JP2016094368A - New crystal of benzimidazole compound, and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new crystal of 2-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazole-5-yl]-1,3- benzoxazole having excellent storage stability capable of maintaining the same quality, when being stored as a pharmaceutical technical product of a therapeutic agent for a neurodegenerative disease or the like; and to provide a production method thereof.SOLUTION: There is provided a crystal of 2-[2-methyl-1-(tetrahydro-2H-piran-4-il)-1H-benzimidazole-5-il]-1,3- benzoxazole in which, in a powder X-ray diffraction spectrum, a diffraction angle (2θ) shows main peaks at 11.6°, 15.9°, 17.4° and 22.1°(±0.2° respectively). A production method thereof is also provided.SELECTED DRAWING: None

Description

  The present invention relates to 2- [2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole (hereinafter referred to as compound X and Novel crystals), and a method for producing the same. The crystal of the compound X of the present invention is useful as a pharmaceutical that can be put into practical use as a drug substance of a therapeutic agent for neurodegenerative diseases and the like. Further, the present invention relates to a pharmaceutical composition containing a novel crystal of compound X of the present invention as an active ingredient.

  2- [2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole (Compound X) is a neurotrophic agent for neurodegenerative diseases and the like. It is a compound expected as a therapeutic or prophylactic agent for diseases involving factor activity (see Patent Document 1).

International Publication No. 2010/137349

In Example 11 of Patent Document 1, it is described that Compound X was obtained as a tan semi-solid, but there is no description about the acquisition of crystals of Compound X and the presence or absence of polymorphs thereof.
When the production method described in Patent Document 1 was further tested, the obtained compound X was obtainable as a solid, but it was confirmed that when the obtained solid was stored for a long period of time, it was transferred to another crystal.
In general, a compound having a crystalline polymorph has different properties depending on the crystalline form, so even the same compound may have completely different effects. When using compounds with crystalline polymorphs as pharmaceuticals, in order to ensure the uniform quality and certain effects that are required for pharmaceuticals, a single crystal with excellent storage stability and moisture resistance is always constant. It is necessary to provide it.
Thus, the present state that the existence form of Compound X and its efficient production method excellent in storage stability and moisture resistance have not been established, and a stable crystal and its production method have been demanded.

An object of the present invention is to provide a novel crystal of Compound X having excellent storage stability that can maintain the same quality when stored as a drug substance of a therapeutic agent for neurodegenerative diseases and the like, and a method for producing the same.
As a result of investigating a stable crystal polymorph of Compound X and an efficient production method thereof, the present inventors have found that the crude crystal of Compound X is much better preserved than being suspended and stirred in a specific solvent. The present inventors have found that a stable crystal having stability is found and have completed the present invention.

That is, the present invention is as follows.
[1] In a powder X-ray diffraction spectrum, diffraction angles (2θ) show main peaks at 11.6 °, 15.9 °, 17.4 °, and 22.1 ° (each ± 0.2 °). Crystal of 2- [2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole.
[2] In the powder X-ray diffraction spectrum, the diffraction angle (2θ) is 10.2 °, 11.6 °, 15.9 °, 17.4 °, 17.9 °, 22.1 °, 27.2 ° The crystal according to [1], which exhibits a main peak at 28.5 ° (each ± 0.2 °).
[3] The crystal according to [1] or [2], which shows an endothermic peak having an extrapolation start temperature of 214 ± 5.0 ° C. in differential scanning calorimetry (DSC).
[4] A pharmaceutical composition comprising the crystal according to any one of [1] to [3] as an active ingredient.
[5] A therapeutic or preventive agent for a disease involving the activity of a neurotrophic factor comprising the crystal according to any one of [1] to [3] as an active ingredient, or an accelerator for a physical therapy effect.
[6] A preventive and / or therapeutic agent for a neurodegenerative disease comprising the crystal according to any one of [1] to [3] as an active ingredient.
[7] The preventive and / or therapeutic agent according to [6], wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or Huntington's chorea.
[8] Treatment or prevention of a disease associated with neurotrophic factor activity, or physical therapy effect, characterized by administering an effective amount of the crystal according to any one of [1] to [3] How to promote.
[9] 2- [2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole is suspended in acetone and then solid The method for preparing a crystal according to any one of [1] to [3], wherein a product is collected by filtration.

  ADVANTAGE OF THE INVENTION According to this invention, the useful pharmaceutical composition containing the crystal | crystallization which has the outstanding storage stability, moisture resistance, etc. as a pharmaceutical active ingredient of therapeutic agents, such as a neurodegenerative disease, and the said crystal | crystallization as an active ingredient is provided. .

2 is a chart showing a powder X-ray diffraction pattern of Compound X Form A crystals. 2 is a chart showing a powder X-ray diffraction pattern of Compound B Form B crystals. It is a chart which shows the powder X-ray-diffraction pattern of the crystal | crystallization of the form C of Compound X. FIG. 2 is a graph showing a characteristic DSC curve of a crystal of Compound X Form A. FIG. 5 is a graph representing a characteristic DSC curve of a crystal of Form X of Compound X. FIG. 2 is a graph showing a characteristic DSC curve of a crystal of Form X of Compound X. It is a chart which shows the result of the water | moisture-content adsorption / desorption test (GVS) of the crystal | crystallization of Form A of Compound X. It is a chart which shows the result of the water | moisture-content adsorption / desorption test (GVS) of the crystal | crystallization of Form B of Compound X. It is a chart which shows the result of the water | moisture-content adsorption / desorption test (GVS) of the crystal | crystallization of Form C of Compound X.

The present invention is described in further detail below.
The present invention relates to a crystalline form of 2- [2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole (Compound X) It is.
The crystals of the compound X of the present invention may be solvates (including hydrates), non-solvates (anhydrides), and anhydrides are preferable.
Examples of hydrates include 0.5 hydrate, 1.0 hydrate, and 1.5 hydrate.
As the solvate other than the hydrate, a solvate of a pharmaceutically acceptable solvent is preferable, and an ethanol solvate crystal (0.5 ethanol solvate, 1.0 ethanol solvate, 1.5 ethanol solvate). ) And the like.

The production method compound X is synthesized through, for example, the following five steps.

Step 1: Production of 4-[(tetrahydro-2H-pyran-4-yl) amino] -3-nitrobenzoic acid
4-[(Tetrahydro-2H-pyran-4-yl) amino] -3-nitrobenzoic acid is synthesized in a suitable inert solvent with 4-fluoro-3-nitrobenzoic acid and 4-aminotetrahydro-2H- It is produced by reacting pyran or a salt thereof in the presence of a base.

  The reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.

  The amount of 4-aminotetrahydro-2H-pyran used is usually 1 to 2 moles, preferably 1 to 1.5 moles per mole of 4-fluoro-3-nitrobenzoic acid.

  Examples of the base used include carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate and cesium carbonate; phosphates such as sodium phosphate and potassium phosphate; hydroxides such as sodium hydroxide and potassium hydroxide And organic amines such as morpholine, piperidine, pyridine, trimethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and the like. Further, 4-aminotetrahydro-2H-pyran may be used separately as a base. The amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of 4-fluoro-3-nitrobenzoic acid.

  Examples of the solvent include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile, dimethylformamide, dimethyl sulfoxide and An aprotic solvent such as N-methylpyrrolidone; a halogenated hydrocarbon such as chloroform, or a mixed solvent thereof is used. 4-Aminotetrahydro-2H-pyran can also be used as a solvent.

Step 2: Step of producing 3-amino-4-[(tetrahydro-2H-pyran-4-yl) amino] benzoic acid
3-Amino-4-[(tetrahydro-2H-pyran-4-yl) amino] benzoic acid is prepared from 4-[(tetrahydro-2H-pyran-4-yl) amino] -3- Nitrobenzoic acid is produced by catalytic reduction or reduction using a metal reducing reagent. Preferably, a catalytic reduction method is used. Hereinafter, the catalytic reduction method will be described.

  The catalytic reduction method is carried out under a hydrogen atmosphere of 1 to 5 atm, or optionally using ammonium formate instead of hydrogen and at a temperature in the range from about 0 ° C. to the boiling point of the solvent used in the presence of a metal catalyst. It can be performed by reacting for 10 minutes to 48 hours.

  Examples of the metal catalyst include palladium-carbon, palladium hydroxide-carbon, rhodium-carbon, Raney nickel, platinum oxide and the like. The amount used is 4-[(tetrahydro-2H-pyran-4-yl) amino]- The amount is usually 0.01% to 100% by weight, preferably 0.1 to 50% by weight, based on 3-nitrobenzoic acid.

  Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol; ether solvents such as tetrahydrofuran; ester solvents such as ethyl acetate; aprotic polar solvents such as N, N-dimethylformamide or the like And the like.

Step 3: Production process of 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride
2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid hydrochloride is synthesized in a suitable inert solvent in 3-amino-4-[(tetrahydro-2H -Pyran-4-yl) amino] benzoic acid is prepared by acting an acylating agent. Examples of the acylating agent include acid halides such as acetyl chloride, and acid anhydrides such as acetic anhydride.

  The reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.

  The amount of the acylating agent used is usually 1 to 5 moles, preferably 1 to 2 moles per mole of 3-amino-4-[(tetrahydro-2H-pyran-4-yl) amino] benzoic acid. is there.

  Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; ester solvents such as ethyl acetate; aprotic polarities such as acetone, acetonitrile, N, N-dimethylformamide, and the like. Solvent; or a mixed solvent thereof.

  Further, by performing the catalytic reduction in Step 2 in the presence of an acylating agent, the metal catalyst is filtered after the reduction, and the filtrate is heated as it is, whereby 4-[(tetrahydro-2H-pyran-4-yl) amino is obtained. It is also possible to directly synthesize 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride from 3-nitrobenzoic acid.

Step 4: Process for producing N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide
N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide is prepared in a suitable inert solvent in the presence of a condensing agent. It is produced by reacting 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride with 2-aminophenol.

  The reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.

  The amount of 2-aminophenol used is usually 1 to 2 moles per mole of 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride. Yes, preferably 1 to 1.5 mol.

Examples of the condensing agent include Bop (1H-1,2,3-benztriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), EDC (1-ethyl-3- (3-dimethylaminopropyl). ) Carbodiimide) or its hydrochloride, DCC (N, N-dicyclohexylcarbodiimide), CDI (carbonyldiimidazole), diethylphosphoryl cyanide and the like. The amount of the condensing agent used is usually 1 to 2 mol per mol of 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride, Preferably it is 1-1.5 mol.
If necessary, 1 equivalent to an excess amount of an organic base such as triethylamine with respect to 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride May be added.

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate: ethers such as tetrahydrofuran and 1,4-dioxane; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide.

  N- (2-Hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide can also be synthesized in a suitable inert solvent using 2-methyl It is also produced by contacting 2-aminophenol after contacting -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride with a halogenating agent. The

  When a halogenating agent is used, the reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.

  Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like. The amount of the halogenating agent used is usually 1 to 10 mol, preferably 1 mol to 1 mol of 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid / hydrochloride. Is 1 to 1.5 mol. Further, a catalytic amount of N, N-dimethylformamide may be added to the reaction system.

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; ethers such as tetrahydrofuran and 1,4-dioxane; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; aromatic hydrocarbons such as benzene and toluene.

Step 5: Production Process of Compound X Compound X dehydrates N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide It is manufactured by doing. Specifically, N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide was dehydrated in a suitable inert solvent. React with a condensing agent.

  The reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 48 hours.

  Examples of dehydrating condensing agents include lower fatty acid anhydrides such as acetic anhydride and propionic anhydride; organic sulfonic acids such as methanesulfonic acid and paratoluenesulfonic acid; phosphorus oxychloride, phosphorus trichloride, diphosphorus pentoxide, sulfuric acid, polyphosphoric acid And inorganic acids such as boric acid.

  Examples of the solvent include ether solvents such as tetrahydrofuran, dioxane, monoglyme, diglyme and dibutyl diglyme; aromatic hydrocarbon solvents such as benzene, toluene, xylene, monochlorobenzene and dichlorobenzene; or a mixed solvent thereof. Used. Moreover, you may use the dehydration condensation agent described above as a solvent.

  The crystal of Compound X produced by referring to the above production method (this crystal form may be abbreviated as Form B if necessary), when stored for a long period of time, other crystals ( (It may be abbreviated as Form A).

Obtaining stable crystals Using the crystals of Form A and Form B of the compound X described above as raw materials, the crystals obtained by suspending in various solvents were evaluated by powder X-ray diffraction, Compound X was found to have multiple crystal polymorphs.
Among them, the diffraction angle (2θ) in powder X-ray diffraction is 11.6 °, 15.9 °, 17.4 °, and 22.1 ° (preferably 10.2 °, 11.6 °, 15.9). Crystals with characteristic peaks at °, 17.4 °, 17.9 °, 22.1 °, 27.2 ° and 28.5 ° (± 0.2 ° respectively) (optionally Form C Is a stable crystal. The powder X-ray diffraction pattern of this crystal is shown in FIG. When used as a pharmaceutical product, this crystal can always exhibit a constant effect without change in quality due to storage.

  A crystal of Form C, which is a crystal of the present invention, is produced by suspending Compound X (including crystals of Form A and B, amorphous, and a mixture thereof) in a solvent, and then filtering a solid. Is done.

  Examples of the solvent include water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone and cyclohexanone; Examples include aprotic solvents such as acetonitrile, mixed solvents thereof, and the like, ketone solvents are preferable, and acetone is more preferable. The suspension temperature may be from 0 ° C to the reflux temperature of the solvent used, and is preferably from 10 ° C to 56 ° C. The suspension time can be appropriately selected from the range of 1 minute to 1 month, and preferably 10 minutes to 48 hours.

  As a method for analyzing the crystal of the present invention thus obtained, a measurement method for analyzing a solid can be generally applied without limitation. Preferably, however, the diffraction angle (2θ, °) or lattice spacing (d, Å) and relative intensity (%). Although the measurement conditions of a powder X-ray diffraction spectrum are not specifically limited, It is preferable to measure on the measurement conditions described in this specification. Powder X-ray diffraction is important because of the nature of the data, the diffraction angle, crystal lattice spacing, and overall pattern are important in identifying the identity of the crystal, and the relative intensity is the crystal growth direction, particle size, and measurement. It should not be construed strictly because it can vary depending on conditions.

  As a crystal analysis method, single crystal X-ray structure analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared absorption spectrum, solid NMR spectrum, or the like may be used in combination. Although these measurement conditions are not specifically limited, It is preferable to measure on the measurement conditions as described in this specification.

Each spectrum obtained by these analysis methods has a certain measurement error due to its nature. A crystal having a peak whose spectral error is within the error range is also included in the scope of the present invention. For example, in the case of powder X-ray diffraction measurement, a crystal having a peak within an error range of ± 0.2 mm at a lattice plane distance represented by d, or a diffraction angle peak represented by 2θ is ± 0. Crystals having a peak within an error range of 2 ° are included in the present invention.
Also, ± 5 ° C. is allowed in the extrapolation start temperature (Tim), endothermic peak temperature (Tpm), etc. of differential scanning calorimetry (DSC). Differential scanning calorimetry (DSC) extrapolation start temperature (Tim) is the temperature at the point where the extrapolated line of the rising end of the endothermic peak curve and the baseline intersect, and melting peak temperature (Tpm) Says the temperature at the peak top of the endothermic peak.

The crystals of Compound X (Form A, Form B, and Form C crystals) exhibit the following physical property values.
(1) Crystal of Form A of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 11.2 °, 13.4 °, 15.8 °, 16.3 °, 17.9 °, 18.2 °, 19.1 °, 19.4 °, 19.6 °, 21.0 °, 21.2 °, 22.2 °, 22.4 °, 22.5 °, 23.3 °, Peaks at 24.0 °, 26.5 °, 27.2 °, 27.4 °, 28.0 °, 29.9 °, 31.4 ° and 34.1 ° (each ± 0.2 °) Preferably 11.2 °, 13.4 °, 15.8 °, 16.3 °, 17.9 °, 18.2 °, 19.1 °, 19.4 °, 19.6 °, 21 Peaks at 0.0 °, 21.2 °, 22.4 °, 22.5 °, 23.3 °, 24.0 °, 27.4 ° and 31.4 ° (each ± 0.2 °) , More preferably 11.2 °, 13.4 °, Characteristic of 5.8 °, 17.9 °, 18.2 °, 19.1 °, 19.4 °, 22.5 °, 24.0 ° and 27.4 ° (each ± 0.2 °) It shows a peak, and particularly preferably shows a main peak at 11.2 °, 17.9 °, 19.1 °, and 24.0 ° (each ± 0.2 °).
In differential scanning calorimetry (DSC), an endothermic peak accompanying dehydration having an extrapolation start temperature (Tim) at 86 ° C. (± 5 ° C.) is shown, and an extrapolation start temperature (Tim) at 200 ° C. (± 5 ° C.). It shows an endothermic peak accompanying melting of the crystal form (form B) that has been transformed by dehydration.

(2) Crystal of Form B of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 9.7 °, 10.9 °, 11.3 °, 11.6 °, 14.0 °, 15.9 °, 16.0 °, 16.2 °, 17.5 °, 17.7 °, 18.6 °, 19.4 °, 19.5 °, 20.1 °, 20.8 °, Peaks at 21.7 °, 22.1 °, 23.4 °, 26.2 °, 27.3 °, 27.7 °, 27.9 ° and 28.1 ° (each ± 0.2 °) Preferably,
9.7 °, 11.3 °, 11.6 °, 14.0 °, 15.9 °, 16.0 °, 16.2 °, 17.7 °, 19.4 °, 19.5 °, Peaks at 21.7 °, 22.1 °, 26.2 °, 27.7 ° and 28.1 ° (each ± 0.2 °), more preferably
11.3 °, 11.6 °, 15.9 °, 16.0 °, 17.7 °, 19.4 °, 21.7 °, 22.1 °, 27.7 ° and 28.1 ° ( Each having a characteristic peak at ± 0.2 °, particularly preferably
Main peaks are shown at 11.6 °, 15.9 °, 16.0 ° and 21.7 ° (each ± 0.2 °).
In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolated onset temperature (Tim) at 198 ° C. (± 5 ° C.) is shown.

(3) Crystal of Form C of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 10.2 °, 11.0 °, 11.6 °, 15.9 °, 16.1 °, 16.6 °, 17.2 °, 17.4 °, 17.9 °, 19.5 °, 21.0 °, 22.1 °, 23.1 °, 23.3 °, 25.3 °, Peaks at 27.2 °, 27.4 °, 28.5 °, 29.2 ° and 36.2 ° (each ± 0.2 °), preferably
10.2 °, 11.6 °, 15.9 °, 16.1 °, 17.4 °, 17.9 °, 19.5 °, 22.1 °, 23.1 °, 23.3 °, Peaks at 27.2 °, 28.5 ° and 29.2 ° (each ± 0.2 °), more preferably
Characteristic at 10.2 °, 11.6 °, 15.9 °, 17.4 °, 17.9 °, 22.1 °, 27.2 ° and 28.5 ° (each ± 0.2 °) Showing a peak, particularly preferably
Main peaks are shown at 11.6 °, 15.9 °, 17.4 ° and 22.1 ° (each ± 0.2 °).
In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 214 ° C. (± 5 ° C.) is shown.

  In general, it is desired that a change in weight due to moisture absorption is small as a pharmaceutical product. Generally, a change in weight of 5% or less is desired by moisture adsorption / desorption isotherm measurement (GVS). The measurement conditions for moisture adsorption / desorption isotherm measurement are not particularly limited, but measurement is preferably performed under the measurement conditions described in this specification.

The crystal of the compound X of the present invention has an action of enhancing the activity of the neurotrophic factor, and in particular, has an action of inducing NXF gene expression that plays an important role in nerve protection.
Accordingly, the crystal of the compound X of the present invention can be used as a therapeutic or prophylactic agent for diseases involving the activity of neurotrophic factor.
Moreover, the crystal | crystallization of this invention compound X can be used as a promoter of the physical therapy effect for recovery | restoration of a body function.
In the present specification, a disease is used in the meaning including a disorder and its symptoms.
In the present specification, treatment is used in the meaning including alleviation of symptoms.

  Examples of the diseases involving the activity of neurotrophic factors include the following cranial neurodegenerative diseases, spinal degenerative diseases, retinal degenerative diseases, peripheral neurodegenerative diseases, and other diseases.

  Neurodegenerative diseases include, for example, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Huntington's disease, Down's syndrome, etc.), cerebral ischemic diseases (stroke, cerebral infarction, transient ischemic attack, subarachnoid Bleeding, ischemic encephalopathy, cerebral infarction (such as lacunar infarction, atherothrombotic cerebral infarction, cardiogenic cerebral infarction, hemorrhagic cerebral infarction, other infarcts)), traumatic brain injury, leukoencephalopathy, and multiple sclerosis Is mentioned.

  Examples of spinal degenerative diseases include amyotrophic lateral sclerosis (ALS), spinal cord injury, spinal cord injury due to various causes, spinal progressive muscular atrophy, and spinal cerebral degeneration (SCD).

  Examples of retinal degenerative diseases include age-related macular degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, hypertensive retinopathy, and glaucoma.

  Examples of peripheral neurodegenerative diseases include diabetic neuropathy, peripheral nerve injury, traumatic peripheral neuropathy, addiction, peripheral neuropathy caused by other toxic substances, peripheral neuropathy caused by cancer chemotherapy, Guillain-Barre syndrome, vitamins Peripheral neuropathy caused by deficiency, amyloid peripheral neuropathy, ischemic peripheral neuropathy, peripheral neuropathy associated with malignant tumor, uremic peripheral neuropathy, peripheral neuropathy due to physical causes, Charcot-Marie-Tooth disease, alcohol Peripheral neuropathy, autonomic abnormalities (subconscious hypoglycemia, gastric paresis, neurogenic diarrhea and constipation, erectile dysfunction, orthostatic hypotension, arrhythmia, heart failure, painless myocardial infarction, sweating abnormality, neurogenic bladder, etc. ), Bladder dysfunction (eg, uninhibited bladder, reflex bladder, autonomous bladder, sensory paralytic bladder, motor paralytic bladder, etc.).

  Other diseases include, for example, depression, schizophrenia, epilepsy, autism, periodontal disease, diabetes, diabetic cardiomyopathy, diabetic foot lesions, inflammatory bowel disease (eg, ulcerative colitis, clones) Disease, etc.), behavioral problems associated with dementia (eg, sputum, aggressive behavior), anxiety, pain, hearing impairment, bone disease (eg, osteoporosis), joint disease (eg, Charcot joint, deformity) Arthropathy, rheumatism, etc.) and Hirschsbrunn disease.

The crystal of the compound X of the present invention is particularly preferably used as a therapeutic or prophylactic agent for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's chorea.
Pharmacological test data that proves that compound X and the like are effective for the above-mentioned diseases are disclosed in Test Examples 1 to 4 of Patent Document 1 (International Publication No. 2010/137349). It is clear that has the same medicinal effect.

  Since the crystal of the compound X of the present invention has low toxicity, the activity of neurotrophic factor is involved as a composition (eg, pharmaceutical composition) formulated as it is or mixed with a pharmaceutically acceptable carrier or the like. For prevention or treatment of diseases, it can be safely administered orally or parenterally to mammals such as humans. “Parenteral” includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and the like.

  The composition of the present invention contains, for example, one or more crystals of the compound X of the present invention and a pharmaceutically acceptable carrier, excipient, and / or additive.

  According to the form of the composition of the present invention, the crystal of the compound X of the present invention and a pharmaceutically acceptable carrier, excipient, and / or additive (eg, pharmaceutical additive) can be obtained by a known method. , Food additives, cosmetic additives) and the like.

  The pharmaceutically acceptable carrier, excipient, and / or additive used in the composition of the present invention can be appropriately selected depending on the specific use of the composition. Moreover, the form of the said composition can also be made into forms, such as various solid and liquid, according to a specific use, for example. For example, when the pharmaceutical composition of the present invention or the crystal of the compound X of the present invention is used as a pharmaceutical product, for example, powders, fine granules, granules, tablets, capsules, suspending agents, Examples include oral preparations such as emulsions, extracts and pills, parenteral preparations such as injections, liquids for external use, suppositories and topical preparations.

  Oral preparations include, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soy lecithin, sucrose, fatty acid ester, talc, magnesium stearate, Carriers and excipients such as polyethylene glycol, magnesium silicate, and silicic anhydride, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, colorants, fragrances, stabilization It can be produced according to a usual method using a pharmaceutical additive such as an agent, a humectant, a preservative, and an antioxidant.

  The dose varies depending on the age, sex, body weight, degree of disease, type of crystal of the compound X of the present invention, dosage form, etc. of the mammal to be administered. About 1 mg to about 2 g as an active ingredient amount per dose, preferably about 5 mg to about 1 g as an active ingredient amount may be administered. In addition, the above-mentioned daily dose can be administered once or divided into several times.

  Among parenteral preparations, injections, liquids for external use, transdermal absorption agents such as gel ointments, suppositories for rectal administration and the like can be produced according to ordinary methods. In order to administer such a parenteral preparation, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, or rectal administration may be used. The topical agent can be produced, for example, by incorporating crystals of the compound X of the present invention into pellets of a sustained release polymer such as an ethylene vinyl acetate polymer. This pellet may be surgically implanted into the tissue to be treated.

  The dose varies depending on the age, sex, weight, disease level, composition of the present invention, type of crystal of the compound X of the present invention, dosage form, etc., but is usually effective for human adults. About 0.1 mg to about 500 mg may be administered as the component amount. In addition, the above-mentioned daily dose can be administered once or divided into several times.

  The crystal purity of the compound X of the present invention can be determined by a known method such as a powder X-ray diffraction measurement method or thermal analysis. The purity of the crystal of the present invention is not necessarily 100%, and is usually 70% or more, preferably 80% or more, more preferably 90% or more, further preferably 95% or more, and most preferably 98% or more. It is. It is preferable that the purity is within this range in order to guarantee the quality as a pharmaceutical product.

  The purity of crystal means the ratio (purity) of Compound X in a specific crystal form to the total amount of Compound X crystals.

  Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Test Examples, and Formulation Examples, but the present invention is not limited thereto.

¹ H-NMR was measured using JNM MA-300 manufactured by JEOL and showed a chemical shift δ (ppm) from tetramethylsilane as an internal standard.
Symbols in the NMR data have the following meanings.
s: singlet d: doublet t: triplet q: quartet m: multiplet
bs: Broad singlet J: Binding constant

Powder X-ray diffraction measurement / apparatus: X-ray Diffraction system X 'pert MPD (PANAlytical) manufactured by Spectris
· _{X-ray: Cu Kα 1/45 kV /} 40 mA
Attachment: Non-reflective Si plate holder Incident slit: 20 mm (automatic) / Divergence prevention slit: 20 mm (automatic)
・ Scanning mode: Continuous ・ Step size: 0.017 °
Scan speed: 0.0213 ° / sec Scan range: 4-40 ° (2θ)
-Integration time: 100 seconds / step

Differential scanning calorimetry (DSC)
・ Device: Q1000 manufactured by TI Instruments
Measurement temperature range: -10 to 280 ° C
・ Temperature increase rate: 10 ° C./min ・ Container: Aluminum hermetic pan (Pin hole)
-Sample amount: 0.5-1.5mg
・ Atmospheric gas flow rate: Dry nitrogen, 50 mL / min

Thermogravimetry (TGA)
・ Device: Q500 manufactured by TI Instruments
・ Measurement temperature range: Room temperature to 250 ℃
・ Temperature increase rate: 10 ° C./min ・ Container: Platinum pan ・ Sample amount: 1.0-2.0 mg
-Atmospheric gas flow rate: dry nitrogen, sample flow rate 60mL / min, balance flow rate 40mL / min

Moisture absorption / desorption isotherm measurement (GVS)
・ HIGA IGAsorb
・ Measurement temperature: 25 ℃
-Container: Stainless steel mesh holder-Sample amount: 5.0-10.0 mg
・ Atmospheric gas flow rate: 250 mL / min ・ Humidity range: 0 to 90% RH (RH means relative humidity) and measured. Measurement starts when the weight reaches equilibrium at the first set relative humidity. However, the maximum time until the weight reaches equilibrium is set to 120 minutes. In addition, when the weight reaches equilibrium at the set relative humidity, a setting is made to shift to the relative humidity of the next step.

High performance liquid chromatogram (HPLC)
・ Measurement equipment: LC-20A manufactured by Shimadzu Corporation
・ Mobile phase (A / B): 0.05% TFA water / 0.05% TFA acetonitrile ・ Column: CAPCELL PAK C18_SG120 5 mm 4.6 mm ID × 250 mm (Shiseido)
-Mobile phase (A / B): 0.05% TFA water / 0.05% TFA acetonitrile

・ Column temperature: 40 ℃
・ Flow rate: 1.0 mL / min
・ UV wavelength: 254 nm
・ Injection volume: 10 μl

Reference example 1
4-[(Tetrahydro-2H-pyran-4-yl) amino] -3-nitrobenzoic acid In a nitrogen stream, 4-fluoro-3-nitrobenzoic acid (990 g), ethanol (4950 g), 4- Aminotetrahydro-2H-pyran hydrochloride (920 g) was added, and triethylamine (2190 g) was added dropwise. The reaction was stirred at 78 ° C. for 10.5 hours. The reaction mixture was cooled to room temperature, water (14.85 kg) was added, and 20% hydrochloric acid (3221 g) was added dropwise. After stirring for a while, the obtained solid was filtered, washed with water (9.9 kg), and dried by ventilation under reduced pressure at 55 ° C. to obtain the title compound (1374 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (m, 2H), 1.95 (d, 2H, J = 10.9 Hz), 3.44-3.53 (m, 2H), 3.84-4.01 (m, 3H) 7.27 (d, 1H, J = 9.2Hz), 7.96 (dd, 1H, J = 9.2, 2.0Hz), 8.21 (d, 1H, J = 7.7Hz), 8.62 (d, 1H, J = 2.0Hz) .

Reference example 2
3-Amino-4-[(tetrahydro-2H-pyran-4-yl) amino] benzoic acid In a reaction vessel, 4-[(tetrahydropyran-4-yl) amino] -3-nitrobenzoic acid (1373 g), THF (17.85 kg) and methanol (5.4 kg) were charged, and 10% -Pd / C (50% moisture, 275 g) was added. The mixture was stirred for 4.5 hours with hydrogen bubbling. The catalyst was filtered and washed with methanol (6.87 kg). The solvent was concentrated under reduced pressure to obtain the title compound (1282 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.36-1.51 (m, 2H), 1.87-1.95 (m, 2H), 3.38-3.48 (m, 2H), 3.85-3.92 (m, 2H), 4.92 ( d, 1H, J = 6.1Hz), 6.52 (d, 1H, J = 8.9Hz), 7.16-7.20 (m, 2H).

Reference example 3
2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxylic acid hydrochloride
To a solution of 3-amino-4-[(tetrahydro-2H-pyran-4-yl) amino] benzoic acid (1280 g) in 1,4-dioxane (23.04 kg), acetyl chloride (702 g) in 1,4-dioxane ( 6.4 kg) solution was added dropwise. The mixture was heated and stirred for 6.5 hours under reflux conditions, then cooled to room temperature, n-hexane (3840 g) was added, and the mixture was stirred for 30 minutes. The obtained solid was filtered, washed with n-hexane (5120 g), and dried under reduced pressure at 45 ° C. to obtain the title compound (1500 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.95-2.02 (m, 2H), 2.49-2.52 (m, 2H), 2.96 (s, 3H), 3.53-3.64 (m, 2H), 4.06 (dd, 2H, J = 11.6, 3.9Hz), 4.82-4.91 (m, 1H), 8.04 (dd, 1H, J = 8.8, 1.3Hz), 8.15 (d, 1H, J = 8.8Hz), 8.27 (d, 1H , J = 1.3Hz).

Reference example 4
N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide Into a reaction vessel, 2-methyl-1- (tetrahydro-2H -Pyran-4-yl) -1H-benzimidazole-5-carboxylic acid hydrochloride (1484 g), 2-aminophenol (710 g), THF (10.39 kg), water (2.97 g) were added, and EDC hydrochloride ( 1150 g) was added and stirred at room temperature. After 2.5 hours, EDC hydrochloride (288 g) was added, and further 4.5 hours later, EDC hydrochloride (48 g) was added. After confirming the completion of the reaction, 5% aqueous sodium carbonate solution (5.94 kg) and water (7.42 kg) were added and stirred for 30 minutes. The resulting crystals were filtered, washed with water (7.42 kg), 2-propanol (7.42 kg) and n-hexane (1.48 kg), and dried under reduced pressure at 50 ° C. to give the title compound (1415 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.82-1.89 (m, 2H), 2.35-2.46 (m, 2H), 2.65 (s, 3H), 3.53-3.61 (m, 2H), 4.01-4.09 ( m, 2H), 4.58-4.68 (m, 1H), 6.84 (td, 1H, J = 8.0, 1.5Hz), 6.93 (dd, 1H, J = 8.1, 1.5Hz), 7.04 (td, 1H, J = 8.0, 1.5Hz), 7.69-7.84 (m, 3H), 8.20 (d, 1H, J = 1.6Hz), 9.56 (s, 1H), 9.78 (s, 1H).

Reference Example 5
2- [2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole (Compound X) Form B
In a reaction vessel, N- (2-hydroxyphenyl) -2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazole-5-carboxamide (650 g), dibutyl diglyme (9.75 kg) ) And boric acid (40.03 g) were added, and the mixture was stirred with heating at 240-250 ° C. for 4 hours. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature, n-hexane (13 kg) was added, and the mixture was stirred for 3.5 hours. The obtained solid was filtered and washed with 2-propanol (5.2 kg) and n-hexane (1.95 kg) to obtain 770 g of a crude product of the title compound.
Further, a crude product of the title compound from 2-methyl-1- (tetrahydro-2H-pyran-4-yl) benzimidazole-5-carboxylic acid hydrochloride (750 g) according to the method described in Reference Example 4 above. 665 g was obtained.
The obtained solids were combined, dissolved by adding chloroform (8.4 kg) and 5% aqueous sodium hydrogen carbonate solution (5.6 kg), stirred and separated, and the aqueous phase was extracted with chloroform (2.8 kg). The organic layer was washed with 20% aqueous sodium chloride solution (4.2 kg), dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (803 g) as crystals having a crystal form abbreviated as Form B. The powder X-ray diffraction pattern chart of the crystal of Form B is shown in FIG. 2, and the DSC chart is shown in FIG.
¹ H-NMR (CDCl ₃ ) δ: 1.88-1.92 (m, 2H), 2.58-2.68 (m, 2H), 2.70 (s, 3H), 3.57-3.64 (m, 2H), 4.21-4.25 (m, 2H), 4.43-4.49 (m, 1H), 7.29 (d, 1H, J = 9.2Hz), 7.33-7.35 (m, 2H), 7.59-7.62 (m, 1H), 7.76-7.78 (m, 1H ), 8.18 (dd, 1H, J = 8.6, 1.6Hz), 8.57 (d, 1H, J = 1.4Hz).
Form B exhibited an endothermic peak associated with melting having an extrapolated onset temperature (Tim) at 198 ° C. (± 5 ° C.) in differential scanning calorimetry (DSC).

Reference Example 6
Compound X Form A Crystals Compound X Form B crystals obtained in Reference Example 5 were transferred to Form A crystals when stored for a certain period of time. A chart of the powder X-ray diffraction pattern of the crystal of Form A is shown in FIG. 1, and a DSC chart is shown in FIG.
¹ H-NMR (CDCl ₃ ) δ: 1.88-1.92 (m, 2H), 2.58-2.68 (m, 2H), 2.70 (s, 3H), 3.57-3.64 (m, 2H), 4.21-4.25 (m, 2H), 4.43-4.49 (m, 1H), 7.29 (d, 1H, J = 9.2Hz), 7.33-7.35 (m, 2H), 7.59-7.62 (m, 1H), 7.76-7.78 (m, 1H) 8.18 (dd, 1H, J = 8.6, 1.6Hz), 8.57 (d, 1H, J = 1.4Hz).
The crystal of Form A of Compound X shows an endothermic peak accompanying dehydration having an extrapolated onset temperature (Tim) at 86 ° C. (± 5 ° C.) in differential scanning calorimetry (DSC), and is 200 ° C. (± 5 ° C.). Shows an endothermic peak accompanying melting of the crystal form (Form B) which has been transformed by dehydration having an extrapolation onset temperature (Tim).

Test Example 1: Polymorphic screening
Method 1
10 mg of Compound X Form A crystals were suspended in 100 μL of each hydrous solvent (solvent: water = 20: 1), and the suspension was stirred at 25 ° C.
Organic solvents studied: isopropanol, acetonitrile, tetrahydrofuran, and acetone In the tetrahydrofuran suspension, 4 mg of Form A crystals were added after 4 days, and the mixture was subsequently stirred at 25 ° C. The crystals after stirring each suspension for 2 weeks were confirmed by powder X-ray diffraction measurement.
As a result, the crystal obtained from the suspension solution of isopropanol is Form B, the crystal obtained from the suspension solution of acetonitrile and acetone is Form C, and the crystal obtained from the suspension solution of tetrahydrofuran. Was a mixture of Form A and Form C.

Method 2
10 mg of Compound X Form B crystals were suspended in 100 μL of each solvent (tetrahydrofuran in 50 μL), and the suspension was stirred at 25 ° C.
Organic solvents studied: ethanol, acetonitrile, tetrahydrofuran, acetone, chlorobenzene, and xylene For tetrahydrofuran, chlorobenzene and toluene, 150 μL was added after one week. The crystals after stirring each suspension for 2 weeks were confirmed by powder X-ray diffraction measurement.
As a result, crystals obtained from the suspension solution of ethanol were Form B, and crystals obtained from the other suspension solutions were Form C.

Method 3
10 mg of a physical mixture (1: 1) of Compound X Form B and Form C crystals obtained in Method 2 was suspended in 100 μL of each solvent (50 μL of tetrahydrofuran), and the suspension was stirred at 25 ° C. .
Organic solvents examined: ethanol, isopropanol, acetonitrile, tetrahydrofuran, cyclopentyl methyl ether, ethyl acetate, acetone, methyl isobutyl ketone, chlorobenzene, and xylene Tetrahydrofuran, cyclopentyl methyl ether and toluene were added 100 μL after one week. The crystals after stirring each suspension for 2 weeks were confirmed by powder X-ray diffraction measurement. As a result, the crystals obtained from all the suspension solutions were Form C.

Test Example 2: Preparation of Compound X Form C Crystals Compound X Form B crystals (1 g) were suspended in 10 mL of an organic solvent and stirred at room temperature for 24 hours. The obtained solid was filtered and dried under reduced pressure at 45 ° C.
Organic solvents studied: acetonitrile, acetone, methyl isobutyl ketone, and dimethoxyethane For the solids suspended in a series of solvents, the results of the crystalline polymorphism of compound X obtained from powder X-ray diffraction measurements are shown in Table 4. An efficient transition to Form C was confirmed when acetone was used as the solvent.

Example 1: Scale-up preparation of Compound X Form C 2- [2-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl]-obtained in Reference Example 5 Acetone (258 mL) was added to 1,3-benzoxazole (43 g), and the mixture was stirred at room temperature for 24 hours. The obtained solid was filtered and dried under reduced pressure at 45 ° C. to obtain Form C crystals (35 g). The powder X-ray diffraction pattern chart of Compound X Form C is shown in FIG. 3, and the DSC chart is shown in FIG.
Compound C Form C exhibited an endothermic peak with melting having an extrapolated onset temperature (Tim) at 214 ° C. (± 5 ° C.) in differential scanning calorimetry (DSC).

Test example 3: moisture adsorption / desorption isotherm test (GVS)
The results of the moisture adsorption / desorption isotherm test in the entire range of 0 to 90% RH are shown in Table 6 and FIGS. None of the crystals of Form X, Form B, and Form C of Compound X showed hygroscopicity.

Test Example 4 Thermogravimetric Analysis (TGA) of Compound X Form C Crystal
Thermogravimetric analysis (TGA) was performed on the crystals of Form A, Form B, and Form C of Compound X. Form A crystals showed a weight loss of 5% or more immediately after the start of measurement (about 30 ° C.), indicating that they were not stable hydrates. Further, Form B and Form C crystals did not show a weight loss up to about 190 ° C.

Test Example 5: Storage stability test (chemical stability)
The crystals of Compound X, Form B and Form C, were stored at 60 ° C., and the amount of residual substances and decomposed products after one month had been quantified by high performance liquid chromatogram (HPLC). As a result, it was confirmed that the decomposition product did not increase and was chemically stable.

Test Example 6: Storage stability test (physical stability)
The crystals of Form X and Form C of Compound X were stored at 60 ° C., 60 ° C.-75% RH, and 25 ° C.-93% RH, and the crystals after one month had been confirmed by powder X-ray diffraction measurement (Table 7).
Form B crystals were found to partially transfer to Form C at 60 ° C., 60 ° C.-75% RH, and part of crystals to Form A at 25 ° C.-93% RH. Showed a physically unstable crystal form. Form C crystals retained the same crystal form under all conditions, indicating that they were physically stable crystals.

  Examples of the preparation of the present invention include the following preparations. However, the present invention is not limited by these formulation examples.

Formulation Example 1: Preparation of capsules 1) Form C crystals of Compound X 30 mg
2) Microcrystalline cellulose 10mg
3) Lactose 19mg
4) Magnesium stearate 1mg
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2: Manufacture of tablets 1) 10 g of compound X form C crystals
2) Lactose 50g
3) Corn starch 15g
4) Carmellose calcium 44g
5) Magnesium stearate 1g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 10 mg of the crystals of the compound of Example 5 per tablet are obtained.

  The crystal of the compound X of the present invention (form C crystal) has excellent storage stability and moisture resistance, and is useful as a drug substance of a therapeutic agent for neurodegenerative diseases and the like.

Claims (9)

  In the powder X-ray diffraction spectrum, diffraction angles (2θ) show main peaks at 11.6 °, 15.9 °, 17.4 °, and 22.1 ° (each ± 0.2 °). Crystals of 2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole.   In the powder X-ray diffraction spectrum, diffraction angles (2θ) are 10.2 °, 11.6 °, 15.9 °, 17.4 °, 17.9 °, 22.1 °, 27.2 ° and 28. The crystal according to claim 1, which exhibits a main peak at 5 ° (each ± 0.2 °).   The crystal according to claim 1 or 2, which shows an endothermic peak having an extrapolation start temperature of 214 ± 5.0 ° C in differential scanning calorimetry (DSC).   The pharmaceutical composition which contains the crystal | crystallization as described in any one of Claims 1-3 as an active ingredient.   The therapeutic or preventive agent of the disease in which the activity of the neurotrophic factor which contains the crystal | crystallization as described in any one of Claims 1-3 as an active ingredient is concerned, or the promoter of a physiotherapy effect.   A preventive and / or therapeutic agent for a neurodegenerative disease comprising the crystal according to any one of claims 1 to 3 as an active ingredient.   The preventive and / or therapeutic agent according to claim 6, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or Huntington's chorea.   A method for treating or preventing a disease involving the activity of a neurotrophic factor or promoting a physiotherapy effect, comprising administering an effective amount of the crystal according to any one of claims 1 to 3.   After suspending 2- [2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-5-yl] -1,3-benzoxazole in acetone, the solid was filtered. The method for preparing a crystal according to claim 1, wherein the crystal is prepared.