JP6985137B2 - Crystal form of sulfonamide compound - Google Patents

Description

The present invention relates to a novel crystalline form of a sulfonamide compound which has a TRPM8 (Transient Receptor Potential Melastatin 8) blocking effect and is useful as a medicine.

しかしながら、特許文献１には、化合物（Ａ）の固体状態、物理化学的性質およびポリモルフィズムに関する記載はなく、示唆もされていない。 The phenomenon in which two or more kinds of crystal forms are obtained in the same compound is called polymorphism, and the individual crystal forms are called mutual crystal polymorphs. Different crystal forms may have different physicochemical properties such as density, melting point, solubility and stability.
Therefore, it is useful to study the polymorphism of compounds that can be pharmaceuticals and to obtain single crystals with excellent physicochemical properties. However, it is not easy to find a single crystal and how to supply it, and it is not easy to find out whether the crystal of a compound that can be a drug has desirable physicochemical properties as a drug. It cannot be understood without evaluating the properties, and requires diligent examination.
On the other hand, Patent Document 1 describes a novel sulfonamide compound having a TRPM8 blocking effect and useful as a pharmaceutical, for example, 4-({(4-cyclopropylisoquinolin-3-yl) [4-yl) represented by the following formula. (Trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (hereinafter, also referred to as compound (A)) is described. Further, Patent Document 2 describes a novel sulfonamide compound produced by using the compound (A).

However, Patent Document 1 does not describe or suggest the solid state, physicochemical properties and polymorphism of compound (A).

International release WO2012 / 124825 International release WO2014 / 042238

The present invention provides novel crystalline forms of sulfonamide compounds used in pharmaceuticals.

As a result of diligent research to solve the above problems, the present inventor has found that the compound (A) described in Patent Document 1 is produced as an amorphous substance, and its stability needs to be investigated. Therefore, as a result of various studies on the physical properties and stability of the forms of the compound (A) and various salts thereof, the compound (A) which is a free form is preferable as the form of the drug substance of the drug, and further, the compound (A) is used. It was found that there are 11 kinds of crystal forms. Among these crystal forms, the C-type crystal was found to be the most thermodynamically stable crystal, and the present invention was completed.

That is, the present invention relates to, but is not limited to, the following items.
Item [1] Powder X-ray diffraction pattern at 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, and 8.9 ° ± 0.2 ° as the diffraction angle represented by 2θ. C-type crystals of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid, characterized by having.
Item [2] The diffraction angles represented by 2θ are 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 8.9 ° ± 0.2 °, 14.3 ° ± 0. 4-({(4-Cyclopropylisoquinolin-3), characterized by having a powder X-ray diffraction pattern at 2 °, 17.6 ° ± 0.2 °, and 20.3 ° ± 0.2 °. -Il) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) C-type crystals of benzoic acid.
Item [3] 4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy), which is characterized by having substantially all peaks of the powder X-ray diffraction pattern shown in FIG. 1. ) Benzyl] amino} sulfonyl) C-type crystals of benzoic acid.
Item [4] Thermogravimetric-The melting point measured by differential thermal analysis is 206 to 209 ° C., 4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. C-shaped crystal of acid.
Item [5] A drug containing the crystal according to any one of the above items [1] to [4].
Item [6] A pharmaceutical composition containing the crystal according to any one of the above items [1] to [4] and a pharmacologically acceptable carrier.
Item [7] A TRPM8 blocker containing the crystal according to any one of the above items [1] to [4].
Item [8] Chronic pain, headache, urinary tract disease, cancer disease, respiratory disease, digestive tract disease, psychiatric disease, neurological disease containing the crystal according to any one of the above items [1] to [4]. , A prophylactic or therapeutic agent for diseases selected from skin diseases and vasomotor disorders.
Item [9] Use of the crystal according to any one of Items [1] to [4] for producing a TRPM8 blocker.
Item [10] To manufacture prophylactic or therapeutic agents for diseases selected from chronic pain, headache, urinary tract disease, cancer disease, respiratory disease, digestive system disease, mental disease, neurological disease, skin disease and vasomotor disorder. Use of the crystal according to any one of the items [1] to [4].
Item [11] 4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid solids are crystallized in a solvent, 4- ({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) A method for preparing C-form crystals of benzoic acid.
Item [12] Item 4 ({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) including addition of seed crystals of C-type crystals of benzoic acid. [11] The preparation method according to the above.
Item [13] 4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) The solid of benzoic acid is amorphous, A-type crystal, B-type crystal, D. The item [ 11] The preparation method according to the above.
Item 6. The preparation method according to Item [11], wherein the solvent is a solvent selected from the following single solvent or mixed solvent.
Single solvent: acetone, methyl ethyl ketone ethanol, isopropyl alcohol, t-butyl methyl ether or diisopropyl ether, or mixed solvent: methyl ethyl ketone / heptane, methyl ethyl ketone / water, ethyl acetate / heptane, ethyl acetate / ethanol, dimethoxyethane / water, dimethoxy ethane / Heptane or acetone / water.

The C-type crystal of the compound (A) of the present invention is novel and has a thermodynamically stable crystal form. In particular, the C-type crystal of the compound (A) of the present invention has a feature of high storage stability such as less formation of related substances when stored under certain conditions, and also has a feature of low hygroscopicity. It is a preferable crystal form as a drug substance.

FIG. 1 is a drawing showing a powder X-ray diffraction pattern of a C-shaped crystal of compound (A). The vertical axis represents the diffraction intensity (unit: count number), and the horizontal axis represents the diffraction angle 2θ (unit: °). FIG. 2 is a drawing showing a thermogravimetric-differential thermal measurement (TG-DTA) curve of a C-shaped crystal of compound (A). The solid line shows the DTA curve, the broken line shows the TG curve, and the dotted line shows the temperature curve. In FIG. 2, the horizontal axis represents time (unit: minutes), and the vertical axis represents the thermogravimetric change (unit:%) for the TG curve and the temperature difference (container only) for the DTA curve. Unit: μV), and temperature (unit: ° C) for the temperature curve. FIG. 3 is a drawing showing a powder X-ray diffraction pattern of a D-type crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 4 is a drawing showing a powder X-ray diffraction pattern of the A-type crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 5 is a drawing showing a powder X-ray diffraction pattern of a mixture of A-type crystals and B-type crystals of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 6 is a drawing showing a powder X-ray diffraction pattern of a mixture of B-type crystals and C-type crystals of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 7 is a drawing showing a powder X-ray diffraction pattern of the E-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 8 is a drawing showing a powder X-ray diffraction pattern of the F-type crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 9 is a drawing showing a powder X-ray diffraction pattern of the G-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 10 is a drawing showing a powder X-ray diffraction pattern of the H-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 11 is a drawing showing a powder X-ray diffraction pattern of the I-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 12 is a drawing showing a powder X-ray diffraction pattern of the J-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 13 is a drawing showing a powder X-ray diffraction pattern of the K-shaped crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG. FIG. 14 is a drawing showing a powder X-ray diffraction pattern of a monosodium salt C-type crystal of compound (A). The vertical axis and the horizontal axis are the same as those in FIG.

The C-shaped crystal of the compound (A) of the present invention is characterized by one or more of the following properties (1) to (3).
(1) The C-shaped crystal of compound (A) of the present invention has substantially all peaks of the powder X-ray diffraction pattern shown in FIG. 1 and / or the thermogravimetric-differential heat shown in FIG. It is preferred to substantially show the measurement (TG-DTA) curve.
(2) In the C-type crystal of the compound (A) of the present invention, the characteristic peak in the powder X-ray diffraction pattern is 5.9 ° ± 0.2 °, 8.8 as the diffraction angle represented by 2θ. ° ± 0.2 ° and 8.9 ° ± 0.2 ° can be mentioned. Other characteristic peaks include 14.3 ° ± 0.2 °, 17.6 ° ± 0.2 °, and 20.3 ° ± 0.2 °.
(3) The C-type crystal of the compound (A) of the present invention has a melting point (extrapolation start temperature) of about 206 to about 209 ° C., and can be particularly around 207.5 ° C.

（式中、Ｅｔはエチルを意味する。） The compound (A) of the present invention can be produced by the method described in Patent Document 1 or the following method.

(In the formula, Et means ethyl.)

(Step 1)
Compound (2) can be produced by reacting compound (1) with a chlorogenic agent in a solvent.
The chlorolytic agent is not particularly limited, and is, for example, N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCH), hydrogen peroxide / hydrochloric acid, chlorine (for example, chlorine gas). , Trichloroisocyanuric acid, copper chloride, sulfryl chloride, t-butyl hypochlorite, sodium hypochlorite, oxalyl chloride, N-chlorophthalimide and the like. Typical examples are N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCH), hydrogen peroxide / hydrochloric acid, chlorine gas, sodium hypochlorite, sulfuryl chloride, and N-chlorophthalimide can be mentioned.

The solvent is not particularly limited as long as it is a solvent inert to the reaction, but for example, esters (for example, ethyl acetate, isopropyl acetate, etc.), aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.), and non-esters. Protonic polar solvents (eg 1,2-dimethoxyethane, N, N-dimethylformamide, N-methylpyrrolidone, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), ethers (eg, diethyl ether, 1,4- Dioxane, tetrahydrofuran, etc.), nitriles (eg, acetonitrile, etc.), and water, or a mixed solvent of two or more of these. Typical examples include esters, aromatic hydrocarbons, ethers, and water.

The addition of the chlorogenic agent for this reaction may vary depending on the reagent used or the reaction conditions, but may be added to the reaction solution at one time, or may be added in several batches or by dropping.
The temperature at which the chlorogenic agent is added in this reaction may vary depending on the reagent used or the reaction conditions, but is usually under cooling to heating, preferably −20 ° C. to 70 ° C. For example, when N-chlorosuccinimide is used in this reaction, the preferred reagent charging temperature is 0 ° C to 50 ° C, and when 1,3-dichloro-5,5-dimethylhydantoin is used, the preferred reagent charging temperature is-. The temperature is 20 ° C. to 10 ° C., and when hydrogen peroxide / hydrochloric acid is used, dropping is preferable, and the reagent dropping temperature is preferably 45 ° C to 70 ° C.

The reaction temperature of this reaction varies depending on the reagent used or the reaction conditions, but is usually under cooling to heating, preferably −20 ° C. to 70 ° C. For example, when N-chlorosuccinimide is used in this reaction, the preferable reaction temperature is 35 to 60 ° C., and when 1,3-dichloro-5,5-dimethylhydantoin is used, the preferable reaction temperature is -20 to 10 ° C. ° C., and when hydrogen peroxide / hydrochloric acid is used, the preferred reaction temperature is 45-70 ° C.
The reaction time of this reaction varies depending on the reagent used or the reaction conditions (for example, the solvent used), but is usually 1 to 36 hours, preferably 1 to 24 hours. For example, when N-chlorosuccinimide is used in this reaction, the preferred reaction time is 2 to 20 hours, and when 1,3-dichloro-5,5-dimethylhydantin is used, the preferred reaction time is 10 to 24 hours. When hydrogen peroxide / hydrochloric acid is used, the preferred reaction time is 1 to 12 hours.
This reaction may be carried out in the presence of an inert gas, for example, nitrogen gas or argon gas.

The equivalent amount of the chlorogenic agent used in this reaction varies depending on the reagent used or the reaction conditions, but is usually preferably about 1 equivalent to an excess amount with respect to 1 equivalent of compound (1), for example, 0.95 to 5 It is 0.0 molar equivalent. For example, when N-chlorosuccinimide is used in this reaction, its preferred equivalent is 1.0 to 1.2 molar equivalents, and when 1,3-dichloro-5,5-dimethylhydantin is used, it is preferred. The equivalent is 1.0 to 1.1 molar equivalents, and when hydrogen peroxide / hydrochloric acid is used, the preferred equivalent of hydrogen peroxide is 0.95 to 1.1 molar equivalents, and the preferred equivalent of hydrochloric acid is 3. .0 to 5.0 molar equivalents.

(Step 2)
Compound (4) can be produced by reacting compound (2) with cyclopropylboronic acid (compound (3)) in the presence of a palladium catalyst, a base and a ligand in a solvent.
The solvent is not particularly limited as long as it is a solvent inert to the reaction, but for example, aromatic hydrocarbons (for example, toluene, xylene, naphthalene, etc.), esters (for example, ethyl acetate, butyl acetate, isopropyl acetate, etc.) and the like. ), Aprotic polar solvents (eg 1,2-dimethoxyethane, N, N-dimethylformamide, N-methylpyrrolidone, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), ethers (eg 1,4- Dioxane, tetrahydrofuran, etc.), nitriles (eg, acetonitrile, etc.), water, etc., or a mixed solvent of two or more of these. Typical examples include aromatic hydrocarbons, aprotic polar solvents, and ethers.

In order to obtain good stirring properties, this reaction is preferably carried out in a two-layer solvent consisting of water and an organic solvent, and in particular, a mixed solvent consisting of water and aromatic hydrocarbons is preferable. A mixed solvent of water and toluene is preferred. When this reaction is carried out with a two-layer solvent, for example, when toluene: water is used, the mixture is usually mixed at a volume ratio of 10: 1 to 1: 5, preferably 2: 1 to 1: 1. Examples include the solvent used.
The palladium catalyst is not particularly limited as long as it is a general palladium catalyst used in the cross-coupling reaction, but for example, palladium chloride, palladium acetate, dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium. (PdCl ₂ (dppf)), tetrakistriphenylphosphine palladium and the like. Typical examples include palladium chloride and palladium acetate.

Examples of the base include alkali metal lower alkoxides (eg, sodium t-butoxide, etc.), inorganic bases (eg, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, etc.) and the like. Typical examples include cesium carbonate, potassium carbonate, potassium phosphate, and sodium carbonate.
The ligand is not particularly limited as long as it is a general ligand used in the cross-coupling reaction, and is, for example, triphenylphosphine, tricyclohexylphosphine, tri (o-tolyl) phosphine, 1,1'. -Bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (S-PHOS), 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl (X-) PHOS), and phosphorus ligands such as 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos). Typical examples include triphenylphosphine and tricyclohexylphosphine.

This reaction can be carried out in the presence of an inert gas, for example, nitrogen gas or argon gas.
The reagent charging temperature for this reaction is usually from cooling to heating, preferably 0 ° C to 40 ° C.
The reaction temperature of this reaction can be 25 to 150 ° C, preferably 80 to 120 ° C.
The reaction time of this reaction is usually 6 to 24 hours, preferably 8 to 16 hours.

The equivalent of each reagent used in this reaction varies depending on the reagent used or the reaction conditions, but is usually 0.03 to 5.0 molar equivalent with respect to one equivalent of compound (2). For example, when palladium acetate is used as the palladium catalyst, its preferred equivalent is 0.03 to 0.1 molar equivalent, and when tricyclohexylphosphine is used as the ligand, its preferred equivalent is 0.06 to 0. It is 2 molar equivalents, and when cesium carbonate is used as the base, its preferred equivalent is 2.0 to 5.0 molar equivalents, and the preferred equivalent of cyclopropylboronic acid (compound (3)) is 1.3-2. It is 0.0 molar equivalent.

(Step 3)
Compound (6) can be produced by condensing compound (4) with compound (5) in the presence of a base in a solvent.
The solvent is not particularly limited as long as it is a solvent inert to the reaction, but for example, ethers (for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), hydrocarbons (for example, toluene, etc.). Xylene, etc.), esters (eg, ethyl acetate, butyl acetate, isopropyl acetate, etc.), ketones (eg, acetone, butanone, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.) Included are 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), and nitriles (eg, acetonitrile, etc.). Typical examples include nitriles, ethers, and hydrocarbons.

As the base, a conventional base can be used, for example, an alkali metal amide (for example, lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide, etc.), an alkali metal carbonate (for example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.). , Potassium hydrogen carbonate, etc.), alkali metals phosphate (eg, sodium phosphate, potassium phosphate, etc.), and organic amines (eg, pyridine, etc.). Typical examples include organic amines.

This reaction may be carried out in the presence of an inert gas, for example, nitrogen gas or argon gas.
The reagent charging temperature for this reaction is usually under cooling to heating, preferably 20 ° C to 60 ° C.
The reaction temperature can be cool to heated, preferably 20 ° C to 60 ° C.
The reaction time of this reaction is usually 4 to 24 hours, preferably 4 to 12 hours.

The equivalent amount of the reagent used in this reaction varies depending on the reagent used or the reaction conditions (for example, the solvent used), but is a preferable amount when, for example, pyridine is used as a base with respect to one equivalent of compound (4). Is 15 to 29 equivalents, and the preferred equivalent of ethyl 4- (chlorosulfonyl) benzoate (compound (5)) is 1.05 to 1.2 equivalents.

(Step 4)
Compound (8) can be produced by condensing compound (6) and compound (7) in a solvent in the presence of a base.
The solvent is not particularly limited as long as it is a solvent inert to the reaction, but for example, ethers (for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), hydrocarbons (for example, toluene, etc.). Xylene, etc.), esters (eg, ethyl acetate, butyl acetate, isopropyl acetate, etc.), ketones (eg, acetone, butanone, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.) Examples thereof include 1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone, sulfoxides (eg, dimethyl sulfoxide, etc.), and nitriles (eg, acetonitrile, etc.). Typical examples include amides and nitriles.

As the base, a conventional base can be used, for example, an alkali metal amide (for example, lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide, etc.), an alkali metal carbonate (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.). Examples thereof include sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metals phosphate (eg, sodium phosphate, potassium phosphate, etc.), and organic amines (eg, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholin, etc.). Typical examples include alkali metal carbonates and diisopropylethylamine.

The reagent charging temperature for this reaction is usually from cooling to heating, preferably 0 ° C to 40 ° C.
The temperature of this reaction can be cool to heated, preferably 15 ° C to 35 ° C.
The reaction time of this reaction is usually 2 to 72 hours, preferably 2 to 24 hours.

The equivalent of the reagent used in this reaction varies depending on the reagent used or the reaction conditions, but for example, when potassium carbonate is used, the preferable amount to be used is 0.9 to 3.0 molar equivalent, which is 1- (bromomethyl). The preferred equivalent of -4- (trifluoromethoxy) benzene (compound (7)) is 1.0 to 1.5 molar equivalents.

(Step 5)
Compound (9) can be produced by subjecting compound (8) to an ester hydrolysis reaction with an alkaline agent (for example, sodium hydroxide, potassium hydroxide, etc.) by a conventional method.
The reaction temperature is 20 to 100 ° C., preferably 50 ° C., and an acid (for example, citric acid, hydrochloric acid, etc.) can be used as the neutralizing agent for neutralizing the reaction solution.

The obtained compound (9) can be recrystallized from a single solvent or a mixed solvent to produce C-type crystals.
As the single solvent, for example, a ketone solvent (acetone, methyl ethyl ketone, etc.), an alcohol solvent (ethanol, isopropyl alcohol, etc.), an ether solvent (t-butylmethyl ether, diisopropyl ether, etc.) and the like can be used. .. Preferred single solvents include, for example, methyl ethyl ketone, ethanol, isopropyl alcohol, t-butyl methyl ether and the like.
As the mixed solvent, for example, methyl ethyl ketone / heptane, methyl ethyl ketone / water, ethyl acetate / heptane, ethyl acetate / ethanol, dimethoxyethane / water, dimethoxyethane / heptane, acetone / water and the like can be used. Preferred mixed solvents include, for example, methyl ethyl ketone / heptane, ethyl acetate / heptane, ethyl acetate / ethanol and acetone / water, with methyl ethyl ketone / heptane and acetone / water being particularly preferred.
The melting temperature is 20 to 56 ° C., preferably 50 ° C., and the temperature condition for recrystallization is 0 to 56 ° C., preferably 10 to 56 ° C., more preferably 20 to 40 ° C. It is also possible to carry out this crystallization reaction by adding seed crystals.

In each reaction, the post-reaction treatment may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting and combining conventional methods such as crystallization, distillation and liquid separation. In the present invention, examples of the crystallization method include known methods, and among them, an industrially advantageous method is preferable, and for example, a recrystallization method is preferable.

According to the above production method, the C-type crystal of compound (A) can be obtained as a single crystal form. In addition, the obtained compound (A) may be a mixture. Here, the mixture means a mixture containing one or more other crystal forms in a weight ratio of 1% or more, and the mixing ratio in the mixture may be arbitrary. In the present invention, a single crystalline form is preferred.

Since the C-form crystal of the compound (A) of the present invention thus obtained is stable, it can be synthesized in large quantities, and it is easy to formulate tablets and the like. It is useful as. Further, even the crystalline mixture of the present invention can be used as a drug substance.
Further, while the conventionally known compound (A) is produced as an amorphous substance containing a solvent that cannot be applied as a pharmaceutical product, the C-shaped crystal of the compound (A) of the present invention is thermodynamically stable. It has the features of good storage stability and low hygroscopicity. Therefore, the C-type crystal of the compound (A) of the present invention can provide a high-quality drug substance.

The C-form crystal of the compound (A) of the present invention thus obtained has a TRPM8 blocking effect, for example, chronic pain, headache, urinary tract disease, cancer disease, respiratory disease, digestive tract disease, psychiatric disease, neurological disease. , Can be used as a prophylactic or therapeutic agent for diseases selected from skin diseases and vasomotor symptoms.

When the C-form crystal of the compound (A) of the present invention is used as an active ingredient for pharmaceutical purposes, it is used together with an inert carrier according to the administration method, and is used as a conventional pharmaceutical preparation (for example, tablets, granules, capsules, powders). , Solution, suspension, milky lotion, injection, drip, etc.) can be formulated and used. Examples of such carriers include binders (eg, gum arabic, gelatin, sorbitol, polyvinylpyrrolidone, etc.), excipients (eg, lactose, sugar, cornstarch, sorbitol, etc.), which are acceptable in general medicine, and glides. Agents (eg, magnesium stearate, talc, polyethylene glycol, etc.), disintegrants (eg, potato starch, etc.) and the like can be mentioned. When it is used as an injection or a drip, it can be formulated using distilled water for injection, physiological saline, an aqueous glucose solution, or the like.

The administration method when the C-form crystal of the compound (A) of the present invention is used for pharmaceutical purposes is not particularly limited, and is a general oral or parenteral method (for example, intravenous, intramuscular, subcutaneous, or nasal). Skin, nasal, other transmucosa, enteral, etc.) can be applied.
When the C-type crystal of the compound (A) of the present invention is used for pharmaceutical purposes, the dose is sufficient to exhibit a medicinal effect according to the potency and characteristics of the C-type crystal of the compound (A) as an active ingredient. It may be set appropriately within the range of the effective amount. The dose will vary depending on the method of administration, age, body weight and condition of the patient, but will be set to a general dose, for example, an appropriate amount in the range of 0.01 to 100 mg / kg body weight per day.

Hereinafter, the present invention will be specifically described with reference to Production Examples, Reference Production Examples, and Test Examples, but the present invention is not limited thereto.
The physical characteristic data of each crystal described in the examples were measured under the following conditions.
(1) Powder X-ray diffractometer: X'Pert Pro (PANNalytical B.V.)
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)

(2) Thermogravimetric-differential thermal measurement (TG-DTA)
The sample was filled in an aluminum open sample reaction vessel, and measurement was performed using only the vessel as a control.
Equipment: TG / DTA7200 (SI Nano Technology Co., Ltd.)
Operating conditions:
Temperature rise rate: 10K / min
Atmosphere: Nitrogen 200mL / min

Production Example 1
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of C-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) D-form crystals of benzoic acid were collected in 5 mg and 50 μL of t-butylmethyl ether was added to obtain a solution. After stirring the solution at room temperature for one day and night, a solid precipitated. Then, the solution was left at 4 ° C. for 3 days, and the precipitated solid was collected by filtration to remove 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl. ) C-shaped crystals of benzoic acid were obtained.
When the thermogravimetric-differential thermal measurement (TG-DTA) of the C-shaped crystal was measured, the melting point (extrapolation start temperature) was about 206 to about 209 ° C, and was particularly observed around 207.5 ° C (FIG. 2). ).
The C-type crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 1 was included.

Table 1 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 1, but the diffraction peaks are not limited thereto.
Table 1

Typical diffraction peak values are, for example, 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 8.9 ° ± 0.2 °, 14.3 ° ± 0.2 °. , 17.6 ° ± 0.2 °, and 20.3 ° ± 0.2 °, or more typical diffraction peak values are, for example, 5.9 ° ± 0.2 °, 8. 8 ° ± 0.2 ° and 8.9 ° ± 0.2 ° are included.

Reference manufacturing example 1
4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of D-form crystal of benzoic acid Ethyl 4-[(4-Cyclopropylisoquinoline-3-yl) Ill) {[4- (trifluoromethoxy) phenyl] methyl} sulfamoyl] 200 mL of tetrahydrofuran and 200 mL of ethanol were added to 30.4 g of benzoate to prepare a solution. 54 mL of 2 mol / L aqueous sodium hydroxide solution was added to this solution, and the mixture was stirred at room temperature for 1 hour. After concentrating to half the volume, the mixture was acidified with 10% aqueous acetic acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and then evaporated. Ethanol was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure at 50 ° C. to obtain 25.8 g of D-form crystals of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. rice field.
The D-form crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, a chart of the powder X-ray diffraction pattern shown in FIG. 3 was provided.

Table 2 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 3, but the diffraction peaks are not limited thereto.
Table 2

Reference manufacturing example 2
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of A-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Il) [4- (Trifluoromethoxy) benzyl] amino} sulfonyl) 1.05 g of benzoic acid monosodium salt was dissolved in 15 mL of ethanol, and 1.9 mL of a 1 mol / L sodium hydroxide aqueous solution was added thereto. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Hexane was added to the obtained residue, the precipitated solid was collected by filtration, and then dried under reduced pressure to obtain 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl]. Amino} sulfonyl) A-form crystals of benzoic acid (916 mg) were obtained.
The A-type crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, a chart of the powder X-ray diffraction pattern shown in FIG. 4 was provided.

Table 3 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 4, but the diffraction peaks are not limited thereto.
Table 3

Reference manufacturing example 3
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of a mixture of A-type and B-type crystals of benzoic acid 4-({(4- (4-) Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) After storing A-form crystals of benzoic acid at 60 ° C for one week, 4-({(4-cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) A mixture of A-type and B-type crystals of benzoic acid was obtained.
A mixture of A-type crystals and B-type crystals of the obtained 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)). Has a chart of the powder X-ray diffraction pattern shown in FIG. 5 in the powder X-ray diffraction measurement.

Table 4 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 5, but the diffraction peaks are not limited thereto.
Table 4

Reference manufacturing example 4
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of a mixture of B-type and C-type crystals of benzoic acid 4-({(4- (4-) Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) A-type crystals of benzoic acid were stored at 60 ° C. and 75% relative humidity (RH) for one week. A mixture of morphic crystals was obtained.
A mixture of B-type crystals and C-type crystals of the obtained 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)). Has a chart of the powder X-ray diffraction pattern shown in FIG. 6 in the powder X-ray diffraction measurement.

Table 5 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 6, but the diffraction peaks are not limited thereto.
Table 5

Reference manufacturing example 5
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of E-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Il) [4- (Trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of D-form benzoic acid crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 30 μL of methanol and 270 μL of water were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the precipitated solid was collected by filtration to obtain E-form crystals of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. ..
The E-form crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 7 was provided.

Table 6 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 7, but the diffraction peaks are not limited thereto.
Table 6

Reference manufacturing example 6
4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of F-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinoline-3-yl) Il) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) D-form crystals of benzoic acid were collected, 500 μL of formamide was added thereto, and the mixture was heated at 100 ° C. to obtain a suspension. After stirring at room temperature for 1 day and night, the mixture was left at 4 ° C. for 3 days. The solid was collected by filtration to give F-form crystals of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid.
The F-type crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 8 was included.

Table 7 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 8, but the diffraction peaks are not limited thereto.
Table 7

Reference manufacturing example 7
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of G-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of benzoic acid D-type crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 210 μL of ethyl acetate and 90 μL of diisopropyl ether were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the lid was removed and the mixture was allowed to stand at room temperature. After 14 days, the solvent evaporates to a dry substance, which is taken out and taken out from G of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. Form crystals were obtained.
The G-type crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, a chart of the powder X-ray diffraction pattern shown in FIG. 9 was provided.

Table 8 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 9, but the diffraction peaks are not limited thereto.
Table 8

Reference manufacturing example 8
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of H-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of benzoic acid D-type crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 90 μL of ethanol and 210 μL of diisopropyl ether were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the lid was removed and the mixture was allowed to stand at room temperature. After 14 days, the solvent evaporates to a dry substance, which is taken out and taken out from H of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. Form crystals were obtained.
The H-form crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 10 was included.

Table 9 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 10, but the diffraction peaks are not limited thereto.
Table 9

Reference manufacturing example 9
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of type I crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of benzoic acid D-type crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 150 μL of cyclohexanone and 150 μL of diisopropyl ether were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the lid was removed and the mixture was allowed to stand at room temperature. After 14 days, the solvent evaporates to a dry substance, which is taken out and taken out from 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid I. Form crystals were obtained.
The obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) type I crystal was subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 11 was included.

Table 10 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 11, but the diffraction peaks are not limited thereto.
Table 10

Reference manufacturing example 10
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of J-form crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of benzoic acid D-type crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 30 μL of cyclohexanone and 270 μL of diisopropyl ether were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the lid was removed and the mixture was allowed to stand at room temperature. After 14 days, the solvent evaporates to a dry substance, which is taken out and taken out from J of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. Form crystals were obtained.
The J-form crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 12 was included.

Table 11 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 12, but the diffraction peaks are not limited thereto.
Table 11

Reference manufacturing example 11
4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of K-shaped crystals of benzoic acid 4-({(4-Cyclopropylisoquinolin-3-3) Ill) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) 200 μL of a tetrahydrofuran solution (15 mg / mL) of benzoic acid D-type crystals was collected and sprayed with nitrogen gas for 3 hours to evaporate the solvent. To this, 150 μL of 1,2-dimethoxyethane and 150 μL of heptane were added, the reaction vessel was covered, and the mixture was stirred at room temperature. After 5 days, the lid was removed and the mixture was allowed to stand at room temperature. After 14 days, the solvent evaporates to a dry substance, which is taken out and taken out from K of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. Form crystals were obtained.
The K-shaped crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) were subjected to powder X-ray diffraction. In the measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 13 was included.

Table 12 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 13, but the diffraction peaks are not limited thereto.
Table 12

Reference manufacturing example 12
4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Production of benzoic acid monosodium salt C-type crystal 4-({(4-Cyclopropylisoquinoline-) 3-Il) [4- (Trifluoromethoxy) benzyl] amino} sulfonyl) 70 μL of 0.1 mol / L sodium hydroxide aqueous solution was added to 0.3 mL of a tetrahydrofuran solution (10 mg / mL) of D-form benzoate crystals. After spraying with nitrogen for about 3 hours, it was left to dry for 1 day. Add 0.3 mL of acetone to this, cover the reaction vessel, stir for 4 days, and then filter out the precipitated solid to remove 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoro). C-type crystals of methoxy) benzyl] amino} sulfonyl) benzoic acid monosodium salt were obtained.
Separately, 50 mg of D-form crystal of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid was dissolved in 0.5 mL of acetone, and 10 mol at room temperature. 10 μL of / L aqueous sodium hydroxide solution was added. A small amount of the C-type crystal obtained above was added as a seed crystal, and 0.25 mL of heptane was added to obtain a solution. Nitrogen was sprayed on this solution for about 1 hour to evaporate the solvent. 0.25 mL of acetone was added thereto, and the mixture was stirred at room temperature to obtain a solid. 0.75 mL of acetone was added, and the mixture was stirred at room temperature for one day and night. The obtained precipitated solid was collected by filtration and washed thoroughly with 0.2 mL of acetone. The obtained solid was dried under reduced pressure at 45 ° C. for about 3 hours, and 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid 1 33.5 mg of sodium salt C-type crystals were obtained.
The C-type crystals of the obtained 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid (compound (A)) monosodium salt are powdered. In the X-ray diffraction measurement, the chart of the powder X-ray diffraction pattern shown in FIG. 14 was included.

Table 13 shows the diffraction peak values as the diffraction angles (2θ ± 0.2 °) for the characteristic diffraction peaks in the powder X-ray diffraction pattern shown in FIG. 14, but is not limited thereto.
Table 13

Test Example 1: Confirmation of stable crystalline form at room temperature Place Sample 1 and Sample 2 shown in Table 14 below in the same reaction vessel, add 0.1 mL of suspension solvent, and cover the reaction vessel. Stirred at room temperature. After stirring at room temperature for the period shown in Table 14, the precipitated solid was collected by filtration and its crystal form was confirmed by powder X-ray diffraction. As a result, C-type crystals were obtained under all conditions as shown in Table 14.
Table 14

From the test results shown in Table 14, the C-type crystal of the compound (A) is any solid form of the compound (A) (for example, an amorphous form, and the above-mentioned A-type crystal, B-type crystal, D-type crystal, and E-type). In any form of crystal, F-type crystal, G-type crystal, H-type crystal, I-type crystal, J-type crystal, or K-type crystal, or any crystal form including a mixed form of two or more of them). It was found to be the most thermodynamically superior solid form.

4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) The novel C-type crystal of benzoic acid has excellent storage stability and hygroscopicity. Since the number is small, it is useful as a drug substance for pharmaceuticals because it is a crystal that exists very stably in a wide temperature range including room temperature.

Claims (14)

Having a powder X-ray diffraction pattern at 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, and 8.9 ° ± 0.2 ° as the diffraction angle represented by 2θ. Characterized by C-type crystals of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid. The diffraction angles represented by 2θ are 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 8.9 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17 It is characterized by having a powder X-ray diffraction pattern at .6 ° ± 0.2 ° and 20.3 ° ± 0.2 °, 4-({(4-cyclopropylisoquinolin-3-yl)] [. 4- (Trifluoromethoxy) benzyl] amino} sulfonyl) C-type crystals of benzoic acid. The diffraction angles represented by 2θ are 5.9 ° ± 0.2 °, 8.8 ° ± 0.2 °, 8.9 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12 .0 ° ± 0.2 °, 12.4 ° ± 0.2 °, 12.8 ° ± 0.2 °, 14.3 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16 8.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.4 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21 .0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.2 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.2 ° ± 0.2 °, 23 8.8 ° ± 0.2 °, 24.2 ° ± 0.2 °, 24.4 ° ± 0.2 °, 24.9 ° ± 0.2 °, 25.2 ° ± 0.2 °, 25 .5 ° ± 0.2 °, 26.1 ° ± 0.2 °, 26.5 ° ± 0.2 °, 27.0 ° ± 0.2 °, 27.4 ° ± 0.2 °, 27 8.8 ° ± 0.2 °, 28.4 ° ± 0.2 °, 28.9 ° ± 0.2 °, 29.4 ° ± 0.2 °, 29.8 ° ± 0.2 °, 30 .3 ° ± 0.2 °, 31.2 ° ± 0.2 °, 31.7 ° ± 0.2 °, 32.7 ° ± 0.2 °, 34.1 ° ± 0.2 °, 34 9.9 ° ± 0.2 °, 35.7 ° ± 0.2 °, 36.2 ° ± 0.2 °, 36.7 ° ± 0.2 °, 37.8 ° ± 0.2 °, 38 4-({(4-Cyclopropylisoquinolin-3-yl)) characterized by having a powder X-ray diffraction pattern at .4 ° ± 0.2 ° and 39.0 ° ± 0.2 ° [ 4- (Trifluoromethoxy) benzyl] amino} sulfonyl) C-type crystals of benzoic acid. C-type crystals of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid having a thermogravimetric-difference thermal measurement of 206-209 ° C. .. A pharmaceutical agent containing the crystal according to any one of claims 1 to 4. A pharmaceutical composition containing the crystal according to any one of claims 1 to 4 and a pharmacologically acceptable carrier. A TRPM8 blocker containing the crystal according to any one of claims 1 to 4. Chronic pain, headache, urinary tract disease, cancer disease, respiratory disease, digestive tract disease, psychiatric disease, neurological disease, skin disease and vasomotor disorder containing the crystal according to any one of claims 1 to 4. A prophylactic or therapeutic agent for the disease selected from. Use of the crystal according to any one of claims 1 to 4 for producing a TRPM8 blocker. Claims for the manufacture of prophylactic or therapeutic agents for diseases selected from chronic pain, headache, urinary disorders, cancer disorders, respiratory disorders, digestive disorders, mental disorders, neurological disorders, skin disorders and vasomotor disorders. Use of the crystal according to any one of Items 1 to 4. 4-({(4-Cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Crystallizing a solid of benzoic acid in a solvent, claim 1-4. The method for preparing C-type crystals of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid according to any one of the above items. A species of C-type crystal of 4-({(4-cyclopropylisoquinoline-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid according to any one of claims 1 to 4. The preparation method according to claim 11, which comprises adding crystals. 4 - ({(4-cyclopropyl-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid solids, A-type crystal, B-type crystals, D-shaped crystal, E-form crystals , F-type crystal, G-type crystal, H-type crystal, I-type crystal, J-type crystal, or K-type crystal, or a mixed form of two or more thereof, according to the preparation method according to claim 11. There,
The diffraction angle of the A-shaped crystal represented by 2θ is 6.4 ° ± 0.2 °, 7.9 ° ± 0.2 °, 8.1 ° ± 0.2 °, 9.0 ° ± 0. .2 °, 9.4 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.6 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.2 ° ± 0 .2 °, 12.4 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.5 ° ± 0 .2 °, 15.9 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.7 ° ± 0.2 °, 17.9 ° ± 0 .2 °, 18.4 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.5 ° ± 0 .2 °, 20.8 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.0 ° ± 0 .2 °, 23.3 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.5 ° ± 0.2 °, 24.8 ° ± 0 .2 °, 25.3 ° ± 0.2 °, 26.2 ° ± 0.2 °, 26.6 ° ± 0.2 °, 26.8 ° ± 0.2 °, 27.2 ° ± 0 .2 °, 27.7 ° ± 0.2 °, 28.1 ° ± 0.2 °, 28.9 ° ± 0.2 °, 29.5 ° ± 0.2 °, 30.1 ° ± 0 .2 °, 30.6 ° ± 0.2 °, 31.2 ° ± 0.2 °, 31.9 ° ± 0.2 °, 32.3 ° ± 0.2 °, 32.9 ° ± 0 It is characterized by having a powder X-ray diffraction pattern at .2 ° and 33.8 ° ± 0.2 °, 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoro). Methoxy) benzyl] amino} sulfonyl) benzoic acid crystals,
A mixture of A-type crystals and B-type crystals has a diffraction angle represented by 2θ of 6.1 ° ± 0.2 °, 7.6 ° ± 0.2 °, 7.9 ° ± 0.2 °, 8.1 ° ± 0.2 °, 9.1 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.2 ° ± 0.2 °, 13.0 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.5 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.8 ° ± 0.2 °, 26.2 ° ± 0.2 °, It is characterized by having a powder X-ray diffraction pattern at 27.2 ° ± 0.2 °, 28.0 ° ± 0.2 °, and 30.4 ° ± 0.2 °, 4-({({(. 4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) Crystal of benzoic acid,
A mixture of B-type crystals and C-type crystals has a diffraction angle represented by 2θ of 5.9 ° ± 0.2 °, 6.1 ° ± 0.2 °, 7.6 ° ± 0.2 °, 8.1 ° ± 0.2 °, 8.7 ° ± 0.2 °, 8.9 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.3 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.3 ° ± 0.2 °, 15.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.0 ° ± 0.2 °, 20.2 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 24.0 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.0 ° ± 0.2 °, 27.0 ° ± 0.2 °, 27.8 ° ± 0.2 °, 28.8 ° ± 0.2 °, 29.6 ° ± 0.2 °, Have a powder X-ray diffraction pattern at 30.5 ° ± 0.2 °, 32.7 ° ± 0.2 °, 36.0 ° ± 0.2 °, and 37.8 ° ± 0.2 °. , Which is a crystal of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid.
The diffraction angle of the D-shaped crystal represented by 2θ is 4.9 ° ± 0.2 °, 6.8 ° ± 0.2 °, 9.2 ° ± 0.2 °, 10.1 ° ± 0. .2 °, 11.8 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0 .2 °, 15.2 ° ± 0.2 °, 16.4 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.2 ° ± 0 .4- ({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoro), characterized by having a powder X-ray diffraction pattern at 2 ° and 20.5 ° ± 0.2 °. Methoxy) benzyl] amino} sulfonyl) benzoic acid crystals,
The diffraction angle of the E-shaped crystal represented by 2θ is 3.0 ° ± 0.2 °, 5.1 ° ± 0.2 °, 7.4 ° ± 0.2 °, 9.2 ° ± 0. .2 °, 10.2 ° ± 0.2 °, 11.3 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.4 ° ± 0.2 °, 13.0 ° ± 0 .2 °, 13.5 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.0 ° ± 0.2 °, 15.3 ° ± 0 .2 °, 16.1 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.8 ° ± 0.2 °, 18.4 ° ± 0 .2 °, 18.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.5 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.6 ° ± 0 .2 °, 21.9 ° ± 0.2 °, 22.6 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.0 ° ± 0 .2 °, 24.7 ° ± 0.2 °, 25.1 ° ± 0.2 °, 25.5 ° ± 0.2 °, 26.5 ° ± 0.2 °, 27.6 ° ± 0 .2 °, 29.3 ° ± 0.2 °, 30.2 ° ± 0.2 °, 30.8 ° ± 0.2 °, 31.5 ° ± 0.2 °, 32.5 ° ± 0 .2 °, 33.8 ° ± 0.2 °, 35.9 ° ± 0.2 °, 36.9 ° ± 0.2 °, 37.7 ° ± 0.2 °, 38.8 ° ± 0 It is characterized by having a powder X-ray diffraction pattern at .2 ° and 39.4 ° ± 0.2 °, 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoro). Methoxy) benzyl] amino} sulfonyl) benzoic acid crystals,
The diffraction angle of the F-shaped crystal represented by 2θ is 7.1 ° ± 0.2 °, 7.4 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.0 ° ± 0. .2 °, 11.8 ° ± 0.2 °, 13.3 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 14.8 ° ± 0 .2 °, 15.0 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.0 ° ± 0 .2 °, 18.5 ° ± 0.2 °, 18.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.6 ° ± 0 .2 °, 20.8 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.5 ° ± 0 .2 °, 22.7 ° ± 0.2 °, 23.2 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 24.5 ° ± 0 .2 °, 25.2 ° ± 0.2 °, 25.8 ° ± 0.2 °, 26.3 ° ± 0.2 °, 27.6 ° ± 0.2 °, 28.5 ° ± 0 .2 °, 28.9 ° ± 0.2 °, 29.5 ° ± 0.2 °, 36.1 ° ± 0.2 °, 36.8 ° ± 0.2 °, 38.2 ° ± 0 It is characterized by having a powder X-ray diffraction pattern at .2 ° and 38.9 ° ± 0.2 °, 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoro). Methoxy) benzyl] amino} sulfonyl) benzoic acid crystals,
The diffraction angle of the G-shaped crystal represented by 2θ is 5.2 ° ± 0.2 °, 6.9 ° ± 0.2 °, 9.1 ° ± 0.2 °, 9.4 ° ± 0. .2 °, 10.4 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.4 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.4 ° ± 0 .2 °, 14.7 ° ± 0.2 °, 15.6 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.3 ° ± 0.2 °, 17.7 ° ± 0 .2 °, 18.3 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.5 ° ± 0.2 °, 22.8 ° ± 0 .2 °, 23.3 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 25.3 ° ± 0.2 °, 27.4 ° ± 0 Powder X-ray diffraction at .2 °, 28.5 ° ± 0.2 °, 29.4 ° ± 0.2 °, 34.4 ° ± 0.2 °, and 37.0 ° ± 0.2 ° Crystals of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid, characterized by having a pattern.
The diffraction angle of the H-shaped crystal represented by 2θ is 3.1 ° ± 0.2 °, 4.8 ° ± 0.2 °, 6.7 ° ± 0.2 °, 9.3 ° ± 0. .2 °, 9.5 ° ± 0.2 °, 10.2 ° ± 0.2 °, 12.6 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.3 ° ± 0 .2 °, 14.3 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.0 ° ± 0 .2 °, 19.7 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.9 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.0 ° ± 0 .2 °, 23.5 ° ± 0.2 °, 24.0 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.5 ° ± 0 Powder X-ray diffraction at .2 °, 27.7 ° ± 0.2 °, 29.7 ° ± 0.2 °, 36.5 ° ± 0.2 °, and 39.0 ° ± 0.2 ° Crystals of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid, characterized by having a pattern.
The diffraction angle of the I-shaped crystal represented by 2θ is 3.2 ° ± 0.2 °, 4.2 ° ± 0.2 °, 5.1 ° ± 0.2 °, 7.5 ° ± 0. .2 °, 8.5 ° ± 0.2 °, 9.2 ° ± 0.2 °, 10.4 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0 .2 °, 14.4 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.6 ° ± 0.2 °, 15.8 ° ± 0 .2 °, 16.7 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.2 ° ± 0 .2 °, 19.8 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.7 ° ± 0 .2 °, 23.1 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.3 ° ± 0.2 °, 25.3 ° ± 0.2 °, 25.8 ° ± 0 .2 °, 27.4 ° ± 0.2 °, 28.2 ° ± 0.2 °, 29.4 ° ± 0.2 °, 30.5 ° ± 0.2 °, and 32.7 ° ± 4-({(4-Cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid, characterized by having a powder X-ray diffraction pattern at 0.2 °. Is a crystal of
The diffraction angle of the J-shaped crystal represented by 2θ is 7.6 ° ± 0.2 °, 8.2 ° ± 0.2 °, 8.6 ° ± 0.2 °, 9.7 ° ± 0. .2 °, 10.3 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.2 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.5 ° ± 0 .2 °, 18.8 ° ± 0.2 °, 19.5 ° ± 0.2 °, 22.3 ° ± 0.2 °, 25.5 ° ± 0.2 °, 26.3 ° ± 0 It is characterized by having a powder X-ray diffraction pattern at .2 ° and 27.5 ° ± 0.2 °, 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoro). It is a crystal of methoxy) benzyl] amino} sulfonyl) benzoic acid, and
The diffraction angles of the K-shaped crystal represented by 2θ are 4.6 ° ± 0.2 °, 7.2 ° ± 0.2 °, 9.2 ° ± 0.2 °, and 9.9 ° ± 0. .2 °, 10.4 ° ± 0.2 °, 11.4 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.5 ° ± 0 .2 °, 14.8 ° ± 0.2 °, 15.1 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.8 ° ± 0 .2 °, 17.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.4 ° ± 0 .2 °, 19.6 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.2 ° ± 0 .2 °, 22.8 ° ± 0.2 °, 23.4 ° ± 0.2 °, 24.0 ° ± 0.2 °, 24.6 ° ± 0.2 °, 24.9 ° ± 0 .2 °, 25.4 ° ± 0.2 °, 25.6 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.1 ° ± 0.2 °, 28.2 ° ± 0 Powder X-ray diffraction at .2 °, 29.6 ° ± 0.2 °, 30.4 ° ± 0.2 °, 32.6 ° ± 0.2 °, and 38.9 ° ± 0.2 ° Crystals of 4-({(4-cyclopropylisoquinolin-3-yl) [4- (trifluoromethoxy) benzyl] amino} sulfonyl) benzoic acid, characterized by having a pattern,
The preparation method. 11. The preparation method according to claim 11, wherein the solvent is a solvent selected from the following single solvent or mixed solvent.
Single solvent: acetone, methyl ethyl ketone ethanol, isopropyl alcohol, t-butyl methyl ether or diisopropyl ether, or mixed solvent: methyl ethyl ketone / heptane, methyl ethyl ketone / water, ethyl acetate / heptane, ethyl acetate / ethanol, dimethoxyethane / water, dimethoxy ethane / Heptane or acetone / water.

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