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WO2016051799A1 - Dérivé de 2-aminohydroquinone et inhibiteur d'agrégation de tau - Google Patents

Dérivé de 2-aminohydroquinone et inhibiteur d'agrégation de tau Download PDF

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WO2016051799A1
WO2016051799A1 PCT/JP2015/004985 JP2015004985W WO2016051799A1 WO 2016051799 A1 WO2016051799 A1 WO 2016051799A1 JP 2015004985 W JP2015004985 W JP 2015004985W WO 2016051799 A1 WO2016051799 A1 WO 2016051799A1
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lower alkyl
salt
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知宏 宮坂
八郎 杉本
哲男 太田
井上　善一
洋平 大江
康夫 井原
明彦 高島
義行 添田
由紀 新崎
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Doshisha Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof

Definitions

  • the present invention relates to a 2-aminohydroquinone derivative and a tau aggregation inhibitor that inhibits the formation of tau aggregates that cause nerve loss and synapse loss.
  • AD Alzheimer's disease
  • Dementia is a type of dementia whose main symptoms are cognitive decline and personality changes.
  • Dementia is a common disease that affects approximately 25% of the Japanese population over the age of 85.
  • According to a trial calculation issued by the Ministry of Health, Labor and Welfare in 2012 there are about 4.62 million elderly people with dementia in Japan, 70% of which are AD.
  • AD Alzheimer's disease
  • acetylcholinesterase inhibitors currently being effective for the prevention and treatment of AD are only partially effective in mild to moderate patients, and a negative view of their effectiveness in patients with advanced disease There are many.
  • AD neuropathological findings in AD patients are characterized by two features: senile plaques composed of ⁇ -amyloid and neurofibrillary tangles (NFT) formed by abnormal polymerization of tau protein
  • NFT neurofibrillary tangles
  • Tau protein is abundant in central neurons and is essential for the function of the nerve axons that make up the neural network of the brain. However, if tau protein forms insoluble aggregates in cells, axonal transport is successful. It causes the death of nerve cells.
  • Patent Document 1 describes a drug mainly composed of a naphthoquinone type compound that inhibits tau aggregation for the improvement of AD symptoms. According to this drug, intracellular tau aggregation is suppressed to some extent, and thus, the symptoms of AD are alleviated by suppressing the formation of NFT.
  • tau aggregation inhibitor does not provide sufficient inhibition of intracellular tau aggregation, and it cannot be said that tauopathy including AD is treated accurately.
  • the present invention has been made in view of such problems, and an object thereof is to provide a 2-aminohydroquinone derivative and a tau aggregation inhibitor capable of sufficiently suppressing intracellular tau aggregation.
  • the compound according to the present invention is a compound consisting of the following formula (I) or a salt thereof.
  • the following formula (II) may have a hetero atom, a double bond, a bridge, or a substituent A 3 in the ring, and the ring directly connected to the nitrogen atom of the ring of the following formula (II)
  • a 4- to 10-membered cyclic amine in which two hydrogen atoms are present (including cyclic amines having 1 to 3 rings), and A 4 and A 5 are H or Lower alkyl.
  • the tau aggregation inhibitor according to the present invention is used for at least one application selected from the group consisting of treatment, diagnosis, symptom reduction and prevention of tauopathy, comprising a compound consisting of the following formula (V) or a salt thereof. Is a tau aggregation inhibitor.
  • R 1 and R 2 are each independently a hydrogen atom or a substituent (this substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, Or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, a chlorine atom) or a straight or branched chain having 1 to 6 carbon atoms, which may have one or more heteroatoms
  • a 6 is H or lower alkyl.
  • intracellular tau aggregation can be sufficiently suppressed.
  • AD tauopathy
  • many societies have been improved by improving the lives of the elderly, reducing the burden of care, and reducing medical expenses. Contribution can be made.
  • FIG. 2 is a diagram showing the tau aggregation inhibitory effect of 2- (4-phenylpiperazin-1-yl) benzene-1,4-diol bisdihydrochloride (KT328) derivative and the like.
  • FIG. 2 is a diagram showing the tau aggregation inhibitory effect of 2- (4-phenylpiperazin-1-yl) benzene-1,4-diol bisdihydrochloride (KT328) derivative and the like.
  • the following formula (II) may have a hetero atom, a double bond, a bridge, or a substituent A 3 in the ring, and the ring directly connected to the nitrogen atom of the ring of the following formula (II)
  • a 4- to 10-membered cyclic amine in which two hydrogen atoms are present (including cyclic amines having 1 to 3 rings), and A 4 and A 5 are H or Lower alkyl.
  • the lower alkyl is, for example, C1-C6 alkyl, preferably C1-C3 alkyl.
  • —A 3 in the formula (I) can be represented as —R—Y, in which case R is (i) a chemical bond, (ii) —CH 2 —, (iii) N, O or A heteroatom composed of S, (iv) —N (R 1 ) CO—, —CON (R 1 ) —, or —N (R 1 ) CON (R 1 ) — (where R 1 is hydrogen, (V) SO 2 , —COO—, a carbonyl group, or a carboxyl group, (iv) a functional group (this functional group is a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group) An ester group, a carboxyl group, an amino group, an amide group, a carbamate group, or a ketone group) or a C1-6 alkyl group or a C2-6 alkenyl group, which may have a hetero atom,
  • Y represents (i) hydrogen, a methyl group, a butyl group, a benzyl group, an amino (carboxy) methyl group, (ii) 1 or an allocyclic or heterocyclic ring optionally having a plurality of independent substituents. It is.
  • the substituent for Y is (a) lower alkyl, lower alkenyl, lower alkynyl, halogen atom, —CHF 2 , —CF 3 , —OCF 3 , (a) directly or branched lower alkylene, lower alkenylene.
  • the following functional groups may be included, and the functional groups include (a) —OH, —O-lower alkyl, (b) —NH 2 , —NH (lower alkyl), —N ( (Lower alkyl) 2 , (c) —N (H, or lower alkyl) —CO— (H, or lower alkyl), (d) —N (H, or lower alkyl) —CO—O—lower alkyl, (e ) -CO-O- (H, or lower alkyl), - CN, -NO 2, (f) -SH, -S- lower alkyl, -SO 2 - lower alkyl, (g) -CO-N ( H, or lower alkyl) 2, -CO-NH- (lower alkyl), (h) -O-CO -N (H, or lower alkyl) 2 -O-CO-NH- (lower alkyl), (i) -O-lower alkylene-
  • the compound comprising the above formula (I) is specifically a compound comprising the following formula (III) or a salt thereof.
  • -A 3 in the formula (III) is as described above.
  • a 1 and A 2 are each independently a substituent (this substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, or an amino group, A hydroxyl group, a thiol group) or a C0-3 alkyl group or a C0-3 alkenyl group which may have a hetero atom, A 4 and A 5 are H or lower alkyl, and Q is Chemical bond, C, N, O, S, or SO 2 .
  • formula (IV) can be any one of the following functional groups.
  • formula (IV) can be any of the following functional groups.
  • the compound comprising the above formula (I) is a compound comprising the following formula (VI) or a salt thereof.
  • Q, —R—Y, A 4 and A 5 are as described above.
  • KT331, KT332, KT323, KT324, KT328, KT326, KT334, KT355, KT356, and KT357 can be synthesized as a substituent A derivative, for example, by the following reaction formula.
  • KT340, KT349, KT358, KT359, KT360, KT361, KT364, and KT372 can be synthesized as a substituent A derivative, for example, by the following reaction formula.
  • KT327 can be synthesized, for example, according to the following reaction formula.
  • KT335, KT339, KT341, KT342, and KT343 can be synthesized as a substituent A derivative, for example, according to the following reaction formula.
  • KT380 and KT381 can be synthesized as 2-piperazinohydroquinone derivatives, for example, according to the following reaction formula.
  • KT370 and KT371 can be synthesized as 2-piperazinohydroquinone derivatives, for example, according to the following reaction formula.
  • KT367 can be synthesized as a 2-amino-6-methylhydroquinone derivative, for example, according to the following reaction formula.
  • KT354 can be synthesized as a 2-amino-5-methylhydroquinone derivative, for example, according to the following reaction formula.
  • —OX is an —O alkyl group, —O acyl group, —OCON (alkyl) 2 group, or —OCO—O alkyl group.
  • a 3 , A 4 and A 5 are as described above.
  • a compound consisting of the following formula (V) or a salt thereof has a tau aggregation inhibitory action, and comprises a group consisting of treatment, diagnosis, symptom reduction and prevention of tauopathy.
  • the present inventors have found a new finding that it is beneficial for at least one selected application and completed the present invention based on this fact.
  • R 1 and R 2 are each independently a hydrogen atom or a substituent (this substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, Or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, a chlorine atom) or a straight or branched chain having 1 to 6 carbon atoms, which may have one or more heteroatoms
  • a 6 is H or lower alkyl.
  • the salt of the above compound also has a tau aggregation inhibitory action.
  • the salt is a pharmacologically acceptable salt, for example, a metal salt such as an alkali metal salt (for example, potassium salt, sodium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), an alkali carbonate, etc.
  • a metal salt such as an alkali metal salt (for example, potassium salt, sodium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), an alkali carbonate, etc.
  • Metal for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • alkali metal hydrogen carbonate for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal hydroxide for example, sodium hydroxide
  • Salts of inorganic bases such as trimethylamine, triethylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkyl-morpholine, DBN, Salts of organic bases such as DBU; hydrochlorides, water bromide Salts of inorganic acids such as acid, hydroiodide, sulfate, nitrate, phosphate; formate, acetate, propionate, oxalate, malonate, succinate, fumarate, Organic acids such as maleate, lactate, malate, citrate, tartrate, citrate, carbonate, picrate, methanesulfonate,
  • the tau aggregation inhibitor according to this embodiment can also contain at least one effective amount selected from the group consisting of the above-mentioned compounds and salts thereof together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier a solid such as an excipient or a liquid such as a diluent is used. Specific examples include magnesium stearate, lactose, starch, gelatin, agar, talc, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, distilled water and the like.
  • Tauopathy is a neurodegenerative disease in which phosphorylated tau is accumulated in nerve cells and glial cells.
  • Tauopathy is, for example, AD, Down's syndrome, frontotemporal dementia, cortical basal ganglia degeneration (CBD), progressive supranuclear palsy (PSP), regulogranular dementia, or neurofibrillary tangle Although it is dementia etc., it is not limited to these.
  • the treatment of tauopathy means preventing or improving the progression of tauopathy, the diagnosis of tauopathy means judging the type and condition of tauopathy, and the reduction of symptoms of tauopathy means the prevention of tauopathy disorders. Meaning to alleviate the degree, prevention of tauopathy symptoms means prevention of tauopathy disorders.
  • the tau aggregation inhibitor according to this embodiment is appropriately formulated with one or more additives selected from pharmaceutically acceptable isotonic agents, buffers, solubilizers, preservatives, and pH adjusters. Can do.
  • the isotonic agent for example, potassium chloride, sodium chloride, boric acid, mannitol, glycerin, propylene glycol, polyethylene glycol, maltose, sucrose, sorbitol, glucose and the like can be used.
  • buffer examples include organic acids such as amino acids and succinic acid, inorganic acids such as boric acid and phosphoric acid, and pharmaceutically acceptable salts thereof.
  • solubilizing agents include polymers such as polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose; surfactants such as polysorbate, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene; propylene glycol and the like Polyhydric alcohols; organic acids such as benzoic acid and sorbic acid; amino acids such as aspartic acid, histidine, glycine and lysine can be used.
  • preservative examples include quaternary ammonium salts such as benzethonium, benzalkonium, and benzododecinium, salts of cationic compounds such as chlorhexidine, and paraoxybenzoic acid esters such as methyl paraoxybenzoate and propyl paraoxybenzoate.
  • quaternary ammonium salts such as benzethonium, benzalkonium, and benzododecinium
  • salts of cationic compounds such as chlorhexidine
  • paraoxybenzoic acid esters such as methyl paraoxybenzoate and propyl paraoxybenzoate.
  • Alcohol compounds such as chlorobutanol and benzyl alcohol can be used.
  • pH adjusters include sulfuric acid, hydrochloric acid, acetic acid, lactic acid, calcium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, etc. can do.
  • the dose of the tau aggregation inhibitor according to this embodiment is not particularly limited as long as an appropriate effect is produced, and is appropriately determined in consideration of the symptom level, sex, age, etc. of the patient to be administered.
  • the amount of the tau aggregation inhibitor can be 0.0001 to 1000 mg per adult per day. This daily dose may be administered once a day, but is preferably divided into several times a day.
  • the tau aggregation inhibitor according to this embodiment can be prepared in a dosage form according to the administration mode.
  • the oral administration form include solid preparations such as granules, pills, tablets, capsules, powders, and liquids, and liquid forms.
  • parenteral administration form it can be set as injection forms, such as an intravenous injection and an intramuscular injection, for example.
  • tau When tau is phosphorylated, it associates to form a tau oligomer. When this tau oligomer grows and has a ⁇ -sheet structure, spherical granular tau aggregates are formed. Granular tau aggregates are thought to be composed of about 40 tau molecules. These granular tau aggregates are linked to form a tau fiber called a paired helical filament (PHF) (NFT).
  • PHF paired helical filament
  • the tau aggregation inhibitor according to this embodiment not only inhibits tau aggregation in the process in which granular tau aggregates are linked to form PHF, but also tau aggregation in the process of forming spherical granular tau aggregates. It also inhibits. Moreover, degeneration of brain neurons occurs not only by mutant tau protein but also by accumulation of normal tau protein, but the tau aggregation inhibitor of the present invention also inhibits aggregation of normal tau protein. Therefore, it becomes possible to prevent or treat tauopathy symptoms including AD.
  • Example 1-1 Synthesis of 2- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride (KT328) (Example 1-1-1) 1- (2,5- Synthesis of dibenzyloxyphenyl) -4-phenylpiperazine Under argon atmosphere, 500 mg of 1,4-dibenzyloxy-2-chlorobenzene was charged with 5.0 mL of 1,4-dioxane, 0.28 mL of 1-phenylpiperazine, and 370 mg of KHMDS. The mixture was stirred at 100 ° C for 30 minutes.
  • the reaction solution was cooled to room temperature, poured into 30 mL of ice water, and extracted with 30 mL of CHCl 3 .
  • the obtained extract was washed with water, dried over Na 2 SO 4 and concentrated.
  • the obtained residue was pulverized with a mixed solution of iPE and hexane to give 430 mg (yield 62%) of the title compound.
  • Example 1-1-2 Synthesis of 2- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride 1- (2,5-dibenzyloxyphenyl) -4-phenylpiperazine 300 mg was dissolved in 6.0 mL of methanol and THF, and 0.50 mL of 4M-HCl / DOX and 60 mg of 10% Pd-C were added. Hydrogen was added and catalytic reduction was performed at room temperature for 4 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with a mixed solution of methanol and AcOEt, collected by filtration, and dried under reduced pressure to give the title compound (201 mg, yield 88%).
  • Example 1-2 Synthesis of 1,4-bis (2,5-dihydroxyphenyl) piperazine dihydrochloride (KT327) (Example 1-2-1) 1,4-bis (2,5-dibenzyl) Synthesis of (oxyphenyl) piperazine Under argon atmosphere, 1,4-dibenzyloxy-2-chlorobenzene (1,66 g) was added with 1,4-dioxane (14.0 mL), piperazine (0.20 g), and KHMDS (1.02 g), and the mixture was stirred at 100 ° C for 50 minutes. . The reaction solution was returned to room temperature, poured into ice water, adjusted to pH 8 with dilute hydrochloric acid, and extracted with CHCl 3 .
  • Example 1-2-2 Synthesis of 1,4-bis (2,5-dihydroxyphenyl) piperazine dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2.
  • Example 1-3 Synthesis of 2- [4- (2-pyridyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride (KT340) (Example 1-3-1) 1- [ Synthesis of 2,5-bis (methoxymethoxy) phenyl] -4- (2-pyridyl) piperazine Under argon atmosphere, 2-chloro-1,4-bis (methoxymethoxy) benzene 0.60 g and 1,4-dioxane 9.0 mL , 1- (2-pyridyl) piperazine 0.51 g and KHMDS 0.62 g were added and stirred at 100 ° C. for 40 minutes.
  • Example 1-3-2 Synthesis of 2- [4- (2-pyridyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride 1- [2,5-bis (methoxymethoxy) phenyl Methanol 2.8 mL and 4M-HCl / DOX 1.95 mL were added to 0.28 g of] -4- (2-pyridyl) piperazine, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution, 10 mL of Et2O was added and stirred at room temperature for 1 hour, and the precipitated powder was collected by filtration. The obtained powder was crystallized from methanol (3.0 mL) and ethanol (9.0 mL) to give the title compound (0.17 g, yield 63%).
  • Example 1-4 Synthesis of 2- (4-acetylpiperazin-1-yl) benzene-1,4-diol hydrochloride (KT341) (Example 1-4-1) 1- (2,5-Di Synthesis of (benzyloxyphenyl) -4- (tert-butoxycarbonyl) piperazine Under argon atmosphere, 1,4-dibenzyloxy-2-chlorobenzene 600 mg, 1,4-dioxane 6.0 mL, 1- (tert-butoxycarbonyl) Piperazine (413 mg) and KHMDS (442 mg) were added, and the mixture was stirred at 100 ° C for 30 minutes.
  • Example 1-4-2 Synthesis of 1- (2,5-dibenzyloxyphenyl) piperazine dihydrochloride
  • 2- (2,5-dibenzyloxyphenyl) -4- (tert-butoxycarbonyl) piperazine 2.4 g was dissolved in 12.0 mL of THF, 10.1 mL of 4M-HCl / DOX was added, and the mixture was stirred at room temperature for 14 hours.
  • 20 mL of Et2O was added and stirred at room temperature for 0.5 hour, and the precipitated powder was collected by filtration to obtain 1.78 g (yield 79%) of the title compound.
  • Example 1-4-4 Synthesis of 2- (4-acetylpiperazin-1-yl) benzene-1,4-diol hydrochloride The title compound was obtained in the same manner as in Example 1-1-2. It was.
  • Example 1-5 Synthesis of 2- (4-benzoylpiperazin-1-yl) benzene-1,4-diol hydrochloride (KT342) (Example 1-5-1) 1-benzoyl-4- (2 Synthesis of, 5-dibenzyloxyphenyl) piperazine The title compound was obtained in the same manner as in Example 1-4-3.
  • Example 1-5-2 Synthesis of 2- (4-benzoylpiperazin-1-yl) benzene-1,4-diol hydrochloride The title compound was obtained in the same manner as in Example 1-1-2. It was.
  • Example 1-6 Synthesis of 2- [4- (isopropylcarbamoyl) piperazin-1-yl] benzene-1,4-diol hydrochloride (KT343) (Example 1-6-1) 1- (2, Synthesis of 5-dibenzyloxyphenyl) -4- (isopropylcarbamoyl) piperazine 1- (2,5-dibenzyloxyphenyl) piperazine 1- (2,5-dibenzyloxyphenyl) piperazine dihydrochloride 0.30 g in dichloromethane To a mixture of 6.0 mL and Et 3 N 0.21 mL, 79 ⁇ L of isopropyl isocyanate was added under ice-cooling and stirring. The reaction mixture stirred at room temperature for 15 hours was washed with water, dried over MgSO4, and concentrated to give 0.29 g (yield 94%) of the title compound.
  • Example 1-6-2 Synthesis of 2- [4- (isopropylcarbamoyl) piperazin-1-yl] benzene-1,4-diol hydrochloride The title compound was synthesized in the same manner as in Example 1-1-2. Was obtained.
  • Example 1-9 Synthesis of 2- (4-methylpiperazin-1-yl) benzene-1,4-diol dihydrochloride (KT324) (Example 1-9-1) 1- (2,5- Synthesis of dibenzyloxyphenyl) -4-methylpiperazine Under an argon atmosphere, 600 mg of 1,4-dibenzyloxy-2-chlorobenzene was mixed with 6.0 mL of 1,4-dioxane, 0.25 mL of 1-methylpiperazine, and 440 mg of KHMDS. The mixture was stirred at 100 ° C for 30 minutes. The reaction solution was cooled to room temperature, poured into ice water, and extracted with CHCl 3 . The obtained extract was washed with water, dried over Na 2 SO 4 and concentrated. The obtained residue was purified by silica gel column chromatography (eluent CHCl 3 / methanol system) to give the title compound (269 mg, yield 38%).
  • Example 1-9-2 Synthesis of 2- (4-methylpiperazin-1-yl) benzene-1,4-diol dihydrochloride 1- (2,5-dibenzyloxyphenyl) -4-methylpiperazine 250 mg was dissolved in each 4.0 mL of methanol and THF, and 0.48 mL of 4M-HCl / DOX and 25 mg of 10% Pd-C were added. Hydrogen was added and catalytic reduction was performed at room temperature for 2 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with Et 2 O, collected by filtration, and dried under reduced pressure to give the title compound (168 mg, yield 93%).
  • Example 1-10 Synthesis of 2-morpholinobenzene-1,4-diol hydrochloride (KT323) (Example 1-10-1) Synthesis of 4- (2,5-dibenzyloxyphenyl) morpholine Argon atmosphere Then, 1,4-dibenzyloxy-2-chlorobenzene (600 mg) was added with 1,4-dioxane (6.0 mL), morpholine (0.19 mL), and KHMDS (440 mg), and the mixture was stirred at 100 ° C. for 30 minutes. The reaction solution was cooled to room temperature, poured into ice water, and extracted with Et 2 O. The obtained extract was washed with water, dried over Na 2 SO 4 and concentrated. The obtained residue was triturated with hexane to give the title compound (495 mg, yield 71%).
  • Example 1-10-2 Synthesis of 2-morpholinobenzene-1,4-diol hydrochloride 250 mg of 4- (2,5-dibenzyloxyphenyl) morpholine was dissolved in 4.0 mL of methanol and THF, and 4M -HCl / DOX 0.33 mL and 10% Pd-C 25 mg were added. Hydrogen was added and catalytic reduction was performed at room temperature for 2 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with Et 2 O, collected by filtration, and dried under reduced pressure to give the title compound (145 mg, yield 94%).
  • Example 1-11 Synthesis of 2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) benzene-1,4-diol hydrochloride (KT349) (Example 1-11- 1) Synthesis of 1- [2,5-bis (methoxymethoxy) phenyl] -4-phenyl-1,2,3,6-tetrahydropyridine 2-chloro-1,4-bis (methoxymethoxy) under argon atmosphere 1,4-Dioxane 30.0 mL, 1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride 1.51 g, and KHMDS 2.83 g were added to 1.50 g of benzene, and the mixture was stirred at 100 ° C.
  • Example 1-11-2 Synthesis of 2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) benzene-1,4-diol hydrochloride 1- [2,5-bis To 0.18 g of (methoxymethoxy) phenyl] -4-phenyl-1,2,3,6-tetrahydropyridine were added 1.8 mL of methanol and 1.27 mL of 4M-HCl / DOX, and the mixture was stirred at room temperature for 2.5 hours. AcOEt 9.0 mL and Et2O 15.0 mL were added to the reaction solution and stirred, and then the precipitated powder was collected by filtration to obtain 87 mg of the title compound (yield 57%).
  • Example 1-12 Synthesis of 2- (4-benzyl-1-piperidyl) benzene-1,4-diol hydrochloride (KT326) (Example 1-12-1) 4-Benzyl-1- (2, Synthesis of 5-dibenzyloxyphenyl) piperidine Under argon atmosphere, add 1,4-dibenzyloxy-2-chlorobenzene 600 mg, 1,4-dioxane 6.0 mL, 4-benzylpiperidine 0.394 mL, and KHMDS 442 mg 100 Stir at 30 ° C. for 30 minutes.
  • the reaction solution was returned to room temperature, poured into 40 mL of ice water, and extracted with 40 mL of a mixed solution of Et 2 O-THF (3: 1 v / v). The obtained extract was washed with saturated brine, dried over MgSO 4 and concentrated. The obtained residue was pulverized with iPE to give the title compound (599 mg, yield 70%).
  • Example 1-12-2 Synthesis of 2- (4-benzyl-1-piperidyl) benzene-1,4-diol hydrochloride 4-Benzyl-1- (2,5-dibenzyloxyphenyl) piperidine 300 mg was dissolved in 4.5 mL each of methanol and THF, and 0.32 mL of 4M-HCl / DOX and 30 mg of 10% Pd-C were added. Hydrogen was added and catalytic reduction was performed at room temperature for 2 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with Et 2 O, collected by filtration, and dried under reduced pressure to give the title compound (192 mg, yield 93%).
  • Example 1-13 Synthesis of 2- (4-phenyl-1-piperidyl) benzene-1,4-diol hydrochloride (KT334) (Example 1-13-1) 1- (2,5-dibenzyl Synthesis of Oxyphenyl) -4-phenylpiperidine The title compound was obtained in the same manner as in Example 1-12-1.
  • Example 1-13-2 Synthesis of 2- (4-phenyl-1-piperidyl) benzene-1,4-diol hydrochloride The title compound was obtained in the same manner as in Example 1-12-2. .
  • Example 1-14 Synthesis of 2- (pyrrolidin-1-yl) benzene-1,4-diol hydrochloride (KT331) (Example 1-14-1) 1- (2,5-dibenzyloxyphenyl) ) Synthesis of pyrrolidine The title compound was obtained in the same manner as in Example 1-12-1.
  • Example 1-14-2 Synthesis of 2- (pyrrolidin-1-yl) benzene-1,4-diol hydrochloride The title compound was obtained in the same manner as in Example 1-12-2.
  • Example 1-15 Synthesis of 2- (azepan-1-yl) benzene-1,4-diol hydrochloride (KT332) (Example 1-15-1) 1- (2,5-dibenzyloxyphenyl) ) Synthesis of azepan The title compound was obtained in the same manner as in Example 1-12-1.
  • Example 1-15-2 Synthesis of 2- (azepan-1-yl) benzene-1,4-diol hydrochloride The title compound was obtained in the same manner as in Example 1-12-2.
  • Example 1-16 Synthesis of 2- (4-isopropylpiperazin-1-yl) benzene-1,4-diol dihydrochloride (KT355) (Example 1-16-1) 1- (2,5- Synthesis of dibenzyloxyphenyl) -4-isopropylpiperazine The title compound was obtained in the same manner as in Example 1-9-1.
  • Example 1-16-2 Synthesis of 2- (4-isopropylpiperazin-1-yl) benzene-1,4-diol dihydrochloride The title compound was obtained in the same manner as in Example 1-9-2. It was.
  • Example 1-17 Synthesis of 2- [4- (3-methoxyphenyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride (KT356) (Example 1-17-1) 1- Synthesis of (2,5-dibenzyloxyphenyl) -4- (3-methoxyphenyl) piperazine The title compound was obtained in the same manner as in Example 1-1-1.
  • Example 1-17-2 Synthesis of 2- [4- (3-methoxyphenyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride The title compound was as in Example 1-1-2 Obtained in a similar manner.
  • Example 1-18 Synthesis of 2- [4- [4- (trifluoromethyl) phenyl] piperazin-1-yl] benzene-1,4-diol dihydrochloride (KT357) (Example 1-18- 1) Synthesis of 1- (2,5-dibenzyloxyphenyl) -4- [4- (trifluoromethyl) phenyl] piperazine The title compound was obtained in the same manner as in Example 1-1-1.
  • Example 1-18-2 Synthesis of 2- [4- [4- (trifluoromethyl) phenyl] piperazin-1-yl] benzene-1,4-diol dihydrochloride The title compound was obtained in Example 1- Obtained in the same manner as 1-2.
  • Example 1-19-2 Synthesis of 2- (4-pyrimidin-2-ylpiperazin-1-yl) benzene-1,4-diol dihydrochloride The title compound was the same as in Example 1-3-2. Obtained by the method.
  • Example 1-20-2 2- [4- (6-methyl-2-pyridyl) piperazin-1-yl] benzene- Synthesis of 1,4-diol dihydrochloride
  • Example 1-3-2 The title compound was obtained in the same manner as in Example 1-3-2.
  • Example 1-21 Synthesis of 2- (4-benzyl-1,4-diazepan-1-yl) benzene-1,4-diol dihydrochloride (KT359) (Example 1-21-1) 1- Synthesis of benzyl-4- [2,5-bis (methoxymethoxy) phenyl] -1,4-diazepane The title compound was obtained in the same manner as in Example 1-3-1.
  • Example 1-21-2 Synthesis of 2- (4-benzyl-1,4-diazepan-1-yl) benzene-1,4-diol dihydrochloride The title compound was obtained as in Example 1-3-2 Obtained in a similar manner.
  • Example 1-22-2 Synthesis of 2- [4-[(4-fluorophenyl) methyl] piperazin-1-yl] benzene-1,4-diol dihydrochloride The title compound was obtained in Example 1-3. Obtained in the same manner as -2.
  • Example 1-23 Synthesis of 2- (3,4-dihydro-1H-isoquinolin-2-yl) benzene-1,4-diol hydrochloride (KT364) (Example 1-23-1) 2- [ Synthesis of 2,5-bis (methoxymethoxy) phenyl] -3,4-dihydro-1H-isoquinoline The title compound was obtained in the same manner as in Example 1-3-1.
  • Example 1-23-2 Synthesis of 2- (3,4-dihydro-1H-isoquinolin-2-yl) benzene-1,4-diol hydrochloride The title compound was the same as in Example 1-3-2. Obtained by the method.
  • Example 1-24 Synthesis of 4- (2,5-dihydroxyphenyl) -1-benzyloxycarbonylpiperazine hydrochloride (KT372) (Example 1-24-1) 1- [2,5-bis (methoxy) Synthesis of (methoxy) phenyl] -4- (benzyloxycarbonyl) piperazine The title compound was obtained in the same manner as in Example 1-3-1.
  • Example 1-24-2 Synthesis of 4- (2,5-dihydroxyphenyl) -1-benzyloxycarbonylpiperazine hydrochloride The title compound was obtained in the same manner as in Example 1-3-2.
  • Example 1-25-3 Synthesis of 2- [4- (2-furylmethyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride The title compound was obtained as in Example 1-3-2 Obtained in a similar manner.
  • Example 1-26 Synthesis of 2- [4- (2-thienylmethyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride (KT381) (Example 1-26-1) 1- Synthesis of [2,5-bis (methoxymethoxy) phenyl] -4- (2-thienylmethyl) piperazine The title compound was obtained in the same manner as in Example 1-25-2.
  • Example 1-26-2 Synthesis of 2- [4- (2-thienylmethyl) piperazin-1-yl] benzene-1,4-diol dihydrochloride The title compound is as in Example 1-3-2 Obtained in a similar manner.
  • Example 1-27 Synthesis of 2- [4- (2,5-dihydroxyphenyl) piperazin-1-yl] acetic acid dihydrochloride (KT371) (Example 1-27-1) 1- (2,5 -Dibenzyloxyphenyl) piperazine synthesis 1- (2,5-dibenzyloxyphenyl) -4- (tert-butoxycarbonyl) piperazine (7.0 g) was dissolved in THF (35.0 mL) and 4M-HCl / DOX (29.5 mL) was added. For 16 hours. To the reaction solution, 100 mL of Et2O was added and stirred at room temperature for 0.5 hour, and the precipitated powder was collected by filtration.
  • Example 1-27-2 2- [ Synthesis of ethyl 4- (2,5-dibenzyloxyphenyl) piperazin-1-yl] acetate 1- (2,5-dibenzyloxyphenyl) piperazine 0.7 g CHCl 3 7.0 mL, acetone 7.0 mL, sodium bicarbonate 0.22 g and 0.23 mL of ethyl 2-bromoacetate were added, and the mixture was stirred for 15 hours with heating under reflux.
  • the reaction solution was returned to room temperature and added to a mixture of CHCl 3 and water, and the organic layer was separated. The obtained organic layer was washed with water, dried over Na 2 SO 4 and concentrated. The obtained residue was purified by silica gel column chromatography (eluent CHCl 3 / acetone system) to give the title compound 0.70 g (yield 81%).
  • Example 1-27-4 Synthesis of 2- [4- (2,5-dihydroxyphenyl) piperazin-1-yl] acetic acid dihydrochloride The title compound was synthesized in the same manner as in Example 1-1-2. Obtained.
  • Example 1-29 Synthesis of 2-methyl-6- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride (KT367) (Example 1-29-1) 1- [ Synthesis of 2,5-bis (methoxymethoxy) -3-methyl-phenyl] -4-phenylpiperazine The title compound was obtained in the same manner as in Example 1-3-1.
  • Example 1-29-2 Synthesis of 2-methyl-6- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride The title compound was the same as in Example 1-3-2 Obtained by the method.
  • Example 1-30 Synthesis of 2-methyl-5- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride (KT354) (Example 1-30-1) 1- ( Synthesis of 2,5-dibenzyloxy-4-methylphenyl) -4-phenylpiperazine Under argon atmosphere, 1,4-dibenzyloxy-2-bromo-5-methylbenzene 1.5 g and 1,4-dioxane 20.0 mL Then, 0.71 mL of 1-phenylpiperazine and 0.94 g of KHMDS were added, and the mixture was stirred at 100 ° C. for 30 minutes.
  • the reaction solution was cooled to room temperature, poured into 30 mL of ice water, adjusted to pH 7 with 2N-hydrochloric acid, and extracted with CHCl 3 .
  • the obtained extract was washed with water, dried over MgSO 4 and concentrated.
  • the obtained residue was purified by silica gel column chromatography (eluent CHCl 3 / hexane system), and pulverized with methanol to give 0.49 g (yield 27%) of the title compound.
  • Example 1-30-2 Synthesis of 2-methyl-5- (4-phenylpiperazin-1-yl) benzene-1,4-diol dihydrochloride 1- (2,5-dibenzyloxy-4- Methylphenyl) -4-phenylpiperazine (250 mg) was dissolved in methanol (12.5 mL) and THF (7.5 mL), and 4M-HCl / DOX (0.4 mL) and 10% Pd-C (25 mg) were added. Hydrogen was added and catalytic reduction was performed for 2 hours at room temperature under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with AcOEt, collected by filtration, and dried under reduced pressure to give the title compound (182 mg, yield 95%).
  • Example 2 Tau aggregation inhibitory activity was measured as shown below. First, a plasmid expressing human type tau 0N4R isoform (383 amino acids) was introduced into Escherichia coli BL21 (DE3) strain, and recombinant tau was purified. The purification method was modified from Taniguchi et al. (2008, JBC, 280, 7614). A soluble fraction was prepared from Escherichia coli after induction of tau expression with isopropyl- ⁇ -thiogalactopyranoside, and fractionation was performed using a phosphocellulose column (Whatman, P11 column).
  • the dried and purified recombinant tau preparation was dissolved in purified water at a concentration of 0.9 mg / ml. Dilute this to a final concentration of 10 ⁇ M flavin T, 0.1M NaCl, 0.45 mg / ml recombinant tau, 10 mM HEPES pH7.4, and various compounds to the desired concentration, and a fluorescent plate reader (TECAN, infinit F200) was used to measure the fluorescence value (excitation light: 360 nm / fluorescence: 465 nm). Thereafter, heparin was added to 60 ⁇ g / ml and incubated at 37 ° C. in a moisturizing box, and the change in fluorescence value with time was measured.
  • the determination of the pharmacological effect was based on the thioflavin fluorescence value after 72 hours incubation as an index, and the decrease in fluorescence value when the thioflavin fluorescence value in the absence of the compound was taken as 100% was evaluated. After incubation for 168 hours and measurement of the fluorescence value, the reaction solution was recovered and a sarkosyl-insoluble fraction was prepared. The sarkosyl insoluble fraction was adjusted to a final concentration of 1% by adding 1/10 volume of 10% N-lauroyl sodium sarcosinate aqueous solution to the collected reaction solution. After incubation at 4 ° C.
  • the mixture was centrifuged at 100,000 ⁇ g for 20 minutes to separate the supernatant and the precipitate.
  • the supernatant fraction was the soluble tau fraction and the precipitate was the sarkosyl insoluble fraction, and the tau yield was analyzed by 10% polyacrylamide gel electrophoresis.
  • a part of the collected reaction solution was fractionated by a sucrose density gradient centrifugation method by the method of Maeda et al. (Maeda et al. 2007, Biochemistry, 46, 3856). After centrifugation, the fraction was divided into 1 to 6 according to the density, and the yield of tau was analyzed by 10% polyacrylamide gel electrophoresis and Western blotting.
  • the tau aggregation inhibitory effect of 2-aminohydroquinone and its derivatives was verified.
  • the concentration of various compounds was 1 ⁇ M. This is a concentration at which isoproterenol, a known tau aggregation inhibitor, inhibits about 80% of the amount of tau aggregation in the absence of the compound.
  • the thioflavin fluorescence value was reduced to 38.9 ⁇ 6.1% in the presence of 1 ⁇ M 2-aminohydroquinone (KT290). From this, it was found that 2-aminohydroquinone has a significantly strong tau aggregation inhibitory effect on isoproterenol.
  • FIG. 1 is a graph showing Th-T fluorescence values after 72 hours of incubation when various 2-aminohydroquinone derivatives are added at 1 ⁇ M.
  • the Th-T fluorescence value on the vertical axis reflects the amount of tau aggregation.
  • 1A shows the effect of KT308 and KT309
  • FIG. 1B shows the effect of KT332
  • FIG. 1C shows the effect of KT330, KT331, and KT332. All have tau aggregation inhibitory effect equivalent to 2-hydroquinone (KT290) as the basic skeleton, and the effect is significantly stronger than known tau aggregation inhibitor compounds such as isoproterenol (iso). found. **, p ⁇ 0.01, n.s., No significant difference (Tukey multiple comparison test).
  • KT327, KT328, and KT340 are compounds that inhibit tau aggregation as much as in the presence of 2-aminohydroquinone (KT290) 1 ⁇ M, and compounds that inhibit tau aggregation inhibition significantly compared to isoproterenol, though not as good as KT290 KT335, KT341, KT342 and KT343 were identified as (Fig. 2).
  • FIG. 2 and 3 are diagrams showing Th-T fluorescence values after 72 hours of incubation when various compounds are added at 1 ⁇ M.
  • the Th-T fluorescence value on the vertical axis reflects the amount of tau aggregation.
  • 2A shows the effect of KT327 and KT328
  • FIG. 2B shows the effect of KT335
  • FIG. 2C shows the effect of KT340
  • FIG. 2D shows the effect of KT341, KT342 and KT343
  • FIG. 2E shows the effect of KT349.
  • 3A is the effect of KT354, KT335, KT356, KT357, KT358, KT359, KT360, KT361, FIG.
  • FIG. 3B is the effect of KT364, KT365, KT367, KT370, KT371, KT372, and
  • FIG. 3C is the effect of KT380, KT381 Show the effect.
  • KT327, KT328, KT340, KT349, and KT359 had the same effect of inhibiting tau aggregation as 2-aminohydroquinone (KT290).
  • KT335, KT341, KT342, KT343, KT354, KT356, KT358, KT361, KT364, KT365, KT367, KT370, KT371, KT372, KT380, and KT381 are also compared to known tau aggregation inhibitors such as isoproterenol (iso). The effect was significantly stronger. **, p ⁇ 0.01 (vs. iso), #; p ⁇ 0.01 (vs. KT290), n.s., No significant difference (Tukey multiple comparison test).

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Abstract

L'invention concerne un inhibiteur d'agrégation de tau qui est capable de supprimer de façon suffisante l'agrégation de tau dans les cellules. L'invention concerne un composé représenté par la formule (I) ou un sel de celui-ci. Ce composé est utilisé pour au moins une application choisie dans le groupe constitué du traitement, du diagnostic, du soulagement des symptômes, et de la prophylaxie de tauopathie.
PCT/JP2015/004985 2014-10-01 2015-09-30 Dérivé de 2-aminohydroquinone et inhibiteur d'agrégation de tau Ceased WO2016051799A1 (fr)

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JPWO2018221731A1 (ja) * 2017-06-02 2020-04-09 富士フイルム富山化学株式会社 タウオパチー予防または治療剤
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11541033B2 (en) 2017-06-02 2023-01-03 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating Alzheimer's disease
US11548878B2 (en) 2017-10-30 2023-01-10 Fujifilm Toyama Chemical Co., Ltd. Emopamil binding protein binding agent and use thereof
US11660287B2 (en) 2017-06-02 2023-05-30 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating spinocerebellar ataxia
US11666551B2 (en) 2017-06-02 2023-06-06 Fujifilm Toyama Chemical Co., Ltd. Agent for reducing amount of amyloid β protein
US11951092B2 (en) 2017-06-02 2024-04-09 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating brain atrophy

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GB1541973A (en) * 1976-01-19 1979-03-14 Oreal Dyeing composition based on diphenylamines and polyhydroxybenzenes
WO2002022587A1 (fr) * 2000-09-18 2002-03-21 Eisai Co., Ltd. Pyridazinones et triazinones ainsi que leur utilisation medicale
WO2007015175A2 (fr) * 2005-06-24 2007-02-08 Friedrich-Alexander-Universität Erlangen-Nürnberg Utilisation d'inhibiteurs de pp-1 pour eviter des problemes d'epissage

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2018221731A1 (ja) * 2017-06-02 2020-04-09 富士フイルム富山化学株式会社 タウオパチー予防または治療剤
US11541033B2 (en) 2017-06-02 2023-01-03 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating Alzheimer's disease
US11660287B2 (en) 2017-06-02 2023-05-30 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating spinocerebellar ataxia
US11666551B2 (en) 2017-06-02 2023-06-06 Fujifilm Toyama Chemical Co., Ltd. Agent for reducing amount of amyloid β protein
US11951092B2 (en) 2017-06-02 2024-04-09 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating brain atrophy
US11548878B2 (en) 2017-10-30 2023-01-10 Fujifilm Toyama Chemical Co., Ltd. Emopamil binding protein binding agent and use thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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