WO2021006267A1 - Sel de dérivé de pyrazole et préparation de dérivé de pyrazole - Google Patents

Sel de dérivé de pyrazole et préparation de dérivé de pyrazole Download PDF

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WO2021006267A1
WO2021006267A1 PCT/JP2020/026541 JP2020026541W WO2021006267A1 WO 2021006267 A1 WO2021006267 A1 WO 2021006267A1 JP 2020026541 W JP2020026541 W JP 2020026541W WO 2021006267 A1 WO2021006267 A1 WO 2021006267A1
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group
salt
preparation
alkyl
substituent
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八郎 杉本
充顕 奥田
眞人 中野
真子 ▲高▼見
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グリーン・テック株式会社
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to salts of pyrazole derivatives, and solid dispersion preparations and self-emulsifying preparations of pyrazole derivatives. More specifically, the present invention relates to a novel salt of a pyrazole derivative and a method for producing the same, a solid dispersion preparation and a self-emulsifying preparation using a free form or salt of a pyrazole derivative, and a pharmaceutical composition containing the preparation.
  • Patent Document 1 the following general formula (I):
  • the pyrazole derivative represented by (1) has a tau aggregation inhibitory action, a ⁇ -secretase inhibitory action, an amyloid ⁇ aggregation inhibitory action and the like, and is effective as a therapeutic means for Alzheimer's disease.
  • the salts of such derivatives are described as hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; sulfates, nitrates, perchlorates.
  • Inorganic acid salts such as salts, phosphates, carbonates and bicarbonates; organic carboxylates such as acetates, oxalates, maleates, tartrates and fumarates; methanesulfonates, trifluoromethanesulfones Organic sulfonates such as acid salts, ethane sulfonates, benzene sulfonates, toluene sulfonates, camphor sulfonates; amino acid salts such as aspartate, glutamate; trimethylamine salts, triethylamine salts, prokine salts, pyridine Salts with amines such as salts and phenethylbenzylamine salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts, preferably hydrochlorides and oxalates. Is disclosed. Further, in the examples of Patent Document 1, a large number
  • An object of the present invention is a pharmaceutically advantageous salt of a pyrazole derivative and a method for producing the same, a pharmaceutically advantageous preparation using a free form or salt of a pyrazole derivative or a method for producing the same, or a pharmaceutical composition containing the preparation.
  • pharmaceutically advantageous means, for example, pharmacokinetic aspects such as exhibiting excellent blood concentration (preferably excellent concentration in brain tissue) or low toxicity to humans and animals. Excellent in physical properties such as excellent in stability over time, high solubility in water or organic solvent, high purity or high elution. Say.
  • the present inventors have studied the combination of the compound represented by the general formula (I) and the salt by trial and error, and have succeeded in producing an alkyl sulfate ester derivative and an alkyl sulfonate derivative, which are obtained. It has been found that the effectiveness of the novel salt compound is increased, and further studies have been carried out to complete the present invention.
  • R represents hydrogen, a chain or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • Ar 1 and Ar 2 are the same or different.
  • the salt according to any one of the above [1] to [6] or the free form according to the above [8] or [9] is selected from oil, surfactant and auxiliary solvent in one or more.
  • Lipids, surfactants, lecithin derivatives, polyvinylpyrrolidone, methacrylate-based polymers with respect to the salt according to any one of [1] to [6] or the free form according to [8] or [9].
  • a solubilized formulation prepared by adding an additive as a solubilizer or solubilizing agent and then preparing by one or more methods selected from pulverization, granulation, mixing, mixed pulverization, granulation, spray drying, heat melt kneading.
  • a pharmaceutical composition containing the solubilized preparation.
  • R represents hydrogen, a chain or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • Ar 1 and Ar 2 are the same or different.
  • the salt of the pyrazole derivative represented by [representing an homocyclic group or a heterocyclic group which may have a substituent] (the salt is not particularly limited and may be any salt).
  • the alkyl sulfate ester salt or alkyl sulfonate shall be described as salts A.
  • the salt compound of the present invention (preferably salts A of the present invention) or the preparation of the present invention is pharmaceutically advantageous.
  • the salt compound of the present invention (preferably salts A of the present invention) or the preparation of the present invention can exhibit an excellent blood concentration, particularly an excellent concentration in brain tissue.
  • the salt compound of the present invention (preferably salts A of the present invention) or the preparation of the present invention is also excellent in stability against changes over time.
  • the salt compound of the present invention (preferably salts A of the present invention) or the preparation of the present invention is less toxic to humans and animals and can be orally administered, preferably once a day. ..
  • the salt compound of the present invention has high solubility in an organic solvent and is a suitable raw material for formulation.
  • the free form of the compound represented by the above general formula (I) and a salt thereof can exhibit excellent blood concentration and intracerebral transferability by converting into a solid dispersion preparation or a self-emulsifying preparation. Is.
  • FIG. 1 is a diagram showing electron micrographs of the solid dispersions of Examples 5 to 8 (Runs 1 to 4, respectively).
  • FIG. 2 is a diagram showing the results of powder X-ray diffraction of the lauryl sulfate ester salt (API) of Example 1 and the solid dispersions of Examples 5 to 8 (Runs 1 to 4, respectively).
  • FIG. 3 is a diagram showing the results of powder X-ray diffraction of the solid dispersion of Example 9.
  • FIG. 4 is a diagram showing the results of changes in plasma concentration in comparison between Example 1 and Comparative Example 1 in Test Example 4.
  • FIG. 5 is a diagram showing the results of changes in plasma concentrations of Examples 1 and 5 to 9 in Test Example 4.
  • FIG. 1 is a diagram showing electron micrographs of the solid dispersions of Examples 5 to 8 (Runs 1 to 4, respectively).
  • FIG. 2 is a diagram showing the results of powder X-ray diffraction of the lauryl sulfate ester salt
  • FIG. 6 is a diagram showing the results of changes in brain concentration in comparison between Example 1 and Comparative Example 1 in Test Example 4.
  • FIG. 7 is a diagram showing the results of changes in brain concentration of Examples 1, 5 to 9 in Test Example 4.
  • FIG. 8 is a diagram showing the results of changes in plasma concentrations of Examples 1, 2, 10 and 12 in Test Example 5.
  • FIG. 9 is a diagram showing the results of changes in brain concentrations of Examples 1, 2, 10 and 12 in Test Example 5.
  • FIG. 10 is a schematic view of a solid dispersion obtained by atomizing or liquefying a solid dispersion preparation by the spray drying method of the present invention or a self-emulsifying preparation, and further spray-drying the self-emulsifying preparation.
  • FIG. 11 is a diagram showing the results of the dissolution test of the tablets obtained in Example 14.
  • FIG. 12 is a diagram showing the results of the dissolution test of the tablets obtained in Example 15.
  • the salt compound of the novel pyrazole derivative of the present invention is, for example, the following general formula (I):
  • R represents hydrogen, a chain or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • Ar 1 and Ar 2 are the same or different.
  • any one or more salts other than the salts A of the present invention are described as the salts B of the present invention, and the salts A of the present invention and the present invention.
  • One or more salts selected from the salts B of the present invention may be collectively referred to as the salt compound of the present invention.
  • salts B of the present invention for example, fatty acid salts of the compound represented by the general formula (I) (for example, butaneate, pentanate, hexanate, heptaneate, octanate, nonaneate, etc.
  • hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide of the compound represented by the general formula (I); sulfate.
  • Inorganic acid salts such as nitrates, perchlorates, phosphates, carbonates, bicarbonates; organic carboxylates such as acetates, oxalates, maleates, tartrates, fumarates; methanesulfones Organic sulfonates such as acid salts, trifluoromethane sulfonates, ethane sulfonates, benzene sulfonates, toluene sulfonates, camphor sulfonates; dodecyl phosphate, tetradecyl phosphate, hexadecyl phosphate , Organic phosphates such as octadecyl phosphate; amino acid salts such as
  • R represents hydrogen, a chain or cyclic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, and preferably represents hydrogen.
  • the chain or cyclic hydrocarbon group is not particularly limited as long as it does not interfere with the effects of the present invention, and is, for example, an alkyl group such as a methyl group, an ethyl group, a propyl group or an isopropyl group (preferably C 1-6 ).
  • Alkenyl group such as vinyl group (preferably C 1-6 ), aryl group such as phenyl group and naphthyl group (preferably C 6-12 ) and the like can be exemplified.
  • the heterocyclic group is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include a heterocyclic group containing 1 to 3 oxygen atoms, a sulfur atom, and a nitrogen atom.
  • a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a furyl group, a thienyl group, an oxazolyl group and the like can be mentioned.
  • the substituent is not particularly limited as long as it does not interfere with the effects of the present invention.
  • an alkyl group such as a methyl group or an ethyl group (preferably C 1-6 ) or an aralkyl group such as a benzyl group (preferably). C 7-10 ), acyl groups such as acetyl group and benzoyl group (preferably C 2-7 ), alkylcarbonyl groups such as tert-butoxycarbonyl group (preferably C 2-7 ), methylsulfonyl group, p-toluene Examples thereof include an alkylsulfonyl group (preferably C 1-6 ) such as a sulfonyl group, a hydroxy group, and a nitro group.
  • the further substituent may be a group commonly used in pharmacy, such as an amino group, a carboxyl group, a hydroxyl group, a (C 1-6 ) alkoxy group, and a (C 1-6 ) alkylthio group.
  • Ar 1 and Ar 2 represent homocyclic or heterocyclic groups which may have substituents, which are the same or different.
  • the ring group may be a monocyclic group or a polycyclic group such as a bicyclic group.
  • the "hypocyclic group” is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include a cyclopropyl group, an adamantyl group, a phenyl group, and a naphthyl group.
  • the "heterocyclic group” is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a frill group, a thienyl group, and an oxazolyl group.
  • the "bicyclic homocyclic group” is not particularly limited as long as it does not interfere with the effect of the present invention, and a naphthyl group or the like can be exemplified.
  • the substituent is not particularly limited as long as it does not interfere with the effects of the present invention.
  • an alkyl group such as a methyl group or an ethyl group (preferably C 1-6 ) or an aralkyl group such as a benzyl group (preferably). C 7-10 ), acyl groups such as acetyl group and benzoyl group (preferably C 2-7 ), alkylcarbonyl groups such as tert-butoxycarbonyl group (preferably C 2-7 ), methylsulfonyl group, p-toluene Examples thereof include an alkylsulfonyl group (preferably C 1-6 ) such as a sulfonyl group, a hydroxy group, and a nitro group.
  • Ar 1 preferably represents a phenyl group which may have a substituent.
  • the substituent of the phenyl group is not particularly limited as long as it does not interfere with the effect of the present invention, but preferably (1) a C 1-3 alkyloxy group which may have a substituent and (2) substitution.
  • heteroaryl group which may have a substituent, (5) a bromine atom, (6) an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent.
  • alkynyl group (7) nitro group
  • (8) acyl group (9) alkylcarbonylamino group, sulfonyl group, sulfinyl group, sulfonyloxy group and the like.
  • (1a) is substituted with a substituent substituted with a which may heterocycloalkyl group a C 1-3 alkyl group "optionally substituted heterocycloalkyl group a C 1-3 alkyl group ,
  • a substituent substituted with a which may heterocycloalkyl group a C 1-3 alkyl group "optionally substituted heterocycloalkyl group a C 1-3 alkyl group The tetrahydrofuran-3-ylmethoxy group, tetrahydrofuran-2-ylmethoxy group, 2- (piperidine-1-yl) ethoxy group, 2- (4-methylpiperazino) ethoxy group, 2- (4-benzylpiperadino).
  • Ethoxy group 2-morpholinoethoxy group, 2-pyrrolidinoethoxy group, ⁇ -D-glucopyranosyloxy group, 2- [4- (tert-butoxycarbonyl) piperazin-1-yl] ethoxy group, 2- [ Examples thereof include a 4- (methylsulfonyl) piperazin-1-yl] ethoxy group and a 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethoxy group.
  • phenyl group having a C 1-3 alkyloxy group substituted with a heterocycloalkyl group optionally having a substituent examples include 2-methoxy-4- (tetra-3-ylmethoxy) phenyl group and 2-.
  • (1b) as a substituent is substituted with a which may cycloalkyl group C 1-3 alkyl group "is substituted with an optionally substituted cycloalkyl group the C 1-3 alkyl group"
  • a substituent is substituted with a which may cycloalkyl group C 1-3 alkyl group "is substituted with an optionally substituted cycloalkyl group the C 1-3 alkyl group"
  • a substituent is substituted with a which may cycloalkyl group C 1-3 alkyl group "is substituted with an optionally substituted cycloalkyl group the C 1-3 alkyl group"
  • a cyclohexylmethoxy group and the like can be exemplified by a cyclohexylmethoxy group and the like.
  • Examples of the "phenyl group having a C 1-3 alkyloxy group substituted with a cycloalkyl group optionally having a substituent" include 4-cyclohexylmethoxy-2-methoxyphenyl group and 2-cyclohexylmethoxy-4-hydroxy.
  • Examples of phenyl group, 2-cyclohexylmethoxy-3-fluorophenyl group, 2-cyclohexylmethoxy-5-fluorophenyl group, 5-chloro-2-cyclohexylmethoxyphenyl group, 2,4-di (cyclohexylmethoxy) phenyl group and the like are exemplified. it can.
  • (1c) as a substituent group substituted by also heteroaryl groups C 1-3 alkyl group "is substituted with an optionally substituted heteroaryl group the C 1-3 alkyl group" Can exemplify a pyridine-2-ylmethoxy group, a pyridine-3-ylmethoxy group, a pyridine-4-ylmethoxy group, a 1-pyrrolylmethoxy group and the like.
  • Examples of the "phenyl group having a C 1-3 alkyloxy group substituted with a heteroaryl group optionally having a substituent" include 4- (pyridine-2-ylmethoxy) phenyl group and 2-methoxy-4- ( Pyridine-2-ylmethoxy) Phenyl group, 2- [2- (piperidin-1-yl) ethoxy] -4- (pyridine-2-ylmethoxy) phenyl group, 2- (2-morpholinoethoxy) -4- (pyridine- 2-Ilmethoxy) Phenyl group, 2- (2-pyrrolidinoethoxy) -4- (pyridine-2-ylmethoxy) phenyl group, 2- [2- (4-methylpiperadino) ethoxy] -4- (pyridine-2-ylmethoxy) ) Phenyl group, 3-methoxy-4- (pyridine-2-ylmethoxy) phenyl group, 2-hydroxy-4- (pyridine-2-ylmethoxy)
  • the (1d) substituted with an optionally substituted aryl group a C 1-3 alkyl group "is substituted with an optionally substituted aryl group a C 1-3 alkyl group", Fenetyloxy group, benzyloxy group, 1-naphthylmethoxy group, diphenylmethoxy group, 4-methoxybenzyloxy group, 2-chloro-6-fluorobenzyloxy group, 2,4-dichlorobenzyloxy group, 4-tert-butyl Examples thereof include a benzyloxy group.
  • phenyl group having a C 1-3 alkyloxy group substituted with an aryl group which may have a substituent examples include 2-methoxy-4-phenethyloxyphenyl group and 4-benzyloxy-2-methoxyphenyl.
  • (1e) as a substituent is substituted with a which may dialkylamino group C 1-3 alkyl group "is substituted with an optionally substituted dialkylamino group the C 1-3 alkyl group"
  • a which may dialkylamino group C 1-3 alkyl group "is substituted with an optionally substituted dialkylamino group the C 1-3 alkyl group" Can be exemplified by 2-dimethylaminoethoxy group, 3-dimethylaminopropoxy group, 2-dimethylamino-1-methylethoxy group, 2-dimethylamino-1-methylethoxy group and the like.
  • Examples of the "phenyl group having a C 1-3 alkyloxy group substituted with a dialkylamino group which may have a substituent" include 4- (3-dimethylaminopropoxy) phenyl group and 2-chloro-4- ( 3-Dimethylaminoethoxy) phenyl group, 2-bromo-5- (3-dimethylaminoethoxy) phenyl group, 2- (2-dimethylaminoethoxy) -4-methoxyphenyl group, 4-diethylamino-2- (2-) Examples thereof include a dimethylamino-1-methylethoxy) phenyl group.
  • Examples of the "phenyl group having a C 1-3 alkyloxy group substituted with an alkyloxy group which may have a substituent" include 2-methoxy-4-methoxyethoxyphenyl group and 2-benzyloxyethoxy-4-. Examples thereof include a methoxyphenyl group.
  • the (1 g) is substituted with an optionally substituted alkyl group the C 1-3 alkyl group "is substituted with an optionally substituted alkyl group the C 1-3 alkyl group", Examples thereof include an isopropoxy group, a 2-methylpropoxy group, a 3-methyl-2-butenyloxy group and the like.
  • phenyl group having a C 1-3 alkyloxy group substituted with an alkyl group which may have a substituent examples include 4-hydroxy-2-isopropoxyphenyl group and 4-isopropoxy-2-methoxyphenyl.
  • Aryloxy Group May Have a Substituent
  • aryloxy group may have a substituent
  • a phenoxy group or the like can be exemplified.
  • phenyl group having an aryloxy group which may have a substituent examples include a 2-phenoxyphenyl group, a 3-phenoxyphenyl group, a 4-phenoxyphenyl group and the like.
  • disubstituted amino group examples include a dimethylamino group and a diethylamino group.
  • disubstituted amino groups a group in which two substituents form a ring together. Examples include imidazole-1-yl group, pyrazole-1-yl group, triazole-2-yl group, pyrrolidine-1-yl group, piperidin-1-yl group, 4-benzylpiperidin-1-yl group, morpholin-.
  • Phenyl group having a disubstituted amino group includes 4-dimethylaminophenyl group, 4-dimethylamino-2-methoxyphenyl group, and 4 -Diethylamino-2-hydroxyphenyl group, 4-diethylamino-2-methoxyphenyl group, 2-dimethylaminophenyl group, 4-bromo-2-dimethylaminophenyl group, 5-bromo-2-dimethylaminophenyl group, 2- Dimethylamino-5-trifluoromethylphenyl group, 2-dimethylamino-4-phenylphenyl group, 2-dimethylamino-5-phenylphenyl group, 4-dimethylamino-3-methoxyphenyl group, 4-dimethylamino-2 -Nitrophenyl group, 4-dimethylamino-2-chlorophenyl group, 4-dimethylamino-2-Nitrophenyl group, 4-dimethylamin
  • aryl group which may have a substituent or a heteroaryl group which may have a substituent includes a phenyl group, a 2-methylphenyl group, and 2 Examples thereof include -ethoxyphenyl group, 1-naphthyl group, 2-naphthyl group, and examples of the "heteroaryl group which may have a substituent” include 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, and the like.
  • Imidazole-1-yl group 1H-1,2,4-triazole-1-yl group, 4-ethoxycarbonyl-1H-1,2,3-triazole-1-yl group, 5-ethoxycarbonyl-1H-1 , 2,3-Triazole-1-yl group, 1-benzyl-1H-1,2,3-triazole-4-yl group, 1-benzyl-1H-1,2,3-triazole-5-yl group, 1-ethoxycarbonylmethyl-1H-1,2,3-triazole-4-yl group, 1-ethoxycarbonylmethyl-1H-1,2,3-triazole-5-yl group, 1H-benzimidazole-1-yl Examples thereof include a group, 1H-tetrazole-5-yl group, 1-benzyl-1H-tetrazol-5-yl group, 1-ethoxycarbonylmethyl-1H-tetrazole-5-yl group and the like.
  • phenyl group having an aryl group which may have a substituent or a heteroaryl group which may have a substituent examples include a 2-phenylphenyl group, a 3-phenylphenyl group, a 4-phenylphenyl group, and 5 -Hydroxy-2-phenylphenyl group, 5-fluoro-2-phenylphenyl group, 5-chloro-2-phenylphenyl group, 5-hydroxy-2- (2-methylphenyl) phenyl group, 2- (2-ethoxy) Phenyl) -5-hydroxyphenyl group, 2- (1-naphthyl) phenyl group, 2- (2-naphthyl) phenyl group, 5-hydroxy-2- (1-naphthyl) phenyl group, 2- (2-pyridyl) Phenyl group, 2- (3-pyridyl) phenyl group, 2- (4-pyridyl) phenyl group, 4-
  • the "phenyl group having a bromine atom” includes 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-bromo-3-hydroxyphenyl group, 2-bromo-4-.
  • Alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent "Alkyl group which may have a substituent, a substituent"
  • alkenyl group which may have an alkenyl group or an alkynyl group which may have a substituent include an isopropyl group, a hydroxymethyl group, an n-propyl group, a 2-cyclopropylethyl group, and a 2- (methoxymethyl) ethyl.
  • phenyl group having an alkyl group which may have a substituent examples include 4-isopropylphenyl group and 2-.
  • Nitro group examples include 2-nitrophenyl group, 4-hydroxy-3-nitrophenyl group, 3-methoxy-4-nitrophenyl group, and 5-methoxy-2-nitrophenyl.
  • phenyl group having an acyl group examples include a 2-hydroxycarbonylphenyl group, a 3-hydroxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, a 3-methoxycarbonylphenyl group, and a 4-methoxycarbonylphenyl group.
  • 2-Dimethylaminocarbonylphenyl group, 3- (di-n-propylaminocarbonyl) phenyl group, 4-acetylphenyl group, 2-formylphenyl group, 4-propionylphenyl group and the like can be exemplified.
  • a phenyl group having an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group, or a sulfonyloxy group is also included in the above-mentioned "phenyl group which may have a substituent".
  • the number of the substituents (1) to (9) above is not particularly limited, and a plurality of the same type or different kinds of substituents may be introduced, but it is preferable that one substituent is introduced.
  • the positions of the substituents (1) to (9) above on the phenyl group are not particularly limited, and may be introduced at any of the ortho-position, meta-position, and para-position, but they are introduced at the para-position. It is preferable to have.
  • the phenyl group represented by Ar 1 has a substituent that is widely used in pharmaceuticals such as a hydroxy group, a methoxy group, and a halogen atom other than a bromine atom. You may.
  • Ar 2 preferably represents a homocyclic or heterocyclic group which may have a substituent, and more preferably a dicyclic homocyclic or heterocyclic group which may have a substituent. , More preferably represents a bicyclic heterocyclic group which may have a substituent.
  • the "bicyclic heterocyclic group” is not particularly limited as long as it does not interfere with the effects of the present invention, but is preferably indole-2-yl group, indole-3-yl group, indole-4-yl group, indole-.
  • Examples of the substituent of the bicyclic heterocyclic group include a methyl group, an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonyl group, a hydroxy group and a nitro group.
  • a methyl group an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonyl group, a hydroxy group and a nitro group.
  • bicyclic heterocyclic group which may have a substituent is not particularly limited as long as it does not interfere with the effect of the present invention, but is preferably an unsubstituted bicyclic heterocyclic group, for example.
  • Ar 1 is preferably a phenyl group having the above-mentioned substituent (1), more preferably a phenyl group having the above-mentioned substituent (1a) or (1c), and further.
  • a 2-methoxy-4- (pyridin-2-ylmethoxy) phenyl group is preferred.
  • Ar 2 preferably has an indol-2-yl group which may have a substituent, an indol-3-yl group which may have a substituent, and a substituent. May have an indol-4-yl group, an indol-5-yl group which may have a substituent, an indol-6-yl group which may have a substituent, an indol-7 which may have a substituent.
  • -Il group benzotriazole-5-yl group which may have a substituent, benzoimidazole-5-yl group which may have a substituent, quinoxalin-6-yl group which may have a substituent.
  • the present invention provides an alkyl sulfate ester salt or an alkyl sulfonate compound of the compound represented by the general formula (I).
  • the "alkyl sulfonate” may contain a “docusate salt”
  • the “alkyl sulfonic acid” may contain a "docusate”.
  • an alkyl sulfate ester salt or an alkyl sulfonate of a compound represented by is an alkyl sulfate ester salt or an alkyl sulfonate of a compound represented by.
  • an alkyl sulfate ester or an alkyl sulfonic acid may be bonded to the compound represented by the general formula (I) by an ionic bond or a non-ionic bond, for example.
  • the alkyl sulfate ester or alkyl sulfonic acid may be bonded to the compound represented by the formula (II) by an ionic bond or may be bonded by a non-ionic bond.
  • the alkyl sulfate ester salt may be simply referred to as an alkyl sulfate salt.
  • Patent Documents 1 and 2 although the organic acid salts are illustrated, the organic sulfonates are those sulfo group to the carbon atom (-SO 3 H) is bonded.
  • the alkyl sulfate ester salt is obtained by ester-bonding sulfuric acid to the alkyl group of alkanol, and it is clear that the difference is completely different depending on the presence or absence of the ester bond.
  • the alkyl sulfate ester salt is used. No description or suggestion is made about. In addition, there is no description or suggestion of higher alkyl sulfonates and docusate salts as organic sulfonates.
  • the alkyl sulfate ester salt and the alkyl sulfonate of the compound represented by the general formula (I) are used in measuring the melting point. It was found that the temperature change from the beginning to the end of melting is small and stable. By having such characteristics, formulation can be preferably carried out.
  • the preparation obtained by formulating the salt compound of the present invention is stable over time.
  • the solution of the active ingredient is important for the formulation of the active ingredient, regardless of the type of formulation.
  • alkyl sulfate ester salt and the alkyl sulfonate of the compound represented by the general formula (I) are used as organic sulfonates in Patent Documents 1 and 2.
  • benzene sulfonate As compared with the specifically disclosed benzene sulfonate, it has a lower melting point and is excellent in solubility in a solvent such as acetone or a lower alcohol, so that it can be suitably formulated.
  • the alkyl group of the alkyl sulfate ester salt is not particularly limited, and for example, an alkyl group having 1 to 24 carbon atoms can be exemplified, and it may be branched or linear. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group.
  • Dodecyl group (lauryl group), tridecyl group, tetradecyl group (myristyl group), pentadecyl group, hexadecyl group (palmityl group), heptadecyl group, octadecyl group (stearyl group), nonadecil group, icosyl group, henicosyl group, docosyl group, Examples thereof include a tricosyl group, a tetracosyl group and an adamantyl group.
  • the alkyl sulfates include methyl sulfate, ethyl sulfate, propyl sulfate, isopropyl sulfate, butyl sulfate, isobutyl sulfate, pentyl sulfate, hexyl sulfate, and heptyl sulfate.
  • alkyl sulfate ester salt examples include lauryl sulfate ester salt, tetradecyl sulfate ester salt (myristyl sulfate ester salt), hexadecyl sulfate ester salt (palmityl sulfate ester salt), hexyl sulfate ester salt and the like.
  • the salt of the compound represented by the general formula (I) is conveniently used.
  • the alkyl group of the alkyl sulfonate is not particularly limited, and for example, an alkyl group having 3 to 24 carbon atoms can be exemplified, and it may be branched or linear. Specifically, for example, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group, dodecyl group (lauryl group).
  • Tridecyl group Tridecyl group, tetradecyl group (myristyl group), pentadecyl group, hexadecyl group (palmityl group), heptadecyl group, octadecyl group (stearyl group), nonadecil group, icosyl group, henicosyl group, docosyl group, tricosyl group, tetracosyl group, Examples thereof include an adamantyl group and a bis (2-ethylhexyl) ester succinic acid group.
  • Alkyl sulfonates include propyl sulfonate, isopropyl sulfonate, butyl sulfonate, isobutyl sulfonate, pentyl sulfonate, hexyl sulfonate, heptyl sulfonate, octyl sulfonate, 2-ethylhexyl.
  • alkyl sulfonate examples include docusate salt, decyl sulfonate (decane sulfonate), dodecyl sulfonate (lauryl sulfonate) and the like.
  • the salt of the compound represented by the general formula (I) is conveniently used.
  • a counter molecule for balancing the charge with the sulfate group or the sulfonic acid group may be present in the same crystal lattice.
  • cations and amines may be mentioned, and specific examples thereof may be sodium salts, potassium salts, calcium salts, ammonium salts and the like of alkyl sulfuric acid or alkyl sulfonic acids.
  • Such a salt compound can be prepared according to a known method, and the preparation method is not limited. For example, it can be prepared by precipitating by concentrating the solvent after salt exchange and addition reaction in a methanol solution or salt exchange and addition reaction in a two-phase system of a water-organic solvent. Further, when the present inventors further investigated the method for preparing the salt compound of the compound of the general formula (I), the compound represented by the general formula (I) had poor solubility in an alcohol solvent or a non-polar solvent. Although it was difficult to prepare the salt, the following novel method was found.
  • the free form of the compound represented by the general formula (I) is completely dissolved in an aprotic polar solvent (for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.).
  • an aprotic polar solvent for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.
  • aprotic polar solvent for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.
  • an alkyl sulfate or alkyl sulfonate of the compound represented by the general formula (I), for example, 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[( 1E) -2- [2-Methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazol can be prepared as an alkyl sulfate ester salt or an alkyl sulfonate.
  • the crystal form of the obtained salt compound is not particularly limited, and may be crystalline, amorphous, solvate, hydrate, or anhydrous.
  • the salt compound of the present invention is a raw material that is easy to formulate due to its excellent physicochemical properties such as high solubility in water and organic solvents, high purity, not easily discolored, and low adhesiveness. is there.
  • the salts A of the present invention have low toxicity, excellent intracerebral transferability and pharmacokinetics, while exhibiting tau aggregation inhibitory activity, ⁇ -secretase inhibitory activity, and amyloid ⁇ aggregation inhibitory activity, similar to the free form. Therefore, it is suitable or ideal as a raw material for pharmaceutical products.
  • the salts A of the present invention are not unconditionally set depending on the type of alkyl sulfate ester salt or alkyl sulfonate, but have a melting point lower than that of the free form (234 ° C.) by 30 ° C. or more, and are suitable raw materials for formulation.
  • the solubility in an organic solvent is also high.
  • the solubility in an acetone / water (9/1 (weight ratio)) solution is 1.5 times or more higher than that in a free form.
  • the salt compound of the present invention preferably salts A of the present invention, more preferably 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[(1E)).
  • a solid dispersion preparation, a self-emulsifying preparation or a solubilized preparation containing the free form of the compound or the salt compound of the present invention (also referred to as the preparation of the present invention in the present disclosure) has excellent pharmacokinetic effects. Shown. Although the detailed reason is unknown, the salt compound of the present invention or the preparation of the present invention described above did not show oral absorbability in the oral administration experiment of mice in the free form, whereas the above-mentioned salt compound of the present invention or the preparation of the present invention had a high blood concentration and a high blood concentration. Shows intracerebral transferability. Therefore, it can be suitably used as a raw material for formulation.
  • the salt compound of the present invention or the preparation of the present invention has a tau aggregation inhibitory action, a ⁇ -secretase inhibitory action, and an amyloid ⁇ aggregation inhibitory action, a disease involving tau, ⁇ -secretase, or amyloid ⁇ , for example, Alzheimer's disease (Familiar Alzheimer's disease and sporadic Alzheimer's disease), senile dementia, Down's disease, Parkinson's disease, thoroughfeld-Jakob's disease, muscular atrophic spinal sclerosis, tauopathy, amyloidosis, diabetic neuropathy, Huntington chorea, multiple occurrences It is effective in the prevention and treatment of sclerosis and the like. Among these neurodegenerative diseases, it is particularly effective in the prevention and treatment of Alzheimer's disease. These diseases are serious to humankind.
  • Patent Documents 1 and 2 describe and claim a specific manufacturing method of the general formula (I).
  • the general formula (I) is a poorly soluble substance
  • Patent Documents 1 and 2 do not describe any method for converting into a salt compound for improving the poor solubility, and no examples are shown.
  • a formulation method for improving the poor solubility of the general formula (I) and examples thereof are not described.
  • specific examples can be specified for the conversion of the general formula (I) to a salt compound.
  • a solid dispersion preparation or a self-emulsifying preparation thereof was produced using the free form and the salt compound of the general formula (I)
  • a case was found in which oral absorbability was improved. Specific examples could be disclosed in the invention.
  • the free form of the general formula (I) or the general formula (II) or the salt compound of the present invention can exhibit excellent oral absorbability by solid-dispersing them.
  • a method for producing the solid dispersion conventionally known means may be followed, and examples thereof include a method for producing an amorphous preparation by a spray drying method, a heat melting kneading method, a mixed pulverization method, a granulation method and the like.
  • a free form of the compound represented by the general formula (I) or a salt compound of the present invention is mixed with a pharmaceutically acceptable polymer, dissolved in an organic solvent or a hydrous organic solvent, and spray-dried (spray-dried).
  • the polymer is usually preferably hydroxymethyl cellulose acetate, carboxymethyl ethyl cellulose, cellulose phthalate acetate, hydroxypropyl methyl phthalate cellulose, methyl phthalate acetate, trimellitic acetate cellulose, hydroxypropyl cellulose phthalate acetate, phthal acetate.
  • Polyvinyl alcohol polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone, polyvinyl pyrrolidone polyvinyl acetate copolymer called PVP-VA, polyethylene having at least a part of the repeating unit in the non-hydrophilic form. It is a non-cellulose polymer selected from polyvinyl alcohol copolymers, polyoxyethylene polyoxypropylene block copolymers, polyethylene glycols, polypropylene glycols, polyvinyl caprolactams, graft copolymers of polyvinyl acetate and the like.
  • the amount ratio (mass ratio) of the free compound of the compound of the formula (I), the alkyl sulfate ester salt or the alkyl sulfonate and the polymer is not particularly limited, and for example, the compound represented by the general formula (I) is free.
  • the polymer may be 1 to 10 or the like, and 2 to 5 are also exemplified.
  • tetrahydrofuran methanol, ethanol, n-propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, acetonitrile, toluene, methylene chloride and the like are used. .. Further, water may be mixed and used. Among them, acetone has a lower boiling point than other solvents, so that it can be removed at a low temperature without remaining in the preparation, which is convenient for ensuring the stability of the drug.
  • the concentration of the solid content (including the salt compound of the present invention) in the solvent is not particularly limited, and is exemplified by 0.1 to 50% by mass, and may be 0.5 to 10% by mass.
  • the salt compound of the present invention exhibits a high concentration of solubility in hydrous acetone, and a normally amorphous solid dispersion can be easily obtained by a spray drying method.
  • Spray-drying process and spray-drying equipment are generally described in Perry's Chemical Engineers' Handbook, 6th Edition (RH Perry, D.W.Green, J.O.Maloney) McGraw-HillBook Co., 1984, pp. 2054-2057. It is described in. Further details on the spray drying process and equipment are outlined in Marshall, "Atomization and Spray-Drying", Volume 50, Chem. Eng. Prog. Monogr. Series 2 (1954).
  • the conditions for spray drying can be appropriately set according to the equipment used, the type of solvent, and the like, and are not particularly limited. Various values are exemplified by appropriately adjusting the liquid feeding rate, spraying temperature, and drying temperature according to the equipment and the scale of the process.
  • the heat-melt-kneading method, the mixed pulverization method, or the granulation method may be carried out by a method known per se, and examples of the carrier used in these methods include solids and semi-solids at room temperature. Examples include cetyl alcohol, stearyl alcohol, stearic acid, palmitic acid, tetraglycerol pentastearate, tetraglycerol monostearate, glycerin monostearate, glycerin monobehate, glycerin behenate, glycerin palmitostearate, and distearyl.
  • Non-polymeric substances such as glycerin, tristearyl glycerin, trypalmityl glycerin, tristearyl glycerin, hardened castor oil, wax, and components such as poroxamer, macrogol, phospholipids, paraffin are also exemplified, and these groups A mixture of components selected from the above can also be used.
  • the free form of the general formula (I) or the general formula (II) (hereinafter, may be referred to as the free form of the present invention) or the salt compound of the present invention can also be converted into a self-emulsifying preparation. It can exhibit excellent oral absorbability.
  • the self-emulsifying preparation containing the free form of the present invention or the salt compound of the present invention refers to the free form of the present invention or the salt compound of the present invention, which is a poorly water-soluble drug, for example, an oil, a hydrophilic surfactant.
  • Self-Emulsifying Drug Delivery System which is composed of activators, lipophilic surfactants, absorption promoters, antioxidants, co-solvents, etc. and is obtained by diluting or mixing in a mixed solution. , SEDDS), etc. (For general SEDDS, reference: Gursoy, NRet al., Biomedicine & Pharmacotherapy 58, 173-182, 2004; Constantines, PP, Pharmaceutical Research 12, 1561-1572, 1995, etc.).
  • the SEDDS of the free form of the present invention or the salt compound of the present invention improves the oral absorbability of the free form of the present invention or the salt compound of the present invention, which is poorly water-soluble, and improves the variation in oral absorbability due to individual differences. be able to.
  • the present inventors have found that when a preparation converted to SEDDS is produced using the above-mentioned salt compound of the present invention (the type of salt is not particularly limited), oral absorbability is further improved.
  • the oil (lipid) is not particularly limited, but for example, soybean oil, olive oil, sesame oil, rapeseed oil, corn oil, castor oil, palm oil, eucalyptus oil, triacetin, Miglyol 812, triglyceride (tricaprylin, trilaurin, etc.) , Glycerin fatty acid ester (glycerin monocaprate, glycerin dicaprate, etc.), propylene glycol fatty acid ester (propylene glycol monocaprate, propylene glycol dicaprate, etc.), polyglycerin fatty acid ester (tetraglycerin polylysinolate, hexaglycerin polylysinolate, etc.) , Condensed polylysinolate, tetraglycerin mixed fatty acid ester, etc.) and the like are exemplified.
  • the amount of oil (lipid) used may be 0.05 to 80 parts by mass with respect to 1 part by
  • hydrophilic surfactant one having an HLB value (Hydrophile-Lipophile Balance value) of 9.0 or more is usually selected, and is not particularly limited.
  • HLB value Hydrophilic Balance value
  • polyoxyethylene lauryl ether and monococonut oil fatty acid polyoxyethylene sorbate are examples of polyoxyethylene lauryl ether and monococonut oil fatty acid polyoxyethylene sorbate.
  • the amount of the hydrophilic surfactant used may be 0.01 to 10 parts by mass with respect to 1 part by mass of the free form or salt compound of the present invention.
  • the lipophilic surfactant one having an HLB value (Hydrophile-Lipophile Balance value) of 0 to less than 9.0 is selected and is not particularly limited, but for example, sorbitan monooleate, propylene glycol monocaprylate (Capryol 90), Propylglycol monolaurate (Lauroglycol 90), propylene glycol lauroglycol (FCC), polyoxyethylene (3) castor oil, polyoxyethylene (10) castor oil, decaglyceryl pentaoleate, diglyceryl monooleate, dioleic acid Examples thereof include hexaglyceryl, polyoxyethylene glycerin oleate (6) (Labrafil 1944), and polyoxyethylene glycerin linolenate (6) (Labrafil 2125).
  • the amount of the lipophilic surfactant used may be 0.01 to 10 parts by mass with respect to 1 part by mass of the free form or salt compound of the present invention.
  • the absorption accelerator is not particularly limited, but for example, sodium salicylate, sodium deoxycholate, sodium myristate, sodium dodecyl sulfate and the like can be added.
  • an antioxidant may be added, and the present invention is not particularly limited, and examples thereof include ascorbic acid, dibutylhydroxytoluene, and butylhydroxyanisole.
  • the amount of the absorption accelerator used may be 0.01 to 5 parts by mass with respect to 1 part by mass of the free form or salt compound of the present invention.
  • the co-solvent used in the free form of the present invention or the self-emulsifying preparation containing the salt compound of the present invention is not particularly limited, and examples thereof include methanol, ethanol, acetone, transctor, PEG400, and glycerin. Further, by adding a solid polymer polymer (PEG1000, PEG6000, etc.), poloxamer (polyoxyethylene polyoxypropylene glycol), polyvinylpyrrolidone, etc., the solubility of SEDDS in the free form and salt compound of the present invention can be enhanced. Can be done.
  • the mass% of the auxiliary solvent used is not particularly limited, and is exemplified in 0.1 to 80% by mass in the SEDDS formulation, and may be 0.5 to 40% by mass.
  • the SEDDS oily liquid is dispersed in water, a solvent or a water-solvent mixed solution, and further solidified excipients, solidified polymers and the like are added. After that, it can be made into a solidified preparation by freeze-drying, spray-drying, granulation, powdering, kneading and melting method, etc., but the solidification method is not particularly limited.
  • the self-emulsifying preparation containing the free form of the present invention or the salt compound of the present invention can be converted into a granule preparation depending on the blending ratio of monoacylglycerol or diacylglycerol to be added to the surfactant used (Fig. 10b). (See), the method of granulation is not particularly limited.
  • the self-emulsifying preparation containing the free form of the present invention or the salt compound of the present invention can be commercialized as a liquid preparation as it is by encapsulating it in a soft capsule or a hard capsule when they are liquid substances.
  • the SEDDS formulation of the free form and the salt compound of the present invention is a semi-solid substance or a solid substance
  • a method of squeezing the SEDDS formulation solution into the porous solidified adsorbent is also used (reference: Gumaste S). G., et al., Pharm. Res. 2013, 30 (3), 3170-3185 and 3186-3199; Krupa A. et al., AAPS PharmSciTech 2015, 16 (3), 623-635).
  • the solidified adsorbent is not particularly limited, and is, for example, crystalline cellulose, silica gel, magnesium aluminometasilicate, porous hydroxypropylmethyl cellulose, porous sugar excipient, the above-mentioned mixed pulverization method or granulation.
  • Examples include carriers used in the method. After being squeezed into the solidified adsorbent, it can be commercialized as tablets, granules, powders and the like.
  • the free form of the present invention or the self-emulsifying preparation containing the salt compound of the present invention can be made into a solid dispersion by using the spray drying method described above.
  • the free form of the present invention or the SEDDS oily substance of the salt compound of the present invention can be dissolved or dispersed in a water-containing solvent in advance, further dissolved by adding a solid polymer, and then dried by a spray drying method (see FIG. 10c). ).
  • the self-emulsifying preparation can be dispersed and stabilized as fine micelle particles in the polymer (references: Yi T., et al., Eur. J. Pharm. Sci. 2008, 34, 274-280). ..
  • the polymer used is not particularly limited, and examples thereof include the above-mentioned solid dispersion polymer.
  • Oil lipid
  • surfactant hydrophilic surfactant or lipophilic surfactant
  • lecithin derivative polyvinylpyrrolidone
  • methacrylate-based polymer polyvinyl alcohol
  • cellulose for the salt compound of the present invention or the free form of the present invention.
  • additives selected from the group consisting of based polymers, polyoxyethylene glycol, sodium lauryl sulfate, poly (lactide-co-glycolide) copolymer (PLGA), co-solvents, sugars, amino acids, acids and bases.
  • solubilizing agent or a solubilizing agent
  • a solubilized preparation prepared by one or more methods selected from pulverization, granulation, mixing, mixed pulverization, granulation, spray drying, and heat melt kneading is also present invention. Included in.
  • the present invention also comprises a free form of the present invention or a salt compound of the present invention, or a solid dispersion preparation, a self-emulsifying preparation or a solubilized preparation containing the same (in the present disclosure, the pharmaceutical composition of the present invention). It may be described as a thing.) Specifically, it contains a pharmaceutical composition containing an alkyl sulfate or an alkyl sulfonate of the compound represented by the general formula (I), and a free form of the compound represented by the general formula (I).
  • a pharmaceutical composition containing a preparation, a self-emulsifying preparation or a solubilized preparation are provided.
  • It may be a pharmaceutical composition containing an alkyl sulfate ester salt of 1H-pyrazole, an alkyl sulfonate or other salt, or a solid dispersion preparation, a self-emulsifying preparation or a solubilized preparation containing the same.
  • the form of the pharmaceutical composition is not limited as long as the salt compound of the present invention or the preparation of the present invention can be ingested in the body.
  • tablets such as orally disintegrating tablets, powders, granules, capsules, liquids, emulsions, elixirs, suspensions, syrups, lozenges, inhalants, suppositories, injections, ointments, eye ointments.
  • Eye drops, nasal drops, ear drops, paps, lotions and the like can be formulated as oral preparations or parenteral preparations. Since it is highly absorbable into blood and easily transferred from blood to central nervous system tissues, it may be formulated as an oral preparation.
  • the pharmaceutical composition of the present invention having the above-mentioned form, as long as it contains the salt compound of the present invention or the preparation of the present invention, is a carrier, a base, and / or a carrier, a base, and / or usually used in the field of preparation, etc.
  • Additives and the like can be appropriately blended and prepared within a range that achieves the object of the present invention. Specifically, for example, excipients, binders, disintegrants, lubricants, colorants, flavoring and flavoring agents, and optionally stabilizers, emulsifiers, absorption enhancers, surfactants, pH regulators, etc.
  • Preservatives, antioxidants, sweeteners and the like can be used, and components generally used as raw materials for pharmaceutical preparations are blended in appropriate amounts within a range that does not impair the effects of the present invention, and are formulated by a conventional method.
  • the content of the salt compound of the present invention or the preparation of the present invention varies depending on the dosage form, administration method, carrier, etc., but is usually 0.01 to 100% by weight in terms of free form in the pharmaceutical composition of the present invention. It is preferably 0.1 to 95% by weight.
  • the excipient that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and is, for example, mannitol, lactose, xylitol, trehalose, sucrose, glucose, starch, corn starch, calcium hydrogen phosphate hydrate, magnesium carbonate. , Calcium carbonate and the like are exemplified.
  • the binder that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, methyl cellulose, and gum arabic.
  • the disintegrant that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and is, for example, corn starch, starch, crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, and citric acid.
  • examples include calcium, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium carboxymethyl starch, agar powder, crospovidone, synthetic aluminum silicate, sucrose fatty acid ester, lactose hydrate, D-mannitol, citric acid anhydride and the like.
  • the lubricant that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid. To.
  • the colorant that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and for example, yellow iron oxide, red iron oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, Edible blue No. 3 etc. are exemplified.
  • the flavoring and odorant that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include lemon, lemon lime, orange, and menthol.
  • the pH adjuster that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and for example, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine and the like. , Or salts thereof, and further, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, etc., or salts thereof are also exemplified.
  • the antioxidant or preservative that may be contained in the pharmaceutical composition of the present invention is not particularly limited, but is, for example, ascorbic acid, 3,5-di-tert-butyl-4-hydroxytoluene, 3-tert-butyl-. Examples thereof include 4-hydroxyanisole, D- ⁇ -tocopherol, and propyl gallate.
  • the sweetener that may be contained in the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include sugar, sucralose, aspartame, stepia, sodium saccharin, acesulfame potassium, and taumatin, and the preparation and pharmaceutical composition of the present invention are oral. It is a particularly important additive when used in internally disintegrating tablets.
  • the dose of the pharmaceutical composition of the present invention is appropriately set and not constant depending on its form, purpose of administration, type of administration target of the agent, age, body weight, and symptoms.
  • the effective human dose of the pharmaceutical composition of the present invention is preferably about 0.01 to 100 mg / kg, more preferably about 0.1 to 20 mg / kg per day in terms of free form.
  • Administration may be performed in a single dose or in several divided doses within a day within a desired dose range.
  • the administration period is also arbitrary. For example, an embodiment in which oral administration is performed once a day is exemplified.
  • the subject of administration of the pharmaceutical composition of the present invention may be a human who needs treatment for a disease for which the above-mentioned salt compound or free form of the present invention is effective, and livestock animals such as cattle, horses and goats. It may be a pet animal such as a dog, a cat or a rabbit, or an experimental animal such as a mouse, a rat, a guinea pig or a monkey. From the viewpoint of oral ingestion, the administration subjects range from patients with initial symptoms mainly treated at home to patients in the middle and terminal stages who require hospitalization and systemic assistance.
  • Alzheimer's disease preferably salts A of the present invention
  • the preparation of the present invention or a pharmaceutical composition containing the same is administered to humans or animals other than humans.
  • Alzheimer's disease and sporadic Alzheimer's disease senile dementia, Down's disease, Parkinson's disease, Creutzfeldt-Jakob disease, muscle atrophic spinal cord sclerosis, tauopathy, amyloidosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis
  • Examples include methods for preventing and / or treating neurodegenerative diseases such as sclerosis.
  • a salt compound of the present invention for preventing and / or treating the disease, or for producing a prophylactic and / or therapeutic agent for the disease.
  • A) or the use of the preparation of the present invention or a pharmaceutical composition containing the same is exemplified.
  • a salt compound of the present invention preferably salts A of the present invention
  • a preparation of the present invention or a pharmaceutical composition containing the same is used for preventing and / or treating the disease. Things are illustrated.
  • a specific compound is selected from a myriad of pyrazole derivatives
  • a specific salt is selected from a myriad of salts.
  • Example 1 (lauryl sulfate ester salt) 3-[(1E) -2- (1H-indole-6-yl) ester] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ester] -1H-
  • a lauryl sulfate ester salt of pyrazole was prepared. The structure is shown below.
  • Example 2 (n-tetradecyl sulfate ester salt) 3-[(1E) -2- (1H-indole-6-yl) ester] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ester] -1H- An n-tetradecyl sulfate ester salt of pyrazole was prepared. The structure is shown below.
  • Example 3 (n-hexadecyl sulfate ester salt) Compound 448 mg (1.0 mmol) of formula (II) was dissolved in 8.0 mL of dimethylformamide (DMF) and stirred at room temperature. DMF-water suspension of n-hexadecyl sulfate [361 mg (1.05 mmol, 1.05 eq) of sodium n-hexadecyl sulfate was dissolved in 3.0 mL of water, and 1.05 mL of 1N hydrochloric acid was added dropwise to make a suspension. A solution diluted by adding 2 mL of DMF] was added, and the mixture was stirred at room temperature for 2 hours.
  • DMF dimethylformamide
  • Example 4 (n-hexyl sulfate ester salt) Compound 448 mg (1.0 mmol) of formula (II) was dissolved in 6.7 mL of dimethylformamide (DMF) and stirred at room temperature. An aqueous solution of n-hexyl sulfate [a clear solution prepared by dissolving 214 mg (1.05 mmol, 1.05 eq) of sodium n-hexyl sulfate in 1.3 mL of water and adding 1.05 mL of 1N hydrochloric acid dropwise] is added thereto, and at room temperature. Stirred for 2 hours. 50 mL of cold distilled water was gradually added to the reaction solution to precipitate amorphous crystals.
  • DMF dimethylformamide
  • Test Example 1 Measurement of melting point
  • the results are shown in Table 1.
  • the manufacturing methods of Examples 10 to 12 in Table 1 will be described later.
  • the melting point of the free form was 234 ° C, and the melting points of nitrate and sulfate were about the same as those of the free form, whereas the melting point of the lauryl sulfate ester salt of Example 1 was as low as 128-132 ° C. It was suggested that alkyl sulfates such as lauryl sulfate are more soluble than free salts and other salts. The melting points of the other Examples 2 to 4 and 10 to 12 were also lower than the melting points of the free form.
  • Test Example 2 Solubility test of various salts in acetone water
  • Alkyl sulfate and alkyl sulfonate were dissolved in acetone / water at high concentrations. From these results, it is possible to dissolve these salts in a hydrous organic solvent and then convert them into a solid amorphous dispersion by a spray drying method, which is advantageous because the drying efficiency is industrially improved.
  • Example 5 Solid dispersion of lauryl sulfate ester 1
  • a solid dispersion of 25% by weight of the compound of formula (II) and 75% by weight of hydroxypropylmethylcellulose (Shin-Etsu Chemical HPMC TC-5E) was spray-dried by Buchi spray dryer B-290 (organic solvent recovery device B-295 manufactured by BUCHI). And the dehumidifying device B-296 was connected) as a spray drying system, and it was manufactured by the following spray drying step (Table 3).
  • FIG. 1 An electron micrograph of the cyclone-collected material is shown in FIG. 1 (Run-1), and the result of powder X-ray diffraction is shown in FIG. 2 (Run1).
  • FIG. 2 also shows the result of powder X-ray diffraction of the lauryl sulfate ester salt (API) of the compound of formula (II).
  • API lauryl sulfate ester salt
  • Example 6 Solid dispersion of lauryl sulfate ester 2
  • a solid amorphous dispersion was prepared by a spray drying method under the conditions that the amount of polymer was 80% by weight and the solid content in the spray liquid was 3.9% as shown in Table 3.
  • 4.7 g of spray-dried material was collected in a cyclone collector, and 0.8 g of adhered dried material was collected in the chamber.
  • the drying weight loss rate after drying was 1.71%, and the yield was 68%.
  • An electron micrograph of the cyclone-collected material is shown in FIG. 1 (Run-2), and the result of powder X-ray diffraction is shown in FIG. 2 (Run2).
  • Example 7 Solid dispersion of lauryl sulfate ester 3
  • a solid amorphous dispersion was prepared by a spray drying method under the conditions that the polymer amount was 75% by weight and the solid content in the spray liquid was 5.5% as shown in Table 3.
  • the spray solution was heated at 60 ° C. for a few minutes before spraying.
  • 6.5 g of spray-dried material was collected in a cyclone collector, and 1.8 g of adhered dried material was collected in the chamber.
  • the drying weight loss rate after drying was 1.82%, and the yield was 74%.
  • An electron micrograph of the cyclone-collected material is shown in FIG. 1 (Run-3), and the result of powder X-ray diffraction is shown in FIG. 2 (Run 3).
  • Example 8 Solid dispersion of lauryl sulfate ester 4
  • a solid amorphous dispersion of 20% by weight of the compound of formula (II) and 80% by weight of hydroxypropylmethylcellulose succinate (Shin-Etsu Chemical HPMCAS MG) was prepared according to Table 3 in the same manner as in Example 5.
  • a 9.2 g spray-dried product was collected in a cyclone collector, and a 1.8 g adherent dried product was collected in the chamber. The drying weight loss rate after drying was 1.82%, and the yield was 81%.
  • An electron micrograph of the cyclone collection is shown in FIG. 1 (Run-4), and the result of powder X-ray diffraction is shown in FIG. 2 (Run 4).
  • Example 9 (free solid dispersion) 1.0 g of a free compound of formula (II) and 3.0 g of hydroxypropylmethylcellulose phthalate (Shin-Etsu Chemical HPMCP HP-55) were added to THF-water (4: 1 (mass ratio), 96 mL) to dissolve and spray solution.
  • THF-water 4: 1 (mass ratio), 96 mL
  • the inlet temperature of the spray dryer was 80-83 ° C.
  • a spray-dried product was collected in a cyclone collector, and further subjected to secondary drying under reduced pressure at room temperature to obtain 3.13 g (78%) of a solid dispersion.
  • the powder X-ray analysis of this solid dispersion is shown in FIG. No crystal peak was observed, and it was found to be amorphous.
  • Test Example 3 Solubility test of various salts and solid dispersions
  • the solubility of the obtained salt and solid dispersion in three kinds of test solutions [distilled water, 0.5% CMC-Na aqueous solution, Japanese Pharmacopoeia dissolution test second solution (JP2 solution)] was measured. 5 mg (free form equivalent) of the evaluation sample was weighed in a glass vial, and 5 mL of each solution was added. Distilled water and a 0.5% aqueous solution of sodium carboxymethyl cellulose (CMC-Na) were stirred at 37 ° C. for 12 hours, and the second solution of the Japanese Pharmacopoeia dissolution test was stirred at room temperature for 2 hours.
  • CMC-Na sodium carboxymethyl cellulose
  • Example 10 After stirring, the test solution was filtered through a 0.45 ⁇ m syringe filter to prepare an evaluation sample. Subsequently, 0.5 mL of the filtrate sample was diluted with 1.0 mL of DMSO to make 1.5 mL, and 10 ⁇ L of the filtrate was added with 190 ⁇ L of acetonitrile to prepare, and LC-MS / MS (manufactured by Waters) was used. The concentration was quantified by the calibration curve method (detection limit: 1 ng / mL). The results are shown in Table 4. The production method of Example 10 or 12 in Table 4 will be described later. It was confirmed that at least Examples 1, 2, 3, 5, 6, 7, 8 and 10 had excellent solubility.
  • the brain was homogenized by adding 4 times the wet weight of MilliQ water, and then acetonitrile was added to prepare a sample for measurement.
  • the free form concentration in each measurement sample was quantified by LC-MS / MS (manufactured by Waters). The results are shown in Tables 5-8 and FIGS. 4-7.
  • the hydrochloride salt which was preferred in Patent Documents 1 and 2, had a higher plasma concentration at the time of oral administration than the free form, but the plasma concentration and the brain of lauryl sulfate were higher than such a hydrochloride. It can be seen that the concentration is remarkably high and excellent. Further, it can be seen that by converting these into solid dispersions, the plasma and brain concentrations are further increased, and the pharmacokinetics are excellent.
  • Example 10 Bis (2-ethylhexyl) succinate ester sulfonate (docusate salt) 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H- A docusate salt of pyrazole was prepared. The structure is shown below.
  • the clear reaction solution was stirred at room temperature for 30 minutes, and then 50 mL of cold distilled water was gradually added to the reaction solution to precipitate amorphous crystals. After allowing the reaction solution to stand at 8 ° C. for 6 hours, the crystals were collected by filtration and washed with 12 mL (4.0 mL ⁇ 3 times) of cold distilled water. After drying the crystals at room temperature under reduced pressure for 24 hours, the desired salt was obtained as a slightly yellowish substance of 831 mg (yield 95%). From 1 H NMR analysis, it was found that the docusate salt was added at a ratio of 1 (molar ratio) to 1 free form.
  • Example 11 (1-decane sulfonate) 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-
  • a 1-decane sulfonate of pyrazole was prepared. The structure is shown below.
  • Example 12 (lauryl sulfonate) 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H- 1-Dodecane sulfonate (lauryl sulfonate) of pyrazole was prepared. The structure is shown below.
  • the lauryl sulfonic acid-adjusted vial was washed with a small amount of DMF-water (0.6 ml of 1: 1 (mass ratio) solution) and then DMF (0.5 mL x 2 times) and added to the reaction solution.
  • Amorphous crystals were precipitated by gradually adding 100 mL of cold distilled water to the reaction solution, which was stirred at room temperature for 40 minutes. After allowing to stand at 8 ° C. for 5 hours, the crystals were collected by filtration and washed twice with a small amount of cold distilled water. The crystals were dried at room temperature under reduced pressure for 24 hours to obtain 1.31 g (yield 93.8%) of a slightly yellowish substance.
  • Test Example 5 Comparison of pharmacokinetics of typical alkyl sulfates and alkyl sulfonates
  • Various types of the free form of the compound of formula (II) Example 1 (lauryl sulfate ester salt), Example 2 (n-tetradecyl sulfate ester salt), Example 10 (docusate salt), Example 12 (lauryl sulfonate salt).
  • the salt was orally administered to ICR mice and their pharmacokinetics were compared.
  • the administration conditions are the same as in Test Example 4.
  • the results are shown in Tables 9-10 and FIGS. 8-9.
  • all of Examples 1, 2, 10 and 12 showed much better blood transfer and intracerebral transfer than the free form.
  • the free body could not be transferred into the brain, but in the above examples, the transfer into the brain was realized.
  • Example 13 Tablet using spray-dried solid dispersion 1 of lauryl sulfate
  • Glyceryl monocaprylate USP / NF35 standard TypeII grade, 120 mg
  • USP / NF35 standard TypeII grade 120 mg
  • the paste-like glyceryl monocaprylate melts 3-[(1E) -2- (1H-indole-6-yl) ethenyl] -5-[ obtained in Example 5 is placed in the same test tube.
  • Example 14 (Conversion and tableting of lauryl sulfate ester salt to self-emulsifying preparation) 3-[(1E) -2- (1H-indole-6-yl) esteryl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy)) obtained in Example 1 Phenyl] Ethenyl] -1H-pyrazol lauryl sulfate ester salt (95.6 mg, 60 mg as a free form), glyceryl monocaprylate (USP / NF35 standard TypeII grade, 120 mg), polyoxyethylene hydrogenated castor oil 60 (120 mg) , Monooleate polyoxyethylene sorbitan (polysorbate 80, 40 mg) was weighed in the same test tube.
  • the test tube was heated on an aluminum block at 60 ° C., and the contents were mixed well with a stainless steel rod to obtain a paste-like substance.
  • Distilled water (0.42 ml) was added thereto and mixed well with a stainless steel rod to obtain an emulsion in water.
  • hydroxypropyl methylcellulose Shin-Etsu Chemical TC-5E, 360 mg
  • lactose monohydrate 360 mg
  • the obtained moist powder was stored under reduced pressure at room temperature for 1 day to obtain a dried mixed powder.
  • a small amount of crospovidone (Kollidon CL) was added to the obtained powder, and the powder was evenly divided into four parts.
  • Each of the three divided portions was compression-molded with a simple tablet presser to produce three 8 mm diameter tablets.
  • the dissolution test of the obtained tablet was performed under the conditions conforming to the Japanese Pharmacopoeia dissolution test method (eluent: Japanese Pharmacopoeia dissolution test second solution pH 6.8, 900 ml, containing 0.1% polysorbate 80; elution temperature 37 ° C; paddle rotation Number: 100 rpm). After sampling the emulsified and dissolved eluate, the supernatant obtained by high-speed centrifugation was separated, diluted with DMSO, and the concentration was measured by LC-MS / MS. The elution rate% is shown in FIG. The tablets of Example 14 showed excellent dissolution.
  • Example 15 (Conversion of lauryl sulfate ester salt to self-emulsifying preparation, adsorption to mannitol Q, and tableting) Glyceryl monocaprylate (USP / NF35 standard TypeII grade, 120 mg), polyoxyethylene hydrogenated castor oil 60 (120 mg), D- ⁇ -tocopheryl succinate polyethylene glycol 1000 (Vitamin E TPGS, 40 mg), poloxamer 188 ( 120 mg) was weighed in a test tube, and the test tube was heated on an aluminum block at 60 ° C. to obtain a uniform transparent mixed solution.
  • Glyceryl monocaprylate USP / NF35 standard TypeII grade, 120 mg
  • polyoxyethylene hydrogenated castor oil 60 120 mg
  • D- ⁇ -tocopheryl succinate polyethylene glycol 1000 Vitamin E TPGS, 40 mg
  • poloxamer 188 120 mg
  • Example 15 After sampling the emulsified and dissolved eluate, the supernatant obtained by high-speed centrifugation was separated, diluted with DMSO, and the concentration was measured by LC-MS / MS. The elution rate% is shown in FIG. The tablets of Example 15 showed excellent dissolution.
  • Example 16 (Conversion of lauryl sulfate ester salt to self-emulsifying preparation, adsorption to carrier solid, and tableting) Glyceryl monocaprylate (USP / NF35 standard TypeII grade, 120 mg), polyoxyethylene hydrogenated castor oil 60 (120 mg), D- ⁇ -tocopheryl succinate polyethylene glycol 1000 (Vitamin E TPGS, 40 mg), poloxamer 188 ( 120 mg) was weighed in a test tube, and the test tube was heated on an aluminum block at 60 ° C. to obtain a uniform transparent mixed solution.
  • Glyceryl monocaprylate USP / NF35 standard TypeII grade, 120 mg
  • polyoxyethylene hydrogenated castor oil 60 120 mg
  • D- ⁇ -tocopheryl succinate polyethylene glycol 1000 Vitamin E TPGS, 40 mg
  • poloxamer 188 120 mg
  • Example 17 (A self-emulsifying preparation of lauryl sulfate is made into a solid dispersion by a spray drying method and further tableted) 3-[(1E) -2- (1H-indole-6-yl) esteryl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy)) obtained in Example 1 Phenyl] ethenyl] -1H-pyrazol lauryl sulfate ester salt (95.6 mg, 60 mg as a free form), glyceryl monocaprylate (USP / NF35 standard TypeII grade, 30 mg), polyoxyethylene hydrogenated castor oil 60 (30 mg) , Monooleate polyoxyethylene sorbitan (polysorbate 80, 20 mg) was weighed in the same test tube.
  • Acetone (4.0 ml) and distilled water (0.6 ml) were added to the test tube, and the mixture was stirred with a magnetic stirrer. After dissolving everything to obtain a uniform solution, hydroxypropyl methylcellulose (Shin-Etsu Chemical HPMC TC-5E, 260 mg) was gradually added and dissolved. The obtained solution was spray-dried using a micro spray dryer to obtain a fluid dry powder (386 mg, recovery rate 89%). From the total amount of powder obtained, 109 mg (containing about 15 mg of drug-free form) was divided into three as one tablet, lactose monohydrate (50 mg) was added to each, and then a simple tablet presser was used. And compression molding was performed to produce three 6 mm diameter tablets.
  • the salt compound of the present invention (preferably salts A of the present invention, more preferably 3-[(1E) -2- (1H-indole-6-yl) ethenyl] of the present invention] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1H-pyrazol alkyl sulfate ester salt or alkyl sulfonate), or a solid dispersion preparation of the free form of the present invention or the salt compound of the present invention
  • the self-emulsifying preparation is useful as a preventive agent or a therapeutic agent for Alzheimer's disease, it can be suitably used in, for example, an industrial field such as pharmaceuticals.

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Abstract

La présente invention concerne (1) un sel d'ester de sulfate d'alkyle ou un sel d'acide alkylsulfonique d'un dérivé de pyrazole représenté par la formule générale (I) [dans laquelle : R représente l'hydrogène, un groupe hydrocarboné cyclique ou en forme de chaîne éventuellement substitué ou un groupe hétérocyclique éventuellement substitué ; et Ar1 et Ar2 sont identiques ou différents et représentent un groupe homocyclique ou hétérocyclique éventuellement substitué], (2) une préparation de dispersion solide ou une préparation auto-émulsionnable d'un sel de dérivé de pyrazole représenté par la formule générale (I), (3) une préparation de dispersion solide ou une préparation auto-émulsionnable d'un dérivé de pyrazole représenté par la formule générale (I) dans un état libre, ou (4) une composition pharmaceutique comprenant l'un quelconque de (1) à (3) qui est pharmaceutiquement efficace en tant que médicament.
PCT/JP2020/026541 2019-07-08 2020-07-07 Sel de dérivé de pyrazole et préparation de dérivé de pyrazole WO2021006267A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012141228A1 (fr) * 2011-04-11 2012-10-18 株式会社ファルマエイト Nouveau dérivé pyrazole
WO2014057772A1 (fr) * 2012-10-10 2014-04-17 株式会社ファルマエイト Nouveau dérivé de pyrazole
JP2014530875A (ja) * 2011-10-21 2014-11-20 シーチェイドファーマシューティカルズ，インコーポレーテッド 医薬組成物及びそれらの使用
JP2015500306A (ja) * 2011-12-13 2015-01-05 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト 高融点疎水性化合物のバイオアベイラビリティが向上した薬学的組成物
WO2016140219A1 (fr) * 2015-03-02 2016-09-09 武田薬品工業株式会社 Suspension ou composition contenant des nanocristaux et son procédé de production
JP2017500332A (ja) * 2013-12-23 2017-01-05 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ 経口医薬組成物
JP2017503866A (ja) * 2014-12-23 2017-02-02 ハンミ ファーム． シーオー．， エルティーディー． デュタステリドを含む自己乳化型薬物送達システムのための組成物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012141228A1 (fr) * 2011-04-11 2012-10-18 株式会社ファルマエイト Nouveau dérivé pyrazole
JP2014530875A (ja) * 2011-10-21 2014-11-20 シーチェイドファーマシューティカルズ，インコーポレーテッド 医薬組成物及びそれらの使用
JP2015500306A (ja) * 2011-12-13 2015-01-05 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト 高融点疎水性化合物のバイオアベイラビリティが向上した薬学的組成物
WO2014057772A1 (fr) * 2012-10-10 2014-04-17 株式会社ファルマエイト Nouveau dérivé de pyrazole
JP2017500332A (ja) * 2013-12-23 2017-01-05 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ 経口医薬組成物
JP2017503866A (ja) * 2014-12-23 2017-02-02 ハンミ ファーム． シーオー．， エルティーディー． デュタステリドを含む自己乳化型薬物送達システムのための組成物
WO2016140219A1 (fr) * 2015-03-02 2016-09-09 武田薬品工業株式会社 Suspension ou composition contenant des nanocristaux et son procédé de production

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