミド、クロロホルム、酢酸エチル、エタノール、２－ブタノール、１，４－ジオキサンおよびシクロヘキサノンから選ばれる溶媒であり、貧溶媒がヘキサン、ヘプタン、トルエンおよび水から選ばれる溶媒である前記２２に記載の製造方法。 19. Water was added to (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide, and the mixture was stirred. 3. The method for producing a C-shaped crystal as described in 2 above, wherein the crystal is crystallized and dried.
20. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide in a mixed solvent of water and water 3. The method for producing a C-shaped crystal as described in 2 above, wherein the crystal is stirred and crystallized in the presence of a seed crystal, and then dried.
21. 21. The production method according to 20 above, wherein the good solvent is acetone.
22. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide in good solvent or poor solvent and poor 9. The method for producing E-type crystals as described in 8 above, wherein the crystals are crystallized by stirring in a solvent mixture and dried.
23. The good solvent is a solvent selected from acetone, methanol, tetrahydrofuran, acetonitrile, benzyl alcohol, formamide, chloroform, ethyl acetate, ethanol, 2-butanol, 1,4-dioxane and cyclohexanone, and the poor solvent is hexane, heptane, toluene and 23. The production method according to 22 above, which is a solvent selected from water.

　本発明のＣ形結晶及びＥ形結晶は、人体に安全な、薬理学的および／または生物学的に許容される溶媒を用いて製造できる。そのため、医薬品の原薬や医薬品の有効成分として非常に有用である。さらに、Ｅ形結晶は室温を含む広い温度範囲において非常に安定に存在する結晶であり、保存時の安定性にも優れている。また、Ｃ形結晶は一定の保存時の安定性を満たし、且つ溶解性において特に良好である。
　ここで、保存時の安定性が良いとは、一定の温度（例えば、室温から６０℃）、常圧下で、短期（約１週間）または長期（約３ヶ月）にわたって保存しても、結晶形の変化、類縁物質量の増加等が起こらないか、または極めて少ないことを意味する。 The C-type crystal and E-type crystal of the present invention can be produced using a pharmacologically and / or biologically acceptable solvent that is safe for the human body. Therefore, it is very useful as an active ingredient of a drug substance or drug. Furthermore, the E-type crystal is a crystal that exists very stably in a wide temperature range including room temperature, and has excellent stability during storage. In addition, C-type crystals satisfy a certain storage stability and are particularly good in solubility.
Here, the stability during storage means that the crystalline form is maintained even when stored for a short time (about 1 week) or for a long time (about 3 months) at a certain temperature (for example, room temperature to 60 ° C.) and normal pressure. Change, increase in the amount of related substances, etc., or very little.

Ｃ形結晶の粉末Ｘ線回折パターンを示す図である。It is a figure which shows the powder X-ray-diffraction pattern of a C-form crystal. Ｃ形結晶のＤＳＣ曲線を示す図である。It is a figure which shows the DSC curve of a C-form crystal. Ｅ形結晶の粉末Ｘ線回折パターンを示す図である。It is a figure which shows the powder X-ray-diffraction pattern of E type crystal | crystallization. Ｅ形結晶のＤＳＣ曲線を示す図である。It is a figure which shows the DSC curve of E type crystal | crystallization. Ａ形結晶の粉末Ｘ線回折パターンを示す図である。It is a figure which shows the powder X-ray-diffraction pattern of A form crystal | crystallization. Ａ形結晶のＤＳＣ曲線を示す図である。It is a figure which shows the DSC curve of A-form crystal. Ｂ形結晶の粉末Ｘ線回折パターンを示す図である。It is a figure which shows the powder X-ray diffraction pattern of a B-form crystal. Ｂ形結晶のＤＳＣ曲線を示す図である。It is a figure which shows the DSC curve of a B-form crystal. Ｃ形結晶の水分吸着測定の結果を示す図である。It is a figure which shows the result of the water | moisture-content adsorption | suction measurement of a C-form crystal. Ｅ形結晶の水分吸着測定の結果を示す図である。It is a figure which shows the result of the water | moisture-content adsorption | suction measurement of E type crystal | crystallization.

　本発明のＣ形結晶は以下の一またはそれ以上により特徴付けられる：（ａ）図１に示される粉末Ｘ線回折パターンおよび／または図２に示される示差走査熱量測定（ＤＳＣ）曲線を有することが好ましい。（ｂ）粉末Ｘ線回折パターンにおける特徴的なピークは２θで表される回折角度として６．２°±０．２°、１０．５°±０．２°、１２．３°±０．２°および１６．４°±０．２°を挙げることができる。（ｃ）ＤＳＣによる融点（補外開始温度）は１０８～１１２℃であり、特に１１１℃を挙げることができる。
　本発明のＣ形結晶は、化合物（Ｉ）に水を加えた後、攪拌して結晶化させることにより得られる。当該結晶化方法では、Ｃ型結晶を種晶として添加することができる。
　また、本発明のＣ形結晶は、化合物（Ｉ）を良溶媒〔ケトン（例えば、アセトン、シクロヘキサノン）、エステル（例えば、酢酸エチル）、アルコール（例えば、メタノール、エタノール、イソプロパノール、２－ブタノール）、エーテル（例えば、テトラヒドロフラン、１，４－ジオキサン）、ニトリル（例えば、アセトニトリル）、アミド（例えば、ホルムアミド）、ハロゲン化炭化水素（例えば、クロロホルム）、およびこれら溶媒の混合溶媒があげられ、好ましくは、アセトン〕および水の混合溶媒中、種晶の存在下で撹拌して結晶化させることによっても得られる。良溶媒および水の混合溶媒の混合比率は、用いる原料および溶媒によって任意に選択し、例えば、アセトンの場合、アセトン：水＝１：１０、１：９、１：８、１：７などあげられる。原料である化合物（Ｉ）の良溶媒の溶液を、種晶の水懸濁液に加えることにより結晶化させることができ、原料である化合物（Ｉ）はＥ形結晶であっても再現性よくＣ形結晶を取得することができる。
　Ｃ形結晶の結晶化は、通常、０℃から溶媒の還流温度、好ましくは室温下で行われる。また、本発明のＣ形結晶の結晶化方法において、原料となる化合物（Ｉ）は、化合物（Ｉ）の溶媒和物または水和物であってもよく、また、Ｃ形結晶以外の結晶だけでなく、粉末、アモルファスまたは油状物質であってもよい。攪拌時間は、例えば、１時間から１週間であり、用いる溶媒の種類、温度等により任意に選択する。析出したＣ形結晶は、溶液をろ過し、または遠心分離等により溶媒と分離した後、５～５０℃で乾燥する。また、必要に応じて減圧下で乾燥してもよい。本発明のＣ形結晶は、常温、相対湿度１０～９５％にて０．２～０．６水和物として存在し、相対湿度１０％で約０．２水和物として存在する。 Form C crystals of the present invention are characterized by one or more of the following: (a) having the powder X-ray diffraction pattern shown in FIG. 1 and / or the differential scanning calorimetry (DSC) curve shown in FIG. Is preferred. (B) The characteristic peaks in the powder X-ray diffraction pattern are 6.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 as diffraction angles represented by 2θ. And 16.4 ° ± 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 108 to 112 ° C., particularly 111 ° C.
The C-form crystal of the present invention can be obtained by adding water to compound (I) and then stirring to crystallize. In the crystallization method, C-type crystals can be added as seed crystals.
The C-form crystal of the present invention comprises compound (I) in a good solvent [ketone (eg, acetone, cyclohexanone), ester (eg, ethyl acetate), alcohol (eg, methanol, ethanol, isopropanol, 2-butanol), Examples include ethers (for example, tetrahydrofuran, 1,4-dioxane), nitriles (for example, acetonitrile), amides (for example, formamide), halogenated hydrocarbons (for example, chloroform), and mixed solvents of these solvents. It can also be obtained by stirring and crystallization in the presence of seed crystals in a mixed solvent of acetone] and water. The mixing ratio of the good solvent and the mixed solvent of water is arbitrarily selected depending on the raw material and the solvent to be used. For example, in the case of acetone, acetone: water = 1: 10, 1: 9, 1: 8, 1: 7, etc. . A good solvent solution of compound (I) as a raw material can be crystallized by adding it to an aqueous suspension of seed crystals, and compound (I) as a raw material can be crystallized with good reproducibility. C-type crystals can be obtained.
Crystallization of the C-form crystal is usually performed at 0 ° C. to the reflux temperature of the solvent, preferably at room temperature. In the method for crystallizing C-type crystals of the present invention, the starting compound (I) may be a solvate or hydrate of compound (I), or only crystals other than C-type crystals. Instead, it may be a powder, amorphous or oily substance. The stirring time is, for example, 1 hour to 1 week, and is arbitrarily selected depending on the type of solvent used, temperature, and the like. The precipitated C-form crystals are dried at 5 to 50 ° C. after filtering the solution or separating from the solvent by centrifugation or the like. Moreover, you may dry under reduced pressure as needed. The C-type crystal of the present invention exists as 0.2 to 0.6 hydrate at normal temperature and 10 to 95% relative humidity, and exists as about 0.2 hydrate at 10% relative humidity.

　本発明のＥ形結晶は以下の一またはそれ以上により特徴付けられる：（ａ）図３に示される粉末Ｘ線回折パターンおよび／または図４に示される示差走査熱量測定（ＤＳＣ）曲線を有することが好ましい。（ｂ）粉末Ｘ線回折パターンにおける特徴的なピークは２θで表される回折角度として１０．２°±０．２°、１１．０°±０．２°、１５．２°±０．２°および１５．６°±０．２°を挙げることができる。（ｃ）ＤＳＣによる融点（補外開始温度）は１６０～１６３℃であり、特に１６２℃を挙げることができる。
　本発明のＥ形結晶は、化合物（Ｉ）を良溶媒（前記良溶媒と同義であり、好ましくは、メタノール、エタノール、酢酸エチル、より好ましくは酢酸エチル）および貧溶媒〔芳香族炭化水素（例えば、ベンゼン、トルエン）、炭化水素（例えば、ヘキサン、ヘプタン）、水、およびこれら溶媒の混合溶媒があげられ、好ましくは、ヘキサン、ヘプタン、トルエン、水、より好ましくはヘキサン〕の混合溶媒中、攪拌して結晶化させることにより得られる。Ｅ形結晶の結晶化は、通常、０℃から溶媒の還流温度で行われ、好ましくは原料を加熱溶解した後、室温まで冷却することにより行われる。また、本発明のＥ型結晶の結晶化方法では、Ｅ型結晶を種晶として添加することができる。原料となる化合物（Ｉ）は、化合物（Ｉ）の溶媒和物または水和物であってもよく、また、Ｅ形結晶以外の結晶だけでなく、粉末、アモルファスまたは油状物質であってもよい。良溶媒および貧溶媒の混合溶媒の混合比率は、用いる原料および溶媒によって任意に選択し、例えば、酢酸エチルおよびヘキサンの場合、酢酸エチル：ヘキサン＝３：１、２：１、１：１、１：２、１：３などあげられる。攪拌時間は、例えば、１時間から１週間であり、用いる溶媒の種類、温度等により任意に選択する。析出したＥ形結晶は、溶液をろ過し、または遠心分離等により溶媒と分離した後、室温から５０℃で乾燥する。また、必要に応じて減圧下で乾燥してもよい。 Form E crystals of the present invention are characterized by one or more of the following: (a) having a powder X-ray diffraction pattern shown in FIG. 3 and / or a differential scanning calorimetry (DSC) curve shown in FIG. Is preferred. (B) The characteristic peaks in the powder X-ray diffraction pattern are 10.2 ° ± 0.2 °, 11.0 ° ± 0.2 °, 15.2 ° ± 0.2 as diffraction angles represented by 2θ. And 15.6 ° ± 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 160 to 163 ° C., particularly 162 ° C.
In the E-type crystal of the present invention, compound (I) is compounded with a good solvent (synonymous with the good solvent, preferably methanol, ethanol, ethyl acetate, more preferably ethyl acetate) and a poor solvent [aromatic hydrocarbon (for example, , Benzene, toluene), hydrocarbon (for example, hexane, heptane), water, and a mixed solvent of these solvents, preferably hexane, heptane, toluene, water, more preferably hexane] in a mixed solvent. And obtained by crystallization. Crystallization of the E-form crystal is usually carried out from 0 ° C. to the reflux temperature of the solvent, preferably by heating and dissolving the raw material and then cooling to room temperature. In the method for crystallizing E-type crystals of the present invention, E-type crystals can be added as seed crystals. Compound (I) as a raw material may be a solvate or hydrate of compound (I), and may be not only crystals other than E-form crystals but also powders, amorphous or oily substances. . The mixing ratio of the mixed solvent of the good solvent and the poor solvent is arbitrarily selected depending on the raw material and the solvent to be used. For example, in the case of ethyl acetate and hexane, ethyl acetate: hexane = 3: 1, 2: 1, 1: 1, 1 : 2, 1: 3, etc. The stirring time is, for example, 1 hour to 1 week, and is arbitrarily selected depending on the type of solvent used, temperature, and the like. The precipitated E-form crystals are dried at room temperature to 50 ° C. after filtering the solution or separating from the solvent by centrifugation or the like. Moreover, you may dry under reduced pressure as needed.

　また、化合物（Ｉ）には、Ａ形結晶、Ｂ形結晶およびＤ形結晶が存在する。
　化合物（Ｉ）のＡ形結晶は、Ｃ形結晶およびＤ形結晶を含む２種類の結晶の混合物である。化合物（Ｉ）のＡ形結晶は、以下の一またはそれ以上により特徴付けられる：（ａ）図５に示される粉末Ｘ線回折パターンおよび／または図６に示される示差走査熱量測定（ＤＳＣ）曲線を有することが好ましい。（ｂ）ＤＳＣによる融点（補外開始温度）はＤ形結晶由来の１０５～１０７℃であり、特に１０６℃を挙げることができる。なお、１０８～１１２℃にＣ形結晶由来の吸熱ピークが観測される場合がある。また、粉末Ｘ線回折パターンにおける特徴的なピークは２θで表される回折角度としてＤ形結晶由来の６．６°±０．２°、及びＣ形結晶の特徴的なピークを挙げることができる。
　化合物（Ｉ）のＡ形結晶は、化合物（Ｉ）を良溶媒（好ましくは酢酸エチル）および貧溶媒（好ましくはヘキサン）の混合溶媒から攪拌して結晶化させることにより得られる。 Compound (I) includes A-type crystals, B-type crystals, and D-type crystals.
The form A crystal of compound (I) is a mixture of two kinds of crystals including a form C crystal and a form D crystal. Form A crystals of compound (I) are characterized by one or more of the following: (a) powder X-ray diffraction pattern shown in FIG. 5 and / or differential scanning calorimetry (DSC) curve shown in FIG. It is preferable to have. (B) The melting point (extrapolated onset temperature) by DSC is 105 to 107 ° C. derived from the D-form crystal, particularly 106 ° C. An endothermic peak derived from C-type crystals may be observed at 108 to 112 ° C. In addition, the characteristic peak in the powder X-ray diffraction pattern can include 6.6 ° ± 0.2 ° derived from the D-form crystal as the diffraction angle represented by 2θ, and the characteristic peak of the C-form crystal. .
Form A crystals of compound (I) can be obtained by stirring and crystallizing compound (I) from a mixed solvent of a good solvent (preferably ethyl acetate) and a poor solvent (preferably hexane).

　化合物（Ｉ）のＢ形結晶は、以下の一またはそれ以上により特徴付けられる：（ａ）図７に示される粉末Ｘ線回折パターンおよび／または図８に示される示差走査熱量測定（ＤＳＣ）曲線を有することが好ましい。（ｂ）粉末Ｘ線回折パターンにおける特徴的なピークは２θで表される回折角度として４．８°±０．２°、９．６°±０．２°、１４．４°±０．２°および１７．１°±０．２°を挙げることができる。（ｃ）ＤＳＣによる融点（補外開始温度）は１１４～１１７℃であり、特に１１６℃を挙げることができる。
　化合物（Ｉ）のＢ形結晶は、化合物（Ｉ）を良溶媒（好ましくは酢酸エチル）および貧溶媒（好ましくはヘキサン）の混合溶媒中、攪拌して結晶化させることにより得られる。 Form B crystals of compound (I) are characterized by one or more of the following: (a) powder X-ray diffraction pattern shown in FIG. 7 and / or differential scanning calorimetry (DSC) curve shown in FIG. It is preferable to have. (B) The characteristic peaks in the powder X-ray diffraction pattern are 4.8 ° ± 0.2 °, 9.6 ° ± 0.2 °, and 14.4 ° ± 0.2 as diffraction angles represented by 2θ. And 17.1 ° ± 0.2 °. (C) The melting point (extrapolated onset temperature) by DSC is 114 to 117 ° C., and particularly 116 ° C. can be mentioned.
Form B crystals of compound (I) can be obtained by stirring and crystallizing compound (I) in a mixed solvent of a good solvent (preferably ethyl acetate) and a poor solvent (preferably hexane).

　本発明において、結晶化の方法としては、公知の方法があげられるが、なかでも、工業的に有利な方法が望ましく、たとえば、再結晶法が好ましい。
　本発明において、化合物（Ｉ）の結晶形としてはＣ形結晶およびＥ形結晶が好ましく、特にＥ形結晶が好ましい。
　本発明の製造方法によれば、化合物（Ｉ）のＣ形結晶およびＥ形結晶を単一の結晶形として取得することができる。また、得られた化合物（Ｉ）は混合物となる場合もある。ここで、混合物とは、１種類以上の他の結晶形を１％以上含有する混合物を意味し、混合物中の混合比率は任意でよい。本発明においては、単一の結晶形が好ましい。
　このようにして得られた本発明の結晶形、特にＣ形結晶およびＥ形結晶（好ましくはＥ形結晶）は、安定な結晶であるため、大量合成が可能となり、錠剤等の製剤化が容易である等の理由から、それ自体、医薬品原薬として有用である。また、本発明の結晶形の混合物であっても医薬品原薬として利用可能である。 In the present invention, known methods may be mentioned as the crystallization method. Among them, industrially advantageous methods are desirable, and for example, a recrystallization method is preferable.
In the present invention, the crystal form of the compound (I) is preferably C-form crystal or E-form crystal, and particularly preferably E-form crystal.
According to the production method of the present invention, the C-form crystal and the E-form crystal of compound (I) can be obtained as a single crystal form. Moreover, the obtained compound (I) may become a mixture. Here, the mixture means a mixture containing 1% or more of one or more other crystal forms, and the mixing ratio in the mixture may be arbitrary. In the present invention, a single crystal form is preferred.
The thus obtained crystal form of the present invention, particularly C-form crystal and E-form crystal (preferably E-form crystal) are stable crystals, so that mass synthesis is possible, and preparation of tablets and the like is easy. As such, it itself is useful as a drug substance. Moreover, even the mixture of crystal forms of the present invention can be used as an active pharmaceutical ingredient.

　本発明は、さらに、薬学的に許容される担体及びＣ形結晶またはＥ形結晶を含有する医薬組成物を提供する。また、本発明はＣ形結晶またはＥ形結晶を含むＩＫｕｒ遮断作用に基づく不整脈、特に心房細動の予防または治療剤を提供する。
　本発明のＣ形結晶またはＥ形結晶を含有する医薬組成物は、当該有効成分化合物の治療上有効量および製薬上許容される担体からなる医薬組成物に製剤化することができる。製薬上許容される担体としては、希釈剤、結合剤（シロップ、アラビアゴム、ゼラチン、ソルビット、トラガカント、ポリビニルピロリドン）、賦形剤（乳糖、ショ糖、コーンスターチ、リン酸カリウム、ソルビット、グリシン）、滑沢剤（ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ）、崩壊剤（バレイショデンプン）および湿潤剤（ラウリル硫酸ナトリウム）等を挙げることができる。
　本発明のＣ形結晶またはＥ形結晶を含有する医薬組成物は、経口的にも非経口的にも投与することができ、好適な医薬製剤の形態で使用することができる。経口投与に好適な医薬製剤として、例えば、錠剤、顆粒剤、カプセル剤、散剤等の固体製剤、または溶液製剤、懸濁液製剤、乳化液製剤等が挙げられる。非経口投与に好適な医薬製剤として、例えば、坐剤、注射剤、点滴剤、および吸入製剤が挙げられる。
　本明細書の医薬組成物は、用量単位、例えば、錠剤、カプセル剤、散剤、注射剤、坐剤あたり、有効成分を約０．００３ｍｇ／ｋｇ～約１００ｍｇ／ｋｇ体重（好ましくは約０．０１ｍｇ／ｋｇ～約３０ｍｇ／ｋｇ、より好ましくは約０．０５ｍｇ／ｋｇ～約１０ｍｇ／ｋｇ）含有し、投与方法、患者の状態、疾患の程度等により適宜増減して投与しうる。 The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and C-form crystals or E-form crystals. The present invention also provides a preventive or therapeutic agent for arrhythmia, particularly atrial fibrillation based on an I Kur blocking action, which comprises C-form crystals or E-form crystals.
The pharmaceutical composition containing the C-form crystal or E-form crystal of the present invention can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the active ingredient compound and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), A lubricant (magnesium stearate, talc, polyethylene glycol, silica), a disintegrant (potato starch), a wetting agent (sodium lauryl sulfate) and the like can be mentioned.
The pharmaceutical composition containing the C-form crystal or E-form crystal of the present invention can be administered orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation. Examples of pharmaceutical preparations suitable for oral administration include solid preparations such as tablets, granules, capsules and powders, or solution preparations, suspension preparations, emulsion preparations and the like. Pharmaceutical formulations suitable for parenteral administration include, for example, suppositories, injections, drops, and inhalation formulations.
The pharmaceutical composition of the present specification is about 0.003 mg / kg to about 100 mg / kg body weight (preferably about 0.01 mg / kg body weight) of active ingredient per dosage unit, for example, tablet, capsule, powder, injection, suppository. / Kg to about 30 mg / kg, more preferably about 0.05 mg / kg to about 10 mg / kg), and the dose may be appropriately increased or decreased depending on the administration method, patient condition, disease severity, and the like.

　以下、実施例等で本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
　なお、実施例に記載した各結晶の物性データは、以下の条件によって測定した。
（１）粉末Ｘ線回折
　装置：Ｘ’Ｐｅｒｔ　Ｐｒｏ（ＰＡＮａｌｙｔｉｃａｌ　Ｂ．Ｖ．）
　操作条件：
　Ｘ線管球：対陰極：銅，管電圧：４５ｋＶ，管電流：４０ｍＡ
　入射光学系：フォーカシング集光ミラー
　受光光学系：高速半導体アレイ検出器（Ｘ－Ｃｅｌｅｒａｔｏｒ）
　サンプルステージ：ＨＴＳサンプルステージ（Ｘ軸方向に４ｍｍ幅で振動）
　積算回数：５回（それぞれ入射角を－２，－１，０，１および２°変更）
　測定範囲：２θ＝３～４０°
（２）示差走査熱量測定（ＤＳＣ）
装置：ＤＳＣ８２１ｅ（メトラー・トレド株式会社）
操作条件：
　昇温速度：１０Ｋ／ｍｉｎ
　雰囲気：窒素４０ｍＬ／ｍｉｎ
（３）溶解度
　装置：ＡＣＱＵＩＴＹ　ＵＰＬＣ　ｓｙｓｔｅｍ（日本ウォーターズ株式会社）
　操作条件：
　検出器：フォトダイオードアレイ検出器（測定波長：３１２　ｎｍ）
　カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ　ＢＥＨ　Ｃ１８　２．１ｍｍφ×５０ｍｍ，１．７μｍ
　カラム温度：４０℃付近の一定温度
　移動相：Ａ；水／トリフルオロ酢酸（２０００：１），Ｂ；アセトニトリル／トリフルオロ酢酸（２０００：１）
　濃度勾配制御

Figure JPOXMLDOC01-appb-T000002
　ミキサー用量：０．５ｍＬ
　流速：１．０ｍＬ／ｍｉｎ
　注入量：１μＬ
（４）類縁物質
　装置：高速液体クロマトグラフＣｌａｓｓ－ＶＰシステム（株式会社島津製作所）
　操作条件：
　検出器：フォトダイオードアレイ（測定波長 ２２０ nm）
　カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３Ｖ ４．６ｍｍφ×１５０ｍｍ、５μｍ
　カラム温度：４０℃付近の一定温度
　移動相：Ａ；水／トリフルオロ酢酸（２０００：１），Ｂ；アセトニトリル／トリフルオロ酢酸（２０００：１）
　濃度勾配制御：Ｂ％５→１００％（６０分）
　流速：１．０ｍＬ／ｍｉｎ
　注入量：５μＬ EXAMPLES Hereinafter, although an Example etc. demonstrate this invention concretely, this invention is not limited at all by these.
The physical property data of each crystal described in the examples was measured under the following conditions.
(1) Powder X-ray diffraction apparatus: X'Pert Pro (PANallytical BV)
Operating conditions:
X-ray tube: anti-cathode: copper, tube voltage: 45 kV, tube current: 40 mA
Incident optical system: Focusing condensing mirror Light receiving optical system: High-speed semiconductor array detector (X-Celerator)
Sample stage: HTS sample stage (vibrates with a width of 4 mm in the X-axis direction)
Total number of times: 5 times (incident angles changed by -2, -1, 0, 1, and 2 °, respectively)
Measurement range: 2θ = 3-40 °
(2) Differential scanning calorimetry (DSC)
Apparatus: DSC821e (Mettler Toledo Co., Ltd.)
Operating conditions:
Temperature increase rate: 10K / min
Atmosphere: Nitrogen 40 mL / min
(3) Solubility Apparatus: ACQUITY UPLC system (Nippon Waters Co., Ltd.)
Operating conditions:
Detector: Photodiode array detector (measurement wavelength: 312 nm)
Column: ACQUITY UPLC BEH C18 2.1 mmφ × 50 mm, 1.7 μm
Column temperature: constant temperature around 40 ° C. Mobile phase: A; water / trifluoroacetic acid (2000: 1), B; acetonitrile / trifluoroacetic acid (2000: 1)
Concentration gradient control
Figure JPOXMLDOC01-appb-T000002
 Mixer dose: 0.5 mL
Flow rate: 1.0 mL / min
Injection volume: 1 μL
(4) Related substances Equipment: High-performance liquid chromatograph Class-VP system (Shimadzu Corporation)
Operating conditions:
Detector: Photodiode array (measurement wavelength 220 nm)
Column: Inertsil ODS-3V 4.6 mmφ × 150 mm, 5 μm
Column temperature: constant temperature around 40 ° C. Mobile phase: A; water / trifluoroacetic acid (2000: 1), B; acetonitrile / trifluoroacetic acid (2000: 1)
Concentration gradient control: B% 5 → 100% (60 minutes)
Flow rate: 1.0 mL / min
Injection volume: 5 μL

実施例１
（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶
　ＷＯ２００９／０４１５５９に記載された方法に準じて合成した化合物（Ｉ）３００ｍｇに水１ｍＬを加え、室温で２日攪拌した。固体をろ過し、水１０ｍＬで洗浄し、室温で３日間風乾し、Ｃ形結晶３２０ｍｇを得た。Ｃ形結晶の物性値は、以下の通りであった。
粉末Ｘ線回折スペクトル：

Figure JPOXMLDOC01-appb-T000003

Figure JPOXMLDOC01-appb-I000004
示差走査熱量測定：
　試料につき、４０μＬ標準アルミパンに充填し、測定を行った。
　その結果、融点（補外開始温度）は１０８℃付近に認められた。
（別法）
　ＷＯ２００９／０４１５５９に記載された方法に準じて合成した化合物（Ｉ）のＥ形結晶（１．００ｇ）を還流下アセトン１２ｍＬに溶解し、アセトン溶液とした。水１００ｍＬにＣ形結晶０．０１ｇを加えて攪拌し懸濁液とした。この懸濁液に攪拌しながらアセトン溶液を徐々に滴下した。固体をろ過し、４０℃で２時間減圧乾燥し、Ｃ形結晶０．９６ｇを得た。
　なお、得られたＣ形結晶は、前述の粉末Ｘ線回折スペクトルと一致した。融点は１１１℃付近に認められた。 Example 1
(2E) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide C-form crystals described in WO2009 / 041559 1 mL of water was added to 300 mg of compound (I) synthesized according to the prepared method, and the mixture was stirred at room temperature for 2 days. The solid was filtered, washed with 10 mL of water, and air-dried at room temperature for 3 days to obtain 320 mg of C-form crystals. The physical properties of the C-type crystals were as follows.
Powder X-ray diffraction spectrum:
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-I000004
Differential scanning calorimetry:
The sample was filled in a 40 μL standard aluminum pan and measured.
As a result, the melting point (extrapolated onset temperature) was found around 108 ° C.
(Alternative method)
An E-form crystal (1.00 g) of compound (I) synthesized according to the method described in WO2009 / 041559 was dissolved in 12 mL of acetone under reflux to obtain an acetone solution. To 100 mL of water, 0.01 g of C-form crystals were added and stirred to obtain a suspension. An acetone solution was gradually added dropwise to the suspension while stirring. The solid was filtered and dried under reduced pressure at 40 ° C. for 2 hours to obtain 0.96 g of C-form crystals.
In addition, the obtained C-type crystal was in agreement with the above-mentioned powder X-ray diffraction spectrum. A melting point was observed around 111 ° C.

実施例２
（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ型結晶
　ＷＯ２００９／０４１５５９に記載された方法に準じて合成した化合物（Ｉ）（６４．５８ｇ）に酢酸エチル６００ｍＬを加え、攪拌しながら１時間加熱還流した。４時間攪拌しながら室温まで冷却した。固体をろ過し、４０℃にて３時間および室温にて１６時間減圧乾燥し、Ｅ型結晶５３．８３ｇを得た。Ｅ形結晶の物性値は、以下の通りであった。
粉末Ｘ線回折スペクトル：

Figure JPOXMLDOC01-appb-T000005

Figure JPOXMLDOC01-appb-I000006
示差走査熱量測定（ＤＳＣ）：
　実施例１に記載した示差走査熱量測定法と同条件で測定した。その結果、融点（補外開始温度）は１６２℃付近に認められた。
（別法）
　ＷＯ２００９／０４１５５９に記載された方法に準じて合成した化合物（Ｉ）１１．００ｇに酢酸エチル１０８ｍＬを加え、８０℃で１時間撹拌した。熱時撹拌しながらｎ－ヘキサン３６ｍＬを加えた後、４０分間撹拌しながら室温まで冷却した。固体をろ過し、５０℃にて減圧乾燥し、Ｅ形結晶１０．３１ｇを得た。
　なお、得られたＥ形結晶は、前述の粉末Ｘ線回折スペクトルと一致した。 Example 2
E-type crystals of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide described in WO2009 / 041559 To the compound (I) synthesized according to the prepared method (64.58 g), 600 mL of ethyl acetate was added, and the mixture was heated to reflux for 1 hour with stirring. Cooled to room temperature with stirring for 4 hours. The solid was filtered and dried under reduced pressure at 40 ° C. for 3 hours and at room temperature for 16 hours to obtain 53.83 g of E-type crystals. The physical properties of the E type crystal were as follows.
Powder X-ray diffraction spectrum:
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-I000006
Differential scanning calorimetry (DSC):
The measurement was performed under the same conditions as in the differential scanning calorimetry described in Example 1. As a result, the melting point (extrapolated onset temperature) was found around 162 ° C.
(Alternative method)
108 mL of ethyl acetate was added to 11.00 g of compound (I) synthesized according to the method described in WO2009 / 041559, and the mixture was stirred at 80 ° C. for 1 hour. 36 mL of n-hexane was added with stirring while hot, and then cooled to room temperature with stirring for 40 minutes. The solid was filtered and dried under reduced pressure at 50 ° C. to obtain 10.31 g of E-form crystals.
The obtained E-form crystal was consistent with the aforementioned powder X-ray diffraction spectrum.

薬理試験例１：麻酔犬における心房有効不応期（ＥＲＰ）に及ぼす影響
（１）外科手術
　両性雑種交雑イヌを用い、ペントバルビタールナトリウムの静脈内投与（導入：３０ｍｇ／ｋｇ，持続：５ｍｇ／ｋｇ／ｈｒ）にて麻酔し、カニューレを気道に挿入して人工呼吸（１５ｃｃ／ｋｇ／ｓｔｒｏｋｅ、２０ｃｙｃｌｅ／ｍｉｎ）を行った。両側前腕正中皮静脈に持続麻酔用および検体投与用のカテーテルをそれぞれ挿入した。左大腿静脈にカテーテルを挿入し、補液を持続投与した（０．５ｍｌ／ｍｉｎ）。正中開胸した後、心のう膜を切開して心臓を露出させ、心房に電気刺激用電極および心筋電図測定用電極を装着した。
（２）ＥＲＰの測定
　心房ＥＲＰの測定は、Ｓ１－Ｓ２期外刺激法を用いて行った。基本刺激周期は２５０ｍｓとし、興奮を誘発する閾値の２～５倍、幅２ｍｓの矩形波刺激を心房に加えた。連続した８回のＳ１刺激後、Ｓ２刺激を加え、Ｓ１－Ｓ２連結期は５ｍｓずつ短縮した。Ｓ２刺激に伴う心房興奮が消失する最長のＳ１－Ｓ２間隔をＥＲＰとした。心房興奮の有無は、心房電図から判断した。安静下においてＥＲＰ（ｍｓ）が２回以上安定して得られることを確認した後、化合物を静脈内投与した。化合物投与から一定時間後にＥＲＰを測定した。薬物投与開始後のＥＲＰを、薬物投与前のＥＲＰと比較し、変化率（％）を算出した。
　その結果、化合物（Ｉ）は、３０μｇ／ｋｇ／ｍｉｎ投与により、１０％以上のＥＲＰ延長作用を示した。 Pharmacological Test Example 1: Effect on Atrial Effective Refractory Period (ERP) in Anesthetized Dogs (1) Surgery Intravenous pentobarbital sodium administration (introduction: 30 mg / kg, sustained: 5 mg / kg /) using a bisexual hybrid dog hr), the cannula was inserted into the airway, and artificial respiration (15 cc / kg / stroke, 20 cycles / min) was performed. Catheters for continuous anesthesia and sample administration were inserted into the bilateral forearm mesenteric veins, respectively. A catheter was inserted into the left femoral vein and the fluid replacement was continuously administered (0.5 ml / min). After midline thoracotomy, the pericardium was incised to expose the heart, and an electrical stimulation electrode and an electrocardiogram measurement electrode were attached to the atrium.
(2) Measurement of ERP Measurement of atrial ERP was performed using the S1-S2 extra-stimulation method. The basic stimulation period was 250 ms, and a rectangular wave stimulus having a width of 2 ms to 2 to 5 times the threshold value for inducing excitation was applied to the atrium. After 8 consecutive S1 stimuli, S2 stimuli were added and the S1-S2 concatenation period was shortened by 5 ms. The longest S1-S2 interval at which atrial excitement associated with S2 stimulation disappears was defined as ERP. The presence or absence of atrial excitement was determined from the atrial electrogram. After confirming that ERP (ms) was stably obtained twice or more under rest, the compound was administered intravenously. ERP was measured after a certain time from compound administration. The ERP after the start of drug administration was compared with the ERP before the drug administration, and the rate of change (%) was calculated.
As a result, Compound (I) exhibited an ERP prolongation effect of 10% or more when administered at 30 μg / kg / min.

試験例１：溶解度測定
　Ｃ形結晶およびＥ形結晶（それぞれ約５ｍｇ）に水２ｍＬを加え、３７℃、１００ｒｐｍで約２１時間振とうした後、遠心分離器で遠心分離（３０００ｒｐｍ，１０ｍｉｎ，３７℃）した。
　上澄みをろ過し、ろ液５００μＬにアセトニトリル５００μＬを加えて混和し、試料溶液とした。Ｅ形結晶のアセトニトリル溶液（０．０２ｍｇ／ｍｌ）５００μＬに水５００μＬを加えて混和し、標準溶液とした。標準溶液および試料溶液１μＬにつき上記の溶解度の条件で高速液体クロマトグラフ法により測定し、次式により飽和溶液濃度を求めて溶解度とした。

Figure JPOXMLDOC01-appb-M000007
　ＡＴ：試料溶液のピーク面積
　ＡＳ：標準溶液のピーク面積
　ＷＳ：標準試料として用いた結晶の量（ｍｇ）

　各々の結晶の３７℃における溶解度測定の結果を表４に示す。Ｃ形結晶の溶解度は１９．８μｇ／ｍＬであり、Ｅ形結晶の溶解度は５．３μｇ／ｍＬであった。これより、Ｃ形結晶はＥ形結晶よりも水に対して高い溶解性を有することが確認された。
Figure JPOXMLDOC01-appb-T000008
 Test Example 1: Solubility Measurement 2 mL of water was added to C-form crystals and E-form crystals (each about 5 mg), shaken at 37 ° C. and 100 rpm for about 21 hours, and then centrifuged (3000 rpm, 10 min, 37 ° C.). )did.
The supernatant was filtered, and 500 μL of acetonitrile was added to 500 μL of the filtrate and mixed to prepare a sample solution. 500 μL of water was added to 500 μL of an E-form crystal acetonitrile solution (0.02 mg / ml) and mixed to obtain a standard solution. The standard solution and 1 μL of the sample solution were measured by the high performance liquid chromatograph method under the above-mentioned solubility conditions, and the saturated solution concentration was determined by the following equation to obtain the solubility.
Figure JPOXMLDOC01-appb-M000007
 A T : Peak area of sample solution A S : Peak area of standard solution W S : Amount of crystals used as standard sample (mg)

Table 4 shows the results of solubility measurement of each crystal at 37 ° C. The solubility of Form C crystals was 19.8 μg / mL, and the solubility of Form E crystals was 5.3 μg / mL. From this, it was confirmed that the C-type crystal has higher solubility in water than the E-type crystal.
Figure JPOXMLDOC01-appb-T000008

試験例２：水分吸着測定
　Ｃ形結晶およびＥ形結晶（それぞれ約５ｍｇ）を石英セルに取り、ＤＶＳ－１型水分吸着装置（Ｓｕｒｆａｃｅ　Ｍｅａｓｕｒｅｍｅｎｔ　Ｓｙｓｔｅｍｓ　Ｌｉｍｉｔｅｄ）を用いて、測定開始時の重量を測定した。２５℃で、段階的（相対湿度０％ＲＨ～９５％ＲＨ）に湿度を変化させた時の重量変化を経時的に記録し、各湿度での平衡重量を求めた。乾燥時（０％ＲＨ）、又は開始時の水分量より換算した無水物を基準とし、各湿度での重量の変化率及び水和数を求めた。
　その結果、図９の通り、Ｃ形結晶は相対湿度約７０％において、約１．６％吸湿し、相対湿度約９５％において、約１．９％吸湿して重量増加した。図１０の通り、Ｅ形結晶は相対湿度約７０％において、約０．３％吸湿し、相対湿度約９５％において、約１．２％吸湿して重量増加した。Ｃ形結晶およびＥ形結晶は、医薬品の原薬として相応しい物性を有していることが確認された。
　また、Ｃ形結晶は、水和ステージがあり、常温、相対湿度１０～９５％にて、０．２～０．６水和物であることが確認された。 Test Example 2: Moisture adsorption measurement C-type crystals and E-type crystals (each about 5 mg) were placed in a quartz cell, and the weight at the start of measurement was measured using a DVS-1 type moisture adsorption device (Surface Measurement Systems Limited). . At 25 ° C., the weight change when the humidity was changed stepwise (relative humidity 0% RH to 95% RH) was recorded over time, and the equilibrium weight at each humidity was determined. The weight change rate and hydration number at each humidity were determined based on the anhydride converted from the amount of water at the time of drying (0% RH) or at the start.
As a result, as shown in FIG. 9, the C-type crystal absorbed about 1.6% at a relative humidity of about 70% and increased its weight by absorbing about 1.9% at a relative humidity of about 95%. As shown in FIG. 10, the E-form crystal absorbed about 0.3% at a relative humidity of about 70%, and increased its weight by absorbing about 1.2% at a relative humidity of about 95%. It was confirmed that C-type crystals and E-type crystals have physical properties suitable as drug substances for pharmaceuticals.
In addition, it was confirmed that the C-type crystal has a hydration stage and is 0.2 to 0.6 hydrate at room temperature and a relative humidity of 10 to 95%.

試験例３：安定性試験
　Ａ形結晶、Ｂ形結晶、Ｃ形結晶およびＥ形結晶を表５の条件で保存し、増加した類縁物質の増加量の合計及び結晶形の変化の有無を確認した。
　その結果、表５の通り、Ａ形結晶は類縁物質が増加した。また、６０℃、７５％ＲＨ保存１週間でＣ形結晶に変化した。Ｂ形結晶は類縁物質が増加した。また、６０℃、７５％ＲＨ保存１週間で一部Ｃ形結晶に変化するロットがあった。Ｅ形結晶には類縁物質の増加は認められなかったが、Ｃ形結晶に類縁物質の若干の増加が確認された。

Figure JPOXMLDOC01-appb-T000009
Test Example 3: Stability test A-form crystal, B-form crystal, C-form crystal and E-form crystal were stored under the conditions of Table 5, and the total amount of increased related substances and the presence or absence of changes in the crystal form were confirmed. .
As a result, as shown in Table 5, related substances increased in the A-form crystal. In addition, it changed to C-type crystals after 1 week of storage at 60 ° C. and 75% RH. B-form crystals increased in related substances. In addition, there was a lot that partially changed to C-type crystals after 1 week of storage at 60 ° C. and 75% RH. Although no increase in the related substance was observed in the E-type crystal, a slight increase in the related substance was confirmed in the C-type crystal.
Figure JPOXMLDOC01-appb-T000009

試験例４：光安定性試験
　Ｃ形結晶およびＥ形結晶について、Ｄ６５蛍光ランプを用い、２週間、総照度１２０万ｌｕｘ・ｈｒ以上および総紫外放射エネルギー２００Ｗ・ｈ／ｍ２以上で曝光し、保存後の類縁物質の増加及び結晶形の変化の有無を確認した。
　その結果、表６の通り、Ｅ形結晶の方が、より安定性に優れていることが確認された。

Figure JPOXMLDOC01-appb-T000010
試験例５：Ａ形結晶及びＢ形結晶の水中での安定性
　Ａ形結晶約１０ｍｇに水１ｍＬを加え、ふたをして約２０時間室温で攪拌した。その後、懸濁物をろ取し、粉末Ｘ線回折にて結晶形の変化を確認した。同様に、Ｂ形結晶約１０ｍｇに水１ｍＬを加え、ふたをして約２０時間室温で攪拌した。その後、懸濁物をろ取し、粉末Ｘ線回折にて結晶形の変化を確認した。その結果、どちらの結晶形もＣ形結晶に変化した。したがってＡ形結晶及びＢ形結晶は、水中で不安定でありＣ形結晶に変化することが確認された。 Test Example 4: Light Stability Test C-type crystals and E-type crystals were exposed to light using a D65 fluorescent lamp for 2 weeks at a total illumination of 1.2 million lux · hr and a total ultraviolet radiation energy of 200 W · h / m 2 or more. The presence or absence of an increase in related substances and a change in crystal form after storage was confirmed.
As a result, as shown in Table 6, it was confirmed that the E-type crystal was more stable.
Figure JPOXMLDOC01-appb-T000010
 Test Example 5: Stability of Form A and Form B Crystals in Water 1 mL of water was added to about 10 mg of Form A crystals, covered, and stirred at room temperature for about 20 hours. Thereafter, the suspension was collected by filtration, and the change in crystal form was confirmed by powder X-ray diffraction. Similarly, 1 mL of water was added to about 10 mg of B-form crystals, the lid was capped, and the mixture was stirred for about 20 hours at room temperature. Thereafter, the suspension was collected by filtration, and the change in crystal form was confirmed by powder X-ray diffraction. As a result, both crystal forms changed to C-type crystals. Accordingly, it was confirmed that the A-form crystal and the B-form crystal were unstable in water and changed to C-form crystals.

試験例６：室温での安定形の確認
　試料１及び試料２ぞれぞれ約１０ｍｇずつを同じ容器に取り、トルエン１ｍＬ、又は水１ｍＬ及びメタノール０．０５ｍＬを加え、ふたをして３日間室温で攪拌した。その後、懸濁物をろ取し、粉末Ｘ線回折にて結晶形を確認した。その結果、表７の通りすべての条件でＥ形結晶が得られた。したがって、Ａ形結晶、Ｂ形結晶、Ｃ形結晶、及びＥ形結晶の中でＥ形結晶が室温で安定形であった。

Figure JPOXMLDOC01-appb-T000011
Test Example 6: Confirmation of stable form at room temperature About 10 mg each of sample 1 and sample 2 are placed in the same container, 1 mL of toluene or 1 mL of water and 0.05 mL of methanol are added, and the lid is covered for 3 days at room temperature. And stirred. Thereafter, the suspension was collected by filtration, and the crystal form was confirmed by powder X-ray diffraction. As a result, E-type crystals were obtained under all conditions as shown in Table 7. Therefore, among the A-form crystals, B-form crystals, C-form crystals, and E-form crystals, the E-form crystals were stable at room temperature.
Figure JPOXMLDOC01-appb-T000011

　（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの新規な結晶形、特にＣ形結晶は一定の保存安定性を満たし、且つ溶解性に優れ、また、Ｅ形結晶は室温を含む広い温度範囲において非常に安定に存在する結晶で保存安定性および光安定性に優れているため、医薬品原薬として有用である。 Novel crystal forms of (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide, especially C form The crystal satisfies a certain storage stability and is excellent in solubility, and the E-form crystal is a crystal that exists very stably in a wide temperature range including room temperature, and is excellent in storage stability and light stability. Useful as an active pharmaceutical ingredient.

Claims (23)

　（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドの結晶。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide crystals. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°および１０．５°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。 In the powder X-ray diffraction spectrum, peaks at diffraction angles represented by 2θ of 6.2 ° ± 0.2 ° and 10.5 ° ± 0.2 ° are shown as (2E) -3- (1H-indazole-3 Form C crystals of -yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°、１０．５°±０．２°および１６．４°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。 In the powder X-ray diffraction spectrum, peaks are shown at 6.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, and 16.4 ° ± 0.2 ° as diffraction angles represented by 2θ (2E ) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide C-form crystals. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として６．２°±０．２°、１０．５°±０．２°、１２．３°±０．２°および１６．４°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。 In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 6.2 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, and 16.4 ° ±. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide shows a peak at 0.2 ° C crystal. 　粉末Ｘ線回折スペクトルが図１に示すパターンを有する、（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。 The (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] powder X-ray diffraction spectrum has the pattern shown in FIG. C-form crystal of but-2-enamide. 　示差走査熱量測定による融点が１０８～１１２℃である（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＣ形結晶。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] butene having a melting point of 108 to 112 ° C. by differential scanning calorimetry -2-Cenamide C crystal. 　示差走査熱量測定による融点が１０８～１１２℃である請求項２～５のいずれかに記載のＣ形結晶。 The C-shaped crystal according to any one of claims 2 to 5, which has a melting point of 108 to 112 ° C by differential scanning calorimetry. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°および１１．０°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。 In the powder X-ray diffraction spectrum, peaks at diffraction angles represented by 2θ of 10.2 ° ± 0.2 ° and 11.0 ° ± 0.2 ° are shown (2E) -3- (1H-indazole-3 E-form crystals of -yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°、１１．０°±０．２°および１５．２°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。 In the powder X-ray diffraction spectrum, peaks are shown at 10.2 ° ± 0.2 °, 11.0 ° ± 0.2 °, and 15.2 ° ± 0.2 ° as diffraction angles represented by 2θ (2E ) -3- (1H-Indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide crystals. 　粉末Ｘ線回折スペクトルにおいて、２θで表される回折角度として１０．２°±０．２°、１１．０°±０．２°、１５．２°±０．２°および１５．６°±０．２°にピークを示す（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。 In the powder X-ray diffraction spectrum, diffraction angles represented by 2θ are 10.2 ° ± 0.2 °, 11.0 ° ± 0.2 °, 15.2 ° ± 0.2 °, and 15.6 ° ±. (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide shows a peak at 0.2 ° E-type crystal. 　粉末Ｘ線回折スペクトルが図３に示すパターンを有する、（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl], whose powder X-ray diffraction spectrum has the pattern shown in FIG. E-form crystal of but-2-enamide. 　示差走査熱量測定による融点が１６０～１６３℃である（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドのＥ形結晶。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] butene having a melting point of 160 to 163 ° C. by differential scanning calorimetry E-form of -2-enamide. 　示差走査熱量測定による融点が１６０～１６３℃である請求項８～１１のいずれかに記載のＥ形結晶。 The E-type crystal according to any one of claims 8 to 11, having a melting point of 160 to 163 ° C as determined by differential scanning calorimetry. 　請求項１～１３のいずれかに記載の結晶を含有する医薬。 A medicament comprising the crystal according to any one of claims 1 to 13. 　請求項１～１３のいずれかに記載の結晶および薬理的に許容しうる担体を含有する医薬組成物。 A pharmaceutical composition comprising the crystal according to any one of claims 1 to 13 and a pharmacologically acceptable carrier. 　請求項１～１３のいずれかに記載の結晶を有効成分として含有するＩＫｕｒ遮断薬。 An I Kur blocking agent comprising the crystal according to any one of claims 1 to 13 as an active ingredient. 　請求項１～１３のいずれかに記載の結晶を有効成分として含有する心不整脈の予防または治療剤。 A preventive or therapeutic agent for cardiac arrhythmia comprising the crystal according to any one of claims 1 to 13 as an active ingredient. 　請求項１～１３のいずれかに記載の結晶を有効成分として含有する心房細動の予防または治療剤。 An agent for preventing or treating atrial fibrillation comprising the crystal according to any one of claims 1 to 13 as an active ingredient. 　（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドに水を加えた後、攪拌して結晶化させ、乾燥させることを特徴とする請求項２に記載のＣ形結晶の製造方法。 Water was added to (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide, and the mixture was stirred. 3. The method for producing a C-type crystal according to claim 2, wherein the crystal is crystallized and dried. 　（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドを良溶媒および水の混合溶媒中、種晶の存在下で攪拌して結晶化させ、乾燥させることを特徴とする請求項２に記載のＣ形結晶の製造方法。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide in a mixed solvent of water and water 3. The method for producing C-form crystals according to claim 2, wherein the crystals are crystallized by stirring in the presence of seed crystals and then dried. 　良溶媒がアセトンである請求項２０に記載の製造方法。 The production method according to claim 20, wherein the good solvent is acetone. 　（２Ｅ）－３－（１Ｈ－インダゾール－３－イル）－Ｎ－（３－メトキシフェニル）－Ｎ－［３－（メチルスルホニル）プロピル］ブト－２－エンアミドを良溶媒中または良溶媒および貧溶媒の混合溶媒中で攪拌して結晶化させ、乾燥させることを特徴とする請求項８に記載のＥ形結晶の製造方法。 (2E) -3- (1H-indazol-3-yl) -N- (3-methoxyphenyl) -N- [3- (methylsulfonyl) propyl] but-2-enamide in good solvent or poor solvent and poor The method for producing E-type crystals according to claim 8, wherein the crystals are crystallized by stirring in a solvent mixture and dried. 　良溶媒がアセトン、メタノール、テトラヒドロフラン、アセトニトリル、ベンジルアルコール、ホルムアミド、クロロホルム、酢酸エチル、エタノール、２－ブタノール、１，４－ジオキサンおよびシクロヘキサノンから選ばれる溶媒であり、貧溶媒がヘキサン、ヘプタン、トルエンおよび水から選ばれる溶媒である請求項２２に記載の製造方法。 The good solvent is a solvent selected from acetone, methanol, tetrahydrofuran, acetonitrile, benzyl alcohol, formamide, chloroform, ethyl acetate, ethanol, 2-butanol, 1,4-dioxane and cyclohexanone, and the poor solvent is hexane, heptane, toluene and The production method according to claim 22, which is a solvent selected from water.
PCT/JP2012/050063 2012-01-05 2012-01-05 Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide Ceased WO2013103004A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2012/050063 WO2013103004A1 (en) 2012-01-05 2012-01-05 Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2012/050063 WO2013103004A1 (en) 2012-01-05 2012-01-05 Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide

Publications (1)

Publication Number Publication Date
WO2013103004A1 true WO2013103004A1 (en) 2013-07-11

Family

ID=48745077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/050063 Ceased WO2013103004A1 (en) 2012-01-05 2012-01-05 Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide

Country Status (1)

Country Link
WO (1) WO2013103004A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009041559A1 (en) * 2007-09-28 2009-04-02 Mitsubishi Tanabe Pharma Corporation Indazole acrylic acid amide compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009041559A1 (en) * 2007-09-28 2009-04-02 Mitsubishi Tanabe Pharma Corporation Indazole acrylic acid amide compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIKKEN KAGAKU KOZA 1 KIHON SOSA I, 5 November 1990 (1990-11-05), pages 184 - 186 *

Similar Documents

Publication Publication Date Title
RU2556206C2 (en) Crystals
ES2217580T3 (en) ORAL COMPOSITIONS OF LEVOSIMENDAN.
US20040229777A1 (en) Crystalline phases of a potent HCV inhibitor
KR20120114174A (en) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof
KR20210102887A (en) Crystalline spirocyclic compound inhibitors of tryptophan hydroxylase 1 (TPH1) for treating diseases or disorders associated with peripheral serotonin
JP2024028460A (en) Crystalline Forms of Compounds and Methods of Producing Crystalline Forms of Compounds
JP2024009114A (en) Crystalline forms of compounds as mineralocorticoid receptor antagonists and methods for their preparation
JP2022173401A (en) crystal
WO2025167362A1 (en) Crystal form b of 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(methylsulfonyl)hexanamide, and use thereof and preparation method therefor
CN103724339B (en) Crystal forms of dihydropyrimidine derivatives
WO2016155578A1 (en) New crystal form of dapagliflozin and preparation method therefor
CN110167947A (en) The solid form of acetic acid [(1S) -1- [(2S, 4R, 5R) -5- (5- amino -2- oxo-thiazol simultaneously [4,5-d] pyrimidin-3-yl) -4- dihydroxy-tetrahydro furans -2- base] propyl] ester
CN102282125A (en) Novel processes and pure polymorphs
CN108473507A (en) The crystal form of Thienopyrimidine compound
JP5888612B2 (en) Crystals of condensed pyridine compound salts
JP2001521023A (en) Dofetilide polymorphism
WO2017020869A1 (en) B crystal form of 2-[(2r)-2-methyl-2-pyrrolidinyl]-1h-benzimidazole-7-carboxamide, preparation method and use
WO2013103004A1 (en) Crystal form of (2e)-3-(1h-indazol-3-yl)-n-(3-methoxyphenyl)-n-[3-(methylsulfonyl)propyl]but-2-enamide
KR102544543B1 (en) Individual co-crystal of l, d-erdosteine
JP6902336B2 (en) 5- [2-[(6-amino) -9H-purine-9-yl] ethylamino] -1-pentanol polycrystal
WO2004020433A1 (en) Novel crystals
CN105308043B (en) Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes
JP2022509701A (en) Crystalline salt of coridalmin
RU2802964C2 (en) Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-il)-n-benzylacetamide
WO2025218652A1 (en) Crystal forms of tetrahydrothiophene derivative as well as preparation method therefor and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12864651

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12864651

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP