WO2017026538A1 - Production method of pyrazine - Google Patents

Production method of pyrazine Download PDF

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Publication number
WO2017026538A1
WO2017026538A1 PCT/JP2016/073695 JP2016073695W WO2017026538A1 WO 2017026538 A1 WO2017026538 A1 WO 2017026538A1 JP 2016073695 W JP2016073695 W JP 2016073695W WO 2017026538 A1 WO2017026538 A1 WO 2017026538A1
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group
compound
mono
examples
alkyl
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PCT/JP2016/073695
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French (fr)
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Shokyo Miki
Keiichiro NAKAOKA
Hiroaki Hoshikawa
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Takeda Pharmaceutical Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • patent document 1 describes the following production method.
  • non-patent document 1 the following compound is known (non-patent document 1) .
  • Provision of an advantageous production method suitable for industrial production of the pyrazine compound has been further desired.
  • patent document 1 WO 2010/147226
  • patent document 3 WO 2007/132841
  • patent document 4 WO 2008/108445
  • non-patent document 1 A Chemtek Product List, Amber Molthech, Aurora Building Block
  • the present invention aims to provide a production method suitable for good yielding and convenient industrial production of a pyrazine compound represented by the following formula (b) .
  • the present invention is as follows.
  • X is a halogen atom
  • one of Ri and R 2 is a substituent
  • the other is a hydrogen atom, or a salt thereof (hereinafter to be abbreviated as compound
  • compound (b) a salt thereof (hereinafter to be abbreviated as compound (b) ) , comprising subjecting a compound represented by the. formula (a) :
  • compound (b) can be produced in a good yield while suppressing byproducts, even when amino group is unprotected. Therefore, the production method can reduce protecting and deprotectxng steps of amino group, and can become a method suitable for convenient
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • examples of the "Ci_6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl,. 3 , 3-dimethylbutyl and 2-ethylbutyl .
  • examples of the "optionally halogenated Ci_6 alkyl group” include a Ci-6 alkyl group
  • Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- bromoethyl, 2 , 2 , 2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2 , 2-difluoropropyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , 4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl .
  • alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-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 and 5-hexenyl.
  • alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl .
  • cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl and adamantyl.
  • examples of the "optionally halogenated C3-10 cycloalkyl group” include a C 3 _i 0 cycloalkyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • cyclopropyl 2,2- difluorocyclopropyl, 2, 3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl group include cyclopropenyl, cyclobutenyl , cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .
  • examples of the "C 6 _i 4 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
  • aralkyl group include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
  • examples of the "Ci-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • examples of the "optionally 5 halogenated Cis alkoxy group” include a Ci_6 alkoxy group
  • examples of the "C 3 -i 0 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy .
  • examples of the "C ' i-6 15 alkylthio group” include methylthio, ethylthio, propylthio, . isopropylthio, butylthio, sec-butylthio, tert-butylthio,
  • examples of the "optionally halogenated Ci-6 alkylthio group” include a Cis alkylthio -group 20 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • difluoromethylthio trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
  • examples of the "Ci-6 alkyl- carbonyl group” include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
  • Ci_ 6 alkyl-carbonyl group include a Ci_ 6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the "Ci-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
  • examples of the "C 6 -i4 aryl- carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the "C 7 _i 6 aralkyl-carbonyl group” include phenylacetyl and
  • examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group” include
  • examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and
  • examples of the "mono- or di-Ci-6 alkyl-carbamoyl group” include methylcarbamoyl
  • examples of the "mono- or di-C 7 -i6 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl .
  • alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
  • examples of the "optionally halogenated Ci_6 alkylsulfonyl group” include a Ci-6
  • alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include
  • methylsulfonyl difluoromethylsulfonyl , trifluoromethylsulfonyl , ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4, 4, 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .
  • examples of the "C6-14 examples of the "C6-14
  • arylsulfonyl group include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
  • substituted include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
  • optionally substituted heterocyclic group an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
  • hydrocarbon group (including “hydrocarbon group” of
  • “optionally substituted hydrocarbon group” include a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C 2 -6 alkynyl group, a C3-10
  • cycloalkyl group a C3-10 cycloalkenyl group, a C 6 _i 4 aryl group and a C 7 _i6 aralkyl group.
  • examples of the "optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent ( s ) selected from the following Substituent Group A.
  • a C 6 _i4 aryloxy group e.g., phenoxy, naphthoxy
  • a 5- to 14-membered aromatic heterocyclyloxy group e.g., pyridyloxy
  • (10) a 3- to . 14-membered non-aromatic heterocyclyloxy group e.g., morpholinyloxy, piperidinyloxy
  • Ci-6 alkyl-carbonyloxy group e.g., acetoxy
  • a C 6 -i4 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 6 -i4 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • Ci-6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a Ce-1 aryl-carbamoyloxy group e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy
  • a 5- to 14-membered aromatic heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy
  • Ci_6 alkylsulfonyloxy group e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy
  • a C 6 _i4 aryloxy-carbonyl group e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,
  • a C 7 -i6 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a 5- to 14-membered aromatic heterocyclylcarbamoyl group e.g., pyridylcarbamoyl, thienylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfonyl group e.g., pyridylsulfonyl, thienylsulfonyl
  • a C6-14 arylsulfinyl group e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl
  • arylsulfinyl group e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl
  • a 5- to 14-membered aromatic heterocyclylsulfinyl group e.g., pyridylsulfinyl, thienylsulfinyl
  • a mono- or di-Ci_ 6 alkylamino group e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
  • a mono- or di-Ce-14 arylamino group e.g., phenylamino
  • (47) a 5- to 14-membered aromatic heterocyclylamino group e.g., pyridylamino
  • Ci-6 alkyl-carbonylamino group e.g., acetylamino, propanoylamino, butanoylamino
  • a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group e.g., N- acetyl-N-methylamino
  • a C 6 -i4 aryl-carbonylamino group_ e.g., phenylcarbonylamino, naphthylcarbonylamino
  • Ci-6 alkoxy-carbonylamino group e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino
  • a Ci-6 alkoxy-carbonylamino group e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino
  • Ci-6 alkylsuifonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • a C 6 _i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group e.g., phenylsulfonylamino
  • the number of the above-mentioned substituents in the "optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3.
  • the respective substituents may be the same or different.
  • heterocyclic group (including “heterocyclic group” of
  • optionally substituted heterocyclic group include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • examples of the "aromatic heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an Oxygen atom.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazdlyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,
  • pyrazinyl pyrimidinyl, pyridazinyl, 1, 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;
  • pyrazolopyrimidinyl oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl,
  • non- aromatic heterocyclic group examples include a 3- to 14-membered
  • non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocyclic group examples include 3- to 8-membered monocyclic non-aromatic
  • heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, _
  • 9- to 14-membered fused polycyclic preferably bi or tricyclic non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl,
  • examples of the "nitrogen- containing heterocyclic group” include a “heterocyclic - group” containing at least one nitrogen atom as a ring-constituting atom.
  • examples of the "optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent (s) selected from the above- mentioned Substituent Group A.
  • substituted heterocyclic group is, for example, 1 to 3.
  • the respective substituents may be the same or different.
  • examples of the "acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C 6 -i4 aryl group, a C 7 _i 6 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated Ci_ 6 alkoxy group, a hydroxy group,
  • acyl group also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
  • the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group
  • the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group
  • hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
  • acyl group examples include a formyl group, a carboxy group, a Ci- 6 alkyl-carbonyl group, a C 2 -6
  • alkenyl-carbonyl group e.g., crotonoyl
  • a C3-10 cycloalkyl- carbonyl group e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl
  • a C3-10 alkenyl-carbonyl group e.g., crotonoyl
  • a C3-10 cycloalkyl- carbonyl group e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl
  • cycloalkenyl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • a cycloalkenyl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • C 6 -i4 aryl-carbonyl group a C 7 _i 6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_ 6 alkoxy- carbonyl group, a C 6 -i4 aryloxy-carbonyl group (e.g.,
  • phenyloxycarbonyl, naphthyloxycarbonyl) a C 7 -i6 aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 2 -6 alkenyl-carbamoyl group (e.g.,
  • diallylcarbamoyl a mono- or di-C 3 -i 0 cycloalkyl-carbamoyl group (e.g. , cyclopropylcarbamoyl) , a mono- or di-C6-i4 aryl- carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C_i 6 aralkyl-carbamoyl group, a 5- to 14-membered aromatic
  • heterocyclylcarbamoyl group e.g., pyridylcarbamoyl
  • a heterocyclylcarbamoyl group e.g., pyridylcarbamoyl
  • thiocarbamoyl group a mono- or di-Ci_ 6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C 2 -6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C3_io
  • cycloalkyl-thiocarbamoyl group e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl
  • a mono- or di-C6-i4 aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • a mono- or di-C 7 _i 6 aralkyl- thiocarbamoyl group e.g., benzylthiocarbamoyl
  • heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • a sulfino group e.g., pyridylthiocarbamoyl
  • Ci_6 alkylsulfinyl group e.g., methylsulfinyl, ethylsulfinyl
  • a sulfo group e.g., methylsulfinyl, ethylsulfinyl
  • Ci-6 alkylsulfonyl group a C6- 14 arylsulfonyl group
  • a phosphono group and a mono- or di-Ci-6 alkylphosphono group e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono
  • examples of the "optionally substituted amino group” include an amino group optionally having "1 or 2 substituents selected from a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a Ce-1 aryl group, a C 7 -i6 aralkyl group, a Ci-e alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C 7 -i 6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5— to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 7 -i6 a
  • optionally substituted amino group examples include an amino group, a mono- or di- (optionally
  • halogenated Ci-6 alkyl e.g., methylamino
  • a mono- or di-C3-io cycloalkylamino group e.g., cyclopropylamino, cyclohexylamino
  • a mono- or di- Ce-14 arylamino group e.g., phenylamino
  • a mono- or di-C 7 _i 6 aralkylamino group e.g., benzylamino, dibenzylamino
  • heterocyclylcarbonylamino group e.g., nicotinoylamino
  • isonicotinoylamino a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,
  • piperidinylcarbonylamino a mono- or di-Ci-e alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to
  • pyridylamino a carbamoylamino group, a (mono- or di-Ci- 6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C 7 -i6 aralkyl-carbamoyl ) amino group (e.g.,
  • Ci_6 alkylsulfonylamino group e.g.,
  • arylsulfonylamino group e.g., phenylsulfonylamino
  • a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl ) amino group e.g., N-acetyl-N- methylamino
  • a (Ci_6 alkyl) (C6-14 aryl-carbonyl) amino group e.g., N-benzoyl-N-methylaminb
  • examples ' of the "optionally substituted carbamoyl group” include a carbamoyl group
  • Ci_ 6 alkyl group optionally having "1 or 2 substituents selected from a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C 3- io cycloalkyl group, a C 6 - i4 aryl group, a C 7 _i 6 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C 6 -i4 aryl-carbonyl group, a C 7 _i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C 7 -i 6 aralky
  • carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 2 -6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C 3 -io cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
  • cyclohexylcarbamoyl a mono- or di-C6-i aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7 _i 6 aralkyl-carbamoyl group, a mono- or di-Ci_ 6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C6-i aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl ) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
  • examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Ci_ 6 alkyl group, a C 2 ⁇ e alkenyl group, a C 3 _i 0 cycloalkyl group, a C 6 - 14 aryl group, a C 7 _i 6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C 7 -i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl
  • thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C 2 -6 alkenyl- thiocarbamoyl group (e . g. , diallylthiocarbamoyl) , a mono- or di-C3-io cycloalkyl-thiocarbamoyl group (e.g.,
  • a mono- or di-Ci-6 alkyl-carbonyl-thiocarbamoyl group e.g., acetylthiocarbamoyl, propionylthiocarbamoyl
  • examples of the "optionally substituted sulfamoyl group” include a sulfamoyl group
  • Ci_ 6 alkyl group optionally having "1 or 2 substituents selected from a Ci_ 6 alkyl group, a C 2 -e alkenyl group, a C 3 _io cycloalkyl group, a C 6 - 14 aryl group, a C 7 _i 6 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C 7 _i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C 7 _i 6 aralkyl-carbam
  • the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl) , a mono- or di-C2-6 alkenyl-sulfamoyl group (e.g.,
  • diallylsulfamoyl a mono- or di-C 3 _i 0 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl ) , a mono- or di-C6-i aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C 7 _i 6 aralkyl-sulfamoyl group (e.g.,
  • benzylsulfamoyl phenethylsulfamoyl
  • a mono- or di-Ci-6 alkyl- carbonyl-sulfamoyl group e.g., acetylsulfamoyl
  • propionylsulfamoyl a mono- or di-C6-i4 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) .
  • a mono- or di-C6-i4 aryl-carbonyl-sulfamoyl group e.g., benzoylsulfamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfamoyl group e.g., pyridylsulfamoyl
  • examples of the "optionally substituted hydroxy group” include a hydroxyl group optionally having "a substituent selected from a Ci- 6 alkyl group, a C 2 -6 alkenyl group, a C 3 _i 0 cycloalkyl group, a C 6 -i4 aryl group, a C 7 _ 16 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a C 6 -i4 aryl- carbonyl group, a C 7 _i6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci_3 ⁇ 4 alkyl-carbamoyl group, a
  • Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci-6 alkoxy group, a C 2 -6
  • alkenyloxy group e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy
  • a C3-10 cycloalkyloxy group e.g., cyclohexyloxy
  • a C6-14 aryloxy group e.g., phenoxy, naphthyloxy
  • aralkyloxy group e.g., benzyloxy, phenethyloxy
  • Ci- 6 alkyl- carbonyloxy group e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • a C6-14 aryl-carbonyloxy group e.g., benzoyloxy
  • a C7-16 aralkyl-carbonyloxy group e.g., benzylcarbonyloxy
  • heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., piperidinylcarbonyloxy
  • a Ci_6 alkoxy-carbonyloxy group e.g., tert-butoxycarbonyloxy
  • heterocyclyloxy group e.g., pyridyloxy
  • carbamoyloxy group e.g., a Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy)
  • Ci-6 alkyl-carbamoyloxy group e.g., methylcarbamoyloxy
  • C7-16 aralkyl-carbamoyloxy group e.g., benzylcarbamoyloxy
  • a Ci-6 alkylsulfonyloxy group e.g., methylsulfonyloxy
  • ethylsulfonyloxy ethylsulfonyloxy
  • a C6-1 arylsulfonyloxy group e.g., phenylsulfonyloxy
  • examples of the "optionally substituted sulfanyl group” include a sulfanyl group optionally having "a substituent selected from a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 -i4 aryl group, a C 7 _ 16 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a C 6 -i4 aryl- carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents
  • Substituent Group A selected from Substituent Group A" and a halogenated sulfanyl group.
  • sulfanyl group include a sulfanyl (-SH) group, a Ci-6 alkylthio group, a C 2 -6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C6-1 arylthio group (e.g., phenylthio, naphthylthio) , a C7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a Ci_ 6 alkyl-carbonylthio group (e.g.,
  • benzoylthio a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
  • examples of the "optionally substituted silyl group” include a silyl group optionally having "1 to 3 substituents selected from a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 -i4 aryl group and a C 7 -i6 aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
  • Preferable examples of the optionally substituted silyl group include a tri-Ci-6 alkylsilyl group (e . g. , trimethylsilyl, tert-butyl (dimethyl) silyl) .
  • alkoxy group shows a Ci-6 alkoxy group.
  • X is a halogen atom.
  • X is preferably a chlorine atom.
  • One of Ri and R 2 is a substituent, and the other is a hydrogen atom.
  • Ri is preferably an amino group or an alkoxy group, each of which is optionally substituted.
  • Ri is more preferably an optionally substituted amino group.
  • Ri is more further preferably an amino group optionally mono- or di-substituted by C -6 alkyl group (s) (e.g., methyl, isopropyl)-.
  • Ri is still more preferably an amino group di-substituted by C -6 alkyl groups (e.g., methyl, isopropyl) (preferably, N- isopropyl-N-methylamino) .
  • R 2 is preferably a hydrogen atom.
  • Compound (a) Preferable specific examples include the following:
  • Ri is an amino group or an alkoxy group, each of which is optionally substituted
  • R 2 is a hydrogen atom.
  • X is a halogen atom
  • Ri is an optionally substituted amino group
  • R2 is a hydrogen atom.
  • X is a chlorine atom
  • Ri is an amino group optionally mono- or di-substituted by Ci_6 alkyl group (s) (e.g., methyl, isopropyl) ;
  • R 2 is a hydrogen atom.
  • X is a chlorine atom
  • Ri is an amino group di-substituted by Ci_ 6 alkyl groups (e.g., methyl, isopropyl) (preferably, N-isopropyl-N-methylamino) ; and R 2 is a hydrogen atom.
  • hydrochloride of compound (a) wherein X is a chlorine atom, Ri is N-isopropyl-N-methylamino, and R 2 is a hydrogen atom can be obtained as crystals, can be purified by crystallization without purification by silica gel
  • Compound (b) Preferable specific examples include the following:
  • R 2 is a hydrogen atom.
  • Ri is an optionally substituted amino group
  • R 2 is a hydrogen atom.
  • Ri is an amino group, optionally mono- or di-substituted by Ci_ 6 alkyl group (s) (e.g., methyl, isopropyl); and
  • R 2 is a hydrogen atom.
  • Ri is an amino group di-substituted by Ci_6 alkyl groups (e.g., methyl, isopropyl) (preferably, N- isopropyl-N-methylamino) ;
  • R 2 is a hydrogen atom.
  • a compound represented by the formula (a) and a compound represented by the formula (b) each may be a salt.
  • salt of a compound represented by the formula (a) and a compound represented by the formula (b) for example, metal salt, ammonium salt, salt with organic base, salt with inorganic acid, salt with organic acid, and salt with basic or acidic amino acid can be mentioned.
  • the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.
  • salt with organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, - triethanolamine, cyclohexylamine, .dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine and the like.
  • the salt with inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate and the like.
  • the salt with organic acid include salts with carboxylic acid (i.e., organic compound having one or more carboxy groups; specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid and the like) ; and sulfonic acid (i.e., organic compound having one or more sulfo groups; specific examples include salts with methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, " camphorsulfonic acid and the like) .
  • carboxylic acid i.e., organic compound having one or more carboxy groups
  • specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,
  • salt with basic amino acid examples include salts with arginine, lysine, ornithine and the like
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Salts of a compound represented by the formula (a) and a compound represented by the formula (b) are preferably salts with inorganic acids, more preferably hydrochloride.
  • Compound (a) and compound (b) each may be a solvate (e.g., hydrate, ethanol solvate), or a non-solvate (e.g., non-hydrate), and both are encompassed in compound (a) or compound (b) .
  • a solvate e.g., hydrate, ethanol solvate
  • a non-solvate e.g., non-hydrate
  • Compound (a) or compound (b) also encompasses a compound labeled with an isotope (e.g., 3 H, n C, 13 C, 14 C, 18 F, 35 S, 125 I etc. ) .
  • an isotope e.g., 3 H, n C, 13 C, 14 C, 18 F, 35 S, 125 I etc.
  • Compound (a) or compound (b) also encompasses a deuterium conversion form wherein X H is converted to 2 H(D) .
  • Compound (b) can be produced by an intramolecular ring closing reaction of compound (a) under basic conditions. This reaction is performed, where necessary, in a solvent that does not adversely influence the reaction.
  • the base examples include metal hydrides (e.g., potassium hydride, sodium hydride etc.), inorganic bases (e.g., alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate,
  • carbonates such as sodium carbonate, potassium carbonate and ⁇ . the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, . potassium tert-butoxide, sodium tert-amyloxide, potassium tert-amyloxide and the like) , organic bases (e.g., trimethylamine, triethylamine,
  • disilazides e.g., lithium hexamethyldisilazide, sodium
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like
  • alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, potassium tert-amyloxide and the like are preferably, and sodium hydroxide and sodium tert-butoxide are particularly preferable.
  • the amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, it is generally about 0.1 mol - about 10 mol, preferably about 0.1 mol - about 5 mol, per 1 mol of compound (a).
  • solvents examples include hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane), ethers (e.g., diethyl ether,
  • the amount of the solvent to be used is generally 3- to 20-fold by weight, preferably 5- to 15-fold by weight, relative to compound (a) .
  • This reaction may be performed, where necessary, in the presence of a phase transfer catalyst.
  • phase transfer catalyst examples include:
  • phase transfer catalyst to be used varies depending on the kind of the base and solvent, and other reaction conditions, it is generally about 0.01 mol - about 2 mol, preferably about 0.1 mol - about 0.5 mol, per 1 mol of compound (a) .
  • the reaction temperature is generally about 0°C to about 150°C, preferably about 10°C to about 110°C.
  • the reaction time varies depending on the kind of compound (a) , the reaction temperature and the like, and is generally about 0.1 hr - about 100 hr, preferably about 0.5 hr - about 24 hr.
  • the thus-obtained compound (b) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • a salt may be formed from a crude product and then isolated and purified.
  • the salt can be formed by treatment of the crude product with
  • the production method of the present invention can be a convenient method suitable for industrial production in a good yield.
  • Compound (a) as a starting material is an intermediate compound in an advantageous production method suitable for industrial production of compound (b) having a superior
  • This reaction can be performed according to a method known per se [e.g., the method described in Jikken Kagaku Koza (Courses in Experimental Chemistry) , the fourth edition, vol. 14, page 370], and generally performed in the presence of a . reducing agent, as necessary, in a solvent that does not
  • Compound (c) can be produced by a method known per se [the method described in Journal of Organometallic Chemistry, 1991, vol. 412 (No. 3), page 301] or a method analogous thereto.
  • the reducing agent examples include aluminum reagents (e.g., lithium aluminum hydride (LiAlH 4 ) , diisobutylaluminum hydride (DIBAL-H) , sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) , alane (A1H 3 ) ) , and boron reagents (e.g. , borane (BH 3 ) , 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH ) , sodium cyanoborohydride (NaBH 3 CN) , and sodium
  • aluminum reagents e.g., lithium aluminum hydride (LiAlH 4 ) , diisobutylaluminum hydride (DIBAL-H) , sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) , alane (A1H 3 )
  • triacetoxyborohydride are preferable, and sodium borohydride is particularly preferable.
  • reaction conditions it is generally about 0.3 mol - about 10 mol, preferably about 1 mol - about 5 mol, per 1 mol of
  • Examples of the solvent that does not adversely influence the reaction include alcohols (e.g., methanol, ethanol,
  • the amount of the solvent to be used is generally 3- to 20-fold by weight, preferably 5- to 15-fold by weight, relative to compound (c) .
  • the reaction temperature is generally about -80°C to about 200°C, preferably about -80°C to about 100°C.
  • the reaction time is generally about 0.1 hr - -about 100 hr, preferably about 0.5 hr - about 24 hr.
  • the thus-obtained compound (a) can be isolated and purified by a known separation and purification means, for , example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • a salt may be formed from a crude product and then isolated and purified.
  • the salt can be formed by treatment of the crude product with
  • a compound represented by the formula (c) may be a salt, and a pharmacologically acceptable salt is preferable.
  • a pharmacologically acceptable salt one similar to those exemplified as a compound
  • compound (a) and/or compound (b) are/is obtained as a free compound, they can be each converted to an object salt according to a method known per se or a method analogous thereto. On the contrary, when they are obtained as salts, they can be each converted to a free form or other object salt according to a method known per se or a method analogous thereto.
  • compound (a) and/or compound (b) contain (s) isomers such as an optical isomer, a stereoisomer, a regioisomer and a rotamer, such isomers and a mixture thereof are also present.
  • isomers such as an optical isomer, a stereoisomer, a regioisomer and a rotamer, such isomers and a mixture thereof are also present.
  • an isomer may be formed by conformation, and such isomers and a mixture thereof are also encompassed in compound (a) or compound (b) .
  • These isomers can be obtained as single products by a synthetic method or separation method known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • a synthetic method or separation method known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • an optical isomer resolved from this compound is also encompassed in compound (a) or (b) ..
  • the optical isomer can be produced according to a method known per se. Specifically, the optical isomer is obtained by using an optically active synthetic intermediate or by
  • the method of optical resolution may be a method known, per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method etc.
  • a method wherein a salt of a racemate with an optically active compound e.g., (+)-mandelic acid, (-)-mandelic acid, (+) -tartaric acid, (-) -tartaric acid, (+) -1-phenethylamine, (-) -1-phenethylamine, cinchonine, (-) -cinchonidine, brucine
  • an optically active compound e.g., (+)-mandelic acid, (-)-mandelic acid, (+) -tartaric acid, (-) -tartaric acid, (+) -1-phenethylamine, (-) -1-phenethylamine, cinchonine, (-) -cinchonidine, brucine
  • a column a chiral column
  • chromatography for example, a mixture of the optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Chemical Industries, Ltd. ) , and developed with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) as an eluent, solely or in admixture to separate the optical isomers.
  • a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Chemical Industries, Ltd. )
  • various buffers e.g., phosphate buffer
  • organic solvents e.g., ethanol, methanol, isopropanol, aceton
  • chromatography for example, a chiral column such as CP- Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like is used to allow separation.
  • a chiral column such as CP- Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like is used to allow separation.
  • a method wherein a racemic mixture is converted into a diastereomeric mixture by chemical reaction with an optically active reagent which is made into a single substance by a typical separation means (e.g., a fractional recrystallization method, a chromatography method) and the like, and is subjected to a' chemical treatment such as hydrolysis and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained.
  • a typical separation means e.g., a fractional recrystallization method, a chromatography method
  • compound (b) when compound (b) contains hydroxy or primary or secondary amino group in a molecule, the compound and an optically active organic acid (e.g., MTPA [oc- methoxy- - (trifluoromethyl) phenylacetic acid], (-)- menthoxyacetic acid) and the like are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively.
  • an optically active organic acid e.g., MTPA [oc- methoxy- - (trifluoromethyl) phenylacetic acid], (-)- menthoxyacetic acid
  • Compound (a) and compound (b) may be crystals, and they are encompassed in compound (a) and compound (b) whether the crystal form is singular or a mixture of the crystal forms.
  • the crystal of compound (a) or compound (b) can be produced by crystallizing compound (a) or compound (b) by applying a crystallization- method known per se.
  • crystallization method examples include
  • crystallization method from a solution crystallization method from vapor, and crystallization method from a melt.
  • the "crystallization method from a solution” is typically a method of shifting a non-saturated state to supersaturated state by varying factors involved in solubility of compounds (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent. Specific examples thereof include a concentration method, a slow cooling method, a reaction method (a diffusion method, an electrolysis method) , a hydrothermal growth method, and a flux method.
  • solvent to be used examples include aromatic hydrocarbons (e.g., benzene, toluene, xylene) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane) , ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane), nitriles (e.g., acetonitrile) , ketones (e.g., acetone), sulfoxides (e.g., dimethyl sulfoxide), acid amides (e.g., N, N-dimethylformamide) , esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol, isopropyl alcohol) , and water. These solvents are used alone or
  • a seed crystal can be used.
  • the "crystallization method from vapor” is, for example, a vaporization method (a sealed tube method, a gas stream method) , a gas phase reaction method, and a chemical
  • the "crystallization method from a melt” is, for example, a normal freezing method (a pulling method, a temperature gradient method, a Bridgman method) , a zone melting method (a zone leveling method, a floating zone method) , and a special growth method (a VLS method, a liquid phase epitaxy method) .
  • the crystallization method include a method comprising dissolving compound (a) or compound (b) in a suitable solvent (e.g., alcohols such as methanol, ethanol and the like, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane) at 20°C to 120°C, and cooling the obtained solution to a temperature not higher than the dissolution temperature (e.g., 0 - 50°C, preferably 0 - 20°C) , and the like.
  • a nitrogen gas and the like may be flown to evaporate the solvent.
  • crystals of compound (a) and (b) of the present invention can be isolated, for example, by filtration and the like.
  • An analysis method of the obtained crystal is generally a method of crystal analysis by powder X-ray diffraction.
  • a method of determining crystal orientation a mechanical method or an optical method and the like can also be used.
  • Each of the crystals of compound (a) and compound (b) obtained by the above-mentioned production method has high purity, high quality, and low hygroscopicity, is not denatured even after- a long-term preservation under general conditions, and is extremely superior in the stability.
  • compound (b) is also superior in the biological properties
  • Compound (b) labeled with or substituted by an isotope can be used, for example, as a tracer used for Positron
  • PET Emission Tomography
  • Compound (a) and compound (b) may each be a
  • cocrystal or a salt thereof means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability etc.).
  • the cocrystal or a salt thereof can be
  • room temperature is about 25°C.
  • reaction mixture was warmed to 20-22°C, stirred at the same temperature for about 2 hr, and neutralized (pH 6.6) with an aqueous sodium hydroxide solution (4 M, 230 mL) at 5°C. The mixture was concentrated, and the residue was
  • reaction mixture was diluted with water (2000 mL) at 50°C or below, and extracted with a mixture of toluene (1200 mL) and 2- butanone (800 mL) .
  • the organic layer was separated, and the aqueous layer was extracted 3 times with a mixture of toluene (1200 mL) and 2-butanone (800 mL) .
  • the combined organic layers were concentrated, and a mixture of ethanol (600 mL) and ethyl acetate (1200 mL) was added to the residue.
  • the mixture was treated with concentrated hydrochloric acid (55.6 mL) at 20- 30°C, and stirred at the same temperature for 2 hr.
  • compound (b) can be produced in a good yield while suppressing byproducts even when amino group is unprotected. Therefore, the production method can reduce the protection and deprotection steps of amino group, and can be a method suitable for convenient industrial

Abstract

The present invention relates to a method of industrially advantageous production of a pyrazine compound. The present invention is a method of producing compound (b) by subjecting compound (a) to an intramolecular ring closing reaction under basic conditions. (wherein each symbol is as described in the DESCRIPTION.)

Description

DESCRIPTION
Title of the Invention: PRODUCTION METHOD OF PYRAZINE
Technical Field
[0001]
The present invention relates to an advantageou
production method suitable for industrial production
pyrazine compound.
[0002]
[Background of the Invention]
[0003]
A pyrazine compound represented by the following formula
Figure imgf000002_0001
[0005]
(wherein each symbol is as described in the DESCRIPTION) has high safety and a superior serotonin 5-HT2c receptor activation action, and is known to be useful as a prophylactic or
therapeutic drug for lower urinary tract symptoms and the like (patent document 1) .
As a production method of the pyrazine compound, patent document 1 describes the following production method.
[0006]
Figure imgf000003_0001
Figure imgf000003_0002
[0007]
(wherein each symbol is as described in the DESCRIPTION) .
Furthermore, as a production method of a compound such as pyrazine compound and the like, the methods described in patent documents 2 to 6 are known.
Also, as an intermediate, the following compound is known (non-patent document 1) .
0008]
Figure imgf000003_0003
Provision of an advantageous production method suitable for industrial production of the pyrazine compound has been further desired.
[Document List]
[Patent Documents]
[0010]
patent document 1: WO 2010/147226
patent document' 2: WO 2010/132015
patent document 3: WO 2007/132841 patent document 4: WO 2008/108445
patent document 5: WO 2009/063991
patent document 6: WO 2009/063993
[non-patent document]
[0011]
non-patent document 1 : A Chemtek Product List, Amber Molthech, Aurora Building Block
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0012]
The present invention aims to provide a production method suitable for good yielding and convenient industrial production of a pyrazine compound represented by the following formula (b) . Means of Solving the Problems
[0013]
The present inventors have found that a compound
represented by the following formula (b) can be produced in a good yield even when amino group is unprotected, by a method suitable for convenient industrial production, by an
intramolecular ring closing reaction under basic conditions by using a compound represented by the following formula (a) as a starting material, which resulted in the completion of the present invention.
[0014]
That is, the present invention is as follows.
[1] A compound represented by the formula (a):
[0015]
Figure imgf000004_0001
(a)
[0016]
wherein X is a halogen atom, one of Ri and R2 is a substituent, and the other is a hydrogen atom, or a salt thereof (hereinafter to be abbreviated as compound
(a)).
[2] The compound of the above-mentioned [1] , wherein Ri is an amino group or an alkoxy group, each of which is optionally substituted, or a salt thereof.
[3] The compound of the above-mentioned [1], wherein ¾ is an optionally substituted amino group, or a salt thereof.
[4] A production method of a compound represented by the formula (b) :
[0017]
Figure imgf000005_0001
[0018]
wherein one of Ri and R2 is a substituent, and the other is a hydrogen atom,
or a salt thereof (hereinafter to be abbreviated as compound (b) ) , comprising subjecting a compound represented by the. formula (a) :
[0019]
Figure imgf000005_0002
(a)
[0020]
wherein X is a halogen atom, and the other symbols are as defined above,
or a salt thereof, to an intramolecular ring closing reaction under basic conditions.
[5] The production method of the above-mentioned [4], wherein Ri is an amino group or an alkoxy group, each of which is optionally substituted.
[6] The production method of the above-mentioned [4], wherein Ri is an optionally substituted amino group.
[Effect of the Invention]
[0021]
According to the present invention, compound (b) can be produced in a good yield while suppressing byproducts, even when amino group is unprotected. Therefore, the production method can reduce protecting and deprotectxng steps of amino group, and can become a method suitable for convenient
industrial production.
To be specific, according to the present invention capable of suppressing byproducts and reducing the number of steps, labor costs can be reduced, the yield can be improved, and finally, the production costs can be radically reduced.
[0022]
(Detailed Description of the Invention)
The present invention is explained in detail in the following.
[0023]
The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the "Ci_6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl,. 3 , 3-dimethylbutyl and 2-ethylbutyl .
In the present specification, examples of the "optionally halogenated Ci_6 alkyl group" include a Ci-6 alkyl group
optionally having .1 to 7, preferably 1 to 5 halogen atoms.
Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- bromoethyl, 2 , 2 , 2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2 , 2-difluoropropyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , 4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl .
In the present specification, examples of the "C2-6
alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-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 and 5-hexenyl.
In the present specification, examples of the "C2-6
alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl .
In the present specification, examples of the "C3-10
cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl and adamantyl.
In the present specification, examples of the "optionally halogenated C3-10 cycloalkyl group" include a C3_i0 cycloalkyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms.
Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2, 3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, examples of the "C3-10
cycloalkenyl group" include cyclopropenyl, cyclobutenyl , cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .
In the present specification, examples of the "C6_i4 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
In the present specification, examples of the "C7_i6
aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
[0024] In the present specification, examples of the "Ci-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "optionally 5 halogenated Cis alkoxy group" include a Ci_6 alkoxy group
optionally having 1 to 7, preferably 1 to 5 halogen atoms.
Specific examples thereof include . methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4 , 4 , 4-trifluorobutoxy, isobutoxy, 'sec- it? butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "C3-i0 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy .
In the present specification, examples of the "C'i-6 15 alkylthio group" include methylthio, ethylthio, propylthio, . isopropylthio, butylthio, sec-butylthio, tert-butylthio,
pentylthio and hexylthio.
In the present specification, examples of the "optionally halogenated Ci-6 alkylthio group" include a Cis alkylthio -group 20 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
25 In the present specification, examples of the "Ci-6 alkyl- carbonyl group" include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
In the present specification, examples of the "optionally
30 halogenated Ci_6 alkyl-carbonyl group" include a Ci_6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
35 In the present specification, examples of the "Ci-6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl .
In the present specification, examples of the "C6-i4 aryl- carbonyl group". include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C7_i6 aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl .
In the present specification, examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl .
[0025]
In the present specification, examples of the "mono- or di-Ci-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N- ethyl-N-methylcarbamoyl .
In the present specification, examples of the "mono- or di-C7-i6 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .
In the present specification, examples of the "Ci-6
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
In the present specification, examples of the "optionally halogenated Ci_6 alkylsulfonyl group" include a Ci-6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include
methylsulfonyl , difluoromethylsulfonyl , trifluoromethylsulfonyl , ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4, 4, 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl . In the present specification, examples of the "C6-14
arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
[0026]
In the present specification, examples of the
"substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
In the present specification, examples of the
"hydrocarbon group" (including "hydrocarbon group" of
"optionally substituted hydrocarbon group") include a Ci_6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10
cycloalkyl group, a C3-10 cycloalkenyl group, a C6_i4 aryl group and a C7_i6 aralkyl group.
[0027]
In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent ( s ) selected from the following Substituent Group A.
[Substituent Group A]
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally, halogenated Ci-6 alkoxy group,
(7) a C6_i4 aryloxy group (e.g., phenoxy, naphthoxy) ,
(8) a C7-i6 aralkyloxy group (e.g., benzyloxy) ,
(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy) , (10) a 3- to .14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy) ,
(11) a Ci-6 alkyl-carbonyloxy group (e.g., acetoxy,
propanoyloxy) ,
(12) a C6-i4 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,
(13) a Ci-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,
(14) a mono- or di-Ci_6 alkyl-carbamoyloxy group (e.g.,
methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,
(15) a Ce-1 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) ,
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) ,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) ,
(18) an optionally halogenated Ci_6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) ,
(19) a Ce-14 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy) ,
(20) an optionally halogenated Ci_6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated Ci-6 alkyl-carbonyl group,
(26) a C6-i4 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a Ci-6 alkoxy-carbonyl group,
(30) a C6_i4 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,
(31) a C7-i6 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) ,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-Ci-6 alkyl-carbamoyl group,
(35) -a C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) ,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,
(37) a 3- to 14-membered " non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl) ,
(38) an optionally halogenated Ci-6 alkylsulfonyl group,
(39) a C6-14 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl) ,
(41) an optionally halogenated Ci_6 alkylsulfinyl group,
(42) a C6-14 arylsulfinyl group (e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl) ,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,, pyridylsulfinyl, thienylsulfinyl) ,
(44) an amino group,
(45) a mono- or di-Ci_6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,
(46) a mono- or di-Ce-14 arylamino group (e.g., phenylamino) , (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino) ,
(48) a C7-i6 aralkylamino group (e.g., benzylamino) ,
(49) a formylamino group,
(50) a Ci-6 alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino) ,
(51) a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group (e.g., N- acetyl-N-methylamino) ,
(52) a C6-i4 aryl-carbonylamino group_ (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,
( 53) a Ci-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino) ,
(54) a C7_i6 aralkyloxy-carbonylamino group (e.g.,
benzyloxycarbonylamino) ,
(55)' a Ci-6 alkylsuifonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,
(56) a C6_i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonylamino,
toluenesulfonylamino) ,
(57) an optionally halogenated Ci_6 alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group,
(61) a C3-10 cycloalkenyl group and
(62) a C6-i4 aryl group.
[0028]
The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
In , the present specification, examples of the
"heterocyclic group" (including "heterocyclic group" of
"optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0029]
In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an Oxygen atom.
Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazdlyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1, 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and
8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocyclic groups such as benzothiophenyl,
benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,
imidazopyridinyl, thienopyridinyl, furopyridinyl,
pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,
thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,
thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,
pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl,
quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl,
phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl and the like.
[0030]
In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non- aromatic heterocyclic group") include a 3- to 14-membered
(preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic
heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, _
tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,
pyrazolidinyl, thiazolinyl, thiazolidinyl,
tetrahydroisothiazolyl, tetrahydrooxazolyl,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,
thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and
9- to 14-membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl,
dihydrobenzothiazolyl, dihydrobenzisothiazolyl,
dihydronaphtho [2 , 3-b] thienyl, tetrahydroisoquinolyl,
tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno [2, 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,
hexahydrophenothiazinyl , hexahydrophenoxazinyl,
tetrahydrophthalazinyl, tetrahydronaphthyridinyl,
tetrahydroquinazolinyl, tetrahydrocinnolinyl,
tetrahydrocarbazolyl, tetrahydro-p-carbo.linyl,
tetrahydroacrydinyl, tetrahydrophenazinyl,
tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.
[0031]
In the present specification, preferable examples of the "7- to 10-membered bridged heterocyclic group" include
quinuclidinyl and ,7-azabicyclo [2.2.1] heptanyl .
In the present specification, examples of the "nitrogen- containing heterocyclic group" include a "heterocyclic - group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent (s) selected from the above- mentioned Substituent Group A.
The number of the substituents in the "optionally
substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
[0032]
In the present specification, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-i4 aryl group, a C7_i6 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated Ci_6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group".
Examples of the "acyl group" also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the
hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
Preferable examples of the "acyl group" include a formyl group, a carboxy group, a Ci-6 alkyl-carbonyl group, a C2-6
alkenyl-carbonyl group (e.g., crotonoyl) , a C3-10 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) , a C3-10
cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl) , a
C6-i4 aryl-carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy- carbonyl group, a C6-i4 aryloxy-carbonyl group (e.g.,
phenyloxycarbonyl, naphthyloxycarbonyl) , a C7-i6 aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g.,
diallylcarbamoyl) , a mono- or di-C3-i0 cycloalkyl-carbamoyl group (e.g. , cyclopropylcarbamoyl) , a mono- or di-C6-i4 aryl- carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C_i6 aralkyl-carbamoyl group, a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a
thiocarbamoyl group, a mono- or di-Ci_6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C3_io
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7_i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,
phenethylthiocarbamoyl) , a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl ) , a sulfino group, a Ci_6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl) , a sulfo group, a Ci-6 alkylsulfonyl group, a C6- 14 arylsulfonyl group, a phosphono group and a mono- or di-Ci-6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .
[0033]
In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-1 aryl group, a C7-i6 aralkyl group, a Ci-e alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-i6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5— to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C7-i6 aralkyl-carbamoyl group, a Ci-6 alkylsulfonyl group and a C6-1 arylsulfonyl group, each of which optionally 5 has 1 to 3 substituents selected from Substituent Group A".
. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally
halogenated Ci-6 alkyl)amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamlno,
10 propylamino, dibutylamino) , a mono- or di-C2-6 alkenylamino
group (e.g., diallylamino) , a mono- or di-C3-io cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino) , a mono- or di- Ce-14 arylamino group (e.g., phenylamino) , a mono- or di-C7_i6 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono-
15 or di- (optionally halogenated Ci-6 alkyl) -carbonylamino group
(e.g., acetylamino, propionylamino) , a mono- or di-C6-i4 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C7-i6 aralkyl-carbonylamino group (e.g., benzylcarbonylamino) , a mono- or di-5- to 14-membered aromatic
20 heterocyclylcarbonylamino group (e.g., nicotinoylamino,
isonicotinoylamino) , a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,
piperidinylcarbonylamino) , a mono- or di-Ci-e alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to
25 14-membered aromatic heterocyclylamino group (e.g.,
pyridylamino) , a carbamoylamino group, a (mono- or di-Ci-6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C7-i6 aralkyl-carbamoyl ) amino group (e.g.,
benzylcarbamoylamino) , a Ci_6 alkylsulfonylamino group (e.g.,
30 methylsulfonylamino, ethylsulfonylamino) , a C6-i4
arylsulfonylamino group (e.g., phenylsulfonylamino) , a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl ) amino group (e.g., N-acetyl-N- methylamino) and a (Ci_6 alkyl) (C6-14 aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylaminb) .
35 [0034] In the present specification, examples' of the "optionally substituted carbamoyl group" include a carbamoyl group
optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-io cycloalkyl group, a C6- i4 aryl group, a C7_i6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-i4 aryl-carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C7-i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
Preferable examples of the optionally substituted
carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3-io cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl) , a mono- or di-C6-i aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7_i6 aralkyl-carbamoyl group, a mono- or di-Ci_6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C6-i aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl ) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
pyridylcarbamoyl ) .
[0035]
In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2~e alkenyl group, a C3_i0 cycloalkyl group, a C6- 14 aryl group, a C7_i6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl- thiocarbamoyl group (e . g. , diallylthiocarbamoyl) , a mono- or di-C3-io cycloalkyl-thiocarbamoyl group (e.g.,
cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-i aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7_i6 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl) , a mono- or di-Ci-6 alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl) , a mono- or di-C6-i4 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .
[0036]
In the present specification, examples of the "optionally substituted sulfamoyl group" include a sulfamoyl group
optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-e alkenyl group, a C3_io cycloalkyl group, a C6- 14 aryl group, a C7_i6 aralkyl group, a Ci_6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C7_i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl) , a mono- or di-C2-6 alkenyl-sulfamoyl group (e.g.,
diallylsulfamoyl) , a mono- or di-C3_i0 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl ) , a mono- or di-C6-i aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C7_i6 aralkyl-sulfamoyl group (e.g.,
benzylsulfamoyl, phenethylsulfamoyl) , a mono- or di-Ci-6 alkyl- carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,
propionylsulfamoyl) , a mono- or di-C6-i4 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) .
[0037]
In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3_i0 cycloalkyl group, a C6-i4 aryl group, a C7_ 16 aralkyl group, a Ci_6 alkyl-carbonyl group, a C6-i4 aryl- carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci_¾ alkyl-carbamoyl group, a mono- or di-C7-i6 aralkyl-carbamoyl group, a Ci-6 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci-6 alkoxy group, a C2-6
alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C7-i6
aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a Ci-6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C6-14 aryl-carbonyloxy group (e.g., benzoyloxy) , a C7-16 aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy) , a 5- to 14-membered aromatic
heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) , a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy) , a Ci_6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyridyloxy) a carbamoyloxy group, a Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a
C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a Ci-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
ethylsulfonyloxy) and a C6-1 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .
[0038]
In the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group, a C7_ 16 aralkyl group, a Ci_6 alkyl-carbonyl group, a C6-i4 aryl- carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents
selected from Substituent Group A" and a halogenated sulfanyl group.
Preferable examples of the optionally substituted
sulfanyl group include a sulfanyl (-SH) group, a Ci-6 alkylthio group, a C2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C6-1 arylthio group (e.g., phenylthio, naphthylthio) , a C7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a Ci_6 alkyl-carbonylthio group (e.g.,
acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio) , a C6-i4 aryl-carbonylthio ' group (e.g.,
benzoylthio) , a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
[0039] • In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group and a C7-i6 aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A".
Preferable examples of the optionally substituted silyl group include a tri-Ci-6 alkylsilyl group (e . g. , trimethylsilyl, tert-butyl (dimethyl) silyl) .
[0040]
In the present specification, the "alkoxy group" shows a Ci-6 alkoxy group.
Each symbol in the formula^ is explained below.
X is a halogen atom.
X is preferably a chlorine atom.
[0041]
One of Ri and R2 ;is a substituent, and the other is a hydrogen atom.
Ri is preferably an amino group or an alkoxy group, each of which is optionally substituted.
Ri is more preferably an optionally substituted amino group.
Ri is more further preferably an amino group optionally mono- or di-substituted by C -6 alkyl group (s) (e.g., methyl, isopropyl)-.
Ri is still more preferably an amino group di-substituted by C -6 alkyl groups (e.g., methyl, isopropyl) (preferably, N- isopropyl-N-methylamino) .
R2 is preferably a hydrogen atom.
- [0042]
Preferable specific examples of Compound (a) include the following:
[0043]
[Compound Aa]
Compound (a) wherein X is a halogen atom;
Ri is an amino group or an alkoxy group, each of which is optionally substituted; and
R2 is a hydrogen atom.
[0044]
[Compound Ba]
Compound (a) wherein
X is a halogen atom;
Ri is an optionally substituted amino group; and
R2 is a hydrogen atom.
[0045]
[Compound Ca]
Compound (a) wherein
X is a chlorine atom;
Ri is an amino group optionally mono- or di-substituted by Ci_6 alkyl group (s) (e.g., methyl, isopropyl) ; and
R2 is a hydrogen atom.
[0046]
[Compound Da]
Compound (a) wherein
X is a chlorine atom;
Ri is an amino group di-substituted by Ci_6 alkyl groups (e.g., methyl, isopropyl) (preferably, N-isopropyl-N-methylamino) ; and R2 is a hydrogen atom.
Particularly, hydrochloride of compound (a) wherein X is a chlorine atom, Ri is N-isopropyl-N-methylamino, and R2 is a hydrogen atom can be obtained as crystals, can be purified by crystallization without purification by silica gel
chromatography, and can be easily industrialized.
[0047]
Preferable specific examples of Compound (b) include the following:
[0048]
[Compound Ab]
Compound (b) wherein Ri is an amino group or an alkoxy group, each of which is optionally substituted; and
R2 is a hydrogen atom.
[0049]
[Compound Bb]
"Compound (b) wherein
Ri is an optionally substituted amino group; and
R2 is a hydrogen atom.
[0050]
[Compound Cb]
Compound (b) wherein
Ri is an amino group, optionally mono- or di-substituted by Ci_6 alkyl group (s) (e.g., methyl, isopropyl); and
R2 is a hydrogen atom.
[0051]
[Compound Db]
Compound (b) wherein Ri is an amino group di-substituted by Ci_6 alkyl groups (e.g., methyl, isopropyl) (preferably, N- isopropyl-N-methylamino) ; and
R2 is a hydrogen atom.
[0052]
A compound represented by the formula (a) and a compound represented by the formula (b) each may be a salt.
As a salt of a compound represented by the formula (a) and a compound represented by the formula (b) , for example, metal salt, ammonium salt, salt with organic base, salt with inorganic acid, salt with organic acid, and salt with basic or acidic amino acid can be mentioned.
[0053]
Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.
[0054]
Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, - triethanolamine, cyclohexylamine, .dicyclohexylamine, Ν,Ν'- dibenzylethylenediamine and the like.
[0055]
Preferable examples of the salt with inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate and the like.
[0056] .
Preferable examples of the salt with organic acid include salts with carboxylic acid (i.e., organic compound having one or more carboxy groups; specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid and the like) ; and sulfonic acid (i.e., organic compound having one or more sulfo groups; specific examples include salts with methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, " camphorsulfonic acid and the like) .
[0057]
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
[0058]
Salts of a compound represented by the formula (a) and a compound represented by the formula (b) are preferably salts with inorganic acids, more preferably hydrochloride.
[0059]
Compound (a) and compound (b) each may be a solvate (e.g., hydrate, ethanol solvate), or a non-solvate (e.g., non-hydrate), and both are encompassed in compound (a) or compound (b) .
Compound (a) or compound (b) also encompasses a compound labeled with an isotope (e.g., 3H, nC, 13C, 14C, 18F, 35S, 125I etc. ) .
Compound (a) or compound (b) also encompasses a deuterium conversion form wherein XH is converted to 2H(D) .
[0060]
Compound (b) can be produced by an intramolecular ring closing reaction of compound (a) under basic conditions. This reaction is performed, where necessary, in a solvent that does not adversely influence the reaction.
[0061]
intramolecular
ring closing
reaction
Figure imgf000027_0001
[0062]
wherein each symbol is as defined above.
[0063]
Examples of the base include metal hydrides (e.g., potassium hydride, sodium hydride etc.), inorganic bases (e.g., alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate,
potassium hydrogen carbonate and the like; alkali metal
carbonates such as sodium carbonate, potassium carbonate and ■. the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, . potassium tert-butoxide, sodium tert-amyloxide, potassium tert-amyloxide and the like) , organic bases (e.g., trimethylamine, triethylamine,
diisopropylethylamine, N-methylmorpholine, 1,8- diazabicyclo [5.4.0] undec-7-ene, pyridine, N, N-dimethylaniline, pyridazine, 4-dimethylaminopyridine) , and alkali metal
disilazides (e.g., lithium hexamethyldisilazide, sodium
hexamethyldisilazide, potassium hexamethyldisilazide) . Of these, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; and alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, potassium tert-amyloxide and the like are preferably, and sodium hydroxide and sodium tert-butoxide are particularly preferable.
While the amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, it is generally about 0.1 mol - about 10 mol, preferably about 0.1 mol - about 5 mol, per 1 mol of compound (a).
[0064]
Examples of the solvent that does not adversely influence the reaction include hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane), ethers (e.g., diethyl ether,
diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane) , alcohols (e.g., methanol, ethanol, propanol, 2-propanol,. butanol, isobutanol, tert-butanol) , nitriles (e.g., acetonitrile etc.), amides (e.g., N,N- "dimethylformamide, N, -dimethylacetamide) , and sulfoxides (e.g., dimethyl sulfoxide) . These solvents may be used in a mixture at an appropriate ratio. Of these, dimethyl sulfoxide and a mixture of dimethyl sulfoxide and N, -dimethylacetamide are preferable
The amount of the solvent to be used is generally 3- to 20-fold by weight, preferably 5- to 15-fold by weight, relative to compound (a) .
[0065]
This reaction may be performed, where necessary, in the presence of a phase transfer catalyst.
Examples of the phase transfer catalyst include
tetrabutylammonium salt, trioctylmethylammonium salt,
benzyldimethyloctadecylammonium salt and the like.
While the amount of the phase transfer catalyst to be used varies depending on the kind of the base and solvent, and other reaction conditions, it is generally about 0.01 mol - about 2 mol, preferably about 0.1 mol - about 0.5 mol, per 1 mol of compound (a) .
[0066]
The reaction temperature is generally about 0°C to about 150°C, preferably about 10°C to about 110°C.
The reaction time varies depending on the kind of compound (a) , the reaction temperature and the like, and is generally about 0.1 hr - about 100 hr, preferably about 0.5 hr - about 24 hr.
The thus-obtained compound (b) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Alternatively, a salt may be formed from a crude product and then isolated and purified. For example, in the case- of hydrochloride, the salt can be formed by treatment of the crude product with
concentrated hydrochloric acid, hydrogen chloride and the like in a mixture of alcohols (e.g., methanol, ethanol etc.) and - ethyl acetate.
[0067]
In the method described in patent document 1, compound (XVII) wherein the amino group of the (2-hydroxyethyl) amino ' moiety is protected is subjected to an intramolecular ring closing reaction, arid the resulting compound is deprotected to give the object product.
On the other hand, in the above-mentioned reaction of the present invention, compound (a) wherein the amino group of the (2-hydroxyethyl) amino moiety is unprotected is directly subjected to an intramolecular ring closing reaction to give the object compound (b) . Therefore, the protection and
deprotection steps of the amino group of the (2- hydroxyethyl) amino moiety are not necessary. In this reaction, moreover, byproducts are suppressed and a good yield (e.g., not less than 75%) can be achieved. Therefore, the production method of the present invention can be a convenient method suitable for industrial production in a good yield.
[00681 '
Compound (a) as a starting material is an intermediate compound in an advantageous production method suitable for industrial production of compound (b) having a superior
serotonin 5-HT2C receptor activation action, and can be
produced, for example, by subjecting a compound represented by the formula (c) or a salt thereof (hereinafter to .be
abbreviated as compound (c) ) as a starting material to a
reductive amination reaction with 2-aminoethanol according to the following method.
[0069]
Figure imgf000030_0001
[0070]
wherein each symbol is as defined above.
This reaction can be performed according to a method known per se [e.g., the method described in Jikken Kagaku Koza (Courses in Experimental Chemistry) , the fourth edition, vol. 14, page 370], and generally performed in the presence of a . reducing agent, as necessary, in a solvent that does not
adversely influence the reaction. Compound (c) can be produced by a method known per se [the method described in Journal of Organometallic Chemistry, 1991, vol. 412 (No. 3), page 301] or a method analogous thereto.
[0071]
While the amount of 2-aminoethanol to be used varies depending on the kind of the solvent, and other reaction
conditions, it is generally about 1 mol - about 10 mol,
preferably about 1 mol - about 5 mol, per 1 mol of compound (c) .
[0072]·
Examples of the reducing agent include aluminum reagents (e.g., lithium aluminum hydride (LiAlH4) , diisobutylaluminum hydride (DIBAL-H) , sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) , alane (A1H3) ) , and boron reagents (e.g. , borane (BH3) , 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH ) , sodium cyanoborohydride (NaBH3CN) , and sodium
triacetoxyborohydride (NaBH (OAc) 3) ) . Of these, sodium
borohydride, sodium cyanoborohydride, and sodium
triacetoxyborohydride are preferable, and sodium borohydride is particularly preferable.
While the amount of the reducing agent to be used varies depending on the kind of the base and solvent, and other
reaction conditions, it is generally about 0.3 mol - about 10 mol, preferably about 1 mol - about 5 mol, per 1 mol of
compound (c) .
[0073]
Examples of the solvent that does not adversely influence the reaction include alcohols (e.g., methanol, ethanol,
propanol, 2-propanol, butanol, isbbutanol, tert-butanol ) , hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane), halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane) , nitriles (e.g., acetonitrile) , carboxylic acids (e.g., acetic acid, trifluoroacetic acid) and the like. Two or more kinds these solvents may be used in a mixture at an appropriate ratio, and may contain water. Of these, alcohols (e.g., methanol, ethanol etc.) are preferable.
The amount of the solvent to be used is generally 3- to 20-fold by weight, preferably 5- to 15-fold by weight, relative to compound (c) .
[0074]
The reaction temperature is generally about -80°C to about 200°C, preferably about -80°C to about 100°C.
The reaction time is generally about 0.1 hr - -about 100 hr, preferably about 0.5 hr - about 24 hr. The thus-obtained compound (a) can be isolated and purified by a known separation and purification means, for , example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Alternatively, a salt may be formed from a crude product and then isolated and purified. For example, in the case of hydrochloride, the salt can be formed by treatment of the crude product with
concentrated hydrochloric acid, hydrogen chloride and the like in a mixture of acetone and ethyl acetate. Compound (a) can also be used without isolation for the next intramolecular ring closing reaction.
[0075]
A compound represented by the formula (c) may be a salt, and a pharmacologically acceptable salt is preferable. As such salt, one similar to those exemplified as a compound
represented by the formula (a) and the like can be mentioned.
[0076]
When compound (a) and/or compound (b) are/is obtained asa free compound, they can be each converted to an object salt according to a method known per se or a method analogous thereto. On the contrary, when they are obtained as salts, they can be each converted to a free form or other object salt according to a method known per se or a method analogous thereto.
[0077]
When compound (a) and/or compound (b) contain (s) isomers such as an optical isomer, a stereoisomer, a regioisomer and a rotamer, such isomers and a mixture thereof are also
encompassed in compound (a) or (b) . In addition, an isomer may be formed by conformation, and such isomers and a mixture thereof are also encompassed in compound (a) or compound (b) . These isomers can be obtained as single products by a synthetic method or separation method known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.). For example, when compound (a), or (b) has optical isomers, an optical isomer resolved from this compound is also encompassed in compound (a) or (b) ..
The optical isomer can be produced according to a method known per se. Specifically, the optical isomer is obtained by using an optically active synthetic intermediate or by
subjecting the racemic final product to an optical resolution according to a known method.
[0078]
The method of optical resolution may be a method known, per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method etc.
1) Fractional recrystallization method
A method wherein a salt of a racemate with an optically active compound (e.g., (+)-mandelic acid, (-)-mandelic acid, (+) -tartaric acid, (-) -tartaric acid, (+) -1-phenethylamine, (-) -1-phenethylamine, cinchonine, (-) -cinchonidine, brucine) is formed, which is separated by a fractional recrystallization method, and if desired, a neutralization step to give a free optical isomer.
[0079]
2) Chiral column method
A method wherein a racemate or a salt thereof is applied to a column (a chiral column) for separation of an optical isomer to allow separation. In the case of a liquid
chromatography, for example, a mixture of the optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Chemical Industries, Ltd. ) , and developed with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) as an eluent, solely or in admixture to separate the optical isomers. In the case of a gas
chromatography, for example, a chiral column such as CP- Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like is used to allow separation.
[0080]
3) Diastereomer method
A method wherein a racemic mixture is converted into a diastereomeric mixture by chemical reaction with an optically active reagent, which is made into a single substance by a typical separation means (e.g., a fractional recrystallization method, a chromatography method) and the like, and is subjected to a' chemical treatment such as hydrolysis and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained. For example, when compound (b) contains hydroxy or primary or secondary amino group in a molecule, the compound and an optically active organic acid (e.g., MTPA [oc- methoxy- - (trifluoromethyl) phenylacetic acid], (-)- menthoxyacetic acid) and the like are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively. When compound (b) has a carboxy group in a molecule, the compound and an optically active amine or optically active alcohol are subjected to condensation reaction to give diastereomers of the amide compound or the ester compound, respectively. The separated diastereomer is converted to an optical isomer of the original compound by acid hydrolysis or base hydrolysis.
[0081]
Compound (a) and compound (b) may be crystals, and they are encompassed in compound (a) and compound (b) whether the crystal form is singular or a mixture of the crystal forms.
The crystal of compound (a) or compound (b) can be produced by crystallizing compound (a) or compound (b) by applying a crystallization- method known per se.
Examples of the crystallization method include
crystallization method from a solution, crystallization method from vapor, and crystallization method from a melt.
[0082]
The "crystallization method from a solution" is typically a method of shifting a non-saturated state to supersaturated state by varying factors involved in solubility of compounds (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent. Specific examples thereof include a concentration method, a slow cooling method, a reaction method (a diffusion method, an electrolysis method) , a hydrothermal growth method, and a flux method. Examples of the solvent to be used include aromatic hydrocarbons (e.g., benzene, toluene, xylene) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane) , ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane), nitriles (e.g., acetonitrile) , ketones (e.g., acetone), sulfoxides (e.g., dimethyl sulfoxide), acid amides (e.g., N, N-dimethylformamide) , esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol, isopropyl alcohol) , and water. These solvents are used alone or in a combination of two or more at an appropriate ratio
(e.g., 1:1 to 1:100 (a volume ratio)). Where necessary, a seed crystal can be used.
The "crystallization method from vapor" is, for example, a vaporization method (a sealed tube method, a gas stream method) , a gas phase reaction method, and a chemical
transportation method.
The "crystallization method from a melt" is, for example, a normal freezing method (a pulling method, a temperature gradient method, a Bridgman method) , a zone melting method (a zone leveling method, a floating zone method) , and a special growth method (a VLS method, a liquid phase epitaxy method) .
[0083] ..
Preferable examples of the crystallization method include a method comprising dissolving compound (a) or compound (b) in a suitable solvent (e.g., alcohols such as methanol, ethanol and the like, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane) at 20°C to 120°C, and cooling the obtained solution to a temperature not higher than the dissolution temperature (e.g., 0 - 50°C, preferably 0 - 20°C) , and the like. In this case, a nitrogen gas and the like may be flown to evaporate the solvent.
The thus obtained crystals of compound (a) and (b) of the present invention can be isolated, for example, by filtration and the like.
An analysis method of the obtained crystal is generally a method of crystal analysis by powder X-ray diffraction. As a method of determining crystal orientation, a mechanical method or an optical method and the like can also be used.
Each of the crystals of compound (a) and compound (b) obtained by the above-mentioned production method has high purity, high quality, and low hygroscopicity, is not denatured even after- a long-term preservation under general conditions, and is extremely superior in the stability. In addition, compound (b) is also superior in the biological properties
(e.g., pharmacokinetics (absorption, distribution, metabolism, excretion) , efficacy expression) and is extremely useful as a medicament .
Compound (b) labeled with or substituted by an isotope can be used, for example, as a tracer used for Positron
Emission Tomography (PET) (PET tracer), and is useful in the field of medical diagnosis and the like.
[0084]
Compound (a) and compound (b) may each be a
pharmaceutically acceptable cocrystal or a salt thereof. Here, the cocrystal or a salt thereof means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability etc.). The cocrystal or a salt thereof can be
produced according to a cocrystallization a method known per se.
[Examples]
[0085]
The present invention is specifically explained in detail in the following by referring to Reference Examples and
Examples, which are not to be construed as limitative.
In the Examples, room temperature is about 25°C.
Example 1
2- [ ( { 3-chloro-5- [methyl (propan-2-yl) amino] pyrazin-2- yl }methyl) amino] ethanol hydrochloride
[0086]
Figure imgf000037_0001
[0087]
3-Chloro-5- [methyl (propari-2-yl) amino] pyrazine-2- carbaldehyde (50 g, 234 mmol) was added to a solution of 2- aminoethanol (28.6 g, 468 mmol) in methanol (500 mL) . The mixture was cooled to 0-10°C, and treated with a 0.05 M sodium hydroxide solution (12.5 mL+rinse 2.5 mL) of sodium borohydride (5.31 g, 140.36 mmol). The mixture was stirred at 0-10°C for 1-2 hr, and hydrochloric acid (6 M, 250 mL) was added thereto at 0-10°C. The reaction mixture was warmed to 20-22°C, stirred at the same temperature for about 2 hr, and neutralized (pH 6.6) with an aqueous sodium hydroxide solution (4 M, 230 mL) at 5°C. The mixture was concentrated, and the residue was
basified (pH 10.4) with an aqueous sodium hydroxide solution (4 M, 130 mL) and extracted with toluene (500 mL) , and the aqueous layer was extracted with toluene (500 mL) . The combined
organic, layers were washed with a 10% aqueous sodium chloride solution (250 mL) and concentrated. To the residue was added a mixture of ethyl acetate (200 mL) and acetone (250 mL) , and the mixture was cooled to 0±10°C and treated with concentrated hydrochloric acid (20.5 mL) at the same temperature. After stirring at the same temperature for 1 hr, the precipitated crystals were collected by filtration, washed with a mixture of acetone (50 mL) and ethyl acetate (100 mL) and dried under reduced pressure at 45-55°C to give the title compound (65.12 g, 94.3%) as a white - pale-brown powder.
1H- MR (500 MHz, DMSO-d6) : δ (ppm) 1.16(d, 6H) , 2.91(s, 3H) , 3.09(t, 2H), 3.72(q, 2H) , 4.25(s, 2H) , 4.69(dt, 1H) , 5.29(t, 1H), 8.17(s, 1H) , 9.26(br. s, 2H)
[0088]
Example 2
N-methyl-N- ( 1-methylethyl ) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1,4] oxazepin-3-amine monohydrochloride
[0089]
Figure imgf000038_0001
[0090]
Sodium t-butoxide (162.81 g 1.69 mol) was suspended in a mixture of dimethyl sulfoxide (900 mL) and N,N- dimethylacetamide (100 mL) . To this mixture was added dropwise a solution of 2- [({ 3-chloro-5- [methyl (propan-2- yl) amino] pyrazin-2-yl }methyl) amino] ethanol hydrochloride (200 g, 0.68 mol) in dimethyl sulfoxide (900 mL) at 20-30°C over about 4 hr, and the container was washed with dimethyl sulfoxide (100 mL) . The mixture was stirred at 20-30°C for 2 hr. The
reaction mixture was diluted with water (2000 mL) at 50°C or below, and extracted with a mixture of toluene (1200 mL) and 2- butanone (800 mL) . The organic layer was separated, and the aqueous layer was extracted 3 times with a mixture of toluene (1200 mL) and 2-butanone (800 mL) . The combined organic layers, were concentrated, and a mixture of ethanol (600 mL) and ethyl acetate (1200 mL) was added to the residue. The mixture was treated with concentrated hydrochloric acid (55.6 mL) at 20- 30°C, and stirred at the same temperature for 2 hr. After stirring at 0-10°C for about 2 hr, the precipitated crystals were collected by filtration, washed with a mixture of ethanol (200 mL) and ethyl acetate (400 mL) , and dried under reduced pressure at 50°C for 20 hr to give the title compound (152.6 g, 86.7%) as a white - pale-yellow powder.
XH NMR (500 MHz, DMSO-d6) : δ (ppm) 1.13 (d, 6H) , 2.86 (s, 3H) , 3.47 (m, 2H) , 4.26 (s, 2H) , 4.39 (m, 2H), 4.67 (m, 1H) , 7.84 (s, 1H) , 10.1 (brs, 2H) .
[0091]
Example 3
N-methyl-N- (1-methylethyl) -6, 7 , 8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepine-3-amine monohydrochloride
[0092]
Figure imgf000039_0001
[0093]
2- [ ( { 3-Chloro-5- [methyl (propan-2-yl ) amino] pyrazin-2- yl }methyl) amino] ethanol hydrochloride (1.5 kg, 5.08 mol) and an aqueous sodium hydroxide solution (4 M, 3.176 L) were added to dimethyl sulfoxide (7.5 L) . The mixture was stirred at 95±5°C for 2 hr. Water (4.5 L) and toluene (15 L) were added to the reaction mixture at room temperature, and the organic layer was separated. The aqueous layer was extracted twice with toluene (15 L) . The combined organic layers were concentrated,
methanol (4.5 L) "was added to the residue, and insoluble
materials were filtered off. 4 M-Hydrogen chloride/ethyl acetate (1.40 L) was added dropwise to the filtrate, and
diisopropyl ether (12 L) was added thereto. After stirring at room temperature for 1 hr, the precipitated crystals were collected by filtration, washed with a mixture of methanol (4.5 L) and diisopropyl ether (9 L), and dried under reduced
pressure at 50°C for 23 hr to give the title compound (1.038 kg, 79.0%) as a white - pale-yellow powder.
1H NMR (500 MHz, DMSO-d6) : δ (ppm) 1.13 (d, 6H) , 2.86 (s, 3H) , 3.47 (m, 2H) , 4.26 (s, 2H) , 4.39 (m, 2H) , 4.67 (m, 1H) , 7.84 1H) , 10.1 (brs, 2H) . [Industrial Applicability]
[0094]
According to the present invention, compound (b) can be produced in a good yield while suppressing byproducts even when amino group is unprotected. Therefore, the production method can reduce the protection and deprotection steps of amino group, and can be a method suitable for convenient industrial
production.
[0095]
This application is based on a patent application No.
2015-157492 filed in Japan (filing date: August 7, 2015), the contents of which are incorporated in full herein.

Claims

Claims
1. A compound represented by the formula (a) :
Figure imgf000041_0001
(a)
wherein X is a halogen atom, one of Ri and ]¾ is a substituent, and the other is a hydrogen atom,
or a salt thereof. 2. The compound according to claim 1, wherein Ri is an amino group or an alkoxy group, each of which is optionally
substituted, or a salt thereof.
3. The compound according to claim 1, wherein Ri is an
optionally substituted amino group, or a salt thereof. .- A production method of a compound represented by the formula b) :
Figure imgf000041_0002
wherein one of Ri and R2 is a substituent, and the other is a hydrogen atom,
or a salt thereof, comprising subjecting a compound represented by the formula (a) :
Figure imgf000041_0003
(a)
wherein X is a halogen atom, and the other symbols are as defined above] ,
or a salt thereof, to an intramolecular ring closing reaction under basic conditions. 5. The production method according to claim 4, wherein Ri is an amino group or an alkoxy group, each of which is optionally substituted.
6. The production method according to claim 4, wherein Ri is an optionally substituted amino group.
PCT/JP2016/073695 2015-08-07 2016-08-04 Production method of pyrazine WO2017026538A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132841A1 (en) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
WO2008108445A1 (en) 2007-03-07 2008-09-12 Takeda Pharmaceutical Company Limited Benzoxazepine derivatives and use thereof
WO2009063993A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Fused pyridine derivative and use thereof
WO2009063991A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Pyridooxazepine derivative and use thereof
WO2010132015A1 (en) 2009-05-12 2010-11-18 Astrazeneca Ab New compounds modulating gamma-secretase and their use in the treatment of alpha beta related pathologies, such as alzheimer's disease
WO2010147226A1 (en) 2009-06-15 2010-12-23 Takeda Pharmaceutical Company Limited Pyrazinooxazepine derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132841A1 (en) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
WO2008108445A1 (en) 2007-03-07 2008-09-12 Takeda Pharmaceutical Company Limited Benzoxazepine derivatives and use thereof
WO2009063993A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Fused pyridine derivative and use thereof
WO2009063991A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Pyridooxazepine derivative and use thereof
WO2010132015A1 (en) 2009-05-12 2010-11-18 Astrazeneca Ab New compounds modulating gamma-secretase and their use in the treatment of alpha beta related pathologies, such as alzheimer's disease
WO2010147226A1 (en) 2009-06-15 2010-12-23 Takeda Pharmaceutical Company Limited Pyrazinooxazepine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 412, no. 3, 1991, pages 301

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