Oxazole compound crystals

Abstract

The present application provides a crystal of a specific oxazole compound having specific inhibitory activity against PDE4, and the crystal shows excellent stability. Specifically, the present application provides a crystal of an oxazole compound represented by formula (5), wherein the crystal has peaks at diffraction angles 2θ (°) of 9.6 ± 0.2, 19.1 ± 0.2 and 21.2 ± 0.2 in an X-ray powder diffraction pattern measured with CuKα characteristic X-rays.

Description

Technical Field

[0001] This invention relates to novel crystals of oxazole compounds, a method for preparing said crystals, etc. Background Technology

[0002] PTLs 1 and 2 report an oxazole compound with specific inhibitory activity against phosphodiesterase (PDE4) and a method for producing the oxazole compound. PDE4 is predominant in inflammatory cells. Inhibition of PDE4 increases intracellular cAMP levels, and the increased cAMP levels downregulate the inflammatory response through the expression of TNF-α, IL-23, or other inflammatory cytokines. Increased cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, the oxazole compound is considered suitable for use as an anti-inflammatory agent. For example, the oxazole compound is considered useful for reducing or eliminating eczema or dermatitis, including atopic dermatitis. PTL 3 discloses an ointment stably containing an oxazole compound with specific inhibitory activity against PDE4, and the ointment is effectively absorbed into the skin. The disclosures of PTLs 1 to 3 are hereby incorporated herein by reference in their entirety.

[0003] Reference List

[0004] Patent documents:

[0005] PTL 1: WO2007 / 058338(JP2009-515872A)

[0006] PTL 2: WO2014 / 034958(JP2015-528433A)

[0007] PTL 3: WO2017 / 115780 Summary of the Invention

[0008] Technical issues

[0009] One object of the present invention is to provide crystals of an oxazole compound (specifically, an oxazole compound represented by formula (5)) that has specific inhibitory activity against PDE4, and said crystals exhibit superior stability.

[0010] Technical solution

[0011] The inventors have discovered a method for preparing a novel, previously unreported crystal using a specific oxazole compound with inhibitory activity against PDE4, and have also found that the novel crystal exhibits excellent stability. The inventors further modified and completed this invention.

[0012] Specifically, the present invention includes, for example, the following topics.

[0013] Project 1. Crystals of oxazole compounds represented by formula (5),

[0014]

[0015] In the X-ray powder diffraction pattern measured using CuKα characteristic X-rays, the crystal has peaks at diffraction angles of 2θ (°) at 9.6±0.2, 19.1±0.2, and 21.2±0.2.

[0016] Project 2. The crystal according to Project 1, wherein in the X-ray powder diffraction pattern measured with CuKα characteristic X-rays, the crystal also has one, two, or three peaks at one, two, or three diffraction angles 2θ (°) selected from 12.6±0.2, 22.8±0.2, and 26.0±0.2.

[0017] Item 3. The crystal according to Item 2, wherein in the X-ray powder diffraction pattern measured with CuKα characteristic X-rays, the crystal also has one or more peaks at one or more diffraction angles 2θ (°) selected from 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2 and 27.6±0.2.

[0018] Project 4. Crystals of oxazole compounds represented by formula (5),

[0019]

[0020] In the infrared absorption spectrum measured using the potassium bromide pellet method, the wavenumbers (cm²) of the crystal at 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2 were... -1 There is an infrared absorption band at ().

[0021] Item 5. A crystal according to any one of Items 1 to 3, wherein, in the infrared absorption spectrum measured using the potassium bromide pellet method, the wavenumber (cm²) of the crystal is 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2. -1 There is an infrared absorption band at ().

[0022] Item 6. The crystal according to Item 4 or 5, wherein, in the infrared absorption spectrum measured using the potassium bromide pellet method, the crystal also exhibits one or more wavenumbers (cm²) selected from 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2. -1 There are one or more infrared absorption bands at ().

[0023] Item 7. The crystal according to any one of Items 1 to 6, wherein the crystal has a melting point of 75°C to 90°C.

[0024] Project 8. Crystals of oxazole compounds represented by formula (5),

[0025]

[0026] The crystal has a melting point of 75°C to 90°C.

[0027] Item 9. A pharmaceutical composition comprising the crystals described in any one of Items 1 to 8.

[0028] Item 10. The pharmaceutical composition according to Item 9 for the treatment and / or prevention of eczema or dermatitis (preferably atopic dermatitis).

[0029] Item 11. The pharmaceutical composition according to Item 9 or 10, wherein the pharmaceutical composition is an ointment.

[0030] Advantages of the present invention

[0031] This invention provides a more stable crystal of a specific oxazole compound that has inhibitory activity against PDE4. Specifically, the crystal has higher thermal stability and is advantageous because it has a higher melting point than conventional crystals of the specific oxazole compound. Attached Figure Description

[0032] Figure 1 The X-ray powder diffraction pattern of type A crystal of compound (5) is shown, measured with CuKα characteristic X-rays.

[0033] Figure 2 The infrared absorption spectrum of type A crystals of compound (5) is shown by the potassium bromide pellet method.

[0034] Figure 3 The X-ray powder diffraction pattern of type B crystals of compound (5) is shown, measured with CuKα characteristic X-rays.

[0035] Figure 4 The infrared absorption spectrum of type B crystals of compound (5) is shown by the potassium bromide pellet method. Detailed Implementation

[0036] The embodiments of the present invention are described in detail below.

[0037] In this invention, the crystals of oxazole compounds include crystals of oxazole compounds represented by the following formula (5).

[0038]

[0039] The oxazole compound exhibits specific inhibitory activity against PDE4 and is effective as an anti-inflammatory agent. In this specification, the oxazole compound represented by formula (5) is sometimes referred to as compound (5). Compound (5) is N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

[0040] Compound (5) can be produced by known methods (e.g., the methods described in any of PTL 1 to 3). However, the crystal form of compound (5) produced by known methods differs from the crystal form of compound (5) covered by this invention. In this specification, the former crystal form is sometimes referred to as type A, and the latter crystal form is sometimes referred to as type B. Specifically, the crystal of compound (5) produced by known methods is type A crystal, while the crystal of compound (5) covered by this invention is type B crystal.

[0041] Type B crystals are crystals of compounds (5) having one or more of the following characteristics. Among the following characteristics (i) to (iii), the type B crystal preferably has at least one characteristic, more preferably at least two characteristics (i.e., characteristics (i) and (ii), characteristics (ii) and (iii), or characteristics (iii) and (i)), and still more preferably all three characteristics.

[0042] Feature (i): Characteristic X-ray powder diffraction pattern

[0043] Preferably, in the X-ray powder diffraction pattern measured with CuKα characteristic X-rays, the type B crystal has peaks at diffraction angles of 2θ (°) at 9.6 ± 0.2, 19.1 ± 0.2, and 21.2 ± 0.2. Of these three peaks, the peak at diffraction angle of 2θ (°) at 19.1 ± 0.2 (sometimes referred to as peak

[12] ) preferably has the lowest intensity. The peak at diffraction angle of 2θ (°) at 21.2 ± 0.2 (sometimes referred to as peak

[16] ) preferably has the highest intensity. The peak at diffraction angle of 2θ (°) at 9.6 ± 0.2 is sometimes referred to as peak [2].

[0044] The intensity ratio of peak

[12] to peak

[16] (peak

[16] / peak

[12] ) is preferably about 1.5 to 2.5, more preferably about 1.6 to 2.4 or 1.7 to 2.3, and still more preferably about 1.8 to 2.2 or about 1.9 to 2.1. The intensity ratio of peak

[12] to peak [2] (peak [2] / peak

[12] ) is preferably about 1.5 to 1.75.

[0045] Preferably, in addition to having the three peaks mentioned above (peak [2], peak

[12] , peak

[16] ), the crystal has one, two, or three peaks at one, two, or three diffraction angles 2θ (°) selected from 12.6±0.2, 22.8±0.2, and 26.0±0.2. The peak at the diffraction angle 2θ (°) at 12.6±0.2 is sometimes referred to as peak [6]. The peak at the diffraction angle 2θ (°) at 22.8±0.2 is sometimes referred to as peak

[18] . The peak at the diffraction angle 2θ (°) at 26.0±0.2 is sometimes referred to as peak

[20] .

[0046] In the most preferred embodiment, the type B crystal has all of the peaks [6],

[18] , and

[20] in addition to peaks [2],

[12] , and

[16] . In this case, the intensity of each of the peaks [6],

[18] , and

[20] is preferably lower than the intensity of peak

[12] . Furthermore, among the intensities of peaks [6],

[18] , and

[20] , the intensity of peak

[20] is preferably the greatest.

[0047] In addition to having the four to six peaks described above (three of peaks [2],

[12] , and

[16] ; and one, two, or three peaks selected from peaks [6],

[18] , and

[20] ), it is also preferable to have one or more peaks at diffraction angles 2θ (°) selected from 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.2). The intensity of each of these one to seven peaks is preferably lower than the intensity of each of the four to six peaks described above. A type B crystal is particularly preferred, having peaks [2],

[12] ,

[16] , [6],

[18] , and

[20] ; and having peaks at diffraction angles of 2θ (°) of 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.2.

[0048] Feature (ii): Characteristic infrared absorption spectrum

[0049] In the infrared absorption spectrum measured using the potassium bromide pellet method, the type B crystal preferably exhibits wavenumbers (cm²) of 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2. -1 There are infrared absorption bands at a wavenumber (cm²) of 1651±2. Among these infrared absorption bands, the wavenumber at 1651±2 is... -1The infrared absorption bands at () are particularly characteristic of type B crystals. These infrared absorption bands originate from the infrared absorption of characteristic functional groups present in compound (5), which is explained in more detail below. (The wavelengths described to the right of the slash " / " in the following description are the wavelengths of the infrared absorption bands of type A crystals described below.)

[0050] 3380 (cm) -1 ): Secondary amide NH stretching vibration

[0051] 2980 (cm) -1 ): -CH2 stretching vibration

[0052] 1651 / 1643 (cm) -1 ): Amide C=O stretching vibration

[0053] 1501 / 1503 (cm) -1 Aromatic C=C stretching vibration

[0054] 1258 / 1261, 1121 / 1119 (cm) -1 ): -CF2 stretching vibration

[0055] 754 / 758 (cm) -1 ): Benzene CH out-of-plane bending vibration.

[0056] In addition to these characteristic infrared absorption bands, the type B crystal also preferably exhibits absorption at one or more (2, 3, 4, 5, 6, or 7) wavenumbers (cm²) selected from 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2. -1 There are one or more infrared absorption bands at ().

[0057] In infrared absorption spectra, the wavenumber (cm²) of one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption bands -1 The error can be ±4, ±3, ±2 or ±1.

[0058] Feature (iii): Characteristic melting point

[0059] The melting point of the type B crystal is preferably between 75°C and 90°C. The lower limit of this range may be 76°C, 77°C, 78°C, 79°C, or 80°C. The upper limit of this range may be 89°C, 88°C, 87°C, 86°C, 85°C, or 84°C. The melting point is preferably between 77°C and 88°C, more preferably between 78°C and 86°C, still more preferably between 79°C and 85°C, and particularly preferably between 80°C and 84°C.

[0060] The melting point is the value measured according to Method 1, Section 2.60, 17th Edition of the Japanese Pharmacopoeia.

[0061] Type B crystals can be prepared by allowing Type A crystals to stand at a temperature above room temperature for an extended period of time. More specifically, Type B crystals can be prepared by allowing Type A crystals to stand at a temperature preferably between 40°C and 60°C, more preferably between 45°C and 55°C, and still more preferably between 48°C and 52°C, for a period of preferably 3 months or longer, and more preferably 4 months or longer, or 5 months or longer. There is no particular upper limit to the static period, provided that Type B crystals are obtainable; for example, the static period is about 6 or 7 months. Preferably, the Type A crystals are placed in a sealed or tightly sealed container. Furthermore, it is preferable that the Type A crystals are placed under conditions unaffected by light (e.g., light-shielding conditions; more specifically, in a light-blocking amber bottle).

[0062] The type A crystals can be prepared by known methods as described above, for example by the method described in any of PTLs 1 to 3. Although not particularly limited, the type A crystals can be prepared by preparing compound (5) according to the reaction route described in PTL 3, and precipitating the crystals of compound (5). The resulting precipitated crystals can be dried and subsequently used as type A crystals. The dried type A crystals are particularly preferably type A crystals that have been allowed to stand at a temperature above room temperature for a longer period of time and used to prepare type B crystals.

[0063]

[0064] *DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether, DMF: N,N-dimethylformamide, 2-EBA: Ethoxybenzoic acid, WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0065] The X-ray powder diffraction pattern, infrared absorption spectrum, and melting point of the type A crystal are described below. In the X-ray powder diffraction pattern measured with CuKα characteristic X-rays, the type A crystal exhibits characteristic peaks at diffraction angles of 2θ (°) at 5.8 ± 0.2, 11.6 ± 0.2, 17.1 ± 0.2, 23.1 ± 0.2, and 26.2 ± 0.2. The type A crystal may also have one or more peaks at one or more diffraction angles of 2θ (°) selected from 10.2 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 18.5 ± 0.2, 22.2 ± 0.2, and 26.7 ± 0.2. In the infrared absorption spectra measured using the potassium bromide pellet method, the type A crystal showed particularly high wavenumbers (cm²) at 3380±5, 2980±5, 1643±2, 1503±2, 1261±2, 1119±2, and 758±2. -1There is an infrared absorption band at ( ). The type A crystal may also have one or more wavenumbers (cm²) selected from 1601±2, 1537±2, 1296±2, 1229±2, 1147±2, 939±2, and 617±2. -1 There are one or more infrared absorption bands at the location. The melting point of the type A crystal (measured according to Method 1, Section 2.60, 17th Edition of the Japanese Pharmacopoeia) is about 56°C to 60°C.

[0066] This invention also covers a pharmaceutical composition containing type B crystals. For example, the pharmaceutical composition contains a pharmaceutically acceptable carrier and type B crystals. There are no particular limitations on such a carrier, and known carriers may be used. The pharmaceutical composition is sometimes referred to as the pharmaceutical composition of this invention.

[0067] The pharmaceutical compositions of the present invention are particularly effective in reducing or eliminating eczema and dermatitis, especially in reducing or eliminating atopic dermatitis. The pharmaceutical compositions of the present invention can be used as preventative and / or therapeutic agents for these diseases.

[0068] There are no particular limitations on the form of the pharmaceutical compositions of the present invention. Examples include topical preparations, oral formulations, injections, etc. Among these, topical preparations are preferred, and ointments are particularly preferred. In the ointment, preferably, the type B crystals (I) are dissolved in a base component, and the base component comprises an ointment base (III) and a solvent (II) for dissolving the compound (5).

[0069] More preferably, an ointment in which the solvent containing dissolved type B crystals (I) is dissolved or dispersed in droplets in the ointment matrix (III).

[0070] Type B crystals (I) can be dissolved in solvent (II) by heating. Preferably, type B crystals (I) are dissolved by heating at a temperature higher than the melting point of type B crystals. For example, heating and dissolution can be carried out at temperatures of 75°C or higher, 76°C or higher, 77°C or higher, 78°C or higher, 79°C or higher, 80°C or higher, 81°C or higher, 82°C or higher, 83°C or higher, 84°C or higher, 85°C or higher, 86°C or higher, 87°C or higher, 88°C or higher, 89°C or higher, or 90°C or higher. There is no particular upper limit to the heating temperature as long as the effect of compound (5) is obtained. For example, the temperature is 100°C or lower, 99°C or lower, 98°C or lower, 97°C or lower, 96°C or lower, 95°C or lower, 94°C or lower, 93°C or lower, 92°C or lower, or 91°C or lower.

[0071] Although there are no particular limitations, type B crystals (I) are present in the ointment in an amount preferably 0.01 to 10 parts by weight, more preferably 0.05 to 7.5 parts by weight, and still more preferably 0.1 to 5 parts by weight per 100 parts by weight of ointment.

[0072] As described above, type B crystals (I) are preferably soluble in solvent (II). The solvent is preferably a polar compound that is liquid at room temperature. Specific examples of the solvent include ethylene carbonate, propylene carbonate, benzyl alcohol, glyceryl triacetate, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyldodecyl alcohol, decyl oleate, isostearyl alcohol, and isopropyl myristate. Ethyl carbonate, propylene carbonate, benzyl alcohol, and glyceryl triacetate are more preferred, and propylene carbonate and glyceryl triacetate are still more preferred. Among these, propylene carbonate is preferred. These solvents can be used alone or in combination of two or more. Specifically, it is preferred to use ethylene carbonate or propylene carbonate alone, or a combination of ethylene carbonate or propylene carbonate with benzyl alcohol and / or glyceryl triacetate.

[0073] Solvent (II) is present in the ointment preferably in an amount of more than 2 parts by weight, more preferably 2.1 parts by weight or more, and still more preferably 2.2 parts by weight or more per part of type B crystals (I). There is no particular upper limit on the amount of solvent (II) as long as the effects of the present invention are achieved. For example, the upper limit is preferably 30 parts by weight or less, more preferably 20 parts by weight or less, and still more preferably 15 parts by weight or less.

[0074] Solvent (II) is present in the ointment in an amount preferably 0.1 to 50 parts by weight, more preferably 0.2 to 25 parts by weight, and still more preferably 0.5 to 20 parts by weight per 100 parts by weight of ointment.

[0075] The solution of type B crystals in the solvent is preferably dissolved or dispersed in the ointment matrix (III) in the form of droplets, and more preferably dispersed in the ointment matrix (III) in the form of droplets.

[0076] Known ointment bases for the production of ointments can be used as ointment bases (III). Examples of such ointment bases include hydrocarbons, and more specifically, oil bases, particularly natural waxes, petroleum waxes, and other hydrocarbons. Examples of natural waxes include beeswax (e.g., unbleached beeswax, non-chemically bleached beeswax, and chemically bleached beeswax) and carnauba wax. Examples of petroleum waxes include paraffin wax and microcrystalline wax. Examples of other hydrocarbons include liquid paraffin and petroleum (e.g., white petroleum and yellow petroleum). These ointment bases can be used alone or in combination of two or more.

[0077] The soft gel matrix (III) is present in the ointment in an amount of preferably 5 to 5000 parts by weight, more preferably 10 to 2500 parts by weight, and still preferably 20 to 1000 parts by weight per part of type B crystals (I).

[0078] The soft gel matrix (III) is present in the ointment in an amount of preferably 50 to 99 parts by weight, more preferably 70 to 98 parts by weight, and still more preferably 80 to 97 parts by weight per 100 parts by weight of ointment.

[0079] Preferably, the ointment base contains at least beeswax. Preferably, the beeswax used is unbleached beeswax; including, for example, non-bleached beeswax (non-chemically bleached beeswax) and unbleached beeswax (unbleached beeswax).

[0080] The beeswax is present in the ointment in an amount preferably from 0.05 to 50 parts by weight, more preferably from 0.1 to 40 parts by weight, and still preferably from 0.2 to 35 parts by weight per part of type B crystals (I).

[0081] Beeswax is present in the ointment in an amount preferably 0.1 to 10 parts by weight, more preferably 0.2 to 9 parts by weight, still more preferably 0.4 to 8 parts by weight, even more preferably 0.5 to 7.5 parts by weight, and particularly preferably 1 to 5 parts by weight per 100 parts by weight of ointment.

[0082] There are no particular limitations on the combination of other ointment bases with beeswax. However, for example, the combination preferably comprises beeswax and at least one of petroleum (preferably white petroleum), liquid paraffin, and paraffin wax.

[0083] In addition to containing an ointment base, the ointment may contain other additives used in ointments (especially pharmaceutical additives), such as fragrance ingredients, colorants, preservatives, absorption enhancers including higher olefinic acids (e.g., oleic acid), or drugs effective in treating other skin conditions.

[0084] As described above, the ointment of the present invention is preferably an ointment in which a solvent (II) in which type B crystals (I) are dissolved is dissolved in or dispersed in droplets in an ointment matrix (III). Examples of methods for producing such an ointment include a method comprising preparing a solution of component (I) in component (II), and mixing the solution with component (III) by stirring. Stirring and mixing can be performed, for example, by a homogenizer, a paddle mixer, or a combination of these mixers.

[0085] When using multiple types of ointment bases (component (III)), it is preferable to premix the multiple ointment bases. In formulations containing multiple ointment bases of component (III), it is preferable to heat and melt solids such as beeswax to mix the ointment bases. For example, when beeswax is used in combination with other ointment bases, it is preferable to premix the beeswax and other ointment bases, preferably by heating.

[0086] In the case of an ointment in which component (II), containing dissolved component (I), is dispersed in component (III) as droplets, the droplet size observed under a polarizing microscope is 100 μm or smaller, preferably about 40 μm or smaller, more preferably about 25 μm or smaller, and still more preferably about 20 μm or smaller. In particular, it is preferable that there are no droplets with a diameter exceeding 100 μm, more preferably that there are no droplets with a diameter exceeding 40 μm, still more preferably that there are no droplets with a diameter exceeding 25 μm, and even more preferably that there are no droplets with a diameter exceeding 20 μm. The desired average droplet size is achieved by adjusting the stirring speed during mixing of the solution and component (III).

[0087] In this specification, the term "comprising" includes both "consisting substantially of" and "composed of". This invention covers all combinations of the elements described in this specification.

[0088] The features (properties, structures, functions, etc.) explained in the embodiments of the present invention can be combined in any way to specifically illustrate the subject matter covered by the present invention. Specifically, the present invention covers all subject matter including different combinations of the combinable features described in this specification.

[0089] Example

[0090] The present invention will be described in more detail below. However, the present invention is not limited to the following embodiments. In the following reaction schemes, when a compound is labeled with a number, the compound may be referred to as "compound (number)". For example, a compound labeled "3" may be referred to as "compound (3)". In addition, in the following reaction schemes, as above, a compound labeled "5" is referred to as compound (5).

[0091] Synthesis of oxazole compounds (Type A crystals)

[0092] Compound (5) (white powder) was prepared according to the method disclosed in Example 352 of PTL 1 (WO2007 / 058338).

[0093] Data for compound (5)

[0094] N-({2-[4-(difluoromethoxy)-3-isopropoxyphenyl]oxazol-4-yl}methyl)-2-ethoxybenzamide: white powder

[0095] 1 H NMR (400MHz, CDCl3): δ = 8.56 (br s,1H,NH),8.23(dd,J=7.6Hz,1.6Hz,1H,ArH),7.66(s,1H,ArH),7.63(d,J=2.0Hz,1H, ArH),7.58(dd,J=8.4Hz,2.0Hz,1H,ArH),7.44-7.39(m,1H,ArH),7.21(d,J=8.0Hz,1H, ArH),7.08-7.04(m,1H,ArH),6.94(d,J=8.0Hz,1H,ArH),6.61(t,J=75.2Hz,1H,CHF2) ,4.68(sept,J=6.93,2H,CH2),1.48(t,J=7.2Hz,3H,CH3),1.39(d,J=5.6Hz,6H,2CH3).

[0096] X-ray powder diffraction pattern of the white powder of compound (5) obtained by measuring CuKα characteristic X-rays. More specifically, the measurements were performed under the following conditions.

[0097] Measuring Instrument - XRD-600 (Shimadzu Corporation)

[0098] Operating conditions - Voltage: 35.0kV, Current: 20.0mA, Sampling tilt angle: 0.0200°.

[0099] Figure 1 The measurement results are shown in Table 1.

[0100] Table 1

[0101]

[0102] The infrared absorption spectrum of the white powder of the obtained compound (5) was measured using the potassium bromide pellet method. More specifically, the measurement was performed under the following conditions.

[0103] Measuring Instruments - IR Prestige-21 (Shimadzu Corporation)

[0104] Operating conditions - Cumulative count: 16, Resolution: 4cm -1 .

[0105] Figure 2 The measurement results are shown.

[0106] The melting point of the white powder of the obtained compound (5) was measured according to Method 1, Section 2.60, 17th Edition of the Japanese Pharmacopoeia. More specifically, the measurement was performed under the following conditions.

[0107] Measuring Instrument - M-565 (BUCHI)

[0108] Operating conditions - The white powder of compound (5) was placed in a dry capillary to form a layer with a thickness of 2.5 mm to 3.5 mm. The bath was gradually heated to 48°C and the capillary containing the white powder was inserted. The temperature was then increased at a rate of 3°C per minute, and when the temperature reached 53°C, it was increased at a rate of 1°C per minute; the sample was then observed.

[0109] Measurements confirmed that the white powder (type A crystals) of compound (5) had a melting point of approximately 56 to 60 °C.

[0110] Using the type A crystal thus obtained as a seed crystal, the crystals of compound (5) prepared according to the method disclosed in PTL 2 (WO2014 / 034958) (specifically, Example 1 (1-10): compound 1) and the method disclosed in PTL 3 (WO2017 / 115780) (specifically, Production Example 4 (compound (11))) also have the same characteristics as described above, and are therefore considered to be type A crystals.

[0111] Preparation of type B crystals 1

[0112] Type A crystals (12g) were placed in an amber glass bottle. The bottle was sealed and stored in an incubator (50±2℃) for 3 months. The X-ray powder diffraction pattern and infrared absorption spectrum of the powder (crystals) collected after storage were measured as described above. Figure 3 Table 2 shows the X-ray powder diffraction patterns, and Figure 4 The infrared absorption spectrum is shown. The melting point was also measured according to the above method, except that "48℃" was changed to "72℃" and "53℃" was changed to "77℃". The measured melting point was approximately 80℃ to 84℃.

[0113] Table 2

[0114]

[0115] These results showed that the X-ray powder diffraction pattern, infrared absorption spectrum, and melting point of the crystals collected after storage were completely different from those of type A crystals. This type of crystal was named "type B crystal".

[0116] As mentioned above, the melting point of type B crystals is higher than that of type A crystals. This fact confirms that type B crystals have superior thermal stability. Prior to this analysis, recrystallization methods using various solvents were employed to search for crystals with superior stability compared to type A crystals; however, no different crystal types were found. Surprisingly, however, it was clarified that type B crystals, which possess higher stability (especially thermal stability), can be prepared by allowing type A crystals to stand at temperatures above room temperature for an extended period of time.

[0117] Preparation of type B crystals 2

[0118] Analysis was performed to use the obtained type B crystal as a seed crystal for further preparation of type B crystals. More specifically, type B crystals were prepared according to the method disclosed in PTL 3 (WO2017 / 115780) as follows.

[0119]

[0120] Add 20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine to 300 mL of ethyl acetate and cool the mixture. Pour in 11.48 g (100 mmol) of methanesulfonyl chloride and stir at 10 °C to 30 °C for 1 hour. Add 17.41 g (200 mmol) of lithium bromide and stir the mixture at 20 °C to 35 °C for 1 hour. Add 100 mL of water to the reaction solution and separate the mixture, then concentrate the organic layer under reduced pressure. Add 300 mL of ethyl acetate to the concentrated residue to dissolve the residue and concentrate the solution again under reduced pressure. Add 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide to the concentrated residue and react at 75 °C to 85 °C for 1 hour. Add 200 mL of water to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C to obtain 27.20 g of compound (3) (yield: 95.01%).

[0121]

[0122] 20.00 g (46.7 mmol) of compound (3), 40 mL of 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65°C to 75°C, followed by separation. 100 mL of a mixture of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was again adjusted to 65°C to 75°C, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, yielding 27.58 g of compound (4) as wet crystals.

[0123] Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine and stirred at 20 °C to 30 °C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and the mixture was reacted at 20 °C to 30 °C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 °C to 50 °C, followed by separation. 60 mL of water and 6 mL of 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was again adjusted to 40 °C to 50 °C. The mixture was separated, and the organic layer was concentrated under reduced pressure. Add 50 mL of ethanol, 20 mL of water, 6 mL of 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon to the concentrated residue, and reflux the mixture for 30 minutes. Remove the activated carbon by filtration, and wash the filtrate with 12 mL of ethanol. Cool the filtrate and add 10 mg of type B crystals (seed crystals) to it to precipitate the crystals. Collect the precipitated crystals by filtration and dry at 60 °C to obtain 18.38 g of compound (5) (88.18%).

[0124] The X-ray powder diffraction pattern, infrared absorption spectrum, and melting point of the obtained crystal were measured as described above. The results obtained are completely consistent with those of the type B crystal described above. This confirms that type B crystals can be directly synthesized using the type B crystal as a seed crystal, without the need to prepare type B crystals using type A crystals.

Claims

1. Crystals of the oxazole compound represented by formula (5), Among them, CuK is used In the characteristic X-ray powder diffraction patterns measured by X-rays, the crystal exhibits diffraction angles of 2° at 9.6±0.2, 12.6±0.2, 19.1±0.2, 21.2±0.2, 22.8±0.2, and 26.0±0.

2. ( There is a peak at ) and The crystal has a melting point of 79°C to 85°C.

2. The crystal according to claim 1, wherein CuK is used. In the characteristic X-ray powder diffraction pattern measured by X-rays, the crystal also exhibits diffraction angles selected from one or more of 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.

2. ( There are one or more peaks at ().

3. The crystal according to claim 1, wherein in the infrared absorption spectrum measured using the potassium bromide pellet method, the wavenumbers (cm²) of the crystal are 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2. -1 There is an infrared absorption band at ().

4. The crystal according to claim 3, wherein in the infrared absorption spectrum measured using the potassium bromide pellet method, the crystal also exhibits one or more wavenumbers (cm²) selected from 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2. -1 There are one or more infrared absorption bands at ().

5. The crystal according to any one of claims 1 to 4, wherein the crystal has a melting point of 80°C to 84°C.

6. A pharmaceutical composition comprising the crystals according to any one of claims 1 to 5.

7. Use of the crystal according to any one of claims 1 to 5 in the preparation of pharmaceutical compositions for the treatment and / or prevention of eczema or dermatitis.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is an ointment.

9. A method for producing a pharmaceutical composition comprising an oxazole compound represented by formula (5), The method includes dissolving crystals of the oxazole compound represented by formula (5) in a solvent. Among them, CuK is used In the characteristic X-ray powder diffraction patterns measured by X-rays, the crystal exhibits diffraction angles of 2° at 9.6±0.2, 12.6±0.2, 19.1±0.2, 21.2±0.2, 22.8±0.2, and 26.0±0.

2. ( There is a peak at ) and The crystal has a melting point of 79°C to 85°C.

10. The production method according to claim 9, wherein CuK is used In the characteristic X-ray powder diffraction pattern measured by X-rays, the crystal also exhibits diffraction angles selected from one or more of 10.4±0.2, 11.9±0.2, 15.0±0.2, 15.9±0.2, 19.7±0.2, 24.7±0.2, and 27.6±0.

2. ( There are one or more peaks at ().

11. The production method according to claim 9, wherein in the infrared absorption spectrum measured by the potassium bromide pellet method, the wavenumber (cm²) of the crystal is 3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2 and 754±2. -1 There is an infrared absorption band at ().

12. The production method according to claim 11, wherein in the infrared absorption spectrum measured using the potassium bromide pellet method, the crystal also exhibits one or more wavenumbers (cm²) selected from 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2. -1 There are one or more infrared absorption bands at ().

13. The production method according to any one of claims 9 to 12, wherein the crystal has a melting point of 80°C to 84°C.

14. The production method according to any one of claims 9 to 12, comprising dissolving the crystal in a solvent by heating at a temperature above the melting point of the crystal.

15. The production method according to claim 14, comprising dissolving the crystals in a solvent by heating at a temperature of 85°C or higher and 91°C or lower.

16. The production method according to any one of claims 9 to 12, wherein the solvent is a polar compound that is liquid at room temperature.

17. The production method according to any one of claims 9 to 12, comprising: Dissolving the crystal in a solvent, and The solvent containing dissolved crystals is mixed with the ointment base.

18. The production method according to claim 17, wherein the ointment base comprises hydrocarbons.

19. The production method according to claim 17, wherein the ointment base comprises at least beeswax.

20. The production method according to claim 17, wherein, The pharmaceutical composition contains a solvent containing dissolved crystals dissolved in or dispersed in the ointment base in the form of droplets.

21. The production method according to claim 20, wherein the droplets have an average particle size of 100 µm or less.

22. The manufacturing method according to claim 17, wherein the pharmaceutical composition is an ointment and further comprises an ointment base.

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