WO2021187547A1 - Cristal de composé de phénylacétate - Google Patents

Cristal de composé de phénylacétate Download PDF

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WO2021187547A1
WO2021187547A1 PCT/JP2021/010991 JP2021010991W WO2021187547A1 WO 2021187547 A1 WO2021187547 A1 WO 2021187547A1 JP 2021010991 W JP2021010991 W JP 2021010991W WO 2021187547 A1 WO2021187547 A1 WO 2021187547A1
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compound
diffraction
degrees
compound according
powder
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修平 大谷
貴裕 川俣
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小野薬品工業株式会社
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms

Definitions

  • Prostaglandin D2 (abbreviated as PGD2) is known as a metabolite of arachidonic acid cascade and is involved in allergic diseases, sleep, hormone secretion, pain, platelet aggregation, glycogen metabolism, tonometry, etc. It is known that (Non-Patent Documents 1 to 11). It is known that DP receptors and CRTH2 receptors are present as PGD2 receptors, among which DP receptors are present in the brain, especially in the subliminal space of the rostral ventral part of the basal forebrain. Is known to be associated with the sleep-inducing action of PGD2 (Non-Patent Document 12). That is, in order to inhibit the sleep-inducing action of PGD2 and make it a therapeutic drug for sleep-wake disorders, it is necessary to have a drug having not only DP antagonistic activity but also transferability to the central nervous system.
  • Patent Document 1 describes that the compound represented by the following general formula (A) specifically binds to and antagonizes the DP receptor.
  • R 1A is (1) hydrogen atom
  • (2) represents such C1 ⁇ 4 alkyl group
  • R 2A is (1) a halogen atom
  • (2) represents such C1 ⁇ 6 alkyl group
  • R 3A is (1) a halogen atom
  • 2) represent like C1 ⁇ 6 alkyl group
  • W a is monocyclic or bicyclic carbon ring of C5 ⁇ 12 , Or a 5- to 12-membered monocyclic or bicyclic heterocycle
  • R 4A represents (1) a hydrogen atom
  • (2) a C1 to 6 alkyl group
  • R 5A represents a C1 to 6 alkyl group, etc.
  • G a (1 ) nitrogen atom, and C1 ⁇ 6 alkylene group containing 0-2 hetero atoms selected from oxygen atom and sulfur atom
  • J a is, C5 ⁇ 12
  • mA represents an integer of 0 or 1-4
  • nA is an integer of 0 or 1-4.
  • iA represents 0 or an integer of 1 to 11.
  • Patent Document 2 describes that the compound represented by the following general formula (B) is a compound that specifically binds to and antagonizes the DP receptor.
  • R 1B is (1) hydrogen atom
  • (2) represents such C1 ⁇ 4 alkyl group
  • E B represents the like -CO- group
  • R 2B is (1) halogen atom, (2 ) C1 to 6 alkyl groups, etc.
  • R 3B represents (1) halogen atom, (2) C1 to 6 alkyl groups, etc.
  • R 4B represents (1) hydrogen atom, (2) C1 to 6 alkyl groups, etc.
  • R 5B represents like C1 ⁇ 6 alkyl group
  • W B represents a monocyclic or bicyclic heterocyclic monocyclic or bicyclic carbon ring of C5 ⁇ 12 or 5 to 12 membered
  • G B is (1) a nitrogen atom
  • J B is mono- or bicyclic of C5 ⁇ 12
  • mB represents an integer of 0 or 1-4
  • nB represents an integer of 0 or 1-4
  • iB represents an integer of 0 or 1-4.
  • R 12B and R 13B represent (1) C1 to 4 alkyl groups which may be independently oxidized, (2) a hydrogen atom, and the like.
  • Patent Document 3 International Publication No. 2020/059790 (hereinafter, may be abbreviated as Patent Document 3), Compound I is described as a compound having DP antagonistic activity. However, the crystalline form of compound I disclosed in the present disclosure is not described in any prior art document.
  • the subject of the present disclosure is to find a compound having both strong antagonistic activity against DP receptor and good central migration, and preventive and / or therapeutic agents for diseases caused by activation of DP receptor, particularly sleep-wake disorder.
  • a therapeutic agent for the above it is to provide a useful compound and a form suitable for the drug substance thereof.
  • a crystalline form (B crystal) of compound I suitable for a drug substance exists (hereinafter referred to as the present invention). May be abbreviated as the disclosed compound).
  • a salt of compound I was found. That is, the present disclosure is, for example, [1] ⁇ 4-Chloro-3-[(2), which is in crystalline form and has a diffraction peak at a diffraction angle (2 ⁇ ) of about 6.4 and / or about 15.3 degrees in the powder X-ray diffraction spectrum.
  • a prophylactic and / or therapeutic agent for DP receptor-mediated diseases which comprises the compound according to the above [1] or [2].
  • [5] DP receptor-mediated characterized in that an effective amount of the compound according to the above [1] or [2] is administered to a patient in need of prevention and / or treatment of a DP receptor-mediated disease. How to prevent and / or treat sexually transmitted diseases, [6] The compound according to the above [1] or [2], or [7] prophylactic and / or therapeutic agent for DP receptor-mediated disease, which is used for the prevention and / or treatment of DP receptor-mediated disease. Provided are embodiments such as the use of the compound according to the above [1] or [2] for producing the above.
  • Compound I has a strong antagonistic activity against the DP receptor and also has good central migration, so that it is a prophylactic and / or therapeutic agent for diseases caused by the activation of the DP receptor, particularly sleep-wake disorder. It is useful as a therapeutic agent for.
  • the compounds of the present disclosure are also excellent in thermodynamic stability, and thus are useful as drug substances for pharmaceutical products.
  • FIG. 1 represents a powder X-ray diffraction spectrum chart of A crystal of Compound I (the vertical axis represents intensities (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • FIG. 2 represents a differential scanning calorimetry (DSC) chart of A crystal of compound I (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)).
  • FIG. 3 represents a powder X-ray diffraction spectrum chart of the B crystal of Compound I (the vertical axis represents intensities (counts), and the horizontal axis represents 2 ⁇ (degrees)).
  • FIG. 4 represents a differential scanning calorimetry (DSC) chart of the B crystal of compound I (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (° C.)).
  • ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxane-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetic acid (compound).
  • I) is the following structural formula (Symbols in formulas Indicates that it is connected to the other side of the paper (that is, ⁇ arrangement). Indicates that it is connected to the front side (that is, ⁇ arrangement) of the paper surface. ) Means the compound represented by.
  • Compound I can be produced by the method shown in the following reaction process formula I in addition to the method shown in Examples described later.
  • the compound represented by the formula (IV) is produced by subjecting the compound represented by the formula (II) (CAS. No. 83194-70-1) to an alkylation reaction using the compound represented by the formula (III). can do.
  • This alkylation reaction is known, for example, in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, acetonitrile, etc.), an alkali metal hydroxide (sodium hydroxide, In the presence of potassium hydroxide, lithium hydroxide, etc.), alkali earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof, or mixtures thereof. It is carried out by reacting at 0 to 100 ° C.
  • the compound represented by the formula (V) can be produced by subjecting the compound represented by the formula (IV) to a deprotection reaction.
  • This deprotection reaction is known and can be carried out as follows.
  • the deprotection reaction of the carboxy group is well known, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, N-methyl-2-pyrrolidone, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.).
  • the compound represented by the formula (IV) subjected to the deprotection reaction may be used after purification after the alkylation reaction, or may be used as a crude product.
  • the compound represented by the formula (VII) is obtained by subjecting the compound represented by the formula (V) and the compound represented by the formula (VI) (CAS. 59833-69-1) or a salt thereof to an amidation reaction.
  • Can be manufactured by Examples of the salt of the compound represented by the formula (VI) include an inorganic acid salt such as a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a phosphate and a nitrate, or an acetate and a lactic acid.
  • Salts tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, ISEthionates, glucronates, or gluconates Organic acid salts such as.
  • This amidation reaction is known, for example. (1) Method using acid halide, (2) Method using mixed acid anhydride, (3) Examples thereof include a method using a condensing agent.
  • the carboxylic acid represented by the formula (V) is mixed with an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and an acid halide agent (oxalyl chloride, etc.) is used.
  • an organic solvent chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.
  • an acid halide agent oxalyl chloride, etc.
  • the obtained acid halide is reacted with an amine represented by the formula (VI) at 0 to 40 ° C. in an organic solvent (dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (sodium bicarbonate solution, sodium hydroxide solution, etc.). It can also be done by.
  • an organic solvent dioxane, tetrahydrofuran, etc.
  • an alkaline aqueous solution sodium bicarbonate solution, sodium hydroxide solution, etc.
  • the carboxylic acid represented by the formula (V) is mixed in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and the base (pyridine, triethylamine, dimethyl, etc.) is used.
  • a condensing agent for example, a carboxylic acid represented by the formula (V) and an amine represented by the formula (VI) are mixed in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.).
  • an organic solvent chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.
  • a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3-( dimethylamino) propyl] carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propyl phosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, T 3 It is carried out by reacting at 0 to 80 ° C. in the presence or absence of 1-hydroxybenztriazole (HOBt) using P) or the like. It is desirable that all of the reactions (1), (2) and (3) be carried out under anhydrous conditions under an atmosphere of an inert gas (argon, nitrogen, etc.).
  • an inert gas argon, nitrogen, etc.
  • the compound described in Example 3 can be produced by subjecting the compound represented by the formula (VII) to a thiolation reaction.
  • This thiolation reaction is known, and the compound represented by the formula (VII) is mixed with a base (sodium hydrogen carbonate, N, N-dimethylaniline) in an organic solvent (for example, tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.).
  • a base sodium hydrogen carbonate, N, N-dimethylaniline
  • organic solvent for example, tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.
  • a thiolation reagent eg, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphethane-2,4-disulfide)
  • phosphine reagent eg, trichlorophosphate, etc.
  • the compound (Compound I) described in Example 4 can be produced by subjecting the compound described in Example 3 to a deprotection reaction.
  • This deprotection reaction is known and can be carried out as follows.
  • the deprotection reaction of the carboxy group is well known, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, N-methyl-2-pyrrolidone, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.).
  • reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
  • a solid-phase supporting reagent supported on a high molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc. may be used as appropriate.
  • the reaction product is prepared by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. , Scavenger resin or column chromatography or purification by methods such as washing and recrystallization. Purification may be performed on a reaction-by-reaction basis or after several reactions have been completed.
  • the compound represented by the formula (III) can be produced by the method shown below.
  • Compound represented by formula (III): 2-[(2R) -oxan-2-yl] ethyl 4-nitrobenzene-1-sulfonate 2-[(2R) -Tetrahydropyran-2-yl] ethanol (CAS. No. 1548595-48-7, 1.50 g) in a solution of methyl t-butyl ether (12.5 mL) with p-nitrobenzenesulfonyl chloride (12.5 mL). CAS. No. 98-74-8) is added, and the mixture is stirred at room temperature for 20 hours.
  • Methyl t-butyl ether (5.3 mL) and 15% aqueous sodium dihydrogen phosphate solution (3.6 mL) are added to the reaction solution to separate the layers.
  • a 0.1% aqueous sodium dihydrogen phosphate solution (3.9 mL) is added to the organic layer to separate the liquids.
  • a 10% aqueous sodium carbonate solution (4.0 mL) is added to the organic layer, and the mixture is separated by stirring at room temperature for 7 hours.
  • the organic layer is washed twice with tap water (3 mL). After concentration under reduced pressure to about 6 mL, add n-heptane (14.1 mL) at 5 ° C. After stirring at 5 ° C.
  • the compound represented by the formula (III) can be obtained by drying the obtained solid at room temperature under reduced pressure for 3 hours.
  • differences in crystal form are particularly distinguished by powder X-ray diffraction spectra and / or differential scanning calorimetry (DSC).
  • the A crystal of compound I is characterized by at least one physicochemical data of (a) and (b) below. Preferably, it is characterized by the physicochemical data of both (a) and (b).
  • (A) (i) Powder X-ray diffraction spectrum shown in FIG. 1, (ii) Diffraction angle (2 ⁇ ) of the powder X-ray diffraction spectrum shown in FIG. 1, (iii) Diffraction angle (2 ⁇ ) shown in Table 1.
  • the B crystal of compound I is characterized by at least one of the physicochemical data of (c) and (d) below. Preferably, it is characterized by the physicochemical data of both (c) and (d).
  • (C) (i) Powder X-ray diffraction spectrum shown in FIG. 3, (ii) Diffraction angle (2 ⁇ ) of the powder X-ray diffraction spectrum shown in FIG. 3, (iii) Diffraction angle (2 ⁇ ) shown in Table 2.
  • One embodiment of the B crystal of Compound I is a crystal form having a diffraction peak at a diffraction angle (2 ⁇ ) of about 6.4 and / or about 15.3 degrees in a powder X-ray diffraction spectrum.
  • One embodiment of the B crystal of Compound I is a crystal form having a diffraction peak at a diffraction angle (2 ⁇ ) of about 6.4 degrees in a powder X-ray diffraction spectrum.
  • One embodiment of the B crystal of Compound I is a crystal form having diffraction peaks at diffraction angles (2 ⁇ ) of about 6.4 and about 15.3 degrees in the powder X-ray diffraction spectrum.
  • a diffraction angle (2 ⁇ ) of about 6.4 and / or about 15.3 degrees preferably a diffraction angle of about 6.4 degrees (2 ⁇ )).
  • a diffraction peak at a diffraction angle (2 ⁇ ) of about 6.4 and about 15.3 degrees preferably a diffraction angle of about 16.7 and / or about 20.4 degrees. It is a crystal form having.
  • a diffraction angle (2 ⁇ ) of about 6.4 and / or about 15.3 degrees preferably a diffraction angle of about 6.4 degrees (2 ⁇ )).
  • One embodiment of the B crystal of compound I is a crystal having diffraction peaks at diffraction angles (2 ⁇ ) of about 6.4, about 15.3, about 16.7 and about 20.4 degrees in a powder X-ray diffraction spectrum. It is a form.
  • One embodiment of the B crystal of Compound I is a diffraction angle (2 ⁇ ) of about 6.4, about 15.3, about 16.7, about 20.4, and about 25.3 degrees in a powder X-ray diffraction spectrum. It is a crystal form having a diffraction peak at.
  • a diffraction angle (2 ⁇ ) of about 6.4 and / or about 15.3 degrees preferably about 6.4 and about 15.3 degrees.
  • One embodiment of the B crystal of Compound I is a diffraction angle (2 ⁇ ) (preferably about 6.4) of about 6.4, about 16.7, and / or about 20.4 degrees in the powder X-ray diffraction spectrum. , About 16.7, and a diffraction peak at a diffraction angle (2 ⁇ ) of about 20.4 degrees).
  • One embodiment of the B crystal of Compound I is a diffraction angle (2 ⁇ ) (preferably about 6.4) of about 6.4, about 16.7, and / or about 20.4 degrees in the powder X-ray diffraction spectrum.
  • a diffraction angle (2 ⁇ ) of about 6.4, about 16.7, and / or about 20.4 degrees preferably about 6. 4.
  • One embodiment of the B crystal of Compound I is that it has a diffraction peak at a diffraction angle (2 ⁇ ) of about 6.4 degrees in the powder X-ray diffraction spectrum, and further has a diffraction peak of about 15.3 degrees, about 16.7 and about 20. It is a crystal form having at least one, two or three diffraction peaks at a diffraction angle (2 ⁇ ) of .4.
  • each crystal form of Compound I is specified by the physicochemical data described in the present specification, but since each spectral data can vary slightly due to its nature, it is strictly solved. Should not be done.
  • the diffraction angle (2 ⁇ ) and overall pattern are important in determining crystal identity, and the relative strength is the direction of crystal growth and particle size. , May vary slightly depending on the measurement conditions.
  • the overall pattern is important in the determination of crystal identity, and it may vary slightly depending on the measurement conditions. Therefore, among the compounds of the present disclosure, those having a pattern similar to that of the powder X-ray diffraction spectrum or DSC as a whole are included in the compounds of the present disclosure.
  • 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 "about” of the endothermic peak onset temperature (° C.) or peak temperature (° C.) in the DSC analysis is ⁇ 2 ° C. in one embodiment and ⁇ 1 ° C. in yet another embodiment.
  • the onset temperature and the peak temperature do not fluctuate.
  • the compounds of the present disclosure 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.
  • a crystal of compound I can be obtained, for example, according to Example 4 in the present specification or Example 12 in Patent Document 3.
  • the compound of the present disclosure can be obtained, for example, by dissolving compound I produced by the method of Examples in the present specification in a solvent under heating or at room temperature, and then cooling.
  • a solvent for example, 1,4-dioxane, ethyl acetate, etc.
  • a mixed solvent of an organic solvent for example, 1,4-dioxane, ethyl acetate, n-heptane, etc.
  • the toxicity of the compounds of the present disclosure is sufficiently low and can be safely used as a pharmaceutical product.
  • the compounds of the present disclosure are suitable for the prevention and / or treatment of DP receptor-mediated diseases.
  • the compounds of the present disclosure can be used to prevent and / or treat DP receptor-mediated diseases.
  • diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress diseases, liver disorders, platelet aggregation and the like.
  • Allergic diseases include allergic bronchopulmonary aspergillosis, systemic mastocytosis, systemic mast cell activation disorder, anaphylactic shock, urticaria, eczema, eosinophilia, itchy disease, and flushing. Diseases and the like can be mentioned.
  • Inflammation includes airway contraction, acne, sinusitis, nasal polyps, irritable vasculitis, contact dermatitis, diseases secondarily caused by behavior associated with itching, chronic obstructive pulmonary disease, pleurisy, osteoarthritis. , Examples include ulcerative colitis and interstitial cystitis.
  • autoimmune diseases include rheumatoid arthritis, polymyositis, graft rejection, multiple sclerosis, Crohn's disease and the like.
  • Cancers that involve the cerebral nerve eg, pediatric brain tumors (eg, neuroblastoma, myeloma, stellate tumor (juvenile hair-like stellate tumor)), lining tumor, cranial pharyngeal tumor, germ cell tumor, etc.
  • pediatric brain tumors eg, neuroblastoma, myeloma, stellate tumor (juvenile hair-like stellate tumor)
  • lining tumor eg., cranial pharyngeal tumor, germ cell tumor, etc.
  • glioma choroidal papilloma, brain stem glioma
  • adult brain tumor eg, adult stellate tumor, adult malignant stellate cell tumor, adult glioblastoma, adult ventricular lining tumor, adult malignant ventricular lining tumor, Adult malignant oligodendroglioma, adult myeloma, adult medulla, adult malignant medulla), glioma (eg, stellate cell tumor, oligodendroglioma, lining tumor, brain stem glioma), pituitary adenoma, Acoustic nerve sheath tumor, retinoblastoma, malignant melanoma of the vine, etc.), respiratory cancer (eg, nasopharyngeal cancer (eg, nasopharyngeal cancer, mesopharyngeal cancer, hypopharyngeal cancer), laryngeal cancer, sinus cancer, lung cancer (eg, n
  • Oral cancer eg, gingival cancer, tongue cancer, salivary adenocarcinoma, etc.
  • urinary cancer eg, penis cancer, renal pelvis / urinary tract cancer, renal cell cancer, testicular (testicle) tumor, prostate cancer, bladder cancer, etc.
  • Cancers involving women eg, genital cancer, uterine cancer (eg, cervical cancer, uterine body cancer (endometrial cancer)), uterine sarcoma, choriocarcinoma (eg, follicular ectopia, chorionic villi cancer, placental villous tumor) , Surviving chorionic villi), vaginal cancer, breast cancer, breast sarcoma, ovarian cancer, ovarian germ cell tumor, etc.), skin cancer (eg, melanoma (malignant melanoma) (eg, malignant melanoma, superficial dilated melanoma) , Nodular mel
  • Neurological disorders include migraine, cerebrovascular accidents, brain trauma and the like.
  • muscle diseases include muscular dystrophy and sarcopenia.
  • Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. Diseases based on daytime morbid sleep apnea can be mentioned.
  • Hypersomnia includes narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome and the like.
  • Circadian rhythm sleep-wake disorder includes shift work type circadian rhythm disorder, irregular sleep / wake rhythm disorder, and the like.
  • Neurodegenerative diseases include Parkinson's disease, Lewy body dementias, Alzheimer's disease and the like.
  • Mental illnesses include depression and bipolar disorder.
  • Examples of the ischemia-reperfusion disorder include heart disease, cerebrovascular disorder, renal disease, liver disease, lung disease, pancreatic disease and the like, or ischemia-reperfusion disorder at the time of organ transplantation.
  • Viral infections include human hepatitis virus (eg, hepatitis B, hepatitis C, hepatitis A and hepatitis E, etc.), human retrovirus, human immunodeficiency virus (eg, HIV1 and HIV2, etc.), human T-cell leukemia.
  • Virus or human T lymphotrophic virus eg, HTLV1 and HTLV2, etc.
  • simple herpesvirus type 1 or 2 Epstein bar (EB) virus, cytomegalovirus, varicella-herpes zoster virus, human herpesvirus (eg, eg) Human herpesvirus 6 etc.), poliovirus, measles virus, ruin virus, Japanese encephalitis virus, mumps virus, influenza virus, cold virus (eg adenovirus, enterovirus, rhinovirus, etc.), severe acute respiratory syndrome (SARS) Onset virus, Ebola virus, West Nile virus, Flavi virus, Echo virus, Coxsackie virus, Corona virus, Respiratory polynuclear (symbol) virus, Rotavirus, Norovirus, Sapovirus, Parvovirus, Wakusina virus, HTL virus, Dengvirus , Hapillomavirus, soft tumor virus, mad dog disease virus, JC virus, arbovirus, encephalitis virus
  • Stress disorders include irritable bowel syndrome, functional gastroenteropathy, atopic dermatitis, bronchial asthma (adult or childhood), tension headache, chronic pain, migraine, school refusal with psychosomatic complaints, eating disorders, etc.
  • Examples include diabetes, high blood pressure, and menopause.
  • liver disorders include drug-induced liver disorders and alcoholic liver disorders.
  • Drug-induced liver injury includes toxic liver injury, allergic liver injury and the like.
  • platelet aggregation include thrombotic thrombocytopenic purpura, EDTA-dependent thrombocytopenia, and the like.
  • the compounds of the present disclosure are preferably suitable for the prevention and / or treatment of sleep-wake disorders.
  • the compounds of the present disclosure are more preferably suitable for the prevention and / or treatment of hypersomnia.
  • the compounds of the present disclosure are: 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 in order to improve the kinetics / absorption of the compound, reduce the dose, and / or 3) reduce the side effects of the compound.
  • the combination drug of the compound of the present disclosure 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 disclosure 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 disclosure 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 as long as it is a disease that complements and / or enhances the prophylactic and / or therapeutic effect of the compound of the present disclosure.
  • the combination drugs to be combined with the compounds of the present disclosure include not only those found so far but also those found in the future.
  • agents for complementing and / or enhancing the prophylactic and / or therapeutic effect of the compounds of the present disclosure on sleep-wake disorders include, for example, psychostimulants (eg, modafinyl, (hydrochloride) methylphenidate, (hydrochloride)).
  • psychostimulants eg, modafinyl, (hydrochloride) methylphenidate, (hydrochloride)
  • Methanphetamine, pemorin, etc. Narcolepsy treatments (eg, ⁇ -hydroxybutyric acid, chlorpromazine, etc.), acetylcholinesterase inhibitors (eg, (hydrochloride) donepezil, physostigmine, (tartrate) rivastigmine, (hydrobromic acid) galantamine, (fumaric acid) ) Zanapezil; TAK-147, taclin, methylphenidate, etc.), NMDA receptor antagonists (eg, ketamine, memantin, dextrometholphan hydrobromide, etc.), dopamine receptor agonists (eg, levodopa, bromocryptin, pergolide, talipexol) , (Hydrogen) pramipexol (hydrate), cabergolin, (hydrochloride) amantazine, etc.), tricyclic antidepressants (eg, amitryptri
  • the dose of the other drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present disclosure and other drugs can be appropriately selected depending on the age and body weight of the administration subject, 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 the compound of the present disclosure. As for other drugs, any two or more kinds may be administered in an appropriate combination in an appropriate ratio.
  • the compound of the present disclosure or a combination drug of the compound of the present disclosure 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 compounds of the present disclosure are administered to mammals (preferably humans, more preferably patients) in pharmaceutically effective amounts.
  • the dose of the compound of the present disclosure 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 orally administered once or several times daily in the range of 0.1 ng to 10 mg per adult, or intravenously in the range of 1 to 24 hours per 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 oral solid preparation or an oral liquid preparation for oral administration When administering the compound of the present disclosure or a concomitant drug of the compound of the present disclosure and another drug, an oral solid preparation or an oral liquid preparation for oral administration, a sustained release preparation for oral administration, a release control preparation, or a release control preparation, or It is used as an injection, an external preparation, an inhalant, a suppository, etc. for parenteral administration.
  • the compound according to one item, [6] The above-mentioned [1], wherein the crystal form has diffraction peaks at diffraction angles (2 ⁇ ) of about 6.4, about 16.7, and about 20.4 degrees in the powder X-ray diffraction spectrum.
  • Compound, [7] The above-mentioned [7] which is a crystal form and has diffraction peaks at diffraction angles (2 ⁇ ) of at least about 6.4, about 15.3, about 16.7 and about 20.4 in a powder X-ray diffraction spectrum.
  • DP receptor-mediated diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation.
  • DP receptor-mediated disease is sleep-wake disorder, and sleep-wake disorder is hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, neurodegenerative disease.
  • the pharmaceutical composition according to the above [17] which is a disease based on hypersomnia associated with, hypersomnia associated with mental illness, and daytime morbid insomnia.
  • a prophylactic and / or therapeutic agent for DP receptor-mediated diseases which comprises the compound according to any one of the above [1] to [14].
  • An effective amount of the compound according to any one of the above [1] to [14] is administered to a patient in need of prevention and / or treatment of a DP receptor-mediated disease.
  • Prevention and / or treatment of DP receptor-mediated diseases [22] The compound according to any one of [1] to [14] above, which is used for the prevention and / or treatment of DP receptor-mediated diseases, and [23] prevention of DP receptor-mediated diseases. And / or use of the compound according to any one of the above [1] to [14] for producing a therapeutic agent.
  • the location of the 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 number in parentheses shown in the NMR section indicates the solvent used for the measurement.
  • the compound names used in the present specification are computer programs that are generally named according to the rules of IUPAC, ACD / Name (registered trademark) of Advanced Chemistry Development, and Lexichem 1.4 of OpenEye Scientific Software. 2 or ChemDraw® Ultra from PerkinElmer, Inc., or named according to the IUPAC nomenclature.
  • HPLC was measured under the following conditions. HPLC condition 1 LCMS was carried out using the Waters i-class system under the following conditions. Column: YMC Triart C 18 2.0 mm ⁇ 30 mm, 1.9 ⁇ m; Flow velocity: 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: (95%: 5%) to (5%: 95%); 1.20 to 1.50 minutes :( 5%: 95%).
  • TFA trifluoroacetic acid
  • HPLC condition 2 HPLC was carried out using the Shimadzu LC-2010 system under the following conditions. Column: Ascentis Express C8 4.6 mm x 150 mm, 2.7 ⁇ m; Flow velocity: 1.0 mL / min; Temperature: 35 ° C.; Mobile phase A: 0.1% aqueous phosphoric acid solution; Mobile phase B: Acetonitrile; Gradient (mobile phase) (A): Describe the ratio of mobile phase (B)): 0 to 20 minutes: (55%: 45%) to (40%; 60%); 20 to 30 minutes: (40%: 60%) to ( 5%: 95%); 30-50 minutes: (5%: 95%); Detector: UV 240 nm.
  • SFC Supercritical fluid chromatography
  • DSC Differential scanning calorimetry
  • Example 1 Methyl (4-chloro-3- ⁇ 2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzamide ⁇ phenyl) acetate Methyl ⁇ 4-chloro-3-[(4-hydroxy-2,6-dimethylbenzoyl) amino] phenyl ⁇ acetate (CAS No. 1351163-96-6, 5.00 g, Bioorganic & Medicinal Chemistry 19 (2011) 6935- 6948, Compound 44), 2- (tetrahydropyran-2-yl) ethanol (CAS. No.
  • Example 2 Methyl [4-chloro-3-( ⁇ 2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil ⁇ amino) phenyl] acetylate Lawesson's reagent (CAS No. 19172-47-5, 21 mg) was added to a toluene (0.4 mL) solution of the compound (40 mg) prepared in Example 1, and the mixture was stirred at 100 ° C. for 24 hours.
  • Example 3 Methyl ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetate
  • SFC supercritical fluid chromatography
  • Example 4 ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxane-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetic acid (compound) I)
  • a 2 mol / L sodium hydroxide aqueous solution (42 mL) was added to a methanol (107 mL) solution of the compound (13.4 g) prepared in Example 3, and the mixture was stirred at room temperature for 1 hour. After adding 1 mol / L hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate.
  • Example 5 ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxane-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetic acid (compound) Crystal of I) (Crystal B)
  • the compound (4.35 g) prepared in Example 4 was dissolved in ethyl acetate (17.4 mL) at about 60 ° C. N-heptane (34.8 mL) was added to this solution. After confirming the precipitation of the crystals, the mixture was cooled to about 25 ° C. and the crystals were collected by filtration. The crystals collected by filtration were dried under reduced pressure at about 50 ° C. to obtain 4.13 g of crystalline white solids (Crystal B).
  • Powder X-ray diffraction spectrum and differential scanning calorimetry [A crystal of compound I]
  • the powder X-ray diffraction spectrum chart of A crystal measured under the above condition 1 is shown in FIG. 1, and the DSC chart is shown in FIG. 2, respectively.
  • Powder X-ray Diffraction Spectrum Table 1 shows the results of the diffraction angles (2 ⁇ ) (degrees) and relative intensities (%) obtained by the powder X-ray diffraction spectrum method of A crystal using Cu—K ⁇ rays.
  • DSC Differential scanning calorimetry
  • Example 6 tert-Butylamine ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ Acetate
  • a 2 mol / L potassium hydroxide aqueous solution (3.2 mL) was added to a methanol (10 mL) solution of the compound (1.00 g) shown in Example 3 at 40 ° C., and the mixture was stirred for 2 hours.
  • Example 6 (1): ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxane-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ Crystals of acetic acid (Compound I) (Crystal B) Ethyl acetate (2.5 mL) and 1 mol / L hydrochloric acid (1.3 mL) were added to the compound (223 mg) shown in Example 6 to separate the solutions, and the aqueous layer was re-extracted with ethyl acetate (1.3 mL). The organic layers were combined and washed twice with 1 mol / L hydrochloric acid (1.3 mL).
  • Example 7 Dicyclohexylamine ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetate
  • a 2 mol / L potassium hydroxide aqueous solution (3.2 mL) was added to a methanol (10 mL) solution of the compound (1.00 g) shown in Example 3 at 40 ° C., and the mixture was stirred for 2 hours.
  • Example 7 (1): ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ Crystals of acetic acid (Compound I) (Crystal B) Ethyl acetate (2.5 mL) and 1 mol / L hydrochloric acid (1.3 mL) were added to the compound (287 mg) shown in Example 7 to separate the solutions, and the aqueous layer was re-extracted with ethyl acetate (1.3 mL). The organic layers were combined and washed twice with 1 mol / L hydrochloric acid (1.3 mL).
  • Example 8 Triethylamine ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ acetate
  • a 2 mol / L potassium hydroxide aqueous solution (3.2 mL) was added to a solution of the compound (250 mg) shown in Example 3 in methanol (10 mL), and the mixture was stirred at 40 ° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure until the amount of the liquid was reduced to about half. The concentrate was filtered and washed with water (0.3 mL).
  • Example 8 (1): ⁇ 4-chloro-3-[(2,6-dimethyl-4- ⁇ 2-[(2R) -oxan-2-yl] ethoxy ⁇ benzene-1-carbotioil) amino] phenyl ⁇ Crystals of acetic acid (Compound I) (Crystal B) Ethyl acetate (2.5 mL) and 1 mol / L hydrochloric acid (1.3 mL) were added to the compound (272 mg) shown in Example 8 to separate the solutions, and the aqueous layer was re-extracted with ethyl acetate (1.3 mL).
  • Biological Example 1 Measurement of DP receptor antagonism using human DP receptor-expressing cells
  • a cAMP-HTRF kit (Seti Medical Lab, 62AM6PEJ) was used to measure DP receptor antagonism.
  • Compound I and prostaglandin D2 (final concentration 10 nmol / L) prepared at various concentrations were added to 384 well plates at 10 ⁇ L / well.
  • Human DP receptor-expressing cells were suspended in phosphate buffer containing 2 ⁇ mo L / L diclofenac and 1 mmol / L IBMX (3-Isobutyl-1-methylxantine) and seeded to 5000 cells / 10 ⁇ L / well.
  • Pharmacokinetic test 1 Measurement of concentration of compound I in cerebrospinal fluid (hereinafter referred to as CSF) (1) Collection of CSF A test substance solution was prepared so that the dose of each test substance was 3 mg / 5 mL / kg. The medium used was 5% DMSO 20% colifol HS15 / propylene glycol (7: 3). The test substance solution was orally administered to male Wistar rats aged 8 to 10 weeks purchased from Charles River Japan. Three hours after administration, the rats were anesthetized and CSF was collected by cisterna magna puncture. The same amount of ethanol (wako) as CSF was taken with the syringe used for collection, and the compound adsorbed on the syringe was recovered by washing.
  • CSF cerebrospinal fluid
  • the compound concentration in CSF was measured using dioxine-2-ylmethoxy) -2,6-dimethylbenzoyl) amino) phenyl) acetic acid and found to be 4.8 ng / mL.
  • the compound concentration in CSF of Compound I was higher than that of the comparative compound, and showed good central transferability.
  • Biological Example 2 Normal rat Awakening time prolonging action Chronic electrodes were placed in the brain and cervical muscles of rats to prepare rats capable of measuring electroencephalogram and electromyogram. After a recovery period of one week or longer, the rat and the biological signal amplifier were connected in a shield box that blocked sound and electrical noise. After acclimatization in the measurement cage for 1 hour or more, various doses of Compound I were orally administered to rats in a single dose, and electroencephalogram and electromyogram were recorded 6 hours after the oral administration. After the measurement was completed, the rats were returned to the breeding cage each time, and the vehicle and each compound were evaluated with a drug holiday of one week or more. The recorded electroencephalogram and electromyogram are shown in SleepSign Ver.
  • the difference between the total wakefulness time of 6 hours after administration of the compound I administration group and the total wakefulness time of 6 hours after administration of the vehicle administration group was expressed as an index of the wakefulness prolonging action.
  • a wake-up time-prolonging effect of 60 minutes was exhibited at a dose of 3 mg / kg, indicating that Compound I is useful as a therapeutic agent for sleep-wake disorders.
  • the stability of the compound of the present disclosure was examined under the storage conditions of Chemical Stability Test Condition 1 or Condition 2. After storage, the residual ratio (%) of the stored sample under each condition was calculated by HPLC with respect to the area percentage of the sample stored at ⁇ 20 ° C. ⁇ Preservation conditions and period> Condition 1 40 ° C: 2 months: Grinding Condition 2 60 ° C.: 1 month: Grinding The comparison target of each sample was stored at ⁇ 20 ° C. [result] The residual ratio (%) of the compound of the present disclosure after storage under condition 1 was 100.0%. The residual ratio (%) of the compound of the present disclosure after storage under condition 2 was 100.0%. The compounds of the present disclosure have been found to be excellent in chemical stability.
  • Example 6 Purification of Compound I
  • the compound shown in Example 6 was found to be a very useful compound.
  • the purity of the compound (Compound I) shown in Example 8 (1) was 99.0 (area%), whereas the purity of the compounds shown in Examples 7 (1) and 6 (1) (1).
  • the purity of Compound I) was 99.4 (area%) and 99.3 (area%).
  • the proportion of impurities contained in the compound (Compound I) shown in Example 8 (1) was 0.30 (area%), whereas that of Example 7 (1) and Example 6 (1).
  • the proportion of impurities contained in) was 0.03 (area%) and 0.02 (area%).
  • the area% was calculated under the condition of HPLC condition 2.
  • Example 7 an emulsion was formed at the time of freeing.
  • Example 6 (1) using the compound shown in Example 6 no emulsion was formed at the time of freezing. From the above, the compound shown in Example 6 was a very excellent compound in terms of the purification procedure and purity improvement of Compound I as compared with the compounds shown in Examples 7 and 8.
  • Compound I has strong DP receptor antagonistic activity and excellent central translocation, and is therefore useful as a prophylactic and / or therapeutic agent for DP receptor-mediated diseases such as sleep-wake disorders.
  • the crystalline form of the present disclosure is useful as a drug substance of a pharmaceutical product.

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Abstract

La présente invention concerne un composé utile et un mode approprié en tant que principe actif pharmaceutique de celui-ci, en tant qu'agent pour traiter et/ou prévenir des maladies provoquées par l'activation d'un récepteur DP, en particulier en tant qu'agent thérapeutique pour des troubles du sommeil.
PCT/JP2021/010991 2020-03-19 2021-03-18 Cristal de composé de phénylacétate WO2021187547A1 (fr)

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Citations (4)

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WO2003078409A1 (fr) * 2002-03-19 2003-09-25 Ono Pharmaceutical Co., Ltd. Composes d'acide carboxylique et medicaments renfermant les composes comme principe actif
WO2005028455A1 (fr) * 2003-09-17 2005-03-31 Ono Pharmaceutical Co., Ltd. Composes d'acide carboxylique et compositions medicinales contenant ceux-ci en tant qu'ingredient actif
WO2009022687A1 (fr) * 2007-08-10 2009-02-19 Ono Pharmaceutical Co., Ltd. Composé d'acide phénylacétique
WO2020059790A1 (fr) * 2018-09-20 2020-03-26 小野薬品工業株式会社 Antagoniste de dp

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TWI481961B (zh) * 2007-08-10 2015-04-21 Fujifilm Corp 正型光阻組成物及使用該組成物之圖案形成方法

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WO2003078409A1 (fr) * 2002-03-19 2003-09-25 Ono Pharmaceutical Co., Ltd. Composes d'acide carboxylique et medicaments renfermant les composes comme principe actif
WO2005028455A1 (fr) * 2003-09-17 2005-03-31 Ono Pharmaceutical Co., Ltd. Composes d'acide carboxylique et compositions medicinales contenant ceux-ci en tant qu'ingredient actif
WO2009022687A1 (fr) * 2007-08-10 2009-02-19 Ono Pharmaceutical Co., Ltd. Composé d'acide phénylacétique
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MAKI IWAHASHI; ATSUSHI NAGANAWA; ATSUSHI KINOSHITA; ATSUSHI SHIMABUKURO; TOSHIHIKO NISHIYAMA; SEIJI OGAWA; YOKO MATSUNAGA; KOHKI T: "Discovery of new orally active prostaglandin Dreceptor antagonists", BIOORGANIC, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 22, 30 August 2011 (2011-08-30), AMSTERDAM, NL, pages 6935 - 6948, XP028328593, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2011.08.065 *
MAKI IWAHASHI; EIJI TAKAHASHI; MOTOYUKI TANAKA; YOKO MATSUNAGA; YUTAKA OKADA; RYOJI MATSUMOTO; FUMIO NAMBU; HISAO NAKAI; MASAAKI T: "Design and synthesis of new prostaglandin Dreceptor antagonists", BIOORGANIC, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 18, 2 August 2011 (2011-08-02), AMSTERDAM, NL, pages 5361 - 5371, XP028389401, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2011.08.007 *

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