JP2007217349A - Crystal form of {4-cyano-4-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]piperidine-1-yl}acetic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel crystal form of ä4-cyano-4-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]piperidine-1-yl}acetic acid having excellent storage stability, which is useful as a pharmaceutical product. <P>SOLUTION: The novel crystal form of ä4-cyano-4-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]piperidine-1-yl}acetic acid is useful as a pharmaceutical product, since it has excellent storage stability showing no change after being stored for about two months. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel crystalline form of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid.

  The phenomenon that a compound crystallizes into two or more different crystal structures is known as polymorphism, and this phenomenon is called crystal polymorphism. Different crystal forms of the same compound are known to cause differences in physical properties such as solubility, dissolution rate, stability, and absorbability. For this reason, even when the same compound is used, a desired action and effect may not be obtained due to a difference in crystal form, and an unexpected action may be caused.

  On the other hand, {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is known as a compound having phosphodiesterase 4 (PDE4) inhibitory activity. (See Patent Document 1). In addition, it is known that a crystal form of the compound (hereinafter referred to as γ-type crystal for convenience in the present specification) was obtained (see Patent Document 2). As a result of researches by the present inventors, it was found that the compound has not only a single crystal of γ type but also five crystal forms (α, β, γ, δ, acetone solvate). .

  However, these references do not discuss the crystalline polymorphs of the compounds at all, nor do they suggest their existence. Furthermore, in order to use the crystal form of the compound as an active pharmaceutical ingredient, a crystal form having stability even after long-term storage has been desired.

International Publication No. 02/14280 Pamphlet International Publication No. 03/66590 Pamphlet

  The object of the present invention is to provide a novel {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid, which is useful as a pharmaceutical product, having excellent stability during storage. Is to provide a simple crystal form.

  As a result of intensive studies to achieve the above object, the present inventors have found {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl}. The present inventors have found that a novel crystalline form of acetic acid is stable even when stored for about 2 months, and completed the present invention.

That is, the present invention
[1] α-type crystals of isolated {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid,
[2] The α-type crystal according to the above [1], having at least one of the physicochemical data represented by A and B below:
A: Powder X-ray diffraction spectrum chart shown in FIG.
B: Infrared absorption spectrum chart shown in FIG. 2 measured using a total reflection method,
[3] The α-type crystal according to the above [1], having at least one of the physicochemical data represented by A1 and B1 below:
A1: The diffraction angle 2θ in the powder X-ray diffraction spectrum is 14.15, 15.02, 16.75, 17.29, 18.09, 20.64, 21.33, 22.25, 24.14, 25.15, 27.43, 28.46 and 33.80 degrees;
B1: In the infrared absorption spectrum measured using the total reflection method, 2953, 1736, 1632, 1508, 1417, 1337, 1291, 1268, 1237, 1176, 1119, 1081, 1038, 986, 939, 912, 878 , 821, 738, 645, 599, 492, 458 and 423 cm ⁻¹ with absorption peaks,
[4] {4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] characterized by having at least one of the following physicochemical data represented by C and D Piperidin-1-yl} acetic acid β-form crystals:
C: Powder X-ray diffraction spectrum chart shown in FIG. 3;
D: Infrared absorption spectrum chart shown in FIG. 4 measured using a total reflection method,
[5] The β-type crystal according to the above [4], which has at least one of the physicochemical data represented by C1 and D1 below:
C1: The diffraction angle 2θ in the powder X-ray diffraction spectrum is 13.61, 14.30, 14.95, 15.67, 16.40, 17.97, 18.26, 18.79, 19.78, 20.10, 21.06, 22.02, 22.66, 23.62, 24.16, 25.39, 26.29, 27.29, 28.02. 29.47, 32.47, 32.93 degrees;
D1: In the infrared absorption spectrum measured using the total reflection method, 2966, 1609, 1510, 1419, 1365, 1333, 1267, 1237, 1157, 1121, 1080, 1028, 977, 963, 887, 847, 804 738, 678, 638, 597, 493, 460 and 420 cm ⁻¹ with absorption peaks,
[6] {4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] obtained by drying the α-type crystal according to [1] by heating under reduced pressure Β-form crystals of piperidin-1-yl} acetic acid,
[7] 1% of the crystal according to any one of [1] to [5], which has a storage stability of about 2 months, and [8] the crystal according to any one of [1] to [5] The present invention relates to a mixture containing the above.

  In the present invention, {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (hereinafter sometimes abbreviated as compound A) is represented by the formula: (A)

It is a compound shown by these.

  In the present invention, {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate (hereinafter sometimes abbreviated as compound B). .) Is the formula (B)

It is a compound shown by these.

In the present invention, the α-form crystal of Compound A is a crystal of an anhydride of Compound A, and is characterized by at least one physicochemical data of (a) and (b) below. Preferably, it is characterized by both physicochemical data (a) and (b). (A) X-ray powder diffraction spectrum shown in FIG. 1 below, or diffraction angle (2θ), full width at half maximum (Å) and relative intensity (%) shown in Table 2 below, (b) total reflection method Infrared absorption spectrum (IR) shown in FIG. 2 measured using, or 2953, 1736, 1632, 1508, 1417, 1337, 1291, 1268, 1237, 1176, 1119, 1081, 1038, 986, 939, 912 , 878, 821, 738, 645, 599, 492, 458 and 423 cm ⁻¹ .

In the present invention, the β-type crystal of Compound A is a crystal of an anhydride of Compound A, and is characterized by at least one physicochemical data of (c) and (d) below. Preferably, it is characterized by both physicochemical data (c) and (d). (C) Powder X-ray diffraction spectrum shown in FIG. 3 below, or diffraction angle (2θ), full width at half maximum (Å) and relative intensity (%) shown in Table 3 below. (D) Total reflection method 4 or 2966, 1609, 1510, 1419, 1365, 1333, 1267, 1237, 1157, 1121, 1080, 1028, 977, 963, 887, 847 , 804, 738, 678, 638, 597, 493, 460 and 420 cm ⁻¹ .

  In the present invention, the γ-type crystal of Compound A is an anhydrous crystal of Compound A, which represents a comparative compound described in International Publication No. 03/66590, and is a diagram described in the pamphlet. 2 (powder X-ray diffraction spectrum chart), FIG. 4 (IR spectrum data), FIG. 7 (DSC measurement chart) and / or FIG. 8 (TG measurement chart). Moreover, it is characterized by the powder X-ray diffraction spectrum shown in FIG. 5 or the infrared absorption spectrum (IR) shown in FIG. 6 in this specification.

  In the present invention, the δ-type crystal of Compound A is an anhydrous crystal of Compound A, and is a powder X-ray diffraction spectrum shown in FIG. 9 below, or a diffraction angle (2θ) shown in Table 5 below. , Characterized by half-width (Å) and relative intensity (%) data.

  In the present invention, the crystal of compound A may be a solvate crystal of compound A. Here, examples of the solvate of compound A include water, alcohol solvents (eg, methanol, ethanol, etc.), ether solvents (eg, 1,4-dioxane, etc.), ketone solvents (eg, acetone, etc.). Solvates such as). Examples of the hydrate of Compound A include Compound B described above. Here, the crystal means a solid substance in which constituent molecules are arranged with a three-dimensional periodicity, and shows a substantially constant melting point and a constant composition.

  In the present invention, the crystalline form of Compound A is preferably an anhydrous crystal, more preferably an α-type crystal, a β-type crystal, and a δ-type crystal, and particularly preferably an α-type crystal and a β-type crystal.

  Each crystal form of Compound A (for example, α-type crystal, β-type crystal, γ-type crystal, δ-type crystal, acetone hydrate crystal, etc.) is specified by the physicochemical data described in this specification. However, each spectral data can vary somewhat in nature and should not be interpreted strictly.

  For example, due to the nature of the powder X-ray diffraction spectrum data, the diffraction angle (2θ) and the overall pattern are important in the identification of crystal identity, and the relative intensity is the crystal growth direction, particle size, and measurement. It may vary somewhat depending on conditions.

  Also, in the infrared absorption spectrum (IR), the overall pattern is important in the identification of crystal identity, and may vary somewhat depending on the measurement conditions.

  Also, in differential scanning calorimetry (DSC), the overall pattern is important in the identification of crystal identity, and may vary somewhat depending on the measurement conditions.

  Accordingly, in the crystal form of the present invention, those having a pattern similar to the powder X-ray diffraction spectrum or infrared absorption (IR) spectrum as a whole are included in the crystal form of the present invention.

  In the present invention, the chemical purity of the crystal is preferably 97.0% or more, more preferably 99.0% or more, still more preferably 99.5% or more, and particularly preferably 100%.

  In the present invention, the drying under reduced pressure is preferably performed at about 25 ° C. or higher. Heating under reduced pressure is preferably performed by heating to about 60 ° C. or higher, more preferably about 80 ° C. or higher, and further preferably about 100 ° C. or higher. The time required for the reduced-pressure drying and heating under reduced pressure is preferably about 1 hour or longer, more preferably about 6 hours or longer, and particularly preferably about 12 hours or longer.

  In the present invention, the storage stability means a change in the chemical purity of a crystal, an increase in the amount of a related substance, and a hydrate (eg, for example, even when stored for a long time (about 2 months) at a constant temperature and normal pressure. It means that there is no change to monohydrate etc.). The temperature is preferably about 20 to 50 ° C., more preferably about 25 to 30 ° C., and particularly preferably about 25 ° C.

  In the present invention, as shown in the examples described later, the α-type crystal or β-type crystal of Compound A is excellent in storage stability, but the γ-type crystal of Compound A becomes monohydrate after long-term storage. Since it changes, there is a concern that quality and the like will change.

In the present invention, the mixture means a mixture containing 1% or more of α-type crystals or β-type crystals of the compound A of the present invention. For example, the compound A contains 1% or more of α-type crystals, and other crystal forms of the compound A other than α-type crystals (for example, β-type crystals, γ-type crystals, δ-type crystals, etc.), salts of the compound A , Or a mixture containing a solid (eg, oil, amorphous, crystal, etc.) of a solvate thereof (eg, compound B, etc.), containing at least 1% of β-type crystals of compound A, and in addition to β-type crystals Other crystal forms (for example, α-type crystal, γ-type crystal, δ-type crystal, etc.), salts of Compound A, or solids (for example, Compound B, etc.) thereof (for example, oily substance, amorphous, crystal) Etc.). The mixing ratio of these mixtures may be arbitrary.
[Method for Producing Crystal of the Present Invention]
In the present invention, each crystal form of Compound A (for example, α-type crystal, β-type crystal, δ-type crystal, acetone solvate crystal, etc., may be abbreviated as crystal form of the present invention hereinafter). Can be produced by a method described below, a method analogous thereto, or a method described in Examples.

  The crystal form of the present invention is obtained by dissolving a γ-type crystal of Compound A or a crystal of Compound B produced by the method described below in a recrystallization operation, that is, in water and / or an organic solvent described below, and Precipitation can be achieved by cooling to 25 ° C. The precipitated crystals are collected by filtration, washed with an organic solvent described later as necessary, and then dried under reduced pressure or heated under reduced pressure to isolate the intended crystal form of the present invention. Examples of the organic solvent include alcohol solvents (eg, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), ether solvents (eg, diethyl ether, isopropyl ether, methyl). t-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, etc.), ketone solvents (for example, acetone, methyl ethyl ketone, 2-butanone, etc.), ester solvents (for example, ethyl acetate, carbonic acid, etc.) Dimethyl, diethyl carbonate, etc.), nitrile solvents (eg, acetonitrile, etc.), amide solvents (eg, N, N-dimethylacetamide, N, N-dimethylformamide, etc.), aliphatic hydrocarbon solvents (eg, For example, n-pentane, n-hexane, n-heptane, cyclohexane, etc.), aromatic hydrocarbon solvents (for example, benzene, toluene, xylene, etc.) may be used as a single solvent, or a plurality of solvents For example, a mixed solvent of a good solvent (good solvent) in which a plurality of solutes are easy to dissolve, a good solvent (good solvent), and a poor solvent in which the solute is difficult to dissolve, a linear alkane system that may contain water A mixed solvent with a solvent (for example, hexane, heptane, etc.), an ester solvent (for example, ethyl acetate), or an ether solvent (for example, methyl t-butyl ether) may be used. The order of operation may be such that a solution in which a solute is dissolved in a good solvent (good solvent) may be added to the poor solvent, or a poor solvent may be added to a solution in which the solute is dissolved in the good solvent (good solvent). Further, a dehydrating solvent (for example, anhydrous methanol, anhydrous tetrahydrofuran, anhydrous acetone, anhydrous acetonitrile, anhydrous ethyl acetate, etc.) may be used as the organic solvent. When drying under reduced pressure, it is preferably performed at about 25 ° C. or higher. In addition, when drying under reduced pressure under heating, it is preferably performed by heating to about 60 ° C. or higher, more preferably about 80 ° C. or higher, and further preferably about 100 ° C. or higher. The time required for the reduced-pressure drying and heating and reduced-pressure drying is preferably about 1 hour or more continuously, more preferably about 6 hours or more, and particularly preferably about 12 hours.

  In the present invention, when an α-type crystal of Compound A is produced, an organic solvent (for example, methanol, ethanol, 1-propanol), an ether solvent (for example, methanol, ethanol, 1-propanol) is preferably used as an organic solvent for dissolving the Compound B crystal. For example, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane), ketone solvent (for example, acetone, methyl ethyl ketone), ester solvent (for example, ethyl acetate), nitrile solvent (for example, acetonitrile), amide Examples thereof include a single solvent of a system solvent (for example, N, N-dimethylformamide), an aliphatic hydrocarbon solvent (for example, n-heptane), or a mixed solvent thereof. In addition, a single solvent of a dehydrated solvent (for example, anhydrous acetonitrile, anhydrous tetrahydrofuran, anhydrous ethyl acetate) or a mixed solvent thereof is also preferable. After dissolving in these solvents, the dried crystals are preferably dried at about 25 ° C. under reduced pressure.

{4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (Compound A) represented by the formula (A) as a raw material for the crystalline form of the present invention Can be produced by a known method, the method described in Example 2 (9) of WO 02/14280 pamphlet. The γ-type crystal of Compound A is a known substance, and was produced by a known method, Comparative Example 1 of International Publication No. 03/66590, or Example 1 described later. Similarly, {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate represented by formula (B) (compound B) Since the crystals thereof are known substances, they were produced by a known method, the method of Example 2 of International Publication No. 03/66590, that is, the method of Reference Example 1 below.
[Application to pharmaceutical products]
The crystalline form of the present invention and the mixture containing the crystalline form are obtained by using compound A as an active ingredient, that is, {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidine-1- In a mammal (eg, human, non-human animal, eg, monkey, sheep, cow, horse, dog, cat, rabbit, rat, mouse, etc.) because it contains acetic acid and has PDE4 inhibitory activity. Inflammatory diseases (eg, asthma, chronic obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), diabetic diseases, allergic diseases (eg, allergic rhinitis, atopic dermatitis, etc.), autoimmune diseases (Eg, ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, multiple sclerosis, collagen disease, etc.), eye diseases (allergic conjunctivitis, seasonal conjunctivitis) ), Osteoporosis, fracture, osteoarthritis, obesity, bulimia, depression, Parkinson's disease, dementia, ischemia-reperfusion injury, leukemia, acquired immune deficiency syndrome (AIDS), shock, It is useful for the prevention and / or treatment of systemic inflammatory response syndrome (SIRS) or pruritus (for example, eye itching, skin pruritus, ear nasal pruritus, systemic pruritus etc.). In the present invention, “prevention” means preventing the establishment of the disease itself, and “treatment” means guiding the disease state in the direction of healing.

  The crystalline form of the present invention is (1) stable as a substance, (2) can be stably supplied in large quantities, and / or (3) is relatively easy to formulate into a dosage form such as a tablet. For this reason, it itself has excellent applicability as a drug substance. The mixture of the present invention can also be used as a drug substance. However, when the crystal form of the present invention is used as a drug substance, α-type crystals and β-type crystals are preferred.

  Examples of preparations that can use the crystalline form of the present invention as an active pharmaceutical ingredient include solid preparations for internal use for oral administration, liquids for internal use, and injections, external preparations, and suppositories for parenteral administration. Etc.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.

  In such a solid preparation for internal use, the crystalline form of the present invention is used as it is or after being mixed or granulated with an additive and formulated into a conventional method. One or more additives may be appropriately blended and used. Examples of additives include excipients (eg, lactose, mannitol, glucose, microcrystalline cellulose, corn starch, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), dispersing agents ( For example, corn starch, etc.), disintegrating agents (for example, calcium calcium glycolate), lubricants (for example, magnesium stearate), stabilizers, solubilizers (for example, glutamic acid, aspartic acid, etc.), water-soluble Polymers (eg, celluloses (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, etc.), synthetic polymers (eg, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, etc.), sweeteners (eg, White sugar, powdered sugar, sucrose, fructose, glucose, lactose, reduced maltose water candy, powdered reduced maltose water candy, glucose fructose liquid sugar, fructose glucose liquid sugar, honey, sorbitol, maltitol, mannitol, xylitol, erythritol, Aspartame, saccharin, sodium saccharin, etc.). Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions / emulsions, syrups, elixirs and the like. In such a solution, the crystal form of the present invention is dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  Among parenteral administration, external dosage forms include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, eye ointments and Nasal drops and the like are included. These include the crystal form of the present invention, and are produced and prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, the crystal form of the present invention is manufactured and prepared by grinding or melting the base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent One or more of these may be mixed and used. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is produced and prepared by melting the crystal form of the present invention in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), One or more selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption enhancers, and anti-rash agents are used in admixture. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is produced and prepared by melting or emulsifying the crystal form of the present invention in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers (eg, polyoxy (Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, and rash prevention agents are used in admixture. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting the crystal form of the present invention in a base, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, a solubilizing agent, a tackifier, and an anti-rash agent are used as a mixture. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting the crystal form of the present invention in a base and spreading it on a support. The base for patch is selected from known or commonly used ones. For example, one or more kinds selected from a polymer base, fats and oils, higher fatty acids, tackifiers, and rash prevention agents are mixed and used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, the crystalline form of the present invention is dissolved, suspended or emulsified in one or more selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent and the like. Manufactured and prepared. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, and sprays are buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride, sodium citrate or citric acid. An isotonic agent such as The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355. Moreover, it does not matter as an aerosol agent.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. The injection is used by dissolving, suspending or emulsifying the crystal form of the present invention in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection may contain a stabilizer, a solubilizer (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. . These are sterilized in the final process or manufactured and prepared by aseptic manipulation. In addition, a sterile solid preparation such as a freeze-dried product can be produced and used by dissolving in sterilized or sterile distilled water for injection or other solvent before use.

  Inhalants for parenteral administration include aerosols, powders for inhalation, or liquids for inhalation, and the liquids for inhalation are used by dissolving or suspending in water or other suitable medium at the time of use. It may be. These inhalants are produced according to known methods.

  For example, in the case of inhalation solutions, preservatives (eg, benzalkonium chloride, parabens, etc.), colorants, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonic agents (eg, chloride) Sodium, concentrated glycerin, etc.), thickeners (for example, carboxyvinyl polymer, etc.), absorption accelerators, and the like, as appropriate.

  In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary.

  A nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used when administering an inhalation solution, and an inhalation administration device for powdered drugs is usually used when administering an inhalable powder.

  In the case of eye drops, isotonic agents (eg, glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, etc.), buffers (eg, phosphoric acid, phosphate, citric acid, acetic acid, ε- Aminocaproic acid, etc.), pH adjusters (eg, hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate, etc.), solubilizers (eg, Polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, etc.), thickener or dispersant (eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc.), stabilizer (eg, edetic acid) , Sodium edetate, etc.), preservatives (eg sorbine) , Potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl p-hydroxybenzoate, are appropriately selected and prepared as required chlorobutanol, etc.) and the like.

  Other compositions for parenteral administration include suppositories for rectal administration, pessaries for intravaginal administration, etc. containing the crystalline form of the present invention and formulated in a conventional manner.

  The drug containing the crystal form of the present invention as an active ingredient is 1) the supplement and / or enhancement of the preventive and / or therapeutic effect of the drug containing the crystal form of the present invention, and 2) the drug containing the crystal form of the present invention. In order to improve the pharmacokinetics / absorption, reduce the dose, and / or 3) reduce the side effects of the drug containing the crystalline form of the present invention, it may be administered in combination with other drugs.

  The drug containing the crystal form of the present invention and another drug in combination may be administered in the form of a combination of both components in one preparation or in the form of separate preparations. Good. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by a time difference may be performed by administering the drug containing the crystal form of the present invention first, and then administering another drug later, or administering the other drug first and containing the crystal form of the present invention. The drug to be administered may be administered later, and each administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. Also good. The dosage of other drugs can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination and the like. For example, 0.01 to 100 parts by weight of another drug may be used with respect to 1 part by weight of the compound of the present invention. Other drugs may be administered by combining one or two or more from the same group and different groups shown below in an appropriate ratio. In addition, other drugs that supplement and / or enhance the preventive and / or therapeutic effects of the drug containing the crystal form of the present invention are not limited to the examples shown below, and based on the mechanism described below, This includes not only what has been found but also what will be found in the future.

Examples of the other drugs include steroid drugs, β ₂ adrenergic receptor stimulants, leukotriene receptor antagonists, thromboxane A ₂ receptor antagonists, thromboxane synthase inhibitors, mediator release inhibitors, antihistamines , Xanthine derivatives, anticholinergic drugs, cytokine inhibitors, prostaglandins, forskolin preparations, elastase inhibitors, metalloprotease inhibitors, expectorants, antibiotics, bisphosphonate preparations, vitamin D preparations, calcium preparations, estrogen preparations, calcitonin Formulation, ipriflavone formulation, anabolic steroid, vitamin K formulation, cathepsin K inhibitor, prostaglandin synthase inhibitor, immunosuppressant, TNF-α antagonist, adhesion molecule inhibitor, 5-lipoxygenase inhibitor, non-steroid Anti-inflammatory drugs, diseases Modified antirheumatic drug, anti-inflammatory enzyme drug, cartilage protective drug, T cell inhibitor, IL-6 inhibitor, interferon gamma agonist, IL-1 inhibitor, glaucoma therapeutic drug, antibacterial drug, antiviral drug, antifungal drug Etc.

  Examples of the steroid drug include amsinonide, difluprednate, betamethasone dipropionate, dexamethasone, triamcinolone, triamcinolone acetonide, hydrocortisone, mometasone furanate, fluocinonide, prednisolone, clobetasol propionate, dexamethasone propionate, propionate, propionate, propionate , Dexamethasone sodium metasulfobenzoate, methylprednisolone, dexamethasone sodium phosphate, betamethasone sodium phosphate, betamethasone valerate, diflorazone acetate, dexamethasone acetate, parameterzone acetate, betamethasone acetate / sodium betamethasone phosphate, methylprednisolone acetate, prednisolone succinate for injection Sodium, butyric acid propionate Dzong, and the like.

β ₂ adrenergic receptor stimulants include, for example, fenoterol hydrobromide, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, salmeterol xinafoate, isoproterenol hydrochloride, orciprenaline hydrochloride, chlorprenalin hydrochloride, epinephrine, trichloride hydrochloride Metoquinol, hexoprenaline mesyl hydrochloride, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pyrbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meladrin tartrate, AR-C68397, levosalbutamol, R-formoterol KUR-1246, KUL-7221, AR-C89855, etc. are mentioned.

  Examples of leukotriene receptor antagonists include pranlukast hydrate, montelukast, zafirlukast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS -635, A-93178, S-36496, BIIL-284, ONO-4057, and the like.

Examples of the thromboxane A ₂ receptor antagonist include ramatroban, seratrodast, domitroban calcium hydrate and the like.

  Examples of the thromboxane synthase inhibitor include ozagrel hydrochloride and imitrodast sodium.

  Examples of mediator release inhibitors include amlexanox, ibudilast, sodium cromoglycate, dazanolast, tranilast, pemirolast potassium, repirinast and the like.

  Antihistamines include, for example, epinastine hydrochloride, triprolidine hydrochloride, alimemazine tartrate, ketotifen fumarate, azelastine hydrochloride, diphenylpyraline teolate, hydroxyzine hydrochloride, hydroxyzine pamoate, dl-chlorpheniramine maleate, alimemazine tartrate, Clemastine fumarate, fexofenadine hydrochloride, olopatadine hydrochloride, cyproheptadine hydrochloride, ebastine, oxatomide, terfenadine, astemizole, loratadine, desloratadine, propetadine hydrochloride, homoacrylcyclozine hydrochloride, cetirizine hydrochloride, mequitazine, bepotastine besylate, emedastine fumarate Diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine tannate, diphenhydramine salicylate, mometasonef Benzoate, mizolastine, acrivastine, BP-294, tipepidine promethazine, TAK-427, ZCR-2060, NIP-530 and the like.

  Examples of xanthine derivatives include aminophylline, theophylline, doxophilin, cypamphylline, diprofylline and the like.

  Examples of the anticholinergic agent include oxitropium bromide, ipratropium bromide, clenbuterol hydrochloride, corintheophylline, mabuterol hydrochloride, trihexyphenidyl hydrochloride, biperidene hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, flutropium bromide, citropium bromide, Temiverine, tiotropium bromide, levatrope (UK-112166) and the like.

  Examples of cytokine inhibitors include suplatast tosylate and the like.

  Examples of prostaglandins (hereinafter abbreviated as PG) include, for example, PGE1 preparations (eg: alprostadil alphadex, alprostadil etc.), PGI2 preparations (eg: beraprost sodium etc.), PG receptor agonists, Examples thereof include PG receptor antagonists. Examples of the PG receptor include PGE2 receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI2 receptor (IP), TX receptor (TP) and the like. Can be mentioned.

  Examples of the elastase inhibitor include ONO-5046, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-31616, DMP-777, L-659286, L-658758, L-680833, L-683845, AE-3763 etc. are mentioned.

  Examples of the metalloproteinase inhibitor include ONO-4817, S-3536, KB-R7785, and the like.

  As an expectorant, for example, ambroxol hydrochloride, fudosteine, L-methylcysteine hydrochloride, bromhexine hydrochloride, tipipezine hibenzate, carbocysteine, L-ethylcysteine hydrochloride, guaifenesin, ammonia fennel, sodium bicarbonate, acetylcysteine, tyloxapol Etc.

  Antibiotics include, for example, erythromycin, clarithromycin, azithromycin, spiramycin, rokitamicin, acetyl spiramycin, erythromycin ethyl succinate, josamycin propionate, erythromycin stearate, acetyl kitasamycin, midecamycin acetate, roxithromycin sulfate, gentamicin sulfate , Fradiomycin sulfate, tobramycin, sulpenicillin, cefmenoxime, colistin, oxytetracycline, polymyxin B, chloramphenicol, micronomycin, dibekacin, sisomycin and the like.

  Bisphosphonate preparations include, for example, alendronate sodium hydrate, ibandronic acid, incadronate disodium, etidronate disodium, olpadronate, clodronate sodium hydrate, zoledronic acid, tiludronate disodium, neridronate, pamidronate disodium Sodium, pyridronate, minodronic acid hydrate, risedronate sodium hydrate, YM175 and the like can be mentioned.

  Examples of vitamin D preparations include alphacalcidol, falecalcitriol, calcitriol, 1α, 25-dihydroxycholecalciferol, dihydrotaxosterol, ST-630, KDR, ED-71, locartol (Ro44-7190), taka Examples include luciol and maxacalcitol.

  Examples of calcium preparations include calcium chloride, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium L-aspartate, calcium hydrogen phosphate, and the like.

  Examples of estrogen preparations include estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinyl Examples include estradiol and mestranol.

  Examples of the calcitonin preparation include calcitonin, salmon calcitonin (STH-32, SMC20-51), chicken calcitonin (MCI-536), cecalciferol, elcatonin, TJN-135 and the like.

  Examples of the ipriflavone preparation include ipriflavone and the like.

  Examples of anabolic steroids include oxymetholone, stanozolol, nandrolone decanoate, nandrolone phenylpropionate, nandrolone cyclohexylpropionate, methenolone acetate, mestanolone, ethylestrenol, carsterone and the like.

  Examples of vitamin K preparations include menatetrenone and phytonadione.

  Examples of the cathepsin K inhibitor include ONO-5334, AAE581, SB462727, and the like.

  Examples of prostaglandin synthase inhibitors include salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, difenpyramide, flunoxaprofen, flurbiprofen, Indomethacin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, persalmid, piperoxene, piroxicam, piroxicam datadex, piroxicamcinnamate, tropine indomethacinate, zaltoprofen, pranoprofen and the like.

  Examples of the immunosuppressant include tacrolimus hydrate, methotrexate, cyclosporine, ascomycin, leflunomide, bucillamine, salazosulfapyridine and the like.

  Examples of the TNF-α inhibitor include infliximab, etanercept, and adalimumab.

  Examples of the adhesion molecule inhibitor include α4 integrin antagonist, anti-Vap-1 antibody and the like.

  Examples of 5-lipoxygenase inhibitors include AA861, ABT-761 and the like.

  Non-steroidal anti-inflammatory drugs include, for example, Sazapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinolyl, fenbufen, Napumeton, Progouritacin, Indomethacin Farnesyl, Acemetacin, Progouritacin Maleate, Ampenac Sodium, Mofezolac, Etodolac, Ibuprofen, Ibuprofen Piconol, Naproxen, Flurbiprofen, Flurbiprofen Axetil, Ketoprofen, Fenoprofen Calcium, thiaprofen, oxaprozin, pranoprofen, loxopro Sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamic acid, glycyrrhetinic acid, tolfenamic acid, fructaphenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, napagel ointment, epilysole, tiaramid hydrochloride, Examples thereof include chinolidine hydrochloride, emorphazone, sulpyrine, migrenin, salidone, cedes G, amidiro-N, sorbone, pilin-type cold medicine, acetaminophen, phenacetin, dimethothiazine mesylate, cimetride combination medicine, non-pyrine-type cold medicine and the like.

  Examples of the disease-modifying anti-rheumatic drug include gold thioglucose, gold sodium thiomalate, auranofin, actarit, D-penicillamine preparation, lobenzalit disodium, bucillamine, hydroxychloroquine, salazosulfapyridine, T-614 and the like. Can be mentioned.

  Examples of the anti-inflammatory enzyme include lysozyme chloride, bromelain, pronase, serrapeptase, streptokinase / streptodornase combination agent, and the like.

  Examples of the cartilage protective agent include sodium hyaluronate.

  Examples of the glaucoma therapeutic agent include pilocarpine hydrochloride, physostigmine salicylate, timolol, isopropyl unoprostone, and the like.

  Antibacterial agents include, for example, sulfamethizole, sulfamethoxazole, ofloxacin, norfloxacin, romefloxacin hydrochloride, enoxacin, ciprofloxacin hydrochloride, sinoxacin, sparfloxacin, tosufloxacin tosylate, nalidixic acid, pipemidic acid Hydrates, pipemidic acid, fleroxacin, levofloxacin and the like can be mentioned.

  Examples of the antiviral drug include idoxuridine, acyclovir and the like.

  Examples of antifungal agents include pimaricin, fluconazole, miconazole, amphotericin B, flucytosine, itraconazole and the like.

  In order to use the crystalline form of the present invention or a combination drug of the crystalline form of the present invention and another drug for the above purpose, it is usually administered systemically or locally in an oral or parenteral form.

  The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but for example, it is orally administered once to several times a day in the range of 1 mg to 1000 mg per adult. Or administered parenterally, once a day to several times per day, in the range of 1 mg to 100 mg per adult, or intravenously in the range of 1 hour to 24 hours per day. In particular, in the case of ophthalmic administration, one dose of one to several drops at a concentration of 0.001 to 10% (w / v) per adult is administered by eye drops 1 to several times a day, or adult 1 A concentration of 0.001 to 10% (w / v) per person is administered by eye ointment once to several times a day.

Of course, as described above, the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient or may be necessary beyond the range.
[Pharmacological activity]
It is known that the crystalline form of the present invention has a strong pharmacological activity comparable to that of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. For example, the method described in International Publication No. 02/14280 pamphlet, International Publication No. 03/66590 pamphlet, International Publication No. 05/007161 pamphlet and the like.
[toxicity]
The toxicity of the crystalline form of the present invention is very low and can be judged to be sufficiently safe for use as a medicament.

  According to the present invention, while maintaining the pharmacological effect of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid, it is safe and active as a drug substance. A novel crystalline form of the anhydride of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid that can be used can be provided. . Among these crystals, α-type crystals and β-type crystals are more useful as drug substances because they have a storage stability of about 2 months.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. Moreover, you may change in the range which does not deviate from the range of this invention.

The physical property data of each crystal described in the examples was performed under the following measurement conditions.
[1] Powder X-ray diffraction spectrum <Measurement conditions>
Device: BRUKER axs BRUKER D8 DISCOVER with GADD (C2),
Target: Cu,
Filter: None,
Voltage: 40 kV,
Current: 40 mA
Exposure time: 5 min.
[2] Infrared absorption (IR) spectrum <measurement conditions>
Apparatus: FTIR-660Plus / SensIR TECHNOLOGIES DuraScope made by JASCO,
Measurement method: Measured by total reflection method
Resolution: 4 cm ⁻¹
Number of scans: 16 times.
[3] Thermogravimetry (TG)
<Measurement conditions>
Equipment: TGA 851e made by METTLER TOLEDO,
Sample amount: about 4.8mg,
Sample cell: Aluminum open cell,
Argon gas flow rate: 20 mL / min,
Temperature increase rate: 5 ° C./min.

Further, the differential scanning calorimetry can be performed under the following measurement conditions.
Differential scanning calorimetry (DSC)
<Measurement conditions>
Equipment: DSC 822e made by METTLER TOLEDO,
Sample amount: 1.15 mg,
Sample cell: Aluminum open cell,
Argon gas flow rate: 40 mL / min,
Temperature increase rate: 5 ° C./min.

  Whether or not the crystal form of the present invention is an anhydrate can be measured by a known method. For example, it was carried out in accordance with a method known as a method for measuring the moisture content of pharmaceuticals, in particular, according to the moisture measurement method listed in the Japanese Pharmacopoeia, in particular, the moisture measurement method (Karl Fischer method) listed in the 14th revised Japanese Pharmacopoeia.

The ester body used as a raw material in the Examples is described in International Publication No. 03/66590. For example, methyl {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1-piperidinyl) acetate is a compound produced in Reference Example 9 of WO 03/66590. It is.
Reference Example 1: {4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid monohydrate (Compound B)

To a methanol solution (200 mL) of methyl {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] -1-piperidinyl) acetate (17.7 g) under ice-cooling, 1N aqueous sodium hydroxide solution (86.6 mL) was added and stirred at room temperature for 2 hours. 2N hydrochloric acid (43 mL) was added to the reaction mixture under ice cooling. The precipitated solid was collected by filtration and washed with methanol-water (1: 2) (150 mL) and diethyl ether to obtain a solid (13.36 g). The solid (12.44 g) obtained above was recrystallized from ethanol (144 mL) -water (96 mL) and dried at 25 ° C. under reduced pressure (3 mmHg) for 12 hours to give the title compound (1 Hydrate) (11.49 g) was obtained.
TLC: 0.48 (chloroform: methanol = 8: 2);
NMR (DMSO-d ₆ ): δ 7.22-7.19 (m, 2H), 7.09 (dd, J = 8.7, 2.1 Hz, 1H), 7.00 (t, J = 74.4 Hz, 1H), 5.01-4.92 (m, 1H), 4.00- 2.60 (br, 1H), 3.24 (s, 2H), 3.04-2.95 (m, 2H), 2.70-2.50 (m, 2H), 2.16-1.80 (m, 6H), 1.80-1.50 ( m, 6H).
Example 1: Crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (γ-type crystal)
The crystals of compound B produced in Reference Example 1 were dried under reduced pressure at 100 ° C. for about 3 hours to obtain the title crystals. The water content of the obtained crystals was measured by TG and the Karl Fischer method, and no weight reduction was observed. Thus, the crystals were confirmed to be anhydrous crystals. Moreover, it was confirmed by a powder X-ray diffraction spectrum and an infrared absorption spectrum (IR) that it was a γ-type crystal.
Powder X-ray diffraction spectrum:

IR (total reflection method): 2954, 1630, 1506, 1420, 1360, 1322, 1274, 1219, 1182, 1105, 1038, 1003, 984, 964, 918, 901, 877, 857, 677, 616, 493, 455 , 420 cm ⁻¹ .
Example 2: Crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (α-type crystal)
100 mg of the compound B crystal produced in Reference Example 1 was weighed into a test tube, sealed with a septum, and then the inside of the test tube was purged with argon using a balloon. The test tube was attached to a 70 ° C. water bath, anhydrous acetonitrile (8 v / w) was added to dissolve the crystals, cooled to room temperature, and allowed to stand for 1 hour. The precipitated crystals were further cooled to 0 to 5 ° C., filtered, and dried under reduced pressure at room temperature to obtain the title crystals having the following physicochemical data. Further, it was confirmed by Karl Fischer method and TG measurement that the obtained crystals were anhydrous.
Powder X-ray diffraction spectrum:

IR (total reflection method): 2953, 1736, 1632, 1508, 1417, 1337, 1291, 1268, 1237, 1176, 1119, 1081, 1038, 986, 939, 912, 878, 821, 738, 645, 599, 492 458, 423 cm ⁻¹ .
Example 3: Crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (β-type crystal)
The α-type crystal of Compound A produced in Example 2 was dried under reduced pressure at 100 ° C. for about 1 day to obtain the title crystal having the following physicochemical data. Moreover, it was confirmed by TG measurement that the obtained crystals were anhydrous.
Powder X-ray diffraction spectrum:

IR (total reflection method): 2966, 1609, 1510, 1419, 1365, 1333, 1267, 1237, 1157, 1121, 1080, 1028, 977, 963, 887, 847, 804, 738, 678, 638, 597, 493 , 460, 420 cm ⁻¹ .
Example 4: Crystal of acetone solvate of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid Crystal of Compound B prepared in Reference Example 1 100 mg was weighed into a test tube, sealed with a septum, and the inside of the test tube was purged with argon using a balloon. The test tube was attached to a 70 ° C. water bath, anhydrous acetone (6 v / w) was added to dissolve the crystals, cooled to room temperature, and allowed to stand for 1 hour. The precipitated crystals were further cooled to 0 to 5 ° C., filtered, and dried under reduced pressure at room temperature to obtain the title crystals having the following physicochemical data. It was confirmed by Karl Fischer method and TG measurement that the obtained crystal was an acetone solvate.
Powder X-ray diffraction spectrum:

IR (total reflection method): 2952, 1704, 1626, 1508, 1416, 1389, 1363, 1271, 1225, 1179, 1118, 1032, 987, 939, 877, 821, 684, 646, 598, 531, 492, 457 cm ^-1 .
Example 5: Crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid (δ-type crystal)
The acetone solvate crystals of Compound A prepared in Example 4 were dried under reduced pressure at 70 ° C. for about 1 day to give the title crystals having the following physicochemical data. Moreover, it was confirmed by TG measurement that the obtained crystals were anhydrous.
Powder X-ray diffraction spectrum:

[Karl Fischer method and TG measurement]
The crystal form produced in each example was measured for moisture content and weight loss of the crystal form by the Karl Fischer method and TG measurement described above.

  The results of Karl Fischer method and TG measurement for each crystal form are shown in Table 6 below.

From this result, it was found that the crystal form of Reference Example 1 was a hydrate containing water of crystallization because water content was 4.45 wt% (wt%) and a weight reduction of 4.33 wt% (wt%) was observed. . On the other hand, the crystal forms of Examples 1, 2, 3 and 5 were presumed to be anhydrous since almost no weight loss due to TG was observed. Further, since the crystal form of Example 4 contains almost no water, it is not a hydrate, and the weight loss due to TG is 12.8% by weight (wt%) when it is assumed to be a monoacetone hydrate of Compound A. Since it was a close value, it was guessed that it was 1 acetone solvate.
[Crystal stability test]
For each crystal form of Examples 1, 2, and 3, the isolated crystal was placed in a screw tube for about 2 months under conditions of room temperature (about 25 ° C.), normal pressure (about 1 atmosphere), and humidity of about 30 to 70%. After storage, powder X-ray diffraction was performed again. The powder X-ray diffraction spectra after re-diffraction of each crystal form are shown in FIGS.

  From this result, the crystal form of Example 1, that is, the γ-type crystal, shows a powder X-ray diffraction spectrum pattern of the crystal form of Reference Example 1, that is, the compound B crystal after about 2 months storage. It was found that the crystal changed from an anhydrous crystal to a hydrate crystal. On the other hand, both the crystal form of Example 2 and the crystal form of Example 3, that is, the α-type crystal and the β-type crystal, show a powder X-ray diffraction spectrum pattern after storage for about 2 months. Since it was almost the same as the diffraction spectrum, it was found that it had a storage stability of about 2 months.

  The novel crystal forms of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid obtained by the present invention, particularly α-type crystals and β-type crystals, It is useful as an active pharmaceutical ingredient because it does not change to a crystalline form of hydrate even after storage for about 2 months and has excellent storage stability.

1 shows a powder X-ray diffraction spectrum chart of α-type crystals of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. An infrared absorption (IR) spectrum chart of an α-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. 1 shows a powder X-ray diffraction spectrum chart of a β-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. An infrared absorption (IR) spectrum chart of a β-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. 1 shows a powder X-ray diffraction spectrum chart of a γ-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. An infrared absorption (IR) spectrum chart of a γ-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. 1 shows a powder X-ray diffraction spectrum chart of an acetone solvate crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. An infrared absorption (IR) spectrum chart of an acetone solvate crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. 1 shows a powder X-ray diffraction spectrum chart of a δ-type crystal of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. The chart which shows the result of the crystal stability test of the gamma-type crystal | crystallization of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. The rightmost shows the powder X-ray diffraction spectrum chart of the γ-type crystal of Compound A, the middle shows the powder X-ray diffraction spectrum chart of the γ-type crystal of Compound A after storage for about 2 months, and the leftmost shows the compound B The powder X-ray-diffraction spectrum chart of the crystal | crystallization of this is represented. The chart which shows the result of the crystal stability test of the alpha-type crystal | crystallization of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. The right represents the powder X-ray diffraction spectrum chart of the α-type crystal of Compound A, and the left represents the powder X-ray diffraction spectrum chart of the α-type crystal of Compound A after storage for about 2 months. The chart which shows the result of the crystal stability test of the beta-type crystal | crystallization of {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid is shown. The right represents the powder X-ray diffraction spectrum chart of the β-type crystal of Compound A, and the left represents the powder X-ray diffraction spectrum chart of the β-type crystal of Compound A after storage for about 2 months.

Claims (8)

Α-type crystals of isolated {4-cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidin-1-yl} acetic acid. The α-type crystal according to claim 1, having at least one of the following physicochemical data represented by A and B:
A: Powder X-ray diffraction spectrum chart shown in FIG.
B: Infrared absorption spectrum chart shown in FIG. 2 measured using a total reflection method. The α-type crystal according to claim 1, having at least one of the following physicochemical data represented by A1 and B1:
A1: The diffraction angle 2θ in the powder X-ray diffraction spectrum is 14.15, 15.02, 16.75, 17.29, 18.09, 20.64, 21.33, 22.25, 24.14, 25.15, 27.43, 28.46 and 33.80 degrees;
B1: In the infrared absorption spectrum measured using the total reflection method, 2953, 1736, 1632, 1508, 1417, 1337, 1291, 1268, 1237, 1176, 1119, 1081, 1038, 986, 939, 912, 878 821, 738, 645, 599, 492, 458 and 423 cm ⁻¹ . {4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidine-1 characterized by having at least one of the following physicochemical data represented by C and D -Yl} acetic acid β-form crystals:
C: Powder X-ray diffraction spectrum chart shown in FIG. 3;
D: Infrared absorption spectrum chart shown in FIG. 4 measured using a total reflection method. The β-type crystal according to claim 4, wherein the β-type crystal has at least one of the following physicochemical data represented by C1 and D1:
C1: The diffraction angle 2θ in the powder X-ray diffraction spectrum is 13.61, 14.30, 14.95, 15.67, 16.40, 17.97, 18.26, 18.79, 19.78, 20.10, 21.06, 22.02, 22.66, 23.62, 24.16, 25.39, 26.29, 27.29, 28.02. 29.47, 32.47, 32.93 degrees;
D1: In the infrared absorption spectrum measured using the total reflection method, 2966, 1609, 1510, 1419, 1365, 1333, 1267, 1237, 1157, 1121, 1080, 1028, 977, 963, 887, 847, 804 738, 678, 638, 597, 493, 460 and 420 cm ⁻¹ . {4-Cyano-4- [3- (cyclopentyloxy) -4- (difluoromethoxy) phenyl] piperidine-1- characterized by being obtained by drying the α-type crystal according to claim 1 by heating under reduced pressure. Yl} acetic acid β-type crystals. The crystal according to any one of claims 1 to 5, which has a storage stability of about 2 months. A mixture comprising 1% or more of the crystal according to any one of claims 1 to 5.

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