[go: up one dir, main page]

WO2013005354A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

Info

Publication number
WO2013005354A1
WO2013005354A1 PCT/JP2011/078611 JP2011078611W WO2013005354A1 WO 2013005354 A1 WO2013005354 A1 WO 2013005354A1 JP 2011078611 W JP2011078611 W JP 2011078611W WO 2013005354 A1 WO2013005354 A1 WO 2013005354A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
reaction
group
optionally substituted
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2011/078611
Other languages
English (en)
Japanese (ja)
Inventor
小池　竜樹
中村　実
隆文 高井
雄一 梶田
敏郎 山下
直博 田家
悠平 宮野鼻
正鷹 村上
信 鎌田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2011147672A external-priority patent/JP2012136500A/ja
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Publication of WO2013005354A1 publication Critical patent/WO2013005354A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/20—Spiro-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound having an excellent amyloid ⁇ production inhibitory effect and useful as a therapeutic or preventive agent for mild cognitive impairment, Alzheimer's disease and the like.
  • Alzheimer's disease and mild cognitive impairment account for the majority of dementia, and the number of patients has increased significantly with the arrival of an aging society.
  • drugs such as acetylcholinesterase inhibitors as therapeutic drugs, and the development of drugs that stop or delay the progression of the disease state or drugs that have a preventive effect is desired.
  • acetylcholinesterase inhibitors As a cause of the onset of Alzheimer's disease, senile plaques and neuronal cell death formed by accumulation of a peptide consisting of about 40 amino acids called amyloid ⁇ (hereinafter sometimes simply referred to as A ⁇ ) are considered.
  • a ⁇ amyloid ⁇
  • a ⁇ is a peptide produced by processing by a degrading enzyme called secretase from a precursor transmembrane protein amyloid precursor (hereinafter sometimes simply referred to as APP), and its main molecular species Are A ⁇ 40 consisting of 40 amino acids and A ⁇ 42 consisting of 42 amino acids. Among them, A ⁇ 42 is likely to aggregate and is considered to play an important role in senile plaque formation or neuronal cell death (Non-patent Document 1). On the other hand, it is known that secretase as a cleaving enzyme includes ⁇ -secretase that cleaves the amino terminus and ⁇ -secretase that cleaves the carboxy terminus.
  • Non-patent Document 2 A curative treatment for Alzheimer's disease that inhibits these secretases and suppresses the production and secretion of A ⁇ has been studied (Non-patent Document 1).
  • ⁇ -secretase has not only APP processing but also functions such as activation by cleavage of Notch receptor, which plays an important role in cell differentiation. Development of a drug that specifically inhibits only the production of A ⁇ is expected (Non-patent Document 3).
  • Patent Document 1 as an amyloid ⁇ production inhibitor, the following formula:
  • Patent Document 2 discloses the following formula as a compound having a amyloid ⁇ level regulating action (use: neurodegenerative disease):
  • Patent Document 3 discloses a cinnamide compound (use: neurodegenerative diseases caused by amyloid ⁇ such as Alzheimer's disease and Down's syndrome) represented by the following formula:
  • Patent Document 4 discloses a polycyclic cinnamamide compound (use: neurodegenerative diseases caused by amyloid ⁇ such as Alzheimer's disease and Down's syndrome) represented by the following formula:
  • Patent Document 5 as an imidazolyl-phenyl-vinyl-heterocycle derivative (use: Alzheimer's disease), the following formula:
  • Patent Document 6 As a ⁇ -secretase modulator, the following formula:
  • Patent Document 7 discloses the following formula as an amyloid ⁇ production inhibitor:
  • Patent Document 8 discloses the following formula as an amyloid ⁇ production inhibitor:
  • Patent Document 9 discloses the following formula as an amyloid ⁇ production inhibitor:
  • Patent Document 10 discloses the following formula:
  • Patent Document 11 includes the following formula:
  • Patent Document 12 includes the following formula:
  • the present invention relates to a heterocyclic compound having an amyloid ⁇ production inhibitory action, which has a chemical structure different from that of known compounds (including the above-mentioned compounds), and a prophylactic agent for diseases such as mild cognitive impairment and Alzheimer's disease containing the heterocyclic compound Or it aims at providing a therapeutic agent.
  • Ring A represents an optionally substituted oxazole ring, an optionally substituted triazole ring, an optionally substituted imidazole ring, an optionally substituted pyridine ring, or an optionally substituted pyrazole ring.
  • Show Ring B represents an optionally substituted benzene ring, an optionally substituted pyridine ring, or an optionally substituted pyrimidine ring
  • Ring E represents a triazole ring in which either Z 1 or Z 2 is a nitrogen atom and the other is a carbon atom
  • Ring G represents an optionally substituted benzene ring, or an optionally substituted 5- or 6-membered aromatic heterocycle
  • X is a bond, -X 1 -, - O - , - OX 1 -, - X 1 O -, - S -, - SX 1 -, - X 1 S -, - NR 1 -, - NR 1 X 1- , or -X 1 NR 1- (Where X 1 represents an optionally substituted methylene group or an optionally substituted ethylene group; R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Y is a bond, -Y 1 -, - CO - , - Y 1 CO -, - CONR 2 -, or -CONR 2 Y 1 - (Where Y 1 represents an optionally substituted methylene group or an optionally substituted ethylene group; R 2 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ) Indicate R 3 represents a substituent, n represents an integer of 0 to 6,
  • a salt thereof according to [1] above represented by: [3] A medicament containing the compound or salt thereof according to [1] above; [4] The medicament according to [3] above, which is a prophylactic or therapeutic drug for mild cognitive impairment or Alzheimer's disease; [5] A method for inhibiting amyloid ⁇ production in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to a mammal; [6] A method for preventing or treating mild cognitive impairment or Alzheimer's disease in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal; [7] The compound of the above-mentioned [1] or a salt thereof for suppressing amyloid ⁇ production; [8] The compound or salt thereof according to [1] above for preventing or treating mild cognitive impairment or Alzheimer's disease; [9] Use of the compound of the above-mentioned [1
  • compound (I) Since the compound represented by formula (I) (hereinafter sometimes referred to as compound (I)) or a salt thereof, or a prodrug thereof has an excellent amyloid ⁇ production inhibitory activity, production of all amyloid ⁇ It is useful as a safe prophylactic or therapeutic agent for diseases that may be related to, such as mild cognitive impairment and Alzheimer's disease.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “C 1-6 alkyl group” and the “C 1-6 alkyl” in the substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl.
  • C 1-6 alkoxy group and the “C 1-6 alkoxy” in the substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, Examples thereof include tert-butoxy, 2-methylbutyloxy, pentyloxy, hexyloxy and the like.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, Examples thereof include tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl. 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, etc. .
  • examples of the “C 2-6 alkenyloxy group” include ethenyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, -Butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3 -Hexenyloxy, 5-hexenyloxy and the like.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, -Pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] Decyl, adamantyl and the like.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, bicyclo [2 2.1] heptyloxy, bicyclo [2.2.2] octyloxy, bicyclo [3.2.1] octyloxy, bicyclo [3.2.2] nonyloxy, bicyclo [3.3.1] nonyloxy, Bicyclo [4.2.1] nonyloxy, bicyclo [4.3.1] decyloxy, adamantyloxy and the like can be mentioned.
  • examples of the “C 6-14 aryl group” and the “C 6-14 aryl” in the substituent include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.
  • examples of the “C 6-10 aryl group” and the “C 6-10 aryl” in the substituent include phenyl, naphthyl (1-naphthyl, 2-naphthyl) and the like.
  • examples of the “C 6-10 aryloxy group” include phenyloxy, naphthyloxy (1-naphthyloxy, 2-naphthyloxy) and the like.
  • hydrocarbon ring group examples include the above “C 3-10 cycloalkyl group” and “C 6-14 aryl group”.
  • C 7-13 aralkyl group and “C 7-13 aralkyl” in a substituent include benzyl, phenethyl, naphthylmethyl (1-naphthylmethyl, 2-naphthylmethyl), biphenylylmethyl, etc. Is mentioned.
  • examples of the “C 7-13 aralkyloxy group” include benzyloxy, phenethyloxy, naphthylmethyloxy (1-naphthylmethyloxy, 2-naphthylmethyloxy), biphenylylmethyloxy and the like.
  • examples of the “C 1-6 alkyl-carbonyloxy group” include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy, pentanoyloxy, 3- Examples thereof include methylbutanoyloxy, 2-methylbutanoyloxy, 2,2-dimethylpropanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • examples of the “C 1-6 alkyl-carbonylamino group” include acetylamino, propanoylamino, butanoylamino, 2-methylpropanoylamino, pentanoylamino, 3- Examples thereof include methylbutanoylamino, 2-methylbutanoylamino, 2,2-dimethylpropanoylamino, hexanoylamino, heptanoylamino and the like.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.
  • examples of the “C 7-13 aralkylthio group” include benzylthio, phenethylthio, naphthylmethylthio (1-naphthylmethylthio, 2-naphthylmethylthio), biphenylylmethylthio and the like.
  • examples of the “C 6-14 arylthio group” include phenylthio, naphthylthio, anthrylthio, phenanthrylthio, acenaphthylenylthio, biphenylylthio and the like.
  • C 1-6 alkylsulfonyl group includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “aromatic heterocyclic group” include an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and nitrogen other than a carbon atom as a ring-constituting atom.
  • examples thereof include 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic groups and condensed aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from atoms.
  • examples of the condensed aromatic heterocyclic group include these 4 to 7-membered monocyclic aromatic heterocyclic groups and 5- or 6-membered aromatic heterocyclic rings containing 1 or 2 nitrogen atoms (eg, pyrrole).
  • Imidazole pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene), or a group in which one or two benzene rings are condensed.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl pyridazinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl eg, 1 -Imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl eg, 2-thiazolyl, 4-thi
  • non-aromatic heterocyclic group for example, as a ring-constituting atom, in addition to a carbon atom, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and Examples thereof include 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atoms.
  • condensed non-aromatic heterocyclic group examples include, for example, these 4- to 7-membered monocyclic non-aromatic heterocyclic groups and 5- or 6-membered aromatic or non-aromatic groups containing 1 or 2 nitrogen atoms.
  • Heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom eg, thiophene
  • a benzene ring examples include a group having two condensed groups.
  • Pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • homopiperidinyl eg, homopiperidino, 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl
  • tetrahydropyridyl eg, 1,2,3,6-tetrahydropyridin-1-yl
  • dihydropyridyl eg, 2,3-dihydropyridin-4-yl
  • morpholinyl eg, morpholino, 2- Morpholinyl
  • thiomorpholinyl eg, thiomorpholino
  • 1,1-dioxidethiomorpholinyl eg, 1,1-dioxidethiomorpholinyl
  • examples of the “5- or 6-membered aromatic heterocycle” include, for example, oxygen atoms and sulfur atoms other than carbon atoms as ring-constituting atoms (the sulfur atoms may be oxidized). And 5- or 6-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen atoms.
  • Suitable examples of the “5- or 6-membered aromatic heterocycle” include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, Examples include thiadiazole, triazole, tetrazole, and triazine.
  • examples of the “C 1-6 alkylene group” include methylene, ethylene, propylene, —CH (CH 3 ) —CH 2 —, —CH 2 —CH (CH 3 ) —.
  • Ring A represents an optionally substituted oxazole ring, an optionally substituted triazole ring, an optionally substituted imidazole ring, an optionally substituted pyridine ring, or an optionally substituted pyrazole ring. Show.
  • Optionally substituted oxazole ring “optionally substituted triazole ring”, “optionally substituted imidazole ring”, “optionally substituted pyridine ring” and “ The “oxazole ring”, “triazole ring”, “imidazole ring”, “pyridine ring” and “pyrazole ring” of the “optionally substituted pyrazole ring” are 1 to 4 (preferably 1) at substitutable positions. Up to 3, more preferably 1 or 2) substituents.
  • a substituent for example, (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 3-10 cycloalkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group; (2) (a) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, (e) a C 1-6 alkylthio group, (f) a C 1-6 alkylsulfonyl group, and (g) a C 6-14 aryl group optionally substituted with 1 to 3 substituents selected from a cyano group; (3) (a) a C 1-6 alkyl group which
  • a ring group (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group; (5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an amino group optionally mono- or di-substituted with a substituent selected from a halogen atom; (6) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aminocarbonyl group optionally mono- or
  • each substituent may be the same or different.
  • the two substituents together with the nitrogen atom to which they are bonded together may be substituted nitrogen-containing A heterocycle may be formed.
  • the “nitrogen-containing heterocycle” of such “optionally substituted nitrogen-containing heterocycle” includes, for example, at least one nitrogen atom in addition to carbon atoms as a ring-constituting atom, and further an oxygen atom, sulfur atom (The sulfur atom may be oxidized) and a 5- to 7-membered nitrogen-containing heterocycle which may contain 1 or 2 heteroatoms selected from nitrogen atoms.
  • nitrogen-containing heterocycle examples include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like.
  • the “nitrogen-containing heterocycle” may have 1 to 5 (preferably 1 to 4) substituents at substitutable positions.
  • substituents include: (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, (e) An oxo group and the like can be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • Ring A is preferably an optionally substituted oxazole ring or an optionally substituted imidazole ring, more preferably 1 to 3 (preferably 1 or 2, more preferably 1).
  • An oxazole ring (preferably bonded to ring B at the 5-position of the oxazole ring), an imidazole ring (preferably the imidazole ring), which may be substituted with a C 1-6 alkyl group (preferably methyl) of Of 2-methyloxazole (preferably bound to ring B at the 5-position of the oxazole ring), 4-methylimidazole (preferably the imidazole ring).
  • a C 1-6 alkyl group preferably methyl
  • Ring B represents an optionally substituted benzene ring, an optionally substituted pyridine ring, or an optionally substituted pyrimidine ring.
  • the “ring” may have 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include the “optionally substituted oxazole ring”, the “optionally substituted triazole ring”, the “optionally substituted imidazole ring” and the “substituted” represented by the ring A described above.
  • the “oxazole ring”, “triazole ring”, “imidazole ring”, “pyridine ring” and “pyrazole ring” of the “optionally substituted pyridine ring” and “optionally substituted pyrazole ring” may have The group illustrated as a good substituent is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • Ring B is preferably an optionally substituted benzene ring or an optionally substituted pyridine ring, more preferably a halogen atom (preferably a fluorine atom) and a C 1-6 alkoxy group (preferably Is a benzene ring or a pyridine ring optionally substituted with 1 to 3 (preferably 1 or 2, more preferably 1) substituents selected from methoxy).
  • a halogen atom preferably a fluorine atom
  • C 1-6 alkoxy group preferably Is a benzene ring or a pyridine ring optionally substituted with 1 to 3 (preferably 1 or 2, more preferably 1) substituents selected from methoxy).
  • Ring E represents a triazole ring in which either Z 1 or Z 2 is a nitrogen atom and the other is a carbon atom.
  • formula (I) is represented by formula (I ′):
  • Ring E is preferably a triazole ring in which Z 1 is a nitrogen atom and Z 2 is a carbon atom.
  • Ring G represents an optionally substituted benzene ring or an optionally substituted 5- or 6-membered aromatic heterocycle.
  • Benzene ring and “5- or 6-membered aromatic heterocycle” of “optionally substituted benzene ring” and “optionally substituted 5- or 6-membered aromatic heterocycle” represented by ring G are: It may have 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include the “optionally substituted oxazole ring”, the “optionally substituted triazole ring”, the “optionally substituted imidazole ring” and the “substituted” represented by the ring A described above.
  • the “oxazole ring”, “triazole ring”, “imidazole ring”, “pyridine ring” and “pyrazole ring” of the “optionally substituted pyridine ring” and “optionally substituted pyrazole ring” may have The group illustrated as a good substituent is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • Ring G is preferably an optionally substituted benzene ring, more preferably a halogen atom (preferably a chlorine atom or a fluorine atom), or 1 to 3 halogen atoms (preferably a fluorine atom). 1 to 3 (preferably 1 or 2) substituents selected from an optionally substituted C 1-6 alkyl group (preferably methyl) and a C 1-6 alkoxy group (preferably methoxy) A benzene ring optionally substituted by
  • X is a bond, -X 1 -, - O - , - OX 1 -, - X 1 O -, - S-, SX 1 -, - X 1 S -, - NR 1 -, - NR 1 X 1 -, Or -X 1 NR 1- (Where X 1 represents an optionally substituted methylene group or an optionally substituted ethylene group; R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ) Indicates.
  • a substituent for example, (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 3-10 cycloalkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group; (2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, (e) a C 1-6 alkylthio group, (f) a C 1-6 alkylsulfonyl group, and (g) a C 6-14 aryl group optionally substituted with 1 to 3 substituents selected from a cyano group; (3) (a) a C 1-6 alkyl group which may be substituted with 1 to
  • a ring group (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group; (5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an amino group optionally mono- or di-substituted with a substituent selected from a halogen atom; (6) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aminocarbonyl group optionally mono- or
  • X 1 is preferably a methylene group or an ethylene group.
  • X is preferably a bond, -X 1 -, - O - , - OX 1 -, - X 1 O -, - S -, - NR 1 - (wherein, X 1 and R 1 are as above defined a shown), more preferably a bond, -X 1.
  • X 1' Represents a methylene group or an ethylene group.
  • Y is a bond, -Y 1 -, - CO - , - Y 1 CO -, - CONR 2 -, or -CONR 2 Y 1 - (Where Y 1 represents an optionally substituted methylene group or an optionally substituted ethylene group; R 2 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ) Indicates.
  • the “C 1-6 alkyl group” of the “C 1-6 alkyl group” may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include “methylene group” and “ethylene group” of “optionally substituted methylene group” and “optionally substituted ethylene group” represented by X 1 , and R 1. in the group exemplified as the "C 1-6 alkyl group” substituent optionally possessed by the "optionally substituted C 1-6 alkyl group” and the like shown. When there are two or more substituents, each substituent may be the same or different.
  • Y 1 is preferably a methylene group or an ethylene group, each of which may be substituted with a hydroxy group, and more preferably a methylene group, —CH 2 —CH 2 —, —C (CH 3 ) (OH). -.
  • R 2 is preferably 1 to 3 selected from (i) a hydrogen atom, or (ii) a halogen atom (preferably a fluorine atom) and a C 3-6 cycloalkyl group (preferably a cyclopropyl group). Or a C 1-6 alkyl group (preferably a methyl group, an ethyl group, or an isopropyl group) that may be substituted with a substituent, more preferably a hydrogen atom, a methyl group, an ethyl group, 2, 2, 2 -A trifluoroethyl group or a cyclopropylmethyl group.
  • Y is preferably, -Y 1 -, - Y 1 CO -, - CONR 2 -, - CO -, - CONR 2 Y 1 - (wherein each symbol is as defined above.), And more preferably, -Y 1 '-, - Y 1' CO -, - CONR 2 '-, - CO -, - CONR 2' Y 1 '- [ wherein, Y 1' are respectively substituted with a hydroxy group And optionally represents a methylene group or an ethylene group, and R 2 ′ represents (i) a hydrogen atom, or (ii) a halogen atom (preferably a fluorine atom) and a C 3-6 cycloalkyl group (preferably a cyclo C 1-6 alkyl group (preferably methyl group, ethyl group, isopropyl group) which may be substituted with 1 to 3 substituents selected from propyl group).
  • R 2 ′ is (i) a hydrogen atom or (ii) a halogen atom (preferably fluorine Atom) and a C 1-6 alkyl group (preferably a methyl group, ethyl group) which may be substituted with 1 to 3 substituents selected from a C 3-6 cycloalkyl group (preferably a cyclopropyl group) Group, isopropyl group) (preferably a hydrogen atom, methyl group, ethyl group, 2,2,2-trifluoroethyl group, cyclopropylmethyl group). ].
  • R 3 represents a substituent.
  • N is preferably 0 or 1, more preferably 0.
  • the compound represented by the formula (I) is preferably Ring A is substituted with an optionally substituted oxazole ring [preferably 1 to 3 (preferably 1 or 2, more preferably 1) C 1-6 alkyl group (preferably methyl).
  • Optionally oxazole ring or an optionally substituted imidazole ring [preferably 1 to 3 (preferably 1 or 2, more preferably 1) C 1-6 alkyl group (preferably An imidazole ring optionally substituted with methyl);
  • Ring B is an optionally substituted benzene ring [preferably 1 to 3 (preferably 1) selected from a halogen atom (preferably a fluorine atom) and a C 1-6 alkoxy group (preferably methoxy) Or a benzene ring which may be substituted with two, more preferably one) substituents, or a pyridine ring which may be substituted [preferably a halogen atom (preferably a fluorine atom) and C 1- A pyridine ring optionally substituted with 1 to 3 (preferably 1
  • each symbol is of the same meaning as above) ⁇ preferably, -Y 1 '-, - Y 1' CO -, - CONR 2 '-, - CO- or -CONR 2' Y 1 '- [wherein, Y 1' may be respectively substituted with a hydroxy group, a methylene R 2 ′ is selected from (i) a hydrogen atom, or (ii) a halogen atom (preferably a fluorine atom) and a C 3-6 cycloalkyl group (preferably a cyclopropyl group).
  • a C 1-6 alkyl group (preferably a methyl group, an ethyl group, or an isopropyl group) that may be substituted with 1 to 3 substituents. And more preferably a methylene group, —CH 2 —CH 2 —, —C (CH 3 ) (OH) —, —CH 2 —CH (OH) —, —CH (OH) —CH 2 —, -CH 2 CO -, - CONR 2 '-, - CO- or -CONR 2' -CH 2 - [wherein, R 2 'is (i) hydrogen atom or (ii) a halogen atom (preferably, fluorine Atom) and a C 1-6 alkyl group (preferably a methyl group, ethyl group) which may be substituted with 1 to 3 substituents selected from a C 3-6 cycloalkyl group (preferably a cyclopropyl group) Group, isopropyl group) (preferably a hydrogen
  • the compound represented by formula (I) is preferably a compound represented by formula (I ′), more preferably in formula (I ′): Ring A is substituted with an optionally substituted oxazole ring [preferably 1 to 3 (preferably 1 or 2, more preferably 1) C 1-6 alkyl group (preferably methyl).
  • Optionally oxazole ring or an optionally substituted imidazole ring [preferably 1 to 3 (preferably 1 or 2, more preferably 1) C 1-6 alkyl group (preferably An imidazole ring optionally substituted with methyl);
  • Ring B is an optionally substituted benzene ring [preferably 1 to 3 (preferably 1) selected from a halogen atom (preferably a fluorine atom) and a C 1-6 alkoxy group (preferably methoxy) Or two, more preferably one) benzene ring optionally substituted with substituents];
  • Ring G may be substituted with an optionally substituted benzene ring [preferably substituted with halogen atom (preferably chlorine atom, fluorine atom) or 1 to 3 halogen atoms (preferably fluorine atom).
  • X is a bond, —X 1 —, —O—, —OX 1 —, —X 1 O—, or —S— (wherein X 1 is as defined above) [preferably a bond hand, -X 1 '-, - O -, - OX 1' -, - X 1 'O-, or -S- (wherein, X 1' represents a methylene group or an ethylene group,.), and And more preferably a bond, a methylene group, an ethylene group, —O—CH 2 —, —CH 2 —O—, or —S—]; Y is —Y 1 —, —CONR 2 —, —CO—, or —CONR 2 Y 1 —
  • C 1-6 alkyl group (preferably methyl group, ethyl group, isopropyl group) optionally substituted with one substituent (preferably hydrogen atom, methyl group, ethyl group, 2,2,2-trimethyl group) Fluoroethyl group, cyclopropylmethyl group).
  • substituent preferably hydrogen atom, methyl group, ethyl group, 2,2,2-trimethyl group
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the compound (I) and salts thereof are collectively referred to as the compound of the present invention.
  • Compound (I) and the starting compound thereof can be prepared by a method known per se, for example, the following production methods A, B, C, D, E, F, G, H, I, J, K, L, M or N Can be produced by the method described in 1. above.
  • room temperature usually indicates 0 to 30 ° C.
  • each symbol in the chemical structural formula described in the production method has the same meaning as described above unless otherwise specified.
  • the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified.
  • a commercially available product can be used as it is.
  • the corresponding precursor also has the same substituent.
  • the raw material compound has a reactive functional group such as amino, carboxy, hydroxy, and heterocyclic group
  • these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Introduction or removal of these protecting groups a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to And so on.
  • P 1 to P 6 are a protecting group for a nitrogen atom, a protecting group for a hydroxy group, or a hydrogen atom of amine or amide, and those known per se can be used.
  • P 1 to P 6 are preferably tert-butyl carbamate group, benzyl carbamate group, benzyl group, methyl group, ethyl group, tert-butyl group, acetyl group and the like.
  • Examples of the “leaving group” represented by LG 1 to LG 15 include, for example, a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkoxy group (eg, methoxy group) C 1-6 alkylthio group (eg, methylthio group, ethylthio group, etc.), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C 6-10 arylsulfonyloxy (For example, benzenesulfonyloxy, p-toluenesulfonyloxy and the like), C 1-6 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl and the like) and the like are used.
  • Each step described below can be performed without solvent or by dissolving or suspending in an appropriate solvent, and two or more solvents may be mixed and used at an appropriate ratio.
  • two or more solvents may be mixed and used at an appropriate ratio.
  • the following solvents are used.
  • Ethers such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol: Aromatic hydrocarbons such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane: Saturated hydrocarbons such as benzene, chlorobenzene, toluene, xylene: Amides such as cyclohexane and hexane: Halogenated hydrocarbons such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide: Nitriles such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane: Sulfoxides such as acetonitrile and propionitrile: Aromatic organic bases such as dimethyl sulfoxide: Acid
  • Inorganic bases Basic salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide: Organic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate: Triethylamine, diethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5- Diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole, piperidine, pyrrolidine, etc
  • Metal alkoxides Alkali metal hydrides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide: Metal amides such as sodium hydride and potassium hydride: Organic lithiums such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide: Methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.
  • Inorganic acids Organic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid: Lewis acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, trifluoromethanesulfonic acid: Boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.
  • Compound (I ′) can be produced by a series of reaction steps from Step A-1 to Step A-4.
  • the above reaction scheme illustrates the case where n is 0 (referred to as compound I′-1).
  • n is 1 to 6
  • the corresponding raw material compound into which n R 3 are introduced may be used, or n R 3 may be introduced at a predetermined position during the production process.
  • Compound (4) is a carboxylic acid (2), or can be the after reactive derivative with the compound (3) is reacted, for removing the protecting group P 1.
  • P 1 is a hydrogen atom, removal of the protecting group can be omitted.
  • Examples of the reactive derivative of the carboxylic acid include acid halides such as acid chlorides and acid bromides, acid amides with pyrazole, imidazole and benzotriazole, mixed acid anhydrides and acids with acetic acid, propionic acid, butyric acid and the like Azide, diethoxyphosphate, diphenoxyphosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide, Active esters such as esters with 1-hydroxybenzotriazole, esters with 6-chloro-1-hydroxybenzotriazole, esters with 1-hydroxy-1H-2-pyridone, 2-pyridylthioester, 2-benzothiazolylthio S Activity thioesters such as Le like.
  • acid halides such as acid chlorides and acid bromides
  • the carboxylic acid (2) may be directly reacted with the compound (3) in the presence of a suitable condensing agent.
  • suitable condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-disubstituted carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, and N, N ′.
  • -Dehydrating agents such as azolides such as carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, 2-chloromethylpyridinium iodide, 2-fluoro-1- 2-halogenopyridinium salts such as methylpyridinium iodide, phosphorylcyanides such as diethylphosphoryl cyanide, 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexa Fluorophosphate (HATU), O- (7-azabenzotriazole-1 -Yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TATU) and the like.
  • azolides such as carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-d
  • the reaction is considered to proceed through a reactive derivative of carboxylic acid (2).
  • Carboxylic acid (2) or a reactive derivative thereof is usually used in an amount of about 0.2 to 5 mol, preferably about 0.5 to 2 mol, per 1 mol of compound (3).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases A solvent such as a solvent or a mixed solvent thereof is preferable.
  • the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing them from the reaction system.
  • a deoxidizer include basic salts and organic bases.
  • basic salts, organic bases, and the like can be used.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 70 ° C.
  • Compound (6) can be produced by reacting compound (4) with carboxylic acid (5) or a reactive derivative thereof. The reaction may be performed according to the same method as in step A-1.
  • Step A-3 Compound (7) can be produced by subjecting compound (6) to an intramolecular cyclization reaction.
  • the reaction can be produced according to a method known per se for producing an oxadiazole ring or a method analogous thereto, for example, a method using a dehydrating agent.
  • the dehydrating agent include diphosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosgene, N, N′-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, acetic anhydride, acetyl chloride, sodium dioxide, thionyl chloride, methanesulfonyl chloride.
  • the dehydrating agent is used in an amount of about 1 to 100 mol or more per 1 mol of compound (6).
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, halogenated hydrocarbons, esters, ketones, nitriles or a mixed solvent thereof are preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-30 hr, preferably 1 hr-10 hr.
  • the reaction temperature is usually 0 to 150 ° C., preferably 0 to 100 ° C.
  • Step A-4) Compound (I′-1) can be produced by converting the leaving group LG 1 of compound (7) to an amino group and then subjecting it to an intramolecular cyclization reaction.
  • the method for converting the leaving group LG 1 to an amino group may be a method known per se or a method analogous thereto, for example, a method of deprotecting phthalic acid after the leaving group LG 1 is substituted with phthalimide. And a method of reducing the azide group after substituting the leaving group LG 1 with an azide group.
  • the intramolecular cyclization reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 72 hr, preferably 30 min to 24 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C.
  • Compounds (2), (3), (4), (5), (6) and (7) may be commercially available products, or can be produced by a method known per se or a method analogous thereto. .
  • Compound (5) can be produced by reacting compound (8) with compound (9) in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, and organic lithiums.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (8).
  • Compound (9) is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (8).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • inert gas stream such as argon gas or nitrogen gas.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compounds (8) and (9) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Y 2 represents a bond, an optionally substituted methylene group, or an optionally substituted ethylene group;
  • R 4 represents a C 1-6 alkyl group;
  • Y 2 "optionally substituted methylene group” represented by and “optionally substituted ethylene group” be represented by Y 1 and "optionally substituted methylene group", “optionally substituted The meaning is the same as “good ethylene group”.
  • Compound (I′-2) can be produced from compound (11) by a series of reaction steps from Step C-4 to Step C-7.
  • Compound (11) can be produced from compound (10) according to step C-1 or from compound (12) according to step C-3.
  • Compound (12) can be produced from compound (10) according to Step C-2.
  • Compound (11) can be produced by reacting compound (10) with an alkylating agent.
  • the alkylating agent include trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate.
  • the alkylating agent is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (10).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, halogenated hydrocarbons, nitriles, sulfoxides, or a mixed solvent thereof. Etc. are preferred.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably 0 to 100 ° C.
  • Compound (11) can also be produced by reacting compound (10) with a halogenating agent.
  • the halogenating agent include phosphorus oxychloride, thionyl chloride and the like.
  • the halogenating agent is used in an amount of about 1-100 mol or more per 1 mol of compound (10). This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C.
  • Compound (12) can be produced by reacting compound (10) with a thiocarbonylating agent.
  • the thiocarbonylating agent include Lawesson's reagent.
  • the thiocarbonylating agent is used in an amount of about 0.5-10 mol, preferably about 0.5-2 mol, per 1 mol of compound (10).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, halogenated hydrocarbons, nitriles, sulfoxides, or a mixed solvent thereof. Etc. are preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C.
  • Compound (11) can be produced by reacting compound (12) with an alkylating agent.
  • the alkylating agent include iodomethane and iodoethane.
  • the alkylating agent is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (12).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent or a mixed solvent thereof is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably 0 to 100 ° C.
  • Compound (13) can be produced by reacting compound (11) with compound (4).
  • Compound (4) is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (11).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent or a mixed solvent thereof is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 20 to 250 ° C., preferably 20 to 150 ° C.
  • Compound (15) can be produced by reacting compound (13) with compound (14) in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • Compound (14) is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • inert gas stream such as argon gas or nitrogen gas.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (16) can be produced by subjecting compound (15) to a reduction reaction.
  • New Experimental Chemistry Course, Volumes 14 and 15 (edited by Chemical Society of Japan), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, Academic Press, Inc., 1989; The method described in Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc. may be used.
  • Compound (I′-2) can be produced by subjecting compound (16) to an intramolecular cyclization reaction.
  • the intramolecular cyclization reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, organic acids, inorganic Solvents such as acids and water or a mixed solvent thereof are preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 72 hr, preferably 30 min to 24 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C.
  • a base may be used as an additive.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 0.1-10 mol, preferably about 0.1-2 mol, per 1 mol of compound (13).
  • Compound (I′-2) can also be produced by subjecting compound (16) to a hydrolysis reaction and then to an intramolecular cyclization reaction.
  • the hydrolysis reaction can also be performed in the presence of an acid or a base for the purpose of promoting the reaction.
  • Examples of the acid include acid chlorides such as acetyl chloride, inorganic acids, organic acids, Lewis acids and the like.
  • Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides and the like.
  • the acid is used in an amount of about 0.01 to 100 mol, preferably about 0.1 to 20 mol, per 1 mol of compound (16).
  • the base is used in an amount of about 0.01-100 mol, preferably about 0.1-20 mol, per 1 mol of compound (16).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 30 min-20 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 0 to 140 ° C.
  • the intramolecular cyclization reaction may be performed according to the same method as in step A-2.
  • Compound (I′-2) can also be produced directly from compound (15) by Step C-6.
  • Compound (I′-3) can be produced from compound (13) by a series of reaction steps from Step D-1 to Step D-2.
  • Compound (I′-3) can be produced by subjecting compound (18) to an intramolecular cyclization reaction. The reaction may be performed according to the same method as in step C-7. Compound (I′-3) can also be produced directly from compound (13) by Step D-1.
  • Compounds (13), (17) and (18) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • compound (I) is referred to as compound (I′-4).
  • Compound (I′-4) is encompassed in compound (I′-2).
  • Compound (I′-4) can be produced from compound (13) by a series of reaction steps from Step E-1 to Step E-4.
  • Compound (19) can be produced by reacting compound (13) with oxygen in the presence of a base.
  • a base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • Oxygen is used in an amount of about 1 mol or more per 1 mol of compound (13).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (21) can be produced by reacting compound (19) with compound (20) in the presence of a base.
  • the reaction may be performed according to the same method as in step C-5.
  • Compound (22) can be produced by subjecting compound (21) to a reduction reaction.
  • the reaction may be performed according to the same method as in step C-6.
  • Compound (I-4) can be produced by subjecting compound (22) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step C-7.
  • Compound (I′-4) can also be produced directly from compound (21) by Step E-3.
  • Compounds (13), (19), (20), (21) and (22) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • compound (I) which is is referred to as compound (I′-5).
  • Compound (I′-5) is encompassed in compound (I′-2).
  • Compound (I′-5) can be produced from compound (13) by a series of reaction steps from Step F-1 to Step F-3.
  • Compound (23) can be produced by reacting compound (13) with the corresponding carbonyl compound in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • the carbonyl compounds include paraformaldehyde, acetaldehyde, acetone and the like.
  • the carbonyl compounds are used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13). This reaction is advantageously performed using a solvent inert to the reaction.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • this reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (I′-5) can be produced by subjecting compound (25) to an intramolecular cyclization reaction in the presence of a cyclizing agent.
  • a cyclizing agent include a mixture of a phosphine reagent and an azo compound, a phosphorane reagent, and the like.
  • the phosphine reagent include triphenylphosphine and tributylphosphine.
  • the azo compound include diethyl azodicarboxylate and 1,1 ′-(azodicarbonyl) piperidine.
  • the phosphorane reagent include cyanomethylene tributylphosphorane.
  • the cyclizing agent is used in an amount of about 1-50 mol, preferably about 1-10 mol, per 1 mol of compound (25).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 60 ° C.
  • Compounds (13), (23), (24) and (25) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • compound (I) which is is referred to as the compound (I′-6).
  • Compound (I′-6) is encompassed in compound (I′-2).
  • Compound (I′-6) can be produced from compound (13) by a series of reaction steps from Step G-1 to Step G-3.
  • Compound (27) can be produced by reacting compound (13) with compound (26) in the presence of a base.
  • the reaction may be performed according to the same method as in step C-5.
  • Compound (28) can be produced by subjecting compound (27) to a reduction reaction.
  • New Experimental Chemistry Course, Volumes 14 and 15 (edited by Chemical Society of Japan), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, Academic Press, Inc., 1989; The method described in Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc. may be used.
  • Compound (I′-6) can be produced by subjecting compound (28) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step C-7.
  • Compound (I′-6) can also be produced directly from compound (27) by Step G-2.
  • Compounds (13), (26), (27) and (28) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • X 3 represents —OX 2 —, —SX 2 —, or —NR 6 X 2 —;
  • R 6 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Optionally substituted C 1-6 alkyl group represented by R 6 are the same meaning as "optionally substituted C 1-6 alkyl group” represented by R 1. Partial structure (1):
  • compound (I) which is is referred to as compound (I′-7).
  • Compound (I′-7) is encompassed in compound (I′-2).
  • Compound (I′-7) can be produced from compound (13) by a series of reaction steps from Step H-1 to Step H-3.
  • Compound (29) can be produced by reacting compound (13) with a halogenating agent in the presence of a base.
  • a base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • the halogenating agent include halogen, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-fluoro-N′-chloromethyltriethylenediamine bis (tetrafluoroborate) and the like.
  • the halogenating agent is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (13).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (31) can be produced by reacting compound (29) with compound (30) and then removing protecting group P 4 .
  • P 4 is a hydrogen atom, removal of the protecting group can be omitted.
  • Compound (30) is used in an amount of about 1 mol or more, preferably about 1-5 mol, per 1 mol of compound (29).
  • a base may be added. Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (29). This reaction is advantageously performed using a solvent inert to the reaction.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (I′-7) can be produced by subjecting compound (31) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step C-7.
  • Compound (I′-7) can also be produced directly from compound (29) by Step H-2.
  • Compounds (13), (29), (30) and (31) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (I′-3) can be produced from compound (I′-2) according to Step I-1.
  • Step I-1) Compound (I′-3) can be produced by reacting compound (I′-2) with compound (32) in the presence of a base. The reaction may be performed according to the same method as in step B-1.
  • Compound (32) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.
  • Compound (34) can be produced by reacting compound (10) with compound (33) in the presence of a base.
  • the reaction may be performed according to the same method as in step C-5.
  • Compound (35) can be produced by subjecting compound (34) to a reduction reaction.
  • the reaction may be performed according to the same method as in step C-6.
  • Compound (36) can be produced by subjecting compound (35) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step C-7.
  • Compound (36) can also be produced directly from compound (34) by Step J-2.
  • Compound (38) can be produced by reacting compound (36) with compound (37) in the presence of a base. The reaction may be performed in the same manner as in step I-1.
  • Compound (I′-3) is obtained by reacting compound (38) with an alkylating agent or halogenating agent according to the same method as in Step C-1, followed by reaction with hydrazines. It can be produced by subjecting to a reaction with compound (2) according to the same method as in step A-2.
  • the hydrazines include hydrazine and hydrazine monohydrate.
  • the hydrazine is used in an amount of about 1-10 mol, preferably about 1-5 mol, per 1 mol of compound (38).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 20 to 250 ° C., preferably 20 to 150 ° C.
  • the compounds (2), (10), (33), (34), (35), (36), (37) and (38) commercially available products may be used, and methods known per se or their equivalents may be used. It can also be manufactured by other methods.
  • Compound (I′-3) can be produced from compound (38) according to Step K-1.
  • Compound (I′-3) can be produced by subjecting compound (38) to a reaction with an alkylating agent or a halogenating agent followed by a reaction with compound (4).
  • the reaction of compound (38) with an alkylating agent or halogenating agent may be carried out according to the same method as in Step C-1.
  • the reaction with compound (4) may be carried out in the same manner as in step C-4.
  • Compounds (4) and (38) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (I′-8) can be produced from compound (29) by a series of reaction steps from Step L-1 to Step L-2.
  • Compound (40) can be produced by reacting compound (29) with compound (39). The reaction may be performed according to the same method as in step H-2.
  • Compound (I′-8) can be produced by subjecting compound (40) to a cyclization reaction in the presence of a cyclizing agent.
  • a cyclizing agent include polyphosphoric acid and Eaton reagent.
  • the cyclizing agent is used in an amount of about 1-100 mol or more per 1 mol of compound (40).
  • a cyclizing agent may be used as a solvent.
  • This reaction may be performed using a solvent inert to the reaction.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons and halogenated hydrocarbons, or mixed solvents thereof are preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 20 to 200 ° C., preferably 50 to 150 ° C.
  • Compound (I′-8) can be further converted into a desired compound by performing a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc., singly or in combination of two or more thereof. it can.
  • a known substituent conversion reaction condensation reaction, oxidation reaction, reduction reaction, etc., singly or in combination of two or more thereof. it can.
  • These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations (ORGANIC ⁇ ⁇ FUNCTIONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PRESS, INC.) Published in 1989. ; Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989, etc.
  • a reaction in which a corresponding Grignard reagent is allowed to act to convert a ketone group into a tertiary alcohol group or a reaction in which a ketone group is reduced with a reducing agent such as sodium borohydride and converted into a secondary alcohol group.
  • a reducing agent such as sodium borohydride
  • Compounds (29), (39) and (40) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (2) can be produced from compound (41b) according to step M-1, from compound (41c) according to step M-4, or from compound (41a) according to step M-5.
  • Compound (41b) can be produced from compound (41a) according to Step M-3, and Compound (41c) can be produced from compound (41a) according to Step M-2.
  • Compound (2) can be produced by removing the protecting group of compound (41b). Removal of the protecting group, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) according to the method as described in, Just do it.
  • Compound (2) can be produced by subjecting compound (41c) to a hydrolysis reaction.
  • the hydrolysis reaction may be performed according to the same method as in Step C-7.
  • Compound (2) can be produced by reacting compound (41a) with carbon dioxide in the presence of a base.
  • Carbon dioxide may be used in an amount of about 1 mol or more per 1 mol of the compound (41a) to carry out the reaction in a carbon dioxide stream.
  • dry ice can also be used as a carbon dioxide source.
  • the base include alkali metal hydrides, metal amides, organolithiums and the like.
  • the base is used in an amount of about 1-2 mol, preferably about 1-1.5 mol, per 1 mol of compound (41a).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (2) can also be produced by subjecting compound (41a) to a reaction with carbon monoxide in the presence of a metal catalyst and water.
  • Carbon monoxide may be used in an amount of about 1 mol or more per 1 mol of compound (41a) to carry out the reaction in a carbon monoxide stream.
  • Water is used in an amount of about 1 mol or more per 1 mol of compound (41a) and can also be used as a solvent.
  • the metal catalyst examples include palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), tris (Dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, complex of palladium (II) acetate and 1,1′-bis (diphenylphosphino) ferrocene Etc.] is preferable.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl
  • the reaction is usually performed in the presence of a base.
  • the base include inorganic bases, organic bases, basic salts and the like.
  • the metal catalyst is used in an amount of about 0.000001 to 5.0 mol, preferably about 0.0001 to 1.0 mol, per 1 mol of compound (41a).
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (41a).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, etc.
  • a solvent or a mixed solvent thereof is preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 5 min to 100 hr.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 100 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (41b) can be produced by reacting compound (41a) with an alkyl chlorocarbonate or dialkyl carbonate in the presence of a base.
  • alkyl chlorocarbonates include methyl chlorocarbonate and ethyl chlorocarbonate.
  • dialkyl carbonates include dimethyl carbonate and diethyl carbonate.
  • the alkyl chlorocarbonates or dialkyl carbonates are used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (41a).
  • the base include alkali metal hydrides, metal amides, organolithiums and the like.
  • the base is used in an amount of about 1-2 mol, preferably about 1-1.5 mol, per 1 mol of compound (41a).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-24 hr.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably ⁇ 78 to 50 ° C.
  • Compound (41b) can also be produced by subjecting compound (41a) to a reaction with carbon monoxide in the presence of a metal catalyst and alcohols.
  • Carbon monoxide may be used in an amount of about 1 mol or more per 1 mol of compound (41a) to carry out the reaction in a carbon monoxide stream.
  • alcohols include methanol and ethanol. The alcohol is used in an amount of about 1 mol or more per 1 mol of the compound (41a), and can also be used as a solvent.
  • the metal catalyst examples include palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), tris (Dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, complex of palladium (II) acetate and 1,1′-bis (diphenylphosphino) ferrocene Etc.] is preferable.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl
  • the reaction is usually performed in the presence of a base.
  • the base include inorganic bases, organic bases, basic salts and the like.
  • the metal catalyst is used in an amount of about 0.000001 to 5.0 mol, preferably about 0.0001 to 1.0 mol, per 1 mol of compound (41a).
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (41a).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, etc.
  • a solvent or a mixed solvent thereof is preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 5 min to 100 hr.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 100 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (41c) can be produced by reacting compound (41a) with cyanide in the presence of a metal catalyst.
  • a metal catalyst examples include sodium cyanide, potassium cyanide, zinc cyanide, potassium hexacyanoferrate (II) and the like.
  • the cyanide is used in an amount of about 0.8 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound (41a).
  • metal catalyst metal complexes having various ligands are used.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium. (II), dichlorobis (triethylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, palladium (II) acetate 1,1′-bis (diphenylphosphino) ferrocene complex, etc.], nickel compounds [Example: tetrakis (triphenylphosphine) nickel (0), bis (triethylphosphine) nickel (II) chloride, bis (triphenylchloride) Phosphine) Nickel (II) ], Copper compound [e.g.
  • the metal catalyst is used in an amount of about 0.0001-5 mol, preferably about 0.001-1 mol, per 1 mol of compound (41a).
  • This reaction is preferably performed in the presence of a base.
  • the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides, basic salts and the like.
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (41a). Further, this reaction may use zinc as an additive.
  • Zinc is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (41a).
  • the reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds, but solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides, esters, water, etc. Or those mixed solvents etc. are preferable.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compounds (41a), (41b), and (41c) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • the compounds (41a), (41b) and (41c) are included in the compound (41) described later, and can also be produced by the following production method N.
  • Compound (41d) has ring A in the oxazole ring Compound (41) in the case of (bonded to ring B at the 5-position of the oxazole ring), and (41e) and (41f) are C 1-6 in which ring A may have a substituent Compound (41) in the case of an oxazole ring which may have an alkyl group (bonded to ring B at the 5-position of the oxazole ring), and compound (41g) has ring A having a substituent A compound (41) in the case of a 1,2,4-triazole ring (bonded to ring B at the 1-position of the triazole ring) optionally having a C 1-6 alkyl group, In compound (41h), ring A may have a substituent. 1-6 imidazole ring which may have an alkyl group compound when it is
  • R 7 represents a substituent such as —COOP 5 , —LG 12 , —CN, etc .
  • R 8 represents an optionally substituted boranyl group, tri-C 1-6 alkylstannyl
  • Each of R 9 to R 15 represents a C 1-6 alkyl group which may have a substituent or a hydrogen atom; the other symbols are as defined above. is there.
  • the “optionally substituted C 1-6 alkyl group” represented by R 9 to R 15 has the same meaning as the “ optionally substituted C 1-6 alkyl group” represented by R 1. Show.
  • Compound (41) can be produced from compound (42) according to Step N-1.
  • Compound (41) can be produced by condensing compound (42) and compound (43a).
  • Examples of the “boranyl group optionally having substituent (s)” represented by R 8 include a dihydroxyboranyl group, a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group.
  • the “tri-C 1-6 alkylstannyl group” represented by R 8 is preferably a tributylstannyl group.
  • the condensation reaction is carried out by reacting compound (42) and compound (43a) in the presence of a metal catalyst.
  • the metal catalyst examples include palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), tris (Dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, complex of palladium (II) acetate and 1,1′-bis (diphenylphosphino) ferrocene Etc.] is preferable.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl
  • the reaction is usually performed in the presence of a base.
  • the base include inorganic bases and basic salts.
  • Compound (43a) is used in an amount of about 0.1-10 mol, preferably about 0.8-2 mol, per 1 mol of compound (42).
  • the metal catalyst is used in an amount of about 0.000001 to 5.0 mol, preferably about 0.0001 to 1.0 mol, per 1 mol of compound (42).
  • the base is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (42).
  • an inert gas stream such as argon gas or nitrogen gas. This reaction is advantageously performed using a solvent inert to the reaction.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent for example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water Or a mixed solvent thereof.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 5 min to 100 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 0 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (41) can also be produced by condensing compound (42) and compound (43b) in the presence of a metal catalyst.
  • a metal catalyst metal complexes having various ligands are used.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium.
  • Compound (43b) is used in an amount of about 0.8 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (42).
  • the metal catalyst is used in an amount of about 0.0001-5 mol, preferably about 0.001-1 mol, per 1 mol of compound (42).
  • This reaction is preferably performed in the presence of a base.
  • the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (42).
  • the reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds, but solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides, esters, water, etc. Or those mixed solvents etc. are preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (41) can also be produced by condensing compound (42) and compound (43b).
  • Compound (43b) is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (42).
  • the reaction can be performed in the presence of a base for the purpose of promoting the reaction.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides, and organic lithiums.
  • the base is used in an amount of about 1-20 mol, preferably about 1-3 mol, per 1 mol of compound (42).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 0 to 200 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (41d) is obtained from Compound (44) according to Step N-6, Compound (41e) is obtained from Compound (46) according to Step N-7, and Compound (41f) is obtained from Compound (48) according to Step N-8. Each can be manufactured.
  • Compound (41d) can be produced by subjecting compound (44) to a condensation reaction with 1-[(isocyanomethyl) sulfonyl] -4-methylbenzene in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides and the like.
  • the base is used in an amount of about 0.8 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (44).
  • 1-[(Isocyanomethyl) sulfonyl] -4-methylbenzene is used in an amount of about 0.8 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (44).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent or a mixed solvent thereof is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (41e) can be produced by subjecting compound (46) and compound (47) to a condensation reaction in the presence of an oxidizing agent and an acid.
  • an oxidizing agent include organic peracids such as perbenzoic acid, m-chloroperbenzoic acid (MCPBA), and peracetic acid, such as perchlorates such as lithium perchlorate, silver perchlorate, and tetrabutylammonium perchlorate.
  • Acid salts such as periodate such as iodobenzene diacetate, sodium periodate, Dess-Martin periodinane, o-iodooxybenzoic acid (IBX), manganic acids such as manganese dioxide and potassium permanganate, such as lead tetraacetate
  • Leads such as pyridinium chlorochromate, pyridinium dichromate, inorganic nitrogen compounds such as acyl nitrate and dinitrogen tetroxide, such as halogen, N-bromosuccinimide (NBS), N-chloro Halogen compounds such as succinimide (NCS), sulfuryl chloride, chloramine T, acid Element, hydrogen peroxide, and the like.
  • the oxidizing agent is used in an amount of about 0.8 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (46).
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.8 to 20 mol, preferably about 1 to 10 mol, per 1 mol of compound (46).
  • the compound (47) include C 1-6 alkyl nitriles such as acetonitrile and propionitrile.
  • Compound (47) is used in an amount of about 0.8 mol or more per 1 mol of compound (46), and can also be used as a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-48 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 100 ° C.
  • Compound (41f) can be produced by subjecting compound (48) and compound (49) to a condensation reaction. In order to accelerate the reaction, the reaction can be performed in the presence of an acid.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.001 to 10 mol, preferably about 0.1 to 2 mol, per 1 mol of compound (48).
  • the compound (49) include ortho acid esters such as trimethyl orthoacetate, triethyl orthopropionate and trimethyl orthoformate.
  • Compound (49) is used in an amount of about 0.8 mol or more per 1 mol of compound (48), and can also be used as a solvent.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatics A solvent such as a group organic base or a mixed solvent thereof is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compounds (41d), (41e) and (41f) may be prepared by methods known per se, such as the method described in Bioorganic & Medicinal Chemistry Letters, Vol. 13, p. 2059 (2003), or the like. It can also be produced according to a method according to these.
  • Compound (46) can be produced from compound (42) according to step N-2, from compound (44) according to step N-4, or from compound (45) according to step N-3.
  • Compound (48) can be produced from compound (46) according to Step N-5.
  • Step N-2 examples include a method of subjecting the compound (42) and tributyl (1-ethoxyvinyl) tin to a condensation reaction.
  • Step N-4 examples include a method in which a Grignard reagent represented by R 9 CH 2 MgBr is added to the aldehyde group of the compound (44) and then subjected to an oxidation reaction.
  • Examples of the step N-3 include a method in which the carboxy group of the compound (45) is converted to wine levamide and then subjected to a reaction with a Grignard reagent represented by R 9 CH 2 MgBr.
  • Examples of the reaction for converting a carboxy group into wine levamide include a reaction of compound (45) with N, O-dimethylhydroxylamine hydrochloride. The reaction may be performed according to the same method as in step A-1.
  • the subsequent reaction with Grignard reagent represented by R 9 CH 2 MgBr is as follows: New Experimental Chemistry Course, Vol.
  • step N-5 examples include a method in which a halogenating agent is allowed to act on the compound (46) which is a ketone to form an ⁇ -haloketone and then subjected to a reaction with an aminating agent or the like.
  • a halogenating agent is allowed to act on the compound (46) which is a ketone to form an ⁇ -haloketone and then subjected to a reaction with an aminating agent or the like.
  • Compound (41g) can be produced by a series of reaction steps from Compound (50) to Step N-9 to Step N-10.
  • Compound (51) can be produced by reacting compound (50) with nitrous acid in the presence of an acid, followed by a reduction reaction.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.01 mol or more per 1 mol of compound (50), and can also be used as a solvent.
  • the nitrites include nitrites such as sodium nitrite and potassium nitrite, and nitrites such as isoamyl nitrite.
  • Nitrous acid is used in an amount of about 0.8 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound (50).
  • the reducing agent include reducing agents such as tin chloride.
  • the reducing agent is used in an amount of about 0.8 to 20 mol, preferably about 1 to 10 mol, per 1 mol of compound (50).
  • the solvent in the reaction with nitrous acid is not particularly limited as long as the reaction proceeds.
  • a solvent such as inorganic acids, organic acids, alcohols, ethers, amides, nitriles, sulfoxides, water, or the like A mixed solvent or the like is preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • the solvent in the reduction reaction is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • Compound (41g) can be produced by condensing compound (51) and compound (52), and then subjecting it to a condensation reaction with compound (53).
  • the compound (52) include alkyl imide thioates such as methyl ethane imide thioate hydroiodide, methyl propanimide thioate hydrochloride, etc., and methods known per se, such as Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry), Volume 21, page 272 (1982), etc. Can do.
  • Compound (52) is used in an amount of about 0.8 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound (51).
  • the solvent in the condensation reaction of the compound (51) and the compound (52) is not particularly limited as long as the reaction proceeds.
  • alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogens Solvents such as fluorinated hydrocarbons, nitriles, and sulfoxides, or mixed solvents thereof are preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 100 ° C.
  • the condensation reaction with compound (53) may be carried out in the same manner as in Step N-8.
  • Compound (41h) can be produced by a series of reaction steps from Compound (50) to Step N-11 to Step N-13.
  • Compound (54) can be produced by reacting compound (50) with a formylation reagent.
  • a formylation reagent examples include N, N-dimethylformamide, N-formylpiperidine, N-formylmorpholine, formic esters such as ethyl formate, a mixture of formic acid and acetic anhydride, and the like.
  • the formylation reagent is used in an amount of about 1-100 mol, preferably about 1-30 mol, per 1 mol of compound (50).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 30 min-50 hr, preferably 30 min-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 0 to 150 ° C.
  • Compound (56) can be produced by reacting compound (54) with an alkylating agent (55) in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal amides and the like.
  • the base is used in an amount of about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (54).
  • the alkylating agent (55) is used in an amount of about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (54).
  • sodium iodide, potassium iodide or the like may be added. This reaction is advantageously performed using a solvent inert to the reaction.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • a mixed solvent or the like is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 150 ° C.
  • Compound (41h) can be produced by subjecting compound (56) to heat treatment in an acetic acid solvent in the presence of ammonium acetate.
  • Ammonium acetate is used in an amount of about 3 to 50 mol, preferably about 5 to 30 mol, per 1 mol of compound (56).
  • the reaction time is usually 10 minutes to 100 hours, preferably 30 minutes to 24 hours.
  • the reaction temperature is usually 0 to 100 ° C., preferably 50 to 100 ° C.
  • Compound (41) is a method known per se, for example, European Journal of Organic Chemistry, Vol. 13, p. 2970 (2006), Synthetic Communications, Vol. 36, p. 2927 (2006). ), Journal of Organic Chemistry, 44, 4160 (1979), Journal of the Chemical Society, 4251 (1954), WO 2008/77649, etc. It can also be produced according to the method described in 1. or a method analogous thereto.
  • Compounds (41), (41d), (41e), (41f), (41g), and (41h) are each independently or independently of a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc. By combining two or more, it can lead to a desired compound. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (Edited by Chemical Society of Japan), Organic Functional Group Preparations 2nd edition, ACADEMIC PRESS, INC., 1989. A method described in Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989 or the like.
  • C 1-6 alkyl oxide is allowed to act in accordance with a method known per se or a method analogous thereto, and 1 or 2 of the halogen atoms is converted to C 1 Can be converted to a -6 alkoxy group.
  • Compounds (42), (43a), (43b), (44), (45), (46), (47), (48), (49), (50), (51), (52), ( 53), (54), (55), and (56) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • the compound (I) is referred to as compound (I′-9).
  • Compound (I′-9) can be produced from compound (29) by a series of reaction steps from Step O-1 to Step O-2.
  • Step O-1) Compound (58) can be produced by reacting compound (29) with compound (57) in the presence of a base.
  • Compound (57) is used in an amount of about 1 mol or more, preferably about 1-2 mol, per 1 mol of compound (29).
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (29).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 150 ° C.
  • Step O-2) Compound (I′-9) can be produced by subjecting compound (58) to a heat treatment in the presence of an acid.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.01 mol or more per 1 mol of compound (58), and can also be used as a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • a solvent such as inorganic acids, organic acids, alcohols, ethers, amides, nitriles, sulfoxides, water, or a mixed solvent thereof is preferable.
  • the reaction time is usually 10 minutes to 100 hours, preferably 10 minutes to 24 hours.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 150 ° C.
  • Compound (I′-9) can be further converted into a desired compound by performing a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc., either alone or in combination of two or more thereof. it can.
  • a known substituent conversion reaction condensation reaction, oxidation reaction, reduction reaction, etc., either alone or in combination of two or more thereof. it can.
  • These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations (ORGANIC ⁇ ⁇ FUNCTIONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PRESS, INC.) Published in 1989. ; Comprehensive Organic Transformation (VCH Publishers Inc.) published in 1989, etc.
  • a ketone group can be converted into a secondary alcohol group by the action of sodium borohydride.
  • Compounds (29), (57) and (58) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (I′-10) can be produced from compound (4) by a series of reaction steps from Step P-1 to Step P-5.
  • the above reaction scheme illustrates the case where n is 0 (referred to as compound I′-10 ′).
  • n is 1 to 6
  • the corresponding raw material compound into which n R 3 are introduced may be used, or n R 3 may be introduced at a predetermined position during the production process.
  • Compound (60) can be produced by reacting compound (4) with carboxylic acid (59) or a reactive derivative thereof. The reaction may be performed according to the same method as in step A-1.
  • Compound (61) can be produced by subjecting compound (60) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step A-3.
  • Step P-3 After the compound (62) is obtained by converting the leaving group LG 16 of the compound (61) to an azide group.
  • Deprotection of the protecting group P 6, after converting the azido group to amino group, subjected to an intramolecular cyclization reaction Can be manufactured. Conversion to an azide group, reduction of the azide group, and intramolecular cyclization reaction may be performed in the same manner as in Step A-4. Removal of the protecting group, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) according to the method as described in, Just do it.
  • Compound (63) can be produced by subjecting compound (62) to an oxidation reaction.
  • Oxidation reaction is, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, published by ACADEMIC PRESS, INC., 1989; The method described in Comprehensive Organic Transformations (VCH Publishers Inc.) 1989 etc. may be used.
  • Compound (I′-10 ′) can be produced by reacting compound (63) with compound (64) in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (63).
  • Compound (64) is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (63).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 150 ° C.
  • Compound (I′-10) can be further converted into a desired compound by performing a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc., either alone or in combination of two or more thereof. it can. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PRESS, INC.), 1989. ; Comprehensive Organic Transformation (VCH Publishers Inc.) published in 1989, etc. For example, a ketone group can be converted into a secondary alcohol group by the action of sodium borohydride.
  • the compound (I) which is is referred to as the compound (I ′′ -11).
  • Compound (I ′′ -11) can be produced from compound (41a) by a series of reaction steps from Step Q-1 to Step Q-7.
  • Compound (I ′′ -12) can be produced from compound (I ′′ -11) by a reaction step of Step Q-8.
  • n is 0 (compound (I ′′ -11) as compound (I ′′ -11 ′) and compound (I ′′ -12) as compound (I ′′ -12 ′)
  • n is 1 to 6
  • the corresponding raw material compound into which n R 3 are introduced may be used, or n R 3 may be introduced at a predetermined position during the production process.
  • Compound (66) can be produced by condensing compound (41a) and 5-chloropent-1-yne (65) in the presence of an organic base and a metal catalyst.
  • the organic base is used in an amount of about 1-100 mol or more per 1 mol of compound (41a).
  • the metal catalyst examples include palladium compounds (eg, dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triethylphosphine) palladium (II), Tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocenepalladium (II) chloride, palladium (II) acetate and 1,1'-bis (diphenylphosphino) ferrocene complex And the like] and a copper compound [eg, copper (I) iodide, etc.].
  • palladium compounds eg, dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, tetrakis (triphenylphosphine
  • the metal catalyst is used in an amount of about 0.000001 to 5 mol, preferably about 0.0001 to 1 mol, per 1 mol of compound (41a).
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • organic bases, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, A solvent such as esters, water, or a mixed solvent thereof is preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C.
  • Compound (68) can be produced by reacting compound (66) with compound (67) in the presence of a base and then reacting with an acid.
  • examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-10 mol, per 1 mol of compound (66).
  • Compound (67) is used in an amount of about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (66).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 150 ° C.
  • tetrabutylammonium iodide or the like may be added.
  • the acid include acid chlorides such as acetyl chloride, inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 1 to 200 mol, preferably about 1 to 50 mol, per 1 mol of compound (66).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent or a mixed solvent thereof is preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 100 ° C.
  • Compound (69) can be produced by reacting compound (68) with an azidating agent in the presence of a base and a catalyst.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-10 mol, per 1 mol of compound (68).
  • the catalyst include copper (II) sulfate.
  • the catalyst is used in an amount of about 0.01 to 5 mol, preferably about 0.01 to 1 mol, per 1 mol of compound (68).
  • the azidating agent include trifluoromethanesulfonyl azide.
  • the azidating agent is used in an amount of about 1-20 mol, preferably about 1-10 mol, per 1 mol of compound (68).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually 0 to 200 ° C., preferably 20 to 100 ° C.
  • Compound (70) can be produced by subjecting compound (69) to an intramolecular cyclization reaction. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like A mixed solvent or the like is preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually 0 to 250 ° C., preferably 20 to 150 ° C. Compound (70) can also be produced directly from compound (68) by Step Q-3.
  • a solvent inert is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, s
  • Compound (71) can be produced by reacting compound (70) with a halogenating agent in the presence of a base.
  • the reaction may be performed according to the same method as in Step H-1.
  • Compound (72) can after reaction of compound (71) with the compound (30) is prepared by removing the protecting group P 4.
  • P 4 is a hydrogen atom, removal of the protecting group can be omitted.
  • the reaction may be performed according to the same method as in step H-2.
  • Compound (I ′′ -11 ′) can be produced by subjecting compound (72) to an intramolecular cyclization reaction.
  • the reaction may be performed according to the same method as in step C-7.
  • Compound (I ′′ -11 ′) can also be produced directly from compound (71) by Step Q-6.
  • Compound (I ′′ -12 ′) can be produced by reacting compound (I ′′ -11 ′) with compound (32) in the presence of a base. The reaction may be performed in the same manner as in step I-1.
  • Compounds (30), (32), (41a), (65), (66), (67), (68), (69), (70), (71) and (72) are commercially available products. It may also be produced by a method known per se or a method analogous thereto.
  • the compound of the present invention can be produced as a configurational isomer or stereoisomer alone or as a mixture thereof.
  • isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) Etc., each can be obtained as a single item.
  • the compounds (2) to (56) those having configurational isomers are isolated and purified by usual separation means such as extraction, recrystallization, distillation, chromatography, etc., when isomerization occurs. And pure compounds can be produced.
  • the compound of the present invention may have a stereoisomer depending on the kind of the substituent, and not only this isomer alone but also a mixture thereof is also included in the present invention.
  • a known hydrolysis reaction, deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, substituent exchange reaction, condensation reaction may be performed as desired.
  • the compounds of the present invention can also be produced by performing each of these alone or in combination of two or more thereof. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (Edited by The Chemical Society of Japan), Organic Functional Group Preparations, 2nd edition, ACADEMIC PRESS, INC., 1989.
  • the compound of the present invention can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractional distillation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • the compound of the present invention When the compound of the present invention is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, a method known per se Alternatively, it can be converted to a free form or other desired salt by a method equivalent thereto.
  • the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, any one of the isomers and a mixture are also included in the compound of the present invention.
  • an optical isomer exists in the compound of the present invention, an optical isomer resolved from a racemate is also included in the compound of the present invention.
  • the compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a mixture of crystal forms.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non-hydrate etc.), and both are included in the compound of the present invention.
  • Compounds labeled with isotopes eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • deuterium converters are also encompassed in the compounds of the present invention.
  • the compound of the present invention labeled or substituted with an isotope or the like can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.
  • a prodrug of the compound of the present invention is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc. and changes to the compound of the present invention.
  • a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated,
  • the prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Drug Development, Volume 7 (Molecular Design), pp. 163-198 (Hirokawa Shoten). May be.
  • the compound of the present invention or a prodrug thereof has excellent amyloid ⁇ production inhibitory activity and has toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.). It is also useful as a pharmaceutical because it is low and has excellent stability and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.).
  • the compound of the present invention or a prodrug thereof has an action of inhibiting amyloid ⁇ production on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a prophylactic / therapeutic agent for diseases that may be related to the production of amyloid ⁇ .
  • Diseases that may be related to the production of amyloid ⁇ include, for example, neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Parkinson's disease), memory disorders (eg, senile dementia, mild cognitive impairment ( MCI), amnesia, etc.), ischemic central neuropathy (eg, brain amyloid angiopathy (CAA), etc.), Down's syndrome and the like.
  • the compound of the present invention or a prodrug thereof is preferably useful as a amyloid ⁇ production inhibitor, a mild cognitive impairment, or a prophylactic or therapeutic agent for Alzheimer's disease.
  • the medicament containing the compound of the present invention or a prodrug thereof is prepared by the compound of the present invention or the method according to a method known per se (eg, the method described in the Japanese Pharmacopoeia, etc.)
  • the prodrug alone or mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders , Granules, capsules (including soft capsules and microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release preparations) Microcapsule), aerosol, film (eg, orally disintegrating film, oral mucosal film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), point Preparations, transdermal preparations
  • a pharmacologically acceptable carrier for example
  • Oral or parenteral eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, lesion, etc.
  • the content of the compound of the present invention or a prodrug thereof in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament.
  • the dose of the medicament of the present invention varies depending on the administration subject, administration route, disease, symptom, and the like.
  • the compound of the present invention when orally administered to an adult patient for the purpose of treating Alzheimer's disease, the compound of the present invention as an active ingredient or a prodrug thereof About 0.001 to about 100 mg / kg body weight, preferably about 0.005 to about 50 mg / kg body weight, more preferably about 0.01 to about 2 mg / kg body weight. It is desirable to administer about 1 to 3 times a day.
  • the pharmacologically acceptable carrier examples include various organic or inorganic carrier substances that are conventionally used as pharmaceutical materials.
  • excipients examples include excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations. , Solubilizing agents, suspending agents, tonicity agents, buffers, soothing agents and the like. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples thereof include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention or a prodrug thereof When the compound of the present invention or a prodrug thereof is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases.
  • the combination agent of the present invention the combined use of the compound of the present invention or a prodrug thereof and a concomitant drug is referred to as “the combination agent of the present invention”.
  • concomitant drugs include acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, etc.), amyloid ⁇ protein production, secretion, accumulation, aggregation and / or deposition inhibitor, ⁇ secretase inhibitor, amyloid ⁇ protein aggregation inhibitor , Amyloid ⁇ vaccine, amyloid ⁇ antibody, amyloid ⁇ -degrading enzyme, etc., brain function activators (eg, idebenone, memantine, vinpocetine, etc.), abnormal behavior associated with the progression of dementia, therapeutic agents such as epilepsy (eg, sedative, anti Anxiety agents, etc.), Alzheimer's disease progression inhibitors, etc.
  • acetylcholinesterase inhibitors eg, donepezil, rivastigmine, galantamine, etc.
  • amyloid ⁇ protein production secretion, accumulation, aggregation and / or deposition inhibitor
  • ⁇ secretase inhibitor
  • apoptosis inhibitors include neuronal differentiation / regeneration accelerators, anti-Parkinson drugs (eg, L-dopa, deprenyl, carbidopa + levodopa, pergolide, ropinirole, cabergoline, pramipexole , Entapron, Razabemid, etc.), muscle atrophy Drugs for lateral sclerosis (eg, riluzole, etc.), antidepressants (eg, fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, reboxetine, mirtazapine, imipramine hydrochloride, duloxetine, escitalopram, mifepristone , Doxepin, etc.), anti-anxiety drugs (eg, alprazolam, bromazepam, chlordiazepoxide, diazepam, etizolam, furtopraz
  • anti-Parkinson drugs
  • the compound of the present invention or a prodrug thereof By combining the compound of the present invention or a prodrug thereof and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or a prodrug thereof, or a concomitant drug is administered alone. (2) The combination drug can be selected according to the patient's symptoms (mild, severe, etc.) (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the therapeutic effect can be sustained. (5) By using the compound of the present invention or a prodrug thereof together with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or a prodrug thereof, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier in accordance with a method known per se.
  • a pharmacologically acceptable carrier for example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) It can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) as a patch, orally disintegrating tablet, orally disintegrating film and the like.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the timing of administration of the compound of the present invention or a prodrug thereof and a concomitant drug is not limited, and the compound of the present invention or a prodrug thereof or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof May be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention or a prodrug thereof and a concomitant drug, and (2) use in combination with the compound of the present invention or a prodrug thereof.
  • the compounding ratio of the compound of the present invention or a prodrug thereof and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention or a prodrug thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. The same content may be used when the compound of the present invention or a prodrug thereof and a concomitant drug are formulated separately.
  • THF Tetrahydrofuran
  • DMF N, N-dimethylformamide
  • DMA N, N-dimethylacetamide
  • DMSO Dimethyl sulfoxide
  • APCI Electrospray ionization method
  • APCI Atmospheric pressure chemical ionization [M + H] + : Molecular ion peak
  • M Molar concentration
  • N Standard Concentration
  • WSC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole monohydrate
  • IPE diisopropyl ether
  • HATU 2- (7-azabenzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate
  • DEAD diethyl azodicarboxylate
  • ADDP 1,1 ′-(azodicarbonyl) piperidine
  • HPLC high performance liquid chromatography
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (—Boc), a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated is observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • the unit of sample concentration (c) in optical rotation ([ ⁇ ] D ) is g / 100 mL.
  • a calculated value (Calcd) and an actual measurement value (Found) are described.
  • the reaction mixture was diluted with ethyl acetate (1.4 L), 20% aqueous ammonia (100 mL) and water (700 mL) were added, and the mixture was filtered through celite. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a mixed solution of the residue in DMF (880 mL), sodium methoxide (28% methanol solution, 170 g) was added dropwise at 0 ° C., followed by stirring at room temperature for 4 hours, and then ice water (300 g) was added.
  • Example 6 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6', 7 '-Tetrahydro-5'H-spiro [1-benzazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -2 (1H) -one
  • Example 10 Optically active 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6 ', 7'-Tetrahydro-5'H-spiro [1-benzazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -2 (1H) -one 3'- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6 ', 7'-tetrahydro A racemic form of -5'H-spiro [1-benzazepine-3,8 '-[1,2,4] triazolo [4,3-a] pyridin] -2 (1H) -one (252 mg) by HPLC (Column: CHIRALCEL
  • Example 11 Optically active 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6 ', 7'-Tetrahydro-5'H-spiro [1-benzazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -2 (1H) -one 3'- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6 ', 7'-tetrahydro A racemic form of -5'H-spiro [1-benzazepine-3,8 '-[1,2,4] triazolo [4,3-a] pyridin] -2 (1H) -one (252 mg) by HPLC (Column: CHIRALCEL
  • Example 15 Optically active 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5,6 ', 7'-Tetrahydro-5'H-spiro [1-benzazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -2 (1H) -one Hydrogen bromide Acid salt optically active 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -4,5 , 6 ', 7'-Tetrahydro-5'H-spiro [1-benzazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -2 (1H) -one A solution of hydrobromic acid (19.22 mg) in
  • reaction mixture was evaporated under reduced pressure, ethanol (5 mL) was added to the residue at room temperature, and the mixture was stirred at the same temperature for 5 min.
  • the reaction mixture was evaporated under reduced pressure, and acetone (5 mL) was added to the residue at room temperature, followed by stirring at the same temperature for 5 minutes.
  • the reaction mixture was evaporated under reduced pressure, and the residue was crystallized from acetone / hexane to give the title compound (54.4 mg).
  • Example 16 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2- (2,2,2-trifluoroethyl) -1,5,6', 7 '-Tetrahydro-5'H-spiro [2-benzazepine-4,8'-[1,2,4] triazolo [4,3-a] pyridine] -3 (2H) -one
  • Example 17 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (2,2,2-trifluoroethyl) -5- (trifluoromethyl)- 1,4,6 ', 7'-Tetrahydro-2H, 5'H-spiro [quinoline-3,8'-[1,2,4] triazolo [4,3-a] pyridin] -2-one
  • the reaction mixture was diluted with ethyl acetate and water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (0.90 g).
  • the reaction mixture was diluted with ethyl acetate and water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by HPLC (C18, 50 mm ID ⁇ 500 mmL, mobile phase: water / acetonitrile (containing 0.1% TFA)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was triturated with ethyl acetate / hexane to give the title compound (16.1 mg).
  • Example 38 8-Fluoro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -5- (2,2,2-trifluoroethyl) -6', 7 '-Dihydro-5'H-spiro [1,5-benzoxazepine-3,8'-[1,2,4] triazolo [4,3-a] pyridine] -4 (5H) -one
  • Example 42 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2- (2,2,2-trifluoroethyl) -6- (trifluoromethyl)- 1,2,6 ', 7'-Tetrahydro-3H, 5'H-spiro [isoquinoline-4,8'-[1,2,4] triazolo [4,3-a] pyridin] -3-one
  • Example 46 6-chloro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -4- (2,2,2-trifluoroethyl) -6', 7 '-Dihydro-5'H-spiro [1,4-benzoxazine-2,8'-[1,2,4] triazolo [4,3-a] pyridine] -3 (4H) -one 6-chloro- 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -6', 7'-dihydro-5'H-spiro [1,4-benzoxazine-2 , 8 '-[1,2,4] triazolo [4,3-a] pyridin] -3 (4H) -one (300 mg) in DMF (5 mL) with sodium hydride (60%, 37.7 mg) was added under a nitrogen atmosphere, and the mixture was
  • Example 64 Optically active 6,7,8-trifluoro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -4- (2,2,2-tri Fluoroethyl) -6 ', 7'-dihydro-5'H-spiro [1,4-benzothiazine-2,8'-[1,2,4] triazolo [4,3-a] pyridine] -3 (4H ) -One 6,7,8-trifluoro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -4- (2,2,2-tri Fluoroethyl) -6 ', 7'-dihydro-5'H-spiro [1,4-benzothiazine-2,8'-[1,2,4] triazolo [4,3-a] pyridine] -3 (4H ) -One racemate (66 mg) was fraction
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (20.2 mg) having a shorter retention time.
  • Example 66 (2RS, 3SR or 2RS, 3RS) -7-Chloro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,4,6', 7 '-Tetrahydro-5'H-spiro [chromene-2,8'-[1,2,4] triazolo [4,3-a] pyridin] -3-ol ethyl 7-chloro-3-hydroxy-3'- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -6 ', 7'-dihydro-5'H-spiro [chromene-2,8'-[1,2 , 4] triazolo [4,3-a] pyridine] -4-carboxylate (200 mg) in 6N hydrochloric acid (5 mL) was stirred at 100 ° C.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (18.2 mg) having a longer retention time.
  • the reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) and 4-chloro-1-[(2- ⁇ [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl ] Carbonyl ⁇ hydrazino) carbonyl] butyl acetate (10.4 g) was obtained.
  • reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate) to give 4-azido-1- ⁇ 5- [3- Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,3,4-oxadiazol-2-yl ⁇ butan-1-ol (6.94 g) was obtained.
  • Example 68 3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,4,6', 7'-tetrahydro-5'H-spiro [chromene-2, 8 '-[1,2,4] triazolo [4,3-a] pyridin] -4-ol 3'-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl ] -6 ', 7'-Dihydro-5'H-spiro [chromene-2,8'-[1,2,4] triazolo [4,3-a] pyridine] -4 (3H) -one (50 mg ) In methanol (2 mL) was added with sodium borohydride (8.55 mg) under ice cooling, and the mixture was stirred for 2 hours under ice cooling under a nitrogen atmosphere.
  • Example 72 (2RS, 4SR or 2RS, 4RS) -7-Chloro-3 '-[3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,4,6', 7 '-Tetrahydro-5'H-spiro [chromene-2,8'-[1,2,4] triazolo [4,3-a] pyridin] -4-ol 7-chloro-3 '-[3-methoxy- 4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -6 ', 7'-dihydro-5'H-spiro [chromene-2,8'-[1,2,4] triazolo [ Sodium borohydride (7.14 mg) was added to a mixture of 4,3-a] pyridin] -4 (3H) -one (45 mg) in methanol (1 mL) at room temperature and stirred at room temperature for 2 hours under a nitrogen
  • Example compounds prepared according to the above methods or methods according to them are shown in the following table. MS in the table indicates actual measurement values.
  • Example 1 (1) 10.0 g of the compound of Example 1 (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g soluble starch (5) Magnesium stearate 3.0 g The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, lactose (70.0 g) and corn starch ( (Lactose, corn starch, soluble starch and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
  • Test Example Measurement of inhibition rate of amyloid ⁇ production using primary neurons Primary neurons were collected from cerebral cortex of rat fetus (CLEA Japan, SD rat, embryonic day 17), B27 additive, L-glutamine, penicillin -Suspended to 500,000 cells / mL with neurobasal medium (Invitrogen) containing streptomycin. Subsequently, 100 ⁇ L each was seeded on a poly L lysine-coated 96-well plate (manufactured by Sumitomo Bakelite) and cultured at 37 ° C. and 5% CO 2 for 7 days. The whole medium was removed and fresh neurobasal medium was added at 75 ⁇ L / well.
  • a neurobasal medium to which the evaluation target compound was added so as to be twice the measured concentration was added 75 ⁇ L / well and cultured for 3 days.
  • the culture supernatant was collected from each well, diluted as appropriate, and subjected to sandwich ELISA for BNT77 antibody-BA27 antibody (for A ⁇ 40) and BNT77 antibody-BC05 antibody (for A ⁇ 42), and the amounts of A ⁇ 40 and A ⁇ 42 were measured.
  • the inhibition rate (%) of amyloid ⁇ production of the compound was calculated by the following formula.
  • the amyloid ⁇ 50 % production inhibition rate (IC 50 value) of a compound is calculated using a statistical analysis software (SAS preclinical package) and a concentration indicating 50% inhibition when the amyloid production amount when no compound is added is defined as 100%. did. Further, 75 ⁇ L / well of a new neurobasal medium was added to the cells after collecting the culture supernatant, and the cells were allowed to stand for about 30 minutes and returned to room temperature.
  • the compound of the present invention or a prodrug thereof exhibits an excellent inhibitory action on amyloid ⁇ production, it can provide a clinically useful prophylactic or therapeutic drug for diseases such as mild cognitive impairment and Alzheimer's disease.
  • the compound of the present invention or a prodrug thereof is useful as a medicine because it is excellent in drug efficacy, low toxicity, stability, pharmacokinetics and the like.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne : un dérivé hétérocyclique ayant une excellente activité inhibitrice sur la production d'amyloïde-â ; et l'utilisation du dérivé hétérocyclique. L'invention concerne un composé représenté par la formule (I) (dans laquelle chaque symbole est tel que défini dans la description) ou un sel de ce composé.
PCT/JP2011/078611 2011-07-01 2011-12-09 Composé hétérocyclique Ceased WO2013005354A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011147672A JP2012136500A (ja) 2010-12-06 2011-07-01 複素環化合物
JP2011-147672 2011-07-01

Publications (1)

Publication Number Publication Date
WO2013005354A1 true WO2013005354A1 (fr) 2013-01-10

Family

ID=47439496

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/078611 Ceased WO2013005354A1 (fr) 2011-07-01 2011-12-09 Composé hétérocyclique

Country Status (1)

Country Link
WO (1) WO2013005354A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156580A1 (fr) * 2007-06-13 2008-12-24 Merck & Co., Inc. Dérivés du triazole destinés au traitement de la maladie d'alzheimer et d'états associés
WO2010098487A1 (fr) * 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Composés hétérocycliques condensés contenant de l'azote et leur utilisation en tant qu'inhibiteurs de production de la bêta-amyloïde
WO2011007756A1 (fr) * 2009-07-13 2011-01-20 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
WO2011006903A1 (fr) * 2009-07-15 2011-01-20 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Dérivés de triazole et d'imidazole substitués en tant que modulateurs de gamma secrétase
JP2011513323A (ja) * 2008-02-29 2011-04-28 シェーリング コーポレイション アルツハイマー病の治療のためのγ−セクレターゼモジュレーター

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156580A1 (fr) * 2007-06-13 2008-12-24 Merck & Co., Inc. Dérivés du triazole destinés au traitement de la maladie d'alzheimer et d'états associés
JP2011513323A (ja) * 2008-02-29 2011-04-28 シェーリング コーポレイション アルツハイマー病の治療のためのγ−セクレターゼモジュレーター
WO2010098487A1 (fr) * 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Composés hétérocycliques condensés contenant de l'azote et leur utilisation en tant qu'inhibiteurs de production de la bêta-amyloïde
WO2011007756A1 (fr) * 2009-07-13 2011-01-20 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
WO2011006903A1 (fr) * 2009-07-15 2011-01-20 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Dérivés de triazole et d'imidazole substitués en tant que modulateurs de gamma secrétase

Similar Documents

Publication Publication Date Title
CN112272670B (zh) 含二并环类衍生物抑制剂、其制备方法和应用
EP2933247B1 (fr) Composé hétérocyclique
US10017508B2 (en) Nitrogenated heterocyclic compound
JP5871909B2 (ja) 複素環化合物及びその用途
JP5433418B2 (ja) 多環式化合物
US20120142672A1 (en) Heterocyclic compound and use thereof
WO2011002067A1 (fr) Composé hétérocyclique et son utilisation
WO2012020780A1 (fr) Composé hétérocyclique et utilisation de celui-ci
JP5888702B2 (ja) 抗癌活性化合物
WO2013005354A1 (fr) Composé hétérocyclique
JP2012136500A (ja) 複素環化合物
US8907089B2 (en) Fused heterocyclic ring derivative and use thereof
WO2013100018A1 (fr) Composé hétérocyclique
HK40036075A (en) Inhibitor containing bicyclic ring derivative, and preparation method and uses therefor
HK1223922A1 (zh) 螺-恶唑酮
HK1172338A (en) Fused heterocyclic ring derivative and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11868908

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11868908

Country of ref document: EP

Kind code of ref document: A1