WO2021153690A1 - Novel crystal form of benzene derivative - Google Patents

Novel crystal form of benzene derivative Download PDF

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WO2021153690A1
WO2021153690A1 PCT/JP2021/003092 JP2021003092W WO2021153690A1 WO 2021153690 A1 WO2021153690 A1 WO 2021153690A1 JP 2021003092 W JP2021003092 W JP 2021003092W WO 2021153690 A1 WO2021153690 A1 WO 2021153690A1
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degrees
powder
compound according
ray diffraction
compound
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PCT/JP2021/003092
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French (fr)
Japanese (ja)
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修平 大谷
貴之 藤戸
直希 西馬
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小野薬品工業株式会社
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Priority to KR1020227025723A priority Critical patent/KR20220132537A/en
Priority to JP2021574120A priority patent/JPWO2021153690A1/ja
Publication of WO2021153690A1 publication Critical patent/WO2021153690A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (hereinafter, may be abbreviated as compound A). Regarding new crystals, etc.
  • the nervous system is roughly divided into the central nervous system and the peripheral nervous system.
  • the peripheral nervous system connects the brain and spinal cord with the peripheral body and is responsible for nerve transmission.
  • the peripheral nervous system can be classified into the somatic nervous system (cerebral spinal nervous system) and the autonomic nervous system.
  • the somatic nervous system is divided into the cranial nerves and the spinal nerves.
  • those that transmit nerve signals (excitement) generated from sensory receptors to the central nerve are classified into afferent or sensory nerve fibers, whereas the brain and Those that transmit nerve signals from the spinal cord to effectors such as muscles and glands are classified as efferent or motile nerve fibers.
  • Cranial nerves are the peripheral nerves that emerge from the brain and are known to consist of 12 pairs, some of which are sensory, some of which are motile, and some of which are mixed nerve fibers.
  • the first to twelfth nerve pairs are called olfactory nerve, optic nerve, moving eye nerve, pulley nerve, trigeminal nerve, abduction nerve, facial nerve, internal ear nerve, lingual nerve, stray nerve, accessory nerve, and sublingual nerve, respectively.
  • the nerves composed of sensory or mixed nerve fibers are known to be the olfactory nerve, the optic nerve, the trigeminal nerve, the facial nerve, the vestibulocochlear nerve, the glossopharyngeal nerve, and the vagus nerve.
  • the spinal nerves are peripheral nerves originating from the spinal cord, and 31 pairs of left and right are known, 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves and 1 pair of caudal nerves. ..
  • the spinal nerves are all composed of mixed nerve fibers, and include sensory fibers (dorsal roots) that go to the skin and the like and motor fibers (ventral roots) that go to skeletal muscles.
  • Sensory nerve fibers that is, sensory nerves
  • the neural signals transmitted to the central nervous system are finally transmitted to each sensory area of the cerebral cortex, for example, the visual cortex, the auditory area, etc., and the sensation is normally recognized.
  • these sensory nerves are affected by axons, myelin sheaths, Schwann cells, etc. due to, for example, viral infection, tumor, cancer, diabetes, ischemia, trauma, compression, drugs, radiotherapy, etc., resulting in cell death or demyelination.
  • Various neuropathy such as myelin may be caused. As a result, accurate neurotransmission is not performed in the impaired sensory nerve, and thus diseases such as deafness and neuropathic pain develop.
  • peripheral neuropathy in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to causes such as metabolic diseases, autoimmune diseases, trauma, drug addiction, etc. be.
  • the disease can damage a single nerve, two or more nerves in separate areas, or multiple nerves at the same time.
  • Symptoms include peripheral stinging, numbness, burning sensation, decreased joint proprioception, decreased vibration sensation, pain (including neuropathic pain), dysesthesia, coldness or burning, and are very complex. It is diverse.
  • peripheral nervous system diseases are diseases whose pathogenesis is unknown or physical damage to nerves. Therefore, when treating them, the symptomatic treatment is mainly aimed at improving the symptoms. Few clinically useful drugs are known that provide symptomatic treatment and provide curative treatment that acts directly on the damaged nervous system.
  • An object of the present invention is to find a compound having a neuroprotective and / or repairing action, and further to find a crystal or the like that is excellent in handling as a pharmaceutical product for the compound.
  • the present inventors have conducted studies to solve the above problems and found that the free form of compound A forms two types of crystals in one embodiment. Also, in one embodiment, a salt of compound A was found.
  • the present invention is, for example, the following aspects.
  • the compound according to [1] which has at least two or more diffraction peaks at a diffraction angle (2 ⁇ ) of about 25.6 degrees.
  • [2-1] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24 degrees.
  • [2-2] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24 degrees.
  • the diffraction angles (2 ⁇ ) are further increased to about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees.
  • the compound according to [2-4] which has at least one diffraction peak.
  • the diffraction angles (2 ⁇ ) of about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees are further set.
  • the compound according to [1] which has at least two or more diffraction peaks at a diffraction angle (2 ⁇ ) of 3 degrees.
  • [7-1] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about.
  • [7-2] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about.
  • the diffraction angles (2 ⁇ ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees.
  • the compound according to [7-4] which has at least one diffraction peak.
  • the diffraction angles (2 ⁇ ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees.
  • the diffraction angles (2 ⁇ ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees.
  • the compound according to [13] which has at least four or more diffraction peaks at a diffraction angle (2 ⁇ ) of 20.9 degrees.
  • the compound according to [19] which has at least four or more diffraction peaks at diffraction angles (2 ⁇ ) of .4 degrees and about 29.7 degrees.
  • the compound according to [27]. [31] The compound according to [27], which comprises the powder X-ray diffraction spectrum chart shown in FIG. [32] The compound according to any one of [27] to [31] and [28-1] to [28-3], which has an endothermic peak temperature of about 114 ° C. in differential scanning calorimetry. [33] The compound according to [32], which comprises the differential scanning calorimetry chart shown in FIG. [34] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid t-butylamine salt.
  • Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and chemotherapeutic drug administration.
  • the agent according to [56] which is a peripheral neuropathy or a peripheral neuropathy associated with Charcot-Marie-Tooth disease.
  • the free form of compound A forms crystals and is easy to handle, so it is useful as a drug substance.
  • the powder X-ray diffraction spectrum chart of the diisopropylamine salt of Compound A is represented (the vertical axis represents intensity (counts) and the horizontal axis represents 2 ⁇ (degrees)).
  • the differential scanning calorimetry (DSC) chart of the diisopropylamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)).
  • the powder X-ray diffraction spectrum chart of the free form (B crystal) of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the differential scanning calorimetry (DSC) chart of the free compound (B crystal) of compound A is represented (the vertical axis represents heat flux (W / g), and the horizontal axis represents temperature (° C.)).
  • the powder X-ray diffraction spectrum chart of the free form (A crystal) of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the differential scanning calorimetry (DSC) chart of the free compound (A crystal) of compound A is represented (the vertical axis represents heat flux (W / g), and the horizontal axis represents temperature (° C.)).
  • the powder X-ray diffraction spectrum chart of the ethylenediamine salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the differential scanning calorimetry (DSC) chart of the ethylenediamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)).
  • the powder X-ray diffraction spectrum chart of the venetamine salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the differential scanning calorimetry (DSC) chart of the venetamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)).
  • the powder X-ray diffraction spectrum chart of the t-butylamine salt of Compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the powder X-ray diffraction spectrum chart of the sodium salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the powder X-ray diffraction spectrum chart of the hemicalcium salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • the nociception threshold when the compound of Example 5 was administered at a dose of 0.3 mg / kg (the vertical axis represents the nociception threshold, and the horizontal axis represents the number of days elapsed after streptozotocin administration). ..
  • the B crystal of compound A is characterized by at least one of the following physicochemical data (a) and (b). Preferably, it is characterized by the physicochemical data of both (a) and (b).
  • (A) It has a diffraction peak at a diffraction angle (2 ⁇ ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 3 or the diffraction angle (2 ⁇ ) shown in Table 2, or the diffraction angle (2 ⁇ ) shown in Table 2.
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum, (b) a differential scanning calorimetry (DSC) chart shown in FIG. 4 below, or a heat absorption peak with a peak temperature of about 86.4 ° C.
  • DSC differential scanning calorimetry
  • the A crystal of compound A is characterized by at least one of the following physicochemical data (c) and (d). Preferably, it is characterized by the physicochemical data of both (c) and (d).
  • C It has a diffraction peak at a diffraction angle (2 ⁇ ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 5 or the diffraction angle (2 ⁇ ) shown in Table 3, or the diffraction angle (c) shown in Table 3 (c).
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum, (d) a differential scanning calorimetry (DSC) chart shown in FIG. 6, or a heat absorption peak with a peak temperature of about 86.8 ° C.
  • the B crystal of compound A in the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22 degrees.
  • a crystalline form having at least two, three, four, five, six, or seven diffraction peaks at diffraction angles (2 ⁇ ) of .2 degrees, about 24.7 degrees, and about 25.6 degrees. ..
  • Another embodiment of the B crystal of compound A is at least about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees.
  • Another embodiment of the B crystal of compound A is at least one or two at a diffraction angle (2 ⁇ ) of about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in the powder X-ray diffraction spectrum. It is a crystal form having a diffraction peak.
  • Another embodiment of the B crystal of compound A is a crystal having diffraction peaks at diffraction angles (2 ⁇ ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in a powder X-ray diffraction spectrum. It is a form.
  • Another aspect of the B crystal of compound A is that it has diffraction peaks at diffraction angles (2 ⁇ ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in the powder X-ray diffraction spectrum. In addition, at least one, two, three or at diffraction angles (2 ⁇ ) of about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees. It is a crystal form having four diffraction peaks.
  • the A crystal of compound A in the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23 degrees. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at a diffraction angle (2 ⁇ ) of 5.5 degrees and about 24.3 degrees.
  • a crystal of compound A is at least about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 23.5 degrees and about 24.3 degrees.
  • a crystal of compound A is a crystal form having a diffraction peak at at least about 6.8 degrees and / or about 10.5 degrees in the powder X-ray diffraction spectrum.
  • a crystal of compound A is a crystal form having diffraction peaks at at least about 6.8 degrees and about 10.5 degrees in the powder X-ray diffraction spectrum.
  • the powder X-ray diffraction spectrum has diffraction peaks at at least about 6.8 ° C and about 10.5 ° C, and further at about 8.2 ° C. and about 12.8 ° C. It is a crystalline form having at least one, two, three or four diffraction peaks at diffraction angles (2 ⁇ ) of about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees.
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum, (f) a differential scanning calorimetry (DSC) chart shown in FIG. 2, or a heat absorption peak with a peak temperature of about 133 ° C.
  • DSC differential scanning calorimetry
  • the crystal of compound A diisopropylamine salt in the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, It is a crystalline form having at least two, three, four, five, or six diffraction peaks at a diffraction angle (2 ⁇ ) of about 20.1 degrees and about 20.9 degrees.
  • compound A diisopropylamine salt in the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 20.1 degrees and about 20.9 degrees.
  • Compound A ethylenediamine salt is in crystalline form in one embodiment.
  • the crystal is characterized by at least one of the following physicochemical data (g) and (h): Preferably, it is characterized by both (g) and (h) physicochemical data.
  • G It has a diffraction peak at a diffraction angle (2 ⁇ ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG.
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum, a differential scanning calorimetry (DSC) chart shown in FIG. 8, or a heat absorption peak with a peak temperature of about 153 ° C.
  • DSC differential scanning calorimetry
  • the crystal of compound A ethylenediamine salt in the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2 ⁇ ) of 23.9 degrees, about 24.4 degrees, and about 29.7 degrees.
  • compound A ethylenediamine salt in the powder X-ray diffraction spectrum, at least about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about. It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of 23.9 degrees, about 24.4 degrees, and about 29.7 degrees.
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum, (j) a differential scanning calorimetry (DSC) chart shown in FIG. 10, or a heat absorption peak with a peak temperature of about 114 ° C.
  • DSC differential scanning calorimetry
  • the crystal of the compound A venetamine salt in the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2 ⁇ ) of 20.4 degrees, about 20.8 degrees, and about 21.2 degrees.
  • the compound A venetamine salt in the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about. It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of 20.4 degrees, about 20.8 degrees, and about 21.2 degrees.
  • crystal of the compound A t-butylamine salt in the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees. , A crystal form having at least 2, 3, 4, 5, or 6 diffraction peaks at diffraction angles (2 ⁇ ) of about 20.7 degrees, about 21.0 degrees, and about 21.9 degrees. ..
  • Another aspect of compound A t-butylamine salt is that in the powder X-ray diffraction spectrum, at least about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees. , A crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 20.7 degrees, about 21.0 degrees, and about 21.9 degrees.
  • crystal of the compound A sodium salt in the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2 ⁇ ) of 18.4 degrees, about 22.9 degrees, and about 25.5 degrees.
  • compound A sodium salt is at least about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of 18.4 degrees, about 22.9 degrees, and about 25.5 degrees.
  • Compound A hemicalcium salt has a crystalline form in one embodiment. And in crystal form, the crystal is characterized by the physicochemical data of (l) below.
  • (L) It has a diffraction peak at a diffraction angle (2 ⁇ ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 13 or the diffraction angle (2 ⁇ ) shown in Table 8, or the diffraction angle shown in Table 8 (l).
  • Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2 ⁇ ) selected from substantially the same diffraction angle (2 ⁇ ) as 2 ⁇ ). It has a diffraction spectrum.
  • the crystal of the compound A hemicalcium salt in the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2 ⁇ ) of about 20.3 degrees, about 20.8 degrees, and about 22.1 degrees.
  • the compound A hemicalcium salt in the powder X-ray diffraction spectrum, at least about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, It is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 20.3 degrees, about 20.8 degrees, and about 22.1 degrees.
  • each crystal form is specified by the physicochemical data described in the present specification, but each spectral data can vary slightly due to its nature and should be understood strictly. is not it.
  • the diffraction angle (2 ⁇ ) and the overall pattern are important in determining the identity of crystals due to their nature, and the relative strength is the direction of crystal growth and the size of particles. , May vary slightly depending on the measurement conditions.
  • the overall pattern is important for the identification of crystal identity, and it may change slightly depending on the measurement conditions.
  • a compound having a pattern similar to that of the powder X-ray diffraction spectrum or DSC as a whole is included in the compound of the present invention.
  • the description of the diffraction angle (2 ⁇ (degrees)) in the powder X-ray diffraction pattern and the onset temperature (° C.) and peak temperature (° C.) of the endothermic peak in the DSC analysis is generally acceptable in the data measurement method. It means that the error range is included, and it means that it is approximately the onset temperature and the peak temperature of the diffraction angle and the endothermic peak.
  • the “about” of the diffraction angle (2 ⁇ (degrees)) in powder X-ray diffraction is ⁇ 0.2 degrees in one embodiment and ⁇ 0.1 degrees in yet another embodiment.
  • the compound of the present invention can be produced, for example, according to the methods shown below, methods similar thereto, or Examples.
  • the seed crystal may or may not be used.
  • Compound A has a neuroprotective and / or repairing effect.
  • Compound A in one embodiment, has a long-lasting neuroprotective and / or repairing effect.
  • neuroprotective and / or repair action include neuroprotection and / or via glial cells (eg, microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, and satellite cells). Restorative action can be mentioned.
  • a mode of neuroprotective and / or repair action via glial cells includes the myelination promoting action of Schwann cells.
  • Compound A Since Compound A has a neuroprotective and / or repairing effect, it can be used as a prophylactic and / or therapeutic agent for neuropathy.
  • neuropathy includes peripheral neuropathy and central neuropathy.
  • Diseases associated with peripheral neuropathy include, for example, diabetic neuropathy, metabolic peripheral neuropathy associated with urinary toxicosis, peripheral neuropathy associated with vitamin B deficiency, diphtheria, botulinum food poisoning, and infection with herpesvirus (herpes zoster).
  • Peripheral neuropathy associated with illness anticonvulsant phenitoin, antibacterial agents (such as chloramphenicol, nitrofurantin, and sulfonamides), chemotherapeutic agents (taxan: paclitaxel, docetaxel, etc., platinum preparations: oxali
  • Immune peripheral neuropathy such as sexual motor neuropathy, peripheral neuropathy associated with allergic diseases such as nodular periarteritis, allergic vasculitis, systemic erythematosus, heavy metals such as lead, mercury, arsenic, and tarium, thinner, etc.
  • Addictive peripheral neuropathy associated with ingestion of toxic substances such as organic solvents, organic phosphorus pesticides, triorsocrecil phosphate (TOCP), or alcohol, peripheral neuropathy due to cancer compression of nerves, hereditary diseases Peripheral neuropathy associated with (eg, hypothyroidism, renal failure, Charcoal-Marie Tooth's disease, Leftham's disease, porphyrinosis, Fabry's disease, and hereditary pressure vulnerability neuropathy).
  • Diseases associated with central neuropathy include, for example, Alzheimer's disease, Parkinson's disease, Levy body dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Huntington's disease, dystonia, prion.
  • Infectious neuropathy such as sclerosis, optic neuromyelitis, concentric sclerosis, acute diffuse encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosis total encephalitis, progressive multifocal leukoencephalopathy, hypoxic encephalopathy and Intoxication / metabolic neuropathy such as pons-central medullary sheath destruction, and vascular neuropathy such as Binswanger's disease can be mentioned.
  • the compound of the present invention 1) Complementing and / or enhancing the prophylactic and / or therapeutic effect of the compound, 2) It may be administered as a combination drug in combination with other drugs for improving the dynamics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound.
  • the combination drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When administered as these separate formulations, simultaneous administration and staggered administration are included.
  • the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later.
  • Each administration method may be the same or different.
  • the disease that exerts a prophylactic and / or therapeutic effect by the above-mentioned combination drug is not particularly limited, and any disease that complements and / or enhances the prophylactic and / or therapeutic effect of the compound of the present invention may be used.
  • combination drugs to be combined with the compound of the present invention include not only those found up to now but also those found in the future.
  • drugs for complementing and / or enhancing the prophylactic and / or therapeutic effect of the compounds of the present invention on neuropathy include, for example, aldose reductase inhibitors, vitamins, and brain protectants.
  • aldose reductase inhibitor examples include epalrestat.
  • vitamin preparations examples include mecobalamin.
  • the brain protective drug examples include edaravone.
  • the dose of the other drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of compound A and other drugs can be appropriately selected depending on the age and body weight of the administration target, administration method, administration time, target disease, symptom, combination and the like. For example, 0.01 to 100 parts by mass of another drug may be used with respect to 1 part by mass of compound A.
  • any two or more kinds may be administered in an appropriate combination in an appropriate ratio.
  • the compound of the present invention or a combination drug of the compound of the present invention and another drug for the above purpose is usually formulated as a suitable pharmaceutical composition together with a pharmaceutically acceptable carrier, and then systemically or systematically. It is administered topically, orally or parenterally.
  • the compound of the present invention is administered to a mammal (preferably a human, more preferably a patient) in a pharmaceutically effective amount.
  • the dose of the compound of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually from once a day to several times in the range of 1 ng to 1000 mg per adult. It can be given orally once or several times a day in the range of 0.1 ng to 10 mg per adult, or intravenously in the range of 1 to 24 hours a day. It is continuously administered within.
  • an amount smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
  • an internal solid preparation or an internal liquid preparation for oral administration When administering the compound of the present invention or a concomitant drug of the compound of the present invention and another drug, an internal solid preparation or an internal liquid preparation for oral administration, a sustained release preparation for oral administration, a release control preparation, or It is used as an injection, an external preparation, an inhalant, a suppository, etc. for parenteral administration.
  • the compound of the present invention is used as a drug substance of the above-mentioned pharmaceutical products.
  • the substance which is an active ingredient is usually used as various additives.
  • it is formulated with a pharmaceutically acceptable carrier such as a solvent, and then administered systemically or topically, orally or parenterally.
  • the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of a pharmaceutical product.
  • the pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient.
  • the pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, improving the usability, and the like.
  • substances such as those described in Yakuji Nippo's 2000 "Encyclopedia of Pharmaceutical Additives” (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
  • Compound A is usually administered systemically or topically, orally or parenterally.
  • Oral preparations include, for example, liquid preparations for internal use (eg, elixirs, syrups, pharmaceutically acceptable liquids, suspensions, emulsions), solid preparations for internal use (eg, tablets (sublingual tablets, oral cavity). (Including disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, troches, etc.
  • parenteral preparations include liquid preparations (for example, intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, eye drops, etc.) and eye drops (eg, aqueous drops).
  • Eye drops aqueous eye drops, aqueous suspended eye drops, viscous eye drops, solubilized eye drops, etc.
  • non-aqueous eye drops non-aqueous eye drops, non-aqueous suspended eye drops, etc.
  • external preparations for example, , Ointments (eye ointments, etc.)
  • eye drops etc.
  • These preparations may be release control agents such as immediate release preparations and sustained release preparations.
  • These preparations can be produced by a known method, for example, the method described in the Japanese Pharmacopoeia.
  • An oral solution is produced by, for example, dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.
  • the solid preparation for internal use as an oral preparation contains, for example, an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.) as an active ingredient, and a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminen metasilicate).
  • a disintegrant eg, calcium fibrous glycolate, etc.
  • a lubricant eg, magnesium stearate, etc.
  • a solubilizing agent glutamic acid, aspartic acid, etc.
  • it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or may be coated with two or more layers.
  • an ointment is produced by triturating or melting an active ingredient as a base.
  • the ointment base is selected from known or commonly used ones.
  • higher fatty acids or higher fatty acid esters eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.
  • waxes eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid ester, etc.
  • surfactants for example, polyoxyethylene alkyl ether phosphates, etc.
  • higher alcohols for example, cetanol, stearyl alcohol, cetostearyl alcohol, etc.
  • silicon oil for example, for example.
  • Dimethylpolysiloxane, etc. Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic vaseline, white vaseline, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oil (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.) , Ester oil, olive oil, sesame oil, terepine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalane, etc.), water, absorption enhancer, anti-fog agent, alone or a mixture of two or more. Used for Further, it may contain a moisturizer, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.
  • glycols eg, ethylene glycol, diethylene glycol, propylene
  • Injections as parenteral preparations include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent before use. Injectables are used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and the like, and combinations thereof are used.
  • this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. May be good.
  • a solubilizing agent for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • an emulsifier for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. May be good.
  • compound A or various salts thereof can be produced according to, for example, the examples described later and methods similar thereto.
  • the seed crystal may or may not be used.
  • the location of separation by chromatography and the solvent in parentheses shown on the TLC indicate the elution solvent or developing solvent used, and the ratio represents the volume ratio.
  • the parentheses shown in the NMR section indicate the solvent used for the measurement.
  • LCMS was performed using the Waters i-class system under the following conditions.
  • TFA trifluoroacetic acid
  • the powder X-ray diffraction spectrum was measured under any of the following conditions.
  • DSC differential scanning calorimetry
  • Condition 1 Equipment: DISCOVERY DSC manufactured by TA Instruments Sample cell: Aluminum pan Nitrogen gas flow rate: 40 mL / min Condition 2 Equipment: METTLER TOLEDO TGA / DSC 3+ Sample cell: Aluminum pan Argon gas Flow rate: 20 mL / min Condition 3 Equipment: Mettler Toledo DSC 3+ Sample cell: Aluminum pan Argon gas Flow rate: 20 mL / min
  • Example 1 Sulfuric acid (0.26 mL) is added to a solution of isopropyl 3- (2-hydroxyphenyl) propanoate 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), and the reaction mixture is mixed at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (73.2 g) having the following physical properties. 1 1 H-NMR (CDCl 3 ): ⁇ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.
  • Example 2 Isopropyl 3- (2- (pent-4-in-1-yloxy) phenyl) propanoate in a solution of the compound (3.00 g) prepared in Example 1 in N, N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added at the same temperature, and the mixture was stirred at the same temperature for 15 minutes. 5-Chloro-1-pentyne (CAS Registry Number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether.
  • Example 3 Isopropyl (E) -3- (2-((5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) penta-4-en-1-yl) Il) Oxy) Phenyl) Propanoate
  • a heptane (2 mL) solution of the compound (1.00 g) prepared in Example 2 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated.
  • Example 3 N- (3-bromophenyl) benzenesulfonamide 3-bromoaniline (1.02 g) in a solution of dichloromethane (20 mL) at 0 ° C. with pyridine (0.95 mL), N, N-dimethyl Aminopyridine (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours.
  • DMAP N, N-dimethyl Aminopyridine
  • Example 4 Isopropyl (E) -3-(2-((5- (3- (phenylsulfonamide) phenyl) penta-4-en-1-yl) oxy) phenyl) propanoate The compound prepared in Example 3.
  • a 1 M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound (146 mg) prepared in Example 4 in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50 ° C. for 8 hours. It was acidified by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (105 mg) having the following physical characteristics.
  • Example 6 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid diisopropylamine salt 1 g of the compound obtained in Example 5 was dissolved in 3.0 mL of isopropyl acetate. After heating to 40 ° C., 1.5 mL of tetrahydrofuran was added. 647 mg of diisopropylamine was added to this solution. When 0.5 mg of seed crystal was added, crystals gradually precipitated. Further, 6.0 mL of isopropyl acetate was added dropwise over 1 hour, and then cooled to 0 ° C. over 2 hours.
  • the mixture was stirred at 0 ° C. for 1 hour, and the crystals were collected by filtration.
  • the crystals collected by filtration were dried at 50 ° C. using a vacuum pump and a sample dryer to obtain 1.07 g of the crystals.
  • the diisopropylamine salt which is the compound of this example, can be precipitated as crystals having a higher purity than other amine salts, and is useful as an intermediate for producing B crystals of compound A.
  • the seed crystal was obtained by the following method. First, 150 mg of the compound obtained in Example 5 was dissolved in 0.75 mL of tetrahydrofuran. After heating the solution to 40 ° C., 51 mg of diisopropylamine was added, and then 1.5 mL of isopropyl acetate was added, and crystals gradually precipitated. Crystals were collected by filtration with stirring at 25 ° C., and the collected crystals were dried at 50 ° C. using a vacuum pump and a sample dryer to obtain seed crystals.
  • Powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 1, and the DSC chart is shown in FIG. 2, respectively.
  • Example 8 Then, 6.3 mL of normal heptane was added to the solution, and 0.03 g of the A crystal described in Example 8 was further added to gradually precipitate crystals. After stirring for 15 hours, 20.7 mL of normal heptane was added dropwise over 2 hours, and then cooled to 0 ° C. over 2 hours. After stirring at 0 ° C. for 1 hour, the crystals were collected by filtration, and the collected crystals were dried at 40 ° C. using a vacuum pump and a sample dryer to obtain seed crystals.
  • Powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 3, and the DSC chart is shown in FIG. 4, respectively.
  • DSC Differential scanning calorimetry
  • Example 7 N-3-[(1E) -5-chloropenta-1-en-1-yl] phenylbenzenesulfonamide Compound (10.0 g) synthesized in Example 3 (1), 2- [(1E) -5-chloropenta-1-ene-1-yl] -4,4,5,5-tetramethyl-1,3,2-dioxaborane (CAS registration number: 126688-98-0) (8.
  • Example 7 (2) N-3-[(1E) -5-iodopenta-1-en-1-yl] phenylbenzenesulfonamide Methyl ethyl ketone (10.0 g) of the compound (10.0 g) synthesized in Example 7 (1). N, N-dimethylformamide (9 mL), concentrated sulfuric acid (29.2 mg) and sodium iodide (22.3 g) were added to the 81 mL) solution, and the mixture was stirred at 75 ° C. for 5 hours. The reaction solution was adjusted to 50 ° C., methyl ethyl ketone (60 mL) was added, the mixture was cooled to room temperature, and then water (50 mL) was added.
  • N-heptane 29 mL was added to the solution adjusted to an internal temperature of 45 ° C., and the mixture was stirred for 10 minutes or more, and then n-heptane (9.3 mL) was further added. After cooling to an internal temperature of 25 ° C. and stirring for 1 hour, the precipitate was filtered. The wet crystals were vacuum dried at 50 ° C. for 12 hours to obtain the title compound (12.0 g) having the following physical characteristics.
  • Example 7 (3): tert-Butyl (benzenesulfonyl) 3-[(1E) -5-iodopenta-1-ene-1-yl] phenylcarbamate DMAP (1.4 g) cooled to an internal temperature of 0 ° C. , Triethylamine (49 mL), di-tert-butyl dicarbonate (66.4 g) in tetrahydrofuran (350 mL) was added dropwise with a solution of compound (100 g) synthesized in Example 7 (2) in tetrahydrofuran (400 mL).
  • reaction solution was stirred for 1 hour, and then 0.5 mol / L sulfuric acid aqueous solution (450 mL) and methyl tert-butyl ether (1000 mL) were added to separate the solutions.
  • the organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and water (300 mL). After concentrating the organic layer to 5 v / w, toluene (600 mL) was added and concentrated to 3.5 v / w. Toluene (600 mL) was added to the concentrate again to concentrate to 3.5 v / w.
  • Isopropyl alcohol 700 mL was added to the concentrated solution whose internal temperature was adjusted to 60 ° C. After cooling to an internal temperature of 30 ° C., 50 mg of seed crystals were added and the mixture was stirred for 1 hour. Further, isopropyl alcohol (1000 mL) was added, and the mixture was stirred for 1 hour. The temperature was adjusted to an internal temperature of 30 to 40 ° C. and stirred for 1 hour, then cooled to an internal temperature of 0 ° C. and stirred for 1 hour, and the precipitate was filtered. The wet crystals were vacuum dried at 40 ° C. for 12 hours to obtain the title compound (108 g) having the following physical property values.
  • the compound (1.0 g) synthesized in Example 7 (3) and N-methyl-2-pyrrolidone ( 0.5 mL) solution was added and the mixture was cooled to an internal temperature of 10 ° C.
  • Example 7 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] diisopropylamine propanoate Crystal
  • Example 7 (4) A 2 mol / L potassium hydroxide aqueous solution (4.0 mL) was added to the solution of the compound synthesized in (1), and the mixture was stirred at an internal temperature of 90 ° C. for 3 hours. After cooling the reaction solution to room temperature, a 35% aqueous citric acid solution (5.0 mL) and isopropyl acetate (5.0 mL) were added.
  • the aqueous layer was extracted with isopropyl acetate (5.0 mL). The combined organic layers were washed successively with 5% aqueous sodium bisulfite solution (4.0 mL), 5% aqueous sodium hydrogen carbonate solution (4.0 mL) and water (4.0 mL). The organic layer was concentrated to 3 v / w. Tetrahydrofuran (1.0 mL) was added to the concentrated solution to adjust the internal temperature to 40 ° C. Diisopropylamine (534 ⁇ L) and tetrahydrofuran (0.5 mL) were added and seed crystals (0.5 mg) were added.
  • Example 7 (6) Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal B)
  • a 20% aqueous citric acid solution (3 mL) was added to a solution of the compound (1.217 g) synthesized in Example 7 (5) in isopropyl acetate (5 mL) to separate the solutions.
  • the organic layer was washed twice with water (3 mL). After the organic layer was concentrated to 2.5 v / w, isopropyl acetate (5 mL) was added and concentrated to 2.5 v / w.
  • Example 8 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal A) 149.6 g of the compound obtained in Example 5 was dissolved in 100 mL of ethyl acetate at room temperature. 900 mL of n-heptane was added to this solution. The solution became slightly cloudy and gradually became two layers, and the crystals clumped at the bottom of the flask and were crushed. Then, the mixture was stirred at room temperature for 3 days, and the crystals were collected by filtration. The crystals collected by filtration were dried in air to obtain 121.3 g of the crystals.
  • Powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 5, and the DSC chart is shown in FIG. 6, respectively.
  • DSC Differential scanning calorimetry
  • Example 9 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid ethylenediamine salt in Example 8 (free form A crystal) 0.4 mL of ethanol was added to 200 mg of the obtained compound, and the mixture was stirred at room temperature. After adding 29 ⁇ L of ethylenediamine to this, 0.8 mL of MTBE was added. After ultrasonic irradiation, 1.2 mL of MTBE (2-methoxy-2-methylpropane) was added, and the mixture was stirred at room temperature for 10 minutes. The solid was collected by filtration and dried at room temperature using a vacuum pump and a sample dryer to obtain 201 mg of the crystals.
  • Powder X-ray diffraction spectrum measurement condition Condition 1 Table 4 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—K ⁇ rays.
  • DSC Differential scanning calorimetry
  • Example 10 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid venetamine salt in Example 8 (free form A crystal) 2 mL of methanol was added to 1 g of the obtained compound. Further, a solution of 450 mg of Venetamine in 1 mL of methanol was added. The solvent was distilled off under reduced pressure, 430 ⁇ L of diethyl ether was added to the residue, and the solvent was distilled off again under reduced pressure. Further, 430 ⁇ L of dichloromethane was added again, and the solvent was distilled off under reduced pressure.
  • Powder X-ray diffraction spectrum measurement condition Condition 1 Table 5 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—K ⁇ rays.
  • DSC Differential scanning calorimetry
  • Example 11 Crystal of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid t-butylamine salt
  • Example 8 free form A crystal
  • To 100 mg of the compound obtained in (1) was dissolved by adding 1.5 mL of ethanol, 1.5 mL of MTBE solution of 13.5 mg of t-butylamine was added, and the mixture was stirred at room temperature for 1 day. The solid was collected by filtration and dried overnight to obtain 113 mg of the crystals.
  • Powder X-ray diffraction spectrum measurement condition Condition 1 Table 6 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—K ⁇ rays.
  • Example 12 Crystals of sodium salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid in Example 8 (free form A crystal) 200 ⁇ L of methanol was added to 100 mg of the obtained compound to dissolve it. 107.4 ⁇ L of a 2 mol / L sodium hydroxide aqueous solution was added thereto, and the mixture was concentrated to dryness. Then, 200 ⁇ L of 2-butanol was added, stirred, and then concentrated to dryness. Then, 200 ⁇ L of 2-butanol was added, and the mixture was stirred at room temperature for 7 days and then at 60 ° C. for 1 day. As it was concentrated to dryness, 100 mg of the crystals were obtained.
  • Powder X-ray diffraction spectrum measurement condition Condition 1
  • Table 7 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—K ⁇ rays.
  • Example 13 Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid hemicalcium salt
  • Example 8 (free form A crystal) 39.8 mg of calcium hydroxide was added to 500 mg of the compound obtained in. 1 mL of methanol and 100 ⁇ L of water were added and ultrasonic waves were applied to prepare a suspension. This was concentrated to dryness. 2.5 mL of isopropyl alcohol and 0.5 mL of water were added, and the mixture was stirred at room temperature for 4 days. The crystals were filtered and dried to obtain 431 mg of the crystals.
  • Powder X-ray diffraction spectrum measurement condition Condition 1 Table 8 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—K ⁇ rays.
  • Example 14 Stability evaluation in crystallization solvent Convergence experiments with competing slurries were carried out for the crystal drug substances described in Example 7 (free body B crystal) and Example 8 (free body A crystal). 50 mg each of free A crystals and B crystals were mixed in vitro, and solvents having various compositions were added to prepare a slurry. After stirring at 0 ° C. to 60 ° C. for 12 hours or more, the crystals were filtered off. The obtained wet crystals were analyzed by powder X-ray diffraction. The results are shown in Tables 9 and 10.
  • the B crystal converged to the B crystal, suggesting that the B crystal is a stable crystal.
  • Example 15 Manufacturability evaluation in the crushing process
  • the crystal drug substances of Example 7 (free body B crystal) and Example 8 (free body A crystal) were described below using AO Jet mill (Seishin Enterprise Co., Ltd.).
  • the uncrushed API was crushed under the crushing conditions of. Crushing conditions: Supply pressure 0.64 MPa, crushing pressure 0.60 MPa, feed rate 2.0 g / min ⁇ Results / Discussion>
  • Crushing conditions Supply pressure 0.64 MPa, crushing pressure 0.60 MPa, feed rate 2.0 g / min ⁇ Results / Discussion>
  • the uncrushed drug substance (10 g) of A crystal was crushed, the entire amount could not be crushed because significant sticking and blockage occurred in the mill body.
  • the uncrushed drug substance (10 g) of B crystal was crushed, no conspicuous adhesion occurred and the entire amount could be crushed. Therefore, B crystal is a crystal form excellent in handling.
  • Example 17 Measurement of bulk density The bulk density was measured for the crystal drug substances described in Example 7 (free body B crystal) and Example 8 (free body A crystal).
  • ⁇ Experimental method> Gently place about 5 g of the crystalfield of Example 7 (free body B crystal) and Example 8 (free body A crystal) in a tare 50 mL glass graduated cylinder, and measure the mass of the packed crystal field drug. It was measured. Then, the apparent volume of the crystal field drug substance was measured when the graduated cylinder was slowly inverted once. The value obtained by dividing the mass of the crystal field drug by the apparent volume was taken as the loose bulk density (loose apparent density).
  • Biological Experimental Example 1 In vitro test using Schwann cells (test method) 1) Preparation of rat Schwann cells The dorsal root ganglion (hereinafter abbreviated as DRG) of 0 to 2 day old newborn rats was excised in a clean bench and collected in DMEM. The collected tube was centrifuged at 400 g at room temperature for 3 minutes, the supernatant was removed, and a 0.25% collagenase solution was added. The extracted DRG was dispersed and separated by incubation at 37 ° C. for 30 minutes, and then centrifuged at 400 g at room temperature for 3 minutes to remove the supernatant, and then 0.25% Trypsin / EDTA and DNase I were added.
  • DRG dorsal root ganglion
  • the cells were statically cultured in a CO 2 incubator under the conditions of 5% CO 2 , 95% Air, and 37 ° C. 2) Compound addition
  • the medium of the cell culture plate was removed by suction with an ejector, and DMEM supplemented with 1% dialyzed FBS and 100 ⁇ mol / L dibutyryl cyclic AMP was added.
  • 10 ⁇ L each of a solution of the compound described in Example 5 dissolved in DMSO (final concentration 0.1, 0.3, 1 or 3 ⁇ mol / L) was added, and 5% CO 2 , 95% Air was added in a CO 2 incubator. , 37 ° C., statically cultured.
  • Table 12 shows the Schwann cell differentiation promotion rate (% of vehicle value) with respect to the medium group when the solution of the compound described in Example 5 of 0.3 or 3 ⁇ mol / L was added. From this, it is considered that the compound described in Example 5 has a strong neuroprotective and / or repairing action.
  • Biological Experimental Example 2 Test Using Streptozotocin-Induced Rat Model
  • Test method 1) Modeling method A rat was prepared by intravenously administering 55 mg / kg of streptozotocin (hereinafter abbreviated as STZ). 2) Measurement of nociception threshold The rat was placed in a transparent acrylic cage for measurement at least once before STZ administration for 10 minutes or more, and the rat was acclimatized to the measurement environment.
  • Example 5 Eight von Frey filaments of 0.4, 0.6, 1, 2, 4, 6, 8, 15 g were applied vertically from under the wire mesh bed to the soles of the hind limbs. A quick escape reaction or a foot swing reaction was regarded as a positive reaction (with a reaction).
  • the compound described in Example 5 was orally administered once a day from 14 days to 28 days after STZ administration, and the dose was 0.03, 0.3, or 3 mg / kg.
  • the nociception thresholds were set to 14 days before STZ administration, 14 days after STZ administration (dose start date of the compound according to Example 5), 21 days (7 days after the start of dosing), 28 days (14 days after the start of dosing), and 35 days.
  • the nociception threshold was measured by the up-down method according to the method of Chaplan et al. (J Neuroscii Methods. 1994; 53: 55-63). The improvement rate of the nociception threshold was calculated based on the following formula.
  • the QA-GS adduct concentration was calculated from the following formula.
  • the QA-GS adduct concentration of the compound described in Example 5 was low, 200 nmol / L or less.
  • Hand1-EST Test POCA® Hand1- used as an index of the reproductive and developmental toxicity of the compound described in Example 5 in the number of viable cells and the differentiation efficiency in the process of differentiation from mouse ES cells to myocardium. It was measured using EST (DS Pharma Biomedical Co., Ltd.) (Le Coz F et al., J. Toxicol., 40 (2): 251-61.2015).
  • a 1000 mg / mL DMSO solution of the compound described in Example 5 was prepared.
  • a 1000 mg / mL DMSO solution of the compound described in Example 5 was diluted with a myocardial differentiation medium to prepare a 1000 ⁇ g / mL solution (final concentration of DMSO 0.1%) of the compound described in Example 5.
  • the cells were sequentially diluted 3-fold with a myocardial differentiation medium (final concentration of DMSO of 0.1%), and the concentration without a precipitate was recorded as the maximum solubility.
  • a myocardial differentiation medium final concentration of DMSO of 0.1%)
  • concentration without a precipitate was recorded as the maximum solubility.
  • Thawed Hand1-ES cells mouse ES cells in which the promoter region of the myocardial differentiation marker Hand1 gene and its downstream were transformed with the luciferase gene using pGL4.17 as a vector
  • were suspended in an undifferentiated maintenance medium and then gelatin-coated 60 mm Dish. was sown and cultured for 2-3 days.
  • trypsin-treated Hand1-ES cells were subcultured in gelatin-coated 60 mm Dish at 2 ⁇ 10 6 cells / 5 mL and cultured overnight. Then, the trypsin-treated Hand1-ES cells were suspended in myocardial differentiation medium, seeded on a Prime Surface® U-bottom 96-well plate at 750 cells / 50 ⁇ L / well, and cultured for 2 hours. After 2 hours, 50 ⁇ L of the compound described in Example 5 or a myocardial differentiation medium containing 5-FU as a positive control was added (final concentration of the compound described in Example 5: 1000,333,111,37.0, 12.
  • the risk of teratogenicity was determined by inputting the obtained maximum solubility, 50% inhibition concentration of viable cell number, and 50% inhibition concentration of differentiation efficiency into the dedicated analysis software POCA Hand1-EST Analysis Software. The criteria for judgment were low risk for probability less than 0.52 and high risk for 0.52 or more (Nagahori et al., Toxicology Letters 259, 44-51). (result) The compounds described in Example 5 had a probability of less than 0.52 and were considered to have a low risk of teratogenicity.
  • Preparation example 1 Compound A (Crystal B) 5 mg-containing tablet The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets containing 5 mg of the active ingredient in one tablet. 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (Crystal B): 50 g -Carboxymethyl cellulose calcium (disintegrant): 20 g -Magnesium stearate (lubricant): 10 g -Microcrystalline cellulose: 920 g
  • Preparation example 2 Injection containing 20 mg of compound A (crystal A) After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled in 5 mL each in an ampoule, lyophilized by a conventional method, and 20 mg of activity in 1 ampoule. Obtain 10,000 ampoules containing the ingredients. 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal A): 200 g ⁇ Mannitol: 20g ⁇ Distilled water: 50L
  • Compound A has a neuroprotective and / or repairing effect, and is therefore useful for the treatment of neuropathy and the like. Further, the crystal of compound A is useful as a drug substance.

Abstract

A compound according to the present invention has a strong neuroprotective action and/or a neurorepair action, and therefore can serve as a therapeutic agent for neurological disorders (e.g., chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic angiitis, diabetic peripheral neuropathy, entrapment syndrome, peripheral neuropathy associated with administration of chemotherapy medication, and peripheral neuropathy associated with Charcot-Marie-Tooth disease). Moreover, the crystals of the compound have excellent handling properties as a bulk drug substance.

Description

ベンゼン誘導体の新規結晶形New crystalline form of benzene derivative
　本発明は、３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸（以下、化合物Ａと略記することがある。）の新規結晶等に関する。 The present invention relates to 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (hereinafter, may be abbreviated as compound A). Regarding new crystals, etc.
　神経系は、中枢神経系と末梢神経系に大別され、なかでも末梢神経系は、脳および脊髄と身体末梢とを連絡し、神経伝達を担う。末梢神経系は、体性神経系（脳脊髄神経系）と自律神経系に分類できる。さらに、体性神経系は脳神経と脊髄神経に分けられる。また、体性神経系を機能的に分類すると、感覚受容器から生じた神経信号（興奮）を中枢神経に伝えるものは求心性、あるいは感覚性の神経線維に分類され、それに対して、脳・脊髄から筋や腺等の効果器に向かう神経信号を伝えるものは遠心性、あるいは運動性の神経線維に分類される。脳神経は脳から出る末梢神経で１２対が知られ、あるものは感覚性、あるものは運動性、またはあるものは混合性の神経線維から成っている。第１～第１２神経対は、それぞれ嗅神経、視神経、動眼神経、滑車神経、三叉神経、外転神経、顔面神経、内耳神経、舌咽神経、迷走神経、副神経、舌下神経と呼ばれる。これらのうち、感覚性または混合性の神経線維から成る神経は、嗅神経、視神経、三叉神経、顔面神経、内耳神経、舌咽神経、迷走神経が知られている。脊髄神経は脊髄から発する末梢神経で左右３１対が知られ、８対の頚神経、１２対の胸神経、５対の腰神経、５対の仙骨神経と１対の尾骨神経が知られている。脊髄神経はすべて混合性の神経線維から成り、皮膚等に行く感覚線維（後根）と骨格筋に行く運動線維（前根）とを含んでいる。 The nervous system is roughly divided into the central nervous system and the peripheral nervous system. Among them, the peripheral nervous system connects the brain and spinal cord with the peripheral body and is responsible for nerve transmission. The peripheral nervous system can be classified into the somatic nervous system (cerebral spinal nervous system) and the autonomic nervous system. Furthermore, the somatic nervous system is divided into the cranial nerves and the spinal nerves. In addition, when the somatic nervous system is functionally classified, those that transmit nerve signals (excitement) generated from sensory receptors to the central nerve are classified into afferent or sensory nerve fibers, whereas the brain and Those that transmit nerve signals from the spinal cord to effectors such as muscles and glands are classified as efferent or motile nerve fibers. Cranial nerves are the peripheral nerves that emerge from the brain and are known to consist of 12 pairs, some of which are sensory, some of which are motile, and some of which are mixed nerve fibers. The first to twelfth nerve pairs are called olfactory nerve, optic nerve, moving eye nerve, pulley nerve, trigeminal nerve, abduction nerve, facial nerve, internal ear nerve, lingual nerve, stray nerve, accessory nerve, and sublingual nerve, respectively. Of these, the nerves composed of sensory or mixed nerve fibers are known to be the olfactory nerve, the optic nerve, the trigeminal nerve, the facial nerve, the vestibulocochlear nerve, the glossopharyngeal nerve, and the vagus nerve. The spinal nerves are peripheral nerves originating from the spinal cord, and 31 pairs of left and right are known, 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves and 1 pair of caudal nerves. .. The spinal nerves are all composed of mixed nerve fibers, and include sensory fibers (dorsal roots) that go to the skin and the like and motor fibers (ventral roots) that go to skeletal muscles.
　感覚性の神経線維、すなわち感覚神経は視覚器、聴覚器、嗅覚器、味覚器および皮膚等の感覚受容器が受け取った光、音、温度や接触等の刺激を中枢神経系に正確に伝える機能を担っている。中枢神経系に伝えられた神経信号は、最終的には大脳皮質の各感覚野、例えば、視覚野、聴覚野等に伝達され、正常に感覚が認識される。しかしながら、これらの感覚神経が、例えば、ウイルス感染、腫瘍、癌、糖尿病、虚血、外傷、圧迫、薬物や放射線療法等により、軸索、ミエリン鞘またはシュワン細胞等が侵され、細胞死や脱髄等の様々な神経障害が引き起こされることがある。その結果、障害が生じた感覚神経では正確な神経伝達が行われないため、例えば、難聴や神経障害性疼痛等の疾患が発症する。これら以外に、特定の感覚神経だけでなく、感覚神経を含む様々な末梢神経が、例えば、代謝疾患、自己免疫疾患等の疾患、外傷、薬物中毒等の原因によって同時に障害を受ける末梢神経障害がある。本症は、単一神経、別々の領域にある２つ以上の神経、または多数の神経が同時に障害を受けることがある。その症状は、末梢部の刺痛、しびれ、灼熱感、関節の固有覚低下、振動覚低下、疼痛（神経障害性疼痛も含む）、異常感覚、冷えまたはほてり等が挙げられ、非常に複雑で多岐に渡っている。 Sensory nerve fibers, that is, sensory nerves, have the function of accurately transmitting stimuli such as light, sound, temperature, and contact received by sensory receptors such as the visual organs, auditory organs, olfactory organs, taste organs, and skin to the central nervous system. Is responsible for. The neural signals transmitted to the central nervous system are finally transmitted to each sensory area of the cerebral cortex, for example, the visual cortex, the auditory area, etc., and the sensation is normally recognized. However, these sensory nerves are affected by axons, myelin sheaths, Schwann cells, etc. due to, for example, viral infection, tumor, cancer, diabetes, ischemia, trauma, compression, drugs, radiotherapy, etc., resulting in cell death or demyelination. Various neuropathy such as myelin may be caused. As a result, accurate neurotransmission is not performed in the impaired sensory nerve, and thus diseases such as deafness and neuropathic pain develop. In addition to these, peripheral neuropathy in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to causes such as metabolic diseases, autoimmune diseases, trauma, drug addiction, etc. be. The disease can damage a single nerve, two or more nerves in separate areas, or multiple nerves at the same time. Symptoms include peripheral stinging, numbness, burning sensation, decreased joint proprioception, decreased vibration sensation, pain (including neuropathic pain), dysesthesia, coldness or burning, and are very complex. It is diverse.
　しかしながら、上記のような末梢神経系疾患はその発生機序が不明な疾患であったり、神経の物理的な損傷であったりするため、それらの治療に際しては、主として症状改善等を目的とした対症療法が行われており、障害を受けた神経系に直接作用する根本治療となるような臨床上有用な薬剤はほとんど知られていない。 However, the above-mentioned peripheral nervous system diseases are diseases whose pathogenesis is unknown or physical damage to nerves. Therefore, when treating them, the symptomatic treatment is mainly aimed at improving the symptoms. Few clinically useful drugs are known that provide symptomatic treatment and provide curative treatment that acts directly on the damaged nervous system.
　本発明の課題は、神経保護および／または修復作用を有する化合物を見出すことであり、さらには、該化合物について、医薬品として取り扱いに優れた結晶等を見出すことである。 An object of the present invention is to find a compound having a neuroprotective and / or repairing action, and further to find a crystal or the like that is excellent in handling as a pharmaceutical product for the compound.
　本発明者らは、上記の課題を解決するために検討を行い、一態様において化合物Ａのフリー体が２種類の結晶を形成することを見出した。また、一態様において、化合物Ａの塩を見出した。
　本発明は、例えば下記の態様である。
［１］結晶形態である、３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸。
［２］粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［１］記載の化合物。
［２－１］粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［１］記載の化合物。
［２－２］粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［１］記載の化合物。
［２－３］粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［１］記載の化合物。
［２－４］粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、および約１４．１度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［２－５］粉末Ｘ線回折スペクトルにおいて、さらに約１２．０度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも１つ以上の回折ピークを有する、［２－４］記載の化合物。
［２－６］粉末Ｘ線回折スペクトルにおいて、さらに約１２．０度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［２－４］記載の化合物。
［３］粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［３－１］粉末Ｘ線回折スペクトルにおいて、少なくとも約８．５度、約８．７度、約１１．２度、約１１．４度、約１２．０度、約１２．９度、約１３．５度、約１３．６度、約１４．１度、約１４．５度、約１５．１度、約１５．９度、約１６．２度、約１６．４度、約１６．６度、約１６．９度、約１７．２度、約１７．４度、約１７．９度、約１８．５度、約１９．２度、約１９．４度、約１９．６度、約２０．２度、約２０．４度、約２０．６度、約２１．７度、約２２．２度、約２２．５度、約２３．０度、約２３．１度、約２４．０度、約２４．５度、約２４．７度、約２５．２度、約２５．６度、約２６．０度、約２７．０度、約２７．１度、約２８．５度、約３１．６度、約３２．３度、約３３．１度、および約３３．３度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［４］図３に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［１］記載の化合物。
［５］示差走査熱量測定において吸熱ピーク温度が約８６．４℃である、［１］～［４］、［２－１］～［２－６］、および［３－１］のいずれか一項に記載の化合物。
［６］図４に示される示差走査熱量測定チャートを特徴とする、［５］記載の化合物。
［７］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［１］記載の化合物。
［７－１］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［１］記載の化合物。
［７－２］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［１］記載の化合物。
［７－３］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［１］記載の化合物。
［７－４］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度および約１０．５度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［７－５］粉末Ｘ線回折スペクトルにおいて、さらに約８．２度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも１つ以上の回折ピークを有する、［７－４］記載の化合物。
［７－６］粉末Ｘ線回折スペクトルにおいて、さらに約８．２度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［７－４］記載の化合物。
［７－７］粉末Ｘ線回折スペクトルにおいて、さらに約８．２度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［７－４］記載の化合物。
［８］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［８－１］粉末Ｘ線回折スペクトルにおいて、少なくとも約５．３度、約６．２度、約６．８度、約８．２度、約１０．５度、約１２．３度、約１２．５度、約１２．８度、約１３．６度、約１４．６度、約１５．８度、約１６．４度、約１７．１度、約１７．８度、約１８．１度、約１８．２度、約１８．７度、約１９．０度、約１９．３度、約１９．６度、約２０．１度、約２０．３度、約２０．５度、約２１．０度、約２１．７度、約２２．０度、約２２．１度、約２２．４度、約２３．５度、約２４．０度、約２４．３度、約２４．７度、約２５．２度、約２５．５度、約２５．８度、約２６．５度、約２７．７度、約２８．０度、約２９．１度、約２９．６度、約２９．８度、約３０．６度、約３１．５度、および約３３．１度の回折角（２θ）に回折ピークを有する、［１］記載の化合物。
［９］図５に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［１］記載の化合物。
［１０］示差走査熱量測定において吸熱ピーク温度が約８６．８℃である、［１］、［７］～［９］、［７－１］～［７－７］、および［８－１］のいずれか一項に記載の化合物。
［１１］図６に示される示差走査熱量測定チャートを特徴とする、［１０］記載の化合物。
［１２］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩。
［１３］結晶形態である、［１２］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩。
［１４］粉末Ｘ線回折スペクトルにおいて、約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［１３］記載の化合物。
［１４－１］粉末Ｘ線回折スペクトルにおいて、約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［１３］記載の化合物。
［１４－２］粉末Ｘ線回折スペクトルにおいて、約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［１３］記載の化合物。
［１４－３］粉末Ｘ線回折スペクトルにおいて、約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［１３］記載の化合物。
［１５］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に回折ピークを有する、［１３］記載の化合物。
［１５－１］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．５度、約８．５度、約９．８度、約１０．６度、約１２．８度、約１３．３度、約１３．４度、約１４．１度、約１５．０度、約１５．２度、約１５．９度、約１６．２度、約１６．５度、約１７．０度、約１７．１度、約１９．３度、約１９．７度、約２０．１度、約２０．９度、約２１．３度、約２１．６度、約２１．９度、約２２．３度、約２２．４度、約２２．７度、約２２．９度、約２３．４度、約２４．０度、約２４．５度、約２５．８度、約２６．５度、約２６．８度、約２７．４度、および約３０．３度の回折角（２θ）に回折ピークを有する、［１３］記載の化合物。
［１６］図１に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［１３］記載の化合物。
［１７］示差走査熱量測定において吸熱ピーク温度が約１３３℃である、［１３］～［１６］、［１４－１］～［１４－３］、および［１５－１］のいずれか一項に記載の化合物。
［１７－１］図２に示される示差走査熱量測定チャートを特徴とする、［１７］記載の化合物。
［１８］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　エチレンジアミン塩。
［１９］結晶形態である、［１８］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　エチレンジアミン塩。
［２０］粉末Ｘ線回折スペクトルにおいて、約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［１９］記載の化合物。
［２０－１］粉末Ｘ線回折スペクトルにおいて、約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［１９］記載の化合物。
［２０－２］粉末Ｘ線回折スペクトルにおいて、約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［１９］記載の化合物。
［２０－３］粉末Ｘ線回折スペクトルにおいて、約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［１９］記載の化合物。
［２１］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に回折ピークを有する、［１９］記載の化合物。
［２２］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．４度、約９．２度、約１２．５度、約１３．０度、約１４．１度、約１４．７度、約１７．８度、約１８．７度、約１９．４度、約２０．０度、約２０．８度、約２１．６度、約２２．５度、約２２．８度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に回折ピークを有する、［１９］記載の化合物。
［２３］図７に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［１９］記載の化合物。
［２４］示差走査熱量測定において吸熱ピーク温度が約１５３℃である、［１９］～［２３］、および［２０－１］～［２０－３］のいずれか一項に記載の化合物。
［２５］図８に示される示差走査熱量測定チャートを特徴とする、［２４］記載の化合物。
［２６］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ベネタミン塩。
［２７］結晶形態である、［２６］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ベネタミン塩。
［２８］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［２７］記載の化合物。
［２８－１］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［２７］記載の化合物。
［２８－２］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［２７］記載の化合物。
［２８－３］粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［２７］記載の化合物。
［２９］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に回折ピークを有する、［２７］記載の化合物。
［３０］粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．３度、約１１．９度、約１２．９度、約１４．９度、約１５．１度、約１５．８度、約１６．６度、約１６．７度、約１８．４度、約１８．８度、約１９．２度、約１９．８度、約１９．９度、約２０．４度、約２０．８度、約２１．２度、約２２．２度、約２３．２度、約２４．４度、約２４．７度、約２５．２度、約２５．７度、約２６．３度、約２６．６度、約２７．１度、約２８．０度、約２８．７度、約２９．２度および約２９．８度の回折角（２θ）に回折ピークを有する、［２７］記載の化合物。
［３１］図９に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［２７］記載の化合物。
［３２］示差走査熱量測定において吸熱ピーク温度が約１１４℃である、［２７］～［３１］、および［２８－１］～［２８－３］のいずれか一項に記載の化合物。
［３３］図１０に示される示差走査熱量測定チャートを特徴とする、［３２］記載の化合物。
［３４］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ｔ－ブチルアミン塩。
［３５］結晶形態である、［３４］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ｔ－ブチルアミン塩。
［３６］粉末Ｘ線回折スペクトルにおいて、約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［３５］記載の化合物。
［３６－１］粉末Ｘ線回折スペクトルにおいて、約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［３５］記載の化合物。
［３６－２］粉末Ｘ線回折スペクトルにおいて、約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［３５］記載の化合物。
［３６－３］粉末Ｘ線回折スペクトルにおいて、約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［３５］記載の化合物。
［３７］粉末Ｘ線回折スペクトルにおいて、少なくとも約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に回折ピークを有する、［３５］記載の化合物。
［３８］粉末Ｘ線回折スペクトルにおいて、少なくとも約８．３度、約９．４度、約１２．１度、約１２．５度、約１４．４度、約１５．５度、約１５．９度、約１６．２度、約１６．７度、約１８．５度、約１８．９度、約１９．７度、約２０．７度、約２１．０度、約２１．９度、約２２．４度、約２２．９度、約２３．１度、約２３．６度、約２４．０度、約２５．１度、約２５．７度、および約２７．７度の回折角（２θ）に回折ピークを有する、［３５］記載の化合物。
［３９］図１１に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［３５］記載の化合物。
［４０］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ナトリウム塩。
［４１］結晶形態である、［４０］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ナトリウム塩。
［４２］粉末Ｘ線回折スペクトルにおいて、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［４１］記載の化合物。
［４３－１］粉末Ｘ線回折スペクトルにおいて、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［４１］記載の化合物。
［４３－２］粉末Ｘ線回折スペクトルにおいて、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［４１］記載の化合物。
［４３－３］粉末Ｘ線回折スペクトルにおいて、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［４１］記載の化合物。
［４４］粉末Ｘ線回折スペクトルにおいて、少なくとも約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に回折ピークを有する、［４１］記載の化合物。
［４５］粉末Ｘ線回折スペクトルにおいて、少なくとも約７．７度、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１５．４度、約１６．２度、約１７．６度、約１７．９度、約１８．４度、約１８．７度、約１９．６度、約１９．９度、約２０．５度、約２１．０度、約２１．４度、約２２．５度、約２２．７度、約２２．９度、約２３．１度、約２４．４度、約２５．３度、約２５．５度、約２６．５度、約２８．４度、約２８．９度、および約２９．２度の回折角（２θ）に回折ピークを有する、［４１］記載の化合物。
［４６］図１２に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［４１］記載の化合物。
［４７］３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ヘミカルシウム塩。
［４８］結晶形態である、［４７］記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ヘミカルシウム塩。
［４９］粉末Ｘ線回折スペクトルにおいて、約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、［４８］記載の化合物。
［４９－１］粉末Ｘ線回折スペクトルにおいて、約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に少なくとも３つ以上の回折ピークを有する、［４８］記載の化合物。
［４９－２］粉末Ｘ線回折スペクトルにおいて、約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に少なくとも４つ以上の回折ピークを有する、［４８］記載の化合物。
［４９－３］粉末Ｘ線回折スペクトルにおいて、約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に少なくとも５つ以上の回折ピークを有する、［４８］記載の化合物。
［５０］粉末Ｘ線回折スペクトルにおいて、少なくとも約約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に回折ピークを有する、［４８］記載の化合物。
［５１］粉末Ｘ線回折スペクトルにおいて、少なくとも約５．３度、約６．６度、約８．２度、約８．８度、約１０．８度、約１１．３度、約１１．８度、約１３．０度、約１３．３度、約１３．７度、約１４．０度、約１４．９度、約１５．６度、約１６．０度、約１６．６度、約１６．７度、約１６．９度、約１７．４度、約１７．６度、約１７．９度、約１８．０度、約１８．６度、約１９．０度、約１９．５度、約１９．８度、約２０．０度、約２０．３度、約２０．８度、約２１．３度、約２１．６度、約２２．１度、約２２．４度、約２２．９度、約２３．２度、約２３．４度、約２３．９度、約２４．４度、約２４．７度、約２５．７度、および約２７．０度の回折角（２θ）に回折ピークを有する、［４８］記載の化合物。
［５２］図１３に示される粉末Ｘ線回折スペクトルチャートを特徴とする、［４８］記載の化合物。
［５３］［１］～［５２］、［２－１］～［２－６］、［３－１］、［７－１］～［７－７］、［８－１］、［１４－１］～［１４－３］、［１５－１］、［１７－１］、［２０－１］～［２０－３］、［２８－１］～［２８－３］、［３６－１］～［３６－３］、［４３－１］～［４３－３］、［４９－１］～［４９－３］のいずれか一項に記載の化合物を含有する医薬組成物。
［５４］［１］～［５２］、［２－１］～［２－６］、［３－１］、［７－１］～［７－７］、［８－１］、［１４－１］～［１４－３］、［１５－１］、［１７－１］、［２０－１］～［２０－３］、［２８－１］～［２８－３］、［３６－１］～［３６－３］、［４３－１］～［４３－３］、［４９－１］～［４９－３］のいずれか一項に記載の化合物を含有するシュワン細胞分化促進剤。
［５５］［１］～［５２］、［２－１］～［２－６］、［３－１］、［７－１］～［７－７］、［８－１］、［１４－１］～［１４－３］、［１５－１］、［１７－１］、［２０－１］～［２０－３］、［２８－１］～［２８－３］、［３６－１］～［３６－３］、［４３－１］～［４３－３］、［４９－１］～［４９－３］のいずれか一項に記載の化合物を含有する神経障害の予防及び／又は治療剤。
［５６］神経障害が末梢神経障害である［５５］記載の剤。
［５７］末梢神経障害が、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、結節性動脈周囲炎、アレルギー性血管炎、糖尿病性末梢神経障害、絞扼性神経障害、化学療法薬投与に伴う末梢神経障害、またはシャルコー・マリー・トゥース病に伴う末梢神経障害である、［５６］記載の剤。 The present inventors have conducted studies to solve the above problems and found that the free form of compound A forms two types of crystals in one embodiment. Also, in one embodiment, a salt of compound A was found.
The present invention is, for example, the following aspects.
[1] Crystal form, 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid.
[2] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees. The compound according to [1], which has at least two or more diffraction peaks at a diffraction angle (2θ) of about 25.6 degrees.
[2-1] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24 degrees. The compound according to [1], which has at least three or more diffraction peaks at diffraction angles (2θ) of 0.7 degrees and about 25.6 degrees.
[2-2] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24 degrees. The compound according to [1], which has at least four or more diffraction peaks at diffraction angles (2θ) of 0.7 degrees and about 25.6 degrees.
[2-3] In the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24 degrees. The compound according to [1], which has at least 5 or more diffraction peaks at diffraction angles (2θ) of 0.7 degrees and about 25.6 degrees.
[2-4] The compound according to [1], which has a diffraction peak at a diffraction angle (2θ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in a powder X-ray diffraction spectrum.
[2-5] In the powder X-ray diffraction spectrum, the diffraction angles (2θ) are further increased to about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees. The compound according to [2-4], which has at least one diffraction peak.
[2-6] In the powder X-ray diffraction spectrum, the diffraction angles (2θ) of about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees are further set. The compound according to [2-4], which has at least two or more diffraction peaks.
[3] In the powder X-ray diffraction spectrum, at least about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24. The compound according to [1], which has a diffraction peak at a diffraction angle (2θ) of 7 degrees and about 25.6 degrees.
[3-1] In the powder X-ray diffraction spectrum, at least about 8.5 degrees, about 8.7 degrees, about 11.2 degrees, about 11.4 degrees, about 12.0 degrees, about 12.9 degrees, about. 13.5 degrees, about 13.6 degrees, about 14.1 degrees, about 14.5 degrees, about 15.1 degrees, about 15.9 degrees, about 16.2 degrees, about 16.4 degrees, about 16. 6 degrees, about 16.9 degrees, about 17.2 degrees, about 17.4 degrees, about 17.9 degrees, about 18.5 degrees, about 19.2 degrees, about 19.4 degrees, about 19.6 degrees , About 20.2 degrees, about 20.4 degrees, about 20.6 degrees, about 21.7 degrees, about 22.2 degrees, about 22.5 degrees, about 23.0 degrees, about 23.1 degrees, about 24.0 degrees, about 24.5 degrees, about 24.7 degrees, about 25.2 degrees, about 25.6 degrees, about 26.0 degrees, about 27.0 degrees, about 27.1 degrees, about 28. The compound according to [1], which has diffraction peaks at diffraction angles (2θ) of 5 degrees, about 31.6 degrees, about 32.3 degrees, about 33.1 degrees, and about 33.3 degrees.
[4] The compound according to [1], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[5] Any one of [1] to [4], [2-1] to [2-6], and [3-1], which has an endothermic peak temperature of about 86.4 ° C. in differential scanning calorimetry. The compounds described in the section.
[6] The compound according to [5], which comprises the differential scanning calorimetry chart shown in FIG.
[7] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24. The compound according to [1], which has at least two or more diffraction peaks at a diffraction angle (2θ) of 3 degrees.
[7-1] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about. The compound according to [1], which has at least three or more diffraction peaks at a diffraction angle (2θ) of 24.3 degrees.
[7-2] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about. The compound according to [1], which has at least four or more diffraction peaks at a diffraction angle (2θ) of 24.3 degrees.
[7-3] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about. The compound according to [1], which has at least 5 or more diffraction peaks at a diffraction angle (2θ) of 24.3 degrees.
[7-4] The compound according to [1], which has a diffraction peak at a diffraction angle (2θ) of at least about 6.8 degrees and about 10.5 degrees in a powder X-ray diffraction spectrum.
[7-5] In the powder X-ray diffraction spectrum, the diffraction angles (2θ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees. The compound according to [7-4], which has at least one diffraction peak.
[7-6] In the powder X-ray diffraction spectrum, the diffraction angles (2θ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees. The compound according to [7-4], which has at least two or more diffraction peaks.
[7-7] In the powder X-ray diffraction spectrum, the diffraction angles (2θ) are further increased to about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees. The compound according to [7-4], which has at least three or more diffraction peaks.
[8] In the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24 degrees. The compound according to [1], which has a diffraction peak at a diffraction angle (2θ) of 3 degrees.
[8-1] In the powder X-ray diffraction spectrum, at least about 5.3 degrees, about 6.2 degrees, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.3 degrees, about. 12.5 degrees, about 12.8 degrees, about 13.6 degrees, about 14.6 degrees, about 15.8 degrees, about 16.4 degrees, about 17.1 degrees, about 17.8 degrees, about 18. 1 degree, about 18.2 degrees, about 18.7 degrees, about 19.0 degrees, about 19.3 degrees, about 19.6 degrees, about 20.1 degrees, about 20.3 degrees, about 20.5 degrees , About 21.0 degrees, about 21.7 degrees, about 22.0 degrees, about 22.1 degrees, about 22.4 degrees, about 23.5 degrees, about 24.0 degrees, about 24.3 degrees, about 24.7 degrees, about 25.2 degrees, about 25.5 degrees, about 25.8 degrees, about 26.5 degrees, about 27.7 degrees, about 28.0 degrees, about 29.1 degrees, about 29. The compound according to [1], which has a diffraction peak at a diffraction angle (2θ) of 6 degrees, about 29.8 degrees, about 30.6 degrees, about 31.5 degrees, and about 33.1 degrees.
[9] The compound according to [1], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[10] In differential scanning calorimetry, the endothermic peak temperature is about 86.8 ° C., [1], [7] to [9], [7-1] to [7-7], and [8-1]. The compound according to any one of the above.
[11] The compound according to [10], which comprises the differential scanning calorimetry chart shown in FIG.
[12] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] diisopropylamine propanoate.
[13] The diisopropylamine salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoate according to [12], which is in crystalline form.
[14] In the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about 20. The compound according to [13], which has at least two or more diffraction peaks at a diffraction angle (2θ) of 9 degrees.
[14-1] In the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about. The compound according to [13], which has at least three or more diffraction peaks at a diffraction angle (2θ) of 20.9 degrees.
[14-2] In the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about. The compound according to [13], which has at least four or more diffraction peaks at a diffraction angle (2θ) of 20.9 degrees.
[14-3] In the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about. The compound according to [13], which has at least 5 or more diffraction peaks at a diffraction angle (2θ) of 20.9 degrees.
[15] In the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about 20 degrees. .. The compound according to [13], which has a diffraction peak at a diffraction angle (2θ) of 9 degrees.
[15-1] In the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 8.5 degrees, about 9.8 degrees, about 10.6 degrees, about 12.8 degrees, about 13.3 degrees, about. 13.4 degrees, about 14.1 degrees, about 15.0 degrees, about 15.2 degrees, about 15.9 degrees, about 16.2 degrees, about 16.5 degrees, about 17.0 degrees, about 17. 1 degree, about 19.3 degrees, about 19.7 degrees, about 20.1 degrees, about 20.9 degrees, about 21.3 degrees, about 21.6 degrees, about 21.9 degrees, about 22.3 degrees , About 22.4 degrees, about 22.7 degrees, about 22.9 degrees, about 23.4 degrees, about 24.0 degrees, about 24.5 degrees, about 25.8 degrees, about 26.5 degrees, about The compound according to [13], which has a diffraction peak at a diffraction angle (2θ) of 26.8 degrees, about 27.4 degrees, and about 30.3 degrees.
[16] The compound according to [13], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[17] In any one of [13] to [16], [14-1] to [14-3], and [15-1], the endothermic peak temperature is about 133 ° C. in the differential scanning calorimetry. The compound described.
[17-1] The compound according to [17], which comprises the differential scanning calorimetry chart shown in FIG.
[18] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid Ethylenediamine salt.
[19] The ethylenediamine salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoate according to [18], which is in crystalline form.
[20] In the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about 23.9 degrees, about 24.4 degrees. The compound according to [19], which has at least two or more diffraction peaks at a diffraction angle (2θ) of about 29.7 degrees.
[20-1] In the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about 23.9 degrees, about 24 degrees. The compound according to [19], which has at least three or more diffraction peaks at diffraction angles (2θ) of .4 degrees and about 29.7 degrees.
[20-2] In the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about 23.9 degrees, about 24 degrees. The compound according to [19], which has at least four or more diffraction peaks at diffraction angles (2θ) of .4 degrees and about 29.7 degrees.
[20-3] In the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about 23.9 degrees, about 24 degrees. The compound according to [19], which has at least 5 or more diffraction peaks at diffraction angles (2θ) of .4 degrees and about 29.7 degrees.
[21] In the powder X-ray diffraction spectrum, at least about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about 23.9 degrees, about 24. The compound according to [19], which has a diffraction peak at a diffraction angle (2θ) of 4 degrees and about 29.7 degrees.
[22] In the powder X-ray diffraction spectrum, at least about 6.4 degrees, about 9.2 degrees, about 12.5 degrees, about 13.0 degrees, about 14.1 degrees, about 14.7 degrees, about 17. 8 degrees, about 18.7 degrees, about 19.4 degrees, about 20.0 degrees, about 20.8 degrees, about 21.6 degrees, about 22.5 degrees, about 22.8 degrees, about 23.9 degrees The compound according to [19], which has a diffraction peak at a diffraction angle (2θ) of about 24.4 degrees and about 29.7 degrees.
[23] The compound according to [19], which comprises the powder X-ray diffraction spectrum chart shown in FIG. 7.
[24] The compound according to any one of [19] to [23] and [20-1] to [20-3], which has an endothermic peak temperature of about 153 ° C. in differential scanning calorimetry.
[25] The compound according to [24], which comprises the differential scanning calorimetry chart shown in FIG.
[26] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid venetamine salt.
[27] The venetamine salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoate according to [26], which is in crystalline form.
[28] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about 20.4 degrees, about 20.8 degrees. The compound according to [27], which has at least two or more diffraction peaks at a diffraction angle (2θ) of about 21.2 degrees.
[28-1] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about 20.4 degrees, about 20 degrees. The compound according to [27], which has at least three or more diffraction peaks at diffraction angles (2θ) of 0.8 degrees and about 21.2 degrees.
[28-2] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about 20.4 degrees, about 20 degrees. The compound according to [27], which has at least four or more diffraction peaks at diffraction angles (2θ) of 0.8 degrees and about 21.2 degrees.
[28-3] In the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about 20.4 degrees, about 20 degrees. The compound according to [27], which has at least 5 or more diffraction peaks at diffraction angles (2θ) of 0.8 degrees and about 21.2 degrees.
[29] In the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about 20.4 degrees, about 20. The compound according to [27], which has a diffraction peak at a diffraction angle (2θ) of 8 degrees and about 21.2 degrees.
[30] In the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.3 degrees, about 11.9 degrees, about 12.9 degrees, about 14.9 degrees, about 15.1 degrees, about 15. 8 degrees, about 16.6 degrees, about 16.7 degrees, about 18.4 degrees, about 18.8 degrees, about 19.2 degrees, about 19.8 degrees, about 19.9 degrees, about 20.4 degrees , About 20.8 degrees, about 21.2 degrees, about 22.2 degrees, about 23.2 degrees, about 24.4 degrees, about 24.7 degrees, about 25.2 degrees, about 25.7 degrees, about Diffraction peaks at diffraction angles (2θ) of 26.3 degrees, about 26.6 degrees, about 27.1 degrees, about 28.0 degrees, about 28.7 degrees, about 29.2 degrees and about 29.8 degrees. The compound according to [27].
[31] The compound according to [27], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[32] The compound according to any one of [27] to [31] and [28-1] to [28-3], which has an endothermic peak temperature of about 114 ° C. in differential scanning calorimetry.
[33] The compound according to [32], which comprises the differential scanning calorimetry chart shown in FIG.
[34] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid t-butylamine salt.
[35] The t-butylamine salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid according to [34], which is in crystalline form.
[36] In the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees, about 20.7 degrees, about 21.0 degrees. The compound according to [35], which has at least two or more diffraction peaks at a diffraction angle (2θ) of about 21.9 degrees.
[36-1] In the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees, about 20.7 degrees, about 21 degrees. The compound according to [35], which has at least three or more diffraction peaks at diffraction angles (2θ) of 0.0 degrees and about 21.9 degrees.
[36-2] In the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees, about 20.7 degrees, about 21 degrees. The compound according to [35], which has at least four or more diffraction peaks at diffraction angles (2θ) of 0.0 degrees and about 21.9 degrees.
[36-3] In the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees, about 20.7 degrees, about 21 degrees. The compound according to [35], which has at least 5 or more diffraction peaks at a diffraction angle (2θ) of 0.0 degrees and about 21.9 degrees.
[37] In the powder X-ray diffraction spectrum, at least about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees, about 20.7 degrees, about 21. The compound according to [35], which has a diffraction peak at a diffraction angle (2θ) of 0 degrees and about 21.9 degrees.
[38] In the powder X-ray diffraction spectrum, at least about 8.3 degrees, about 9.4 degrees, about 12.1 degrees, about 12.5 degrees, about 14.4 degrees, about 15.5 degrees, about 15. 9 degrees, about 16.2 degrees, about 16.7 degrees, about 18.5 degrees, about 18.9 degrees, about 19.7 degrees, about 20.7 degrees, about 21.0 degrees, about 21.9 degrees , About 22.4 degrees, about 22.9 degrees, about 23.1 degrees, about 23.6 degrees, about 24.0 degrees, about 25.1 degrees, about 25.7 degrees, and about 27.7 degrees The compound according to [35], which has a diffraction peak at a diffraction angle (2θ).
[39] The compound according to [35], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[40] 3-[2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] sodium propanoate salt.
[41] The sodium salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoate according to [40], which is in crystalline form.
[42] In the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 18.4 degrees, about 22.9 degrees. The compound according to [41], which has at least two or more diffraction peaks at a diffraction angle (2θ) of about 25.5 degrees.
[43-1] In the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 18.4 degrees, about 22. The compound according to [41], which has at least three or more diffraction peaks at diffraction angles (2θ) of 9.9 degrees and about 25.5 degrees.
[43-2] In the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 18.4 degrees, about 22. The compound according to [41], which has at least four or more diffraction peaks at diffraction angles (2θ) of 9.9 degrees and about 25.5 degrees.
[43-3] In the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 18.4 degrees, about 22. The compound according to [41], which has at least 5 or more diffraction peaks at diffraction angles (2θ) of 9.9 degrees and about 25.5 degrees.
[44] In the powder X-ray diffraction spectrum, at least about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 18.4 degrees, about 22. The compound according to [41], which has a diffraction peak at a diffraction angle (2θ) of 9 degrees and about 25.5 degrees.
[45] In the powder X-ray diffraction spectrum, at least about 7.7 degrees, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about 15. 4 degrees, about 16.2 degrees, about 17.6 degrees, about 17.9 degrees, about 18.4 degrees, about 18.7 degrees, about 19.6 degrees, about 19.9 degrees, about 20.5 degrees , About 21.0 degrees, about 21.4 degrees, about 22.5 degrees, about 22.7 degrees, about 22.9 degrees, about 23.1 degrees, about 24.4 degrees, about 25.3 degrees, about The compound according to [41], which has diffraction peaks at diffraction angles (2θ) of 25.5 degrees, about 26.5 degrees, about 28.4 degrees, about 28.9 degrees, and about 29.2 degrees.
[46] The compound according to [41], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[47] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid hemicalcium salt.
[48] The hemicalcium salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoate, which is in crystalline form.
[49] In the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, about 20.3 degrees, about 20.8 degrees. The compound according to [48], which has at least two or more diffraction peaks at a diffraction angle (2θ) of degrees and about 22.1 degrees.
[49-1] In the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, about 20.3 degrees, about 20 degrees. The compound according to [48], which has at least three or more diffraction peaks at diffraction angles (2θ) of .8 degrees and about 22.1 degrees.
[49-2] In the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, about 20.3 degrees, about 20 degrees. The compound according to [48], which has at least four or more diffraction peaks at diffraction angles (2θ) of .8 degrees and about 22.1 degrees.
[49-3] In the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, about 20.3 degrees, about 20 degrees. The compound according to [48], which has at least 5 or more diffraction peaks at diffraction angles (2θ) of .8 degrees and about 22.1 degrees.
[50] In the powder X-ray diffraction spectrum, at least about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, about 20.3 degrees, about 20 degrees. The compound according to [48], which has a diffraction peak at a diffraction angle (2θ) of .8 degrees and about 22.1 degrees.
[51] In the powder X-ray diffraction spectrum, at least about 5.3 degrees, about 6.6 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 11.3 degrees, about 11. 8 degrees, about 13.0 degrees, about 13.3 degrees, about 13.7 degrees, about 14.0 degrees, about 14.9 degrees, about 15.6 degrees, about 16.0 degrees, about 16.6 degrees , About 16.7 degrees, about 16.9 degrees, about 17.4 degrees, about 17.6 degrees, about 17.9 degrees, about 18.0 degrees, about 18.6 degrees, about 19.0 degrees, about 19.5 degrees, about 19.8 degrees, about 20.0 degrees, about 20.3 degrees, about 20.8 degrees, about 21.3 degrees, about 21.6 degrees, about 22.1 degrees, about 22. 4 degrees, about 22.9 degrees, about 23.2 degrees, about 23.4 degrees, about 23.9 degrees, about 24.4 degrees, about 24.7 degrees, about 25.7 degrees, and about 27.0 degrees The compound according to [48], which has a diffraction peak at a diffraction angle (2θ) of degrees.
[52] The compound according to [48], which comprises the powder X-ray diffraction spectrum chart shown in FIG.
[53] [1] to [52], [2-1] to [2-6], [3-1], [7-1] to [7-7], [8-1], [14- 1] to [14-3], [15-1], [17-1], [20-1] to [20-3], [28-1] to [28-3], [36-1] A pharmaceutical composition containing the compound according to any one of [36-3], [43-1] to [43-3], and [49-1] to [49-3].
[54] [1] to [52], [2-1] to [2-6], [3-1], [7-1] to [7-7], [8-1], [14- 1] to [14-3], [15-1], [17-1], [20-1] to [20-3], [28-1] to [28-3], [36-1] A Schwann cell differentiation promoter containing the compound according to any one of [36-3], [43-1] to [43-3], and [49-1] to [49-3].
[55] [1] to [52], [2-1] to [2-6], [3-1], [7-1] to [7-7], [8-1], [14- 1] to [14-3], [15-1], [17-1], [20-1] to [20-3], [28-1] to [28-3], [36-1] -Prevention and / or treatment of neuropathy containing the compound according to any one of [36-3], [43-1] to [43-3], [49-1] to [49-3]. Agent.
[56] The agent according to [55], wherein the neuropathy is a peripheral neuropathy.
[57] Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and chemotherapeutic drug administration. The agent according to [56], which is a peripheral neuropathy or a peripheral neuropathy associated with Charcot-Marie-Tooth disease.
　化合物Ａのフリー体は結晶を形成し、取扱いに優れるため、医薬品原薬として有用である。 The free form of compound A forms crystals and is easy to handle, so it is useful as a drug substance.
化合物Ａのジイソプロピルアミン塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the diisopropylamine salt of Compound A is represented (the vertical axis represents intensity (counts) and the horizontal axis represents 2θ (degrees)). 化合物Ａのジイソプロピルアミン塩の示差走査熱量測定（ＤＳＣ）チャートを表す（縦軸は熱流束（Ｗ／ｇ）を表し、横軸は温度（℃）を表す。）。The differential scanning calorimetry (DSC) chart of the diisopropylamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)). 化合物Ａのフリー体（Ｂ晶）の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the free form (B crystal) of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのフリー体（Ｂ晶）の示差走査熱量測定（ＤＳＣ）チャートを表す（縦軸は熱流束（Ｗ／ｇ）を表し、横軸は温度（℃）を表す。）。The differential scanning calorimetry (DSC) chart of the free compound (B crystal) of compound A is represented (the vertical axis represents heat flux (W / g), and the horizontal axis represents temperature (° C.)). 化合物Ａのフリー体（Ａ晶）の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the free form (A crystal) of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのフリー体（Ａ晶）の示差走査熱量測定（ＤＳＣ）チャートを表す（縦軸は熱流束（Ｗ／ｇ）を表し、横軸は温度（℃）を表す。）。The differential scanning calorimetry (DSC) chart of the free compound (A crystal) of compound A is represented (the vertical axis represents heat flux (W / g), and the horizontal axis represents temperature (° C.)). 化合物Ａのエチレンジアミン塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the ethylenediamine salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのエチレンジアミン塩の示差走査熱量測定（ＤＳＣ）チャートを表す（縦軸は熱流束（Ｗ／ｇ）を表し、横軸は温度（℃）を表す。）。The differential scanning calorimetry (DSC) chart of the ethylenediamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)). 化合物Ａのベネタミン塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the venetamine salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのベネタミン塩の示差走査熱量測定（ＤＳＣ）チャートを表す（縦軸は熱流束（Ｗ／ｇ）を表し、横軸は温度（℃）を表す。）。The differential scanning calorimetry (DSC) chart of the venetamine salt of compound A is represented (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)). 化合物Ａのｔ－ブチルアミン塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the t-butylamine salt of Compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのナトリウム塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the sodium salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). 化合物Ａのヘミカルシウム塩の粉末Ｘ線回折スペクトルチャートを表す（縦軸は強度（counts）を表し、横軸は２θ（度）を表す。）。The powder X-ray diffraction spectrum chart of the hemicalcium salt of compound A is represented (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). ストレプトゾトシンモデルにおいて、実施例５の化合物を０．３ｍｇ／ｋｇの投与量で投与した場合における侵害受容閾値を表す（縦軸は侵害受容閾値を、横軸はストレプトゾトシン投与後の経過日数を表す。）。In the streptozotocin model, the nociception threshold when the compound of Example 5 was administered at a dose of 0.3 mg / kg (the vertical axis represents the nociception threshold, and the horizontal axis represents the number of days elapsed after streptozotocin administration). ..
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明において、３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸（化合物Ａ）とは、以下の構造式 In the present invention, 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (Compound A) has the following structural formula.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
で表される化合物を意味する。 It means a compound represented by.
　化合物ＡのＢ晶は、以下の（ａ）および（ｂ）の少なくとも一つの物理化学データによって特徴づけられる。好ましくは、（ａ）および（ｂ）の両方の物理化学データによって特徴づけられる。（ａ）図３に示される粉末Ｘ線回折スペクトルチャートもしくは表２に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表２に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトル、（ｂ）以下の図４に示される示差走査熱量測定（ＤＳＣ）チャート、またはピーク温度が約８６．４℃である吸熱ピークを有する。 The B crystal of compound A is characterized by at least one of the following physicochemical data (a) and (b). Preferably, it is characterized by the physicochemical data of both (a) and (b). (A) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 3 or the diffraction angle (2θ) shown in Table 2, or the diffraction angle (2θ) shown in Table 2. Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum, (b) a differential scanning calorimetry (DSC) chart shown in FIG. 4 below, or a heat absorption peak with a peak temperature of about 86.4 ° C.
　化合物ＡのＡ晶は、以下の（ｃ）および（ｄ）の少なくとも一つの物理化学データによって特徴づけられる。好ましくは、（ｃ）および（ｄ）の両方の物理化学データによって特徴づけられる。（ｃ）図５に示される粉末Ｘ線回折スペクトルチャートもしくは表３に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表３に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトル、（d）図６に示される示差走査熱量測定（ＤＳＣ）チャート、またはピーク温度が約８６．８℃である吸熱ピークを有する。 The A crystal of compound A is characterized by at least one of the following physicochemical data (c) and (d). Preferably, it is characterized by the physicochemical data of both (c) and (d). (C) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 5 or the diffraction angle (2θ) shown in Table 3, or the diffraction angle (c) shown in Table 3 (c). Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum, (d) a differential scanning calorimetry (DSC) chart shown in FIG. 6, or a heat absorption peak with a peak temperature of about 86.8 ° C.
　化合物ＡのＢ晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、６つ、又は７つの回折ピークを有する結晶形態である。 In some embodiments of the B crystal of compound A, in the powder X-ray diffraction spectrum, about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22 degrees. A crystalline form having at least two, three, four, five, six, or seven diffraction peaks at diffraction angles (2θ) of .2 degrees, about 24.7 degrees, and about 25.6 degrees. ..
　化合物ＡのＢ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に回折ピークを有する結晶形態である。 Another embodiment of the B crystal of compound A is at least about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2θ) of about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees.
　化合物ＡのＢ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、約８．７度、約１１．２度、および約１４．１度の回折角（２θ）に少なくとも１つ又は２つの回折ピークを有する結晶形態である。 Another embodiment of the B crystal of compound A is at least one or two at a diffraction angle (2θ) of about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in the powder X-ray diffraction spectrum. It is a crystal form having a diffraction peak.
　化合物ＡのＢ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、および約１４．１度の回折角（２θ）に回折ピークを有する結晶形態である。 Another embodiment of the B crystal of compound A is a crystal having diffraction peaks at diffraction angles (2θ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in a powder X-ray diffraction spectrum. It is a form.
　化合物ＡのＢ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、および約１４．１度の回折角（２θ）に回折ピークを有し、さらに、約１２．０度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも１つ、２つ、３つまたは４つの回折ピークを有する結晶形態である。 Another aspect of the B crystal of compound A is that it has diffraction peaks at diffraction angles (2θ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in the powder X-ray diffraction spectrum. In addition, at least one, two, three or at diffraction angles (2θ) of about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees. It is a crystal form having four diffraction peaks.
　化合物ＡのＡ晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As an aspect of the A crystal of compound A, in the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23 degrees. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at a diffraction angle (2θ) of 5.5 degrees and about 24.3 degrees.
　化合物ＡのＡ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に回折ピークを有する結晶形態である。 Another embodiment of the A crystal of compound A is at least about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2θ) of about 23.5 degrees and about 24.3 degrees.
　化合物ＡのＡ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度および／または約１０．５度に回折ピークを有する結晶形態である。 Another aspect of the A crystal of compound A is a crystal form having a diffraction peak at at least about 6.8 degrees and / or about 10.5 degrees in the powder X-ray diffraction spectrum.
　化合物ＡのＡ晶の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度および約１０．５度に回折ピークを有する結晶形態である。 Another aspect of the A crystal of compound A is a crystal form having diffraction peaks at at least about 6.8 degrees and about 10.5 degrees in the powder X-ray diffraction spectrum.
　化合物ＡのＡ晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度および約１０．５度に回折ピークを有し、さらに約８．２度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも1つ、２つ、３つまたは４つの回折ピークを有する結晶形態である。 In some embodiments of the A crystal of compound A, the powder X-ray diffraction spectrum has diffraction peaks at at least about 6.8 ° C and about 10.5 ° C, and further at about 8.2 ° C. and about 12.8 ° C. It is a crystalline form having at least one, two, three or four diffraction peaks at diffraction angles (2θ) of about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩（化合物Ａ　ジイソプロピルアミン塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｅ）および（ｆ）の少なくとも一つの物理化学データによって特徴づけられる。好ましくは、（ｅ）および（ｆ）の両方の物理化学データによって特徴づけられる。（ｅ）図１に示される粉末Ｘ線回折スペクトルチャートもしくは表１に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表１に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトル、（ｆ）図２に示される示差走査熱量測定（ＤＳＣ）チャート、またはピーク温度が約１３３℃である吸熱ピークを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid diisopropylamine salt (Compound A diisopropylamine salt) has a crystalline form in one embodiment. And in crystalline form, the crystal is characterized by at least one of the following physicochemical data (e) and (f): Preferably, it is characterized by the physicochemical data of both (e) and (f). (E) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 1 or the diffraction angle (2θ) shown in Table 1, or the diffraction angle (e) shown in Table 1. Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum, (f) a differential scanning calorimetry (DSC) chart shown in FIG. 2, or a heat absorption peak with a peak temperature of about 133 ° C.
　化合物Ａ　ジイソプロピルアミン塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of compound A diisopropylamine salt, in the powder X-ray diffraction spectrum, about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, It is a crystalline form having at least two, three, four, five, or six diffraction peaks at a diffraction angle (2θ) of about 20.1 degrees and about 20.9 degrees.
　化合物Ａ　ジイソプロピルアミン塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に回折ピークを有する結晶形態である。 As another aspect of compound A diisopropylamine salt, in the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, It is a crystal form having diffraction peaks at diffraction angles (2θ) of about 20.1 degrees and about 20.9 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　エチレンジアミン塩（化合物Ａ　エチレンジアミン塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｇ）および（ｈ）の少なくとも一つの物理化学データによって特徴づけられる。好ましくは、（ｇ）および（ｈ）の両方の物理化学データによって特徴づけられる。（ｇ）図７に示される粉末Ｘ線回折スペクトルチャートもしくは表４に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表４に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトル、（ｈ）図８に示される示差走査熱量測定（ＤＳＣ）チャート、またはピーク温度が約１５３℃である吸熱ピークを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid ethylenediamine salt (Compound A ethylenediamine salt) is in crystalline form in one embodiment. When in crystalline form, the crystal is characterized by at least one of the following physicochemical data (g) and (h): Preferably, it is characterized by both (g) and (h) physicochemical data. (G) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 7 or the diffraction angle (2θ) shown in Table 4, or the diffraction angle (g) shown in Table 4 (g). Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum, a differential scanning calorimetry (DSC) chart shown in FIG. 8, or a heat absorption peak with a peak temperature of about 153 ° C.
　化合物Ａ　エチレンジアミン塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of compound A ethylenediamine salt, in the powder X-ray diffraction spectrum, about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2θ) of 23.9 degrees, about 24.4 degrees, and about 29.7 degrees.
　化合物Ａ　エチレンジアミン塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．４度、約９．２度、約１４．７度、約２０．８度、約２１．６度、約２３．９度、約２４．４度、および約２９．７度の回折角（２θ）に回折ピークを有する結晶形態である。 As another aspect of compound A ethylenediamine salt, in the powder X-ray diffraction spectrum, at least about 6.4 degrees, about 9.2 degrees, about 14.7 degrees, about 20.8 degrees, about 21.6 degrees, about. It is a crystal form having diffraction peaks at diffraction angles (2θ) of 23.9 degrees, about 24.4 degrees, and about 29.7 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ベネタミン塩（化合物Ａ　ベネタミン塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｉ）および（ｊ）の少なくとも一つの物理化学データによって特徴づけられる。好ましくは、（ｉ）および（ｊ）の両方の物理化学データによって特徴づけられる。（ｅ）図９に示される粉末Ｘ線回折スペクトルチャートもしくは表５に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表５に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトル、（ｊ）図１０に示される示差走査熱量測定（ＤＳＣ）チャート、またはピーク温度が約１１４℃である吸熱ピークを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid venetamine salt (Compound A venetamine salt) is in crystalline form in one embodiment. When in crystalline form, the crystal is characterized by at least one of the following physicochemical data (i) and (j): Preferably, it is characterized by the physicochemical data of both (i) and (j). (E) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 9 or the diffraction angle (2θ) shown in Table 5, or the diffraction angle (e) shown in Table 5 (e). Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum, (j) a differential scanning calorimetry (DSC) chart shown in FIG. 10, or a heat absorption peak with a peak temperature of about 114 ° C.
　化合物Ａ　ベネタミン塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of the compound A venetamine salt, in the powder X-ray diffraction spectrum, about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2θ) of 20.4 degrees, about 20.8 degrees, and about 21.2 degrees.
　化合物Ａ　ベネタミン塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．３度、約１５．８度、約１８．４度、約１８．８度、約２０．４度、約２０．８度、および約２１．２度の回折角（２θ）に回折ピークを有する結晶形態である。 As another embodiment of the compound A venetamine salt, in the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.3 degrees, about 15.8 degrees, about 18.4 degrees, about 18.8 degrees, about. It is a crystal form having diffraction peaks at diffraction angles (2θ) of 20.4 degrees, about 20.8 degrees, and about 21.2 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ｔ－ブチルアミン塩（化合物Ａ　ｔ－ブチルアミン塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｋ）の物理化学データによって特徴づけられる。（ｋ）図１１に示される粉末Ｘ線回折スペクトルチャートもしくは表６に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表６に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトルを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid t-butylamine salt (Compound A t-butylamine salt) is used in one embodiment. When in crystalline form, the crystal is characterized by the physicochemical data of (k) below. (K) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 11 or the diffraction angle (2θ) shown in Table 6, or the diffraction angle (k) shown in Table 6 (k). Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum.
　化合物Ａ　ｔ－ブチルアミン塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of the compound A t-butylamine salt, in the powder X-ray diffraction spectrum, about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees. , A crystal form having at least 2, 3, 4, 5, or 6 diffraction peaks at diffraction angles (2θ) of about 20.7 degrees, about 21.0 degrees, and about 21.9 degrees. ..
　化合物Ａ　ｔ－ブチルアミン塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約８．３度、約１４．４度、約１５．５度、約１６．７度、約１８．９度、約２０．７度、約２１．０度、および約２１．９度の回折角（２θ）に回折ピークを有する結晶形態である。 Another aspect of compound A t-butylamine salt is that in the powder X-ray diffraction spectrum, at least about 8.3 degrees, about 14.4 degrees, about 15.5 degrees, about 16.7 degrees, about 18.9 degrees. , A crystal form having diffraction peaks at diffraction angles (2θ) of about 20.7 degrees, about 21.0 degrees, and about 21.9 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ナトリウム塩（化合物Ａ　ナトリウム塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｌ）の物理化学データによって特徴づけられる。（ｌ）図１２に示される粉末Ｘ線回折スペクトルチャートもしくは表７に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表７に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトルを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid sodium salt (Compound A sodium salt) is in crystalline form in one embodiment. When in crystal form, the crystal is characterized by the physicochemical data of (l) below. (L) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 12 or the diffraction angle (2θ) shown in Table 7, or the diffraction angle (2θ) shown in Table 7. Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum.
　化合物Ａ　ナトリウム塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of the compound A sodium salt, in the powder X-ray diffraction spectrum, about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about. It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2θ) of 18.4 degrees, about 22.9 degrees, and about 25.5 degrees.
　化合物Ａ　ナトリウム塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約９．７度、約１０．７度、約１３．１度、約１３．８度、約１５．１度、約１８．４度、約２２．９度、および約２５．５度の回折角（２θ）に回折ピークを有する結晶形態である。 Another aspect of compound A sodium salt is at least about 9.7 degrees, about 10.7 degrees, about 13.1 degrees, about 13.8 degrees, about 15.1 degrees, about in the powder X-ray diffraction spectrum. It is a crystal form having diffraction peaks at diffraction angles (2θ) of 18.4 degrees, about 22.9 degrees, and about 25.5 degrees.
　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ヘミカルシウム塩（化合物Ａ　ヘミカルシウム塩）は、一実施形態において結晶形態であり、結晶形態であるとき、その結晶は以下の（ｌ）の物理化学データによって特徴づけられる。（ｌ）図１３に示される粉末Ｘ線回折スペクトルチャートもしくは表８に示される回折角（２θ）と実質的に同じ回折角（２θ）に回折ピークを有する、または表８に示される回折角（２θ）と実質的に同じ回折角（２θ）から選択される回折角（２θ）に少なくとも１つ、２つ、３つ、４つ、５つ、もしくは５つ超のピークを有する、粉末Ｘ線回折スペクトルを有する。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid hemicalcium salt (Compound A hemicalcium salt) has a crystalline form in one embodiment. And in crystal form, the crystal is characterized by the physicochemical data of (l) below. (L) It has a diffraction peak at a diffraction angle (2θ) substantially the same as the powder X-ray diffraction spectrum chart shown in FIG. 13 or the diffraction angle (2θ) shown in Table 8, or the diffraction angle shown in Table 8 (l). Powder X-rays having at least one, two, three, four, five, or more than five peaks at a diffraction angle (2θ) selected from substantially the same diffraction angle (2θ) as 2θ). It has a diffraction spectrum.
　化合物Ａ　ヘミカルシウム塩の結晶のある態様としては、粉末Ｘ線回折スペクトルにおいて、約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に少なくとも２つ、３つ、４つ、５つ、又は６つの回折ピークを有する結晶形態である。 As a certain aspect of the crystal of the compound A hemicalcium salt, in the powder X-ray diffraction spectrum, about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, It is a crystalline form having at least two, three, four, five, or six diffraction peaks at diffraction angles (2θ) of about 20.3 degrees, about 20.8 degrees, and about 22.1 degrees.
　化合物Ａ　ヘミカルシウム塩の別の態様としては、粉末Ｘ線回折スペクトルにおいて、少なくとも約５．３度、約８．２度、約８．８度、約１０．８度、約１８．６度、約２０．３度、約２０．８度および約２２．１度の回折角（２θ）に回折ピークを有する結晶形態である。 As another embodiment of the compound A hemicalcium salt, in the powder X-ray diffraction spectrum, at least about 5.3 degrees, about 8.2 degrees, about 8.8 degrees, about 10.8 degrees, about 18.6 degrees, It is a crystal form having diffraction peaks at diffraction angles (2θ) of about 20.3 degrees, about 20.8 degrees, and about 22.1 degrees.
　本発明において、各結晶形は、本明細書に記載された物理化学データによって特定されるものであるが、各スペクトルデータは、その性質上多少変わり得るものであるから、厳密に解されるべきではない。 In the present invention, each crystal form is specified by the physicochemical data described in the present specification, but each spectral data can vary slightly due to its nature and should be understood strictly. is not it.
　例えば、粉末Ｘ線回折スペクトルデータは、その性質上、結晶の同一性の認定においては、回折角（２θ）や全体的なパターンが重要であり、相対強度は結晶成長の方向、粒子の大きさ、測定条件によって多少変わり得る。 For example, in powder X-ray diffraction spectrum data, the diffraction angle (2θ) and the overall pattern are important in determining the identity of crystals due to their nature, and the relative strength is the direction of crystal growth and the size of particles. , May vary slightly depending on the measurement conditions.
　また、ＤＳＣデータにおいても、結晶の同一性の認定においては、全体的なパターンが重要であり、測定条件によって多少変わり得る。 Also, in the DSC data, the overall pattern is important for the identification of crystal identity, and it may change slightly depending on the measurement conditions.
　したがって、本発明の化合物において、粉末Ｘ線回折スペクトルまたはＤＳＣとパターンが、それぞれ全体的に類似するものは、本発明の化合物に含まれるものである。 Therefore, in the compound of the present invention, a compound having a pattern similar to that of the powder X-ray diffraction spectrum or DSC as a whole is included in the compound of the present invention.
　本明細書中、粉末Ｘ線回折パターンにおける回折角（２θ（度））及びＤＳＣ分析における吸熱ピークのオンセット温度（℃）及びピーク温度（℃）の記載は、当該データ測定法において通常許容される誤差範囲を含むことを意味し、おおよそその回折角及び吸熱ピークのオンセット温度及びピーク温度であることを意味する。例えば、粉末Ｘ線回折における回折角（２θ（度））の「約」は、ある態様としては±０．２度であり、さらに別の態様としては、±０．１度である。ＤＳＣ分析における吸熱ピークのオンセット温度（℃）またはピーク温度（℃）の「約」は、ある態様としては±２℃であり、別の態様としては±１℃であり、さらに別の態様としては±０．３℃である。 In the present specification, the description of the diffraction angle (2θ (degrees)) in the powder X-ray diffraction pattern and the onset temperature (° C.) and peak temperature (° C.) of the endothermic peak in the DSC analysis is generally acceptable in the data measurement method. It means that the error range is included, and it means that it is approximately the onset temperature and the peak temperature of the diffraction angle and the endothermic peak. For example, the “about” of the diffraction angle (2θ (degrees)) in powder X-ray diffraction is ± 0.2 degrees in one embodiment and ± 0.1 degrees in yet another embodiment. The "approx." Of the endothermic peak onset temperature (° C.) or peak temperature (° C.) in DSC analysis is ± 2 ° C. in one embodiment, ± 1 ° C. in another embodiment, and yet in another embodiment. Is ± 0.3 ° C.
　本発明において、本発明の化合物は、例えば以下に示す方法、これらに準ずる方法または実施例に従って製造することが出来る。なお、再結晶を行う際、種晶は、使用しても、または使用しなくてもよい。 In the present invention, the compound of the present invention can be produced, for example, according to the methods shown below, methods similar thereto, or Examples. When recrystallizing, the seed crystal may or may not be used.
　［毒性］
　化合物Ａの毒性は低いものであるため、医薬品として安全に使用することができる。 [toxicity]
Since the toxicity of compound A is low, it can be safely used as a pharmaceutical product.
　［医薬品への適用］
　化合物Ａは、神経保護および／または修復作用を有する。
　化合物Ａは、一実施形態において、持続性に優れた神経保護および／または修復作用を有する。 [Application to pharmaceutical products]
Compound A has a neuroprotective and / or repairing effect.
Compound A, in one embodiment, has a long-lasting neuroprotective and / or repairing effect.
　そのため、化合物Ａは、例えば、神経障害を伴う疾患の治療に有用である。
　本発明において、神経保護および／または修復作用のある態様としては、グリア細胞（例えば、ミクログリア、アストロサイト、オリゴデンドロサイト、上衣細胞、シュワン細胞、および衛星細胞など）を介した神経保護および／または修復作用が挙げられる。グリア細胞を介した神経保護および／または修復作用のある態様としては、シュワン細胞のミエリン化促進作用が挙げられる。 Therefore, compound A is useful, for example, in the treatment of diseases associated with neuropathy.
In the present invention, aspects of neuroprotective and / or repair action include neuroprotection and / or via glial cells (eg, microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, and satellite cells). Restorative action can be mentioned. A mode of neuroprotective and / or repair action via glial cells includes the myelination promoting action of Schwann cells.
　化合物Ａは、神経保護および／または修復作用を有するため、神経障害の予防および／または治療剤として使用することができる。 Since Compound A has a neuroprotective and / or repairing effect, it can be used as a prophylactic and / or therapeutic agent for neuropathy.
　本発明において、神経障害には、末梢神経障害や中枢神経障害が含まれる。
　末梢神経障害を伴う疾患としては、例えば、糖尿病性神経障害、尿毒症に伴う代謝性末梢神経障害、ビタミンB欠乏に伴う末梢神経障害、ジフテリア、ボツリヌス食中毒、およびヘルペスウィルス（帯状疱疹）などの感染症に伴う末梢神経障害、抗けいれん薬のフェニトイン、抗菌薬（クロラムフェニコール、ニトロフラントイン、およびスルホンアミド系薬剤など）、化学療法薬（タキサン系：パクリタキセル、およびドセタキセルなど、プラチナ製剤：オキサリプラチン、シスプラチン、カルボプラチン、およびネダアプラチンなど、ビンカアルカロイド系：ビンブラスチン、ビンクリスチン、およびビンデシンなど）、または鎮静薬（バルビタールおよびヘキソバルビタールなど）の投与に伴う薬剤性末梢神経障害、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、絞扼性神経障害（例えば、手根管症候群、胸郭出口症候群、肘部管症候群、梨状筋症候群、足根管症候群、および腓骨神経絞扼障害など）、多巣性運動ニューロパチーなどの免疫性末梢神経障害、結節性動脈周囲炎、アレルギー性血管炎、全身性エリテマトーデスなどのアレルギー疾患に伴う末梢神経障害、鉛、水銀、ヒ素、およびタリウムなどの重金属、シンナーなどの有機溶媒、有機リン系殺虫剤、リン酸トリオルソクレシル（TOCP）など毒性物質、またはアルコールの摂取に伴う中毒性末梢神経障害、がんが神経を圧迫することによる末梢神経障害、遺伝性疾患（例えば、甲状腺機能低下症、腎不全、シャルコー・マリー・トゥース病、レフサム病、ポルフィリン症、ファブリー病、および遺伝性圧脆弱性ニューロパチーなど）に伴う末梢神経障害などが挙げられる。 In the present invention, neuropathy includes peripheral neuropathy and central neuropathy.
Diseases associated with peripheral neuropathy include, for example, diabetic neuropathy, metabolic peripheral neuropathy associated with urinary toxicosis, peripheral neuropathy associated with vitamin B deficiency, diphtheria, botulinum food poisoning, and infection with herpesvirus (herpes zoster). Peripheral neuropathy associated with illness, anticonvulsant phenitoin, antibacterial agents (such as chloramphenicol, nitrofurantin, and sulfonamides), chemotherapeutic agents (taxan: paclitaxel, docetaxel, etc., platinum preparations: oxali Drug-induced peripheral neuropathy associated with administration of vinca alkaloids: vinblastin, vincristin, and bindesin, or sedatives (such as barbital and hexobarbital), chronic inflammatory demyelinating, such as platin, cisplatin, carboplatin, and nedaaplatin. Polyneuritis, Gillan Valley syndrome, strangulation neuropathy (eg, carpal canal syndrome, thoracic outlet syndrome, elbow canal syndrome, pear muscle syndrome, ankle canal syndrome, and peroneal nerve strangulation disorder), multiple nests Immune peripheral neuropathy such as sexual motor neuropathy, peripheral neuropathy associated with allergic diseases such as nodular periarteritis, allergic vasculitis, systemic erythematosus, heavy metals such as lead, mercury, arsenic, and tarium, thinner, etc. Addictive peripheral neuropathy associated with ingestion of toxic substances such as organic solvents, organic phosphorus pesticides, triorsocrecil phosphate (TOCP), or alcohol, peripheral neuropathy due to cancer compression of nerves, hereditary diseases Peripheral neuropathy associated with (eg, hypothyroidism, renal failure, Charcoal-Marie Tooth's disease, Leftham's disease, porphyrinosis, Fabry's disease, and hereditary pressure vulnerability neuropathy).
　中枢神経障害を伴う疾患としては、例えば、アルツハイマー病、パーキンソン病、レビー小体型認知症、前頭側頭葉変性症、進行性核上性麻痺、大脳皮質基底核変性症、ハンチントン病、ジストニア、プリオン病、多系統萎縮症、脊髄小脳変性症、筋萎縮性側索硬化症、原発性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、痙性対麻痺、脊髄空洞症、多発性硬化症、視神経脊髄炎、同心円硬化症、急性散在性脳脊髄炎、炎症性広汎性硬化症、亜急性硬化症全脳炎、進行性多巣性白質脳症などの感染性神経障害、低酸素脳症や橋中心髄鞘破壊症などの中毒・代謝性神経障害、およびBinswanger病などの血管性神経障害などが挙げられる。 Diseases associated with central neuropathy include, for example, Alzheimer's disease, Parkinson's disease, Levy body dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Huntington's disease, dystonia, prion. Disease, multisystem atrophy, spinal cerebral degeneration, muscular atrophic lateral cord sclerosis, primary lateral cord sclerosis, bulbous muscular atrophy, spinal muscular atrophy, spastic antiparalysis, spinal cavities, multiple Infectious neuropathy such as sclerosis, optic neuromyelitis, concentric sclerosis, acute diffuse encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosis total encephalitis, progressive multifocal leukoencephalopathy, hypoxic encephalopathy and Intoxication / metabolic neuropathy such as pons-central medullary sheath destruction, and vascular neuropathy such as Binswanger's disease can be mentioned.
　本発明の化合物は、
１）その化合物の予防および／または治療効果の補完および／または増強、
２）その化合物の動態・吸収改善、投与量の低減、および／または
３）その化合物の副作用の軽減のために他の薬物と組み合わせて、併用薬として投与してもよい。 The compound of the present invention
1) Complementing and / or enhancing the prophylactic and / or therapeutic effect of the compound,
2) It may be administered as a combination drug in combination with other drugs for improving the dynamics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound.
　本発明の化合物と他の薬物の併用薬は、１つの製剤中に両成分を配合した配合剤の形態で投与してもよく、また別々の製剤にして投与する形態をとってもよい。この別々の製剤にして投与する場合には、同時投与および時間差による投与が含まれる。また、時間差による投与は、本発明の化合物を先に投与し、他の薬物を後に投与してもよいし、他の薬物を先に投与し、本発明の化合物を後に投与してもよい。それぞれの投与方法は同じでも異なっていてもよい。 The combination drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When administered as these separate formulations, simultaneous administration and staggered administration are included. In addition, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. Each administration method may be the same or different.
　上記併用薬により、予防および／または治療効果を奏する疾患は特に限定されず、本発明の化合物の予防および／または治療効果を補完および／または増強する疾患であればよい。 The disease that exerts a prophylactic and / or therapeutic effect by the above-mentioned combination drug is not particularly limited, and any disease that complements and / or enhances the prophylactic and / or therapeutic effect of the compound of the present invention may be used.
　また、本発明の化合物と組み合わせる併用薬としては、現在までに見出されているものだけでなく今後見出されるものも含まれる。 In addition, the combination drugs to be combined with the compound of the present invention include not only those found up to now but also those found in the future.
　本発明の化合物の神経障害に対する予防および／または治療効果の補完および／または増強のための他の薬物としては、例えば、アルドース還元酵素阻害薬、ビタミン剤、および脳保護薬が挙げられる。アルドース還元酵素阻害薬としては、エパルレスタットが挙げられる。ビタミン剤としては、メコバラミンなどが挙げられる。脳保護薬としては、エダラボンが挙げられる。 Other drugs for complementing and / or enhancing the prophylactic and / or therapeutic effect of the compounds of the present invention on neuropathy include, for example, aldose reductase inhibitors, vitamins, and brain protectants. Examples of the aldose reductase inhibitor include epalrestat. Examples of vitamin preparations include mecobalamin. Examples of the brain protective drug include edaravone.
　前記他の薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、化合物Ａと他の薬剤の配合比は、投与対象の年齢及び体重、投与方法、投与時間、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、化合物Ａ１質量部に対し、他の薬剤を０．０１乃至１００質量部用いればよい。他の薬剤は任意の２種以上を適宜の割合で組み合わせて投与してもよい。 The dose of the other drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of compound A and other drugs can be appropriately selected depending on the age and body weight of the administration target, administration method, administration time, target disease, symptom, combination and the like. For example, 0.01 to 100 parts by mass of another drug may be used with respect to 1 part by mass of compound A. As for other drugs, any two or more kinds may be administered in an appropriate combination in an appropriate ratio.
　本発明の化合物または本発明の化合物と他の薬剤の併用剤を上記の目的で用いるには、通常、薬学的に許容される担体とともに適当な医薬組成物として製剤化したうえで、全身的または局所的に、経口または非経口の形で投与される。 In order to use the compound of the present invention or a combination drug of the compound of the present invention and another drug for the above purpose, it is usually formulated as a suitable pharmaceutical composition together with a pharmaceutically acceptable carrier, and then systemically or systematically. It is administered topically, orally or parenterally.
　本発明の化合物は、薬学的有効量で哺乳動物（好ましくはヒト、より好ましくは患者）へ投与される。 The compound of the present invention is administered to a mammal (preferably a human, more preferably a patient) in a pharmaceutically effective amount.
　本発明の化合物の投与量は、年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、通常、成人一人当たり、一回につき、１ｎｇから１０００ｍｇの範囲で一日一回から数回経口投与されるか、または成人一人当たり、一回につき、０．１ｎｇから１０ｍｇの範囲で一日一回から数回非経口投与されるか、または一日１時間から２４時間の範囲で静脈内に持続投与される。もちろん前記したように、投与量は種々の条件により変動するので、上記投与量より少ない量で十分な場合もあるし、また範囲を越えて投与の必要な場合もある。 The dose of the compound of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually from once a day to several times in the range of 1 ng to 1000 mg per adult. It can be given orally once or several times a day in the range of 0.1 ng to 10 mg per adult, or intravenously in the range of 1 to 24 hours a day. It is continuously administered within. Of course, as described above, since the dose varies depending on various conditions, an amount smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
　本発明の化合物又は本発明の化合物と他の薬剤の併用剤を投与する際には、経口投与のための内服用固形剤若しくは内服用液剤、経口投与における徐放性製剤、放出制御製剤、または非経口投与のための注射剤、外用剤、吸入剤若しくは坐剤等として用いられる。 When administering the compound of the present invention or a concomitant drug of the compound of the present invention and another drug, an internal solid preparation or an internal liquid preparation for oral administration, a sustained release preparation for oral administration, a release control preparation, or It is used as an injection, an external preparation, an inhalant, a suppository, etc. for parenteral administration.
　本発明の化合物は、上記医薬品の原薬として使用される。 The compound of the present invention is used as a drug substance of the above-mentioned pharmaceutical products.
　本発明の化合物を単剤として、あるいは他の薬剤を組み合わせて併用剤として、上記の疾患の予防および／または治療の目的に用いるには、有効成分である当該物質を、通常、各種の添加剤または溶媒等の薬学的に許容される担体とともに製剤化したうえで、全身的または局所的に、経口または非経口の形で投与される。ここで、薬学的に許容される担体とは、一般的に医薬品の製剤に用いられる、有効成分以外の物質を意味する。薬学的に許容される担体は、その製剤の投与量において薬理作用を示さず、無害で、有効成分の治療効果を妨げないものが好ましい。また、薬学的に許容される担体は、有効成分および製剤の有用性を高める、製剤化を容易にする、品質の安定化を図る、または使用性を向上させる等の目的で用いることもできる。具体的には、薬事日報社２０００年刊「医薬品添加物事典」（日本医薬品添加剤協会編集）等に記載されているような物質を、適宜目的に応じて選択すればよい。 In order to use the compound of the present invention as a single agent or in combination with other agents as a concomitant agent for the purpose of prevention and / or treatment of the above-mentioned diseases, the substance which is an active ingredient is usually used as various additives. Alternatively, it is formulated with a pharmaceutically acceptable carrier such as a solvent, and then administered systemically or topically, orally or parenterally. Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of a pharmaceutical product. The pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, the pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, improving the usability, and the like. Specifically, substances such as those described in Yakuji Nippo's 2000 "Encyclopedia of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
　化合物Ａは、通常、全身的または局所的に、経口または非経口の形で投与される。経口剤としては、例えば、内服用液剤（例えば、エリキシル剤、シロップ剤、薬剤的に許容される水剤、懸濁剤、乳剤）、内服用固形剤（例えば、錠剤（舌下錠、口腔内崩壊錠を含む）、丸剤、カプセル剤（ハードカプセル、ソフトカプセル、ゼラチンカプセル、マイクロカプセルを含む）、散剤、顆粒剤、トローチ剤）等が挙げられる。非経口剤としては、例えば、液剤（例えば、注射剤（硝子体内注射剤、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤、点滴剤等）、点眼剤（例えば、水性点眼剤（水性点眼液、水性懸濁点眼液、粘性点眼液、可溶化点眼液等）、非水性点眼剤（非水性点眼液、非水性懸濁点眼液等））等）、外用剤（例えば、軟膏（眼軟膏等））、点耳剤等が挙げられる。これらの製剤は、速放性製剤、徐放性製剤などの放出制御剤であってもよい。これらの製剤は公知の方法、例えば、日本薬局方に記載の方法等により製造することができる。 Compound A is usually administered systemically or topically, orally or parenterally. Oral preparations include, for example, liquid preparations for internal use (eg, elixirs, syrups, pharmaceutically acceptable liquids, suspensions, emulsions), solid preparations for internal use (eg, tablets (sublingual tablets, oral cavity). (Including disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, troches, etc. Examples of parenteral preparations include liquid preparations (for example, intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, eye drops, etc.) and eye drops (eg, aqueous drops). Eye drops (aqueous eye drops, aqueous suspended eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspended eye drops, etc.)), external preparations (for example, , Ointments (eye ointments, etc.)), eye drops, etc. These preparations may be release control agents such as immediate release preparations and sustained release preparations. These preparations can be produced by a known method, for example, the method described in the Japanese Pharmacopoeia.
　経口剤としての内服用液剤は、例えば、有効成分を一般的に用いられる希釈剤（例えば、精製水、エタノールまたはそれらの混液等）に溶解、懸濁または乳化されることにより製造される。さらにこの液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香剤、保存剤、緩衝剤等を含有していてもよい。 An oral solution is produced by, for example, dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Further, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.
　経口剤としての内服用固形剤は、例えば、有効成分を賦形剤（例えば、ラクトース、マンニトール、グルコース、微結晶セルロース、デンプン等）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等）、崩壊剤（例えば、繊維素グリコール酸カルシウム等）、滑沢剤（例えば、ステアリン酸マグネシウム等）、安定剤、溶解補助剤（グルタミン酸、アスパラギン酸等）等と混合し、常法に従って製剤化される。また、必要によりコーティング剤（例えば、白糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等）で被覆していてもよいし、また２以上の層で被覆していてもよい。 The solid preparation for internal use as an oral preparation contains, for example, an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.) as an active ingredient, and a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminen metasilicate). Mix with a disintegrant (eg, calcium fibrous glycolate, etc.), a lubricant (eg, magnesium stearate, etc.), a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.), etc. It is formulated according to. Further, if necessary, it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or may be coated with two or more layers.
　非経口剤としての外用剤は公知の方法または通常使用されている処方により製造される。例えば、軟膏剤は有効成分を基剤に研和または溶融させて製造される。軟膏基剤は公知あるいは通常使用されているものから選ばれる。例えば、高級脂肪酸または高級脂肪酸エステル（例えば、アジピン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、アジピン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステル、オレイン酸エステル等）、ロウ類（例えば、ミツロウ、鯨ロウ、セレシン等）、界面活性剤（例えば、ポリオキシエチレンアルキルエーテルリン酸エステル等）、高級アルコール（例えば、セタノール、ステアリルアルコール、セトステアリルアルコール等）、シリコン油（例えば、ジメチルポリシロキサン等）、炭化水素類（例えば、親水ワセリン、白色ワセリン、精製ラノリン、流動パラフィン等）、グリコール類（例えば、エチレングリコール、ジエチレングリコール、プロピレングリコール、ポリエチレングリコール、マクロゴール等）、植物油（例えば、ヒマシ油、オリーブ油、ごま油、テレピン油等）、動物油（例えば、ミンク油、卵黄油、スクワラン、スクワレン等）、水、吸収促進剤、かぶれ防止剤から選ばれるもの単独または２種以上を混合して用いられる。さらに、保湿剤、保存剤、安定化剤、抗酸化剤、着香剤等を含んでいてもよい。 External preparations as parenteral preparations are manufactured by known methods or commonly used formulations. For example, an ointment is produced by triturating or melting an active ingredient as a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes. (For example, beeswax, whale wax, selecin, etc.), surfactants (for example, polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (for example, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicon oil (for example, for example. Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic vaseline, white vaseline, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oil (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.) , Ester oil, olive oil, sesame oil, terepine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalane, etc.), water, absorption enhancer, anti-fog agent, alone or a mixture of two or more. Used for Further, it may contain a moisturizer, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.
　非経口剤としての注射剤には溶液、懸濁液、乳濁液および用時溶剤に溶解または懸濁して用いる固形の注射剤を包含される。注射剤は、例えば有効成分を溶剤に溶解、懸濁または乳化させて用いられる。溶剤として、例えば注射用蒸留水、生理食塩水、植物油、プロピレングリコール、ポリエチレングリコール、エタノールのようなアルコール類等およびそれらの組み合わせが用いられる。さらにこの注射剤は、安定剤、溶解補助剤（例えば、グルタミン酸、アスパラギン酸、ポリソルベート８０（登録商標）等）、懸濁化剤、乳化剤、無痛化剤、緩衝剤、保存剤等を含んでいてもよい。これらは最終工程において滅菌するか無菌操作法によって製造される。また無菌の固形剤、例えば凍結乾燥品を製造し、その使用前に無菌化または無菌の注射用蒸留水または他の溶剤に溶解して使用することもできる。 Injections as parenteral preparations include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent before use. Injectables are used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and the like, and combinations thereof are used. Further, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. May be good. These are sterilized in the final step or manufactured by aseptic technique. It is also possible to produce a sterile solid preparation, for example, a lyophilized product, which is sterilized or dissolved in sterile distilled water for injection or other solvent before use.
　本発明において、化合物Ａまたはその各種塩は、例えば後記する実施例、これらに準ずる方法に従って製造することが出来る。なお、再結晶を行う際、種晶は、使用しても、または使用しなくてもよい。 In the present invention, compound A or various salts thereof can be produced according to, for example, the examples described later and methods similar thereto. When recrystallizing, the seed crystal may or may not be used.
　以下、実施例および生物学的実施例によって本発明を詳述するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples and Biological Examples, but the present invention is not limited thereto.
　クロマトグラフィーによる分離の箇所およびＴＬＣに示されているカッコ内の溶媒は、使用した溶出溶媒または展開溶媒を示し、割合は体積比を表す。 The location of separation by chromatography and the solvent in parentheses shown on the TLC indicate the elution solvent or developing solvent used, and the ratio represents the volume ratio.
　ＮＭＲの箇所に示されているカッコ内は測定に使用した溶媒を示す。 The parentheses shown in the NMR section indicate the solvent used for the measurement.
　本明細書中に用いた化合物名は、一般的にＩＵＰＡＣの規則に準じて命名を行うコンピュータプログラム、Advanced Chemistry Development社のACD/Name（登録商標）、OpenEye Scientific Software社のLexichem Toolkit 1.4.2またはPerkinElmer社のChemDraw（登録商標）Ultraを用いるか、または、ＩＵＰＡＣ命名法に準じて命名したものである。 Compound names used herein are computer programs that are generally named according to IUPAC rules, ACD / Name® from Advanced Chemistry Development, Lexichem Toolkit 1.4.2 from OpenEye Scientific Software, or It is named using ChemDraw® Ultra manufactured by Perkin Elmer or according to the IUPAC nomenclature.
　ＬＣＭＳはWaters i-classシステムを使用し、以下の条件で実施した。
カラム：YMC Triart　Ｃ１８　２．０ｍｍ×３０ｍｍ，１．９μｍ；流量：１．０ｍＬ／分；温度：３０℃；移動相Ａ：０．１％トリフルオロ酢酸（ＴＦＡ）水溶液；移動相Ｂ：０．１％ＴＦＡアセトニトリル溶液：グラジエント（移動相（Ａ）：移動相（Ｂ）の比率を記載）：０～０．１０分：（９５％：５％）；０．１０～１．２０分：（９５％：５％）から（５％：９５％）；１．２０～１．５０分：（５％：９５％）。 LCMS was performed using the Waters i-class system under the following conditions.
Column: YMC Triart C 18 2.0 mm × 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30 ° C.; Mobile phase A: 0.1% trifluoroacetic acid (TFA) aqueous solution; Mobile phase B: 0 .1% TFA acetonitrile solution: gradient (state the ratio of mobile phase (A): mobile phase (B)): 0 to 0.10 minutes: (95%: 5%); 0.10 to 1.20 minutes: From (95%: 5%) to (5%: 95%); 1.20 to 1.50 minutes: (5%: 95%).
　粉末Ｘ線回折スペクトルは以下のいずれかの条件で測定した。
条件１
装置：リガク製　ＳｍａｒｔＬａｂ
ターゲット：Ｃｕ
電圧：４５ｋＶ
電流：２００ｍＡ
走査速度：３０度／ｍｉｎ
条件２
装置：ＰＡＮａｌｙｔｉｃａｌ製　ＥＮＰＹＲＥＡＮ
ターゲット：Ｃｕ
電圧：４５ｋＶ
電流：４０ｍＡ
走査速度：０．１６４度／ｓｅｃ
　示差走査熱量測定（ＤＳＣ）は以下のいずれかの条件で測定した。
条件１
装置：ティー・エイ・インスツルメント製　Ｄｉｓｃｏｖｅｒｙ　ＤＳＣ
試料セル：アルミニウムパン
窒素ガス流量：４０ｍＬ／ｍｉｎ
条件２
装置：メトラー・トレド製　ＴＧＡ／ＤＳＣ　３＋
試料セル：アルミニウムパン
アルゴンガス流量：２０ｍＬ／ｍｉｎ
条件３
装置：メトラー・トレド製　ＤＳＣ　３＋
試料セル：アルミニウムパン
アルゴンガス流量：２０ｍＬ／ｍｉｎ The powder X-ray diffraction spectrum was measured under any of the following conditions.
Condition 1
Equipment: Rigaku SmartLab
Target: Cu
Voltage: 45kV
Current: 200mA
Scanning speed: 30 degrees / min
Condition 2
Equipment: PANalytical ENPYREAN
Target: Cu
Voltage: 45kV
Current: 40mA
Scanning speed: 0.164 degrees / sec
The differential scanning calorimetry (DSC) was measured under any of the following conditions.
Condition 1
Equipment: DISCOVERY DSC manufactured by TA Instruments
Sample cell: Aluminum pan Nitrogen gas flow rate: 40 mL / min
Condition 2
Equipment: METTLER TOLEDO TGA / DSC 3+
Sample cell: Aluminum pan Argon gas Flow rate: 20 mL / min
Condition 3
Equipment: Mettler Toledo DSC 3+
Sample cell: Aluminum pan Argon gas Flow rate: 20 mL / min
実施例１：イソプロピル　３－（２－ヒドロキシフェニル）プロパノエート
　３，４－ジヒドロクマリン（５０．０ｇ）のイソプロピルアルコール（５００ｍＬ）溶液に、硫酸（０．２６ｍＬ）を加え、反応混合物を室温で２時間撹拌した。反応混合物を減圧濃縮し、得られた残さを酢酸エチルで希釈した。飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮し、以下の物性値を有する標題化合物（７３．２ｇ）を得た。
1Ｈ-ＮＭＲ(ＣＤＣｌ3)：δ　1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35。 Example 1: Sulfuric acid (0.26 mL) is added to a solution of isopropyl 3- (2-hydroxyphenyl) propanoate 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), and the reaction mixture is mixed at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (73.2 g) having the following physical properties.
1 1 H-NMR (CDCl 3 ): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.
実施例２：イソプロピル　３－（２－（ペンタ－４－イン－１－イルオキシ）フェニル）プロパノエート
　実施例１で製造した化合物（３．００ｇ）のＮ，Ｎ－ジメチルアセトアミド（２５ｍＬ）溶液に、室温で炭酸セシウム（９．３９ｇ）を加え、同温で１５分間撹拌した。反応溶液に室温で５－クロロ－１－ペンチン（ＣＡＳ登録番号：１４２６７－９２－６）（１．６３ｇ）を加え、６０℃で３時間撹拌した。反応溶液に水を加え、ジエチルエーテルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：０→５：１）によって精製することにより、以下の物性値を有する標題化合物（２．４０ｇ）を得た。
ＨＰＬＣ保持時間（分）：１．１３。 Example 2: Isopropyl 3- (2- (pent-4-in-1-yloxy) phenyl) propanoate in a solution of the compound (3.00 g) prepared in Example 1 in N, N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added at the same temperature, and the mixture was stirred at the same temperature for 15 minutes. 5-Chloro-1-pentyne (CAS Registry Number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 5: 1) to give the title compound (2.40 g) having the following physical property values.
HPLC retention time (minutes): 1.13.
実施例３：イソプロピル　（Ｅ）－３－（２－（（５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ペンタ－４－エン－１－イル）オキシ）フェニル）プロパノエート
　実施例２で製造した化合物（１．００ｇ）のヘプタン（２ｍＬ）溶液に、室温で４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン（１．１７ｇ）と４－ジメチルアミノ安息香酸（６０．２ｍｇ）を加え、１００℃で４時間撹拌した。反応溶液を室温まで冷却後、濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１→４：１）によって精製することにより、以下の物性値を有する標題化合物（５０３ｍｇ）を得た。
ＨＰＬＣ保持時間（分）：１．３８。 Example 3: Isopropyl (E) -3- (2-((5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) penta-4-en-1-yl) Il) Oxy) Phenyl) Propanoate In a heptane (2 mL) solution of the compound (1.00 g) prepared in Example 2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give the title compound (503 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.38.
実施例３（１）：Ｎ－（３－ブロモフェニル）ベンゼンスルホンアミド
　３－ブロモアニリン（１．０２ｇ）のジクロロメタン（２０ｍＬ）溶液に、０℃でピリジン（０．９５ｍＬ）、Ｎ，Ｎ－ジメチルアミノピリジン（以下、ＤＭＡＰと略記）（７２．４ｍｇ）および塩化ベンゼンスルホニル（１．１０ｇ）を加え、室温で２時間撹拌した。反応溶液を濃縮後、得られた残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→２：１）によって精製することにより、以下の物性値を有する標題化合物（１．９６ｇ）を得た。
ＨＰＬＣ保持時間（分）：０．９８。 Example 3 (1): N- (3-bromophenyl) benzenesulfonamide 3-bromoaniline (1.02 g) in a solution of dichloromethane (20 mL) at 0 ° C. with pyridine (0.95 mL), N, N-dimethyl Aminopyridine (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (1.96 g) having the following physical properties. rice field.
HPLC retention time (minutes): 0.98.
実施例４：イソプロピル　（Ｅ）－３－（２－（（５－（３－（フェニルスルホンアミド）フェニル）ペンタ－４－エン－１－イル）オキシ）フェニル）プロパノエート
　実施例３で製造した化合物（１８０ｍｇ）のＴＨＦ（３ｍＬ）溶液に、実施例３（１）で製造した化合物（１６８ｍｇ）、クロロ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）（０．０３５ｇ）および２Ｍリン酸三カリウム水溶液（０．６７ｍＬ）を加え、６０℃で１時間撹拌した。反応溶液を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：１→２：１）によって精製することにより、以下の物性値を有する標題化合物（１１３ｍｇ）を得た。
ＨＰＬＣ保持時間（分）：１．２４ Example 4: Isopropyl (E) -3-(2-((5- (3- (phenylsulfonamide) phenyl) penta-4-en-1-yl) oxy) phenyl) propanoate The compound prepared in Example 3. In a solution of (180 mg) in THF (3 mL), the compound (168 mg) prepared in Example 3 (1), chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'- Biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II) (0.035 g) and a 2M tripotassium phosphate aqueous solution (0.67 mL) were added, and the mixture was stirred at 60 ° C. for 1 hour. .. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (113 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.24
実施例５：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸 Example 5: 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　実施例４で製造した化合物（１４６ｍｇ）のＴＨＦ（０．５ｍＬ）とメタノール（０．１ｍＬ）の溶液に、１Ｍ水酸化リチウム水溶液（０．５ｍＬ）を加え、５０℃で８時間撹拌した。１Ｍ塩酸を加え酸性にし、酢酸エチルで抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧濃縮することにより、以下の物性値を有する標題化合物（１０５ｍｇ）を得た。
形態：非晶質
ＨＰＬＣ保持時間（分）：１．１０
1Ｈ-ＮＭＲ(ＣＤ3ＯＤ)：δ　1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45-7.49, 7.55, 7.75-7.78。 A 1 M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound (146 mg) prepared in Example 4 in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50 ° C. for 8 hours. It was acidified by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (105 mg) having the following physical characteristics.
Form: Amorphous HPLC retention time (minutes): 1.10
1 1 H-NMR (CD 3 OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45 -7.49, 7.55, 7.75-7.78.
実施例６：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩の結晶
　実施例５で得られた化合物１ｇを酢酸イソプロピル３．０ｍＬに溶解させた。４０℃に加熱した後、テトラヒドロフラン１．５ｍＬを添加した。この溶液にジイソプロピルアミン６４７ｍｇを加えた。種結晶を０．５ｍg添加すると徐々に結晶が析出した。さらに、酢酸イソプロピル６．０ｍＬを１時間かけて滴加した後、０℃まで2時間かけて冷却した。０℃で１時間撹拌し、結晶をろ取した。ろ取した結晶を真空ポンプ，検体乾燥器を用いて５０℃で乾燥し、該結晶を１．０７ｇ得た。本実施例化合物であるジイソプロピルアミン塩は、他のアミン塩と比べて純度の高い結晶として析出させることができ、化合物ＡのＢ晶の製造中間体として有用である。 Example 6 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid diisopropylamine salt 1 g of the compound obtained in Example 5 Was dissolved in 3.0 mL of isopropyl acetate. After heating to 40 ° C., 1.5 mL of tetrahydrofuran was added. 647 mg of diisopropylamine was added to this solution. When 0.5 mg of seed crystal was added, crystals gradually precipitated. Further, 6.0 mL of isopropyl acetate was added dropwise over 1 hour, and then cooled to 0 ° C. over 2 hours. The mixture was stirred at 0 ° C. for 1 hour, and the crystals were collected by filtration. The crystals collected by filtration were dried at 50 ° C. using a vacuum pump and a sample dryer to obtain 1.07 g of the crystals. The diisopropylamine salt, which is the compound of this example, can be precipitated as crystals having a higher purity than other amine salts, and is useful as an intermediate for producing B crystals of compound A.
　なお、種結晶は以下の方法により取得した。まず、実施例５で得られた化合物１５０ｍｇをテトラヒドロフラン０．７５ｍＬに溶解させた。当該溶液を４０℃に加熱した後、ジイソプロピルアミン５１ｍｇを加え、次いで酢酸イソプロピル１．５ｍＬ追加したところ徐々に結晶が析出した。２５℃で撹拌しながら結晶をろ取し、ろ取した結晶を真空ポンプおよび検体乾燥器を用いて５０℃で乾燥することにより種晶を得た。 The seed crystal was obtained by the following method. First, 150 mg of the compound obtained in Example 5 was dissolved in 0.75 mL of tetrahydrofuran. After heating the solution to 40 ° C., 51 mg of diisopropylamine was added, and then 1.5 mL of isopropyl acetate was added, and crystals gradually precipitated. Crystals were collected by filtration with stirring at 25 ° C., and the collected crystals were dried at 50 ° C. using a vacuum pump and a sample dryer to obtain seed crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図１に、ＤＳＣチャートを図２にそれぞれ示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件２
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表１に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 1, and the DSC chart is shown in FIG. 2, respectively.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 2
Table 1 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000003
Figure JPOXMLDOC01-appb-I000003
（２）示差走査熱量測定（ＤＳＣ）
測定条件：条件２
試料量：６．０ｍｇ
昇温速度：１０℃／ｍｉｎ（２５～３００℃）
　吸熱ピーク：オンセット温度約１２５℃、ピーク温度約１３３℃
実施例７：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸の結晶（Ｂ晶）
　実施例５で得られた化合物１０ｇに酢酸イソプロピル３０ｍＬを加えて、３５℃に加熱した。その後、ノルマルヘプタンを２１ｍＬ添加した。種結晶を０．１ｇ添加すると徐々に結晶が析出した。３時間撹拌後、ノルマルヘプタン６９ｍＬを２時間かけて滴加した後、０℃まで２時間かけて冷却した。０℃で１時間撹拌したのち、結晶をろ取した。ろ取した結晶を真空ポンプ，検体乾燥器を用いて４０℃で乾燥し、該結晶を９．６３ｇ得た。
　なお、種結晶は以下の方法により取得した。まず、実施例５で得られた化合物３ｇに酢酸イソプロピル９ｍＬを加えて、３５℃に加熱した。その後、当該溶液にノルマルヘプタンを６．３ｍＬ添加し、さらに実施例８記載のＡ晶を０．０３ｇ添加すると徐々に結晶が析出した。１５時間撹拌後、ノルマルヘプタン２０．７ｍＬを２時間かけて滴加した後、０℃まで２時間かけて冷却した。０℃で１時間撹拌したのち、結晶をろ取し、ろ取した結晶を真空ポンプおよび検体乾燥器を用いて４０℃で乾燥することにより種晶を取得した。 (2) Differential scanning calorimetry (DSC)
Measurement condition: Condition 2
Sample amount: 6.0 mg
Heating rate: 10 ° C / min (25 to 300 ° C)
Endothermic peak: Onset temperature approx. 125 ° C, peak temperature approx. 133 ° C
Example 7 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal B)
30 mL of isopropyl acetate was added to 10 g of the compound obtained in Example 5, and the mixture was heated to 35 ° C. Then, 21 mL of normal heptane was added. When 0.1 g of seed crystals were added, crystals gradually precipitated. After stirring for 3 hours, 69 mL of normal heptane was added dropwise over 2 hours, and then cooled to 0 ° C. over 2 hours. After stirring at 0 ° C. for 1 hour, the crystals were collected by filtration. The crystals collected by filtration were dried at 40 ° C. using a vacuum pump and a sample dryer to obtain 9.63 g of the crystals.
The seed crystal was obtained by the following method. First, 9 mL of isopropyl acetate was added to 3 g of the compound obtained in Example 5, and the mixture was heated to 35 ° C. Then, 6.3 mL of normal heptane was added to the solution, and 0.03 g of the A crystal described in Example 8 was further added to gradually precipitate crystals. After stirring for 15 hours, 20.7 mL of normal heptane was added dropwise over 2 hours, and then cooled to 0 ° C. over 2 hours. After stirring at 0 ° C. for 1 hour, the crystals were collected by filtration, and the collected crystals were dried at 40 ° C. using a vacuum pump and a sample dryer to obtain seed crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図３に、ＤＳＣチャートを図４にそれぞれ示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件２
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表２に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 3, and the DSC chart is shown in FIG. 4, respectively.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 2
Table 2 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000004
Figure JPOXMLDOC01-appb-I000004
（２）示差走査熱量測定（ＤＳＣ）
測定条件：条件３
試料量：６．５ｍｇ
昇温速度：０．０１℃／ｍｉｎ（８５．５～８８．５℃）
　吸熱ピーク：オンセット温度約８６．２℃、ピーク温度約８６．４℃
　なお、化合物ＡのＢ晶は実施例７（１）～（６）に示した方法でも取得することができる。 (2) Differential scanning calorimetry (DSC)
Measurement condition: Condition 3
Sample amount: 6.5 mg
Heating rate: 0.01 ° C / min (85.5 to 88.5 ° C)
Endothermic peak: Onset temperature approx. 86.2 ° C, peak temperature approx. 86.4 ° C
The B crystal of compound A can also be obtained by the methods shown in Examples 7 (1) to (6).
実施例７（１）：Ｎ－３－［（１Ｅ）－５－クロロペンタ－１－エン－１－イル］フェニルベンゼンスルホンアミド
　実施例３（１）で合成した化合物（１０.０ｇ）、２－［（１Ｅ）－５－クロロペンタ―１－エン―１－イル］－４，４，５，５－テトラメチル－１，３，２－ジオキサボラン（ＣＡＳ登録番号：１２６６８８－９８－０）（８．８６ｇ）のテトラヒドロフラン（６０ｍＬ）溶液にクロロ（クロチル）［（ｐ－ジメチルアミノフェニル）（ジ―ｔｅｒｔ―ブチルホスヒノ）］パラジウム（ＩＩ）（１４．８ｍｇ）およびリン酸カリウム（２０．４ｇ）の水（３２ｍL）溶液を加え、６０℃で１時間撹拌した。反応溶液を室温まで冷却した後、メチルｔｅｒｔ－ブチルエーテル（１００ｍL）を加えた。分液後、有機層を１ｍoｌ／L塩酸水溶液（３０ｍL）、１０％食塩水（３０ｍL）、１０％食塩水（３０ｍL）で順次洗浄した。有機層にメチルｔｅｒｔ－ブチルエーテル（５ｍL）に懸濁させた活性炭（０．３ｇ）を加えて３０分間撹拌した後、不溶物をセライトろ過した。セライトをメチルｔｅｒｔ－ブチルエーテル（４０ｍL）で掛け洗った後、ろ液を３ｖ／ｗまで濃縮した。濃縮液にトルエン（３０ｍL）を加え、３ｖ／ｗまで濃縮した。再度、濃縮液にトルエン（３０ｍL）を加え、３ｖ／ｗまで濃縮した。内温４５℃に温調した濃縮液にｎ－ヘプタン（２０ｍL）を加えて１５分間以上撹拌した後、さらにｎ－ヘプタン（４０ｍL）を加えた。内温２５℃に冷却して１時間撹拌した後、沈殿物をろ過した。湿結晶を１２時間５０℃で真空乾燥して、以下の物性値を有する標題化合物（１０．０ｇ）を得た。性状：微黄色固体1Ｈ-ＮＭＲ(ＣＤＣｌ3、４００MHｚ)：δ　7.81-7.79 (m, 2H), 7.56-7.52 (m, 1H), 7.47-7.42 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.09-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.33 (d, J = 16.0 Hz, 1H), 6.11 (dt, J = 16.0, 7.2 Hz, 1H), 3.56 (t, J = 6.4 Hz, 2H), 2.37-2.32 (m, 2H), 1.96-1.89 (m, 2H)。 Example 7 (1): N-3-[(1E) -5-chloropenta-1-en-1-yl] phenylbenzenesulfonamide Compound (10.0 g) synthesized in Example 3 (1), 2- [(1E) -5-chloropenta-1-ene-1-yl] -4,4,5,5-tetramethyl-1,3,2-dioxaborane (CAS registration number: 126688-98-0) (8. 86 g) of chloro (crotyl) [(p-dimethylaminophenyl) (di-tert-butylphosphino)] palladium (II) (14.8 mg) and potassium phosphate (20.4 g) in a solution of tetrahydrofuran (60 mL) in water (20.4 g). 32 mL) solution was added, and the mixture was stirred at 60 ° C. for 1 hour. After cooling the reaction solution to room temperature, methyl tert-butyl ether (100 mL) was added. After the liquid separation, the organic layer was washed successively with 1 mol / L hydrochloric acid aqueous solution (30 mL), 10% saline solution (30 mL), and 10% saline solution (30 mL). Activated carbon (0.3 g) suspended in methyl tert-butyl ether (5 mL) was added to the organic layer, and the mixture was stirred for 30 minutes, and then the insoluble matter was filtered through Celite. After washing the Celite with methyl tert-butyl ether (40 mL), the filtrate was concentrated to 3 v / w. Toluene (30 mL) was added to the concentrate and concentrated to 3 v / w. Toluene (30 mL) was added to the concentrate again, and the mixture was concentrated to 3 v / w. N-heptane (20 mL) was added to the concentrated solution whose internal temperature was adjusted to 45 ° C., and the mixture was stirred for 15 minutes or more, and then n-heptane (40 mL) was further added. After cooling to an internal temperature of 25 ° C. and stirring for 1 hour, the precipitate was filtered. The wet crystals were vacuum dried at 50 ° C. for 12 hours to obtain the title compound (10.0 g) having the following physical characteristics. Properties: Light yellow solid 1 1 H-NMR (CDCl 3 , 400 MHz): δ 7.81-7.79 (m, 2H), 7.56-7.52 (m, 1H), 7.47-7.42 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.09-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.33 (d, J = 16.0 Hz, 1H), 6.11 (dt, J = 16.0, 7.2 Hz, 1H), 3.56 (t, J = 6.4 Hz, 2H), 2.37-2.32 (m, 2H), 1.96-1.89 (m, 2H).
実施例７（２）：Ｎ－３－［（１Ｅ）－５－ヨードペンタ－１－エン－１－イル］フェニルベンゼンスルホンアミド
　実施例７（１）で合成した化合物（１０．０ｇ）のメチルエチルケトン（８１ｍL）溶液にＮ，Ｎ－ジメチルホルムアミド（９ｍL）、濃硫酸（２９．２ｍｇ）およびヨウ化ナトリウム（２２．３ｇ）を加え、７５℃で５時間撹拌した。反応溶液を５０℃に調整してメチルエチルケトン（６０ｍL）を加え、室温まで冷却した後、水（５０ｍL）を加えた。分液後、有機層を１０％亜硫酸水素ナトリウム水溶液（６０ｍL）で洗浄した。有機層にトルエン（３０ｍL）および水（５０ｍL）を加えて分液した。有機層を水（５０ｍL）で洗浄した後、４ｖ／ｗまで濃縮した。濃縮液にトルエン（３０ｍL）を加え、４ｖ／ｗまで濃縮した。再度、濃縮液にトルエン（３０ｍL）を加え、４ｖ／ｗまで濃縮した。濃縮液にトルエンを加えて液量を４．７ｖ／ｗに調製した。内温４５℃に温調した溶液にｎ－ヘプタン（２９ｍL）を加えて１０分間以上撹拌した後、さらにｎ－ヘプタン（９．３ｍL）を加えた。内温２５℃に冷却して１時間撹拌した後、沈殿物をろ過した。湿結晶を１２時間５０℃で真空乾燥して、以下の物性値を有する標題化合物（１２．０ｇ）を得た。
性状：微褐色固体
1Ｈ-ＮＭＲ(ＣＤＣｌ3、４００MHｚ)：δ　7.80-7.78 (m, 2H), 7.56-7.52 (m, 1H), 7.47-7.42 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.10-7.05 (m, 2H), 6.91-6.89 (m, 1H), 6.79 (brs, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.08 (dt, J = 16.0, 7.2 Hz, 1H), 3.21 (t, J = 6.8 Hz, 2H), 2.33-2.27 (m, 2H), 2.01-1.94 (m, 2H)。 Example 7 (2): N-3-[(1E) -5-iodopenta-1-en-1-yl] phenylbenzenesulfonamide Methyl ethyl ketone (10.0 g) of the compound (10.0 g) synthesized in Example 7 (1). N, N-dimethylformamide (9 mL), concentrated sulfuric acid (29.2 mg) and sodium iodide (22.3 g) were added to the 81 mL) solution, and the mixture was stirred at 75 ° C. for 5 hours. The reaction solution was adjusted to 50 ° C., methyl ethyl ketone (60 mL) was added, the mixture was cooled to room temperature, and then water (50 mL) was added. After the liquid separation, the organic layer was washed with a 10% aqueous sodium hydrogen sulfite solution (60 mL). Toluene (30 mL) and water (50 mL) were added to the organic layer to separate the liquids. The organic layer was washed with water (50 mL) and then concentrated to 4 v / w. Toluene (30 mL) was added to the concentrate and concentrated to 4 v / w. Toluene (30 mL) was added to the concentrate again, and the mixture was concentrated to 4 v / w. Toluene was added to the concentrated solution to adjust the amount of the solution to 4.7 v / w. N-heptane (29 mL) was added to the solution adjusted to an internal temperature of 45 ° C., and the mixture was stirred for 10 minutes or more, and then n-heptane (9.3 mL) was further added. After cooling to an internal temperature of 25 ° C. and stirring for 1 hour, the precipitate was filtered. The wet crystals were vacuum dried at 50 ° C. for 12 hours to obtain the title compound (12.0 g) having the following physical characteristics.
Properties: Light brown solid
1 1 H-NMR (CDCl 3 , 400 MHz): δ 7.80-7.78 (m, 2H), 7.56-7.52 (m, 1H), 7.47-7.42 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H) , 7.10-7.05 (m, 2H), 6.91-6.89 (m, 1H), 6.79 (brs, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.08 (dt, J = 16.0, 7.2 Hz, 1H ), 3.21 (t, J = 6.8 Hz, 2H), 2.33-2.27 (m, 2H), 2.01-1.94 (m, 2H).
実施例７（３）：ｔｅｒｔ－ブチル＝（ベンゼンスルホニル）３－［（１Ｅ）－５－ヨードペンタ－１－エン－１－イル］フェニルカルバマート
　内温０℃に冷却したＤＭＡＰ（１．４ｇ）、トリエチルアミン（４９ｍL）、二炭酸ジ―ｔｅｒｔ―ブチル（６６．４ｇ）のテトラヒドロフラン（３５０ｍL）溶液に、実施例７（２）で合成した化合物（１００ｇ）のテトラヒドロフラン（４００ｍL）溶液を滴加した。反応溶液を１時間撹拌した後、０．５ｍoｌ／L硫酸水溶液（４５０ｍL）およびメチルｔｅｒｔ－ブチルエーテル（１０００ｍL）を加えて分液した。有機層を５％炭酸水素ナトリウム水溶液（３００ｍL）、水（３００ｍL）で順次洗浄した。有機層を５ｖ／ｗに濃縮した後、トルエン（６００ｍL）を加えて３．５ｖ／ｗまで濃縮した。再度、濃縮液にトルエン（６００ｍL）を加えて３．５ｖ／ｗまで濃縮した。内温６０℃に温調した濃縮液にイソプロピルアルコール（７００ｍL）を加えた。内温３０℃に冷却した後、種結晶５０ｍｇを添加して１時間撹拌した。さらにイソプロピルアルコール（１０００ｍL）を加えて、１時間撹拌した。内温３０～４０℃に温調して１時間撹拌した後、内温０℃に冷却して１時間撹拌し、沈殿物をろ過した。湿結晶を１２時間４０℃で真空乾燥して、以下の物性値を有する標題化合物（１０８ｇ）を得た。
性状：微桃赤色固体
1Ｈ-ＮＭＲ(ＣＤＣｌ3、４００MHｚ)：δ　8.02-7.99 (m, 2H), 7.69-7.65 (m, 1H), 7.59-7.55 (m, 2H), 7.40-7.33 (m, 2H), 7.25-7.24 (m, 1H), 7.10-7.07 (m, 1H), 6.46 (d, J = 16.0 Hz, 1H), 6.18 (dt, J = 16.0, 6.8 Hz, 1H), 3.24 (t, J = 6.8 Hz, 2H), 2.38-2.32 (m, 2H), 2.04-1.99 (m, 2H), 1.34 (s, 9H)。 Example 7 (3): tert-Butyl = (benzenesulfonyl) 3-[(1E) -5-iodopenta-1-ene-1-yl] phenylcarbamate DMAP (1.4 g) cooled to an internal temperature of 0 ° C. , Triethylamine (49 mL), di-tert-butyl dicarbonate (66.4 g) in tetrahydrofuran (350 mL) was added dropwise with a solution of compound (100 g) synthesized in Example 7 (2) in tetrahydrofuran (400 mL). The reaction solution was stirred for 1 hour, and then 0.5 mol / L sulfuric acid aqueous solution (450 mL) and methyl tert-butyl ether (1000 mL) were added to separate the solutions. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and water (300 mL). After concentrating the organic layer to 5 v / w, toluene (600 mL) was added and concentrated to 3.5 v / w. Toluene (600 mL) was added to the concentrate again to concentrate to 3.5 v / w. Isopropyl alcohol (700 mL) was added to the concentrated solution whose internal temperature was adjusted to 60 ° C. After cooling to an internal temperature of 30 ° C., 50 mg of seed crystals were added and the mixture was stirred for 1 hour. Further, isopropyl alcohol (1000 mL) was added, and the mixture was stirred for 1 hour. The temperature was adjusted to an internal temperature of 30 to 40 ° C. and stirred for 1 hour, then cooled to an internal temperature of 0 ° C. and stirred for 1 hour, and the precipitate was filtered. The wet crystals were vacuum dried at 40 ° C. for 12 hours to obtain the title compound (108 g) having the following physical property values.
Properties: Fine peach red solid
1 1 H-NMR (CDCl 3 , 400 MHz): δ 8.02-7.99 (m, 2H), 7.69-7.65 (m, 1H), 7.59-7.55 (m, 2H), 7.40-7.33 (m, 2H), 7.25- 7.24 (m, 1H), 7.10-7.07 (m, 1H), 6.46 (d, J = 16.0 Hz, 1H), 6.18 (dt, J = 16.0, 6.8 Hz, 1H), 3.24 (t, J = 6.8 Hz) , 2H), 2.38-2.32 (m, 2H), 2.04-1.99 (m, 2H), 1.34 (s, 9H).
実施例７（４）：プロパン－２－イル＝３－（２－｛（４Ｅ）－５－３－［（ベンゼンスルホニル）（ｔｅｒｔ－ブトキシカルボニル）アミノ］フェニルペンタ－４－エン－１－イル｝オキシフェニル）プロパノアート
　実施例１で合成した化合物（４７３ｍｇ）のイソプロピルアルコール（３．１ｍL）溶液に、実施例７（３）で合成した化合物（１．０ｇ）およびＮ－メチル－２－ピロリドン（０．５ｍL）溶液を加えて内温１０℃に冷却した。この溶液に、内温１０℃に冷却したナトリウム―ｔｅｒｔ―ブトキシド（２１８．７ｍｇ）のＮ－メチル－２－ピロリドン（２．０ｍL）溶液を滴下した。３０分間以上撹拌して、以下の物性値を有する標題化合物の溶液を得た。
シリカゲルカラムクロマトグラフィー精製品の性状：白色固体
1Ｈ-ＮＭＲ(ＣＤＣｌ3、４００MHｚ)：δ　8.02-7.99 (m, 2H), 7.67-7.63 (m, 1H), 7.57-7.54 (m, 2H), 7.40-7.33 (m, 2H), 7.24-7.23 (m, 1H), 7.20-7.16 (m, 2H), 7.09-7.06 (m, 1H), 6.89-6.83 (m, 2H), 6.45 (d, J = 16.0 Hz, 1H), 6.29 (dt, J = 16.0, 7.2 Hz, 1H), 5.04-4.98 (m, 1H), 4.03 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.62-2.59 (m, 2H), 2.47-2.42 (m, 2H), 2.04-1.99 (m, 2H), 1.34 (s, 9H), 1.21 (d, J = 6.4 Hz, 6H)。 Example 7 (4): Propane-2-yl = 3- (2-{(4E) -5-3-[(benzenesulfonyl) (tert-butoxycarbonyl) amino] phenylpenta-4-ene-1-yl } Oxyphenyl) Propanoart In a solution of the compound (473 mg) synthesized in Example 1 in isopropyl alcohol (3.1 mL), the compound (1.0 g) synthesized in Example 7 (3) and N-methyl-2-pyrrolidone ( 0.5 mL) solution was added and the mixture was cooled to an internal temperature of 10 ° C. A solution of sodium-tert-butoxide (218.7 mg) in N-methyl-2-pyrrolidone (2.0 mL) cooled to an internal temperature of 10 ° C. was added dropwise to this solution. The mixture was stirred for 30 minutes or more to obtain a solution of the title compound having the following physical characteristics.
Silica Gel Column Chromatography Refined Product Properties: White Solid
1 1 H-NMR (CDCl 3 , 400 MHz): δ 8.02-7.99 (m, 2H), 7.67-7.63 (m, 1H), 7.57-7.54 (m, 2H), 7.40-7.33 (m, 2H), 7.24- 7.23 (m, 1H), 7.20-7.16 (m, 2H), 7.09-7.06 (m, 1H), 6.89-6.83 (m, 2H), 6.45 (d, J = 16.0 Hz, 1H), 6.29 (dt, J = 16.0, 7.2 Hz, 1H), 5.04-4.98 (m, 1H), 4.03 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.62-2.59 (m, 2H) ), 2.47-2.42 (m, 2H), 2.04-1.99 (m, 2H), 1.34 (s, 9H), 1.21 (d, J = 6.4 Hz, 6H).
実施例７（５）：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩の結晶
　実施例７（４）で合成した化合物の溶液に２ｍoｌ／L水酸化カリウム水溶液（４．０ｍL）を加え、内温９０℃で３時間撹拌した。反応溶液を室温に冷却した後、３５％クエン酸水溶液（５．０ｍL）および酢酸イソプロピル（５．０ｍL）を加えた。有機層と水層を分液した後、水層を酢酸イソプロピル（５．０ｍL）で抽出した。合わせた有機層を５％亜硫酸水素ナトリウム水溶液（４．０ｍL）、５％炭酸水素ナトリウム水溶液（４．０ｍL）、水（４．０ｍL）で順次洗浄した。有機層を３ｖ／ｗまで濃縮した。濃縮液にテトラヒドロフラン（１．０ｍL）を加えて内温４０℃に温調した。ジイソプロピルアミン（５３４μL）およびテトラヒドロフラン（０．５ｍL）を加えて、種結晶（０．５ｍｇ）を添加した。酢酸イソプロピル（６．０ｍL）を滴加して内温０℃に冷却した。２時間撹拌した後、沈殿物をろ過した。湿結晶を１２時間５０℃で真空乾燥して、以下の物性値を有する標題化合物（９１３ｍｇ）を得た。
性状：白色固体
Ｈ-ＮＭＲ(ＣＤＣｌ3、４００MHｚ)：δ　7.89-7.86 (m, 2H), 7.47-7.35 (m, 4H), 7.25-7.20 (m, 2H), 7.15-7.08 (m, 2H), 6.87-6.78 (m, 3H), 6.40 (dt, J = 15.6, 6.8 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 4.02 (t, J = 5.6 Hz, 2H), 3.35-3.25 (m, 2H), 2.99-2.95 (m, 2H), 2.62-2.58 (m, 2H), 2.42-2.38 (m, 2H), 2.00-1.94 (m, 2H), 1.36 (d, J = 6.8 Hz, 12H)。 Example 7 (5): Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] diisopropylamine propanoate Crystal Example 7 (4) A 2 mol / L potassium hydroxide aqueous solution (4.0 mL) was added to the solution of the compound synthesized in (1), and the mixture was stirred at an internal temperature of 90 ° C. for 3 hours. After cooling the reaction solution to room temperature, a 35% aqueous citric acid solution (5.0 mL) and isopropyl acetate (5.0 mL) were added. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with isopropyl acetate (5.0 mL). The combined organic layers were washed successively with 5% aqueous sodium bisulfite solution (4.0 mL), 5% aqueous sodium hydrogen carbonate solution (4.0 mL) and water (4.0 mL). The organic layer was concentrated to 3 v / w. Tetrahydrofuran (1.0 mL) was added to the concentrated solution to adjust the internal temperature to 40 ° C. Diisopropylamine (534 μL) and tetrahydrofuran (0.5 mL) were added and seed crystals (0.5 mg) were added. Isopropyl acetate (6.0 mL) was added dropwise and the mixture was cooled to an internal temperature of 0 ° C. After stirring for 2 hours, the precipitate was filtered. The wet crystals were vacuum dried at 50 ° C. for 12 hours to obtain the title compound (913 mg) having the following physical characteristics.
Properties: White solid H-NMR (CDCl 3 , 400 MHz): δ 7.89-7.86 (m, 2H), 7.47-7.35 (m, 4H), 7.25-7.20 (m, 2H), 7.15-7.08 (m, 2H) , 6.87-6.78 (m, 3H), 6.40 (dt, J = 15.6, 6.8 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 4.02 (t, J = 5.6 Hz, 2H), 3.35- 3.25 (m, 2H), 2.99-2.95 (m, 2H), 2.62-2.58 (m, 2H), 2.42-2.38 (m, 2H), 2.00-1.94 (m, 2H), 1.36 (d, J = 6.8) Hz, 12H).
実施例７（６）：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸の結晶（Ｂ晶）
　実施例７（５）で合成した化合物（１．２１７ｇ）の酢酸イソプロピル（５ｍL）溶液に２０％クエン酸水溶液（３ｍL）を加えて分液した。有機層を水（３ｍL）で２回洗浄した。有機層を２．５ｖ／ｗに濃縮した後、酢酸イソプロピル（５ｍL）を加えて２．５ｖ／ｗまで濃縮した。濃縮液に酢酸イソプロピル（１ｍL）とｎ－ヘプタン（１ｍL）を加えた。内温４０℃に温調した後、ｎ－ヘプタン（１．６１ｍL）を滴加した。種結晶（１．０ｍｇ）を添加して３０分間以上撹拌した後、内温３５℃に降温した。３時間以上撹拌した後、ｎ－ヘプタン（０．３ｍL）、ｎ－ヘプタン（０．３ｍL）、ｎ－ヘプタン（５．７９ｍL）を順次滴加した。内温０℃に冷却して１時間撹拌し、沈殿物をろ過した。湿結晶を１２時間４０℃で真空乾燥して、化合物ＡのＢ晶（９２０ｍｇ）を得た。 Example 7 (6): Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal B)
A 20% aqueous citric acid solution (3 mL) was added to a solution of the compound (1.217 g) synthesized in Example 7 (5) in isopropyl acetate (5 mL) to separate the solutions. The organic layer was washed twice with water (3 mL). After the organic layer was concentrated to 2.5 v / w, isopropyl acetate (5 mL) was added and concentrated to 2.5 v / w. Isopropyl acetate (1 mL) and n-heptane (1 mL) were added to the concentrate. After adjusting the internal temperature to 40 ° C., n-heptane (1.61 mL) was added dropwise. After adding seed crystals (1.0 mg) and stirring for 30 minutes or more, the temperature was lowered to an internal temperature of 35 ° C. After stirring for 3 hours or more, n-heptane (0.3 mL), n-heptane (0.3 mL), and n-heptane (5.79 mL) were sequentially added dropwise. The mixture was cooled to an internal temperature of 0 ° C., stirred for 1 hour, and the precipitate was filtered. The wet crystals were vacuum dried at 40 ° C. for 12 hours to obtain B crystals (920 mg) of compound A.
実施例８：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸の結晶（Ａ晶）
　実施例５で得られた化合物を１４９．６ｇを酢酸エチル１００ｍＬに室温で溶解させた。この溶液にｎ－へプタン９００ｍＬを加えた。溶液が少し白く濁り、徐々に２層になり、結晶がフラスコの底で塊になったため、これを砕いた。その後、室温で３日間撹拌し、結晶をろ取した。ろ取した結晶を空気中で乾燥し、該結晶を１２１．３ｇ得た。 Example 8 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal A)
149.6 g of the compound obtained in Example 5 was dissolved in 100 mL of ethyl acetate at room temperature. 900 mL of n-heptane was added to this solution. The solution became slightly cloudy and gradually became two layers, and the crystals clumped at the bottom of the flask and were crushed. Then, the mixture was stirred at room temperature for 3 days, and the crystals were collected by filtration. The crystals collected by filtration were dried in air to obtain 121.3 g of the crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図５に、ＤＳＣチャートを図６にそれぞれ示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件３
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表３に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 5, and the DSC chart is shown in FIG. 6, respectively.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 3
Table 3 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000005
Figure JPOXMLDOC01-appb-I000005
（２）示差走査熱量測定（ＤＳＣ）
測定条件：条件３
試料量：６．４ｍｇ
昇温速度：０．０１℃／ｍｉｎ（８５．５～８８．５℃）
　吸熱ピーク：オンセット温度約８６．３℃、ピーク温度約８６．８℃ (2) Differential scanning calorimetry (DSC)
Measurement condition: Condition 3
Sample amount: 6.4 mg
Heating rate: 0.01 ° C / min (85.5 to 88.5 ° C)
Endothermic peak: Onset temperature approx. 86.3 ° C, peak temperature approx. 86.8 ° C
実施例９：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　エチレンジアミン塩の結晶
　実施例８（フリー体Ａ晶）で得られた化合物２００ｍｇにエタノール０．４ｍＬを加えて室温で撹拌した。この中にエチレンジアミン２９μＬを加えた後、ＭＴＢＥ０．８ｍＬを添加した。超音波照射した後、ＭＴＢＥ（２－メトキシ－２－メチルプロパン）１．２ｍＬを追加して室温で１０分撹拌した。固体をろ取し、真空ポンプ、検体乾燥器を用いて室温で乾燥し、該結晶を２０１ｍｇ得た。 Example 9 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid ethylenediamine salt in Example 8 (free form A crystal) 0.4 mL of ethanol was added to 200 mg of the obtained compound, and the mixture was stirred at room temperature. After adding 29 μL of ethylenediamine to this, 0.8 mL of MTBE was added. After ultrasonic irradiation, 1.2 mL of MTBE (2-methoxy-2-methylpropane) was added, and the mixture was stirred at room temperature for 10 minutes. The solid was collected by filtration and dried at room temperature using a vacuum pump and a sample dryer to obtain 201 mg of the crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図７に、ＤＳＣチャートを図８にそれぞれ示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件１
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表４に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 7, and the DSC chart is shown in FIG. 8, respectively.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 1
Table 4 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-I000006
（２）示差走査熱量測定（ＤＳＣ）
測定条件：条件１
試料量：１．０ｍｇ
昇温速度：１０℃／ｍｉｎ（２０～１６０℃）
　吸熱ピーク：オンセット温度約１４８℃、ピーク温度約１５３℃ (2) Differential scanning calorimetry (DSC)
Measurement condition: Condition 1
Sample amount: 1.0 mg
Heating rate: 10 ° C / min (20-160 ° C)
Endothermic peak: Onset temperature approx. 148 ° C, peak temperature approx. 153 ° C
実施例１０：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ベネタミン塩の結晶
　実施例８（フリー体Ａ晶）で得られた化合物１ｇにメタノール２ｍＬを加えた。さらにベネタミン４５０ｍｇをメタノール１ｍＬに溶かした溶液を加えた。溶媒を減圧留去し、残渣にジエチルエーテル４３０μＬを加えて再度溶媒を減圧留去した．さらに再度ジクロロメタン４３０μＬを加えて溶媒を減圧留去した。アセトニトリル３ｍＬと水０．１５ｍＬを加えて超音波照射した後、室温で１時間撹拌した。アセトニトリル１．８ｍＬと水０．１ｍＬを加えてを加えて室温で５日間撹拌した。固体をろ取し、真空ポンプ、検体乾燥器を用いて室温で一晩乾燥し、該結晶を６１５ｍｇ得た。 Example 10 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid venetamine salt in Example 8 (free form A crystal) 2 mL of methanol was added to 1 g of the obtained compound. Further, a solution of 450 mg of Venetamine in 1 mL of methanol was added. The solvent was distilled off under reduced pressure, 430 μL of diethyl ether was added to the residue, and the solvent was distilled off again under reduced pressure. Further, 430 μL of dichloromethane was added again, and the solvent was distilled off under reduced pressure. After adding 3 mL of acetonitrile and 0.15 mL of water and irradiating with ultrasonic waves, the mixture was stirred at room temperature for 1 hour. 1.8 mL of acetonitrile and 0.1 mL of water were added, and the mixture was stirred at room temperature for 5 days. The solid was collected by filtration and dried overnight at room temperature using a vacuum pump and a sample dryer to obtain 615 mg of the crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図９に、ＤＳＣチャートを図１０にそれぞれ示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件１
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表５に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG. 9, and the DSC chart is shown in FIG. 10, respectively.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 1
Table 5 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000007
Figure JPOXMLDOC01-appb-I000007
（２）示差走査熱量測定（ＤＳＣ）
測定条件：条件１
試料量：１．０ｍｇ
昇温速度：１０℃／ｍｉｎ（２０～１６０℃）
　吸熱ピーク：オンセット温度約１１２℃、ピーク温度約１１４℃ (2) Differential scanning calorimetry (DSC)
Measurement condition: Condition 1
Sample amount: 1.0 mg
Heating rate: 10 ° C / min (20-160 ° C)
Endothermic peak: Onset temperature approx. 112 ° C, peak temperature approx. 114 ° C
実施例１１：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ｔ－ブチルアミン塩の結晶
　実施例８（フリー体Ａ晶）で得られた化合物１００ｍｇにエタノール１．５ｍＬを加え溶解させ、ｔ－ブチルアミン１３．５ｍｇのＭＴＢＥ１．５ｍＬ溶液を加えて室温で１日撹拌した。固体をろ取後、一晩乾燥し、該結晶を１１３ｍｇ得た。 Example 11 : Crystal of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid t-butylamine salt Example 8 (free form A crystal) ) To 100 mg of the compound obtained in (1) was dissolved by adding 1.5 mL of ethanol, 1.5 mL of MTBE solution of 13.5 mg of t-butylamine was added, and the mixture was stirred at room temperature for 1 day. The solid was collected by filtration and dried overnight to obtain 113 mg of the crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図１１に示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件１
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表６に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 1
Table 6 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000008
Figure JPOXMLDOC01-appb-I000008
実施例１２：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ナトリウム塩の結晶
　実施例８（フリー体Ａ晶）で得られた化合物１００ｍｇにメタノール２００μＬ投入し溶解させた。ここに２ｍｏｌ/Ｌの水酸化ナトリウム水溶液１０７．４μＬ投入し、濃縮乾固した。その後２－ブタノール２００μＬ投入し撹拌後、濃縮乾固した。その後、２－ブタノール２００μＬ投入し、室温で７日間撹拌後、６０℃で１日間撹拌した。そのまま濃縮乾固し、該結晶を１００ｍｇ得た。 Example 12 : Crystals of sodium salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid in Example 8 (free form A crystal) 200 μL of methanol was added to 100 mg of the obtained compound to dissolve it. 107.4 μL of a 2 mol / L sodium hydroxide aqueous solution was added thereto, and the mixture was concentrated to dryness. Then, 200 μL of 2-butanol was added, stirred, and then concentrated to dryness. Then, 200 μL of 2-butanol was added, and the mixture was stirred at room temperature for 7 days and then at 60 ° C. for 1 day. As it was concentrated to dryness, 100 mg of the crystals were obtained.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図１２に示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件１
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表７に示す。 A powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 1
Table 7 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000009
Figure JPOXMLDOC01-appb-I000009
実施例１３：３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ヘミカルシウム塩の結晶
　実施例８（フリー体Ａ晶）で得られた化合物５００ ｍｇに水酸化カルシウム３９．８ｍｇを加えた。メタノール１ｍＬ、水１００μＬを加え超音波を当て、懸濁液とした。これを濃縮乾固した。イソプロピルアルコール２．５ｍＬと水０．５ｍＬを加え、室温で４日間撹拌した。結晶をろ過、乾燥し、該結晶を４３１ｍｇ得た。 Example 13 : Crystals of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid hemicalcium salt Example 8 (free form A crystal) 39.8 mg of calcium hydroxide was added to 500 mg of the compound obtained in. 1 mL of methanol and 100 μL of water were added and ultrasonic waves were applied to prepare a suspension. This was concentrated to dryness. 2.5 mL of isopropyl alcohol and 0.5 mL of water were added, and the mixture was stirred at room temperature for 4 days. The crystals were filtered and dried to obtain 431 mg of the crystals.
　下記の条件で測定した該結晶の粉末Ｘ線回析スペクトルチャートを図１３に示す。
　（１）粉末Ｘ線回折スペクトル
測定条件：条件１
　Ｃｕ－Ｋα線を使用した粉末Ｘ線回折スペクトル法で得られた回折角（２θ）（度）および相対強度（％）の結果を表８に示す。 The powder X-ray diffraction spectrum chart of the crystal measured under the following conditions is shown in FIG.
(1) Powder X-ray diffraction spectrum measurement condition: Condition 1
Table 8 shows the results of the diffraction angles (2θ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectral method using Cu—Kα rays.
Figure JPOXMLDOC01-appb-I000010
Figure JPOXMLDOC01-appb-I000010
実施例１４：晶析溶媒中での安定性評価
　実施例７（フリー体Ｂ晶）および実施例８（フリー体Ａ晶）記載の結晶原薬について、競合スラリーによる収束実験を実施した。
　フリー体Ａ晶とＢ晶を各５０ mgずつ試験管内で混合し、各種組成の溶媒を加えてスラリーとした。０℃～６０℃にて１２時間以上撹拌した後、結晶をろ別した。得られた湿結晶を粉末Ｘ線回折にて分析した。結果を表９および表１０に示す。 Example 14: Stability evaluation in crystallization solvent Convergence experiments with competing slurries were carried out for the crystal drug substances described in Example 7 (free body B crystal) and Example 8 (free body A crystal).
50 mg each of free A crystals and B crystals were mixed in vitro, and solvents having various compositions were added to prepare a slurry. After stirring at 0 ° C. to 60 ° C. for 12 hours or more, the crystals were filtered off. The obtained wet crystals were analyzed by powder X-ray diffraction. The results are shown in Tables 9 and 10.
Figure JPOXMLDOC01-appb-I000011
Figure JPOXMLDOC01-appb-I000011
Figure JPOXMLDOC01-appb-I000012
Figure JPOXMLDOC01-appb-I000012
　いずれの溶媒組成、温度においても、Ｂ晶へ収束したことから、Ｂ晶が安定晶であることが示唆される。 At any solvent composition and temperature, the B crystal converged to the B crystal, suggesting that the B crystal is a stable crystal.
実施例１５：粉砕工程における製造性評価
　実施例７（フリー体Ｂ晶）および実施例８（フリー体Ａ晶）の結晶原薬について、A-O Jet mill（株式会社セイシン企業）を使用して、以下の粉砕条件で未粉砕原薬を粉砕した。
粉砕条件：供給圧 ０．６４ＭＰａ、粉砕圧 ０．６０ＭＰａ、フィード速度 ２．０ｇ／ｍｉｎ
＜結果・考察＞
　Ａ晶の未粉砕原薬（１０ g）を粉砕した場合には、ミル本体内で著しい固着・閉塞が発生したため、全量の粉砕は不可能であった。Ｂ晶の未粉砕原薬（１０ g）を粉砕した場合には、目立った固着は発生せず、全量の粉砕可能であったことから、Ｂ晶は取扱いに優れた結晶形である。 Example 15: Manufacturability evaluation in the crushing process The crystal drug substances of Example 7 (free body B crystal) and Example 8 (free body A crystal) were described below using AO Jet mill (Seishin Enterprise Co., Ltd.). The uncrushed API was crushed under the crushing conditions of.
Crushing conditions: Supply pressure 0.64 MPa, crushing pressure 0.60 MPa, feed rate 2.0 g / min
<Results / Discussion>
When the uncrushed drug substance (10 g) of A crystal was crushed, the entire amount could not be crushed because significant sticking and blockage occurred in the mill body. When the uncrushed drug substance (10 g) of B crystal was crushed, no conspicuous adhesion occurred and the entire amount could be crushed. Therefore, B crystal is a crystal form excellent in handling.
実施例１６：溶解度評価
　実施例７（フリー体Ｂ晶）および実施例８（フリー体Ａ晶）記載の結晶原薬について、Crystal-16（Avantium Technologies，BV）を用いる動的溶解法により溶解度を測定した。
＜実験方法＞
　あらかじめ秤量した実施例７（フリー体Ｂ晶）及び実施例８（フリー体Ａ晶）並びに溶媒（ｎ-へプタンと酢酸イソプロピルの混媒；ｎ-ヘプタン／酢酸イソプロピル=3.6/4.35、4.8/4.35、12/4.35）を透明なガラスバイアル内で混合し、徐々に（０．１℃／ｍｉｎで）加熱・降温した。各バイアルの濁度をモニターし、温度プロファイルと共にプロットして、各結晶の溶解及び沈殿点を記録した。溶解点の溶液の濃度（固体と溶媒の質量に基づいて計算した）を、記録した温度での飽和濃度として処理し、溶解度をこの濃度に基づいて計算した。
＜結果・考察＞
　いずれの溶媒組成（ｎ-へプタンと酢酸イソプロピルの混媒）においても、40℃以下の温度域において、Ｂ晶と比較してＡ晶の溶解度が高い値を示した。 Example 16: Solubility evaluation The solubility of the crystal drug substances described in Example 7 (free body B crystal) and Example 8 (free body A crystal) was determined by a dynamic dissolution method using Crystal-16 (Avantium Technologies, BV). It was measured.
<Experimental method>
Pre-weighed Examples 7 (free B crystal) and 8 (free A crystal) and solvent (mixture of n-heptane and isopropyl acetate; n-heptane / isopropyl acetate = 3.6 / 4.35, 4.8 / 4.35 , 12 / 4.35) was mixed in a transparent glass vial, and gradually heated and lowered (at 0.1 ° C./min). The turbidity of each vial was monitored and plotted with a temperature profile to record the dissolution and precipitation points of each crystal. The concentration of the solution at the dissolution point (calculated based on the mass of solid and solvent) was treated as the saturation concentration at the recorded temperature and the solubility was calculated based on this concentration.
<Results / Discussion>
In any of the solvent compositions (mixture of n-heptane and isopropyl acetate), the solubility of A crystal was higher than that of B crystal in the temperature range of 40 ° C. or lower.
実施例１７：かさ密度の測定
　実施例７（フリー体Ｂ晶）および実施例８（フリー体Ａ晶）記載の結晶原薬について、かさ密度を測定した。
＜実験方法＞
　風袋引きした50 mLガラス製メスシリンダー内に静かに実施例７（フリー体Ｂ晶）および実施例８（フリー体Ａ晶）の結晶原薬約5 gを入れ、充填した結晶原薬の質量を測定した。その後、メスシリンダーをゆっくりと1回反転させたときの結晶原薬の見かけの体積を測定した。結晶原薬の質量を見かけの体積で除した値をルーズかさ密度（緩め見かけ密度）とした。その後、メスシリンダーをフルイ振とう器（株式会社飯田製作所、ふるい振盪機 ES-65型）にセットし、3分間振動を与えたあとの体積を測定した。結晶原薬をタップ後の見かけの体積で除した値をタップかさ密度（固め見かけ密度）とした。結果を表１１に示す。
＜結果・考察＞
　Ａ晶と比較し、Ｂ晶はルーズかさ密度、タップかさ密度ともに高い値を示したことから、Ｂ晶の方が流動性が高く、取扱いに優れた結晶形である。 Example 17: Measurement of bulk density The bulk density was measured for the crystal drug substances described in Example 7 (free body B crystal) and Example 8 (free body A crystal).
<Experimental method>
Gently place about 5 g of the crystalfield of Example 7 (free body B crystal) and Example 8 (free body A crystal) in a tare 50 mL glass graduated cylinder, and measure the mass of the packed crystal field drug. It was measured. Then, the apparent volume of the crystal field drug substance was measured when the graduated cylinder was slowly inverted once. The value obtained by dividing the mass of the crystal field drug by the apparent volume was taken as the loose bulk density (loose apparent density). After that, the measuring cylinder was set in a sieve shaker (Iida Seisakusho Co., Ltd., sieve shaker ES-65 type), and the volume was measured after vibrating for 3 minutes. The value obtained by dividing the crystalline drug substance by the apparent volume after tapping was taken as the tap bulk density (consolidated apparent density). The results are shown in Table 11.
<Results / Discussion>
Compared with A crystal, B crystal showed higher values in both loose bulk density and tap bulk density, so B crystal has higher fluidity and is a crystal form that is easier to handle.
Figure JPOXMLDOC01-appb-I000013
Figure JPOXMLDOC01-appb-I000013
生物学的実験例１：シュワン細胞を用いたｉｎ　ｖｉｔｒｏ試験
（試験方法）
１）ラットシュワン細胞の調製
　クリーンベンチ内で生後０～２日の新生仔ラットの後根神経節（以下ＤＲＧと略す）を摘出し、ＤＭＥＭ中に回収した。回収後のチューブを室温にて４００ｇ、３分間、遠心分離し、上清を除去後、０．２５％コラゲナーゼ溶液を添加した。３７℃、３０分間のインキュベートにより摘出ＤＲＧを分散・分離させた後、室温にて４００ｇ、３分間遠心分離し、上清を除去後、０．２５％Trypsin/EDTAとDNaseIを添加した。３７℃、３０分間のインキュベート後、１０％ＦＢＳを添加したＤＭＥＭ（１０％ＦＢＳ－ＤＭＥＭ）でｔｒｙｐｓｉｎを不活化し、室温にて４００ｇ、３分間遠心分離した。上清を除去後、１０％ＦＢＳ－ＤＭＥＭを添加して細胞懸濁液を調製し、フィルター（直径７０μｍ）に通した。フィルターを通した細胞懸濁液の細胞数をカウントし、２．０×１０５ ｃｅｌｌｓ／ｍＬに調製した後、ポリ－Ｄ－リジンコート９６－ｗｅｌｌ ｂｌａｃｋ－ｃｌｅａｒ ｐｌａｔｅに１００μＬ／ｗｅｌｌずつ播種し、ＣＯ２インキュベーターにて５％ＣＯ２、９５％Ａｉｒ、３７℃の条件下で静置培養した。
２）化合物添加
　細胞培養プレートの培地をアスピレーターで吸引除去し、１％透析済みＦＢＳと１００μｍｏｌ／Ｌ ｄｉｂｕｔｙｒｙｌ ｃｙｃｌｉｃ ＡＭＰを添加したＤＭＥＭを添加した。その後、ＤＭＳＯに溶解した実施例５記載の化合物の溶液（終濃度０．１、０．３、１または３μｍｏｌ／Ｌ）を１０μＬずつ添加し、ＣＯ２インキュベーターにて５％ＣＯ２、９５％Ａｉｒ、３７℃の条件下で静置培養した。
３）細胞免疫染色
　化合物処置後３日に細胞培養プレートの各ｗｅｌｌにホルムアルデヒドを添加し、室温で３０分以上静置した。上清を除去後、０．３％ＴｒｉｔｏｎＸ－１００溶液を添加し、室温で２０分以上静置した。上清を除去後、５μｇ／ｍＬ 抗ｍｙｅｌｉｎｅ－ａｓｓｏｃｉａｔｅｄ ｇｌｙｃｏｐｒｏｔｅｉｎ抗体（抗ＭＡＧ抗体）溶液を添加し、室温で６０分以上または４℃（許容範囲：１～９℃）で一晩静置した。０．１％ＴｒｉｔｏｎＸ－１００溶液で３回洗浄した後、１０μｇ／ｍＬ Ａｌｅｘａ ｆｌｕｏｒ ４８８ ａｎｔｉ－ｍｏｕｓｅ ＩｇＧ溶液を添加し、室温で６０分以上または４℃で一晩静置した。０．１％ＴｒｉｔｏｎＸ－１００溶液で４回洗浄した後、１μｇ／ｍＬ Ｈｏｅｃｈｓｔ３３３４２溶液を添加し、核を染色した。
（評価方法）
　蛍光画像のＭＡＧ陽性面積と細胞核数を算出し、それぞれ５視野／ｗｅｌｌの総和を各ｗｅｌｌのＭＡＧ陽性面積及び細胞核数とした。その後、各ｗｅｌｌのＭＡＧ陽性面積を細胞核数で除した値（ＭＡＧ／細胞核数値）を算出し、以下の式により媒体群に対するシュワン細胞分化促進率を求めた。 Biological Experimental Example 1: In vitro test using Schwann cells (test method)
1) Preparation of rat Schwann cells The dorsal root ganglion (hereinafter abbreviated as DRG) of 0 to 2 day old newborn rats was excised in a clean bench and collected in DMEM. The collected tube was centrifuged at 400 g at room temperature for 3 minutes, the supernatant was removed, and a 0.25% collagenase solution was added. The extracted DRG was dispersed and separated by incubation at 37 ° C. for 30 minutes, and then centrifuged at 400 g at room temperature for 3 minutes to remove the supernatant, and then 0.25% Trypsin / EDTA and DNase I were added. After incubation at 37 ° C. for 30 minutes, trypsin was inactivated with DMEM (10% FBS-DMEM) supplemented with 10% FBS, and 400 g was centrifuged at room temperature for 3 minutes. After removing the supernatant, 10% FBS-DMEM was added to prepare a cell suspension, which was passed through a filter (diameter 70 μm). The number of cells in the filtered cell suspension was counted and prepared to 2.0 × 10 5 cells / mL, and then 100 μL / well was seeded on a poly-D-lysine coat 96-well black-clear plate. The cells were statically cultured in a CO 2 incubator under the conditions of 5% CO 2 , 95% Air, and 37 ° C.
2) Compound addition The medium of the cell culture plate was removed by suction with an ejector, and DMEM supplemented with 1% dialyzed FBS and 100 μmol / L dibutyryl cyclic AMP was added. Then, 10 μL each of a solution of the compound described in Example 5 dissolved in DMSO (final concentration 0.1, 0.3, 1 or 3 μmol / L) was added, and 5% CO 2 , 95% Air was added in a CO 2 incubator. , 37 ° C., statically cultured.
3) Cell immunostaining Formaldehyde was added to each well of the cell culture plate 3 days after the compound treatment, and the cells were allowed to stand at room temperature for 30 minutes or more. After removing the supernatant, a 0.3% Triton X-100 solution was added, and the mixture was allowed to stand at room temperature for 20 minutes or longer. After removing the supernatant, a 5 μg / mL anti-myeline-associated glycoprotein antibody (anti-MAG antibody) solution was added, and the mixture was allowed to stand at room temperature for 60 minutes or longer or at 4 ° C. (tolerance: 1 to 9 ° C.) overnight. After washing 3 times with 0.1% Triton X-100 solution, 10 μg / mL Alexa fluor 488 anti-mouse IgG solution was added, and the mixture was allowed to stand at room temperature for 60 minutes or more or at 4 ° C. overnight. After washing 4 times with 0.1% Triton X-100 solution, 1 μg / mL Hoechst 33342 solution was added and the nuclei were stained.
(Evaluation method)
The MAG-positive area and the number of cell nuclei of the fluorescence image were calculated, and the sum of 5 visual fields / well was taken as the MAG-positive area and the number of cell nuclei of each well. Then, the value (MAG / cell nucleus value) obtained by dividing the MAG positive area of each well by the number of cell nuclei was calculated, and the Schwann cell differentiation promotion rate for the medium group was determined by the following formula.
Figure JPOXMLDOC01-appb-M000014
Figure JPOXMLDOC01-appb-M000014
（結果）
　０．３または３μｍｏｌ／Ｌの実施例５記載の化合物の溶液を添加した場合の媒体群に対するシュワン細胞分化促進率（％ ｏｆ ｖｅｈｉｃｌｅ値）は、表１２のとおりであった。このことから、実施例５記載の化合物は強力な神経保護および／または修復作用を有すると考えられる。 (result)
Table 12 shows the Schwann cell differentiation promotion rate (% of vehicle value) with respect to the medium group when the solution of the compound described in Example 5 of 0.3 or 3 μmol / L was added. From this, it is considered that the compound described in Example 5 has a strong neuroprotective and / or repairing action.
Figure JPOXMLDOC01-appb-I000015
Figure JPOXMLDOC01-appb-I000015
生物学的実験例２：ストレプトゾトシン誘発ラットモデルを用いた試験
　実施例５記載の化合物の糖尿病性末梢神経障害における治療効果を評価するため、ストレプトゾトシンモデルを用いたｉｎ ｖｉｖｏ試験を行った。
（試験方法）
１）モデル作成法
　ラットに５５ ｍｇ／ｋｇのストレプトゾトシン（以下ＳＴＺと略す）を単回静脈内投与することで作製した。
２）侵害受容閾値の測定
　ＳＴＺ投与までに１回以上、ラットを測定用の透明アクリルケージに１０分間以上入れ、測定環境にラットを馴化させた．０．４、０．６、１、２、４、６、８、１５ ｇの８本のｖｏｎ Ｆｒｅｙフィラメントを、金網床の下から後肢足底部に垂直に適用した。すばやい逃避反応あるいは足振り反応を陽性反応（反応あり）とした。実施例５記載の化合物は、ＳＴＺ投与後１４日から２８日まで１日１回経口投与し、投与量は０．０３、０．３、または３ｍｇ／ｋｇとした。また侵害受容閾値は、ＳＴＺ投与前、ＳＴＺ投与後１４日（実施例５記載の化合物の投薬開始日）、２１日（投薬開始後７日）、２８日（投薬開始後１４日）および３５日（休薬後７日）において、実施例５記載の化合物の投与２時間後に測定した。
（評価方法）
　Ｃｈａｐｌａｎらの方法（Ｊ Ｎｅｕｒｏｓｃｉ Ｍｅｔｈｏｄｓ. １９９４；５３：５５－６３）に従い，ｕｐ－ｄｏｗｎ法にて侵害受容閾値を測定した。また、侵害受容閾値の改善率は以下の式に基づき算出した。 Biological Experimental Example 2: Test Using Streptozotocin-Induced Rat Model In order to evaluate the therapeutic effect of the compound described in Example 5 on diabetic peripheral neuropathy, an in vivo test using a streptozotocin model was performed.
(Test method)
1) Modeling method A rat was prepared by intravenously administering 55 mg / kg of streptozotocin (hereinafter abbreviated as STZ).
2) Measurement of nociception threshold The rat was placed in a transparent acrylic cage for measurement at least once before STZ administration for 10 minutes or more, and the rat was acclimatized to the measurement environment. Eight von Frey filaments of 0.4, 0.6, 1, 2, 4, 6, 8, 15 g were applied vertically from under the wire mesh bed to the soles of the hind limbs. A quick escape reaction or a foot swing reaction was regarded as a positive reaction (with a reaction). The compound described in Example 5 was orally administered once a day from 14 days to 28 days after STZ administration, and the dose was 0.03, 0.3, or 3 mg / kg. The nociception thresholds were set to 14 days before STZ administration, 14 days after STZ administration (dose start date of the compound according to Example 5), 21 days (7 days after the start of dosing), 28 days (14 days after the start of dosing), and 35 days. (7 days after drug suspension), the measurement was performed 2 hours after administration of the compound described in Example 5.
(Evaluation method)
The nociception threshold was measured by the up-down method according to the method of Chaplan et al. (J Neuroscii Methods. 1994; 53: 55-63). The improvement rate of the nociception threshold was calculated based on the following formula.
Figure JPOXMLDOC01-appb-M000016
Figure JPOXMLDOC01-appb-M000016
（結果）
　実施例５記載の化合物を０．３ｍｇ／ｋｇの投与量で投与した場合の侵害受容閾値の結果を図１４に、侵害受容閾値改善率を表１３に示す。化合物Ａは末梢神経障害において強力な鎮痛作用を発揮した。また投薬開始後７日から侵害受容閾値の改善が認められ、その作用は休薬後７日においても持続しており、持続的な鎮痛作用が認められた。 (result)
The results of the nociception threshold when the compound described in Example 5 was administered at a dose of 0.3 mg / kg are shown in FIG. 14, and the nociception threshold improvement rate is shown in Table 13. Compound A exerted a strong analgesic effect in peripheral neuropathy. In addition, an improvement in the nociception threshold was observed from 7 days after the start of administration, and the effect was sustained even 7 days after the drug was withdrawn, and a continuous analgesic effect was observed.
Figure JPOXMLDOC01-appb-I000017
Figure JPOXMLDOC01-appb-I000017
生物学的実験例３：反応性代謝物測定試験
　実施例５記載の化合物の反応性代謝物とｑｕａｔｅｒｎａｒｙ　ａｍｍｏｎｉｕｍ　ｇｌｕｔａｔｈｉｏｎｅ（ＱＡ－ＧＳＨ）との複合体をＬＣ／ＭＳ／ＭＳで半定量し（Ｓｏｇｌｉａ　ＪＲ　ｅｔ　ａｌ．，Ｃｈｅｍ．Ｒｅｓ．Ｔｏｘｉｃｏｌ．１９（３），４８０－４９０，２００６）、ＮＡＤＰＨに依存した反応性代謝物量を測定した。
　１００ｍＭ　リン酸バッファー（ｐＨ７．４）１８７．５μＬに２０ｍｇ／ｍＬのヒト肝ミクロソーム（Ｘｅｎｏｔｅｃｈ）を１２．５μＬ（終濃度：１ｍｇ／ｍＬ）、１０ｍｍｏｌ／Ｌ　ＱＡ－ＧＳＨを２５μＬ（終濃度：１ｍｍｏｌ／Ｌ）、０．５ｍｍｏｌ／Ｌ　実施例５記載の化合物の溶液（ＤＭＳＯ：アセトニトリル：水＝５：３８：５７）を５μＬ（実施例５記載の化合物の終濃度：１０μｍｏｌ／Ｌ）添加した。３７℃の水浴で３分間プレインキュベーション後、２５ｍｍｏｌ／Ｌ　ＮＡＤＰＨを２０μＬ（終濃度：２ｍｍｏｌ／Ｌ）添加して反応を開始した。反応１時間後にＩＳ含有アセトニトリル５００μＬを混和して反応を停止した。反応を停止した試料中に生成した反応性代謝物とＱＡ－ＧＳＨとの複合体（ＱＡ－ＧＳ付加体）をＬＣ／ＭＳ／ＭＳで分析した。測定はＱＡ－ＧＳ付加体内部標準物質（ＩＳ）とともに実施した。 Biological Experimental Example 3: Reactive Metabolite Measurement Test The complex of the reactive metabolite of the compound described in Example 5 and quaternary ammonia glutathione (QA-GSH) was semi-quantified by LC / MS / MS (Soglia JR). The amount of reactive metabolites dependent on et al., Chem. Res. Toxicol. 19 (3), 480-490, 2006) and NADPH was measured.
12.5 μL (final concentration: 1 mg / mL) of 20 mg / mL human liver microsomes (Xenotech) in 187.5 μL of 100 mM phosphate buffer (pH 7.4), and 25 μL (final concentration: 1 mmol / L) of 10 mmol / L QA-GSH. L), 0.5 mmol / L A solution of the compound described in Example 5 (DMSO: acetonitrile: water = 5:38:57) was added in an amount of 5 μL (final concentration of the compound described in Example 5: 10 μmol / L). After pre-incubation in a water bath at 37 ° C. for 3 minutes, 20 μL (final concentration: 2 mmol / L) of 25 mmol / L NADPH was added to initiate the reaction. One hour after the reaction, 500 μL of IS-containing acetonitrile was mixed to terminate the reaction. The complex (QA-GS adduct) of the reactive metabolite and QA-GS produced in the sample in which the reaction was stopped was analyzed by LC / MS / MS. Measurements were performed with the QA-GS adduct internal standard (IS).
　下式より、ＱＡ－ＧＳ付加体濃度を算出した。 The QA-GS adduct concentration was calculated from the following formula.
Figure JPOXMLDOC01-appb-M000018
Figure JPOXMLDOC01-appb-M000018
　（結果）
　実施例５記載の化合物のＱＡ－ＧＳ付加体濃度は低く、２００ｎｍｏｌ／Ｌ以下であった。 (result)
The QA-GS adduct concentration of the compound described in Example 5 was low, 200 nmol / L or less.
生物学的実験例４：Ｈａｎｄ１－ＥＳＴ試験
　実施例５記載の化合物の生殖発生毒性を、マウスＥＳ細胞から心筋への分化過程における生細胞数と分化効率を指標にしたＰＯＣＡ（登録商標）Ｈａｎｄ１－ＥＳＴ（ＤＳ　ファーマバイオメディカル株式会社）を用いて測定した（Ｌｅ　Ｃｏｚ　Ｆ　ｅｔ　ａｌ．，Ｊ．Ｔｏｘｉｃｏｌ．，４０（２）：２５１－６１．２０１５）。
　実施例５記載の化合物の１０００ｍｇ／ｍＬ　ＤＭＳＯ溶液を調製した。実施例５記載の化合物の１０００ｍｇ／ｍＬ　ＤＭＳＯ溶液を心筋分化培地で希釈し，実施例５記載の化合物の１０００μｇ／ｍＬ液（ＤＭＳＯの終濃度０．１％）を調製した。目視で沈殿物の有無を確認しながら、心筋分化培地（ＤＭＳＯの終濃度０．１％）で順次３倍希釈し、沈殿物が無い濃度を最大溶解度として記録した。
　融解したＨａｎｄ１－ＥＳ細胞（ｐＧＬ４．１７をベクターとし心筋分化マーカーＨａｎｄ１遺伝子のプロモーター領域とその下流にルシフェラーゼ遺伝子を形質転換したマウスＥＳ細胞）を未分化維持培地に懸濁後、ゼラチンコートした６０ｍｍ　Ｄｉｓｈに播種し、２－３日培養した。培養２－３日後、トリプシン処理をしたＨａｎｄ１－ＥＳ細胞をゼラチンコートした６０ｍｍ　Ｄｉｓｈに２×１０６ｃｅｌｌｓ／５ｍＬで継代し、一晩培養した。その後、トリプシン処理をしたＨａｎｄ１－ＥＳ細胞を、心筋分化培地に懸濁後、ＰｒｉｍｅＳｕｒｆａｃｅ（登録商標）Ｕ底９６ｗｅｌｌプレートに７５０ｃｅｌｌｓ／５０μＬ／ｗｅｌｌで播種し、２時間培養した。２時間後、実施例５記載の化合物あるいは陽性対照である５－ＦＵを含む心筋分化培地５０μＬを添加し（実施例５記載の化合物の終濃度：１０００，３３３，１１１，３７．０，１２．３，４．１２及び１．３７μｇ／ｍＬ、５－ＦＵの終濃度：１，０．３３３，０．１１１，０．０３７０，０．０１２３，０．００４１２及び０．００１３７μｇ／ｍＬ、ＤＭＳＯの終濃度：０．１％）、５日間培養した。実施例５記載の化合物あるいは５－ＦＵを５日間曝露した後、生細胞数を測定するためにＣｅｌｌＴｉｔｅｒ－Ｆｌｕｏｒ（登録商標）（Ｐｒｏｍｅｇａ）を添加し、ＳｐｅｃｔｒａＭａｘ　Ｍ５ｅ　ｐｌａｔｅ　ｒｅａｄｅｒ（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ）を用いて，励起波長Ｅｘ　３９０ｎｍ及び蛍光波長Ｅｍ　５０５ｎｍの蛍光を測定した。さらに、分化効率を測定するためにＳｔｅａｄｙ－Ｇｌｏ（登録商標）（Ｐｒｏｍｅｇａ）を添加し、ＳｐｅｃｔｒａＭａｘ　Ｍ５ｅ　ｐｌａｔｅ　ｒｅａｄｅｒを用いて、発光を測定した。専用解析ソフトＰＯＣＡ　Ｈａｎｄ１－ＥＳＴ　Ａｎａｌｙｓｉｓ　Ｓｏｆｔｗａｒｅに、求めた最大溶解度、生細胞数の５０％阻害濃度及び分化効率の５０％阻害濃度を入力し、催奇形性リスクを判定した。判定の基準はＰｒｏｖａｂｉｌｉｔｙ　０．５２未満を低リスク、０．５２以上を高リスクとした（Ｎａｇａｈｏｒｉ　ｅｔ　ａｌ．，Ｔｏｘｉｃｏｌｏｇｙ　Ｌｅｔｔｅｒｓ　２５９，４４－５１）。
（結果）
　実施例５記載の化合物は、ｐｒｏｂａｂｉｌｉｔｙが０．５２未満であり、催奇形性のリスクは低いと考えられた。 Biological Experimental Example 4: Hand1-EST Test POCA® Hand1- used as an index of the reproductive and developmental toxicity of the compound described in Example 5 in the number of viable cells and the differentiation efficiency in the process of differentiation from mouse ES cells to myocardium. It was measured using EST (DS Pharma Biomedical Co., Ltd.) (Le Coz F et al., J. Toxicol., 40 (2): 251-61.2015).
A 1000 mg / mL DMSO solution of the compound described in Example 5 was prepared. A 1000 mg / mL DMSO solution of the compound described in Example 5 was diluted with a myocardial differentiation medium to prepare a 1000 μg / mL solution (final concentration of DMSO 0.1%) of the compound described in Example 5. While visually confirming the presence or absence of a precipitate, the cells were sequentially diluted 3-fold with a myocardial differentiation medium (final concentration of DMSO of 0.1%), and the concentration without a precipitate was recorded as the maximum solubility.
Thawed Hand1-ES cells (mouse ES cells in which the promoter region of the myocardial differentiation marker Hand1 gene and its downstream were transformed with the luciferase gene using pGL4.17 as a vector) were suspended in an undifferentiated maintenance medium and then gelatin-coated 60 mm Dish. Was sown and cultured for 2-3 days. After 2-3 days of culturing, trypsin-treated Hand1-ES cells were subcultured in gelatin-coated 60 mm Dish at 2 × 10 6 cells / 5 mL and cultured overnight. Then, the trypsin-treated Hand1-ES cells were suspended in myocardial differentiation medium, seeded on a Prime Surface® U-bottom 96-well plate at 750 cells / 50 μL / well, and cultured for 2 hours. After 2 hours, 50 μL of the compound described in Example 5 or a myocardial differentiation medium containing 5-FU as a positive control was added (final concentration of the compound described in Example 5: 1000,333,111,37.0, 12. Final concentrations of 3,4.12 and 1.37 μg / mL, 5-FU: 1,0.333,0.111,0.0370,0.0123,0.00412 and 0.00137 μg / mL, final DMSO Concentration: 0.1%), cultured for 5 days. After exposure to the compound described in Example 5 or 5-FU for 5 days, CellTiter-Fluor® (Promega) was added to measure the viable cell number, and a SpectraMax M5e plate reader (Molecular Devices) was used. , Excitation wavelength Ex 390 nm and fluorescence wavelength Em 505 nm fluorescence were measured. Furthermore, Steady-Glo® (Promega) was added to measure the differentiation efficiency, and luminescence was measured using a SpectraMax M5e plate reader. The risk of teratogenicity was determined by inputting the obtained maximum solubility, 50% inhibition concentration of viable cell number, and 50% inhibition concentration of differentiation efficiency into the dedicated analysis software POCA Hand1-EST Analysis Software. The criteria for judgment were low risk for probability less than 0.52 and high risk for 0.52 or more (Nagahori et al., Toxicology Letters 259, 44-51).
(result)
The compounds described in Example 5 had a probability of less than 0.52 and were considered to have a low risk of teratogenicity.
［製剤例］
　製剤例１：
化合物Ａ（Ｂ晶）　５ｍｇ含有錠
　以下の各成分を常法により混合した後打錠して、一錠中に５ｍｇの活性成分を含有する錠剤１万錠を得る。
・３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸（Ｂ晶）：５０ｇ
・カルボキシメチルセルロースカルシウム（崩壊剤）：２０ｇ
・ステアリン酸マグネシウム（潤滑剤）：１０ｇ
・微結晶セルロース：９２０ｇ [Formulation example]
Preparation example 1 :
Compound A (Crystal B) 5 mg-containing tablet The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets containing 5 mg of the active ingredient in one tablet.
3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (Crystal B): 50 g
-Carboxymethyl cellulose calcium (disintegrant): 20 g
-Magnesium stearate (lubricant): 10 g
-Microcrystalline cellulose: 920 g
　製剤例２：
化合物Ａ（Ａ晶）　２０ｍｇ含有注射剤
　以下の各成分を常法により混合した後、溶液を常法により滅菌し、５ｍＬずつアンプルに充填し、常法により凍結乾燥し、１アンプル中２０ｍｇの活性成分を含有するアンプル１万本を得る。
・３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸（Ａ晶）：２００ｇ　
・マンニトール：２０ｇ
・蒸留水：５０Ｌ Preparation example 2 :
Injection containing 20 mg of compound A (crystal A) After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled in 5 mL each in an ampoule, lyophilized by a conventional method, and 20 mg of activity in 1 ampoule. Obtain 10,000 ampoules containing the ingredients.
3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid (crystal A): 200 g
・ Mannitol: 20g
・ Distilled water: 50L
　化合物Ａは、神経保護および／または修復作用を有するため、神経障害等の治療に有用である。また、化合物Ａの結晶は、医薬品原薬として有用である。 Compound A has a neuroprotective and / or repairing effect, and is therefore useful for the treatment of neuropathy and the like. Further, the crystal of compound A is useful as a drug substance.

Claims (25)

  1. 　結晶形態である、３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸。 Crystal form, 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid.
  2. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、および約１４．１度の回折角（２θ）に回折ピークを有する、請求項１記載の化合物。 The compound according to claim 1, which has a diffraction peak at a diffraction angle (2θ) of at least about 8.7 degrees, about 11.2 degrees, and about 14.1 degrees in a powder X-ray diffraction spectrum.
  3. 　粉末Ｘ線回折スペクトルにおいて、さらに約１２．０度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に少なくとも１つ以上の回折ピークを有する、請求項２記載の化合物。 In the powder X-ray diffraction spectrum, at least one or more at a diffraction angle (2θ) of about 12.0 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, and about 25.6 degrees. The compound according to claim 2, which has a diffraction peak.
  4. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約８．７度、約１１．２度、約１２．０度、約１４．１度、約１８．５度、約２２．２度、約２４．７度、および約２５．６度の回折角（２θ）に回折ピークを有する、請求項１記載の化合物。 In the powder X-ray diffraction spectrum, at least about 8.7 degrees, about 11.2 degrees, about 12.0 degrees, about 14.1 degrees, about 18.5 degrees, about 22.2 degrees, about 24.7 degrees, The compound according to claim 1, which has a diffraction peak at a diffraction angle (2θ) of about 25.6 degrees.
  5. 　図３に示される粉末Ｘ線回折スペクトルチャートを特徴とする、請求項１記載の化合物。 The compound according to claim 1, characterized by the powder X-ray diffraction spectrum chart shown in FIG.
  6. 　示差走査熱量測定において吸熱ピーク温度が約８６．４℃である、請求項１～５のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 5, wherein the endothermic peak temperature is about 86.4 ° C. in the differential scanning calorimetry.
  7. 　図４に示される示差走査熱量測定チャートを特徴とする、請求項６記載の化合物。 The compound according to claim 6, characterized by the differential scanning calorimetry chart shown in FIG.
  8. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度および約１０．５度の回折角（２θ）に回折ピークを有する、請求項１記載の化合物。 The compound according to claim 1, which has a diffraction peak at a diffraction angle (2θ) of at least about 6.8 degrees and about 10.5 degrees in a powder X-ray diffraction spectrum.
  9. 　粉末Ｘ線回折スペクトルにおいて、さらに約８．２度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、請求項８記載の化合物。 In the powder X-ray diffraction spectrum, at least two or more at diffraction angles (2θ) of about 8.2 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees. The compound according to claim 8, which has a diffraction peak.
  10. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約６．８度、約８．２度、約１０．５度、約１２．８度、約１８．２度、約２３．５度、および約２４．３度の回折角（２θ）に回折ピークを有する、請求項１記載の化合物。 In the powder X-ray diffraction spectrum, at least about 6.8 degrees, about 8.2 degrees, about 10.5 degrees, about 12.8 degrees, about 18.2 degrees, about 23.5 degrees, and about 24.3 degrees. The compound according to claim 1, which has a diffraction peak at the diffraction angle (2θ) of the above.
  11. 　図５に示される粉末Ｘ線回折スペクトルチャートを特徴とする、請求項１記載の化合物。 The compound according to claim 1, characterized by the powder X-ray diffraction spectrum chart shown in FIG.
  12. 　示差走査熱量測定において吸熱ピーク温度が約８６．８℃である、請求項１、8～１１のいずれか一項に記載の化合物。 The compound according to any one of claims 1 and 8 to 11, wherein the endothermic peak temperature is about 86.8 ° C. in the differential scanning calorimetry.
  13. 　図６に示される示差走査熱量測定チャートを特徴とする、請求項１２記載の化合物。 The compound according to claim 12, characterized by the differential scanning calorimetry chart shown in FIG.
  14. 　３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩。 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid diisopropylamine salt.
  15. 　結晶形態である、請求項１４記載の３－［２－［（Ｅ）－５－［３－（ベンゼンスルホンアミド）フェニル］ペンタ－４－エノキシ］フェニル］プロパン酸　ジイソプロピルアミン塩。 The diisopropylamine salt of 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid according to claim 14, which is in crystalline form.
  16. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に少なくとも２つ以上の回折ピークを有する、請求項１５記載の化合物。 In the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about 20.9 degrees. The compound according to claim 15, which has at least two or more diffraction peaks at the diffraction angle (2θ) of the above.
  17. 　粉末Ｘ線回折スペクトルにおいて、少なくとも約６．５度、約９．８度、約１０．６度、約１７．１度、約１９．３度、約２０．１度、および約２０．９度の回折角（２θ）に回折ピークを有する、請求項１５記載の化合物。 In the powder X-ray diffraction spectrum, at least about 6.5 degrees, about 9.8 degrees, about 10.6 degrees, about 17.1 degrees, about 19.3 degrees, about 20.1 degrees, and about 20.9 degrees. The compound according to claim 15, which has a diffraction peak at the diffraction angle (2θ) of the above.
  18. 　図１に示される粉末Ｘ線回折スペクトルチャートを特徴とする、請求項１５記載の化合物。 The compound according to claim 15, which comprises the powder X-ray diffraction spectrum chart shown in FIG.
  19. 　示差走査熱量測定において吸熱ピーク温度が約１３３℃である、請求項１５～１８のいずれか一項に記載の化合物。 The compound according to any one of claims 15 to 18, wherein the endothermic peak temperature is about 133 ° C. in the differential scanning calorimetry.
  20. 　図２に示される示差走査熱量測定チャートを特徴とする、請求項１９記載の化合物。 The compound according to claim 19, characterized by the differential scanning calorimetry chart shown in FIG.
  21. 　請求項１～２０のいずれか一項に記載の化合物を含有する医薬組成物。 A pharmaceutical composition containing the compound according to any one of claims 1 to 20.
  22. 　請求項１～２０のいずれか一項に記載の化合物を含有するシュワン細胞分化促進剤。 A Schwann cell differentiation promoter containing the compound according to any one of claims 1 to 20.
  23. 　請求項１～２０のいずれか一項に記載の化合物を含有する神経障害の予防および／または治療剤。 A prophylactic and / or therapeutic agent for neuropathy containing the compound according to any one of claims 1 to 20.
  24. 　神経障害が末梢神経障害である請求項２３記載の剤。 The agent according to claim 23, wherein the neuropathy is a peripheral neuropathy.
  25. 　末梢神経障害が、慢性炎症性脱髄性多発神経炎、ギランバレー症候群、結節性動脈周囲炎、アレルギー性血管炎、糖尿病性末梢神経障害、絞扼性神経障害、化学療法薬投与に伴う末梢神経障害、またはシャルコー・マリー・トゥース病に伴う末梢神経障害である、請求項２４記載の剤。 Peripheral neuropathy includes chronic inflammatory demyelinating polyneuritis, Guillain-Barré syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, peripheral neuropathy associated with chemotherapy drug administration , Or the agent according to claim 24, which is a peripheral neuropathy associated with Charcoal-Marie-Tooth disease.
PCT/JP2021/003092 2020-01-29 2021-01-28 Novel crystal form of benzene derivative WO2021153690A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4529119B2 (en) * 2001-08-09 2010-08-25 小野薬品工業株式会社 Carboxylic acid derivative compound and drug containing the compound as an active ingredient
JP2011503030A (en) * 2007-11-12 2011-01-27 アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ Drugs active against neuropathic pain
WO2020027150A1 (en) * 2018-07-31 2020-02-06 小野薬品工業株式会社 Benzene derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4529119B2 (en) * 2001-08-09 2010-08-25 小野薬品工業株式会社 Carboxylic acid derivative compound and drug containing the compound as an active ingredient
JP2011503030A (en) * 2007-11-12 2011-01-27 アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ Drugs active against neuropathic pain
WO2020027150A1 (en) * 2018-07-31 2020-02-06 小野薬品工業株式会社 Benzene derivative

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