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WO2001066541A1 - Procede de preparation de derives d'hydrazine - Google Patents

Procede de preparation de derives d'hydrazine Download PDF

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Publication number
WO2001066541A1
WO2001066541A1 PCT/JP2001/001750 JP0101750W WO0166541A1 WO 2001066541 A1 WO2001066541 A1 WO 2001066541A1 JP 0101750 W JP0101750 W JP 0101750W WO 0166541 A1 WO0166541 A1 WO 0166541A1
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Prior art keywords
group
optionally substituted
formula
represented
hydrocarbon group
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PCT/JP2001/001750
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English (en)
Japanese (ja)
Inventor
Hideya Mizufune
Minoru Nakamura
Hiroaki Yamamoto
Shokyo Miki
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to AU2001241042A priority Critical patent/AU2001241042A1/en
Publication of WO2001066541A1 publication Critical patent/WO2001066541A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to a method for producing a hydrazine derivative by reducing a hydrazone derivative; a method for alkylating a hydrazine derivative; a method for producing a hydrazine derivative by reducing and alkylating a hydrazone derivative; a method for reducing a hydrazine derivative with a carbonyl compound And a method of subjecting a hydrazine derivative to reductive alkylation and a reductive alkylation reaction with a carbonyl compound.
  • Japanese Patent Application No. 2000-17956 discloses various novel anticoagulant FXa inhibitors that are effective for the prevention and treatment of myocardial infarction, cerebral thrombosis, etc .:
  • a conductor is disclosed.
  • One of the methods for producing this acyl hydrazine derivative is described in Japanese Patent Application No. 2000-17956 (W 000/78747), which is a method for producing the acyl hydrazine derivative by reducing the imine moiety. Production methods for alkylating moieties are disclosed.
  • references (b), (c) and (d) describe that various amines are alkylated by a combination of sodium borohydride and a carboxylic acid or by sodium triacyloxyborohydride. Is the alkylation of hydrazine derivatives. No reductive alkylation of the drazone derivative is described.
  • Reference (e) describes a method of alkylating nitrogen substituted with a phenyl group of a phenylhydrazine derivative with a combination of sodium borohydride and a carboxylic acid. It is not described that the nitrogen substituted with the alkylidene group of the obtained nitrogen-hydrazone derivative is reductively alkylated.
  • references ⁇ and (g) describe a method for reductive alkylation of a hydrazine derivative with a carbonyl compound, but the method uses highly toxic sodium cyanoborohydride as a reducing agent. During post-processing, toxic cyan gas is generated, and there is a problem that post-processing waste liquid processing is required.
  • the hydrazine derivative can be safely derived into a hydrazine derivative by using a solid, easy-to-handle amineporan complex as a reducing agent.
  • the hydrazine derivative can be alkylated with a combination of a borohydride complex compound and sulfonic acid or a triacyloxyborohydride complex compound.
  • the hydrazone derivative can be hydrogenated with a hydrogen hydride complex.
  • the nitrogen of the hydrazone can be alkylated simultaneously with the reduction by the combination of the compound and the sulfonic acid or the triacyloxyborohydride complex compound.4)
  • the hydrazine derivative having a substituted 2-substituted nitrogen atom is converted to a carbonyl compound in the presence of a reducing agent. Reacts with to form a 3-substituted hydrazine derivative, 5).
  • aryl (, heteroaryl or alkane) sulfonylchlora It has been found that sulfonamidation with an amide leads to an acylhydrazine derivative useful as an FXa inhibitor, thereby completing the present invention.
  • R 1 R 2 , R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group.
  • RR 2 , R 3, and R 4 may combine with each other to form a ring] or a salt thereof with a polanamine complex having a melting point of 25 ° C or higher (solid state at room temperature).
  • a polanamine complex of the formula Using a polamine amine complex of the formula)
  • RR 2 , R 3 and R 4 are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group (preferably, One of R 1 and R 2 is not a hydrogen atom, more preferably neither R 1 nor R 2 is a hydrogen atom), and R 1 R 2 , R 3 and R 4 are each other A hydrazone derivative represented by the formula: or a salt thereof, with a trioxyloxyborohydride complex compound, a borohydride complex compound and a compound represented by the formula R 5 '_COOH , R 5 ′ represents a hydrogen atom or a hydrocarbon group which may be substituted], and a carboxylic acid represented by the formula (II ⁇ ):
  • R 1 , R 2 , R 3 and R 4 are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group ( Preferably, one of R 1 and R 2 is not a hydrogen atom, and more preferably, neither R 1 nor R 2 is a hydronizing atom), and RR 2 , R 3 and R 4 are bonded to each other the to hydrazone derivative or a salt thereof may also be 'to form a ring, is reacted with bets Riashirokishi borohydride complex compounds, beauty formula R 5 Oyo borohydride complex compounds' - COOH [wherein , R 5 ′ represents a hydrogen atom or a hydrocarbon group which may be substituted], and a carboxylic acid represented by the formula (II ⁇ ):
  • R 1 and R 2 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group,
  • R 5 represents an optionally substituted hydrocarbon group], or a hydrazine derivative thereof or a salt thereof with a reducing agent (preferably , A polyanamine complex having a melting point of 25 ° C. or higher, a triacyloxyborohydride complex compound, or a borohydride complex compound, and a compound represented by the formula R 5 ′ —COOH wherein R 5 ′ may be a hydrogen atom or may be substituted A carboxylic acid of the formula:
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R 3 and R 4 May combine with each other to form a ring].
  • R 3 and R 4 May combine with each other to form a ring.
  • R 1 and R 2 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group,
  • R 1 and R 2 may combine with each other to form a ring], or a salt thereof, with a triacyloxyborohydride complex compound and a compound of formula (V)
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R 3 and R 4 May combine with each other to form a ring], or a borohydride complex compound represented by the formula: R 5 ′ —COOH [where 5 ′ is a hydrogen atom or substituted A hydrocarbon group which may be represented by the formula: 6
  • each symbol is as defined above, or a salt thereof.
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group
  • R 7 represents an optionally substituted hydrocarbon group
  • 7 represents R 2
  • X 1 may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably a bond or an optionally substituted alkylene group) A group, more preferably, an alkylene group which may be substituted), and D represents an oxygen atom or a sulfur atom.
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and D represents an oxygen atom or a sulfur atom].
  • R 8 represents a nitrogen-protecting group
  • D represents an oxygen atom or a sulfur atom.
  • R 8 represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom] and a hydrazine derivative or a salt thereof represented by the formula (V)
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R 3 and R 4 May combine with each other to form a ring] with a carbonyl compound represented by the formula (VI I)
  • R 8 represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom] and a hydrazine derivative or a salt thereof represented by the formula (V)
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R 3 and R 4 May be bonded to each other to form a ring], in contrast to the carbonyl compound represented by the formula (VII)
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof.
  • R 5 represents an optionally substituted hydrocarbon group
  • R 8 is a protecting group for a nitrogen atom.
  • D represents an oxygen atom or a sulfur atom.
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted T group, and R 3 and R 4 May be bonded to each other to form a ring] with a carbonyl compound represented by the formula (XI)
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof.
  • R 8 represents a protecting group for a nitrogen atom
  • D represents an oxygen atom or a sulfur atom
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof, Formula (XIV)
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R 3 and R 4 May combine with each other to form a ring
  • n 1 or 2
  • m 2 or 3
  • D represents an oxygen atom or a sulfur atom.
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof.
  • the compound represented by the formula (II) or a salt thereof and the compound represented by the formula (III) or (II ⁇ ) or a salt thereof obtained by the above-mentioned production method are useful as a drug such as an FXa inhibitor, It is also useful as other pharmaceuticals, pesticides, foods, cosmetics and chemicals or intermediates thereof.
  • R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, among which an optionally substituted acyl group Is preferred.
  • hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R 1 examples include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, and the like. Formula hydrocarbon groups are preferred.
  • aliphatic chain hydrocarbon group examples include a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
  • alkyl group for example, methyl, ethyl, n-propyl, isopyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-methylpropyl —Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n —Octyl, 1-methylheptyl, nonyl, etc.
  • Examples include an alkyl group (preferably ( ⁇ alkyl or the like)).
  • alkenyl group examples include bier, aryl, isoprobenyl, 2-methylaryl, 1-propenyl, 2-methyl_1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- Ethyl 1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2 - to hexenyl Le, the 3-hexenyl, 4 one hexenyl, etc.
  • C 2 _ 6 alkenyl group cyclohexenyl, etc., to 5 and the like.
  • alkynyl group examples include ethynyl, 1-propynyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- to hexynyl, the 3-key Shin Il, 4 one to Kisheru include C 2 _ 6 alkynyl group hexynyl, etc., to 5.
  • the “alicyclic hydrocarbon group” as an example of the hydrocarbon group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
  • cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, c 3 such Shikurono nil - 9 cycloalkyl, and the like.
  • cycloalkenyl group examples include 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-11-yl, 3-cyclohexene-11-yl, 1- cyclobutene one 1 one I le, 1 over sheet Kuropenten -. 1 one I le, 1 Shikuro hexene one 1 one I le, etc.
  • C 3 _ 9 consequent Roarukeniru group such as 1-cycloheptene one 1 Iru the like.
  • cycloalkadienyl group examples include C 4, such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, and 2,5-cyclohexadiene-1-yl — 6 cycloalkajenyl group and the like.
  • the "Ariru group" as examples of the hydrocarbon group a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example phenyl, naphthyl, anthryl, Fuenanto Lil, such Asenafuchireniru C 6 - 1 4 Ariru Groups and the like are preferable, and phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.
  • hydrocarbon group examples include the above-mentioned alicyclic hydrocarbons such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, and fluorenyl.
  • alicyclic hydrocarbons such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, and fluorenyl.
  • examples thereof include a bi- or tricyclic hydrocarbon group derived from the condensation of two or three identical or different groups (preferably two or more groups) selected from a hydrogen group and an aromatic hydrocarbon group.
  • the heterocyclic group of the “optionally substituted heterocyclic group” represented by R 1 includes, for example, an oxygen atom, a sulfur atom, a nitrogen atom, or the like as an atom (ring atom) constituting a ring system.
  • an aromatic monocyclic heterocyclic group for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 2,4-oxadiazolyl, 1,3,4-oxadazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 5- or 6-membered aromatic monocyclic heterocyclic and fused aromatic heterocyclic groups such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • Benzoflael benzo [b] chenyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, Benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2_benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalaragel , Naphthyridinyl, purinyl, buteridinyl, kyrvazolyl, Q!
  • -Kyrupolinil ⁇ -carbolinyl, ercarborinyl, acridinil, phenoxazinyl, phenothiazinyl, fenazinyl, fenoxathiinyl, thianthrenyl, fenatrilinyl, indone [L, 2-b] pyridazinyl, pyrazo opening [l, 5-a] pyridyl, imidazo. [1,
  • non-aromatic heterocyclic group examples include 3- to 8-membered groups such as oxilanyl, azetidinyl, oxeynyl, ceynyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydrovinylanyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
  • saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group aliphatic heterocyclic group or the like, or 1,2,3,4-tetrahydroxylyl, 1,2,3 And non-aromatic heterocyclic groups in which some or all of the above-mentioned aromatic monocyclic heterocyclic groups or aromatic condensed heterocyclic groups are saturated, such as 1,4-tetrahydroisoquinolyl. It is.
  • optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. May be in conversion.
  • optionally substituted hydrocarbon group and “optionally substituted heterocyclic group” represented by R 1 may have a O Kiso group, For example, if the R 1 Gabe Nzopiraniru, R 1 Habe Benzo- ⁇ -pyronyl, benzo-T-pyronyl and the like may be formed.
  • Ariru group in the "optionally substituted Ariru group” as the substituent for example phenyl, naphthyl, anthryl, Fuenantoriru, such Asenafuchire sulfonyl (:. 6 - 1 4 Ariru group, etc.
  • substituent of the aryl group include a lower alkoxy group (eg, 6 alkoxy groups such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and a lower alkyl group (eg, methyl, ethyl). , propyl, etc.
  • lower alkenyl groups e.g. Biel, C etc. Ariru 2 - 6 alkenyl group
  • a lower alkynyl group e.g. Echiniru, C 2 _ 6 alkynyl group propargyl Etc.
  • an optionally substituted amino group an optionally substituted hydroxyl group, a cyano group, Amidino groups and the like may be mentioned, and these optional substituents may be substituted at 1 to 3 substitutable positions.
  • Optionally substituted amino group, “optionally substituted hydroxyl group”, and “optionally substituted amidino group” as substituents of "optionally substituted aryl group"'' May be ⁇ optionally substituted '' as a substituent which the ⁇ optionally substituted hydrocarbon group '' and ⁇ optionally substituted heterocyclic group '' represented by R 1 may have And the same as the “good amino group”, “optionally substituted hydroxyl group”, and “optionally substituted amidino group”.
  • the Shikuroa alkyl group in the "optionally substituted cycloalkyl group” as a substituent such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cyclo, ⁇ 3 of heptyl and the like cyclohexane - mentioned such cycloalkyl groups are Can be
  • examples of the substituent of the cycloalkyl group include the same number of the same substituents as those in the above-mentioned “optionally substituted aryl group”.
  • the cyclo alkenyl group in the "optionally substituted cycloalkenyl group” as the substituent for example Shikuropuro Bae sulfonyl, cyclobutenyl, Shikuropen thenyl, C 3 of cyclohexenyl etc. cyclohexane - like 6 cycloalkenyl group.
  • substituent of the optionally substituted cycloalkenyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”.
  • alkyl group in the “optionally substituted alkyl group” as a substituent examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , Isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc.
  • examples of the substituent of the alkyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”.
  • alkenyl group in the “optionally substituted alkenyl group” as the substituent examples include, for example, vinyl, aryl, isoprobenyl, 2-methylaryl, 1-propyl, 2-methyl-1-propenyl, -Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4 one methyl - 3 _ pentenyl, cyclohexenyl 1, cyclohexenyl 2, to 3-hexenyl, 4 one hexenyl, C 2 _ 6 alkenyl groups such as cyclohexenyl can be mentioned, et al are to 5 scratch.
  • substituent of the alkenyl group examples include the same number of the same substituents as in the above-mentioned “optionally substituted “option
  • alkynyl group in the “optionally substituted alkynyl group” as a substituent examples include, for example, ethynyl, 1-propenyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentyl two Le, 4 _ pentynyl, 1 one to Kisheru, 2 into single Kisheru, three to the hexynyl, 4 one to hexynyl include C 2 _ 6 alkynyl group hexynyl, etc., to 5.
  • substituent of the alkynyl group examples include the same number of the same substituents as those in the above-mentioned “optionally substituted aryl group”.
  • heterocyclic group in the “optionally substituted heterocyclic group” as a substituent a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like as an atom (ring atom) constituting a ring system 1
  • an aromatic monocyclic heterocyclic group for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 2,4-year-old oxadiazolyl, 1,3,4-monoxaziazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-tria 5- to 6-membered aromatic monocyclic heterocyclic groups and fused aromatic heterocyclic groups such as zolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • aromatic monocyclic heterocyclic group for example, furyl, phenyl, pyrrolyl
  • non-aromatic heterocyclic group for example, 3- to 8-membered groups such as oxilael, azetidinyl, oxeynyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholinel, piperazinyl and the like ( (Preferably 5 to 6 members) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydridoquinolyl, 1,2,3 Fragrance such as 4,4-tetrahydroisoquinolyl
  • Non-aromatic heterocyclic groups in which double bonds of part or all of the aromatic monocyclic heterocyclic group or the aromatic condensed heterocyclic group are saturated are exemplified.
  • the "optionally substituted heterocyclic group optionally” is the substituent that may have as a substituent, a lower alkyl group (e.g. methyl, Echiru, propyl, etc. ( ⁇ -6 alkyl Le group), lower alkenyl groups (e.g. vinyl, C 2 etc. Ariru - like 6 alkenyl group), a lower alkynyl group (e.g. Echiniru, C 2 of propargyl - like 6 alkynyl group), Ashiru groups (e.g. formyl, Asechiru, propionyl, etc.
  • a lower alkyl group e.g. methyl, Echiru, propyl, etc. ( ⁇ -6 alkyl Le group
  • lower alkenyl groups e.g. vinyl, C 2 etc. Ariru - like 6 alkenyl group
  • a lower alkynyl group e.g. Echiniru, C 2 of propargyl - like 6
  • Optionally substituted amino group as a substituent which the "optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R 1 may have The ⁇ optionally substituted imidoyl group '', ⁇ optionally substituted amidino group '', ⁇ optionally substituted hydroxyl group '' and ⁇ optionally substituted thiol group ''
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • optionally halogenated alkoxy eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trimethoxy
  • 2,2,2-trichloromouth ethoxy, etc. which may be substituted with a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl) Pill, heptyl, Isopuchiru, t one heptyl
  • Examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl and position a lower alkyl group (e.g. methyl, Echiru, propyl, isopropyl, heptyl, t one heptyl, pentyl, a hexyl, etc., to C -! 6 alkyl group), Ararukiru group (for example benzyl, c 7 _ 1 such phenethyl 0 Ararukiru group), Ariru group (e.g.
  • Hue sulfonyl, 1 one naphthyl, C 6 _ 1 such as 2 _ naphthyl 0 Ariru group) 1 may have such Piperajie And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino such as 1-pyrrolyl, 1-imidazolyl and the like.
  • the “optionally substituted rubamoyl group” includes unsubstituted rubamoyl groups, N-monosubstituted rubamoyl groups and N, N-disubstituted rubamoyl groups.
  • N-monosubstituted rubamoyl group means a disubstituted group having one substituent on a nitrogen atom, such as a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl). , isobutyl, t-butyl, etc. C WINCH 6 alkyl group hexyl etc. pentyl,), lower alkenyl groups (e.g. vinyl, Ariru, isopropenyl, propenyl, C 2 etc. hexenyl butenyl, pentenyl, to - 6 ⁇ alkenyl group), a cycloalkyl group (e.g.
  • Araruki Le group e.g. benzyl, C y- i Ararukiru group such as phenethyl, preferably phenylene Le -. C i-4 alkyl group, etc.
  • reel alkenyl group e.g., C 8
  • reel alkenyl group preferably represented phenylene Lou C 2 _ 4 alkenyl group
  • the heterocyclic group e.g., the above-described R 1 And the like as the “heterocyclic group” as the substituent in the “optionally substituted hydrocarbon group”.
  • the lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, aralkyl group, aryl alkenyl group, and heterocyclic group may have a substituent.
  • substituents examples include a hydroxyl group and a substituted an amino group [the amino group optionally has, for example, a lower alkyl group (for instance methyl, Echiru, propyl, isopropyl, heptyl, isobutanol chill, t one heptyl, etc. C WINCH 6 alkyl group hexyl etc. pentyl,), One or more of an acyl group (eg, formyl, acetyl, propionyl, pivaloyl, etc., 6-alkanoyl, benzoyl, etc.), a lipoxyl group, a 6-alkoxy monopropylonyl group, etc.
  • a lower alkyl group for instance methyl, Echiru, propyl, isopropyl, heptyl, isobutanol chill, t one heptyl, etc.
  • Halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • nitro group for example, cyano group
  • lower optionally substituted by 1 to 5 halogen atoms for example, fluorine, chlorine, bromine, iodine, etc.
  • halogen atoms for example, fluorine, chlorine, bromine, iodine, etc.
  • alkyl group and a lower alkoxy group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
  • Examples of the lower alkyl group include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, and particularly, methyl, ethyl and the like. Is preferred.
  • Examples of the lower alkoxy group include C alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, and particularly methoxy, ethoxy and the like. Are preferred. Further, it is preferable that one or two to three (preferably one or two) of these substituents are the same or different.
  • N, N-disubstituted rubamoyl group means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is an “N-monosubstituted carbamoyl group” described above. And the other are, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t- heptyl, pentyl, C i-6 alkyl groups hexyl, etc., to such), C 3 - 6 Shikuroaruki Le group (e.g. cyclopropyl, cyclobutyl, cyclohexyl, etc.
  • Ararukiru group e.g. Benzyl, phenethyl and the like, preferably a phenyl 4- alkyl group and the like.
  • two substituents may form a cyclic amino group together with a nitrogen atom.
  • examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl and 1-pyrrolidinylcaprolyl.
  • Ruponiru, piperidinocarbonyl, morpholinocarbonyl, 1 Piperajiniruka Ruponiru and 4-position a lower alkyl group e.g.
  • substituents of the “optionally substituted thiocarbamoyl group” and the “optionally substituted sulfamoyl group” include the same substituents as those of the above-mentioned “optionally substituted carbamoyl group”. No.
  • carboxyl group which may be esterified include, in addition to a free carboxyl group, a lower alkoxycarbonyl group, a 7-reoxycarbonyl group, an aralkyloxycarbonyl group and the like.
  • lower alkoxycarbonyl group examples include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycapillonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl And the like.
  • 6- alkoxy mono-propyl groups such as oxycarbonyl and neopentyloxy carbonyl, among which C 3 alkoxy-propyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are preferable.
  • the " ⁇ reel O carboxymethyl Cal Poni Le group” for example, phenoxy force Ruponiru, 1 one naphthoxycarbonyl, 2 one naphthoquinone C 6 _ 1 Q Ariruokishi such deer Lupo sulfonyl - force Ruponiru group and the like.
  • the " ⁇ Lal Kill O alkoxycarbonyl group” such as benzyl O carboxymethyl Cal Po two Le, Hue phenethyl Ruo carboxymethyl cull Poni Le etc. (3 7 _ 1 4 Ararukiruokishi one carboxymethyl sulfonyl group
  • aryloxycarbonyl group and the “aralkyloxycarbonyl group” may have a substituent.
  • substituents include the above-mentioned N-monosubstituents such as lubamoyl group.
  • the same numbers as those described as the substituents of the aryl group and the aralkyl group as examples of the substituent are used.
  • Examples of the ⁇ sulfonic group derived from sulfonic acid '' as a substituent include those in which the above-mentioned ⁇ N-monosubstituent rubamoyl group '' has one substituent on a nitrogen atom and a sulfonyl bond, and the like.
  • acyl such as C 6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl is exemplified.
  • Examples of the ⁇ carboxylic acid-derived acyl group '' as a substituent include those in which a hydrogen atom or a substituent having one of the above-mentioned ⁇ N-monosubstituent rubamoyl groups '' on a nitrogen atom is bonded to carbonyl.
  • Preferred examples include ⁇ -ealkanols such as formyl, acetyl, propionyl, and vivaloyl, and acyls such as benzoyl.
  • substitution is hydrocarbon group which may be substituted” represented by R 1
  • heterocyclic ring which may be substituted represented by R 1
  • a "optionally substituted amino group” or an “optionally substituted amino group” (optionally possessed by an “optionally substituted hydrocarbon group” for R 1) formyl group; "and the like as similar) is a sulfonyl group, Karuponiru group, Chio carbonyl group, a group formed by combining with such Okishikaruponiru group the like Karupokishi Le group.
  • R 1 described above As the substituents of the "optionally substituted hydrocarbons" represented by the formulas, there may be mentioned a “sulfonic group derived from a sulfonic acid", a “carboxylic group derived from a carboxylic acid”, a “carboxyl group which may be esterified” and the like. Or properly, “Ashiru group derived from a carboxylic acid” is more preferable.
  • the “optionally substituted acyl group” represented by R 1 includes a group represented by the formula
  • R 6 represents a optionally substituted hydrocarbon group or an optionally substituted double heterocyclic group
  • R 7 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 7 And R 2 or the substituent of X 1 and R 7 may be bonded to each other to form a ring
  • X 1 is a bond, an optionally substituted alkylene group or an optionally substituted imino group ( Preferably an alkylene group which may be substituted)
  • D represents an oxygen atom or a sulfur atom.
  • R 8 represents a protecting group for an amino group
  • R 7 represents a hydrogen atom or a hydrocarbon group which may be substituted
  • the substituents of R 7 and R 2 or X 1 and R 7 are mutually bonded.
  • X 1 may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably an optionally substituted alkylene group).
  • D represents an oxygen atom or a sulfur atom. ], Etc. are also preferably used.
  • R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, among which a hydrogen atom or a substituted Hydrocarbon groups which may be present are preferred.
  • Examples of the ⁇ optionally substituted hydrocarbon group '' represented by R 2 include the same as the aforementioned ⁇ optionally substituted hydrocarbon group '' represented by R 1 , An optionally substituted C ⁇ 4 lower alkyl group is preferred.
  • the aforementioned R 1 The same as the optionally substituted acyl group j can be mentioned, and among them, the ⁇ optionally substituted hydrocarbon group '' represented by R 1 described above Preferred are an sulfonic acid-derived acyl group, a carboxylic acid-derived acyl group, and an optionally esterified hydroxyl group.
  • R 2 is preferably bonded to R 1 to form a ring, and R 1 has the formula
  • R 6 represents a optionally substituted hydrocarbon group or an optionally substituted double heterocyclic group
  • R 7 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 7 And R 2 or the substituent of X 1 and R 7 may be bonded to each other to form a ring
  • X 1 is a bond, an optionally substituted alkylene group or an optionally substituted imino group ( Preferably an alkylene group which may be substituted)
  • D represents an oxygen atom or a sulfur atom.
  • R 8 represents a protecting group for an amino group
  • R 7 represents a hydrogen atom or a hydrocarbon group which may be substituted
  • the substituents of R 7 and R 2 or X 1 and R 7 are mutually bonded.
  • X 1 may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably an optionally substituted alkylene group).
  • D represents an oxygen atom or a sulfur atom.
  • R 2 is preferably bonded to a substituent of R 7 or X 1 to form a ring.
  • nitrogen-containing heterocyclic groups include, as atoms (ring atoms) constituting a ring system, one to three (preferably one to two) hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. 5 to 7-membered aromatic heterocyclic group containing at least one (preferably 1 to 3, more preferably 1 to 2), or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic) Group heterocyclic group).
  • nitrogen-containing aromatic heterocyclic group examples include, for example, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxazinediazole, 1,2,4-oxaziazole.
  • non-aromatic heterocyclic group examples include, for example, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopidazine, 2,4-thiazolidinedione, 2,4-oxazolidinedione, hydantoin, Examples thereof include 5- to 7-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups) such as rhodanine, succinimide, maleimide, thiomaleimide and phthalimide.
  • Such a nitrogen-containing heterocyclic group is referred to as a “bivalent nitrogen-containing heterocyclic group which may be substituted” (a divalent group formed by the bonding of R 2 and R 7 ). It may have the same substituent as the substituent which the “heterocyclic group” may have, and a substituent selected from an oxo group and a thioxo group.
  • R 2 and R 7 combine to form a ring, they form an “optionally substituted divalent nitrogen-containing heterocyclic group” with one N—X 1 —CD—N—.
  • divalent nitrogen-containing heterocyclic group in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom is used as an atom (ring atom) constituting a ring system.
  • Divalent 5- to 8-membered nitrogen-containing heterocyclic group containing 2 or 3 preferably a divalent 5- to 8-membered nitrogen-containing heterocyclic group composed of a carbon atom and two nitrogen atoms
  • divalent nitrogen-containing heterocyclic groups have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R 2 is bonded, and have a “divalent 5 to 8
  • a specific example of such a divalent 5- to 8-membered nitrogen-containing cyclic amide group is, for example, 2-oxoimidazolidin-1,1,3-diyl, 2 —Oxoimidazolone-1, 3-diyl, 2-year-old oxopiperazine-1, 4, diyl, 2-oxo-1, 2,3,4, tetrahydropyrazine-1,4, diyl, 2-oxohomopyrazine-1 1 , 4 gil, 5-oxo homopyrazine 1, 4 gil, 2 oxo 1, 4 diazacyclooctane 1, 4 dimethyl, 5 oxo 1, 4-diazacyclooctane 1 1 , 4 gil
  • the substituent of the “divalent nitrogen-containing heterocyclic group” in the above-mentioned “optionally substituted divalent nitrogen-containing heterocyclic group” is, for example, a substituent other than one oxo group or thioxo group.
  • Optionally substituted lower alkoxy group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted thiocal Examples include a bamoyl group and an optionally substituted sulfamoyl group. These optional substituents may be substituted at 1 to 3 (preferably 1 or 2) at substitutable positions.
  • ⁇ substituents of the optionally substituted amino group J include one to two optionally substituted alkyl groups, optionally substituted rubamoyl groups, and optionally substituted A carbamoyl group, an optionally substituted sulfamoyl group, Examples include a carboxyl group which may be steered, an acyl group derived from a sulfonic acid, an acyl group derived from a carboxylic acid, and the like; "optionally substituted alkyl group”;"optionally substituted rubamoyl” A thiocarbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a carboxyl group which may be esterified, an acyl group derived from sulfonic acid, and As the ⁇ carboxylic acid-derived acyl group '', the ⁇ optionally substituted alkyl group '' as a substituent of the ⁇ optionally substituted hydrocarbon group ''
  • Preferred examples of the "optionally substituted amino group" include (1) methylation, Echiru, n- propyl, isopropyl, n one-butyl, isobutyl, sec- butyl Le, lower (C ⁇ 6) alkyl group such as tert- butyl, (2) mono- or di-lower (C preparative 6) alkyl force A substituent selected from ( ⁇ -6 alkanol and (5) benzoyl such as (3) C j- 6 alkylsulfonyl such as (3) methanesulfonyl and ethanesulfonyl, (4) formyl, acetyl, propionyl, and vivaloil; And amino which may have 2 to 2.
  • Examples of the lower alkyl group in the “optionally substituted lower alkyl group” include C alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particularly preferred are methyl, X tyl and the like.
  • Examples of the substituent include a halogen atom (e.g.
  • Examples of the “optionally substituted lower alkylidene group” include alkylidene such as methylidene and ethylidene.
  • Examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an amino group, And any of these substituents may be substituted with 1 to 5 at a substitutable position. (Preferably 1 or 2) may be substituted.
  • Examples of the “optionally substituted lower aralkylidene group” include C 6 ⁇ such as benzylidene.
  • the lower alkoxy group in the "optionally substituted lower alkoxy group optionally substituted with a halogen atom" for example methoxy, ethoxy, n- Purobokishi, Isopuropoki shea, n- butoxy, isobutoxy, sec- butoxy, etc.
  • a halogen atom for example methoxy, ethoxy, n- Purobokishi, Isopuropoki shea, n- butoxy, isobutoxy, sec- butoxy, etc.
  • tert- butoxy 6 Alkoxy groups and the like are mentioned, and methoxy, ethoxy and the like are particularly preferable.
  • the ⁇ carboxyl group which may be esterified '' is the same as the carboxyl group which may be esterified as a substituent of the ⁇ optionally substituted hydrocarbon group '' represented by R 1 described above. Things.
  • the “optionally substituted hydroxyl group” and the “optionally substituted mercapto group” as the substituents that the “divalent nitrogen-containing heterocyclic group” may have “hydroxyl group” and “mercapto group”
  • the substituent which the group may have is, for example, a lower alkyl group which may be substituted, an olepoxyl group which may be esterified, an rubamoyl group which may be substituted, and a substituted A thiocarbamoyl group, an optionally substituted sulfamoyl group, a sulfonic acid-derived acyl group, and a carboxylic acid-derived acyl group.
  • lower alkyl group examples include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • substituents which may have a halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • an aryl group which may be substituted for example, Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl C i _ 6 alkyl group), a lower alkoxy group (e.g.
  • the sulfur atom may be oxidized, and has, for example, a structure represented by S (O) k [k is an integer of 0 to 2]. May be.
  • divalent nitrogen-containing heterocyclic group for example, Z CH) H 2 / m
  • D represents an oxygen atom or a sulfur atom
  • n represents 1 or 2
  • m represents 2 or 3. And the like.
  • n is preferably 1.
  • D represents an oxygen atom or a sulfur atom
  • ⁇ represents 1 or 2 (preferably 1). And the like.
  • divalent nitrogen-containing heterocyclic group examples include 2-oxopiperazine-1,4-diyl and 2-oxo-1,2,3,4-tetrahydropyrazine-1,4-diyl. Is most preferred.
  • substituent of X 1 and R 2 may be bonded to each other to form a ring, and a divalent group represented by X 1 —CD—N (R 2 ) — A divalent nitrogen-containing heterocyclic group ".
  • divalent nitrogen-containing heterocyclic group in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom is used as an atom (ring atom) constituting a ring system.
  • 5- to 8-membered nitrogen-containing heterocyclic group containing 1 to 3 preferably a divalent 5- to 7-membered nitrogen-containing heterocyclic group composed of a carbon atom and one nitrogen atom Is mentioned.
  • divalent nitrogen-containing heterocyclic groups have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R 2 is bonded, and to form a 8-membered nitrogen-containing cyclic amide group "but as the substituent of the" divalent nitrogen-containing heterocyclic group "in such” two optionally substituted divalent nitrogen-containing heterocyclic group ", R 7 and R 2 is bonded to each other to form an “optionally substituted divalent nitrogen-containing complex” And the same substituents as the “divalent nitrogen-containing heterocyclic group” in the “ring group” may have.
  • the “divalent nitrogen-containing heterocyclic group” formed by the substituent of X 1 and R 2 bonded to each other is, for example, a group represented by the formula
  • D represents an oxygen atom or a sulfur atom
  • n ′ represents 0 or 1
  • m ′ represents 2 or 3. And the like.
  • m ′ is preferably 2 and n ′ is preferably 0.
  • 2-pyrrolidone-1,3-diyl is most preferred.
  • R 3 and R 4 each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group; An optionally substituted hydrocarbon group is preferred.
  • optionally substituted hydrocarbon group represented by R 3 and R 4 examples include the same as the aforementioned “optionally substituted hydrocarbon group” represented by R 1 . Among them, optionally substituted — 4 lower alkyl groups and optionally substituted phenyl groups are preferred.
  • Examples of the “optionally substituted heterocyclic group” represented by R 3 and R 4 include the same as the aforementioned “optionally substituted heterocyclic group” represented by R 1 .
  • Examples of the ⁇ optionally substituted acyl group '' represented by R 3 and R 4 include the same as the above-mentioned ⁇ optionally substituted acyl group '' represented by R 1 above.
  • hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R 3 and R 4 may have are, for example, (1) an optionally substituted amino group, (2) It may be an imidoyl group which may be substituted or (3) a nitrogen-containing bicyclic group which may be substituted.
  • the cyclic amino group includes For example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and a lower alkyl group at the 4-position (for example, C6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.) ), Ararukiru groups (e.g.
  • benzyl, etc. C 7 ⁇ 0 ⁇ aralkyl groups such as phenethyl), ⁇ Li Ichiru group (e.g. phenyl, 1_ naphthyl, 2-naphthyl C 6 - 1 () ⁇ Li Lumpur group) 3-8 membered or 1 Piperajiniru like have a like (good Mashiku are cited and cyclic Amino 5-6 membered), such cyclic amino group, the above was R 1 It may have the same number of the same substituents as those in the “optionally substituted hydrocarbon group” shown.
  • the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted hydrocarbon group-substituted amino group” may be replaced with an “optionally substituted diamino group” at the ⁇ -position.
  • the "optionally substituted amino group” as (1) forms an amino group substituted with the "optionally substituted imidoyl group” as (2) described later.
  • Formula 1 N (R ") 1 C (R ') NR"' [wherein, R "represents a hydrogen atom or an optionally substituted hydrocarbon group, and R"'represents a hydrogen atom, And R ′ represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group derived from sulfonic acid, a substituted or unsubstituted hydrocarbon group, or an optionally substituted hydrocarbon group.
  • Optionally substituted amino group, optionally substituted mercapto group or substituted Or an optionally substituted hydroxyl group] are also included in the “optionally substituted amino group”.
  • the “optionally substituted hydrocarbon group” represented by R ′ ′′, R ′ and R ′′ includes the “optionally substituted hydrocarbon group” represented by R 1 described above.
  • Examples of the “carboxylic acid-derived acyl group” represented by R ′′ ′ and R ′ include the “optionally substituted hydrogen urine group” represented by R 1 described above.
  • Examples of the substituent that may be possessed include the same as the ⁇ carboxylic acid-derived acyl group '', and the ⁇ optionally substituted hydroxyl group '' represented by R ′ is represented by R 1 described above.
  • substituents which the "optionally substituted hydrocarbon group” may have include the same as the "optionally substituted hydroxyl group", and the "substituted or substituted” represented by R ' as also an amino group ", the be” replacement represented by the R 1
  • R ' an amino group which may have 1 to 2 amino groups.
  • Examples of the “carboxylic acid-derived acyl group” represented by R ′ ′′ include, for example, “carboxy” as a substituent which the aforementioned “optionally substituted hydrocarbon group” represented by R 1 may have The same as the “acid-derived acyl group” can be mentioned, but the “carboxylic acid-derived acyl group” represented by R 1 is, for example, a group represented by the formula —COOR ′ ′′ ′′, wherein R ′ ′ ′′ ′ is substituted Or a hydrocarbon group which may be esterified, such as a group represented by the following formula:
  • R ′′ ′ examples include, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” represented by R 1 described above.
  • hydrocarbon group in R '"'" optionally substituted hydrocarbon group "represented by, for example, 6 alkyl, C 2 _ 6 alkenyl, C 3 - 6 consequent opening alkyl, C 6 - 10 Ariru, C 6 - i. Aryl- 1-4 alkyl and the like.
  • substituents that the “hydrocarbon group” may have include, for example, the same as the substituents that the aforementioned “optionally substituted hydrocarbon group” represented by R 1 may have Similar numbers are included.
  • Examples of the group represented by the formula (1) COOR '"' include, among others, an alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycal 6) alkanoyloxy C- 6 alkoxy-carbonyl group (eg, pivaloyloxymethoxycarponyl, 1- (acetoxy) ethoxycarbonyl, acetoxy tert-butoxycarpoel, etc.) _ 6 Alkoxy mono-lponyloxy-Alkoxy mono-lponyl group (eg, ethoxycarponyloxy methoxycarbonyl, etc.), 5- ⁇ - 4 Alkyl-2-oxo-l-oxo-l-oxylene-14-yl-Alkoxy mono-lponyl group (eg, 5-methyl-2-oxodoxolen-4-ylmethoxycarbonyl). '
  • amino group optionally substituted more specifically, for example amino group (preferably, phenyl) C 6 _ 10 ⁇ Li Ichiru group further optionally substituted mode no or G.
  • alkylamino group e.g. Mechiruamino, Echirua amino, benzyl methyl ⁇ amino, Jimechiruamino, Jechiruamino, diisobutyl amino, diisopropyl amine.
  • R represents a hydrogen atom or a hydrocarbon group which may be substituted (preferably, a hydrogen atom or a lower (C ⁇ ) alkyl group); '' Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, or an carboxylic acid-derived acyl group (preferably, a hydrogen atom or a carboxylic acid-derived acyl group)
  • R ′ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxyl group (preferably, hydrogen atom, a lower (( ⁇ _ 6) alkyl group, an amino group or a mono- or di- lower (C ⁇ ) alkyl amino group),] a group represented
  • R ′ represents an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino, ethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.)
  • the “optionally substituted imidoyl group” as (2) forms an optionally substituted amidino group.
  • amidino group one or two lower ((: ⁇ alkyl group, a lower (( ⁇ _ 6) Arukanoi group, optionally substituted with like Benzoiru group Good amidino groups (eg, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-jetylamidino, N-methyl-N'-getylamidino, N —Formylamidino, N-acetylamidino, etc.).
  • lower e.g, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-jetylamidino, N-methyl-N'-getylamidino, N —Formylamidino, N-acetylamidino, etc.
  • R ''' is hydrogen, lower alkyl (e.g. methylation, Echiru, propyl, isopropyl, heptyl, C WINCH 6 alkyl group isobutyl), Ashiru groups (e.g. formyl, Acetyl, propionyl, pivaloyl, etc.
  • lower alkyl e.g. methylation, Echiru, propyl, isopropyl, heptyl, C WINCH 6 alkyl group isobutyl
  • Ashiru groups e.g. formyl, Acetyl, propionyl, pivaloyl, etc.
  • a hydroxyl group can be mentioned, as preferable examples of R 'are hydrogen, lower alkyl groups (e.g. methyl, Echiru, propyl, isopropyl, heptyl, isobutyl, etc.
  • An optionally substituted amino group eg, one or two identical or different lower alkyl groups (eg, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (eg, formyl, Amino group, hydrazino group, 5- or 6-membered cyclic amino group which may be substituted with C 6 alkanol such as acetyl, propionyl, pivaloyl, benzoyl, etc.
  • an optionally substituted amino group eg, one or two identical or different lower alkyl groups (eg, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (eg, formyl, Amino group, hydrazino group, 5- or 6-membered cyclic amino group which may be substituted with C 6 alkanol
  • a hydroxyl group e.g. methoxy, ethoxy, Purobokishi, isoproterenol epoxy, butoxy, isobutoxy, etc. ( ⁇ _ 6 alkoxy group), a mercapto group, lower alkylthio group (e.g., methylthio, Echiruchio, propylthio, isopropylthio Chio, Puchiruchio, C _ e alkylthio group such Isopuchiruchio) and the like. in the above formulas, is preferably hydrogen.
  • R ′ is preferably hydrogen, a lower alkyl group or an optionally substituted amino group, and particularly preferably a lower alkyl group or an optionally substituted amino group.
  • An amino group is preferable, and an amino group which may be substituted (preferably, an amino group which may be substituted with C 4 alkyl) is particularly preferable.
  • nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” as (3), at least a nitrogen atom other than a carbon atom as an atom (ring atom) constituting a ring system is used.
  • An aromatic nitrogen-containing heterocyclic group which may contain 1 (preferably 1 to 3) and may further contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom; And an aromatic nitrogen-containing heterocyclic group (aliphatic heterocyclic group).
  • aromatic nitrogen-containing heterocyclic group examples include, for example, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazolyl, 1H-imidazolyl-4-yl, etc.) , Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3 , 4-Asiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-1, liazolyl 1-yl, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl And aromatic monocyclic nitrogen-containing heterocyclic groups such as pyridyl (2-, 3- or 4-pyridyl), pyridazin
  • non-aromatic nitrogen-containing heterocyclic group examples include partially reduced forms of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidel, etc.), as well as azetidinyl, pyrrolidinyl, piperidyl ( 2-, 3- or 4-pibelidyl), morpholinyl, thiomorpholinyl, piperazinyl (such as 1-piperazinyl), homopiperazinyl, and the like. Among them, a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group is preferable.
  • the same substituents as those described above for the “heterocyclic group” for R 1 can be used. Further, the nitrogen atom constituting the nitrogen-containing heterocyclic group may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” may be bonded to each other to form a ring (eg, a benzene ring or the like).
  • an optionally substituted nitrogen-containing heterocyclic group and the like are preferable, and especially an optionally substituted aromatic nitrogen-containing heterocyclic group. Are preferred.
  • R 3 and R 4 are preferably bonded to each other to form a ring together with adjacent carbon atoms, and such a cyclic group may be substituted, and is preferably a cyclic group having a substituent.
  • substituent those similar to the aforementioned substituents of R 3 and R 4 are used.
  • cyclic group examples include a monovalent or divalent cyclic hydrocarbon group or a heterocyclic group (preferably a heterocyclic group).
  • hydrocarbon group as the “cyclic group” includes a saturated or unsaturated cyclic monovalent or divalent hydrocarbon group.
  • cyclic saturated hydrocarbon group a cycloalkyl group (e.g., consequent opening, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, Shikurookuchiru, C 3 _ 9 cycloalkyl such cyclononyl, preferably, C 5 - 7 cycloalkyl, more preferably a hexyl etc.) and the like cyclohexane.
  • a cycloalkyl group e.g., consequent opening, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, Shikurookuchiru
  • C 3 _ 9 cycloalkyl such cyclononyl, preferably, C 5 - 7 cycloalkyl, more preferably a hexyl etc.
  • unsaturated cyclic hydrocarbon groups include cycloalkenyl groups (for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-1-ynole, 3- cyclohexene - 1 one I le, 1-cyclobutene one 1-I le, -1-cyclopentene one 1-I le, etc.
  • the aforementioned “saturated or unsaturated cyclic hydrocarbon group” is converted from any carbon atom having a bond to water. A group formed by removing one elementary atom.
  • heterocyclic group as the “cyclic group” includes, as atoms (ring atoms) constituting a ring system, one to three heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. (Preferably 1 or 2) at least 1 (preferably not 1) And more preferably 1 or 2) and a 5- or 6-membered divalent saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).
  • non-aromatic heterocyclic group for example, a 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, etc. And a heterocyclic group (aliphatic heterocyclic group).
  • divalent heterocyclic group as the “cyclic group” include a group formed by adding one bond to any atom having the above-mentioned “non-aromatic heterocyclic group”. Is mentioned.
  • piperidine which may be substituted is preferable.
  • X 2 represents a bond, an optionally substituted alkylene group or an optionally substituted diamino group (preferably a bond), and ⁇ represents an optionally substituted chain hydrocarbon.
  • Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a nitrogen-containing heterocyclic group which may be substituted. Or a group represented by the formula:
  • X 2 represents a bond, an optionally substituted alkylene group or an optionally substituted diamino group (preferably a bond)
  • A represents a cyclic group which may be substituted
  • Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a nitrogen-containing heterocyclic group which may be substituted.
  • the “chain hydrocarbon group” in the “optionally substituted chain hydrocarbon group” represented by Y the “optionally substituted hydrocarbon group” represented by R 1 Or a divalent or branched chain formed by removing one or two hydrogen atoms from one carbon atom in the "linear or branched (preferably linear) aliphatic hydrocarbon group”
  • an optionally substituted alkylene group e.g., the same as the “optionally substituted alkylene group” represented by X 1 and X 2 described below
  • the formula CH - (CH 2) k -. wherein, k, is an integer of 0-5] a group represented by the Is mentioned.
  • an optionally substituted lower alkyl group such as the same as the above-mentioned “optionally substituted lower alkyl group” as a substituent of the “optionally substituted divalent nitrogen-containing heterocyclic group”
  • an optionally substituted rubamoyl group [the above-mentioned “substituted And the like as the “optionally substituted carbamoyl group” as a substituent of the “optionally divalent nitrogen-containing heterocyclic group”, preferably a carbamoyl group, N-mono-lower (( ⁇ _ 6) alkyl force Luba Yl group, N, N
  • Examples of the “cyclic group” of the “optionally substituted cyclic group” represented by A include a divalent or trivalent cyclic hydrocarbon group or a heterocyclic group (preferably a heterocyclic group).
  • Examples of the “hydrocarbon group” as the “cyclic group” of the “optionally substituted cyclic group” represented by A include a saturated or unsaturated cyclic divalent or trivalent hydrocarbon group.
  • Examples of the cyclic divalent saturated hydrocarbon group a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Shikurohepu chill, Shikurookuchiru, C 3, such as cyclononyl - 9 cycloalkyl, preferably ,
  • group e.g., c 5 _ 7 cycloalkylene, preferably 1, such as xylene to 4-cyclopropyl
  • the unsaturated cyclic divalent hydrocarbon group is a cycloalkenyl group (for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-1). one I le, 3-cyclopropyl hexene one 1-I le, 1 Shikurobuten one 1-I le, etc.
  • C 3 _ 6 cycloalkenyl groups such as 1-cyclopentene one 1-I le), cycloalkadienyl groups (e.g. C4-16 cycloalkadienyl groups such as, 2,4-cyclohexene.
  • ⁇ Li Ichiru group e.g., phenyl, C 6, such as naphthyl Le - like 1 0 Ariru group, preferably, any position (preferably such as phenyl), different carbon atoms, more preferably, farthest Removed one hydrogen atom Among them, phenylene are preferred, especially, 1, 4-phenylene is preferred.
  • C 5 _ 7 cycloalkylene preferably xylene to 1, 4 Shikuro
  • phenylene ' preferably, 1, 4 one phenylene, etc.
  • the “saturated or unsaturated cyclic trivalent hydrocarbon group” is as described above.
  • examples of the group include a “saturated or unsaturated cyclic divalent hydrocarbon group” formed by removing one hydrogen atom from any carbon atom having a bond.
  • the “divalent heterocyclic group” as the “cyclic group” of the “optionally substituted cyclic group” represented by A as the atoms (ring atoms) constituting the ring system, in addition to carbon atoms, oxygen 5 to 6 members containing at least 1 (preferably 1 to 3, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms, sulfur atoms and nitrogen atoms And a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).
  • divalent aromatic heterocyclic group examples include, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3 5-membered aromatic heterocycles such as, 4-thiadiazole, 1,2,3-triazol, 1,2,4-triazol, and, for example, pyridine, pyridazine, pyrimidine, 1,2 ,,, It is obtained by removing two hydrogen atoms from two different ring atoms (at least one of which is a carbon atom) such as a 6-membered aromatic heterocycle such as 4-triazine and 1,3,5-triazine. And other di
  • divalent non-aromatic heterocyclic group examples include 5- to 6-membered saturated or unsaturated (preferably saturated) groups such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, and piperazin.
  • Divalent groups obtained by removing two hydrogen atoms from two different ring atoms (at least one of which is a carbon atom) such as a non-aromatic heterocyclic group (aliphatic heterocyclic group) And the like.
  • the above “divalent non-aromatic heterocyclic group” has a bond Examples include a group formed by adding one bond to a carbon atom.
  • A is preferably phenylene which may be substituted, piperidine which may be substituted and the like.
  • Z is (1) an optionally substituted amino group, (2) And (3) a nitrogen-containing heterocyclic group which may be substituted.
  • Examples of the substituent in the “optionally substituted amino group” represented by Z include the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R 1 described above. But the two substituents may combine with the nitrogen atom to form a cyclic amino group.
  • examples of the cyclic amino group include 1-azetidinyl, Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and a lower alkyl group at the 4-position (eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.
  • aralkyl group e.g. benzyl, C 7 such as phenethyl - like 1 D Ararukiru group
  • Ariru group e.g. phenyl, 1 one naphthyl, C 6 2-naphthyl and the like -.
  • E ⁇ Lumpur group 3-8 membered or 1 Piperajiniru like have a like (rather preferably is mentioned and cyclic Amino the 5-6 membered), such cyclic amino group, the above was R 1 It may have the same number of the same substituents as those in the “optionally substituted hydrocarbon group” shown.
  • the ⁇ optionally substituted hydrocarbon group '' as a substituent in the ⁇ amino group substituted by an optionally substituted hydrocarbon group '' represented by Z is ⁇
  • the ⁇ optionally substituted amino group '' represented by Z forms an amino group substituted by the ⁇ optionally substituted imidoyl group '' represented by Z described below.
  • N (R '') — C (R ') N-R''' wherein R '' represents a hydrogen atom or an optionally substituted hydrocarbon group; '' Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, or an acyl group derived from a carboxylic acid, and R '' represents a hydrogen atom, an optionally substituted hydrocarbon group.
  • An carboxylic acid-derived acyl group, an optionally substituted amino group, an optionally substituted mel group A capto group or an optionally substituted hydroxyl group] are also included in the “optionally substituted amino group” represented by Z.
  • ⁇ carboxylic acid-derived acyl group '' represented by R ′ ′′ ′ for example, as the substituent which the aforementioned ⁇ optionally substituted hydrocarbon group '' represented by R 1 may have The same ones as the “carboxylic acid-derived acyl group” can be mentioned, but the “carboxylic acid-derived acyl group” represented by R 1 is, for example, a group represented by the formula COOR ′ ′′ ′′ wherein R ′ ′′ ′′ is substituted And a carboxyl group which may be esterified, such as a group represented by the following formula:
  • Poniru group e.g., methoxycarbonyl, ethoxycarbonyl Cal Poni le, etc. isopropoxyphenyl Cal Poniru
  • ⁇ - 6 alk noisy Ruo Kishi alkoxy Ichiriki Ruponiru group e.g., pivaloyl I Ruo carboxymethyl methoxy Cal Poni le, 1 i (Asetokishi) ethoxycarbonyl, Asetokishi tert-butoxycarbonyl, etc.
  • alkoxy-carbonyl- 1-6- alkoxycarbonyl group eg, ethoxycarbonyloxymethoxycarbonyl, etc.
  • 5-alkyl-1-oxo-dioxolene-4-yl-6-alkoxy —Capillonyl groups eg, 5-methyl-2-oxo-dioxo-l-41-methoxycarbonyl
  • the “optionally substituted amino group” represented by Z may be, for example, an amino group, a C 6 ⁇ 0 aryl group (preferably phenyl), etc.
  • Good mono- or di-lower (peto 6 ) alkylamino groups eg methylamino, ethylamino, benzylmethylamino, dimethylamino, getylamino, diisobutylamino, diisopropylamino, N-ethyl-1-butylamino, benzylmethylamino) Mino, etc.
  • N (R, ')-C (R,) N-R'"
  • R"' is a hydrogen atom or a hydrocarbon group which may be substituted (preferably, hydrogen Represents an atom or a lower (C ⁇ e) alkyl group)
  • R '"" represents a hydrogen atom, an optionally substituted hydroxyl group, and an optionally substituted hydrocarbon group represents an
  • alkylamino group for example, guanidino group, formimidoylamino group, acetimidoylamino group, etc.
  • 5- to 6-membered cyclic amino group for example, piperidino group, etc.
  • R ′ may be an optionally substituted amino group (preferably amino, methylamino, ethylamino, propylamino, dimethylamino, acetylamino,
  • the “optionally substituted imidoyl group” represented by Z forms an optionally substituted amidino group.
  • Specific examples of such an amidino group which may be substituted include one or two lower (C- 6 ) alkyl groups, lower (C- 6 ) alkanol groups, and benzoyl groups.
  • R ''' is hydrogen, lower alkyl (e.g. methylation, Echiru, propyl, isopropyl, butyl, C physician 6 alkyl le groups isobutyl), Ashiru groups (e.g. formyl, Asechiru , Propionyl, vivaloyl, etc.
  • lower alkyl e.g. methylation, Echiru, propyl, isopropyl, butyl, C physician 6 alkyl le groups isobutyl
  • Ashiru groups e.g. formyl, Asechiru , Propionyl, vivaloyl, etc.
  • R ′ are hydrogen, lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.). 6 alkyl groups), an optionally substituted amino group (eg, 1 to 2 identical or different lower alkyl groups (eg, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (For example, formyl , Acetyl, propionyl, pivaloyl, etc.
  • lower alkylthio e.g. methylthio, Echiruchio, propylthio, I Sopuropiruchio ,
  • R ′ ′′ ′ hydrogen is preferable.
  • R ′ is preferably hydrogen, a lower alkyl group or an amino group which may be substituted, and among them, a lower alkyl group or an amino group which may be substituted is preferable.
  • An amino group (preferably an amino optionally substituted with C 4 alkyl) is preferred.
  • nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by Z, at least one nitrogen atom other than a carbon atom as an atom (ring atom) constituting a ring system is used. (Preferably 1 to 3) aromatic nitrogen-containing cyclic groups which may further contain 1 to 3 heteroatoms selected from oxygen atoms and sulfur atoms, and saturated or unsaturated non-aromatics Group-containing nitrogen-containing heterocyclic group (aliphatic heterocyclic group).
  • aromatic nitrogen-containing heterocyclic group examples include, for example, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazole 111-yl, 1H-imidazo-l 4-yl, etc.), pyrazolyl, 1 , 2,3-oxosaziazolyl, 1,2,4-oxodiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-111, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl), pyridazinyl, pyri.midinyl, etc.
  • non-aromatic nitrogen-containing heterocyclic group examples include partially reduced forms of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidel, etc.), as well as, for example, azetidinyl, Mouth V-dinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl, etc.), homopiperazinyl, etc., among which 5- to 6-membered non-aromatics Monocyclic nitrogen-containing heterocyclic groups are preferred.
  • substituents for the “nitrogen-containing heterocyclic group” represented by Z those similar to the substituents for the “heterocyclic group” represented by R 1 described above are used. Also forms a nitrogen-containing heterocyclic group Nitrogen atoms may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” represented by Z may combine with each other to form a ring (eg, a benzene ring or the like).
  • Z is preferably a nitrogen-containing heterocyclic group which may be substituted, and particularly preferably an aromatic nitrogen-containing heterocyclic group which may be substituted.
  • the ⁇ optionally substituted hydrocarbon group '' represented by R 5 or R 5 ′ is the same as the ⁇ optionally substituted hydrocarbon group '' represented by R 1 described above.
  • R 5 is preferably unsubstituted at the ⁇ -position, and a group represented by R 5 ′ —CH 2 — [R 5 ′ is a hydrogen atom or an optionally substituted hydrocarbon group That is, it is preferably a group formed by adding a methylene group to R 5 ′.
  • R 5 optionally substituted lower (Ji alkyl group, an optionally substituted lower (c 2 - 4) an alkenyl group is preferable, also optionally substituted lower (C 4) alkyl group such as There further preferred R 5 'is a hydrogen atom, substituted There may lower even.. ( ⁇ - 4) alkyl group, an optionally substituted lower (C 2 - 4) such as an alkenyl group are preferable ,, More preferred are a hydrogen atom and an optionally substituted lower (C ⁇ 4 ) alkyl group.
  • Optionally substituted hydrocarbon group “optionally substituted lower ((: 4 ) alkyl group”) and “optionally substituted lower (C 2 _) represented by R 5 or R 5 ′ 4 )
  • the substituent which the “alkenyl group” may have is a substituent which may be possessed by the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R 1 described above.
  • the same groups as the above groups can be mentioned, and among them, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally esterified carboxyl group and the like are preferably used.
  • R 6 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and among them, an optionally substituted hydrocarbon group is preferable.
  • the “optionally substituted hydrocarbon group” for R 6 the same as the aforementioned “optionally substituted hydrocarbon group” for R 1 can be mentioned.
  • atom or C 2 - 4 alkenyl which may be Ariru substituted with (. good Mashiku is phenyl, 1 one-naphthyl, 2-naphthyl and the like 6 _ 14 Ariru group) are preferable.
  • ⁇ The ⁇ optionally substituted heterocyclic group '' represented by R 6 includes the same as the ⁇ optionally substituted heterocyclic group '' represented by R 1 described above.
  • the ⁇ optionally substituted hydrocarbon group '' represented by R 7 includes the same as the ⁇ optionally substituted hydrocarbon group '' represented by R 1 described above. , which may be inter alia substituted ( ⁇ _ 4 lower alkyl group is preferred in the formula, the "protecting group of the Amino group” represented by R 8, for example, formyl group, C u alkyl -. power Ruponiru group (e.g.
  • C u alkyl chromatography alkylsulfonyl group C ⁇ 6 alkoxy -. group (e.g., methoxycarbonyl, butoxycarbonyl, tert- butyl O butoxycarbonyl group, etc.), 0 6 _ Ararukiruokishi carbonyl group (e.g., base Nji Ruo alkoxycarbonyl group), C 2 _ 6 alkenyl over carbonitrile el groups (e.g.
  • Lil O alkoxycarbonyl, etc. C 6 - 1 0 ⁇ Li one Rukaruponiru group ( In example phenylene Rukaruponiru, naphthylcarbonyl), C 6 _ 1 0 ⁇ reel sulfonyl group (e.g., phenylalanine sulfonyl, naphthylsulfonyl, etc.), C
  • Ararukiru Ichiriki Ruponiru group e.g. downy Njirukaruponiru etc.
  • C bets 6 alkyl Le group e.g. methyl, etc.
  • C 7 _ 1 8 7 aralkyl group e.g. benzyl, Jifuenirume -. Chill, trityl, full Orenylmethyloxycarbonyl
  • substituents such as a halogen atom (eg, fluorine, chlorine, bromine, etc.) and a nitro group at a substitutable position.
  • the “protecting group for an amino group” represented by R 8 is preferably a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an aryloxycarbonyl group, a fluorenylmethyloxycarbonyl group, a C 6 alkyloxy group.
  • a carbonyl group eg, methoxycarbonyl, ethoxycarbonyl, etc.
  • an aralkyl group eg, benzyl, diphenylmethyl, trityl group, etc.
  • benzyloxycarbonyl group e.g., an aryloxycarbyl group
  • Aralkyl tombs e.g, benzyl, diphenylmethyl, trityl, etc.
  • ⁇ optionally substituted alkylene group '' represented by X 1 and X 2 Definitive as the "alkylene group", for example, methylene, ethylene, propylene, blanking styrene, straight-chain lower (C ⁇ 6) alkylene and the like, such as pentylene, among which methylene, ethylene, etc. ( ⁇ _ 4 alkylene or the like are preferable
  • the substituent of the “alkylene group” include an optionally substituted lower alkyl group [optionally substituted as a substituent of the “optionally substituted divalent nitrogen-containing heterocyclic group”.
  • lower alkyl groups for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.
  • 6 alkyl, etc.)] substituted optionally may force be Rubamoiru group, as a substituent of the [pre-marked with "two optionally substituted divalent nitrogen-containing heterocyclic group", " Such conversion is good force Rubamoiru group optionally "and the like, preferably, the force Rubamoi Le group, N- mono-lower (() alkyl force Rubamoiru group, N, N- di-lower (Ji DOO 6) alkyl force Rubamoiru Group, etc.), a cyano group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, a carboxyl group which may be esterified (the above-mentioned optionally substituted
  • the “optionally substituted imino group” represented by X 1 and X 2 is represented, for example, by the formula —N (R 9 ) —wherein R 9 represents a hydrogen atom or a substituent. R 9 is preferably a hydrogen atom, a hydrocarbon group which may be substituted, or the like.
  • the durazone derivative (compound I, VI I) is reacted with a polanamine complex
  • the “poranamine complex having a melting point of 25 ° C. or more” used has a melting point of 25 ° C. or more (preferably, a melting point of 30 ° C. or more)
  • Polamine complex in the solid state at room temperature (15 to 25 ° C) such as porane ⁇ ( 4- alkylamine complex, porane ⁇ dimethylamine complex such as porane ⁇ tributylamine complex, etc.
  • Polan di C w alkylamine complexes etc. Pollan 'trimethylamine Pollen tri alkylamine emissions complexes such as complexes, Pollan-Echirenjiamin complex, borane-dimethyl ⁇ amino pyridine complex, Pollan-4 one-methylmorpholine complex, Pollan-4 monounsaturated Enyl morpholine complexes, porane 2,6-lutidine complexes, among which porane dimethylamine complex, porane '' A trimethylamine complex and a porane tributylamine complex are preferably used, and these polamine amine complexes may be dispersed or dissolved in the reaction solvent.
  • the hydrazine derivative (compound I, VI I) or the hydrazine derivative (compound ⁇ ) is reacted with a “combination of a borohydride complex compound and a carboxylic acid” or a “triacyloxyborohydride complex compound” to form a hydrazine derivative (compound ⁇ ⁇ ).
  • borohydride complex compounds used in the method for producing borohydride, metal borohydride, alkali metal borohydride, alkaline earth metal borohydride, quaternary ammonium borohydride
  • metal borohydride alkali metal borohydride
  • alkaline earth metal borohydride alkaline earth metal borohydride
  • quaternary ammonium borohydride sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, barium borohydride, etc., as well as sodium borohydride and alkali (earth) metal salts
  • R 5 ′ represents a hydrogen atom or a hydrocarbon group which may be substituted
  • R 5 ′ represents a hydrogen atom or a hydrocarbon group which may be substituted
  • a preferable example is an aliphatic carboxylic acid which may be substituted.
  • alkyl-carboxylic acids such as formic acid, acetic acid, and propionic acid, C 6 ⁇ .
  • Halogenated C. alkyl alkyl carboxylic acids such as cycloalkyl monoacetic acid, chloroacetic acid, bromoacetic acid, and trifluoroacetic acid. , Halogenated C .
  • Cycloalkyl Ichiriki carboxylic acid wherein single amino acid wherein the nitrogen atom is protected, such as benzyl O alkoxycarbonyl Dali Singh [, as the protective group for the nitrogen atom, the "protecting group for the nitrogen atom" represented by R 8 will be described later And the like)), and optionally substituted aromatic carboxylic acids (eg, benzoic acid, picolinic acid, furan carboxylic acid, etc.).
  • aromatic carboxylic acids eg, benzoic acid, picolinic acid, furan carboxylic acid, etc.
  • aliphatic carboxylic acids which may be substituted Is preferably used.
  • the substituent R 5 ′ in the resulting compound represents methyl and ethyl, respectively.
  • triacyloxyborohydride complex compound a compound obtained by reacting the above borohydride complex compound with 3 equivalents of a carboxylic acid (for example, the same as the above carboxylic acid, preferably an aliphatic carboxylic acid, etc.)
  • carboxylic acid for example, the same as the above carboxylic acid, preferably an aliphatic carboxylic acid, etc.
  • examples thereof include sodium triformyloxyborohydride, sodium triacetoxyborohydride, sodium tribenzoyloxyborohydride, and the like.
  • the substituent R 5 ′ represents methyl and ethyl, respectively.
  • borohydride complex compound When a “combination of a borohydride complex compound and a carboxylic acid” is used as a reducing agent, the borohydride complex compound used and the carboxylic acid react in the reaction system, and a part or all of them react.
  • a “triacyloxyborohydride complex compound” may be formed.
  • a hydrazine derivative (compounds IV, IV ', XI II, XIV) and a carbonyl compound (compound V) are reacted in the presence of a "reducing agent" to form a hydrazine derivative (compounds III, ⁇ ⁇ ', XI, XI ', XI I , XI I '), the "reducing agent" used is the above-mentioned "poranamine complex having a melting point of 25 ° C or more", "combination of borohydride complex compound and carboxylic acid” or "triacyroxy acid".
  • borohydride complex compounds such as lithium aluminum hydride, trimethoxylithium aluminum hydride, tree tert-butoxylithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, hydrogen Sodium borohydride, sodium trimethoxyborohydride, triacetoxyborohydride
  • Metal hydride compounds such as lithium, lithium borohydride and lithium triethylborohydride are also preferably used. Further, a catalytic reduction method using a catalyst may be used.
  • Such a catalyst examples include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, and palladium barium sulfate; platinum catalysts such as platinum oxide, platinum carbon, and platinum black; rhodium catalysts such as rhodium carbon and rhodium alumina; ruthenium oxide
  • palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, and palladium barium sulfate
  • platinum catalysts such as platinum oxide, platinum carbon, and platinum black
  • rhodium catalysts such as rhodium carbon and rhodium alumina
  • ruthenium oxide The reaction is carried out in a hydrogen atmosphere using a ruthenium catalyst such as ruthenium carbon or Raney nickel.
  • the method for deprotection of the ⁇ protecting group for an amino group '' represented by R 8 is a method known per se or a method analogous thereto, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate or the like Are used.
  • a preferred method of “deprotection” is a reduction method which can be performed simultaneously with the reduction of the double bond in the ring of compound VI, VIII, XI, ⁇ .
  • a preferable reduction method is a method of reacting hydrogen or a hydrogen donor (formic acid and a salt thereof, cyclohexene, sodium hypophosphite, saturated hydrazine, etc.) in the presence of a catalyst.
  • the aforementioned “reducing agent” catalyst is used.
  • Particularly preferred is a method in which formic acid or a salt thereof is used as a hydrogen donor. This method does not require a special reactor, and is industrially advantageous.
  • a solvent used is not particularly limited as long as the reaction is not affected. No restrictions.
  • aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, pentane and heptane, esters such as ethyl acetate and butyl acetate, getyl ether, diisopropyl ether and tributyl methyl ester Ethers such as ter, tetrahydrofuran, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol Alcohol, such as phenol, 2-methyl-1-propanol, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ - Examples include amides such as methylpiperidone, dimethylsulfoxide, hexamethylphosphoric amide, dimethylimidazolidinone
  • the amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, particularly preferably 5 to 20 times the weight of the hydrazone derivative (compounds I, IV, VII). .
  • the amount of the polanamine complex used is 0.34 to 10 times, preferably 0.5 to 7 times, particularly preferably 0.1 to 10 times the mol of the hydrazone derivative (compound 1, 1 V, VII). It is 5 to 3 times the mole.
  • the reaction with the polanamine complex is preferably performed in the presence of an acid.
  • an acid is not particularly limited as long as the reaction proceeds, but hydrochloric acid, hydrobromic acid, oxalic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • inorganic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, and trifluoroacetic acid.
  • the amount of these acids to be used is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 2 to 4 moles, per mole of the hydrazone derivative (compounds I, IV, VII).
  • the reaction temperature with the polanamine complex is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 100 hours, preferably 1 to 100 hours. 550 hours, particularly preferably 1-25 hours.
  • a hydrazine derivative (compound I, VI I) or a hydrazine derivative (compound II) is reacted with a combination of a borohydride complex and a carboxylic acid or a triacyloxyborohydride complex to form a hydrazine derivative (compounds ⁇ ,, ⁇ ').
  • the solvent used may be carboxylic acid itself as a raw material, and is not particularly limited as long as it does not affect the reaction, and may be mixed with the same solvent as in Production method 1. .
  • the amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, more preferably 5 to 50 times the weight of the hydrazone derivative (compounds I and VII) or the hydrazine derivative (compound II). 20 times the weight.
  • the amount of the borohydride complex compound or triacyloxyborohydride complex compound used is 1 to 20 times that of the hydrazone derivative (compound I, VII) or the hydrazine derivative (compound ⁇ ).
  • the molar amount is preferably 1 to 15 times, particularly preferably 1 to 10 times.
  • the amount of the carboxylic acid used is 3 to 200 times, preferably 3 to 150 times, the molar amount of the hydrazone derivative (the compound I or VI I) or the hydrazine derivative (the compound II).
  • the molar amount is twice, particularly preferably 3 to 30 times.
  • the reaction temperature of the borohydride complex compound with the combination of the fatty acid or the triacyloxyborohydride complex compound is usually 0 to 150 ° C, preferably 10 to 100 ° C, and particularly preferably 10 to 50 ° C.
  • the reaction time is generally 1 to 50 hours, preferably 1 to 25 hours, particularly preferably 1 to 10 hours.
  • a hydrazine derivative (compounds IV, IV ', XI II, XIV) is reacted with a carbonyl compound (compound V) in the presence of a reducing agent to give a hydrazine derivative (compounds III, III', XI, ⁇ ', XI I, ⁇ ⁇ )
  • the solvent used in the method for producing is not particularly limited, as long as it does not affect the reaction, and the same solvent as used in the above-mentioned production method 1 or 2 is used.
  • the amount of the solvent used in this reaction is 5 to 50 times by weight, preferably 5 to 30 times by weight, particularly preferably 5 to 20 times by weight, relative to the hydrazine derivative (compounds IV, IV ', XIII, XIV). It is twice.
  • the amount of the carbonyl compound (compound V) used is 0.34 to 10 times, preferably 0.5 to 7 times the amount of the hydrazine derivative (compounds IV, IV ′, XIII, XIV). And particularly preferably 0.5 to 3 moles.
  • the amount of the reducing agent such as a polanamine complex used is 0.34 to 10 times, preferably 0.5 to 7 times the amount of the hydrazine derivative (compounds IV, IV ', XIII, XIV). And particularly preferably 0.5 to 3 moles.
  • This reaction is preferably carried out in the presence of an acid.
  • an acid is not particularly limited as long as the reaction proceeds, and examples thereof include hydrochloric acid, hydrobromic acid, oxalic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Inorganic acids and organic acids such as methanesulfonic acid, P-toluenesulfonic acid, acetic acid, propionic acid and trifluoroacetic acid are used.
  • the use of these acids The amount is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 1 to 4 moles relative to the hydrazine derivative (compounds IV, IV ', XIII, XIV).
  • the reaction temperature is generally 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is generally 1 to 100 hours, preferably 1 to 50 hours. Particularly preferred is 1 to 25 hours.
  • the solvent used is not particularly limited as long as the reaction is not affected.
  • nitriles such as acetonitrile and propionitrile are used.
  • the amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, particularly preferably 5 to 20 times the weight of the hydrazine derivative (compound VI).
  • the amount of the carbonyl compound (compound V) used is 1 to 10 moles, preferably 1 to 7 moles, and particularly preferably 1 to 3 moles relative to the hydrazine derivative (compound VI).
  • This reaction is preferably performed in the presence of an acid.
  • an acid is not particularly limited as long as the reaction proceeds, and examples thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Inorganic acids and organic acids such as methanesulfonic acid, p'-toluenesulfonic acid, acids, propionic acid and trifluoroacetic acid are used.
  • the amount of these acids to be used is 1 to 0 mol, preferably 1 to 5 mol, particularly preferably 1 to 4 mol, per mol of the hydrazone derivative (compound IV).
  • the reaction temperature is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 100 hours, preferably 1 to 40 hours, particularly preferably. 'Is 1-30 hours.
  • the hydrazine derivative (compounds VI, VI II, XI, ⁇ ) is reduced and deprotected with formic acid or a salt thereof, and then a halide such as sulfonyl chloride (compound I »[in the compound of formula IX, Examples of the halogen atom represented include fluorine, chlorine, and bromine, and chlorine is preferably used.)
  • the solvent used is not particularly limited as long as it does not affect the reaction. Besides the same, nitriles such as acetonitrile and propionitrile, and ketones such as acetone and 2-butaneone are used.
  • the amount of the solvent used in the reduction and deprotection and the subsequent reaction with a halide such as a sulfonyl chloride is 5 to 50 times the weight of the hydrazine derivative (Compound VI, VI II, XI, XI '). It is preferably 5 to 30 times by weight, particularly preferably 5 to 20 times by weight.
  • the amount of formic acid or a salt thereof used in the reduction and deprotection reactions is 1 to 10 times, preferably 1 to 7 times, the mol of the hydrazine derivative (compounds VI, VI ⁇ , XI, ⁇ ), particularly 1 to 7 times. Preferably it is 1 to 3 moles.
  • the reduction and deprotection reactions are preferably performed in the presence of a catalyst.
  • a catalyst include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, and barium palladium monosulfate; platinum oxide; platinum carbon;
  • a platinum catalyst such as Rhodium catalyst such as rhodium carbon and rhodium alumina, a ruthenium catalyst such as ruthenium oxide and ruthenium carbon, and Raney nickel are used.
  • the amount of these catalysts used is about 0.0001 to about 2 mol, preferably about 0.001 to about 1 mol, based on the hydrazine derivative (compounds VI, VIII, XI, ⁇ ). Is a mole.
  • the temperature in the reduction and deprotection reactions is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 50 hours, preferably 1 to 25 hours. Hours, particularly preferably 1 to 10 hours.
  • the reaction with a halide such as sulfonyl chloride may be performed in the presence of a base.
  • a base examples include alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxy.
  • Metal alkoxides having 1 to 6 carbon atoms such as lithium, tert-butoxide, sodium methoxide, sodium methoxide, sodium ethoxide, carboxyl-iert-butoxide, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, Inorganic bases such as potassium carbonate and sodium bicarbonate, such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, Tertiary amines such as cyclohexyldimethylamine, pyridine, lutidine, ⁇ -collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used.
  • lithium hydroxide potassium hydroxide, sodium hydroxide, sodium carbonate
  • Inorganic bases such as potassium carbonate and sodium bicarbonate
  • the amount of the base to be used is 1 to 100 times, preferably 1 to 50 times, more preferably 1 to 100 times the mol of the hydrazine derivative (the hydrazine compound ⁇ , ⁇ , ⁇ , ⁇ '). It is 10-fold molar.
  • the temperature in the reaction with an octogenide such as sulfonyl chloride is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 0 to 50 ° C, and the reaction time is usually It is 1 to 50 hours, preferably 1 to 25 hours, particularly preferably 1 to 10 hours.
  • the starting compounds I, IV, IV, V, VI, IX, and XI II used in the above Production Methods 1 to 5 can be produced by a method known per se or a method analogous thereto.
  • the formula (vr) for compound (vr), the formula
  • n 1 or 2
  • m 2 or 3
  • D represents an oxygen atom or a sulfur atom, and a salt thereof and a halide (compound IX) such as sulfonyl chloride.
  • compound IX a halide
  • n 1 or 2
  • m 2 or 3
  • D represents an oxygen atom or a sulfur atom, and a salt thereof and a halide (compound IX) such as sulfonyl chloride.
  • compound IX such as sulfonyl chloride
  • O-diphenylphosphinyl N-alkylhydroxylamine can be produced by reacting 0-diphenylphosphinic chloride or the like with N-alkylhydroxylamine.
  • the compound When the compound is obtained in a free state by each of the above-mentioned reactions of the present invention, it may be converted to a salt according to a conventional method, and when the compound is obtained as a salt, a free form or another salt is obtained according to a conventional method. Can also be converted to
  • Compounds II, III, ⁇ , ⁇ , ⁇ , and ⁇ ⁇ ⁇ thus obtained can be obtained from the reaction mixture by a method known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, and the like. Isolation and purification can be performed by using means such as chromatography.
  • the salts of compounds II, III, ⁇ ′, ⁇ , ⁇ , ⁇ ′ may be prepared by adding a mineral acid or an organic acid to the compounds ⁇ , III, III ′, X, XII, XII ′ according to a method known per se. It can be manufactured by such means.
  • Compounds II, III, ⁇ ′, ⁇ , ⁇ , ⁇ and salts thereof may be hydrates, and both hydrates and non-hydrates are included in the scope of the present invention. It is.
  • the compounds II, III, ⁇ , ⁇ , XII, ⁇ obtained by the production method of the present invention are useful, for example, as pharmaceuticals, agricultural chemicals, foods, cosmetics, chemicals or intermediates thereof.
  • the compound having the group represented by is safe, low-toxic, inhibits FXa, and has an anticoagulant effect.
  • Deep vein thrombosis peripheral vascular disease, adult respiratory distress syndrome, chronic kidney disease (eg, dysuria nephropathy, chronic glomerulonephritis, Ig A nephropathy, etc.), diabetic circulatory disorders, pain, nerves, etc. : Thrombocytopenia due to dialysis, thrombocytopenia during major surgery, arteriosclerosis, cancer metastasis, systemic inflammatory response syndrome (SIRS) or pancreatic intravascular coagulation syndrome (DIC) occurring in patients with inflammation and cancer, transplant rejection Various organ failures caused by reaction, organ protection or functional improvement at the time of transplantation, shock or progression of DIC (for example, lung failure, liver failure, renal failure, heart failure)
  • N-benzyloxycarbonyldaricin 100 g, 478 g 1
  • 2,2-diethoxyshetilamine 76.4 g, 574 ol
  • ethyl acetate 800 mL
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride under ice-cooling.
  • Salt 110 g, 574 mmol
  • ethyl acetate 200 mL
  • 1N-hydrochloric acid 500 mL was added to separate the layers, and the aqueous layer was further extracted with ethyl acetate (500 mL ⁇ 2).
  • reaction solution was transferred to a 300 ml eggplant-shaped flask, and separated by adding water (40 ml), a 2N-sodium hydroxide aqueous solution (200 ml) and tetrahydrofuran (40 ml).
  • the aqueous layer was extracted with tetrahydrofuran / ethyl acetate (1: 1, 40 ml + 20 ml), and the organic layers were combined, washed with city water (100 ml ⁇ 2), and then concentrated under reduced pressure.
  • reaction solution was transferred to a 100-ml eggplant-type corben, and city water (10 ml) and 2N-sodium hydroxide (75 ml) were added to precipitate a solid. After stirring under ice cooling, the crystals were collected by filtration and sprinkled and washed with city water. The crude product was washed with methanol (2.75 ml) under heating and reflux, and the crystals were cooled on ice and collected by filtration, dried at 40 ° C under reduced pressure, and dried under reduced pressure at 40 ° C. Thus, ethyl [1- (4-pyridyl) -4-piperidinyl] amino ⁇ -2-piperazinone (400 mg) was obtained. (76% yield)
  • a polan-dimethylamine complex (298 mg, 5.06 t ol) was added with stirring under ice-cooling, followed by a 4N hydrochloric acid / ethyl acetate solution (3.50 ml, 14.2 nether ol). After stirring at the same temperature for 1 hour, the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the mixture was extracted with city water (20 ml) and 0.25 N hydrochloric acid (20 ml).
  • a polan-dimethylamine complex (5.24 g, 89 mL) was added, and a solution of concentrated hydrochloric acid in methanol-denatured ethanol (1Z3 dilution, lllml, 445 m fflol) was added in 10 minutes. The mixture was stirred for 1 hour. After stirring at room temperature for about 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (800 mL) was extracted with concentrated water (800 mL ⁇ 2).
  • Tetrahydrofuran (iOml) was added to the concentrated residue, and sodium borohydride (1.53 g, 40.4 mol) was added thereto under ice-cooling in a nitrogen stream, and formic acid (10 ml) was further added dropwise.
  • 1N-hydrochloric acid 40 ml
  • ethyl acetate 20 ml
  • 1N-hydrochloric acid 10 ml ⁇ 4
  • the aqueous layers were combined, a 4N-7K aqueous sodium oxide solution (120 ml) was added, and the mixture was extracted with ethyl acetate (40 ml ⁇ 4).
  • the organic layers were combined, washed with city water (100 ml ⁇ 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and dried to give an oil (1.43 g).
  • the reaction solution was concentrated under reduced pressure, 50 ml of 1N-hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate (50 ml, 20 ml).
  • the acidic aqueous layer was adjusted to pH 7.0 with a 5N aqueous sodium hydroxide solution, and extracted with ethyl acetate (200 ml ⁇ 1 time, 250 ml ⁇ 2 times).
  • the aqueous layer was adjusted to pH 8.7 with a 5N aqueous sodium hydroxide solution, and further extracted with ethyl acetate (150 ml).
  • the ethyl acetate extract layers were combined and washed with water (70 ml ⁇ 3 times).
  • Piperidone form 1_ (4_pyridyl) -4- -piperidone 5.22 g of the above oily residue in 93 ml of dehydrated ethanol in 54 g of ammonium formate L (24.43 awake 01) and 2.33 g of 10% palladium on carbon (containing 50% water) was added thereto, and the mixture was refluxed for 1 hour under a nitrogen stream. The mixture was returned to room temperature and concentrated under reduced pressure.
  • the mixture was concentrated under reduced pressure, 50 ml of 1N hydrochloric acid was added, and the mixture was washed with ethyl acetate (50 ml ⁇ 2 times).
  • the acidic aqueous layer was adjusted to pH 8.0 with 1N-sodium hydroxide.
  • Ethyl acetate extraction was performed (100 ml ⁇ 3 times).
  • the aqueous layer was adjusted to pH 10 with 1H-sodium hydroxide, and further extracted with ethyl acetate (120 ml ⁇ 1).
  • the extracted layers were combined, washed with water (50 ml ⁇ 3 times), and then dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure to obtain 3.50 g of a pale yellow oil.
  • the oily substance is 4-benziloxycarponyl [1-(4-pyridyl) -4-piberidinylmethylamino] -2, -oxo- 1,2,3,4-tetrahydrovira Jin was confirmed.
  • Table 2 Reaction time and additional raw materials (Table 2)
  • Piperidone 1_ (4-pyridyl) -4-piperidone 3.50 g (7.64 mmol) of the above oil and 93 ml of absolute ethanol were charged, and ammonium formate 1.01 g (16.02 mol) and 10 % Pd-C (50 wet) 1.53g, in a nitrogen stream
  • the mixture was heated under reflux for 1 hour. After cooling to room temperature and removing the catalyst by filtration, the mixture was concentrated under reduced pressure.
  • Tetrahydrofuran (U. 8 ml) was added to the concentrated residue, and sodium borohydride (889 mg, 23.5 t ol) was added while stirring under ice-water cooling in a nitrogen stream, followed by formic acid (11.8 ml). It was dropped in 30 minutes. After stirring for 30 minutes as it was, the mixture was stirred at room temperature for 4 hours and left overnight. After completion of the reaction, the reaction solution was added to city water (10 ml) and 4N-sodium hydroxide aqueous solution (60 ml).
  • This oil is 1 H-band R with 4-benzyloxycarbonyl-1- (1- (4-pyridyl) -4-piperidinylmethylamino) -2-oxo--1,2,3,4- It was confirmed to be tetrahydropyrazine.
  • Ethanol, ammonium formate 1.39 g (22.Ommol) and 10% palladium-carbon (containing 50 water) 1.05 g were added to 4.38 g of the above oily residue, and heated under a nitrogen stream for 1 hour and 20 minutes. Refluxed. After returning to room temperature, the catalyst was removed by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure.
  • the reaction was performed for 6 days. After completion of the reaction, water (15 ml) and 4N-sodium hydroxide aqueous solution a5 ml) were added to the reaction solution, and the mixture was extracted four times with ethyl acetate. The organic layers were combined, washed once with city water, and then concentrated under reduced pressure. The residue was washed with ethanol (3 ml) while heating under reflux, stirred under ice-cooling, and the crystals were collected by filtration, dried at 40 ° C under reduced pressure, and dried under 4- (6-chloronaphthalene-2-sulfonyl) -1-(2
  • a 100 ml eggplant-shaped flask is charged with 3- (3,4-dimethoxybenzylideneamino) -2-thioxo-1,3-thiazolidine-4-one (634 mg, 2.14 mmol'l) and acetic acid (8 ml), and a nitrogen gas stream is supplied.
  • sodium triacetoxyborohydride (4.54 g, 21.4 mmol) was slowly added.
  • sodium triacetoxyborohydride (10.2 g, 48.1 ol) and acetic acid (7 ml) were added.
  • a 100 ml eggplant-shaped flask is charged with nitrogen (3,4-methylenedioxybenzylideneamino) homopiperidine (500 mg, 2.03 IMO1), toluene (5 ml) and sodium borohydride (768 mg, 20.3 mmol) in a nitrogen stream.
  • Formic acid (3 ml) was added dropwise while stirring under ice-water cooling. After stirring for 1 hour as it was, the reaction was allowed to proceed at room temperature for 3 days, and sodium borohydride (386 mg, 10.2 rinse) and formic acid (2.5 ml) were added during the reaction.
  • a 1- (3,4-; no) homopiperidine (500 mg, 2.03 bandol) and acetic acid (10 ml) are charged into a 100-ml eggplant-shaped flask, and sodium triacetoxyborohydride (4.30 g) is stirred in a nitrogen stream at room temperature at room temperature. , 20.3 bandits) and reacted for 33.5 hours.
  • city water (20 ml) and 4N-sodium hydroxide aqueous solution (75 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml ⁇ 3).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'un dérivé d'hydrazine (II) par réduction d'un dérivé d'hydrazone (I) à l'aide d'un complexe d'amine-borane solide. [R?1, R2, R3 et R4¿ représentent chacun hydrogène, un groupe d'hydrocarbure éventuellement substitué, ou analogue]. Grâce à ce procédé, il est possible de préparer des dérivés d'hydrazine qui sont utiles comme médicaments, produits chimiques agricoles, produits alimentaires, cosmétiques, produits chimiques, ou des intermédiaires de ces derniers à partir de matières premières facilement disponibles suivant un itinéraire convergent en quelques étapes et en toute sécurité par une manipulation aisée de réactifs et de déchets, d'où son intérêt au niveau industriel.
PCT/JP2001/001750 2000-03-08 2001-03-07 Procede de preparation de derives d'hydrazine Ceased WO2001066541A1 (fr)

Priority Applications (1)

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AU2001241042A AU2001241042A1 (en) 2000-03-08 2001-03-07 Process for the preparation of hydrazine derivatives

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JP2000068670 2000-03-08

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074762A1 (fr) * 2001-03-15 2002-09-26 Takeda Chemical Industries, Ltd. Procede relatif a l'elaboration de derive sulfone
WO2003042187A1 (fr) * 2001-11-13 2003-05-22 Morphochem Aktiengesellschaft für kombinatorische Chemie Inhibiteurs de serine protease
WO2007056159A3 (fr) * 2005-11-03 2008-10-16 Redpoint Bio Corp Derives d'hydrazone et utilisations de ceux-ci
US8193168B2 (en) 2007-02-02 2012-06-05 Redpoint Bio Corporation Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4243803A (en) * 1979-07-05 1981-01-06 Bristol-Myers Company Production of 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
EP0180890A2 (fr) * 1984-11-05 1986-05-14 Kali-Chemie Pharma GmbH Procédé de réduction diastéréosélective de 3-amino-1-benzoxépine-5(2H)-ones
EP0189004A2 (fr) * 1984-12-27 1986-07-30 Ciba-Geigy Ag Procédé de préparation de composés particuliers de l'indole, substitués en position 3 et leurs intermédiaires
WO1996017824A2 (fr) * 1994-12-09 1996-06-13 Biomembrane Inst Composes et procedes d'analyse de monosaccharides
JPH11172131A (ja) * 1997-12-12 1999-06-29 Kanto Chem Co Inc チタンイエローの安定化組成物
JP2000229925A (ja) * 1999-02-15 2000-08-22 Sumika Fine Chemicals Co Ltd ヒドラジン誘導体の製造方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4243803A (en) * 1979-07-05 1981-01-06 Bristol-Myers Company Production of 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
EP0180890A2 (fr) * 1984-11-05 1986-05-14 Kali-Chemie Pharma GmbH Procédé de réduction diastéréosélective de 3-amino-1-benzoxépine-5(2H)-ones
EP0189004A2 (fr) * 1984-12-27 1986-07-30 Ciba-Geigy Ag Procédé de préparation de composés particuliers de l'indole, substitués en position 3 et leurs intermédiaires
WO1996017824A2 (fr) * 1994-12-09 1996-06-13 Biomembrane Inst Composes et procedes d'analyse de monosaccharides
JPH11172131A (ja) * 1997-12-12 1999-06-29 Kanto Chem Co Inc チタンイエローの安定化組成物
JP2000229925A (ja) * 1999-02-15 2000-08-22 Sumika Fine Chemicals Co Ltd ヒドラジン誘導体の製造方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074762A1 (fr) * 2001-03-15 2002-09-26 Takeda Chemical Industries, Ltd. Procede relatif a l'elaboration de derive sulfone
WO2003042187A1 (fr) * 2001-11-13 2003-05-22 Morphochem Aktiengesellschaft für kombinatorische Chemie Inhibiteurs de serine protease
WO2007056159A3 (fr) * 2005-11-03 2008-10-16 Redpoint Bio Corp Derives d'hydrazone et utilisations de ceux-ci
US8193168B2 (en) 2007-02-02 2012-06-05 Redpoint Bio Corporation Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release

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