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WO1999002524A1 - Composes antifongiques a base de triazole - Google Patents

Composes antifongiques a base de triazole Download PDF

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Publication number
WO1999002524A1
WO1999002524A1 PCT/JP1998/003034 JP9803034W WO9902524A1 WO 1999002524 A1 WO1999002524 A1 WO 1999002524A1 JP 9803034 W JP9803034 W JP 9803034W WO 9902524 A1 WO9902524 A1 WO 9902524A1
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WIPO (PCT)
Prior art keywords
group
compound
difph
phenyl
fph
Prior art date
Application number
PCT/JP1998/003034
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English (en)
Japanese (ja)
Inventor
Toshiyuki Konosu
Takuya Uchida
Sadao Oida
Hiroshi Yasuda
Original Assignee
Sankyo Company, Limited
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Filing date
Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU79379/98A priority Critical patent/AU7937998A/en
Publication of WO1999002524A1 publication Critical patent/WO1999002524A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • Ar 1 represents a phenyl group or a fuunyl group having 1 to 3 substituents (the substituent represents a halogen atom or a trifluoromethyl group);
  • a r 2 is a phenyl group, a naphthyl group, a 5- or 6-membered aromatic heterocyclic group (the heterocyclic group has 1 to 4 nitrogen, oxygen or sulfur atoms), a condensed bicyclic aromatic heterocyclic group (The heterocyclic group has 1 to 4 nitrogen, oxygen, or sulfur atoms), a fuunyl group having 1 to 3 substituents selected from Substituent Group B, and 1 to 3 selected from Substituent Group B.
  • 1 ⁇ and 13 ⁇ 4 2 are the same or different and each represents a hydrogen atom or a lower alkyl group, p is represents 0, 1, 2 or 3,
  • q 0, 1 or 2
  • r represents 0, 1 or 2 (the sum of p, q and r is 3 or less), and A represents a group selected from the following substituent group A.
  • the substituent group A is
  • a substituent group consisting of Substituent group B includes a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen, a lower alkyl group substituted with a hydroxyl group, a lower alkyl group substituted with a halogen and a hydroxyl group, in substituted lower alkoxy group, a lower alkoxy group substituted with a hydroxyl group, a lower ⁇ alkoxy group substituted with a c port plasminogen and a hydroxyl group, a nitro group, Shiano group, - S (0) m R 3 group (R 3 is represents a lower alkyl group substituted with a lower alkyl group or a halogen atom, m represents 0, 1 or 2), -.
  • R ⁇ R 2 and the “lower alkyl group” in the substituent group B represent a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. —Butyl, tert-butyl, pentyl and hexyl groups. Among them, preferred is an alkyl group having 1 to 3 carbon atoms, and more preferred is a methyl or ethyl group.
  • the “lower alkoxy group” in the substituent group B represents a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert. —Butoxy, pentyloxy or hexyloxy groups, among which alkoxy groups having 1 to 3 carbon atoms are preferred, and methoxy or ethoxy groups are more preferred.
  • the “5- or 6-membered aromatic heterocyclic group” of Ar 2 represents a 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen or sulfur atoms, and is, for example, furyl, chenyl, pyrrolyl, pyrazolyl , Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazi And preferably a 5- or 6-membered aromatic heterocyclic group having one or two nitrogen, oxygen or sulfur atoms, more preferably a furyl, phenyl or pyridyl group. is there.
  • fused bicyclic aromatic heterocyclic group of Ar 2 represents a fused bicyclic aromatic heterocyclic group having 1 to 4 nitrogen, oxygen or sulfur atoms, such as quinolyl, isoquinolyl, benzofuranyl, Examples include benzothiopheninole, indolinole, benzimidazolyl, benzoxazolyl, tetrazopyridyl, prenyl, quinoxalinyl, pteridinyl and benzothiazolyl groups, and preferably quinolyl, benzothiophenyl or indolyl group.
  • the “lower alkyl group substituted with halogen” in the substituent group B represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, for example, chloromethinole, dichloromethinole, Trik ⁇ ⁇ methinole, chloroenoline, dichloroethinole, trichloroethinole, tetrachloroethinole, chloropropinole, chlorobutinole, clopentyl, crohexyl, fnorolelomethyl, diphnolelomethinole, trifluorophenol , Difluoroethyl, trifluorofluoryl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluorochloro, tetrafluorophenol, perfluoro
  • fluoropropyl, trichloromethyl, 2-chloroethyl, and 3-chloropropyl groups and more preferably a trichloromethyl or trifluoromethyl group.
  • the ⁇ lower alkyl group substituted with a hydroxyl group '' of the substituent group B represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which is substituted with a hydroxyl group, for example, hydroxymethyl phenol, hydroxymethyl, Dihydroxyshetil.
  • Hydroxypropyl, Dihydro Examples thereof include oxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups. Of these, preferred is an alkyl group having 2 to 5 carbon atoms, which is substituted with a hydroxyl group.
  • 2-hydroxyxethyl 3-hydroxypropynole, 2,3-dihydroxypropynole, 4-hydroxyptynole, 1-hydroxyl, 1-methynolephine, 1-ethynole, 3-hydroxypropynole, 1-ethynole, 2-hyd Roxypropyl, 1-ethyl-1-hydroxypropyl group, and the like, and more preferably, 2-hydroxyl, 1-ethyl-13-hydroxypropyl, 1-ethyl-2-hydroxyl. It is a propyl or 1-ethyl-1-1-hydroxypropyl group.
  • the “lower alkyl group substituted with a halogen and a hydroxyl group” in the substituent group B represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which is substituted with a halogen atom and a hydroxyl group.
  • Examples thereof include xyl, hydroxychloroethyl, and hydroxycyclopropyl groups.
  • alkyl group having 1 to 4 carbon atoms substituted with a fluorine atom and a hydroxyl group preferred is an alkyl group having 1 to 4 carbon atoms substituted with a fluorine atom and a hydroxyl group.
  • Orthomethyl, 2-hydroxy-1,1,1-difluoroethyl, 3-hydroxy-1,1,1,2,2-tetrafuronolepropyl, 4- Hydroxy-1,2,2,3,3-tetrafluorobutyl group and the like can be mentioned. More preferably, 2-hydroxy-11,1-difluoroethyl or 4-hydroxy-12,2 is preferred. , 3,3-tetrafluorobutyl group.
  • the “lower alkoxy group substituted with halogen” in the substituent group B represents a straight-chain or branched alkoxy group having 1 to 6 carbon atoms and substituted with a halogen atom, for example, chloromethoxy, dichloromethoxy.
  • Trichloromethoxy black mouth ethoxy, black mouth ethoxy, black mouth ethoxy, black mouth ethoxy, black mouth pentinoleoxy, black mouth hexinoleoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorethoxy, difluoroethoxy, trifluorofluoro Ethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoropropoxy, tetrafluoropropo Xy, fluoropentyloxy, fluoroxyhexoxy, trifluoropropoxy, tetrafluorophenol, bromomethoxy, bromoethoxy, bromopropoxy, bromobutoxy, bromopentyloxybromohexyloxy, etc.
  • an alkoxy group having 1 to 3 carbon atoms which is preferably substituted by a fluorine atom or a chlorine atom, such as chloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy, 2-dichloroethoxy, 2,2,2-trichloroethoxy, 3_propynoleoxy, phlorenomethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2— Trifluoroethoxy, 1, 1, 2, 2 — Tet Fluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 2,2,3,3-tetrafluoropropoxy and the like. More preferred are difluoromethoxy, trifluoromethoxy, 2,2, It is 2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or 2,2,3,3-tetrafluoropropoxy and the
  • the “lower alkoxy group substituted by a hydroxyl group” in the substituent group B represents a straight-chain or branched alkoxy group having 1 to 6 carbon atoms and substituted by a hydroxyl group, for example, hydroxy shetyloxy, hydroxy A propyloxy, dihydroxypropyloxy, hydroxybutyloxy, hydroxypentyloxy, hydroxyhexyloxy group, etc., and preferably a carbon number substituted by a hydroxyl group.
  • Two to five alkyloxy groups for example, 2-hydroxypropynoleoxy, 3-hydroxypropynoleoxy, 4-hydroxybutynoleoxy, (1-ethyl ⁇ ⁇ —3-hydroxy Doxypropyl) oxy, (1-ethyl-12-hydroxypropyl) oxy group, and the like, and more preferably, 2-hydroxyloxy, (1-ethyl) -3-Hydroxypropyl) oxy and (1-ethyl-12-hydroxypropyl) oxy.
  • the “lower alkoxy group substituted with a halogen and a hydroxyl group” in the substituent group ⁇ represents a linear or branched alkoxy group having 1 to 6 carbon atoms and substituted with a halogen atom and a hydroxyl group.
  • Hydroxyfluoroethoxy, Hydroxydifluoroet Hydroxy, hydroxyfluoropropoxy, hydroxytetrafluoropropoxy, hydroxytetrafluorobutoxy, hydroxytetrafluoropentyloxy, hydroxychloroethoxy, hydroxydichloroe Among them, preferred is an alkoxy group having 1 to 4 carbon atoms, which is substituted by a fluorine atom and a hydroxyl group.
  • 2-hydroxy-1,1,1-difluoro Ethoxy 3-hydroxy-1,1,1,2,2-tetrafluoropropoxy, 4-hydroxy-2,2,3,3-tetrafluorobutoxy, and the like are more preferred.
  • Substituent Group B "- S ( ⁇ ) m R 3 group”, R 3 "one S (O) 2 OR 3 group,” ⁇ Pi "one OS (O) 2 R 3 group” is preferably An alkyl group having 1 to 3 carbon atoms or an alkyl group having 1 to 3 carbon atoms substituted by a fluorine atom, such as methyl, ethyl, propyl, isopropyl, fluoromethyl, dif / reolomethyl, trifluoromethyl, Fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, perfluoropropyl group and the like, more preferably methyl, trifluoromethyl or 2,2,2-trifluoroethyl Group.
  • m in the “S ( ⁇ ) m R 3 group” is preferably 2.
  • those preferred as the “lower alkyl” for the substituent are a methyl group, and a “halogen atom” for the substituent. Is preferably a fluorine or chlorine atom, and a preferable as the “lower alkyl group substituted with halogen” for the substituent is a trifluoromethyl group.
  • imidazolyl, pyrazolyl, triazolyl and tetrazolyl group optionally having substituent (s) are 1-imidazolyl, 4,5-dichloroimidazolyl, 1-pyrazolyl, 3- (trifluoromethyl) 1 It is a 1-pyrazolyl, 1,2,4-triazolone 1-inole, 1,2,4-triazol-1141, 2-tetrazolyl or 1-tetrazolyl group.
  • a r 1 is, for example, phenyl, dichlorophenyl, difluorophenyl, dibromophenyl, chlorophenol, phenololenophenol, bromophenylene, triphenololenophenol, trichlorophenol, tribromophenylene, tribromophenylene.
  • Ar 2 includes, for example, phenyl, fluorophenyl, chlorophenyl, diphenylolenophenyl, dichlorophenyl, (triphenololenomethyl) phenyl, (trichloromethylphenyl, trichlorophenol) Nore, (difluoromethoxy) phenyl, (trifnorolemethoxy) phenyl, (2,2,2-trinoleoxyethoxy) phenyl, (1,1,2,2-tetrafluoroethoxy) phenyl, (2,2,3,3-tetrafluoropropoxy) phenyl, Fluoro (2,2,3,3-tetrafluoropropoxy) phenyl, nitrophenyl, fluoro-nitrophenyl, cyanophenyl, cyanofluoro Phenyl, black cyanophenyl, (methylthio) phenyl, (methylsulfur Phenyl, (methylsul
  • the “substituent group Bl” includes an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, and a carbon number substituted with fluorine or chlorine.
  • 1 to 3 alkyl groups substituted by fluorine or chlorine C 1 -C 3 alkoxy, nitro, cyano, S (O) 2 R 3 (where R 3 is substituted by C 1 -C 3 alkyl or fluorine or chlorine An alkyl group having 1 to 3 carbon atoms), one S (O) 2 ⁇ R 3 group (R 3 is as defined above), one OS (O) 2 R 3 group (R 3 is As defined above), imidazolyl group, pyrazolyl group, triazolyl group and tetrazolyl group (the imidazolyl group, pyrazolyl group, triazolyl group and tetrazolyl group are alkyl groups having 1 to 3 carbon atoms, fluorine atom, chlorine Or a group of 1 to 2 carbon atoms, which may be substituted with an alkyl group having 1 to 3 carbon atoms, which is substituted with an atom, a bromine atom, or fluorine or chlorine.
  • substituted group Bl is preferably the following “substituent group B2”.
  • Substituent group B 2 includes a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a fluoromethyl group, a difluoromethinole group, a trifluorenomethylenole group, a 2-fluoroethynole group, and a 2,2-difluoroethyl group.
  • It is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a hydrogen atom, a methyl or ethyl group.
  • p is preferably 1, 2 or 3, and more preferably 1 or 2.
  • q is preferably 0.
  • r is preferably 0.
  • the sum of p, q and r is preferably 1 or 2.
  • A is preferably a group represented by the formula (A-1) or (A-3) in the substituent group A, and most preferably a group represented by the formula (A-1).
  • “Pharmacologically acceptable salts” of compound (1) include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid Salts of carboxylic acids such as acetic acid, cunic acid, malic acid, etc. It is preferably a salt of an inorganic acid (especially hydrochloride or nitrate) or a salt of a carboxylic acid (especially fumarate, maleate or oxalate).
  • the hydrate of the compound (1) and the hydrate of the salt of the compound (1) are also included in the compound of the present invention.
  • the triazole compound (1) of the present invention has 1 to 4 asymmetric carbons, and has optical isomers and diastereomers, and those having a double bond include E-type or Z-type geometric isomers. Cis and trans isomers based on the mode of substitution on the heterocyclic group of A.
  • the compound (1) of the present invention includes one or a mixture of these isomers.
  • optical isomers can be separated by a general optical resolution technique, or the two enantiomers can be obtained by an asymmetric synthesis technique. Diastereomers, geometric isomers, and cis and trans isomers can be separated by using ordinary separation methods such as fractional recrystallization and chromatography.
  • Preferred compounds as the compound having the formula (1) of the present invention are the following compounds.
  • Ar 1 is a phenyl group having one or two substituents (the substituent is a fluorine atom, a chlorine atom, or a trifluoromethyl group).
  • Ar 2 is a phenyl group, a naphthyl group, a 5- or 6-membered aromatic heterocyclic group (the heterocyclic group has one or two nitrogen, oxygen or sulfur atoms), and the substituent group B 1 A fluorine group having one or two substituents selected from the group consisting of: a substituent group ⁇ a naphthyl group having one or two substituents selected from one or a group of substituents 1 one or more selected from the group Is a compound which is a 5- or 6-membered aromatic heterocyclic group having two substituents (the heterocyclic group has one or two nitrogen, oxygen or sulfur atoms).
  • Ar 2 is a phenyl group, a naphthyl group, a phenyl group having one or two substituents selected from substituent group B1, or one or two substituents selected from substituent group B1 A compound which is a naphthyl group having a group.
  • a r 2 is phenylene Honoré, 1 Nafuchinore, 2 Nafuchinore, 4 one fluoro phenyl-4- black port phenyl, 2, 4-diphenyl Honoré Oro phenyl, 4- (Torifuruorome chill) phenyl, 4 — (Trifnorolemethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 4-nitrophenyl, 4-cyanophenylene, 4-cyano-2-phenylenophenylene, 4-cyano 3 —Funolelophenyl, 4 -— (Trifluoromethylthio) phenyl, 4 -— (Trifluoromethanesulfonole) Phenyle, 4-(Trifluorolenomethanol) / Feninole, 4 — [(2, 2 , 2—Trifluoroethoxy) sulfonyl] pheninole, 4- (1-
  • 1 ⁇ and 1 2 are the same or different, a hydrogen atom or a C 1 to compound a three Al kill group carbon.
  • a r 1 is 1 or Fuyuniru group having two substituents (said substituent is a fluorine atom, a chlorine atom or a triflate Ruo ii methyl group.), And, A r 2 is phenylene Group, naphthyl group, 5- or 6-membered aromatic heterocyclic group (the heterocyclic group has one or two nitrogen, oxygen or sulfur atoms), and one or two selected from substituent group B 1 A substituent having a substituent, a naphthyl group having 1 or 2 substituents selected from Substituent Group B 1 or a 5 or 5 having 1 or 2 substituents selected from Substituent Group B 1 6-membered aromatic Hajime Tamaki (said heterocyclic group is one or two nitrogen, oxygen or that have a sulfur atom), and 1 ⁇ 1 and 1 2 are the same or different, a hydrogen atom or a carbon atoms A compound having 1 to 3 alkyl groups, a p-force of 1, 2 or 3,
  • a r 1 is 1 or phenyl group having two substituents (said substituent is a fluorine atom, a chlorine atom or a triflate Ruo ii methyl group.),
  • a r 2 is phenylene
  • a phenyl group having 1 or 2 substituents selected from substituent group B 1 or a naphthyl group having 1 or 2 substituents selected from substituent group B 1 , 1 ⁇ and 1 ⁇ 2 are the same or different and are a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, p is 1, 2 or 3, and q and r are 0.
  • Ar 2 is phenyl, 1-naphthinole, 2-naphthinole, 4-funolene, or 4-phenyl , 4-Diphnoleolopheninole, 4- (Trifluoroenomethinole) phenyl, 4- (Trifluoromethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phen 2 nore, 4 12 trohueninore, 4—cyanofenore, 4—cyanone—2 funoreo Mouth feni / re, 4—cyanone 3—funoleolofeninole, 4- E) Feninole, 4-1 (Trifluoromethanesulfonyl) Feninole, 4— (Trifluoromethanesulfoninoleoxy) Feninole, 4— [(2,2,2-Trifrenole mouth
  • CN is cyano
  • Et is ethyl
  • Fur is frill
  • Imid is imidazolyl
  • Ind is indolyl
  • iPr is isopropyl
  • iQuin is isoquinolyl
  • Me is methyl
  • N0 2 is nitro
  • Np is naphthyl
  • Ph phenyl
  • Pr means propyl
  • Pyr means pyridyl
  • p Yza pyrazolyl
  • Quin quinolyl “Thi” Choi two Shows the group Al, A 2 and A 3 each represent a group represented by the formula (A-1), (A-2) or (A-3) selected from the substituent group A.
  • preferred compounds include, for example, Exemplified Compound Nos. 2, 12, 14, 18, 26, 31, 38, 55, 64, 65, 66, 67, 74, 82,
  • particularly preferred compounds include
  • the compound having the formula (1) of the present invention can be easily produced by the methods shown as the following [Method A] to [Method F].
  • the portion corresponding to Ar 2 when the portion corresponding to Ar 2 has a hydroxyl group, it can be produced, if necessary, by protecting it according to a conventional method. For example, it has a hydroxyl group protected by various protecting groups described in a review by Green et al. ("Protective Groups in Organic Synthesis, 2nd Edition” Ed. By TWGreen & PGM Wuts, 1991, John Wiley & Sons, Inc.) It can be manufactured using raw materials.
  • hydroxyl-protecting group examples include tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilinole (where the lower alkyl moiety is as defined above); t-butyldiphenylsilyl (Where the lower alkyl moiety has the same meaning as described above, and the aryl moiety represents an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl).
  • tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilinole (where the lower alkyl moiety is as defined above); t-butyldiphenylsilyl (Where the lower alkyl moiety has the same meaning as described above, and the aryl moiety represents an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl).
  • Benzyl group which may have a substituent such as benzinole, 4-methoxybenzylinole, 4-nitrobenzyl, 4-methylbenzyl, 4-bromobenzyl (the substituent is lower alkoxy, nitro, lower alkyl) Or a halogen, wherein lower alkoxy, lower alkyl and halogen are as defined above); a triarylmethyl group such as triphenylmethyl (where the aryl moiety is as defined above); A lower alkanol group such as acetyl (the lower alkanol is an alkanol having 2 to 4 carbon atoms); an aryl carbon group such as benzoyl (where the aryl moiety has the same meaning as described above) and the like. , Preferably t-butyldiphenylsilyl, 4-methoxybenzyl, acetyl or benzyl.
  • a zone I le group such as benzinole, 4-methoxybenzylinole,
  • Method A is a method for producing a compound having the formula (1) of the present invention, and is represented by the following reaction formula.
  • Ar 2 , R ⁇ R 2 , A, p, q and r have the same meanings as described above, and X represents the same or different and represents an oxygen or sulfur atom.
  • This method is applicable to alcohol and / or thiol compounds (2-1), (2-2) or (2 This is achieved by reacting 3) with an aldehyde compound (3).
  • Compounds (2-1), (2-2) and (2-3), which are the starting materials for this reaction, can be produced by methods B, C, D and E described below.
  • the aldehyde compound (3) can be produced by the method disclosed in JP-A-8-333350 or a method analogous thereto. Further, among the aldehyde compounds (3), compounds having p of 1, 2, or 3 can also be produced by the below-mentioned Method F.
  • reaction of compound (2-1), (2-2) or (2-3) with compound (3) is usually carried out in an inert solvent under acidic conditions while removing water produced by the reaction.
  • Examples of the acid used include inorganic acids such as hydrogen chloride, sulfuric acid, and nitric acid, Lewis acids such as boron trifluoride, methanesulfonic acid, benzenesulfonic acid, P-tonoleenesulfonic acid, camphorsnolephonic acid And sulfonic acids (p-toluenesulfonic acid in particular).
  • inorganic acids such as hydrogen chloride, sulfuric acid, and nitric acid
  • Lewis acids such as boron trifluoride, methanesulfonic acid, benzenesulfonic acid, P-tonoleenesulfonic acid, camphorsnolephonic acid And sulfonic acids (p-toluenesulfonic acid in particular).
  • the amount of the acid used is 1 to 3 molar equivalents, preferably 1.2 to 1.7 molar equivalents, relative to compound (2-1), (2-2) or (2-3). .
  • an acid equivalent to the basic group is further required.
  • the aldehyde (3) can be used in an amount of 1 to 2 molar equivalents relative to the compound (2-1), (2-2) or (2-3), preferably in an amount of 1.1 to 1.5 molar equivalents. is there.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • solvents include, for example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, getyl ether, tetrahydrofuran.
  • Non-protonic solvents such as ethers can be used, but halogenated hydrocarbons (particularly dichloromethane) are preferred.
  • the reaction temperature varies depending on the types of raw materials, catalysts and solvents used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent.
  • the reaction time depends on the types of raw materials, catalysts and solvents used, and the reaction temperature. However, it is usually 1 to 24 hours, preferably 1 to 5 hours.
  • the water generated in the reaction can be removed by azeotropic distillation with the solvent used, but a dehydrating agent such as molecular bus can also be used.
  • the target compound (1) of this reaction can be collected from the reaction mixture by a conventional method after neutralizing the reaction solution with aqueous sodium bicarbonate or the like.
  • it can be obtained by adding an organic solvent immiscible with water to a residue obtained by distilling off the solvent of the reaction mixture or the reaction mixture, washing with water, and distilling off the solvent.
  • the obtained compound (1) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the target compound (1) can be derived by removing the protecting group.
  • the removal of the protecting group varies depending on the type, but is generally known in the field of organic synthetic chemistry, and is described in "I. Method, Protective Groups in Organic Synthesis, 2nd Edition, etc. d. By TW Green & P, GM Wuts, 1991, John Wiley & Sons, Inc., etc.) or a method equivalent thereto.
  • the compound (1) thus obtained can be converted to a pharmacologically acceptable salt by adding a pharmacologically acceptable acid in a solvent.
  • solvents used include aromatic hydrocarbons such as benzene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as ether, tetrahydrofuran, and dioxane, and ethyl acetate.
  • aromatic hydrocarbons such as benzene
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • ethers such as ether, tetrahydrofuran, and dioxane
  • ethyl acetate examples include esters, methanol, alcohols such as ethanol, nitriles such as acetonitrile, hydrocarbons such as hexane and cyclohexane, and mixed solvents thereof.
  • the acid used may be any pharmacologically acceptable one, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid
  • carboxylic acids such as acids, cunic acid, and malic acid
  • snorenoic acids such as methanesulfonic acid, ethanesnoleic acid, benzenesulfonic acid, and toluenesulfonic acid
  • amino acids such as glutamic acid and aspartic acid.
  • the desired salt is usually obtained as a crystal or powder from a solution of compound (1) and the acid added. Further, it can be obtained as a precipitate by adding a solvent that does not dissolve the salt to the solution containing the salt, or can be obtained by removing the solvent from the solution containing the salt.
  • Method B is a method for producing an alcohol compound (2-1) used as a raw material in Method A, and is represented by the following reaction formula. Step B—Two steps
  • Ar R 1 and R 2 have the same meanings as described above, and R 5 represents a lower alkyl group, an alkenyl group having 3 to 6 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. And R 6 represents a lower alkyl group.
  • the lower alkyl group for R 5 and R 6 is as defined above.
  • As the alkenyl group having 3 to 6 carbon atoms for R 5 for example, a butyl, propyl, butenyl, pentenyl or hexyl group can be mentioned, and a 1-propyl group (aryl group) is preferable. ).
  • Examples of the aralkyl group having 7 to 12 carbon atoms include a benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl or naphthylethyl group, and a benzyl group is preferable.
  • Step B-1 is a step for producing an amide compound (5). This step is carried out by reacting the nitrile compound (4) with water in an inert solvent in the presence of a catalyst.
  • the solvent used in the reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but preferably includes water or a mixed solvent containing water.
  • the solvent used together with water include ethers such as ether, tetrahydropyran, dioxane, and dimethoxetane, petroleum ethers, hydrocarbons such as hexane, benzene, and toluene, methanol, ethanol, and propanol.
  • ethers such as ether, tetrahydropyran, dioxane, and dimethoxetane
  • petroleum ethers hydrocarbons such as hexane, benzene, and toluene
  • methanol ethanol
  • propanol propanol
  • ketones such as acetone and methyl ethyl ketone
  • ketones particularly, acetone
  • the catalyst to be used is not particularly limited as long as it is a catalyst usually used in organic synthetic chemistry to convert nitriles to amides.
  • a catalyst usually used in organic synthetic chemistry to convert nitriles to amides.
  • Alkali bases such as carbonated sodium carbonate, sodium hydroxide and potassium hydroxide
  • inorganic acids such as sulfuric acid and hydrochloric acid
  • organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid
  • hydrogen peroxide tert-butyl hydroperoxide And the like.
  • Alkali bases (particularly sodium carbonate) and hydrogen peroxide are preferred.
  • These catalysts may be used alone or in a mixture.
  • the reaction temperature varies depending on the types of the starting materials, the catalyst and the solvent to be used, but is usually in the range of 140 ° C. to the boiling point of the solvent, preferably 0 to 40 ° C.
  • the reaction time varies depending on the type of starting materials, catalysts and solvents used, and the reaction temperature, but is usually 1 to 24 hours, preferably 5 to 18 hours.
  • the nitrile compound (4) to be used can be produced by a method generally described in JP-A-8-534246 or a method analogous thereto.
  • the amide compound (5) can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water, and distilling off the solvent.
  • the obtained amide compound (5) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the amide compound (5) is reacted with an alcohol represented by the formula R 5 OH (wherein R 5 has the same meaning as described above) in a solvent under acidic conditions to give an ester.
  • This is a step of producing the compound (6).
  • the acid used is not particularly limited, but examples thereof include inorganic acids such as hydrogen chloride, sulfuric acid, and nitric acid, Lewis acids such as boron trifluoride, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Examples thereof include sulfonic acids such as trifluoromethanesulfonic acid and carboxylic acids such as trifluoroacetic acid, and preferred are sulfonic acids (particularly, trifluoromethanesulfonic acid).
  • the amount of the acid used is usually 1 to 100 molar equivalents, preferably 30 to 40 molar equivalents, relative to the amide compound (5).
  • Alcohols used are those of the formula R 5 OH, such as methanol, Etano one Honoré, Purono, 0 Nord, 2 Purono ⁇ 0 Nonore, butanol, can be cited ⁇ Lil alcohol and base down benzyl alcohol, Preferably it is propanol.
  • the molar ratio of the alcohols is 1 equivalent to 100 equivalents to the amide compound (5), but preferably a large excess is used as a solvent.
  • the reaction solvent does not hinder the reaction and dissolves the starting compound to some extent.
  • the above alcohols themselves, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and hydrocarbons such as petroleum ether, hexane, benzene, benzene, tonolene, and xylene And ethers such as ethynole ether and tetrahydrofuran, and mixtures thereof, and preferably the above-mentioned alcohols themselves.
  • the reaction temperature varies depending on the types of raw materials, catalysts and solvents used, but is usually in the range of 40 to 150 ° C, preferably 80 to 120 ° C.
  • the reaction time varies depending on the starting materials, catalysts and solvents used and the reaction temperature, but is usually from 1 to 24 hours, preferably from 8 to 12 hours.
  • the ester compound (6) can be collected from the reaction mixture by a conventional method after neutralizing the reaction solution with an aqueous sodium hydrogen carbonate solution or the like. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water, and distilling off the solvent.
  • Step B-3 is a step of reacting the ester compound (6) with a reducing agent in a solvent to produce an alcohol compound (7).
  • Examples of the reducing agent used include diborane, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, borane such as disiamylborane, texylborane, catecholborane, sodium borohydride, lithium borohydride and the like.
  • Commonly used reducing agents such as borohydrides, lithium aluminum hydride, sodium aluminum bis (methoxetoxy) hydride, metal hydrides such as diisobutylaluminum hydride and aluminum dimethylhydride may be mentioned. And preferably borohydrides (particularly lithium borohydride).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples thereof include ethers such as tetrahydrofuran, dioxane, and dimethoxetane or methanol, ethanol, and the like.
  • ethers such as tetrahydrofuran, dioxane, and dimethoxetane or methanol, ethanol, and the like.
  • propanol Alcohols are alcohols (especially ethanol) when using borohydrides as reducing agents, and ethers (especially tetrahydrobran) when using borane or metal hydrides as reducing agents. It is.
  • the reaction is carried out at a temperature of from 150 ° C. to room temperature (preferably from 10 ° C. to 5 ° C.).
  • the reaction time varies mainly depending on the reaction temperature and the solvent, but is usually from 1 to 24 hours (preferably 5 to 5 hours). It is 15 to 15 hours).
  • the alcohol compound (7) can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water, and distilling off the solvent.
  • the obtained alcohol compound (7) can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • step B-4 the alcohol compound (7) is reacted with a thionylating agent such as thionyl chloride, thionyl bromide, or thioerdiimidazozol in a solvent in the presence of a base to form a cyclic sulfite.
  • the subsequent step is a step of producing a cyclic sulfonic ester compound (8) by reacting with an oxidizing agent in a solvent.
  • the malonate used is a compound represented by the formula CH 2 (COOR 6 ) 2 (wherein R 6 is as defined above), such as dimethyl malonate, getyl malonate, and dipropyl malate. And getyl malonate.
  • the alkali metal salt of malonate is malonate and sodium hydride.
  • Alkali metal hydrides preferably sodium hydride
  • Solvents include alkali metal alkoxides (preferably sodium ethoxide) such as sodium methoxide and sodium methoxide
  • Medium 1 obtained by mixing
  • the alkali metalated malonate can be used usually in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, based on the cyclic sulfonic acid ester compound (8).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
  • examples include amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, ether, tetrahydropyran, and dioxane.
  • ethers such as dimethoxyethane, alcohols such as methanol and ethanol, and hydrocarbons such as petroleum ether, hexane, benzene, and toluene.
  • amides particularly, Dimethylformamide.
  • the reaction temperature is from room temperature to 100 ° C (preferably 40 to 60 ° C).
  • the reaction time varies depending mainly on the reaction temperature and the type of solvent, but is usually 1 to 15 hours (preferably 1 to 15 hours). 1 to 3 hours).
  • the mixture is treated with an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid to give the ester compound (9).
  • a mineral acid such as hydrochloric acid or sulfuric acid
  • Step B-6 is a step of producing the desired alcohol compound (2-1) by reacting the diester compound (9) with a reducing agent in a solvent, and can be achieved in the same manner as in Step B-3. Can be.
  • Method C is a method for separately producing the alcohol compound (2-1), and is represented by the following reaction formula. 4e
  • R 7 represents a lower alkyl group or an aralkyl group having 7 to 12 carbon atoms
  • R 8 represents a lower alkyl group, a lower alkyl group substituted with a halogen atom, an aryl group having 6 to 10 carbon atoms or a lower alkyl group
  • And represents an aryl group having 6 to 10 carbon atoms substituted with a group.
  • the lower alkyl group, the halogen atom and the aralkyl group having 7 to 12 carbon atoms are as defined above.
  • Examples of the aryl group having 6 to 10 carbon atoms include a phenyl or naphthyl group, and a phenyl group is preferable.
  • Step C-1 is a step of reacting the oxazolidinone compound (10) with a reducing agent in a solvent to produce an alcohol compound (11).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • ethers such as tetrahydrofuran, dioxane, and dimethoxetane or methanol, ethanol, and propanol
  • alcohols include ethers (particularly, tetrahydrofuran).
  • the reducing agent used include borohydrides such as lithium borohydride and sodium borohydride, and metal hydrides such as lithium aluminum hydride and bis (methoxhetoxy) aluminum sodium. And bis (methoxyethoxy) aluminum sodium hydride.
  • the reaction is carried out at a temperature of ⁇ 78 ° C. to room temperature (preferably ⁇ 50 ° C. to ⁇ 30 ° C.).
  • the reaction time varies depending mainly on the reaction temperature and the solvent, but is usually 1 to 24 hours (preferably 2 to 24 hours). To 4 hours).
  • the oxazolidinone compound (10) can be obtained by the method described in J. Org. Chem., Vol. 60, p. 3000 (1995) or a method analogous thereto.
  • the alcohol compound (11) can be collected from the reaction mixture by a conventional method. For example, after pouring a substance that decomposes a reducing agent, for example, hydrochloric acid, acetic acid, water, etc. into the reaction mixture to stop the reaction, adding an organic solvent that does not mix with water, washing with water, and distilling off the solvent.
  • a reducing agent for example, hydrochloric acid, acetic acid, water, etc.
  • Step C-12 is a step of reacting the alcohol compound (1, 1) with a sulfonylating agent in a solvent in the presence of a base to obtain a sulfonic acid ester compound (12).
  • the sulfonylating agent is a compound represented by the formula R 8 S ⁇ 2 —L or (R 8 S ⁇ 2 ) 2 ⁇ (wherein R 8 is as defined above, and L is the halogen atom or a leaving group that substitutes for the halogen atom.
  • methanesulfonyl chloride p-toluenesulfonyl chloride, mesitylenesolephoninolechloride, chloromethanesulfoninolechloride, methanesulfonic anhydride or trifluorosulfonic acid.
  • trifluoromethanesulfonic anhydride Preferred is trifluoromethanesulfonic anhydride.
  • the base is not particularly limited as long as it is a base usually used in synthetic organic chemistry.
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • examples include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, petroleum ether, hexane, and the like.
  • non-protonic solvents such as hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane, chlorophonolem and 1,2-dichloroethane.
  • hydrocarbons such as benzene and toluene
  • halogenated hydrocarbons such as dichloromethane, chlorophonolem and 1,2-dichloroethane.
  • Preferred solvents among these are hydrocarbons, especially toluene.
  • the reaction is carried out at a temperature of ⁇ 78 ° C. to room temperature (preferably 140 ° C. to room temperature).
  • the reaction time varies mainly depending on the reaction temperature and the solvent, but is usually 0.5 to 4 hours (preferably 0.5 to 1 hour).
  • the sulfonic acid ester compound (12) is used for the next reaction in step C13 without purification, usually without purification.
  • the reaction mixture can be collected by a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water, and distilling off the solvent. If necessary, it can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step C-3 is a step of producing a diester compound (13) by reacting an alkali metalated malonate with a sulfonate compound (12) in a solvent.
  • the alkali metalated malonate used can be obtained in the same manner as in Step B-5.
  • the alkali metalated malonate can be used usually in an amount of 1 to 5 molar equivalents, preferably 2 to 4 molar equivalents, based on the sulfonic acid ester compound (12).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
  • examples include amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, ether, tetrahydropyran, and dioxane.
  • Dimethoxy Examples include ethers such as ethanol, alcohols such as methanol and ethanol, and hydrocarbons such as petroleum ether, hexane, benzene, and toluene. Amides (particularly, dimethylformamide) are preferred. C).
  • the reaction is carried out at a temperature from room temperature to 100 ° C (preferably from room temperature to 50 ° C).
  • the reaction time varies depending mainly on the reaction temperature and the type of the solvent, but is usually 1 to 15 hours (preferably 1 to 15 hours). Is 1.5 to 3 hours).
  • Step C-14 is a step of producing an alcohol compound (14) by reacting the diester compound (13) with a reducing agent in a solvent. This step can be achieved in the same manner as in Step B-3.
  • Step C-15 is a step of reacting the alkali metal salt of triazole with the compound (14) in a solvent to produce the alcohol compound (2-1).
  • the alkali metal salt of triazole is prepared by reacting an alkali metal hydride (preferably sodium hydride) such as sodium hydride, lithium hydride, or potassium hydride with triazole in a 1: 1 ratio in a solvent. Is done.
  • an alkali metal hydride preferably sodium hydride
  • sodium hydride such as sodium hydride, lithium hydride, or potassium hydride
  • triazole in a 1: 1 ratio in a solvent. Is done.
  • the alkali metal salt of triazole can be used usually in an amount of 1 to 5 molar equivalents, preferably 3 to 4 molar equivalents, relative to compound (14).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide. And preferably dimethylformamide.
  • the reaction temperature is from room temperature to 120 ° C (preferably 80 ° C to 100 ° C).
  • the reaction time varies depending mainly on the reaction temperature and the type of solvent, but is usually 1 to 15 hours (preferably 1 to 15 hours). 3 to 6 hours).
  • the alcohol compound (2-1) can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water, and distilling off the solvent.
  • the obtained alcohol compound (2-1) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Method D is a method for producing a monothiol compound (2-2), which is a raw material of Method A, and is represented by the following reaction formula.
  • Step D-1 is a step of producing a monoester compound (15) by protecting only one of the hydroxyl groups of the alcohol compound (2-1) with an acyl group represented by the formula R 9 CO.
  • the method used in this step is not particularly limited as long as it is a general acylation protection reaction used in the field of organic synthetic chemistry.
  • the method described in the above-mentioned review of Green et al. Or a method similar thereto can be used.
  • this step can be achieved by reacting the alcohol compound (2-1) with an acylating agent in an inert solvent in the presence of a base.
  • the acylating agent used is represented by the formula R 9 CO—L or (R 9 CO) 20, wherein R 9 and L are as defined above, for example, alkanoic acid such as acetic anhydride.
  • alkanoic acid such as acetic anhydride.
  • alkanol halides such as acetyl chloride, and arylcarbonyl halides such as benzoyl chloride, and acetic anhydride is preferred.
  • the above acylating agent can be used usually in an amount of 0.5 to 1.5 molar equivalents, preferably 1.0 to 1.1 molar equivalents, to the alcohol compound (2-1).
  • the base used include organic amines such as pyridine, 4- (dimethylamino) pyridine, and triethylamine, and pyridine is preferred.
  • solvent used examples include aromatic hydrocarbons such as benzene, halogenated hydrocarbons such as dichloromethane, chloroform, ethers such as tetrahydrofuran and dioxane, pyridine, and triethylamine.
  • aromatic hydrocarbons such as benzene
  • halogenated hydrocarbons such as dichloromethane, chloroform
  • ethers such as tetrahydrofuran and dioxane
  • pyridine examples of the solvent used include aromatic hydrocarbons such as benzene, halogenated hydrocarbons such as dichloromethane, chloroform, ethers such as tetrahydrofuran and dioxane, pyridine, and triethylamine.
  • Organic amines and the like can be mentioned, but the same organic amine as the base used is preferably used as the solvent.
  • the reaction is usually performed at a temperature in the range of ⁇ 20 ° C. to room temperature (preferably 0 ° C. to room temperature), and the reaction time varies depending on the reaction conditions, but is usually 30 minutes to 24 hours (preferably 1 to 2 hours). It is.
  • the monoester compound (15) can be collected from the reaction mixture by a conventional method. For example, add an organic solvent that does not mix with water to the reaction mixture, It is obtained by washing with water and distilling off the solvent. This step can also be achieved by using an enzymatic reaction (a method described in the Society of Synthetic Organic Chemistry, Japan, Vol. 53, p. 668, p. 1989).
  • this step can be achieved by reacting the alcohol compound (2-1) with an acyltransferase in the presence of an acyl group donor in a solvent.
  • hydrolytic enzymes such as lipase and esterase, and lipase is preferable.
  • solvent used examples include halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methylethylketone, and acetonitrile.
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • ethers such as tetrahydrofuran and dioxane
  • ketones such as acetone and methylethylketone
  • acetonitrile examples include nonprotonic solvents such as various nitriles, preferably acetone or acetonitrile.
  • the acyl group donor used is represented by the formula R 9 CO—E, wherein R 9 is as defined above, and E represents an alkenyloxy or alkoxy group.
  • acetates such as isopropyl, isopropyl acetate and ethyl acetate, and most preferably isopropyl acetate.
  • the acyl group donor is generally used in a large excess amount with respect to the substrate, and may be used as a reaction solvent.
  • the reaction is carried out at a temperature lower than the optimum temperature of the enzyme, usually at a temperature of ⁇ 20 ° C. to room temperature (preferably 0 ° C. to room temperature).
  • the reaction time depends on the type of substrate, amount of enzyme, and type of enzyme.
  • the reaction is terminated by filtering off the enzyme.
  • the monoester compound (15) is obtained by distilling off the solvent from the filtrate. In this step, in addition to the desired monoester compound (15), The product may be by-produced, but can be removed by ordinary separation and purification procedures such as chromatography, recrystallization, and reprecipitation.
  • Step D-2 is a step in which the monoester compound (15) is reacted with a sulfonylating agent in a solvent in the presence of a base to obtain a sulfonic acid ester compound (16).
  • the sulfolating agent is a compound represented by the formula R 8 S 0 2 —L or (R 8 S 0 2 ) 20 (wherein R 8 and L are as defined above), for example, Methanesulfojuruku Mouth lid, p-tonolenesnolehoninolechloride, mesitylenesolephoninolechloride, chloromethanesnolefonichloride, methanesnolefonic anhydride, trifnoroleromethanesulphonic anhydride And preferably methanesulfoyl chloride.
  • the base is not particularly limited as long as it is a base usually used in organic synthetic chemistry, and examples thereof include organic bases such as triethylamine, diisopropylethylamine, pyridine, and lutidine. Min.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, petroleum ether, hexane, benzene, and tonoleene.
  • Non-protonic solvents such as hydrocarbons, dichloromethane, chloroform, and halogenated hydrocarbons such as 1,2-dichloroethane. Preferred solvents among these are halogenated hydrocarbons, especially dichloromethane.
  • the reaction is carried out at a temperature of ⁇ 40 ° C. to room temperature (preferably 0 ° C. to room temperature), and the reaction time varies depending mainly on the reaction temperature and the solvent, but is usually 0.1 to 4 hours (preferably 0.1 to 4 hours). 2 to 1 hour).
  • the sulfonic acid ester compound (16) in this step can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to a reaction mixture, washing with water, and distilling off the solvent.
  • Step D-3 is a step of producing a thiol ester compound (17) by reacting the sulfonic acid ester compound (16) with an alkali metal salt of thioic acid in an inert solvent.
  • the thioic acid used is represented by the formula! ⁇ ° ⁇ 31 "1 (wherein, R 1 G is as described above), and examples thereof include thioacetic acid and thiobenzoic acid. Is thioacetic acid.
  • the alkali metal salt of thioic acid is obtained by mixing thioic acid and an alkali metal hydride (preferably sodium hydride) such as lithium hydride, sodium hydride and potassium hydride in a 1: 1 mixture in a solvent.
  • an alkali metal hydride preferably sodium hydride
  • lithium hydride, sodium hydride and potassium hydride in a 1: 1 mixture in a solvent.
  • Examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, ethers such as tetrahydrofuran and dioxane, esters such as ethyl ethyl acetate, acetone, and methyl ethyl ketone. And non-protonic solvents such as ketones such as acetonitrile and nitriles such as acetonitrile, and amides (particularly dimethylformamide) are preferred.
  • amides such as dimethylformamide and dimethylacetamide
  • ethers such as tetrahydrofuran and dioxane
  • esters such as ethyl ethyl acetate, acetone, and methyl ethyl ketone.
  • non-protonic solvents such as ketones such as acetonitrile and nitriles such as acetonitrile, and amides (particularly dimethylformamide) are preferred.
  • the reaction is usually carried out at room temperature to 100 ° C. (preferably 30 ° C. to 50 ° C.).
  • the reaction time varies depending mainly on the reaction temperature, but is usually 30 minutes to 4 hours (preferably 1 to 4 hours) 2 hours).
  • the thiol ester compound (17) can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to a reaction mixture, washing with water, and distilling off the solvent.
  • Step D-4 is a step of subjecting the thiol ester compound (17) to a transesterification or hydrolysis reaction to produce a monothiol compound (2-2).
  • This step is achieved by allowing a base to act on the thiol ester compound (17) in a solvent.
  • a base examples include alkali metal alcoholates such as sodium methoxide and sodium ethoxide, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and preferably sodium methoxide. is there.
  • Examples of the solvent to be used include alcohols such as methanol and ethanol or water or a mixed solvent thereof, and preferably alcohols (particularly methanol).
  • the reaction is usually carried out at a temperature of ⁇ 30 ° C. to room temperature (preferably ⁇ 5 ° C. to 10 ° C.), and the reaction time is usually 0.1 to 2 hours (preferably 0.3 to 0.7 hours). ).
  • the monothiol compound (2-2) can be collected from the reaction mixture by a conventional method.
  • the reaction mixture is neutralized by adding an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid, and then an organic solvent that is immiscible with water is added, followed by washing with water and distilling off the solvent.
  • a mineral acid such as hydrochloric acid or sulfuric acid
  • the obtained thiol ester compound (2-2) is used without further purification in the acetalization reaction described in the above-mentioned Method A.
  • Method E is a method for producing a dithiol compound (2-3) which is a raw material compound of method A, and is represented by the following reaction formula.
  • a r R ⁇ R 2 , R 8 and R 1Q are as defined above.
  • the E-1 step is a method for producing a bissulfonic acid ester compound (18) by reacting an alcohol compound (2-1) with a sulfonylating agent.
  • This step can be achieved by the same method as in Step D-2, except that the sulfonylating agent is used at 2 molar equivalents relative to the alcohol compound (2-1).
  • Step E-2 is a step of reacting the bissulfonic acid ester compound (18) with an alkali metal salt of thioic acid to produce a bisthiol ester compound (19). This step can be achieved by the same method as in Step D-3.
  • step E-3 the bisthiol ester compound (19) is transesterified or added.
  • This is a process for producing a dithiol compound (2-3) by subjecting it to a water splitting reaction. This step can be achieved by the same method as in Step D-4.
  • Method F is a method for producing a compound having 2 or 3 of the aldehyde compound (3), which is the starting compound of Method A, and is represented by the following reaction formula.
  • This method involves reacting a commercially available (triphenylphosphoraylidene) acetoaldehyde with an aldehyde compound (3-1) having two fewer carbon atoms (ie, one less p) than the aldehyde compound (3).
  • Step F-1 the aldehyde compound (3-2), which has 4 fewer carbon atoms (that is, p is 2 less) than the aldehyde compound (3), is described in the literature (Te trahedron Let et. (P. 67 (1982)) by reacting (triphenylphosphoraylidene) crotonaldehyde (Step F-2) or by adding (triphenylphosphoranylidene) to the aldehyde compound (3-2). This is achieved by reacting acetoaldehyde with 2 molar equivalents (Step F-3).
  • the reaction solvent is not particularly limited as long as it does not disturb the reaction by dissolving the starting aldehyde compound and the phosphorane reagent to some extent, and includes, for example, benzene and toluene.
  • Aromatic hydrocarbons such as chlorobenzene, halogenated hydrocarbons such as 1,2-dichloroethane, methanol, ethanol, propano
  • Alcohols such as 2-propanol, nitriles such as acetonitrile, esters such as ethyl acetate, amides such as, N-dimethylformamide and N, N-dimethylacetamide , Sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxetane; ketones such as acetone and methylethyl ketone; water; and And is preferably an aromatic hydrocarbon (particularly toluene).
  • the reaction is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent (preferably from room temperature to 60 ° C), and the reaction time is usually from 1 to 24 hours (preferably from 1 to 5 hours).
  • the amount of the phosphorane reagent used in the reaction is usually 0.5 to 1.5 molar equivalents relative to the aldehyde compound (3-1) or (3-2) ( Preferably, it is 0.7 to 1.2 molar equivalent).
  • the F-3 step usually 1.5 to 5 molar equivalents (preferably 1.5 to 2.5 molar equivalents) to the aldehyde compound (3-1) or (3-2). is there.
  • the aldehyde compounds (3-1) and (3-2), which are the starting compounds for this reaction, can be produced by the method disclosed in JP-A-8-33350 or a method analogous thereto. It can also be produced by a carbon chain extension reaction similar to the method F using an aldehyde compound having a shorter carbon chain than the aldehyde compound as a starting compound.
  • the compounds of the present invention represented by the formula (1) and pharmacologically acceptable salts thereof exhibit excellent antifungal activity against various fungi and have low toxicity, so that they are useful as active ingredients of antifungal agents. is there.
  • the compound represented by the formula (1) and a pharmacologically acceptable salt thereof When used as an antifungal agent, they may be mixed with a pharmacologically acceptable excipient or diluent by itself or an appropriate pharmacologically acceptable salt. It can be administered orally, such as tablets, capsules, granules, powders or syrups, or parenterally, such as injections.
  • excipients eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylsenorellose, carboxymethylsenorellose, canoleboximetinolecellulose calcium, and internally cross-linked carboxymethylcellulose sodium; Dextran; pullulan; silicates such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate magnesium; phosphates such as calcium phosphate; carbonates such as calcium carbonate; calcium sulfate; , A binder (eg, the above-mentioned excipient; gelatin; polyvinylpyrrolidone; macrogol, etc.); a disintegrant (eg, the above-mentitol, suc
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 5 mg) and the upper limit is 200 mg (preferably 100 mg) per dose. in the case of the pulse administration is once per limit 0. l mg (preferably 0. 5 mg), against the upper 6 0 Omg (preferably, 5 0 0ni g) adults per day 1-6 It is desirable to administer according to the symptoms.
  • the reaction solution was added to 10 Oml of aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate.
  • the organic layer was washed with saturated saline, dried, and the solvent was distilled off.
  • the obtained oily residue was subjected to column chromatography using silica gel. Further The residue was eluted with a mixed solvent of ethyl acetate-hexane (3: 1) to give the title compound (322 mg, yield 71%) as a colorless oil.
  • the compound of (6) could also be synthesized by the following methods (7) to (10).
  • Example 1 In the same manner as (1 1), (4 S, 5R) -5 Phenolic phenol 1) 2- (hydroxymethyl) 14-methynole 6- (1H-1,2,4-1triazo-1-yl 1-yl) 1-1,5-hexanediol (2E, 4E) — 5 -— [4- (trifluoromethyl) phenyl] _ 2, 4-pentagenal obtained according to the method described in 8-33 33 50 To give the trans compound, the title compound, as a colorless oil in a yield of 72%, and the cis isomer as a colorless oil in a yield of 13%.
  • Example 1 (6S) or 1— (10) obtained from (4S, 5R) -5- (2,4-difluorophenyl) -12- (hydroxymethyl) 14-methyl-16- (1 H-1, 2, 4 _ triazono 1-inole)-1,5-hexanodiol 262mg (0.77 mmol) was dissolved in dichloromethane (3 ml), and triethylamine (174 mg, 1.72 mol) and methanesulfonyl chloride (192 mg, 1.68 ⁇ 01) were added under ice-cooling. After the mixture was stirred for 17 minutes under ice cooling, ethyl acetate and water were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 376 mg (yield 98%) of a crude product of the title compound as an amorphous solid.
  • IR spectrum vmax CHC1 3 cm— 1 1693, 1615, 1499, 1420, 1355, 1274, 1138, 1107, 965, 852.
  • Example 1 (4S, 5R) -5- (2,4-difluorene feninole) 1-2— (hydroxymethinole) 1-4-methinole-6— (1H) in the same manner as (1 1) -1,2,4-Triazo- 1-inole 1-, 5-hexanediol 20 Omg (0.59 mmol) and described in Reference Example 1 (E) —4 -— (trifluoromethylsulfonyl) By reacting with 232 mg (0.88 mmol) of cinnamaldehyde, 208 mg (yield 60%) of the title compound was obtained as an amorphous solid.
  • Example 1 In the same manner as in (11), (4S, 5R) -5- (2,4 difluorene phenyl) 1-2- (hydroxymethinole) 1-4-methyl-6- (1H-1 , 2,4-triazolyl-1-yl) 1-1,5-hexanediol 10 Omg (0.30 mmol) and described in Reference Example 3 (1E, 3E) —5— [4— ( 1 H—1,2,4-triazolyl-1-yl) phenyl] —1,3-pentagenal 98 mg (0.44 mmol) (1) -1 10-camphorsnolefonic acid The reaction was carried out in the presence of 223 mg (0.96 mmol) to give 9 Omg (yield 56%) of the title compound at a melting point of 94-96.5 ° C (recrystallization solvent: 2-propanol-hexane).
  • Example 11 (4S, 5R) -15- (2,4-difluoromethyl) 1-2- (hydroxymethyl) 1-methyl-16- (1H-) 1,2,4—triazolyl-11-yl) 1,1,5-hexanediol 1 48 mg (0.43 thigh ol) and 6-honolenominole 2-naphthalenecanolebonini trinole 9 described in Reference Example 4 5mg To give 98.6 mg (yield: 45%) of the trans isomer as a colorless crystalline powder having a melting point of 153 ° C (recrystallization solvent: toluene-l-xane). The cis isomer (71.9 mg, yield 33%) was obtained as an amorphous solid.
  • Example 11 In the same manner as in (1 1), (4S, 5R) -5- (2,4-difluoromethyl phenyl) -12- (hydroxymethynole) -14-methyl-16- (1H- 1,2,4_triazono 1-yl) 1,1,5-hexanediole 20 Omg (0 ⁇ 59) and described in Reference Example 5 (E) —3-Fluoro-4- [(E) —3 [Oxo-l-l-propenyl] benzonitrile was reacted with 138 mg (0.89 mol) to give 193 mg (66% yield) of the trans isomer, which was the title compound. 9 Omg of the isomer (31% yield) was obtained as an amorphous solid.
  • Example 1 In the same manner as in (1 1), (4S, 5R) -5- (2,4-difluoromethyl phenyl) 1-2- (hydroxymethinole) 14-methyl-16- (1H- 1, 2, 4 _triazole-11-yl) 1-1,5-hexanediole 20 Omg (0.59 mmol) and (E) — 2-fluoro-4— [(E) —3-oxo-1 2— described in Reference Example 6 [Propenyl] benzonitrile (153 mg, 0.85 mmol) was reacted to give 54 mg (19% yield) of the title compound and 57 mg (20% yield) of the cis isomer. Each was obtained as an amorphous solid.
  • Example 1 In the same manner as in Example 1 (1 1), (4 S, 5 R) — 5 — (2, 4 — difluoro feninole) 1-2 — (hydroxymethinole) 1-4 — methinole 6 — (1 H-1,2,4-triazol-1-yl) 1,1-hexanediol 200 mg and 2-fluoro-4-[(1E, 3E) -5-oxo1-1,3 described in Reference Example 7 [Pentadenyl] benzonitrile (175 mg) was reacted and treated to give 235 mg (77% yield) of the trans-isomer and 45 mg (14% yield) of the cis isomer, each of which was an amorphous solid. As obtained.
  • Example 1 (4S, 5R) -5- (2,4-difluorenol) 2- (hydroxymethinole) -4-methyl-1-6_ (1H) -1, 2, 4-Triazono 1-inole) 1,5-hexanediole 10 Omg (0.29 mmol) and commercially available 5-bromo-12-thiophene levanorehide 84 mg (0.44 mmol), (1) The reaction was carried out in the presence of 150 mg (0.66 mmol) of 10-camphorsulfonic acid to give 5 Omg (33%) of the title compound as an amorphous solid.
  • Example 1 (4S, 5R) -15— (2,4 difluorene phenyl) 1-2— (hydroxymethinole) 1-4—methinole 6— (1H—1) , 2,4-triazole-1-yl) 1-1,5-hexanediol 20 Omg (0.59 mmol) and (E) — 3- (3-quinolyl) 1-2-propena
  • 93 mg Yield 31%)
  • cis isomer 42 mg (yield 14%), each of which were colorless. Obtained as an oil.
  • (E) 14 [(E) — 3—oxo — 1-propionyl] benzonitrile (Mo 1. Cryst. Liq. Cryst, 123, 257, (1985) 1.00 g (6.4 mmol) and 1.93 g (6.3 ol) of (triphenylphosphoraylidene) acetoaldehyde were dissolved in 30 ml of toluene, and the mixture was heated at 85 ° C for 1 hour. The mixture was stirred for another hour, and further stirred at 105 ° C for one hour.
  • IR spectrum vmax KBr cm— 1 1713, 1695, 1605, 1591, 1520, 1443, 1277, 1207, 1153, 983, 838, 821, 674.
  • IR spectrum vmax KBr cm— 1 : 1700, 1627, 1603, 1522, 1276, 1236, 1180, 1138.
  • a mixture of commercially available dimethyl 2,6-naphthalenedicarboxylate (5.00 g, 20.5 ol), potassium carbonate (4.25 g, 30.8 ol), 1,4-dioxane (100 ml) and water (60 ml) was prepared. The mixture was stirred at 90 ° C for 5 hours. After cooling, 50 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered. The aqueous layer was separated from the filtrate, and adjusted to pH 2 by adding 2N hydrochloric acid.
  • the methyl 2,6-naphthalenedicarboxylate 4.08 g (17.7 mmol) described in (1) was treated with an excess of thiol chloride in pyridine by a conventional method, and concentrated under reduced pressure to obtain an acid chloride. I made it. This was suspended in 4 Oml of tetrahydrofuran, and 23 ml (354 mol) of a 29% aqueous ammonia solution was gradually added to the vigorously stirred under ice-cooling. After leaving the mixture at room temperature overnight, 5 Oml of tetrahydrofuran and 40 ml of dilute sodium hydrogencarbonate aqueous solution were added, and the tetrahydrofuran layer was separated.
  • the powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give 20 Omg tablets per tablet. These tablets can be sugar-coated if necessary.
  • this powder After mixing the powder of the above formulation and passing through a 60-mesh sieve, this powder is placed in a 250 mg No. 3 gelatin capsule to prepare a forcepsel.
  • the antifungal activity of the compounds was evaluated by the minimum inhibitory concentration (MIC) determined by the following method.
  • Measurement method for fungi such as Candida sp. (Journal of the Japanese Society for Medical Mycology, Vol. 36, p. 62 (1995)): Dissolve the test drug in dimethyl sulfoxide and add 3- (morpholino) propanesulfonic acid After dilution with buffer (pH 7.0) RPMI 1640 medium (Dainippon Pharmaceutical), 100 parts were dispensed into microplates. Colonies of the test fungi were suspended in physiological saline to prepare a viable count in LxlO 3 to 5xl0 3 CFU / ml in RPMI 1640 medium.
  • the bacterial solution was inoculated in a volume of 100 / l and cultured at 35 ° C for 24 hours, and the absorbance (630 nm) was measured to determine whether the bacteria had grown.
  • the minimum inhibitory concentration (MIC) was expressed as the minimum concentration that inhibited the growth of bacteria to 20% or less compared to the control without drug.
  • test drug is dissolved in dimethinolesuloxide and 3- (morpholino) propane After dilution with a sulfonic acid buffer (pH 7.0) RPMI 1640 medium, the mixture was dispensed into microplates at 100 ⁇ . Collected spores on potato dextrose agar of the test bacteria with physiological saline, the suspension was allowed to stand to remove the precipitate, prepared spore count of about 2xl0 4 CFU / ml in RPMI 1640 medium (manufactured by Dainippon Pharmaceutical) did.
  • a sulfonic acid buffer pH 7.0
  • the bacterial solution was inoculated in an amount of 100 ⁇ l each, and cultured at 35 ° C. for 24 hours. Then, bacterial growth was visually determined.
  • the minimum inhibitory concentration (MIC) was expressed as the minimum concentration that inhibited the growth of bacteria to 25% or less compared to the control without drug. The lower the MIC value of a compound, the stronger the antifungal activity.
  • Table 2 shows the result of comparing the compound (1) of the present invention with the compound disclosed in JP-A-8-333550.
  • Example 3 of the present invention showed superior antifungal activity as compared with the compound disclosed as Example 15 in JP-A-8-33350.
  • This result indicates that, as shown by the general formula (1), the compound of the present invention in which the 4-position is a CH 2 — group has superior antifungal activity as compared with the compound in which the 4-position is S (sulfur atom) It shows that it has.
  • Candida albicans (Candida albicans SANK 10569) 4 X 1 0 6 to 9 X 1 0 6 or mice inoculated with (1 group 1 0 rats), the inoculation 1, after 4 and 24 hours, their respective agents S OmgZk g Was orally administered, and the survival rate was examined on days 14 and 21 after inoculation of the bacteria.
  • Table 3 shows the results of comparison between the compounds of Examples 1 to 5 of the present invention and commercially available fluconazole. [Table 3] Compound viability on dioxane ring (%)
  • the present invention relates to a general formula having excellent antifungal activity.
  • a r 2 is an optionally substituted phenyl group, a naphthyl group, 5- or 6-membered heteroaromatic ⁇ like;
  • R 1 And R 2 are a hydrogen atom or a lower alkyl group;
  • P is 0, 1, 2 or 3;
  • q is 0, 1 or 2;
  • r is 0, 1 or 2;
  • a pharmacologically acceptable salt thereof a composition for preventing or treating fungal infections containing them as an active ingredient, and a medicament for preventing or treating fungal infections.
  • Ar 1 represents a phenyl group or a phenyl group having 1 to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group);

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Abstract

L'invention a trait à des composés, représentés par la formule générale (I) suivante, faisant montre d'une remarquable activité antifongique ou à leurs sels, acceptables du point de vue pharmaceutique. Elle concerne également des compositions visant au traitement ou à la prévention d'infections d'origine fongique et contenant les composés précités en tant qu'ingrédient actif. Elle porte, en outre, sur l'utilisation de ces composés pour la production de médicaments agissant de façon curative et préventive sur des infections d'origine fongique ainsi que sur des méthodes thérapeutiques et prophylactiques en relation avec ce type d'infection, lesquelles méthodes consistent à administrer une dose efficace du point de vue pharmacologique de ces composés à des animaux à sang chaud.
PCT/JP1998/003034 1997-07-08 1998-07-06 Composes antifongiques a base de triazole WO1999002524A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000582A1 (fr) * 1999-06-24 2001-01-04 Abbott Laboratories Preparation de derives de carbonate et de carbamate a substitution quinoline
EP1083175A3 (fr) * 1999-09-09 2001-04-11 Sankyo Company Limited Dérivés de triazole à activité antifongique
WO2001072743A1 (fr) * 2000-03-27 2001-10-04 Sankyo Company, Limited Composes triazoles possedant une liaison amide
WO2002040472A1 (fr) * 2000-11-16 2002-05-23 Sankyo Company, Limited Fongicides à base de carbamoyl-triazoles
US6713455B2 (en) 2001-09-17 2004-03-30 Ortho-Mcneil Pharmaceutical, Inc. 6-O-carbamate-11,12-lacto-ketolide antimicrobials
WO2004026862A1 (fr) * 2002-09-20 2004-04-01 Sankyo Company, Limited Compose hydrosoluble de triazole
CZ297383B6 (cs) * 1999-09-09 2006-11-15 Sankyo Company Limited Deriváty triazolu s protiplísnovými úcinky
US9783508B2 (en) 2012-08-07 2017-10-10 Basilea Pharmaceutica Ag Process for the manufacture of isavuconazole or ravuconazole

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08333350A (ja) * 1995-04-06 1996-12-17 Sankyo Co Ltd トリアゾール抗真菌剤
JPH10158167A (ja) * 1996-10-04 1998-06-16 Sankyo Co Ltd トリアゾール誘導体を含有する医薬

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08333350A (ja) * 1995-04-06 1996-12-17 Sankyo Co Ltd トリアゾール抗真菌剤
JPH10158167A (ja) * 1996-10-04 1998-06-16 Sankyo Co Ltd トリアゾール誘導体を含有する医薬

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6417366B2 (en) 1999-06-24 2002-07-09 Abbott Laboratories Preparation of quinoline-substituted carbonate and carbamate derivatives
JP4724337B2 (ja) * 1999-06-24 2011-07-13 アボット・ラボラトリーズ キノリン置換カルボネート及びカルバメート誘導体の調製
CN100355734C (zh) * 1999-06-24 2007-12-19 艾博特公司 喹啉取代的碳酸酯和氨基甲酸酯衍生物
US6579986B2 (en) 1999-06-24 2003-06-17 Abbott Laboratories Preparation of quinoline-substituted carbonate and carbamate derivatives
WO2001000582A1 (fr) * 1999-06-24 2001-01-04 Abbott Laboratories Preparation de derives de carbonate et de carbamate a substitution quinoline
JP2003503388A (ja) * 1999-06-24 2003-01-28 アボット・ラボラトリーズ キノリン置換カルボネート及びカルバメート誘導体の調製
US6392082B1 (en) 1999-09-09 2002-05-21 Sankyo Company, Limited Triazole derivatives having antifungal activity
US6391903B1 (en) 1999-09-09 2002-05-21 Sankyo Company, Limited Triazole derivatives having antifungal activity
US6337403B1 (en) 1999-09-09 2002-01-08 Sankyo Company, Limited Triazole derivatives having antifungal activity
AU778073B2 (en) * 1999-09-09 2004-11-11 Sankyo Company Limited Triazole derivatives having antifugal activity
CZ297383B6 (cs) * 1999-09-09 2006-11-15 Sankyo Company Limited Deriváty triazolu s protiplísnovými úcinky
EP1083175A3 (fr) * 1999-09-09 2001-04-11 Sankyo Company Limited Dérivés de triazole à activité antifongique
RU2232761C2 (ru) * 2000-03-27 2004-07-20 Санкио Компани, Лимитед Производные триазола амидного типа, фармацевтическая композиция на их основе и способ профилактики или лечения
WO2001072743A1 (fr) * 2000-03-27 2001-10-04 Sankyo Company, Limited Composes triazoles possedant une liaison amide
WO2002040472A1 (fr) * 2000-11-16 2002-05-23 Sankyo Company, Limited Fongicides à base de carbamoyl-triazoles
US6713455B2 (en) 2001-09-17 2004-03-30 Ortho-Mcneil Pharmaceutical, Inc. 6-O-carbamate-11,12-lacto-ketolide antimicrobials
WO2004026862A1 (fr) * 2002-09-20 2004-04-01 Sankyo Company, Limited Compose hydrosoluble de triazole
US9783508B2 (en) 2012-08-07 2017-10-10 Basilea Pharmaceutica Ag Process for the manufacture of isavuconazole or ravuconazole
US10590092B2 (en) 2012-08-07 2020-03-17 Basilea Pharmaceutica Ag Process for the manufacture of isavuconazole or ravuconazole

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