TECHNICAL FIELD

The present invention relates to a crystal of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate (hereinafter to be referred to as compound 1).

BACKGROUND ART

Compound 1 described in patent document 1 is a compound that inhibits the TCP4/Î²-Catenin transcription pathway by inhibiting CREB binding protein (CBP) in the Wnt signal transduction pathway, and is useful for the treatment of various carcinomass (e.g., lung cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, rectal colon cancer, lymphoma, blood cancer), restenosis relating to angioplasty, angiogenesis abnormality, polycystic kidney, tuberous sclerosis, Alzheimer's disease, neurodegenerative diseases (e.g., glaucoma, macular degeneration, Parkinson's disease, Alzheimer's disease) and fibrosis (e.g., idiopathic pulmonary fibrosis).

DOCUMENT LISTPatent Documents

patent document 1: WO 2009/148192

SUMMARY OF THE INVENTIONProblems to be Solved by the Invention

In general, the property of a crystal of a compound utilizable as a pharmaceutical product exerts a marked influence on the bioavailability of a drug, purity of a drug substance, formulation of a preparation and the like.

Therefore, the problem of the present invention is to provide a crystal of compound 1 expected to be utilized as a drug substance of a pharmaceutical product.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt to solve the aforementioned problem and found a crystal of compound 1, and completed the present invention.

That is, the present invention provides the following [1]-[14].

[1] A crystal of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate or hydrate thereof.
[2] A crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate.
[3] The crystal of [2], showing diffraction peak at diffraction angle (2Î¸Â±0.2Â°) of 15.9Â°, in powder X-ray diffraction.
[3A] The crystal of [2], showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â° and 18.0Â°, in powder X-ray diffraction.
[3B] The crystal of [2], showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 18.0Â° and 23.2Â°, in powder X-ray diffraction.
[3C] The crystal of [2], showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 3.2Â°, 15.9Â°, 18.0Â°, 23.2Â° and 24.8Â°, in powder X-ray diffraction.
[3D] The crystal of [2], showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 3.2Â°, 8.2Â°, 11.0Â°, 14.3Â°, 15.9Â°, 18.0Â°, 19.3Â°, 23.2Â°, 24.8Â° and 28.5Â°, in powder X-ray diffraction.
[4] A crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing peaks at chemical shifts (ppm) of 15.8, 56.4, 127.8, 157.4 and 168.6, in ¹³C solid-state NMR spectrum.
[5] A production method of a crystal of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate or hydrate thereof, comprising a step of crystallizing from a solvent selected from the group consisting of an alcohol solvent, water and a combination of these.
[6] A pharmaceutical composition comprising the crystal of any one of [1]-[3D] as an active ingredient.
[7] An antitumor agent comprising the crystal of any one of [1]-[3D] as an active ingredient.
[8] The antitumor agent of [7], wherein the tumor is lung cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, rectal colon cancer, lymphoma or blood cancer.
[9] A method of preventing or treating tumor, comprising administering a pharmacologically effective amount of any one of the crystals of [1]-[3D] to a patient.
[10] The method of [9], wherein the tumor is lung cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, rectal colon cancer, lymphoma or blood cancer.
[11] The crystal of any one of [1]-[3D], for use for the prophylaxis or treatment of tumor.
[12] The crystal of [11], wherein the tumor is lung cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, rectal colon cancer, lymphoma or blood cancer.
[13] Use of the crystal of any one of [1]-[3D] in the production of an antitumor agent.
[14] Use of the crystal of [11], wherein the tumor is lung cancer, breast cancer, stomach cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, rectal colon cancer, lymphoma or blood cancer.

Effect of the Invention

The crystal of compound 1 provided by the present invention has good property as a drug substance of a pharmaceutical product.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of crystal A obtained in Example 1, wherein the horizontal axis shows diffraction angle (2Î¸), and the vertical axis shows peak intensity.

FIG. 2 shows a powder X-ray diffraction pattern of crystal B obtained in Example 2, wherein the horizontal axis shows diffraction angle (2Î¸), and the vertical axis shows peak intensity.

FIG. 3 shows a powder X-ray diffraction pattern of crystal C obtained in Example 3, wherein the horizontal axis shows diffraction angle (2Î¸), and the vertical axis shows peak intensity.

FIG. 4 shows a powder X-ray diffraction pattern of crystal D obtained in Example 4, wherein the horizontal axis shows diffraction angle (2Î¸), and the vertical axis shows peak intensity.

FIG. 5 shows a powder X-ray diffraction pattern of an amorphous form of compound 1 obtained in Comparative Example 1, wherein the horizontal axis shows diffraction angle (2Î¸), and the vertical axis shows peak intensity.

FIG. 6 is a graph showing the hygroscopicity of crystal A obtained in Example 1, wherein the horizontal axis shows relative humidity (RH), and the vertical axis shows variation (%) in the mass.

FIG. 7 is a graph showing the thermal stability of crystal A obtained in Example 1.

FIG. 8 shows the ¹³C solid-state NMR spectrum of crystal A obtained in Example 1.

DESCRIPTION OF EMBODIMENTS

Preferable crystals in the present specification include a crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing a diffraction peak at diffraction angle (2Î¸Â±0.2Â°) of 15.9Â°, in powder X-ray diffraction;

a crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â° and 18.0Â°, in powder X-ray diffraction;

a crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 18.0Â° and 23.2Â°, in powder X-ray diffraction;

a crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 3.2Â°, 15.9Â°, 18.0Â°, 23.2Â° and 24.8Â°, in powder X-ray diffraction;

a crystal of hydrate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 3.2Â°, 8.2Â°, 11.0Â°, 14.3Â°, 15.9Â°, 18.0Â°, 19.3Â°, 23.2Â°, 24.8Â° and 28.5Â°, in powder X-ray diffraction;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing a diffraction peak at diffraction angle (2Î¸Â±0.2Â°) of 10.3Â°;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 10.3Â° and 10.8Â°, in powder X-ray diffraction;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 10.3Â°, 10.8Â° and 22.9Â°, in powder X-ray diffraction;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 10.3Â°, 10.8Â°, 14.4Â° and 22.9Â°, in powder X-ray diffraction;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 10.3Â°, 10.8Â°, 14.4Â°, 22.9Â° and 23.3Â°, in powder X-ray diffraction;

a crystal of methanolate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 7.9Â°, 10.3Â°, 10.8Â°, 13.1Â°, 14.4Â°, 20.9Â°, 22.9Â°, 23.3Â°, 24.7Â° and 26.5Â°, in powder X-ray diffraction;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing a diffraction peak at diffraction angle (2Î¸Â±0.2Â°) of 8.3Â°;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 8.3Â° and 18.6Â°, in powder X-ray diffraction;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 8.3Â°, 13.0Â° and 18.6Â°, in powder X-ray diffraction;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 8.3Â°, 13.0Â°, 15.8Â° and 18.6Â°, in powder X-ray diffraction;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 8.3Â°, 12.7Â°, 13.0Â°, 15.8Â° and 18.6Â°, in powder X-ray diffraction;

a crystal of anhydride of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 8.3Â°, 12.7Â°, 13.0Â°, 15.3Â°, 15.8Â°, 17.1Â°, 18.6Â°, 19.6Â°, 23.8Â° and 24.9Â°, in powder X-ray diffraction;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing a diffraction peak at diffraction angle (2Î¸Â±0.2Â°) of 18.4Â°;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â° and 18.4Â°, in powder X-ray diffraction;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 18.4Â° and 25.5Â°, in powder X-ray diffraction;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 18.4Â°, 20.9Â° and 25.5Â°, in powder X-ray diffraction;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 18.4Â°, 20.9Â°, 24.8Â° and 25.5Â°, in powder X-ray diffraction;

a crystal of dimethyl sulfoxide solvate of 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate, showing diffraction peaks at diffraction angles (2Î¸Â±0.2Â°) of 15.9Â°, 17.2Â°, 18.4Â°, 20.9Â°, 21.9Â°, 24.2Â°, 24.6Â°, 24.8Â°, 25.5Â° and 28.5Â°, in powder X-ray diffraction, and the like.

In general, the diffraction angle (2Î¸) in powder X-ray diffraction produces an error within the range of Â±0.2Â°. Therefore, the value of the above-mentioned diffraction angle needs to be understood to include numerical values within the range of about Â±0.2Â°. Therefore, not only the crystals showing peaks at completely identical diffraction angles in powder X-ray diffraction, but also crystals showing peaks at diffraction angles different only by about Â±0.2Â° are also encompassed in the present invention.

Therefore, in the present specification, for example, â€œshowing a diffraction peak at a diffraction angle (2Î¸Â±0.2Â°) of 15.9Â°â€ means that it â€œshows a diffraction peak at a diffraction angle (2Î¸) of 15.7Â° 16.1Â°â€ , and the same applies to other diffraction angles.

Production Method of a Crystal of Compound 1 or Solvate Thereof

A crystal of compound 1 or solvate thereof can be produced by dissolving compound 1 or a salt thereof in a solvent by heating, and crystallizing same by cooling under stirring. Examples of the solvate include hydrate, methanolate, dimethyl sulfoxide solvate and the like. The solvate of compound 1 is preferably a hydrate.

Examples of the crystal of compound 1 or solvate thereof include below-mentioned crystal A-D. The obtained crystal of compound 1 or solvate thereof varies depending on the crystallization conditions such as the kind of the solvent and the like. Those of ordinary skill in the art can appropriately produce a desired crystal by reference to the below-mentioned production method of crystals.

Compound 1 or a salt thereof to be used for crystallization may have any form, and may be a hydrate or an anhydride, may be amorphous or crystalline (including one composed of plural polycrystallines), and may be a mixture of these.

The solvent used for crystallization includes, for example, alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol and the like; acetonitrile; dimethyl sulfoxide (DMSO); amide solvents such as N,N-dimethylformamide (DMF) and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and the like; saturated hydrocarbon solvents such as hexane, heptane and the like; ketone solvents such as acetone, methylethyl ketone and the like; ether solvents such as t-butyl methyl ether, tetrahydrofuran (THF) and the like; dichloromethane and water. These solvents may be used alone or a mixture of two or more kinds thereof may be used.

The amount of the solvent to be used can be appropriately selected wherein an amount capable of dissolving compound 1 or a salt thereof by heating or an amount that enables stirring of a suspension obtained by adding a solvent to compound 1 or a salt thereof is the lower limit, and an amount free of a marked decrease in the yield of crystal is the upper limit.

The crystal obtained by the above-mentioned method has a form of a single crystal. This crystal form is stable, does not easily transit to other crystal form or amorphous form, has good property and is also suitable for formulation.

In crystallization, a seed crystal (crystal of desired compound 1 and the like) may or may not be added. While the temperature at which a seed crystal is added is not particularly limited, it is preferably 0Â° C.-60Â° C.

As the temperature at which compound 1 or a salt thereof is dissolved by heating, a temperature at which compound 1 is dissolved can be appropriately selected according to the solvent. Preferred is a temperature range from a temperature at which a solvent used for crystallization starts refluxing to 50Â° C., and more preferred is 55Â° C.-65Â° C.

Since cooling during crystallization may afford a crystal with different form (polymorphism) when the cooling is rapid. Therefore, cooling is desirably performed after appropriately adjusting the cooling rate in consideration of the quality of crystal and influence on the particle size and the like. Cooling at 5Â° C.-40Â° C./h is preferable, and cooling at a rate of 5Â° C.-25Â° C./h is more preferable.

While the final crystallization temperature can be appropriately selected according to the desired object such as yield, quality and the like of the crystal, it is preferably âˆ’25Â° C.-30Â° C.

The object crystal can be obtained by separating the crystal obtained by crystallization by a general filtration operation, washing the filtered crystal with a solvent as necessary, and drying same. As the solvent to be used for washing the crystal, those similar to the solvents used for crystallization can be used. Examples of the solvent to be used for washing include acetone, methylethyl ketone, ethyl acetate, and t-butyl methyl ether.

The crystal separated by the filtration operation can be dried by leaving in the air or a nitrogen stream as appropriate, or by heating.

The drying time can be selected as appropriate as the time necessary for the residual solvent to become less than a given amount, and according to the production amount, dryer, drying temperature and the like. Drying can be performed under ventilation or under reduced pressure. The depressurization level can be appropriately selected according to the production amount, dryer, drying temperature and the like. The obtained crystal can also be left in the air as necessary after drying.

The above-mentioned crystal can also be produced by, in the above-mentioned production method of compound 1, performing the production method of the crystal of compound 1 or solvate thereof sequentially after the synthesis of compound 1.

First, an amorphous form of compound 1 is explained. Compound 1 can be produced by synthesize according to the method described in patent document 1. When crystal B is heated in an oven at 50Â° C. overnight, it changes into an amorphous form.

Crystals A-D are now explained below.

Crystal A is a crystal of a hydrate of compound 1, and has a melting point of 164Â° C. Crystal A can be produced by resuspending in or crystallizing from water, ethyl acetate, methyl acetate, dichloromethane, or an aqueous solution containing 50 mass % of water. Such crystal is a more preferable embodiment.

Crystal B is a crystal of a methanolate of compound 1, and has a melting point of 136Â° C. Crystal B can be produced by resuspending in or crystallizing from a solvent containing methanol or methanol.

Crystal C is a crystal of an anhydride of compound 1, and has a melting point of 172Â° C. Crystal C can be produced by resuspending in or crystallizing from a solvent such as acetone, acetonitrile, isopropanol, tetrahydrofuran and the like.

Crystal D is a crystal of a dimethyl sulfoxide solvate of compound 1. Crystal D can be produced by resuspending in or crystallizing from DMSO.

The crystal of compound 1 or solvate thereof can be formulated according to a conventional method. Examples of the dosage form of formulation include oral preparation (tablet, granule, powder, capsule, syrup etc.), injection (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration etc.), and external preparation (transdermal absorption preparation (ointment, adhesive preparation etc.), eye drop, nasal drop, suppository etc.).

When an oral solid preparation (tablet, granule, powder, capsule etc.) is produced, additives such as excipient, binder, disintegrant, lubricant, colorant and the like are added as necessary to the crystal of compound 1 or solvate thereof, and an oral solid preparation is produced by a conventional method. When an oral solid preparation is produced, coating may be applied as necessary.

Examples of the excipient include lactose, cornstarch, crystalline cellulose and the like, and examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. Examples of the disintegrant include calcium carboxymethylcellulose, croscarmellose sodium and the like, and examples of the lubricant include magnesium stearate, calcium stearate and the like. Examples of the colorant include titanium oxide and the like, and examples of the coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like. Usable additives are not limited to these.

These oral solid preparations can generally contain 0.001-99.5 mass %, preferably 0.01-90 mass % and the like, of the crystal of compound 1.

When an injection (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration etc.) is produced, pH adjuster, buffering agent, suspending agent, solubilizing agent, antioxidant, preservative (antiseptic), isotonicity agent and the like are added as necessary to the crystal of compound 1, and injection can be produced by a conventional method. The injection may be formed as a use-time dissolution type freeze-dry preparation by freeze-drying.

As the pH adjuster and buffering agent, organic acid or inorganic acid and/or a salt thereof and the like can be used. As the suspending agent, methylcellulose, polysorbate 80, sodium carboxymethylcellulose and the like can be used; as the solubilizing agent, polysorbate 80, polyoxyethylene sorbitan monolaurate and the like can be used. As the antioxidant, Î±-tocopherol and the like can be used; as the preservative, methyl p-hydroxybenzoate, ethyl parahydroxybenzoate and the like can be used; as the isotonicity agent, glucose, sodium chloride, mannitol and the like can be used. The pH adjuster, buffering agent, suspending agent, solubilizing agent, antioxidant, preservative (antiseptic), and isotonicity agent are not limited to these.

These injections can generally contain 0.000001-99.5 mass %, preferably 0.00001-90 mass % and the like of the crystal of compound 1 relative to the total mass of the injection.

When an external preparation is produced, a base starting material is added to the crystal of compound 1 and, for example, preservative, stabilizer, pH adjuster, antioxidant, colorant and the like are added as necessary, and an external preparation can be produced by a conventional method.

As the base starting material to be used, various starting materials generally used for pharmaceutical products, quasi-drugs, cosmetics and the like can be used. Specifically, for example, starting materials such as animal and vegetable oils, mineral oil, ester oil, waxes, emulsifier, higher alcohols, fatty acids, silicon oil, surfactant, phospholipids, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, purified water and the like can be mentioned.

These external preparations can generally contain 0.000001-99.5 mass %, preferably 0.00001-90 mass % and the like of the crystal of compound 1.

While the dose of the crystal of compound 1 or solvate thereof varies depending on the level of symptom, age, sex, body weight, administration form, kind of salt, specific kind of the disease and the like, in the case of an adult, generally about 30 Î¼g-10 g, preferably 100 Î¼g-5 g, further preferably 100 Î¼g-1 g, is administered per day by oral administration, and about 30 Î¼g-1 g, preferably 100 Î¼g-500 mg, further preferably 100 Î¼g-300 mg, is administered per day by injection administration, each in one to several portions.

EXAMPLES

The present invention is explained in detail in the following by referring to Comparative Examples and Examples, which are not to be construed as limitative. The â€œroom temperatureâ€ is a temperature within the range of 1-30Â° C.

The chemical shift of ¹H-NMR (proton nuclear magnetic resonance) spectrum was recorded in Î´ unit (ppm) to tetramethylsilane, and the coupling constant was recorded in hertz (Hz). The abbreviations of splitting patterns are as follows. s: singlet, d: doublet, t: triplet, q: quartette, m: multiplet, brs: broad singlet, brd: broad doublet.

Comparative Example 1Preparation of Amorphous Compound 1

According to the production method described in patent document 1, compound 1 was obtained as a solid.

¹H-NMR (600 MHz, METHANOL-d₄) Î´ (ppm): 1.15 (d, J=6 Hz, 3H), 2.65 (s, 3H), 3.12 (d, J=18 Hz, 1H), 3.35 (d, J=7 Hz, 2H), 3.48 (d, J=18 Hz, 1H), 4.15 (m, 1H), 4.32 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 5.33 (d, J=16 Hz, 1H), 5.41 (d, J=16 Hz, 1H), 5.44 (d, J=7 Hz, 1H), 5.64 (d, J=10 Hz, 1H), 7.07 (dd, J=9, 1 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.24 (t, J=7 Hz, 1H), 7.27 (d, J=7 Hz, 2H), 7.34 (t, J=8 Hz, 2H), 7.55 (dd, J=8, 4 Hz, 1H), 7.60 (brd, J=6 Hz, 1H), 7.62 (dd, J=8, 7 Hz, 1H), 7.88 (dd, J=8, 1 Hz, 1H), 8.38 (dd, J=8, 2 Hz, 1H), 8.90 (dd, J=4, 2 Hz, 1H).

Example 1Preparation of a Crystal of Hydrate of Compound 1 (Crystal A)

To compound 1 (149.72 mg) obtained in Comparative Example 1 was added a ethanol/water mixed solution (volume ratio 1:1, 4.0 mL) and the mixture was stirred with heating. As a result, it was completely dissolved at about 93Â° C. The mixture was allowed to slowly cool to room temperature, and precipitation of a solid was confirmed. The precipitate was collected by filtration through a glass filter, washed with heptane, and air dried at 60Â° C. to give the title crystal (111.35 mg) as a white solid.

Example 2Preparation of a Crystal of Methanolate of Compound 1 (Crystal B)

Crystal A (100 mg) was dissolved in methanol (1000 mL), and the mixture was stirred at room temperature overnight, and heated under reduced pressure at 45Â° C. to evaporate the solvent to give the title crystal.

Example 3Preparation of Crystal of Anhydride of Compound 1 (Crystal C)

Crystal A (100 mg) was dissolved in ethanol (1000 mL), and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and dried at 45Â° C. for 12 hr to give the title crystal.

Example 4Preparation of Crystal of Dimethyl Sulfoxide Solvate of Compound 1 (Crystal D)

DMSO (1 mL) was added to crystal B (2000 mg), and the mixture was stirred at 50Â° C. overnight. The solution was cooled to room temperature and the precipitated solid was collected by filtration to give the title crystal.

Experimental Example 1Measurement of Powder X-Ray Diffraction

Respective crystals obtained in Examples 1-4 were placed on a sample table of a powder X-ray diffraction apparatus, and measurement was performed under the following conditions.

(Measurement Conditions)

apparatus: Rigaku MiniFlex II Desktop X-ray Diffractometer
X-ray used: Cu KÎ± ray
detector: scintillation counter
tube voltage: 30 kV
tube electric current: 15 mA
KÎ² filter: nickel filter
divergence slit: 1.25Â°
scattering slit: 1.25Â°
receiving slit: 0.3 mm
soller slit: 5Â° (divergence angle)
scan rate: 5Â°/min
sampling interval: 0.02Â°
scan range: 3Â°-36Â°
sample holder: aluminum holder

The powder X-ray crystal diffraction of crystal A obtained in Example 1 was measured, and the diffraction pattern shown in FIG. 1 and Table 1 was obtained.

TABLE 12Î¸ [Â°]peak intensity [counts]3.26506.42318.24848.91519.63699.935811.046411.74312.332313.320214.348115.141515.9202718.079219.347721.231122.228722.639623.269524.860325.910226.322627.141928.543930.18630.97432.912333.49934.255

The powder X-ray crystal diffraction of crystal B obtained in Example 2 was measured, and the diffraction pattern shown in FIG. 2 and Table 2 was obtained.

TABLE 22Î¸ [Â°]peak intensity [counts]7.946710.3171610.8116913.148214.486715.58516.032416.330516.9127189.039718.338619.321919.832320.217620.946921.623721.927722.9100923.376224.748325.126426.557026.932127.614429.212629.621529.919231.57434.282

The powder X-ray crystal diffraction of crystal C obtained in Example 3 was measured, and the diffraction pattern shown in FIG. 3 and Table 3 was obtained.

TABLE 32Î¸ [Â°]peak intensity [counts]5.01116.61967.73908.317889.013310.724911.210912.790513.0140714.210815.360615.8128116.833917.168618.025218.6171019.676720.512920.930821.944123.037123.320223.860224.737124.964325.642026.435327.59328.310228.813529.323030.07630.610431.421731.715132.35234.4125

The powder X-ray crystal diffraction of crystal D obtained in Example 4 was measured, and the diffraction pattern shown in FIG. 4 and Table 4 was obtained.

TABLE 42Î¸ [Â°]peak intensity [counts]7.798.098.3149.1512.62412.91714.11015.41715.95216.92617.22818.411219.21319.72120.94021.93222.81523.72324.23224.63424.83525.54826.31826.52128.22028.53429.12029.31729.81031.01431.51832.4832.8834.213

Similarly, the powder X-ray diffraction pattern of the solid obtained in Comparative Example 1 is shown in FIG. 5. From FIG. 5, it was confirmed that the solid obtained in Comparative Example 1 was amorphous.

Experimental Example 2Hygroscopicity Evaluation

The hygroscopicity of crystal A obtained in Example 1 was evaluated by a dynamic water adsorption measuring apparatus. A sample mounting part of the apparatus was maintained at 25Â° C., and the relative humidity (RH) was set stepwisely within the range of 5-95% RH. The humidity was controlled by changing the relative flow of 0% RH dry nitrogen and 100% RH humidified nitrogen. The sample weight was confirmed at for 2 min intervals by a micro balance, and the humidity was sequentially changed at the time point when the weight shift range for 5 min was below 0.01%. The results are shown in FIG. 6.

As shown in FIG. 6, the crystal obtained in Example 1 showed low hygroscopicity within the relative humidity range of 35-75% RH, and the weight change was about 2.5% at the maximum.

Experimental Example 3Evaluation of Thermal Stability

Using X-ray diffraction-differential scanning simultaneous calorimetry apparatus (X-ray-DSC), whether the crystal form of crystal A obtained in Example 1 changes upon heating was observed. The results are shown in FIG. 7.

The right graph of FIG. 7 shows thermal behavior when crystal A obtained in Example 1 was heated from 40Â° C. to 100Â° C. at 1Â° C./min, and the left spectrum of FIG. 7 shows time-course changes in the powder X ray crystal diffraction pattern of crystal A due to the heating. In the thermal behavior on the right in FIG. 7, an endothermic peak suggesting desorption of hydrated water in crystal A at 43Â° C.-48Â° C.; however, the diffraction pattern did not change at that time. When the temperature was around 90Â° C., the weight of crystal A decreased, and the powder X-ray diffraction pattern changed clearly. Crystal A is thermally stable.

Experimental Example 4Evaluation of Solid Stability

The solid obtained in Example 1 or Comparative Example 1 was preserved for 3 months under the following 3 kinds of preservation conditions. The absorbance at wavelength 226 nm was measured by high performance liquid chromatography (HPLC), and the content of impurity contained in the crystal was measured every other month.

(Preservation Conditions)(1) âˆ’20Â° C.(2) 40Â° C./75% RH(3) 60Â° C.

From the peak area of the obtained chromatogram, a value obtained by dividing the total area of respective peaks other than the peak showing compound 1, by the total area of all the obtained peaks, from the peaks contained in the above-mentioned solid, was taken as impurity content (%), and is shown in Table 5. By comparison of the impurity contents 3 months later, preservation under the condition of 40Â° C., 75% RH resulted in an about 4% increase in the impurity content of the amorphous form of Comparative Example 1 and an about 1.6% increase in the crystal of Example 1, as compared to preservation under the condition of âˆ’20Â° C. Even when preserved under the condition of 60Â° C., Comparative Example 1 showed an increase by not less than 1.1% and Example 1 showed an increase by not more than 0.5% as compared to preservation under the condition of âˆ’20Â° C. Therefore, the crystal of Example 1 was more stable than the amorphous form of Comparative Example 1 under high temperature conditions and high humidity conditions, and had preferable property as a drug substance for pharmaceutical products.

TABLE 5impurity content (%)preservation1 month2 months3 monthsconditionslaterlaterlaterComparativeâˆ’20Â° C.â€‰â€‰2.462.602.57Example 140Â° C./75% RH3.354.626.5160Â° C.3.103.413.68Example 1âˆ’20Â° C.â€‰â€‰0.240.170.2440Â° C./75% RH0.651.021.8060Â° C.0.530.590.72

Experimental Example 5Measurement of ¹³C Solid-State NMR Spectrum

The ¹³C solid-state NMR spectrum in Example 1 was measured under the following conditions.

apparatus used: Avance 400 MHz (manufactured by BRUKER) 7 mm-CPMAS probe (manufactured by BRUKER)
measured nucleus: ¹³C (resonance frequency: 100.6248425 MHz)
measurement temperature: room temperature (22Â° C.)
pulse mode: CPTOSS measurement
rotation number: 5000 Hz
pulse repeat time: 3 sec
contact time: 1 milli second
cumulated number: 2048 times
standard substance: glycine (outside standard: 176.03 ppm).

The ¹³C solid-state NMR spectrum was measured using Avance400 MHz (manufactured by Bruker) equipped with a 7 mm-CPMAS probe manufactured by Bruker, and according to the CPTOSS method (spinning side band elimination method) of carbon core (resonance frequency 100.6 MHz). A sample tube enclosing about 300 mg of a solid sample was rotated at 5 kHz, and measured at contact time 1 milli second, pulse waiting time 3 sec, cumulated number 2048 times, room temperature (22Â° C.). The chemical shift was normalized by the outside standard method wherein the carbonyl carbon of glycine was 176.03 ppm.

The ¹³C solid-state NMR spectrum of crystal A obtained in Example 1 is shown in FIG. 8. In FIG. 8, the ¹³C solid-state NMR spectrum of crystal A confirmed that it has peaks of chemical shifts (ppm) 15.8, 56.4, 127.8, 157.4 and 168.6.