Crystals of vitamin D derivatives or their solvates

Abstract

Provided are crystals of a vitamin D derivative represented by formula (1) or crystals of a solvate of a vitamin D derivative represented by formula (1). Such crystals are useful as a pharmaceutical for promoting induction of differentiation of oligodendrocyte progenitor cells into oligodendrocytes.

Description

[Technical Field]

[0001] The present invention relates to a crystal of a vitamin D derivative or a crystal of a solvate thereof which has an effect of promoting the induction of oligodendrocyte differentiation and is useful for the prevention or treatment of, for example, multiple sclerosis, multiple system atrophy, Alzheimer's disease, cerebral infarction, and the like. [Background technology]

[0002] Oligodendrocytes form myelin sheaths around the axons of neurons, and their main role is to increase the conduction velocity by inducing saltatory conduction. They are also involved in the metabolism of neurons.

[0003] Demyelination and hypomyelination have been reported in several inflammatory demyelinating, neurodegenerative, and psychiatric disorders. Demyelination is the destruction and loss of myelin, which leads to various neurological symptoms. Multiple sclerosis is a well-known neuroimmune disease that causes demyelination. Other central nervous system inflammatory demyelinating diseases that cause demyelination include neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, and Krabbe disease. Peripheral nervous system demyelinating diseases include Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, and Charcot-Marie-Tooth disease. Furthermore, ischemic stroke often involves demyelination, which subsequently leads to functional decline. It has also been reported that in Alzheimer's disease, a neurodegenerative disease, demyelination inhibits plastic changes in the myelin sheath, leading to a decline in cognitive function.

[0004] Furthermore, hypomyelination has been confirmed in the brains of patients with various psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD), attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), and depression due to drug addiction, and a link between the disorders has been suggested.

[0005] Therefore, it is important to restore normal conditions of demyelination and hypomyelination in the treatment of the central or peripheral nervous system.

[0006] Recently, it has been reported that 1α,25-dihydroxyvitamin D3 promotes the differentiation of oligodendrocyte precursor cells and neural stem cells into oligodendrocytes (Non-Patent Documents 1 and 2). Two pathways are known for the actions of 1α,25-dihydroxyvitamin D3 and its derivatives (Non-Patent Document 3). One pathway is genomic action, in which 1α,25-dihydroxyvitamin D3 binds to the vitamin D receptor (VDR), a nuclear receptor, to regulate gene expression. The other pathway is non-genomic action, in which 1α,25-dihydroxyvitamin D3 binds to protein disulfide isomerase A3 (PDIA3) to induce signal transduction. At present, it is not fully clear whether the oligodendrocyte differentiation-inducing effect of 1α,25-dihydroxyvitamin D3 reported in Non-Patent Documents 1 and 2 is due to a genomic or non-genomic pathway. Meanwhile, the primary action of 1α,25-dihydroxyvitamin D3 and its derivatives is calcium-phosphorus metabolism. In general, derivatives with strong genomic effects, as expressed by transcriptional activity, have strong calcium metabolism effects, which may increase blood calcium levels and cause hypercalcemia. For this reason, there is a limit to the dosage, and in some cases, the desired pharmacological effect may not be achieved.

[0007] Furthermore, it has been reported that the central transfer of 1α,25-dihydroxyvitamin D3 is extremely low (Non-Patent Documents 4 and 5). These documents indicate that extremely high doses of 1α,25-dihydroxyvitamin D3 are required to achieve sufficient concentrations in the brain. However, high-dose administration of 1α,25-dihydroxyvitamin D3 is difficult because it causes an increase in blood calcium levels.

[0008] Therefore, there is a strong demand for vitamin D derivatives with excellent central transport properties that can exert their effects in the brain, and even for vitamin D derivatives that uncouple their myelin regeneration promoting effect from their blood calcium increasing effect. However, no such derivatives have been reported to date. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] AGde la Fuente et al.,Journal of Cell Biology,2015,211(5),975-985 [Non-patent document 2] HAShirazi et al., Experimental and Molecular Pathology,2015,98(2),240-245 [Non-patent document 3] MAZmijewski et al., Experimental Dermatology,2020,29,876-884 [Non-patent document 4] MRDurk et al.,The Journal of Neuroscience,2014,34(21),7091-7101 [Non-patent document 5] ECYChow et al.,The American Journal of Physiology:Endocrinology and Metabolism,2013,304(9),E977-989 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a novel crystal of a vitamin D derivative or a crystal of a solvate thereof that has an excellent effect of promoting the induction of oligodendrocyte differentiation. [Means for solving the problem]

[0011] As a result of intensive research aimed at the above object, the present inventors have found that vitamin D derivatives with specific structures have a particularly excellent effect of promoting the induction of oligodendrocyte differentiation. Furthermore, the present inventors have found that some of these compounds have crystals that are chemically stable and have a structure suitable for use as pharmaceutical active ingredients.

[0012] That is, the present invention relates to a crystal of a vitamin D derivative represented by formula (1) or a crystal of a solvate thereof. Formula (1): [ka] [In the formula, R represents any one of the structures Ra, Rb, Rc, Rd, Re, and Rf in the following formula.] [ka] [Effects of the Invention]

[0013] The present invention provides a crystal of a vitamin D derivative or a crystal of a solvate thereof, which has an excellent effect of promoting the induction of oligodendrocyte differentiation and is useful for the prevention or treatment of, for example, multiple sclerosis, multiple system atrophy, Alzheimer's disease, cerebral infarction, etc. The crystals of the present invention can be used as bulk materials for the production of pharmaceuticals. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A). [Figure 2]FIG. 2 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B). [Figure 3] FIG. 3 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C). [Figure 4] FIG. 4 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D). [Figure 5] FIG. 5 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound E). [Figure 6] FIG. 6 is a powder X-ray diffraction spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound F). [Figure 7]FIG. 7 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound A). [Figure 8] FIG. 8 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B). [Figure 9] FIG. 9 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound C). [Figure 10] FIG. 10 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D). [Figure 11] FIG. 11 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound E). [Figure 12]FIG. 12 is a solid-state NMR (C) spectrum of a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound F). DETAILED DESCRIPTION OF THE INVENTION

[0015] The production of the crystals of the vitamin D derivative of the present invention represented by the above formula (1) will be described below.

[0016] The vitamin D derivative represented by formula (1) above can be synthesized by any method. For example, a vitamin D derivative in which R = Ra, Rb, Rc, Rd, or Rf in formula (1) above can be synthesized by the procedure shown in Scheme 1. Specifically, in step 1 (step 1 in the figure), compound (2) and cyclic amine compound (3) (Amine (3) in the figure) are coupled in the presence of a base to obtain compound (4). Then, in step 2 (step 2 in the figure), the protecting group of the hydroxy group is deprotected and purified to obtain crude compound (1) [R = Ra, Rb, Rc, Rd, or Rf] (crude (1) in the figure). In step 3 (step 3 in the figure), crude compound (1) (crude (1) in the figure) is recrystallized to obtain the desired compound (1).

[0017] [ka]

[0018] The cyclic amine compound (3) used in the coupling reaction with compound (2) (Step 1, Step 1 in the figure) may be in the free form or a salt. The amount of cyclic amine compound (3) used in this reaction is 1 to 5 molar equivalents of compound (2), preferably 3 to 5 molar equivalents. The base used in this step is not particularly limited, but preferred bases include potassium carbonate, potassium bicarbonate, and cesium carbonate. The base is added in an amount of 1 to 5 molar equivalents of compound (2), preferably 3 to 5 molar equivalents. To accelerate this reaction, potassium iodide or sodium iodide may be added to the reaction mixture. The amount of potassium iodide or sodium iodide added is preferably 1 to 2 molar equivalents of compound (2). The solvent is also not particularly limited, but preferred solvents include N,N-dimethylformamide and N-methyl-2-pyrrolidone. The reaction temperature for this coupling reaction is preferably 40°C to 90°C, and the reaction time is preferably 6 to 48 hours.

[0019] After completing step 1, the product may be purified before proceeding to the deprotection reaction (step 2, Step 2 in the figure), or the crude product from step 1 may be used for the deprotection reaction (step 2). When purifying after step 1, it is preferable to purify by silica gel column chromatography. As the solvent for silica gel column chromatography purification, a mixed solvent of heptane / ethyl acetate or hexane / ethyl acetate is preferably used.

[0020] The conditions for the deprotection reaction (Step 2) in Scheme 1 above are not particularly limited as long as they are conditions for deprotecting a silyl-based protecting group, but examples include deprotection using tetrabutylammonium fluoride (TBAF) and deprotection using hydrochloric acid. Preferred conditions include adding 1 to 3 molar equivalents of tetrabutylammonium fluoride (TBAF) per hydroxy group of compound (2) (or compound (3) if purified after Step 1) in tetrahydrofuran (THF) and stirring at room temperature to reflux temperature. Another preferred condition is adding 1 to 3 molar equivalents of hydrochloric acid per hydroxy group of compound (2) (or compound (3) if purified after Step 1) in a solvent such as acetone or 2-butanone and stirring at room temperature. The concentration of hydrochloric acid is preferably 1 M to 6 M.

[0021] Furthermore, a vitamin D derivative in which R=Re in the above formula (1) can be synthesized according to the following scheme 2. [ka]

[0022] That is, known compound (5) is reduced with diisobutylaluminum hydride (DIBAL reduction) to obtain aldehyde (6) (step 4, step 4 in the figure), and then morpholine is introduced by reductive amination to obtain compound (7) (step 5, step 5 in the figure). Crude compound (1) [R = Re] (crude (1) [R = Re] in the figure) can be obtained by deprotection (step 6, step 6 in the figure).

[0023] The DIBAL reduction in step 4 proceeds in about 0.5 to 2 hours by adding 1 to 2 molar equivalents of diisobutylaluminum hydride (DIBAL-H) ​​to compound (5) in toluene at −78° C. to 0° C.

[0024] The reductive amination reagent in step 5 is preferably sodium triacetoxyborohydride or sodium cyanoborohydride. The solvent is not particularly limited, but tetrahydrofuran (THF) is a preferred solvent. Alternatively, the reaction may be carried out using morpholine as the solvent. The reductive amination reaction proceeds, for example, by reacting compound (6) with 1 to 5 molar equivalents of morpholine and 1 to 3 molar equivalents of a reducing agent in THF. A deprotection reaction (step 6) is then carried out to obtain crude compound (1) [R = Re] (crude (1) [R = Re] in the figure). The deprotection reaction in step 6 proceeds under the same conditions as in Scheme 1.

[0025] Compounds (4), (6), and (7), which are intermediates on the way to obtaining crude compound (1) [R = Re] (crude (1) [R = Re] in the figure), can be purified by silica gel column chromatography or can be carried on to the next step without purification. When purifying the intermediates, heptane and ethyl acetate are preferably used as the mobile solvent for silica gel column chromatography. Specifically, the intermediates can be purified by increasing the ethyl acetate ratio in a gradient from heptane / ethyl acetate = 98 / 2 to heptane / ethyl acetate = 70 / 30.

[0026] The crystals of the present invention can be obtained by recrystallizing crude compound (1) of formula (1) obtained by the above-mentioned production method (Step 3 in Scheme 1 above, or Step 7 in Scheme 2 above). Examples of recrystallization solvents include acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, acetone, and water. Preferred solvents include acetonitrile, methanol, ethanol, and water. The amount of solvent used for recrystallization can be 10 to 100 times (v / w) the crude weight. The production method involves adding the recrystallization solvent to the crude compound, heating to 40 to 70°C, preferably 45 to 65°C, to dissolve the compound, and then cooling to room temperature or 0°C to produce crystals.

[0027] Alternatively, the crystals of the present invention can be obtained by neutralizing and crystallizing the crude compound (1) of formula (1) obtained by the above-mentioned production method. Specifically, hydrochloric acid is added to the crude compound (1) of formula (1) to prepare a hydrochloride solution. While stirring the hydrochloride solution of the crude compound (1) of formula (1) under ice cooling, a base is added to adjust the pH to about 7.5 to 11, preferably about 8 to 10, to obtain crystals of the vitamin D derivative represented by formula (1). When preparing the hydrochloride solution, 1 to 6 M hydrochloric acid is used, with 1 to 2 M hydrochloric acid being preferred. The neutralization can be carried out using an aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, with a preferred base being a 1 to 5 M aqueous sodium hydroxide solution. Neutralization can be carried out by dropwise addition of a base at a temperature between 0°C and room temperature, preferably 0 to 20°C or 0 to 10°C. After neutralization, the mixture is stirred at a temperature of 0°C to room temperature, preferably 10 to 35°C or 20 to 30°C for 30 minutes to 3 hours, and then filtered and dried to obtain the desired crystals of the vitamin D derivative represented by the above formula (1).

[0028] If the crystals obtained by the above-mentioned recrystallization or neutralization crystallization are not of a purity suitable for use as a pharmaceutical, the LC purity can be increased by heating and stirring the low-purity crystals in a slurry state. The solvent used for stirring in the slurry state is not particularly limited, but examples include acetonitrile, methanol, ethanol, and water. The stirring temperature is preferably room temperature to 60°C. Generally, purity can be improved by heating and stirring in an amount and temperature at which the low-purity crystals do not completely dissolve, cooling to room temperature or 0°C, and then filtering the crystals. A part of the crystals obtained by the above-mentioned recrystallization or neutralization crystallization may exist as a solvate of compound (1) with a solvent such as the recrystallization solvent.

[0029] The crystals of the present invention are characterized by powder X-ray diffraction (XRD) spectra, differential scanning calorimetry (DSC) and / or solid-state NMR spectra. The powder X-ray diffraction (XRD) spectra of these crystals show characteristic patterns, and each crystal has a specific diffraction angle 2θ value. These crystals also show characteristic thermal behavior in differential scanning calorimetry (DSC). The solid-state NMR spectra of these crystals show characteristic patterns, and each crystal has a specific chemical shift (ppm).

[0030] The present invention relates to crystals of the compounds represented by the formula (1), and preferred embodiments thereof will be described below with reference to crystals of each compound.

[0031] <Compound name> (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (A)) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (B)) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (C)) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (D)) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (E)) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (F))

[0032] The crystals of Compound (A) have characteristic peaks at 2θ=14.2°, 16.3°, 17.9°, and 18.5° in the powder X-ray diffraction spectrum, more specifically, characteristic peaks at 2θ=8.9°, 14.2°, 16.3°, 17.9°, and 18.5°. The crystals of Compound (A) have an endothermic peak with an extrapolated onset temperature of 171°C in differential scanning calorimetry (DSC). The crystals of Compound (A) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 13.6 ppm, 19.2 ppm, 117.2 ppm, 121.8 ppm, 133.6 ppm, and 138.5 ppm.

[0033] The crystals of compound (B) have characteristic peaks at 2θ=14.2°, 16.2°, 17.9°, 18.5°, and 24.3° in the powder X-ray diffraction spectrum, and more specifically, characteristic peaks at 8.9°, 14.2°, 16.2°, 17.9°, 18.5°, 24.3°, and 30.4°. The crystals of compound (B) have an endothermic peak with an extrapolated onset temperature of 187°C in differential scanning calorimetry (DSC). The crystals of compound (B) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 13.1 ppm, 19.7 ppm, 117.1 ppm, 123.2 ppm, 132.6 ppm, and 139.2 ppm.

[0034] The crystals of compound (C) have characteristic peaks at 2θ=14.1°, 15.2°, 15.8°, 16.6°, and 18.8° in the powder X-ray diffraction spectrum, and more specifically, characteristic peaks at 2θ=14.1°, 15.2°, 15.8°, 16.6°, 17.2°, 18.8°, 21.3°, and 22.6°. The crystals of compound (C) have an endothermic peak with an extrapolated onset temperature of 159°C in differential scanning calorimetry (DSC). The crystals of compound (C) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 16.6 ppm, 18.0 ppm, 118.1 ppm, 120.4 ppm, 137.2 ppm, and 138.8 ppm.

[0035] The crystals of compound (D) have characteristic peaks at 2θ=14.6°, 16.2°, 16.5°, and 18.3° in the powder X-ray diffraction spectrum, and more specifically, characteristic peaks at 2θ=12.4°, 14.6°, 16.2°, 16.5°, and 18.3°. The crystals of compound (D) have an endothermic peak with an extrapolated onset temperature of 171°C in differential scanning calorimetry (DSC). The crystals of compound (D) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 13.0 ppm, 18.6 ppm, 116.6 ppm, 123.6 ppm, 132.5 ppm, and 141.1 ppm.

[0036] The crystals of compound (E) have characteristic peaks at 2θ=13.5°, 16.4°, 18.1°, and 20.3° in the powder X-ray diffraction spectrum, more specifically, characteristic peaks at 13.5°, 16.4°, 16.7°, 18.1°, and 20.3°. The crystals of compound (E) have an endothermic peak with an extrapolated onset temperature of 194°C in differential scanning calorimetry (DSC). The crystals of compound (E) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 14.3 ppm, 19.4 ppm, 117.4 ppm, 122.2 ppm, 133.2 ppm, and 139.6 ppm.

[0037] The crystals of compound (F) have characteristic peaks at 2θ=16.1°, 16.4°, and 17.3° in the powder X-ray diffraction spectrum, more specifically, characteristic peaks at 2θ=13.7°, 15.3°, 16.1°, 16.4°, 17.3°, 19.1°, and 19.6°. The crystals of compound (F) have an endothermic peak with an extrapolated onset temperature of 218°C in differential scanning calorimetry (DSC). The crystals of compound (F) also have 13 In the C solid-state NMR spectrum, it has characteristic chemical shifts at 13.4 ppm, 14.2 ppm, 18.3 ppm, 117.4 ppm, 123.0 ppm, 132.6 ppm, and 140.0 ppm.

[0038] Here, the term "characteristic peak" refers to a specific peak that characterizes the overall pattern of each of the X-ray powder diffraction spectrum and solid-state NMR spectrum of each crystalline form. The crystals specified by the diffraction angle or chemical shift of the present invention also include those that exhibit peaks other than the above-mentioned characteristic peaks.

[0039] Because the position and relative intensity of the diffraction angle 2θ in a powder X-ray diffraction spectrum can vary somewhat depending on the measurement conditions, even if 2θ differs slightly, the identity of the crystalline form should be determined by appropriately referring to the overall spectral pattern, and crystals within this error range are also included in the present invention. The error in 2θ can be, for example, ±0.2°. That is, crystals identified by the above diffraction angles also include those that match within a range of ±0.2°. When determining the identity of crystalline forms using powder X-ray diffraction, even if the number of peaks is small, it may be possible to determine that the crystals are the same if multiple peaks that match within an error of ±0.2° are observed. When analyzing a substance containing a mixture, such as a tablet, the peaks of multiple components, such as excipients, are mixed in, as compared to when the analytical sample is a drug substance powder. As a result, peaks from multiple components, such as excipients, may overlap, resulting in peaks that cannot be distinguished. Therefore, it is even more appropriate to determine that the crystals are the same if multiple peaks that match within an error of ±0.2° are observed.

[0040] The present invention also encompasses crystals within the error range resulting from the measurement conditions (e.g., the apparatus) of the powder X-ray diffraction spectrum. In differential scanning calorimetry (DSC), the extrapolated peak onset temperature is the temperature at the onset of an exothermic or endothermic peak, and refers to the exothermic or endothermic onset temperature determined by extrapolation. The exothermic and endothermic peaks in differential scanning calorimetry (DSC) may also vary somewhat depending on the measurement conditions. Possible error ranges include, for example, ±5°C or ±2°C. In other words, crystals identified by the above peaks also include those that match within a range of ±2°C to ±5°C.

[0041] in general, 13 Chemical shifts in C solid-state NMR spectra also have errors. Such errors are, for example, within ±0.25 ppm, typically within ±0.5 ppm. That is, crystal forms identified by the above chemical shifts include those that match within a range of ±0.25 ppm to ±0.5 ppm. Furthermore, differences in the rotational frequency and measuring equipment used during measurement can cause peak intensities to change, or peaks to appear or disappear. When determining the identity of crystalline forms using solid-state NMR spectra, even if the number of peaks is small, it can sometimes be determined that the crystals are identical if multiple peaks that match within an error of ±0.25 ppm (or, in some cases, within ±0.5 ppm) are identified. When analyzing a sample containing a mixture such as a tablet, the peaks of multiple components such as excipients contained in the tablet will be mixed in, unlike when the raw drug powder is used as the analytical sample. As a result, peaks from multiple components may overlap, resulting in peaks that cannot be distinguished. Therefore, if multiple peaks that match within an error of ±0.25 ppm (or ±0.5 ppm in some cases) are confirmed, it is appropriate to judge them as the same crystal.

[0042] Furthermore, powder X-ray diffraction spectra, differential scanning calorimetry (DSC) and 13For any analytical result value of the C solid-state NMR spectrum, the difference between the actual measured value of a crystalline standard, for example, each crystal obtained by the method described in the Examples of the present application, and the numerical value of each analytical result described in the present application is also allowed as a measurement error. In other words, crystals whose diffraction angles, endothermic and exothermic peaks coincide within the error range calculated by such a method are also included in the crystals of the present invention.

[0043] When analyzing a mixture such as a tablet, the peak intensity tends to be smaller than when the drug substance powder is used as the analytical sample. Therefore, when analyzing the identity of the crystalline form in a mixture using solid-state NMR or XRD, it is acceptable to extend the measurement time and it is also useful to increase the number of integrations.

[0044] In the present invention, the crystal of the vitamin D derivative represented by formula (1) or the crystal of its solvate is advantageous over non-crystalline forms in terms of handling during production or storage, stability, etc.

[0045] The crystal of the vitamin D derivative represented by formula (1) of the present invention, or a crystal of a solvate thereof, can be clinically applied as a remyelination promoter and can be used as a therapeutic agent for diseases associated with demyelination or dysmyelination, such as multiple sclerosis, neuromyelitis optica, progressive multifocal leukoencephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1-associated myelopathy, HIV-associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's disease, and ischemic stroke.

[0046] Therapeutic agents containing the crystals of the vitamin D derivatives or their solvates as active ingredients of the present invention are prepared into pharmaceutical compositions using carriers, bases, excipients, and other additives commonly used in pharmaceutical formulations. The carriers, bases, and excipients used in pharmaceutical compositions may be solid or liquid, and examples include lactose, magnesium stearate starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, medium-chain fatty acid triglycerides, and other commonly used carriers, bases, and excipients. Administration may be oral, such as in the form of tablets, pills, capsules, soft capsules, granules, powders, or liquids, or parenterally, such as by intravenous or intramuscular injection, suppository, transdermal, or nasal route.

[0047] The effective therapeutic or prophylactic dose of the active ingredient in the therapeutic agent of the present invention varies depending on the route of administration, the patient's age, sex, and severity of the disease, but is usually about 0.1 to 10,000 μg / day, and the frequency of administration is usually 1 to 3 times / day or 1 to 3 times / week, and it is preferable to prepare a formulation that satisfies these conditions. However, since the dosage varies depending on various conditions, a smaller dosage than the above-mentioned range may be sufficient, or a dosage exceeding the above-mentioned range may be required. [Example]

[0048] The present disclosure will be specifically described below with reference to examples. However, the present invention is not limited to the following examples. For example, the synthesis methods, purification methods, and crystallization methods of the compounds exemplified in the following examples are merely exemplary methods for obtaining the crystals of the present invention, and the crystals of the present invention are not limited to crystals obtained only by the synthesis methods, purification methods, and crystallization methods disclosed below.

[0049] The structures of the compounds relating to the crystals of the examples and the novel compounds isolated during synthesis are as follows: 1 The results were confirmed by 1 H-NMR spectroscopy or mass spectrometry using LC / MS (liquid chromatograph / mass spectrometer).

[0050] 1 For H-NMR spectra, a JEOL JNM-ECZ400S (400 MHz) was used. When the solvent was CDCl3, the peak of tetramethylsilane (0.0 ppm) or the peak of chloroform (7.26 ppm) was used as the standard peak, and when the solvent was CD3OD, the peak of methanol (3.30 ppm) was used as the standard peak. 1 For H-NMR spectra (400 MHz, CD3OD, or CDCl3), the chemical shifts (δ: ppm) and coupling constants (J: Hz) are shown. The following abbreviations stand for: s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, and m = multiplet.

[0051] For the LC / MS results, [M+H] of each compound + The value of the molecular mass (Obs. MS): that is, the molecular mass [M] of the compound plus the proton [H] + (measured values ​​with ' ' added)

[0052] The powder X-ray diffraction spectrum of the crystals according to the examples was measured under the following conditions. Apparatus: Rigaku MiniFlex600-C, radiation source: Cu·Kα, wavelength: 1.541862(10 -10 m), Tube voltage-tube current: 40 kV-15 mA, Detector: High-speed one-dimensional detector D / tex Ultra2, Scan range: 3 to 40°, Step condition: 0.01°, Measurement speed: 10° per minute, DS: 1 / 4°, IHS: 10 mm, Incident / receiving solar slit: 2.5°, Kβ filter (Ni)

[0053] The differential scanning calorimetry in the examples was measured under the following conditions. Apparatus: TA Instruments Q-200, Heating rate: 5°C per minute, Atmosphere: Helium, Sample pan: Aluminum, Measurement temperature range: 40-250°C Solid-state NMR spectrum of the crystal according to the example ( 13 C) was measured under the following conditions. Apparatus: Bruker Biospin AvanceIII 500 (MAS rotor: 3.2 mm Φ) Measurement nuclei: 13 C Observation frequency: 125.8MHz Measurement mode: VCAP / MAS MAS rotation speed: 12kHz Contact time: 2 ms Pulse repetition time: 5 seconds External standard: glycine (α-type crystal) (measurement was performed by setting the carbonyl peak of α-type crystal glycine at 176.03 ppm, and the peak of trimethylsilane (TMS) at 0 ppm)

[0054] [Example 1] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound (A))

[0055] [ka]

[0056] <Step 1 (Introduction of pyrrolidine ring)> A DMF solution [100 mL] of a mixture of the known compound (S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (CAS No. 1621978-74-2, compound (A-1), A-1 in the figure) [8.45 g, 11.8 mmol], the known compound (3S)-3-(difluoromethyl)pyrrolidine hydrochloride (CAS No. 1638744-40-7) [3.00 g, 19.0 mmol], and potassium carbonate [6.51 g, 47.1 mmol] was heated and stirred at 60 °C for 24 hours. The mixture was transferred to water [250 mL] and extracted with ethyl acetate [200 mL]. The organic phase was washed with saturated brine [100 mL], dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [heptane / ethyl acetate system] to obtain (S)-1-((S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-3-(difluoromethyl)pyrrolidine (compound (A-2), in the figure) [4.75 g, 7.13 mmol].

[0057] <Step 2 (Deprotection)> To a THF solution (60 mL) of compound (A-2) (4.75 g, 7.13 mmol), TBAF (1 M THF solution, 22 mL, 22 mmol) was added at room temperature, and the mixture was refluxed for 5 hours. The mixture was transferred to saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (A) (crude), compound A (crude) in the figure). Exact Mass = 437.31(C 26 H 41 F2NO2)Obs. mass = 438.35 (M+H)

[0058] <Step 3 (crystallization)> A mixed solvent of acetonitrile [90 mL] and methanol [10 mL] was added to the crude product (compound (A) (crude)) obtained in step 2, and the mixture was stirred in an oil bath at 50 °C. After confirming that the crude product had dissolved, heating was stopped and the mixture was cooled to room temperature in the oil bath, resulting in precipitation of crystals. The crystals were collected to give (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (A), compound A in the figure) [1.86 g, 4.25 mmol].

[0059] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 5.78 (1H, td, J = 57.0, 6.0 Hz), 4.06-3.95 (2H, m), 2.82 (2H, dd, J = 18.8, 10.0 Hz), 2.66-2.50 (4H, m), 2.44-1.92 (11H, m), 1.86-1.23 (13H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s). Exact Mass = 437.31(C 26 H 41 F2NO2)Obs. mass = 438.35 (M+H)

[0060] <Evaluation of the crystals of compound (A)> The XRD pattern of the obtained crystals of compound (A) is shown in Figure 1. Diffraction peaks were observed at 2θ angles of 8.9°, 14.2°, 16.3°, 16.6°, 17.9°, 18.5°, 20.1°, 22.6°, 22.9°, and 30.3°.

[0061] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of Compound (A) was 171°C.

[0062] The obtained crystals of compound (A) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 13.6 ppm, 19.2 ppm, 22.9 ppm, 29.4 ppm, 46.0 ppm, 57.2 ppm, 65.8 ppm, 67.5 ppm, 117.2 ppm, 121.8 ppm, 133.6 ppm, and 138.5 ppm.

[0063] [Example 2] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (B))

[0064] [ka]

[0065] <Step 1 (Introduction of pyrrolidine ring)> A DMF solution (49.5 mL) of a mixture of the known compound (S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (CAS No. 1621978-74-2, compound (A-1), A-1 in the figure) [4.95 g, 6.90 mmol], the known compound (3R)-3-(difluoromethyl)pyrrolidine hydrochloride (CAS No. 1443983-89-8) [2.26 g, 14.3 mmol], and potassium carbonate [4.97 g, 36.0 mmol] was heated and stirred at 60°C for 22 hours. The mixture was transferred to saturated brine [100 mL] and extracted with ethyl acetate [100 mL]. The organic phase was washed with saturated brine [100 mL], dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography [heptane / ethyl acetate system] to give (R)-1-((S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-3-(difluoromethyl)pyrrolidine (compound (B-2), in the figure) [1.93 g, 2.90 mmol].

[0066] <Step 2 (Deprotection)> To a THF solution [26 mL] of compound (B-2) [1.93 g, 2.90 mmol], TBAF [1 M THF solution, 8.7 mL, 8.7 mmol] was added at room temperature, and the mixture was stirred at 60 °C for 4.5 hours. The mixture was transferred to saturated aqueous sodium bicarbonate [100 mL] and extracted with ethyl acetate [100 mL, twice]. The organic phase was back-extracted with 1 M hydrochloric acid [100 mL]. The aqueous phase was neutralized with 5 M aqueous sodium hydroxide [20 mL], and saturated aqueous sodium bicarbonate [20 mL] was added, resulting in a white suspension. This mixture was extracted with ethyl acetate [100 mL], and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (B) (crude), compound B (crude) in the figure) [1.67 g]. Exact Mass = 437.31(C 26 H 41 F2NO2)Obs. mass = 438.35 (M+H)

[0067] <Step 3 (crystallization)> A mixed solvent of acetonitrile [36 mL] and methanol [4 mL] was added to the crude product (compound (B) (crude)) [1.67 g] obtained in step 2, and the mixture was stirred at 60 °C in an oil bath. After confirming that the crude product had dissolved, heating was stopped and the mixture was cooled to room temperature in the oil bath, resulting in precipitation of crystals. The crystals were collected to give (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (B), compound B in the figure) [905.0 mg, 2.07 mmol].

[0068] 1H-NMR (CD3OD) δ: 6.22 (1H, d, J = 10.7 Hz), 5.89 (1H, d, J = 10.7 Hz), 5.76 (1H, td, J = 57.0, 5.0 Hz), 4.06-3.96 (2H, m), 2.84 (1H, dd, J = 12.0, 3.8 Hz), 2.65-2.52 (5H, m), 2.47-1.49 (21H, m), 1.40-1.22 (4H, m), 1.05 (3H, d, J = 6.3 Hz), 0.60 (3H, s).Exact Mass = 437.31(C 26 H 41 F2NO2)Obs. mass = 438.35 (M+H)

[0069] <Evaluation of the crystals of compound (B)> The XRD pattern of the obtained crystals of compound (B) is shown in Figure 2. Peaks were observed at diffraction angles 2θ = 8.9°, 14.2°, 16.2°, 17.9°, 18.5°, 19.1°, 20.1°, 22.6°, 23.0°, 24.3°, and 30.4°.

[0070] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of Compound (B) was 187°C.

[0071] The obtained crystals of compound (B) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 13.1 ppm, 19.7 ppm, 23.2 ppm, 29.3 ppm, 46.3 ppm, 65.8 ppm, 67.7 ppm, 117.1 ppm, 123.2 ppm, 132.6 ppm, and 139.2 ppm.

[0072] [Example 3] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (C))

[0073] [ka]

[0074] <Step 1 (Introduction of pyrrolidine ring)> The known compound (S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (CAS No. 1621978-74-2, compound (A-1), A-1 in the figure) [7.33 g, 10.2 mmol] and the known compound (3R)-3-(1,1-difluoroethyl)pyrrolidine hydrochloride (CAS No. A mixture of 2708341-81-3) [1.88 g, 11.0 mmol] and potassium carbonate [5.65 g, 40.9 mmol] in a mixture of DMF [80 mL] and methanol [40 mL] was heated and stirred at 60 °C for 17 hours. The mixture was transferred to saturated brine [100 mL] and extracted with ethyl acetate [200 mL]. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography [heptane / ethyl acetate system] to obtain (R)-1-((S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-3-(1,1-difluoroethyl)pyrrolidine (compound (C-2), C-2 in the figure) [3.23 g, 4.75 mmol]. Exact Mass = 679.50(C 39 H 71 F2NO2Si2)Obs. mass = 680.60 (M+H)

[0075] <Step 2 (Deprotection)> To a THF solution (60 mL) of compound (C-2) (3.23 g, 4.75 mmol), TBAF (1 M THF solution, 15 mL, 15 mmol) was added at room temperature, and the mixture was refluxed for 4 hours. The mixture was transferred to a saturated aqueous solution of sodium bicarbonate and extracted with a mixture of heptane and ethyl acetate (1 / 1) (100 mL). The organic phase was back-extracted with 1 M hydrochloric acid (100 mL). The aqueous phase was neutralized with 5 M aqueous sodium hydroxide (20 mL), and then saturated aqueous sodium bicarbonate (20 mL) was added, resulting in a white suspension. This mixture was extracted with ethyl acetate [100 mL], and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (C) (crude), compound C (crude) in the figure) [1.088 g, 2.41 mmol]. Exact Mass = 451.33(C 27 H 43 F2NO2)Obs. mass = 452.40 (M+H)

[0076] <Step 3 (crystallization)> Acetonitrile [20 mL] was added to the crude product (compound (C) (crude)) [1.088 g, 2.41 mmol] obtained in step 2, and the mixture was stirred at 50 ° C in an oil bath. After confirming that the crude product had dissolved, heating was stopped and the mixture was cooled to room temperature in the oil bath, resulting in precipitation of crystals. The crystals were collected to give (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (C), compound C in the figure) [835 mg, 1.85 mmol].

[0077] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.0 Hz), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 11.9, 3.7 Hz), 2.72-1.51 (27H, m), 1.45-1.20 (3H, m), 1.05 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 451.33(C 27 H 43 F2NO2)Obs. mass = 452.40 (M+H)

[0078] <Evaluation of the crystals of compound (C)> The XRD pattern of the obtained crystals of compound (C) is shown in Figure 3. Peaks were observed at diffraction angles 2θ of 14.1°, 15.2°, 15.8°, 16.6°, 17.2°, 18.8°, 20.5°, 21.0°, 21.3°, and 22.6°.

[0079] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of Compound (C) was 159°C.

[0080] The obtained crystals of compound (C) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 16.6 ppm, 18.0 ppm, 26.2 ppm, 27.3 ppm, 28.6 ppm, 46.3 ppm, 64.7 ppm, 65.5 ppm, 67.9 ppm, 118.1 ppm, 120.4 ppm, 137.2 ppm, and 138.8 ppm.

[0081] [Example 4] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (D))

[0082] [ka]

[0083] <Step 1 (Introduction of pyrrolidine ring)> A solution of the known compound (S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (CAS No. 1621978-74-2, compound (A-1), A-1 in the figure) [4.86 g, 6.78 mmol], the known compound (3S)-3-(2,2-difluoroethyl)pyrrolidine hydrochloride (CAS No. 2708342-85-0) [2.01 g, 11.7 mmol], and potassium carbonate [4.50 g, 32.6 mmol] in DMF [30 mL] was heated and stirred at 60 °C for 20 hours. The mixture was transferred to saturated brine [100 mL] and extracted with ethyl acetate [100 mL]. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography [heptane / ethyl acetate system] to give (S)-1-((S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-3-(2,2-difluoroethyl)pyrrolidine (compound (D-2), D-2 in the figure) [3.08 g, 4.53 mmol]. Exact Mass = 679.50(C 39 H 71 F2NO2Si2)Obs. mass = 680.60 (M+H)

[0084] <Step 2 (Deprotection)> To a THF solution [55 mL] of compound (D-2) [3.08 g, 4.53 mmol], TBAF [1 M THF solution, 14 mL, 14 mmol] was added at room temperature, and the mixture was refluxed for 4.5 hours. The mixture was transferred to a saturated aqueous solution of sodium bicarbonate and extracted with a mixture of heptane and ethyl acetate (1 / 1) [100 mL]. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with ethyl acetate [75 mL], and the organic phase was back-extracted with 1 M hydrochloric acid [100 mL]. The aqueous phase was neutralized with 5 M aqueous sodium hydroxide [20 mL] and further adjusted to pH 10 with saturated aqueous sodium bicarbonate [30 mL]. This mixture was extracted with ethyl acetate [100 mL], and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (D) (crude), compound D (crude) in the figure) [1.14 g, 2.52 mmol]. Exact Mass = 451.33(C 27 H 43 F2NO2)Obs. mass = 452.35 (M+H)

[0085] <Step 3 (crystallization)> A mixed solvent of acetonitrile [19 mL] and methanol [1 mL] was added to the crude product (compound (D) (crude)) [1.14 g, 2.52 mmol] obtained in step 2, and the mixture was stirred at 50 °C in an oil bath. After confirming that the crude product had dissolved, heating was stopped and the mixture was cooled to room temperature in the oil bath, resulting in precipitation of crystals. The crystals were collected to give (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (D), compound D in the figure) [786.6 mg, 1.74 mmol].

[0086] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 6.03-5.72 (2H, m), 4.06-3.95 (2H, m), 2.83 (1H, dd, J = 12.3, 3.7 Hz), 2.76 (1H, t, J = 8.2 Hz), 2.70 (1H, t, J = 7.8 Hz), 2.59 (1H, dd, J = 13.3, 3.7 Hz), 2.43-2.10 (8H, m), 2.09-1.46 (16H, m), 1.43-1.16 (3H, m), 1.05 (3H, d, J = 6.4 Hz), 0.60 (3H, s). Exact Mass = 451.33(C 27 H 43 F2NO2)Obs. mass = 452.35 (M+H)

[0087] <Evaluation of the crystals of compound (D)> The XRD pattern of the obtained crystals of compound (D) is shown in Figure 4. Diffraction peaks were observed at 2θ angles of 12.4°, 14.6°, 16.2°, 16.5°, 18.3°, 18.5°, 19.2°, 19.6°, 19.8°, and 22.7°.

[0088] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of compound (D) was 171°C.

[0089] The obtained crystals of compound (D) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 13.0 ppm, 18.6 ppm, 23.7 ppm, 30.3 ppm, 45.8 ppm, 66.2 ppm, 67.2 ppm, 116.6 ppm, 123.6 ppm, 132.5 ppm, and 141.1 ppm.

[0090] [Example 5] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (E))

[0091] [ka]

[0092] <Step 1 (DIBAL-H reduction)> To a 75 mL toluene solution of the known compound (R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butanenitrile [CAS No. 2489320-15-0, 6.73 g, 11.8 mmol, compound (E-1), E-1 in the figure], diisobutylaluminum hydride [DIBAL-H, 1.5 M hexane solution, 12.5 mL, 18.75 mmol] was added at −20°C so that the internal temperature did not exceed 0°C. The mixture was stirred at −15°C for 30 minutes. The mixture was quenched with 10 mL of saturated Rochelle's salt (potassium sodium tartrate) solution and allowed to warm to room temperature. Saturated Rochelle salt (potassium sodium tartrate) aqueous solution [30 mL] was further added to the mixture, and the mixture was stirred at room temperature for 1 hour. The aqueous phase was separated, and the organic phase was washed twice with saturated Rochelle salt (potassium sodium tartrate) aqueous solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude (R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butanal (compound (E-2), E-2 in the figure) [7.87 g]. This crude product was used in the next reaction without further purification.

[0093] <Step 2 (reductive amination)> Sodium triacetoxyborohydride (3.74 g, 17.6 mmol) was added to a THF solution (65 mL) of crude compound (E-2) (7.87 g) and morpholine (13 mL) obtained in Step 1 at room temperature, and the mixture was stirred at the same temperature for 3 hours. The mixture was quenched with water (5 mL), and saturated brine (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-((R)-3-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)butyl)morpholine (compound (E-3), E-3 in the figure) [8.29 g]. This crude product was used in the next reaction without further purification.

[0094] <Step 3 (Deprotection)> Crude compound (E-3) [8.29 g] obtained in step 2 was dissolved in a mixture of acetone [100 mL] and water [8 mL]. 2 M hydrochloric acid [23.6 mL, 57.2 mmol] was added to the solution at room temperature and stirred at the same temperature for 3 hours. Water [90 mL] was added to the mixture, which was then extracted with ethyl acetate [100 mL]. The aqueous phase was cooled in an ice bath, adjusted to pH 10 with 2 M aqueous sodium hydroxide [12 mL], and stirred at room temperature for 1 hour. The mixture was filtered to collect the solid and dried to obtain crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (E) (crude), compound E (crude) in the figure) [3.54 g].

[0095] <Step 4 (neutralization crystallization)> To a solution of crude compound (E) (3.54 g) obtained in step 3 in acetone (35 mL) was added 1 M hydrochloric acid (10.2 mL). Water (52 mL) was added to the solution, followed by 1 M hydrochloric acid (6.8 mL). The solution was extracted with ethyl acetate, and the aqueous phase was adjusted to pH 10 with 2 M aqueous sodium hydroxide. The mixture was stirred at room temperature for 1 hour and filtered to collect the solid. The solid was dried to obtain the desired compound (E) (compound E in the figure) (3.16 g, 7.57 mmol) as crystals.

[0096] 1 H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.88 (1H, d, J = 11.4 Hz), 4.06-3.95 (2H, m), 3.69 (4H, t, J = 4.6 Hz), 2.83 (1H, dd, J = 11.9, 4.1 Hz), 2.59 (1H, dd, J = 13.7, 3.7 Hz), 2.50-2.37 (6H, m), 2.33 (1H, td, J = 11.4, 5.3 Hz), 2.23-2.13 (2H, m), 2.06-1.93 (4H, m), 1.88-1.47 (9H, m), 1.39-1.27 (4H, m), 0.98 (3H, d, J = 6.4 Hz), 0.58 (3H, s). Exact Mass = 417.32(C 26 H 43 NO3)Obs. mass = 418.35 (M+H)

[0097] <Evaluation of the crystals of compound (E)> The XRD pattern of the obtained crystals of compound (E) is shown in Figure 5. Peaks were observed at diffraction angles 2θ of 13.5°, 15.1°, 16.4°, 16.7°, 17.2°, 17.7°, 18.1°, 18.6°, 20.3°, and 21.6°.

[0098] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of Compound (E) was 194°C.

[0099] The obtained crystals of compound (E) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 14.3 ppm, 19.4 ppm, 23.2 ppm, 24.9 ppm, 29.0 ppm, 29.8 ppm, 45.9 ppm, 57.7 ppm, 67.0 ppm, 117.4 ppm, 122.2 ppm, 133.2 ppm, and 139.6 ppm.

[0100] [Example 6] Preparation of crystals of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (F))

[0101] [ka]

[0102] <Step 1 (Introduction of a morpholine ring)> To a solution of the known compound (S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate (CAS No. 1621978-74-2, compound (A-1), A-1 in the figure) [20.3 g, 28.3 mmol] in N-methyl-pyrrolidone [160 mL], 3,3-dimethylmorpholine (CAS No. 59229-63-9) [7.0 mL, 11.7 mmol], potassium iodide [5.56 g, 33.5 mmol], and potassium carbonate [10.89 g, 78.79 mmol] were added, and the mixture was heated and stirred at 70°C for 16 hours. Heptane [120 mL] and water [120 mL] were added to the mixture, and the aqueous phase was removed. The aqueous phase was extracted with ethyl acetate [100 mL]. The combined organic phase was washed twice with 10% aqueous sodium thiosulfate solution [100 mL]. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-((S)-2-((1R,3aS,7aR,E)-4-(2-((3R,5R)-3,5-bis((t-butyldimethylsilyl)oxy)cyclohexylidene)ethylidene)-7a-methyloctahydro-1H-inden-1-yl)propyl)-3,3-dimethylmorpholine (compound (F-2), F-2 in the figure) [19.22 g]. This crude product was used in the next reaction without further purification. Exact Mass = 659.51(C 39 H 73 NO3Si2)Obs. mass = 660.35 (M+H)

[0103] <Step 2 (Deprotection)> To a solution of crude compound (F-2) [19.22 g] obtained in Step 1 in 2-butanone [100 mL], 2 M hydrochloric acid [100 mL, 200 mmol] was added at room temperature, and the mixture was stirred for 75 minutes. The mixture was extracted with heptane [100 mL]. The aqueous phase was then washed with a mixed solvent of heptane [50 mL] and 2-butanone [50 mL]. The aqueous phase was neutralized with 5 M aqueous sodium hydroxide [100 mL] while stirring at 0 °C. Saturated aqueous sodium bicarbonate [50 mL] was then added to adjust the pH to 10, resulting in a white suspension. This mixture was stirred at room temperature for 1 hour, and the mixture was filtered to collect the solid. The solid was then dried to give crude (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (F) (crude), compound F (crude) in the figure) [11.71 g, 27.13 mmol]. Exact Mass = 431.34(C 27 H 45 NO3)Obs. mass = 432.20 (M+H)

[0104] <Step 3 (Slurry washing for crystal purification)> Ethanol [460 mL] was added to the crude compound (F) [23.20 g, 53.75 mmol] produced by the methods of steps 1 and 2, and the mixture was stirred in an oil bath at 60 °C for 16 hours. After cooling to room temperature, the crystals were collected to obtain crystals of 1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound (F), compound F in the figure) [18.61 g, 43.12 mmol].

[0105] 1H-NMR (CD3OD) δ: 6.21 (1H, d, J = 11.0 Hz), 5.89 (1H, d, J = 11.4 Hz), 4.06-3.94 (2H, m), 3.82-3.78 (1H, m), 3.65-3.59 (1H, m), 3.39 (1H, d, J = 11.0 Hz), 3.32 (1H, s), 2.85-2.81 (1H, m), 2.73-2.69 (1H, m), 2.62-2.56 (2H, m), 2.40 (1H, dd, J = 13.5, 3.4 Hz), 2.33-2.13 (4H, m), 2.07-1.97 (3H, m), 1.87-1.81 (1H, m), 1.78-1.72 (1H, m), 1.67-1.50 (6H, m), 1.37-1.25 (3H, m), 1.06-1.04 (6H, m), 1.01 (3H, s), 0.60 (3H, s). Exact Mass = 431.34(C 27 H 45 NO3)Obs. mass = 432.20 (M+H)

[0106] <Evaluation of the crystals of compound (F)> The XRD pattern of the obtained crystals of compound (F) is shown in Figure 6. Peaks were observed at diffraction angles 2θ of 13.7°, 15.3°, 16.1°, 16.4°, 17.3°, 19.1°, 19.6°, 21.2°, 22.8°, and 24.1°.

[0107] The extrapolated onset temperature of the endothermic peak in differential scanning calorimetry (DSC) of the crystals of compound (F) was 218°C.

[0108] The obtained crystals of compound (F) 13 The C solid-state NMR spectrum is shown in Figure 7. Peaks were observed at chemical shifts of 13.4 ppm, 14.2 ppm, 18.3 ppm, 23.7 ppm, 25.2 ppm, 28.3 ppm, 29.5 ppm, 46.4 ppm, 117.4 ppm, 123.0 ppm, 132.6 ppm, and 140.0 ppm.

[0109] [Example 7] Evaluation of the effect of promoting differentiation of rat oligodendrocyte precursor cells The action of the vitamin D derivatives of the present invention in promoting the differentiation of oligodendrocyte precursor cells (OPCs) was evaluated by immunostaining for myelin basic protein (MBP).

[0110] (1) Collection of rat oligodendrocyte precursor cells Forebrains were collected from 1-day-old SD rats (Charles River Japan, Japan) and crushed using a 70 μm cell strainer (Falcon #352350). Cell suspensions were prepared by lysing the forebrains in oligodendrocyte precursor cell isolation medium (20% FBS / 2 mM Glutamax (Gibco #35050-061) / 1 mM sodium pyruvate (Gibco #11360-070) / 1% penicillin-streptomycin (Invitrogen #15140-122) / DMEM (Gibco #11960-044)). The cell suspensions were seeded into poly-D-lysine-coated T75 flasks (Thermo Fisher Scientific #132704) and cultured at 37°C and 5% CO for 10 days. After incubation, the flasks were shaken at 37°C, 100 rpm on a rotary shaker (Waken Pharmaceutical #WB-101SRC) for approximately 1 hour, and the supernatant was discarded to remove microglia. Oligodendrocyte progenitor cell isolation medium was then added to the flasks, and the flasks were similarly shaken at 37°C, 200 rpm for approximately 22 hours. The supernatant was then collected to prepare oligodendrocyte progenitor cells.

[0111] (2) Evaluation of the effect of promoting differentiation of oligodendrocyte precursor cells The prepared oligodendrocyte precursor cells were suspended in differentiation medium (2% B27 (Thermo Fisher Scientific #17504-044) / 1% penicillin-streptomycin (Invitrogen #15140-122) / 1% sodium pyruvate (Fujifilm Wako Pure Chemical #191-03061) / 10 ng / mL CNTF (PeproTech #AF-450-13) / DMEM (Gibco #11960-044)) and plated at 0.65 × 10 cells onto a 96-well plate coated with poly-L-ornithine (Fujifilm Wako Pure Chemical #163-27421). 4 Cells were seeded at 1000 cells / well. After seeding, a solution prepared from a 20 mM DMSO solution of the test compound in differentiation medium (triiodothyronine (T3, positive control) = 30 nM, or a vitamin D derivative of the present invention = 2 μM), or a solution prepared from DMSO in differentiation medium was added to the wells so that the DMSO concentration in the wells was 0.1%, and the cells were cultured for 4 days (37°C, 5% CO2). Test compounds were evaluated in N = 3 or N = 6. After incubation, the cells were fixed in 4% paraformaldehyde solution for 30 minutes at room temperature, washed with PBS, permeabilized with 0.1% Trion X-100 (Sigma #X100-100ML) in PBS for 3 minutes at room temperature, blocked with 3% BSA (Sigma #A9647-10G) in PBS for 1 hour at room temperature, incubated with a primary antibody (MBP antibody (Abcam #ab40390) at 2.5 μg / mL for 24 hours at 4°C), washed with PBS, incubated with a secondary antibody (Alexa488 anti-rabbit IgG (Thermo Fisher Scientific #(A)-11034) at 5 μg / mL for 1 hour at room temperature), washed with PBS, and then immunostained for MBP using Hoechst 33342 (DOJINDO #NU043) at 10 μg / mL for 5 minutes at room temperature. Images of each well were then taken using a fluorescence microscope (KEYENCE #BZ-X800), and the numbers of MBP-positive cells and Hoechst33342-positive cells were counted using an image analysis application (KEYENCE #BZ-X800 Analyzer), and the ratio (MBP-positive cells / Hoechst33342-positive cells) was calculated.

[0112] (3) Results The results are shown in the table below. Note that the significant differences in the table below are those obtained when a t-test was performed on the DMSO group, as follows: *: <0.05 **: <0.01 ***: <0.001 ****: <0.0001 ns: no significant difference

[0113] [Table 1-1] [Table 1-2] [Table 1-3]

[0114] As shown in Tables 1-1, 1-2 and 1-3, the vitamin D derivatives of the present invention exhibited a strong promoting effect on the induction of differentiation of oligodendrocyte precursor cells when evaluated by immunostaining.

[0115] [Example 8] Mouse brain distribution assessment

[0116] Test 1 (1 mg / kg administration test) The test compound (10 mg / mL ethanol solution) was diluted 100-fold with 0.1% Trion X-100 (SIGMA #X100-100ML) / physiological saline to prepare a dosing solution. This dosing solution was administered orally (1 mg / kg) to C57BL / 6J mice (8-week-old, male, N=3). Mice were euthanized at 0.25, 0.5, 1, 2, 4, and 8 hours after administration, and plasma and brain samples were taken. Brains were homogenized using a Tissue Lyser II (QIAGEN #85300), and the test compound was extracted from the brain by adding acetonitrile and centrifuging (Tomy Seiko MX-307, 12,000 rpm, 5 minutes). Similarly, the test compound was extracted from plasma by adding acetonitrile and centrifuging. The concentration of the test compound in each extracted sample was measured using LC / MS / MS (SHIMADZU UFLC / MS / MS (8050)).

[0117] The plasma and brain concentrations of each test compound evaluated at the time of maximum brain concentration (brain Cmax) are shown in the table below as mean ± SD (standard deviation). The brain / plasma concentration ratio (mean brain concentration divided by mean plasma concentration) is also shown in the table below.

[0118] [Table 2]

[0119] Study 2 (0.2 mg / kg administration study) The test compound (2 mg / mL ethanol solution) was diluted 100-fold with 0.1% Trion X-100 (SIGMA #X100-100ML) / physiological saline to prepare a dosing solution. This dosing solution was administered orally (0.2 mg / kg) to C57BL / 6J mice (8-week-old, male, N=3). Mice were euthanized at 0.25, 0.5, 1, 2, 4, and 8 hours after administration, and plasma and brain samples were taken. Brains were homogenized using a Tissue Lyser II (QIAGEN #85300), and the test compound was extracted from the brain by adding acetonitrile and centrifuging (Tomy Seiko MX-307, 12,000 rpm, 5 minutes). Similarly, the test compound was extracted from plasma by adding acetonitrile and centrifuging. The concentration of the test compound in each extracted sample was measured using LC / MS / MS (SHIMADZU UFLC / MS / MS (8050)).

[0120] The plasma and brain concentrations of each test compound evaluated at the time of maximum brain concentration (brain Cmax) are shown in the table below as mean ± SD (standard deviation). The brain / plasma concentration ratio (mean brain concentration divided by mean plasma concentration) is also shown in the table below.

[0121] [Table 3]

[0122] All of the compounds of the present invention showed a brain concentration / plasma concentration ratio of 1.03 to 2.38 even under oral administration conditions. Non-Patent Document 5 reports that the brain concentration / blood concentration ratio of 1α,25-dihydroxyvitamin D3 is 0.007±0.003. Therefore, it can be said that the compounds of the present invention have significantly improved central transferability compared to 1α,25-dihydroxyvitamin D3.

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, R represents any one of the structures Ra, Rb, Rc, Rd, Re, and Rf in the following formula. 【Chemistry 2】 ］ or a crystal of a solvate of a vitamin D derivative represented by formula (1).

2. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

3. The crystal according to claim 2, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 14.2°, 16.3°, 17.9°, and 18.5° in its powder X-ray diffraction spectrum.

4. The crystal according to claim 2, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 8.9°, 14.2°, 16.3°, 17.9° and 18.5° in its powder X-ray diffraction spectrum.

5. The crystal according to claim 2, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 1 below.

6. Solid-state NMR spectrum ( １３ The crystal according to claim 2, characterized in that in C), the crystal has peaks at chemical shifts (±0.5 ppm) of 13.6 ppm, 19.2 ppm, 117.2 ppm, 121.8 ppm, 133.6 ppm, and 138.5 ppm.

7. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 7 below.

8. The crystal according to claim 3, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 171±5°C.

9. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

10. The crystal according to claim 9, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 14.2°, 16.2°, 17.9°, 18.5° and 24.3° in its powder X-ray diffraction spectrum.

11. The crystal according to claim 9, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 8.9°, 14.2°, 16.2°, 17.9°, 18.5°, 24.3° and 30.4° in its powder X-ray diffraction spectrum.

12. The crystal according to claim 9, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 2 below.

13. Solid-state NMR spectrum ( １３ The crystal according to claim 9, characterized in that in C), the crystal has peaks at chemical shifts (±0.5 ppm) of 13.1 ppm, 19.7 ppm, 117.1 ppm, 123.2 ppm, 132.6 ppm, and 139.2 ppm.

14. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 8 below.

15. The crystal according to claim 10, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 187±5°C.

16. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

17. The crystal according to claim 16, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 14.1°, 15.2°, 15.8°, 16.6°, and 18.8° in its powder X-ray diffraction spectrum.

18. The crystal according to claim 16, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 14.1°, 15.2°, 15.8°, 16.6°, 17.2°, 18.8°, 21.3° and 22.6° in its powder X-ray diffraction spectrum.

19. The crystal of claim 16, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 3 below.

20. Solid-state NMR spectrum ( １３ The crystal according to claim 16, characterized in that in C), it has peaks at chemical shifts (±0.5 ppm) of 16.6 ppm, 18.0 ppm, 118.1 ppm, 120.4 ppm, 137.2 ppm, and 138.8 ppm.

21. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 9 below.

22. The crystal according to claim 17, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 159±5°C.

23. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

24. The crystal according to claim 23, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 14.6°, 16.2°, 16.5°, and 18.3° in a powder X-ray diffraction spectrum.

25. The crystal according to claim 23, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 12.4°, 14.6°, 16.2°, 16.5°, and 18.3° in a powder X-ray diffraction spectrum.

26. The crystal according to claim 23, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 4 below.

27. Solid-state NMR spectrum ( １３ The crystal according to claim 23, characterized in that in C), it has peaks at chemical shifts (±0.5 ppm) of 13.0 ppm, 18.6 ppm, 116.6 ppm, 123.6 ppm, 132.5 ppm, and 141.1 ppm.

28. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 10 below.

29. The crystal according to claim 24, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 171±5°C.

30. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

31. The crystal according to claim 30, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 13.5°, 16.4°, 18.1°, and 20.3° in a powder X-ray diffraction spectrum.

32. The crystal according to claim 30, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 13.5°, 16.4°, 16.7°, 18.1°, and 20.3° in a powder X-ray diffraction spectrum.

33. The crystal of claim 30, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 5 below.

34. Solid-state NMR spectrum ( １３ The crystal according to claim 30, characterized in that in C), the crystal has peaks at chemical shifts (±0.5 ppm) of 14.3 ppm, 19.4 ppm, 117.4 ppm, 122.2 ppm, 133.2 ppm, and 139.6 ppm.

35. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 11 below.

36. The crystal according to claim 31, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 194±5°C.

37. The crystal according to claim 1, which is a crystal of (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol.

38. 38. The crystal according to claim 37, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 16.1°, 16.4°, and 17.3° in a powder X-ray diffraction spectrum.

39. 38. The crystal according to claim 37, characterized in that it has peaks at diffraction angles (2θ±0.2°) of 13.7°, 15.3°, 16.1°, 16.4°, 17.3°, 19.1° and 19.6° in a powder X-ray diffraction spectrum.

40. 38. The crystal of claim 37, wherein the powder X-ray diffraction spectrum has the pattern shown in Figure 6 below.

41. Solid-state NMR spectrum ( １３ The crystal according to claim 37, characterized in that in C), the crystal has peaks at chemical shifts (±0.5 ppm) of 13.4 ppm, 14.2 ppm, 18.3 ppm, 117.4 ppm, 123.0 ppm, 132.6 ppm, and 140.0 ppm.

42. Solid-state NMR spectrum ( １３ C) has the pattern shown in Figure 12 below.

43. The crystal according to claim 38, wherein the extrapolated onset temperature of the endothermic peak in differential thermal analysis is 218±5°C.

44. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition for promoting the induction of differentiation from oligodendrocyte precursor cells to oligodendrocytes, comprising the crystal according to any one of claims 1 to 43 as an active ingredient.

46. A remyelination promoter comprising the crystal according to any one of claims 1 to 43 as an active ingredient.

47. A method for treating multiple sclerosis, neuromyelitis optica, and progressive multifocal alopecia, comprising administering to a patient the crystal of any one of claims 1 to 43 as an active ingredient. a therapeutic agent for one or more diseases selected from the group consisting of encephalopathy, multiple system atrophy, acute disseminated encephalomyelitis, atopic myelitis, HTLV-1 associated myelopathy, HIV associated leukoencephalopathy, Krabbe disease, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, depression due to drug addiction, autism, Alzheimer's type dementia, and ischemic stroke.

Images