Crystal form of cyclohexenone compound

Abstract

The purpose of the present disclosure is to provide a crystal form of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohexa-2-en-1-one, this crystal form being of superior stability and desirable in terms of production. The present disclosure provides a crystal form which, in the powder X-ray diffraction spectrum (CuKα), demonstrates diffraction angles (2θ ± 0.2°) that have characteristic peaks at 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8°.

Description

Crystalline forms of cyclohexenone compounds

[0001] [Cross-reference to related applications] This application claims priority to Japanese Patent Application No. 2022-019058, filed on February 9, 2022, the entire disclosure of which is incorporated herein by reference. The present disclosure relates to a crystalline form of a cyclohexenone compound useful as an active pharmaceutical ingredient for pharmaceuticals, and a pharmaceutical composition comprising the crystalline form.

[0002] Neurodegenerative diseases are broadly classified as central or peripheral, depending on the location of the nerve damage. Representative central nerve disorders include Alzheimer's disease, amyotrophic lateral sclerosis, and cerebrospinal cord injury. Representative peripheral nerve disorders include sensory neuropathy, such as neuropathic pain and hypoesthesia, and autonomic neuropathy, accompanied by constipation and dysuria. Although the pathological mechanisms of neurodegenerative diseases vary, they are thought to involve neurite degeneration and atrophy and / or neuronal cell death. Currently, there are few therapeutic drugs that can fundamentally improve nerve damage in these diseases.

[0003] Patent Document 1 discloses that 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one exhibits a nerve growth promoting effect and is useful as a pharmaceutical for preventing and treating brain diseases such as dementia, and Patent Document 2 discloses that the same compound is useful as a therapeutic agent for urinary disorders. However, 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one has insufficient pharmacokinetics in a standard formulation (Patent Document 3).

[0004] Furthermore, when a compound is used as an active ingredient or drug substance of a pharmaceutical, the compound generally needs to be chemically and physically stable in order to maintain stable quality and / or to facilitate storage and management.

[0005] International Publication No. WO99 / 08987 International Publication No. WO2002 / 066024 International Publication No. WO2013 / 147072

[0006] An object of the present disclosure is to provide a novel compound having excellent neurite outgrowth activity, and a further object of the present disclosure is to provide a stable crystalline form of the novel compound that is useful as an active ingredient or active pharmaceutical ingredient in pharmaceuticals.

[0007] As a result of extensive research to solve the above problems, it was found that a compound represented by the following formula (I)

[0008]

[0009] It has been found that a novel cyclohexenone compound represented by the formula (chemical name: 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (hereinafter also referred to as "compound (I)") has a nerve growth promoting effect (an effect of increasing neurite growth and / or the proportion of adenocytes), and is useful as a pharmaceutical for treating diseases that improve by promoting nerve growth, including neurodegenerative diseases, pain, and / or lower urinary tract disorders. Furthermore, it has been found that compound (I) exists in three crystalline forms (form I crystal, form II crystal, and form III crystal), and these crystalline forms have low hygroscopicity and excellent solid-state stability.

[0010] That is, the present disclosure provides the following [1] to

[15] .

[0011] [1] A crystalline form of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one having at least three peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8° in a powder X-ray diffraction spectrum (CuKα).

[0012] [2] The crystalline form according to [1], which has peaks at diffraction angles (2θ±0.2°) of 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8° in a powder X-ray diffraction spectrum (CuKα).

[0013] [3] The crystalline form according to [1] or [2], whose powder X-ray diffraction spectrum is substantially the same as that shown in Figure 1.

[0014] [4] The crystalline form according to any one of [1] to [3], which has an endothermic peak at a peak temperature of around 35°C in differential scanning calorimetry (DSC measurement).

[0015] [5] A pharmaceutical composition containing the crystalline form according to any one of [1] to [4].

[0016] [6] A crystalline form of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one having at least five peaks at diffraction angles (2θ±0.2°) selected from 6.1°, 11.4°, 12.5°, 15.1°, 19.4°, and 24.0° in a powder X-ray diffraction spectrum (CuKα).

[0017] [7] The crystalline form according to [6], which has peaks at diffraction angles (2θ±0.2°) of 6.1°, 11.4°, 12.5°, 15.1°, 19.4°, and 24.0° in a powder X-ray diffraction spectrum (CuKα).

[0018] [8] The crystalline form according to [6] or [7], having a powder X-ray diffraction spectrum substantially the same as that shown in Figure 3.

[0019] [9] The crystalline form according to any one of [6] to [8], which has an endothermic peak at a peak temperature (peak top value) of around 34°C in differential scanning calorimetry (DSC measurement).

[0020]

[10] A pharmaceutical composition containing the crystalline form according to any one of [6] to [9].

[0021]

[11] A crystalline form of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one having at least five peaks at diffraction angles (2θ±0.2°) selected from 11.2°, 12.4°, 14.1°, 14.9°, 18.8°, and 19.4° in a powder X-ray diffraction spectrum (CuKα).

[0022]

[12] The crystalline form according to

[11] , which has peaks at diffraction angles (2θ±0.2°) of 11.2°, 12.4°, 14.1°, 14.9°, 18.8°, and 19.4° in a powder X-ray diffraction spectrum (CuKα).

[0023]

[13] The crystalline form according to

[11] or

[12] , having a powder X-ray diffraction spectrum substantially the same as that shown in Figure 5.

[0024]

[14] The crystalline form according to any one of

[11] to

[13] , which has an endothermic peak at a peak temperature (peak top value) of around 34°C in differential scanning calorimetry (DSC measurement).

[0025]

[15] A pharmaceutical composition containing the crystalline form according to any one of

[11] to

[14] .

[0026] According to the present disclosure, compound (I) is provided, which is useful as a compound having a nerve growth-promoting effect. Also, compound (I) is provided, which is useful as a compound having excellent pharmacokinetics and / or an effect of improving urinary function. Furthermore, compound (I) of the present disclosure is a novel compound, and its crystalline form, stable crystalline form of compound (I), and production method thereof are currently unknown. In the present disclosure, the crystalline forms of compound (I) (type I crystal, type II crystal, type III crystal) are superior to other crystalline forms in terms of, for example, handleability (lower hygroscopicity) and / or quality control, and are therefore useful forms when the compound is used as an active pharmaceutical ingredient for pharmaceuticals.

[0027] Furthermore, the residual solvents in the Type I crystals, Type II crystals, and Type III crystals of the present disclosure are below the standard value set out in the ICH Guidelines for Residual Solvents in Pharmaceuticals, and are therefore safe as pharmaceuticals.

[0028] 1 shows a powder X-ray diffraction spectrum (CuKα) of the I-type crystal of compound (I) obtained in Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This shows a differential scanning calorimetry (DSC) curve of the I-type crystal of compound (I) obtained in Example 1. This shows a powder X-ray diffraction spectrum (CuKα) of the II-type crystal of compound (I) obtained in Example 2 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This shows a differential scanning calorimetry (DSC) curve of the II-type crystal of compound (I) obtained in Example 2. This shows a powder X-ray diffraction spectrum (CuKα) of the III-type crystal of compound (I) obtained in Example 3 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This shows a differential scanning calorimetry (DSC) curve of the III-type crystal of compound (I) obtained in Example 3. 1 shows a moisture adsorption / desorption isotherm for type I crystals of compound (I) obtained in Example 1. 2 shows a moisture adsorption / desorption isotherm for type II crystals of compound (I) obtained in Example 2. 3 shows a moisture adsorption / desorption isotherm for type III crystals of compound (I) obtained in Example 3. 4 shows a graph of residual urine volume for each group. Values ​​indicate mean ± S.E. The n numbers for each group are 10, 10, 12, and 12 from left to right. * : p<0.05, significant difference compared to Vehicle by Dunnett's test N.S.: no significant difference compared to Vehicle by Dunnett's test #: p<0.05, significant difference compared to Compound (I) by Student's t-test ##: p<0.01, significant difference compared to Vehicle by Student's t-test

[0029] As used herein, singular forms (e.g., a, an, the) include both the singular and the plural unless otherwise specified in the present specification or unless clearly contradictory in the context. Unless otherwise specified, when simply referring to "Compound (I)" in the present specification, it means 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one, and is used in the sense of including both "amorphous form" and "crystal."

[0030] The compound (I) can be synthesized, for example, according to the method described in Synthesis Example 1 below, but is not limited to this method.

[0031] As used herein, the terms "crystal" and "amorphous body" are used in the usual sense in the technical field of medicine to which the present disclosure pertains. As used herein, the term "crystal" and related terms used herein, such as "crystalline form" and "crystalline morphology," are used interchangeably. Furthermore, as used herein, the term "amorphous" and related terms used herein, such as "amorphous body" and "amorphous form," are used interchangeably.

[0032] The crystals of the present disclosure can be isolated and purified by well-known separation and purification techniques such as recrystallization, crystallization, distillation, and column chromatography.

[0033] As used herein, and unless otherwise specified, the term "crystalline," and related terms used herein, when used to describe a compound, substance, modification, material, component, or product, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams and Wilkins, Baltimore, MD (2005); United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

[0034] As used herein, and unless otherwise specified, the term "crystalline form" and related terms herein refer to a solid form that is crystalline. Crystalline forms include single-component crystalline forms and multi-component crystalline forms, and can optionally include, but are not limited to, co-crystals, salts (including pharmaceutically acceptable salts), polymorphs, solvates, hydrates, and / or other molecular complexes. In certain embodiments, a crystalline form of a substance can be substantially free of amorphous forms and / or other crystalline forms. In certain embodiments, a crystalline form of a substance can contain less than about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50% by weight of one or more amorphous forms and / or other crystalline forms.

[0035] The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike salts, cocrystals typically do not involve hydrogen transfer between the cocrystal former and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal former and Compound (I) in the crystal structure.

[0036] As used herein, and unless otherwise specified, the terms "polymorph," "polymorphic form," and related terms herein refer to two or more crystalline forms of substantially the same molecule, molecular group, and / or ion. As with different crystalline forms, different polymorphs can have different physical properties, such as, for example, melting point, heat of fusion, solubility, dissolution characteristics, and / or vibrational spectra (as a result of the arrangement or conformation of the molecules and / or ions in the crystal lattice). Differences in physical properties can affect pharmaceutical parameters, such as storage stability, compressibility, and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can arise from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors faster when composed of one polymorph than when composed of another), mechanical changes (e.g., tablets disintegrating during storage when a kinetically favored polymorph transforms into a thermokinetically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to degradation at high humidity). As a result of differences in solubility / dissolution, some solid-state transitions may result in a loss of efficacy in extreme cases and toxicity in other extreme cases. In addition, physical properties may be important in processing (e.g., one polymorph may be more prone to solvate formation or may be difficult to filter and wash to remove impurities, and particle shape and size distribution may differ between polymorphs).

[0037] As used herein, and unless otherwise specified, the terms "amorphous," "amorphous form," and related terms used herein mean that the substance, component, or product is substantially not crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order.

[0038] The term "pharmaceutically acceptable salts" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable salts may be safe for consumption by animals or humans.

[0039] Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, such as infrared (IR) and Raman spectroscopy, solid and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, atomic analysis, and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more techniques, such as, but not limited to, X-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Useful techniques for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to resolve diffraction peaks associated with a single phase in a sample containing two or more solid phases. Other methods useful for analyzing powder diffraction data include unit cell indexing, which allows one skilled in the art to determine unit cell parameters from samples containing crystalline powders.

[0040] In powder X-ray diffraction patterns, due to the nature of the data, the diffraction angle and overall pattern may be important when determining the identity of a crystal. The relative intensities of powder X-ray diffraction patterns may vary somewhat depending on the direction of crystal growth, particle size, measurement conditions, etc., and therefore should not be interpreted strictly.

[0041] The values ​​obtained from various patterns may have some errors depending on the direction of crystal growth, particle size, measurement conditions, etc. Therefore, in this specification, the values ​​of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error in the range of about ±0.2°.

[0042] Furthermore, the measurement temperature of an endothermic peak in a differential scanning calorimetry (DSC) curve may vary depending on the rate of temperature rise per minute, the purity of the sample, etc. In this specification, the term "in the vicinity" of a DSC measurement temperature value means a temperature value within ±2, 3, 4, or 5°C of that value.

[0043] In one embodiment of the present disclosure, the type I crystal of compound (I) has, for example, the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1 and the differential scanning calorimetry (DSC measurement) curve shown in FIG. 2.

[0044] Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type I crystal of compound (I) include diffraction angles (2θ±0.2°) of 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8°.

[0045] The type I crystal of compound (I) according to the present disclosure is a crystalline form having at least three or more peaks selected from the above-mentioned peaks, preferably a crystalline form having at least five or more peaks selected from the above-mentioned peaks, and particularly preferably a crystalline form having all of the above-mentioned peaks.

[0046] The endothermic peak in the differential scanning calorimetry (DSC) curve of the type I crystal of Compound (I) can be, for example, around 33°C to 37°C, preferably around 34°C to 36°C, more preferably around 35°C.

[0047] A crystalline form according to the present disclosure may be characterized by any combination of the above embodiments, which are not mutually exclusive. For example, a crystalline form may be characterized by any combination of the above peaks in an X-ray diffraction pattern and the above endothermic peaks measured by DSC.

[0048] In some embodiments, the crystalline forms disclosed herein may include multiple crystals with spatially regular atomic arrangements (crystalline polymorphs) and may result in different physicochemical properties. In some embodiments, the crystalline forms disclosed herein may be mixtures containing crystalline polymorphs.

[0049] In certain embodiments, the crystalline forms of Compound (I) disclosed herein can be physically and / or chemically pure. In certain embodiments, the crystalline forms of the compounds disclosed herein can be at least about 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, or 80% physically and / or chemically pure. In some embodiments, the crystalline forms of the compounds disclosed herein are substantially pure. As used herein, and unless otherwise specified, a sample comprising a particular crystalline or amorphous form that is "substantially pure," e.g., substantially free of other solid forms and / or other compounds, in certain embodiments contains less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other solid forms and / or other compounds.

[0050] In some embodiments, the crystalline form of Compound (I) disclosed herein is stable upon exposure to conditions of about 25, 30, or 35°C and about 65, 70, 75, 80, or 85% relative humidity for about 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, or 156 weeks or more and about 160, 156, 150, 138, 126, 114, 102, 90, 78, 66, 54, 42, 30, 24, 18, 12, or 6 weeks or less. The conditions may be closed or open conditions. As used herein, "closed" conditions may refer to a closed or sealed bottle containing a sample during a stability experiment, and "open" conditions may refer to an open bottle. In certain embodiments, the crystalline forms of Compound (I) disclosed herein are stable upon exposure to conditions of about 25°C and about 60% relative humidity for about four weeks. In some embodiments, the conditions are closed conditions. That is, the crystalline forms of the compounds disclosed herein exhibit excellent storage stability over extended periods of time. As used herein, "stable" means that the increase in impurities compared to the initial impurity level is no more than about 1.0, 0.5, 0.3, 0.1, 0.05, or 0.01%. Stability can also be demonstrated, for example, by an X-ray diffraction pattern that maintains at least 10, 20, 30, 40, 50, 60, 70, 80, or 90% of the original peaks at (2θ±0.2°).

[0051] The crystalline forms of the present disclosure may be solvated (e.g., hydrated, etc.) or unsolvated. Compounds labeled with isotopes (e.g., deuterium, H, C, S, I, etc.) are also encompassed within the compounds described herein or pharmaceutically acceptable salts thereof.

[0052] In one embodiment of the present disclosure, type I crystals of compound (I) can be obtained, for example, by a method comprising: step (i-1) adding compound (I) to solvent I-1 and dissolving it; and step (i-2) adding solvent I-2 to the solution of compound (I) obtained in step (i-1) and stirring the mixture to crystallize compound (I). In such an embodiment, examples of solvent I-1 include methanol, ethanol, 1-propanol, 2-propanol, and acetone.

[0053] In step (i-1), the amount of compound (I) added is not particularly limited, but for example, 0.1 to 20 g, preferably 0.5 to 5 g, by mass of compound (I) can be added to 10 mL of solvent I-1. The temperature in step (i-1) is appropriately set depending on the solvent used, and is set between 20°C and the boiling point of the solvent.

[0054] In this embodiment, solvent I-2 may be, for example, water. The ratio (v / v) of solvent I-1 to solvent I-2 may be, for example, 0 to 50 ml, preferably 0 to 20 ml, of solvent I-2 per 10 ml of solvent I-1. The temperature for crystallization in step (i-2) is appropriately set depending on the solvent used and is set between -20°C and 30°C.

[0055] Alternatively, the compound (I) can be crystallized by adding the solvent I-1 and the solvent I-2 simultaneously, dissolving them by heating, and then cooling and stirring.

[0056] The stirring in the crystallization in step (i-2) is carried out by appropriately using a stirrer, stirring blade, magnetic stirrer, etc. depending on the amount of solvent, the size of the reaction vessel, etc. The stirring speed is usually 1 to 1200 rpm, and preferably 10 to 600 rpm.

[0057] The thus obtained type I crystals have a chemical purity of Compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the type I crystals have a chemical purity of Compound (I) of 95% or more, more preferably 99% or more.

[0058] The I-type crystal of compound (I) may be any crystal containing the I-type crystal, and may be a single crystal of the I-type crystal or a polymorphic mixture containing other crystals. Preferably, 90% by weight or more of the I-type crystal is the I-type crystal, and more preferably 95% by weight or more of the I-type crystal.

[0059] In one embodiment of the present disclosure, the type II crystal of compound (I) has, for example, the powder X-ray diffraction spectrum (CuKα) shown in FIG. 3 and the differential scanning calorimetry (DSC measurement) curve shown in FIG. 4.

[0060] Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type II crystal of compound (I) include diffraction angles (2θ±0.2°) of 6.1°, 11.4°, 12.5°, 15.1°, 19.4°, and 24.0°.

[0061] The type II crystal of compound (I) according to the present disclosure is a crystal having at least five or more peaks selected from the above-mentioned peaks, and particularly preferably a crystal having all of the above-mentioned peaks.

[0062] The endothermic peak in the differential scanning calorimetry (DSC) curve of the Type II crystal of Compound (I) may be, for example, around 32°C to 36°C, preferably around 33°C to 35°C, and more preferably around 34°C.

[0063] In one embodiment of the present disclosure, Form II crystals of Compound (I) can be obtained, for example, by a method comprising: Step (ii-1) adding Compound (I) to Solvent II and dissolving it; and Step (ii-2) cooling the solution of Compound (I) obtained in Step (ii-1) to crystallize Compound (I). In such an embodiment, Solvent II can be, for example, acetonitrile.

[0064] In step (ii-1), the amount of compound (I) added is not particularly limited, but for example, 1 to 4 g, preferably 1.5 to 3.5 g, by mass of compound (I) can be added to 10 mL of solvent II. The temperature in step (ii-1) is appropriately set between 15 and 40°C. The temperature in the crystallization in step (ii-2) is set between -10 and 5°C. Preferably, the mixture is cooled from the temperature in step (ii-1) to less than 3°C and maintained at a temperature of less than 3°C.

[0065] The crystallization in step (ii-2) may be carried out under stirring. In this case, stirring is carried out using a stirrer, stirring blades, or the like as appropriate depending on the amount of solvent, the size of the reaction vessel, and the like. The stirring operation can also be carried out, for example, by shaking the reaction vessel. The stirring speed is usually 1 to 600 rpm, and preferably 10 to 100 rpm.

[0066] The thus obtained type II crystal has a chemical purity of 90% or more of compound (I), which can be measured by high performance liquid chromatography (HPLC). Preferably, the type II crystal has a chemical purity of 95% or more of compound (I), more preferably 99% or more of compound (I).

[0067] The type II crystal of compound (I) may be any type containing type II crystal, and may be a single type II crystal or a polymorphic mixture containing other crystals. Preferably, 90% by weight or more of the type II crystal is type II crystal, and more preferably 95% by weight or more of the type II crystal.

[0068] In one embodiment of the present disclosure, the Form III crystal of Compound (I) has, for example, the powder X-ray diffraction spectrum (CuKα) shown in FIG. 5 and the differential scanning calorimetry (DSC measurement) curve shown in FIG. 6.

[0069] Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type III crystal of compound (I) include 11.2°, 12.4°, 14.1°, 14.9°, 18.8°, and 19.4° in terms of diffraction angle (2θ±0.2°).

[0070] The Form III crystal of Compound (I) according to the present disclosure is a crystal having at least five or more peaks selected from the above peaks, and particularly preferably a crystal having all of the above peaks.

[0071] The endothermic peak in the differential scanning calorimetry (DSC) curve of the Form III crystal of Compound (I) can be, for example, around 32°C to 36°C, preferably around 33°C to 35°C, and more preferably around 34°C.

[0072] In one embodiment of the present disclosure, the Form III crystal of Compound (I) can be obtained, for example, by a method comprising: Step (iii-1) adding the Form II crystal of Compound (I) to Solvent III-1 and stirring; and Step (iii-2) recovering a solid of Compound (I) from the suspension of Compound (I) obtained in Step (iii-1). In such an embodiment, Solvent III-1 can be a mixed solvent of methanol and water. When a mixed solvent of methanol and water is used, the ratio (v / v) can be, for example, 1 to 15 ml, preferably 5 to 11 ml, of water per 100 ml of methanol.

[0073] In step (iii-1), the amount of the Type II crystal of Compound (I) to be added is not particularly limited, but for example, 1 to 5 g, preferably 1.5 to 2.5 g, by mass of Compound (I) can be added to 10 mL of Solvent III-1. The temperature in step (iii-1) is appropriately set depending on the solvent used and is set between 0 and 8°C.

[0074] The recovery method in step (iii-2) can be a wide variety of methods that can be used in the technical field to which the present disclosure pertains, including filtration, washing with an organic solvent, and drying under reduced pressure.

[0075] The stirring in step (iii-1) is carried out using a stirrer, stirring blade, magnetic stirrer, etc. as appropriate depending on the amount of solvent, the size of the reaction vessel, etc. The stirring speed is usually 1 to 600 rpm, and preferably 10 to 300 rpm.

[0076] The thus obtained type III crystal has a chemical purity of 90% or more of compound (I), which can be measured by high performance liquid chromatography (HPLC). Preferably, the type III crystal has a chemical purity of 95% or more of compound (I), more preferably 99% or more of compound (I).

[0077] The type III crystal of compound (I) may be any type containing type III crystal, and may be a single type III crystal or a polymorphic mixture containing other crystals. Preferably, 90% by weight or more of the type III crystal is type III crystal, and more preferably 95% by weight or more of the type III crystal.

[0078] As shown in the Examples below, the Type I crystals, Type II crystals, and Type III crystals of Compound (I) according to the present disclosure all have low hygroscopicity and excellent solid-state stability (storage stability, etc.). It is important for pharmaceutical active ingredients and active ingredients in pharmaceuticals to have solid-state stability in industrial operations and to maintain quality.

[0079] In addition, solvents used in the production of pharmaceuticals may be toxic, and from the viewpoint of safety, it is desirable that the amount of solvent remaining in the production process is as small as possible. However, the type I crystals, type II crystals, and type III crystals of compound (I) do not contain residual solvents in amounts equal to or greater than the limit stipulated in the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines.

[0080] Therefore, the type I crystals, type II crystals, and type III crystals of compound (I) according to the present disclosure have excellent properties required as pharmaceuticals or active pharmaceutical ingredients.

[0081] The type I crystals, type II crystals, and type III crystals of compound (I) according to the present disclosure have excellent neurite outgrowth activity, and are useful as pharmaceuticals for treating diseases that improve by promoting nerve growth, including neurodegenerative diseases, pain, and / or lower urinary tract disorders, due to, for example, the neurite outgrowth activity and / or the activity of increasing the proportion of adenocytes.

[0082] When using the Type I crystals, Type II crystals and / or Type III crystals of Compound (I) as a medicine, various administration forms can be adopted depending on the purpose of prevention or treatment, with or without pulverizing the Type I crystals, Type II crystals and / or Type III crystals, and such forms may be, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, dry syrups, etc.; and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, injections, etc., with oral preparations being preferred. These pharmaceutical compositions can be produced using pharmaceutically acceptable carriers by formulation methods known and commonly used by those skilled in the art.

[0083] As pharmaceutical carriers, various organic or inorganic carrier substances commonly used as formulation materials are used, and are incorporated as excipients, binders, disintegrants, lubricants, coating agents in solid formulations, and as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0084] Examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate, and the like.

[0085] Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, candy powder, and hypromellose.

[0086] Examples of disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch.

[0087] Lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, sodium stearyl fumarate, and the like.

[0088] Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose.

[0089] The solvent may be water, propylene glycol, or saline.

[0090] Examples of solubilizing agents include polyethylene glycol, ethanol, α-cyclodextrin, macrogol 400, polysorbate 80, and the like.

[0091] Suspending agents include carrageenan, crystalline cellulose / carmellose sodium, and polyoxyethylene hydrogenated castor oil.

[0092] Examples of the isotonic agent include sodium chloride, glycerin, potassium chloride, and the like.

[0093] Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate.

[0094] Examples of soothing agents include procaine hydrochloride and lidocaine.

[0095] Examples of preservatives include ethyl parahydroxybenzoate, cresol, and benzalkonium chloride.

[0096] Antioxidants include sodium sulfite, ascorbic acid, natural vitamin E, and the like.

[0097] Examples of coloring agents include titanium oxide, iron sesquioxide, food blue No. 1, and copper chlorophyll.

[0098] Flavoring agents include aspartame, saccharin, sucralose, l-menthol, mint flavor, and the like.

[0099] Examples of stabilizers include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0100] When preparing oral solid preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, and odor-correcting agents, etc., are added to the Type I crystals, Type II crystals, and / or Type III crystals of Compound (I), and then tablets, coated tablets, granules, powders, capsules, etc. can be produced by conventional methods.

[0101] The amount of Form I crystals, Form II crystals and / or Form III crystals of Compound (I) to be formulated in each dosage unit form is not fixed depending on the symptoms of the patient to which it is to be administered or on the dosage form, etc., but it is generally desirable that the amount per dosage unit form be about 0.05 to 1000 mg for oral preparations, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.

[0102] Furthermore, the daily dose of the Type I crystals, Type II crystals and / or Type III crystals of Compound (I) in the pharmaceutical preparations having each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but it is usually about 0.05 to 5000 mg, preferably 0.1 to 1000 mg, per day for an adult (body weight 50 kg), and this is preferably administered once a day or in divided doses about 2 to 3 times a day.

[0103] The present disclosure will be described in more detail below with reference to examples, but the present disclosure is not limited to these examples. Although the present disclosure has been fully explained with reference to examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not deviate from the scope of the present disclosure, they are included in the present disclosure.

[0104] Unless otherwise specified, the various reagents used in the examples were commercially available products. NMR spectra were measured using an AL400 (400 MHz; JEOL) with tetramethylsilane as the internal standard when the deuterated solvent contained tetramethylsilane, or with the non-deuterated proton peak remaining in the NMR solvent as the internal standard otherwise. All δ values ​​are shown in ppm.

[0105] The meanings of the abbreviations are as follows: s: singlet t: triplet m: multiplet CDCl3: deuterated chloroform

[0106] Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to one of the following test conditions after lightly crushing an appropriate amount of the test substance in an agate mortar as required.

[0107] Apparatus: PANalytical EMPYREAN reflection method (focusing method) Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scan range: 2θ = 5.0 to 40.0° Step: 2θ = 0.0131° Averaging time / step: 8.670 s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Receiving slit: 8.0 mm

[0108] The handling of the devices, including data processing, was in accordance with the methods and procedures specified for each device.

[0109] The values ​​obtained from various spectra may vary slightly depending on the direction of crystal growth, particle size, measurement conditions, etc. Therefore, these values ​​should not be interpreted strictly.

[0110] Differential Scanning Calorimetry (DSC Measurement) DSC measurement was carried out under the following test conditions.

[0111] Apparatus: DSC1 STAR System manufactured by METTER TOLEDO Sample: Approximately 1 mg Sample container: Aluminum Heating range: 25 to 290°C Heating rate: 10°C / min. Atmospheric gas: Nitrogen Nitrogen gas flow rate: 50 mL / min. Handling of the apparatus, including data processing, followed the methods and procedures specified for each apparatus.

[0112] 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one, which will be described later, is sometimes referred to as Compound A.

[0113] Synthesis Example 1 Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (compound (I))

[0114] To a solution of 48.1 g of sodium tert-butoxide in 550 mL of tetrahydrofuran, a solution of 72.9 g of 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one in 150 mL of tetrahydrofuran was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes. A solution of 56.8 g of methyl iodide in 50 mL of tetrahydrofuran was added to the reaction solution, and the mixture was stirred under ice-cooling for 0.5 hours and at room temperature for 1.5 hours. Under ice-cooling, a saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by distillation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 61.5 g of the title compound.

[0115] Example 1: Preparation of Form I Crystals of Compound (I) 4 mL of methanol and 3 mL of water were added to 1.00 g of Compound (I), and the mixture was heated and stirred, and then allowed to cool to room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain 892 mg of the title crystals. 1 The H-NMR spectrum was as follows: NMR (CDCl) δ ppm 1.15 (s, 6H), 1.20-1.48 (m, 24H), 1.50-1.63 (m, 2H), 1.75 (s, 3H), 1.75-1.85 (m, 2H), 2.13-2.24 (m, 2H), 2.45 (t, J = 6.8 Hz, 2H), 3.33 (s, 3H), 3.36 (t, J = 6.8 Hz, 2H).

[0116] The powder X-ray diffraction spectrum (CuKα) is shown in FIG.

[0117] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8° (CuKα)

[0118] The results of differential scanning calorimetry (DSC) of the I-type crystal are as follows: Differential scanning calorimetry curve: shown in Figure 2. Endothermic peak (peak top value) in the differential scanning calorimetry curve: around 35°C

[0119] Example 2: Preparation of Form II Crystals of Compound (I) 4 mL of acetonitrile was added to 1,000 mg of Compound (I) to dissolve it, and the mixture was ice-cooled. The precipitate was collected by filtration, and the solid was recovered and dried under reduced pressure at room temperature for about 45 minutes to obtain 747.0 mg of the title crystals.

[0120] The powder X-ray diffraction spectrum (CuKα) is shown in FIG.

[0121] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 6.1°, 11.4°, 12.5°, 15.1°, 19.4°, and 24.0° (CuKα)

[0122] The results of differential scanning calorimetry (DSC) of the type II crystal are as follows: Differential scanning calorimetry curve: shown in Figure 4. Endothermic peak (peak top value) in the differential scanning calorimetry curve: around 34°C

[0123] To 650 mg of the type II crystals of compound (I) obtained in Example 2, 3.25 mL of a methanol / water mixture (9:1 v / v) was added, and the suspension was stirred at 4° C. for about 100 minutes, followed by filtration to collect the solid, which was then dried under reduced pressure at room temperature for about 25 minutes. To 500 mg of this solid, 2.5 mL of a methanol / water mixture (9:1 v / v) was added, and the suspension was stirred at 4° C. for about 19 hours, followed by filtration to collect the solid, which was then dried under reduced pressure at room temperature for about 25 minutes to obtain 335.6 mg of the title crystals.

[0124] The powder X-ray diffraction spectrum (CuKα) is shown in FIG.

[0125] The characteristic diffraction angles are as follows: Characteristic diffraction angles (2θ±0.2°): 11.2°, 12.4°, 14.1°, 14.9°, 18.8°, and 19.4°

[0126] The results of differential scanning calorimetry (DSC) of the III crystal are as follows: Differential scanning calorimetry curve: shown in Figure 6. Endothermic peak (peak top value) in the differential scanning calorimetry curve: around 34°C

[0127] Test Example 1: Solid-state stability test The solid-state stability of the type I crystals, type II crystals, and type III crystals of Compound (I) obtained in Examples 1 to 3 was evaluated after storage for 4 weeks. Storage conditions: 25°C / 60% RH (closed system) Storage period: 4 weeks Storage amount: approximately 25 mg Storage container: glass bottle

[0128] The purity of compound (I) and the amount of related substances (the amount of substances detected other than compound (I)) were analyzed by weighing approximately 1 mg of sample and dissolving it in 2 mL of acetonitrile. 5 μL of this solution was accurately measured and analyzed by HPLC using the following method. The instrumentation, including data processing, was performed according to the method and procedure specified for each instrument. Column: YMC-Triart C8 (4.6 × 150 mm, 3 μm) manufactured by YMC Co., Ltd. UV detection: 248 nm Column temperature: 40°C Flow rate: 1 mL / min Sample cooler: 25°C Sample concentration: 0.5 mg / mL Mobile phase A: Water / acetonitrile (1:1 v / v) mixture Mobile phase B: Acetonitrile The gradient is shown in Table 1.

[0129]

[0130] The results are shown in Table 2 below.

[0131]

[0132] As shown in Table 2, there was almost no change in purity for the I-type crystals, II-type crystals, and III-type crystals of Compound (I). Furthermore, there was almost no increase in the amount of related substances for the I-type crystals, II-type crystals, and III-type crystals of Compound (I). It was found that the I-type crystals, II-type crystals, and III-type crystals of Compound (I) were all extremely stable crystals.

[0133] Test Example 2: Dynamic Moisture Adsorption / Desorption Test A moisture adsorption / desorption test was carried out on the type I crystals, type II crystals, and type III crystals of Compound (I) obtained in Examples 1 to 3 after storage for 4 weeks. The moisture adsorption / desorption test was carried out under the following conditions. Approximately 10 mg of sample was placed in a dedicated quartz holder, and the weight of the sample at each humidity was continuously measured and recorded under the following conditions. The handling of the equipment, including data processing, was carried out in accordance with the method and procedure specified for each equipment. Apparatus: VTI SA+ (TA Instruments) Drying temperature: 25°C Heating rate: 1°C / min Drying equilibrium: Confirm that there is no decrease of 0.01 wt% in 5 minutes, within a range not exceeding 120 minutes Measurement temperature: 25°C Humidification equilibrium: Confirm that there is no increase of 0.01 wt% in 5 minutes, within a range not exceeding 120 minutes Relative humidity program: Increase in 5% RH increments from 5 to 95% RH, and decrease in 5% RH increments from 95% RH to 5% RH The weight changes within the measurement condition ranges obtained in these tests are shown in Figures 7 to 9.

[0134] As shown in Figures 7 to 9, it was revealed that the I-type crystals, II-type crystals and III-type crystals of Compound (I) were all almost non-hygroscopic at a relative humidity of 95% in a moisture adsorption / desorption test.

[0135] Therefore, the type I crystals, type II crystals and type III crystals of compound (I) have low hygroscopicity and are excellent candidate compounds for pharmaceutical development from the viewpoint of industrial production of pharmaceuticals with stable quality.

[0136] Furthermore, the type I crystals, type II crystals, and type III crystals of compound (I) are highly stable as described above, and on the other hand, by adding these crystals to water together with an amphiphilic compound such as hydroxypropylmethylcellulose, dimethyl sulfoxide (DMSO), etc., a drug suspension or drug solution of compound (I) can be prepared.

[0137] Test Example 3 Pharmacokinetics The required amount of compound (I) was weighed and a drug suspension was prepared in 0.5% hydroxypropylmethylcellulose. Each group consisted of two rats, and each drug suspension was orally administered to male rats (Crl:CD (SD)) using an oral gavage (the dose of this compound was 10 mg / kg). Blood was collected from the jugular vein using a syringe and needle at each blood collection point (0.5, 1, 2, 4, 8, and 24 hours after administration) (the anticoagulant was heparin sodium). The collected blood was centrifuged (13,000 rpm, 2 minutes, 4°C) to prepare plasma, which was then deproteinized and the compound concentration in the plasma was measured by LC / MS / MS (LCMS-8040 (Shimadzu) or API4000 (AB SCIEX), LC: 30-A, 20-A series (Shimadzu) or Waters Acquity (Waters)). Preparation of drug suspension, administration, and measurement of compound concentration were carried out in the same manner as above, except that Compound A was used instead of Compound (I). The results are shown in Table 3.

[0138] As shown in Table 3, it was confirmed that compound (I) had a 1900-fold or greater improvement in area under the blood drug concentration-time curve AUC and an 1100-fold improvement in maximum blood concentration Cmax compared to compound A. Therefore, compound (I) was shown to have unexpectedly superior pharmacokinetics to compound A, a known compound.

[0139]

[0140] Test Example 4: Evaluation of efficacy in diabetic (DM) model rats To examine the effect of the compound in a diabetic model, bladder function was analyzed by cystometry with reference to the method of Saitoh et al. (European Journal of Pharmacology 501 (2004) 143-149).

[0141] Streptozotocin (STZ) was dissolved in citrate buffer (0.1 M citric acid, pH 4.2) at a concentration of 32.5 mg / mL to prepare an STZ solution, which was then intraperitoneally administered (65 mg / kg) to SD rats to induce DM. Sham-operated rats were treated in the same manner, except that citrate buffer was used instead of STZ solution.

[0142] The day after model creation and 4 weeks later, blood was collected from the tail vein under conscious conditions, and blood glucose levels were measured. An Antsense III (Horiba, Ltd.) was used for blood glucose measurement. Individuals with blood glucose levels of 300 mg / dL or higher the day after model creation and 4 weeks later were considered to have established DM models and were used for subsequent procedures.

[0143] Administration of the test substances (Compound A, Compound (I)) was initiated the day after model creation. Vehicle or compound administration solution was orally administered twice a day, morning and evening, at a volume of 10 mL / kg for 4 weeks. On the day after the final administration of the test substance, the rats were subjected to abdominal section under isoflurane anesthesia, and a catheter for measuring intravesical pressure (PE-90, Becton Dickinson and Company) was inserted from the top of the bladder. After abdominal closure, the rats were placed in a restraining cage, and after 30 minutes or more had elapsed since the isoflurane anesthesia was released, a urethane solution (0.8 g / kg) was administered subcutaneously.

[0144] A pressure transducer (DX-360, Nihon Kohden Corporation) and an infusion pump (TE-331S, Terumo Corporation) were connected to the other end of the catheter inserted into the bladder via a three-way stopcock. The intravesical pressure during continuous intravesical infusion of saline (infusion rate: 12 mL / hr) was measured using the pressure transducer and a polygraph (AP-641G, Nihon Kohden Corporation) and continuously recorded on a computer via PowerLab (ML866, AD Instruments) (sampling rate: 20 / sec). Furthermore, urination volume was automatically measured using an electronic balance [GX-200, A&D Corporation] placed directly below the restraint cage and continuously recorded on a computer via PowerLab (sampling rate: 20 / sec). The recording and analysis of urinary function parameters were performed using PowerLab dedicated analysis software Chart 5 (ver. 5.5.6, AD Instruments).

[0145] Immediately after urethane anesthesia, saline was continuously infused into the bladder (infusion rate: 3 mL / hr) for approximately 1.5 hours to allow the animals to become accustomed to the cystometry environment. After acclimatization to the cystometry environment, urinary function (intravesical pressure, voided urine volume, and residual urine volume) was measured by cystometry (infusion rate: 12 mL / hr).

[0146] As shown in FIG. 10, it was revealed that compound (I) exhibited a more remarkable efficacy than compound A.

[0147] Test Example 5 Measurement of Nerve Growth Promoting Activity To evaluate the nerve growth promoting activity, a neurite bearing assay (proportion of neurite-bearing cells) and a neurite length assay (neurite length) were analyzed with reference to the method of Topalli et al. (Brain Research 1030 (2004) 116-124).

[0148] ND3 neuronal cell line (European Collection of Authenticated Cell Cultures) was seeded in a 24-well plate (0.6 × 10 cells) in DMEM medium containing 10% fetal bovine serum. 4cells / 1 mL). After 24 hours, the medium of the seeded cells was removed, and a solution of compound (I) serially diluted with dimethyl sulfoxide (DMSO) and adjusted to a final DMSO concentration of 0.1% in DMEM containing 0.1% bovine serum albumin was added to the cells (evaluation was performed in duplicate). Six hours after addition, the proportion of neurite-bearing cells (number of cells with processes longer than the diameter of the cell body / total number of cells) and neurite length per cell were analyzed. In addition, the same test as above was performed except that compound A was used instead of compound (I). The total cell number, proportion of neurite-bearing cells, and neurite length per cell were analyzed using the MetaMorph Neurite Outgrowth Application Module (Molecular Devices Japan Co., Ltd.). The cell counts are shown relative to the number of cells in the wells to which DMSO was added, which was set to 1 (Tables 4 and 5). Table 5 shows the relative activity of Compound A when the maximum activity of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound (I)) in each test was set to 1. The test was performed multiple times, and the average values ​​are shown. Data for cell counts of 0.5 or more were used. Therefore, when the cell count was less than 0.5, the process length per cell and the proportion of process-bearing cells were indicated as "-".

[0149] As shown in Table 4, when compound (I) was added at 1 to 100 μM, the relative cell number was 0.5 or more.

[0150]

[0151] As shown in Table 5, it was confirmed that Compound (I) has a superior nerve growth promoting effect compared to Compound A.

[0152]

Claims

1. A crystalline form of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one having at least three peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8° in a powder X-ray diffraction spectrum (CuKα).

2. The crystalline form described in claim 1, which has peaks at diffraction angles (2θ±0.2°) of 7.0°, 14.0°, 17.5°, 19.5°, 21.0°, 23.7°, and 24.8° in its powder X-ray diffraction spectrum (CuKα).

3. The crystalline form of claim 1 or 2, having a powder X-ray diffraction spectrum substantially the same as that shown in Figure 1.

4. The crystalline form according to any one of claims 1 to 3, which has an endothermic peak at a peak temperature of around 35°C in differential scanning calorimetry (DSC).

5. A pharmaceutical composition containing the crystalline form according to any one of claims 1 to 4.