WO2020059841A1 - Agent thérapeutique pour maladies à prions - Google Patents

Agent thérapeutique pour maladies à prions Download PDF

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WO2020059841A1
WO2020059841A1 PCT/JP2019/036887 JP2019036887W WO2020059841A1 WO 2020059841 A1 WO2020059841 A1 WO 2020059841A1 JP 2019036887 W JP2019036887 W JP 2019036887W WO 2020059841 A1 WO2020059841 A1 WO 2020059841A1
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group
ring
optionally substituted
compound
npr
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石橋　大輔
教行 西田
賢志 水田
岳志 石川
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国立大学法人 長崎大学
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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
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • C07D295/12—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 or doubly bound nitrogen atoms
    • C07D295/135—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a compound having an effect of suppressing abnormal prion production and a therapeutic agent for prion disease containing the compound as an active ingredient.
  • Prion disease is a fatal neurodegenerative disease that is thought to cause the accumulation of abnormal prion proteins in the brain.
  • prion disease occurs in a wide range of animals such as livestock such as cattle, sheep, and deer, pets, and wild animals, and thus can be used as veterinary medicine.
  • Patent Document 1 exhibits an excellent effect in preventing the onset and progression of prion disease (Compound 1, GN8) (Non-Patent Document 1). Further, improved compounds thereof have been found (Patent Documents 2 and 3).
  • the present inventors have increased the number of compound libraries and the accuracy of calculation parameters in order to search for more effective compounds, and evaluated the efficacy of the compounds obtained after recalculation in the experimental system of the prion disease model, and demonstrated excellent effects.
  • the structure development was carried out using a compound having the formula (1) as a lead compound, and a novel compound as a candidate for a therapeutic agent for prion disease mentioned in the present invention was found.
  • An object of the present invention is to provide a compound having an effect of suppressing abnormal prion production and useful as a therapeutic agent for prion disease.
  • Ring A represents a C 5-10 hydrocarbon ring or a 5- to 10-membered heterocyclic ring
  • R 1 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted 5- to 6-membered monocyclic aromatic heterocyclic group
  • R 2 represents a hydrogen atom or an oxo group
  • R 1 and R 2 combine to form a C 4-8 hydrocarbon ring
  • R 3 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted amino group
  • Y is -NR 4 R 5 or
  • R 4 and R 5 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group;
  • X represents O or NR 6 ;
  • Ring B represents a 4- to 8-membered nitrogen-containing non-aromatic heterocycle;
  • n represents 0 or 1;
  • R 6 represents a C 1-6 alkyl group, a C 3-10 cycloalkyl group or an optionally substituted C 1-6 alkyl-carbonyl group.
  • ring A is a C 6-10 arene ring or a 5- to 10-membered non-aromatic heterocycle; R 1 is substituted with 1 to 3 substituents selected from (1) a hydrogen atom, (2) a C 1-6 alkyl group or (3) (a) a 5- to 6-membered monocyclic aromatic heterocyclic group.
  • 5- or 6-membered monocyclic aromatic heterocyclic ring which may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group which may be substituted and (b) a C 3-10 cycloalkyl group Group;
  • R 2 is a hydrogen atom or an oxo group;
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring;
  • R 3 is 1 to 3 substituents selected from (1) a hydrogen atom, (2) a C 1-6 alkyl group or (3) (a) a 5- to 6-membered monocyclic non-aromatic heterocyclic group.
  • R 4 and R 5 each independently represent (1) a hydrogen atom or (2) (a) a mono- or di-C 1-6 alkylamino group and (b) a 5- to 6-membered monocyclic non-aromatic
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a heterocyclic group
  • Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle
  • X is O or NR 6
  • n is 0 or 1
  • R 6 is 1-3 substituents selected from (1) C 1-6 alkyl group, (2) C 3-10 cycloalkyl group and (3) 5- to 6-membered monocyclic non-aromatic heterocyclic group.
  • a C 1-6 alkyl-carbonyl group optionally substituted with a group; The compound according to [1] or a salt thereof. [3] Formula (I):
  • Ring A represents a C 5-10 hydrocarbon ring or a 5- to 10-membered heterocyclic ring
  • R 1 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted 5- to 6-membered monocyclic aromatic heterocyclic group
  • R 2 represents a hydrogen atom or an oxo group
  • R 1 and R 2 combine to form a C 4-8 hydrocarbon ring
  • R 3 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted amino group
  • Y is -NR 4 R 5 or
  • R 4 and R 5 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group;
  • X represents O or NR 6 ;
  • Ring B represents a 4- to 8-membered nitrogen-containing non-aromatic heterocycle;
  • n represents 0 or 1;
  • R 6 represents a C 1-6 alkyl group, a C 3-10 cycloalkyl group or an optionally substituted C 1-6 alkyl-carbonyl group.
  • a therapeutic agent for prion disease comprising a compound represented by the formula (I) or a salt thereof as an active ingredient
  • the compound of the present invention has an effect of suppressing abnormal prion production, and is useful as a therapeutic drug for prion disease.
  • FIG. 1 shows the direct binding of compounds to recombinant PrP using SPR analysis.
  • FIG. 2 shows the effect of NPR-130 and NPR-162 on cytotoxicity in prion uninfected cells (N2a-58).
  • FIG. 3 shows the dose response of anti-prion compounds (NPR-130 and NPR-162) to aberrant prion protein (PrP Sc ) in prion-infected cells (N2a-FK).
  • FIG. 4 shows images obtained by observing the effect of anti-prion compounds (NPR-130 and NPR-162) on prion-infected cells (N2a-FK) under a microscope.
  • FIG. 5 shows the evaluation of NPR-130 and -162 using the prion bioassay system.
  • FIG. 6 shows PrD Sc expression in the brain and spleen at 100 dpi and the terminal stage of infection of prion-infected mice to which NPR-130 or -162 was administered.
  • FIG. 7 shows the pathological changes in the brain and spleen at 100 ° d.p.i. of prion-infected mice to which NPR-130 or -162 was administered.
  • FIG. 8 shows the effect of NPRS compounds (26 types) on PrP Sc in cells continuously infected with prions (N2a-FK).
  • FIG. 9 shows anti-prion compounds (NPRS-3, -6, -7, -9, -11, -17, -19, -20) against abnormal prion protein (PrP Sc ) in prion-infected cells (N2a-FK). , -21, -23, -24, -25).
  • FIG. 10 shows a binding affinity screening for PrP of a compound NPRS group using SPR analysis.
  • FIG. 11 shows the direct binding of compounds to recombinant PrP using SPR analysis.
  • FIG. 12 shows the direct binding of compounds to recombinant PrP using SPR analysis.
  • C 1-6 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • C 3-10 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [2.2.1] heptyl, bicyclo [ 2.2.2] octyl, bicyclo [3.2.1] octyl and adamantyl.
  • C 1-6 alkyl-carbonyl group includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Dimethylpropanoyl, hexanoyl and heptanoyl are mentioned.
  • examples of the “5- to 6-membered monocyclic aromatic heterocyclic group” include, as ring-constituting atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon atoms.
  • a 5- or 6-membered monocyclic aromatic heterocyclic group containing Preferred examples of the “5- to 6-membered monocyclic aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, Examples include 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.
  • examples of the “5- to 6-membered monocyclic non-aromatic heterocyclic group” include, as ring-constituting atoms, 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen other than carbon atoms. 5- to 6-membered monocyclic non-aromatic heterocyclic groups containing atoms.
  • Preferred examples of the "5- to 6-membered monocyclic non-aromatic heterocyclic group" include tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrolinyl Isothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl
  • examples of the “C 5-10 hydrocarbon ring” include a C 5-10 cycloalkane ring, a C 5-10 cycloalkene ring, and a C 6-10 arene ring.
  • Preferable examples of the “C 5-10 cycloalkane ring” include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, and a cyclodecane ring.
  • C 5-10 cycloalkene ring examples include a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a cyclooctene ring, a cyclononene ring, and a cyclodecene ring.
  • C 6-10 arene ring examples include a benzene ring and a naphthalene ring.
  • examples of the “C 4-8 hydrocarbon ring” include a C 4-8 cycloalkane ring, a C 4-8 cycloalkene ring, and a C 6 arene ring.
  • Preferable examples of the “C 4-8 cycloalkane ring” include a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, and a cyclooctane ring.
  • C 4-8 cycloalkene ring examples include a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, and a cyclooctene ring.
  • C 6 arene ring examples include a benzene ring.
  • the “5- to 10-membered heterocycle” includes, for example, 5- to 10-membered heterocycles each containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon.
  • Examples include 10-membered aromatic heterocycles and 5- to 10-membered non-aromatic heterocycles.
  • Preferred examples of the "5- to 10-membered aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,2 5- to 6-membered monocyclic aromatic heterocycles such as 4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole and triazine ; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine,
  • Preferred examples of the "5- to 10-membered non-aromatic heterocycle” include tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydroisothiazole, and tetrahydroisothiazole.
  • the “4- to 8-membered nitrogen-containing non-aromatic heterocycle” includes, for example, two nitrogen atoms or one nitrogen atom and one oxygen atom in addition to a carbon atom as a constituent atom. Examples thereof include a 4- to 8-membered nitrogen-containing non-aromatic heterocycle.
  • Preferable examples of the “4- to 8-membered nitrogen-containing aromatic heterocycle” include diazetidine (eg, 1,3-diazetidine), oxazetidine (eg, 1,3-oxazetidine), tetrahydropyrazole, tetrahydroimidazole, oxazolidine, Isoxazolidine, piperazine, morpholine, oxazepan (eg, 1,4-oxazepan), diazepan (eg, 1,4-diazepan), diazacyclooctane (eg, 1,5-diazacyclooctane), oxazocan (eg, 1,4-oxazocan).
  • diazetidine eg, 1,3-diazetidine
  • oxazetidine eg, 1,3-oxazetidine
  • tetrahydropyrazole tetrahydroimidazole
  • the “optionally substituted amino group” includes, for example, an optionally substituted C 1-6 alkyl group, C 3-10 cycloalkyl group and C 1-6 alkyl-carbonyl group And an amino group which may be substituted with one or two substituents selected from Preferable examples of the optionally substituted amino group include an amino group, an optionally substituted mono- or di-C 1-6 alkylamino group, an optionally substituted mono- or di-C 3 -10 cycloalkylamino group, and optionally substituted mono- or di-C 1-6 alkyl-carbonylamino group.
  • the “mono- or di-C 1-6 alkylamino group” includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino , N-ethyl-N-methylamino.
  • examples of the “mono- or di-C 3-10 cycloalkylamino group” include cyclopropylamino and cyclohexylamino.
  • examples of the “mono- or di-C 1-6 alkyl-carbonylamino group” include acetylamino, propanoylamino, and butanoylamino.
  • examples of the substituent “optionally substituted” include, for example, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a C 1-6 alkyl group, a C 3-10 cycloalkyl A C 1-6 alkyl-carbonyl group, a 5- to 6-membered monocyclic aromatic heterocyclic group, a 5- to 6-membered monocyclic non-aromatic heterocyclic group, and an optionally substituted amino group.
  • the number of substituents is, for example, 1 to 5, preferably 1 to 3. When there are a plurality of substituents, each substituent may be the same or different.
  • Ring A represents a C 5-10 hydrocarbon ring or a 5- to 10-membered heterocyclic ring.
  • C 5-10 hydrocarbon ring represented by ring A
  • a C 6-10 arene ring eg, a benzene ring
  • a 5- to 10-membered heterocyclic ring eg, a benzopyran ring, a dihydroquinoline ring
  • a 5- to 10-membered non-aromatic heterocyclic ring eg, a benzopyran ring, a dihydroquinoline ring
  • Ring A is preferably a C 6-10 arene ring (eg, a benzene ring) or a 5- to 10-membered non-aromatic heterocycle (eg, a benzopyran ring, a dihydroquinoline ring), and more preferably a C 6-10 An arene ring (eg, a benzene ring).
  • R 1 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted 5- to 6-membered monocyclic aromatic heterocyclic group
  • R 2 represents a hydrogen atom or an oxo group
  • 1 and R 2 combine to form a C 4-8 hydrocarbon ring.
  • an optionally substituted C 1-6 alkyl group eg, methyl, Tert-butyl, 2-methylbutan-2-yl
  • C 3-10 cycloalkyl groups eg, cyclohexyl
  • R 1 is Preferably, (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) an optionally substituted C 1-6 alkyl group (eg, methyl, tert-butyl) , 2-methylbutan-2-yl) and (b) a 5- to 6-membered monocyclic aromatic optionally substituted by 1 to 3 substituents selected from C 3-10 cycloalkyl groups (eg, cyclohexyl) A group heterocyclic group (eg, tetrazolyl); More preferably, it is selected from (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • a hydrogen atom (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • a C 3-10 cycloalkyl group A 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl) which may be substituted with 1 to 3 substituents selected from, for example, cyclohexyl); More preferably, it may be substituted with 1 to 3 substituents selected from (1) hydrogen atom or (2) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • substituents selected from a C 1-6 alkyl group eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • a C 3-10 cycloalkyl group eg, cyclohexyl
  • An optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group eg, tetrazolyl
  • C 4-8 hydrocarbon ring formed by combining R 1 and R 2 , a C 4-8 cycloalkene ring (eg, a cyclohexene ring) is preferable.
  • R 3 represents a hydrogen atom, a C 1-6 alkyl group or an optionally substituted amino group.
  • an optionally substituted C 1-6 alkyl group eg, ethyl
  • an optionally substituted C 1- A 6- alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl) is preferred.
  • R 3 is Preferably, (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, ethyl) or (3) (a) an optionally substituted C 1-6 alkyl group (eg, ethyl) and (B) an amino group optionally substituted with one or two substituents selected from an optionally substituted C 1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl); More preferably, (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, ethyl) or (3) (a) a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) A) a C 1-6 alkyl group (eg, ethyl) which may be substituted with 1 to 3 substituents selected from the group consisting of: and (b) a 5- to 6-membered monocyclic non-aromatic heterocyclic
  • Y is -NR 4 R 5 or
  • R 4 and R 5 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • X represents O or NR 6
  • ring B represents 4 to 8 indicates membered nitrogen Motohi aromatic heterocycle
  • n is 0 or 1 indicates
  • R 6 is C 1-6 alkyl, C 3-10 cycloalkyl group or an optionally substituted C 1-6 alkyl -Represents a carbonyl group.
  • Examples of the “substituent” of the “optionally substituted C 1-6 alkyl group” for R 4 or R 5 include a mono- or di-C 1-6 alkylamino group (eg, diethylamino) and 5 to A 6-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl) is preferred.
  • R 4 and R 5 are preferably each independently (1) a hydrogen atom or (2) (a) a mono- or di-C 1-6 alkylamino group (eg, diethylamino) and (b) 5 to A C 1-6 alkyl group (eg, ethyl, n-propyl) which may be substituted with 1 to 3 substituents selected from a 6-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl). .
  • the “4- to 8-membered non-aromatic heterocycle” represented by ring B is preferably a morpholine ring when X represents O, and a piperazine ring when X represents NR 6 .
  • R 6 As the “substituent” of the “optionally substituted C 1-6 alkyl-carbonyl group” for R 6 , a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) is preferable.
  • R 6 is Preferably, (1) a C 1-6 alkyl group (eg, methyl, isopropyl), (2) a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl) or (3) a 5- to 6-membered monocyclic non-aromatic.
  • a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl) which may be substituted with 1 to 3 substituents selected from a group heterocyclic group (eg, pyrrolidinyl), More preferably, it is (1) a C 1-6 alkyl group (eg, isopropyl) or (2) a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl), More preferably, it is a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl).
  • Ring A is a C 6-10 arene ring (eg, benzene ring) or a 5- to 10-membered non-aromatic heterocycle (eg, benzopyran ring, dihydroquinoline ring);
  • R 1 is (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) an optionally substituted C 1-6 alkyl group (eg, methyl, tert- Butyl, 2-methylbutan-2-yl) and (b) a 5- to 6-membered monocyclic ring which may be substituted by 1 to 3 substituents selected from C 3-10 cycloalkyl groups (eg, cyclohexyl) An aromatic heterocyclic group (eg, tetrazolyl);
  • R 2 is a hydrogen atom or an oxo group;
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring
  • R 4 and R 5 each independently represent (1) a hydrogen atom or (2) (a) a mono- or di-C 1-6 alkylamino group (eg, diethylamino) and (b) a 5- to 6-membered A C 1-6 alkyl group (eg, ethyl, n-propyl) which may be substituted with 1 to 3 substituents selected from a cyclic non-aromatic heterocyclic group (eg, morpholinyl); Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle (eg, a morpholine ring, a piperazine ring); X is O or NR 6 ; n is 0 or 1; R 6 represents (1) a C 1-6 alkyl group (eg, methyl, isopropyl), (2) a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl) or (3) a 5- to 6-membered monocycl
  • Ring A is a C 6-10 arene ring (eg, benzene ring) or a 5- to 10-membered non-aromatic heterocycle (eg, benzopyran ring, dihydroquinoline ring);
  • R 1 is selected from (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • a C 3-10 cycloalkyl group A 5- to 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl) which may be substituted with 1 to 3 substituents selected from, for example, cyclohexyl);
  • R 2 is a hydrogen atom or an oxo group;
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring (eg, a cyclohexene ring);
  • R 3 represents (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, ethyl) or (3) (a) a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl)
  • A) a C 1-6 alkyl group eg
  • R 4 and R 5 each independently represent (1) a hydrogen atom or (2) (a) a mono- or di-C 1-6 alkylamino group (eg, diethylamino) and (b) a 5- to 6-membered A C 1-6 alkyl group (eg, ethyl, n-propyl) which may be substituted with 1 to 3 substituents selected from a cyclic non-aromatic heterocyclic group (eg, morpholinyl); Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle (eg, a morpholine ring, a piperazine ring); X is O or NR 6 ; n is 0 or 1; R 6 represents (1) a C 1-6 alkyl group (eg, methyl, isopropyl), (2) a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl) or (3) a 5- to 6-membered monocycl
  • Ring A is a C 6-10 arene ring (eg, a benzene ring); R 1 is selected from (1) a hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl) or (3) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • a C 3-10 cycloalkyl group A 5- to 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl) which may be substituted with 1 to 3 substituents selected from, for example, cyclohexyl);
  • R 2 is a hydrogen atom;
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring (eg, a cyclohexene ring);
  • R 3 is a C 1-6 alkyl-carbonyl group (optionally substituted with 1 to 3 substituents selected from a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl, piperidinyl))
  • R 4 and R 5 each independently represent (1) a hydrogen atom or (2) (a) a mono- or di-C 1-6 alkylamino group (eg, diethylamino) and (b) a 5- to 6-membered A C 1-6 alkyl group (eg, ethyl, n-propyl) which may be substituted with 1 to 3 substituents selected from a cyclic non-aromatic heterocyclic group (eg, morpholinyl); Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle (eg, a piperazine ring); X is NR 6 ; n is 0; R 6 is (1) a C 1-6 alkyl group (eg, isopropyl) or (2) a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl); Compound (I).
  • a mono- or di-C 1-6 alkylamino group eg, dieth
  • Ring A is a C 6-10 arene ring (eg, a benzene ring); R 1 may be substituted with 1 to 3 substituents selected from (1) a hydrogen atom or (2) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • R 1 to 3 substituents selected from a C 1-6 alkyl group eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • R 2 is a hydrogen atom
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring (eg, a cyclohexene ring)
  • R 3 is a C 1-6 alkyl-carbonyl group (optionally substituted with 1 to 3 substituents selected from a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl, piperidinyl))
  • Y is
  • Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle (eg, a piperazine ring);
  • X is NR 6 ;
  • n is 0;
  • R 6 is a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl); Compound (I).
  • Ring A is a C 6-10 arene ring (eg, a benzene ring); R 1 may be substituted with 1 to 3 substituents selected from (1) a hydrogen atom or (2) (a) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl).
  • R 1 to 3 substituents selected from a C 1-6 alkyl group eg, methyl, tert-butyl, 2-methylbutan-2-yl
  • R 2 is a hydrogen atom
  • R 1 and R 2 combine to form a C 4-8 cycloalkene ring (eg, a cyclohexene ring)
  • R 3 is (a) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) (eg, , Ethyl) and (b) a C 1-6 alkyl- which may be substituted with 1 to 3 substituents selected from a 5- to 6-membered monocyclic
  • R 4 and R 5 are each independently 1 to 3 substituents selected from (1) a hydrogen atom or (2) a 5- to 6-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl).
  • An optionally substituted C 1-6 alkyl group eg, n-propyl
  • Ring B is a 4- to 8-membered nitrogen-containing non-aromatic heterocycle (eg, a piperazine ring)
  • X is NR 6 ; n is 0 or 1; R 6 is a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl); Compound (I).
  • examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. And the like.
  • the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an aluminum salt; and an ammonium salt.
  • salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Salts with dicyclohexylamine and N, N-dibenzylethylenediamine are mentioned.
  • salt with an inorganic acid examples include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, and phosphoric acid.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , P-toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine and ornithine.
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid.
  • salts when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; or acetic acid, phthalic acid And salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
  • acetic acid phthalic acid
  • organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • inorganic salts such as alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt, etc.) An ammonium salt and the like.
  • the compound (I) may be labeled with an isotope (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) or the like. Further, compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate. Further, a deuterium conversion product obtained by converting 1 H to 2 H (D) is also included in the compound (I).
  • an isotope eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I
  • compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate.
  • a deuterium conversion product obtained by converting 1 H to 2 H (D) is also included in the compound (I).
  • an isomer such as an enantiomer or a diastereomer may exist. All such isomers and mixtures thereof are included within the scope of the present invention. Further, isomers due to conformation or tautomerism may be generated, and such isomers or a mixture thereof are also included in the compound (I) of the present invention.
  • the compound (I) in which R 1 is an optionally substituted tetrazolyl and n is 0 can be produced according to the following scheme.
  • Reaction conditions can be determined as appropriate, for example, with reference to the examples.
  • the compound (I) in which R 1 and R 2 combine to form a C 4-8 hydrocarbon ring and n is 0 can be produced according to the following scheme.
  • compound (I) can be produced according to the following scheme.
  • n 0 or 1
  • Z represents a leaving group such as a halogen atom (eg, a chlorine atom) or a methanesulfonate group, and other symbols are as defined above.)
  • Reaction conditions can be determined as appropriate, for example, with reference to the examples.
  • a protecting group is introduced into the reactive site in advance by a means known per se, if necessary.
  • the protecting group may be removed by a method known per se to produce a compound included in the scope of the present invention.
  • the starting compound or intermediate has an amino group, a carboxyl group, or a hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry and the like.
  • the target compound can be obtained by removing the protecting group as necessary.
  • ⁇ Compound (I) obtained by the above production method can be isolated and purified by a known means, for example, solvent extraction, pH conversion of a solution, phase transfer, crystallization, recrystallization, chromatography.
  • the compound (I) of the present invention has an effect of suppressing abnormal prion production, and is useful as a therapeutic agent for prion disease and the like.
  • Primary disease is classified into sporadic, familial (hereditary), and acquired (infectious), and the compound of the present invention is preferably administered to familial prion disease and acquired prion disease. It is preferably administered for prion diseases.
  • Prion diseases include sheep scrapie, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, chronic wasting disease, transmissible mink encephalopathy, feline spongiform encephalopathy, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia.
  • the compound of the present invention is suitable for Creutzfeldt-Jakob disease and the like.
  • treatment includes amelioration of symptoms, prevention of severe symptoms, maintenance of remission, and prevention of recurrence.
  • the compound (I) of the present invention has an inhibitory effect on the production of abnormal prion, and the compound (I) of the present invention exhibits drug efficacy, pharmacokinetics (eg, absorption, distribution, metabolism, excretion), solubility ( Eg, water-soluble), interaction with other drugs (eg, drug metabolizing enzyme inhibitory action), safety (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity) It is also excellent in stability (eg, chemical stability, stability against enzymes), and thus is useful as a medicine. Therefore, the compound (I) of the present invention is intended to suppress the production of abnormal prions in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans). Can be used.
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans.
  • the compound (I) of the present invention can be administered orally or parenterally to a mammal (preferably a human) as a medicament as it is or in combination with a pharmacologically acceptable carrier.
  • a mammal preferably a human
  • a drug of the present invention will be described in detail.
  • Examples of the dosage form of the medicament of the present invention include tablets (eg, sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally disintegrating tablets), pills, granules, powders, capsules (eg, soft capsules) Or microcapsules), syrups, emulsions, suspensions, and films (eg, orally disintegrating films, oral mucosa-sticking films) and the like.
  • Examples of the dosage form of the medicament of the present invention include injections, drops, transdermals (eg, iontophoresis transdermals), suppositories, ointments, nasal preparations, pulmonary preparations, eye drops. And the like.
  • the medicament of the present invention may be a controlled release preparation such as an immediate release preparation or a sustained release preparation (eg, a sustained release microcapsule).
  • the medicament of the present invention can be produced by a known production method generally used in the field of formulation technology (eg, a method described in the Japanese Pharmacopoeia). Further, the medicine of the present invention may contain, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, coloring agents which are usually used in the field of pharmaceutical preparations. Additives such as preservatives, fragrances, flavoring agents, stabilizers, and thickeners can be appropriately contained in appropriate amounts. The above-mentioned pharmacologically acceptable carriers include these additives.
  • tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc.
  • pills and granules can be manufactured using excipients, binders, disintegrants.
  • Powders and capsules can be manufactured using excipients and the like, syrups can be manufactured using sweeteners and the like, emulsions and suspensions can be manufactured using suspending agents, surfactants, emulsifiers and the like.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate.
  • binders include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
  • disintegrants include starch, calcium carbonate.
  • lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc.
  • sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80.
  • the tablet may be added to the compound (I) of the present invention by, for example, an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, , Starch, calcium carbonate), a binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000) and compression-molded. Then, if necessary, it can be produced by coating in a manner known per se for the purpose of taste masking, enteric coating or persistence.
  • an excipient eg, lactose, sucrose, starch
  • a disintegrant eg, , Starch, calcium carbonate
  • a binder eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose
  • a lubricant eg, talc,
  • Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, bengalara, titanium dioxide) can be used.
  • the injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, infusions, and the like.
  • Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention in a sterile aqueous or oily liquid.
  • the aqueous liquid include physiological saline, isotonic liquid containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride) and the like.
  • the aqueous liquid contains a suitable solubilizing agent, for example, an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant (eg, polysorbate 80, HCO-50). May be.
  • the oily liquid examples include sesame oil and soybean oil.
  • the oily liquid may contain a suitable solubilizer.
  • the solubilizer include benzyl benzoate and benzyl alcohol.
  • the injection includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, procaine hydrochloride), a stabilizer (eg, human serum albumin, polyethylene glycol). And a preservative (eg, benzyl alcohol, phenol) and the like.
  • the prepared injection solution can be usually filled into an ampoule.
  • the content of the compound (I) of the present invention in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 2 to about 100% by weight, based on the whole preparation. It is about 85% by weight, more preferably about 5 to about 70% by weight.
  • the content of the additive in the medicament of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. is there.
  • the compound (I) of the present invention is stable, has low toxicity and can be used safely.
  • the daily dose of the compound (I) of the present invention varies depending on the condition and weight of the patient, the type of the compound, the administration route, and the like.
  • the daily dose is about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg of the compound (I) of the present invention, and these may be administered once or twice to twice. It can be administered in three divided doses.
  • the compound (I) of the present invention When the compound (I) of the present invention is administered parenterally, it is usually administered in the form of a liquid (eg, injection).
  • the single dose of the compound (I) of the present invention varies depending on an administration subject, a target organ, a symptom, an administration method and the like, and is, for example, usually about 0.01 to about 100 mg, preferably about 0.01 mg / kg body weight. It is preferred to administer from about 50 mg, more preferably from about 0.01 to about 20 mg, of Compound (I) of the invention by intravenous injection.
  • N- (4- (Hydroxymethyl) phenyl) -2- (pyrrolidin-1-yl) propanamide (489 mg) was dissolved in dichloromethane (10 mL), and Dess-Martin periodinane (1.0 g) was added. And stirred for 12 hours.
  • the reaction solution was diluted with a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, and dried over magnesium sulfate.
  • N- (4-Acetylphenyl) 2-bromoacetamide 750 mg was dissolved in tetrahydrofuran (20 mL), and pyrrolidine (288 ⁇ L) and potassium carbonate (809 mg) were added, followed by stirring at room temperature for 20 hours.
  • 6-Amino-3,4-dihydronaphthalen-1 (2H) -one (1.2 g) was dissolved in dichloromethane (20 mL) and cooled to 0 ° C., followed by 2-bromoacetamide (1.1 mL) and triethylamine (2 mL). .2 mL) and stirred at room temperature for 12 hours.
  • the reaction solution was diluted with water (50 mL) and extracted with dichloromethane. The extract was washed with brine and dried over magnesium sulfate.
  • 6-Methyl-2-oxo-2H-chromen-3-carbaldehyde (46 mg) was dissolved in methanol (1.5 mL), and 1-cyclohexylpiperazine (42 mg), tert-butyl isocyanide (29 ⁇ L), and trimethylsilyl azide (33 ⁇ L) were dissolved.
  • Example 1 was prepared using N- (4-formylphenyl) -2- (pyrrolidin-1-yl) acetamide (46 mg), 1-cyclohexylpiperazine (34 mg), cyclohexyl isocyanide (25 ⁇ L), and trimethylsilyl azide (40 ⁇ L). To give the title compound (70 mg, yield 65%).
  • Example 1 was prepared using N- (4-formylphenyl) -2- (piperidin-1-yl) acetamide (49 mg), 1-cyclohexylpiperazine (34 mg), cyclohexyl isocyanide (25 ⁇ L), and trimethylsilyl azide (40 ⁇ L). To give the title compound (32 mg, yield 29%).
  • Example 1 was prepared using N- (4-formylphenyl) -2- (piperidin-1-yl) acetamide (49 mg), diethylaminoethylamine (23 mg), tert-butyl isocyanide (27 ⁇ L), and trimethylsilyl azide (40 ⁇ L). To give the title compound (20 mg, yield: 21%).
  • Example 1 was prepared using N- (4-formylphenyl) -2- (pyrrolidin-1-yl) acetamide (46 mg), morpholine (17 mg), tert-butyl isocyanide (25 ⁇ L), and trimethylsilyl azide (40 ⁇ L). The reaction was carried out according to the method described to obtain the title compound (48 mg, yield 56%).
  • 1 H NMR 500 MHz, CDCl 3 ) ⁇ 1.70 (s, 9H), 1.87-2.00 (m, 4H), 2.39-2.42 (m, 2H), 2.63-2.66.
  • N- (5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) acetamide 800 mg was dissolved in tetrahydrofuran (8 mL), and 1-cyclohexylpiperazine (1.5 g) was added. Cooled to ° C. After adding titanium tetrachloride (219 ⁇ L) and stirring for 2 hours, the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with aqueous ammonia and ethyl acetate (1: 1; 8 mL), and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate.
  • N- (4- (2-hydroxyethyl) phenyl) -2- (pyrrolidin-1-yl) acetamide (170 mg) is dissolved in dichloromethane (5 mL), cooled to 0 ° C., and then methanesulfonic acid chloride (94 mg). , Triethylamine (141 ⁇ L) was added, and the mixture was stirred at room temperature for 12 hours.
  • the reaction solution was diluted with water (20 mL) and extracted with dichloromethane. The extract was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was used for the next reaction without purification.
  • NPR-130 and -162 Reagents and antibodies
  • NPRS-1 (Example 1), -2 (Example 2), -3 (Example 3), -4 (Example 4), -5 ( (Example 5), -6 (Example 6), -7 (Example 7), -8 (Example 8), -9 (Example 9), -10 (Example 10), -11 (Example) 11), -12 (Example 12), -13 (Example 13), -14 (Example 21), -15 (Example 14), -16 (Example 15), -17 (Example 16) , -18 (Example 17), -19 (Example 18), -20 (Example 19), -21 (Example 20), -22 (Example 22), -23 (Example 15), -17 (Example 16) , -18 (Example 17), -19 (Example 18), -20 (Example 19), -21 (Example 20), -22 (Exa
  • NPR-56 purchased from ASINEX (Ishibashi et al. (2016). EBioMedicine, Vol. 9, p238-249) and GN8 (2-pyrrolidin-1-yl-N- [4- [ 4- (2-pyrrolidin-1-yl-acetylamino) -benzyl] -phenyl] -acetamide, molecular weight 420) was used as a positive control for anti-prion drugs (Kuwata et al. (2007). Proc Natl Acad Sci USA 104, 11921-11926). These compounds were completely dissolved in 100% dimethyl sulfoxide (DMSO) and adjusted to 10 mM as a stock solution.
  • DMSO dimethyl sulfoxide
  • PrP-specific antibodies (Santa Cruz Biotechnology, M20; SPI-Bio, SAF32, SAF61, SAF83), Iba-1 antibody (WAKO, 019-19741 (IHC)) and GFAP antibody (DAKO, Z033429) are commercially available.
  • IHC Iba-1 antibody
  • GFAP antibody DAKO, Z033429
  • Horseradish peroxidase-conjugated anti-goat Jackson ImmunoResearch
  • anti-mouse GE Healthcare Life Sciences
  • SPR Surface Plasmon Resonance
  • N2a-58 cells established from N2a cells overexpressing PrP C, to integrate mouse PRNP gene in neuro 2a cells.
  • N2a-FK cells established from N2a-58 cells were infected with Fukuoka-1 (mouse-adapted Gerstmann-Straussler-Scheinker strain) strain. The cells were incubated at 37 ° C.
  • PrP Sc For detection of PrP Sc , cell lysates were digested with 20 ⁇ g / mL proteinase K (PK; Nakarai Tesuque) at 37 ° C for 30 minutes. After the addition of SDS-sample buffer, the sample is applied to a 15% SDS-PAGE gel and transferred to a PVDF membrane. Subsequently, in order to detect PrP Sc , M20 was supplied as a primary antibody (1: 1000), and anti-goat IgG-HRP was supplied as a secondary antibody (1: 5000). Bands were visualized using the Clarity Western ECL Substrate Western Blotting Detection Kit (Bio-Rad). Band intensity was quantified using Image J software (National Institutes of Health).
  • Immunofluorescence staining of prion-infected cells was performed as follows. The cells were cultured on a chamber slide (BD Falcon) and treated with DMSO, each of the drugs NPR-130, -162, and 23 kinds of NPRS drugs at a concentration of up to 10 ⁇ M for 48 hours as a control. The cells were then washed twice with PBS and then fixed with 4% formaldehyde for 30 minutes at room temperature. After permeabilization with 0.5% Triton X-100, slides were treated with 5% skim milk and reacted for 1 hour at room temperature. Slides were reacted with 3M guanidine thiocyanate for 5 minutes at room temperature for detection of PrP Sc .
  • the cells were then used at 4 ° C. overnight with SAF61 (1: 200) as the primary antibody for detection of PrP Sc , followed by Alexa Fluor® 488 conjugated anti-mouse IgG (Invitrogen) (1: 500).
  • SAF61 1: 200
  • Alexa Fluor® 488 conjugated anti-mouse IgG 1: 500
  • Nuclei were stained with Vectashield mounting medium containing DAPI (Vector Laboratories).
  • the aggresome was detected using a ProteoStat (registered trademark) aggresome detection kit (Enzo Life Science), and then detected at a fluorescence wavelength of 600 nm with an excitation wavelength of 500 nm. All images were visualized using a confocal laser scanning microscope LSM700 (Carl Zeiss).
  • mice Five. In vivo injection experiment 4-week-old male ddY mice were purchased from SLC (Hamamatsu, Japan). The mouse brain was inoculated with 20 ⁇ L of a 10 -1 dilution of a brain homogenate prepared from a terminal mouse infected with the FK-1 strain. Various compounds (NPR-130 and -162) were dissolved in physiological saline containing 0.25% DMSO, and mice were intraperitoneally administered with 2.0 mg of the compound / kg / day every other day. Mice inoculated intraperitoneally with saline containing 0.25% DMSO were used as controls. Mice were monitored until the end of the disease or every other day until sacrifice.
  • Clinical onset was defined as the presence of two or more symptoms such as oily or yellowish hair, hunchback, weight loss, yellow pubic hair, ataxic gait and non-parallel hind limbs.
  • Mice were sacrificed at clinical onset (100 dpi) or terminal and brain and spleen were removed. Right hemisphere and spleen sections of the brain were immediately frozen and homogenized in 20% (weight / volume) in PBS.
  • All proteins were mixed with an equal volume of 2 ⁇ lysis buffer (300 mM NaCl, 1% Triton-X-100, 1% sodium deoxycholate and 100 mM Tris-HCl; pH 7.5). Extracted. The remaining brain and spleen were fixed with 10% neutral buffered formalin for pathological analysis.
  • TBST Tris-buffered saline
  • the primary antibody was an anti-IBA-1 antibody (WAKO, 019-19741) and an anti-GFAP antibody (DAKO, Z033429) overnight at room temperature, followed by EnVision® polymer horseradish peroxidase (HRP) -conjugated anti-rabbit IgG. (DAKO, K4002) at room temperature for 60 minutes. Visualization was performed using 3,3-diaminobenzidine (DAB; Dojindo Laboratories, D006) as a chromogenic substrate for immunostaining.
  • DAB 3,3-diaminobenzidine
  • the autoclave formic acid method treatment for PrP Sc staining was performed according to the method described in Ishibashi, D. et al., (2012) J Virol 86, 4947-4955, and SAF32 (1: 200) was used as the primary antibody. And analyzed according to the method described above.
  • FIG. 1 shows the direct binding of compounds to recombinant PrP using SPR analysis. Specifically, FIG. 1 shows sensorgrams of NPR-130 and NPR-162 for binding to mouse or human PrP23-231. Compound concentrations are 0, 0.2, 0.4, 0.8, 1.6, 3.1, 6.3, 12.5, 25 and 50 ⁇ M from the bottom.
  • Fig. 2 shows the effect of NPR-130 and NPR-162 on cytotoxicity in prion uninfected cells (N2a-58).
  • N2a-58 cells were treated with the solvents DMSO, NPR-130, and -162 at 10 ⁇ M, and the number of cells 48 hours later was examined.
  • the upper part of the figure shows the cell viability.
  • the lower part shows a photograph under a phase contrast microscope. Bars are 100 ⁇ m.
  • FIG. 3 shows the dose response of anti-prion compounds (NPR-130 and NPR-162) to aberrant prion protein (PrP Sc ) in prion-infected cells (N2a-FK).
  • NPR-130 and NPR-162 prion-infected cells
  • PrP Sc prion-infected cells
  • FIG. 2 shows that N2a-FK cells were treated with NPR-130 and -162 compounds at different concentrations (0, 0.1, 0.5, 1, 5 and 10 ⁇ M) for 48 hours, and PrP was detected by Western blotting.
  • 4 shows the expression of Sc .
  • FIG. 4 shows images obtained by observing the effects of anti-prion compounds (NPR-130 and NPR-162) on prion-infected cells (N2a-FK) under a microscope.
  • the upper panel shows the localization of PrP Sc in N2a-FK cells treated with 10 ⁇ M NPR-130 or -162 for 48 hours using immunofluorescence staining. PrP Sc and nuclei were detected using SAF61 antibody (green) and DAPI (blue), respectively.
  • the lower panel observed the expression of aggresome after compound treatment. Intracellular aggresomes are shown in red. Each stained cell was visualized by a confocal laser scanning microscope. Scale bar represents 10 micrometers.
  • FIG. 5 shows the evaluation of NPR-130 and -162 using the prion bioassay system. Specifically, FIG. 5 shows that NPR-130 or -162 from day 2 (dpi) after brain inoculation of 10% ⁇ Fukuoka-1 (FK-1) prion strain-infected brain emulsion into 4-week-old ddy mice. 2 shows the survival curves of mice infected with prions, which received any of the compounds.
  • FIG. 6 shows PrP Sc expression in brain and spleen at 100 dpi and in the terminal stage of infection of prion-infected mice administered with NPR-130 and -162.
  • the upper row shows the results of measuring the PrP Sc levels in the brain and spleen of each prion-infected mouse at 110 dpi.
  • PrP Sc was analyzed by Western blot using M20 antibody as the primary antibody. The accumulation amount of PrP Sc was measured and graphed by measuring the band intensity.
  • the lower part shows the results of measuring the PrP Sc levels in the brain and spleen as described above, after sacrificing each prion-infected mouse at the end of infection (after onset). Two-way analysis of variance was performed by Tukey-Kramer test for multiple comparisons. * P ⁇ 0.05 and ** P ⁇ 0.01 are indicated.
  • FIG. 7 shows pathological changes in the brain and spleen at 100 dpi of prion-infected mice administered with NPR-130 and -162. From the top, the degree of vacuolar degeneration, microglial activation, astrocyte activation, and accumulation of PrP Sc were observed under a microscope. The lower panel shows the accumulation of PrP Sc in the spleen. The degree of vacuole formation in the thalamus site of the mouse brain was compared by HE staining, and the vacuole occupied area in each section was calculated. Microglial activation in the thalamus region of the mouse brain was analyzed by analyzing Iba-1 expression by immunohistochemical staining and quantifying IBA-1 positive cells.
  • Astrocyte activation in the thalamus region of the mouse brain was analyzed by analyzing GFAP expression by immunohistochemical staining and quantifying GFAP-positive cells. Accumulation of PrP Sc in the thalamus site and spleen of mouse brain was analyzed for SAF32 antibody positive reactions. In histological analysis, all scale bars represent 50 micrometers. The graph on the right is a graph of each staining positive rate. In the bars of the graph, white indicates the solvent administration group (vehicle), gray indicates the NPR-130 administration group, and black indicates the NPR-162 administration group. Statistical significance was performed by two-way analysis of variance with Tukey-Kramer test for multiple comparisons and used in histological analysis in brain area thalamus (Thalamus). * P ⁇ 0.05 and ** P ⁇ 0.01.
  • FIG. 8 shows the effect of NPRS compounds (26 types) on PrP Sc in cells (N2a-FK) infected with persistent prions. Specifically, FIG. 8 shows screening of anti-prion drug candidates in N2a-FK cells. All compounds were added to cells at 10 ⁇ M and treated for 48 hours. PrP Sc was detected by Western blotting. DMSO-treated cells served as negative controls. Molecular weights (kDa) are shown on the left side of each panel. Lane numbers in each panel indicate individual candidate compounds of the NPRS series. Statistical significance performs two-way analysis of variance by Tukey Kramer's test for multiple comparisons, red bars indicate an IC 50 measured compound. * P ⁇ 0.05 and ** P ⁇ 0.01.
  • FIG. 9 shows anti-prion compounds (NPRS-3, -6, -7, -9, -11, -17, -19, -20) against aberrant prion protein (PrP Sc ) in prion-infected cells (N2a-FK). , -21, -23, -24, -25).
  • N2a-FK cells were NPRS-3, -6, -7, -9, -11, -17, -19, -20, -21, -23, -24, -25
  • FIG. 10 shows the binding affinity screening for PrP of the compound NPRS group using SPR analysis as a bar graph quantifying the binding ability of each compound to human and mouse PrP23-231. Specifically, FIG. 10 shows the relative response (RU) obtained from various NPRS compounds when binding to human (top) and mouse (bottom) PrP using the Biacore® T200 instrument. The result as a primary screening of a prion compound is shown. Compound concentration is 10 ⁇ M.
  • FIG. 11 shows the direct binding of a compound to recombinant PrP using SPR analysis. Specifically, FIG. 11 shows a sensorgram of each NPRS group for binding to human PrP23-231. Compound concentrations are 0, 0.2, 0.4, 0.8, 1.6, 3.1, 6.3, 12.5, 25 and 50 ⁇ M from the bottom.
  • FIG. 12 shows the direct binding of compounds to recombinant PrP using SPR analysis. Specifically, FIG. 12 shows a sensorgram of each NPRS group for binding to mouse PrP23-231. Compound concentrations are 0, 0.2, 0.4, 0.8, 1.6, 3.1, 6.3, 12.5, 25 and 50 ⁇ M from the bottom.
  • NPR-130 in cultured cells the toxicity study NPR-130 of -162, in order to evaluate the interaction between -162 and PrP C, cells after compound addition in N2a-58 cells derived from mouse neuroblastoma The survival rate was examined. After adding the compound at 10 ⁇ M, no change was observed in the cell viability 48 hours later, and no change was observed in the cell morphology under a phase-contrast microscope, and there was no expression of cytotoxicity (FIG. 2). .
  • To selectively detect PrP Sc persistent prion infected cells were incubated with anti-PrP monoclonal antibodies and revealed aggregated PrP Sc (green) in the cells after treatment with guanidine thiocyanate.
  • the expression of PrP Sc in N2a-FK cells treated with NPR-130 and -162 for 48 hours was significantly reduced (upper row in FIG. 4).
  • the cells were stained with Proteostat, which detects aggregated proteins containing aggresomes in the cells.
  • Aggresomes are established by aggregation of various unnecessary proteins, and are intracellular inclusions that coexist with the accumulation of phosphorylated tau and ⁇ -synuclein in pathological tissues and cell culture models of conformational diseases. Aggresomes are large complexes of abnormal proteins that are resistant to degradation and are therefore sequestered as inclusion bodies. It is believed that sequestered aggresomes can be degraded by the autophagy system. A recent report suggests that P62, a key factor in aggresome formation, interacts closely with PrP Sc and promotes degradation via the autophagy system in cells persistently infected with prions. It has been reported.
  • NPR-130 and NPR-162 affected aggresome levels in prion persistently infected cells.
  • an aggresome detection probe Proteostat
  • Many agrisomes were detected in the cytoplasm of N2a-FK cells treated only with DMSO (red in the lower part of FIG. 4).
  • Treatment with the anti-prion compounds NPR-130 and NPR-162 at 10 ⁇ M for 48 hours not only suppressed PrP Sc in N2a-FK cells, but also significantly reduced the number of intracellular aggresomes (FIG. 4, lower panel).
  • NPR-130 and NPR-162 compounds are useful as therapeutic candidates for prolonging survival in prion infection.
  • the expression of PrP Sc in the spleen was significantly reduced as compared to the vehicle-administered (vehicle) group (FIG. 6, lower right).
  • the expression level of the NPR-130 administration group was similar to that of the solvent administration (vehicle) group. This means that the NPR-130 and NPR-162 compounds can suppress the accumulation of PrP Sc in a living body during prion infection.
  • microglia is determined by the expression of EF hand protein and IBA-1 protein (also known as allograft inflammatory factor 1: AIF1), a marker of activated microglia (Ito, D. et al., (1998) Brain Res Mol Brain Res 57, 1-9, etc.).
  • IBA-1 positive cells were significantly reduced in the NPR-130 and NPR-162 administration groups compared to the vehicle administration (vehicle) group (the second row from the top in FIG. 7).
  • Astrocyte expression was significantly reduced in the NPR-130 and NPR-162 administration groups compared to the vehicle administration (vehicle) group (third row from the top in FIG. 7).
  • the expression of PrP Sc was significantly reduced in the NPR-130 and NPR-162 administration groups compared to the vehicle administration (vehicle) group (fourth row from the top in FIG. 7).
  • the expression of PrP Sc in the spleen was significantly reduced in the NPR-130 and NPR-162 administration groups as compared to the vehicle administration (vehicle) group (bottom row in FIG. 7).
  • the above results indicate that NPR-130 and NPR-162 compounds suppress the accumulation of PrP Sc in vivo during prion infection and also suppress the development of vacuolar degeneration and gliosis with neuronal death, which is a major pathological change It means you can do it.
  • compounds that reduced the expression level of PrP Sc by 50% or more are NPRS-3, -6, -7, -9, -11, -17, -19, -20, -21, -23,- There were 24 and -25 in total.
  • prion-infected cells (N2a-FK) of PrP NPRS-3 to reduce the expression level of calculation more than 50% PrP Sc an IC 50 for inhibiting effect of NPRS in Sc, -6, -7, -9, -11,
  • IC 50 concentration of the effect on PrP Sc in a total of 12 compounds, -17, -19, -20, -21, -23, -24, -25 after prion infection of N2a-58 cells, The established prion persistently infected cells were treated at a concentration of 0.1, 0.5, 1, 5, or 10 ⁇ M for 48 hours, and the change in the expression level of PrP Sc in the cell lysate was examined by Western blotting.
  • SPR Surface plasmon resonance
  • the binding affinity of each compound was measured, and NPRS-3, -6, -7, -9, -11, -17, -19, -20, -21, -23, -24, and -25 in total number of compounds were confirmed to have an ability to bind to human and murine PrP C.
  • the binding relative reaction (RU) was determined by the previously reported GN8 and NPR-56 (Ishibashi D, et al. EBioMedicine 9 (2016) 238-249), and NPR-130 and -162 which had an effect on prion-infected mice. The binding ability was equal to or higher than that of. In particular, NPRS-19 and NPRS-23 had several times higher binding ability (FIG. 10).
  • the NPRS compound is expected to be a novel compound having utility as an anti-prion drug, without impairing its anti-prion effect and binding ability to PrPC, using NPR-130 and NPR-162 as lead compounds. It suggests.
  • the compound of the present invention has an effect of suppressing abnormal prion production and is useful as a therapeutic agent for prion disease and the like.

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Abstract

L'objectif de l'invention est de fournir un composé qui a pour effet de supprimer la production anormale de prions et qui est utile en tant qu'agent thérapeutique pour des maladies à prions. L'invention concerne un composé représenté par la formule (I) (les symboles dans la formule sont décrits dans la description) ou un sel de celui-ci, et un agent thérapeutique pour les maladies à prions, l'agent thérapeutique contenant le composé en tant que principe actif.
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