WO2017057695A1 - Dérivé de diphénylpyrazol et son utilisation à des fins médicales - Google Patents

Dérivé de diphénylpyrazol et son utilisation à des fins médicales Download PDF

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WO2017057695A1
WO2017057695A1 PCT/JP2016/079058 JP2016079058W WO2017057695A1 WO 2017057695 A1 WO2017057695 A1 WO 2017057695A1 JP 2016079058 W JP2016079058 W JP 2016079058W WO 2017057695 A1 WO2017057695 A1 WO 2017057695A1
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group
reaction
derivative
diphenylpyrazole
acceptable salt
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PCT/JP2016/079058
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和之 徳丸
康文 後藤
慶一 沖村
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東レ株式会社
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a diphenylpyrazole derivative and its pharmaceutical use.
  • Mucosa-associated lymphoid tissue lymphoma transcription protein 1 (hereinafter referred to as MALT1) is a cysteine protease, and a nuclear factor kappa-light-chain-enhancer is known as a nuclease.
  • NF- ⁇ B signaling is activated by degrading proteins such as A20 and CYLD (Non-patent Documents 1 and 2).
  • the NF- ⁇ B signal controls immune responses such as survival, differentiation, and activation of B cells and T cells.
  • various autoimmune diseases It is known that it can develop.
  • MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma ABSC-DLBCL
  • the protease activity of MALT1 is enhanced and is involved in the development of diseases accompanied by immune abnormalities (non-patented) Reference 3).
  • MALT1 gene Mocosa-associated lymphphoid transcription gene 1; hereinafter referred to as MALT1 gene
  • Non-patent Document 5 autoimmune disease-like pathologies such as these occur spontaneously.
  • Non-patent Document 6 examples of compounds that inhibit MALT1 protease activity include oligopeptide compounds such as Z-VRPR-fmk (Non-patent Document 6), phenylfuran derivatives (Patent Document 1), phenothiazine derivatives (Patent Document 2), and triazole derivatives ( Non-patent document 7) is known.
  • rimonabant (Patent Document 3) is a celecoxib (4- (1- (p-tolyl) -3- (trifluoromethyl) compound having a cyclooxygenase inhibitory action.
  • Non-patent Document 8 is a diphenylpyrazol-3-ylcarbonylguanidine derivative (Patent Document 4) as a compound having a sodium ion / proton exchange transporter 1 inhibitory action. ) Has been reported.
  • Patent Documents 1 to 4 and Non-Patent Documents 1 to 8 do not describe that a compound having a diphenylpyrazole skeleton inhibits the protease activity of MALT1, and do not suggest its possibility.
  • the present invention aims to provide a compound having a diphenylpyrazole skeleton that inhibits the protease activity of MALT1 and exhibits a therapeutic or preventive effect on autoimmune diseases such as multiple sclerosis and psoriasis. .
  • the present invention provides a diphenylpyrazole derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • R 1 and R 2 each independently represent a halogen atom or an alkoxy group having 1 to 3 carbon atoms
  • R 3 represents one or two hydrogen atoms, each independently a halogen atom.
  • R 4 represents a hydrogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 3 carbon atoms. Represents an alkyl group.
  • R 1 and R 2 are each independently a chlorine atom or a methoxy group
  • R 3 is a hydrogen atom, a carbon atom or a carbon atom.
  • R 4 is a hydrogen atom, a hydroxyl group, an amino group or a methyl group Is preferred.
  • R 1 and R 2 are each independently a chlorine atom or a methoxy group, and R 3 is a halogen atom at the 3-position.
  • R 3 is a halogen atom at the 3-position.
  • a high MALT1 inhibitory activity can be expected, and an excellent therapeutic or preventive effect in autoimmune diseases can be expected.
  • the present invention also provides a medicament and a MALT1 inhibitor containing the diphenylpyrazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the medicament is preferably a therapeutic or prophylactic agent for autoimmune diseases
  • the therapeutic or prophylactic agent for autoimmune diseases is preferably a therapeutic or prophylactic agent for multiple sclerosis or psoriasis. More preferred.
  • the diphenylpyrazole derivative of the present invention or a pharmacologically acceptable salt thereof has an action of strongly inhibiting the protease activity of MALT1, and has a therapeutic effect or prophylaxis against autoimmune diseases such as multiple sclerosis and psoriasis. The effect can be demonstrated.
  • the diphenylpyrazole derivative of the present invention is characterized by being represented by the following general formula (I).
  • R 1 and R 2 each independently represent a halogen atom or an alkoxy group having 1 to 3 carbon atoms
  • R 3 represents one or two hydrogen atoms, each independently a halogen atom.
  • R 4 represents a hydrogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 3 carbon atoms. Represents an alkyl group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Alkoxy group having 1 to 3 carbon atoms means a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.
  • Aryl group means a monocyclic or bicyclic aromatic hydrocarbon group containing only carbon atoms, and examples thereof include a phenyl group and a naphthyl group (for example, a 1-naphthyl group or a 2-naphthyl group). Can be mentioned.
  • the “heteroaryl group” is a 4-membered to 4-membered hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • a 7-membered monocyclic aromatic heterocyclic group or a condensed aromatic heterocyclic group can be mentioned.
  • the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5-membered or 6-membered aromatic group containing 1 or 2 nitrogen atoms.
  • heterocycles eg pyrrole, imidazole, pyrazole, pyrazine, pyridine or pyrimidine
  • 5-membered aromatic heterocycles containing one sulfur atom eg thiophene
  • benzene rings And a group derived from a condensed ring.
  • a furyl group for example, 2-furyl group or 3-furyl group
  • a thienyl group for example, 2-thienyl group or 3-thienyl group
  • a pyridyl group for example, 2-pyridyl group, 3-pyridyl group, or 4 -Pyridyl group
  • pyrimidinyl group for example, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group or 6-pyrimidinyl group
  • pyridazinyl group for example, 3-pyridazinyl group or 4-pyridazinyl group
  • pyrazinyl group for example, 2-pyrazinyl group
  • pyrrolyl group for example, 1-pyrrolyl group, 2-pyrrolyl group or 3-pyrrolyl group
  • imidazolyl group for example, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group or 5 -Imid
  • Alkyl group having 1 to 3 carbon atoms means a methyl group, an ethyl group, a propyl group, or an isopropyl group.
  • the diphenylpyrazole derivative represented by the above general formula (I) may have optical isomers or diastereomers, but the diphenylpyrazole derivative represented by the above general formula (I) has only a single isomer. Also included are racemic and diastereomeric mixtures.
  • diphenylpyrazole derivative represented by the above general formula (I) other tautomers and geometric isomers may exist depending on the type of the substituent. In this specification, although it may describe only with one form of those isomers, these isomers are also included in this invention, and what isolate
  • the sulfonylguanidine moiety of the diphenylpyrazole derivative represented by the above general formula (I) there can exist three isomers having different double bond positions as shown in Scheme 1 below. Furthermore, in each isomer, there can be an E-isomer and a Z-isomer based on the geometry of the double bond. The present invention includes all these isomers.
  • the present invention also includes a prodrug of the diphenylpyrazole derivative represented by the above general formula (I).
  • the prodrug of the diphenylpyrazole derivative represented by the above general formula (I) is a compound that is enzymatically or chemically converted into the diphenylpyrazole derivative represented by the above general formula (I) in vivo.
  • the active body of the prodrug of the diphenylpyrazole derivative represented by the above general formula (I) is a diphenylpyrazole derivative represented by the above general formula (I), but the diphenylpyrazole represented by the above general formula (I)
  • the derivative prodrug itself may have activity.
  • Examples of the group that forms a prodrug of the diphenylpyrazole derivative represented by the above general formula (I) include known literature (for example, “Drug Development”, Hirokawa Shoten, 1990, Vol. 7, p.163-198 and Progress in Medicine, Vol. 5, 1985, p. 2157-2161).
  • Examples of the “pharmacologically acceptable salt” of the diphenylpyrazole derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphorus.
  • Inorganic acid salts such as acid salts or oxalates, malonates, citrates, fumarate, lactates, malates, succinates, tartrate, acetates, trifluoroacetates, maleates, Gluconate, benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate
  • Organic salts such as aspartate, glutamate or cinnamate, but hydrochloride, sulfate, hydrobromide, maleate, benzoate or methanesulfonic acid
  • the diphenylpyrazole derivative represented by the above general formula (I) may be a crystal, and the diphenylpyrazole represented by the above general formula (I) may be a single crystal form or a crystal form mixture. Included in the derivative.
  • the diphenylpyrazole derivative represented by the above general formula (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a known cocrystallization method.
  • the diphenylpyrazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof may form an anhydride, hydrate or solvate.
  • the diphenylpyrazole derivative represented by the above general formula (I) may be labeled with a radioisotope, and examples of the radioisotope to be labeled include 3 H, 14 C or 125 I.
  • diphenylpyrazole derivative represented by the above general formula (I) may be a deuterium converter.
  • the diphenylpyrazole derivative represented by the above general formula (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent.
  • the starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by known methods.
  • the diphenylpyrazole derivative represented by the above general formula (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by known means.
  • Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
  • each isomer can be obtained as a single compound by a known method.
  • Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.
  • diphenylpyrazole derivative (I) can be obtained by, for example, the method described in Scheme 2.
  • R 5 represents a protecting group for a carboxyl group
  • X independently represents a leaving group
  • other symbols are as defined above.
  • Examples of the protecting group for the carboxyl group represented by R 5 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, and a benzyl group.
  • Examples of the leaving group represented by X include a halogen atom such as a fluorine atom, chlorine atom, bromine atom or iodine atom, an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group, or a phenoxy group.
  • a halogen atom such as a fluorine atom, chlorine atom, bromine atom or iodine atom
  • an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group, or a phenoxy group.
  • alkylsulfonylamino group such as an arylsulfonyl group, a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonylamino group, or an alkylsulfonyloxy group or a trifluoromethanesulfonylamino group in which a hydrogen atom may be substituted with a halogen atom Group or an azolyl group such as imidazol-1-yl group or pyrazol-1-yl group.
  • the diphenylpyrazole-3-carboxylic acid ester derivative (IV) can be obtained by a dehydration condensation reaction between the diketone derivative (II) and the hydrazine derivative (III).
  • the amount of the hydrazine derivative (III) used in the dehydration condensation reaction is preferably 0.5 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the diketone derivative (II).
  • the reaction solvent used in the dehydration condensation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • Alcohol solvents, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane or the like
  • a mixed solvent may be mentioned, but an alcohol solvent such as methanol, ethanol, isopropyl alcohol or tert-butyl alcohol is preferable.
  • the reaction temperature of the dehydration condensation reaction is preferably ⁇ 30 ° C. to 300 ° C., more preferably 0 ° C. to 150 ° C.
  • the reaction time of the dehydration condensation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the diketone derivative (II) and hydrazine derivative (III) used in the dehydration condensation reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the diphenylpyrazol-3-ylmethanol derivative (V) can be obtained by a reduction reaction of the diphenylpyrazole-3-carboxylic acid ester derivative (IV).
  • Examples of the reducing agent used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride, and boron-based reducing agents such as sodium borohydride or lithium borohydride.
  • Aluminum-based reducing agents such as aluminum or diisobutylaluminum hydride are preferred.
  • the amount of the reducing agent used in the reduction reaction is preferably 0.3 to 100 equivalents, more preferably 0.5 to 20 equivalents, relative to the diphenylpyrazole-3-carboxylic acid ester derivative (IV).
  • the reaction solvent used for the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a reaction solvent used for the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • Alcohol solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, toluene or xylene
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, toluene or xylene
  • An aromatic hydrocarbon solvent such as the above or a mixed solvent thereof is preferable
  • an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane is preferable.
  • the reaction temperature of the reduction reaction is preferably ⁇ 100 ° C. to 200 ° C., more preferably ⁇ 50 ° C. to 50 ° C.
  • the reaction time of the reduction reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the pyrazole derivative (VI) can be obtained by a sulfonylation reaction of a diphenylpyrazol-3-ylmethanol derivative (V). Alternatively, it can also be obtained by a halogenation reaction of diphenylpyrazol-3-ylmethanol derivative (V).
  • Examples of the sulfonylating agent used in the sulfonylation reaction include methanesulfonyl chloride, toluenesulfonyl chloride, and trifluoromethanesulfonic anhydride, and methanesulfonyl chloride is preferable.
  • the amount of the sulfonylating agent used in the sulfonylation reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents, relative to the diphenylpyrazol-3-ylmethanol derivative (V).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N-ethyldiisopropylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or a mixture thereof, but triethylamine, N-ethyldiisopropylamine or pyridine and the like.
  • the organic base is preferred.
  • the reaction solvent used for the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a reaction solvent used for the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • Alcohol solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, toluene or
  • An aromatic hydrocarbon solvent such as xylene
  • a basic solvent such as pyridine or 2,6-lutidine, or a mixed solvent thereof may be mentioned, and a basic solvent such as pyridine or 2,6-lutidine is preferable.
  • the reaction temperature of the sulfonylation reaction is preferably ⁇ 100 ° C. to 200 ° C., more preferably ⁇ 50 ° C. to 50 ° C.
  • the reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • halogenating agent used in the halogenation reaction examples include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride and phosphoryl chloride, with thionyl chloride being preferred.
  • the amount of the halogenating agent used in the halogenation reaction is preferably 0.5 to 1000 equivalents, more preferably 0.8 to 100 equivalents, relative to the diphenylpyrazol-3-ylmethanol derivative (V).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N-ethyldiisopropylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or a mixture thereof, but triethylamine, N-ethyldiisopropylamine or pyridine and the like.
  • the organic base is preferred.
  • a reaction solvent may be used if desired.
  • the reaction solvent to be used is appropriately selected depending on the type of reagent to be used, but is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol
  • Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane
  • aromatics such as toluene or xylene Group hydrocarbon solvents
  • basic solvents such as pyridine or 2,6-lutidine
  • chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof.
  • the reaction temperature of the halogenation reaction is preferably ⁇ 100 ° C. to 200 ° C., more preferably ⁇ 20 ° C. to 150 ° C.
  • the reaction time of the halogenation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII) can be obtained by a substitution reaction between the pyrazole derivative (VI) and phthalimide potassium (VII).
  • the amount of potassium phthalimide (VII) used for the substitution reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents, relative to the pyrazole derivative (VI).
  • the reaction solvent used for the substitution reaction is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol or tert-butyl alcohol, N, N-dimethylformamide, N, Aprotic polar solvents such as N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, or a mixed solvent thereof
  • An aprotic polar solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide is preferable.
  • the reaction temperature of the substitution reaction is preferably ⁇ 30 ° C. to 300 ° C., more preferably 0 ° C. to 150 ° C.
  • the reaction time for the substitution reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the diphenylpyrazol-3-ylmethylamine derivative (IX) can be obtained by deprotecting the N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII) in the presence of hydrazine monohydrate.
  • the amount of hydrazine monohydrate used in the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents with respect to the N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII). .
  • the reaction solvent used in the deprotection reaction is not particularly limited as long as it does not inhibit the reaction.
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol or tert-butyl alcohol, N, N-dimethylformamide, N Aprotic polar solvents such as N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, or mixtures thereof
  • the solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol.
  • the reaction temperature of the deprotection reaction is preferably ⁇ 30 ° C. to 300 ° C., more preferably 0 ° C. to 150 ° C.
  • the reaction time for the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the guanidine derivative (XI) can be obtained by a guanidination reaction between a diphenylpyrazol-3-ylmethylamine derivative (IX) and a guanidinating agent (X).
  • the amount of the guanidinating agent (X) used for the guanidination reaction is preferably 0.5 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the diphenylpyrazol-3-ylmethylamine derivative (IX).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, and mixtures thereof.
  • organic bases such as triethylamine, N, N-diisopropylethylamine or the like
  • organic bases such as pyridine are preferred.
  • the reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile
  • N Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, but ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are preferred.
  • a nitrile solvent such as aceton
  • the reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.
  • the reaction time of the guanidinolysis reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the guanidinating agent (X) used for the guanidination reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the diphenylpyrazole derivative (I) can be obtained by a sulfonylation reaction of a guanidine derivative (XI) and a sulfonylating agent (XII).
  • the amount of the sulfonylating agent (XII) used in the sulfonylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the guanidine derivative (XI).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, sodium hydrogen carbonate or potassium hydrogen carbonate, etc.
  • Alkali metal carbonates such as sodium carbonate, sodium carbonate and potassium carbonate, or a mixture thereof, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide are preferred.
  • the reaction solvent used in the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • nitrile solvents such as acetonitrile or propionitrile, N Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, ketone solvent such as acetone or methyl ethyl ketone, water or a mixed solvent thereof, but a mixed solvent of water and ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane is preferable.
  • the reaction temperature of the sulfonylation reaction is preferably ⁇ 78 ° C. to 100 ° C., more preferably ⁇ 20 ° C. to 50 ° C.
  • the reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the sulfonylating agent (XII) used for the sulfonylation reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the guanidine derivative (XIV) can be obtained by a guanidination reaction between a diphenylpyrazol-3-ylmethylamine derivative (IX) and a guanidinating agent (XIII).
  • the amount of the guanidinating agent (XIII) used in the guanidination reaction is preferably 0.5 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the diphenylpyrazol-3-ylmethylamine derivative (IX).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, and mixtures thereof.
  • organic bases such as triethylamine, N, N-diisopropylethylamine or the like
  • organic bases such as pyridine are preferred.
  • the reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile
  • N Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, but ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are preferred.
  • a nitrile solvent such as aceton
  • the reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.
  • the reaction time of the guanidinolysis reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the guanidinating agent (XIII) used for the guanidination reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the diphenylpyrazole derivative (I) can be obtained by deprotecting the guanidine derivative (XIV) in the presence of an acid.
  • Examples of the acid used for the deprotection reaction include hydrochloric acid, 10 wt% hydrogen chloride / methanol solution, 4 mol / L hydrogen chloride / ethyl acetate solution, trifluoroacetic acid or hydrofluoric acid, but 4 mol / L hydrochloric acid / Ethyl acetate solution or trifluoroacetic acid is preferred.
  • the amount of acid used for the deprotection reaction is preferably 0.5 to 1000 equivalents, more preferably 1 to 100 equivalents, relative to the guanidine derivative (XIV).
  • the reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • diethyl ether tetrahydrofuran, dimethoxyethane, or 1,4-dioxane.
  • An ether solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof.
  • ester solvents such as ethyl acetate or propyl acetate or chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane.
  • the reaction temperature for the deprotection reaction is preferably ⁇ 78 ° C. to 200 ° C., more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time for the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 50 hours.
  • the carbamic imido acid derivative (XVI) can be obtained by a carbamimidation reaction of a diphenylpyrazol-3-ylmethylamine derivative (IX) and a carboximidic acid derivative (XV).
  • the amount of the carboximidic acid derivative (XV) used for the carbamimidation reaction is preferably 0.5 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the diphenylpyrazol-3-ylmethylamine derivative (IX).
  • a base may be used if desired.
  • the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, and mixtures thereof.
  • organic bases such as triethylamine, N, N-diisopropylethylamine or the like
  • organic bases such as pyridine are preferred.
  • the reaction solvent used for the carbamimidation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • nitrile solvents such as acetonitrile or propionitrile, N Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixed solvents thereof, and ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are used.
  • nitrile solvents such as acetonitrile or pro
  • the reaction temperature of the carbamimidation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.
  • the reaction time of the carbamimidation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the carboximidic acid derivative (XV) used for the carbamimidation reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the diphenylpyrazole derivative (I) can be obtained by a guanidinolation reaction of a carbamimic acid derivative (XVI) and an amine derivative (XVII).
  • the amount of the amine derivative (XVII) used for the guanidinolation reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 20 equivalents, relative to the carbamic imido acid derivative (XVI).
  • the reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile
  • N Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane
  • esters such as ethyl acetate or propyl acetate
  • the solvent include chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or mixed solvents thereof, and nitrile solvents such as acetonitrile or propionitrile are preferable.
  • the reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.
  • the reaction time of the guanidinolysis reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the amine derivative (XVII) used for the guanidinolation reaction can be purchased, or can be produced by a known method or a method analogous thereto.
  • the medicament and MALT1 inhibitor of the present invention are characterized by containing a diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • MALT1 inhibition means inhibiting the protease activity of MALT1.
  • MALT1 inhibitor means a compound having an action of inhibiting the protease activity of MALT1 to eliminate or attenuate the activity.
  • Autoimmune disease is a general term for diseases that cause symptoms when the immune system responds excessively to normal cells and tissues and attacks them. For example, psoriasis, multiple sclerosis Disease, rheumatism, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, uveitis or rheumatic polymyalgia.
  • the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is characterized by suppressing the function of MALT1 by inhibiting the protease activity of MALT1, that is, the substrate cleavage activity. Therefore, the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is a medicament for a disease for which improvement of the disease state or amelioration of symptoms can be expected by inhibiting the protease activity of MALT1, particularly for the treatment of autoimmune diseases. It can be used as an agent or a preventive agent.
  • the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof has an action of inhibiting the protease activity of MALT1.
  • the in vitro test include a method for evaluating cleavage of a substrate (for example, BCL10 protein) by MALT1 (Cancer Cell, 2012, Vol. 22, p. 825-837). Further, the NF- ⁇ B transcription activity inhibitory action caused by inhibiting the protease activity of MALT1 can be evaluated using a reporter gene assay (WO 2009/065897).
  • Diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof suppresses the function of MALT1 using IL-2 (interleukin-2) using a lymphocyte cell line (for example, Jurkat T cell).
  • IL-2 interleukin-2
  • a lymphocyte cell line for example, Jurkat T cell
  • Production amount can be evaluated as an index.
  • IL-2 production as an index for example, Jurkat T cell is co-stimulated with Phorbol 12-myristate 13-acetate and Ionomycin, or co-stimulated with CD3 and CD28, depending on MALT1
  • a method of measuring IL-2 production induced by sterilization (Cancer Cell, 2012, Vol. 22, p. 825-837).
  • pathological model it can be evaluated using a pathological model that the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is effective for the treatment or prevention of an autoimmune disease.
  • pathological models include the imiquimod-induced psoriasis model (The Journal of Dermatological Science, 2013, Vol. 71, No. 1, p. 29-36), experimental autoimmune encephalomyelitis model (Journal of NeuroscienceResearch). 2006, Vol. 84, p. 1225-1234), collagen arthritis model (Annual Review of Immunology, 1984, Vol. 2, p. 199-218), dextran sulfate sodium-induced colitis model (Laboratory Investigation, 1993).
  • the effectiveness of the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of an autoimmune disease can be determined by, for example, reducing the protease activity of MALT1, using the above in vitro test, or It can be evaluated using a decrease in NF- ⁇ B transcriptional activity caused by inhibiting the protease activity of MALT1 or a decrease in the production amount of IL-2 which is an index of the function of MALT1.
  • the effectiveness of treating or preventing psoriasis can be reduced by using the above-mentioned imiquimod-induced psoriasis model, for example, by reducing the thickness of the auricle that increases with the progression of symptoms in the psoriasis model. It can be evaluated as an indicator.
  • the diphenylpyrazole derivative (I) or a pharmaceutically acceptable salt thereof is administered to a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human), particularly human In addition, it can be used as a useful medicament (in particular, a therapeutic or prophylactic agent for autoimmune diseases).
  • a mammal eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human
  • a useful medicament in particular, a therapeutic or prophylactic agent for autoimmune diseases.
  • the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof may be used as it is.
  • Additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or tonicity agents may be mixed as appropriate.
  • said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate.
  • examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. , Ointments, creams or patches. Further, it may be a known continuous preparation.
  • the above-mentioned medicament preferably contains 0.00001 to 90% by weight, more preferably 0.01 to 70% by weight of the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof.
  • the dose is appropriately selected according to the patient's symptoms, age and body weight, and administration method.
  • the daily active ingredient amount for an adult is 0.1 ⁇ g to 1 g for an injection and 1 ⁇ g to 10 g for an oral preparation.
  • 1 ⁇ g to 10 g is preferable, and each patch can be administered once or several times.
  • Examples of the pharmacologically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, etc. Sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).
  • the above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic effect or preventive effect or reduce the dose.
  • the commercially available compound was used about the compound which is not described in the synthesis method by the compound used for the synthesis
  • “Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively.
  • Amine silica gel DM1020 (Fuji Silysia Chemical Co., Ltd.) was used as the amine silica gel, and YFLC W-prep2XY (Yamazen Co., Ltd.) was used as the flash chromatography.
  • YFLC W-prep2XY Yamazen Co., Ltd.
  • Monowave 300 (Anton Paar) was used.
  • the organic layer was washed with 1 mol / L hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • the obtained crude product (3.0 g) and potassium phthalimide (1.7 g) were dissolved in N, N-dimethylformamide (15 mL), and then stirred at 80 ° C. for 6 hours.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 1 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) benzenesulfonamide: 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.030 g) synthesized in Reference Example 6 was dissolved in tetrahydrofuran (0.5 mL), An 8 mol / L aqueous sodium hydroxide solution (0.021 mL) and benzenesulfonyl chloride (8.5 ⁇ L) were added.
  • the reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 1) (0.015 g).
  • Example 2 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-methoxybenzenesulfonamide: Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) synthesized in Reference Example 6 and 3-methoxybenzenesulfonyl chloride (39 ⁇ L), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 2) (0.030 g) was obtained.
  • Example 3 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-chlorobenzenesulfonamide: Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) synthesized in Reference Example 6 and 3-chlorobenzenesulfonyl chloride (29 ⁇ L) In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 3) (0.030 g) was obtained.
  • Example 4 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-cyanobenzenesulfonamide: Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.10 g) synthesized in Reference Example 6 and 3-cyanobenzenesulfonyl chloride (84 mg), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 4) (0.067 g) was obtained.
  • Example 5 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-fluorobenzenesulfonamide: Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.10 g) synthesized in Reference Example 6 and 3-fluorobenzenesulfonyl chloride (55 ⁇ L), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 5) (0.068 g) was obtained.
  • Example 6 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) pyridine-2-sulfonamide: 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) synthesized in Reference Example 6 and pyridine-2-sulfonyl chloride (0.037 g) The title compound (hereinafter, the compound of Example 6) (0.043 g) was obtained in the same manner as in Example 1.
  • Example 7 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) thiophene-2-sulfonamide: 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.056 g) synthesized in Reference Example 6 and thiophene-2-sulfonyl chloride (0.037 g) The title compound (hereinafter, the compound of Example 7) (0.031 g) was obtained in the same manner as in Example 1.
  • the obtained crude product and potassium phthalimide (0.87 g) were dissolved in N, N-dimethylformamide (15 mL) and stirred at 80 ° C. for 4 hours.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • the obtained crude product was recrystallized (hexane-ethyl acetate) to obtain the title compound (1.6 g).
  • Example 9 Synthesis of N- (amino (((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) benzenesulfonamide: 2-Benzenesulfonyl-3-((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -1- (tert-butoxycarbonyl) synthesized in Reference Example 20 ) Using guanidine (0.14 g), the title compound (hereinafter, the compound of Example 9) (0.10 g) was obtained in the same manner as in Example 8.
  • Example 12 Synthesis of N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) hydrazinecarboximide N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) carbamic imidophenyl (0.050 g) synthesized in Reference Example 22 was added to acetonitrile (0.050 g). 2 mL), hydrazine monohydrate (0.021 mL) was added, and the mixture was stirred at 80 ° C. for 1 hour.
  • Example 13 Evaluation of inhibition of protease activity of MALT1: The diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof inhibits the protease activity of MALT1 according to the method described in the literature (Cancer Cell, 2012, Vol. 22, p.825-837). Similarly, evaluation was performed in an in vitro experimental system. That is, it was evaluated by measuring the degree of decrease of the fluorescence value by the compound with respect to the increase of the fluorescence value caused by cleaving the artificial peptide substrate fluorescently labeled by the recombinant MALT1.
  • A) Production of recombinant GST-fused MALT1 A vector in which the full-length cDNA of the human MALT1 gene (GenBank accession number: AB02618.1) amplified by PCR is incorporated into the SalI site downstream of the GST gene of the pGEX6P3 vector (GE Healthcare) (hereinafter referred to as “in frame”) PGEX6P3-MALT1 vector). Subsequently, the pGEX6P3-MALT1 vector was transformed into Escherichia coli for protein expression (BL21-RIL-codon plus-DE3, Agilent), then subjected to ampicillin resistance screening and analysis by colony PCR, and an E. coli strain expressing recombinant GST-fused MALT1.
  • Got. Protein expression was induced with isopropyl- ⁇ -thiogalactopyranoside. After induction of expression, the E. coli precipitate was recovered from the E. coli culture solution by centrifugation, and the E. coli precipitate was disrupted and centrifuged to obtain a supernatant. The supernatant was purified using a GSTrap FF column (GE Health Care) to obtain a recombinant GST-fused MALT1.
  • the fluorescence value of the first measurement was “F1”, and the fluorescence value of the second measurement was “F2”.
  • F2-F1 of “test compound non-added (DMSO only added), enzyme-free and substrate-added well” is “Fback”, and “test compound non-added (DMSO only added), enzyme-added and substrate-added well”
  • F2-F1 is “Fpositive”
  • F2-F1 of “well of test compound addition, enzyme addition and substrate addition” is “Fsample”
  • the IC 50 value of each test compound is shown in Table 1. As is clear from the results in Table 1, it was shown that the diphenylpyrazole derivative (I) of the present invention or a pharmacologically acceptable salt thereof has an action of inhibiting the protease activity of MALT1.
  • Example 14 Inhibitory effect of pinna thickening in imiquimod-induced psoriasis model mice: The fact that the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof exerts a therapeutic effect on psoriasis, which is one of autoimmune diseases, is described in the literature (The Journal of Dermatological Science, 2014, No. 1). 76, No. 2, p. 96-103) and evaluated in an in vivo experimental system using imiquimod-induced psoriasis model mice. That is, it evaluated by verifying the inhibitory effect by the compound with respect to the thickening of the auricle, using the thickness of the auricle as the symptom progression of the imiquimod-induced psoriasis model as an index.
  • the administered drug solution was orally administered twice a day in the morning and afternoon for 3 days from the 7th day to the 9th day after the induction (dose volume was 10 mL / kg).
  • dose volume was 10 mL / kg.
  • a group to which 0.5% methylcellulose-0.025% Tween 20 solution was similarly administered was provided as a solvent administration group.
  • the thickness of the auricle before administration of imiquimod on the induction day (before induction) and the thickness of the auricle on the 10th day after the induction were measured using a digital micrometer (Mitutoyo), and the change (10 days after the induction)
  • the thickness of the auricle—the thickness of the auricle before induction) was used as an index for evaluating drug efficacy.
  • Steel test was performed using statistical analysis software EXSAS (ver. 7.6).
  • the evaluation results of the compound of Example 1 are shown in FIG.
  • the vertical axis in the figure shows the change in thickness of the pinna ( ⁇ m), and the horizontal axis shows each administration group.
  • “*” In the figure indicates a statistically significant (P ⁇ 0.05) difference compared to the solvent administration group.
  • the thickness of the pinna in the solvent administration group increased by 153 ⁇ m.
  • the changes remained at 98 ⁇ m, 87 ⁇ m, and 68 ⁇ m, respectively, and were significantly reduced compared to changes in the thickness of the pinna in the solvent administration group.
  • the diphenylpyrazole derivative (I) of the present invention or a pharmacologically acceptable salt thereof exerts a therapeutic effect on psoriasis.
  • the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof of the present invention has an action of strongly inhibiting the protease activity of MALT1, it can be used as a therapeutic or preventive agent for autoimmune diseases such as psoriasis. .

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Abstract

Le problème abordé par la présente invention est de pourvoir à un composé ayant un squelette diphénylpyrazol, qui peut inhiber l'activité protéasique de MALT1 et manifeste un effet thérapeutique ou prophylactique sur les maladies auto-immunes telles que le psoriasis. La solution selon l'invention porte sur un dérivé de diphénylpyrazol représenté par la formule (1) ou sur un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2016/079058 2015-09-30 2016-09-30 Dérivé de diphénylpyrazol et son utilisation à des fins médicales WO2017057695A1 (fr)

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WO2018020474A1 (fr) 2016-07-29 2018-02-01 Lupin Limited Composés de thiazolo-pyridine substitués en tant qu'inhibiteurs de malt1
WO2018159650A1 (fr) * 2017-02-28 2018-09-07 東レ株式会社 Dérivé de guanidine et son utilisation médicinale
CN109476599A (zh) * 2016-07-29 2019-03-15 东丽株式会社 胍衍生物和其医药用途
EP3736277A1 (fr) 2016-07-29 2020-11-11 Lupin Limited Composés de thiazolo-pyridine substitués en tant qu'inhibiteurs de malt1
JP2021527654A (ja) * 2018-06-18 2021-10-14 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体
JP2021528401A (ja) * 2018-06-18 2021-10-21 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体

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WO2018020474A1 (fr) 2016-07-29 2018-02-01 Lupin Limited Composés de thiazolo-pyridine substitués en tant qu'inhibiteurs de malt1
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JP2021527654A (ja) * 2018-06-18 2021-10-14 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体
JP2021528401A (ja) * 2018-06-18 2021-10-21 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体
JP7296407B2 (ja) 2018-06-18 2023-06-22 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体
JP7296408B2 (ja) 2018-06-18 2023-06-22 ヤンセン ファーマシューティカ エヌ．ベー． Ｍａｌｔ１阻害剤としてのピラゾール誘導体

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