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WO2004014843A1 - Composés amino substitués et utilisation de ces composés - Google Patents

Composés amino substitués et utilisation de ces composés Download PDF

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Publication number
WO2004014843A1
WO2004014843A1 PCT/JP2003/010045 JP0310045W WO2004014843A1 WO 2004014843 A1 WO2004014843 A1 WO 2004014843A1 JP 0310045 W JP0310045 W JP 0310045W WO 2004014843 A1 WO2004014843 A1 WO 2004014843A1
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group
substituent
compound
alkyl group
salt
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PCT/JP2003/010045
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English (en)
Japanese (ja)
Inventor
Osamu Uchikawa
Kazuyoshi Aso
Tatsuki Koike
Naoki Tarui
Keisuke Hirai
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Takeda Chemical Industries, Ltd.
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Priority to AU2003254844A priority Critical patent/AU2003254844A1/en
Publication of WO2004014843A1 publication Critical patent/WO2004014843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to diseases caused by excellent amyloid protein production / secretion / substituted amino compounds and amyloid] 3 protein having inhibitory activity, such as neurodegenerative diseases (eg, Alzheimer's disease, senile dementia, Down's syndrome, Parkinson's disease) ), Amyloid angiopathy, and agents that are effective in the prevention and treatment of neuronal damage in cerebrovascular disorders.
  • neurodegenerative diseases eg, Alzheimer's disease, senile dementia, Down's syndrome, Parkinson's disease
  • Amyloid angiopathy eg, Alzheimer's disease, senile dementia, Down's syndrome, Parkinson's disease
  • agents that are effective in the prevention and treatment of neuronal damage in cerebrovascular disorders e.g, Alzheimer's disease, senile dementia, Down's syndrome, Parkinson's disease
  • Panoletzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary tangles, along with neuronal degeneration.
  • the senile plaque most characteristic of Alzheimer's disease is composed mainly of amyloid 3 protein (hereinafter sometimes abbreviated as ⁇ ) (Biochem. Biophys. Res. Comm dish. 122, 1131 (1984) ), Biological components are deposited in the brain.
  • A consisting of 40 or 42 amino acids (hereinafter abbreviated as A ⁇ 1-40 and A] 31-42, respectively) is toxic to nerve cells and has neurofibrillary tangles. It is known to cause a dagger.
  • APP Amyloid Precursor
  • Protein gene may be mutated, and cells transfected with this mutated gene have been shown to increase production and secretion of A] 3 (eg, Nature 360, 672 (1992), Science 259, 514 (1993), Science 264, 1336 (1994), etc.).
  • agents that inhibit the production and secretion of A0 are effective in the prevention and treatment of diseases caused by A3 (eg, Alheimer's disease, Down's syndrome, etc.).
  • neurotrophic factor-like action includes (1) survival and maintenance of nerve cells, and (2) promotion of synapse formation. JP2003 / 010045
  • Neurodegenerative diseases e.g., Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt's Jakob disease, amyotrophic spinal cord lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis
  • Cerebral vascular disorders eg, cerebral infarction, cerebral hemorrhage, etc.
  • EP-A-652009 discloses a peptide derivative having a protease inhibitory action and an A ⁇ production inhibitory action at a cell level.
  • This A] 3 is based on its precursor protein, AP P (Amyloid Precursor
  • ] 3 Increased protein in the brain, such as patients who are likely to suffer from diseases caused by the disease (eg, Alzheimer's disease, Down's syndrome, etc.), and patients whose A] 3 protein increases in the brain due to trauma, etc.
  • an agent that inhibits 0-secretase inhibits the production, secretion, and aggregation of A] 3, and is considered to be useful as a preventive and therapeutic agent for the disease.
  • the following compounds are known as substituted amino compounds.
  • W098 / 50342 contains formulas useful for the treatment of diseases involving excessive cysteine and serine protease activity, including osteoporosis, periodontal disease and arthritis
  • R represents an aryl group, an arylalkyl group, a heterocyclic group, and the like, and R and represents an alkyl group, a cycloalkyl group, an arylalkyl group, a heterocyclic group, and the like. ] Is described.
  • WOO 2/02512 has a formula RnNH-CH (R 1 ) — CH (OH), which has a] 3 secretase inhibitory action and a] 3 amyloid production, secretion and aggregation inhibitory action and is useful as a therapeutic drug for Alzheimer's disease.
  • RnNH-CH (R 1 ) — CH (OH) which has a] 3 secretase inhibitory action and a] 3 amyloid production, secretion and aggregation inhibitory action and is useful as a therapeutic drug for Alzheimer's disease.
  • Rn is an aryl group which may have a substituent
  • R 1 is an alkyl group, an alkenyl group, a cycloalkyl group, etc.
  • R 2 and R 3 are hydrogen, an alkyl group, etc. Represents an alkyl group, an alkyl-cycloalkyl group, an alkylaryl group and the like. ] Is described. Purpose of the invention
  • the present inventors have conducted various studies on compounds having a] 3 secretase inhibitory action and A) 3 production 'secretion' aggregation inhibitory action. As a result, a compound represented by the following formula (1 ') was unexpectedly obtained. Have excellent inhibitory activity on secretase and ⁇ ] 3 production, secretion and aggregation, and found that the formula (I) included in the formula (I ′) is a novel compound described in the text. The present invention has been completed based on the findings.
  • the ring ⁇ represents an aromatic ring which may have a substituent
  • R 1 is an aryl group which may have a substituent, a arylalkyl group which may have a substituent, a heteroaryl group which may have a substituent, or a group which has a substituent. have a 6 cycloalkyl group or an optionally substituted - heteroaryl one 6 alkyl group to good, but it may also have a substituent C i _ 6 alkyl group which may have a substituent C 3 also good C 3 _ 6 cycloalkyl one 6 alkyl group,
  • R 2 is a hydrogen atom, an aryl group which may have a substituent, an aryl 6 alkyl group which may have a substituent, a heteroaryl group which may have a substituent, a substituent 6 a cycloalkyl group, - it may also have a record, heteroaryl one C i-6 alkyl group which may have a substituent group or an optionally substituted C 3
  • R 3 is ⁇ Li one may have a substituent Lou C i _ 6 alkyl group, which may have a Teroari one to which may have a substituent Lou C Bok 6 alkyl group or a substituted group I Rere C 2 _ 1 0 alkyl group (However, the 1- or 2-position C 2 is substituted with Okiso based on - 1 0 ⁇ alkyl group is excluded>,
  • the bond shown by a solid line and a dashed line represents a single bond or a double bond, and X represents an oxygen atom, a sulfur atom or a nitrogen atom, even if it has a substituent. X is not OH when are all single bonds),
  • Y represents an oxygen atom or a sulfur atom.
  • R 1 is not a carboxymethyl group, and N- [1-( ⁇ [3- (1H-imidazole-11-yl) propyl] amino ⁇ acetyl) 12 —Methylbutyl] —2 -— ((3-Methoxybenzoyl) amino) Excluding benzamide. ] Or a salt thereof,
  • R 1 is an aryl group which may have a substituent, an aryl group which may have a substituent, a C 6 alkyl group which may have a substituent, a heteroaryl which may have a substituent. Or a heteroaryl C- 6 alkyl group which may have a substituent or
  • heteroaryl R 1 is the may have a good Ariru one C 6 alkyl group or a location substituent be substituted one C - 6 above (1) is an alkyl group SL placement of the compound ,
  • R 3 has an aryl-C 6 alkyl group which may have a substituent, a heteroaryl C i-e alkyl group which may have a substituent or a substituent.
  • Ring A is a formula
  • R 4 and R 5 independently represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Is a group represented by The compound according to the above (1),
  • Ring A is a benzene ring which may have a substituent
  • R 1 is a benzyl group which may have a substituent
  • R 2 is a hydrogen atom
  • R 3 has a substituent.
  • R ", R 2 and R 3 independently represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, Other symbols are above
  • Aspartic acid protease inhibitor containing a compound represented by the formula or a salt thereof or a prodrug thereof,
  • R 1 ′ R 2 ′ and R 3 are independently a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, Other symbols are above
  • a secletase inhibitor comprising a compound represented by the formula or a salt thereof or a prodrug thereof,
  • the effective amount of the 3-secretase inhibitor described in (14) above is administered to a mammal, (i) a neurodegenerative disease, (ii) a neuropathy, (iii) a memory disorder, (iv) Mental illness, (V) myopathy, (V i) mild cognitive impairment, or
  • R 1 ′ R 2 and R 3 independently represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, Other symbols are above
  • the ring A represents an “aromatic ring which may have a substituent”, and examples of the “aromatic ring” include: (a) a monocyclic or fused ring 2 or tricyclic C 6 14 Ariru (e.g., benzene, naphthalene, indene, anthracene etc.) or (b) carbon nitrogen besides atom atom, 5 to containing four to no heteroatoms 1 selected from sulfur and oxygen atoms 14-membered heteroaryl (eg, thiophene, benzothiophene, benzofuran, benzimidazonole, benzoxazol, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, Furan, phenoxathiin, pyrrole, imidazole, pyrazo ⁇ ⁇ ⁇ oxaziazole, pyridine, virazine, pyrimidine,
  • substituent for these aromatic rings include (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (2) -3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (3 ) nitro, (4) Shiano, (5) halogenated or may be one 6 alkyl, (6) Nono halogenated which may be C 3 _ 6 cycloalkyl, may be (7) halogenated — 6 alkoxy, (8) optionally halogenated C — 6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C — 6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino) , etc.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • -3 alkylenedioxy eg, methylenedioxy
  • Ariru one carbonyl e.g., Ben Zoiru, 1 one naphthoyl, 2-naphthoyl
  • Ariruokishi Ichiriki Ruponiru eg, such as phenoxy force / Reponiru
  • Ararukiruokishi one local Boniru e.g., Benzyloxycarbonyl, phenethyloxycarbonyl, etc., 5- or 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbol) , 1-pyrrolidinylmethyl Luca Lupo - Le etc.), mono- ⁇ preparative 6 Al kill - power Rubamoiru (e.g., methylcarbamoy
  • E Ji carbamoyl di - C i _ 6 Anorekinore force Norebamoiru (eg, dimethylcarbamoyl, Jechirukaruba Moyle , such as E chill methylcarbamoyl), C 6 - 1 0 Ariel Lubamoyl (Eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocyclic carpamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylca / levamoyl, 4-pyridylka / levamoyl, 2 one Chenirukaru Bamoiru, 3-Choi carbamoylmethyl, etc.), 6 alkylsulfonyl (e.g., methylsulfonyl, etc. Echirusuruhonir
  • benzenesolephoninole 1-naphthalenes-le-honinole, 2-naphthalenes-norehole, etc.
  • forminoleamino — 6-alkyl mono-l-poxamide (eg, acetamide, etc.), C 6 — 10
  • Aryl lipoxamide eg, phenylcarboxamide, naphthylcarboxamide, etc.
  • 6 alkoxy lipoxamide eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.
  • alkylsulfonylamino eg, Methylsulfonylamino, ethylsulfonylamino, etc.
  • an acylamino selected from (15) alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C.
  • Aryl-carbonyloxy eg,
  • C ⁇ 6 alkoxy monocarbonyloxy eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, putoxycarboninoleoxy, etc.
  • Mono alkyl monofunctional rubamoyloxy eg, methylcarbamoinoleoxy, T-carbamoyloxy, etc.
  • G-6-alkyl-rubamoyloxy eg, dimethylcarbamoyloxy, getylcarbamoyloxy, etc.
  • C6 ⁇ 0 aryl-carbamoyloxy eg, phenyl carbamoyloxy, naphthyl carbamoyloxy, etc.
  • halogenated C 6 alkyl examples include, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.).
  • alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifinoleo methinole, ethyl, 21-promoetinole, 2,2,2-trifluoroethyl, pentafluoroethyl, propinole, 3,3,3 -Trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutynole, sec-butyl, tert-butyl, pentyl, isopentinole, neopentinole,
  • halogenated optionally may ⁇ 3 _ 6 cycloalkyl
  • halogenated optionally may ⁇ 3 _ 6 cycloalkyl
  • halogen atoms e.g., fluorine, chlorine, odor Iodine, optionally C 3 optionally having iodine
  • - 6 cycloalkyl e.g., Shikuropuropi Honoré, Shikuropuchi ⁇ cyclopentyl Honoré, cyclohexylene hexyl etc.
  • cyclopropyl cyclopentinole
  • cyclopentyl cyclohexyl
  • 4,4-dichlorocyclohexanol 2,2,3,3-tetrafluorocyclopentyl
  • 4-chlorocyclohexyl and the like.
  • halogenated C i-e alkoxy has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • 6- alkoxy eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hex ⁇ / oxy, etc.
  • Examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluoroptoxy, isopoxy, Examples include sec-butoxy, pentinoleoxy, and hexyloxy.
  • the “optionally halogenated 6 alkylthio” may have, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Ci-6 alkylthio (eg, methylthio, ethylthio, propinorethio, isopropinorethio, butinorethio, sec-petitinorethio, tert-butylthio, pentylthio, hexylthio, etc.) and the like.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • Ci-6 alkylthio eg, methylthio, ethylthio, propinorethio, isopropinorethio, butinorethio, sec-petitinorethio, tert-butylthio, pentylthio, hexyl
  • methylthio difluoromethylthio, trifluoromethylthio, ethinorethio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutynolethio, pentinorethio, hexylthio and the like.
  • Examples of the above “5- to 7-membered saturated cyclic amino” include morpholino, thiomo-noreholino, piperazine-1-yl, 4-substituted piperazine-1-yl, piperidino, pyrrolidine-11-yl and the like. Is mentioned.
  • Examples of the above “5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms” include, for example, 21- or 3-Chenyl, 2 _ , 3- or 4-pyridyl, 2- or 3-furyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl and the like.
  • the aromatic ring may have one or more, preferably 1 to 5 of these substituents at substitutable positions, and may be the same or different when the number of substituents is two or more.
  • R 1 is an aryl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, a heteroaryl group which may have a substituent, a group, Teroari one Lou C _ 6 also to good Rere by Arukinore group, Ji may have a substituent alkyl group which may have a substituent C 3 _ 6 consequent opening alkyl group or it may have a substituent group C 3 -6 cycloalkyl one
  • R 1 Represented by R 1 as "Ariru group", C 6 - 1 4 Ariru, for example, phenyl, 1-naphthyl, 2 _ naphthyl, 2-indenyl, 2-anthryl etc. is Ru mentioned. Preferably, it is a fuel.
  • Ararukiru for example, benzyl, Fuenechinore, Ziv Eni Honoré methylate Honoré, triflumizole Eni Honoré methylate Honoré, 1 one naphthylmethyl, 2-naphthylmethyl, Examples thereof include 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, and 5-phenylopentyl.
  • Benginore is Benginore.
  • heteroaryl group represented by R 1 is a 5- to 10-membered aromatic heterocyclic group, for example, 2-, 3- or 4-pyridyl, 1-, 2- or 3-indolinole, 2- or 3- Chenyl and the like. Preferably, it is 2-, 3- or 4-pyridyl.
  • heteroaryl in the “heteroaryl-alkyl group” for R 1 , for example, the same groups as described above, and as the “0 ⁇ 6 alkyl group”, for example, methyl, ethyl, propyl, isopropyl, Examples include butinore, isoptyl, sec-butyl, tert-butinole, pentyl, hexyl, and the like, and specific examples thereof include pyridylmethyl.
  • Shikuroarukinore group represented by R 1, for example, Shikuropuropi Le, Shikuropuchinore, cyclopentyl, cyclohexyl and the like cyclohexylene.
  • Examples of the “. ⁇ Alkylalkyl” represented by R 1 include, for example, a group formed by combining the above-mentioned cycloalkyl group and an alkyl group, for example, pentylmethyl in the mouth, and hexylmethyl in the mouth. And the like.
  • substituent of these groups include the same groups as the “substituents” of the “optionally substituted aromatic ring” shown in the above ring A, and one or more substituents at substitutable positions And preferably 1 to 5, and when the number of substituents is 2 or more, they may be the same or different.
  • the “optionally substituted — 6 alkyl group J” represented by R 1 is preferably the aforementioned “substituted” of the “optionally substituted aromatic ring” represented by ring A Group "is a substituent other than the substituent described in (18).
  • R 2 is a hydrogen atom, an aryl group which may have a substituent, a aryl C 6 alkyl group which may have a substituent, a heteroaryl group which may have a substituent, substituted heteroaryl primary alkyl group to be, may have a substituent - 6 alkyl group, or may have a substituent group C 3 - shows the 6 cycloalkyl group.
  • R 2 which may have a substituent Ariru group", “optionally substituted Ariru ten preparative 6 alkyl group”, "terrorism to which may have a substituent Aryl group, an optionally substituted heteroaryl- 1-6 alkyl group, an optionally substituted alkyl group, and an optionally substituted C 3 — 6 cycloalkyl group "," optionally substituted Ariru group represented by the above R 1 ",” optionally substituted Ariru eleven 6 Al kill group ",” substituent Optionally substituted heteroaryl group “,” optionally substituted heteroaryl-1-C-6 alkyl group ",” optionally substituted substituent " Alkyl group "and include the same groups as the” optionally substituted ⁇ 3 _ 6 cycloalkyl group ".
  • R 2 is preferably a hydrogen atom.
  • R 3 may be an aryl C 6 alkyl group which may have a substituent, a heteroaryl C 6 alkyl group which may have a substituent, or may have a substituent. Bully Shows an alkyl group.
  • aryl group optionally having substituent (s) 6 alkyl group and the “heteroaryl alkyl group optionally having substituent (s)” for R 3 , those described above for R 1 And the same groups as the “aryl-1C- 6 alkyl group optionally having substituent (s)” and the “heteroaryl-1Ci-ealkyl group optionally having substituent (s)".
  • C 2 _ 1 0 alkyl group having a substituent represented by R 3 - as "C 2 1 0 alkyl group", for example, Echiru, propyl, isopropyl, butyl, I Sopuchinore, sec - Puchinore, tert- Buchinore, pentyl, Kishinore, heptyl, Okuchiru, Noel, decyl, and among others, C 4 - and the like as a 1 0 alkyl groups are preferred examples.
  • substituent include the same groups as the “substituent” of the “aromatic ring which may have a substituent” represented by the above-mentioned ring A.
  • the carbon atom bonded to the amino group or the carbon atom adjacent to the carbon atom C 2 ⁇ in which the carbon atom, that is, the 1- or 2-position of the alkyl group is substituted with an oxo group Excludes alkyl groups.
  • R 3 represents an aryl-alkyl group which may have a substituent, a heteroaryl-C i- 6 alkyl group which may have a substituent, or a C ⁇ i which may have a substituent. .
  • An alkyl group is preferable, and a benzyl group which may have a substituent is particularly preferable.
  • the bonding site shown by a solid line and a broken line represents a single bond or a double bond
  • X represents an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent.
  • the compound represented by the formula (I) includes not only a compound that is carbonyl or thiocarbonyl, but also a compound that forms an enol by keto-enol tautomerism. However, this excludes the case where all the binding sites shown by the solid and broken lines are single bonds and X is OH. Therefore, Accessories ⁇ 5
  • R 6 and R 7 are a hydrogen atom, a hydrocarbon group which may have a substituent), and the like.
  • R 6 and R 7 examples include, for example, “having a substituted group” represented by R, R 2 and R 3 below. And the like. "
  • an oxygen atom is preferable.
  • Y represents an oxygen atom or a sulfur atom, particularly preferably an oxygen atom.
  • R ′′, R 2 ′ and R 3 ′ in the formula (1) independently represent a hydrogen atom, may have a substituent! /, May have a hydrocarbon group or a substituent. And a heterocyclic group.
  • R 1 ′, R 2 ′ and R 3 ′ represented by “optionally substituted hydrocarbon group”
  • hydrocarbon group for example, alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, fused to a benzene ring Ji may 3 _ 6 cycloalkyl, C 6 _ 1 4 Ariru or C 7 - 9 aral kill and the like.
  • the “C alkyl” includes, for example, methyl, ethyl, propyl, isopyl pill, ptynole, isoptyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • the - as the "C” 6 cycloalkyl “includes, for example, cyclopropyl, Shikuropuchi Le, consequent opening pentyl, hexyl consequent opening thereof.
  • C 7 _ 1 9 Ararukiru for example, benzyl, phenethyl, Jifue Nirumechiru, triphenylmethyl, 1 one naphthylmethyl, 2 one naphthylmethyl, 2, 2-diphenyl Eni Honoré ethyl Honoré, 3-phenylene Norepuropinore Benzyl, preferably 4-benzyl-2-leptinole, 5-phenylpentyl and the like.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R ls s R 2 and R 3 include, for example, a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom 5 to 14 membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of (i) 5 to 14 membered (preferably Is a 5- to 10-membered) aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring, or (iii) a 7- to 10-membered bridged heterocyclic ring obtained by removing any one hydrogen atom And monovalent groups.
  • Examples of the “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic ring” include, for example, thiophene, benzothiophene, benzofuran, benzimidazonole, benzoxazonole, benzothiazonole, and benziso Thiazonore, Naft
  • Examples of the “5- to 10-membered non-aromatic heterocycle” include pyrrolidine, imidazoline, virazolidine, virazoline, piperidine, piperazine, morpholine, and thiomorpholine.
  • Examples of the “7- to 10-membered bridged heterocyclic ring” include quinuclidine, 7-azabicyclo [2.2.1] heptane, and the like.
  • Examples of the preferred "heterocyclic group” the nitrogen atom in addition to carbon atoms, one or two kinds of hetero atoms selected from sulfur atom and an oxygen atom, a 5- including the four from 1 1 0-membered (single (Cyclic or bicyclic) It is a heterocyclic group.
  • aromatic heterocyclic groups such as 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinole, 3-isothiazolinole, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-isoindolinyl, such as 1— , 2 or 3 monopyrrolidinyl, 2 or 4 imidazolinyl, 2 or 3 or 4 pyrazolidinyl, piperidino, 2 or 3 or 4 piperidyl, 1 or 2 piperidinyl, morpholino, etc.
  • a non-aromatic heterocyclic group such as 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinole, 3-isothiazolinole, 3-isoxazolyl, 1-indolyl, 2-indolyl, 2-isoindolinyl, such as 1— , 2 or 3 monopyrrolidinyl, 2 or 4
  • a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom is more preferable.
  • ring A is a benzene ring which may have a substituent
  • the A ring is a formula
  • R 4 and R 5 each independently represent a hydrogen atom, may have a substituent V, may have a hydrocarbon group or may have a substituent, and each represents a heterocyclic group. ]
  • heterocyclic group examples include the “optionally substituted hydrocarbon group” and the “substituted hydrocarbon group” represented by R 1 ′, R 2 ′ and R 3 ′ above. Heterocyclic group which may have a group ".
  • R 1 is not a carboxymethyl group
  • Examples of the compound represented by the formula (I) include a benzene ring in which ring A may have a substituent, a benzyl group in which R 1 may have a substituent, and a hydrogen atom in which R 1 is a hydrogen atom. And a compound wherein R 3 is a benzyl group which may have a substituent, and X and Y are oxygen atoms.
  • R 3 is 3-methoxybenzyl, 3-chlorobenzoyl, 3-methoxycanoleboninolebenzinole, 3-pheninolebenzyl, 3-phenoxybenzyl, 3-trifluoro.
  • Compounds of formula (I) which are a lomethylbenzyl group, a 2-naphthylmethyl group, an n-hexyl group, a 2-chenomethyl group or an indole-3-methyl group are also preferred.
  • the compound of the formula (I) include: ⁇ ′ — ⁇ (IS) —1-benzyl-3 — [(3-methoxybenzyl) amino] -12-oxopropyl ⁇ —N, N-dipropylisophthalamide or And salts thereof.
  • a pharmacologically acceptable salt is preferable, and examples thereof 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. .
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. Is mentioned.
  • salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , -'- dibenzylethylenediamine. Salts such as min.
  • salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ⁇ -Salts with toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine, and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.
  • the compound represented by the formula (I) or (1 ′) used in the present invention may be a hydrate or a non-hydrate. Further, when the compound represented by the formula (I) or the formula (I,) used in the present invention exists as a configurational isomer (a configuration isomer), a diastereomer, a conformer, or the like, If desired, each can be isolated by a separation / purification means known per se. When the compound represented by the formula (I) or the formula (1 ′) used in the present invention is in a racemic form, it is separated into an (S) form and an (R) form by ordinary optical resolution. Each of the optically active substances and the racemates is also included in the present invention.
  • the compound represented by the formula (I) or the formula (1 ′) used in the present invention or a salt thereof [Hereinafter, it may be referred to as compound (I) or (). ] May be used as a prodrug.
  • a prodrug include compounds which are converted into compound (I) or (1 ') by a reaction with an enzyme or gastric acid under physiological conditions in vivo, that is, enzymatically. Oxidation, reduction, hydrolysis, etc. cause compound (I) or
  • the prodrug of compound (I) or ( ⁇ ) may be a compound in which the amino group of compound (I) or (1 ′) is acylated, alkynolelated, or phosphorylated (eg, compound (I) or (1 ′) Of the amino group is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-12-chloro-1,3-dioxolen-1-41-f) methoxycarbonylation, tetrahydro-lofraninolayido, pyrrolidyl Methylated, bivaloyoxymethylated, tert-butylated compounds, etc.); compounds in which the hydroxyl group of compound (I) or (1 ′) is acylated, alkylated, phosphorylated, or borated (eg, Com
  • the prodrug of compound (I) or (I,) is available from Hirokawa Shoten 1990
  • the compound (I) or () may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • an isotope eg, 3 H, 14 C, 35 S, 125 I, etc.
  • a method for producing a compound represented by the formula (I) or a salt thereof (hereinafter, sometimes collectively simply referred to as compound (I)) will be described below.
  • the starting materials and intermediates shown in the following production methods may form a salt similar to the salt of the compound represented by the above formula (I).
  • the compound represented by the formula ( ⁇ ) or a salt thereof is the following compound
  • Compound (la) or a salt thereof can be produced by subjecting compound (II) or a salt thereof to protection of an amino group, followed by an oxidation reaction and a subsequent deprotection reaction.
  • Examples of the protecting group for the amino group include Ce alkyl-monocarbonyl which may have a substituent (for example, acetyl, propionyl, etc.), formyl, phenol-carbonyl, and alkoxy-monocarbonyl (for example, Ethoxycarbonyl, ethoxycanoleponinole, tert-butoxycanolepone / re, etc.), phenoxycanoleponinole
  • benz O propoxycarbonyl El C 7 - 10 Ararukiruokishi one carboxymethyl sulfonyl (e.g., benzyl O alkoxycarbonyl), trityl is used.
  • a halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • an alkyl monocarbonyl for example, acetinol, propionyl, butyryl, etc.
  • a nitro group and the like are used. Or about three.
  • the method for introducing and removing the protecting group is known per se or according to the method. A method (eg, the method described in Protective 'Groups' in 'Organic' Chemistry (JFW McOmie et al., Plenum Press)) is used.
  • Compound (II) or a salt thereof is produced, for example, according to the method described in WO 02/02512 or a method analogous thereto.
  • the oxidizing agent is used in an amount of 0.5 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of the protected amino group of compound (II) or a salt thereof.
  • Examples of such an oxidizing agent include active manganese dioxide, pyridium dichromate chromate (PCC), pyridinium dichromate (PDC), dimethyl sulfoxide anhydride (for example, acetic anhydride, trifluoroacetic anhydride, etc.), dimethyl sulfoxide chloride- Dimethyl sulfoxide salt histylfuryl, dimethyl sulfoxide oxalyl monochloride, dimethyl sulfoxide chloride, and dimethyl sulfoxide cyclyl carbonyl in the presence of acids (e.g., phosphoric acid, trifluoroacetic acid, dichloroacetic acid, etc.) (DCC), ruthenium tetroxide, ruthenium dioxide and sodium periodate.
  • active manganese dioxide active manganese dioxide
  • PCC pyridium dichromate chromate
  • PDC pyridinium dichromate
  • dimethyl sulfoxide anhydride for example
  • This oxidation reaction for example, compound catalyst amount relative to the protective body or its salt 1 mole of Amino group (II) (0. 1 mole 0/0 to 10 mole 0/0, preferred properly 1 mol 0 / 0-5 mole 0/0) of a transition metal catalyst (e.g., Bisukurorobisu (g Lihue - Le phosphine) ruthenium, etc. tetraalkyl ammonium Niu arm perruthenate) and 1 to 10 equivalents, preferably 1 to 5 equivalents
  • a co-oxidizing agent for example, orthodylbenzene, N-methylmorpholine oxide, etc.
  • the solvent used at this time can be appropriately selected depending on the type of the oxidizing agent.
  • examples thereof include ethers (eg, tetrahydrofuran, dioxane, dimethyl ether), and halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride).
  • halogen-based solvents eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride.
  • ketones for example, acetone, methylethylenoketone, etc.
  • aprotic polar solvents for example, N, N-dimethylformamide, dimethylsulfoxide, etc.
  • the reaction time is 0.5 to 48 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is appropriately selected depending on the type of the oxidizing agent, and the reaction can be carried out at a temperature of from 80 ° C to 100 ° C, preferably from 70 ° C to 30 ° C.
  • Compound (II) or a salt thereof can also be produced by the method shown in Method B (Scheme 2) or Method C (Scheme 3) below.
  • B method
  • Compound (V) or a salt thereof is, for example, tetrahedron (Tetrahedi: on), vol. 55,
  • the compound (IV) or a reactive derivative thereof or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base.
  • Compound (IV) can be obtained, for example, by subjecting a commercially available reagent to functional group conversion by a known method, in addition to using a commercially available reagent, or by a method described in WO 02/02512 or a method analogous thereto. Therefore, it can also be manufactured.
  • Examples of the reactive derivative of carboxylic acid include acid anhydride, active natural ester (for example, ⁇ -nitropheninole ester, N-hydroxysuccinimide ester, pentafluorophenylinole ester, 1-hydroxybenzotriazole). Esters, etc.), acid halides (eg, acid chloride, acid bromide, etc.), imidazolides or mixed acid anhydrides (eg, anhydrides with methynoleic carbonic acid, anhydrides with ethyl carbonic acid, etc.).
  • active natural ester for example, ⁇ -nitropheninole ester, N-hydroxysuccinimide ester, pentafluorophenylinole ester, 1-hydroxybenzotriazole.
  • Esters, etc. include acid halides (eg, acid chloride, acid bromide, etc.), imidazolides or mixed acid anhydrides (eg, anhydrides with methynoleic carbonic acid, an
  • Q 1 is a leaving group [for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine)], methanes-le-funoreoxy, benzene-snole. Honinolexy,
  • ether solvents for example, dimethyl ether, tetrahydrofuran, dioxane, etc.
  • hydrocarbon solvents for example, Benzene, toluene, hexane, heptane, etc.
  • halogenated solvents eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.
  • non-protonic polar solvents eg, N, N_dimethinoleformamide, Dimethyl sulfoxide, acetonitrile, etc.
  • Bases used include triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine,
  • Organic bases such as 4-methylmorpholine and pyridine, alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, hydrogen carbonate) Sodium, potassium bicarbonate, etc.) and alkali metal or alkaline earth metal hydroxides (for example, sodium hydroxide, ⁇ oxidation power, etc.).
  • alkali metal or alkaline earth metal carbonates eg, sodium carbonate, potassium carbonate, etc.
  • alkali metal or alkaline earth metal bicarbonates eg, hydrogen carbonate
  • alkali metal or alkaline earth metal hydroxides for example, sodium hydroxide, ⁇ oxidation power, etc.
  • condensing agent to be used examples include a condensing agent used for peptide synthesis, and specific examples thereof include, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ⁇ -ethyl -—'- 3-dimethylaminopropylcarboimide.
  • Diimide and its hydrochloride benzotriazole-1-yl lithris (dimethylamino) phosphoyudiumhexafluorophosphoride, benzotriazole gray 1-inolate rispyrrolidinophosphonium hexafenole phosphide, getyl cyanophosphate, diphenylphos Folyl azide, ⁇ -hydric oxy-5-norbornene-1,2,3-carboxyimide and the like. These may be used alone or in combination with 1-sevendroxybenzotriazole, 1-hydroxy-17-za.
  • the carboxylic acid or the reactive derivative thereof or the salt thereof represented by the compound (IV) is about 0.5 to 10 mole equivalent, preferably about 1 to 5 mole per mole of the compound (III) or a salt thereof.
  • Molar equivalents are used and the condensing agent is used in about 0.5 to 10 molar equivalents, preferably about 1 to 6 molar equivalents.
  • the base may be used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 6 molar equivalents.
  • the reaction temperature is about 150 to 200 ° C., preferably about 120 to 100 ° C.
  • the reaction time is about 0.5 to 96 hours, preferably about 0.5. To 72 hours, more preferably about 1 to 24 hours.
  • Compound (VI) or a salt thereof can be produced by subjecting compound (V) or a salt thereof to an oxidation reaction.
  • an oxidizing agent used for the oxidation reaction for example, Mechanical peracids (eg, m-chloroperbenzoic acid, peracetic acid, 3,5-dinitroperbenzoic acid, etc.), alkyl hydroperoxides (eg, tert-butyl hydroperoxide), hydrogen peroxide water and the like are used. These may be used alone or in combination with a metal complex (for example, palmitium tri-tert-butoxide, vanadium acetyl acetonate oxide, and liponyl molybdenum oxide).
  • a metal complex for example, palmitium tri-tert-butoxide, vanadium acetyl acetonate oxide, and liponyl molybdenum oxide.
  • the reaction may be carried out in the presence of a base.
  • a base examples include organic bases such as triethylamine, 4-dimethylaminopyridine, ⁇ , ⁇ -dipropylpropylethylamine, triethylenediamine, 4-methylmorpholine, and pyridine, and alkali metals or alkaline earth metals.
  • Carbonates eg, sodium carbonate, carbonated lime, etc.
  • alkali metal or alkaline earth metal hydrogencarbonates eg, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.
  • alkali metal or alkaline earth metal water Oxides eg, sodium hydroxide, potassium hydroxide, etc.
  • solvent used include water, protic polar solvents (eg, methanol, ethanol, etc.), ether solvents (eg, getyl ether, tetrahydrofuran, dioxane, etc.), and hydrocarbon solvents (eg, benzene, toluene, etc.).
  • halogenated solvents eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.
  • non-protonic polar solvents eg, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide, dimethylsulfoxide, acetonitrile, etc.
  • the oxidizing agent is used in an amount of about 0.5 to 10 monoequivalents, preferably about 1 to 5 molar equivalents, and the base is used in an amount of about 0.5 to 10 molar equivalents, per 1 mol of (V) or a salt thereof. Preferably, about 1 to 5 molar equivalents are used.
  • the reaction temperature is about 150 to 200 ° C., preferably about 120 to 100 ° C., and the reaction time is about 0.5 to 96 hours, preferably about 1 to 24 hours. It is.
  • Compound (II) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with an amine represented by the formula R 3 NH 2 or a salt thereof. If necessary, the reaction may be performed in the presence of a base.
  • the base include organic bases such as triethylamine, 4-dimethylaminopyridine, ⁇ , ⁇ -diisopropylpropylethylamine, triethylendiamine, 4-methylmonorephorin, and pyridine, and alkali metal or alkaline earth metals.
  • Carbonates eg, sodium carbonate, potassium carbonate, etc.
  • Alkali metal or alkaline earth metal bicarbonate eg, sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal or alkaline earth metal hydroxide eg, sodium hydroxide, potassium hydroxide, etc.
  • ether solvents eg, dimethyl ether, tetrahydrofuran, dioxane, etc.
  • hydrocarbon solvents eg, benzene, toluene, hexane, heptane, etc.
  • halogen solvents eg, dichloromethane, dichloroethane
  • Chloroform e.g., Chloroform, carbon tetrachloride, etc.
  • aprotic polar solvents eg, N, N-dimethinoleformamide, dimethyl sulfoxide, aceto-tolyl, etc.
  • the salt is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents
  • the base is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents.
  • the reaction temperature is about 150 to 200 ° C., preferably about 120 to 100 ° C.
  • the reaction time is about 0.5 to 96 hours, preferably about 1 to 2 hours. 4 hours.
  • Compound (II) or a salt thereof can also be produced from compound (VI) or a salt thereof by the method shown in Method C (Scheme 3). ⁇
  • Compound (VII) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with a metal azide.
  • the metal azide include sodium azide, lithium azide, trimethylsilyl azide and the like. If necessary, ammonium chloride, boron trifluoride getyl ether complex, titanate The reaction may be performed in the presence of trisopropoxide or the like.
  • the solvent used include water, protic polar solvents (eg, methanol, ethanol, etc.), ether solvents (eg, jeti / ether, tetrahydrofuran, dioxane, etc.), and hydrocarbon solvents (eg, benzene, tonolene).
  • the metal azide is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, relative to 1 mol of the compound (VI) or a salt thereof, and the reaction temperature is about 150 to 200 °. C, preferably about 20 to 100 ° C, and a reaction time of about 0.5 to 9
  • Compound (VIII) or a salt thereof can be produced by reduction reaction of compound (VIII) or a salt thereof.
  • This reaction is a known reduction reaction, for example, a catalytic reduction reaction using a transition metal catalyst (for example, palladium-carbon, Lindlar catalyst, Raney nickel, etc.), a metal hydride complex compound (for example, lithium aluminum hydride, disobutyl hydride) Aluminum, sodium borohydride, sodium cyanoborohydride, etc.), and a reduction reaction using diborane, triphenylenophosphine, thiol, sulfide, or the like.
  • This reaction is described in, for example, Journal of Organic Chemistry (J. Org. Chem.), Vol. 50, pp. 3095-3103 (1985), Synthesis (p. 590) (1975), or a method analogous thereto. Can be done with a transition metal catalyst (for example, palladium-carbon, Lindlar catalyst, Raney nickel, etc.), a metal
  • Compound (II) or a salt thereof can be produced using compound (VIII) or a salt thereof and an aldehyde compound represented by the formula R 3 -CHO or a salt thereof under conditions of a reductive alkylation reaction.
  • a ether solvent eg, dimethyl ether, tetrahydrofuran, dioxane, etc.
  • a hydrocarbon solvent eg, benzene, toluene, hexane, heptane, etc.
  • a halogen solvent eg, Dichloromethane, dichloroethane, chlorohonolem, carbon tetrachloride, etc.
  • alcoholic solvents eg, methanol, ethanol, n-propanol, isopropanol, etc.
  • aprotic polar solvents eg, N, N-dimethyl
  • It can be produced by reacting in the presence of a metal hydride complex compound (for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride).
  • a metal hydride complex compound for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride.
  • the metal hydride complex is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents.
  • the reaction temperature is about 0 to 200 ° C, preferably about 20 to 100 ° C
  • the reaction time is about 0.5 to 96 hours, preferably about 1 to 24 hours.
  • the compound (lb) in which X is NR 6 (R 6 represents a hydrocarbon group which may have a substituent) and Y is an oxygen atom can be obtained, for example, by the method D
  • PG is a protecting group
  • R 6 is a hydrocarbon group which may have a substituent, and other symbols are as defined above.
  • an ether solvent eg, dimethyl ether, tetrahydrofuran, dioxane, etc.
  • a hydrocarbon solvent eg, benzene, toluene, hexane, heptane, etc.
  • a halogen solvent eg, Dichloromethane, dichloroethane, chlorophonolem, carbon tetrachloride, etc.
  • alcoholic solvents eg, methanol, ethanol, n-propanol, isopropanol, etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, dimethylsulfoxide
  • Acetonitrile, etc. acetic acid or the like or a mixed solvent thereof, compound (IX) or a salt thereof, and an amine of the formula R 6 -NH 2 or a salt thereof, with a metal-hydrogen complex compound (for example, Sodium boronalumiofuran, dio
  • the metal hydride complex is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents.
  • the reaction temperature is about 0 to 200 ° C, preferably about 20 to 100 ° C, and the reaction time is about 0.5 to 96 hours, preferably about 1 to 24 hours.
  • the reductive amination reaction may be carried out by a method described in Jana Nano Reb Chemical Society, Perkin Trans 1 (J. Chem. Soc, Perkin Trans 1), pp. 2527-2530 (1998) or a method analogous thereto. it can.
  • R 7 is a hydrogen atom or a hydrocarbon group which may have a substituent, and other symbols. Is as defined above. ]
  • Compound (IX) shown in Scheme 4 is subjected to a condensation reaction with hydroxylamine derivative H 2 N-OR 7 or a salt thereof, followed by deprotection in the same manner as shown in Scheme 1.
  • Compound (Ic) can be produced.
  • the condensation reaction of the compound (IX) or a salt thereof with the hydroxylamine derivative H 2 N-OR 7 or a salt thereof may be carried out in the presence of a base, if necessary.
  • the base examples include organic bases such as triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine, and pyridine; Alkaline earth metal carbonates (eg, sodium carbonate, lithium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, sodium hydrogen carbonate, hydrogen bicarbonate, etc.), alkaline metal or alkaline metal Hydroxides of lithium earth metals (for example, sodium hydroxide, potassium hydroxide, etc.) and the like. Further, the reaction may be performed in the presence of an alkali metal or alkaline earth metal acetate (for example, sodium acetate, potassium acetate, or the like).
  • organic bases such as triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine, and pyridine
  • the solvent used examples include water, alcoholic solvents (eg, methanol, ethanol, n-propanol, isopropanol, etc.), acetic acid, pyridine and the like.
  • hydroxylamine or a salt thereof is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of the compound (XI) or a salt thereof.
  • the base is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 5 molar equivalents.
  • the reaction temperature is about 150 to 200 ° C, preferably about 120 to 100 ° C, and the reaction time is about 0.5 to 96 hours, preferably about 1 to 24 hours.
  • Compound (Id) in which X is an unsubstituted amino group and Y is an oxygen atom in compound (I) or a salt thereof can be produced, for example, according to the method shown in Scheme 4. That is, in the reductive amination reaction step shown in Scheme 4, ammonia or a salt thereof (such as ammonium chloride) may be used in place of the amine represented by R 6 —NH 2 or a salt thereof. Also, the reductive amination reaction is
  • X is an unsubstituted amino group.
  • the compound (Id) in which the group, Y is an oxygen atom is obtained by subjecting the compound (XI) or a salt thereof to a reduction reaction as shown in, for example, the method shown in Method F (Scheme 6) and then shown in Scheme 1. It can also be produced by performing a deprotection reaction in the same manner as in the method.
  • R 7 in the compound (lb) or a salt thereof is a benzyl group or the like, the compound can also be produced by performing a reduction reaction in the same manner.
  • This reduction reaction is a known reduction reaction, for example, a catalytic reduction reaction using a transition metal catalyst (for example, rhodium, platinum oxide, palladium carbon, Raney nickel, etc.), a metal hydride complex compound (for example, lithium aluminum hydride,
  • a transition metal catalyst for example, rhodium, platinum oxide, palladium carbon, Raney nickel, etc.
  • a metal hydride complex compound for example, lithium aluminum hydride
  • the reaction can be carried out using a reduction reaction using diisobutyl aluminum, sodium borohydride, sodium cyanoborohydride, or the like, or a reduction reaction using diborane or the like.
  • This reaction is performed, for example, in Journal of Organic Chemistry (J. Org. Chem.), Vol. 37, pp. 335 (1972), Synthesis, pp. 995 (1989) , Journal of American Chemical Society (J. Am. Chem.
  • the compound (Ie) of the present invention (I) or a salt thereof, wherein X and Y are each a sulfur atom, can be produced, for example, by Method G (Scheme 7).
  • Compound (Ie) or a salt thereof is obtained by treating compound (Ia) or a salt thereof in the presence of a sulfurizing agent (for example, phosphorus pentasulfide, Lawesson's reagent, Tavi's reagent, etc.), or compound (XI) or a salt thereof. Is treated with a sulfurizing agent, and then subjected to a deprotection reaction in the same manner as shown in Scheme 1 to produce the compound.
  • a sulfurizing agent for example, phosphorus pentasulfide, Lawesson's reagent, Tavi's reagent, etc.
  • ether solvents eg, dimethyl ether, tetrahydrofuran, hexane, etc.
  • hydrocarbon solvents eg, benzene, toluene, hexane, heptane, etc.
  • halogen solvents eg, dichloromethane
  • Dichloroethane Dichloroethane
  • black honolem carbon tetrachloride, etc.
  • non-protonic polar solvents eg, N, N-dimethylformamide, dimethylsulfoxide, acetutrinole
  • the sulfurizing agent is used in an amount of about 0.5 to 10 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of the compound (Ia) or (XI) or a salt thereof.
  • the reaction temperature is about 150-200 ° C, preferably about 0-100 ° C, and the reaction time is about 0.5-96 hours, preferably about 1-24 hours.
  • Compound (I f) wherein X is an optionally substituted amino group and Y is a sulfur atom in compound (I) or a salt thereof of the present invention was obtained, for example, by Schemes 4, 5, 6 and the like.
  • the compound (lb), (Ic), (Id) or a salt thereof can be produced by treating the compound (lb), (Ic), (Id) or a salt thereof with a sulfide agent in the same manner as in Scheme 7.
  • the compound (Ig) of the present invention (I) or a salt thereof, wherein X is a sulfur atom and Y is an oxygen atom, can be produced, for example, by the method shown in Method H (Scheme 8). (Scheme 8)
  • Compound (Ih) in which X is an oxygen atom and Y is a sulfur atom in compound (I) or a salt thereof of the present invention is, for example, compound (II) or These salts can be produced by treating with a sulfurizing agent in the same manner as in Scheme 7, and then subjecting them to an oxidation reaction in the same manner as in Schemes 1 and 4. At that time, if necessary, the amino group can be protected and deprotected as described above.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound used in each of the above production methods may form a salt similar to compound (I) as long as the reaction is not hindered.
  • a protecting group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the protecting group of Amino groups such as alkyl Ichiriki be substituted Noreboniru (e.g., Asechiru, propionyl, etc.), formyl, phenylene Luke Noreboninore, C, _ 6 alkoxy one carbonylation Honoré (e.g., Methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), pheny / reoxycarbonyl (eg, benzoxycarbonyl, etc.), C7 ⁇ .
  • Aralkyloxy lponyl eg, benzyloxycarbonyl, etc.
  • trityl phthaloyl Which is used.
  • halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • alkyl-carbonyl for example, acetyl, pentionyl, butyryl, etc.
  • a nitro group and the like are used. Is about one to three.
  • the protecting group for the carboxy group may have a substituent — 6-alkyl (for example, methyl, ethyl, propynole, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used.
  • a substituent include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), 6- alkyl-carbonyl (for example, acetyl, propionyl, butyryl, etc.), formyl, nitro group and the like.
  • the number of groups is about one to three.
  • the protective group for hydroxy group for example an optionally substituted C - 6 alkyl Le (e.g., methyl, Echiru, propyl, isopropyl, butyl, etc. tert- Puchinore), phenyl, C 7 - 1 0 Ararukiru (Eg, benzinole), — 6-alkyl alcohol (eg, acetyl, propiole, etc.), formyl, phenyloxycarbonyl, C.
  • Examples include aralkyloxycarbonyl (for example, benzyloxycarbol and the like), bilanyl, furanyl, silyl and the like.
  • halogen atoms for example, fluorine, chlorine, bromine, iodine, etc.
  • alkyl phenyl, C0 aralkyl, nitro groups, etc.
  • the number of substituents is about 1 to 4 It is.
  • Compound (I) and Compound (1) have an inhibitory action on aspartic protease, especially an excellent inhibitory action on 3-secretase, and further have an inhibitory action on amyloid] 3 protein production 'secretion' aggregation and low toxicity.
  • the compound (I) and the compound (II) are useful as pharmaceuticals for (1) neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, Kreuzfeld's Jakop ' Disease, amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc.), (2) cerebrovascular disorders (eg, associated with cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis) Cerebral circulatory insufficiency), head trauma, spinal cord injury, neuropathy during sequela of encephalitis or cerebral palsy, (3) memory impairment (eg, senile dementia, amnesia, etc.) or (4) mental illness ( (Eg, depression, panic disorder, schizophrenia, etc.) (5) It is useful for prevention and treatment of myopathy (muscular disease, myopathy).
  • neurodegenerative diseases eg, senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, Kreuzfeld's Jakop ' Disease
  • Compound (I) and compound (1 ') are also useful for the prevention and treatment of mild cognitive impairment (mild memory impairment), amyloid angiopathy.
  • Compound (I) and compound (II) may be used in combination with other medicines for the above-mentioned treatment and prevention.
  • concomitant drugs include, for example, drugs for treating Alzheimer's disease (for example, cerebral function stimulants such as cholinesterase inhibitors such as donezil, rivastigmine, galantamine, and zanadi ⁇ ; ), Anti-Parkinson drugs (eg L-dopa, deprenyl, carbidopa + levodopa, perugolide, ropi-eronole, power benoregorin, pramizoxo-zole, entacabron, lazabemide, etc.), amyotrophic spinal cord lateral sclerosis Therapeutic agents (eg, riluzole, mecacermin, gabapentin, etc.), neurotrophic factors, antidepressants (eg, fluoxetine, satraline, paroxetine, benlafaxine, nefazo
  • Compounds (I) and (1,) can be formulated according to a method known per se.
  • Compound (I) or () can be used as it is or in a pharmacologically acceptable carrier at an appropriate amount in the formulation process.
  • Oral preparations such as tablets (including sublingual tablets and buccal tablets), capsules (including soft capsules and microcapsules), powders, granules, troches and syrups;
  • injections eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions, etc.
  • external preparations eg, transdermal preparations, ointments, etc.
  • suppositories eg, rectum
  • parenteral preparations such as suppositories, vaginal suppositories, pellets, nasal preparations, pulmonary preparations (inhalants), sustained-release preparations, and eye drops.
  • a sublingual tablet, an orally disintegrating tablet, a syrup, an external preparation, a nasal preparation and the like are preferable.
  • These preparations can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) in a manner appropriate to the form.
  • the content of compound (I) or (1 ′) is 0.
  • the dosage varies depending on the administration subject, administration route, disease and the like.For example, as an Alzheimer's disease therapeutic drug, for adults (about 6 O kg), as an oral preparation, once a day Or (I ⁇ ) as about 0.1 to 500 mg, preferably about 1 to; L 0 O mg, more preferably 5 to 10 O mg, and administered in 1 B 1 to several times be able to.
  • the above-mentioned “other drug” and the compound (I) or (1 ′) of the present invention may be mixed according to a method known per se, formulated into one pharmaceutical composition and used in combination. May be separately formulated and administered to the same subject at the same time or at staggered times.
  • the pharmacologically acceptable carrier used in the production of the composition of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, and binders in solid formulations. Agents, disintegrants; solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
  • Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Binders include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropinoresenololose, hydroxypropinolemethinoresenorelose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carbohydrate Xymethylcellulose sodium and the like.
  • disintegrant examples include starch, carboxymethylcellulose, carboxymethylcellulose canolesum, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • Solubilizers include, for example, polyethylene glycol, propylene glycol,
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetium chloride, and dariserin monostearate; for example, polyvinyl alcohol, polyvinyl alcohol And hydrophilic polymers such as burpyrrolidone, sodium ureboxoxymethylcellulose sodium, methinoresenorelose, hydroxymethinoresenorelose, hydroxyshethylsenorelose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetium chloride, and dariserin monostearate
  • polyvinyl alcohol polyvinyl alcohol
  • hydrophilic polymers such as burpyrrolidone, sodium ureboxoxymethylcellulose sodium, methinoresenore
  • buffers such as phosphate, acetate, carbonate, and citrate.
  • Examples of the soothing agent include benzyl alcohol.
  • preservative examples include paraoxybenzoic acid esters, chloroptanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite, ascorbic acid and the like.
  • the ⁇ -NMR spectrum was measured using a Varian Gemini 200 (200 MHz) or Mercury 300 (300 MHz) using tetramethylsilane as an internal standard, and the total ⁇ value was measured in parts per miUion (ppm). ).
  • the numerical values shown for the mixed solvents are volume mixing ratios of each solvent unless otherwise specified. % Means weight percent unless otherwise specified. The elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified. Sili force gel, Sili force gel 60 (100-230 mesh) unless otherwise noted
  • CDC1 3 deuterated chloroform
  • DMSO-d 6 heavy dimethyl sulfoxide
  • NMK proton nuclear magnetic resonance
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran run
  • % wt%.
  • MS mass spectrum
  • Sodium hydroxide (8.84 g, 221 mMol) is added to a mixed solvent (40 OmL) of dimethyl isophthalate (39.Og, 20 lmmo1) in methanol / 7j (1: 1) and heated for 1 hour and 30 minutes Refluxed. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, followed by extraction with water. Subsequently, concentrated aqueous hydrochloric acid was added to the aqueous extraction solution to make an acidic solution, which was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in DMF (50 OmL).
  • tert-butyl-1 (3 S) -1 3— ( ⁇ 3— [(dipropylamino) carbonyl] benzoyl) amino) 1-2-oxo-1
  • 4-pheninolebutynole (3-methoxybenzyl) Powerbamate (71 6 mg, 0.114 mmo 1) was dissolved in 4N hydrogen chloride / ethyl acetate solution (1 OmL) and left at room temperature for 15 minutes. The solvent was distilled off, and the residue was crystallized by adding getyl ether to give the title compound (25.4 mg, 38%).
  • tert-butyl-1 (3S) -3-( ⁇ 3-[(dipropylamino) carbinole] benzoyl ⁇ amino) -1-2-oxo-14-pheninolebutynole (3-methoxybenzyl) olebamate (129mg, Dissolve 0.25 mmo 1) in ethanol (5 mL), add hydroxyammonium chloride (17.lmg, 0.246 mmo 1), pyridine (84 L, 1.03 mmo 1), and add at 60 ° C. Stirred for 1 hour.
  • Jiasutereoma B ⁇ -NMR (CDC1 3) ⁇ : 0.70 (3 ⁇ , br s), 0.95 (3H, br s), 1.48 (2H, br s), 1.64 (2H, br s), 2.20-2.51 (5H, m), 3.08 (2H, br s), 3.25-3.50 (4H, m), 3.77 (3H, s), 3.80 (1H, br s), 4.15 (2H, br s), 4.75 (1H, br s) , 6.88 (1H, ra), 7.20-7.39 (lOH, m), 7.99 (2H, m), 9.18 (2H, m), hidden (1H),
  • Jiasutereoma B ⁇ - NMR (CDC1 3) ⁇ : 0.68 (3 ⁇ , m), 0.92 (3H, m), 1.43 - 1.66 (4H, ra), 3.07-3.17 (4H, m), 3.38-3.46 (3H, m), 3.85 (1H, ra), 4.17 (2H, ra), 5.03-5.20 (IH, m), 7.11-7.59 (10H, m), 7.74-7.87 (3H, ra), 8.34 (IH, ra) , 8.70 (IH, ra), 9.60 (IH, ra), hidden (1H),
  • Primer set prepared with reference to the gene base sequence: 5 * -ggcaccaccaaccttcgt-3 ′ (SEQ ID NO: 2) and F1ag peptide encoding salt No. 3) and 2 Opmol each were added, and the PCR reaction was carried out using MiniCycler TM (MJRESERCH) using KOD (Toyobo) (reaction conditions: 1 cycle for 2 minutes at 98, 98 ° C).
  • a plasmid containing a DNA fragment was recovered in about 250b.
  • clone No. FG04087 digested with Ap a I Thereafter, a DNA fragment of about 1.2 kb was recovered by agarose gel electrophoresis, and the DNA fragment was mixed with an expression plasmid pcDNA 3.1 (-) (Funakoshi) for animal cells digested with Ap I and Kpn I. , Ligationffigh (Toyobo), and ligated using E.
  • agarose gel electrophoresis was performed to recover a DNA fragment of about 1.1 kb. Further, after pBACE1 was digested with ApaI, agarose gel electrophoresis was performed to recover a DNA fragment of about 5.7 kb. These three fragments were ligated using Ligation High (Toyobo) and transformed into E. coli JM109 competent cells (Takara Shuzo) to obtain plasmid pBACE2.
  • the obtained cDNA fragment has the nucleotide sequence represented by SEQ ID NO: 6, and encodes the amino acid sequence represented by SEQ ID NO: 7 at the 1st to 1527th positions of the base sequence. I was
  • the cells were collected, and 5111 suspension buffer (0.01 M Tris—HC 1 (pH8), 0.1 M NaCl, 1 mM EDTA, 0.5 mM PMSF) After the addition, the mixture was crushed using an ultrasonic crusher (Tomiichi Seiko U R-200 P) (crushing conditions: output 5, 5 seconds). The lysate was centrifuged (500 g, 10 minutes), and the supernatant was further ultracentrifuged (100,000 g, 45 minutes).
  • 5111 suspension buffer (0.01 M Tris—HC 1 (pH8), 0.1 M NaCl, 1 mM EDTA, 0.5 mM PMSF
  • the precipitate was solubilized with 0.5 mL of solubilization buffer (0.05 M Tris-HCl (pH8), 0.05 M octyl- / 3-darcoside ImM EDTA, 0.5 mM PMS F). (4 ° C, 2.5 hours), followed by ultracentrifugation (100,000 g, 45 minutes). The supernatant was purified using 100 ⁇ L of anti-F1 ag antibody (Sigma). As a result, 4 ⁇ g of the desired recombinant human secretase of about 70 kDa was obtained.
  • Dulbecco's modified Eagle's medium (abbreviated as DMEM): Made by Mizu Pharmaceutical Co., Ltd.
  • FCS fetal calf serum
  • penicillin 5000 U / mL
  • streptomycin 5 mg / mL
  • Phosphate / saline buffer manufactured by Bio White Tucker
  • Block Ace (trade name): manufactured by Dainippon Pharma
  • Bovine serum albumin (abbreviated as BSA): Sigma Culture flask: Falcon
  • IMR-32 cells are the cells that were cultured in 750 mL, 10% carbon dioxide, and 90% air at 37 ° C until they became confluent (full). After culturing, IMR-32 cells are the cells that were cultured in 750 mL, 10% carbon dioxide, and 90% air at 37 ° C until they became confluent (full). After culturing, IMR-32 cells are the cells that are cultured in 750 mL, 10% carbon dioxide, and 90% air at 37 ° C until they became confluent (full). After culturing, IMR-32 cells are the cells.
  • the DMF solution containing the test substance was dissolved in 0.75 mL of 0.2% BSA / DMEM, added to the above plate, and further cultured for 24 hours.
  • a DMF solution containing no test substance dissolved in 0.75 mL of 0.2% BSA / DMEM was used.
  • the supernatant was collected and used as measurement samples for ⁇ (1-40) and ⁇ (1-42).
  • the BNT-77 antibody was used as a primary antibody.
  • ⁇ (1-40) was measured, ⁇ -27 antibody was used as a secondary antibody.
  • ⁇ (1-42) was measured, the BC-05 antibody was used as a secondary antibody.
  • BNT-77 antibody dissolved in 0.1% carbonate buffer (pH 9.6) at a concentration of 5 g / mL was added to a 96-well plate in an amount of 5 ⁇ L each, and left at 4 ° C for 1 hour. After the plate surface was washed three times with PBS, 125 ⁇ L of a blocking solution (25% block ace / 0.25% suloff CA / PBS) was added. In this state, it was stored at 4 ° C. until the supernatant was added in (1) above.
  • the plate surface is washed three times with PBS, and then the primary reaction buffer (20 mM phosphate buffer, H 7.0; 400 mM NaCl; 2 mM EDTA; 10% Block Ace; 0.2% BSA; 0.25% Sluroff CA) Add 25 ⁇ L Added.
  • the primary reaction buffer (20 mM phosphate buffer, H 7.0; 400 mM NaCl; 2 mM EDTA; 10% Block Ace; 0.2% BSA; 0.25% Sluroff CA) Add 25 ⁇ L Added.
  • A] 3 (1 -40) or A (1-42) standard diluted in 100 ⁇ L of supernatant and primary reaction buffer concentration of 1000, 200,
  • the plate was washed three times with PBS, and HRP-labeled in a buffer solution for secondary reaction (20 mM phosphate buffer, pH 7.0; 400 mM NaC1: 2 mM EDTA; 1% BSA) Secondary antibody (BA-27 antibody or BC-05 antibody, HRP: horseradish peroxidase) 100 x L ⁇ Additive [I. After ⁇ (1-40) was left at room temperature for 6 hours , Wash with PBS 6 times, and color reaction solution (TMB Peroxidase Substrate (trade name), ; £ ⁇ ] 3 ⁇ 4 && 1 (1 & 7

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Abstract

L'invention concerne les composés représentés par la formule générale (I) et des inhibiteurs de β-secrétase contenant ces composés : (I). A représente un noyau aromatique qui peut comprendre un substituant ; R1 représente arylalkyle C0-6, hétéroarylalkyle C0-6, alkyle C1-6 ou analogues, qui peuvent être chacun éventuellement substitués, R2 représente hydrogène, arylalkyle C0-6 ou hétéroarylalkyle C0-6 éventuellement substitués, ou analogues ; R3 représente arylalkyle C0-6, hétéroarylalkyle C0-6, alkyle C2-10, ou analogues, pouvant être chacun éventuellement substitué ; X et Y représentent chacun l'oxygène, ou analogue ; et chaque liaison représentée soit par une ligne continue soit par une ligne discontinue représente une liaison simple ou double.
PCT/JP2003/010045 2002-08-09 2003-08-07 Composés amino substitués et utilisation de ces composés WO2004014843A1 (fr)

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WO2009091016A1 (fr) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. Dérivé d'aminodihydrothiazine condensée
WO2010038686A1 (fr) 2008-09-30 2010-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé d'aminodihydrothiazine fusionné inédit
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US8426584B2 (en) 2011-01-21 2013-04-23 Eisai R&D Management Co., Ltd. Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives
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US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
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US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US9079914B2 (en) 2009-07-22 2015-07-14 Eisai R&D Management Co., Ltd. Fused aminodihydro-oxazine derivatives
US9139594B2 (en) 2009-07-22 2015-09-22 Eisai R&D Management Co., Ltd. Fused aminodihydropyrimidone derivatives
US9175013B2 (en) 2011-01-21 2015-11-03 Eisai R&D Management Co., Ltd. Fused aminodihydrothiazine derivatives
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity

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