WO2009119858A1 - Benzene compound, and use thereof for medical purposes - Google Patents

Benzene compound, and use thereof for medical purposes Download PDF

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Publication number
WO2009119858A1
WO2009119858A1 PCT/JP2009/056400 JP2009056400W WO2009119858A1 WO 2009119858 A1 WO2009119858 A1 WO 2009119858A1 JP 2009056400 W JP2009056400 W JP 2009056400W WO 2009119858 A1 WO2009119858 A1 WO 2009119858A1
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carbon atoms
atom
atoms
iii
pharmaceutically acceptable
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PCT/JP2009/056400
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French (fr)
Japanese (ja)
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薫 田代
正壽 城内
真以子 濱田
邦夫 菅原
弘 坂下
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田辺三菱製薬株式会社
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Definitions

  • the present invention relates to a benzene compound and its use as a medicine.
  • Patent Documents 1 to 3 describe 2-aminopropane useful as an inhibitor of (acute or chronic) rejection in organ or bone marrow transplantation, and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases.
  • a 1,3-diol compound is disclosed.
  • FTY720 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride
  • FTY720-P 2-amino-2-phosphoryloxymethyl-4- (4-octylphenyl) butanol
  • FTY720-P includes four types of S1P receptors (hereinafter also referred to as S1P1 to 5) among five types of sphingosine-1-phosphate (hereinafter also referred to as S1P) receptors (hereinafter also referred to as S1P1 to 5, respectively). It acts as an agonist (other than S1P2) (Non-patent Document 1). Recently, it was reported that S1P1 in the S1P receptor is essential for the export of mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an S1P1 agonist, thereby down-regulating S1P1 on lymphocytes.
  • Non-Patent Document 2 the conventional 2-aminopropane-1,3-diol compound is concerned about the occurrence of transient bradycardia as a side effect, and in order to solve this problem, 2-aminopropane-1,3-diol Many novel compounds obtained by chemical structural modification of diol compounds have been reported.
  • Patent Document 4 is an aminopropanol derivative as a S1P receptor modulator with a phosphate group
  • Patent Documents 5 and 6 are both S1P acceptors.
  • aminopropanol derivatives as body regulators are disclosed, trihaloalkyl groups such as trifluoromethyl groups are not disclosed as substituents on the benzene ring.
  • Patent Document 7 discloses that the bradycardia of a compound in which the substituent on the benzene ring of FTY720 is a trihaloalkyl group or a cyano group is weak.
  • those compounds disclosed therein contain only alkyloxy or alkylthio having 6 to 9 carbon atoms as substituents on the benzene ring bonded to the ortho position of the trihaloalkyl group or cyano group, A compound having a substituent in the alkyl group or a compound having an unsaturated bond in the alkyl group is not shown.
  • An object of the present invention is to provide a novel benzene compound which is excellent in immunosuppressive action, rejection reaction inhibitory action and the like and has reduced side effects such as bradycardia.
  • the gist of the present invention is as follows. [1] The following general formula (II-1) or (II-2)
  • R II-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R II-2 is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, or an alkyl having 1 to 4 carbon atoms which may be substituted with any of halogen atoms
  • R II-3 is a hydrogen atom or alkyl having 1 to 4 carbon atoms
  • a II-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a II-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms.
  • the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
  • b a halogen atom.
  • c a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
  • d a double bond and a triple bond at the chain end.
  • Y II-2 is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons
  • a II-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom.
  • a II-2 is a hydrogen atom, P ( ⁇ O) (OH) 2 , O—P ( ⁇ O) (OH) 2 , COOH, SO 3 H, 1H-tetrazol-5-yl, OH, or 1 to 4 alkoxy
  • XII is an oxygen atom or a sulfur atom
  • Y II-1 represents CH 2 CH 2 or CH ⁇ CH
  • Z II represents a single bond or alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms.
  • R I is a hydrogen atom or P ( ⁇ O) (OH) 2
  • X I is an oxygen atom or a sulfur atom
  • Y I is CH 2 CH 2 or CH ⁇ CH
  • R I-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R I-2 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom
  • R I-3 and R I-4 may be the same or different, and each represents a hydrogen atom or alkyl having 1 to 4 carbon atoms
  • a I represents a straight alkyl having 5 to 9 carbon atoms
  • a I represents It has 1 to 6 functional groups selected from any of the following four groups a to d.
  • R III-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R III-2 is a hydrogen atom or P ( ⁇ O) (OH) 2
  • a III-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a III-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
  • b a halogen atom.
  • Y III-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms
  • a III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom.
  • a III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms
  • B III represents an alkyl having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group, or may be substituted with a halogen atom
  • R IV-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R IV-2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, acyl having 1 to 20 carbon atoms, alkoxycarbonyl having 2 to 21 carbon atoms, or a substituent capable of leaving in vivo
  • R IV-3 is a hydrogen atom, P ( ⁇ O) (OH) 2 or P ( ⁇ O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 are phosphoric acid groups A protecting group or a substituent that is eliminated in vivo).
  • R IV-4 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom
  • a IV-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a IV-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
  • b a halogen atom.
  • Y IV is alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms
  • a IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom.
  • XIV represents an oxygen atom or a sulfur atom.
  • R V-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • XV is a single bond, Oxygen atom, Sulfur atom, -SO-, -SO 2- , Carbonyl, —NR V-2 —
  • R V-2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or an alkyl having 1 to 7 carbon atoms which may have a substituent.
  • Acyl or C2-C7 alkoxycarbonyl or the following general formula
  • R V-3 has an optionally substituted alkyl having 1 to 20 carbon atoms, an optionally substituted alkenyl having 2 to 20 carbon atoms, and a substituent. Or a alkynyl group having 2 to 20 carbon atoms or an alkoxy group having 1 to 20 carbon atoms which may have a substituent.
  • a V is a hydrogen atom, Optionally substituted alkyl having 1 to 20 carbon atoms ⁇ double bond, triple bond, oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR V-4 —
  • R V-4 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, an acyl having 1 to 7 carbon atoms which may have a substituent, or 2 to 7 carbon atoms.
  • a ring containing one nitrogen atom, oxygen atom or sulfur atom as a constituent atom of the ring It may have a heterocycloalkylene having 3 to 7 member atoms, and may have a double bond, a triple bond or a substituent at the chain end.
  • Heteroaryl having a number of 5 to 10 or a hetero atom having 3 to 7 ring atoms containing 1 to 2 optionally substituted nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms May have cycloalkyl ⁇ , Aryl having 6 to 10 carbon atoms which may have a substituent, A cycloalkyl having 3 to 7 carbon atoms which may have a substituent, A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as a ring constituting atom, or a substituent Or a heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, V V represents a single bond or an alkylene having 1 to 6 carbon atoms which may have a substituent, Y V is a single bond, oxygen atom, sulfur atom, —CO
  • V V represents an optionally substituted alkylene having 1 to 6 carbon atoms
  • Y V may be a double bond or a triple bond
  • n V is 0-3, provided that n V when Y V is a double bond or triple bond represents a 1-3
  • Z V is an alkylene having 1 to 6 carbon atoms which may have a substituent
  • An optionally substituted heteroarylene having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, or having a substituent; also good 1-2 nitrogen atoms, heterocycloalkylene of constituting atoms is 3 to 7 rings containing an oxygen atom or a sulfur atom as
  • B V is a hydrogen atom
  • Cyano, —CO—NH—SO 2 —R V-9 (where R V-9 is an alkyl having 1 to 6 carbon atoms which may have a substituent, and 6 to 6 carbon atoms which may have a substituent) 10 aryls, optionally substituted cycloalkyl having 3 to 7 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms
  • a ring containing 5 to 10 heteroaryl atoms or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 ring atoms Represents a heterocycloalkyl of ⁇ 7), OH or the following formula
  • Y II-1 is CH 2 CH 2 in the general formula (II-1) or (II-2), or A pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  • a II-1 is straight-chain alkyl having 5 to 9 carbon atoms
  • a II-3 is an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted 1 to 2 sulfur atom or oxygen atom as a ring constituting atom, 9.
  • a II-3 represents the following general formula
  • R II-4 and R II-5 may be the same or different and each is a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom, An alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a halogen atom is shown.
  • a pharmaceutically acceptable acid addition salt thereof, or a hydrate or a solvate thereof may be shown.
  • Z II is a single bond or alkyl having 1 to 4 carbon atoms. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  • R I-3 and R I-4 are both hydrogen atoms in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Or solvate.
  • a III-1 is a linear alkyl having 5 to 9 carbon atoms, or A III-3 in general formula (III-2) is substituted.
  • the above [3] which is a good aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 9 ring atoms containing 1 to 2 optionally substituted sulfur atoms or oxygen atoms as ring constituting atoms Or the compound according to any one of [24], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  • the number of substituents is 1 to 3, and each substituent is the same or different.
  • a III-3 represents the following general formula
  • R III-3 and R III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom.
  • Y III-2 is trimethylene in general formula (III-2), or a pharmaceutically acceptable acid addition salt thereof Or a hydrate or solvate thereof.
  • X III-2 is methine
  • B III is bound to A III-2
  • Y III-1 , X III-2 , A III- 2 the compound according to any one of the above [3] or [24] to [29], wherein the carbon atom to which B III and the amino group are bonded forms cyclopentyl, or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
  • X III-2 is a nitrogen atom
  • Y III-1 is C ⁇ O
  • B III is a hydrogen atom or methyl.
  • a IV-1 is a linear alkyl having 5 to 9 carbon atoms
  • a IV-2 may be substituted aryl having 6 to 10 carbon atoms or optionally substituted 1 or 2 sulfur atoms or oxygen atoms as ring constituent atoms.
  • the number of substituents is 1 to 3, and each substituent is the same or different.
  • a IV-2 represents the following general formula
  • R IV-7 and R IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom.
  • a pharmaceutically acceptable compound thereof, or a pharmaceutically acceptable compound thereof according to any one of the above [4] or [34] to [36] which is a group represented by the following formula: Acid addition salts, or hydrates or solvates thereof.
  • Y IV is trimethylene in the general formula (IV-2), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
  • R IV-2 is a hydrogen atom
  • R IV-3 is P ( ⁇ O) (OR IV-5 ) (OR IV-6 )
  • R IV-5 and R IV-6 represent a substituent that is eliminated in vivo.
  • B v is COOR v-6 , P ( ⁇ O) (OR v ⁇ 7 ) (OR v ⁇ 8 ), O—P ( ⁇ O) (OR v ⁇ 7 ) ( OR v-8 ) or OH, or a pharmaceutically acceptable salt or hydrate or solvate thereof.
  • Y v is a single bond, —NR v-5 —, —NR v-5 CO— or —CONR v-5 —. Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • Z v represents an alkylene having 1 to 6 carbon atoms which may have a substituent, an arylene having 6 to 10 carbon atoms which may have a substituent, or a substituent.
  • X v is a single bond, an oxygen atom, a sulfur atom, carbonyl, or —NR v-2 —, or any one of the above [5] or [42] to [46] A compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • Phosphoric acid mono ⁇ [1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl ⁇ ester, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese, j. 2- ⁇ [4-heptyloxy-3- (trifluoromethyl) benzyl] amino ⁇ ethanol, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, k. Phosphoric acid mono (2- ⁇ [4-heptyloxy-3- (trifluoromethyl) benzyl] amino ⁇ ethyl) ester, or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof, l.
  • a pharmaceutical composition comprising a compound according to any of [1] to [48] above and a pharmaceutically acceptable carrier.
  • autoimmune disease Treatment or prevention of autoimmune disease; resistance to organ or tissue transplantation or prevention or suppression of acute or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; and / or The pharmaceutical composition according to the above [49], which is used for treatment or prevention of allergic diseases.
  • the pharmaceutical composition according to the above [50] wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis and / or type I diabetes.
  • the allergic disease is atopic dermatitis, allergic rhinitis and / or asthma.
  • the compound of the present invention has the following general formula (I)
  • R I is a hydrogen atom or P ( ⁇ O) (OH) 2
  • X I is an oxygen atom or a sulfur atom
  • Y I is CH 2 CH 2 or CH ⁇ CH
  • R I-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R I-2 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom
  • R I-3 and R I-4 may be the same or different and are each a hydrogen atom or an alkyl having 1 to 4 carbon atoms
  • a I represents straight-chain alkyl having 5 to 9 carbon atoms
  • a I has 1 to 6 functional groups selected from any of the following four groups a to d.
  • alkyl having 1 to 6 carbon atoms When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms.
  • b a halogen atom.
  • c a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
  • d double bond and triple bond at the chain end. Indicates.
  • R II-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R II-2 is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, or an alkyl having 1 to 4 carbon atoms which may be substituted with any of halogen atoms
  • R II-3 is a hydrogen atom or alkyl having 1 to 4 carbon atoms
  • a II-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a II-1 may have 1 to 6 functional groups selected from any of the following four groups a to d (a, alkyl having 1 to 6 carbon atoms; the same carbon atom) When two alkyl groups are substituted, the two alkyl groups and the carbon atom to which they are bonded can form a cycloalkyl having 3 to 6 carbon atoms.
  • Y II-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms
  • a II-3 is an optionally substituted aryl having 6 to 10 carbon atoms, or an optionally substituted 1 to 2 nitrogen atom, oxygen atom or sulfur atom as a ring constituting atom.
  • a II-2 is a hydrogen atom or P ( ⁇ O) (OH) 2 , O—P ( ⁇ O) (OH) 2 , COOH, SO 3 H, 1H-tetrazol-5-yl, OH, or 1 to 4 alkoxy
  • XII is an oxygen atom or a sulfur atom
  • Y II-1 is CH 2 CH 2 or CH ⁇ CH
  • Z II represents a single bond or alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms.
  • R III-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R III-2 is a hydrogen atom or P ( ⁇ O) (OH) 2
  • a III-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a III-1 may have 1 to 6 functional groups selected from any of the following four groups a to d (a, alkyl having 1 to 6 carbon atoms; the same carbon atom) When two alkyl groups are substituted, the two alkyl groups and the carbon atom to which they are bonded can form a cycloalkyl having 3 to 6 carbon atoms.
  • b a halogen atom.
  • Y III-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms
  • a III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom.
  • a III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms
  • B III represents a C 1-4 alkyl which may be substituted with a hydrogen atom or a hydroxyl group, or may be substituted with a halogen atom
  • B III is bonded to A III-2, and Y III-1 , X III-2 , A III-2 , B III and a cycloalkane having 4 to 7 membered carbon atoms to which the amino group is bonded, or a ring
  • a heterocycloalkane containing one nitrogen atom having 4 to 7 constituent atoms may be
  • R IV-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • R IV-2 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, acyl having 1 to 20 carbon atoms or alkoxycarbonyl having 2 to 21 carbon atoms, or a substituent capable of leaving in vivo
  • R IV-3 is a hydrogen atom, P ( ⁇ O) (OH) 2 or P ( ⁇ O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 are phosphoric acid groups A protecting group or a substituent that is eliminated in vivo).
  • R IV-4 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom
  • a IV-1 represents straight-chain alkyl having 5 to 9 carbon atoms
  • a IV-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
  • b a halogen atom.
  • Y IV represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms
  • a IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted 1 to 2 nitrogen atom, oxygen atom or sulfur atom as a ring constituting atom.
  • R V-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom
  • XV is a single bond, Oxygen atom, Sulfur atom, -SO-, -SO 2- , Carbonyl, —NR V-2 —
  • R V-2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or an alkyl having 1 to 7 carbon atoms which may have a substituent.
  • Acyl or C2-C7 alkoxycarbonyl or the following general formula
  • R V-3 has an optionally substituted alkyl having 1 to 20 carbon atoms, an optionally substituted alkenyl having 2 to 20 carbon atoms, and a substituent. Or a alkynyl group having 2 to 20 carbon atoms or an alkoxy group having 1 to 20 carbon atoms which may have a substituent.
  • a V is a hydrogen atom, Optionally substituted alkyl having 1 to 20 carbon atoms ⁇ double bond, triple bond, oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR V-4 —
  • R V-4 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, an acyl having 1 to 7 carbon atoms which may have a substituent, or 2 to 7 carbon atoms.
  • a ring containing one nitrogen atom, oxygen atom or sulfur atom as a constituent atom of the ring It may have a heterocycloalkylene having 3 to 7 member atoms, and may have a double bond, a triple bond or a substituent at the chain end.
  • Heteroaryl having a number of 5 to 10 or a hetero atom having 3 to 7 ring atoms containing 1 to 2 optionally substituted nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms May have cycloalkyl ⁇ , Aryl having 6 to 10 carbon atoms which may have a substituent, A cycloalkyl having 3 to 7 carbon atoms which may have a substituent, A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as a ring constituting atom, or a substituent Or a heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, V V represents a single bond or an alkylene having 1 to 6 carbon atoms which may have a substituent, Y V is a single bond, oxygen atom, sulfur atom, —CO
  • V V represents an optionally substituted alkylene having 1 to 6 carbon atoms
  • Y V may be a double bond or a triple bond
  • n V is 0-3, provided that n V when Y V is a double bond or triple bond represents a 1-3
  • Z V is an alkylene having 1 to 6 carbon atoms which may have a substituent
  • An optionally substituted heteroarylene having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, or having a substituent; also good 1-2 nitrogen atoms, heterocycloalkylene of constituting atoms is 3 to 7 rings containing an oxygen atom or a sulfur atom as
  • B V is a hydrogen atom
  • Cyano, —CO—NH—SO 2 —R V-9 (where R V-9 is an alkyl having 1 to 6 carbon atoms which may have a substituent, and 6 to 6 carbon atoms which may have a substituent) 10 aryls, optionally substituted cycloalkyl having 3 to 7 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms
  • a ring containing 5 to 10 heteroaryl atoms or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 ring atoms Represents a heterocycloalkyl of ⁇ 7), OH or the following formula
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the alkyl having 1 to 3 carbon atoms means a linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl and the like.
  • the alkyl having 1 to 4 carbon atoms means straight or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl.
  • tertiary butyl hereinafter, “tertiary” may be expressed as t- or tert-).
  • the alkyl having 1 to 6 carbon atoms means straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl. And tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl and the like.
  • the straight-chain alkyl having 5 to 9 carbon atoms is n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl.
  • the alkyl having 1 to 20 carbons means straight or branched alkyl having 1 to 20 carbons, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl Tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. Can be mentioned.
  • cycloalkyl having 3 to 6 carbon atoms examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl having 3 to 7 carbon atoms examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Examples of a 4- to 7-membered cycloalkane and a heterocycloalkane containing one nitrogen atom having 4 to 7 member atoms include cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, A homopiperidine etc. can be mentioned.
  • the alkyl having 1 to 4 carbon atoms substituted with a halogen atom and the alkyl having 1 to 4 carbon atoms when substituted with a halogen atom are the above halogen atoms having 1 to 5 carbon atoms having 1 to 4 carbon atoms.
  • fluororoisopropyl, difluoroisopropyl, fluoro n-butyl, trifluoro n-butyl, pentafluoro n-butyl, etc. some or all of the fluorine atoms of the substituents exemplified here are substituted with other halogen atoms. Can be mentioned.
  • the alkyl having 1 to 4 carbon atoms in the case of being substituted with a hydroxyl group means the above-mentioned alkyl having 1 to 4 carbon atoms substituted with a hydroxyl group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy Hydroxyethyl, dihydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, hydroxyisopropyl, dihydroxyisopropyl, hydroxybutyl, dihydroxybutyl and the like can be mentioned.
  • the alkenyl having 2 to 20 carbon atoms means straight or branched alkenyl having 2 to 20 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl.
  • the alkynyl having 2 to 20 carbon atoms means a straight chain or branched alkynyl having 2 to 20 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl.
  • the alkoxy having 1 to 4 carbon atoms means a straight or branched alkoxy having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, t-butoxy and the like can be mentioned.
  • the alkyl having 1 to 4 carbon atoms substituted by alkoxy having 1 to 4 carbon atoms is the above-mentioned alkoxy having 1 to 4 carbon atoms described above.
  • alkyls examples include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, n-propoxyethyl, isobutoxypropyl, t-butoxybutyl and the like.
  • the alkoxy having 1 to 20 carbon atoms means a straight or branched alkoxy having 1 to 20 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, t-butoxy, pentyloxy, isopentyloxy, tertiary pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy Hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icodecyloxy and the like.
  • Acyl having 1 to 7 carbons means alkanoyl or aroyl having 1 to 7 carbons, and alkanoyl is a linear or branched alkanoyl having 1 to 7 carbons such as formyl, acetyl, Examples include propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like. Examples of aroyl include benzoyl.
  • Acyl having 1 to 20 carbons means alkanoyl or aroyl having 1 to 20 carbons, and alkanoyl is a carbonyl bonded to a hydrogen atom or a linear or branched alkyl having 1 to 19 carbons.
  • alkanoyl is a carbonyl bonded to a hydrogen atom or a linear or branched alkyl having 1 to 19 carbons.
  • formyl, acetyl, propionyl, myristoyl, palmitoyl, stearoyl and the like can be mentioned, and examples of aroyl include benzoyl and naphthoyl.
  • the C2-C7 alkoxycarbonyl is a linear or branched alkoxy having 1-6 carbon atoms bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n -Butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • the alkoxycarbonyl having 2 to 21 carbon atoms is a straight chain or branched alkoxy having 1 to 20 carbon atoms bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, Examples thereof include t-butoxycarbonyl, heptyloxycarbonyl, decyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl and the like.
  • the substituent that RIV -2 is eliminated in vivo is a substituent that is chemically or enzymatically eliminated after the compound is administered or absorbed in vivo, and specifically includes acetyl, benzoyl N-acylglycyl, acyloxyacetyl, glycyl, alanyl, vanillyl and the like.
  • a I , A II-1 , A III-1 , A IV-1 is substituted with alkyl having 1 to 6 carbon atoms
  • a I , A II-1 , A III-1 , A IV-1 Specific examples include methyl n-pentyl, methyl n-hexyl, methyl n-heptyl, ethyl n-heptyl, propyl n-heptyl, dimethyl n-heptyl, methyl n-octyl, ethyl n-octyl, dimethyl n- Examples include octyl, methyl n-nonyl, ethyl n-nonyl, dimethyl n-nonyl and the like.
  • a I , A II-1 , A III-1 , A IV-1 are substituted by two alkyl groups having 1 to 6 carbon atoms bonded to the same carbon, and these two alkyl groups are bonded to each other When the carbon atom forms a cycloalkyl having 3 to 6 carbon atoms, specific examples of A I , A II-1 , A III-1 , A IV-1 include 5- (1-methylcyclo Propan-1-yl) pentyl, 3- (1-propylcyclopropan-1-yl) propyl, 1-hexylcyclopropan-1-yl, 1-hexylcyclobutan-1-yl, 4- (1-ethylcyclopentane) -1-yl) butyl, 3- (1-methylcyclohexane-1-yl) propyl and the like.
  • a I , A II-1 , A III-1 , A IV-1 is substituted with a halogen atom
  • specific examples of A I , A II-1 , A III-1 , A IV-1 Is 5-fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, trifluoro n-pentyl, trifluoro n-hexyl, trifluoro n-heptyl, trifluoro n-octyl , Trifluoro n-nonyl, pentafluoro n-pentyl, pentafluoro n-hexyl, pentafluoro n-heptyl, pentafluoro n-octyl, pentafluoro n-nonyl, 1-fluoroheptyl, 2-fluoroheptyl, 3-fluoro
  • a II-1 , A III-1 , A IV-1 has a double bond, triple bond, or cycloalkyl having 3 to 6 carbon atoms in the chain or at the chain end
  • a II-1 , A III-1 and A IV-1 include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-hexynyl, n-heptynyl, n-octynyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, 2-pentylcyclopropan-1-yl, (2-butylcyclopropan-1-yl) methyl, (2-ethylcyclopropan-1-yl) propyl, 3- (3-methylcyclohexane-1-yl) propyl, 4- (4-methylcycl
  • aryl having 6 to 10 carbon atoms examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • Heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms is pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl , Thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl and the like.
  • Examples of the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • Examples of the cycloalkyl having 3 to 7 carbon atoms optionally condensed with benzene include 1,2,3,4-tetrahydronaphthyl, indanyl, 6,7,8,9-tetrahydro-5H-benzocycloheptyl and the like. Can be mentioned.
  • heterocycloalkyl having 5 to 7 ring atoms containing 1 to 2 nitrogen atoms or oxygen atoms as ring atoms include piperidyl, piperazinyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl and the like. be able to.
  • heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms is, for example, aziridyl, azetidyl, piperidyl, piperazinyl, pyrrolidinyl, morpholyl, Mention may be made of thiomorpholyl, tetrahydrofuryl, tetrahydropyranyl and the like.
  • the alkylene having 1 or 2 carbon atoms is methylene or ethylene.
  • alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms include, for example, methylene, ethylene, trimethylene, tetramethylene, propylene, cyclopropylene, fluoromethylene, difluoromethylene, fluoroethylene, difluoroethylene , Fluorotrimethylene, difluorotrimethylene, fluorotetramethylene, difluorotetramethylene and the like.
  • alkylene having 1 to 5 carbon atoms examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propylene, ethylethylene, methyltrimethylene, dimethyltrimethylene, cyclopropylidene, cyclopropylene, (cyclopropylidene) ethylene, And cyclopropylene-methylene.
  • the alkylene having 1 to 6 carbon atoms means linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene, etc. Can be mentioned.
  • alkenylene having 2 to 5 carbon atoms examples include vinylene, propenylene, butenylene, pentenylene, methylvinylene, dimethylvinylene, ethylvinylene, methylpropenylene, dimethylpropenylene and the like.
  • alkynylene having 2 to 5 carbon atoms examples include ethynylene, propynylene, butynylene, pentynylene, methylpropynylene, dimethylpropynylene and the like.
  • arylene having 6 to 10 carbon atoms examples include phenylene and naphthylene.
  • cycloalkylene having 3 to 7 carbon atoms examples include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and the like.
  • Heteroarylene having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 ring atoms is pyrrolylene, imidazolylene, pyrazolylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene, furylene , Thienylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, indoleylene, isoindolylene, indolizinylene, indazolylene, benzofurylene, benzothienylene, quinolylene, isoquinolylene and the like.
  • Heterocycloalkylene having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms is, for example, aziridylene, azetidylene, piperidylene, piperazinylene, pyrrolidinylene, morpholinylene, Mention may be made of thiomorpholinylene, tetrahydrofurylene, tetrahydropyranylene and the like.
  • Aryl having 6 to 10 carbon atoms “Heteroaryl having 5 to 10 ring atoms including 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms”, “3 to 3 carbon atoms”
  • the number of substituents that the “7 cycloalkyl” and the “heterocycloalkyl having 5 to 7 ring atoms containing 1 to 2 nitrogen atoms or oxygen atoms as ring atoms” may have 1 to 5, preferably 1 or 2.
  • substituents examples include alkyl having 1 to 4 carbon atoms which may be substituted with the aforementioned halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; Alkylthio; alkylsulfinyl having 1 to 4 carbon atoms; alkylsulfonyl having 1 to 4 carbon atoms; alkylcarbonyl having 2 to 5 carbon atoms; halogen atom as described above; cyano; nitro; cycloalkyl having 3 to 7 carbon atoms as described above An aryl having 6 to 10 carbon atoms as described above; an aralkyloxy having 7 to 14 carbon atoms; and an aryloxy having 6 to 10 carbon atoms; and two of them substituted together with an oxo or halogen atom; Alkylene having 3 to 4 carbon atoms which may be substituted; alkyleneoxy having 2 to 3 carbon atoms which may be substituted with oxo or
  • the alkoxy having 1 to 4 carbon atoms in the case of being substituted with a halogen atom means that the aforementioned alkoxy having 1 to 4 carbon atoms is substituted with 1 to 5 halogen atoms, such as fluoromethoxy, Difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, pentafluoroethoxy, difluoro n-propoxy, trifluoro n-propoxy, fluoroisopropoxy, trifluoroisopropoxy, difluoro n-butoxy, trifluoro n-butoxy, etc.
  • Other examples include those in which some or all of the fluorine atoms of the substituents exemplified here are substituted with other halogen atoms.
  • the alkylthio having 1 to 4 carbon atoms, the alkylsulfinyl having 1 to 4 carbon atoms, and the alkylsulfonyl having 1 to 4 carbon atoms are each composed of the above-described alkyl having 1 to 4 carbon atoms. , Methylthio, ethylthio, propylthio, methanesulfinyl, methanesulfonyl and the like.
  • the alkylcarbonyl having 2 to 5 carbon atoms is a compound in which the alkyl moiety is bonded to the alkyl having 1 to 4 carbon atoms described above, and examples thereof include methylcarbonyl and ethylcarbonyl.
  • Aralkyloxy having 7 to 14 carbon atoms refers to alkoxy having 1 to 4 carbon atoms described above substituted with aryl having 6 to 10 carbon atoms as described above.
  • benzyloxy, phenethyloxy, naphthylmethoxy, naphthyl Ethoxy and the like can be mentioned.
  • the aryloxy having 6 to 10 carbon atoms is a compound in which an oxygen atom is bonded to the aforementioned aryl having 6 to 10 carbon atoms, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • alkylene having 3 to 4 carbon atoms examples include trimethylene, tetramethylene, methyltrimethylene and the like.
  • the alkylene having 3 to 4 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the alkylene having 3 to 4 carbon atoms described above are substituted with halogen atoms.
  • alkyleneoxy having 2 to 3 carbon atoms examples include ethyleneoxy, trimethyleneoxy, propyleneoxy and the like.
  • alkyleneoxy having 2 to 3 carbon atoms is, for example, —O—C ( ⁇ O) —CH 2 —, —C ( ⁇ O) —CH 2 —O—, —O—.
  • C ( ⁇ O) —CH 2 —CH 2 —, —C ( ⁇ O) —CH 2 —CH 2 —O—, —O—CH 2 —C ( ⁇ O) —CH 2 —, —CH 2 —C ( ⁇ O) —CH 2 —O— and the like can be mentioned.
  • the alkyleneoxy having 2 to 3 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the alkyleneoxy having 2 to 3 carbon atoms described above are substituted with a halogen atom.
  • alkylenedioxy having 1 to 2 carbon atoms examples include methylenedioxy and ethylenedioxy.
  • the alkylenedioxy having 1 to 2 carbon atoms when substituted with oxo includes, for example, —O—C ( ⁇ O) —O—, —O—CH 2 —C ( ⁇ O) —O— and the like. Can be mentioned.
  • the alkylenedioxy having 1 to 2 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the aforementioned alkylenedioxy having 1 to 2 carbon atoms are substituted with halogen atoms. is there.
  • Examples of the optionally substituted benzene that may be condensed with an optionally substituted cycloalkyl having 3 to 7 carbon atoms include unsubstituted benzene, benzene substituted with a halogen atom, and a hydroxyl group. Examples thereof include benzene, benzene substituted with an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, and benzene substituted with alkoxy having 1 to 4 carbon atoms.
  • the protecting groups for the phosphate groups of R IV-5 , R IV-6 , R V-7 and R V-8 are alkyl such as methyl, ethyl and t-butyl, substituted ethyl such as cyanoethyl and pyridylethyl, benzyl And aralkyl such as phenyl, phenylamino and the like.
  • R IV-5 , R IV-6 , R V-7, and R V-8 are the substituents that are eliminated in vivo, and are chemically or enzymatically desorbed after the compound is administered or absorbed in vivo.
  • Specific examples include alkyl such as isopropyl, t-butyl, hexadecyl and octadecyl, alkyloxyalkyl such as hexadecyloxypropyl and octadecyloxyethyl, and acyloxyalkyl such as pivaloyloxymethyl.
  • Alkyloxycarbonyloxyalkyl such as methoxycarbonyloxymethyl and isopropoxycarbonyloxymethyl
  • S-acylthioethyl such as acetylthioethyl and pivaloylthioethyl
  • substituted phenyl substituted benzyl, or the following formula
  • R ′ represents a side chain of a natural amino acid such as glycine, alanine, valine, R ′′ represents a hydrogen atom, or alkyl having 1 to 4 carbon atoms
  • P ( O) (OR IV-5 ) (OR IV-6 )
  • P ( O) (OR V-7 ) (OR V-8 )
  • Such a structure can also be formed.
  • the phenyl group may be further substituted.
  • R V-6 is eliminated in vivo is a substituent that is chemically or enzymatically eliminated after the compound is administered or absorbed in vivo, and specifically includes methyl, ethyl, and the like.
  • Alkyl such as isopropyl, t-butyl, acyloxyalkyl such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, etc.
  • alkoxycarbonyloxyalkyl alkoxycarbonyloxyalkyl.
  • the substituent is not particularly limited, and examples thereof include the substituents exemplified below.
  • Alkyl having 1 to 20 carbon atoms which may be substituted alkenyl having 2 to 20 carbon atoms which may be substituted, alkynyl having 2 to 20 carbon atoms which may be substituted, carbon number which may be substituted 1 to 20 alkylidene, optionally substituted cyclic group, oxo, hydroxyl group, optionally substituted alkoxy having 1 to 20 carbon atoms, optionally substituted alkenyloxy having 2 to 20 carbon atoms, substituted Optionally substituted alkynyloxy having 2 to 20 carbon atoms, optionally substituted alkylthio having 1 to 20 carbon atoms, optionally substituted alkenylthio having 2 to 20 carbon atoms, optionally substituted carbon number Alkynylthio having 2 to 20 carbon atoms,
  • substitutable positions may be substituted at any substitutable position by any number of substitutable positions.
  • substituents include the same ones as described above, and they may be substituted at any substitutable position by any number that can be substituted. .
  • the alkylidene having 1 to 20 carbon atoms means a linear or branched alkylidene having 1 to 20 carbon atoms.
  • the alkenyloxy having 2 to 20 carbon atoms means a straight chain or branched alkenyloxy having 1 to 20 carbon atoms, such as ethenyloxy, n-propenyloxy, isopropenyloxy, n-butenyloxy, isobutenyl.
  • the alkynyloxy having 2 to 20 carbon atoms means linear or branched alkynyloxy having 1 to 20 carbon atoms, such as ethynyloxy, n-propynyloxy, isopropynyloxy, n-butynyloxy, isobutynyl Nyloxy, secondary butynyloxy, t-butynyloxy, pentynyloxy, isopentynyloxy, tertiary pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy, dodecynyloxy, tridecynyloxy, tetradecyl Examples include nyloxy, pentadecynyloxy, hexadecynyloxy, heptadecynyloxy,
  • the alkylthio having 1 to 20 carbon atoms, the alkylsulfinyl having 1 to 20 carbon atoms, and the alkylsulfonyl having 1 to 20 carbon atoms are each composed of the above-described alkyl having 1 to 20 carbon atoms, , Methylthio, ethylthio, propylthio, pentylthio, decylthio, pentadecylthio, icosylthio, methanesulfinyl, decylsulfinyl, icosylsulfinyl, methanesulfonyl, decylsulfonyl, icosylsulfonyl and the like.
  • the alkenylthio having 2 to 20 carbon atoms, the alkenylsulfinyl having 2 to 20 carbon atoms, and the alkenylsulfonyl having 2 to 20 carbon atoms are configured such that each alkenyl part is the alkenyl having 2 to 20 carbon atoms described above, For example, ethenylthio, propenylthio, pentenylthio, decenylthio, pentadecenylthio, icocenylthio, ethenylsulfinyl, decenylsulfinyl, icocenylsulfinyl, ethenylsulfonyl, decenylsulfonyl, icocenylsulfonyl, etc. Can do.
  • each alkynyl moiety is composed of the alkynyl having 2 to 20 carbon atoms described above, Examples include ethynylthio, propynylthio, pentynylthio, decynylthio, pentadecynylthio, icosinylthio, ethynylsulfinyl, decynylsulfinyl, icosinylsulfinyl, ethynylsulfonyl, decynylsulfonyl, icosinylsulfonyl and the like.
  • alkoxycarbonyl having 2 to 20 carbon atoms the acyl having 1 to 20 carbon atoms, the aralkyloxy having 7 to 14 carbon atoms and the aryloxy having 6 to 10 carbon atoms are as described above.
  • cyclic group in the “optionally substituted cyclic group” means “carbocycle” or “heterocycle” and includes, for example, aryl having 6 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, A heteroaryl having 5 to 10 ring atoms containing 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms Heterocycles having 3 to 7 atoms in the ring included as aryl, including aryls having 6 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms.
  • Heteroaryl having 5 to 10 ring atoms as ring atoms, hetero ring having 3 to 7 rings having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms Cycloalkyl is The same meanings as defined above.
  • R 1 is a hydrogen atom
  • P ( ⁇ O) (OH) 2 Preferred examples of X I include an oxygen atom
  • preferred examples of Y I include CH 2 CH 2 .
  • Preferable examples of Y 1 include CH 2 CH 2 .
  • Preferred examples of R I-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyano. More preferable examples include trifluoromethyl and cyano. An even more preferred example is fluoromethyl.
  • R I-2 examples include methyl, ethyl, hydroxymethyl, hydroxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl, and more preferred. Examples include methyl, ethyl, and hydroxymethyl, and more preferable examples include hydroxymethyl.
  • Preferable examples of R I-3 and R I-4 are the same or different and include a hydrogen atom, methyl, and ethyl, and more preferable examples include a hydrogen atom.
  • straight-chain alkyl having a carbon number of 5-8 has a functional group, as a more preferred example, include one or two alkyl of 1 carbon atoms
  • Straight chain alkyl having 7 or 8 carbon atoms straight chain alkyl having 1 to 5 halogen atoms, straight chain alkyl having 6 to 8 carbon atoms, or a double bond in one chain 7 straight chain alkyls, 1 or 7 straight chain alkyls with 7 chain ends, or 7 straight chain chains with 1 chain end triple bonds Mention may be made of alkyl.
  • a I is a straight-chain alkyl having 5 to 9 carbon atoms, following a one of the functional groups (a in ⁇ d, alkyl having 1 to 6 carbon atoms. b, a fluorine atom. c, a double bond or a triple bond in the chain. d, double bond and triple bond at the chain end. )
  • a I more specifically, 1-methylheptyl, 2-methylheptyl, 6-methylheptyl, 3,7-dimethyl octyl, 4,4,5,5,5-pentafluoro-pentyl, 6 -Fluorohexyl, 8-fluorooctyl, 2-heptenyl, 4-heptenyl, 6-heptenyl, 7-octenyl, 2-heptynyl, or 3-heptynyl, and more preferred examples include 6-methylheptyl, Mention may be made of 3,7-dimethyloctyl, 8-fluorooctyl or 7-octenyl.
  • Preferred examples of the group represented by the general formula (II-1) are shown below.
  • Preferred examples of X II can be exemplified an oxygen atom.
  • Preferable examples of Y II-1 include CH 2 CH 2 .
  • Preferred examples of R II-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and more preferred examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
  • a preferred example of R II-3 is a hydrogen atom.
  • R II-2 examples include methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. More preferred examples include methyl, ethyl, hydroxymethyl and methoxyethyl, and more preferred examples include hydroxymethyl.
  • Preferred examples of A II-2 include a hydrogen atom, P ( ⁇ O) (OH) 2 , O—P ( ⁇ O) (OH) 2 or COOH, and another preferred example includes OH. be able to.
  • P ( ⁇ O) (OH) 2 , O—P ( ⁇ O) (OH) 2 , and OH can be given as more preferable examples.
  • Preferable examples of Z II include a single bond or alkylene having 1 to 4 carbon atoms, and more preferable examples include a single bond, methylene and dimethylene.
  • a II-1 include linear alkyl having 5 to 9 carbon atoms (eg, 5, 6, 7 or 8) which may have a functional group, and more preferred examples include 1 or 2 linear alkyl having 7 or 8 carbon atoms which may have 1 alkyl, 1 or 2 carbon atoms which may have 1 or 5 halogen atoms, 6 or 7 Or a straight alkyl having 8 carbon atoms, a straight chain alkyl having 7 carbon atoms which may have one double bond in the chain, and a 7 carbon atom having 1 triple bond in the chain.
  • Straight chain alkyl straight chain alkyl having 6 or 7 carbon atoms that may have one double bond at the chain end, straight chain of 7 carbon atoms that may have one triple bond at the chain end
  • a straight chain alkyl having 5 to 9 carbon atoms can be mentioned as a more preferable example.
  • a II-1 include n-heptyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 6-methylheptyl, 1-ethylheptyl, 3,7-dimethyloctyl, 4,4,5,5,5-pentafluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 5-hexenyl, 1-heptenyl, 4-heptenyl, 6-heptenyl, 7-octenyl, 2 Mention may be made of -heptynyl, 4-heptynyl or 6-heptynyl.
  • Preferred examples of the group represented by the general formula (II-2) are shown below.
  • Preferred examples of Y II-2 include trimethylene or propenylene, trimethylene or the following general formula
  • a group shown in the above is a more preferable example, and trimethylene is an even more preferable example.
  • Preferred examples of A II-3 include a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Mention may be made of heteroaryl having 5 to 9 atoms. As a more preferred example of A II-3 , when it is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom.
  • R II-4 and R II-5 may be the same or different and each is a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom, An alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a halogen atom is shown. ) The group represented by these can be mentioned.
  • Preferred examples of the substituent when A II-3 has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom, List chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C ( ⁇ O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferable examples include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, and difluoromethylenedioxy.
  • Bets can be, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom. More specifically, preferred examples of A II-3 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl. Preferred examples of X II , Y II-1 , R II-1 , R II-3 , R II-2 , A II-2 and Z II are the same as the groups shown in the general formula (II-1). Can be mentioned.
  • a preferred example of R III-2 is a hydrogen atom.
  • a preferred example of X III-1 is an oxygen atom.
  • Preferred examples of R III-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and more preferred examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
  • Y III-1 is preferably methylene, and both A III-2 and B III are preferably alkyl having 1 to 3 carbon atoms.
  • X III-2 is methine
  • B III is bound to A III-2 , Y III-1 , X III-2 , A III-2 , B III and an amino group are bound. It is preferred that the carbon atom is cyclopentyl.
  • X III-2 is methine
  • more preferred examples of Y III-1 , A III-2 and B III are
  • Y III-1 is preferably C ⁇ O and B III is preferably a hydrogen atom or methyl.
  • B III is preferably a hydrogen atom or methyl.
  • a III-1 include linear alkyl having 5 to 9 carbon atoms, and n-heptyl and n-octyl can be further preferable examples.
  • Preferred examples of the group represented by the general formula (III-2) are shown below.
  • Preferred examples of Y III-2 include trimethylene or propenylene, trimethylene or the following general formula
  • a group shown in the above is a more preferable example, and trimethylene is an even more preferable example.
  • Preferred examples of A III-3 include a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Heteroaryl having 5 to 9 atoms can be mentioned, and phenyl which may be substituted can be mentioned as a more preferable example.
  • the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom.
  • R III-3 and R III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a group having a carbon number of 1-4 or a halogen atom.
  • Preferred examples of the substituent when A III-3 further has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom , Chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C ( ⁇ O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluoride
  • R III-2 , X III-1 , R III-1 , X III-2 , Y III-1 , A III-2 , B III include groups represented by the above general formula (III-1) The same group can be mentioned.
  • Preferred examples of the group represented by the general formula (IV-1) are shown below.
  • Preferred examples of X IV can be mentioned oxygen atom.
  • Preferable examples of R IV-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and trifluoromethyl or cyano can be more preferable examples.
  • An even more preferred example is fluoromethyl.
  • Preferred examples of R IV-2 include a hydrogen atom or acyl having 1 to 20 carbon atoms.
  • a preferred example of R IV-3 when R IV-2 is a substituent capable of leaving in vivo includes a hydrogen atom.
  • R IV-3 when R IV-2 is acyl having 1 to 20 carbons or alkoxycarbonyl having 2 to 21 carbons include a hydrogen atom.
  • Preferred examples of R IV-3 when R IV-2 is a hydrogen atom include P ( ⁇ O) (OR IV-5 ) (OR IV-6 ), (R IV-5 and R IV-6 A protective group for a phosphate group or a substituent that is eliminated in vivo).
  • Preferable examples of R IV-5 and R IV-6 are the same or different and include hexadecyl, pivaloyloxymethyl, isopropoxycarbonyloxymethyl, acetylthioethyl, and phenyl.
  • Preferable examples of A IV-1 include linear alkyl having 5 to 9 carbon atoms, and more preferable examples include n-heptyl and n-octyl.
  • Preferred examples of the group represented by the general formula (IV-2) are shown below.
  • Preferred examples of X IV, R IV-1, R IV-2, R IV-3, R IV-4, and Y IV include the same groups as those in the general formula (IV-1).
  • Preferred examples of Y IV include trimethylene or propenylene, and trimethylene or the following general formula
  • a preferred example of A IV-2 is a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Heteroaryl having 5 to 9 atoms can be mentioned, and phenyl which may be substituted can be mentioned as a more preferable example.
  • the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom.
  • R IV-7 and R IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a group having a carbon number of 1-4 or a halogen atom.
  • Preferred examples of the substituent when A IV-2 further has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom , Chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C ( ⁇ O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluoride
  • a IV-2 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.
  • B V examples include a hydrogen atom, COOR V-6 (where R V-6 is as defined above), P ( ⁇ O) (OH) 2 , O—P ( ⁇ O). (OH) 2 , cyano, CO—NH—SO 2 —R V-9 (where R V-9 is as defined above), OH, or the following formula
  • B V COOR v-6 , P ( ⁇ O) (OR v-7 ) (OR v-8 ), OP ( ⁇ O) (OR v-7 ) (OR v-8 ) ), OH.
  • V V include a single bond and optionally substituted alkylene having 1 to 6 carbon atoms.
  • a single bond, methylene, dimethylene, propylene, and 3,3-hydroxymethylpropylene can be used. Furthermore, it can mention as a more preferable example.
  • Preferred examples of Y V, a single bond, -NR V-5 -, - NR V-5 CO -, - CONR V-5 - may be mentioned, as preferred examples, a single bond, -NH- , —N (CH 3 ) —, —N (CH 2 CH 3 ) —, —NHCO— (wherein the group represented by R V-5 (eg, methyl, ethyl) is Zv A ring may be formed together with atoms on the group represented by the following formula :), and a single bond or —NH— can be further preferred examples.
  • Preferred examples of n V is 0 or 1, can be mentioned as more preferred example 1.
  • Z V is have alkylene good having 1 to 6 carbon atoms which may have a substituent, an arylene good 6 to 10 carbon atoms which may have a substituent, or a substituent
  • the heterocycloalkylene having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as the ring constituting atoms may be mentioned as another preferred example.
  • R V-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano. More preferable examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
  • Preferred examples of X V, a single bond, an oxygen atom, a sulfur atom, a carbonyl, -NR V-2 - can be exemplified, it can be exemplified an oxygen atom as a more preferable example.
  • Preferred examples of A V is in the chain or the chain ends, be mentioned alkyl optionally 1 carbon atoms of a good linear or branched substituted to phenyl and 1-8 have a substituent Can do.
  • Preferred examples of the substituent that the “optionally substituted phenyl” has include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, fluorine atom, A chlorine atom, a bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy can be mentioned.
  • Examples of the pharmaceutically acceptable acid addition salt of the compound of the present invention include inorganic acid salts and organic acid salts.
  • solvate of the compound of the present invention examples include solvates with water, ethanol, ethyl acetate and the like.
  • the compounds of the present invention include the above general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2) and In addition to the compound (V) and pharmaceutically acceptable acid addition salts and hydrates and solvates thereof, geometrical isomers, optically active isomers and tautomers thereof are also included.
  • Synthesis method of the compound of the present invention examples include the following methods.
  • R I , R I-3 and R I-4 in the general formula (I) are all represented by a hydrogen atom, X I is an oxygen atom, and Y I is represented by —CH 2 CH 2 —.
  • Compound (II-1) is synthesized according to the following scheme (I-II).
  • R I-1 , R I-2 and A I have the same meanings as those in the general formula (I), R I a , R I b , R I c are protecting groups, and X I a is a leaving group.
  • the leaving group, X I b represents a leaving group or a hydroxyl group, and PB I represents a leaving group containing phosphorus.
  • R I a in the formula is not particularly limited as long as it protects the phenolic hydroxyl group.
  • alkyl specifically methyl, ethyl etc.
  • aralkyl benzyl etc.
  • R I b in the formula is not particularly limited as long as it protects the hydroxyl group.
  • an acyl preferably having about 2 to 4 carbon atoms, specifically acetyl, etc.
  • a trialkylsilyl specifically trimethylsilyl, etc.
  • a benzyl or a substituent that forms an acetal compound specifically methoxy) Methyl, tetrahydropyranyl, etc.
  • R I-2 has a hydroxyl group
  • the hydroxyl group may be protected with a suitable protecting group, and specific examples of the protecting group R I d include the same groups as R I b .
  • R I b and R I d can be bonded to form a cyclic acetal.
  • the protecting group represented by R I c in the formula is not particularly limited as long as it protects the amino group.
  • acyl preferably having about 2 to 4 carbon atoms, specifically acetyl etc.
  • carbamate specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.
  • the leaving group represented by X I a is eliminated during the reaction between the intermediate (I-II-1) and the phosphorus compound and does not inhibit the reaction during the subsequent reaction with the aldehyde (I-II-3). If there is no particular limitation.
  • halogen atoms specifically iodine atom, bromine atom, chlorine atom, etc.
  • methanesulfonyloxy, toluenesulfonyloxy and the like can be mentioned.
  • X I b represents a leaving group
  • the leaving group is not particularly limited as long as it is eliminated when alkylating a phenolic hydroxyl group and does not inhibit the reaction.
  • a halogen atom specifically an iodine atom, a bromine atom, a chlorine atom, etc.
  • the like can be mentioned.
  • a compound (I-II-1) having a leaving group X I a synthesized by a known method (WO 2007/069712, pages 23 to 28) is reacted with a phosphorus compound to remove phosphorus.
  • an intermediate (I-II-2) having a leaving group PB I is obtained.
  • PB I is triarylphosphonium
  • intermediate (I-II-2) can be obtained by reacting compound (I-II-1) with triarylphosphine. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene.
  • the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration.
  • PB I is P (O) (OR I e ) 2
  • intermediate (I-II-2) can be obtained by Arbuzov reaction of compound (I-II-1) and phosphite triester.
  • the reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours.
  • the desired product can be obtained by distilling off or distilling excess phosphorous acid triester.
  • the intermediate (I-II-2) is compounded with compound (I-II-1) in the presence of an additive such as tetraalkylammonium or cesium carbonate. It can also be obtained by reacting a phosphonic acid diester.
  • the reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is an intermediate containing phosphorus (I-II-2) and a known method (for example, Tetrahedron, Vol. 57 (2001), pages 6531-6538, Journal of Organic Chemistry. ) Condensation of aldehyde (I-II-3) synthesized according to Volume 69 (2004) 7765-7768), followed by reduction of the resulting olefin, followed by deprotection of protecting group R I a To obtain a phenolic intermediate (I-II-4). If PB I is triarylphosphonium, the conditions of normal Wittig reaction are used.
  • a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at ⁇ 30 ° C. to reflux for about 30 minutes to 12 hours.
  • the Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB I is P (O) of the (OR I e) 2, the conditions of normal Horner-Wadsworth-Emmons reaction are used.
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C. to reflux for about 30 minutes to 12 hours.
  • Olefin can preferentially obtain E form.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction.
  • a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)).
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound.
  • R I a is methyl, it can be used in a methylene chloride solvent.
  • acyl such as acetyl, methoxymethyl or tetrahydropyranyl
  • benzyl R I a hydrogenolysis, such as substituted benzyl, or benzyloxymethyl, a protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R I a is above double bonds It can also be performed simultaneously with the reduction of
  • the third step is to alkylate the phenolic hydroxyl group of intermediate (I-II-4) using intermediate (I-II-5) and X I b -A I , followed by R I b , R I c And when R I-2 has a hydroxyl group, the protecting group R I d protecting it is deprotected to obtain the compound (II-1) of the present invention.
  • Intermediates (I-II-5) used for alkylation include commercially available halides and alcohols, those obtained by halogen-exchange of halides, those obtained by exchanging hydroxyl groups of alcohols with leaving groups X I b , and commercially available carboxylic acids. Alcohol or the like obtained by reducing can be used.
  • bromoalkyl alcohol is fluorinated with a generally known fluorinating reagent to form a fluoroalkyl alcohol, and then the alcohol moiety is converted to a leaving group X I b by a generally known method.
  • a generally known fluorinating reagent to form a fluoroalkyl alcohol
  • the alcohol moiety is converted to a leaving group X I b by a generally known method.
  • Examples include I b —A I , or alcohol A I —OH obtained by reducing the corresponding carboxylic acid or the like.
  • a reagent used for alkylating the phenolic hydroxyl group of intermediate (I-I-4) when X I b represents a leaving group, intermediate (I-II-5) and potassium carbonate or hydrogenated
  • inorganic bases such as sodium
  • the reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours.
  • a polar solvent such as N, N-dimethylformamide
  • an ether solvent such as tetrahydrofuran
  • X I b represents a hydroxyl group
  • the alkylation of the phenolic hydroxyl group of the intermediate (I-II-4) can be carried out by using a phosphine compound such as triphenylphosphine and an azodicarboxylic acid derivative such as azodicarboxylic acid diisopropyl ester. Mitsunobu reaction using can also be used.
  • the reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C.
  • R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid.
  • the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • an alcoholic solvent such as ethanol
  • an ether solvent such as tetrahydrofuran
  • water or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • the first step is to protect the compound (II-2) in which R I in the general formula (I) is a hydrogen atom and R I-2 is ⁇ -hydroxyalkyl, whereby the oxazoline compound (I-III-1) is protected. ).
  • the reaction can be carried out using orthoacetate as a reagent in a polar solvent such as acetonitrile or N, N-dimethylformamide, a halogen solvent such as methylene chloride, or a hydrocarbon solvent such as toluene.
  • a base such as N, N-diisopropylethylamine or an acid such as p-toluenesulfonic acid can be added.
  • the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is to synthesize fluoride (I-III-2) by fluorinating the hydroxyl group of compound (I-III-1).
  • the fluorinating agent include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI).
  • DAST diethylaminosulfur trifluoride
  • DFI 2,2-difluoro-1,3-dimethylimidazolidine
  • the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane.
  • the reaction conditions include ⁇ 78 ° C. to room temperature for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • This step can also be performed by a method in which a fluoride ion is allowed to act after converting the hydroxyl group of compound (I-III-1) to the corresponding sulfonate form.
  • a fluoride ion is allowed to act after converting the hydroxyl group of compound (I-III-1) to the corresponding sulfonate form.
  • a fluoride ion is allowed to act after converting the hydroxyl group of compound (I-III-1) to the corresponding sulfonate form.
  • TBAF tetrabutylammonium fluoride
  • the third step is to prepare the compound (II-3) of the present invention by deprotecting the compound (I-III-2).
  • This step can be performed using a normal deprotection reaction. Specifically, it can be performed using an acid such as hydrochloric acid or trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol or a mixed solvent thereof and water at room temperature to 100 ° C. for about 30 minutes to 12 hours.
  • the reaction solution can be purified by a conventional method to obtain the desired product.
  • R I , R I-3 , and R I-4 are all hydrogen atoms, and A I has 5 carbon atoms that do not have a triple bond functional group as a functional group in the chain or at the chain end.
  • a compound (II-4) in which ⁇ 9 alkyl and R I-1 is trifluoromethyl or cyano is synthesized by the following scheme (I-IV).
  • R I-1 ′ is trifluoromethyl or cyano
  • a I ′ is alkyl having 5 to 9 carbon atoms and having no triple bond functional group as a functional group in the chain or at the chain end
  • R I b , R I c represents a protecting group
  • X I c and X I d represent a leaving group
  • R I-2 , X I and Y I have the same meanings as those in the general formula (I).
  • R I b and R I c in the formula are as defined above.
  • the leaving group represented by X I c is not particularly limited as long as it can be activated and removed by a catalyst during the Sonogashira reaction.
  • a halogen atom preferably an iodine atom, a bromine atom, etc.
  • trifluoromethanesulfonyloxy and the like can be mentioned.
  • the leaving group represented by X I d is not particularly limited as long as it is eliminated during the substitution reaction with alkoxide or thiol anion.
  • a halogen atom specifically a fluorine atom, etc.
  • toluenesulfonyloxy and the like can be mentioned.
  • the first step is a reaction for obtaining an intermediate (I-IV-3) by condensation of the compound (I-IV-1) having a leaving group X I d and the compound (I-IV-2).
  • This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran.
  • a base an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used.
  • Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is a method known from intermediate (I-IV-3) and intermediate (I-II-3) (eg, Tetrahedron, Vol. 57 (2001), pages 6531 to 6538, Chemical and Fur.
  • An intermediate (I-IV-4) synthesized by Chemical and Pharmaceutical Bulletin Vol. 53 (2005) pp. 100-102) is condensed by the Sonogashira reaction to form an intermediate containing a triple bond ( This is a reaction to obtain I-IV-5).
  • the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II).
  • organic bases such as triethylamine, inorganic bases such as ammonia, copper compounds such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl
  • additives such as phosphine compounds.
  • the reaction conditions include ice-cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the third step is a reaction in which the triple bond of intermediate (I-IV-5) is reduced to obtain intermediate (I-IV-6).
  • the reagent used when Y I is —CH 2 CH 2 — and A I ′ is an alkyl having 5 to 9 carbon atoms which does not contain a double bond in the chain or at the chain end, may be used for the usual reduction of unsaturated carbon bonds.
  • a homogeneous catalyst such as a heterogeneous catalyst rhodium complex (such as chlorotris (triphenylphosphine) rhodium (I)) such as palladium carbon, Raney nickel, palladium carbon ethylenediamine complex was used.
  • Catalytic hydrogenation can be mentioned.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the reaction used when Y I is —CH ⁇ CH— or A I ′ is a carbon 5-9 alkyl having a double bond functional group includes a Lindlar catalyst, a nickel-graphite-ethylenediamine complex, a diene compound, Examples thereof include catalytic hydrogenation performed in the presence of a catalyst whose activity is controlled, such as various complexes of phosphine compounds and rhodium. It is also possible to use a reduction reaction with a metal hydride such as diisobutylaluminum hydride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the fourth step is a reaction for obtaining the compound (II-4) of the present invention by deprotecting the intermediate (II-IV-6).
  • R I b , R I c and R I-2 have a hydroxyl group
  • the deprotection of the protecting group R I d protecting it is not particularly limited as long as it is used for deprotecting a normal protecting group. All the protecting groups can be deprotected at once or stepwise.
  • R I b and R I d are bonded to form a cyclic acetal, when R I c is t- butyloxycarbonyl group, by catalytic amount of acid deprotection of the cyclic acetal, stronger then acidic conditions R I c can be deprotected by using.
  • the conditions used for the deprotection of the acetal at this time include a catalytic amount of hydrochloric acid or toluenesulfonic acid in an alcoholic solvent such as methanol, or a mixed solution of an alcoholic solvent and another organic solvent. Examples include about 30 minutes to 12 hours at ° C.
  • the deprotection conditions for R I c carried out following the deprotection of acetal include an inorganic acid such as hydrochloric acid, trifluoroacetic acid or the like in an equivalent amount or more, an alcoholic solvent such as ethanol, or an ether solvent such as tetrahydrofuran. , Water, or a mixed solvent thereof for about 10 minutes to 12 hours at 80 ° C. under ice-cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R I , R I-3 and R I-4 are all hydrogen atoms
  • X I is a sulfur atom
  • Y I is —CH 2 CH 2 —
  • a I is in the chain or at the chain end.
  • the compound (II-5) represented by alkyl having 5 to 9 carbon atoms which does not have a double bond or triple bond functional group as a functional group is synthesized by the following scheme (IV).
  • R I f a hydrogen atom or a protecting group
  • R I b, R I c is a protecting group
  • X I a, X I e is a leaving group
  • PB I represents a leaving group containing phosphorus
  • R I-1 and R I-2 are the symbols in general formula (I) and Synonymous.
  • R I b , R I c , X I a , and PB I are as defined above.
  • R I f in the formula is not particularly limited as long as it protects a hydrogen atom or a carboxyl group.
  • alkyl specifically methyl, ethyl etc.
  • aralkyl benzyl etc.
  • the leaving group represented by X I e is not particularly limited as long as it is eliminated during the substitution reaction with alkylthioion A I ′′ S — .
  • a halogen atom specifically a fluorine atom, etc.
  • toluenesulfonyloxy and the like can be mentioned.
  • an alkylthio group is introduced at the 4-position by condensation of a benzoic acid derivative (IV-1) having a leaving group X I e at the 4-position with a thiol (IV-2), and an intermediate ( Reaction to obtain IV-3).
  • This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran.
  • a base an inorganic base such as potassium carbonate or sodium hydride, or an organic base such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene can be used.
  • the reaction conditions include about ⁇ 30 to 80 ° C. and about 10 minutes to 10 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is a reaction in which the carboxyl group of the intermediate (IV-3) is reduced to obtain the intermediate (IV-4) having a hydroxyl group.
  • the reagent used for the reduction is not particularly limited as long as it is usually used, but alkali metals such as sodium and alkaline earth metals, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and hydrogenation. Examples thereof include metal hydrogen complex compounds such as sodium boron, boron compounds such as diborane, and catalytic hydrogenation using a homogeneous or heterogeneous catalyst.
  • a temperature and time appropriate for the reducing reagent to be used are selected.
  • Specific examples include reduction in diborane, lithium aluminum hydride, lithium borohydride, alcohol solvent such as ethanol or alcohol, which is carried out at ⁇ 30 ° C. to reflux for 10 minutes to 12 hours in an ether solvent such as tetrahydrofuran.
  • Examples thereof include reduction with sodium borohydride or calcium borohydride, which is carried out in a mixed solvent of a system solvent and an ether solvent such as tetrahydrofuran for about 30 minutes to 24 hours under ice-cooling to reflux. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the third step is a reaction to convert the hydroxyl group of intermediate (I-V-4) to the leaving group X I a.
  • the reagent is not particularly limited as long as it is a reagent capable of converting an alcoholic hydroxyl group into X I a .
  • Reagents used when X I a is halogen include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride and combinations of these with reaction aids such as triphenylphosphine, base, hydrochloric acid, hydrobromic acid, iodide Examples thereof include inorganic acids such as hydrogen acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, thionyl halide, ⁇ -haloenamine and the like.
  • reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at ⁇ 30 ° C. to 130 ° C. for about 10 minutes to 6 hours.
  • an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at ⁇ 30 ° C. to 130 ° C. for about 10 minutes to 6 hours.
  • an inorganic acid a two-phase reaction of an aqueous solution or an organic solvent such as toluene and water can be performed.
  • a reagent used when X I a is a sulfonyloxy group a combination of a sulfonyl chloride such as methanesulfonyl chloride or toluenesulfonyl chloride and an organic base such as triethylamine or pyridine is used.
  • the reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at ⁇ 30 ° C. to 50 ° C. for about 5 minutes to 3 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the fourth step is to obtain an intermediate having a leaving group X I a and (I-V-5) a phosphorus compound is reacted intermediate having a leaving group PB I containing phosphorus (I-V-6) Reaction It is.
  • PB I is triarylphosphonium
  • intermediate (IV-6) can be obtained by reacting intermediate (IV-5) with triarylphosphine. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene.
  • the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration.
  • PB I is P (O) (OR I e ) 2
  • intermediate (IV-6) can be obtained by Arbuzov reaction of intermediate (IV-5) and phosphite triester.
  • the reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours.
  • the desired product can be obtained by distilling off or distilling excess phosphorous acid triester.
  • intermediate (IV-6) is intermediate (IV-5) in the presence of an additive such as tetraalkylammonium or cesium carbonate. It can also be obtained by reacting phosphonic acid diester.
  • the reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • intermediate (I-V-3) containing phosphorus and aldehyde (I-II-3) separately synthesized are condensed, and the resulting olefin is subsequently reduced, thereby intermediate (I Reaction to obtain -V-7).
  • PB I is triarylphosphonium
  • the conditions of normal Wittig reaction are used.
  • a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at ⁇ 30 ° C. to reflux for about 30 minutes to 12 hours.
  • the Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • PB I is P (O) of the (OR I e) 2
  • the conditions of normal Horner-Wadsworth-Emmons reaction are used.
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C.
  • the reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction.
  • a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)).
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the protecting group R I d protecting it is removed to remove the present invention.
  • compound (II-5) is obtained.
  • the deprotection of intermediate (IV-7) is not particularly limited as long as it can be used for the deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can.
  • R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid.
  • Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R I in formula (I) R I-3 , R I-4 are both hydrogen atom, and X is represented by sulfur atom (I-I-6)
  • R I b and R I c represent a protecting group
  • X I f represents a hydroxyl-activating group
  • Y I , R I-1 , R I-2 and A I represent those in the general formula (I)).
  • R I b and R I c in the formula are as defined above.
  • the first step is a compound (I-VI-1) synthesized by a known method (WO 2007/069712, pages 37 to 38) and a thiol (I-VI-) obtained by a generally known synthesis method.
  • This step can be performed in an ether solvent such as dioxane or a hydrocarbon solvent such as toluene in the presence of a palladium catalyst.
  • the palladium catalyst include palladium acetate (II) and tris (dibenzylideneacetone) dipalladium (0).
  • a phosphine compound or a base can be added as a reaction aid.
  • Examples of the phosphine compound include triphenylphosphine and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.
  • examples of the base include inorganic bases such as cesium carbonate and organic bases such as N, N-diisopropylethylamine.
  • examples of the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the protecting group R I d protecting it is removed to remove the compound of the present invention.
  • This is a reaction to obtain (II-6).
  • the deprotection of the intermediate (I-VI-3) is not particularly limited as long as it is used for the deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can.
  • R I b is a protecting group deprotectable by an acid such as methoxymethyl and R I c is t-butyloxycarbonyl, it can be simultaneously deprotected by an acid.
  • Examples of the acid in this case include inorganic acids such as hydrochloric acid and trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R I-3 ′ and R I-4 ′ represent one or both of alkyl having 1 to 4 carbon atoms, R I , X I , Y I , R I-1 , R I-2 And A I have the same meaning as each symbol in formula (I).
  • the compound (II-7) of the present invention is synthesized by alkylating the amino group of the compound (I-VII-1) having a primary amino group among the compounds of the present invention.
  • a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used.
  • an aldehyde having the same carbon number as R I-3 ′ or R I-4 ′ and compound (I-VII-1) are mixed with an alcohol solvent such as methanol, dichloroethane or the like.
  • the target product can be obtained by reacting in a halogen-based solvent using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide.
  • a catalyst such as Raney nickel or platinum oxide.
  • the generation of a Schiff base and the reduction reaction can also be sequentially performed.
  • an acid such as acetic acid can be added as a reaction accelerator. Examples of reaction conditions are about 30 minutes to 10 hours at about 50 ° C. under ice cooling.
  • purification or the like can be performed by a usual method to obtain the target product.
  • R I-3 'and R I-4' is methyl
  • R I-3 'and R I-4' is methyl
  • R I b and R I c are protecting groups
  • R I g is a protecting group or —A I
  • X I a is a leaving group
  • X I g is a leaving group or hydroxyl group
  • PB I contains phosphorus.
  • X I , R I-1 , R I-2 and A I have the same meanings as symbols in the general formula (I).
  • R I b , R I c , X I a , and PB I are as defined above. If X I g is a leaving group, examples of the leaving group leaves upon alkylation of a phenolic hydroxyl group or thiol group, is not particularly limited as long as it does not inhibit the reaction.
  • R I g in the formula is a protecting group
  • R I g is not particularly limited as long as it protects a phenol group or a thiol group.
  • R I g, X is when an oxygen atom alkyl (such as methyl), aralkyl (4-methoxybenzyl, etc.), or the like protecting group forming acetal (methoxymethyl and ethoxyethyl) can be mentioned.
  • X I is a sulfur atom, alkyl (methyl, etc.), aralkyl (4-methoxybenzyl, etc.), protecting group forming thioacetal (methoxymethyl or phenylthiomethyl, acetamidomethyl and the like) and the like.
  • a phosphorus compound is reacted with a compound (I-VIII-1) having a leaving group X I a synthesized by a known method (WO 2007/069712, pages 41 to 43) and a phosphorus compound.
  • an intermediate (I-VIII-2) having a leaving group PB I is obtained.
  • PB I is triarylphosphonium
  • intermediate (I-VIII-2) is obtained by reacting intermediate (I-VIII-1) with triarylphosphine in the presence of an additive such as tetraalkylammonium or cesium carbonate. Obtainable.
  • reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration.
  • PB I is P (O) (OR I e ) 2
  • intermediate (I-VIII-2) can be obtained by Arbuzov reaction of intermediate (I-VIII-1) and phosphite triester.
  • the reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C.
  • intermediate (I-VIII-2) can also be obtained by reaction of intermediate (I-VIII-1) with phosphonic acid diester.
  • the reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • PB I is P (O) of the (OR I e) 2
  • the conditions of normal Horner-Wadsworth-Emmons reaction are used.
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C.
  • the conditions used for the deprotection of the protecting group R I g performed subsequently is not particularly limited insofar as the conditions that alkenylene does not react, for example, when R I g is 4-methoxybenzyl, 2,3-dichloro -5 6- the oxidation reaction with dicyano-1,4-benzoquinone (DDQ) or the like, R if I g is silyl such as trialkylsilyl, deprotection with fluorine compound of an inorganic acid or tetrabutylammonium fluoride and the like such as hydrochloric acid Can be mentioned.
  • R I g is a partial structure of the invention compound as R I g (I-I- 8) is not necessary to deprotect R I g, alkyl phenol or thi
  • the third step is to alkylate the phenolic hydroxyl group or thiol group of intermediate (I-VIII-3), followed by protecting group for protecting R I b , R I c and R I-2 when they have a hydroxyl group
  • R I d R I d is as defined above
  • the reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours.
  • X I g is a hydroxyl group
  • the alkylation in the case of Intermediate (I-VIII-3) having a phenolic hydroxyl group phosphine compounds such as triphenylphosphine and azodicarboxylate such as diisopropyl azodicarboxylate Mitsunobu reaction using a derivative can also be used.
  • the reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C.
  • R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid.
  • the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • an alcoholic solvent such as ethanol
  • an ether solvent such as tetrahydrofuran
  • water or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • R I b , R I c and R I h represent a protecting group
  • X I g represents a leaving group or a hydroxyl group
  • X I , Y I , R I-2 and A I represent the general formula (I) It is synonymous with each symbol in.
  • Specific examples of R I b , R I c and X I g in the formula are as defined above.
  • the protecting group represented by R I h in the formula is not particularly limited as long as it protects a phenol group or a thiol group.
  • R I h examples include alkyl (such as methyl), aralkyl (such as 4-methoxybenzyl), and a protecting group that forms an acetal (such as methoxymethyl and ethoxyethyl) when X I is an oxygen atom. Further, when X I is a sulfur atom, alkyl (methyl, etc.), aralkyl (4-methoxybenzyl, etc.), protecting group forming thioacetal (methoxymethyl or phenylthiomethyl, acetamidomethyl and the like) and the like.
  • the first step is to deprotect the protecting group R I h of the compound (I-IX-1) having a difluoromethyl group synthesized by a known method (WO 2007/069712, pages 45 to 48). Reaction for obtaining a functional intermediate or a thiol intermediate (I-IX-2).
  • R I h is benzyl
  • a hydrogenolysis reaction using a homogeneous catalyst such as palladium carbon or Raney nickel is used, and in the case of 4-methoxybenzyl, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • the oxidation reaction by (DDQ) or the like can include deprotection with an inorganic acid such as hydrochloric acid or a fluorine compound such as tetrabutylammonium fluoride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the phenolic hydroxyl group or thiol group of intermediate (I-IX-2) is alkylated, and when R I b , R I c and R I-2 have a hydroxyl group, a protecting group for protecting it
  • R I d R I d is as defined above
  • the reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours.
  • X I g is a hydroxyl group
  • the alkylation in the case of Intermediate (I-IX-2) having a phenolic hydroxyl group phosphine compounds such as triphenylphosphine and azodicarboxylate such as diisopropyl azodicarboxylate Mitsunobu reaction using a derivative can also be used.
  • the reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C.
  • R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid.
  • the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • an alcoholic solvent such as ethanol
  • an ether solvent such as tetrahydrofuran
  • water or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • R I b , R I c and R I i represent a protecting group
  • X I c and X I d represent a leaving group
  • a I ′′ represents a double bond or a triple bond in the chain or at the chain end.
  • C 5-9 alkyl having no functional group, R I-2 , X I and Y I have the same meanings as those in the general formula (I).
  • Specific examples of R I b , R I c , X I c and X I d in the formula are the same as described above.
  • the protecting group represented by R I i in the formula is not particularly limited as long as it protects the hydroxyl group. For example, trialkylsilyl (specifically, t-butyldimethylsilyl and the like) can be mentioned.
  • the first step is a reaction for obtaining an intermediate (IX-3) by condensation of a raw material (IX-1) having a leaving group X I d and an alcohol or thiol (IX-2).
  • This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran.
  • a base an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done.
  • reaction conditions are about 30 minutes to 24 hours at about 80 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • a compound (IX-1) having a leaving group X I d as a phenolic hydroxyl group or thiol as a raw material.
  • Is alkylated examples include a combination of an alkylating agent such as an alkyl halide and an inorganic base such as potassium carbonate or sodium hydride.
  • the reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 10 minutes to 12 hours.
  • a polar solvent such as N, N-dimethylformamide
  • an ether solvent such as tetrahydrofuran
  • Mitsunobu reaction can also be used for alkylation of a phenolic hydroxyl group.
  • the second step is a reaction in which the formyl group of intermediate (IX-3) is reduced to hydroxymethyl and then the protective group R I i is introduced.
  • the reagent used for the reduction of the formyl group is not particularly limited as long as it is usually used, but metal hydrides such as diisobutylaluminum hydride, metal hydride complex compounds such as lithium aluminum hydride and sodium borohydride. And catalytic hydrogenation using a homogeneous or heterogeneous catalyst.
  • a temperature and a time appropriate for the reducing reagent to be used are selected. Specific examples include lithium aluminum hydride, reduction with lithium borohydride performed in an ether solvent such as tetrahydrofuran at ⁇ 30 ° C.
  • a silylating agent such as t-butyldimethylchlorosilane is used as a reagent, and a base such as imidazole or triethylamine can be added as a reaction accelerator. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the third step is a reaction in which intermediate (IX-4) and intermediate (I-IV-4) are condensed by Sonogashira reaction to obtain intermediate (IX-5) containing a triple bond.
  • the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II).
  • organic bases such as triethylamine, inorganic bases such as ammonia, copper compounds such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl
  • additives such as phosphine compounds.
  • the reaction conditions include ice-cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the fourth step is a reaction in which the triple bond of intermediate (IX-5) is reduced to obtain intermediate (IX-6).
  • the reagent used when Y I is —CH 2 CH 2 — is not limited as long as it is a reagent used for normal reduction of unsaturated carbon bonds, but is not limited to palladium carbon, Raney nickel, palladium carbon ethylenediamine complex, etc. Examples thereof include catalytic hydrogenation using a homogeneous catalyst such as a homogeneous catalyst rhodium complex (chlorotris (triphenylphosphine) rhodium (I) and the like).
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the reaction used when Y I is —CH ⁇ CH— is catalytic hydrogen carried out in the presence of a catalyst with regulated activity such as Lindlar catalyst, nickel-graphite-ethylenediamine complex, various complexes of diene, phosphine and rhodium. Addition may be mentioned. It is also possible to use a reduction reaction with a metal hydride such as diisobutylaluminum hydride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • a catalyst with regulated activity such as Lindlar catalyst, nickel-graphite-ethylenediamine complex, various complexes of diene, phosphine and rhodium. Addition may be mentioned. It is also possible to use a reduction reaction with a metal hydride such as diisobutylaluminum hydride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R I i of the compound (IX-6) is deprotected, and the hydroxyl group of the obtained compound is fluorinated to synthesize a fluorinated substance (IX-7).
  • Deprotection of the protecting group R I i can be carried out using a conventional deprotection reaction.
  • a fluorine compound such as tetrabutylammonium fluoride can be used.
  • the conditions for this reaction include an ice-based cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • Examples of the reagent used for the subsequent fluorination include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI).
  • DAST diethylaminosulfur trifluoride
  • DFI 2,2-difluoro-1,3-dimethylimidazolidine
  • the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane.
  • the reaction conditions include ⁇ 78 ° C. to room temperature for about 30 minutes to 12 hours.
  • purification or the like can be performed by a usual method to obtain the target product.
  • this process can also be performed by the method of making a fluoride ion act after converting a hydroxyl group into a corresponding sulfonate body.
  • reaction is carried out in an ether solvent such as tetrahydrofuran at room temperature to 80 ° C. for about 1 to 24 hours.
  • a dehydrating agent such as molecular sieves can be added to this reaction.
  • purification or the like can be performed by a usual method to obtain the target product.
  • R I i is trialkylsilyl
  • fluorination can be performed without deprotecting R I i .
  • the sixth step is a reaction for obtaining the compound (II-10) of the present invention by deprotecting the intermediate (IX-7).
  • R I b , R I c and R I-2 have a hydroxyl group
  • deprotection of the protecting group R I d (R I d has the same meaning as described above) for protecting the hydroxyl group includes the usual protecting group. It will not specifically limit if it is used for deprotection, All the protecting groups can be deprotected at once or in steps.
  • R I b and R I d combine to form a cyclic acetal, and R I c is t-butyloxycarbonyl
  • the cyclic acetal is deprotected with a catalytic amount of acid, followed by stronger acidic conditions.
  • R I c can be deprotected.
  • the conditions used for the deprotection of the acetal at this time include a catalytic amount of hydrochloric acid or toluenesulfonic acid in an alcoholic solvent such as methanol, or a mixed solution of an alcoholic solvent and another organic solvent. Examples include about 30 minutes to 12 hours at ° C.
  • ethers such as alcoholic solvent or tetrahydrofuran such as ethanol-based In a solvent, water or a mixed solvent thereof, for about 10 minutes to 5 hours may be mentioned under ice-cooling to room temperature.
  • purification or the like can be performed by a usual method to obtain the target product.
  • a hardly soluble solvent such as diisopropyl ether can be added to the reaction solution, and the precipitated target product can be collected by filtration.
  • This step is to obtain the compound (II-11) of the present invention by a known synthesis method (WO 2007/069712, pages 53 to 56).
  • the phosphorylated form (II-11) can be synthesized from the alcohol form (I-XI-1) in three steps using the above known synthesis method.
  • R I in the general formula (I) is P ( ⁇ O) (OH) 2
  • R I-3 and R I-4 are both represented by alkyl having 1 to 4 carbon atoms.
  • (I-XI-1) as a raw material,
  • R I-3 ′′ and R I-4 ′′ both represent alkyl having 1 to 4 carbon atoms, and X I , Y I , R I-1 , R I-2 and A I represent the general formula (It is synonymous with each symbol in (I).) Can be synthesized by the same method, omitting the protection of the amino group or amino group and hydroxyl group in the first step of scheme (I-XI).
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-1) in which heptyl, Z II is alkylene having 2 to 4 carbon atoms, and A II-2 is alkoxy having 1 to 4 carbon atoms is synthesized by the following scheme (II-II) .
  • R II-1 and R II-2 are as defined in the general formula (II-1), R II a is a protecting group, and R II b is 1 to 4 represents alkyl.
  • Protecting group represented by R II a in the formula is not particularly limited as long as it protects an amino group.
  • acyl preferably having about 2 to 4 carbon atoms, specifically acetyl etc.
  • carbamate specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.
  • R II-2 has a hydroxyl group
  • the hydroxyl group may be protected with a suitable protecting group
  • the protecting group R II c is specifically acyl (preferably having about 2 to 4 carbon atoms, Specific examples include acetyl), trialkylsilyl (specifically trimethylsilyl, etc.), benzyl or a substituent that forms an acetal compound (specifically methoxymethyl, tetrahydropyranyl, etc.).
  • the first step is protecting the amino group (II-II-2) by protecting the amino group of the compound (II-II-1) synthesized by a known method (WO 2007/069712, pages 8 to 13). Is synthesized.
  • This step can be performed using a normal amino group protecting reaction. Specifically, when acyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like is used as the protecting group R II a , this step is performed in a two-phase system of an alcohol such as methanol, or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture.
  • Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate.
  • an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator.
  • the reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the hydroxyl group of the protected amino group (II-II-2) is oxidized to synthesize the aldehyde (II-II-3).
  • This step can be performed using an oxidation reaction of a normal alcohol to an aldehyde. Specifically, by DMSO oxidation using various DMSO activators such as pyridinium chlorochromate, oxalyl chloride, DCC, sulfur trioxide-pyridine complex, and oxidation using N-oxoammonium compounds (for example, TEMPO oxidation). The object can be obtained.
  • the reaction conditions include ⁇ 78 ° C. to 50 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the third step is to synthesize intermediate (II-II-4) by condensing aldehyde (II-II-3) with a commercially available phosphorus reagent containing R II b .
  • a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C 6 H 5 ) 3 )
  • normal Wittig reaction conditions are used.
  • a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at ⁇ 30 ° C. to reflux for about 30 minutes to 12 hours.
  • the Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • a commercially available phosphorus reagent contains P (O) (OR II d ) 2 (R II d represents alkyl having 1 to 4 carbon atoms, the same shall apply hereinafter)
  • R II d represents alkyl having 1 to 4 carbon atoms, the same shall apply hereinafter
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C. to reflux for about 30 minutes to 12 hours.
  • Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the fourth step is a reaction for obtaining the compound (II-I-1) of the present invention by reducing the olefin moiety of the intermediate (II-II-4) and then deprotecting the protecting group R II a .
  • the reagent used for the reduction of the olefin is not limited as long as it is a reagent used for the reduction of a normal olefin.
  • a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) rhodium (I And hydrogenation using a homogeneous catalyst.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product.
  • the conditions for the subsequent deprotection of the protecting group R II a are not particularly limited as long as they can be used for the deprotection of ordinary protecting groups.
  • R II a is acyl such as acetyl
  • an alcohol type Examples include a method using an inorganic base such as sodium hydroxide in a mixed solvent of water and water, and a method using an acid such as hydrochloric acid or trifluoroacetic acid if the protecting group is t-butyloxycarbonyl.
  • an inorganic base such as sodium hydroxide in a mixed solvent of water and water
  • an acid such as hydrochloric acid or trifluoroacetic acid if the protecting group is t-butyloxycarbonyl.
  • hydrogenolysis such as benzyloxycarbonyl
  • the protecting group which can be deprotected by catalytic hydrogenation conditions the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • an alcoholic solvent such as ethanol
  • an ether solvent such as tetrahydrofuran
  • water or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • purification or the like can be performed by a usual method to obtain the target product.
  • Z II is alkylene having 2 to 4 carbon atoms
  • a II-2 is alkoxy having 1 to 4 carbon atoms
  • Y II- Other compounds in which 1 is —CH 2 CH 2 — can be synthesized in the same manner.
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-2) in which heptyl, Z II is methylene, and A II-2 is COOH is synthesized by the following scheme (II-III).
  • R II-1 and R II-2 have the same meanings as symbols in formula (II-1), and R II a represents a protecting group.
  • R II a represents a protecting group.
  • the first step is an acid treatment of compound (II-III-1) wherein n is 0 and R II b is methyl in intermediate (II-II-4) in scheme (II-II), followed by aldehyde
  • the carboxylic acid compound (II-III-2) is synthesized by oxidation.
  • the acid treatment include a method using an acid such as hydrochloric acid, and the reaction conditions include concentrated hydrochloric acid in water and at about 60 ° C. for 30 minutes to 2 hours under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent oxidation of the aldehyde to the carboxylic acid can be carried out by using a general method.
  • a target product can be obtained by oxidation or pernication using permanganate, chromic acid, oxygen, hydrogen peroxide, or organic peroxide.
  • the reaction conditions include ⁇ 78 ° C. to 50 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is a reaction for obtaining the compound (II-I-2) of the present invention by deprotecting the protecting group R II a of the carboxylic acid form (II-III-2).
  • the deprotection conditions are not particularly limited as long as they are used for the deprotection of ordinary protecting groups.
  • R II a is acyl such as acetyl, it is used in a mixed solvent of an alcohol solvent and water.
  • a method using decomposition or catalytic hydrogenation can be mentioned.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the compounds represented by the general formulas (II-1) and (II-2) other compounds in which Z II is methylene and A II-2 is COOH can also be synthesized by the same method.
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-3) in which heptyl, Z II is a single bond, and A II-2 is represented by COOH is synthesized by the following scheme (II-IV).
  • R II-1 and R II-2 have the same meanings as symbols in formula (II-1), and R II a represents a protecting group.
  • R II a represents a protecting group.
  • This step is a reaction for obtaining the compound (II-I-3) of the present invention by oxidizing the aldehyde form (II-II-3) to a carboxylic acid form and then deprotecting the protecting group R II a. .
  • Oxidation from an aldehyde to a carboxylic acid form, and subsequent deprotection, can be carried out using the same procedure as in Scheme (II-III) to obtain the desired product.
  • the compounds represented by the general formulas (II-1) and (II-2) other compounds in which Z II is a single bond and A II-2 is COOH can be synthesized by the same method. .
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-4) in which heptyl, Z II is ethylene, and A II-2 is COOH is synthesized by the following scheme (II-V).
  • R II-1 and R II-2 have the same meanings as the symbols in formula (II-1), R II a represents a protecting group, and R II e represents an alkyl group having 1 to 4 carbon atoms. .) Specific examples of R II a in the formula are as defined above.
  • the first step is to condense an intermediate (II-II-3) with a phosphorus reagent containing a commercially available R II e O—C ( ⁇ O) — group (R II e is as described above).
  • II-V-1) is synthesized.
  • a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C 6 H 5 ) 3 )
  • P (C 6 H 5 ) 3 ) 3 normal Wittig reaction conditions are used.
  • a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at ⁇ 30 ° C. to reflux for about 30 minutes to 12 hours.
  • the Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the commercially available phosphorus-containing reagent contains P (O) (OR II d ) 2 , normal Horner-Wadsworth-Emmons reaction conditions are used.
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C. to reflux for about 30 minutes to 12 hours.
  • Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is a reaction for obtaining the compound (II-I-4) of the present invention by reducing the olefin part of the intermediate (II-V-1) and then deprotecting the protecting groups R II a and R II e. is there.
  • the reagent used for the reduction of the olefin is not limited as long as it is a reagent used for the reduction of a normal olefin.
  • a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) rhodium (I And hydrogenation using a homogeneous catalyst.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product.
  • the conditions for the subsequent deprotection of the protecting groups R II a and R II e are not particularly limited as long as they are used for the deprotection of ordinary protecting groups.
  • R II a is acyl such as acetyl
  • a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, or a protective group such as t-butyloxycarbonyl is used as hydrochloric acid.
  • a method using an acid such as trifluoroacetic acid is used.
  • hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time.
  • R II e The conditions for deprotection by hydrolysis of R II e are the same as those for R II a.
  • a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, hydrochloric acid or trifluoro Examples include a method using an acid such as acetic acid. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • Z II is ethylene
  • a II-2 is COOH
  • Y II-1 is —CH 2 CH 2 —.
  • Compounds can also be synthesized by similar methods.
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-5) in which heptyl, Z II is alkylene having 1 to 3 carbon atoms, and A II-2 is OH is synthesized by the following scheme (II-VI).
  • R II-1 and R II-2 have the same meanings as symbols in the general formula (II-1), and R II a represents a protecting group.
  • R II a represents a protecting group.
  • the carboxylic acid compound (II-VI-1) synthesized in Scheme (II-III), Scheme (II-IV) and Scheme (II-V) is reduced to an alcohol, followed by protecting group R II
  • the compound (II-I-5) of the present invention is obtained by deprotecting a.
  • Reduction of carboxylic acid to alcohol can be performed by using a general method. Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like.
  • the reaction conditions include ⁇ 78 ° C. to 50 ° C. for about 30 minutes to 24 hours.
  • R II a is acyl such as acetyl
  • an alcohol type examples include a method using an inorganic base such as sodium hydroxide in a mixed solvent of water and water, and a method using an acid such as hydrochloric acid or trifluoroacetic acid if the protecting group is t-butyloxycarbonyl.
  • the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the compounds represented by the general formulas (II-1) and (II-2) other compounds in which Z II is alkylene having 1 to 3 carbon atoms and A II-2 is OH are also produced in the same manner. Can be synthesized.
  • R II-3 in the general formula (II-1) is a hydrogen atom
  • X II is an oxygen atom
  • Y II-1 is —CH 2 CH 2 —
  • a II-1 is n—
  • Compound (II-I-6) in which heptyl, Z II is alkylene having 1 to 4 carbon atoms, and A II-2 is P ( ⁇ O) (OH) 2 was synthesized by the following scheme (II-VII) Is done.
  • R II-1 and R II-2 are as defined in the general formula (II-1), R II a is a protecting group, R II f is a carbon number 1 to 4 represents an alkyl group.
  • R II a in the formula are as defined above.
  • a phosphorus reagent for example, tetraethyl methylenediphosphonate containing aldehyde (II-II-3) and commercially available P ( ⁇ O) (OR II f ) 2 (R II f is as described above) is used.
  • An intermediate (II-VII-1) is synthesized by condensing a phosphorus compound and then reducing the olefin moiety. For the condensation, the conditions of a normal Horner-Wadsworth-Emmons reaction are used.
  • a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about ⁇ 20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned.
  • purification or the like can be performed by a usual method to obtain the target product.
  • the reagent used for the subsequent olefin reduction is not limited as long as it is a reagent used for ordinary olefin reduction.
  • a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) And catalytic hydrogenation using a homogeneous catalyst such as rhodium (I).
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned.
  • An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product.
  • the second step is a reaction for obtaining the compound (II-I-6) of the present invention by deprotecting the protecting groups R II a and R II f of the intermediate (II-VII-1).
  • the conditions for the deprotection of the protecting group R II a is not particularly limited as long as it is used in the deprotection of conventional protecting groups, for example, alcohol solvents, if R II a is acyl such as acetyl and water And a method using an inorganic base such as sodium hydroxide in a mixed solvent, and a method using an acid such as hydrochloric acid or trifluoroacetic acid as a protective group such as t-butyloxycarbonyl.
  • benzyl R II a hydrogenolysis, such as benzyloxycarbonyl
  • the deprotection of R II a is a double bond in the first step It can be performed simultaneously with the reduction.
  • R II f can be deprotected using a Lewis acid such as trimethylsilyl bromide.
  • the reaction conditions include, for example, about 10 minutes to 24 hours at 80 ° C. under ice cooling in a halogen-based solvent such as methylene chloride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • Z II is alkylene having 1 to 4 carbon atoms
  • a II-2 is P ( ⁇ O) (OH) 2
  • Y Other compounds in which II-1 is —CH 2 CH 2 — can also be synthesized by the same method.
  • the compound (II-I-7) of the present invention is obtained by a known synthesis method (WO 2007/069712, pages 53 to 56).
  • the phosphorylated form (II-I-7) can be synthesized from the alcohol form (II-VIII-1) in three steps using the above-mentioned known synthesis method.
  • a compound represented by the general formula (II-2) in which R II-3 is a hydrogen atom, Z II is methylene, and A II-2 is OP ( ⁇ O) (OH) 2 is synthesized by the same method. Can do.
  • R III-2 in the general formula (III-1) is a hydrogen atom
  • X III-1 is an oxygen atom
  • Y III-1 is methylene
  • X III-2 is methine
  • a III- 1 is n-heptyl
  • a III-2 is methylene
  • B III is methylene
  • B III is bonded to A III-2
  • Y III-1 , X III-2 and the carbon atom to which the amino group is bonded is a hydrogen atom
  • X III-1 is an oxygen atom
  • Y III-1 is methylene
  • X III-2 is methine
  • a III- 1 is n-heptyl
  • a III-2 is methylene
  • B III is methylene
  • B III is bonded to A III-2
  • Y III-1 , X III-2 and the carbon atom to which the amino group is bonded is synthesized by the following scheme (III-II).
  • X III a and X III b represent a leaving group
  • Y III represents an activating group during the condensation reaction
  • R III-1 has the same meaning as the symbol in general formula (III-1).
  • the leaving group represented by X III a in the formula is not particularly limited as long as it is eliminated during the substitution reaction with the alkoxide ion (CH 3 (CH 2 ) 7 —O ⁇ ).
  • a halogen atom specifically a fluorine atom, etc.
  • toluenesulfonyloxy and the like can be mentioned.
  • the leaving group represented by X III b in the formula is not particularly limited as long as it is eliminated during the introduction reaction or condensation reaction of the activating group Y III .
  • halogen atom preferably an iodine atom, a bromine atom, etc.
  • trifluoromethanesulfonyloxy and the like can be mentioned.
  • the above leaving group and activating group are used in an appropriate combination depending on the type of condensation reaction.
  • an n-heptyloxy group is introduced into the 4-position by condensation of a benzoic acid derivative (III-II-1) with a leaving group X III a at the 4-position and n-heptanol, and an intermediate (III- II-2) is obtained.
  • This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran.
  • an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used.
  • Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the second step is a reaction in which the carboxylic acid moiety of intermediate (III-II-2) is converted to leaving group X III b to obtain intermediate (III-II-3).
  • This step is a reaction in which a carboxylic acid is converted into an amine compound using a Curtius rearrangement reaction or a Schmitt reaction, and then a compound having a leaving group X III b is obtained using a Sandmeyer reaction or the like.
  • As the reaction conditions normal Curtius rearrangement reaction, Schmitt reaction, and Sandmeyer reaction conditions can be used. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • the third step is a reaction for converting the compound (III-II-3) having a leaving group X III b into an intermediate (III-II-4) having an activating group Y III .
  • Conditions of this step is according to the type of Y III it is appropriate selected, for example, Y III is the case of boric acid esters can be used the following conditions.
  • the solvent can be an ether solvent such as 1,4-dioxane or tetrahydrofuran, or a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, and the reaction can be carried out in the presence of a base and a palladium catalyst.
  • an organic base such as potassium acetate or diisopropylethylamine, or an inorganic base such as cesium carbonate or tripotassium phosphate
  • an inorganic base such as cesium carbonate or tripotassium phosphate
  • palladium catalyst palladium complexes such as dichlorobis (tricyclohexylphosphine) palladium (II) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) can be used.
  • a palladium compound such as palladium acetate and a reaction aid such as tri-t-butylphosphine can be used in combination.
  • diboron compounds such as bis (neopentyl glycolate) diboron and bispinacolato diboron can be used.
  • the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours.
  • the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.
  • the fourth step is a reaction for converting an intermediate (III-II-4) having an activating group Y III into an intermediate (III-II-5) having a cyclopentanone.
  • Y III is a boric acid ester
  • general conjugate addition reaction conditions can be used. Specifically, in ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbon solvents such as toluene, and high polar solvents such as N, N-dimethylformamide, bases such as cesium carbonate and tripotassium phosphate, and palladium
  • ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran
  • hydrocarbon solvents such as toluene
  • high polar solvents such as N, N-dimethylformamide
  • bases such as cesium carbonate and tripotassium phosphate
  • palladium The reaction can be carried out in the presence of a catalyst.
  • reaction is carried out in a water-containing or two-phase solvent such as tetrahydrofuran and water, 1,2-dimethoxyethane and water in the presence of a base such as sodium hydroxide, sodium carbonate, thallium hydroxide and a palladium catalyst.
  • a reaction aid such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl or 2- (di-t-butylphosphino) biphenyl can be added depending on the case.
  • the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours.
  • the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.
  • the fifth step is a reaction for converting the intermediate (III-II-5) having cyclopentanone into the compound (III-I-1) of the present invention.
  • This step is a reaction in which the ketone moiety is converted to hydantoin using the Bucherer-Burgs method or the like, then hydrolyzed to amino acid, and then the amino acid is obtained by reduction of the carboxylic acid.
  • the reaction conditions for the step of converting to hydantoin include a temperature of 0 ° C. to 60 ° C. for about 30 minutes to 48 hours.
  • the subsequent hydrolysis can be carried out using an acid such as hydrochloric acid or sulfuric acid, or a base such as potassium hydroxide, and the reaction conditions include 80 ° C.
  • the subsequent reduction from carboxylic acid to alcohol can be carried out by using a general method.
  • Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like.
  • the reaction conditions include ⁇ 78 ° C. to 100 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R III-2 is a hydrogen atom
  • X III-1 is an oxygen atom
  • Y III-1 is methylene
  • a III-2 is methylene
  • B III is methylene
  • B III is bonded to A III-2, and together with Y III , X III-2 and the carbon atom to which the amino group is bonded, forms cyclopentane.
  • Other compounds can also be synthesized by the same method.
  • the compound (III-I-2) in which R III-2 in the general formula (III-1) is P ( ⁇ O) (OH) 2 is represented by the following scheme (III-III) Is synthesized.
  • the compound (III-I-2) of the present invention is obtained by a known synthesis method (WO 2007/069712, pages 53 to 56).
  • the phosphorylated form (III-I-2) can be synthesized from the alcohol form (III-III-1) in three steps using the above-mentioned known synthesis method.
  • a compound in which R III-2 in General Formula (III-2) is P ( ⁇ O) (OH) 2 can also be synthesized by the same method.
  • R IV-3 in the general formula (IV-1) is a hydrogen atom
  • R IV-2 is alkyl having 1 to 4 carbons
  • 2 to Compound (IV-I-1) represented by 21 alkoxycarbonyl is synthesized by the following scheme (IV-II).
  • R IV-1 , R IV-4 , X IV and A IV-1 have the same meanings as those in the general formula (IV-1), and R IV a is alkyl having 1 to 4 carbon atoms, carbon Represents an acyl having 1 to 20 carbon atoms or an alkoxycarbonyl having 2 to 21 carbon atoms.
  • This step comprises subjecting the compound (IV-I-1) of the present invention by alkylating, acylating or alkoxycarbonylating the amino group of the compound (IV-II-1) having a primary amino group.
  • alkylation of the amino group a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used.
  • a reductive amination reaction an aldehyde having the same carbon number as that of R IV a and the compound (IV-II-1) are mixed with borohydride in an alcohol solvent such as methanol or a halogen solvent such as dichloroethane.
  • the target product can be obtained by reacting with a reducing agent such as sodium, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • a reducing agent such as sodium, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide.
  • a catalyst such as Raney nickel or platinum oxide.
  • the generation of a Schiff base and the reduction reaction can also be sequentially performed.
  • an acid such as acetic acid can be added as a reaction accelerator. Examples of reaction conditions are about 30 minutes to 10 hours at about 50 ° C. under ice cooling.
  • purification or the like can be performed by a usual method to obtain the target product.
  • R IV a is methyl
  • an Eschweiler-Clarke methylation reaction using a reducing agent such as formic acid and formaldehyde or formaldehyde and sodium cyanoborohydride can also be used.
  • the acylation or alkoxycarbonylation of an amino group can be performed using a normal amino group acylation reaction or alkoxycarbonylation reaction. Specifically, it can be carried out in an alcohol such as methanol, or in a two-phase system or a mixture of water and an organic solvent such as ethyl acetate or chloroform.
  • Examples of the reagent used include acid chlorides such as acetyl chloride, stearoyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate.
  • an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator.
  • the reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R IV-3 is a hydrogen atom
  • R IV-2 is alkyl having 1 to 4 carbons
  • alkoxycarbonyl having 2 to 21 carbons The compounds represented can also be synthesized by the same method.
  • the compound (IV-I-2) in which R IV-2 in the general formula (IV-1) is a hydrogen atom is synthesized according to the following scheme (IV-III).
  • R IV b represents a protecting group
  • the protecting group represented by R IV b in the formula is not particularly limited as long as it protects the amino group.
  • acyl preferably having about 2 to 4 carbon atoms, specifically acetyl etc.
  • carbamate specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.
  • the first step is to synthesize an amino group protected compound (IV-III-1) by protecting the amino group of the compound (IV-II-1) having a primary amino group among the compounds of the present invention.
  • This step can be performed using a normal amino group protecting reaction. Specifically, when acyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like is used as the protecting group R IV b , this step is performed in a two-phase system of an alcohol such as methanol or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture.
  • Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate.
  • an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator.
  • the reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
  • R IV-4 contains a hydroxyl group
  • the hydroxyl group can also be protected with an appropriate protecting group such as acyl, alkoxycarbonyl, benzyl and the like.
  • the second step is to convert the hydroxyl group of the protected amino group (IV-III-1) into a substituent R IV-3 containing phosphorus.
  • appropriate reagents and conditions are selected depending on the type of RIV-3 .
  • R IV-3 is a bis (pivaloyloxymethyl) phosphoryl group
  • a combination of bis (pivaloyloxymethyl) phosphoryl chloride and triethylamine can be used, and R IV-3 can be bis (S-acetyl).
  • the third step is a reaction for obtaining the compound (IV-I-2) of the present invention by deprotecting the protecting group of the intermediate (IV-III-2).
  • the deprotection conditions are not particularly limited as long as they are used for deprotection of ordinary protecting groups.
  • R IV b is acyl such as acetyl
  • a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, or hydrochloric acid if it is a protecting group such as t-butyloxycarbonyl
  • a method using an acid such as trifluoroacetic acid.
  • the reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • an alcoholic solvent such as ethanol
  • an ether solvent such as tetrahydrofuran
  • water or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours.
  • purification or the like can be performed by a usual method to obtain the target product.
  • a compound in which R IV-2 is a hydrogen atom can also be synthesized by the same method.
  • V V in the general formula (V) is —CH 2 —V V a — (where V V a is a single bond or a C 1-5 which may have a substituent)
  • Y V represents —NR V-5 a — (wherein R V-5 a represents a hydrogen atom or an alkyl having 1 to 6 carbon atoms which may have a substituent).
  • V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent
  • Y V is a single bond
  • n V is 1
  • Compound (VI-2), which is a group represented by the following formula, can be synthesized by the following scheme (V-II).
  • a V , B V , R V-1 , Z V , X V , and n V are synonymous with each symbol in the general formula (V).
  • step (V-II-1) and step (V-II-2) compound (V-II-1) was reacted with compound (V-II-2) or compound (V-II-3).
  • compound (VI-1) or compound (VI-2) is obtained by subsequent reduction.
  • This reaction is carried out in the presence of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. in the presence of methanol, ethanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, etc. It is carried out in an active solvent.
  • an acidic catalyst such as acetic acid, p-toluenesulfonic acid, boron trifluoride / diethyl ether complex may be added.
  • a phase transfer catalyst such as tetra-n-butylammonium hydroxide is used. Etc. may be added. Usually, it is carried out at a temperature of 0 to 100 ° C. for 10 minutes to 20 hours.
  • X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (VII) is carried out to remove the compound (VI -1) or compound (VI-2).
  • the compound (VI-3) and the compound (V) in which Y V in the general formula (V) is a double bond, n V is 0, and B V is COOR V-6 VI-4) can be synthesized by the following scheme (V-III).
  • R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V).
  • PR V-6 b represents a leaving group containing phosphorus.
  • a V , R V-1 , V V , and X V have the same meanings as the symbols in general formula (V).
  • Step (V-III-1) is a step of obtaining an alkene by reaction of compound (V-III-1) and compound (V-III-2).
  • PR V-6 b is triarylphosphonium
  • normal Wittig reaction conditions are used.
  • the compound (V-III-2) is treated with a base such as sodium ethoxide, potassium t-butoxide, sodium hydride to generate an ylide, and this is reacted with the compound (V-III-1).
  • compound (VI-3) is obtained.
  • the reaction is carried out for 30 minutes to 12 hours under the condition of -30 ° C to reflux.
  • Step (V-III-2) is a step of obtaining carboxylic acid (VI-4) by hydrolysis.
  • reaction conditions conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used.
  • the reaction is usually carried out at 0 ° C. under reflux for about 1 to 48 hours.
  • X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (V-III) is carried out to remove the compound (VI -3) or compound (VI-4).
  • R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V).
  • a V , R V-1 , V V , and X V represent the general formula ( It is synonymous with each symbol in V).
  • step (V-IV-1) and step (V-IV-3) compound (VI-5) is obtained by reducing compound (VI-3) or compound (VI-4). Alternatively, it is a step of obtaining the compound (VI-6).
  • the reaction conditions are not particularly limited as long as they are usually performed, and examples include catalytic reduction using a catalyst such as palladium, platinum, or nickel. In this case, the reaction is usually carried out at a reflux temperature from 0 ° C. in a hydrogen atmosphere in an alcohol solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene.
  • Step (V-IV-2) is a step for obtaining carboxylic acid (VI-6) from ester (VI-5) by hydrolysis.
  • reaction conditions conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used.
  • the reaction is usually carried out at 0 ° C. under reflux for about 1 to 48 hours.
  • X V -A V contains an —NH— structure or a carbonyl structure
  • the compound is protected by carrying out the step of scheme (V-IV) and deprotecting, if necessary, after protecting with an appropriate protecting group.
  • (VI-5) or compound (VI-6) is obtained.
  • the compound (VI-9) and the compound (VI-10), which are groups represented by the following formula, can be synthesized by the following scheme (VV).
  • R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V).
  • a V , R V-1 , R V-5 , V V , X V 1 , Z V , and n V have the same meanings as symbols in the general formula (V).
  • Step (VV-1) and Step (VV-3) are carried out by reacting Compound (VV-1) with Compound (VV-2) or Compound (VV-3).
  • compound (VI-7) or (VI-9) is obtained.
  • the condensing agent that activates the carboxylic acid include dicyclohexylcarbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, and hydrochloride thereof. These condensing agents are used alone or in combination with additives such as N-hydroxysuccinimide, hydroxybenzotriazole, 4-dimethylaminopyridine and the like.
  • compound (VV-1) may be converted to acid chloride with thionyl chloride, oxalyl chloride or the like and then reacted with compound (VV-2) or compound (VV-3). Conversion to the acid chloride is carried out in an inert solvent such as dichloromethane, for example, from ⁇ 30 ° C. to reflux temperature. N, N-dimethylformamide may be added. The reaction between the acid chloride and the compound (VV-2) or (VV-3) is carried out at ⁇ 30 ° C.
  • an inert solvent such as dichloromethane and N, N-dimethylformamide
  • step (VV-2) and step (VV-4) carboxylic acid (VI-8) is obtained by hydrolysis reaction from compound (VI-7) or (VI-9). Alternatively, (VI-10) is obtained.
  • a base such as triethylamine in an inert solvent such as dichloromethane.
  • step (VV-2) and step (VV-4) carboxylic acid (VI-8) is obtained by hydrolysis reaction from compound (VI-7) or (VI-9).
  • step (VI-10) is obtained.
  • Conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used. Usually, it is carried out at 0 ° C. to reflux temperature for 1 hour to 48 hours.
  • Step (V-VI-1) is a step of obtaining compound (VI-11) having a hydroxyl group by reducing compound (V-VI-1).
  • the reaction conditions are not particularly limited as long as they are usually used. Examples include reduction with diborane and substituted borane performed in an ether solvent such as tetrahydrofuran at ⁇ 30 ° C. to 50 ° C. for about 10 minutes to 24 hours. .
  • X V -A V contains an —NH— structure and a carbonyl structure
  • the compound is protected by carrying out the step of scheme (V-VI) after deprotection with an appropriate protecting group, if necessary, and then deprotected. (VI-11) is obtained.
  • Step (V-VII-1) is a step of obtaining acyl sulfonamide compound (VI-12) by reaction of carboxylic acid compound (V-VII-1) with sulfonamide compound (V-VII-2). It is. After activating the carboxylic acid compound with a reagent such as 1,1′-carbonyldiimidazole, the sulfonamide compound in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene To give an acylsulfonamide compound.
  • the reaction conditions are not particularly limited as long as they are usually performed. For example, the reaction is performed at ⁇ 30 ° C. to reflux temperature in an inert solvent such as tetrahydrofuran.
  • an acylsulfonamide compound may be obtained by reacting a carboxylic acid compound and a sulfonamide compound in the presence of a condensation reagent such as 2-chloro-1-methylpyridinium iodide.
  • a condensation reagent such as 2-chloro-1-methylpyridinium iodide.
  • the conditions are not particularly limited as long as they are usually used.
  • a base such as N, N-diisopropylethylamine or 4-dimethylaminopyridine may be used alone or in combination with several bases.
  • the reaction is performed at ⁇ 30 ° C. to reflux temperature in an inert solvent such as dimethylformamide.
  • X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (V-VII) is carried out to remove the compound (VI -12) is obtained.
  • a V , R V-1 , V V , X V , Y V , Z V , and n V are synonymous with each symbol in the general formula (V).
  • Step (V-VIII-1) is a step of converting compound (V-VIII-1) to compound (VI-13).
  • the reagents and conditions used for the reaction are not particularly limited as long as they are usually used.
  • compound (V-VIII-1) is reacted with hydroxylammonium chloride in the presence of a base such as potassium carbonate, sodium acetate or triethylamine.
  • the reaction can be mentioned.
  • Examples of the conditions in this case include performing a polar solvent such as ethanol, methanol, and water at 0 ° C. to reflux temperature.
  • Step (V-VIII-2) is a step of converting compound (VI-13) to compound (VI-14).
  • the reaction reagent and conditions are not particularly limited as long as they are usually used.
  • compound (VI-13) and 1,1′-carbonyldiimidazole or ethyl chlorocarbonate are mixed with an inert solvent such as tetrahydrofuran. And reacting in toluene.
  • the reaction temperature can be about 0 ° C. to the reflux temperature.
  • X V -A V contains an —NH— structure or a carbonyl structure
  • these are protected with an appropriate protecting group, and then the step of scheme (V-VIII) is carried out to remove the compound (VI -13) or compound (VI-14).
  • X V a represents an oxygen atom or a sulfur atom
  • X V b represents a leaving group such as a bromine atom, or a hydroxyl group.
  • a V , R V-1 , and V V represent each of the general formula (V). (It is synonymous with symbol.)
  • Step (V-IX-1) is a step of alkylating the phenolic hydroxyl group or thiol group of compound (V-IX-2) to obtain compound (V-IX-1).
  • the reagent used include a combination of compound (V-IX-1) and an inorganic base such as potassium carbonate or sodium hydroxide when X V b represents a leaving group.
  • the reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours.
  • a phosphine compound such as triphenylphosphine and an azodicarboxylic acid derivative such as azodicarboxylic acid diisopropyl ester are used.
  • Mitsunobu reaction using can also be used.
  • the reaction conditions in this case include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran.
  • V V a or V V is a single bond
  • Compound (VX-1) in which is an oxygen atom or a sulfur atom can be synthesized by the following scheme (VX).
  • R V-6 a represents a group other than hydrogen atom in R V-6 defined by the general formula (V)
  • X V a represents an oxygen atom or a sulfur atom
  • X V c represents a leaving group.
  • step (VX-1) compound (VX-4) is obtained by condensation of compound (VX-2) having leaving group X V c and compound (VX-3). It is a reaction.
  • This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran.
  • a base an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C.
  • Step (VX-2) is a reaction in which the ester of compound (VX-4) is reduced to obtain compound (VX-5) having a hydroxyl group.
  • the reagent used for the reduction is not particularly limited as long as it is usually used, but alkali metals such as sodium and alkaline earth metals, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and sodium borohydride. Metal hydrogen complex compounds such as diborane, catalytic hydrogenation using a homogeneous or heterogeneous catalyst, and the like.
  • a temperature and a time appropriate for the reducing reagent to be used are selected.
  • Step (VX-3) is a step of oxidizing the hydroxyl group of compound (VX-5) to obtain aldehyde compound (VX-1). This step can be performed using an oxidation reaction of a normal alcohol to an aldehyde.
  • DMSO oxidation using various dimethyl sulfoxide activators such as pyridinium chlorochromate, oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide-pyridine complex, and oxidation using N-oxoammonium compounds (for example, TEMPO
  • the target product can be obtained by oxidation.
  • the reaction conditions include ⁇ 78 ° C. to 50 ° C. for about 30 minutes to 24 hours.
  • V-II-1 a compound in which V V a or V V is methylene ( V-XI-1) can be synthesized by the following scheme (V-XI).
  • step (V-XI-1) an aldehyde compound (V-XI-2) is synthesized by oxidizing compound (V-XI-2) synthesized by a known method (for example, WO2007 / 069712, pages 8 to 56).
  • This is a step of obtaining XI-1).
  • This step can be performed using an oxidation reaction from a normal alcohol to an aldehyde. Specifically, the reaction reagents and reaction conditions described in the step (VX-3) in the scheme (VX) can be given.
  • R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V)
  • V V b represents a carbon that may have a single bond or a substituent.
  • a V , R V-1 and X V have the same meanings as those in the general formula (V).
  • step (V-XII-1) is the step (V-III-1) in the scheme (V-III)
  • step (V-XII-2) is the step (V-IV) in the scheme (V-IV).
  • step (V-XII-3) is in step (V-IV-2) in scheme (V-IV)
  • step (V-XII-4) is in scheme (V-VI).
  • step (V-XI-5) can be exemplified by those described in step (VX-3) in scheme (VX).
  • V-VIII-1 is an oxygen atom or sulfur atom
  • V V is —CH 2 —V V a — (where V V a is a single bond) Or an optionally substituted alkylene having 1 to 5 carbon atoms
  • Y V is —NR V-5 a — (where R V-5 a is a hydrogen atom and has a substituent.
  • V-XIII-1 a compound represented by formula (V-XIII-1), or X V is an oxygen atom or a sulfur atom, and V V is —CH 2 —V V a — (wherein V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent), Y V is a single bond, n V is 1, and B V -Z V -is represented by the following formula:
  • V-XIII-2 which is a group represented by the following formula, can be synthesized by the following scheme (V-XIII).
  • V V a represents an oxygen atom or a sulfur atom
  • V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent
  • R V-5 a represents a hydrogen atom
  • R V-1 , A V , Z V and n V have the same meanings as those in the general formula (V).
  • step (V-XIII-1) and step (V-XIII-2) compound (V-II-1) was reacted with compound (V-XIII-3) or compound (V-XIII-4)
  • compound (V-XIII-1) or compound (V-XIII-2) is obtained by subsequent reduction.
  • Examples of the reaction reagent, reaction conditions, and the like can be the same as those in step (V-II-1) and step (V-II-2) in scheme (VII).
  • X V a -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then scheme (V-XIII) is carried out to remove the compound (V-XIII— 1) or compound (V-XIII-2) is obtained.
  • the compound of the present invention can be converted to an acid addition salt by treating with an acid in an appropriate solvent (water, alcohol, ether, etc.) as necessary. Moreover, it can be set as a hydrate or a solvate by processing the obtained this invention compound with water, a hydrous solvent, or another solvent (for example, alcohol etc.).
  • an appropriate solvent water, alcohol, ether, etc.
  • it can be set as a hydrate or a solvate by processing the obtained this invention compound with water, a hydrous solvent, or another solvent (for example, alcohol etc.).
  • the compound of the present invention treats or prevents autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes, etc.); humans, dogs, cats Transplantation of mammalian organs or tissues such as cattle, horses, pigs, monkeys, mice (eg, heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, extremities, muscles, nerves, fat pulp, duodenum, Resistance to skin, islet cell transplantation, including xenotransplantation or prevention or suppression of acute rejection or chronic rejection; graft versus host (GvH) disease by bone marrow transplantation; allergic disease (eg, atopic dermatitis , Allergic rhinitis, asthma, etc.).
  • autoimmune diseases eg, rheum
  • prevention means an act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has not developed a disease, disorder or symptom.
  • Treatment means an act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has already developed a disease, disorder or symptom. Therefore, the act of administering to an individual who has already developed illness, disease, or symptom in order to prevent worsening of the symptom, seizure, or recurrence is an aspect of “treatment”.
  • the compound of the present invention When the compound of the present invention is used as a pharmaceutical, the compound of the present invention is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, solubilizer, etc.) It can be administered orally or parenterally in the form of the resulting pharmaceutical composition or formulation (oral, injection, etc.).
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, solubilizer, etc.
  • the pharmaceutical composition can be formulated according to a usual method.
  • parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (transdermal administration, ophthalmic administration, transpulmonary / bronchial administration, nasal administration) Administration or rectal administration, etc.).
  • the content of the compound of the present invention that can be combined with the carrier can vary depending on the individual to be treated and the specific dosage form.
  • the specific dose for a specific patient will be determined according to various factors including age, weight, general health, sex, diet, administration time, method of administration, excretion rate and degree of specific disease being treated.
  • the dose of the compound of the present invention depends on age, body weight, general health condition, sex, meal, administration time, administration method, excretion rate, and the degree of the disease being treated at that time of the patient, or other Determined by considering factors.
  • the compound of the present invention has no effect on heart rate and can be used safely.
  • the daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, etc. Is administered about 0.01 to 50 mg / person / day subcutaneously, intravenously, intramuscularly, transdermally, ophthalmically, pulmonary / bronchially, nasally or rectally, and orally about 0.01 to 150 mg / person / day is administered.
  • reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate.
  • organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product (3.16 g) as a colorless oil.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml) and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), cis-4-hepten-1-ol (0.404 ml) and ⁇ 5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. .
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), trans-2-hepten-1-ol (0.409 ml) and ⁇ 5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. .
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 6-hepten-1-ol (0.400 ml) and ⁇ 5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 15 hours.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 3-heptin-1-ol (0.376 ml) and ⁇ 5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours.
  • the solvent was evaporated under reduced pressure to give 560 mg of a colorless oil.
  • the colorless oil (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr.
  • the reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml) and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 2-heptin-1-ol (0.372 ml) and ⁇ 5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours.
  • 6-Heptynoic acid (2.00 g) is dissolved in 1,2-dichloroethane (30 ml), and catalytic amounts of N, N-dimethylformamide and oxalyl chloride (3.30 ml) are added at 0 ° C., and 2 at room temperature. Stir for hours. The temperature was returned again to 0 ° C., methanol (20 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then the solvent was concentrated.
  • (+)-Potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred while warming to room temperature, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (1.31 g) as a colorless oil.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), compound 9-1 (0.321 ml) and ⁇ 5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 6 hours.
  • the solvent was evaporated under reduced pressure to give 610 mg of a pale yellow oil.
  • the pale yellow oil (610 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr.
  • the reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (440 mg) as a white powder.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 4,4,5,5,5-pentafluoropentanol (0.406 ml) and ⁇ 5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added at room temperature. For 5 hours.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 3-nonanol (0.518 ml) and ⁇ 5- [2- (4-hydroxy- 3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), (S)-(+)-2-octanol (0.463 ml) and ⁇ 5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), (R)-( ⁇ )-2-octanol (0.463 ml) and ⁇ 5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 2-octanol (0.469 ml) and ⁇ 5- [2- (4-hydroxy- 3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • the solvent was evaporated under reduced pressure to give 680 mg of a white solid.
  • the white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium carbon (200 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere.
  • the reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated.
  • the obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr.
  • the reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.
  • the solvent was evaporated under reduced pressure to give 740 mg of a white solid.
  • the white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium on carbon (400 mg) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere.
  • the reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated.
  • the obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr.
  • the reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (490 mg) as a white powder.
  • 2-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (50 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice-cooling. The mixture was further stirred at room temperature for 20 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.27 ml), compound 19-1 (0.310 ml) and ⁇ 5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (500 mg) was added, and the mixture was stirred at room temperature for 4 and a half hours.
  • 6-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (60 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice-cooling. The mixture was further stirred at room temperature for 4 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), compound 20-1 (0.372 ml) and ⁇ 5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl ⁇ carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • N, N-diisopropylethylamine (0.512 ml) and trimethyl orthoacetate (0.221 ml) were added to a solution of compound 3-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did.
  • N, N-Diisopropylethylamine (0.431 ml) and trimethyl orthoacetate (0.203 ml) were added to a solution of compound 4-1 (330 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-Diisopropylethylamine (0.312 ml) and trimethyl orthoacetate (0.147 ml) were added to a solution of compound 5-4 (250 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did.
  • N, N-Diisopropylethylamine (0.342 ml) and trimethyl orthoacetate (0.159 ml) were added to a solution of compound 6-1 (260 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-diisopropylethylamine (0.373 ml) and trimethyl orthoacetate (0.174 ml) were added to a solution of compound 10-4 (290 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-Diisopropylethylamine (0.379 ml) and trimethyl orthoacetate (0.177 ml) were added to a solution of compound 11-1 (300 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-diisopropylethylamine (0.521 ml) and trimethyl orthoacetate (0.245 ml) were added to a solution of compound 12-1 (460 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-Diisopropylethylamine (0.491 ml) and trimethyl orthoacetate (0.230 ml) were added to a solution of compound 15-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did.
  • N, N-diisopropylethylamine (0.390 ml) and trimethyl orthoacetate (0.182 ml) were added to a solution of compound 17-1 (330 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 4 hours. did.
  • N, N-diisopropylethylamine (0.302 ml) and trimethyl orthoacetate (0.146 ml) were added to a solution of compound 19-2 (240 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 5 hours. did.
  • N, N-diisopropylethylamine (0.528 ml) and trimethyl orthoacetate (0.248 ml) were added to a solution of compound 20-2 (420 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 4 hours. did.
  • Triethyl phosphonoacetate (518 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min.
  • a solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction mixture was concentrated, chloroform (5 ml) and methanol (5 ml) were added, p-toluenesulfonic acid monohydrate (127 mg) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (355 mg) as a white powder.
  • Triethylamine (0.139 ml) and di-t-butyl dicarbonate (144 mg) were added to a solution of compound 39-4 (190 mg) in methanol (10 ml), and the mixture was stirred at room temperature for 18 hours. Further, di-t-butyl dicarbonate (100 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 210 mg of a colorless oil.
  • Tetraethyl methylene diphosphonate (663 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min.
  • a solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was ice-cooled, 2% aqueous sodium sulfite solution (500 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the object product (29.2 g) as a red-brown oil.
  • reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.

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Abstract

Disclosed is a novel benzene compound which has an excellent immunosuppressing activity, an excellent rejection-inhibiting effect and others, and is reduced in adverse side effects including bradycardia. Specifically disclosed is a compound represented by general formula (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2) or (V).

Description

ベンゼン化合物及びその医薬用途Benzene compounds and their pharmaceutical uses
　本発明はベンゼン化合物及びその医薬としての用途に関する。 The present invention relates to a benzene compound and its use as a medicine.
　近年、シクロスポリンやＦＫ５０６のようなカルシニューリン阻害薬が臓器移植を受けた患者の拒絶反応を抑制するために使用されている。しかしながら、シクロスポリンのような、ある種のカルシニューリン阻害薬は腎毒性、肝毒性、神経毒性等の有害な副作用を起こすことがある。このため、移植患者における拒絶反応を抑えるためにさらに安全で有効性の高い薬剤の開発が進められている。
　特許文献１～３には臓器又は骨髄移植における（急性又は慢性の）拒絶反応の抑制剤として、また乾癬、ベーチェット病などの様々な自己免疫疾患及びリウマチ疾患の治療薬として有用な２－アミノプロパン－１，３－ジオール化合物を開示している。
　これらの化合物の一つである、２－アミノ－２－［２－（４－オクチルフェニル）エチル］プロパン－１，３－ジオール塩酸塩（以下、ＦＴＹ７２０と称することもある。）は腎移植における拒絶反応の抑制剤及び多発性硬化症の治療薬として現在臨床開発中の化合物である。ＦＴＹ７２０は生体内においてスフィンゴシンキナーゼによってリン酸化ＦＴＹ７２０［以下、ＦＴＹ７２０－Ｐと称することもある。例えば、２－アミノ－２－ホスホリルオキシメチル－４－（４－オクチルフェニル）ブタノールが挙げられる］に速やかに変換される。ＦＴＹ７２０－Ｐは５種類のスフィンゴシン－１－リン酸（以下、Ｓ１Ｐと称することもある。）受容体（以下、それぞれＳ１Ｐ１～５と称することもある。）の中の４種類のＳ１Ｐ受容体（Ｓ１Ｐ２以外）にアゴニストとして作用する（非特許文献１）。
　最近、Ｓ１Ｐ受容体の中のＳ１Ｐ１が胸腺及び２次リンパ系組織からの成熟リンパ球の移出に必須であることが報告された。ＦＴＹ７２０－ＰはＳ１Ｐ１アゴニストとして作用することで、リンパ球上のＳ１Ｐ１をダウンレギュレーションする。その結果、胸腺及び２次リンパ系組織からの成熟リンパ球の移出が阻害され、血中の循環成熟リンパ球を２次リンパ系組織内に隔離させることで、免疫抑制作用を発揮することが示唆されている（非特許文献２）。
　その一方で、従来の２－アミノプロパン－１，３－ジオール化合物は一過性の徐脈発現が副作用として懸念されており、この問題を解決するために、２－アミノプロパン－１，３－ジオール化合物を化学構造的に修飾した新規な化合物が多数報告されている。それらのなかで、ＦＴＹ７２０が有するベンゼン環に置換基を加えた化合物として、特許文献４はリン酸基のついたＳ１Ｐ受容体調節剤としてのアミノプロパノール誘導体、特許文献５、同６はともにＳ１Ｐ受容体調節剤としてのアミノプロパノール誘導体を開示しているが、これらの中ではベンゼン環上の置換基として、トリハロアルキル基、例えばトリフルオロメチル基は開示されていない。最近公開された特許文献７には、ＦＴＹ７２０が有するベンゼン環上の置換基がトリハロアルキル基又はシアノ基である化合物の徐脈が弱いことが開示されている。しかし、そこで開示されているそれらの化合物には、トリハロアルキル基又はシアノ基のオルト位に結合するベンゼン環上の置換基として、炭素数６～９のアルキルオキシ又はアルキルチオしか含まれておらず、アルキル基に置換基を有する化合物や、アルキル基中に不飽和結合を有する化合物などは示されていない。またこれらＦＴＹ７２０が有するベンゼン環上の置換基がトリハロアルキル基又はシアノ基である化合物の極性部分を構造修飾した化合物についても徐脈等の副作用の軽減した免疫調節剤として有望との報告はない。 In recent years, calcineurin inhibitors such as cyclosporine and FK506 have been used to suppress rejection in patients who have undergone organ transplantation. However, certain calcineurin inhibitors, such as cyclosporine, can cause adverse side effects such as nephrotoxicity, hepatotoxicity, and neurotoxicity. For this reason, development of safer and more effective drugs is being promoted to suppress rejection in transplant patients.
Patent Documents 1 to 3 describe 2-aminopropane useful as an inhibitor of (acute or chronic) rejection in organ or bone marrow transplantation, and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases. A 1,3-diol compound is disclosed.
One of these compounds, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride (hereinafter sometimes referred to as FTY720) is used in kidney transplantation. It is a compound currently in clinical development as an inhibitor of rejection and a therapeutic agent for multiple sclerosis. FTY720 is phosphorylated by sphingosine kinase in vivo, and may be referred to as FTY720 [hereinafter referred to as FTY720-P]. For example, 2-amino-2-phosphoryloxymethyl-4- (4-octylphenyl) butanol can be mentioned]. FTY720-P includes four types of S1P receptors (hereinafter also referred to as S1P1 to 5) among five types of sphingosine-1-phosphate (hereinafter also referred to as S1P) receptors (hereinafter also referred to as S1P1 to 5, respectively). It acts as an agonist (other than S1P2) (Non-patent Document 1).
Recently, it was reported that S1P1 in the S1P receptor is essential for the export of mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an S1P1 agonist, thereby down-regulating S1P1 on lymphocytes. As a result, the migration of mature lymphocytes from the thymus and secondary lymphoid tissues is inhibited, and it is suggested that the immunosuppressive effect is exhibited by isolating circulating mature lymphocytes in the blood in the secondary lymphoid tissues. (Non-Patent Document 2).
On the other hand, the conventional 2-aminopropane-1,3-diol compound is concerned about the occurrence of transient bradycardia as a side effect, and in order to solve this problem, 2-aminopropane-1,3-diol Many novel compounds obtained by chemical structural modification of diol compounds have been reported. Among them, as a compound in which a substituent is added to the benzene ring of FTY720, Patent Document 4 is an aminopropanol derivative as a S1P receptor modulator with a phosphate group, and Patent Documents 5 and 6 are both S1P acceptors. Although aminopropanol derivatives as body regulators are disclosed, trihaloalkyl groups such as trifluoromethyl groups are not disclosed as substituents on the benzene ring. Recently published Patent Document 7 discloses that the bradycardia of a compound in which the substituent on the benzene ring of FTY720 is a trihaloalkyl group or a cyano group is weak. However, those compounds disclosed therein contain only alkyloxy or alkylthio having 6 to 9 carbon atoms as substituents on the benzene ring bonded to the ortho position of the trihaloalkyl group or cyano group, A compound having a substituent in the alkyl group or a compound having an unsaturated bond in the alkyl group is not shown. In addition, there is no report as a promising immunomodulator with reduced side effects such as bradycardia for compounds in which the polar part of the compound in which the substituent on the benzene ring of FTY720 is a trihaloalkyl group or a cyano group is modified.
国際公開パンフレットＷＯ９４／０８９４３号International publication pamphlet WO94 / 08943 国際公開パンフレットＷＯ９６／０６０６８号International pamphlet WO96 / 06068 国際公開パンフレットＷＯ９８／４５４２９号International Publication Pamphlet WO 98/45429 国際公開パンフレットＷＯ０２／０７６９９５号International Publication Pamphlet WO02 / 076995 国際公開パンフレットＷＯ２００４／０９６７５２号International publication pamphlet WO2004 / 096752 国際公開パンフレットＷＯ２００４／１１０９７９号International publication pamphlet WO2004 / 110979 国際公開パンフレットＷＯ２００７／０６９７１２号International Publication Pamphlet WO2007 / 069712
　本発明の目的は、免疫抑制作用、拒絶反応抑制作用等に優れ、徐脈等の副作用が軽減された新規なベンゼン化合物を提供することにある。 An object of the present invention is to provide a novel benzene compound which is excellent in immunosuppressive action, rejection reaction inhibitory action and the like and has reduced side effects such as bradycardia.
　本発明者らは上記のような事情を考慮に入れてさらに研究を行った結果、後述するような特定の構造式を有するベンゼン化合物が所期の目的を達成できることを見出して本発明を完成した。 As a result of further studies taking the above circumstances into consideration, the present inventors have found that a benzene compound having a specific structural formula as described below can achieve the intended purpose, and completed the present invention. .
　すなわち、本発明の要旨は以下の通りである。
［１］下記一般式（ＩＩ－１）又は（ＩＩ－２） That is, the gist of the present invention is as follows.
[1] The following general formula (II-1) or (II-2)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
［式中、
ＲＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＩ－２は水酸基、炭素数１～４のアルコキシ又はハロゲン原子のいずれかで置換されていても良い炭素数１～４のアルキル、
ＲＩＩ－３は水素原子又は炭素数１～４のアルキル、
ＡＩＩ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
ｄ、当該鎖端の二重結合、三重結合。）、
ＹＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
ＡＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキル、
ＡＩＩ－２は水素原子、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、ＣＯＯＨ、ＳＯ３Ｈ、１Ｈ－テトラゾール－５－イル、ＯＨ又は炭素数１～４のアルコキシ、
ＸＩＩは酸素原子又は硫黄原子、
ＹＩＩ－１はＣＨ２ＣＨ２又はＣＨ＝ＣＨ、及び
ＺＩＩは単結合又は１～２個のフッ素原子で置換されていてもよい炭素数１～４のアルキレンを示す。］
で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２］下記一般式（Ｉ） [Where:
R II-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R II-2 is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, or an alkyl having 1 to 4 carbon atoms which may be substituted with any of halogen atoms,
R II-3 is a hydrogen atom or alkyl having 1 to 4 carbon atoms,
A II-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A II-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
Y II-2 is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
A II-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
A II-2 is a hydrogen atom, P (═O) (OH) 2 , O—P (═O) (OH) 2 , COOH, SO 3 H, 1H-tetrazol-5-yl, OH, or 1 to 4 alkoxy,
XII is an oxygen atom or a sulfur atom,
Y II-1 represents CH 2 CH 2 or CH═CH, and Z II represents a single bond or alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms. ]
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[2] The following general formula (I)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式中、
ＲＩは水素原子又はＰ（＝Ｏ）（ＯＨ）２、
ＸＩは酸素原子又は硫黄原子、
ＹＩはＣＨ２ＣＨ２又はＣＨ＝ＣＨ、
ＲＩ-１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩ-２は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ＲＩ-３及びＲＩ-４は同一又は異なっていても良く、それぞれ水素原子又は炭素数１～４のアルキル、及び
ＡＩは炭素数５～９の直鎖のアルキルを示し、ＡＩは次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有している。
ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換されている場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
ｄ、当該鎖端の二重結合、三重結合。を示す。］
で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３］下記一般式（ＩＩＩ－１）又は（ＩＩＩ－２） [Where:
R I is a hydrogen atom or P (═O) (OH) 2 ,
X I is an oxygen atom or a sulfur atom,
Y I is CH 2 CH 2 or CH═CH,
R I-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R I-2 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
R I-3 and R I-4 may be the same or different, and each represents a hydrogen atom or alkyl having 1 to 4 carbon atoms, and A I represents a straight alkyl having 5 to 9 carbon atoms, and A I represents It has 1 to 6 functional groups selected from any of the following four groups a to d.
a, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. Indicates. ]
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[3] The following general formula (III-1) or (III-2)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［式中、
ＲＩＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＩＩ－２は水素原子又はＰ（＝Ｏ）（ＯＨ）２、
ＡＩＩＩ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
ｄ、当該鎖端の二重結合、三重結合。）、
ＹＩＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
ＡＩＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキル、
ＡＩＩＩ－２は水素原子又は炭素数１～３のアルキル、
ＢＩＩＩは水素原子又は水酸基で置換されていても良いか若しくはハロゲン原子で置換されていても良い炭素数１～４のアルキルを示し、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ－２、ＢＩＩＩ及びアミノ基の結合している炭素原子が４～７員環のシクロアルカン、若しくは環の構成原子数が４～７の窒素原子を一つ含んだヘテロシクロアルカンを形成しても良く、
ＸＩＩＩ－１は酸素原子又は硫黄原子、
ＸＩＩＩ－２はメチン又は窒素原子、及び
ＹＩＩＩ－１は炭素数１～２のアルキレン又はＣ＝Ｏを示す。］
で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［４］下記一般式（ＩＶ－１）又は（ＩＶ－２） [Where:
R III-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R III-2 is a hydrogen atom or P (═O) (OH) 2 ,
A III-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A III-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
Y III-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
A III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
A III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms,
B III represents an alkyl having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group, or may be substituted with a halogen atom, and B III is bonded to A III-2 and Y III-1 , X III-2 , A III-2 , B III and the amino group to which the carbon atom is bonded include a 4- to 7-membered cycloalkane or a nitrogen atom having 4 to 7 member atoms Heterocycloalkanes may be formed,
X III-1 represents an oxygen atom or a sulfur atom,
X III-2 represents a methine or nitrogen atom, and Y III-1 represents an alkylene having 1 to 2 carbon atoms or C═O. ]
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[4] The following general formula (IV-1) or (IV-2)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［式中、
ＲＩＶ－１は、ハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＶ－２は水素原子、炭素数１～４のアルキル、炭素数１～２０のアシル、炭素数２～２１のアルコキシカルボニル、又は生体内で脱離する置換基、
ＲＩＶ－３は水素原子、Ｐ（＝Ｏ）（ＯＨ）２又はＰ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）（ＲＩＶ－５及びＲＩＶ－６はリン酸基の保護基若しくは生体内で脱離する置換基を示す。）、
ＲＩＶ－４は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ＡＩＶ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＶ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
ｄ、当該鎖端の二重結合、三重結合。）、
ＹＩＶは炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
ＡＩＶ－２は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルを示し、及び
ＸＩＶは酸素原子又は硫黄原子を示す。］
で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［５］下記一般式（Ｖ） [Where:
R IV-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R IV-2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, acyl having 1 to 20 carbon atoms, alkoxycarbonyl having 2 to 21 carbon atoms, or a substituent capable of leaving in vivo.
R IV-3 is a hydrogen atom, P (═O) (OH) 2 or P (═O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 are phosphoric acid groups A protecting group or a substituent that is eliminated in vivo).
R IV-4 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
A IV-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A IV-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
Y IV is alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
A IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Alternatively, it represents a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom, and XIV represents an oxygen atom or a sulfur atom. ]
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[5] The following general formula (V)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
［式中、
ＲＶ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＸＶは単結合、
酸素原子、
硫黄原子、
－ＳＯ－、
－ＳＯ２－、
カルボニル、
－ＮＲＶ－２－（ここで、ＲＶ－２は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、又は
下記一般式 [Where:
R V-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
XV is a single bond,
Oxygen atom,
Sulfur atom,
-SO-,
-SO 2- ,
Carbonyl,
—NR V-2 — (wherein R V-2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or an alkyl having 1 to 7 carbon atoms which may have a substituent. Acyl or C2-C7 alkoxycarbonyl), or the following general formula
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（ここで、ＲＶ－３は置換基を有していても良い炭素数１～２０のアルキル、置換基を有していても良い炭素数２～２０のアルケニル、置換基を有していても良い炭素数２～２０のアルキニル又は置換基を有していても良い炭素数１～２０のアルコキシを示す。）で表される基を示し、
ＡＶは水素原子、
置換基を有していても良い炭素数１～２０のアルキル｛当該鎖中に二重結合、三重結合、酸素原子、硫黄原子、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－４－（ここで、ＲＶ－４は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、カルボニル、置換基を有していても良い炭素数６～１０のアリーレン、置換基を有していても良い炭素数３～７のシクロアルキレン、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを有していてもよく、また、当該鎖端に二重結合、三重結合、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを有していてもよい｝、
置換基を有していても良い炭素数６～１０のアリール、
置換基を有していても良い炭素数３～７のシクロアルキル、
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示し、
ＶＶは単結合又は置換基を有していても良い炭素数１～６のアルキレンを示し、
ＹＶは単結合、酸素原子、硫黄原子、－ＣＯ－、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－５－、－ＮＲＶ－５ＣＯ－、－ＣＯＮＲＶ－５－、－ＮＲＶ－５ＳＯ２－又は－ＳＯ２ＮＲＶ－５－を示し（ここで、ＲＶ－５は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、
さらにＶＶが置換基を有していても良い炭素数１～６のアルキレンを示す場合には、ＹＶは二重結合又は三重結合であってもよく、
ｎＶは０～３、但しＹＶが二重結合又は三重結合の場合にはｎＶは１～３を示し、
ＺＶは置換基を有していても良い炭素数１～６のアルキレン、
置換基を有していても良い炭素数６～１０のアリーレン、
置換基を有していても良い炭素数３～７のシクロアルキレン、
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレン
（但し、ＹＶが二重結合の場合には、
置換基を有していても良い炭素数１～６のアルキレン、
置換基を有していても良い炭素数３～７のシクロアルキレン又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを示し、
ＹＶが三重結合の場合には、
置換基を有していても良い炭素数１～６のアルキレンを示し、
さらに、ｎｖが２又は３の場合、ＺＶは同一であっても又は異なっていても良い。）
を示し、及び
ＢＶは水素原子、
ＣＯＯＲＶ－６（ここで、ＲＶ－６は水素原子又は炭素数１～４のアルキル若しくは生体内で脱離する置換基を示す。）、
ＳＯ３ＲＶ－６（ここで、ＲＶ－６は上記と同義を示す。）、
Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）、
Ｏ－Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）（ここで、ＲＶ－７及びＲＶ－８は水素原子、リン酸基の保護基、又は生体内で脱離する置換基を示す。）、
シアノ、
－ＣＯ－ＮＨ－ＳＯ２－ＲＶ－９（ここで、ＲＶ－９は置換基を有しても良い炭素数１～６のアルキル、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子又は硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示す。）、
ＯＨ、又は
下記式 (Here, R V-3 has an optionally substituted alkyl having 1 to 20 carbon atoms, an optionally substituted alkenyl having 2 to 20 carbon atoms, and a substituent. Or a alkynyl group having 2 to 20 carbon atoms or an alkoxy group having 1 to 20 carbon atoms which may have a substituent.
A V is a hydrogen atom,
Optionally substituted alkyl having 1 to 20 carbon atoms {double bond, triple bond, oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR V-4 — ( Here, R V-4 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, an acyl having 1 to 7 carbon atoms which may have a substituent, or 2 to 7 carbon atoms. A carbonyl, an arylene having 6 to 10 carbon atoms which may have a substituent, a cycloalkylene having 3 to 7 carbon atoms which may have a substituent, and a substituent. A heteroarylene having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 ring constituent atoms, or optionally having 1 to 2 substituents A ring containing one nitrogen atom, oxygen atom or sulfur atom as a constituent atom of the ring It may have a heterocycloalkylene having 3 to 7 member atoms, and may have a double bond, a triple bond or a substituent at the chain end. A ring-constituting atom containing an optionally substituted cycloalkyl having 3 to 7 carbon atoms, an optionally substituted nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. Heteroaryl having a number of 5 to 10 or a hetero atom having 3 to 7 ring atoms containing 1 to 2 optionally substituted nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms May have cycloalkyl},
Aryl having 6 to 10 carbon atoms which may have a substituent,
A cycloalkyl having 3 to 7 carbon atoms which may have a substituent,
A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as a ring constituting atom, or a substituent Or a heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms,
V V represents a single bond or an alkylene having 1 to 6 carbon atoms which may have a substituent,
Y V is a single bond, oxygen atom, sulfur atom, —CO—, —SO—, —SO 2 —, —NR V-5 —, —NR V-5 CO—, —CONR V-5 —, —NR V -5 SO 2 -or -SO 2 NR V-5- (wherein R V-5 has a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or a substituent. An optionally substituted acyl having 1 to 7 carbon atoms or alkoxycarbonyl having 2 to 7 carbon atoms).
In addition, when V V represents an optionally substituted alkylene having 1 to 6 carbon atoms, Y V may be a double bond or a triple bond,
n V is 0-3, provided that n V when Y V is a double bond or triple bond represents a 1-3,
Z V is an alkylene having 1 to 6 carbon atoms which may have a substituent,
Arylene having 6 to 10 carbon atoms which may have a substituent,
A cycloalkylene having 3 to 7 carbon atoms which may have a substituent,
An optionally substituted heteroarylene having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, or having a substituent; also good 1-2 nitrogen atoms, heterocycloalkylene of constituting atoms is 3 to 7 rings containing an oxygen atom or a sulfur atom as a constituent atom of the ring (however, if Y V is a double bond,
Alkylene having 1 to 6 carbons which may have a substituent,
Ring structure containing optionally substituted cycloalkylene having 3 to 7 carbon atoms or optionally having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent. Represents heterocycloalkylene having 3 to 7 atoms,
If Y V is a triple bond,
An alkylene having 1 to 6 carbon atoms which may have a substituent;
Furthermore, when n v is 2 or 3, Z V may be the same or different. )
And B V is a hydrogen atom,
COOR V-6 (wherein R V-6 represents a hydrogen atom, an alkyl having 1 to 4 carbon atoms, or a substituent capable of leaving in vivo),
SO 3 R V-6 (where R V-6 has the same meaning as above),
P (= O) (OR V-7 ) (OR V-8 ),
OP (= O) (OR V-7 ) (OR V-8 ) (where R V-7 and R V-8 are hydrogen atoms, phosphate protecting groups, or are eliminated in vivo. Represents a substituent).
Cyano,
—CO—NH—SO 2 —R V-9 (where R V-9 is an alkyl having 1 to 6 carbon atoms which may have a substituent, and 6 to 6 carbon atoms which may have a substituent) 10 aryls, optionally substituted cycloalkyl having 3 to 7 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms A ring containing 5 to 10 heteroaryl atoms or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 ring atoms Represents a heterocycloalkyl of ˜7),
OH or the following formula
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
で表される基を示す。］
で表される化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［６］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-３が水素原子である上記［１］に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［７］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＸＩＩが酸素原子である上記［１］又は［６］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［８］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＹＩＩ－１がＣＨ２ＣＨ２である上記［１］又は［６］～［７］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［９］一般式（ＩＩ－１）中、
ＡＩＩ－１が炭素数５～９の直鎖のアルキルであるか、
一般式（ＩＩ－２）中、
ＡＩＩ－３が置換されていても良い炭素数６～１０のアリール又は
置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリール
である上記［１］又は［６］～［８］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１０］一般式（ＩＩ－２）中、
ＡＩＩ－３は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
ハロゲン原子；
炭素数６～１０のアリールから選択される置換基である
上記［１］又は［６］～［９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１１］一般式（ＩＩ－２）中、ＡＩＩ－３が下記一般式 The group represented by these is shown. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[6] The compound according to the above [1], wherein R II-3 is a hydrogen atom in general formula (II-1) or (II-2), or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof Hydrates or solvates.
[7] The compound according to any one of the above [1] or [6], wherein X II is an oxygen atom in general formula (II-1) or (II-2), or a pharmaceutically acceptable acid addition thereof Salts, or hydrates or solvates thereof.
[8] The compound according to any one of [1] or [6] to [7] above, wherein Y II-1 is CH 2 CH 2 in the general formula (II-1) or (II-2), or A pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[9] In general formula (II-1),
A II-1 is straight-chain alkyl having 5 to 9 carbon atoms,
In general formula (II-2),
A II-3 is an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted 1 to 2 sulfur atom or oxygen atom as a ring constituting atom, 9. The compound according to any one of [1] or [6] to [8] above, which is 9 heteroaryl, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[10] In general formula (II-2),
When A II-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each may be substituted with a halogen atom. Good alkyl of 1 to 4 carbons;
Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
A halogen atom;
The compound according to any one of the above [1] or [6] to [9], which is a substituent selected from aryl having 6 to 10 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, or water thereof Japanese solvate or solvate.
[11] In general formula (II-2), A II-3 represents the following general formula
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（式中、
ＲＩＩ－４及びＲＩＩ－５は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ、又は
ハロゲン原子を示す。）
で表される基である上記［１］又は［６］～［１０］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１２］一般式（ＩＩ－２）中、ＹＩＩ－２がトリメチレンである上記［１］又は［６］～［１１］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１３］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-１がトリフルオロメチルである上記［１］又は［６］～［１２］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１４］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-２がヒドロキシメチルである上記［１］又は［６］～［１３］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１５］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＡＩＩ－２が水素原子、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２又はＣＯＯＨである上記［１］又は［６］～［１４］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１６］一般式（ＩＩ－１）又は（ＩＩ－２）中、ＺＩＩが単結合又は炭素数１～４のアルキルである上記［１］又は［６］～［１５］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１７］一般式（Ｉ）中、ＲＩ-３及びＲＩ-４がともに水素原子である上記［２］に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１８］一般式（Ｉ）中、ＸＩが酸素原子である上記［２］又は［１７］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［１９］一般式（Ｉ）中、ＹＩがＣＨ２ＣＨ２である上記［２］又は［１７］～［１８］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２０］一般式（Ｉ）中、
ＡＩは炭素数５～９の直鎖のアルキルを示し、以下ａ～ｄのいずれか１つの官能基
（ａ、炭素数１～６のアルキル。
ｂ、フッ素原子。
ｃ、当該鎖中の、二重結合、三重結合。又は
ｄ、当該鎖端の二重結合、三重結合。）
を有する上記［２］又は［１７］～［１９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２１］一般式（Ｉ）中、ＲＩ-１がトリフルオロメチルである上記［２］又は［１７］～［２０］いずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２２］一般式（Ｉ）中、ＲＩ-２がヒドロキシメチルである上記［２］又は［１７］～［２１］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２３］一般式（Ｉ）中、ＲＩが水素原子である上記［２］又は［１７］～［２２］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２４］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ－１が酸素原子である上記［３］に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２５］一般式（ＩＩＩ－１）中、ＡＩＩＩ－１が炭素数５～９の直鎖のアルキルであるか、一般式（ＩＩＩ－２）中、ＡＩＩＩ－３が置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールである上記［３］又は［２４］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２６］一般式（ＩＩＩ－２）中、ＡＩＩＩ－３は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；ハロゲン原子；炭素数６～１０のアリールから選択される置換基である上記［３］又は［２４］～［２５］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２７］一般式（ＩＩＩ－２）中、ＡＩＩＩ－３が下記一般式 (Where
R II-4 and R II-5 may be the same or different and each is a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom,
An alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a halogen atom is shown. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or a solvate thereof. The compound according to any one of [1] or [6] to [10] above,
[12] The compound according to any one of the above [1] or [6] to [11], wherein Y II-2 is trimethylene in general formula (II-2), or a pharmaceutically acceptable acid addition salt thereof Or a hydrate or solvate thereof.
[13] The compound according to any one of the above [1] or [6] to [12], wherein R II-1 is trifluoromethyl in the general formula (II-1) or (II-2), or a compound thereof Pharmaceutically acceptable acid addition salts, or hydrates or solvates thereof.
[14] The compound according to any one of [1] or [6] to [13] above, wherein R II-2 is hydroxymethyl in general formula (II-1) or (II-2), or a pharmaceutical product thereof A top acceptable acid addition salt, or a hydrate or solvate thereof.
[15] In general formula (II-1) or (II-2), A II-2 is a hydrogen atom, P (═O) (OH) 2 , O—P (═O) (OH) 2 or COOH. A compound according to any one of the above [1] or [6] to [14], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[16] In any one of the above [1] or [6] to [15], in the general formula (II-1) or (II-2), Z II is a single bond or alkyl having 1 to 4 carbon atoms. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[17] The compound according to the above [2], wherein R I-3 and R I-4 are both hydrogen atoms in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Or solvate.
[18] The compound according to any one of the above [2] or [17], wherein X I is an oxygen atom in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof Or a solvate.
[19] The compound according to any one of the above [2] or [17] to [18], wherein Y I is CH 2 CH 2 in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
[20] In general formula (I),
A I represents straight-chain alkyl having 5 to 9 carbon atoms, and any one of functional groups a to d below (a, alkyl having 1 to 6 carbon atoms.
b, a fluorine atom.
c, a double bond or a triple bond in the chain. Or d, a double bond or a triple bond at the chain end. )
The compound according to any one of the above [2] or [17] to [19], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[21] The compound according to any one of the above [2] or [17] to [20], wherein R I-1 is trifluoromethyl in general formula (I), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
[22] The compound according to any one of the above [2] or [17] to [21], wherein R I-2 is hydroxymethyl in general formula (I), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
[23] The compound according to any one of the above [2] or [17] to [22], wherein R I is a hydrogen atom in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or Hydrate or solvate of
[24] The compound of the above-mentioned [3], wherein X III-1 is an oxygen atom in general formula (III-1) or (III-2), or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof Hydrates or solvates.
[25] In general formula (III-1), A III-1 is a linear alkyl having 5 to 9 carbon atoms, or A III-3 in general formula (III-2) is substituted. [3] The above [3], which is a good aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 9 ring atoms containing 1 to 2 optionally substituted sulfur atoms or oxygen atoms as ring constituting atoms Or the compound according to any one of [24], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[26] In General Formula (III-2), when A III-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent is the same or different. Each selected from alkyl having 1 to 4 carbon atoms optionally substituted with a halogen atom; alkoxy having 1 to 4 carbon atoms optionally substituted with a halogen atom; halogen atom; aryl having 6 to 10 carbon atoms Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The compound according to any one of [3] or [24] to [25] above,
[27] In general formula (III-2), A III-3 represents the following general formula
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
（式中、ＲＩＩＩ－３及びＲＩＩＩ－４は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基である上記［３］又は［２４］～［２６］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２８］一般式（ＩＩＩ－２）中、ＹＩＩＩ－２がトリメチレンである上記［３］又は［２４］～［２７］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［２９］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＲＩＩＩ-１がトリフルオロメチルである上記［３］又は［２４］～［２８］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３０］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２がメチンである場合、ＹＩＩＩ-１がメチレンで、ＡＩＩＩ-２及びＢＩＩＩがともに炭素数１～３のアルキルである上記［３］又は［２４］～［２９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３１］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２がメチンで、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ-２、ＢＩＩＩ及びアミノ基が結合している炭素原子がシクロペンチルを形成する上記［３］又は［２４］～［２９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３２］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２が窒素原子である場合、ＹＩＩＩ-１がＣ＝Ｏ、ＢＩＩＩが水素原子又はメチルである上記［３］又は［２４］～［２９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３３］一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＲＩＩＩ－２が水素原子である上記［３］又は［２４］～［３２］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３４］一般式（ＩＶ－１）又は（ＩＶ－２）中、ＸＩＶが酸素原子である上記［４］に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３５］一般式（ＩＶ－１）中、ＡＩＶ－１が炭素数５～９の直鎖のアルキルであるか、
一般式（ＩＶ－２）中、ＡＩＶ－２が置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールである上記［４］又は［３４］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３６］一般式（ＩＶ－２）中、ＡＩＶ－２は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
ハロゲン原子；
炭素数６～１０のアリール
から選択される置換基である上記［４］又は［３４］～［３５］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３７］一般式（ＩＶ－２）中、ＡＩＶ－２が下記一般式 (In the formula, R III-3 and R III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable compound thereof, or a pharmaceutically acceptable compound thereof according to any one of [3] or [24] to [26] above, Acid addition salts, or hydrates or solvates thereof.
[28] The compound according to any one of the above [3] or [24] to [27], wherein Y III-2 is trimethylene in general formula (III-2), or a pharmaceutically acceptable acid addition salt thereof Or a hydrate or solvate thereof.
[29] The compound according to any one of the above [3] or [24] to [28], wherein R III-1 is trifluoromethyl in the general formula (III-1) or (III-2), or a compound thereof Pharmaceutically acceptable acid addition salts, or hydrates or solvates thereof.
[30] In the general formula (III-1) or (III-2), when X III-2 is methine, Y III-1 is methylene, and A III-2 and B III both have 1 to 3 carbon atoms. The compound according to any one of the above [3] or [24] to [29], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[31] In general formula (III-1) or (III-2), X III-2 is methine, B III is bound to A III-2, and Y III-1 , X III-2 , A III- 2 , the compound according to any one of the above [3] or [24] to [29], wherein the carbon atom to which B III and the amino group are bonded forms cyclopentyl, or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
[32] In the general formula (III-1) or (III-2), when X III-2 is a nitrogen atom, Y III-1 is C═O and B III is a hydrogen atom or methyl. ] Or the compound according to any one of [24] to [29], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[33] The compound according to any one of [3] or [24] to [32] above, wherein R III-2 is a hydrogen atom in general formula (III-1) or (III-2), or a pharmaceutical product thereof A top acceptable acid addition salt, or a hydrate or solvate thereof.
[34] The compound according to [4], wherein XIV is an oxygen atom in general formula (IV-1) or (IV-2), or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Or solvate.
[35] In the general formula (IV-1), A IV-1 is a linear alkyl having 5 to 9 carbon atoms,
In general formula (IV-2), A IV-2 may be substituted aryl having 6 to 10 carbon atoms or optionally substituted 1 or 2 sulfur atoms or oxygen atoms as ring constituent atoms. The compound according to any one of the above [4] or [34], which is a heteroaryl having 5 to 9 ring atoms, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or Solvate.
[36] In the general formula (IV-2), when A IV-2 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent is the same or different. Each having 1 to 4 carbon atoms optionally substituted with a halogen atom;
Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
A halogen atom;
The compound according to any one of the above [4] or [34] to [35], which is a substituent selected from aryl having 6 to 10 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, or water thereof Japanese solvate or solvate.
[37] In general formula (IV-2), A IV-2 represents the following general formula
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（式中、ＲＩＶ－７及びＲＩＶ－８は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基である上記［４］又は［３４］～［３６］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３８］一般式（ＩＶ－２）中、ＹＩＶがトリメチレンである、上記［４］又は［３４］～［３７］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［３９］一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－１がトリフルオロメチルである上記［４］又は［３４］～［３８］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［４０］一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－２が生体内で脱離する置換基、ＲＩＶ－３が水素原子である上記［４］又は［３４］～［３９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［４１］一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－２が水素原子、ＲＩＶ－３がＰ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）（ＲＩＶ－５及びＲＩＶ－６は生体内で脱離する置換基を示す。）である上記［４］又は［３４］～［３９］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
［４２］一般式（Ｖ）中、ＢｖがＣＯＯＲｖ－６、Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）、Ｏ－Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）又はＯＨである上記［５］に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４３］一般式（Ｖ）中、Ｙｖが単結合、－ＮＲｖ－５－、－ＮＲｖ－５ＣＯ－又は－ＣＯＮＲｖ－５－である上記［５］又は［４２］のいずれかに記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４４］一般式（Ｖ）中、Ｚｖが置換基を有していても良い炭素数１～６のアルキレン、置換基を有していても良い炭素数６～１０のアリーレン又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンである上記［５］又は［４２］～［４３］のいずれかに記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４５］一般式（Ｖ）中、ｎｖが１である上記［５］又は［４２］～［４４］のいずれかに記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４６］一般式（Ｖ）中、Ｒｖ－１がトリフルオロメチル又はシアノである上記［５］又は［４２］～［４５］のいずれかに記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４７］一般式（Ｖ）中、Ｘｖが単結合、酸素原子、硫黄原子、カルボニル又は－ＮＲｖ－２－である上記［５］又は［４２］～［４６］のいずれかに記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４８］以下のａ～ｍのいずれかである上記［１］～［４７］のいずれかに記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
　ａ．２－アミノ－２－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｂ．２－アミノ－４－｛４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｃ．２－アミノ－２－｛２－［４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｄ．２－アミノ－４－｛４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｅ．２－アミノ－２－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｆ．２－アミノ－４－｛４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｇ．［３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンチル］ホスホン酸、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｈ．［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｉ．リン酸モノ｛［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メチル｝エステル、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
　ｊ．２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エタノール、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
　ｋ．リン酸モノ（２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エチル）エステル、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
　ｌ．（３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピル）ホスホン酸、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
　ｍ．１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。
［４９］上記［１］～［４８］のいずれかの化合物及び製薬上許容しうる担体を含有する医薬組成物。
［５０］自己免疫疾患の治療又は予防；器官又は組織の移植に対する抵抗又は急性拒絶反応若しくは慢性拒絶反応の予防又は抑制；骨髄移植による移植片対宿主（ＧｖＨ）病の治療又は予防；及び／又はアレルギー性疾患治療又は予防のために用いられる上記［４９］に記載の医薬組成物。
［５１］自己免疫疾患が関節リウマチ、多発性硬化症、脳脊髄炎、全身性エリテマトーデス、ループス腎炎、ネフローゼ症候群、乾癬及び／又はＩ型糖尿病である上記［５０］に記載の医薬組成物。
［５２］アレルギー性疾患がアトピー性皮膚炎、アレルギー性鼻炎及び／又は喘息である上記［５０］に記載の医薬組成物。 (In the formula, R IV-7 and R IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable compound thereof, or a pharmaceutically acceptable compound thereof according to any one of the above [4] or [34] to [36], which is a group represented by the following formula: Acid addition salts, or hydrates or solvates thereof.
[38] The compound according to any one of the above [4] or [34] to [37], wherein Y IV is trimethylene in the general formula (IV-2), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.
[39] The compound according to [4] or [34] to [38], wherein R IV-1 is trifluoromethyl in the general formula (IV-1) or (IV-2), or a compound thereof Pharmaceutically acceptable acid addition salts, or hydrates or solvates thereof.
[40] In the above general formula (IV-1) or (IV-2), R IV-2 is a substituent capable of leaving in vivo, and R IV-3 is a hydrogen atom. [39] The compound according to any one of [39], or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
[41] In the general formula (IV-1) or (IV-2), R IV-2 is a hydrogen atom, R IV-3 is P (═O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 represent a substituent that is eliminated in vivo.) The compound according to any one of [4] or [34] to [39] above, or a pharmaceutically acceptable salt thereof Acid addition salts, or hydrates or solvates thereof.
[42] In the general formula (V), B v is COOR v-6 , P (═O) (OR v−7 ) (OR v−8 ), O—P (═O) (OR v−7 ) ( OR v-8 ) or OH, or a pharmaceutically acceptable salt or hydrate or solvate thereof.
[43] Any one of the above [5] or [42], wherein in general formula (V), Y v is a single bond, —NR v-5 —, —NR v-5 CO— or —CONR v-5 —. Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[44] In the general formula (V), Z v represents an alkylene having 1 to 6 carbon atoms which may have a substituent, an arylene having 6 to 10 carbon atoms which may have a substituent, or a substituent. The above [5] or [42], which is a heterocycloalkylene having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have [43] The compound according to any one of the above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[45] The compound according to any one of the above [5] or [42] to [44], wherein n v is 1 in the general formula (V), or a pharmaceutically acceptable salt thereof, or a hydration thereof Or solvate.
[46] The compound according to any one of the above [5] or [42] to [45], wherein R v-1 is trifluoromethyl or cyano, or a pharmaceutically acceptable salt thereof, in the general formula (V) Or a hydrate or solvate thereof.
[47] In the general formula (V), X v is a single bond, an oxygen atom, a sulfur atom, carbonyl, or —NR v-2 —, or any one of the above [5] or [42] to [46] A compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[48] The compound according to any one of the above [1] to [47], which is any of the following a to m, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof: object.
a. 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrates or solvates of
b. 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Product, or solvate,
c. 2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrates or solvates of
d. 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Product, or solvate,
e. 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or Hydrates or solvates of
f. 2-Amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Product, or solvate,
g. [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or a solvate,
h. [1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof,
i. Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese,
j. 2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethanol, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof,
k. Phosphoric acid mono (2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethyl) ester, or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof,
l. (3-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} propyl) phosphonic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof,
m. 1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
[49] A pharmaceutical composition comprising a compound according to any of [1] to [48] above and a pharmaceutically acceptable carrier.
[50] Treatment or prevention of autoimmune disease; resistance to organ or tissue transplantation or prevention or suppression of acute or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; and / or The pharmaceutical composition according to the above [49], which is used for treatment or prevention of allergic diseases.
[51] The pharmaceutical composition according to the above [50], wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis and / or type I diabetes.
[52] The pharmaceutical composition according to the above [50], wherein the allergic disease is atopic dermatitis, allergic rhinitis and / or asthma.
　本発明によれば、優れた末梢血リンパ球減少作用を有し、徐脈等の副作用が軽減された新規な化合物を提供可能である。 According to the present invention, it is possible to provide a novel compound having excellent peripheral blood lymphocyte depletion action and reduced side effects such as bradycardia.
　以下に本発明の詳細を説明する。
　以下、上記一般式（Ｉ）、（ＩＩ－１）、（ＩＩ－２）、（ＩＩＩ－１）、（ＩＩＩ－２）、（ＩＶ－１）、（ＩＶ－２）及び（Ｖ）で表される化合物を、各々、化合物（Ｉ）、化合物（ＩＩ－１）、化合物（ＩＩ－２）、化合物（ＩＩＩ－１）、化合物（ＩＩＩ－２）、化合物（ＩＶ－１）、化合物（ＩＶ－２）及び化合物（Ｖ）と表記することもある。 Details of the present invention will be described below.
Hereinafter, it is represented by the general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2) and (V). The compounds obtained are respectively referred to as compound (I), compound (II-1), compound (II-2), compound (III-1), compound (III-2), compound (IV-1), compound (IV -2) and compound (V).
　本発明化合物は、下記一般式（Ｉ） The compound of the present invention has the following general formula (I)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
（式中、
ＲＩは水素原子又はＰ（＝Ｏ）（ＯＨ）２、
ＸＩは酸素原子又は硫黄原子、
ＹＩはＣＨ２ＣＨ２又はＣＨ＝ＣＨ、
ＲＩ-１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩ-２は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ＲＩ-３及びＲＩ-４は同一又は異なっていても良く、それぞれ水素原子又は炭素数１～４のアルキル、
ＡＩは炭素数５～９の直鎖のアルキルを示し、ＡＩは次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有している。
ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。
ｄ、当該鎖端の二重結合、三重結合。
を示す。）、 (Where
R I is a hydrogen atom or P (═O) (OH) 2 ,
X I is an oxygen atom or a sulfur atom,
Y I is CH 2 CH 2 or CH═CH,
R I-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R I-2 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
R I-3 and R I-4 may be the same or different and are each a hydrogen atom or an alkyl having 1 to 4 carbon atoms,
A I represents straight-chain alkyl having 5 to 9 carbon atoms, and A I has 1 to 6 functional groups selected from any of the following four groups a to d.
a, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
d, double bond and triple bond at the chain end.
Indicates. ),
下記一般式（ＩＩ－１）、（ＩＩ－２） The following general formulas (II-1) and (II-2)
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（式中、
ＲＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＩ－２は水酸基、炭素数１～４のアルコキシ又はハロゲン原子のいずれかで置換されていても良い炭素数１～４のアルキル、
ＲＩＩ－３は水素原子又は炭素数１～４のアルキル、
ＡＩＩ－１は炭素数５～９の直鎖のアルキルを示し、
ＡＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。
ｄ、当該鎖端の二重結合、三重結合。）、
ＹＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレンを示し、
ＡＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルを示し、
ＡＩＩ－２は水素原子又はＰ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、ＣＯＯＨ、ＳＯ３Ｈ、１Ｈ－テトラゾール－５－イル、ＯＨ又は炭素数１～４のアルコキシ、
ＸＩＩは酸素原子又は硫黄原子、
ＹＩＩ－１はＣＨ２ＣＨ２又はＣＨ＝ＣＨ、
ＺＩＩは単結合若しくは１～２個のフッ素原子で置換されていてもよい炭素数１～４のアルキレン
を示す。）、 (Where
R II-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R II-2 is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, or an alkyl having 1 to 4 carbon atoms which may be substituted with any of halogen atoms,
R II-3 is a hydrogen atom or alkyl having 1 to 4 carbon atoms,
A II-1 represents straight-chain alkyl having 5 to 9 carbon atoms,
A II-1 may have 1 to 6 functional groups selected from any of the following four groups a to d (a, alkyl having 1 to 6 carbon atoms; the same carbon atom) When two alkyl groups are substituted, the two alkyl groups and the carbon atom to which they are bonded can form a cycloalkyl having 3 to 6 carbon atoms.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
d, double bond and triple bond at the chain end. ),
Y II-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
A II-3 is an optionally substituted aryl having 6 to 10 carbon atoms, or an optionally substituted 1 to 2 nitrogen atom, oxygen atom or sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
A II-2 is a hydrogen atom or P (═O) (OH) 2 , O—P (═O) (OH) 2 , COOH, SO 3 H, 1H-tetrazol-5-yl, OH, or 1 to 4 alkoxy,
XII is an oxygen atom or a sulfur atom,
Y II-1 is CH 2 CH 2 or CH═CH,
Z II represents a single bond or alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms. ),
下記一般式（ＩＩＩ－１）、（ＩＩＩ－２） The following general formulas (III-1) and (III-2)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
（式中、
ＲＩＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＩＩ－２は水素原子又はＰ（＝Ｏ）（ＯＨ）２、
ＡＩＩＩ－１は炭素数５～９の直鎖のアルキルを示し、
ＡＩＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。
ｄ、当該鎖端の二重結合、三重結合）、
ＹＩＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレンを示し、
ＡＩＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルを示し、
ＡＩＩＩ－２は水素原子又は炭素数１～３のアルキル、
ＢＩＩＩは水素原子又は水酸基で置換されていても良いか若しくはハロゲン原子で置換されていても良い炭素数１～４のアルキルを示し、
ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ－２、ＢＩＩＩ及びアミノ基の結合している炭素原子が４～７員環のシクロアルカン、若しくは環の構成原子数が４～７の窒素原子を一つ含んだヘテロシクロアルカンを形成しても良く、
ＸＩＩＩ－１は酸素原子又は硫黄原子、
ＸＩＩＩ－２はメチン又は窒素原子、
ＹＩＩＩ－１は炭素数１～２のアルキレン又はＣ＝Ｏ
を示す。）、 (Where
R III-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R III-2 is a hydrogen atom or P (═O) (OH) 2 ,
A III-1 represents straight-chain alkyl having 5 to 9 carbon atoms,
A III-1 may have 1 to 6 functional groups selected from any of the following four groups a to d (a, alkyl having 1 to 6 carbon atoms; the same carbon atom) When two alkyl groups are substituted, the two alkyl groups and the carbon atom to which they are bonded can form a cycloalkyl having 3 to 6 carbon atoms.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
d, double bond at the chain end, triple bond),
Y III-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
A III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
A III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms,
B III represents a C 1-4 alkyl which may be substituted with a hydrogen atom or a hydroxyl group, or may be substituted with a halogen atom;
B III is bonded to A III-2, and Y III-1 , X III-2 , A III-2 , B III and a cycloalkane having 4 to 7 membered carbon atoms to which the amino group is bonded, or a ring A heterocycloalkane containing one nitrogen atom having 4 to 7 constituent atoms may be formed,
X III-1 represents an oxygen atom or a sulfur atom,
X III-2 is a methine or nitrogen atom,
Y III-1 represents alkylene having 1 to 2 carbon atoms or C═O.
Indicates. ),
下記一般式（ＩＶ－１）、（ＩＶ－２） The following general formulas (IV-1) and (IV-2)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、
ＲＩＶ－１は、ハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＲＩＶ－２は水素原子又は炭素数１～４のアルキル、炭素数１～２０のアシル又は炭素数２～２１のアルコキシカルボニル、若しくは生体内で脱離する置換基、
ＲＩＶ－３は水素原子、Ｐ（＝Ｏ）（ＯＨ）２又はＰ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）（ＲＩＶ－５及びＲＩＶ－６はリン酸基の保護基若しくは生体内で脱離する置換基を示す。）、
ＲＩＶ－４は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ＡＩＶ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＶ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
（ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
ｂ、ハロゲン原子。
ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。
ｄ、当該鎖端の二重結合、三重結合。）、
ＹＩＶは炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレンを示し、
ＡＩＶ－２は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルを示し、
ＸＩＶは酸素原子又は硫黄原子
を示す。）、又は (Where
R IV-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
R IV-2 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, acyl having 1 to 20 carbon atoms or alkoxycarbonyl having 2 to 21 carbon atoms, or a substituent capable of leaving in vivo.
R IV-3 is a hydrogen atom, P (═O) (OH) 2 or P (═O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 are phosphoric acid groups A protecting group or a substituent that is eliminated in vivo).
R IV-4 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
A IV-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A IV-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
b, a halogen atom.
c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain.
d, double bond and triple bond at the chain end. ),
Y IV represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
A IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted 1 to 2 nitrogen atom, oxygen atom or sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
X IV represents an oxygen atom or a sulfur atom. ), Or
下記一般式（Ｖ） The following general formula (V)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
（式中、
ＲＶ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
ＸＶは単結合、
酸素原子、
硫黄原子、
－ＳＯ－、
－ＳＯ２－、
カルボニル、
－ＮＲＶ－２－（ここで、ＲＶ－２は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、又は
下記一般式 (Where
R V-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
XV is a single bond,
Oxygen atom,
Sulfur atom,
-SO-,
-SO 2- ,
Carbonyl,
—NR V-2 — (wherein R V-2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or an alkyl having 1 to 7 carbon atoms which may have a substituent. Acyl or C2-C7 alkoxycarbonyl), or the following general formula
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（ここで、ＲＶ－３は置換基を有していても良い炭素数１～２０のアルキル、置換基を有していても良い炭素数２～２０のアルケニル、置換基を有していても良い炭素数２～２０のアルキニル又は置換基を有していても良い炭素数１～２０のアルコキシを示す。）で表される基を示し、
ＡＶは水素原子、
置換基を有していても良い炭素数１～２０のアルキル｛当該鎖中に二重結合、三重結合、酸素原子、硫黄原子、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－４－（ここで、ＲＶ－４は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、カルボニル、置換基を有していても良い炭素数６～１０のアリーレン、置換基を有していても良い炭素数３～７のシクロアルキレン、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを有していてもよく、また、当該鎖端に二重結合、三重結合、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを有していてもよい｝、
置換基を有していても良い炭素数６～１０のアリール、
置換基を有していても良い炭素数３～７のシクロアルキル、
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示し、
ＶＶは単結合又は置換基を有していても良い炭素数１～６のアルキレンを示し、
ＹＶは単結合、酸素原子、硫黄原子、－ＣＯ－、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－５－、－ＮＲＶ－５ＣＯ－、－ＣＯＮＲＶ－５－、－ＮＲＶ－５ＳＯ２－又は－ＳＯ２ＮＲＶ－５－を示し（ここで、ＲＶ－５は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、
さらにＶＶが置換基を有していても良い炭素数１～６のアルキレンを示す場合には、ＹＶは二重結合又は三重結合であってもよく、
ｎＶは０～３、但しＹＶが二重結合又は三重結合の場合にはｎＶは１～３を示し、
ＺＶは置換基を有していても良い炭素数１～６のアルキレン、
置換基を有していても良い炭素数６～１０のアリーレン、
置換基を有していても良い炭素数３～７のシクロアルキレン、
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレン
（但し、ＹＶが二重結合の場合には、
置換基を有していても良い炭素数１～６のアルキレン、
置換基を有していても良い炭素数３～７のシクロアルキレン又は
置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを示し、
ＹＶが三重結合の場合には、
置換基を有していても良い炭素数１～６のアルキレンを示し、
さらに、ｎｖが２又は３の場合、ＺＶは同一であっても又は異なっていても良い。）
を示し、及び
ＢＶは水素原子、
ＣＯＯＲＶ－６（ここで、ＲＶ－６は水素原子又は炭素数１～４のアルキル若しくは生体内で脱離する置換基を示す。）、
ＳＯ３ＲＶ－６（ここで、ＲＶ－６は上記と同義を示す。）、
Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）、
Ｏ－Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）（ここで、ＲＶ－７及びＲＶ－８は水素原子、リン酸基の保護基、又は生体内で脱離する置換基を示す。）、
シアノ、
－ＣＯ－ＮＨ－ＳＯ２－ＲＶ－９（ここで、ＲＶ－９は置換基を有しても良い炭素数１～６のアルキル、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子又は硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示す。）、
ＯＨ、又は
下記式 (Here, R V-3 has an optionally substituted alkyl having 1 to 20 carbon atoms, an optionally substituted alkenyl having 2 to 20 carbon atoms, and a substituent. Or a alkynyl group having 2 to 20 carbon atoms or an alkoxy group having 1 to 20 carbon atoms which may have a substituent.
A V is a hydrogen atom,
Optionally substituted alkyl having 1 to 20 carbon atoms {double bond, triple bond, oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR V-4 — ( Here, R V-4 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, an acyl having 1 to 7 carbon atoms which may have a substituent, or 2 to 7 carbon atoms. A carbonyl, an arylene having 6 to 10 carbon atoms which may have a substituent, a cycloalkylene having 3 to 7 carbon atoms which may have a substituent, and a substituent. A heteroarylene having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 ring constituent atoms, or optionally having 1 to 2 substituents A ring containing one nitrogen atom, oxygen atom or sulfur atom as a constituent atom of the ring It may have a heterocycloalkylene having 3 to 7 member atoms, and may have a double bond, a triple bond or a substituent at the chain end. A ring-constituting atom containing an optionally substituted cycloalkyl having 3 to 7 carbon atoms, an optionally substituted nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. Heteroaryl having a number of 5 to 10 or a hetero atom having 3 to 7 ring atoms containing 1 to 2 optionally substituted nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms May have cycloalkyl},
Aryl having 6 to 10 carbon atoms which may have a substituent,
A cycloalkyl having 3 to 7 carbon atoms which may have a substituent,
A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as a ring constituting atom, or a substituent Or a heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms,
V V represents a single bond or an alkylene having 1 to 6 carbon atoms which may have a substituent,
Y V is a single bond, oxygen atom, sulfur atom, —CO—, —SO—, —SO 2 —, —NR V-5 —, —NR V-5 CO—, —CONR V-5 —, —NR V -5 SO 2 -or -SO 2 NR V-5- (wherein R V-5 has a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or a substituent. An optionally substituted acyl having 1 to 7 carbon atoms or alkoxycarbonyl having 2 to 7 carbon atoms).
In addition, when V V represents an optionally substituted alkylene having 1 to 6 carbon atoms, Y V may be a double bond or a triple bond,
n V is 0-3, provided that n V when Y V is a double bond or triple bond represents a 1-3,
Z V is an alkylene having 1 to 6 carbon atoms which may have a substituent,
Arylene having 6 to 10 carbon atoms which may have a substituent,
A cycloalkylene having 3 to 7 carbon atoms which may have a substituent,
An optionally substituted heteroarylene having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, or having a substituent; also good 1-2 nitrogen atoms, heterocycloalkylene of constituting atoms is 3 to 7 rings containing an oxygen atom or a sulfur atom as a constituent atom of the ring (however, if Y V is a double bond,
Alkylene having 1 to 6 carbons which may have a substituent,
Ring structure containing optionally substituted cycloalkylene having 3 to 7 carbon atoms or optionally having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent. Represents heterocycloalkylene having 3 to 7 atoms,
If Y V is a triple bond,
An alkylene having 1 to 6 carbon atoms which may have a substituent;
Furthermore, when n v is 2 or 3, Z V may be the same or different. )
And B V is a hydrogen atom,
COOR V-6 (wherein R V-6 represents a hydrogen atom, an alkyl having 1 to 4 carbon atoms, or a substituent capable of leaving in vivo),
SO 3 R V-6 (where R V-6 has the same meaning as above),
P (= O) (OR V-7 ) (OR V-8 ),
OP (= O) (OR V-7 ) (OR V-8 ) (where R V-7 and R V-8 are hydrogen atoms, phosphate protecting groups, or are eliminated in vivo. Represents a substituent).
Cyano,
—CO—NH—SO 2 —R V-9 (where R V-9 is an alkyl having 1 to 6 carbon atoms which may have a substituent, and 6 to 6 carbon atoms which may have a substituent) 10 aryls, optionally substituted cycloalkyl having 3 to 7 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms A ring containing 5 to 10 heteroaryl atoms or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 ring atoms Represents a heterocycloalkyl of ˜7),
OH or the following formula
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
で表される基を示す。）
で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物である（以下、本発明化合物と表記することもある。）。 The group represented by these is shown. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof (hereinafter sometimes referred to as the compound of the present invention).
　本発明において用いられる記号及び用語の定義について、以下に詳述する。
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。 Definitions of symbols and terms used in the present invention will be described in detail below.
A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
　炭素数１～３のアルキルとは、直鎖又は分枝鎖の炭素数１～３のアルキルを意味し、例えば、メチル、エチル、ｎ－プロピル、イソプロピル等を挙げることができる。 The alkyl having 1 to 3 carbon atoms means a linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl and the like.
　炭素数１～４のアルキルとは、直鎖又は分枝鎖の炭素数１～４のアルキルを意味し、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、第２級ブチル、第３級ブチル（以下、「第３級」をｔ－又はｔｅｒｔ－と表記することがある。）等を挙げることができる。 The alkyl having 1 to 4 carbon atoms means straight or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl. And tertiary butyl (hereinafter, “tertiary” may be expressed as t- or tert-).
　炭素数１～６のアルキルとは、直鎖又は分枝鎖の炭素数１～６のアルキルを意味し、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、第２級ブチル、第３級ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ネオヘキシル等を挙げることができる。 The alkyl having 1 to 6 carbon atoms means straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl. And tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl and the like.
　炭素数５～９の直鎖のアルキルとは、ｎ－ペンチル、ｎ－ヘキシル、ｎ－ヘプチル、ｎ－オクチル、ｎ－ノニルである。 The straight-chain alkyl having 5 to 9 carbon atoms is n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl.
　炭素数１～２０のアルキルとは、直鎖又は分枝鎖の炭素数１～２０のアルキルを意味し、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、第２級ブチル、第３級ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ネオヘキシル、ヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシル、ノナデシル、イコシル等を挙げることができる。 The alkyl having 1 to 20 carbons means straight or branched alkyl having 1 to 20 carbons, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl Tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. Can be mentioned.
　炭素数３～６のシクロアルキルとは、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等を挙げることができる。 Examples of the cycloalkyl having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
　炭素数３～７のシクロアルキルとは、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等を挙げることができる。 Examples of the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
　４～７員環のシクロアルカン及び環の構成原子数が４～７の窒素原子を一つ含んだヘテロシクロアルカンとは、例えば、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、アゼチジン、ピロリジン、ピペリジン、ホモピペリジン等を挙げることができる。 Examples of a 4- to 7-membered cycloalkane and a heterocycloalkane containing one nitrogen atom having 4 to 7 member atoms include cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, A homopiperidine etc. can be mentioned.
　ハロゲン原子で置換された炭素数１～４のアルキル及びハロゲン原子で置換されている場合の炭素数１～４のアルキルとは、前述の炭素数１～４のアルキルが１～５個のハロゲン原子で置換されたものを意味し、例えば、フルオロメチル、ジフルオロメチル、トリフルオロメチル、フルオロエチル、ジフルオロエチル、トリフルオロエチル、ペンタフルオロエチル、フルオロｎ－プロピル、トリフルオロｎ－プロピル、ペンタフルオロｎ－プロピル、フルオロイソプロピル、ジフルオロイソプロピル、フルオロｎ－ブチル、トリフルオロｎ－ブチル、ペンタフルオロｎ－ブチル等の他、ここで例示した置換基のフッ素原子の一部又は全部が他のハロゲン原子に置換されたもの等を挙げることができる。 The alkyl having 1 to 4 carbon atoms substituted with a halogen atom and the alkyl having 1 to 4 carbon atoms when substituted with a halogen atom are the above halogen atoms having 1 to 5 carbon atoms having 1 to 4 carbon atoms. For example, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoro n-propyl, trifluoro n-propyl, pentafluoro n- In addition to propyl, fluoroisopropyl, difluoroisopropyl, fluoro n-butyl, trifluoro n-butyl, pentafluoro n-butyl, etc., some or all of the fluorine atoms of the substituents exemplified here are substituted with other halogen atoms. Can be mentioned.
　水酸基で置換されている場合の炭素数１～４のアルキルとは、上述の炭素数１～４のアルキルが水酸基で置換されたものを意味し、例えば、ヒドロキシメチル、１－ヒドロキシエチル、２－ヒドロキシエチル、ジヒドロキシエチル、１－ヒドロキシプロピル、２－ヒドロキシプロピル、３－ヒドロキシプロピル、ヒドロキシイソプロピル、ジヒドロキシイソプロピル、ヒドロキシブチル、ジヒドロキシブチル等を挙げることができる。 The alkyl having 1 to 4 carbon atoms in the case of being substituted with a hydroxyl group means the above-mentioned alkyl having 1 to 4 carbon atoms substituted with a hydroxyl group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy Hydroxyethyl, dihydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, hydroxyisopropyl, dihydroxyisopropyl, hydroxybutyl, dihydroxybutyl and the like can be mentioned.
　炭素数２～２０のアルケニルとは、直鎖又は分枝鎖の炭素数２～２０のアルケニルを意味し、例えば、エテニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、ペンテニル、イソペンテニル、ヘキセニル、イソヘキセニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル、ヘキサデセニル、ヘプタデセニル、オクタデセニル、ノナデセニル、イコセニル等を挙げることができる。 The alkenyl having 2 to 20 carbon atoms means straight or branched alkenyl having 2 to 20 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl. , Heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icocenyl and the like.
　炭素数２～２０のアルキニルとは、直鎖又は分枝鎖の炭素数２～２０のアルキニルを意味し、例えば、エチニル、プロピニル、イソプロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル、ウンデシニル、ドデシニル、トリデシニル、テトラデシニル、ペンタデシニル、ヘキサデシニル、ヘプタデシニル、オクタデシニル、ノナデシニル、イコシニル等を挙げることができる。 The alkynyl having 2 to 20 carbon atoms means a straight chain or branched alkynyl having 2 to 20 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl. , Undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, icosinyl and the like.
　炭素数１～４のアルコキシとは、直鎖又は分枝鎖の炭素数１～４のアルコキシを意味し、例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、第２級ブトキシ、ｔ－ブトキシ等を挙げることができ、炭素数１～４のアルコキシで置換された炭素数１～４のアルキルとは、上記に示した炭素数１～４のアルコキシが上述の炭素数１～４のアルキルに結合したものであり、例えば、メトキシメチル、メトキシエチル、メトキシプロピル、エトキシメチル、ｎ－プロポキシエチル、イソブトキシプロピル、ｔ－ブトキシブチル等を挙げることができる。 The alkoxy having 1 to 4 carbon atoms means a straight or branched alkoxy having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, t-butoxy and the like can be mentioned. The alkyl having 1 to 4 carbon atoms substituted by alkoxy having 1 to 4 carbon atoms is the above-mentioned alkoxy having 1 to 4 carbon atoms described above. To 4 alkyls, and examples include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, n-propoxyethyl, isobutoxypropyl, t-butoxybutyl and the like.
　炭素数１～２０のアルコキシとは、直鎖又は分枝鎖の炭素数１～２０のアルコキシを意味し、例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、第２級ブトキシ、ｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、第３級ペンチルオキシ、ヘキシルオキシ、ヘプチルオキシ、オクチルオキシ、ノニルオキシ、デシルオキシ、ウンデシルオキシ、ドデシルオキシ、トリデシルオキシ、テトラデシルオキシ、ペンタデシルオキシ、ヘキサデシルオキシ、ヘプタデシルオキシ、オクタデシルオキシ、ノナデシルオキシ、イコデシルオキシ等を挙げることができる。 The alkoxy having 1 to 20 carbon atoms means a straight or branched alkoxy having 1 to 20 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, t-butoxy, pentyloxy, isopentyloxy, tertiary pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy Hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icodecyloxy and the like.
　炭素数１～７のアシルとは、炭素数１～７のアルカノイル又はアロイルを意味し、アルカノイルとは炭素数１～７の直鎖又は分枝鎖状のアルカノイルであり、例えば、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイル等を挙げることができる。またアロイルとしてはベンゾイル等を挙げることができる。 Acyl having 1 to 7 carbons means alkanoyl or aroyl having 1 to 7 carbons, and alkanoyl is a linear or branched alkanoyl having 1 to 7 carbons such as formyl, acetyl, Examples include propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like. Examples of aroyl include benzoyl.
　炭素数１～２０のアシルとは、炭素数１～２０のアルカノイル又はアロイルを意味し、アルカノイルとは水素原子又は直鎖若しくは分枝鎖の炭素数１～１９のアルキルにカルボニルが結合したものであり、例えば、ホルミル、アセチル、プロピオニル、ミリストイル、パルミトイル、ステアロイル等を挙げることができ、またアロイルとしてはベンゾイル、ナフトイル等を挙げることができる。 Acyl having 1 to 20 carbons means alkanoyl or aroyl having 1 to 20 carbons, and alkanoyl is a carbonyl bonded to a hydrogen atom or a linear or branched alkyl having 1 to 19 carbons. For example, formyl, acetyl, propionyl, myristoyl, palmitoyl, stearoyl and the like can be mentioned, and examples of aroyl include benzoyl and naphthoyl.
　炭素数２～７のアルコキシカルボニルとは、直鎖又は分枝鎖の炭素数１～６のアルコキシにカルボニルが結合したものであり、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ｎ－ブトキシカルボニル、イソブトキシカルボニル、ｔ－ブトキシカルボニル、ｎ－ペンチルオキシカルボニル、イソペンチルオキシカルボニル、第３級ペンチルオキシカルボニル、ヘキシルオキシカルボニル等を挙げることができる。 The C2-C7 alkoxycarbonyl is a linear or branched alkoxy having 1-6 carbon atoms bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n -Butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl and the like.
　炭素数２～２１のアルコキシカルボニルとは、直鎖又は分枝鎖の炭素数１～２０のアルコキシにカルボニルが結合したものであり、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ｎ－ブトキシカルボニル、ｔ－ブトキシカルボニル、ヘプチルオキシカルボニル、デシルオキシカルボニル、ヘプタデシルオキシカルボニル、オクタデシルオキシカルボニル等を挙げることができる。 The alkoxycarbonyl having 2 to 21 carbon atoms is a straight chain or branched alkoxy having 1 to 20 carbon atoms bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, Examples thereof include t-butoxycarbonyl, heptyloxycarbonyl, decyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl and the like.
　ＲＩＶ－２の生体内で脱離する置換基とは、化合物が生体内に投与若しくは吸収された後、化学的若しくは酵素的に脱離する置換基であり、具体的には、アセチル、ベンゾイル、Ｎ－アシルグリシル、アシルオキシアセチル、グリシル、アラニル、バニリル等が挙げられる。 The substituent that RIV -2 is eliminated in vivo is a substituent that is chemically or enzymatically eliminated after the compound is administered or absorbed in vivo, and specifically includes acetyl, benzoyl N-acylglycyl, acyloxyacetyl, glycyl, alanyl, vanillyl and the like.
　ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１が炭素数１～６のアルキルにより置換されている場合、ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の具体的な例としては、メチルｎ－ペンチル、メチルｎ－ヘキシル、メチルｎ－ヘプチル、エチルｎ－ヘプチル、プロピルｎ－ヘプチル、ジメチルｎ－ヘプチル、メチルｎ－オクチル、エチルｎ－オクチル、ジメチルｎ－オクチル、メチルｎ－ノニル、エチルｎ－ノニル、ジメチルｎ－ノニル等を挙げることができる。 When A I , A II-1 , A III-1 , A IV-1 is substituted with alkyl having 1 to 6 carbon atoms, A I , A II-1 , A III-1 , A IV-1 Specific examples include methyl n-pentyl, methyl n-hexyl, methyl n-heptyl, ethyl n-heptyl, propyl n-heptyl, dimethyl n-heptyl, methyl n-octyl, ethyl n-octyl, dimethyl n- Examples include octyl, methyl n-nonyl, ethyl n-nonyl, dimethyl n-nonyl and the like.
　ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１が同じ炭素に結合する２つの炭素数１～６のアルキルにより置換されており、それら２つのアルキル基とそれらが結合している炭素原子が炭素数３～６のシクロアルキルを形成している場合、ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の具体的な例としては、５－（１－メチルシクロプロパン－１－イル）ペンチル、３－（１－プロピルシクロプロパン－１－イル）プロピル、１－ヘキシルシクロプロパン－１－イル、１－ヘキシルシクロブタン－１－イル、４－（１－エチルシクロペンタン－１－イル）ブチル、３－（１－メチルシクロヘキサン－１－イル）プロピル等を挙げることができる。 A I , A II-1 , A III-1 , A IV-1 are substituted by two alkyl groups having 1 to 6 carbon atoms bonded to the same carbon, and these two alkyl groups are bonded to each other When the carbon atom forms a cycloalkyl having 3 to 6 carbon atoms, specific examples of A I , A II-1 , A III-1 , A IV-1 include 5- (1-methylcyclo Propan-1-yl) pentyl, 3- (1-propylcyclopropan-1-yl) propyl, 1-hexylcyclopropan-1-yl, 1-hexylcyclobutan-1-yl, 4- (1-ethylcyclopentane) -1-yl) butyl, 3- (1-methylcyclohexane-1-yl) propyl and the like.
　ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１がハロゲン原子により置換されている場合、ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の具体的な例としては、５－フルオロペンチル、６－フルオロヘキシル、７－フルオロヘプチル、８－フルオロオクチル、９－フルオロノニル、トリフルオロｎ－ペンチル、トリフルオロｎ－ヘキシル、トリフルオロｎ－ヘプチル、トリフルオロｎ－オクチル、トリフルオロｎ－ノニル、ペンタフルオロｎ－ペンチル、ペンタフルオロｎ－ヘキシル、ペンタフルオロｎ－ヘプチル、ペンタフルオロｎ－オクチル、ペンタフルオロｎ－ノニル、１－フルオロヘプチル、２－フルオロヘプチル、３－フルオロヘプチル、４－フルオロヘプチル、５－フルオロヘプチル、６－フルオロヘプチル、１－フルオロオクチル、２－フルオロオクチル、３－フルオロオクチル、４－フルオロオクチル、５－フルオロオクチル、６－フルオロオクチル、７－フルオロオクチル等の他、ここで例示した置換基のフッ素原子の一部又は全部が他のハロゲン原子に置換されたもの等を挙げることができる。 When A I , A II-1 , A III-1 , A IV-1 is substituted with a halogen atom, specific examples of A I , A II-1 , A III-1 , A IV-1 Is 5-fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, trifluoro n-pentyl, trifluoro n-hexyl, trifluoro n-heptyl, trifluoro n-octyl , Trifluoro n-nonyl, pentafluoro n-pentyl, pentafluoro n-hexyl, pentafluoro n-heptyl, pentafluoro n-octyl, pentafluoro n-nonyl, 1-fluoroheptyl, 2-fluoroheptyl, 3-fluoro Heptyl, 4-fluoroheptyl, 5-fluoroheptyl, 6-fluoroheptyl, 1- In addition to lurooctyl, 2-fluorooctyl, 3-fluorooctyl, 4-fluorooctyl, 5-fluorooctyl, 6-fluorooctyl, 7-fluorooctyl, etc., some or all of the fluorine atoms of the substituents exemplified here Examples thereof include those substituted with other halogen atoms.
　ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１が鎖中又は鎖端に、二重結合、三重結合、炭素数３～６のシクロアルキルを有している場合、ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の具体的な例としては、ｎ－ペンテニル、ｎ－ヘキセニル、ｎ－ヘプテニル、ｎ－オクテニル、ｎ－ノネニル、ｎ－ヘキシニル、ｎ－ヘプチニル、ｎ－オクチニル、ヘキサジエニル、ヘプタジエニル、オクタジエニル、ノナジエニル、２－ペンチルシクロプロパン－１－イル、（２－ブチルシクロプロパン－１－イル）メチル、（２－エチルシクロプロパン－１－イル）プロピル、３－（３－メチルシクロヘキサン－１－イル）プロピル、４－（４－メチルシクロヘキサン－１－イル）ブチル等を挙げることができる。 When A I , A II-1 , A III-1 , A IV-1 has a double bond, triple bond, or cycloalkyl having 3 to 6 carbon atoms in the chain or at the chain end, A I , Specific examples of A II-1 , A III-1 and A IV-1 include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-hexynyl, n-heptynyl, n-octynyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, 2-pentylcyclopropan-1-yl, (2-butylcyclopropan-1-yl) methyl, (2-ethylcyclopropan-1-yl) propyl, 3- (3-methylcyclohexane-1-yl) propyl, 4- (4-methylcyclohexane-1-yl) butyl and the like can be mentioned.
　ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の鎖中に、酸素原子、硫黄原子が挿入されている場合、ＡＩ、ＡＩＩ－１、ＡＩＩＩ－１、ＡＩＶ－１の具体的な例としては、ブトキシエチル、プロポキシプロピル、エトキシブチル、ブチルチオエチル、プロピルチオプロピル、エチルチオブチル等を挙げることができる。 When an oxygen atom or a sulfur atom is inserted into the chain of A I , A II-1 , A III-1 , A IV-1 , A I , A II-1 , A III-1 , A IV- Specific examples of 1 include butoxyethyl, propoxypropyl, ethoxybutyl, butylthioethyl, propylthiopropyl, ethylthiobutyl and the like.
　炭素数６～１０のアリールとはフェニル、１－ナフチル、２－ナフチル等を挙げることができる。 Examples of aryl having 6 to 10 carbon atoms include phenyl, 1-naphthyl, 2-naphthyl and the like.
　１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリールとは、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、フリル、チエニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、インドリル、イソインドリル、インドリジニル、インダゾリル、ベンゾフリル、ベンゾチエニル、キノリル、イソキノリル等を挙げることができる。 Heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms is pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl , Thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl and the like.
　炭素数３～７のシクロアルキルとは、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル等を挙げることができる。 Examples of the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
　ベンゼンと縮合していても良い炭素数３～７のシクロアルキルとは、例えば、１，２，３，４－テトラヒドロナフチル、インダニル、６，７，８，９－テトラヒドロ－５Ｈ－ベンゾシクロヘプチル等を挙げることができる。 Examples of the cycloalkyl having 3 to 7 carbon atoms optionally condensed with benzene include 1,2,3,4-tetrahydronaphthyl, indanyl, 6,7,8,9-tetrahydro-5H-benzocycloheptyl and the like. Can be mentioned.
　１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルとは、例えば、ピペリジル、ピペラジニル、モルホリル、テトラヒドロフリル、テトラヒドロピラニル等を挙げることができる。 Examples of the heterocycloalkyl having 5 to 7 ring atoms containing 1 to 2 nitrogen atoms or oxygen atoms as ring atoms include piperidyl, piperazinyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl and the like. be able to.
　１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルとは、例えば、アジリジル、アゼチジル、ピペリジル、ピペラジニル、ピロリジニル、モルホリル、チオモルホリル、テトラヒドロフリル、テトラヒドロピラニル等を挙げることができる。 The heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms is, for example, aziridyl, azetidyl, piperidyl, piperazinyl, pyrrolidinyl, morpholyl, Mention may be made of thiomorpholyl, tetrahydrofuryl, tetrahydropyranyl and the like.
　炭素数１～２のアルキレンとは、メチレン、エチレンである。 The alkylene having 1 or 2 carbon atoms is methylene or ethylene.
　１～２個のフッ素原子で置換されていてもよい炭素数１～４のアルキレンとは、例えばメチレン、エチレン、トリメチレン、テトラメチレン、プロピレン、シクロプロピレン、フルオロメチレン、ジフルオロメチレン、フルオロエチレン、ジフルオロエチレン、フルオロトリメチレン、ジフルオロトリメチレン、フルオロテトラメチレン、ジフルオロテトラメチレン等を挙げることができる。 Examples of the alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms include, for example, methylene, ethylene, trimethylene, tetramethylene, propylene, cyclopropylene, fluoromethylene, difluoromethylene, fluoroethylene, difluoroethylene , Fluorotrimethylene, difluorotrimethylene, fluorotetramethylene, difluorotetramethylene and the like.
　炭素数１～５のアルキレンとは、例えばメチレン、エチレン、トリメチレン、テトラメチレン、ペンタメチレン、プロピレン、エチルエチレン、メチルトリメチレン、ジメチルトリメチレン、シクロプロピリデン、シクロプロピレン、（シクロプロピリデン）エチレン、シクロプロピレン－メチレン等を挙げることができる。 Examples of alkylene having 1 to 5 carbon atoms include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propylene, ethylethylene, methyltrimethylene, dimethyltrimethylene, cyclopropylidene, cyclopropylene, (cyclopropylidene) ethylene, And cyclopropylene-methylene.
　炭素数１～６のアルキレンとは、直鎖又は分枝鎖の炭素数１～６のアルキレンを意味し、例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、エチルエチレン、ペンタメチレン、ヘキサメチレン等を挙げることができる。 The alkylene having 1 to 6 carbon atoms means linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene, etc. Can be mentioned.
　炭素数２～５のアルケニレンとは、ビニレン、プロペニレン、ブテニレン、ペンテニレン、メチルビニレン、ジメチルビニレン、エチルビニレン、メチルプロぺニレン、ジメチルプロペニレン等を挙げることができる。 Examples of the alkenylene having 2 to 5 carbon atoms include vinylene, propenylene, butenylene, pentenylene, methylvinylene, dimethylvinylene, ethylvinylene, methylpropenylene, dimethylpropenylene and the like.
　炭素数２～５のアルキニレンとは、エチニレン、プロピニレン、ブチニレン、ペンチニレン、メチルプロピニレン、ジメチルプロピニレン等を挙げることができる。 Examples of the alkynylene having 2 to 5 carbon atoms include ethynylene, propynylene, butynylene, pentynylene, methylpropynylene, dimethylpropynylene and the like.
　炭素数６～１０のアリーレンとは、フェニレン、ナフチレン等を挙げることができる。 Examples of arylene having 6 to 10 carbon atoms include phenylene and naphthylene.
　炭素数３～７のシクロアルキレンとは、例えば、シクロプロピレン、シクロブチレン、シクロペンチレン、シクロヘキシレン、シクロヘプチレン等を挙げることができる。 Examples of the cycloalkylene having 3 to 7 carbon atoms include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and the like.
　１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレンとは、ピロリレン、イミダゾリレン、ピラゾリレン、ピリジレン、ピリダジニレン、ピリミジニレン、ピラジニレン、フリレン、チエニレン、オキサゾリレン、イソオキサゾリレン、チアゾリレン、イソチアゾリレン、インドリレン、イソインドリレン、インドリジニレン、インダゾリレン、ベンゾフリレン、ベンゾチエニレン、キノリレン、イソキノリレン等を挙げることができる。 Heteroarylene having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 ring atoms is pyrrolylene, imidazolylene, pyrazolylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene, furylene , Thienylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, indoleylene, isoindolylene, indolizinylene, indazolylene, benzofurylene, benzothienylene, quinolylene, isoquinolylene and the like.
　１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンとは、例えば、アジリジレン、アゼチジレン、ピペリジレン、ピペラジニレン、ピロリジニレン、モルホリニレン、チオモルホリニレン、テトラヒドロフリレン、テトラヒドロピラニレン等を挙げることができる。 Heterocycloalkylene having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms is, for example, aziridylene, azetidylene, piperidylene, piperazinylene, pyrrolidinylene, morpholinylene, Mention may be made of thiomorpholinylene, tetrahydrofurylene, tetrahydropyranylene and the like.
　「炭素数６～１０のアリール」、「１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール」、「炭素数３～７のシクロアルキル」及び「１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキル」が有していてもよい置換基の数は１～５、好ましくは１又は２である。置換基の例としては、既述のハロゲン原子で置換されていても良い炭素数１～４のアルキル；ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；炭素数１～４のアルキルチオ；炭素数１～４のアルキルスルフィニル；炭素数１～４のアルキルスルホニル；炭素数２～５のアルキルカルボニル；既述のハロゲン原子；シアノ；ニトロ；既述の炭素数３～７のシクロアルキル；既述の炭素数６～１０のアリール；炭素数７～１４のアラルキルオキシ；及び炭素数６～１０のアリールオキシ；並びにそれらのうち２つの置換基が一緒になってオキソ若しくはハロゲン原子で置換されていても良い炭素数３～４のアルキレン；オキソ若しくはハロゲン原子で置換されていても良い炭素数２～３のアルキレンオキシ；及びオキソ若しくはハロゲン原子で置換されていても良い炭素数１～２のアルキレンジオキシを挙げることができる。
　ハロゲン原子で置換されている場合の炭素数１～４のアルコキシとは、前述の炭素数１～４のアルコキシが１～５個のハロゲン原子で置換されたものを意味し、例えば、フルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、ジフルオロエトキシ、トリフルオロエトキシ、ペンタフルオロエトキシ、ジフルオロｎ－プロポキシ、トリフルオロｎ－プロポキシ、フルオロイソプロポキシ、トリフルオロイソプロポキシ、ジフルオロｎ－ブトキシ、トリフルオロｎ－ブトキシ等の他、ここで例示した置換基のフッ素原子の一部又は全部が他のハロゲン原子に置換されたもの等を挙げることができる。 “Aryl having 6 to 10 carbon atoms”, “Heteroaryl having 5 to 10 ring atoms including 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms”, “3 to 3 carbon atoms” The number of substituents that the “7 cycloalkyl” and the “heterocycloalkyl having 5 to 7 ring atoms containing 1 to 2 nitrogen atoms or oxygen atoms as ring atoms” may have 1 to 5, preferably 1 or 2. Examples of the substituent include alkyl having 1 to 4 carbon atoms which may be substituted with the aforementioned halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; Alkylthio; alkylsulfinyl having 1 to 4 carbon atoms; alkylsulfonyl having 1 to 4 carbon atoms; alkylcarbonyl having 2 to 5 carbon atoms; halogen atom as described above; cyano; nitro; cycloalkyl having 3 to 7 carbon atoms as described above An aryl having 6 to 10 carbon atoms as described above; an aralkyloxy having 7 to 14 carbon atoms; and an aryloxy having 6 to 10 carbon atoms; and two of them substituted together with an oxo or halogen atom; Alkylene having 3 to 4 carbon atoms which may be substituted; alkyleneoxy having 2 to 3 carbon atoms which may be substituted with oxo or halogen atom; and oxo or Substituted with androgenic atoms can be exemplified good alkylenedioxy having 1 or 2 carbon atoms also.
The alkoxy having 1 to 4 carbon atoms in the case of being substituted with a halogen atom means that the aforementioned alkoxy having 1 to 4 carbon atoms is substituted with 1 to 5 halogen atoms, such as fluoromethoxy, Difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, pentafluoroethoxy, difluoro n-propoxy, trifluoro n-propoxy, fluoroisopropoxy, trifluoroisopropoxy, difluoro n-butoxy, trifluoro n-butoxy, etc. Other examples include those in which some or all of the fluorine atoms of the substituents exemplified here are substituted with other halogen atoms.
　炭素数１～４のアルキルチオ、炭素数１～４のアルキルスルフィニル、炭素数１～４のアルキルスルホニルとは、それぞれのアルキル部が既述の炭素数１～４のアルキルで構成されており、例えば、メチルチオ、エチルチオ、プロピルチオ、メタンスルフィニル、メタンスルホニル等を挙げることができる。 The alkylthio having 1 to 4 carbon atoms, the alkylsulfinyl having 1 to 4 carbon atoms, and the alkylsulfonyl having 1 to 4 carbon atoms are each composed of the above-described alkyl having 1 to 4 carbon atoms. , Methylthio, ethylthio, propylthio, methanesulfinyl, methanesulfonyl and the like.
　炭素数２～５のアルキルカルボニルとは、アルキル部が既述の炭素数１～４のアルキルにカルボニルが結合したものであり、例えば、メチルカルボニル、エチルカルボニル等を挙げることができる。 The alkylcarbonyl having 2 to 5 carbon atoms is a compound in which the alkyl moiety is bonded to the alkyl having 1 to 4 carbon atoms described above, and examples thereof include methylcarbonyl and ethylcarbonyl.
　炭素数７～１４のアラルキルオキシとは、既述の炭素数６～１０のアリールで置換された既述の炭素数１～４のアルコキシであり、例えば、ベンジルオキシ、フェネチルオキシ、ナフチルメトキシ、ナフチルエトキシ等を挙げることができる。 Aralkyloxy having 7 to 14 carbon atoms refers to alkoxy having 1 to 4 carbon atoms described above substituted with aryl having 6 to 10 carbon atoms as described above. For example, benzyloxy, phenethyloxy, naphthylmethoxy, naphthyl Ethoxy and the like can be mentioned.
　炭素数６～１０のアリールオキシとは、既述の炭素数６～１０のアリールに酸素原子が結合したものであり、例えば、フェノキシ、１－ナフトキシ、２－ナフトキシ等を挙げることができる。 The aryloxy having 6 to 10 carbon atoms is a compound in which an oxygen atom is bonded to the aforementioned aryl having 6 to 10 carbon atoms, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
　炭素数３～４のアルキレンとは、例えば、トリメチレン、テトラメチレン、メチルトリメチレン等を挙げることができる。オキソで置換されている場合の炭素数３～４のアルキレンとは、例えば、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－、－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－ＣＨ２－、－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－等を挙げることができる。ハロゲン原子で置換されている場合の炭素数３～４のアルキレンとは、既述の炭素数３～４のアルキレンにおける水素原子の一部又は全部がハロゲン原子に置換されたものである。 Examples of the alkylene having 3 to 4 carbon atoms include trimethylene, tetramethylene, methyltrimethylene and the like. The alkylene having 3 to 4 carbon atoms when substituted with oxo is, for example, —C (═O) —CH 2 —CH 2 —, —CH 2 —C (═O) —CH 2 —, —C (= O) -CH 2 -CH 2 -CH 2 -, - CH 2 -C (= O) -CH 2 -CH 2 - and the like. The alkylene having 3 to 4 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the alkylene having 3 to 4 carbon atoms described above are substituted with halogen atoms.
　炭素数２～３のアルキレンオキシとは、例えば、エチレンオキシ、トリメチレンオキシ、プロピレンオキシ等を挙げることができる。オキソで置換されている場合の炭素数２～３のアルキレンオキシとは、例えば、－Ｏ－Ｃ（＝Ｏ）－ＣＨ２－、－Ｃ（＝Ｏ）－ＣＨ２－Ｏ－、－Ｏ－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－Ｏ－、－Ｏ－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－、－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－Ｏ－等を挙げることができる。ハロゲン原子で置換されている場合の炭素数２～３のアルキレンオキシとは、既述の炭素数２～３のアルキレンオキシにおける水素原子の一部又は全部がハロゲン原子で置換されたものである。 Examples of the alkyleneoxy having 2 to 3 carbon atoms include ethyleneoxy, trimethyleneoxy, propyleneoxy and the like. When substituted with oxo, alkyleneoxy having 2 to 3 carbon atoms is, for example, —O—C (═O) —CH 2 —, —C (═O) —CH 2 —O—, —O—. C (═O) —CH 2 —CH 2 —, —C (═O) —CH 2 —CH 2 —O—, —O—CH 2 —C (═O) —CH 2 —, —CH 2 —C (═O) —CH 2 —O— and the like can be mentioned. The alkyleneoxy having 2 to 3 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the alkyleneoxy having 2 to 3 carbon atoms described above are substituted with a halogen atom.
　炭素数１～２のアルキレンジオキシとは、例えば、メチレンジオキシ、エチレンジオキシ等を挙げることができる。オキソで置換されている場合の炭素数１～２のアルキレンジオキシとは、例えば、－Ｏ－Ｃ（＝Ｏ）－Ｏ－、－Ｏ－ＣＨ２－Ｃ（＝Ｏ）－Ｏ－等を挙げることができる。ハロゲン原子で置換されている場合の炭素数１～２のアルキレンジオキシとは、既述の炭素数１～２のアルキレンジオキシにおける水素原子の一部又は全部がハロゲン原子に置換されたものである。 Examples of the alkylenedioxy having 1 to 2 carbon atoms include methylenedioxy and ethylenedioxy. The alkylenedioxy having 1 to 2 carbon atoms when substituted with oxo includes, for example, —O—C (═O) —O—, —O—CH 2 —C (═O) —O— and the like. Can be mentioned. The alkylenedioxy having 1 to 2 carbon atoms when substituted with a halogen atom is one in which part or all of the hydrogen atoms in the aforementioned alkylenedioxy having 1 to 2 carbon atoms are substituted with halogen atoms. is there.
　置換されていても良い炭素数３～７のシクロアルキルが縮合していてもよい置換されていても良いベンゼンとは、例えば無置換のベンゼン、ハロゲン原子で置換されたベンゼン、水酸基で置換されたベンゼン、ハロゲン原子又は水酸基で置換されていてもよい炭素数１～４のアルキルで置換されたベンゼン、炭素数１～４のアルコキシで置換されたベンゼンなどが挙げられる。 Examples of the optionally substituted benzene that may be condensed with an optionally substituted cycloalkyl having 3 to 7 carbon atoms include unsubstituted benzene, benzene substituted with a halogen atom, and a hydroxyl group. Examples thereof include benzene, benzene substituted with an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, and benzene substituted with alkoxy having 1 to 4 carbon atoms.
　ＲＩＶ－５、ＲＩＶ－６、ＲＶ－７及びＲＶ－８のリン酸基の保護基とは、メチル、エチル、ｔ－ブチル等のアルキル、シアノエチル、ピリジルエチル等の置換エチル、ベンジル等のアラルキル、フェニル、フェニルアミノ等を挙げることができる。 The protecting groups for the phosphate groups of R IV-5 , R IV-6 , R V-7 and R V-8 are alkyl such as methyl, ethyl and t-butyl, substituted ethyl such as cyanoethyl and pyridylethyl, benzyl And aralkyl such as phenyl, phenylamino and the like.
　ＲＩＶ－５、ＲＩＶ－６、ＲＶ－７及びＲＶ－８の生体内で脱離する置換基とは、化合物が生体内に投与若しくは吸収された後、化学的若しくは酵素的に脱離する置換基であり、具体的な例としては、イソプロピル、ｔ－ブチル、ヘキサデシル、オクタデシル等のアルキル、ヘキサデシルオキシプロピルやオクタデシルオキシエチル等のアルキルオキシアルキル、ピバロイルオキシメチル等のアシルオキシアルキル、メトキシカルボニルオキシメチルやイソプロポキシカルボニルオキシメチル等のアルキルオキシカルボニルオキシアルキル、アセチルチオエチルやピバロイルチオエチル等のＳ－アシルチオエチル、置換フェニル、置換ベンジル、若しくは下記式 R IV-5 , R IV-6 , R V-7, and R V-8 are the substituents that are eliminated in vivo, and are chemically or enzymatically desorbed after the compound is administered or absorbed in vivo. Specific examples include alkyl such as isopropyl, t-butyl, hexadecyl and octadecyl, alkyloxyalkyl such as hexadecyloxypropyl and octadecyloxyethyl, and acyloxyalkyl such as pivaloyloxymethyl. Alkyloxycarbonyloxyalkyl such as methoxycarbonyloxymethyl and isopropoxycarbonyloxymethyl, S-acylthioethyl such as acetylthioethyl and pivaloylthioethyl, substituted phenyl, substituted benzyl, or the following formula
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（Ｒ’はグリシン、アラニン、バリン等の天然アミノ酸の側鎖、Ｒ’’は水素原子、又は炭素数１～４のアルキルを示す。）で表される構造を挙げることができ、また、Ｐ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）、Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）及びＯ－Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）は、下記式 (R ′ represents a side chain of a natural amino acid such as glycine, alanine, valine, R ″ represents a hydrogen atom, or alkyl having 1 to 4 carbon atoms), and a structure represented by P (= O) (OR IV-5 ) (OR IV-6 ), P (= O) (OR V-7 ) (OR V-8 ) and OP (= O) (OR V-7 ) (OR V-8 ) is the following formula
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
のような構造を形成することもできる。この場合、フェニル基はさらに置換されていても良い。 Such a structure can also be formed. In this case, the phenyl group may be further substituted.
　ＲＶ－６の生体内で脱離する置換基とは、化合物が生体内に投与若しくは吸収された後、化学的若しくは酵素的に脱離する置換基であり、具体的には、メチル、エチル、イソプロピル、ｔ－ブチル等のアルキル、アセトキシメチル、プロピオニルオキシメチル、ピバロイルオキシメチル、ベンゾイルオキシメチル等のアシルオキシアルキル、１－（エトキシカルボニルオキシ）エチル、１－（シクロヘキシルオキシカルボニルオキシ）エチル等のアルコキシカルボニルオキシアルキル等が挙げられる。 The substituent that R V-6 is eliminated in vivo is a substituent that is chemically or enzymatically eliminated after the compound is administered or absorbed in vivo, and specifically includes methyl, ethyl, and the like. Alkyl such as isopropyl, t-butyl, acyloxyalkyl such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, etc. And alkoxycarbonyloxyalkyl.
　本明細書中、「置換基を有していても良い」における「置換基」について特段説明がない場合には、その置換基は特に限定されないが、例えば以下に例示する置換基が挙げられる。置換されていても良い炭素数１～２０のアルキル、置換されていても良い炭素数２～２０のアルケニル、置換されていても良い炭素数２～２０のアルキニル、置換されていても良い炭素数１～２０のアルキリデン、置換されていても良い環状基、オキソ、水酸基、置換されていても良い炭素数１～２０のアルコキシ、置換されていても良い炭素数２～２０のアルケニルオキシ、置換されていても良い炭素数２～２０のアルキニルオキシ、置換されていても良い炭素数１～２０のアルキルチオ、置換されていても良い炭素数２～２０のアルケニルチオ、置換されていても良い炭素数２～２０のアルキニルチオ、置換されていても良い炭素数１～２０のアルキルスルフィニル、置換されていても良い炭素数２～２０のアルケニルスルフィニル、置換されていても良い炭素数２～２０のアルキニルスルフィニル、置換されていても良い炭素数１～２０のアルキルスルホニル、置換されていても良い炭素数２～２０のアルケニルスルホニル、置換されていても良い炭素数２～２０のアルキニルスルホニル、置換されていても良い炭素数２～２１のアルコキシカルボニル、置換されていても良い炭素数１～２０のアシル、置換されていても良い炭素数６～１０のアリール、置換されていても良い炭素数７～１４のアラルキルオキシ、置換されていても良い炭素数６～１０のアリールオキシ、シアノ、ニトロ、置換されていても良いアミノ、ハロゲン原子、カルボキシ等が挙げられ、これらは置換可能な任意の位置に、置換可能な任意の数だけ置換していても良い。
　また置換基がさらに置換されている場合、その置換基の例としては、前述と同じものが挙げられ、それらは置換可能な任意の位置に、置換可能な任意の数だけ置換していても良い。 In the present specification, when there is no particular description of the “substituent” in “may have a substituent”, the substituent is not particularly limited, and examples thereof include the substituents exemplified below. Alkyl having 1 to 20 carbon atoms which may be substituted, alkenyl having 2 to 20 carbon atoms which may be substituted, alkynyl having 2 to 20 carbon atoms which may be substituted, carbon number which may be substituted 1 to 20 alkylidene, optionally substituted cyclic group, oxo, hydroxyl group, optionally substituted alkoxy having 1 to 20 carbon atoms, optionally substituted alkenyloxy having 2 to 20 carbon atoms, substituted Optionally substituted alkynyloxy having 2 to 20 carbon atoms, optionally substituted alkylthio having 1 to 20 carbon atoms, optionally substituted alkenylthio having 2 to 20 carbon atoms, optionally substituted carbon number Alkynylthio having 2 to 20 carbon atoms, alkylsulfinyl having 1 to 20 carbon atoms which may be substituted, alkenylsulfinyl having 2 to 20 carbon atoms which may be substituted, Optionally substituted alkynylsulfinyl having 2 to 20 carbon atoms, optionally substituted alkylsulfonyl having 1 to 20 carbon atoms, optionally substituted alkenylsulfonyl having 2 to 20 carbon atoms, optionally substituted C2-C20 alkynylsulfonyl, optionally substituted C2-C21 alkoxycarbonyl, optionally substituted C1-C20 acyl, optionally substituted C6-C10 Aryl, optionally substituted aralkyloxy having 7 to 14 carbon atoms, optionally substituted aryloxy having 6 to 10 carbon atoms, cyano, nitro, optionally substituted amino, halogen atom, carboxy, etc. These may be substituted at any substitutable position by any number of substitutable positions.
Further, when the substituent is further substituted, examples of the substituent include the same ones as described above, and they may be substituted at any substitutable position by any number that can be substituted. .
　炭素数１～２０のアルキリデンとは、直鎖又は分枝鎖の炭素数１～２０のアルキリデンを意味し、例えば、メチリデン、エチリデン、ｎ－プロピリデン、イソプロピリデン、ｎ－ブチリデン、イソブチリデン、第２級ブチリデン、第３級ブチリデン、ｎ－ペンチリデン、イソペンチリデン、ネオペンチリデン、ｎ－ヘキシリデン、イソヘキシリデン、ネオヘキシリデン、ヘプチリデン、オクチリデン、ノニリデン、デシリデン、ウンデシリデン、ドデシリデン、トリデシリデン、テトラデシリデン、ペンタデシリデン、ヘキサデシリデン、ヘプタデシリデン、オクタデシリデン、ノナデシリデン、イコシリデン等を挙げることができる。 The alkylidene having 1 to 20 carbon atoms means a linear or branched alkylidene having 1 to 20 carbon atoms. For example, methylidene, ethylidene, n-propylidene, isopropylidene, n-butylidene, isobutylidene, secondary Butylidene, Tertiary butylidene, n-pentylidene, isopentylidene, neopentylidene, n-hexylidene, isohexylidene, neohexylidene, heptylidene, octylidene, nonylidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, dedecylidene, dedecylidene , Nonadecylidene, icosilidene and the like.
　炭素数２～２０のアルケニルオキシとは、直鎖又は分枝鎖の炭素数１～２０のアルケニルオキシを意味し、例えば、エテニルオキシ、ｎ－プロペニルオキシ、イソプロペニルオキシ、ｎ－ブテニルオキシ、イソブテニルオキシ、第２級ブテニルオキシ、ｔ－ブテニルオキシ、ペンテニルオキシ、イソペンテニルオキシ、第３級ペンテニルオキシ、ヘキセニルオキシ、ヘプテニルオキシ、オクテニルオキシ、ノネニルオキシ、デセニルオキシ、ウンデセニルオキシ、ドデセニルオキシ、トリデセニルオキシ、テトラデセニルオキシ、ペンタデセニルオキシ、ヘキサデセニルオキシ、ヘプタデセニルオキシ、オクタデセニルオキシ、ノナデセニルオキシ、イコセニルオキシ等を挙げることができる。 The alkenyloxy having 2 to 20 carbon atoms means a straight chain or branched alkenyloxy having 1 to 20 carbon atoms, such as ethenyloxy, n-propenyloxy, isopropenyloxy, n-butenyloxy, isobutenyl. Oxy, secondary butenyloxy, t-butenyloxy, pentenyloxy, isopentenyloxy, tertiary pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy, dodecenyloxy, tridecenyloxy, tetra Examples include decenyloxy, pentadecenyloxy, hexadecenyloxy, heptadecenyloxy, octadecenyloxy, nonadecenyloxy, icocenyloxy and the like.
　炭素数２～２０のアルキニルオキシとは、直鎖又は分枝鎖の炭素数１～２０のアルキニルオキシを意味し、例えば、エチニルオキシ、ｎ－プロピニルオキシ、イソプロピニルオキシ、ｎ－ブチニルオキシ、イソブチニルオキシ、第２級ブチニルオキシ、ｔ－ブチニルオキシ、ペンチニルオキシ、イソペンチニルオキシ、第３級ペンチニルオキシ、ヘキシニルオキシ、ヘプチニルオキシ、オクチニルオキシ、ノニニルオキシ、デシニルオキシ、ウンデシニルオキシ、ドデシニルオキシ、トリデシニルオキシ、テトラデシニルオキシ、ペンタデシニルオキシ、ヘキサデシニルオキシ、ヘプタデシニルオキシ、オクタデシニルオキシ、ノナデシニルオキシ、イコシニルオキシ等を挙げることができる。 The alkynyloxy having 2 to 20 carbon atoms means linear or branched alkynyloxy having 1 to 20 carbon atoms, such as ethynyloxy, n-propynyloxy, isopropynyloxy, n-butynyloxy, isobutynyl Nyloxy, secondary butynyloxy, t-butynyloxy, pentynyloxy, isopentynyloxy, tertiary pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy, dodecynyloxy, tridecynyloxy, tetradecyl Examples include nyloxy, pentadecynyloxy, hexadecynyloxy, heptadecynyloxy, octadecynyloxy, nonadecynyloxy, icosinyloxy and the like.
　炭素数１～２０のアルキルチオ、炭素数１～２０のアルキルスルフィニル、炭素数１～２０のアルキルスルホニルとは、それぞれのアルキル部が既述の炭素数１～２０のアルキルで構成されており、例えば、メチルチオ、エチルチオ、プロピルチオ、ペンチルチオ、デシルチオ、ペンタデシルチオ、イコシルチオ、メタンスルフィニル、デシルスルフィニル、イコシルスルフィニル、メタンスルホニル、デシルスルホニル、イコシルスルホニル等を挙げることができる。 The alkylthio having 1 to 20 carbon atoms, the alkylsulfinyl having 1 to 20 carbon atoms, and the alkylsulfonyl having 1 to 20 carbon atoms are each composed of the above-described alkyl having 1 to 20 carbon atoms, , Methylthio, ethylthio, propylthio, pentylthio, decylthio, pentadecylthio, icosylthio, methanesulfinyl, decylsulfinyl, icosylsulfinyl, methanesulfonyl, decylsulfonyl, icosylsulfonyl and the like.
　炭素数２～２０のアルケニルチオ、炭素数２～２０のアルケニルスルフィニル、炭素数２～２０のアルケニルスルホニルとは、それぞれのアルケニル部が既述の炭素数２～２０のアルケニルで構成されており、例えば、エテニルチオ、プロペニルチオ、ペンテニルチオ、デセニルチオ、ペンタデセニルチオ、イコセニルチオ、エテニルスルフィニル、デセニルスルフィニル、イコセニルスルフィニル、エテニルスルホニル、デセニルスルホニル、イコセニルスルホニル等を挙げることができる。 The alkenylthio having 2 to 20 carbon atoms, the alkenylsulfinyl having 2 to 20 carbon atoms, and the alkenylsulfonyl having 2 to 20 carbon atoms are configured such that each alkenyl part is the alkenyl having 2 to 20 carbon atoms described above, For example, ethenylthio, propenylthio, pentenylthio, decenylthio, pentadecenylthio, icocenylthio, ethenylsulfinyl, decenylsulfinyl, icocenylsulfinyl, ethenylsulfonyl, decenylsulfonyl, icocenylsulfonyl, etc. Can do.
　炭素数２～２０のアルキニルチオ、炭素数２～２０のアルキニルスルフィニル、炭素数２～２０のアルキニルスルホニルとは、それぞれのアルキニル部が既述の炭素数２～２０のアルキニルで構成されており、例えば、エチニルチオ、プロピニルチオ、ペンチニルチオ、デシニルチオ、ペンタデシニルチオ、イコシニルチオ、エチニルスルフィニル、デシニルスルフィニル、イコシニルスルフィニル、エチニルスルホニル、デシニルスルホニル、イコシニルスルホニル等を挙げることができる。 The alkynylthio having 2 to 20 carbon atoms, the alkynylsulfinyl having 2 to 20 carbon atoms, and the alkynylsulfonyl having 2 to 20 carbon atoms, each alkynyl moiety is composed of the alkynyl having 2 to 20 carbon atoms described above, Examples include ethynylthio, propynylthio, pentynylthio, decynylthio, pentadecynylthio, icosinylthio, ethynylsulfinyl, decynylsulfinyl, icosinylsulfinyl, ethynylsulfonyl, decynylsulfonyl, icosinylsulfonyl and the like.
　炭素数２～２０のアルコキシカルボニル、炭素数１～２０のアシル、炭素数７～１４のアラルキルオキシ及び炭素数６～１０のアリールオキシは上述の通りである。 The alkoxycarbonyl having 2 to 20 carbon atoms, the acyl having 1 to 20 carbon atoms, the aralkyloxy having 7 to 14 carbon atoms and the aryloxy having 6 to 10 carbon atoms are as described above.
　「置換されていても良い環状基」における「環状基」とは「炭素環」又は「複素環」を意味し、例えば、炭素数６～１０のアリール、炭素数３～７のシクロアルキル、１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルが挙げられ、炭素数６～１０のアリール、炭素数３～７のシクロアルキル、１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルは前述と同じ意味を表す。 The “cyclic group” in the “optionally substituted cyclic group” means “carbocycle” or “heterocycle” and includes, for example, aryl having 6 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, A heteroaryl having 5 to 10 ring atoms containing 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms, 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms Heterocycles having 3 to 7 atoms in the ring included as aryl, including aryls having 6 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms. Heteroaryl having 5 to 10 ring atoms as ring atoms, hetero ring having 3 to 7 rings having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms Cycloalkyl is The same meanings as defined above.
　以下に、上記一般式（Ｉ）に示される基の好ましい例を示す。
　ＲＩの好ましい例としては水素原子を挙げることができ、別の好ましい例としては、Ｐ（＝Ｏ）（ＯＨ）２を挙げることができる。
　ＸＩの好ましい例としては酸素原子を挙げることができ、またＹＩの好ましい例としてはＣＨ２ＣＨ２を挙げることができる。
　Ｙ１の好ましい例としては、ＣＨ２ＣＨ２を挙げることができる。
　ＲＩ－１の好ましい例としては、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル又はシアノを挙げることができ、トリフルオロメチル又はシアノをより好ましい例として挙げることができ、トリフルオロメチルをさらにより好ましい例として挙げることができる。
　ＲＩ－２の好ましい例としては、メチル、エチル、ヒドロキシメチル、ヒドロキシエチル、フルオロメチル、フルオロエチル、２，２－ジフルオロエチル、２，２，２－トリフルオロエチルを挙げることができ、より好ましい例としては、メチル、エチル、ヒドロキシメチルを挙げることができ、さらに好ましい例としてヒドロキシメチルを挙げることができる。
　ＲＩ－３及びＲＩ－４の好ましい例としては、それぞれ同一又は異なって、水素原子、メチル、エチルを挙げることができ、より好ましい例として水素原子を挙げることができる。
　ＡＩの好ましい例としては、官能基を有している炭素数５～８の直鎖アルキルを挙げることができ、より好ましい例としては、１又は２個の炭素数１のアルキルを有している炭素数７又は８の直鎖アルキル、ハロゲン原子を１～５個有している炭素数５、６又は8の直鎖アルキル、１個の鎖中の二重結合を有している炭素数７の直鎖アルキル、１個の鎖端の二重結合を有している炭素数７又は８の直鎖アルキル、又は１個の鎖端の三重結合を有している炭素数７の直鎖アルキルを挙げることができる。
　ＡＩのより好ましい例としては、炭素数５～９の直鎖のアルキルであって、以下ａ～ｄのいずれか１つの官能基
（ａ、炭素数１～６のアルキル。
ｂ、フッ素原子。
ｃ、当該鎖中の、二重結合、三重結合。
ｄ、当該鎖端の二重結合、三重結合。）
を有する基を挙げることができる。
　ＡＩの好ましい例をより具体的に挙げると、１－メチルヘプチル、２－メチルヘプチル、６－メチルヘプチル、３，７－ジメチルオクチル、４，４，５，５，５－ペンタフルオロペンチル、６－フルオロヘキシル、８－フルオロオクチル、２－ヘプテニル、４－ヘプテニル、６－ヘプテニル、７－オクテニル、２－ヘプチニル、又は３－ヘプチニルを挙げることができ、更に好ましい例としては、６－メチルヘプチル、３，７－ジメチルオクチル、８－フルオロオクチル、又は７－オクテニルを挙げることができる。 Below, the preferable example of group shown by the said general formula (I) is shown.
A preferred example of R 1 is a hydrogen atom, and another preferred example is P (═O) (OH) 2 .
Preferred examples of X I include an oxygen atom, and preferred examples of Y I include CH 2 CH 2 .
Preferable examples of Y 1 include CH 2 CH 2 .
Preferred examples of R I-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyano. More preferable examples include trifluoromethyl and cyano. An even more preferred example is fluoromethyl.
Preferred examples of R I-2 include methyl, ethyl, hydroxymethyl, hydroxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl, and more preferred. Examples include methyl, ethyl, and hydroxymethyl, and more preferable examples include hydroxymethyl.
Preferable examples of R I-3 and R I-4 are the same or different and include a hydrogen atom, methyl, and ethyl, and more preferable examples include a hydrogen atom.
Preferred examples of A I can be mentioned straight-chain alkyl having a carbon number of 5-8 has a functional group, as a more preferred example, include one or two alkyl of 1 carbon atoms Straight chain alkyl having 7 or 8 carbon atoms, straight chain alkyl having 1 to 5 halogen atoms, straight chain alkyl having 6 to 8 carbon atoms, or a double bond in one chain 7 straight chain alkyls, 1 or 7 straight chain alkyls with 7 chain ends, or 7 straight chain chains with 1 chain end triple bonds Mention may be made of alkyl.
More preferred examples of A I is a straight-chain alkyl having 5 to 9 carbon atoms, following a one of the functional groups (a in ~ d, alkyl having 1 to 6 carbon atoms.
b, a fluorine atom.
c, a double bond or a triple bond in the chain.
d, double bond and triple bond at the chain end. )
The group which has can be mentioned.
Taking preferred examples of A I more specifically, 1-methylheptyl, 2-methylheptyl, 6-methylheptyl, 3,7-dimethyl octyl, 4,4,5,5,5-pentafluoro-pentyl, 6 -Fluorohexyl, 8-fluorooctyl, 2-heptenyl, 4-heptenyl, 6-heptenyl, 7-octenyl, 2-heptynyl, or 3-heptynyl, and more preferred examples include 6-methylheptyl, Mention may be made of 3,7-dimethyloctyl, 8-fluorooctyl or 7-octenyl.
　以下に、上記一般式（ＩＩ－１）に示される基の好ましい例を示す。
　ＸＩＩの好ましい例としては、酸素原子を挙げることができる。
　ＹＩＩ－１の好ましい例としては、ＣＨ２ＣＨ２を挙げることができる。
　ＲＩＩ－１の好ましい例としては、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル又はシアノを挙げることができ、トリフルオロメチル又はシアノをより好ましい例として挙げることができ、トリフルオロメチルをさらにより好ましい例として挙げることができる。
　ＲＩＩ－３の好ましい例としては、水素原子を挙げることができる。
　ＲＩＩ－２の好ましい例としては、メチル、エチル、ヒドロキシメチル、ヒドロキシエチル、メトキシエチル、フルオロメチル、フルオロエチル、２，２－ジフルオロエチル、２，２，２－トリフルオロエチルを挙げることができ、より好ましい例としては、メチル、エチル、ヒドロキシメチル、メトキシエチルを挙げることができ、さらに好ましい例としてヒドロキシメチルを挙げることができる。
　ＡＩＩ－２の好ましい例としては、水素原子、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２又はＣＯＯＨを挙げることができ、別の好ましい例としてＯＨを挙げることができる。なかでも、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、ＯＨをより好ましい例として挙げることができる。
　ＺＩＩの好ましい例としては、単結合又は炭素数１～４のアルキレンを挙げることができ、単結合、メチレン、ジメチレンをより好ましい例として挙げることができる。
　ＡＩＩ－１の好ましい例としては、官能基を有していても良い炭素数５～９（例、５、６、７又は８）の直鎖アルキルを挙げることができ、より好ましい例としては、１又は２個の炭素数１個のアルキルを有していてもよい炭素数７又は８の直鎖アルキル、１又は５個のハロゲン原子を有していても良い炭素数５、６、７又は８の直鎖アルキル、鎖中に１個の二重結合を有していても良い炭素数７の直鎖アルキル、鎖中に１個の三重結合を有していても良い炭素数７の直鎖アルキル、鎖端に１個の二重結合を有していても良い炭素数６又は７の直鎖アルキル、鎖端に１個の三重結合を有していても良い炭素数７の直鎖アルキルを挙げることができ、炭素数５～９の直鎖のアルキルをより好ましい例として挙げることができる。
　ＡＩＩ－１の好ましい例をより具体的に挙げると、ｎ－ヘプチル、ｎ－オクチル、１－メチルヘプチル、２－メチルヘプチル、６－メチルヘプチル、１－エチルヘプチル、３，７－ジメチルオクチル、４，４，５，５，５－ペンタフルオロペンチル、６－フルオロヘキシル、７－フルオロヘプチル、８－フルオロオクチル、５－ヘキセニル、１－ヘプテニル、４－ヘプテニル、６－ヘプテニル、７－オクテニル、２－ヘプチニル、４－ヘプチニル、又は６－ヘプチニルを挙げることができる。 Preferred examples of the group represented by the general formula (II-1) are shown below.
Preferred examples of X II, can be exemplified an oxygen atom.
Preferable examples of Y II-1 include CH 2 CH 2 .
Preferred examples of R II-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and more preferred examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
A preferred example of R II-3 is a hydrogen atom.
Preferred examples of R II-2 include methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. More preferred examples include methyl, ethyl, hydroxymethyl and methoxyethyl, and more preferred examples include hydroxymethyl.
Preferred examples of A II-2 include a hydrogen atom, P (═O) (OH) 2 , O—P (═O) (OH) 2 or COOH, and another preferred example includes OH. be able to. Among these, P (═O) (OH) 2 , O—P (═O) (OH) 2 , and OH can be given as more preferable examples.
Preferable examples of Z II include a single bond or alkylene having 1 to 4 carbon atoms, and more preferable examples include a single bond, methylene and dimethylene.
Preferred examples of A II-1 include linear alkyl having 5 to 9 carbon atoms (eg, 5, 6, 7 or 8) which may have a functional group, and more preferred examples include 1 or 2 linear alkyl having 7 or 8 carbon atoms which may have 1 alkyl, 1 or 2 carbon atoms which may have 1 or 5 halogen atoms, 6 or 7 Or a straight alkyl having 8 carbon atoms, a straight chain alkyl having 7 carbon atoms which may have one double bond in the chain, and a 7 carbon atom having 1 triple bond in the chain. Straight chain alkyl, straight chain alkyl having 6 or 7 carbon atoms that may have one double bond at the chain end, straight chain of 7 carbon atoms that may have one triple bond at the chain end A straight chain alkyl having 5 to 9 carbon atoms can be mentioned as a more preferable example.
More specifically, preferred examples of A II-1 include n-heptyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 6-methylheptyl, 1-ethylheptyl, 3,7-dimethyloctyl, 4,4,5,5,5-pentafluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 5-hexenyl, 1-heptenyl, 4-heptenyl, 6-heptenyl, 7-octenyl, 2 Mention may be made of -heptynyl, 4-heptynyl or 6-heptynyl.
　以下に、上記一般式（ＩＩ－２）に示される基の好ましい例を示す。
　ＹＩＩ－２の好ましい例としては、トリメチレン又はプロペニレンを挙げることができ、トリメチレン又は、下記一般式 Preferred examples of the group represented by the general formula (II-2) are shown below.
Preferred examples of Y II-2 include trimethylene or propenylene, trimethylene or the following general formula
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、各記号は上記で定義した通りである。）中に示される基をより好ましい例として、トリメチレンをさらにより好ましい例として挙げることができる。
　ＡＩＩ－３の好ましい例としては、置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールを挙げることができる。
　ＡＩＩ－３のより好ましい例としては、無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれ
ハロゲン原子で置換されていても良い炭素数１～４のアルキル；
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
ハロゲン原子；
炭素数６～１０のアリールから選択される置換基を挙げることができる。
　ＡＩＩ－３の更に好ましい例としては、置換されていても良いフェニルをより好ましい例として挙げることができ、特に、下記一般式 (In the formula, each symbol is as defined above.) A group shown in the above is a more preferable example, and trimethylene is an even more preferable example.
Preferred examples of A II-3 include a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Mention may be made of heteroaryl having 5 to 9 atoms.
As a more preferred example of A II-3 , when it is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom. Alkyl having 1 to 4 carbon atoms which may be substituted with:
Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
A halogen atom;
Examples thereof include a substituent selected from aryl having 6 to 10 carbon atoms.
As a more preferred example of A II-3 , phenyl which may be substituted may be mentioned as a more preferred example.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、
ＲＩＩ－４及びＲＩＩ－５は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ、又は
ハロゲン原子を示す。）
で表される基を挙げることができる。
　ＡＩＩ－３が置換基を有している場合における置換基の好ましい例としては、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、メチルチオ、メタンスルフィニル、メタンスルホニル、メチルカルボニル、フッ素原子、塩素原子、臭素原子、シアノ、ニトロ、シクロプロピル、フェニル、ベンジルオキシ、フェノキシ、トリメチレン、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシを挙げることができ、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、フッ素原子、塩素原子、臭素原子、シクロプロピル、フェニル、トリメチレン、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシをより好ましい例として挙げることができ、メチル、トリフルオロメチル、トリフルオロメトキシ、フッ素原子、塩素原子をさらにより好ましい例として挙げることができる。
　ＡＩＩ－３の好ましい例をより具体的に挙げると、メチルフェニル、（トリフルオロメチル）フェニル、（トリフルオロメトキシ）フェニル、クロロフェニル、ジクロロフェニル、フルオロ（トリフルオロメチル）フェニルを挙げることができる。
　ＸＩＩ、ＹＩＩ－１、ＲＩＩ－１、ＲＩＩ－３、ＲＩＩ－２、ＡＩＩ－２及びＺＩＩの好ましい例としては、上記一般式（ＩＩ－１）に示される基と同様の基を挙げることができる。 (Where
R II-4 and R II-5 may be the same or different and each is a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom,
An alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a halogen atom is shown. )
The group represented by these can be mentioned.
Preferred examples of the substituent when A II-3 has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom, List chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C (═O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferable examples include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, and difluoromethylenedioxy. Bets can be, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom.
More specifically, preferred examples of A II-3 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.
Preferred examples of X II , Y II-1 , R II-1 , R II-3 , R II-2 , A II-2 and Z II are the same as the groups shown in the general formula (II-1). Can be mentioned.
　以下に、上記一般式（ＩＩＩ－１）における上記一般式（Ｉ）に示される基の好ましい例を示す。
　ＲＩＩＩ－２の好ましい例としては水素原子を挙げることができる。
　ＸＩＩＩ－１の好ましい例としては酸素原子を挙げることができる。
　ＲＩＩＩ－１の好ましい例としては、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル又はシアノを挙げることができ、トリフルオロメチル又はシアノをより好ましい例として挙げることができ、トリフルオロメチルをさらにより好ましい例として挙げることができる。
　ＸＩＩＩ－２がメチンである場合、ＹＩＩＩ-１がメチレンで、ＡＩＩＩ-２及びＢＩＩＩがともに炭素数１～３のアルキルであることが好ましい。
　別の好ましい例として、ＸＩＩＩ-２がメチンで、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ-２、ＢＩＩＩ及びアミノ基が結合している炭素原子がシクロペンチルであることが好ましい。
　ＸＩＩＩ－２がメチンの場合、ＹＩＩＩ－１、ＡＩＩＩ－２、ＢＩＩＩの更に好ましい例は、下記一般式 Preferred examples of the group represented by the general formula (I) in the general formula (III-1) are shown below.
A preferred example of R III-2 is a hydrogen atom.
A preferred example of X III-1 is an oxygen atom.
Preferred examples of R III-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and more preferred examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
When X III-2 is methine, Y III-1 is preferably methylene, and both A III-2 and B III are preferably alkyl having 1 to 3 carbon atoms.
As another preferred example, X III-2 is methine, B III is bound to A III-2 , Y III-1 , X III-2 , A III-2 , B III and an amino group are bound. It is preferred that the carbon atom is cyclopentyl.
When X III-2 is methine, more preferred examples of Y III-1 , A III-2 and B III are
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（式中、各記号は上記で定義した通りである。）中に示される基を挙げることができる。
　更に別の好ましい例としては、ＸＩＩＩ-２が窒素原子である場合、ＹＩＩＩ-１がＣ＝Ｏ、ＢＩＩＩが水素原子又はメチルであることが好ましい。
　ＸＩＩＩ－２が窒素原子の場合、ＹＩＩＩ－１、ＡＩＩＩ－２、ＢＩＩＩの更に好ましい例は、下記一般式 (Wherein each symbol is as defined above), the groups shown in the above can be mentioned.
As yet another preferred example, when X III-2 is a nitrogen atom, Y III-1 is preferably C═O and B III is preferably a hydrogen atom or methyl.
When X III-2 is a nitrogen atom, more preferred examples of Y III-1 , A III-2 and B III are
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（式中、各記号は上記で定義した通りである。）中に示される基又は、下記一般式 (Wherein each symbol is as defined above) or a group represented by the following general formula
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（式中、各記号は上記で定義した通りである。）中に示される基を挙げることができる。
　ＡＩＩＩ－１の好ましい例としては、炭素数５～９の直鎖のアルキルを挙げることができ、ｎ－ヘプチル、ｎ－オクチルをさらに好ましい例として挙げることができる。 (Wherein each symbol is as defined above), the groups shown in the above can be mentioned.
Preferable examples of A III-1 include linear alkyl having 5 to 9 carbon atoms, and n-heptyl and n-octyl can be further preferable examples.
　以下に、上記一般式（ＩＩＩ－２）に示される基の好ましい例を示す。
　ＹＩＩＩ－２の好ましい例としては、トリメチレン又はプロペニレンを挙げることができ、トリメチレン又は下記一般式 Preferred examples of the group represented by the general formula (III-2) are shown below.
Preferred examples of Y III-2 include trimethylene or propenylene, trimethylene or the following general formula
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
（式中、各記号は上記で定義した通りである。）中に示される基をより好ましい例として、トリメチレンをさらにより好ましい例として挙げることができる。
　ＡＩＩＩ－３の好ましい例としては、置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールを挙げることができ、置換されていても良いフェニルをより好ましい例として挙げることができる。
　ＡＩＩＩ－３のより好ましい例としては、無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれ
ハロゲン原子で置換されていても良い炭素数１～４のアルキル；
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
ハロゲン原子；
炭素数６～１０のアリール
から選択される置換基を挙げることができる。
　ＡＩＩＩ－３の更に好ましい例としては、下記一般式 (In the formula, each symbol is as defined above.) A group shown in the above is a more preferable example, and trimethylene is an even more preferable example.
Preferred examples of A III-3 include a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Heteroaryl having 5 to 9 atoms can be mentioned, and phenyl which may be substituted can be mentioned as a more preferable example.
As a more preferred example of A III-3 , when it is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom. Alkyl having 1 to 4 carbon atoms which may be substituted with:
Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
A halogen atom;
Examples thereof include a substituent selected from aryl having 6 to 10 carbon atoms.
More preferable examples of A III-3 include the following general formula:
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中、ＲＩＩＩ－３及びＲＩＩＩ－４は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基を挙げることができる。
　ＡＩＩＩ－３がさらに置換基を有している場合における置換基の好ましい例としては、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、メチルチオ、メタンスルフィニル、メタンスルホニル、メチルカルボニル、フッ素原子、塩素原子、臭素原子、シアノ、ニトロ、シクロプロピル、フェニル、ベンジルオキシ、フェノキシ、トリメチレン、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシを挙げることができ、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、フッ素原子、塩素原子、臭素原子、シクロプロピル、フェニル、トリメチレン、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシをより好ましい例として挙げることができ、メチル、トリフルオロメチル、トリフルオロメトキシ、フッ素原子、塩素原子をさらにより好ましい例として挙げることができる。
　ＡＩＩＩ－３の好ましい例をより具体的に挙げると、メチルフェニル、（トリフルオロメチル）フェニル、（トリフルオロメトキシ）フェニル、クロロフェニル、ジクロロフェニル、フルオロ（トリフルオロメチル）フェニルを挙げることができる。
　ＲＩＩＩ－２、ＸＩＩＩ－１、ＲＩＩＩ－１、ＸＩＩＩ－２、ＹＩＩＩ－１、ＡＩＩＩ－２、ＢＩＩＩの好ましい例としては、上記一般式（ＩＩＩ－１）に示される基と同様の基を挙げることができる。 (In the formula, R III-3 and R III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a group having a carbon number of 1-4 or a halogen atom.
Preferred examples of the substituent when A III-3 further has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom , Chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C (═O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, difluoromethylenedioxy. Can be exemplified, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom.
More specifically, preferred examples of A III-3 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.
Preferred examples of R III-2 , X III-1 , R III-1 , X III-2 , Y III-1 , A III-2 , B III include groups represented by the above general formula (III-1) The same group can be mentioned.
　以下に、上記一般式（ＩＶ－１）に示される基の好ましい例を示す。
　ＸＩＶの好ましい例としては酸素原子を挙げることができる。
　ＲＩＶ－１の好ましい例としては、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル又はシアノを挙げることができ、トリフルオロメチル又はシアノをより好ましい例として挙げることができ、トリフルオロメチルをさらにより好ましい例として挙げることができる。
　ＲＩＶ－２の好ましい例としては、水素原子又は炭素数１～２０のアシルを挙げることができる。
　ＲＩＶ－２が、生体内で脱離する置換基である場合のＲＩＶ－３の好ましい例としては、水素原子を挙げることができる。
　ＲＩＶ－２が炭素数１～２０のアシル又は炭素数２～２１のアルコキシカルボニルである場合のＲＩＶ－３の好ましい例としては、水素原子を挙げることができる。
　ＲＩＶ－２が水素原子である場合のＲＩＶ－３の好ましい例としては、Ｐ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）、（ＲＩＶ－５及びＲＩＶ－６はリン酸基の保護基若しくは生体内で脱離する置換基を示す。）を挙げることができる。
　ＲＩＶ－５及びＲＩＶ－６の好ましい例としては、それぞれ同一又は異なって、ヘキサデシル、ピバロイルオキシメチル、イソプロポキシカルボニルオキシメチル、アセチルチオエチル、フェニルが挙げられる。
　ＡＩＶ－１の好ましい例としては、炭素数５～９の直鎖のアルキルを挙げることができ、ｎ－ヘプチル、ｎ－オクチルをより好ましい例として挙げることができる。 Preferred examples of the group represented by the general formula (IV-1) are shown below.
Preferred examples of X IV can be mentioned oxygen atom.
Preferable examples of R IV-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and trifluoromethyl or cyano can be more preferable examples. An even more preferred example is fluoromethyl.
Preferred examples of R IV-2 include a hydrogen atom or acyl having 1 to 20 carbon atoms.
A preferred example of R IV-3 when R IV-2 is a substituent capable of leaving in vivo includes a hydrogen atom.
Preferred examples of R IV-3 when R IV-2 is acyl having 1 to 20 carbons or alkoxycarbonyl having 2 to 21 carbons include a hydrogen atom.
Preferred examples of R IV-3 when R IV-2 is a hydrogen atom include P (═O) (OR IV-5 ) (OR IV-6 ), (R IV-5 and R IV-6 A protective group for a phosphate group or a substituent that is eliminated in vivo).
Preferable examples of R IV-5 and R IV-6 are the same or different and include hexadecyl, pivaloyloxymethyl, isopropoxycarbonyloxymethyl, acetylthioethyl, and phenyl.
Preferable examples of A IV-1 include linear alkyl having 5 to 9 carbon atoms, and more preferable examples include n-heptyl and n-octyl.
　以下に、上記一般式（ＩＶ－２）に示される基の好ましい例を示す。
　ＸＩＶ、ＲＩＶ－１、ＲＩＶ－２、ＲＩＶ－３、ＲＩＶ－４及びＹＩＶの好ましい例としては、上記一般式（ＩＶ－１）における基と同様の基を挙げることができる。
　ＹＩＶの好ましい例としてはトリメチレン又はプロペニレンを挙げることができ、トリメチレン又は下記一般式 Preferred examples of the group represented by the general formula (IV-2) are shown below.
Preferred examples of X IV, R IV-1, R IV-2, R IV-3, R IV-4, and Y IV include the same groups as those in the general formula (IV-1). .
Preferred examples of Y IV include trimethylene or propenylene, and trimethylene or the following general formula
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、各記号は上記で定義した通りである。）中に示される基をより好ましい例として、トリメチレンをさらにより好ましい例としてあげることができる。
　ＡＩＶ－２の好ましい例としては、置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールを挙げることができ、置換されていても良いフェニルをより好ましい例として挙げることができる。
　ＡＩＶ－２のより好ましい例としては、無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれ
ハロゲン原子で置換されていても良い炭素数１～４のアルキル；
ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
ハロゲン原子；
炭素数６～１０のアリール
から選択される置換基を挙げることができる。
　ＡＩＶ－２の更に好ましい例としては、下記一般式 (In the formula, each symbol is as defined above.) The group shown in the above is a more preferred example, and trimethylene is a more preferred example.
A preferred example of A IV-2 is a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted sulfur atom or oxygen atom as a ring constituting atom. Heteroaryl having 5 to 9 atoms can be mentioned, and phenyl which may be substituted can be mentioned as a more preferable example.
As a more preferred example of A IV-2 , when it is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each is a halogen atom. Alkyl having 1 to 4 carbon atoms which may be substituted with:
Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
A halogen atom;
Examples thereof include a substituent selected from aryl having 6 to 10 carbon atoms.
More preferable examples of A IV-2 include the following general formula:
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（式中、ＲＩＶ－７及びＲＩＶ－８は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基を挙げることができる。
　ＡＩＶ－２がさらに置換基を有している場合における置換基の好ましい例としては、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、メチルチオ、メタンスルフィニル、メタンスルホニル、メチルカルボニル、フッ素原子、塩素原子、臭素原子、シアノ、ニトロ、シクロプロピル、フェニル、ベンジルオキシ、フェノキシ、トリメチレン、－Ｃ（＝Ｏ）－ＣＨ２－ＣＨ２－、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシを挙げることができ、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、フッ素原子、塩素原子、臭素原子、シクロプロピル、フェニル、トリメチレン、エチレンオキシ、メチレンジオキシ、ジフルオロメチレンジオキシをより好ましい例として挙げることができ、メチル、トリフルオロメチル、トリフルオロメトキシ、フッ素原子、塩素原子をさらにより好ましい例として挙げることができる。
　ＡＩＶ－２の好ましい例をより具体的に挙げると、メチルフェニル、（トリフルオロメチル）フェニル、（トリフルオロメトキシ）フェニル、クロロフェニル、ジクロロフェニル、フルオロ（トリフルオロメチル）フェニルを挙げることができる。 (In the formula, R IV-7 and R IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a group having a carbon number of 1-4 or a halogen atom.
Preferred examples of the substituent when A IV-2 further has a substituent include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, methylcarbonyl, fluorine atom , Chlorine atom, bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, trimethylene, —C (═O) —CH 2 —CH 2 —, ethyleneoxy, methylenedioxy, difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, difluoromethylenedioxy You can gel, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom.
More specifically, preferred examples of A IV-2 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.
　以下に、上記一般式（Ｖ）に示される基の好ましい例を示す。 Hereinafter, preferable examples of the group represented by the general formula (V) will be shown.
　ＢＶの好ましい例としては、水素原子、ＣＯＯＲＶ－6（ここで、ＲＶ－6は、上記と同義である。）、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、シアノ、ＣＯ－ＮＨ－ＳＯ２－ＲＶ－９（ここで、ＲＶ－９は、上記と同義である。）、ＯＨ、又は下記式 Preferred examples of B V include a hydrogen atom, COOR V-6 (where R V-6 is as defined above), P (═O) (OH) 2 , O—P (═O). (OH) 2 , cyano, CO—NH—SO 2 —R V-9 (where R V-9 is as defined above), OH, or the following formula
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
で表される基を挙げることができる。
　ＢＶのより好ましい例としては、ＣＯＯＲｖ－６、Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）、Ｏ－Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）、ＯＨを挙げることができる。
　ＢＶの好ましい例をより具体的に挙げると、水素原子、ＣＯＯＨ、ＣＯＯＣＨ３、ＣＯＯＣＨ２ＣＨ３、ＣＯＯＣ（ＣＨ３）３、ＣＯＯＮａ、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、シアノ、ＣＯ－ＮＨ－ＳＯ２－ＣＨ３、ＣＯ－ＮＨ－ＳＯ２－ベンゼン、ＯＨ、又は下記式 The group represented by these can be mentioned.
As more preferred examples of B V , COOR v-6 , P (═O) (OR v-7 ) (OR v-8 ), OP (═O) (OR v-7 ) (OR v-8 ) ), OH.
More specifically, preferable examples of B V are hydrogen atom, COOH, COOCH 3 , COOCH 2 CH 3 , COOC (CH 3 ) 3 , COONa, P (═O) (OH) 2 , O—P (= O) (OH) 2 , cyano, CO—NH—SO 2 —CH 3 , CO—NH—SO 2 -benzene, OH, or
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
で表される基を挙げることができ、さらに好ましい例としては、ＣＯＯＨ、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、又はＯＨを挙げることができる。
　ＶＶの好ましい例としては、単結合、置換基を有していても良い炭素数１～６のアルキレンを挙げることができ、単結合、メチレン、ジメチレン、プロピレン、３，３－ヒドロキシメチルプロピレンを、さらに好ましい例として挙げることができる。
　ＹＶの好ましい例としては、単結合、－ＮＲＶ－５－、－ＮＲＶ－５ＣＯ－、－ＣＯＮＲＶ－５－を挙げることができ、より好ましい例としては、単結合、－ＮＨ－、－Ｎ（ＣＨ３）－、－Ｎ（ＣＨ２ＣＨ３）－、－ＮＨＣＯ－を挙げることができ（ここで、ＲＶ－５で表される基（例、メチル、エチル）は、Ｚｖで示される基上の原子と共に環を構成しても良い。）、単結合又は－ＮＨ－をさらに好ましい例として挙げることができる。
　ｎＶの好ましい例は、０又は１であり、１をさらに好ましい例として挙げることができる。
　ＺＶの好ましい例としては、置換基を有していても良い炭素数１～６のアルキレン、置換基を有していても良い炭素数６～１０のアリーレン、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを挙げることができ、別の好ましい例としては、置換基を有していても良い炭素数３～７のシクロアルキレンを挙げることができる。
　ＺＶの好ましい例をより具体的に挙げると、ジメチレン、プロピレン、ブチレン、アミノ（ヒドロキシ）シクロペンチレン、アミノ（（ＯＨ）２（Ｏ＝）Ｐ－Ｏ）ペンチレン、ピロリジン、ヒドロキシピロリジン、フェニレン、ヒドロキシカルボニルフェニレン、メトキシカルボニルフェニレン、エトキシカルボニルフェニレンを挙げることができる。
　ＲＶ－１の好ましい例としては、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル又はシアノを挙げることができ、トリフルオロメチル又はシアノをより好ましい例として挙げることができ、トリフルオロメチルをさらにより好ましい例として挙げることができる。
　ＸＶの好ましい例としては、単結合、酸素原子、硫黄原子、カルボニル、－ＮＲＶ－２－を挙げることができ、より好ましい例として酸素原子を挙げることができる。
　ＡＶの好ましい例としては、鎖中又は鎖端に、置換基を有していてもよいフェニルに置換されていても良い直鎖又は分枝鎖状の炭素数１～８のアルキルを挙げることができる。「置換基を有していてもよいフェニル」が有している置換基の好ましい例としては、メチル、エチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、メチルチオ、メタンスルフィニル、メタンスルホニル、フッ素原子、塩素原子、臭素原子、シアノ、ニトロ、シクロプロピル、フェニル、ベンジルオキシ、フェノキシを挙げることができる。
　ＡＶの好ましい例をより具体的に挙げると、ｎ－ヘプチル、ｎ－オクチル、３－フェニルプロピル、５－フェニルペンチル、６－フェニルヘキシル、３－（ビフェニル－４－イル）プロピル、３－（ビフェニル－３－イル）プロピル、３－（３－フェノキシフェニル）プロピル、３－（３－ベンジルオキシフェニル）プロピル、５－（３－メチルフェニル）ペンチル、５－（ビフェニル－４－イル）ペンチル、５－（ビフェニル－３－イル）ペンチル、５－（２－フェノキシフェニル）ペンチル、５－（３－ベンジルオキシフェニル）ペンチルを挙げることができる。 And more preferable examples include COOH, P (═O) (OH) 2 , O—P (═O) (OH) 2 , or OH.
Preferred examples of V V include a single bond and optionally substituted alkylene having 1 to 6 carbon atoms. A single bond, methylene, dimethylene, propylene, and 3,3-hydroxymethylpropylene can be used. Furthermore, it can mention as a more preferable example.
Preferred examples of Y V, a single bond, -NR V-5 -, - NR V-5 CO -, - CONR V-5 - may be mentioned, as preferred examples, a single bond, -NH- , —N (CH 3 ) —, —N (CH 2 CH 3 ) —, —NHCO— (wherein the group represented by R V-5 (eg, methyl, ethyl) is Zv A ring may be formed together with atoms on the group represented by the following formula :), and a single bond or —NH— can be further preferred examples.
Preferred examples of n V is 0 or 1, can be mentioned as more preferred example 1.
Preferred examples of Z V is have alkylene good having 1 to 6 carbon atoms which may have a substituent, an arylene good 6 to 10 carbon atoms which may have a substituent, or a substituent The heterocycloalkylene having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as the ring constituting atoms may be mentioned as another preferred example. And cycloalkylene having 3 to 7 carbon atoms which may have
Taking preferred examples of Z V more specifically, dimethylene, propylene, butylene, amino (hydroxy) cyclopentylene, amino ((OH) 2 (O = ) P-O) pentylene, pyrrolidine, hydroxypyrrolidine, phenylene, Examples thereof include hydroxycarbonylphenylene, methoxycarbonylphenylene, and ethoxycarbonylphenylene.
Preferable examples of R V-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano. More preferable examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.
Preferred examples of X V, a single bond, an oxygen atom, a sulfur atom, a carbonyl, -NR V-2 - can be exemplified, it can be exemplified an oxygen atom as a more preferable example.
Preferred examples of A V is in the chain or the chain ends, be mentioned alkyl optionally 1 carbon atoms of a good linear or branched substituted to phenyl and 1-8 have a substituent Can do. Preferred examples of the substituent that the “optionally substituted phenyl” has include methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, methanesulfinyl, methanesulfonyl, fluorine atom, A chlorine atom, a bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy can be mentioned.
Taking preferred examples of A V more specifically, n- heptyl, n- octyl, 3-phenylpropyl, 5-phenylpentyl, 6-phenyl-hexyl, 3- (biphenyl-4-yl) propyl, 3- ( Biphenyl-3-yl) propyl, 3- (3-phenoxyphenyl) propyl, 3- (3-benzyloxyphenyl) propyl, 5- (3-methylphenyl) pentyl, 5- (biphenyl-4-yl) pentyl, Examples thereof include 5- (biphenyl-3-yl) pentyl, 5- (2-phenoxyphenyl) pentyl, and 5- (3-benzyloxyphenyl) pentyl.
　本発明化合物の製薬上許容しうる酸付加塩としては、無機酸塩、有機酸塩などが挙げられる。 Examples of the pharmaceutically acceptable acid addition salt of the compound of the present invention include inorganic acid salts and organic acid salts.
　本発明化合物の溶媒和物としては、水、エタノール、酢酸エチル等との溶媒和物などを挙げることができる。 Examples of the solvate of the compound of the present invention include solvates with water, ethanol, ethyl acetate and the like.
　また、本発明化合物には上記一般式（Ｉ）、（ＩＩ－１）、（ＩＩ－２）、（ＩＩＩ－１）、（ＩＩＩ－２）、（ＩＶ－１）、（ＩＶ－２）及び（Ｖ）の化合物及びその製薬上許容しうる酸付加塩及びそれらの水和物、及び溶媒和物の他に、それらの幾何異性体、光学活性体、互変異性体も包含される。 The compounds of the present invention include the above general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2) and In addition to the compound (V) and pharmaceutically acceptable acid addition salts and hydrates and solvates thereof, geometrical isomers, optically active isomers and tautomers thereof are also included.
　本発明化合物の合成方法
　本発明化合物の合成方法としては以下のような方法を例示することができる。 Synthesis method of the compound of the present invention Examples of the synthesis method of the compound of the present invention include the following methods.
　１）本発明化合物のうち、一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＸＩが酸素原子、ＹＩが－ＣＨ２ＣＨ２－で表される化合物（Ｉ－Ｉ－１）は以下のスキーム（Ｉ－ＩＩ）により合成される。 1) Among the compounds of the present invention, R I , R I-3 and R I-4 in the general formula (I) are all represented by a hydrogen atom, X I is an oxygen atom, and Y I is represented by —CH 2 CH 2 —. Compound (II-1) is synthesized according to the following scheme (I-II).
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
（式中、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義であり、ＲＩ ａ、ＲＩ ｂ、ＲＩ ｃは保護基、ＸＩ ａは脱離基、ＸＩ ｂは脱離基又は水酸基を示し、ＰＢＩはリンを含む脱離基を示す。）
　式中のＲＩ ａはフェノール性水酸基を保護するものであれば特に限定されない。例えばアルキル（具体的にはメチル、エチルなど）、アラルキル（ベンジルなど）等が挙げられる。式中のＲＩ ｂは水酸基を保護するものであれば特に限定されない。例えば、アシル（好ましくは炭素数２～４程度のもの、具体的にはアセチルなど）、トリアルキルシリル（具体的にはトリメチルシリルなど）、ベンジル又はアセタール化合物を形成する置換基（具体的にはメトキシメチル、テトラヒドロピラニルなど）が挙げられる。ＲＩ－２が水酸基を有する場合、その水酸基は適当な保護基で保護されていても良く、その保護基ＲＩ ｄとしては具体的にはＲＩ ｂと同様のものが挙げられる。また、ＲＩ ｂとＲＩ ｄが結合し、環状のアセタールを形成することもできる。（以下同じ。）式中のＲＩ ｃで示される保護基はアミノ基を保護するものであれば特に限定されない。例えば、アシル（好ましくは炭素数２～４程度のもの、具体的にはアセチルなど）、カルバメート（具体的にはｔ－ブチルオキシカルボニルやベンジルオキシカルボニルなど）等が挙げられる。ＸＩ ａで示される脱離基は、中間体（Ｉ－ＩＩ－１）とリン化合物との反応時に脱離し、次のアルデヒド（Ｉ－ＩＩ－３）との反応時に反応を阻害しないものであれば特に限定されない。例えば、ハロゲン原子（具体的にはヨウ素原子、臭素原子、塩素原子など）、メタンスルホニルオキシ、トルエンスルホニルオキシ等が挙げられる。ＰＢＩで示されるリンを含む脱離基としては、トリアリールホスホニウム（具体的にはＰ（Ｃ６Ｈ５）３）やＰ（Ｏ）（ＯＲＩ ｅ）２（ＲＩ ｅは炭素数１～４のアルキルを示す。以下同じ。）が挙げられる。ＸＩ ｂが脱離基を示す場合、その脱離基としてはフェノール性水酸基のアルキル化時に脱離し、反応を阻害しないものであれば特に限定されない。例えば、ハロゲン原子（具体的にはヨウ素原子、臭素原子、塩素原子など）等が挙げられる。 (In the formula, R I-1 , R I-2 and A I have the same meanings as those in the general formula (I), R I a , R I b , R I c are protecting groups, and X I a is a leaving group. The leaving group, X I b represents a leaving group or a hydroxyl group, and PB I represents a leaving group containing phosphorus.)
R I a in the formula is not particularly limited as long as it protects the phenolic hydroxyl group. For example, alkyl (specifically methyl, ethyl etc.), aralkyl (benzyl etc.) and the like can be mentioned. R I b in the formula is not particularly limited as long as it protects the hydroxyl group. For example, an acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl, etc.), a trialkylsilyl (specifically trimethylsilyl, etc.), a benzyl or a substituent that forms an acetal compound (specifically methoxy) Methyl, tetrahydropyranyl, etc.). When R I-2 has a hydroxyl group, the hydroxyl group may be protected with a suitable protecting group, and specific examples of the protecting group R I d include the same groups as R I b . Further, R I b and R I d can be bonded to form a cyclic acetal. (The same shall apply hereinafter.) The protecting group represented by R I c in the formula is not particularly limited as long as it protects the amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned. The leaving group represented by X I a is eliminated during the reaction between the intermediate (I-II-1) and the phosphorus compound and does not inhibit the reaction during the subsequent reaction with the aldehyde (I-II-3). If there is no particular limitation. For example, halogen atoms (specifically iodine atom, bromine atom, chlorine atom, etc.), methanesulfonyloxy, toluenesulfonyloxy and the like can be mentioned. The leaving group containing phosphorus represented by PB I, (P (C 6 H 5 in particular) 3) triaryl phosphonium or P (O) (OR I e ) 2 (R I e is 1 carbon atoms -4 represents alkyl, the same shall apply hereinafter). When X I b represents a leaving group, the leaving group is not particularly limited as long as it is eliminated when alkylating a phenolic hydroxyl group and does not inhibit the reaction. For example, a halogen atom (specifically an iodine atom, a bromine atom, a chlorine atom, etc.) and the like can be mentioned.
　第一工程は公知の方法（ＷＯ２００７／０６９７１２号公報、２３～２８ページ）によって合成される脱離基ＸＩ ａを有する化合物（Ｉ－ＩＩ－１）とリン化合物を反応させてリンを含む脱離基ＰＢＩを有する中間体（Ｉ－ＩＩ－２）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、中間体（Ｉ－ＩＩ－２）は化合物（Ｉ－ＩＩ－１）とトリアリールホスフィンを反応させることによって得ることができる。反応条件としては、ジエチルエーテル、ベンゼン、トルエン等の不活性溶媒中、室温～還流で３０分～１２時間程度が挙げられる。反応後は、必要に応じて溶媒の留去、冷却、ジイソプロピルエーテルやヘキサン等の難溶性溶媒の添加を行った後、析出した固体を濾取することによって目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－ＩＩ－２）は化合物（Ｉ－ＩＩ－１）と亜リン酸トリエステルのＡｒｂｕｚｏｖ反応によって得ることができる。反応条件としては、溶媒を用いないかキシレン等の不活性溶媒中、５０℃～１７０℃で３０分～１２時間程度が挙げられる。反応後は、過剰の亜リン酸トリエステルの留去や蒸留を行うことによって目的物を得ることができる。また、ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－ＩＩ－２）はテトラアルキルアンモニウムや炭酸セシウム等の添加物存在下、化合物（Ｉ－ＩＩ－１）とホスホン酸ジエステルを反応させることによっても得ることができる。反応条件としては、テトラヒドロフランやキシレン等の不活性溶媒中又はＮ，Ｎ－ジメチルホルムアミド等の極性溶媒中、氷冷下～５０℃で３０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the first step, a compound (I-II-1) having a leaving group X I a synthesized by a known method (WO 2007/069712, pages 23 to 28) is reacted with a phosphorus compound to remove phosphorus. In this reaction, an intermediate (I-II-2) having a leaving group PB I is obtained. When PB I is triarylphosphonium, intermediate (I-II-2) can be obtained by reacting compound (I-II-1) with triarylphosphine. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB I is P (O) (OR I e ) 2 , intermediate (I-II-2) can be obtained by Arbuzov reaction of compound (I-II-1) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. When PB I is P (O) (OR I e ) 2 , the intermediate (I-II-2) is compounded with compound (I-II-1) in the presence of an additive such as tetraalkylammonium or cesium carbonate. It can also be obtained by reacting a phosphonic acid diester. The reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程はリンを含んだ中間体（Ｉ－ＩＩ－２）と公知の方法（例えば、テトラヘドロン　（Tetrahedron）　第５７巻（２００１年）６５３１～６５３８ページ、ジャーナル　オブ　オーガニック　ケミストリー　（Journal of Organic Chemistry）第６９巻(２００４年)７７６５～７７６８ページ）によって合成されるアルデヒド（Ｉ－ＩＩ－３）を縮合し、続いて得られたオレフィン体を還元後、保護基ＲＩ ａを脱保護することによって、フェノール性中間体（Ｉ－ＩＩ－４）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、テトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド等の塩基を用い、－３０℃～還流で３０分～１２時間程度が挙げられる。非プロトン性極性溶媒中、塩を含まない条件で反応を行うことでＺ体を優先的に得たり、Ｓｃｈｌｏｓｓｅｒの改良法により、Ｅ体を優先的に得ることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。オレフィンはＥ体を優先的に得ることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行う二重結合の還元に用いられる試薬としては、通常のオレフィンの還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル等の不均一系触媒又はロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、精製等を行い、目的物を得ることができる。引き続いて行う保護基ＲＩ ａの脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されないが、例えば、ＲＩ ａがメチルであれば塩化メチレン溶媒中で三臭化ホウ素等のルイス酸を用いた方法、アセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、メトキシメチルやテトラヒドロピラニル、ｔ－ブチル等のエーテル系の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。なお、ＲＩ ａにベンジル、置換ベンジル又はベンジルオキシメチル等の加水素分解、接触水素添加条件によって脱保護できる保護基を用いた場合には、ＲＩ ａの脱保護は、上述の二重結合の還元と同時に行うこともできる。 The second step is an intermediate containing phosphorus (I-II-2) and a known method (for example, Tetrahedron, Vol. 57 (2001), pages 6531-6538, Journal of Organic Chemistry. ) Condensation of aldehyde (I-II-3) synthesized according to Volume 69 (2004) 7765-7768), followed by reduction of the resulting olefin, followed by deprotection of protecting group R I a To obtain a phenolic intermediate (I-II-4). If PB I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at −30 ° C. to reflux for about 30 minutes to 12 hours. The Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB I is P (O) of the (OR I e) 2, the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting group R I a are not particularly limited as long as they are used for the usual deprotecting of the protecting group. For example, if R I a is methyl, it can be used in a methylene chloride solvent. A method using a Lewis acid such as boron tribromide, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water if acyl such as acetyl, methoxymethyl or tetrahydropyranyl, Examples of ether-based protecting groups such as t-butyl include a method using an acid such as hydrochloric acid or trifluoroacetic acid. In the case of using benzyl R I a, hydrogenolysis, such as substituted benzyl, or benzyloxymethyl, a protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R I a is above double bonds It can also be performed simultaneously with the reduction of
　第三工程は中間体（Ｉ－ＩＩ－４）のフェノール性水酸基を、中間体（Ｉ－ＩＩ－５）とＸＩ ｂ－ＡＩを用いてアルキル化し、続いてＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合それを保護する保護基ＲＩ ｄを脱保護することによって、本発明化合物（Ｉ－Ｉ－１）を得る反応である。アルキル化に用いる中間体（Ｉ－ＩＩ－５）としては、市販のハロゲン化物やアルコール、ハロゲン化物をハロゲン交換したもの、アルコールの水酸基を脱離基ＸＩ ｂに交換したもの、市販のカルボン酸を還元したアルコール等を用いることができる。例えば、ブロモアルキルアルコールを一般的に知られているフッ素化試薬でフッ素化し、フルオロアルキルアルコールとした後、アルコール部分を一般的に知られている方法で脱離基ＸＩ ｂへと変換したＸＩ ｂ－ＡＩ、又は該当するカルボン酸等を還元して得られるアルコールＡＩ－ＯＨが挙げられる。中間体（Ｉ－ＩＩ－４）が有するフェノール性水酸基のアルキル化に用いられる試薬としては、ＸＩ ｂが脱離基を示す場合、中間体（Ｉ－ＩＩ－５）と炭酸カリウムや水素化ナトリウム等の無機塩基の組み合わせが挙げられる。反応条件としては、Ｎ，Ｎ－ジメチルホルムアミド等の極性溶媒やテトラヒドロフラン等のエーテル系溶媒中、氷冷下～８０℃で３０分～１２時間程度が挙げられる。また、ＸＩ ｂが水酸基を示す場合、中間体（Ｉ－ＩＩ－４）が有するフェノール性水酸基のアルキル化には、トリフェニルホスフィン等のホスフィン化合物とアゾジカルボン酸ジイソプロピルエステル等のアゾジカルボン酸誘導体を用いた光延反応も用いることができる。この時の反応条件としては、テトラヒドロフラン等のエーテル系溶媒中、氷冷下～５０℃で１０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行う脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、全ての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成しＲＩ ｃがｔ－ブチルオキシカルボニルである場合、酸によって同時に脱保護できる。このときの酸としては、塩酸等の無機酸やトリフルオロ酢酸等が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is to alkylate the phenolic hydroxyl group of intermediate (I-II-4) using intermediate (I-II-5) and X I b -A I , followed by R I b , R I c And when R I-2 has a hydroxyl group, the protecting group R I d protecting it is deprotected to obtain the compound (II-1) of the present invention. Intermediates (I-II-5) used for alkylation include commercially available halides and alcohols, those obtained by halogen-exchange of halides, those obtained by exchanging hydroxyl groups of alcohols with leaving groups X I b , and commercially available carboxylic acids. Alcohol or the like obtained by reducing can be used. For example, bromoalkyl alcohol is fluorinated with a generally known fluorinating reagent to form a fluoroalkyl alcohol, and then the alcohol moiety is converted to a leaving group X I b by a generally known method. Examples include I b —A I , or alcohol A I —OH obtained by reducing the corresponding carboxylic acid or the like. As a reagent used for alkylating the phenolic hydroxyl group of intermediate (I-II-4), when X I b represents a leaving group, intermediate (I-II-5) and potassium carbonate or hydrogenated The combination of inorganic bases, such as sodium, is mentioned. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours. In addition, when X I b represents a hydroxyl group, the alkylation of the phenolic hydroxyl group of the intermediate (I-II-4) can be carried out by using a phosphine compound such as triphenylphosphine and an azodicarboxylic acid derivative such as azodicarboxylic acid diisopropyl ester. Mitsunobu reaction using can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　２）本発明化合物のうち、一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＲＩ－２がω－フルオロアルキルで表される化合物（Ｉ－Ｉ－３）は以下のスキーム（Ｉ－ＩＩＩ）によっても合成される。 2) Among the compounds of the present invention, the compound (II) in which R I , R I-3 and R I-4 in the general formula (I) are all hydrogen atoms and R I-2 is ω-fluoroalkyl -3) is also synthesized by the following scheme (I-III).
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
（式中、ＸＩ、ＹＩ、ＲＩ－１及びＡＩは一般式（Ｉ）における各記号と同義である。） (In the formula, X I , Y I , R I-1 and A I have the same meanings as symbols in the general formula (I).)
　第一工程は一般式（Ｉ）中のＲＩが水素原子、ＲＩ－２がω－ヒドロキシアルキルである化合物（Ｉ－Ｉ－２）を保護することによって、オキサゾリン体（Ｉ－ＩＩＩ－１）を合成するものである。本工程はアセトニトリルやＮ，Ｎ－ジメチルホルムアミド等の極性溶媒、塩化メチレン等のハロゲン系溶媒、又はトルエン等の炭化水素溶媒中、試薬としてオルト酢酸エステルを用い、反応を行うことができる。また反応の促進を目的としてＮ，Ｎ－ジイソプロピルエチルアミン等の塩基、又はｐ－トルエンスルホン酸等の酸を加えることができる。反応条件としては、室温～還流で３０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is to protect the compound (II-2) in which R I in the general formula (I) is a hydrogen atom and R I-2 is ω-hydroxyalkyl, whereby the oxazoline compound (I-III-1) is protected. ). In this step, the reaction can be carried out using orthoacetate as a reagent in a polar solvent such as acetonitrile or N, N-dimethylformamide, a halogen solvent such as methylene chloride, or a hydrocarbon solvent such as toluene. For the purpose of promoting the reaction, a base such as N, N-diisopropylethylamine or an acid such as p-toluenesulfonic acid can be added. The reaction conditions include room temperature to reflux for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は化合物（Ｉ－ＩＩＩ－１）の水酸基をフッ素化することによって、フッ化物（Ｉ－ＩＩＩ－２）を合成するものである。フッ素化剤としては三フッ化ジエチルアミノ硫黄（ＤＡＳＴ）や２，２－ジフルオロ－１，３－ジメチルイミダゾリジン（ＤＦＩ）等を挙げることができる。本工程は塩化メチレン等のハロゲン系溶媒、若しくはヘキサン等の炭化水素溶媒中で反応を行うことができる。反応条件としては、－７８℃～室温で３０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。また、本工程は化合物（Ｉ－ＩＩＩ－１）の水酸基を対応するスルホナート体に変換後、フッ化物イオンを作用させる方法によっても行うことができる。例えばｐ－トルエンスルホニルフルオリドとテトラブチルアンモニウムフルオリド（ＴＢＡＦ）を用いる場合、テトラヒドロフラン等のエーテル系溶媒中、室温～８０℃で１時間～２４時間程度反応させる。この反応にはモレキュラーシーブス等の脱水剤を加えることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is to synthesize fluoride (I-III-2) by fluorinating the hydroxyl group of compound (I-III-1). Examples of the fluorinating agent include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI). In this step, the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane. The reaction conditions include −78 ° C. to room temperature for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. This step can also be performed by a method in which a fluoride ion is allowed to act after converting the hydroxyl group of compound (I-III-1) to the corresponding sulfonate form. For example, when p-toluenesulfonyl fluoride and tetrabutylammonium fluoride (TBAF) are used, the reaction is carried out in an ether solvent such as tetrahydrofuran at room temperature to 80 ° C. for about 1 to 24 hours. A dehydrating agent such as molecular sieves can be added to this reaction. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は化合物（Ｉ－ＩＩＩ－２）を脱保護することによって本発明化合物（Ｉ－Ｉ－３）を調製するものである。本工程は通常の脱保護反応を用いて行うことができる。具体的には塩酸やトリフルオロ酢酸等の酸を用いて行うことができる。反応条件としては、エタノール等のアルコール性溶媒若しくはそれらと水の混合溶媒中、室温～１００℃で、３０分～１２時間程度が挙げられる。反応液は通常の方法により、精製等を行い、目的物を得ることができる。 The third step is to prepare the compound (II-3) of the present invention by deprotecting the compound (I-III-2). This step can be performed using a normal deprotection reaction. Specifically, it can be performed using an acid such as hydrochloric acid or trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol or a mixed solvent thereof and water at room temperature to 100 ° C. for about 30 minutes to 12 hours. The reaction solution can be purified by a conventional method to obtain the desired product.
　３）一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＡＩが鎖中又は鎖端に官能基として三重結合の官能基を有さない炭素数５～９のアルキル、ＲＩ－１がトリフルオロメチル又はシアノである化合物（Ｉ－Ｉ－４）は以下のスキーム（Ｉ－ＩＶ）により合成される。 3) In general formula (I), R I , R I-3 , and R I-4 are all hydrogen atoms, and A I has 5 carbon atoms that do not have a triple bond functional group as a functional group in the chain or at the chain end. A compound (II-4) in which ˜9 alkyl and R I-1 is trifluoromethyl or cyano is synthesized by the following scheme (I-IV).
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
（式中、ＲＩ－１’はトリフルオロメチル又はシアノ、ＡＩ’は鎖中又は鎖端に官能基として三重結合の官能基を有さない炭素数５～９のアルキル、ＲＩ ｂ、ＲＩ ｃは保護基、ＸＩ ｃ、ＸＩ ｄは脱離基を示し、ＲＩ－２、ＸＩ、ＹＩは一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃは前述したものと同義である。ＸＩ ｃで示される脱離基としては薗頭反応の際に触媒によって活性化され脱離できるものであれば特に限定されない。例えば、ハロゲン原子（好ましくはヨウ素原子、臭素原子など）、トリフルオロメタンスルホニルオキシ等が挙げられる。ＸＩ ｄで示される脱離基は、アルコキシド又はチオールアニオンによる置換反応の際に脱離するものであれば特に限定されない。例えば、ハロゲン原子（具体的にはフッ素原子など）、トルエンスルホニルオキシ等が挙げられる。 (Wherein R I-1 ′ is trifluoromethyl or cyano, A I ′ is alkyl having 5 to 9 carbon atoms and having no triple bond functional group as a functional group in the chain or at the chain end, R I b , R I c represents a protecting group, X I c and X I d represent a leaving group, and R I-2 , X I and Y I have the same meanings as those in the general formula (I).)
R I b and R I c in the formula are as defined above. The leaving group represented by X I c is not particularly limited as long as it can be activated and removed by a catalyst during the Sonogashira reaction. For example, a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyloxy and the like can be mentioned. The leaving group represented by X I d is not particularly limited as long as it is eliminated during the substitution reaction with alkoxide or thiol anion. For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned.
　第一工程は脱離基ＸＩ ｄを有する化合物（Ｉ－ＩＶ－１）と化合物（Ｉ－ＩＶ－２）の縮合により、中間体（Ｉ－ＩＶ－３）を得る反応である。本工程はＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシドといった極性溶媒や、テトラヒドロフラン等のエーテル系溶媒中、塩基の存在下、行うことができる。塩基としては、水素化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基、カリウムｔ－ブトキシド等のアルコキシド、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン等の有機塩基を用いて行うことができる。反応条件としては、氷冷下～１００℃程度で１０分～１０時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is a reaction for obtaining an intermediate (I-IV-3) by condensation of the compound (I-IV-1) having a leaving group X I d and the compound (I-IV-2). This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（Ｉ－ＩＶ－３）と中間体（Ｉ－ＩＩ－３）より公知の方法（例えば、テトラヘドロン（Tetrahedron）　第５７巻（２００１年）６５３１～６５３８ページ、ケミカル　アンド　ファーマシューティカル　ブレティン（Chemical and Pharmaceutical Bulletin）第５３巻(２００５年)１００～１０２ページ）によって合成される中間体（Ｉ－ＩＶ－４）を薗頭反応により縮合して、三重結合を含む中間体（Ｉ－ＩＶ－５）を得る反応である。用いられる触媒としてはテトラキス（トリフェニルホスフィン）パラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、ジクロロビス（アセトニトリル）パラジウム（ＩＩ）等のパラジウム化合物が挙げられる。また反応を促進するために、トリエチルアミン等の有機塩基やアンモニア等の無機塩基、ヨウ化銅や臭化銅等の銅化合物、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル等のホスフィン化合物等の添加物を加えることもできる。反応条件としては、テトラヒドロフランやジオキサン等のエーテル系溶媒、アセトニトリルやジメチルホルムアミド等の極性溶媒、又はベンゼン等の炭化水素溶媒中、氷冷化～還流で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is a method known from intermediate (I-IV-3) and intermediate (I-II-3) (eg, Tetrahedron, Vol. 57 (2001), pages 6531 to 6538, Chemical and Fur. An intermediate (I-IV-4) synthesized by Chemical and Pharmaceutical Bulletin Vol. 53 (2005) pp. 100-102) is condensed by the Sonogashira reaction to form an intermediate containing a triple bond ( This is a reaction to obtain I-IV-5). Examples of the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II). In order to accelerate the reaction, organic bases such as triethylamine, inorganic bases such as ammonia, copper compounds such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl It is also possible to add additives such as phosphine compounds. The reaction conditions include ice-cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は中間体（Ｉ－ＩＶ－５）の三重結合を還元して中間体（Ｉ－ＩＶ－６）を得る反応である。ＹＩが－ＣＨ２ＣＨ２－及びＡＩ’が鎖中又は鎖端に二重結合を含まない炭素数５～９のアルキルの時に用いられる試薬としては、通常の不飽和炭素結合の還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル、パラジウム炭素エチレンジアミン複合体等の不均一系触媒ロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。一方、ＹＩが－ＣＨ＝ＣＨ－又はＡＩ’が二重結合の官能基を有する炭素５～９のアルキルの時に用いられる反応としては、Ｌｉｎｄｌａｒ触媒、ニッケル－グラファイト－エチレンジアミン錯体、ジエン化合物とホスフィン化合物及びロジウムの各種錯体など活性を調節した触媒の存在下に行われる接触水素添加が挙げられる。また水素化ジイソブチルアルミニウムなどの金属水素化物による還元反応を用いることも可能である。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is a reaction in which the triple bond of intermediate (I-IV-5) is reduced to obtain intermediate (I-IV-6). The reagent used when Y I is —CH 2 CH 2 — and A I ′ is an alkyl having 5 to 9 carbon atoms which does not contain a double bond in the chain or at the chain end, may be used for the usual reduction of unsaturated carbon bonds. Although it will not be limited if it is a reagent used, for example, a homogeneous catalyst such as a heterogeneous catalyst rhodium complex (such as chlorotris (triphenylphosphine) rhodium (I)) such as palladium carbon, Raney nickel, palladium carbon ethylenediamine complex was used. Catalytic hydrogenation can be mentioned. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product. On the other hand, the reaction used when Y I is —CH═CH— or A I ′ is a carbon 5-9 alkyl having a double bond functional group includes a Lindlar catalyst, a nickel-graphite-ethylenediamine complex, a diene compound, Examples thereof include catalytic hydrogenation performed in the presence of a catalyst whose activity is controlled, such as various complexes of phosphine compounds and rhodium. It is also possible to use a reduction reaction with a metal hydride such as diisobutylaluminum hydride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第四工程は中間体（Ｉ－ＩＶ－６）を脱保護することによって本発明化合物（Ｉ－Ｉ－４）を得る反応である。ＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合それを保護する保護基ＲＩ ｄの脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、全ての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成し、ＲＩ ｃがｔ－ブチルオキシカルボニル基である場合、触媒量の酸によって環状のアセタールを脱保護し、次により強い酸性条件を用いることによってＲＩ ｃの脱保護を行うことができる。このときのアセタールの脱保護に用いられる条件としては、メタノール等のアルコール性溶媒やアルコール性溶媒と他の有機溶媒の混合溶液中、触媒量の塩酸やトルエンスルホン酸を用い、氷冷下～８０℃で３０分～１２時間程度が挙げられる。一方アセタールの脱保護に続いて行われるＲＩ ｃの脱保護の条件としては、当量以上の塩酸等の無機酸やトリフルオロ酢酸等を用い、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The fourth step is a reaction for obtaining the compound (II-4) of the present invention by deprotecting the intermediate (II-IV-6). When R I b , R I c and R I-2 have a hydroxyl group, the deprotection of the protecting group R I d protecting it is not particularly limited as long as it is used for deprotecting a normal protecting group. All the protecting groups can be deprotected at once or stepwise. For example R I b and R I d are bonded to form a cyclic acetal, when R I c is t- butyloxycarbonyl group, by catalytic amount of acid deprotection of the cyclic acetal, stronger then acidic conditions R I c can be deprotected by using. The conditions used for the deprotection of the acetal at this time include a catalytic amount of hydrochloric acid or toluenesulfonic acid in an alcoholic solvent such as methanol, or a mixed solution of an alcoholic solvent and another organic solvent. Examples include about 30 minutes to 12 hours at ° C. On the other hand, the deprotection conditions for R I c carried out following the deprotection of acetal include an inorganic acid such as hydrochloric acid, trifluoroacetic acid or the like in an equivalent amount or more, an alcoholic solvent such as ethanol, or an ether solvent such as tetrahydrofuran. , Water, or a mixed solvent thereof for about 10 minutes to 12 hours at 80 ° C. under ice-cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　４）一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＸＩが硫黄原子、ＹＩが－ＣＨ２ＣＨ２－、ＡＩが鎖中又は鎖端に官能基として二重結合又は三重結合の官能基を有さない炭素数５～９のアルキルで表される化合物（Ｉ－Ｉ－５）は以下のスキーム（Ｉ－Ｖ）により合成される。 4) In the general formula (I), R I , R I-3 and R I-4 are all hydrogen atoms, X I is a sulfur atom, Y I is —CH 2 CH 2 —, and A I is in the chain or at the chain end. The compound (II-5) represented by alkyl having 5 to 9 carbon atoms which does not have a double bond or triple bond functional group as a functional group is synthesized by the following scheme (IV).
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
（式中、ＲＩ ｆは水素原子又は保護基、ＲＩ ｂ、ＲＩ ｃは保護基、ＸＩ ａ、ＸＩ ｅは脱離基、ＡＩ’’は鎖中又は鎖端に二重結合又は三重結合の官能基を有さない炭素数５～９のアルキル、ＰＢＩはリンを含む脱離基を示し、ＲＩ－１、ＲＩ－２は一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃ、ＸＩ ａ、ＰＢＩは前述したものと同義である。式中のＲＩ ｆは水素原子又はカルボキシル基を保護するものであれば特に限定されない。例えばアルキル（具体的にはメチル、エチルなど）、アラルキル（ベンジルなど）等が挙げられる。ＸＩ ｅで示される脱離基は、アルキルチオイオンＡＩ’’Ｓ－による置換反応の際に脱離するものであれば特に限定されない。例えば、ハロゲン原子（具体的にはフッ素原子など）、トルエンスルホニルオキシ等が挙げられる。 (Wherein, the R I f a hydrogen atom or a protecting group, R I b, R I c is a protecting group, X I a, X I e is a leaving group, A I '' double in the chain or chain end Alkyl having 5 to 9 carbon atoms and having no bond or triple bond functional group, PB I represents a leaving group containing phosphorus, R I-1 and R I-2 are the symbols in general formula (I) and Synonymous.)
In the formula, R I b , R I c , X I a , and PB I are as defined above. R I f in the formula is not particularly limited as long as it protects a hydrogen atom or a carboxyl group. For example, alkyl (specifically methyl, ethyl etc.), aralkyl (benzyl etc.) and the like can be mentioned. The leaving group represented by X I e is not particularly limited as long as it is eliminated during the substitution reaction with alkylthioion A I ″ S — . For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned.
　第一工程は４位に脱離基ＸＩ ｅのついた安息香酸誘導体（Ｉ－Ｖ－１）とチオール（Ｉ－Ｖ－２）の縮合により４位にアルキルチオ基を導入し、中間体（Ｉ－Ｖ－３）を得る反応である。本工程はＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシドといった極性溶媒や、テトラヒドロフラン等のエーテル系溶媒中、塩基の存在下、行うことができる。塩基としては、炭酸カリウムや水素化ナトリウム等の無機塩基、トリエチルアミンや１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン等の有機塩基を用いて行うことができる。反応条件としては、－３０～８０℃程度で１０分～１０時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the first step, an alkylthio group is introduced at the 4-position by condensation of a benzoic acid derivative (IV-1) having a leaving group X I e at the 4-position with a thiol (IV-2), and an intermediate ( Reaction to obtain IV-3). This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as potassium carbonate or sodium hydride, or an organic base such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene can be used. Examples of the reaction conditions include about −30 to 80 ° C. and about 10 minutes to 10 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（Ｉ－Ｖ－３）のカルボキシル基を還元して、水酸基を有する中間体（Ｉ－Ｖ－４）を得る反応である。還元に用いられる試薬としては、通常用いられているものであれば特に限定されないが、ナトリウム等のアルカリ金属やアルカリ土類金属、水素化ジイソブチルアルミニウム等の金属水素化物、水素化アルミニウムリチウムや水素化ホウ素ナトリウム等の金属水素錯化合物、ジボラン等のホウ素化合物、均一系又は不均一系の触媒を用いた接触水素添加等が挙げられる。反応条件は、用いる還元試薬に適切な温度と時間が選ばれる。具体的なものとしては、テトラヒドロフラン等のエーテル系溶媒中－３０℃～還流で１０分～１２時間程度行われるジボラン、水素化アルミニウムリチウム、水素化ホウ素リチウムによる還元、エタノール等のアルコール系溶媒又はアルコール系溶媒とテトラヒドロフラン等のエーテル系溶媒の混合溶媒中、氷冷下～還流で３０分～２４時間程度行われる水素化ホウ素ナトリウムや水素化ホウ素カルシウムによる還元等が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is a reaction in which the carboxyl group of the intermediate (IV-3) is reduced to obtain the intermediate (IV-4) having a hydroxyl group. The reagent used for the reduction is not particularly limited as long as it is usually used, but alkali metals such as sodium and alkaline earth metals, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and hydrogenation. Examples thereof include metal hydrogen complex compounds such as sodium boron, boron compounds such as diborane, and catalytic hydrogenation using a homogeneous or heterogeneous catalyst. As the reaction conditions, a temperature and time appropriate for the reducing reagent to be used are selected. Specific examples include reduction in diborane, lithium aluminum hydride, lithium borohydride, alcohol solvent such as ethanol or alcohol, which is carried out at −30 ° C. to reflux for 10 minutes to 12 hours in an ether solvent such as tetrahydrofuran. Examples thereof include reduction with sodium borohydride or calcium borohydride, which is carried out in a mixed solvent of a system solvent and an ether solvent such as tetrahydrofuran for about 30 minutes to 24 hours under ice-cooling to reflux. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は中間体（Ｉ－Ｖ－４）の水酸基を脱離基ＸＩ ａへと変換する反応である。試薬としては、アルコール性水酸基をＸＩ ａに変換できる試薬であれば特に限定されない。ＸＩ ａがハロゲンの時に用いられる試薬としてはＮ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、四塩化炭素やそれらとトリフェニルホスフィン、塩基等の反応補助剤の組み合わせ、塩酸、臭化水素酸、ヨウ化水素酸といった無機酸、三臭化リン、五臭化リン、三塩化リン、五塩化リン、ヨウ素、臭素、塩素、ハロゲン化チオニル、α－ハロエナミン等が挙げられる。反応条件としては、塩化メチレン等のハロゲン系溶媒やテトラヒドロフラン等のエーテル系溶媒などの有機溶媒中、－３０℃～１３０℃で１０分～６時間程度が挙げられる。なお、無機酸使用時には水溶液又はトルエン等の有機溶媒と水の二相系での反応も行える。ＸＩ ａがスルホニルオキシ基の時に用いられる試薬としては塩化メタンスルホニルや塩化トルエンスルホニル等の塩化スルホニルとトリエチルアミンやピリジン等の有機塩基の組み合わせが用いられる。反応条件としては、塩化メチレン等のハロゲン系溶媒やテトラヒドロフラン等のエーテル系溶媒などの有機溶媒中、－３０℃～５０℃で５分～３時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is a reaction to convert the hydroxyl group of intermediate (I-V-4) to the leaving group X I a. The reagent is not particularly limited as long as it is a reagent capable of converting an alcoholic hydroxyl group into X I a . Reagents used when X I a is halogen include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride and combinations of these with reaction aids such as triphenylphosphine, base, hydrochloric acid, hydrobromic acid, iodide Examples thereof include inorganic acids such as hydrogen acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, thionyl halide, α-haloenamine and the like. Examples of the reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at −30 ° C. to 130 ° C. for about 10 minutes to 6 hours. In addition, when an inorganic acid is used, a two-phase reaction of an aqueous solution or an organic solvent such as toluene and water can be performed. As a reagent used when X I a is a sulfonyloxy group, a combination of a sulfonyl chloride such as methanesulfonyl chloride or toluenesulfonyl chloride and an organic base such as triethylamine or pyridine is used. Examples of the reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at −30 ° C. to 50 ° C. for about 5 minutes to 3 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第四工程は脱離基ＸＩ ａを有する中間体（Ｉ－Ｖ－５）とリン化合物を反応させてリンを含む脱離基ＰＢＩを有する中間体（Ｉ－Ｖ－６）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、中間体（Ｉ－Ｖ－６）は中間体（Ｉ－Ｖ－５）とトリアリールホスフィンを反応させることによって得ることができる。反応条件としては、ジエチルエーテル、ベンゼン、トルエン等の不活性溶媒中、室温～還流で３０分～１２時間程度が挙げられる。反応後は、必要に応じて溶媒の留去、冷却、ジイソプロピルエーテルやヘキサン等の難溶性溶媒の添加を行った後、析出した固体を濾取することによって目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－Ｖ－６）は中間体（Ｉ－Ｖ－５）と亜リン酸トリエステルのＡｒｂｕｚｏｖ反応によって得ることができる。反応条件としては、溶媒を用いないかキシレン等の不活性溶媒中、５０℃～１７０℃で３０分～１２時間程度が挙げられる。反応後は、過剰の亜リン酸トリエステルの留去や蒸留を行うことによって目的物を得ることができる。また、ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－Ｖ－６）はテトラアルキルアンモニウムや炭酸セシウム等の添加物存在下、中間体（Ｉ－Ｖ－５）とホスホン酸ジエステルを反応させることによっても得ることができる。反応条件としては、テトラヒドロフランやキシレン等の不活性溶媒中又はＮ，Ｎ－ジメチルホルムアミド等の極性溶媒中、氷冷下～５０℃で３０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The fourth step is to obtain an intermediate having a leaving group X I a and (I-V-5) a phosphorus compound is reacted intermediate having a leaving group PB I containing phosphorus (I-V-6) Reaction It is. When PB I is triarylphosphonium, intermediate (IV-6) can be obtained by reacting intermediate (IV-5) with triarylphosphine. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB I is P (O) (OR I e ) 2 , intermediate (IV-6) can be obtained by Arbuzov reaction of intermediate (IV-5) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. When PB I is P (O) (OR I e ) 2 , intermediate (IV-6) is intermediate (IV-5) in the presence of an additive such as tetraalkylammonium or cesium carbonate. It can also be obtained by reacting phosphonic acid diester. The reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第五工程はリンを含んだ中間体（Ｉ－Ｖ－６）と別途合成されるアルデヒド（Ｉ－ＩＩ－３）を縮合し、続いて得られたオレフィンを還元することによって、中間体（Ｉ－Ｖ－７）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、テトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド等の塩基を用い、－３０℃～還流で３０分～１２時間程度が挙げられる。非プロトン性極性溶媒中、塩を含まない条件で反応を行うことでＺ体を優先的に得たり、Ｓｃｈｌｏｓｓｅｒの改良法により、Ｅ体を優先的に得ることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。オレフィンはＥ体を優先的に得ることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行う二重結合の還元に用いられる試薬としては、通常のオレフィンの還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル等の不均一系触媒又はロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the fifth step, intermediate (I-V-3) containing phosphorus and aldehyde (I-II-3) separately synthesized are condensed, and the resulting olefin is subsequently reduced, thereby intermediate (I Reaction to obtain -V-7). If PB I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at −30 ° C. to reflux for about 30 minutes to 12 hours. The Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB I is P (O) of the (OR I e) 2, the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第六工程は中間体（Ｉ－Ｖ－７）のＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合、それを保護する保護基ＲＩ ｄを脱保護することによって、本発明化合物（Ｉ－Ｉ－５）を得る反応である。中間体（Ｉ－Ｖ－７）の脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、すべての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成しＲＩ ｃがｔ－ブチルオキシカルボニルである場合、酸によって同時に脱保護できる。このときの酸としては、塩酸等の無機酸やトリフルオロ酢酸等が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the sixth step, when R I b , R I c and R I-2 of the intermediate (IV-7) have a hydroxyl group, the protecting group R I d protecting it is removed to remove the present invention. In this reaction, compound (II-5) is obtained. The deprotection of intermediate (IV-7) is not particularly limited as long as it can be used for the deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can. For example, when R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　５）一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、Ｘが硫黄原子で表される化合物（Ｉ－Ｉ－６）は以下のスキーム（Ｉ－ＶＩ）により合成される。 5) R I in formula (I), R I-3 , R I-4 are both hydrogen atom, and X is represented by sulfur atom (I-I-6) The following scheme (I-VI ).
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
（式中、ＲＩ ｂ、ＲＩ ｃは保護基を、ＸＩ ｆは水酸基の活性化基を示し、ＹＩ、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃは前述したものと同義である。ＸＩ ｆで示される水酸基の活性化基としては、トリフルオロメタンスルホニルやトルエンスルホニル等のスルホニルが挙げられる。 (Wherein R I b and R I c represent a protecting group, X I f represents a hydroxyl-activating group, and Y I , R I-1 , R I-2 and A I represent those in the general formula (I)). (It is synonymous with each symbol.)
R I b and R I c in the formula are as defined above. The activation group for a hydroxyl group represented by X I f, a sulfonyl such as trifluoromethanesulfonyl and toluenesulfonyl.
　第一工程は公知の方法（ＷＯ２００７／０６９７１２号公報、３７～３８ページ）によって合成される化合物（Ｉ－ＶＩ－１）と一般的に知られている合成法で得られるチオール（Ｉ－ＶＩ－２）ＡＩ－ＳＨの縮合によって中間体（Ｉ－ＶＩ－３）を得る反応である。本工程はジオキサン等のエーテル系溶媒やトルエン等の炭化水素溶媒中、パラジウム触媒の存在下、行うことができる。パラジウム触媒としては酢酸パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）等が挙げられる。また本反応には反応補助剤として、ホスフィン化合物や塩基を加えることができる。ホスフィン化合物としてはトリフェニルホスフィンや４、５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン等が挙げられる。一方、塩基としては炭酸セシウム等の無機塩基やＮ，Ｎ－ジイソプロピルエチルアミン等の有機塩基が挙げられる。反応条件としては、室温～還流で３０分～２４時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is a compound (I-VI-1) synthesized by a known method (WO 2007/069712, pages 37 to 38) and a thiol (I-VI-) obtained by a generally known synthesis method. 2) Reaction for obtaining an intermediate (I-VI-3) by condensation of A I -SH. This step can be performed in an ether solvent such as dioxane or a hydrocarbon solvent such as toluene in the presence of a palladium catalyst. Examples of the palladium catalyst include palladium acetate (II) and tris (dibenzylideneacetone) dipalladium (0). In this reaction, a phosphine compound or a base can be added as a reaction aid. Examples of the phosphine compound include triphenylphosphine and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene. On the other hand, examples of the base include inorganic bases such as cesium carbonate and organic bases such as N, N-diisopropylethylamine. Examples of the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（Ｉ－ＶＩ－３）のＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合それを保護する保護基ＲＩ ｄを脱保護することによって、本発明化合物（Ｉ－Ｉ－６）を得る反応である。中間体（Ｉ－ＶＩ－３）の脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、すべての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂがメトキシメチル等の酸によって脱保護可能な保護基でありＲＩ ｃがｔ－ブチルオキシカルボニルである場合、酸によって同時に脱保護できる。この場合の酸としては、塩酸等の無機酸やトリフルオロ酢酸等が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the second step, when R I b , R I c and R I-2 of the intermediate (I-VI-3) have a hydroxyl group, the protecting group R I d protecting it is removed to remove the compound of the present invention. This is a reaction to obtain (II-6). The deprotection of the intermediate (I-VI-3) is not particularly limited as long as it is used for the deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can. For example, when R I b is a protecting group deprotectable by an acid such as methoxymethyl and R I c is t-butyloxycarbonyl, it can be simultaneously deprotected by an acid. Examples of the acid in this case include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　６）本発明化合物のうち、一般式（Ｉ）中のＲＩ－３及びＲＩ－４のどちらか一方又はＲＩ－３及びＲＩ－４の両方が炭素数１～４のアルキルで表される化合物（Ｉ－Ｉ－７）は以下のスキーム（Ｉ－ＶＩＩ）によって合成される。 Table Of, in the general formula (I) in the R I-3 and R either of I-4, or R I-3 and R I-4 in both of 1 to 4 carbon atoms alkyl of 6) Compound of the present invention The resulting compound (II-7) is synthesized by the following scheme (I-VII).
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
（式中、ＲＩ－３’及びＲＩ－４’はどちらか一方又は両方が炭素数１～４のアルキルを示し、ＲＩ、ＸＩ、ＹＩ、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義である。） (Wherein R I-3 ′ and R I-4 ′ represent one or both of alkyl having 1 to 4 carbon atoms, R I , X I , Y I , R I-1 , R I-2 And A I have the same meaning as each symbol in formula (I).)
　本工程は、本発明化合物のうち１級アミノ基を有する化合物（Ｉ－ＶＩＩ－１）のアミノ基をアルキル化することによって、本発明化合物（Ｉ－Ｉ－７）を合成するものである。この合成には、還元的アミノ化反応やハロゲン化アルキルと塩基を用いたアミンのアルキル化反応を用いることができる。還元的アミノ化反応を用いる場合、ＲＩ－３’又はＲＩ－４’の炭素数と同じ炭素数を有するアルデヒドと化合物（Ｉ－ＶＩＩ－１）をメタノール等のアルコール系溶媒やジクロロエタン等のハロゲン系溶媒中、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム等の還元剤を用いて反応させることにより、目的物を得ることができる。還元には、水素とラネーニッケルや酸化白金等の触媒を用いて行うこともできる。またこの反応は、シッフ塩基の生成と還元反応を逐次行うこともできる。この還元的アミノ化反応には、反応促進剤として酢酸等の酸を加えることができる。反応条件としては、氷冷下～５０℃程度で３０分～１０時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。ＲＩ－３’及びＲＩ－４’がメチルの時には、ギ酸とホルムアルデヒド、又はホルムアルデヒドと水素化シアノホウ素ナトリウム等の還元剤を用いたＥｓｃｈｗｅｉｌｅｒ－Ｃｌａｒｋｅのメチル化反応を用いることもできる。 In this step, the compound (II-7) of the present invention is synthesized by alkylating the amino group of the compound (I-VII-1) having a primary amino group among the compounds of the present invention. For this synthesis, a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used. When the reductive amination reaction is used, an aldehyde having the same carbon number as R I-3 ′ or R I-4 ′ and compound (I-VII-1) are mixed with an alcohol solvent such as methanol, dichloroethane or the like. The target product can be obtained by reacting in a halogen-based solvent using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide. In this reaction, the generation of a Schiff base and the reduction reaction can also be sequentially performed. In this reductive amination reaction, an acid such as acetic acid can be added as a reaction accelerator. Examples of reaction conditions are about 30 minutes to 10 hours at about 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R I-3 'and R I-4' is methyl, it is also possible to use the methylation reaction of Eschweiler-Clarke using formic acid and formaldehyde, or formaldehyde and a reducing agent such as sodium cyanoborohydride.
　７）本発明化合物のうち、一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＹＩが－ＣＨ＝ＣＨ－で表される化合物（Ｉ－Ｉ－８）は以下のスキーム（Ｉ－ＶＩＩＩ）によって合成される。 7) Among the compounds of the present invention, compounds represented by the general formula (I) wherein R I , R I-3 and R I-4 are all hydrogen atoms and Y I is represented by —CH═CH— (II— 8) is synthesized by the following scheme (I-VIII).
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
（式中、ＲＩ ｂ及びＲＩ ｃは保護基、ＲＩ ｇは保護基又は－ＡＩ、ＸＩ ａは脱離基、ＸＩ ｇは脱離基又は水酸基、ＰＢＩはリンを含む脱離基を示し、ＸＩ、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃ、ＸＩ ａ、ＰＢＩは前述したものと同義である。ＸＩ ｇが脱離基を示す場合、その脱離基としてはフェノール性水酸基やチオール基のアルキル化時に脱離し、反応を阻害しないものであれば特に限定されない。例えば、ハロゲン原子（具体的にはヨウ素原子、臭素原子、塩素原子など）等が挙げられる。式中のＲＩ ｇが保護基を示す場合、ＲＩ ｇはフェノール基又はチオール基を保護するものであれば特に限定されない。ＲＩ ｇの例として、Ｘが酸素原子のときにはアルキル（メチルなど）、アラルキル（４－メトキシベンジルなど）、アセタールを形成する保護基（メトキシメチルやエトキシエチルなど）等が挙げられる。また、ＸＩが硫黄原子のときには、アルキル（メチルなど）、アラルキル（４－メトキシベンジルなど）、チオアセタールを形成する保護基（メトキシメチルやフェニルチオメチル、アセタミドメチルなど）等が挙げられる。 Wherein R I b and R I c are protecting groups, R I g is a protecting group or —A I , X I a is a leaving group, X I g is a leaving group or hydroxyl group, and PB I contains phosphorus. And represents a leaving group, and X I , R I-1 , R I-2 and A I have the same meanings as symbols in the general formula (I).
In the formula, R I b , R I c , X I a , and PB I are as defined above. If X I g is a leaving group, examples of the leaving group leaves upon alkylation of a phenolic hydroxyl group or thiol group, is not particularly limited as long as it does not inhibit the reaction. For example, a halogen atom (specifically an iodine atom, a bromine atom, a chlorine atom, etc.) and the like can be mentioned. If R I g in the formula is a protecting group, R I g is not particularly limited as long as it protects a phenol group or a thiol group. Examples of R I g, X is when an oxygen atom alkyl (such as methyl), aralkyl (4-methoxybenzyl, etc.), or the like protecting group forming acetal (methoxymethyl and ethoxyethyl) can be mentioned. Further, when X I is a sulfur atom, alkyl (methyl, etc.), aralkyl (4-methoxybenzyl, etc.), protecting group forming thioacetal (methoxymethyl or phenylthiomethyl, acetamidomethyl and the like) and the like.
　第一工程は公知の方法（ＷＯ２００７／０６９７１２号公報、４１～４３ページ）によって合成される脱離基ＸＩ ａを有する化合物（Ｉ－ＶＩＩＩ－１）とリン化合物を反応させてリンを含む脱離基ＰＢＩを有する中間体（Ｉ－ＶＩＩＩ－２）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、中間体（Ｉ－ＶＩＩＩ－２）はテトラアルキルアンモニウムや炭酸セシウム等の添加物存在下、中間体（Ｉ－ＶＩＩＩ－１）とトリアリールホスフィンを反応させることによって得ることができる。反応条件としては、ジエチルエーテル、ベンゼン、トルエン等の不活性溶媒中、室温～還流で３０分～１２時間程度が挙げられる。反応後は、必要に応じて溶媒の留去、冷却、ジイソプロピルエーテルやヘキサン等の難溶性溶媒の添加を行った後、析出した固体を濾取することによって目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－ＶＩＩＩ－２）は中間体（Ｉ－ＶＩＩＩ－１）と亜リン酸トリエステルのＡｒｂｕｚｏｖ反応によって得ることができる。反応条件としては、溶媒を用いないかキシレン等の不活性溶媒中、５０℃～１７０℃で３０分～１２時間程度が挙げられる。反応後は、過剰の亜リン酸トリエステルの留去や蒸留を行うことによって目的物を得ることができる。また、ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、中間体（Ｉ－ＶＩＩＩ－２）は中間体（Ｉ－ＶＩＩＩ－１）とホスホン酸ジエステルの反応によっても得ることができる。反応条件としては、テトラヒドロフランやキシレン等の不活性溶媒中又はＮ，Ｎ－ジメチルホルムアミド等の極性溶媒中、氷冷下～５０℃で３０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the first step, a phosphorus compound is reacted with a compound (I-VIII-1) having a leaving group X I a synthesized by a known method (WO 2007/069712, pages 41 to 43) and a phosphorus compound. In this reaction, an intermediate (I-VIII-2) having a leaving group PB I is obtained. When PB I is triarylphosphonium, intermediate (I-VIII-2) is obtained by reacting intermediate (I-VIII-1) with triarylphosphine in the presence of an additive such as tetraalkylammonium or cesium carbonate. Obtainable. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB I is P (O) (OR I e ) 2 , intermediate (I-VIII-2) can be obtained by Arbuzov reaction of intermediate (I-VIII-1) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. When PB I is P (O) (OR I e ) 2 , intermediate (I-VIII-2) can also be obtained by reaction of intermediate (I-VIII-1) with phosphonic acid diester. The reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for about 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程はリンを含んだ中間体（Ｉ－ＶＩＩＩ－２）と別途合成したアルデヒド（Ｉ－ＩＩ－３）を縮合し、得られたオレフィン体の保護基ＲＩ ｇを脱保護することによって、フェノール性中間体又はチオール性中間体（Ｉ－ＶＩＩＩ－３）を得る反応である。ＰＢＩがトリアリールホスホニウムの場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、テトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド等の塩基を用い、－３０℃～還流で３０分～１２時間程度が挙げられる。非プロトン性極性溶媒中、塩を含まない条件で反応を行うことでＺ体を優先的に得たり、Ｓｃｈｌｏｓｓｅｒの改良法により、Ｅ体を優先的に得ることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。ＰＢＩがＰ（Ｏ）（ＯＲＩ ｅ）２の場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。オレフィンはＥ体を優先的に得ることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。引き続いて行う保護基ＲＩ ｇの脱保護に用いられる条件としては、アルケニレンが反応しない条件であれば特に限定されないが、例えばＲＩ ｇが４－メトキシベンジルの場合、２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（ＤＤＱ）等による酸化反応を、ＲＩ ｇがトリアルキルシリル等のシリルの場合、塩酸等の無機酸やテトラブチルアンモニウムフルオリド等のフッ素化合物による脱保護を挙げることができる。また、ＲＩ ｇとして発明化合物（Ｉ－Ｉ－８）の部分構造である－ＡＩを用いた場合には、ＲＩ ｇを脱保護する必要はなく、次の工程におけるフェノール又はチオールのアルキル化も省略することができる。 By the second step of condensation of intermediates containing phosphorus (I-VIII-2) separately synthesized aldehyde (I-II-3), deprotecting the protecting group R I g of the resulting olefin body , A reaction to obtain a phenolic intermediate or a thiol intermediate (I-VIII-3). If PB I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at −30 ° C. to reflux for about 30 minutes to 12 hours. The Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB I is P (O) of the (OR I e) 2, the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The conditions used for the deprotection of the protecting group R I g performed subsequently, is not particularly limited insofar as the conditions that alkenylene does not react, for example, when R I g is 4-methoxybenzyl, 2,3-dichloro -5 6- the oxidation reaction with dicyano-1,4-benzoquinone (DDQ) or the like, R if I g is silyl such as trialkylsilyl, deprotection with fluorine compound of an inorganic acid or tetrabutylammonium fluoride and the like such as hydrochloric acid Can be mentioned. In the case of using the -A I is a partial structure of the invention compound as R I g (I-I- 8) is not necessary to deprotect R I g, alkyl phenol or thiol in the next step Can also be omitted.
　第三工程は中間体（Ｉ－ＶＩＩＩ－３）のフェノール性水酸基又はチオール基をアルキル化し、続いてＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合、それを保護する保護基ＲＩ ｄ（ＲＩ ｄは前述と同義）を脱保護することによって、本発明化合物（Ｉ－Ｉ－８）を得る反応である。中間体（Ｉ－ＶＩＩＩ－３）が有するフェノール性水酸基又はチオール性水酸基のアルキル化に用いられる試薬としては、ＸＩ ｇが脱離基を示す場合、中間体（Ｉ－ＶＩＩＩ－４）と炭酸カリウムや水素化ナトリウム等の無機塩基の組み合わせが挙げられる。反応条件としては、Ｎ，Ｎ－ジメチルホルムアミド等の極性溶媒やテトラヒドロフラン等のエーテル系溶媒中、氷冷下～８０℃で３０分～１２時間程度が挙げられる。また、ＸＩ ｇが水酸基を示し、中間体（Ｉ－ＶＩＩＩ－３）がフェノール性水酸基を有する場合のアルキル化には、トリフェニルホスフィン等のホスフィン化合物とアゾジカルボン酸ジイソプロピルエステル等のアゾジカルボン酸誘導体を用いた光延反応も用いることができる。この時の反応条件としては、テトラヒドロフラン等のエーテル系溶媒中、氷冷下～５０℃で１０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行う脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、全ての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成しＲＩ ｃがｔ－ブチルオキシカルボニルである場合、酸によって同時に脱保護できる。このときの酸としては、塩酸等の無機酸やトリフルオロ酢酸等が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is to alkylate the phenolic hydroxyl group or thiol group of intermediate (I-VIII-3), followed by protecting group for protecting R I b , R I c and R I-2 when they have a hydroxyl group In this reaction, R I d (R I d is as defined above) is deprotected to give the compound (II-8) of the present invention. The reagents used in the alkylation of a phenolic hydroxyl group or thiol hydroxyl intermediate (I-VIII-3) having, if X I g is a leaving group, intermediates (I-VIII-4) carbonate Examples include combinations of inorganic bases such as potassium and sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours. Further, X I g is a hydroxyl group, the alkylation in the case of Intermediate (I-VIII-3) having a phenolic hydroxyl group, phosphine compounds such as triphenylphosphine and azodicarboxylate such as diisopropyl azodicarboxylate Mitsunobu reaction using a derivative can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　８）一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＲＩ－１がジフルオロメチルで表される化合物（Ｉ－Ｉ－９）は以下のスキーム（Ｉ－ＩＸ）によっても合成される。 8) The compound (II-9) in which R I , R I-3 and R I-4 in general formula (I) are all hydrogen atoms and R I-1 is difluoromethyl has the following scheme ( I-IX).
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
（式中、ＲＩ ｂ、ＲＩ ｃ及びＲＩ ｈは保護基、ＸＩ ｇは脱離基又は水酸基を示し、ＸＩ、ＹＩ、ＲＩ－２、ＡＩは一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃ、ＸＩ ｇの具体的な例は前述と同義である。式中のＲＩ ｈで示される保護基としては、フェノール基又はチオール基を保護するものであれば特に限定されない。ＲＩ ｈの例として、ＸＩが酸素原子のときにはアルキル（メチルなど）、アラルキル（４－メトキシベンジルなど）、アセタールを形成する保護基（メトキシメチルやエトキシエチルなど）等が挙げられる。また、ＸＩが硫黄原子のときには、アルキル（メチルなど）、アラルキル（４－メトキシベンジルなど）、チオアセタールを形成する保護基（メトキシメチルやフェニルチオメチル、アセタミドメチルなど）等が挙げられる。 (Wherein R I b , R I c and R I h represent a protecting group, X I g represents a leaving group or a hydroxyl group, and X I , Y I , R I-2 and A I represent the general formula (I) It is synonymous with each symbol in.)
Specific examples of R I b , R I c and X I g in the formula are as defined above. The protecting group represented by R I h in the formula is not particularly limited as long as it protects a phenol group or a thiol group. Examples of R I h include alkyl (such as methyl), aralkyl (such as 4-methoxybenzyl), and a protecting group that forms an acetal (such as methoxymethyl and ethoxyethyl) when X I is an oxygen atom. Further, when X I is a sulfur atom, alkyl (methyl, etc.), aralkyl (4-methoxybenzyl, etc.), protecting group forming thioacetal (methoxymethyl or phenylthiomethyl, acetamidomethyl and the like) and the like.
　第一工程は公知の方法（ＷＯ２００７／０６９７１２号公報、４５～４８ページ）によって合成されるジフルオロメチル基を有する化合物（Ｉ－ＩＸ－１）の保護基ＲＩ ｈを脱保護することによって、フェノール性中間体又はチオール性中間体（Ｉ－ＩＸ－２）を得る反応である。ＲＩ ｈがベンジルの場合、パラジウム炭素やラネーニッケル等の均一系触媒を用いた加水素分解反応を、４－メトキシベンジルの場合、２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（ＤＤＱ）等による酸化反応を、トリアルキルシリル等のシリル基の場合、塩酸等の無機酸やテトラブチルアンモニウムフルオリド等のフッ素化合物による脱保護を挙げることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is to deprotect the protecting group R I h of the compound (I-IX-1) having a difluoromethyl group synthesized by a known method (WO 2007/069712, pages 45 to 48). Reaction for obtaining a functional intermediate or a thiol intermediate (I-IX-2). When R I h is benzyl, a hydrogenolysis reaction using a homogeneous catalyst such as palladium carbon or Raney nickel is used, and in the case of 4-methoxybenzyl, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone In the case of a silyl group such as trialkylsilyl, the oxidation reaction by (DDQ) or the like can include deprotection with an inorganic acid such as hydrochloric acid or a fluorine compound such as tetrabutylammonium fluoride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（Ｉ－ＩＸ－２）のフェノール性水酸基又はチオール基をアルキル化し、続いてＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合、それを保護する保護基ＲＩ ｄ（ＲＩ ｄは前述と同義）を脱保護することによって、本発明化合物（Ｉ－Ｉ－９）を得る反応である。中間体（Ｉ－ＩＸ－２）が有するフェノール性水酸基又はチオール性水酸基のアルキル化に用いられる試薬としては、ＸＩ ｇが脱離基を示す場合、中間体（Ｉ－ＶＩＩＩ－４）と炭酸カリウムや水素化ナトリウム等の無機塩基の組み合わせが挙げられる。反応条件としては、Ｎ，Ｎ－ジメチルホルムアミド等の極性溶媒やテトラヒドロフラン等のエーテル系溶媒中、氷冷下～８０℃で３０分～１２時間程度が挙げられる。また、ＸＩ ｇが水酸基を示し、中間体（Ｉ－ＩＸ－２）がフェノール性水酸基を有する場合のアルキル化には、トリフェニルホスフィン等のホスフィン化合物とアゾジカルボン酸ジイソプロピルエステル等のアゾジカルボン酸誘導体を用いた光延反応も用いることができる。この時の反応条件としては、テトラヒドロフラン等のエーテル系溶媒中、氷冷下～５０℃で１０分～６時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行う脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、全ての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成しＲＩ ｃがｔ－ブチルオキシカルボニルである場合、酸によって同時に脱保護できる。このときの酸としては、塩酸等の無機酸やトリフルオロ酢酸等が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the second step, the phenolic hydroxyl group or thiol group of intermediate (I-IX-2) is alkylated, and when R I b , R I c and R I-2 have a hydroxyl group, a protecting group for protecting it In this reaction, R I d (R I d is as defined above) is deprotected to give the compound (II-9) of the present invention. The reagents used in the alkylation of a phenolic hydroxyl group or thiol hydroxyl intermediate (I-IX-2) having, if X I g is a leaving group, intermediates (I-VIII-4) carbonate Examples include combinations of inorganic bases such as potassium and sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours. Further, X I g is a hydroxyl group, the alkylation in the case of Intermediate (I-IX-2) having a phenolic hydroxyl group, phosphine compounds such as triphenylphosphine and azodicarboxylate such as diisopropyl azodicarboxylate Mitsunobu reaction using a derivative can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R I b and R I d combine to form a cyclic acetal and R I c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　９）一般式（Ｉ）中のＲＩ、ＲＩ－３、ＲＩ－４がともに水素原子、ＲＩ－１がフルオロメチルで表される化合物（Ｉ－Ｉ－１０）は以下のスキーム（Ｉ－Ｘ）によっても合成される。 9) Compound (II-10) in which R I , R I-3 and R I-4 in general formula (I) are all hydrogen atoms and R I-1 is fluoromethyl is represented by the following scheme ( IX).
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
（式中、ＲＩ ｂ、ＲＩ ｃ及びＲＩ ｉは保護基、ＸＩ ｃ及びＸＩ ｄは脱離基を示し、ＡＩ’’は鎖中又は鎖端に二重結合又は三重結合の官能基を有さない炭素数５～９のアルキル、ＲＩ－２、ＸＩ、ＹＩは一般式（Ｉ）における各記号と同義である。）
　式中のＲＩ ｂ、ＲＩ ｃ、ＸＩ ｃ、ＸＩ ｄの具体的な例は前述と同じである。式中のＲＩ ｉで示される保護基としては水酸基を保護するものであれば特に限定されない。例えばトリアルキルシリル（具体的にはｔ－ブチルジメチルシリルなど）が挙げられる。 (Wherein R I b , R I c and R I i represent a protecting group, X I c and X I d represent a leaving group, and A I ″ represents a double bond or a triple bond in the chain or at the chain end. (C 5-9 alkyl having no functional group, R I-2 , X I and Y I have the same meanings as those in the general formula (I).)
Specific examples of R I b , R I c , X I c and X I d in the formula are the same as described above. The protecting group represented by R I i in the formula is not particularly limited as long as it protects the hydroxyl group. For example, trialkylsilyl (specifically, t-butyldimethylsilyl and the like) can be mentioned.
　第一工程は脱離基ＸＩ ｄのついた原料（Ｉ－Ｘ－１）とアルコール又はチオール（Ｉ－Ｘ－２）の縮合により中間体（Ｉ－Ｘ－３）を得る反応である。本工程はＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシド等の極性溶媒や、テトラヒドロフラン等のエーテル系溶媒中、塩基の存在下、行うことができる。塩基としては、水素化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基、カリウムｔ－ブトキシド等のアルコキシド、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン等の有機塩基を用いて行うことができる。反応条件としては、氷冷下～８０℃程度で３０分～２４時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。また、化合物（Ｉ－Ｘ－１）の脱離基ＸＩ ｄがフェノール性水酸基又はチオールのものを原料として使用することも可能であり、その場合、この第一工程は、フェノール性水酸基又はチオールのアルキル化となる。このアルキル化に用いられる試薬としては、ハロゲン化アルキル等のアルキル化剤と炭酸カリウムや水素化ナトリウム等の無機塩基の組み合わせが挙げられる。反応条件としては、Ｎ，Ｎ－ジメチルホルムアミド等の極性溶媒やテトラヒドロフラン等のエーテル系溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。また、フェノール性水酸基のアルキル化には、光延反応も用いることができる。 The first step is a reaction for obtaining an intermediate (IX-3) by condensation of a raw material (IX-1) having a leaving group X I d and an alcohol or thiol (IX-2). This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of the reaction conditions are about 30 minutes to 24 hours at about 80 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In addition, it is also possible to use a compound (IX-1) having a leaving group X I d as a phenolic hydroxyl group or thiol as a raw material. Is alkylated. Examples of the reagent used for this alkylation include a combination of an alkylating agent such as an alkyl halide and an inorganic base such as potassium carbonate or sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 10 minutes to 12 hours. Moreover, Mitsunobu reaction can also be used for alkylation of a phenolic hydroxyl group.
　第二工程は中間体（Ｉ－Ｘ－３）のホルミル基を還元してヒドロキシメチルとした後、保護基ＲＩ ｉを導入する反応である。ホルミル基の還元に用いられる試薬としては、通常用いられているものであれば特に限定されないが、水素化ジイソブチルアルミニウム等の金属水素化物、水素化アルミニウムリチウムや水素化ホウ素ナトリウム等の金属水素錯化合物、均一系又は不均一系の触媒を用いた接触水素添加等が挙げられる。反応条件は、用いる還元試薬に適切な温度と時間が選ばれる。具体的なものとしては、テトラヒドロフラン等のエーテル系溶媒中－３０℃～室温で１０分～３時間程度行われる水素化アルミニウムリチウム、水素化ホウ素リチウムによる還元、エタノール等のアルコール系溶媒又はアルコール系溶媒とテトラヒドロフラン等のエーテル系溶媒の混合溶媒中、氷冷下～室温で１０分～３時間程度行われる水素化ホウ素ナトリウムや水素化ホウ素カルシウムによる還元等が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。保護基ＲＩ ｉの導入には通常の保護基の導入反応が用いられる。ＲＩ ｉにトリアルキルシリル基を用いる場合、試薬としてはｔ－ブチルジメチルクロロシラン等のシリル化剤が用いられ、反応促進剤としてイミダゾールやトリエチルアミン等の塩基を加えることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is a reaction in which the formyl group of intermediate (IX-3) is reduced to hydroxymethyl and then the protective group R I i is introduced. The reagent used for the reduction of the formyl group is not particularly limited as long as it is usually used, but metal hydrides such as diisobutylaluminum hydride, metal hydride complex compounds such as lithium aluminum hydride and sodium borohydride. And catalytic hydrogenation using a homogeneous or heterogeneous catalyst. As the reaction conditions, a temperature and a time appropriate for the reducing reagent to be used are selected. Specific examples include lithium aluminum hydride, reduction with lithium borohydride performed in an ether solvent such as tetrahydrofuran at −30 ° C. to room temperature for about 10 minutes to 3 hours, alcohol solvents such as ethanol or alcohol solvents. And reduction with sodium borohydride or calcium borohydride performed in a mixed solvent of an ether solvent such as tetrahydrofuran and the like under ice-cooling to room temperature for about 10 minutes to 3 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. For introducing the protecting group R I i, a conventional protecting group introduction reaction is used. When a trialkylsilyl group is used for R I i , a silylating agent such as t-butyldimethylchlorosilane is used as a reagent, and a base such as imidazole or triethylamine can be added as a reaction accelerator. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は中間体（Ｉ－Ｘ－４）と中間体（Ｉ－ＩＶ－４）を薗頭反応により縮合して、三重結合を含む中間体（Ｉ－Ｘ－５）を得る反応である。用いられる触媒としてはテトラキス（トリフェニルホスフィン）パラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、ジクロロビス（アセトニトリル）パラジウム（ＩＩ）等のパラジウム化合物が挙げられる。また反応を促進するために、トリエチルアミン等の有機塩基やアンモニア等の無機塩基、ヨウ化銅や臭化銅等の銅化合物、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル等のホスフィン化合物等の添加物を加えることもできる。反応条件としては、テトラヒドロフランやジオキサン等のエーテル系溶媒、アセトニトリルやジメチルホルムアミド等の極性溶媒、又はベンゼン等の炭化水素溶媒中、氷冷化～還流で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is a reaction in which intermediate (IX-4) and intermediate (I-IV-4) are condensed by Sonogashira reaction to obtain intermediate (IX-5) containing a triple bond. . Examples of the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II). In order to accelerate the reaction, organic bases such as triethylamine, inorganic bases such as ammonia, copper compounds such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl It is also possible to add additives such as phosphine compounds. The reaction conditions include ice-cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第四工程は中間体（Ｉ－Ｘ－５）の三重結合を還元して中間体（Ｉ－Ｘ－６）を得る反応である。ＹＩが－ＣＨ２ＣＨ２－の時に用いられる試薬としては、通常の不飽和炭素結合の還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル、パラジウム炭素エチレンジアミン複合体等の不均一系触媒ロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。一方、ＹＩが－ＣＨ＝ＣＨ－の時に用いられる反応としては、Ｌｉｎｄｌａｒ触媒、ニッケル－グラファイト－エチレンジアミン錯体、ジエンとホスフィンとロジウムの各種錯体など活性を調節した触媒の存在下に行われる接触水素添加が挙げられる。また水素化ジイソブチルアルミニウムなどの金属水素化物による還元反応を用いることも可能である。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The fourth step is a reaction in which the triple bond of intermediate (IX-5) is reduced to obtain intermediate (IX-6). The reagent used when Y I is —CH 2 CH 2 — is not limited as long as it is a reagent used for normal reduction of unsaturated carbon bonds, but is not limited to palladium carbon, Raney nickel, palladium carbon ethylenediamine complex, etc. Examples thereof include catalytic hydrogenation using a homogeneous catalyst such as a homogeneous catalyst rhodium complex (chlorotris (triphenylphosphine) rhodium (I) and the like). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product. On the other hand, the reaction used when Y I is —CH═CH— is catalytic hydrogen carried out in the presence of a catalyst with regulated activity such as Lindlar catalyst, nickel-graphite-ethylenediamine complex, various complexes of diene, phosphine and rhodium. Addition may be mentioned. It is also possible to use a reduction reaction with a metal hydride such as diisobutylaluminum hydride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第五工程は化合物（Ｉ－Ｘ－６）のＲＩ ｉを脱保護し、得られた化合物の水酸基をフッ素化することによって、フッ化物体（Ｉ－Ｘ－７）を合成するものである。保護基ＲＩ ｉの脱保護は通常の脱保護反応を用いて行うことができる。ＲＩ ｉがトリアルキルシリルの場合に用いられる試薬としては、テトラブチルアンモニウムフルオリド等のフッ素化合物を用いることができる。この反応の条件としては、テトラヒドロフラン等のエーテル系溶媒中、氷冷化～還流で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続いて行われるフッ素化に使われる試薬としては三フッ化ジエチルアミノ硫黄（ＤＡＳＴ）や２，２－ジフルオロ－１，３－ジメチルイミダゾリジン（ＤＦＩ）等を挙げることができる。本工程は塩化メチレン等のハロゲン系溶媒、又はヘキサン等の炭化水素溶媒中で反応を行うことができる。反応条件としては、－７８℃～室温で３０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。また本工程は、水酸基を対応するスルホナート体に変換後、フッ化物イオンを作用させる方法によっても行うことができる。例えばｐ－トルエンスルホニルフルオリドとテトラブチルアンモニウムフルオリド（ＴＢＡＦ）を用いる場合、テトラヒドロフラン等のエーテル系溶媒中、室温～８０℃で１時間～２４時間程度反応させる。この反応にはモレキュラーシーブス等の脱水剤を加えることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、ＲＩ ｉがトリアルキルシリルの場合、ＲＩ ｉの脱保護を行うことなくフッ素化を行うことも可能である。 In the fifth step, R I i of the compound (IX-6) is deprotected, and the hydroxyl group of the obtained compound is fluorinated to synthesize a fluorinated substance (IX-7). . Deprotection of the protecting group R I i can be carried out using a conventional deprotection reaction. As a reagent used when R I i is trialkylsilyl, a fluorine compound such as tetrabutylammonium fluoride can be used. The conditions for this reaction include an ice-based cooling to reflux for about 30 minutes to 24 hours in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Examples of the reagent used for the subsequent fluorination include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI). In this step, the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane. The reaction conditions include −78 ° C. to room temperature for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Moreover, this process can also be performed by the method of making a fluoride ion act after converting a hydroxyl group into a corresponding sulfonate body. For example, when p-toluenesulfonyl fluoride and tetrabutylammonium fluoride (TBAF) are used, the reaction is carried out in an ether solvent such as tetrahydrofuran at room temperature to 80 ° C. for about 1 to 24 hours. A dehydrating agent such as molecular sieves can be added to this reaction. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R I i is trialkylsilyl, fluorination can be performed without deprotecting R I i .
　第六工程は中間体（Ｉ－Ｘ－７）を脱保護することによって本発明化合物（Ｉ－Ｉ－１０）を得る反応である。ＲＩ ｂ、ＲＩ ｃ及びＲＩ－２が水酸基を有する場合、それを保護する保護基ＲＩ ｄ（ＲＩ ｄは前述と同義である。）の脱保護には、通常の保護基の脱保護に用いられるものであれば特に限定されず、全ての保護基を一度に又は段階的に脱保護することができる。例えばＲＩ ｂとＲＩ ｄが結合し環状のアセタールを形成し、ＲＩ ｃがｔ－ブチルオキシカルボニルである場合、触媒量の酸によって環状のアセタールを脱保護し、次により強い酸性条件を用いることによってＲＩ ｃの脱保護を行うことができる。このときのアセタールの脱保護に用いられる条件としては、メタノール等のアルコール性溶媒やアルコール性溶媒と他の有機溶媒の混合溶液中、触媒量の塩酸やトルエンスルホン酸を用い、氷冷下～８０℃で３０分～１２時間程度が挙げられる。一方、アセタールの脱保護に続いて行われるＲＩ ｃの脱保護の条件としては、当量以上の塩酸等の無機酸やトリフルオロ酢酸等を用い、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水又はそれらの混合溶媒中、氷冷下～室温で１０分～５時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。また、反応溶液にジイソプロピルエーテル等の難溶性溶媒を加え析出する目的物をろ取することもできる。 The sixth step is a reaction for obtaining the compound (II-10) of the present invention by deprotecting the intermediate (IX-7). When R I b , R I c and R I-2 have a hydroxyl group, deprotection of the protecting group R I d (R I d has the same meaning as described above) for protecting the hydroxyl group includes the usual protecting group. It will not specifically limit if it is used for deprotection, All the protecting groups can be deprotected at once or in steps. For example, when R I b and R I d combine to form a cyclic acetal, and R I c is t-butyloxycarbonyl, the cyclic acetal is deprotected with a catalytic amount of acid, followed by stronger acidic conditions. By using it, R I c can be deprotected. The conditions used for the deprotection of the acetal at this time include a catalytic amount of hydrochloric acid or toluenesulfonic acid in an alcoholic solvent such as methanol, or a mixed solution of an alcoholic solvent and another organic solvent. Examples include about 30 minutes to 12 hours at ° C. On the other hand, the conditions for the deprotection of R I c which is performed subsequent to the deprotection of the acetal, with inorganic acids or trifluoroacetic acid such as hydrochloric acid in equivalent amount or more, ethers such as alcoholic solvent or tetrahydrofuran such as ethanol-based In a solvent, water or a mixed solvent thereof, for about 10 minutes to 5 hours may be mentioned under ice-cooling to room temperature. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In addition, a hardly soluble solvent such as diisopropyl ether can be added to the reaction solution, and the precipitated target product can be collected by filtration.
　１０）本発明化合物のうち、一般式（Ｉ－Ｉ）中のＲＩがＰ（＝Ｏ）（ＯＨ）２、ＲＩ－３及びＲＩ－４がともに水素原子で表される化合物（Ｉ－Ｉ－１１）は以下のスキーム（Ｉ－ＸＩ）により合成される。 10) Among the compounds of the present invention, a compound (I) in which R I in the general formula (II) is P (═O) (OH) 2 , and R I-3 and R I-4 are both represented by a hydrogen atom. -I-11) is synthesized according to the following scheme (I-XI).
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
（式中、ＸＩ、ＹＩ、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義である。） (In the formula, X I , Y I , R I-1 , R I-2 and A I have the same meanings as those in the general formula (I).)
　この工程は公知（ＷＯ２００７／０６９７１２号公報、５３～５６ページ）の合成法によって、本発明化合物（Ｉ－Ｉ－１１）を得るものである。上記の公知の合成法を用いて、アルコール体（Ｉ－ＸＩ－１）から三段階でリン酸化体（Ｉ－Ｉ－１１）を合成することができる。 This step is to obtain the compound (II-11) of the present invention by a known synthesis method (WO 2007/069712, pages 53 to 56). The phosphorylated form (II-11) can be synthesized from the alcohol form (I-XI-1) in three steps using the above known synthesis method.
　１１）本発明化合物のうち、一般式（Ｉ）中のＲＩがＰ（＝Ｏ）（ＯＨ）２、ＲＩ－３及びＲＩ－４がともに炭素数１～４のアルキルで表される化合物は原料として（Ｉ－ＸＩ－１）の代わりに、 11) Among the compounds of the present invention, R I in the general formula (I) is P (═O) (OH) 2 , R I-3 and R I-4 are both represented by alkyl having 1 to 4 carbon atoms. Instead of (I-XI-1) as a raw material,
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
（式中、ＲＩ－３’’及びＲＩ－４’’はともに炭素数１～４のアルキルを示し、ＸＩ、ＹＩ、ＲＩ－１、ＲＩ－２及びＡＩは一般式（Ｉ）における各記号と同義である。）
を用い、スキーム（Ｉ－ＸＩ）の第一工程のアミノ基又はアミノ基と水酸基の保護を省略し、同様の方法により合成することができる。 (Wherein R I-3 ″ and R I-4 ″ both represent alkyl having 1 to 4 carbon atoms, and X I , Y I , R I-1 , R I-2 and A I represent the general formula (It is synonymous with each symbol in (I).)
Can be synthesized by the same method, omitting the protection of the amino group or amino group and hydroxyl group in the first step of scheme (I-XI).
　１２）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩが炭素数２～４のアルキレン、ＡＩＩ－２が炭素数１～４のアルコキシで表される化合物（ＩＩ－Ｉ－１）は以下のスキーム（ＩＩ－ＩＩ）により合成される。 12) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-1) in which heptyl, Z II is alkylene having 2 to 4 carbon atoms, and A II-2 is alkoxy having 1 to 4 carbon atoms is synthesized by the following scheme (II-II) .
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
（式中、ｎは０～２、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基、ＲＩＩ ｂは炭素数１～４のアルキルを示す。）
　式中のＲＩＩ ａで示される保護基はアミノ基を保護するものであれば特に限定されない。例えば、アシル（好ましくは炭素数２～４程度のもの、具体的にはアセチルなど）、カルバメート（具体的にはｔ－ブチルオキシカルボニルやベンジルオキシカルボニルなど）等が挙げられる。
　ＲＩＩ－２が水酸基を有する場合、その水酸基は適当な保護基で保護されていても良く、その保護基ＲＩＩ ｃとしては具体的にはアシル（好ましくは炭素数２～４程度のもの、具体的にはアセチルなど）、トリアルキルシリル（具体的にはトリメチルシリルなど）、ベンジル又はアセタール化合物を形成する置換基（具体的にはメトキシメチル、テトラヒドロピラニルなど）が挙げられる。 (Wherein n is 0 to 2, R II-1 and R II-2 are as defined in the general formula (II-1), R II a is a protecting group, and R II b is 1 to 4 represents alkyl.)
Protecting group represented by R II a in the formula is not particularly limited as long as it protects an amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned.
When R II-2 has a hydroxyl group, the hydroxyl group may be protected with a suitable protecting group, and the protecting group R II c is specifically acyl (preferably having about 2 to 4 carbon atoms, Specific examples include acetyl), trialkylsilyl (specifically trimethylsilyl, etc.), benzyl or a substituent that forms an acetal compound (specifically methoxymethyl, tetrahydropyranyl, etc.).
　第一工程は公知の方法（ＷＯ２００７／０６９７１２号公報、８～１３ページ）によって合成される化合物（ＩＩ－ＩＩ－１）のアミノ基を保護することによってアミノ基保護体（ＩＩ－ＩＩ－２）を合成するものである。本工程は通常のアミノ基保護反応を用いて行うことができる。具体的には、保護基ＲＩＩ ａとしてアシル、アルキルオキシカルボニル又はベンジルオキシカルボニル等を用いる場合、本工程はメタノール等のアルコール中、又は水と酢酸エチルやクロロホルム等の有機溶媒の二相系又は混合液中で行うことができる。用いられる試薬としては塩化アセチルや塩化ベンジルオキシカルボニル等の酸塩化物、無水酢酸やジ－ｔ－ブチルジカルボナート等の酸無水物が挙げられる。本反応には反応促進剤として、トリエチルアミン等の有機塩基又は重曹等の無機塩基を加えることができる。反応条件としては、氷冷下～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is protecting the amino group (II-II-2) by protecting the amino group of the compound (II-II-1) synthesized by a known method (WO 2007/069712, pages 8 to 13). Is synthesized. This step can be performed using a normal amino group protecting reaction. Specifically, when acyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like is used as the protecting group R II a , this step is performed in a two-phase system of an alcohol such as methanol, or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture. Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程はアミノ基保護体（ＩＩ－ＩＩ－２）の水酸基を酸化し、アルデヒド体（ＩＩ－ＩＩ－３）を合成するものである。本工程は通常のアルコールのアルデヒドへの酸化反応を用いて行うことができる。具体的には、クロロクロム酸ピリジニウム、塩化オキザリル、ＤＣＣ、三酸化硫黄－ピリジン錯体等の各種ＤＭＳＯ活性化剤を用いたＤＭＳＯ酸化やＮ－オキソアンモニウム化合物を用いた酸化（例えば、ＴＥＭＰＯ酸化）により目的物を得ることができる。反応条件としては、－７８℃～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the second step, the hydroxyl group of the protected amino group (II-II-2) is oxidized to synthesize the aldehyde (II-II-3). This step can be performed using an oxidation reaction of a normal alcohol to an aldehyde. Specifically, by DMSO oxidation using various DMSO activators such as pyridinium chlorochromate, oxalyl chloride, DCC, sulfur trioxide-pyridine complex, and oxidation using N-oxoammonium compounds (for example, TEMPO oxidation). The object can be obtained. The reaction conditions include −78 ° C. to 50 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程はアルデヒド体（ＩＩ－ＩＩ－３）とＲＩＩ ｂを含む市販のリン試薬を縮合させることにより、中間体（ＩＩ－ＩＩ－４）を合成するものである。市販のリン試薬がトリアリールホスホニウム（具体的にはＰ（Ｃ６Ｈ５）３）を含む場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、テトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド等の塩基を用い、－３０℃～還流で３０分～１２時間程度が挙げられる。非プロトン性極性溶媒中、塩を含まない条件で反応を行うことでＺ体を優先的に得たり、Ｓｃｈｌｏｓｓｅｒの改良法により、Ｅ体を優先的に得ることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。市販のリン試薬がＰ（Ｏ）（ＯＲＩＩ ｄ）２（ＲＩＩ ｄは炭素数１～４のアルキルを示す。以下同じ。）を含む場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。オレフィンはＥ体を優先的に得ることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The third step is to synthesize intermediate (II-II-4) by condensing aldehyde (II-II-3) with a commercially available phosphorus reagent containing R II b . When a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C 6 H 5 ) 3 ), normal Wittig reaction conditions are used. For example, a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at −30 ° C. to reflux for about 30 minutes to 12 hours. The Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When a commercially available phosphorus reagent contains P (O) (OR II d ) 2 (R II d represents alkyl having 1 to 4 carbon atoms, the same shall apply hereinafter), the conditions of the normal Horner-Wadsworth-Emmons reaction are used. It is done. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第四工程は中間体（ＩＩ－ＩＩ－４）のオレフィン部分を還元後、保護基ＲＩＩ ａを脱保護することによって、本発明化合物（ＩＩ－Ｉ－１）を得る反応である。
　オレフィンの還元に用いられる試薬としては、通常のオレフィンの還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル等の不均一系触媒又はロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、精製等を行い、目的物を得ることができる。引き続いて行う保護基ＲＩＩ ａの脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されないが、例えば、ＲＩＩ ａがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。なお、ＲＩＩ ａにベンジル、ベンジルオキシカルボニル等の加水素分解、接触水素添加条件によって脱保護できる保護基を用いた場合には、ＲＩＩ ａの脱保護は、上述の二重結合の還元と同時に行うこともできる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩが炭素数２～４のアルキレン、ＡＩＩ－２が炭素数１～４のアルコキシ、ＹＩＩ－１が－ＣＨ２ＣＨ２－であるその他の化合物も同様の方法によって合成することができる。 The fourth step is a reaction for obtaining the compound (II-I-1) of the present invention by reducing the olefin moiety of the intermediate (II-II-4) and then deprotecting the protecting group R II a .
The reagent used for the reduction of the olefin is not limited as long as it is a reagent used for the reduction of a normal olefin. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) rhodium (I And hydrogenation using a homogeneous catalyst. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting group R II a are not particularly limited as long as they can be used for the deprotection of ordinary protecting groups. For example, if R II a is acyl such as acetyl, an alcohol type Examples include a method using an inorganic base such as sodium hydroxide in a mixed solvent of water and water, and a method using an acid such as hydrochloric acid or trifluoroacetic acid if the protecting group is t-butyloxycarbonyl. . In the case of using benzyl R II a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), Z II is alkylene having 2 to 4 carbon atoms, A II-2 is alkoxy having 1 to 4 carbon atoms, Y II- Other compounds in which 1 is —CH 2 CH 2 — can be synthesized in the same manner.
　１３）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩがメチレン、ＡＩＩ－２がＣＯＯＨで表される化合物（ＩＩ－Ｉ－２）は以下のスキーム（ＩＩ－ＩＩＩ）により合成される。 13) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-2) in which heptyl, Z II is methylene, and A II-2 is COOH is synthesized by the following scheme (II-III).
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
（式中、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基を示す。）
　式中のＲＩＩ ａの具体的な例は前述と同義である。 (Wherein R II-1 and R II-2 have the same meanings as symbols in formula (II-1), and R II a represents a protecting group.)
Specific examples of R II a in the formula are as defined above.
　第一工程はスキーム（ＩＩ－ＩＩ）中の中間体（ＩＩ－ＩＩ－４）においてｎが０、ＲＩＩ ｂがメチルである化合物（ＩＩ－ＩＩＩ－１）を酸処理してアルデヒドとし、続く酸化によりカルボン酸体（ＩＩ－ＩＩＩ－２）を合成するものである。酸処理には塩酸等の酸を用いた方法が挙げられ、反応条件としては、水中で濃塩酸を用い、氷冷下～６０℃で３０分～２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。続くアルデヒドからカルボン酸への酸化は一般な方法を用いることにより行うことができる。具体的には、過マンガン酸塩、クロム酸、酸素、過酸化水素、有機過酸化物を用いた酸化やピニック酸化により目的物を得ることができる。反応条件としては、－７８℃～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is an acid treatment of compound (II-III-1) wherein n is 0 and R II b is methyl in intermediate (II-II-4) in scheme (II-II), followed by aldehyde The carboxylic acid compound (II-III-2) is synthesized by oxidation. Examples of the acid treatment include a method using an acid such as hydrochloric acid, and the reaction conditions include concentrated hydrochloric acid in water and at about 60 ° C. for 30 minutes to 2 hours under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent oxidation of the aldehyde to the carboxylic acid can be carried out by using a general method. Specifically, a target product can be obtained by oxidation or pernication using permanganate, chromic acid, oxygen, hydrogen peroxide, or organic peroxide. The reaction conditions include −78 ° C. to 50 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程はカルボン酸体（ＩＩ－ＩＩＩ－２）の保護基ＲＩＩ ａを脱保護することによって、本発明化合物（ＩＩ－Ｉ－２）を得る反応である。脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されないが、例えば、ＲＩＩ ａがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等である場合、塩酸やトリフルオロ酢酸等の酸を用いた方法、ベンジル、ベンジルオキシカルボニル等の保護基であれば、加水素分解、接触水素添加を用いた方法が挙げられる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩがメチレン、ＡＩＩ－２がＣＯＯＨであるその他の化合物も同様の方法によって合成することができる。 The second step is a reaction for obtaining the compound (II-I-2) of the present invention by deprotecting the protecting group R II a of the carboxylic acid form (II-III-2). The deprotection conditions are not particularly limited as long as they are used for the deprotection of ordinary protecting groups. For example, when R II a is acyl such as acetyl, it is used in a mixed solvent of an alcohol solvent and water. A method using an inorganic base such as sodium hydroxide, a method using t-butyloxycarbonyl or the like, a method using an acid such as hydrochloric acid or trifluoroacetic acid, or a hydrogenated group if it is a protecting group such as benzyl or benzyloxycarbonyl. A method using decomposition or catalytic hydrogenation can be mentioned. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), other compounds in which Z II is methylene and A II-2 is COOH can also be synthesized by the same method.
　１４）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩが単結合であり、ＡＩＩ－２がＣＯＯＨで表される化合物（ＩＩ－Ｉ－３）は以下のスキーム（ＩＩ－ＩＶ）により合成される。 14) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-3) in which heptyl, Z II is a single bond, and A II-2 is represented by COOH is synthesized by the following scheme (II-IV).
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
（式中、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基を示す。）
　式中のＲＩＩ ａの具体的な例は前述と同義である。 (Wherein R II-1 and R II-2 have the same meanings as symbols in formula (II-1), and R II a represents a protecting group.)
Specific examples of R II a in the formula are as defined above.
　本工程はアルデヒド体（ＩＩ－ＩＩ－３）を酸化しカルボン酸体へとした後、保護基ＲＩＩ ａを脱保護することによって、本発明化合物（ＩＩ－Ｉ－３）を得る反応である。アルデヒドからカルボン酸体への酸化、及び続く脱保護はスキーム（ＩＩ－ＩＩＩ）と同様の手法を用いて目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩが単結合、ＡＩＩ－２がＣＯＯＨであるその他の化合物も同様の方法によって合成することができる。 This step is a reaction for obtaining the compound (II-I-3) of the present invention by oxidizing the aldehyde form (II-II-3) to a carboxylic acid form and then deprotecting the protecting group R II a. . Oxidation from an aldehyde to a carboxylic acid form, and subsequent deprotection, can be carried out using the same procedure as in Scheme (II-III) to obtain the desired product. Of the compounds represented by the general formulas (II-1) and (II-2), other compounds in which Z II is a single bond and A II-2 is COOH can be synthesized by the same method. .
　１５）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩがエチレン、ＡＩＩ－２がＣＯＯＨで表される化合物（ＩＩ－Ｉ－４）は以下のスキーム（ＩＩ－Ｖ）により合成される。 15) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-4) in which heptyl, Z II is ethylene, and A II-2 is COOH is synthesized by the following scheme (II-V).
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
（式中、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基、ＲＩＩ ｅは炭素数１～４のアルキル基を示す。）
　式中のＲＩＩ ａの具体的な例は前述と同義である。 (Wherein R II-1 and R II-2 have the same meanings as the symbols in formula (II-1), R II a represents a protecting group, and R II e represents an alkyl group having 1 to 4 carbon atoms. .)
Specific examples of R II a in the formula are as defined above.
　第一工程はアルデヒド体（ＩＩ－ＩＩ－３）と市販のＲＩＩ ｅＯ－Ｃ（＝Ｏ）－基（ＲＩＩ ｅは前述の通り）を含むリン試薬を縮合させることにより、中間体（ＩＩ－Ｖ－１）を合成するものである。市販のリン試薬がトリアリールホスホニウム（具体的にはＰ（Ｃ６Ｈ５）３）を含む場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、テトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド等の塩基を用い、－３０℃～還流で３０分～１２時間程度が挙げられる。非プロトン性極性溶媒中、塩を含まない条件で反応を行うことでＺ体を優先的に得たり、Ｓｃｈｌｏｓｓｅｒの改良法により、Ｅ体を優先的に得ることもできる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。市販のリンを含んだ試薬がＰ（Ｏ）（ＯＲＩＩ ｄ）２を含む場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。オレフィンはＥ体を優先的に得ることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The first step is to condense an intermediate (II-II-3) with a phosphorus reagent containing a commercially available R II e O—C (═O) — group (R II e is as described above). II-V-1) is synthesized. When a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C 6 H 5 ) 3 ), normal Wittig reaction conditions are used. For example, a base such as sodium hydride or potassium t-butoxide is used in an ether solvent such as tetrahydrofuran, and the reaction can be performed at −30 ° C. to reflux for about 30 minutes to 12 hours. The Z-form can be preferentially obtained by carrying out the reaction in an aprotic polar solvent without containing a salt, or the E-form can be preferentially obtained by Schlosser's modified method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When the commercially available phosphorus-containing reagent contains P (O) (OR II d ) 2 , normal Horner-Wadsworth-Emmons reaction conditions are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can preferentially obtain E form. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（ＩＩ－Ｖ－１）のオレフィン部分を還元後、保護基ＲＩＩ ａとＲＩＩ ｅを脱保護することによって、本発明化合物（ＩＩ－Ｉ－４）を得る反応である。オレフィンの還元に用いられる試薬としては、通常のオレフィンの還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル等の不均一系触媒又はロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、精製等を行い、目的物を得ることができる。引き続いて行う保護基ＲＩＩ ａ及びＲＩＩ ｅの脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されない。例えば、ＲＩＩ ａがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。なお、ＲＩＩ ａにベンジル、ベンジルオキシカルボニル等の加水素分解、接触水素添加条件によって脱保護できる保護基を用いた場合には、ＲＩＩ ａの脱保護は、上述の二重結合の還元と同時に行うこともできる。ＲＩＩ ｅの加水分解による脱保護の条件はＲＩＩ ａと同様のものが挙げられ、アルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩがエチレン、ＡＩＩ－２がＣＯＯＨ、ＹＩＩ－１が－ＣＨ２ＣＨ２－であるその他の化合物も同様の方法によって合成することができる。 The second step is a reaction for obtaining the compound (II-I-4) of the present invention by reducing the olefin part of the intermediate (II-V-1) and then deprotecting the protecting groups R II a and R II e. is there. The reagent used for the reduction of the olefin is not limited as long as it is a reagent used for the reduction of a normal olefin. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) rhodium (I And hydrogenation using a homogeneous catalyst. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting groups R II a and R II e are not particularly limited as long as they are used for the deprotection of ordinary protecting groups. For example, when R II a is acyl such as acetyl, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, or a protective group such as t-butyloxycarbonyl is used as hydrochloric acid. And a method using an acid such as trifluoroacetic acid. In the case of using benzyl R II a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time. The conditions for deprotection by hydrolysis of R II e are the same as those for R II a. A method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, hydrochloric acid or trifluoro Examples include a method using an acid such as acetic acid. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), Z II is ethylene, A II-2 is COOH, and Y II-1 is —CH 2 CH 2 —. Compounds can also be synthesized by similar methods.
　１６）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩが炭素数１～３のアルキレン、ＡＩＩ－２がＯＨで表される化合物（ＩＩ－Ｉ－５）は以下のスキーム（ＩＩ－ＶＩ）により合成される。 16) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-5) in which heptyl, Z II is alkylene having 1 to 3 carbon atoms, and A II-2 is OH is synthesized by the following scheme (II-VI).
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
（式中、ｍは０～２、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基を示す。）
　式中のＲＩＩ ａの具体的な例は前述と同義である。 (In the formula, m is 0 to 2, R II-1 and R II-2 have the same meanings as symbols in the general formula (II-1), and R II a represents a protecting group.)
Specific examples of R II a in the formula are as defined above.
　本工程はスキーム（ＩＩ－ＩＩＩ）、スキーム（ＩＩ－ＩＶ）及びスキーム（ＩＩ－Ｖ）で合成されるカルボン酸体（ＩＩ－ＶＩ－１）を還元し、アルコールとした後、保護基ＲＩＩ ａを脱保護することによって、本発明化合物（ＩＩ－Ｉ－５）を得る反応である。カルボン酸からアルコールへの還元は一般な方法を用いることにより行うことができる。具体的には、水素化ジイソブチルアルミニウム等の金属水素化物、水素化リチウムアルミニウム等の金属水素錯化合物による還元、ジボラン及び置換ボランによる還元等を挙げることができる。反応条件としては、－７８℃～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。引き続いて行う保護基ＲＩＩ ａの脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されないが、例えば、ＲＩＩ ａがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。なお、ＲＩＩ ａにベンジル、ベンジルオキシカルボニル等の加水素分解、接触水素添加条件によって脱保護できる保護基を用いた場合には、ＲＩＩ ａの脱保護は、上述の二重結合の還元と同時に行うこともできる。また反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩが炭素数１～３のアルキレン、ＡＩＩ－２がＯＨであるその他の化合物も同様の方法によって合成することができる。 In this step, the carboxylic acid compound (II-VI-1) synthesized in Scheme (II-III), Scheme (II-IV) and Scheme (II-V) is reduced to an alcohol, followed by protecting group R II In this reaction, the compound (II-I-5) of the present invention is obtained by deprotecting a. Reduction of carboxylic acid to alcohol can be performed by using a general method. Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like. The reaction conditions include −78 ° C. to 50 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The conditions for the subsequent deprotection of the protecting group R II a are not particularly limited as long as they can be used for the deprotection of ordinary protecting groups. For example, if R II a is acyl such as acetyl, an alcohol type Examples include a method using an inorganic base such as sodium hydroxide in a mixed solvent of water and water, and a method using an acid such as hydrochloric acid or trifluoroacetic acid if the protecting group is t-butyloxycarbonyl. . In the case of using benzyl R II a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R II a is a reduction of the double bond of the above It can be done at the same time. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), other compounds in which Z II is alkylene having 1 to 3 carbon atoms and A II-2 is OH are also produced in the same manner. Can be synthesized.
　１７）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＸＩＩが酸素原子、ＹＩＩ－１が－ＣＨ２ＣＨ２－、ＡＩＩ－１がｎ－ヘプチル、ＺＩＩが炭素数１～４のアルキレン、ＡＩＩ－２がＰ（＝Ｏ）（ＯＨ）２で表される化合物（ＩＩ－Ｉ－６）は以下のスキーム（ＩＩ－ＶＩＩ）により合成される。 17) Among the compounds of the present invention, R II-3 in the general formula (II-1) is a hydrogen atom, X II is an oxygen atom, Y II-1 is —CH 2 CH 2 —, and A II-1 is n— Compound (II-I-6) in which heptyl, Z II is alkylene having 1 to 4 carbon atoms, and A II-2 is P (═O) (OH) 2 was synthesized by the following scheme (II-VII) Is done.
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
（式中、ｑは１～４、ＲＩＩ－１、ＲＩＩ－２は一般式（ＩＩ－１）における各記号と同義であり、ＲＩＩ ａは保護基、ＲＩＩ ｆは炭素数１～４のアルキル基を示す。）
　式中のＲＩＩ ａの具体的な例は前述と同義である。 (Wherein q is 1 to 4, R II-1 and R II-2 are as defined in the general formula (II-1), R II a is a protecting group, R II f is a carbon number 1 to 4 represents an alkyl group.)
Specific examples of R II a in the formula are as defined above.
　第一工程はアルデヒド体（ＩＩ－ＩＩ－３）と市販のＰ（＝Ｏ）（ＯＲＩＩ ｆ）２（ＲＩＩ ｆは前述の通り）を含むリン試薬（例えば、メチレンジホスホン酸テトラエチル）を縮合させリン化合物とした後、オレフィン部分を還元することにより中間体（ＩＩ－ＶＩＩ－１）を合成するものである。縮合は、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、ベンゼン等の炭化水素溶媒やテトラヒドロフラン等のエーテル系溶媒中、水素化ナトリウムやカリウムｔ－ブトキシド、リチウムヘキサメチルジシラザン等の塩基を用い、－２０℃～還流で３０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。引き続いて行うオレフィンの還元に用いられる試薬としては、通常のオレフィンの還元に用いられる試薬であれば限定されないが、例えばパラジウム炭素やラネーニッケル等の不均一系触媒又はロジウム錯体（クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）など）等の均一系触媒を用いた接触水素添加が挙げられる。反応条件としては、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中、１～２０気圧の水素圧の下、氷冷下～還流で３０分～１週間が挙げられる。なお、反応速度や化合物の安定性等に応じて、反応液に酢酸等の酸又はトリエチルアミン等の塩基を加えることもできる。反応後は、精製等を行い、目的物を得ることができる。 In the first step, a phosphorus reagent (for example, tetraethyl methylenediphosphonate) containing aldehyde (II-II-3) and commercially available P (═O) (OR II f ) 2 (R II f is as described above) is used. An intermediate (II-VII-1) is synthesized by condensing a phosphorus compound and then reducing the olefin moiety. For the condensation, the conditions of a normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent olefin reduction is not limited as long as it is a reagent used for ordinary olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) And catalytic hydrogenation using a homogeneous catalyst such as rhodium (I). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product.
　第二工程は中間体（ＩＩ－ＶＩＩ－１）の保護基ＲＩＩ ａとＲＩＩ ｆを脱保護することによって、本発明化合物（ＩＩ－Ｉ－６）を得る反応である。保護基ＲＩＩ ａの脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されないが、例えば、ＲＩＩ ａがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。なお、ＲＩＩ ａにベンジル、ベンジルオキシカルボニル等の加水素分解、接触水素添加条件によって脱保護できる保護基を用いた場合には、ＲＩＩ ａの脱保護は、第一工程の二重結合の還元と同時に行うこともできる。ＲＩＩ ｆの脱保護の条件としては、臭化トリメチルシリル等のルイス酸を用いて行うことができる。また反応条件としては、塩化メチレン等のハロゲン系溶媒中、氷冷下～８０℃で１０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩ－１）及び（ＩＩ－２）で表される化合物のうち、ＺＩＩが炭素数１～４のアルキレン、ＡＩＩ－２がＰ（＝Ｏ）（ＯＨ）２、ＹＩＩ－１が－ＣＨ２ＣＨ２－であるその他の化合物も同様の方法によって合成することができる。 The second step is a reaction for obtaining the compound (II-I-6) of the present invention by deprotecting the protecting groups R II a and R II f of the intermediate (II-VII-1). The conditions for the deprotection of the protecting group R II a, is not particularly limited as long as it is used in the deprotection of conventional protecting groups, for example, alcohol solvents, if R II a is acyl such as acetyl and water And a method using an inorganic base such as sodium hydroxide in a mixed solvent, and a method using an acid such as hydrochloric acid or trifluoroacetic acid as a protective group such as t-butyloxycarbonyl. Incidentally, benzyl R II a, hydrogenolysis, such as benzyloxycarbonyl, when using the deprotection can be protected group by catalytic hydrogenation conditions, the deprotection of R II a is a double bond in the first step It can be performed simultaneously with the reduction. R II f can be deprotected using a Lewis acid such as trimethylsilyl bromide. The reaction conditions include, for example, about 10 minutes to 24 hours at 80 ° C. under ice cooling in a halogen-based solvent such as methylene chloride. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), Z II is alkylene having 1 to 4 carbon atoms, A II-2 is P (═O) (OH) 2 , Y Other compounds in which II-1 is —CH 2 CH 2 — can also be synthesized by the same method.
　１８）本発明化合物のうち、一般式（ＩＩ－１）中のＲＩＩ－３が水素原子、ＺＩＩがメチレン、ＡＩＩ－２がＯＰ（＝Ｏ）（ＯＨ）２で表される化合物（ＩＩ－Ｉ－７）は以下のスキーム（ＩＩ－ＶＩＩＩ）により合成される。 18) Among the compounds of the present invention, a compound represented by the formula (II-1) wherein R II-3 is a hydrogen atom, Z II is methylene, and A II-2 is OP (═O) (OH) 2 ( II-I-7) is synthesized according to the following scheme (II-VIII).
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
（式中、ＸＩＩ、ＹＩＩ－１、ＲＩＩ－１、ＲＩＩ－２及びＡＩＩ－１は一般式（ＩＩ－１）における各記号と同義である。） (Wherein X II , Y II-1 , R II-1 , R II-2 and A II-1 have the same meanings as the symbols in formula (II-1).)
　この工程は公知（ＷＯ２００７／０６９７１２号公報、５３～５６ページ）の合成法によって、本発明化合物（ＩＩ－Ｉ－７）を得るものである。上記の公知の合成法を用いて、アルコール体（ＩＩ－ＶＩＩＩ－１）から三段階でリン酸化体（ＩＩ－Ｉ－７）を合成することができる。一般式（ＩＩ－２）中のＲＩＩ－３が水素原子、ＺＩＩがメチレン、ＡＩＩ－２がＯＰ（＝Ｏ）（ＯＨ）２、で表される化合物も同様の方法によって合成することができる。 In this step, the compound (II-I-7) of the present invention is obtained by a known synthesis method (WO 2007/069712, pages 53 to 56). The phosphorylated form (II-I-7) can be synthesized from the alcohol form (II-VIII-1) in three steps using the above-mentioned known synthesis method. A compound represented by the general formula (II-2) in which R II-3 is a hydrogen atom, Z II is methylene, and A II-2 is OP (═O) (OH) 2 is synthesized by the same method. Can do.
　１９）本発明化合物のうち、一般式（ＩＩＩ－１）中のＲＩＩＩ－２が水素原子、ＸＩＩＩ－１が酸素原子、ＹＩＩＩ－１がメチレン、ＸＩＩＩ－２がメチン、ＡＩＩＩ－１がｎ－ヘプチル、ＡＩＩＩ－２がメチレン、ＢＩＩＩがメチレンで、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２及びアミノ基の結合している炭素原子とともにシクロペンチルを形成している化合物（ＩＩＩ－Ｉ－１）は以下のスキーム（ＩＩＩ－ＩＩ）により合成される。 19) Among the compounds of the present invention, R III-2 in the general formula (III-1) is a hydrogen atom, X III-1 is an oxygen atom, Y III-1 is methylene, X III-2 is methine, A III- 1 is n-heptyl, A III-2 is methylene, B III is methylene, B III is bonded to A III-2, and Y III-1 , X III-2 and the carbon atom to which the amino group is bonded. Compound (III-I-1) forming cyclopentyl is synthesized by the following scheme (III-II).
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
（式中、ＸＩＩＩ ａ、ＸＩＩＩ ｂは脱離基、ＹＩＩＩは縮合反応時の活性化基を示し、ＲＩＩＩ－１は一般式（ＩＩＩ－１）における記号と同義である。）
　式中のＸＩＩＩ ａで示される脱離基は、アルコキシドイオン（ＣＨ３（ＣＨ２）７－Ｏ－）による置換反応の際に脱離するものであれば特に限定されない。例えば、ハロゲン原子（具体的にはフッ素原子など）、トルエンスルホニルオキシ等が挙げられる。式中のＸＩＩＩ ｂで示される脱離基は、活性化基ＹＩＩＩの導入反応若しくは縮合反応時に脱離するものであれば特に限定されない。例えば、ハロゲン原子（好ましくはヨウ素原子、臭素原子など）、トリフルオロメタンスルホニルオキシ等が挙げられる。ＹＩＩＩで示される活性化基としてはリチウムやマグネシウム等の金属を含んだ置換基、若しくはケイ素やホウ素等の非金属元素を含む置換基があげられる。上記脱離基と活性化基は縮合反応の種類に応じて適切な組み合わせで用いられる。 (Wherein X III a and X III b represent a leaving group, Y III represents an activating group during the condensation reaction, and R III-1 has the same meaning as the symbol in general formula (III-1).)
The leaving group represented by X III a in the formula is not particularly limited as long as it is eliminated during the substitution reaction with the alkoxide ion (CH 3 (CH 2 ) 7 —O − ). For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned. The leaving group represented by X III b in the formula is not particularly limited as long as it is eliminated during the introduction reaction or condensation reaction of the activating group Y III . For example, a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyloxy and the like can be mentioned. The activating group represented by Y III substituent containing metal such as lithium or magnesium, or a substituted group containing a silicon or non-metallic elements such as boron and the like. The above leaving group and activating group are used in an appropriate combination depending on the type of condensation reaction.
　第一工程は４位に脱離基ＸＩＩＩ ａのついた安息香酸誘導体（ＩＩＩ－ＩＩ－１）とｎ－ヘプタノールの縮合により４位にｎ－ヘプチルオキシ基を導入し、中間体（ＩＩＩ－ＩＩ－２）を得る反応である。本工程はＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシド等の極性溶媒や、テトラヒドロフラン等のエーテル系溶媒中、塩基の存在下、行うことができる。塩基としては、水素化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基、カリウムｔ－ブトキシド等のアルコキシド、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン等の有機塩基を用いて行うことができる。反応条件としては、氷冷下～１００℃程度で１０分～１０時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 In the first step, an n-heptyloxy group is introduced into the 4-position by condensation of a benzoic acid derivative (III-II-1) with a leaving group X III a at the 4-position and n-heptanol, and an intermediate (III- II-2) is obtained. This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第二工程は中間体（ＩＩＩ－ＩＩ－２）のカルボン酸部分を脱離基ＸＩＩＩ ｂへと変換し中間体（ＩＩＩ－ＩＩ－３）を得る反応である。本工程は、カルボン酸をクルチウス転位反応又はシュミット反応等を用い、アミン化合物へと変換した後、ザンドマイヤー反応等を用いて、脱離基ＸＩＩＩ ｂを有する化合物を得る反応である。反応条件としては、通常のクルチウス転位反応やシュミット反応、ザンドマイヤー反応の条件を用いることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is a reaction in which the carboxylic acid moiety of intermediate (III-II-2) is converted to leaving group X III b to obtain intermediate (III-II-3). This step is a reaction in which a carboxylic acid is converted into an amine compound using a Curtius rearrangement reaction or a Schmitt reaction, and then a compound having a leaving group X III b is obtained using a Sandmeyer reaction or the like. As the reaction conditions, normal Curtius rearrangement reaction, Schmitt reaction, and Sandmeyer reaction conditions can be used. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は脱離基ＸＩＩＩ ｂを有する化合物（ＩＩＩ－ＩＩ－３）を活性化基ＹＩＩＩを有する中間体（ＩＩＩ－ＩＩ－４）へと変換する反応である。本工程の条件は、ＹＩＩＩの種類に応じて適切なものが選ばれるが、例えばＹＩＩＩがホウ酸エステルの場合、次のような条件を用いることができる。溶媒には１，４－ジオキサンやテトラヒドロフラン等のエーテル系溶媒やＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシドといった極性溶媒を用い、塩基及びパラジウム触媒の存在下、反応を行うことができる。塩基としては、酢酸カリウムやジイソプロピルエチルアミンといった有機塩基、炭酸セシウムやリン酸三カリウム等の無機塩基を用いることができる。パラジウム触媒としては、ジクロロビス（トリシクロヘキシルホスフィン）パラジウム（ＩＩ）やジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）等のパラジウム錯体を用いることができる。また、酢酸パラジウム等のパラジウム化合物とトリｔ－ブチルホスフィン等の反応補助剤を組み合わせて用いることもできる。ホウ酸試薬としては、ビス（ネオペンチルグリコラート）ジボロンやビスピナコラートジボロン等のジボロン化合物を用いることができる。反応条件としては、室温～還流で３０分～２４時間程度が例示される。反応後は、通常の方法により抽出、洗浄、乾燥、溶媒除去等を行い、必要に応じてシリカゲルカラムクロマトグラフィー、再結晶等により精製を行うことによって目的物を得ることができる。 The third step is a reaction for converting the compound (III-II-3) having a leaving group X III b into an intermediate (III-II-4) having an activating group Y III . Conditions of this step is according to the type of Y III it is appropriate selected, for example, Y III is the case of boric acid esters can be used the following conditions. The solvent can be an ether solvent such as 1,4-dioxane or tetrahydrofuran, or a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, and the reaction can be carried out in the presence of a base and a palladium catalyst. As the base, an organic base such as potassium acetate or diisopropylethylamine, or an inorganic base such as cesium carbonate or tripotassium phosphate can be used. As the palladium catalyst, palladium complexes such as dichlorobis (tricyclohexylphosphine) palladium (II) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) can be used. Further, a palladium compound such as palladium acetate and a reaction aid such as tri-t-butylphosphine can be used in combination. As the boric acid reagent, diboron compounds such as bis (neopentyl glycolate) diboron and bispinacolato diboron can be used. Examples of the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours. After the reaction, the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.
　第四工程は活性化基ＹＩＩＩを有する中間体（ＩＩＩ－ＩＩ－４）をシクロペンタノンを有する中間体（ＩＩＩ－ＩＩ－５）へと変換する反応である。本工程の条件は、ＹＩＩＩがホウ酸エステルの場合、一般的な共役付加反応の条件を用いることができる。具体的には１，２－ジメトキシエタンやテトラヒドロフラン等のエーテル系溶媒やトルエン等の炭化水素溶媒、Ｎ，Ｎ－ジメチルホルムアミド等の高極性溶媒中、炭酸セシウム、リン酸三カリウム等の塩基及びパラジウム触媒の存在下、反応を行うことができる。また、テトラヒドロフランと水、１，２－ジメトキシエタンと水のような含水系若しくは二相系の溶媒中、水酸化ナトリウム、炭酸ナトリウム、水酸化タリウム等の塩基及びパラジウム触媒の存在下、反応を行うこともできる。さらに、場合に応じて２－ジシクロへキシルホスフィノ－２’，６’－ジメトキシビフェニルや２－（ジｔ－ブチルホスフィノ）ビフェニルといった反応補助剤を加えることができる。反応条件としては、室温～還流で３０分～２４時間程度が例示される。反応後は、通常の方法により抽出、洗浄、乾燥、溶媒除去等を行い、必要に応じてシリカゲルカラムクロマトグラフィー、再結晶等により精製を行うことによって目的物を得ることができる。 The fourth step is a reaction for converting an intermediate (III-II-4) having an activating group Y III into an intermediate (III-II-5) having a cyclopentanone. As the conditions for this step, when Y III is a boric acid ester, general conjugate addition reaction conditions can be used. Specifically, in ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbon solvents such as toluene, and high polar solvents such as N, N-dimethylformamide, bases such as cesium carbonate and tripotassium phosphate, and palladium The reaction can be carried out in the presence of a catalyst. In addition, the reaction is carried out in a water-containing or two-phase solvent such as tetrahydrofuran and water, 1,2-dimethoxyethane and water in the presence of a base such as sodium hydroxide, sodium carbonate, thallium hydroxide and a palladium catalyst. You can also. Furthermore, a reaction aid such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl or 2- (di-t-butylphosphino) biphenyl can be added depending on the case. Examples of the reaction conditions include room temperature to reflux and about 30 minutes to 24 hours. After the reaction, the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.
　第五工程はシクロペンタノンを有する中間体（ＩＩＩ－ＩＩ－５）を本発明化合物（ＩＩＩ－Ｉ－１）へと変換する反応である。本工程は、ケトン部分をＢｕｃｈｅｒｅｒ－Ｂｕｒｇｓ法等を用いて、ヒダントインに変換した後加水分解しアミノ酸へと導き、続くカルボン酸の還元によりアミノアルコールを得る反応である。ヒダントインに変換する工程の反応条件としては、０℃～６０℃で３０分～４８時間程度が挙げられる。次の加水分解は、塩酸や硫酸等の酸や、水酸化カリウム等の塩基を用いて行うことができ、その反応条件としては、８０℃～１２０℃で３０分～４８時間程度が挙げられる。続くカルボン酸からアルコールへの還元は一般な方法を用いることにより行うことができる。具体的には、水素化ジイソブチルアルミニウム等の金属水素化物、水素化リチウムアルミニウム等の金属水素錯化合物による還元、ジボラン及び置換ボランによる還元等を挙げることができる。反応条件としては、－７８℃～１００℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＩＩ－１）及び（ＩＩＩ－２）で表される化合物のうち、ＲＩＩＩ－２が水素原子、ＸＩＩＩ－１が酸素原子、ＹＩＩＩ－１がメチレン、ＸＩＩＩ－２がメチン、ＡＩＩＩ－２がメチレン、ＢＩＩＩがメチレンで、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ、ＸＩＩＩ－２及びアミノ基の結合している炭素原子とともにシクロペンタンを形成しているその他の化合物も同様の方法によって合成することができる。 The fifth step is a reaction for converting the intermediate (III-II-5) having cyclopentanone into the compound (III-I-1) of the present invention. This step is a reaction in which the ketone moiety is converted to hydantoin using the Bucherer-Burgs method or the like, then hydrolyzed to amino acid, and then the amino acid is obtained by reduction of the carboxylic acid. The reaction conditions for the step of converting to hydantoin include a temperature of 0 ° C. to 60 ° C. for about 30 minutes to 48 hours. The subsequent hydrolysis can be carried out using an acid such as hydrochloric acid or sulfuric acid, or a base such as potassium hydroxide, and the reaction conditions include 80 ° C. to 120 ° C. for 30 minutes to 48 hours. The subsequent reduction from carboxylic acid to alcohol can be carried out by using a general method. Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like. The reaction conditions include −78 ° C. to 100 ° C. for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (III-1) and (III-2), R III-2 is a hydrogen atom, X III-1 is an oxygen atom, Y III-1 is methylene, X III-2 Is methine, A III-2 is methylene, B III is methylene, B III is bonded to A III-2, and together with Y III , X III-2 and the carbon atom to which the amino group is bonded, forms cyclopentane. Other compounds can also be synthesized by the same method.
　２０）本発明化合物のうち、一般式（ＩＩＩ－１）中のＲＩＩＩ－２がＰ（＝Ｏ）（ＯＨ）２である化合物（ＩＩＩ－Ｉ－２）は以下のスキーム（ＩＩＩ－ＩＩＩ）により合成される。 20) Among the compounds of the present invention, the compound (III-I-2) in which R III-2 in the general formula (III-1) is P (═O) (OH) 2 is represented by the following scheme (III-III) Is synthesized.
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
（式中、ＸＩＩＩ－１、ＸＩＩＩ－２、ＹＩＩＩ－１、ＡＩＩＩ－１、ＡＩＩＩ－２、ＢＩＩＩ及びＲＩＩＩ－１は一般式（ＩＩＩ－１）における記号と同義である。） (Wherein X III-1 , X III-2 , Y III-1 , A III-1 , A III-2 , B III and R III-1 are as defined in the general formula (III-1)) .)
　この工程は公知（ＷＯ２００７／０６９７１２号公報、５３～５６ページ）の合成法によって、本発明化合物（ＩＩＩ－Ｉ－２）を得るものである。上記の公知の合成法を用いて、アルコール体（ＩＩＩ－ＩＩＩ－１）から三段階でリン酸化体（ＩＩＩ－Ｉ－２）を合成することができる。一般式（ＩＩＩ－２）中のＲＩＩＩ－２がＰ（＝Ｏ）（ＯＨ）２である化合物も同様の方法によって合成することができる。 In this step, the compound (III-I-2) of the present invention is obtained by a known synthesis method (WO 2007/069712, pages 53 to 56). The phosphorylated form (III-I-2) can be synthesized from the alcohol form (III-III-1) in three steps using the above-mentioned known synthesis method. A compound in which R III-2 in General Formula (III-2) is P (═O) (OH) 2 can also be synthesized by the same method.
　２１）本発明化合物のうち、一般式（ＩＶ－１）中のＲＩＶ－３が水素原子、ＲＩＶ－２が炭素数１～４のアルキル、炭素数１～２０のアシル又は炭素数２～２１のアルコキシカルボニルで表される化合物（ＩＶ－Ｉ－１）は以下のスキーム（ＩＶ－ＩＩ）により合成される。 21) Among the compounds of the present invention, R IV-3 in the general formula (IV-1) is a hydrogen atom, R IV-2 is alkyl having 1 to 4 carbons, acyl having 1 to 20 carbons, or 2 to Compound (IV-I-1) represented by 21 alkoxycarbonyl is synthesized by the following scheme (IV-II).
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
（式中、ＲＩＶ－１、ＲＩＶ－４、ＸＩＶ及びＡＩＶ－１は一般式（ＩＶ－１）における各記号と同義であり、ＲＩＶ ａは炭素数１～４のアルキル、炭素数１～２０のアシル又は炭素数２～２１のアルコキシカルボニルを示す。） (Wherein R IV-1 , R IV-4 , X IV and A IV-1 have the same meanings as those in the general formula (IV-1), and R IV a is alkyl having 1 to 4 carbon atoms, carbon Represents an acyl having 1 to 20 carbon atoms or an alkoxycarbonyl having 2 to 21 carbon atoms.)
　本工程は本発明化合物のうち１級アミノ基を有する化合物（ＩＶ－ＩＩ－１）のアミノ基をアルキル化、アシル化又はアルコキカルボニル化することにより本発明化合物（ＩＶ－Ｉ－１）を得るものである。アミノ基のアルキル化には、還元的アミノ化反応やハロゲン化アルキルと塩基を用いたアミンのアルキル化反応を用いることができる。還元的アミノ化反応を用いる場合、ＲＩＶ ａの炭素数と同じ炭素数を有するアルデヒドと化合物（ＩＶ－ＩＩ－１）をメタノール等のアルコール系溶媒やジクロロエタン等のハロゲン系溶媒中、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム等の還元剤を用いて反応させることにより、目的物を得ることができる。還元には、水素とラネーニッケルや酸化白金等の触媒を用いて行うこともできる。またこの反応は、シッフ塩基の生成と還元反応を逐次行うこともできる。この還元的アミノ化反応には、反応促進剤として酢酸等の酸を加えることができる。反応条件としては、氷冷下～５０℃程度で３０分～１０時間程度が例示される。反応後は、通常の方法により精製等を行い、目的物を得ることができる。ＲＩＶ ａがメチルの時には、ギ酸とホルムアルデヒド、又はホルムアルデヒドと水素化シアノホウ素ナトリウム等の還元剤を用いたＥｓｃｈｗｅｉｌｅｒ－Ｃｌａｒｋｅのメチル化反応を用いることもできる。アミノ基のアシル化又はアルコキシカルボニル化には、通常のアミノ基アシル化反応又はアルコキシカルボニル化反応を用いて行うことができる。具体的には、メタノール等のアルコール中、又は水と酢酸エチルやクロロホルム等の有機溶媒の二相系若しくは混合液中で行うことができる。用いられる試薬としては塩化アセチル、塩化ステアロイルや塩化ベンジルオキシカルボニル等の酸塩化物、無水酢酸やジ－ｔ－ブチルジカルボナート等の酸無水物が挙げられる。本反応には反応促進剤として、トリエチルアミン等の有機塩基又は重曹等の無機塩基を加えることができる。反応条件としては、氷冷下～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＶ－２）中の、ＲＩＶ－３が水素原子、ＲＩＶ－２が炭素数１～４のアルキル、炭素数１～２０のアシル又は炭素数２～２１のアルコキシカルボニルで表される化合物も同様の方法によって合成することができる。 This step comprises subjecting the compound (IV-I-1) of the present invention by alkylating, acylating or alkoxycarbonylating the amino group of the compound (IV-II-1) having a primary amino group. To get. For the alkylation of the amino group, a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used. When a reductive amination reaction is used, an aldehyde having the same carbon number as that of R IV a and the compound (IV-II-1) are mixed with borohydride in an alcohol solvent such as methanol or a halogen solvent such as dichloroethane. The target product can be obtained by reacting with a reducing agent such as sodium, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide. In this reaction, the generation of a Schiff base and the reduction reaction can also be sequentially performed. In this reductive amination reaction, an acid such as acetic acid can be added as a reaction accelerator. Examples of reaction conditions are about 30 minutes to 10 hours at about 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R IV a is methyl, an Eschweiler-Clarke methylation reaction using a reducing agent such as formic acid and formaldehyde or formaldehyde and sodium cyanoborohydride can also be used. The acylation or alkoxycarbonylation of an amino group can be performed using a normal amino group acylation reaction or alkoxycarbonylation reaction. Specifically, it can be carried out in an alcohol such as methanol, or in a two-phase system or a mixture of water and an organic solvent such as ethyl acetate or chloroform. Examples of the reagent used include acid chlorides such as acetyl chloride, stearoyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In general formula (IV-2), R IV-3 is a hydrogen atom, R IV-2 is alkyl having 1 to 4 carbons, acyl having 1 to 20 carbons, or alkoxycarbonyl having 2 to 21 carbons. The compounds represented can also be synthesized by the same method.
　２２）本発明化合物のうち、一般式（ＩＶ－１）中のＲＩＶ－２が水素原子で表される化合物（ＩＶ－Ｉ－２）は以下のスキーム（ＩＶ－ＩＩＩ）により合成される。 22) Among the compounds of the present invention, the compound (IV-I-2) in which R IV-2 in the general formula (IV-1) is a hydrogen atom is synthesized according to the following scheme (IV-III).
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
（式中、ＸＩＶ、ＡＩＶ－１、ＲＩＶ－１、ＲＩＶ－３及びＲＩＶ－４は一般式（ＩＶ－１）における各記号と同義であり、ＲＩＶ ｂは保護基を示す。）
　式中のＲＩＶ ｂで示される保護基はアミノ基を保護するものであれば特に限定されない。例えば、アシル（好ましくは炭素数２～４程度のもの、具体的にはアセチルなど）、カルバメート（具体的にはｔ－ブチルオキシカルボニルやベンジルオキシカルボニルなど）等が挙げられる。 (Wherein X IV , A IV-1 , R IV-1 , R IV-3 and R IV-4 have the same meanings as those in formula (IV-1), and R IV b represents a protecting group) .)
The protecting group represented by R IV b in the formula is not particularly limited as long as it protects the amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned.
　第一工程は本発明化合物のうち１級アミノ基を有する化合物（ＩＶ－ＩＩ－１）のアミノ基を保護することによってアミノ基保護体（ＩＶ－ＩＩＩ－１）を合成するものである。本工程は通常のアミノ基保護反応を用いて行うことができる。具体的には、保護基ＲＩＶ ｂとしてアシル、アルキルオキシカルボニル又はベンジルオキシカルボニル等を用いる場合、本工程はメタノール等のアルコール中、又は水と酢酸エチルやクロロホルム等の有機溶媒の二相系又は混合液中で行うことができる。用いられる試薬としては塩化アセチルや塩化ベンジルオキシカルボニル等の酸塩化物、無水酢酸やジ－ｔ－ブチルジカルボナート等の酸無水物が挙げられる。本反応には反応促進剤として、トリエチルアミン等の有機塩基又は重曹等の無機塩基を加えることができる。反応条件としては、氷冷下～５０℃で３０分～２４時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。また、ＲＩＶ－４に水酸基を含む場合、その水酸基もアシル、アルコキシカルボニル、ベンジル等の適切な保護基で保護しておくことができる。 The first step is to synthesize an amino group protected compound (IV-III-1) by protecting the amino group of the compound (IV-II-1) having a primary amino group among the compounds of the present invention. This step can be performed using a normal amino group protecting reaction. Specifically, when acyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like is used as the protecting group R IV b , this step is performed in a two-phase system of an alcohol such as methanol or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture. Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In addition, when R IV-4 contains a hydroxyl group, the hydroxyl group can also be protected with an appropriate protecting group such as acyl, alkoxycarbonyl, benzyl and the like.
　第二工程はアミノ基保護体（ＩＶ－ＩＩＩ－１）の水酸基をリンを含んだ置換基ＲＩＶ－３へと変換するものである。本工程はＲＩＶ－３の種類によって適切な試薬と条件が選ばれる。例えばＲＩＶ－３がビス(ピバロイルオキシメチル)ホスホリル基の場合、ビス(ピバロイルオキシメチル)ホスホリルクロリドとトリエチルアミンの組み合わせ等を用いることができ、ＲＩＶ－３がビス（Ｓ－アセチル－２－チオエチル）ホスホリル基の場合、ビス（Ｓ－アセチル－２－チオエチル）－Ｎ，Ｎ－ジイソプロピルホスホルアミダイトと１Ｈ－テトラゾールを作用させた後メタクロロ過安息香酸によって酸化する方法等を挙げることができる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。 The second step is to convert the hydroxyl group of the protected amino group (IV-III-1) into a substituent R IV-3 containing phosphorus. In this step, appropriate reagents and conditions are selected depending on the type of RIV-3 . For example, when R IV-3 is a bis (pivaloyloxymethyl) phosphoryl group, a combination of bis (pivaloyloxymethyl) phosphoryl chloride and triethylamine can be used, and R IV-3 can be bis (S-acetyl). In the case of a -2-thioethyl) phosphoryl group, mention is made of a method in which bis (S-acetyl-2-thioethyl) -N, N-diisopropyl phosphoramidite and 1H-tetrazole are reacted and then oxidized with metachloroperbenzoic acid. Can do. After the reaction, purification or the like can be performed by a usual method to obtain the target product.
　第三工程は中間体（ＩＶ－ＩＩＩ－２）の保護基を脱保護することによって、本発明化合物（ＩＶ－Ｉ－２）を得る反応である。脱保護の条件としては、通常の保護基の脱保護に用いられるものであれば特に限定されない。例えば、ＲＩＶ ｂがアセチル等のアシルであればアルコール系溶媒と水との混合溶媒中で水酸化ナトリウム等の無機塩基を用いた方法、ｔ－ブチルオキシカルボニル等の保護基であれば、塩酸やトリフルオロ酢酸等の酸を用いた方法等が挙げられる。反応条件としては、エタノール等のアルコール性溶媒やテトラヒドロフラン等のエーテル系溶媒、水、又はそれらの混合溶媒中、氷冷下～８０℃で１０分～１２時間程度が挙げられる。反応後は、通常の方法により精製等を行い、目的物を得ることができる。なお、一般式（ＩＶ－２）で表される化合物のうち、ＲＩＶ－２が水素原子である化合物も、同様の方法で合成することができる。 The third step is a reaction for obtaining the compound (IV-I-2) of the present invention by deprotecting the protecting group of the intermediate (IV-III-2). The deprotection conditions are not particularly limited as long as they are used for deprotection of ordinary protecting groups. For example, if R IV b is acyl such as acetyl, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, or hydrochloric acid if it is a protecting group such as t-butyloxycarbonyl And a method using an acid such as trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formula (IV-2), a compound in which R IV-2 is a hydrogen atom can also be synthesized by the same method.
　２３）発明化合物のうち、一般式（Ｖ）中のＶＶが－ＣＨ２－ＶＶ ａ－（ここでＶＶ ａは単結合又は置換基を有していても良い炭素数１～５のアルキレンを示す）、ＹＶが－ＮＲＶ－５ ａ－（ここでＲＶ－５ ａは水素原子、置換基を有していても良い炭素数１～６のアルキルを示す）で表される化合物（Ｖ－Ｉ－１）、又は、
ＶＶが－ＣＨ２－ＶＶ ａ－（ここでＶＶ ａは単結合又は置換基を有しても良い炭素数１～５のアルキレンを示す）、ＹＶが単結合、ｎＶが１であり、ＢＶ－（ＺＶ）ｎＶ
－が下記一般式 23) Among the compounds of the invention, V V in the general formula (V) is —CH 2 —V V a — (where V V a is a single bond or a C 1-5 which may have a substituent) Y V represents —NR V-5 a — (wherein R V-5 a represents a hydrogen atom or an alkyl having 1 to 6 carbon atoms which may have a substituent). Compound (VI-1) or
V V is —CH 2 —V V a — (where V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent), Y V is a single bond, and n V is 1 And B V − (Z V ) n V
-Is the following general formula
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
（ここで、当該式で表される基は任意の位置に置換基ＢＶを有する含窒素ヘテロシクロアルキルを示す）
で表される基である化合物（Ｖ－Ｉ－２）は以下のスキーム（Ｖ－ＩＩ）により合成することができる。 (Here, the group represented by the formula represents a nitrogen-containing heterocycloalkyl having a substituent B V at any position)
Compound (VI-2), which is a group represented by the following formula, can be synthesized by the following scheme (V-II).
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
（式中、ＡＶ、ＢＶ、ＲＶ－１、ＺＶ、ＸＶ、ｎＶは一般式（Ｖ）における各記号と同義である。 (In the formula, A V , B V , R V-1 , Z V , X V , and n V are synonymous with each symbol in the general formula (V).
　工程（Ｖ－ＩＩ－１）及び工程（Ｖ－ＩＩ－２）は、化合物（Ｖ－ＩＩ－１）と化合物（Ｖ－ＩＩ－２）又は化合物（Ｖ－ＩＩ－３）とを反応させた後に還元して化合物（Ｖ－Ｉ－１）又は化合物（Ｖ－Ｉ－２）を得る工程である。この反応は、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム等の存在下、メタノール、エタノール、ジクロロメタン、１，２－ジクロロエタン、テトラヒドロフラン、アセトニトリル、１，４－ジオキサン等の不活性溶媒中で行なわれる。必要に応じて酸性触媒、例えば酢酸、ｐ－トルエンスルホン酸、三フッ化ホウ素・ジエチルエーテル錯体等を添加しても良く、また必要に応じて相間移動触媒、例えば水酸化テトラ－ｎ－ブチルアンモニウム等を添加しても良い。通常０～１００℃の温度下で、１０分～２０時間で行なわれる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、これらを適切な保護基で保護した後、スキーム（Ｖ－ＩＩ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－１）又は化合物（Ｖ－Ｉ－２）を得る。 In step (V-II-1) and step (V-II-2), compound (V-II-1) was reacted with compound (V-II-2) or compound (V-II-3). In this step, compound (VI-1) or compound (VI-2) is obtained by subsequent reduction. This reaction is carried out in the presence of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. in the presence of methanol, ethanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, etc. It is carried out in an active solvent. If necessary, an acidic catalyst such as acetic acid, p-toluenesulfonic acid, boron trifluoride / diethyl ether complex may be added. If necessary, a phase transfer catalyst such as tetra-n-butylammonium hydroxide is used. Etc. may be added. Usually, it is carried out at a temperature of 0 to 100 ° C. for 10 minutes to 20 hours. When X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (VII) is carried out to remove the compound (VI -1) or compound (VI-2).
　２４）発明化合物のうち、一般式（Ｖ）中のＹＶが二重結合、ｎＶが０であり、ＢＶがＣＯＯＲＶ－６で表される化合物（Ｖ－Ｉ－３）及び化合物（Ｖ－Ｉ－４）は以下のスキーム（Ｖ－ＩＩＩ）により合成することができる。 24) Among the compounds of the invention, the compound (VI-3) and the compound (V) in which Y V in the general formula (V) is a double bond, n V is 0, and B V is COOR V-6 VI-4) can be synthesized by the following scheme (V-III).
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
（式中、ＲＶ－６ ａは一般式（Ｖ）で定義されるＲＶ－６のうち水素原子を除く基を示す。ＰＲＶ－６ ｂはリンを含む脱離基を示す。ＡＶ、ＲＶ－１、ＶＶ、ＸＶは一般式（Ｖ）における各記号と同義である。） (In the formula, R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V). PR V-6 b represents a leaving group containing phosphorus. A V , R V-1 , V V , and X V have the same meanings as the symbols in general formula (V).)
　工程（Ｖ－ＩＩＩ－１）は、化合物（Ｖ－ＩＩＩ－１）と化合物（Ｖ－ＩＩＩ－２）との反応により、アルケンを得る工程である。ＰＲＶ－６ ｂがトリアリールホスホニウムの場合、通常のＷｉｔｔｉｇ反応の条件が用いられる。例えば、化合物（Ｖ－ＩＩＩ－２）をナトリウムエトキシド、カリウムｔ－ブトキシド、水素化ナトリウム等の塩基で処理することによりイリドを発生させ、これと化合物（Ｖ－ＩＩＩ－１）とを反応させることにより、化合物（Ｖ－Ｉ－３）を得る。通常－３０℃から還流の条件で３０分から１２時間程度反応させる。ＰＲＶ－６ ｂがＰ（Ｏ）（ＯＲＶ－６ ｃ）２（ＲＶ－６ ｃは炭素数１から４のアルキルを示す）の場合、通常のＨｏｒｎｅｒ－Ｗａｄｓｗｏｒｔｈ－Ｅｍｍｏｎｓ反応の条件が用いられる。例えば、水素化ナトリウム、ナトリウムエトキシド等の塩基を化合物（Ｖ－ＩＩＩ－２）と反応させた後、これと化合物（Ｖ－ＩＩＩ－１）とを反応させることより化合物（Ｖ－Ｉ－３）を得る。通常－２０℃から還流で３０分から１２時間程度反応させる。その場合オレフィンはＥ体を優先的に得ることができる。
　工程（Ｖ－ＩＩＩ－２）は、加水分解によりカルボン酸（Ｖ－Ｉ－４）を得る工程である。反応条件は、エタノール、テトラヒドロフラン等の溶媒中、水酸化ナトリウム水溶液等を作用させる条件が用いられる。通常０℃から還流で１時間から４８時間程度反応させる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、これらを適切な保護基で保護した後、スキーム（Ｖ－ＩＩＩ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－３）または化合物（Ｖ－Ｉ－４）を得る。 Step (V-III-1) is a step of obtaining an alkene by reaction of compound (V-III-1) and compound (V-III-2). When PR V-6 b is triarylphosphonium, normal Wittig reaction conditions are used. For example, the compound (V-III-2) is treated with a base such as sodium ethoxide, potassium t-butoxide, sodium hydride to generate an ylide, and this is reacted with the compound (V-III-1). Thus, compound (VI-3) is obtained. Usually, the reaction is carried out for 30 minutes to 12 hours under the condition of -30 ° C to reflux. When PR V-6 b is P (O) (OR V-6 c ) 2 (R V-6 c represents alkyl having 1 to 4 carbon atoms), the conditions of the normal Horner-Wadsworth-Emmons reaction are used. It is done. For example, after reacting a base such as sodium hydride or sodium ethoxide with compound (V-III-2), this is reacted with compound (V-III-1) to give compound (VI-3 ) Usually, the reaction is performed at −20 ° C. under reflux for about 30 minutes to 12 hours. In that case, the olefin can preferentially obtain E form.
Step (V-III-2) is a step of obtaining carboxylic acid (VI-4) by hydrolysis. As the reaction conditions, conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used. The reaction is usually carried out at 0 ° C. under reflux for about 1 to 48 hours. When X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (V-III) is carried out to remove the compound (VI -3) or compound (VI-4).
　２５）発明化合物のうち、一般式（Ｖ）中のＹＶが単結合、ｎＶが１であり、ＺＶがエチレン、ＢＶがＣＯＯＲＶ－６で表される化合物（Ｖ－Ｉ－５）および化合物（Ｖ－Ｉ－６）は以下のスキーム（Ｖ－ＩＶ）により合成することができる。 25) Of the invention compounds of the general formula (V) Y V is a single bond in the, n V is 1, compound Z V is ethylene, the B V is represented by COOR V-6 (V-I -5 ) And compound (VI-6) can be synthesized by the following scheme (V-IV).
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
（式中、ＲＶ－６ ａは一般式（Ｖ）で定義されるＲＶ－６のうち水素原子を除く基を示す。ＡＶ、ＲＶ－１、ＶＶ、ＸＶは一般式（Ｖ）における各記号と同義である。） (Wherein R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V). A V , R V-1 , V V , and X V represent the general formula ( It is synonymous with each symbol in V).
　工程（Ｖ－ＩＶ－１）及び工程（Ｖ－ＩＶ－３）は、化合物（Ｖ－Ｉ－３）又は化合物（Ｖ－Ｉ－４）を還元することにより、化合物（Ｖ－Ｉ－５）又は化合物（Ｖ－Ｉ－６）を得る工程である。反応条件は通常行なわれている条件であれば特に限定されないが、例えば、パラジウム、白金、ニッケル等触媒として用いた接触還元が挙げられる。この場合通常、エタノール等のアルコール系溶媒、ジオキサン等のエーテル系溶媒、又はトルエン等の炭化水素溶媒中水素雰囲気下０℃から還流温度で行なわれる。
　工程（Ｖ－ＩＶ－２）は、加水分解によりエステル（Ｖ－Ｉ－５）から、カルボン酸（Ｖ－Ｉ－６）を得る工程である。反応条件は、エタノール、テトラヒドロフラン等の溶媒中、水酸化ナトリウム水溶液等を作用させる条件が用いられる。通常０℃から還流で１時間から４８時間程度反応させる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、必要に応じてこれらを適切な保護基で保護した後、スキーム（Ｖ－ＩＶ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－５）又は化合物（Ｖ－Ｉ－６）を得る。 In step (V-IV-1) and step (V-IV-3), compound (VI-5) is obtained by reducing compound (VI-3) or compound (VI-4). Alternatively, it is a step of obtaining the compound (VI-6). The reaction conditions are not particularly limited as long as they are usually performed, and examples include catalytic reduction using a catalyst such as palladium, platinum, or nickel. In this case, the reaction is usually carried out at a reflux temperature from 0 ° C. in a hydrogen atmosphere in an alcohol solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene.
Step (V-IV-2) is a step for obtaining carboxylic acid (VI-6) from ester (VI-5) by hydrolysis. As the reaction conditions, conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used. The reaction is usually carried out at 0 ° C. under reflux for about 1 to 48 hours. In the case where X V -A V contains an —NH— structure or a carbonyl structure, the compound is protected by carrying out the step of scheme (V-IV) and deprotecting, if necessary, after protecting with an appropriate protecting group. (VI-5) or compound (VI-6) is obtained.
　２６）発明化合物のうち、一般式（Ｖ）中のＹＶが－ＮＲＶ－５ＣＯ－、ＢＶがＣＯＯＲＶ－６で表される化合物（Ｖ－Ｉ－７）及び化合物（Ｖ－Ｉ－８）、又は、ＹＶが－ＣＯ－、ｎＶが１であり、ＢＶ－ＺＶ－が下記一般式 26) Among the compounds of the invention, the compound (VI-7) and the compound (VI) in which Y V in the general formula (V) is represented by —NR V-5 CO— and B V is represented by COOR V-6 -8), or Y V is —CO—, n V is 1, and B V —Z V — is the following general formula
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
（ここで、当該式で表される基は任意の位置に置換基ＣＯＯＲＶ－６を有する含窒素ヘテロシクロアルキルを示す。）
で表される基である化合物（Ｖ－Ｉ－９）及び化合物（Ｖ－Ｉ－１０）は以下のスキーム（Ｖ－Ｖ）により合成することができる。 (Here, the group represented by the formula represents a nitrogen-containing heterocycloalkyl having a substituent COOR V-6 at an arbitrary position.)
The compound (VI-9) and the compound (VI-10), which are groups represented by the following formula, can be synthesized by the following scheme (VV).
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
（式中、ＲＶ－６ ａは一般式（Ｖ）で定義されるＲＶ－６のうち水素原子を除く基を示す。ＡＶ、ＲＶ－１、ＲＶ－５、ＶＶ、ＸＶ、ＺＶ、ｎＶは一般式（Ｖ）における各記号と同義である。） (In the formula, R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V). A V , R V-1 , R V-5 , V V , X V 1 , Z V , and n V have the same meanings as symbols in the general formula (V).
　工程（Ｖ－Ｖ－１）及び工程（Ｖ－Ｖ－３）は、化合物（Ｖ－Ｖ－１）と化合物（Ｖ－Ｖ－２）又は化合物（Ｖ－Ｖ－３）との反応によりアミド化合物（Ｖ－Ｉ－７）又は（Ｖ－Ｉ－９）を得る工程である。カルボン酸を活性化する縮合剤として、例えばジシクロヘキシルカルボジイミド、Ｎ－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド又はその塩酸塩等が挙げられる。これらの縮合剤を単独で、あるいはＮ－ヒドロキシスクシンイミド、ヒドロキシベンゾトリアゾール、４－ジメチルアミノピリジン等の添加剤を組み合わせて用いる。通常、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミド等の不活性溶媒中、－３０℃から８０℃の温度で行なわれる。また、化合物（Ｖ－Ｖ－１）をチオニルクロリド、オキサリルクロリド等で酸クロリドに変換した後、化合物（Ｖ－Ｖ－２）又は化合物（Ｖ－Ｖ－３）と反応させても良い。酸クロリドへの変換は、例えばジクロロメタン等の不活性溶媒中、－３０℃から還流温度で行なわれる。Ｎ，Ｎ－ジメチルホルムアミドを添加しても良い。酸クロリドと化合物（Ｖ－Ｖ－２）又は（Ｖ－Ｖ－３）との反応は、例えばジクロロメタン等の不活性溶媒中、トリエチルアミン等の塩基の存在下、－３０℃から還流温度で行なわれる。
　工程（Ｖ－Ｖ－２）及び工程（Ｖ－Ｖ－４）は、化合物（Ｖ－Ｉ－７）又は（Ｖ－Ｉ－９）から加水分解反応によりカルボン酸（Ｖ－Ｉ－８）、又は（Ｖ－Ｉ－１０）を得る工程である。エタノール、テトラヒドロフラン等の溶媒中、水酸化ナトリウム水溶液等を作用させる条件が用いられる。通常０℃から還流温度で１時間から４８時間で行なわれる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、必要に応じてこれらを適切な保護基で保護した後、スキーム（Ｖ－Ｖ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－７）、化合物（Ｖ－Ｉ－８）、化合物（Ｖ－Ｉ－９）又は化合物（Ｖ－Ｉ－１０）を得る。 Step (VV-1) and Step (VV-3) are carried out by reacting Compound (VV-1) with Compound (VV-2) or Compound (VV-3). In this step, compound (VI-7) or (VI-9) is obtained. Examples of the condensing agent that activates the carboxylic acid include dicyclohexylcarbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, and hydrochloride thereof. These condensing agents are used alone or in combination with additives such as N-hydroxysuccinimide, hydroxybenzotriazole, 4-dimethylaminopyridine and the like. Usually, it is carried out in an inert solvent such as dichloromethane and N, N-dimethylformamide at a temperature of −30 ° C. to 80 ° C. Alternatively, compound (VV-1) may be converted to acid chloride with thionyl chloride, oxalyl chloride or the like and then reacted with compound (VV-2) or compound (VV-3). Conversion to the acid chloride is carried out in an inert solvent such as dichloromethane, for example, from −30 ° C. to reflux temperature. N, N-dimethylformamide may be added. The reaction between the acid chloride and the compound (VV-2) or (VV-3) is carried out at −30 ° C. to reflux temperature in the presence of a base such as triethylamine in an inert solvent such as dichloromethane. .
In step (VV-2) and step (VV-4), carboxylic acid (VI-8) is obtained by hydrolysis reaction from compound (VI-7) or (VI-9). Alternatively, (VI-10) is obtained. Conditions in which an aqueous sodium hydroxide solution or the like is used in a solvent such as ethanol or tetrahydrofuran are used. Usually, it is carried out at 0 ° C. to reflux temperature for 1 hour to 48 hours. In the case where X V —A V contains an —NH— structure or a carbonyl structure, the compound is protected by carrying out the step of scheme (VV) after deprotection with an appropriate protecting group, if necessary, and then deprotecting (VI-7), compound (VI-8), compound (VI-9) or compound (VI-10) is obtained.
　２７）発明化合物のうち、一般式（Ｖ）中のＢＶ－（ＺＶ）ｎＶ－がＨＯＣＨ２－（ＺＶ）ｍＶ－（ここでｍＶは０～２を示す）で表される化合物（Ｖ－Ｉ－１１）は以下のスキーム（Ｖ－ＶＩ）により合成することができる。 27) Of the invention compounds of the general formula (V) in the B V - (Z V) nV - is HOCH 2 - (Z V) mV - ( compound represented by wherein m V is 0 to 2) (VI-11) can be synthesized by the following scheme (V-VI).
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
（式中、ＡＶ、ＲＶ－１、ＶＶ、ＸＶ、ＹＶ、ＺＶは一般式（Ｖ）における各記号と同義である。） (In the formula, A V , R V-1 , V V , X V , Y V , and Z V are synonymous with each symbol in the general formula (V).)
　工程（Ｖ－ＶＩ－１）は、化合物（Ｖ－ＶＩ－１）を還元することにより水酸基を有する化合物（Ｖ－Ｉ－１１）を得る工程である。反応条件は通常用いられているものであれば特に限定されないが、例えばテトラヒドロフラン等のエーテル系溶媒中、－３０℃から５０℃で、１０分から２４時間程度行なわれるジボラン及び置換ボランによる還元が挙げられる。ＸＶ－ＡＶに－ＮＨ－構造及びカルボニル構造を含む場合、必要に応じてこれを適切な保護基で保護した後、スキーム（Ｖ－ＶＩ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－１１）を得る。 Step (V-VI-1) is a step of obtaining compound (VI-11) having a hydroxyl group by reducing compound (V-VI-1). The reaction conditions are not particularly limited as long as they are usually used. Examples include reduction with diborane and substituted borane performed in an ether solvent such as tetrahydrofuran at −30 ° C. to 50 ° C. for about 10 minutes to 24 hours. . In the case where X V -A V contains an —NH— structure and a carbonyl structure, the compound is protected by carrying out the step of scheme (V-VI) after deprotection with an appropriate protecting group, if necessary, and then deprotected. (VI-11) is obtained.
　２８）発明化合物のうち、一般式（Ｖ）中のＢＶが－ＣＯ－ＮＨ－ＳＯ２－ＲＶ－９で表される化合物（Ｖ－Ｉ－１２）は以下のスキーム（Ｖ－ＶＩＩ）により合成することができる。 28) Among the compounds of the invention, the compound (VI-12) in which B V in the general formula (V) is represented by —CO—NH—SO 2 —R V-9 is represented by the following scheme (V-VII): Can be synthesized.
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
（式中、ＡＶ、ＲＶ－１、ＲＶ－９、ＶＶ、ＸＶ、ＹＶ、ＺＶ、ｎＶは、一般式（Ｖ）における各記号と同義である。） (In the formula, A V , R V-1 , R V-9 , V V , X V , Y V , Z V , and n V have the same meanings as those in the general formula (V).)
　工程（Ｖ－ＶＩＩ－１）は、カルボン酸化合物（Ｖ－ＶＩＩ－１）とスルホンアミド化合物（Ｖ－ＶＩＩ－２）との反応により、アシルスルホンアミド化合物（Ｖ－Ｉ－１２）を得る工程である。カルボン酸化合物を例えば１，１’－カルボニルジイミダゾールのような試薬により活性化した後、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エンのような塩基の存在下スルホンアミド化合物と反応させることにより、アシルスルホンアミド化合物を得る。反応条件は通常行なわれている条件であれば特に限定されないが、例えばテトラヒドロフランのような不活性溶媒中、－３０℃から還流温度で行なわれる。また、カルボン酸化合物とスルホンアミド化合物とを、ヨウ化２－クロロ－１－メチルピリジニウムのような縮合試薬共存下反応させることより、アシルスルホンアミド化合物を得ても良い。この場合も通常用いられる条件であれば特に限定されないが、例えばＮ，Ｎ－ジイソプロピルエチルアミン、４－ジメチルアミノピリジンのような塩基を単独であるいは数種の塩基を併用して、Ｎ，Ｎ’－ジメチルホルムアミドのような不活性溶媒中－３０℃から還流温度で行なわれる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、これらを適切な保護基で保護した後、スキーム（Ｖ－ＶＩＩ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－１２）を得る。 Step (V-VII-1) is a step of obtaining acyl sulfonamide compound (VI-12) by reaction of carboxylic acid compound (V-VII-1) with sulfonamide compound (V-VII-2). It is. After activating the carboxylic acid compound with a reagent such as 1,1′-carbonyldiimidazole, the sulfonamide compound in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene To give an acylsulfonamide compound. The reaction conditions are not particularly limited as long as they are usually performed. For example, the reaction is performed at −30 ° C. to reflux temperature in an inert solvent such as tetrahydrofuran. Alternatively, an acylsulfonamide compound may be obtained by reacting a carboxylic acid compound and a sulfonamide compound in the presence of a condensation reagent such as 2-chloro-1-methylpyridinium iodide. Also in this case, the conditions are not particularly limited as long as they are usually used. For example, a base such as N, N-diisopropylethylamine or 4-dimethylaminopyridine may be used alone or in combination with several bases. The reaction is performed at −30 ° C. to reflux temperature in an inert solvent such as dimethylformamide. When X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (V-VII) is carried out to remove the compound (VI -12) is obtained.
　２９）発明化合物のうち、一般式（Ｖ）中のＢＶが－Ｃ（＝ＮＯＨ）ＮＨ２で表される化合物（Ｖ－Ｉ－１３）又はＢＶが下記式 29) invention of the compounds of the general formula (V) in the B V is -C (= NOH) compound represented by NH 2 (V-I-13 ) or B V satisfies the following formula
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
で表される基である化合物（Ｖ－Ｉ－１４）は以下のスキーム（Ｖ－ＶＩＩＩ）により合成することができる。 Compound (VI-14), which is a group represented by the following formula, can be synthesized by the following scheme (V-VIII).
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
（式中、ＡＶ、ＲＶ－１、ＶＶ、ＸＶ、ＹＶ、ＺＶ、ｎＶは一般式（Ｖ）における各記号と同義である。） (In the formula, A V , R V-1 , V V , X V , Y V , Z V , and n V are synonymous with each symbol in the general formula (V).)
　工程（Ｖ－ＶＩＩＩ－１）は、化合物（Ｖ－ＶＩＩＩ－１）を化合物（Ｖ－Ｉ－１３）に変換する工程である。反応に用いる試薬、条件は通常用いられているものであれば特に限定されないが、例えば化合物（Ｖ－ＶＩＩＩ－１）を、炭酸カリウム、酢酸ナトリウム、トリエチルアミンのような塩基の存在下塩化ヒドロキシルアンモニウムと反応させることを挙げることができる。この場合の条件は、例えばエタノール、メタノール、水のような極性溶媒を用い０℃から還流温度で行なうことを挙げることができる。
　工程（Ｖ－ＶＩＩＩ－２）は、化合物（Ｖ－Ｉ－１３）を化合物（Ｖ－Ｉ－１４）に変換する工程である。反応試薬、条件は通常用いられているものであれば特に限定されないが、例えば化合物（Ｖ－Ｉ－１３）と、１，１’－カルボニルジイミダゾールあるいはクロロ炭酸エチルとを、不活性溶媒例えばテトラヒドロフラン、トルエン中で反応させることを挙げることができる。反応温度は０℃から還流温度程度を挙げることができる。ＸＶ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、これらを適切な保護基で保護した後、スキーム（Ｖ－ＶＩＩＩ）の工程を実施し、脱保護することにより化合物（Ｖ－Ｉ－１３）または化合物（Ｖ－Ｉ－１４）を得る。 Step (V-VIII-1) is a step of converting compound (V-VIII-1) to compound (VI-13). The reagents and conditions used for the reaction are not particularly limited as long as they are usually used. For example, compound (V-VIII-1) is reacted with hydroxylammonium chloride in the presence of a base such as potassium carbonate, sodium acetate or triethylamine. The reaction can be mentioned. Examples of the conditions in this case include performing a polar solvent such as ethanol, methanol, and water at 0 ° C. to reflux temperature.
Step (V-VIII-2) is a step of converting compound (VI-13) to compound (VI-14). The reaction reagent and conditions are not particularly limited as long as they are usually used. For example, compound (VI-13) and 1,1′-carbonyldiimidazole or ethyl chlorocarbonate are mixed with an inert solvent such as tetrahydrofuran. And reacting in toluene. The reaction temperature can be about 0 ° C. to the reflux temperature. In the case where X V -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then the step of scheme (V-VIII) is carried out to remove the compound (VI -13) or compound (VI-14).
　３０）スキーム（Ｖ－ＩＩ）中の化合物（Ｖ－ＩＩ－１）及びスキーム（Ｖ－ＩＩＩ）中の化合物（Ｖ－ＩＩＩ－１）のうち、ＸＶが酸素原子又は硫黄原子である化合物（Ｖ－ＩＸ－１）は、以下のスキーム（Ｖ－ＩＸ）により合成することができる。 30) Of the compound (V-II-1) in scheme (V-II) and the compound (V-III-1) in scheme (V-III), a compound wherein X V is an oxygen atom or a sulfur atom ( V-IX-1) can be synthesized by the following scheme (V-IX).
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
（式中、ＸＶ ａは酸素原子又は硫黄原子を、ＸＶ ｂは脱離基、例えば臭素原子、又は水酸基を示す。ＡＶ、ＲＶ－１、ＶＶは一般式（Ｖ）における各記号と同義である。） (In the formula, X V a represents an oxygen atom or a sulfur atom, X V b represents a leaving group such as a bromine atom, or a hydroxyl group. A V , R V-1 , and V V represent each of the general formula (V). (It is synonymous with symbol.)
　工程（Ｖ－ＩＸ－１）は化合物（Ｖ－ＩＸ－２）のフェノール性水酸基又はチオール基をアルキル化し、化合物（Ｖ－ＩＸ－１）を得る工程である。用いられる試薬としては、ＸＶ ｂが脱離基を示す場合、化合物（Ｖ－ＩＸ－１）と炭酸カリウムや水酸化ナトリウム等の無機塩基の組み合わせが挙げられる。反応条件としては、Ｎ，Ｎ－ジメチルホルムアミド等の極性溶媒やテトラヒドロフラン等のエーテル系溶媒中、氷冷下～８０℃で３０分～１２時間程度が挙げられる。また、ＸＶ ｂが水酸基を示し、化合物（Ｖ－ＩＸ－２）がフェノール性水酸基を有する場合のアルキル化には、トリフェニルホスフィン等のホスフィン化合物とアゾジカルボン酸ジイソプロピルエステル等のアゾジカルボン酸誘導体を用いた光延反応も用いることができる。この場合の反応条件としては、テトラヒドロフラン等のエーテル系溶媒中、氷冷下～５０℃で１０分～６時間程度が挙げられる。ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、必要に応じこれらを適切な保護基で保護した後、工程（Ｖ－ＩＸ－１）を行ない、脱保護することにより化合物（Ｖ－ＩＸ－１）を得る。 Step (V-IX-1) is a step of alkylating the phenolic hydroxyl group or thiol group of compound (V-IX-2) to obtain compound (V-IX-1). Examples of the reagent used include a combination of compound (V-IX-1) and an inorganic base such as potassium carbonate or sodium hydroxide when X V b represents a leaving group. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 30 minutes to 12 hours. For alkylation when X V b represents a hydroxyl group and the compound (V-IX-2) has a phenolic hydroxyl group, a phosphine compound such as triphenylphosphine and an azodicarboxylic acid derivative such as azodicarboxylic acid diisopropyl ester are used. Mitsunobu reaction using can also be used. The reaction conditions in this case include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. When containing an -NH- structure or carbonyl structure A V, after protecting needed them with a suitable protecting group, performs step (V-IX-1), compound by deprotection (V-IX- 1) is obtained.
　３１）スキーム（Ｖ－ＩＩ）中の化合物（Ｖ－ＩＩ－１）及びスキーム（Ｖ－ＩＩＩ）中の化合物（Ｖ－ＩＩＩ－１）のうち、ＶＶ ａ又はＶＶが単結合、ＸＶが酸素原子又は硫黄原子である化合物（Ｖ－Ｘ－１）は、以下のスキーム（Ｖ－Ｘ）により合成することができる。 31) Among the compound (V-II-1) in the scheme (V-II) and the compound (V-III-1) in the scheme (V-III), V V a or V V is a single bond, X V Compound (VX-1) in which is an oxygen atom or a sulfur atom can be synthesized by the following scheme (VX).
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
（式中、ＲＶ－６ ａは一般式（Ｖ）で定義されるＲＶ－６のうち水素原子を除く基を、ＸＶ ａは酸素原子又は硫黄原子を、ＸＶ ｃは脱離基、例えばフッ素原子を示す。ＡＶ、ＲＶ－１は一般式（Ｖ）における各記号と同義である。） (Wherein R V-6 a represents a group other than hydrogen atom in R V-6 defined by the general formula (V), X V a represents an oxygen atom or a sulfur atom, and X V c represents a leaving group. Represents a fluorine atom, for example, and A V and R V-1 have the same meanings as symbols in the general formula (V).
　工程（Ｖ－Ｘ－１）は、脱離基ＸＶ ｃを有する化合物（Ｖ－Ｘ－２）と化合物（Ｖ－Ｘ－３）との縮合により、化合物（Ｖ－Ｘ－４）を得る反応である。本工程はＮ，Ｎ－ジメチルホルムアミドやジメチルスルホキシドといった極性溶媒や、テトラヒドロフラン等のエーテル系溶媒中、塩基の存在下、行なうことができる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基、カリウムｔ－ブトキシド等のアルコキシド、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン等の有機塩基を用いて行なうことができる。反応条件としては、氷冷下～１００℃程度で１０分～１０時間程度が例示される。
　工程（Ｖ－Ｘ－２）は化合物（Ｖ－Ｘ－４）のエステルを還元して、水酸基を有する化合物（Ｖ－Ｘ－５）を得る反応である。還元に用いられる試薬としては、通常用いられるものであれば特に限定されないが、ナトリウム等のアルカリ金属やアルカリ土類金属、水素化ジイソブチルアルミニウム等の金属水素化物、水素化アルミニウムリチウムや水素化ホウ素ナトリウム等の金属水素錯化合物、ジボラン等のホウ素化合物、均一系又は不均一系の触媒を用いた接触水素添加等が挙げられる。反応条件は、用いる還元試薬に適切な温度と時間が選ばれる。具体的なものとしては、テトラヒドロフラン等のエーテル系溶媒中－３０℃～還流で１０分～１２時間程度行なわれるジボラン、水素化アルムニウムリチウム、水素化ホウ素リチウムによる還元、エタノール等のアルコール系溶媒又はアルコール系溶媒とテトラヒドロフラン等のエーテル系溶媒の混合溶媒中、氷冷下～還流で３０分～２４時間程度行なわれる水素化ホウ素ナトリウムや水素化ホウ素カルシウムによる還元等が挙げられる。
　工程（Ｖ－Ｘ－３）は化合物（Ｖ－Ｘ－５）の水酸基を酸化し、アルデヒド化合物（Ｖ－Ｘ－１）を得る工程である。本工程は通常のアルコールのアルデヒドへの酸化反応を用いて行なうことができる。具体的には、クロロクロム酸ピリジニウムや、オキサリルクロリド、ジシクロヘキシルカルボジイミド、三酸化硫黄－ピリジン錯体等の各種ジメチルスルホキシド活性化剤を用いたＤＭＳＯ酸化、Ｎ－オキソアンモニウム化合物を用いた酸化（例えば、ＴＥＭＰＯ酸化）により目的物を得ることができる。反応条件としては、－７８℃～５０℃で３０分～２４時間程度が挙げられる。 In step (VX-1), compound (VX-4) is obtained by condensation of compound (VX-2) having leaving group X V c and compound (VX-3). It is a reaction. This step can be carried out in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of reaction conditions are about 10 minutes to 10 hours at about 100 ° C. under ice cooling.
Step (VX-2) is a reaction in which the ester of compound (VX-4) is reduced to obtain compound (VX-5) having a hydroxyl group. The reagent used for the reduction is not particularly limited as long as it is usually used, but alkali metals such as sodium and alkaline earth metals, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and sodium borohydride. Metal hydrogen complex compounds such as diborane, catalytic hydrogenation using a homogeneous or heterogeneous catalyst, and the like. As the reaction conditions, a temperature and a time appropriate for the reducing reagent to be used are selected. Specific examples include reduction with diborane, lithium aluminum hydride, lithium borohydride performed in an ether solvent such as tetrahydrofuran at −30 ° C. to reflux for about 10 minutes to 12 hours, an alcohol solvent such as ethanol, or the like. Examples thereof include reduction with sodium borohydride or calcium borohydride, which is carried out in a mixed solvent of an alcohol solvent and an ether solvent such as tetrahydrofuran under ice-cooling to reflux for about 30 minutes to 24 hours.
Step (VX-3) is a step of oxidizing the hydroxyl group of compound (VX-5) to obtain aldehyde compound (VX-1). This step can be performed using an oxidation reaction of a normal alcohol to an aldehyde. Specifically, DMSO oxidation using various dimethyl sulfoxide activators such as pyridinium chlorochromate, oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide-pyridine complex, and oxidation using N-oxoammonium compounds (for example, TEMPO The target product can be obtained by oxidation. The reaction conditions include −78 ° C. to 50 ° C. for about 30 minutes to 24 hours.
　３２）スキーム（Ｖ－ＩＩ）中の化合物（Ｖ－ＩＩ－１）及びスキーム（Ｖ－ＩＩＩ）中の化合物（Ｖ－ＩＩＩ－１）のうち、ＶＶ ａ又はＶＶがメチレンである化合物（Ｖ－ＸＩ－１）は、以下のスキーム（Ｖ－ＸＩ）により合成することができる。 32) Of the compound (V-II-1) in scheme (V-II) and the compound (V-III-1) in scheme (V-III), a compound in which V V a or V V is methylene ( V-XI-1) can be synthesized by the following scheme (V-XI).
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
（式中、ＡＶ、ＲＶ－１、ＸＶは一般式（Ｖ）における各記号と同義である。） (In the formula, A V , R V-1 and X V have the same meanings as the symbols in the general formula (V).)
　工程（Ｖ－ＸＩ－１）は、公知の方法（例えば、ＷＯ２００７／０６９７１２号公報、８～５６ページ）によって合成される化合物（Ｖ－ＸＩ－２）を酸化することにより、アルデヒド化合物（Ｖ－ＸＩ－１）を得る工程である。本工程は通常のアルコールからアルデヒドへの酸化反応を用いて行なうことができる。具体的には、スキーム（Ｖ－Ｘ）中の工程（Ｖ－Ｘ－３）に記載した反応試薬、反応条件を挙げることができる。 In step (V-XI-1), an aldehyde compound (V-XI-2) is synthesized by oxidizing compound (V-XI-2) synthesized by a known method (for example, WO2007 / 069712, pages 8 to 56). This is a step of obtaining XI-1). This step can be performed using an oxidation reaction from a normal alcohol to an aldehyde. Specifically, the reaction reagents and reaction conditions described in the step (VX-3) in the scheme (VX) can be given.
　３３）化合物（Ｖ－ＸＩＩ－１）を出発原料とし、下記のスキーム（Ｖ－ＸＩＩ）を実施することにより、エチレン鎖を導入した化合物（Ｖ－ＸＩＩ－３）、（Ｖ－ＸＩＩ－４）、（Ｖ－ＸＩＩ－５）、（Ｖ－ＸＩＩ－６）を合成することができる。 33) Compounds (V-XII-3) and (V-XII-4) having an ethylene chain introduced by carrying out the following scheme (V-XII) using compound (V-XII-1) as a starting material , (V-XII-5) and (V-XII-6) can be synthesized.
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
（式中、ＲＶ－６ ａは一般式（Ｖ）で定義されるＲＶ－６のうち水素原子を除く基を示し、ＶＶ ｂは単結合又は置換基を有していても良い炭素数１～３のアルキルを示す。ＡＶ、ＲＶ－１、ＸＶは一般式（Ｖ）における各記号と同義である。） (Wherein R V-6 a represents a group excluding a hydrogen atom in R V-6 defined by the general formula (V), and V V b represents a carbon that may have a single bond or a substituent. Represents an alkyl of the formulas 1 to 3. A V , R V-1 and X V have the same meanings as those in the general formula (V).
　各工程の反応試薬、反応条件等は、これまで記載したものと同様のものを例示することができる。すなわち、工程（Ｖ－ＸＩＩ－１）はスキーム（Ｖ－ＩＩＩ）中の工程（Ｖ－ＩＩＩ－１）に、工程（Ｖ－ＸＩＩ－２）はスキーム（Ｖ－ＩＶ）中の工程（Ｖ－ＩＶ－１）に、工程（Ｖ－ＸＩＩ－３）はスキーム（Ｖ－ＩＶ）中の工程（Ｖ－ＩＶ－２）に、工程（Ｖ－ＸＩＩ－４）はスキーム（Ｖ－ＶＩ）中の工程（Ｖ－ＶＩ－１）に、工程（Ｖ－ＸＩ－５）はスキーム（Ｖ－Ｘ）中の工程（Ｖ－Ｘ－３）に記載したものを例示することができる。 The reaction reagents, reaction conditions, etc. in each step can be exemplified by those similar to those described so far. That is, the step (V-XII-1) is the step (V-III-1) in the scheme (V-III), and the step (V-XII-2) is the step (V-IV) in the scheme (V-IV). In step IV-1), step (V-XII-3) is in step (V-IV-2) in scheme (V-IV) and step (V-XII-4) is in scheme (V-VI). In step (V-VI-1), step (V-XI-5) can be exemplified by those described in step (VX-3) in scheme (VX).
　３４）スキーム（Ｖ－ＶＩＩＩ）中の化合物（Ｖ－ＶＩＩＩ－１）のうち、ＸＶが酸素原子又は硫黄原子、ＶＶが－ＣＨ２－ＶＶ ａ－（ここでＶＶ ａは単結合又は置換基を有していても良い炭素数１～５のアルキレンを示す）、ＹＶが－ＮＲＶ－５ ａ－（ここでＲＶ－５ ａは水素原子、置換基を有していても良い炭素数１～６のアルキルを示す）で表される化合物（Ｖ－ＸＩＩＩ－１）、又は、ＸＶが酸素原子又は硫黄原子、ＶＶが－ＣＨ２－ＶＶ ａ－（ここでＶＶ ａは単結合又は置換基を有しても良い炭素数１～５のアルキレンを示す）、ＹＶが単結合、ｎＶが１であり、ＢＶ－ＺＶ－が下記式 34) Of the compounds (V-VIII-1) in the scheme (V-VIII), X V is an oxygen atom or sulfur atom, and V V is —CH 2 —V V a — (where V V a is a single bond) Or an optionally substituted alkylene having 1 to 5 carbon atoms, and Y V is —NR V-5 a — (where R V-5 a is a hydrogen atom and has a substituent. Or a compound represented by formula (V-XIII-1), or X V is an oxygen atom or a sulfur atom, and V V is —CH 2 —V V a — (wherein V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent), Y V is a single bond, n V is 1, and B V -Z V -is represented by the following formula:
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
（ここで、当該式で表される基は任意の位置にシアノ基を有する含窒素ヘテロシクロアルキルを示す）
で表される基である化合物（Ｖ－ＸＩＩＩ－２）は、以下のスキーム（Ｖ－ＸＩＩＩ）により合成することができる。 (Here, the group represented by the formula represents a nitrogen-containing heterocycloalkyl having a cyano group at an arbitrary position)
Compound (V-XIII-2), which is a group represented by the following formula, can be synthesized by the following scheme (V-XIII).
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
（式中、ＸＶ ａは酸素原子又は硫黄原子を示し、ＶＶ ａは単結合又は置換基を有しても良い炭素数１～５のアルキレンを、ＲＶ－５ ａは水素原子、置換基を有していても良い炭素数１～６のアルキルを示す。ＲＶ－１、ＡＶ、ＺＶ、ｎＶは一般式（Ｖ）における各記号と同義である。） (Wherein X V a represents an oxygen atom or a sulfur atom, V V a represents a single bond or an alkylene having 1 to 5 carbon atoms which may have a substituent, R V-5 a represents a hydrogen atom, An alkyl having 1 to 6 carbon atoms which may have a group, and R V-1 , A V , Z V and n V have the same meanings as those in the general formula (V).
　工程（Ｖ－ＸＩＩＩ－１）及び工程（Ｖ－ＸＩＩＩ－２）は、化合物（Ｖ－ＩＩ－１）と化合物（Ｖ－ＸＩＩＩ－３）又は化合物（Ｖ－ＸＩＩＩ－４）とを反応させた後に還元して化合物（Ｖ－ＸＩＩＩ－１）又は化合物（Ｖ－ＸＩＩＩ－２）を得る工程である。反応試薬、反応条件等は、スキーム（Ｖ－ＩＩ）中の工程（Ｖ－ＩＩ－１）及び工程（Ｖ－ＩＩ－２）と同様のものを挙げることができる。ＸＶ ａ－ＡＶに－ＮＨ－構造又はカルボニル構造を含む場合、これらを適切な保護基で保護した後、スキーム（Ｖ－ＸＩＩＩ）を実施し、脱保護することにより化合物（Ｖ－ＸＩＩＩ－１）又は化合物（Ｖ－ＸＩＩＩ－２）を得る。 In step (V-XIII-1) and step (V-XIII-2), compound (V-II-1) was reacted with compound (V-XIII-3) or compound (V-XIII-4) In this step, compound (V-XIII-1) or compound (V-XIII-2) is obtained by subsequent reduction. Examples of the reaction reagent, reaction conditions, and the like can be the same as those in step (V-II-1) and step (V-II-2) in scheme (VII). In the case where X V a -A V contains an —NH— structure or a carbonyl structure, these are protected with an appropriate protecting group, and then scheme (V-XIII) is carried out to remove the compound (V-XIII— 1) or compound (V-XIII-2) is obtained.
　本発明化合物は、必要に応じて適当な溶媒（水、アルコール、エーテルなど）中、酸と処理することにより、酸付加塩とすることができる。また、得られた本発明化合物を水、含水溶媒又はその他の溶媒（例えば、アルコール等）と処理することにより、水和物又は溶媒和物とすることができる。 The compound of the present invention can be converted to an acid addition salt by treating with an acid in an appropriate solvent (water, alcohol, ether, etc.) as necessary. Moreover, it can be set as a hydrate or a solvate by processing the obtained this invention compound with water, a hydrous solvent, or another solvent (for example, alcohol etc.).
　本発明化合物は、自己免疫疾患（例えば、関節リウマチ、多発性硬化症、脳脊髄炎、全身性エリテマトーデス、ループス腎炎、ネフローゼ症候群、乾癬、Ｉ型糖尿病等）の治療又は予防；ヒト、イヌ、ネコ、ウシ、ウマ、ブタ、サル、ネズミ等の哺乳動物の器官又は組織の移植（例えば、心臓、腎臓、肝臓、肺、骨髄、角膜、膵臓、小腸、四肢、筋肉、神経、脂肪髄、十二指腸、皮膚、膵島細胞等の移植、異種移植を含む）に対する抵抗又は急性拒絶反応若しくは慢性拒絶反応の予防又は抑制；骨髄移植による移植片対宿主（ＧｖＨ）病；アレルギー性疾患（例えば、アトピー性皮膚炎、アレルギー性鼻炎、喘息等）の治療又は予防に有用である。 The compound of the present invention treats or prevents autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes, etc.); humans, dogs, cats Transplantation of mammalian organs or tissues such as cattle, horses, pigs, monkeys, mice (eg, heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, extremities, muscles, nerves, fat pulp, duodenum, Resistance to skin, islet cell transplantation, including xenotransplantation or prevention or suppression of acute rejection or chronic rejection; graft versus host (GvH) disease by bone marrow transplantation; allergic disease (eg, atopic dermatitis , Allergic rhinitis, asthma, etc.).
　また、本発明において、「予防」とは病気や疾患や症状を発症していない個体に対して本発明化合物又はこれを含有する医薬組成物を投与する行為を意味している。また、「治療」とは既に病気や疾患や症状を発症した個体に対して本発明化合物又はこれを含有する医薬組成物を投与する行為を意味している。従って、既に病気や疾患や症状を発症した個体に対し、症状等の悪化防止や発作防止や再発防止のために投与する行為は「治療」の一態様である。 In the present invention, “prevention” means an act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has not developed a disease, disorder or symptom. “Treatment” means an act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has already developed a disease, disorder or symptom. Therefore, the act of administering to an individual who has already developed illness, disease, or symptom in order to prevent worsening of the symptom, seizure, or recurrence is an aspect of “treatment”.
　本発明化合物を医薬として用いる場合、本発明化合物を製薬上許容しうる担体（賦形剤、結合剤、崩壊剤、矯味剤、矯臭剤、乳化剤、希釈剤、溶解補助剤など）と混合して得られる医薬組成物あるいは製剤（経口剤、注射剤など）の形態で経口的又は非経口的に投与することができる。医薬組成物は通常の方法にしたがって製剤化することができる。 When the compound of the present invention is used as a pharmaceutical, the compound of the present invention is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, solubilizer, etc.) It can be administered orally or parenterally in the form of the resulting pharmaceutical composition or formulation (oral, injection, etc.). The pharmaceutical composition can be formulated according to a usual method.
　本明細書において非経口とは、皮下注射、静脈内注射、筋肉内注射、腹腔内注射、点滴法あるいは局所投与（経皮的投与、経眼的投与、経肺・気管支的投与、経鼻的投与又は経直腸的投与など）などを含むものである。 In this specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (transdermal administration, ophthalmic administration, transpulmonary / bronchial administration, nasal administration) Administration or rectal administration, etc.).
　担体と組み合わせることのできる本発明化合物の含有量は、治療される個体と特定投与形態とに応じて変えることができる。ただし、特定患者の特定用量は、年齢、体重、全般的健康状態、性別、食事、投与時間、投与方法、排泄率及び治療中の特定疾患の程度を含む種々の因子に応じて決定される。 The content of the compound of the present invention that can be combined with the carrier can vary depending on the individual to be treated and the specific dosage form. However, the specific dose for a specific patient will be determined according to various factors including age, weight, general health, sex, diet, administration time, method of administration, excretion rate and degree of specific disease being treated.
　本発明化合物の投与量は、年齢、体重、一般的健康状態、性別、食事、投与時間、投与方法、排泄速度、患者のその時に治療を行っている病状の程度に応じ、それら、あるいはその他の要因を考慮して決められる。本発明化合物は、心拍数に与える影響がなく安全に使用することができ、その１日当たりの投与量は、患者の状態や体重、化合物の種類、投与経路などによって異なるが、たとえば非経口的には皮下、静脈内、筋肉内、経皮的、経眼的、経肺・気管支的、経鼻的又は直腸内に、約０．０１～５０ｍｇ／人／日投与され、また経口的には約０．０１～１５０ｍｇ／人／日投与される。 The dose of the compound of the present invention depends on age, body weight, general health condition, sex, meal, administration time, administration method, excretion rate, and the degree of the disease being treated at that time of the patient, or other Determined by considering factors. The compound of the present invention has no effect on heart rate and can be used safely. The daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, etc. Is administered about 0.01 to 50 mg / person / day subcutaneously, intravenously, intramuscularly, transdermally, ophthalmically, pulmonary / bronchially, nasally or rectally, and orally about 0.01 to 150 mg / person / day is administered.
　本発明をより詳細に説明するために、以下に実施例を挙げるが、本発明はこれらにより何ら限定されるものではない。 In order to describe the present invention in more detail, examples are given below, but the present invention is not limited to these examples.
　実施例１
２－アミノ－２－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 1
2-Amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１－１）８－フルオロオクタノールの合成（化合物１－１） (1-1) Synthesis of 8-fluorooctanol (Compound 1-1)
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　８－ブロモオクタノール（３．００ｇ）のテトラヒドロフラン（３０ｍｌ）溶液に、テトラブチルアンモニウムフルオリドの１ｍｏｌ／ｌテトラヒドロフラン溶液（７１．７ｍｌ）を加え、７時間還流した。反応溶液を濃縮し、水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（１．９５ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２３（１Ｈ、ｂｒｓ）、１．３２－１．４４（８Ｈ、ｍ）、１．５４－１．６１（２Ｈ、ｍ）、１．６３－１．６９（１Ｈ、ｍ）、１．６９－１．７６（１Ｈ、ｍ）、３．６４（２Ｈ、ｔ、Ｊ＝６．５Ｈｚ）、４．４３（２Ｈ、ｄｔ、Ｊ＝４７．２、６．２Ｈｚ）。 To a solution of 8-bromooctanol (3.00 g) in tetrahydrofuran (30 ml) was added a 1 mol / l tetrahydrofuran solution (71.7 ml) of tetrabutylammonium fluoride, and the mixture was refluxed for 7 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.95 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.23 (1H, brs), 1.32-1.44 (8H, m), 1.54-1.61 (2H, m), 63-1.69 (1H, m), 1.69-1.76 (1H, m), 3.64 (2H, t, J = 6.5 Hz), 4.43 (2H, dt, J = 47) .2, 6.2 Hz).
　（１－２）１－フルオロ－８－ヨードオクタンの合成（化合物１－２） (1-2) Synthesis of 1-fluoro-8-iodooctane (Compound 1-2)
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　化合物１－１（１．９３ｇ）を塩化メチレン（４０ｍｌ）に溶解させ、氷冷下トリエチルアミン（１．９８ｍｌ）と塩化メタンスルホニル（１．０６ｍｌ）を加え、そのまま氷冷下で４０分間攪拌した。反応液を塩化メチレン（６０ｍｌ）で希釈後、有機層を水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣の２－ブタノン（８０ｍｌ）溶液にヨウ化ナトリウム（２．１５ｇ）を加え、３時間還流した。反応溶液を濃縮し、水を加えた後、酢酸エチルで抽出した。有機層をチオ硫酸ナトリウム水溶液、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（３．１６ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３２－１．４４（８Ｈ、ｍ）、１．６２－１．６９（１Ｈ、ｍ）、１．６９－１．７５（１Ｈ、ｍ）、１．８２（２Ｈ、ｑｕｉｎｔ、Ｊ＝７．１Ｈｚ）、３．１９（２Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、４．４４（２Ｈ、ｄｔ、Ｊ＝４７．１、６．２Ｈｚ）。 Compound 1-1 (1.93 g) was dissolved in methylene chloride (40 ml), triethylamine (1.98 ml) and methanesulfonyl chloride (1.06 ml) were added under ice cooling, and the mixture was stirred as such for 40 minutes under ice cooling. The reaction mixture was diluted with methylene chloride (60 ml), the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in 2-butanone (80 ml), sodium iodide (2.15 g) was added and refluxed for 3 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product (3.16 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.32-1.44 (8H, m), 1.62-1.69 (1H, m), 1.69-1.75 (1H, m ), 1.82 (2H, quint, J = 7.1 Hz), 3.19 (2H, t, J = 7.0 Hz), 4.44 (2H, dt, J = 47.1, 6.2 Hz) .
　（１－３）（５－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルの合成（化合物１－３） (1-3) (5- {2- [4- (8-Fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (compound 1-3)
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　公知の方法（例えば、ＷＯ２００７／０６９７１２号公報、５８～６２ページ）により合成した｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（４９４ｍｇ）、化合物１－２（３４９ｍｇ）を加え、８０℃にて１時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（４４０ｍｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３０－１．４２（６Ｈ、ｍ）、１．４２－１．５３（２Ｈ、ｍ）、１．４３（３Ｈ、ｓ）、１．４４（３Ｈ、ｓ）、１．４７（９Ｈ、ｓ）、１．６２－１．６９（１Ｈ、ｍ）、１．６９－１．７７（１Ｈ、ｍ）、１．７７－１．８３（２Ｈ、ｍ）、１．９２－１．９８（２Ｈ、ｍ）、２．５１－２．５６（２Ｈ、ｍ）、３．６９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、３．８９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．４４（２Ｈ、ｄｔ、Ｊ＝４７．２、Ｊ＝６．２Ｈｚ）、５．００（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２８（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）、７．３５（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 {5- [2- (4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3 synthesized by a known method (for example, WO2007 / 069712, pp. 58-62) -Dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was dissolved in N, N-dimethylformamide (10 ml), and potassium carbonate (494 mg) and compound 1-2 (349 mg) were added at 80 ° C. Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (440 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.30-1.42 (6H, m), 1.42-1.53 (2H, m), 1.43 (3H, s), 44 (3H, s), 1.47 (9H, s), 1.62-1.69 (1H, m), 1.69-1.77 (1H, m), 1.77-1.83 ( 2H, m), 1.92-1.98 (2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 ( 2H, d, J = 11.7 Hz), 4.00 (2H, t, J = 6.3 Hz), 4.44 (2H, dt, J = 47.2, J = 6.2 Hz), 5.00 (1H, brs), 6.88 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.35 (1H, d, J = 1.6 Hz) .
　（１－４）２－アミノ－２－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１－４） (1-4) Synthesis of 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 1-4 )
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　化合物１－３（４４０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（３３０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４１０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．２５－１．５１（８Ｈ、ｍ）、１．５５－１．８０（６Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．４２（２Ｈ、ｄｔ、Ｊ＝４７．６、６．２Ｈｚ）、５．４１（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８６（３Ｈ、ｂｒｓ）。 Compound 1-3 (440 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (330 mg) as a white powder.
MS (ESI) m / z: 410 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.25-1.51 (8H, m), 1.55-1.80 (6H, m), 2.58-2.63 (2H) M), 3.52 (4H, d, J = 4.8 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.42 (2H, dt, J = 47.6, 6. 2Hz), 5.41 (2H, t, J = 5.1 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.86 ( 3H, brs).
　実施例２
（Ｚ）－２－アミノ－２－｛２－［４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 2
(Z) -2-Amino-2- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（２－１）（Ｚ）－２－アミノ－２－｛２－［４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物２－１） Synthesis of (2-1) (Z) -2-amino-2- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 2 -1)
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、シス－４－ヘプテン－１－オール（０．４０４ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（Ｚ）－（５－｛２－［４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを黄色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４３０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、１．７１－１．８０（４Ｈ、ｍ）、１．９４－２．０２（２Ｈ、ｍ）、２．１４－２．２１（２Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．９Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝５．９Ｈｚ）、５．３３－５．４２（４Ｈ、ｍ）、７．１７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８５（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml) and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), cis-4-hepten-1-ol (0.404 ml) and {5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography, and (Z)-(5- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3- Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (430 mg) as a white powder.
MS (ESI) m / z: 376 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 7.5 Hz), 1.71-1.80 (4H, m), 1.94-2.02 (2H, m), 2.14-2.21 (2H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.05 (2H, t, J = 5.9 Hz), 5.33-5.42 (4H, m), 7.17 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.85 (3H, brs).
　実施例３
（Ｅ）－２－アミノ－２－｛２－［４－（２－ヘプテニルオキシ－３－トリフルオロメチルフェニル）エチル］プロパン－１，３－ジオール塩酸塩 Example 3
(E) -2-Amino-2- {2- [4- (2-heptenyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride
　（３－１）（Ｅ）－２－アミノ－２－｛２－［４－（２－ヘプテニルオキシ－３－トリフルオロメチルフェニル）エチル］プロパン－１，３－ジオール塩酸塩の合成（化合物３－１） (3-1) Synthesis of (E) -2-amino-2- {2- [4- (2-heptenyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (Compound 3- 1)
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、トランス－２－ヘプテン－１－オール（０．４０９ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（Ｅ）－（５－｛２－［４－（２－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを黄色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５００ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８７（３Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．２３－１．３７（４Ｈ、ｍ）、１．７４－１．７８（２Ｈ、ｍ）、２．０２－２．０８（２Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．９Ｈｚ）、４．６１（２Ｈ、ｄ、Ｊ＝５．６Ｈｚ）、５．４０（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、５．６３（１Ｈ、ｄｔ、Ｊ＝１５．３、５．６Ｈｚ）、５．８５（１Ｈ、ｄｔ、Ｊ＝１５．３、６．８Ｈｚ）、７．１９（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８６（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), trans-2-hepten-1-ol (0.409 ml) and {5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography, and (E)-(5- {2- [4- (2-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3- Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.
MS (ESI) m / z: 376 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.87 (3H, t, J = 7.1 Hz), 1.23-1.37 (4H, m), 1.74-1.78 (2H, m), 2.02-2.08 (2H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.40 (2H, t, J = 5.1 Hz), 5.63 (1H, dt, J = 15.3, 5.6 Hz), 5.85 ( 1H, dt, J = 15.3, 6.8 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.86 (3H, brs) ).
　実施例４
２－アミノ－２－｛２－［４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 4
2-Amino-2- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（４－１）２－アミノ－２－｛２－［４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物４－１） (4-1) Synthesis of 2-amino-2- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 4-1)
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、６－ヘプテン－１－オール（０．４００ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で１５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを淡黄色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、白色粉末を得た。その白色粉末をＨＰＬＣで精製し、得られた残渣に塩化水素含有エーテル（１ｍｏｌ／ｌ、１５ｍｌ）を加え塩酸塩とした後、析出物を濾取、乾燥し目的物（４２０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３８－１．４９（４Ｈ、ｍ）、１．６８－１．８０（４Ｈ、ｍ）、２．００－２．０７（２Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．７Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．９４（１Ｈ、ｄ、Ｊ＝１０．２Ｈｚ）、５．００（１Ｈ、ｄｄ、Ｊ＝１７．２、１．５Ｈｚ）、５．４０（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、５．８０（１Ｈ、ｄｄｔ、Ｊ＝１７．２、１０．２、６．７Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８４（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 6-hepten-1-ol (0.400 ml) and {5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a pale yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was concentrated, and the residue was washed with diethyl ether to obtain a white powder. The white powder was purified by HPLC, and hydrogen chloride-containing ether (1 mol / l, 15 ml) was added to the resulting residue to form a hydrochloride. The precipitate was collected by filtration and dried to give the desired product (420 mg) as a white powder. Obtained.
MS (ESI) m / z: 376 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.38-1.49 (4H, m), 1.68-1.80 (4H, m), 2.00-2.07 (2H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.94 (1H, d, J = 10.2 Hz), 5.00 (1H, dd, J = 17.2, 1.5 Hz), 5.40 (2H, t, J = 5.0 Hz), 5.80 ( 1H, ddt, J = 17.2, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.84 (3H, brs).
　実施例５
２－アミノ－２－｛２－［４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 5
2-Amino-2- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（５－１）７－フルオロヘプタノールの合成（化合物５－１） (5-1) Synthesis of 7-fluoroheptanol (Compound 5-1)
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　７－ブロモヘプタノール（３．００ｇ）のテトラヒドロフラン（５０ｍｌ）溶液に、テトラブチルアンモニウムフルオリドの１ｍｏｌ／ｌテトラヒドロフラン溶液（６７．８ｍｌ）を加え、５時間還流した。反応溶液を濃縮し、水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（１．９７ｇ）を淡褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２１（１Ｈ、ｂｒｓ）、１．３２－１．４６（６Ｈ、ｍ）、１．５５－１．６１（２Ｈ、ｍ）、１．６２－１．６９（１Ｈ、ｍ）、１．６９－１．７６（１Ｈ、ｍ）、３．６２－３．６８（２Ｈ、ｍ）、４．４４（２Ｈ、ｄｔ、Ｊ＝４７．６、６．２Ｈｚ）。 To a solution of 7-bromoheptanol (3.00 g) in tetrahydrofuran (50 ml) was added a 1 mol / l tetrahydrofuran solution (67.8 ml) of tetrabutylammonium fluoride and refluxed for 5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.97 g) as a pale-brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.21 (1H, brs), 1.32-1.46 (6H, m), 1.55-1.61 (2H, m), 62-1.69 (1H, m), 1.69-1.76 (1H, m), 3.62-3.68 (2H, m), 4.44 (2H, dt, J = 47.6) 6.2 Hz).
　（５－２）１－フルオロ－７－ヨードヘプタンの合成（化合物５－２） (5-2) Synthesis of 1-fluoro-7-iodoheptane (Compound 5-2)
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　化合物５－１（１．９７ｇ）を塩化メチレン（３０ｍｌ）に溶解させ、氷冷下トリエチルアミン（２．６４ｍｌ）と塩化メタンスルホニル（１．２５ｍｌ）を加え、そのまま氷冷下で４時間攪拌した。反応液を塩化メチレン（６０ｍｌ）で希釈後、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣の２－ブタノン（６０ｍｌ）溶液にヨウ化ナトリウム（２．４３ｇ）を加え、３時間還流した。反応溶液を濃縮し、水を加えた後、ジエチルエーテルで抽出した。有機層をチオ硫酸ナトリウム水溶液、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（３．３１ｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３２－１．４６（６Ｈ、ｍ）、１．６３－１．６９（１Ｈ、ｍ）、１．６９－１．７５（１Ｈ、ｍ）、１．７６－１．８７（２Ｈ、ｍ）、３．１９（２Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、４．４４（２Ｈ、ｄｔ、Ｊ＝４７．５、６．２Ｈｚ）。 Compound 5-1 (1.97 g) was dissolved in methylene chloride (30 ml), triethylamine (2.64 ml) and methanesulfonyl chloride (1.25 ml) were added under ice cooling, and the mixture was stirred for 4 hours under ice cooling. The reaction mixture was diluted with methylene chloride (60 ml), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in 2-butanone (60 ml), sodium iodide (2.43 g) was added and refluxed for 3 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (3.31 g) as a yellow oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.32-1.46 (6H, m), 1.63-1.69 (1H, m), 1.69-1.75 (1H, m ) 1.76-1.87 (2H, m), 3.19 (2H, t, J = 7.0 Hz), 4.44 (2H, dt, J = 47.5, 6.2 Hz).
　（５－３）（５－｛２－［４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルの合成（化合物５－３） (5-3) (5- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (compound 5-3)
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（５９３ｍｇ）、化合物５－２（４６５ｍｇ）を加え、８０℃にて１時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（６３０ｍｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３６－１．５２（６Ｈ、ｍ）、１．４３（３Ｈ、ｓ）、１．４４（３Ｈ、ｓ）、１．４７（９Ｈ、ｓ）、１．６４－１．７０（１Ｈ、ｍ）、１．７０－１．７８（１Ｈ、ｍ）、１．７８－１．８４（２Ｈ、ｍ）、１．９２－１．９８（２Ｈ、ｍ）、２．５１－２．５６（２Ｈ、ｍ）、３．６９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、３．８９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．４４（２Ｈ、ｄｔ、Ｊ＝４７．３、Ｊ＝６．１Ｈｚ）、５．００（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２８（１Ｈ、ｂｒｓ）、７．３５（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (593 mg) and compound 5-2 (465 mg) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (630 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.36-1.52 (6H, m), 1.43 (3H, s), 1.44 (3H, s), 1.47 (9H, s), 1.64-1.70 (1H, m), 1.70-1.78 (1H, m), 1.78-1.84 (2H, m), 1.92-1.98 ( 2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 (2H, d, J = 11.7 Hz), 4. 00 (2H, t, J = 6.3 Hz), 4.44 (2H, dt, J = 47.3, J = 6.1 Hz), 5.00 (1H, brs), 6.88 (1H, d , J = 8.4 Hz), 7.28 (1H, brs), 7.35 (1H, d, J = 1.9 Hz).
　（５－４）２－アミノ－２－｛２－［４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物５－４） (5-4) Synthesis of 2-amino-2- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 5-4 )
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　化合物５－３（６３０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジイソプロピルエーテルにて洗浄し、目的物（３００ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３４－１．３８（４Ｈ、ｍ）、１．３８－１．４８（２Ｈ、ｍ）、１．５５－１．６３（２Ｈ、ｍ）、１．６３－１．７９（４Ｈ、ｍ）、２．５９－２．６４（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．７Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．４３（２Ｈ、ｄｔ、Ｊ＝４７．４、６．１Ｈｚ）、５．４１（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４４－７．４６（２Ｈ、ｍ）、７．８９（３Ｈ、ｂｒｓ）。 Compound 5-3 (630 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (300 mg) as a white powder.
MS (ESI) m / z: 396 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.34-1.38 (4H, m), 1.38-1.48 (2H, m), 1.55-1.63 (2H) M), 1.63-1.79 (4H, m), 2.59-2.64 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.06 (2H) , T, J = 6.1 Hz), 4.43 (2H, dt, J = 47.4, 6.1 Hz), 5.41 (2H, t, J = 5.0 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.44-7.46 (2H, m), 7.89 (3H, brs).
　実施例６
２－アミノ－２－｛２－［４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 6
2-Amino-2- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（６－１）２－アミノ－２－｛２－［４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物６－１） (6-1) Synthesis of 2-amino-2- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 6-1)
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、３－ヘプチン－１－オール（０．３７６ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて３０分攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（３３０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．３６－１．４６（２Ｈ、ｍ）、１．７３－１．８０（２Ｈ、ｍ）、２．０７－２．１２（２Ｈ、ｍ）、２．５７－２．６４（４Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．１３（２Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、５．４０（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．２２（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４４－７．４７（２Ｈ、ｍ）、７．８７（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 3-heptin-1-ol (0.376 ml) and {5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (330 mg) as a white powder.
MS (ESI) m / z: 374 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.90 (3H, t, J = 7.2 Hz), 1.36-1.46 (2H, m), 1.73-1.80 (2H, m), 2.07-2.12 (2H, m), 2.57-2.64 (4H, m), 3.52 (4H, d, J = 4.8 Hz), 4.13 (2H, t, J = 6.6 Hz), 5.40 (2H, t, J = 5.0 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.44-7.47 ( 2H, m), 7.87 (3H, brs).
　実施例７
２－アミノ－２－｛２－［４－（５－ヘキセニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 7
2-Amino-2- {2- [4- (5-hexenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（７－１）２－アミノ－２－｛２－［４－（５－ヘキセニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物７－１） (7-1) Synthesis of 2-amino-2- {2- [4- (5-hexenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 7-1)
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（４９４ｍｇ）、６－ブロモ－１－ヘキセン（０．２０１ｍｌ）を加え、８０℃にて１時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、無色油状物を５６０ｍｇ得た。その無色油状物（５６０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４２０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３６２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．４６－１．５４（２Ｈ、ｍ）、１．６８－１．８０（４Ｈ、ｍ）、２．０５－２．１１（２Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．０７（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．９６（１Ｈ、ｄ、Ｊ＝１０．２Ｈｚ）、５．０３（１Ｈ、ｂｒｄ、Ｊ＝１７．１Ｈｚ）、５．３９（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、５．８１（１Ｈ、ｄｄｔ、Ｊ＝１７．１、１０．２、６．７Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８２（３Ｈ、ｂｒｓ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and 6-bromo-1-hexene (0.201 ml) were added, and the mixture was stirred at 80 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 560 mg of a colorless oil. The colorless oil (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.
MS (ESI) m / z: 362 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.46-1.54 (2H, m), 1.68-1.80 (4H, m), 2.05-2.11 (2H) M), 2.58-2.63 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.07 (2H, t, J = 6.2 Hz), 4.96 (1H, d, J = 10.2 Hz), 5.03 (1H, brd, J = 17.1 Hz), 5.39 (2H, t, J = 5.0 Hz), 5.81 (1H, ddt, J = 17.1, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.82 (3H, brs) ).
　実施例８
２－アミノ－２－｛２－［４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 8
2-Amino-2- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（８－１）２－アミノ－２－｛２－［４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物８－１） (8-1) Synthesis of 2-amino-2- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 8-1)
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、２－ヘプチン－１－オール（０．３７２ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを淡黄色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５００ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８３（３Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．２５－１．３２（２Ｈ、ｍ）、１．３３－１．４２（２Ｈ、ｍ）、１．７４－１．７９（２Ｈ、ｍ）、２．１９－２．２３（２Ｈ、ｍ）、２．５９－２．６５（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．９０（２Ｈ、ｓ）、５．４１（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、７．２５（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、７．４７－７．４９（２Ｈ、ｍ）、７．８７（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml) and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 2-heptin-1-ol (0.372 ml) and {5- [2- ( 4-hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a pale yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.
MS (ESI) m / z: 374 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.83 (3H, t, J = 7.2 Hz), 1.25-1.32 (2H, m), 1.33-1.42 (2H, m), 1.74-1.79 (2H, m), 2.19-2.23 (2H, m), 2.59-2.65 (2H, m), 3.52 (4H , D, J = 4.8 Hz), 4.90 (2H, s), 5.41 (2H, t, J = 5.1 Hz), 7.25 (1H, d, J = 9.2 Hz), 7 .47-7.49 (2H, m), 7.87 (3H, brs).
　実施例９
２－アミノ－２－｛２－［４－（６－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 9
2-Amino-2- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（９－１）６－ヘプチン－１－オールの合成（化合物９－１） (9-1) Synthesis of 6-heptin-1-ol (Compound 9-1)
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　６－ヘプチン酸（２．００ｇ）を１，２－ジクロロエタン（３０ｍｌ）に溶解し、０℃にて触媒量のＮ，Ｎ－ジメチルホルムアミドとオキザリルクロリド（３．３０ｍｌ）を加え、室温で２時間攪拌した。再び０℃に戻し、反応液にメタノール（２０ｍｌ）を加え、３０分攪拌した後、溶媒を濃縮した。得られた残渣にジエチルエーテルと水を加え、ジエチルエーテルで抽出後、飽和炭酸水素ナトリウム水溶液と食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去し淡黄色油状物を得た。その油状物をテトラヒドロフラン（４０ｍｌ）に溶解させ、－７８℃にて１ｍｏｌ／ｌ水素化ジイソブチルアルミニウム／トルエン溶液（３６．９ｍｌ）を滴下し、－７８℃で２時間攪拌した。反応液に（＋）－酒石酸ナトリウムカリウム水溶液を加え室温まで昇温しながら攪拌した後、酢酸エチルで抽出後、飽和炭酸水素ナトリウム水溶液、水そして食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を濃縮した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（１．３１ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２４（１Ｈ、ｂｒｓ）、１．４６－１．５４（２Ｈ、ｍ）、１．５４－１．６３（４Ｈ、ｍ）、１．９５（１Ｈ、ｔ、Ｊ＝２．６Ｈｚ）、２．１９－２．２３（２Ｈ、ｍ）、３．６３－３．６９（２Ｈ、ｍ）。 6-Heptynoic acid (2.00 g) is dissolved in 1,2-dichloroethane (30 ml), and catalytic amounts of N, N-dimethylformamide and oxalyl chloride (3.30 ml) are added at 0 ° C., and 2 at room temperature. Stir for hours. The temperature was returned again to 0 ° C., methanol (20 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then the solvent was concentrated. Diethyl ether and water were added to the resulting residue, extracted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oil. It was. The oil was dissolved in tetrahydrofuran (40 ml), 1 mol / l diisobutylaluminum hydride / toluene solution (36.9 ml) was added dropwise at −78 ° C., and the mixture was stirred at −78 ° C. for 2 hours. (+)-Potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred while warming to room temperature, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (1.31 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.24 (1H, brs), 1.46-1.54 (2H, m), 1.54-1.63 (4H, m), 95 (1H, t, J = 2.6 Hz), 2.19-2.23 (2H, m), 3.63-3.69 (2H, m).
　（９－２）２－アミノ－２－｛２－［４－（６－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物９－２） (9-2) Synthesis of 2-amino-2- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 9-2)
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、化合物９－１（０．３２１ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で６時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（６－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５００ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．４８－１．５２（４Ｈ、ｍ）、１．６９－１．７８（４Ｈ、ｍ）、２．１４－２．１９（２Ｈ、ｍ）、２．５６－２．６３（２Ｈ、ｍ）、２．７５（１Ｈ、ｔ、Ｊ＝２．４Ｈｚ）、３．５１（４Ｈ、ｄ、Ｊ＝４．６Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．３９（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．１９（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４３－７．４５（２Ｈ、ｍ）、７．７９（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), compound 9-1 (0.321 ml) and {5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.
MS (ESI) m / z: 374 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.48-1.52 (4H, m), 1.69-1.78 (4H, m), 2.14-2.19 (2H) M), 2.56-2.63 (2H, m), 2.75 (1H, t, J = 2.4 Hz), 3.51 (4H, d, J = 4.6 Hz), 4.06 (2H, t, J = 6.2 Hz), 5.39 (2H, t, J = 5.0 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.43-7.45 ( 2H, m), 7.79 (3H, brs).
　実施例１０
２－アミノ－２－｛２－［４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 10
2-Amino-2- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
（１０－１）６－フルオロヘキサノールの合成（化合物１０－１）
Figure JPOXMLDOC01-appb-C000095
 (10-1) Synthesis of 6-fluorohexanol (Compound 10-1)
Figure JPOXMLDOC01-appb-C000095
　６－ブロモヘキサノール（３．００ｇ）のテトラヒドロフラン（５０ｍｌ）溶液に、テトラブチルアンモニウムフルオリドの１ｍｏｌ／ｌテトラヒドロフラン溶液（７８．５ｍｌ）を加え、５時間還流した。反応溶液を濃縮し、水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（１．１６ｇ）を褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２４（１Ｈ、ｂｒｓ）、１．３６－１．４９（４Ｈ、ｍ）、１．５３－１．６４（２Ｈ、ｍ）、１．６４－１．７１（１Ｈ、ｍ）、１．７１－１．７７（１Ｈ、ｍ）、３．６３－３．６７（２Ｈ、ｍ）、４．４５（２Ｈ、ｄｔ、Ｊ＝４７．１、６．２Ｈｚ）。 To a solution of 6-bromohexanol (3.00 g) in tetrahydrofuran (50 ml), a 1 mol / l tetrahydrofuran solution (78.5 ml) of tetrabutylammonium fluoride was added and refluxed for 5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.16 g) as a brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.24 (1H, brs), 1.36-1.49 (4H, m), 1.53-1.64 (2H, m), 64-1.71 (1H, m), 1.71-1.77 (1H, m), 3.63-3.67 (2H, m), 4.45 (2H, dt, J = 47.1) 6.2 Hz).
　（１０－２）１－フルオロ－６－ヨードヘキサンの合成（化合物１０－２） (10-2) Synthesis of 1-fluoro-6-iodohexane (Compound 10-2)
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　化合物１０－１（１．１６ｇ）を塩化メチレン（２０ｍｌ）に溶解させ、氷冷下トリエチルアミン（１．７６ｍｌ）と塩化メタンスルホニル（０．８９６ｍｌ）を加え、そのまま氷冷下で３時間攪拌した。反応液を塩化メチレン（２０ｍｌ）で希釈後、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣の２－ブタノン（６０ｍｌ）溶液にヨウ化ナトリウム（１．７４ｇ）を加え、６時間還流した。反応溶液を濃縮し、水を加えた後、ジエチルエーテルで抽出した。有機層をチオ硫酸ナトリウム水溶液、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、目的物（１．７６ｇ）を淡褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４０－１．５２（４Ｈ、ｍ）、１．６４－１．７１（１Ｈ、ｍ）、１．７１－１．７９（１Ｈ、ｍ）、１．８０－１．８９（２Ｈ、ｍ）、３．２０（２Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、４．４５（２Ｈ、ｄｔ、Ｊ＝４７．５、６．１Ｈｚ）。 Compound 10-1 (1.16 g) was dissolved in methylene chloride (20 ml), triethylamine (1.76 ml) and methanesulfonyl chloride (0.896 ml) were added under ice cooling, and the mixture was stirred as such for 3 hours under ice cooling. The reaction mixture was diluted with methylene chloride (20 ml), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Sodium iodide (1.74 g) was added to a solution of the obtained residue in 2-butanone (60 ml), and the mixture was refluxed for 6 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.76 g) as a pale-brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.40-1.52 (4H, m), 1.64-1.71 (1H, m), 1.71-1.79 (1H, m ), 1.80-1.89 (2H, m), 3.20 (2H, t, J = 6.8 Hz), 4.45 (2H, dt, J = 47.5, 6.1 Hz).
　（１０－３）（５－｛２－［４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルの合成（化合物１０－３） (10-3) (5- {2- [4- (6-Fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (Compound 10-3)
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（５９３ｍｇ）、化合物１０－２（４１６ｍｇ）を加え、８０℃にて１時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（５００ｍｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４２－１．６０（４Ｈ、ｍ）、１．４３（３Ｈ、ｓ）、１．４４（３Ｈ、ｓ）、１．４７（９Ｈ、ｓ）、１．６６－１．７４（１Ｈ、ｍ）、１．７４－１．７９（１Ｈ、ｍ）、１．７９－１．８５（２Ｈ、ｍ）、１．９４－１．９９（２Ｈ、ｍ）、２．５１－２．５６（２Ｈ、ｍ）、３．６９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、３．８９（２Ｈ、ｄ、Ｊ＝１１．７Ｈｚ）、４．０１（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．４５（２Ｈ、ｄｔ、Ｊ＝４７．５、Ｊ＝６．１Ｈｚ）、４．９９（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２８（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）、７．３５（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (593 mg) and compound 10-2 (416 mg) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (500 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.42-1.60 (4H, m), 1.43 (3H, s), 1.44 (3H, s), 1.47 (9H, s), 1.66-1.74 (1H, m), 1.74-1.79 (1H, m), 1.79-1.85 (2H, m), 1.94-1.99 ( 2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 (2H, d, J = 11.7 Hz), 4. 01 (2H, t, J = 6.2 Hz), 4.45 (2H, dt, J = 47.5, J = 6.1 Hz), 4.99 (1H, brs), 6.88 (1H, d , J = 8.4 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.35 (1H, d, J = 1.6 Hz).
　（１０－４）２－アミノ－２－｛２－［４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１０－４） (10-4) Synthesis of 2-amino-2- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 10-4) )
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　化合物１０－３（５００ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（３７０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３８２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３８－１．４９（４Ｈ、ｍ）、１．５８－１．６４（１Ｈ、ｍ）、１．６４－１．７９（５Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．７Ｈｚ）、４．０７（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．４３（２Ｈ、ｄｔ、Ｊ＝４７．５、６．１Ｈｚ）、５．４０（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８３（３Ｈ、ｂｒｓ）。 Compound 10-3 (500 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (370 mg) as a white powder.
MS (ESI) m / z: 382 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.38-1.49 (4H, m), 1.58-1.64 (1H, m), 1.64-1.79 (5H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.07 (2H, t, J = 6.2 Hz), 4.43 (2H, dt, J = 47.5, 6.1 Hz), 5.40 (2H, t, J = 5.0 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.43- 7.46 (2H, m), 7.83 (3H, brs).
　実施例１１
２－アミノ－２－｛２－［４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 11
2-Amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１１－１）２－アミノ－２－｛２－［４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１１－１） (11-1) Synthesis of 2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 11-1) )
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（４９４ｍｇ）、８－ブロモ－１－オクテン（０．２４７ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、淡黄色油状物を６１０ｍｇ得た。その淡黄色油状物（６１０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４４０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．２９－１．４６（６Ｈ、ｍ）、１．６６－１．７９（４Ｈ、ｍ）、１．９８－２．０５（２Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．９３（１Ｈ、ｄ、Ｊ＝１０．２Ｈｚ）、５．０３（１Ｈ、ｄｄ、Ｊ＝１７．２、１．９Ｈｚ）、５．４０（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、５．８０（１Ｈ、ｄｄｔ、Ｊ＝１７．２、１０．２、６．７Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８５（３Ｈ、ｂｒｓ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and 8-bromo-1-octene (0.247 ml) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 610 mg of a pale yellow oil. The pale yellow oil (610 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (440 mg) as a white powder.
MS (ESI) m / z: 390 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.29-1.46 (6H, m), 1.66-1.79 (4H, m), 1.98-2.05 (2H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.8 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.93 (1H, d, J = 10.2 Hz), 5.03 (1H, dd, J = 17.2, 1.9 Hz), 5.40 (2H, t, J = 5.1 Hz), 5.80 ( 1H, ddt, J = 17.2, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.85 (3H, brs).
　実施例１２
２－アミノ－２－｛２－［４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 12
2-Amino-2- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１２－１）２－アミノ－２－｛２－［４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１２－１） (12-1) 2-amino-2- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol Synthesis of hydrochloride (compound 12-1)
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、４，４，５，５，５－ペンタフルオロペンタノール（０．４０６ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５９０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４４０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．７２－１．７９（２Ｈ、ｍ）、１．９３－２．０２（２Ｈ、ｍ）、２．３０－２．４５（２Ｈ、ｍ）、２．５８－２．６７（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．６Ｈｚ）、４．１８（２Ｈ、ｔ、Ｊ＝５．９Ｈｚ）、５．３９（２Ｈ、ｔ、Ｊ＝４．９Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．４５－７．４８（２Ｈ、ｍ）、７．７７（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 4,4,5,5,5-pentafluoropentanol (0.406 ml) and {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added at room temperature. For 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} -2,2 -Dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester was obtained as a colorless oily substance, and concentrated hydrochloric acid (1.5 ml) was added to an ethanol (15 ml) solution of the oily substance at 80 ° C. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (590 mg) as a white powder.
MS (ESI) m / z: 440 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.72-1.79 (2H, m), 1.93-2.02 (2H, m), 2.30-2.45 (2H) M), 2.58-2.67 (2H, m), 3.51 (4H, d, J = 4.6 Hz), 4.18 (2H, t, J = 5.9 Hz), 5.39 (2H, t, J = 4.9 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.45-7.48 (2H, m), 7.77 (3H, brs).
　実施例１３
２－アミノ－２－｛２－［４－（１－エチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 13
2-Amino-2- {2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１３－１）２－アミノ－２－｛２－［４－（１－エチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１３－１） (13-1) Synthesis of 2-amino-2- {2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 13-1) )
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、３－ノナノール（０．５１８ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（５－｛２－［４－（１－エチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２,２－ジメチル－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４６０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８４（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、０．８８（３Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、１．１９－１．３９（８Ｈ、ｍ）、１．５４－１．６９（４Ｈ、ｍ）、１．７３－１．７９（２Ｈ、ｍ）、２．５７－２．６２（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．４２－４．４８（１Ｈ、ｍ）、５．４１（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４２（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４４（１Ｈ、ｂｒｓ）、７．８６（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 3-nonanol (0.518 ml) and {5- [2- (4-hydroxy- 3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (460 mg) as a white powder.
MS (ESI) m / z: 406 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.84 (3H, t, J = 6.9 Hz), 0.88 (3H, t, J = 7.4 Hz), 1.19-1 .39 (8H, m), 1.54-1.69 (4H, m), 1.73-1.79 (2H, m), 2.57-2.62 (2H, m), 3.52 (4H, d, J = 4.8 Hz), 4.42-4.48 (1H, m), 5.41 (2H, t, J = 5.1 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.44 (1H, brs), 7.86 (3H, brs).
　実施例１４
（Ｒ）－２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 14
(R) -2-Amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１４－１）（Ｒ）－２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１４－１） (14-1) Synthesis of (R) -2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride ( Compound 14-1)
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、（Ｓ）－（＋）－２－オクタノール（０．４６３ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（Ｒ）－（２,２－ジメチル－５－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを白色固体として得た。その固体のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジイソプロピルエーテルにて洗浄し、目的物（５２０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８５（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２２（３Ｈ、ｄ、Ｊ＝６．１Ｈｚ）、１．２２－１．３１（６Ｈ、ｍ）、１．３１－１．４３（２Ｈ、ｍ）、１．５２－１．６６（２Ｈ、ｍ）、１．７４－１．７８（２Ｈ、ｍ）、２．５７－２．６２（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．５５－４．６２（１Ｈ、ｍ）、５．４０（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４１－７．４４（２Ｈ、ｍ）、７．８３（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), (S)-(+)-2-octanol (0.463 ml) and {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain (R)-(2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1, 3-Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give the object product (520 mg) as a white powder.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.85 (3H, t, J = 6.8 Hz), 1.22 (3H, d, J = 6.1 Hz), 1.22-1 .31 (6H, m), 1.31-1.43 (2H, m), 1.52-1.66 (2H, m), 1.74-1.78 (2H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.55-4.62 (1H, m), 5.40 (2H, t, J = 5. 1 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.41-7.44 (2H, m), 7.83 (3H, brs).
　実施例１５
（Ｓ）－２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 15
(S) -2-Amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１５－１）（Ｓ）－２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１５－１） (15-1) Synthesis of (S) -2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride ( Compound 15-1)
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、（Ｒ）－（－）－２－オクタノール（０．４６３ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（Ｓ）－（２,２－ジメチル－５－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを白色固体として得た。その固体のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５１０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８５（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２２（３Ｈ、ｄ、Ｊ＝５．９Ｈｚ）、１．２２－１．３１（６Ｈ、ｍ）、１．３１－１．４３（２Ｈ、ｍ）、１．５２－１．６７（２Ｈ、ｍ）、１．７３－１．７８（２Ｈ、ｍ）、２．５７－２．６２（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．７Ｈｚ）、４．５５－４．６２（１Ｈ、ｍ）、５．３９（２Ｈ、ｔ、Ｊ＝５．１Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４１－７．４４（２Ｈ、ｍ）、７．８３（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), (R)-(−)-2-octanol (0.463 ml) and {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain (S)-(2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1, 3-Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (510 mg) as a white powder.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.85 (3H, t, J = 6.9 Hz), 1.22 (3H, d, J = 5.9 Hz), 1.22-1 .31 (6H, m), 1.31-1.43 (2H, m), 1.52-1.67 (2H, m), 1.73-1.78 (2H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.7 Hz), 4.55-4.62 (1H, m), 5.39 (2H, t, J = 5. 1 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.41-7.44 (2H, m), 7.83 (3H, brs).
　実施例１６
２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 16
2-Amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１６－１）２－アミノ－２－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１６－１） (16-1) Synthesis of 2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 16-1) )
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（４０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、２－オクタノール（０．４６９ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で３時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（２,２－ジメチル－５－｛２－［４－（１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを白色固体として得た。その固体のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４７０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８４（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２２（３Ｈ、ｄ、Ｊ＝６．０Ｈｚ）、１．２２－１．３１（６Ｈ、ｍ）、１．３２－１．４３（２Ｈ、ｍ）、１．５２－１．６７（２Ｈ、ｍ）、１．７３－１．７８（２Ｈ、ｍ）、２．５６－２．６１（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．８Ｈｚ）、４．５５－４．６１（１Ｈ、ｍ）、５．３９（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４０－７．４４（２Ｈ、ｍ）、７．７９（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 2-octanol (0.469 ml) and {5- [2- (4-hydroxy- 3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (470 mg) as a white powder.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.84 (3H, t, J = 6.9 Hz), 1.22 (3H, d, J = 6.0 Hz), 1.22-1 .31 (6H, m), 1.32-1.43 (2H, m), 1.52-1.67 (2H, m), 1.73-1.78 (2H, m), 2.56 -2.61 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.55-4.61 (1H, m), 5.39 (2H, t, J = 5. 0 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.40-7.44 (2H, m), 7.79 (3H, brs).
　実施例１７
（Ｒ）－２－アミノ－２－｛２－［４－（３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 17
(R) -2-Amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１７－１）（Ｒ）－２－アミノ－２－｛２－［４－（３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１７－１） (17-1) (R) -2-Amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride Synthesis (Compound 17-1)
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（４９４ｍｇ）、（Ｒ）－（－）－シトロネリルブロミド（０．２９１ｍｌ）を加え、８０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、白色固体を６８０ｍｇ得た。その白色固体（６８０ｍｇ）を酢酸エチル（２０ｍｌ）に溶解させ、１０％パラジウム炭素（２００ｍｇ）を加え、水素雰囲気下、室温で６時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮した。得られた残渣をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４２０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４２０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８４（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、０．８９（３Ｈ、ｄ、Ｊ＝６．４Ｈｚ）、１．１０－１．２０（３Ｈ、ｍ）、１．２１－１．３６（３Ｈ、ｍ）、１．４５－１．５４（２Ｈ、ｍ）、１．６０－１．７０（１Ｈ、ｍ）、１．７１－１．７９（３Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．６Ｈｚ）、４．０４－４．１４（２Ｈ、ｍ）、５．４０（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８３（３Ｈ、ｂｒｓ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and (R)-(-)-citronellyl bromide (0.291 ml) were added, and the mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 680 mg of a white solid. The white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium carbon (200 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.
MS (ESI) m / z: 420 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.84 (6H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.4 Hz), 1.10-1 .20 (3H, m), 1.21-1.36 (3H, m), 1.45-1.54 (2H, m), 1.60-1.70 (1H, m), 1.71 −1.79 (3H, m), 2.58−2.63 (2H, m), 3.52 (4H, d, J = 4.6 Hz), 4.04−4.14 (2H, m) 5.40 (2H, t, J = 5.0 Hz), 7.20 (1H, d, J = 8.7 Hz), 7.43-7.46 (2H, m), 7.83 (3H, brs).
　実施例１８
（Ｓ）－２－アミノ－２－｛２－［４－（３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 18
(S) -2-Amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１８－１）（Ｓ）－２－アミノ－２－｛２－［４－（３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１８－１） (18-1) (S) -2-Amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride Synthesis (Compound 18-1)
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（４９４ｍｇ）、（Ｓ）－（＋）－シトロネリルブロミド（０．２９１ｍｌ）を加え、８０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、白色固体を７４０ｍｇ得た。その白色固体（６８０ｍｇ）を酢酸エチル（２０ｍｌ）に溶解させ、１０％パラジウム炭素（４００ｍｇ）を加え、水素雰囲気下、室温で６時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮した。得られた残渣をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（４９０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４２０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８４（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、０．８９（３Ｈ、ｄ、Ｊ＝６．５Ｈｚ）、１．０９－１．２０（３Ｈ、ｍ）、１．２１－１．３５（３Ｈ、ｍ）、１．４５－１．５４（２Ｈ、ｍ）、１．６１－１．７１（１Ｈ、ｍ）、１．７２－１．７９（３Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．９Ｈｚ）、４．０５－４．１３（２Ｈ、ｍ）、５．４０（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８３（３Ｈ、ｂｒｓ）。 {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and (S)-(+)-citronellyl bromide (0.291 ml) were added, and the mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 740 mg of a white solid. The white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium on carbon (400 mg) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (490 mg) as a white powder.
MS (ESI) m / z: 420 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.84 (6H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.5 Hz), 1.09-1 .20 (3H, m), 1.21-1.35 (3H, m), 1.45-1.54 (2H, m), 1.61-1.71 (1H, m), 1.72 -1.79 (3H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.05-4.13 (2H, m) 5.40 (2H, t, J = 5.0 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.83 (3H, brs).
　実施例１９
２－アミノ－２－｛２－［４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 19
2-Amino-2- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（１９－１）２－メチル－１－ヘプタノールの合成（化合物１９－１） (19-1) Synthesis of 2-methyl-1-heptanol (Compound 19-1)
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　２－メチルヘプタン酸（２．００ｇ）をテトラヒドロフラン（５０ｍｌ）に溶解させ、氷冷下でテトラヒドロフラン－ボラン・テトラヒドロフラン溶液（１ｍｏｌ／ｌ、１７．７ｍｌ）を滴下した後、そのまま氷冷下３０分、さらに室温で２０時間攪拌した。反応液に水、１ｍｏｌ／ｌ塩酸水溶液を加え、酢酸エチルで抽出後、水、飽和炭酸水素ナトリウム水溶液そして飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（１．７３ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３６－１．４４（７Ｈ、ｍ）、１．０５－１．１４（１Ｈ、ｍ）、１．２０－１．４２（６Ｈ、ｍ）、１．５７－１．６６（２Ｈ、ｍ）、３．３９－３．４３（１Ｈ、ｍ）、３．４８－３．５３（１Ｈ、ｍ）。 2-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (50 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice-cooling. The mixture was further stirred at room temperature for 20 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (1.73 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.36-1.44 (7H, m), 1.05-1.14 (1H, m), 1.20-1.42 (6H, m ), 1.57-1.66 (2H, m), 3.39-3.43 (1H, m), 3.48-3.53 (1H, m).
　（１９－２）２－アミノ－２－｛２－［４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物１９－２） (19-2) Synthesis of 2-amino-2- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 19-2) )
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　トリフェニルホスフィン（６２５ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．２７ｍｌ）、化合物１９－１（０．３１０ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（５００ｍｇ）を加え、室温で４時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（２,２－ジメチル－５－｛２－［４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（２９０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、０．９７（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）、１．１６－１．３９（７Ｈ、ｍ）、１．４１－１．５１（１Ｈ、ｍ）、１．７３－１．７８（２Ｈ、ｍ）、１．８２－１．９１（１Ｈ、ｍ）、２．５７－２．６２（２Ｈ、ｍ）、３．５１（４Ｈ、ｄ、Ｊ＝４．５Ｈｚ）、３．８２－３．８６（１Ｈ、ｍ）、３．９０－３．９４（１Ｈ、ｍ）、５．３９（２Ｈ、ｔ、Ｊ＝４．９Ｈｚ）、７．１７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４２－７．４６（２Ｈ、ｍ）、７．７６（３Ｈ、ｂｒｓ）。 Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.27 ml), compound 19-1 (0.310 ml) and {5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added, and the mixture was stirred at room temperature for 4 and a half hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (290 mg) as a white powder.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.16-1 .39 (7H, m), 1.41-1.51 (1H, m), 1.73-1.78 (2H, m), 1.82-1.91 (1H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.5Hz), 3.82-3.86 (1H, m), 3.90-3.94 (1H, m) 5.39 (2H, t, J = 4.9 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.42-7.46 (2H, m), 7.76 (3H, brs).
　実施例２０
２－アミノ－２－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩 Example 20
2-Amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride
　（２０－１）６－メチル－１－ヘプタノールの合成（化合物２０－１） (20-1) Synthesis of 6-methyl-1-heptanol (Compound 20-1)
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　６－メチルヘプタン酸（２．００ｇ）をテトラヒドロフラン（６０ｍｌ）に溶解させ、氷冷下でテトラヒドロフラン－ボラン・テトラヒドロフラン溶液（１ｍｏｌ／ｌ、１７．７ｍｌ）を滴下した後、そのまま氷冷下３０分、さらに室温で４時間攪拌した。反応液に水、１ｍｏｌ／ｌ塩酸水溶液を加え、酢酸エチルで抽出後、水、飽和炭酸水素ナトリウム水溶液そして飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（１．７２ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８７（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、１．１４－１．２５（３Ｈ、ｍ）、１．２５－１．３７（４Ｈ、ｍ）、１．４８－１．６０（３Ｈ、ｍ）、３．６４（２Ｈ、ｂｒｓ）。 6-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (60 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice-cooling. The mixture was further stirred at room temperature for 4 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (1.72 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 1.14-1.25 (3H, m), 1.25-1.37 (4H) , M), 1.48-1.60 (3H, m), 3.64 (2H, brs).
　（２０－２）２－アミノ－２－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール塩酸塩の合成（化合物２０－２） (20-2) Synthesis of 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 20-2) )
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　トリフェニルホスフィン（７５０ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジイソプロピル（４０％トルエン溶液、１．５１ｍｌ）、化合物２０－１（０．３７２ｍｌ）と｛５－［２－（４－ヒドロキシ－３－トリフルオロメチルフェニル）エチル］－２,２－ジメチル－１,３－ジオキサン－５－イル｝カルバミン酸ｔ－ブチルエステル（６００ｍｇ）を加え、室温で３時間半攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製し（２,２－ジメチル－５－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－１,３－ジオキサン－５－イル）カルバミン酸ｔ－ブチルエステルを無色油状物として得た。その油状物のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（５３０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８５（６Ｈ、ｄ、Ｊ＝６．７Ｈｚ）、１．１２－１．１８（２Ｈ、ｍ）、１．２７－１．３６（２Ｈ、ｍ）、１．３６－１．４３（２Ｈ、ｍ）、１．４６－１．５５（１Ｈ、ｍ）、１．６７－１．７９（４Ｈ、ｍ）、２．５８－２．６３（２Ｈ、ｍ）、３．５２（４Ｈ、ｄ、Ｊ＝４．６Ｈｚ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．４２（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）、７．８４（３Ｈ、ｂｒｓ）。 Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), compound 20-1 (0.372 ml) and {5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (530 mg) as a white powder.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.85 (6H, d, J = 6.7 Hz), 1.12-1.18 (2H, m), 1.27-1.36 (2H, m), 1.36-1.43 (2H, m), 1.46-1.55 (1H, m), 1.67-1.79 (4H, m), 2.58-2 .63 (2H, m), 3.52 (4H, d, J = 4.6 Hz), 4.06 (2H, t, J = 6.2 Hz), 5.42 (2H, t, J = 5. 0 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.43-7.46 (2H, m), 7.84 (3H, brs).
　実施例２１
２－アミノ－４－｛４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 21
2-Amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２１－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２１－１） (21-1) 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline Synthesis of Compound 21-1
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　化合物１－４（２５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３０２ｍｌ）、オルト酢酸トリメチル（０．１４２ｍｌ）を加え、１２０℃にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を２８０ｍｇ得た。その褐色油状物（２８０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（７８ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．３３５ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．３３６ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３４０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３５－１．４５（６Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．４９－１．５５（２Ｈ、ｍ）、１．６０－１．７２（２Ｈ、ｍ）、１．７３－１．８９（４Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．７０（２Ｈ、ｍ）、３．８７－３．９３（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．４０（２Ｈ、ｄｔ、Ｊ＝４７．６、６．２Ｈｚ）、７．０５（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．３９（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４０（１Ｈ、ｂｒｓ）。 To a solution of compound 1-4 (250 mg) in N, N-dimethylformamide (10 ml) was added N, N-diisopropylethylamine (0.302 ml) and trimethyl orthoacetate (0.142 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 280 mg of a brown oil. To a solution of the brown oil (280 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (78 mg) and di-t-butyldiethylphosphoramidite (0.335 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.336 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (340 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 1.35 to 1.45 (6H, m), 1.48 (18H, s), 1.49 to 1.55 (2H, m), 1 .60-1.72 (2H, m), 1.73-1.89 (4H, m), 2.01 (3H, s), 2.52-2.70 (2H, m), 3.87 −3.93 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.40 (2H, dt, J = 47.6, 6.2 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8) .6 Hz), 7.40 (1H, brs).
　（２１－２）２－アミノ－４－｛４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２１－２） (21-2) Synthesis of 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 21-2)
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　化合物２１－１（３４０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２００ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４９０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３５－１．４６（６Ｈ、ｍ）、１．４６－１．５６（２Ｈ、ｍ）、１．６１－１．６８（１Ｈ、ｍ）、１．６８－１．７４（１Ｈ、ｍ）、１．７５－１．８２（２Ｈ、ｍ）、１．９２－１．９８（２Ｈ、ｍ）、２．６３－２．７２（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０２（２Ｈ、ｍ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．４０（２Ｈ、ｄｔ、Ｊ＝４７．５、６．１Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 21-1 (340 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (200 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 490 [M + H]
1 H-NMR (CD 3 OD ) δ (ppm): 1.35-1.46 (6H, m), 1.46-1.56 (2H, m), 1.61-1.68 (1H, m), 1.68-1.74 (1H, m), 1.75-1.82 (2H, m), 1.92-1.98 (2H, m), 2.63-2.72 ( 2H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.05 (2H, t, J = 6.2 Hz), 4.40 (2H, dt, J = 47.5, 6.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m).
　実施例２２
（Ｚ）－２－アミノ－４－｛４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 22
(Z) -2-Amino-4- {4- (4-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２２－１）（Ｚ）－４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２２－１） (22-1) (Z) -4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2 -Synthesis of Oxazoline (Compound 22-1)
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　化合物２－１（３４０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４４５ｍｌ）、オルト酢酸トリメチル（０．２１０ｍｌ）を加え、１２０℃にて４時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３７０ｍｇ得た。その褐色油状物（３７０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１１６ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４９７ｍｌ）を加え、室温で３時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４９８ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３００ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、１．４８（１８Ｈ、ｓ）、１．７９－１．９０（４Ｈ、ｍ）、２．００－２．０７（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．２２－２．２８（２Ｈ、ｍ）、２．５２－２．７０（２Ｈ、ｍ）、３．８７－３．９４（２Ｈ、ｍ）、４．０３（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、４．１９（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３３（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、５．３１－５．４７（２Ｈ、ｍ）、７．０４（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４１（１Ｈ、ｂｒｓ）。 To a solution of compound 2-1 (340 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.445 ml) and trimethyl orthoacetate (0.210 ml) were added and stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 370 mg of a brown oil. To a solution of the brown oil (370 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (116 mg) and di-t-butyldiethylphosphoramidite (0.497 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.498 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (300 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 7.5 Hz), 1.48 (18H, s), 1.79-1.90 (4H, m) 2.00-2.07 (2H, m), 2.01 (3H, s), 2.22-2.28 (2H, m), 2.52-2.70 (2H, m), 3 .87-3.94 (2H, m), 4.03 (2H, t, J = 6.0 Hz), 4.19 (1H, d, J = 9.0 Hz), 4.33 (1H, d, J = 9.0 Hz), 5.31-5.47 (2H, m), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.41 (1H, brs).
　（２２－２）（Ｚ）－２－アミノ－４－｛４－（４－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２２－２） Synthesis of (22-2) (Z) -2-amino-4- {4- (4-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 22-2)
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　化合物２２－１（３００ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（３００ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、１．７８－１．８６（２Ｈ、ｍ）、１．９１－２．００（２Ｈ、ｍ）、２．００－２．０６（２Ｈ、ｍ）、２．２２－２．２８（２Ｈ、ｍ）、２．６１－２．７６（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０1（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝５．９Ｈｚ）、５．３１－５．４６（２Ｈ、ｍ）、７．０６（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４３（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４６（１Ｈ、ｂｒｓ）。 Compound 22-1 (300 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (300 mg ) Was obtained as a white solid.
MS (ESI) m / z: 456 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 7.5 Hz), 1.78-1.86 (2H, m), 1.91-2.00 ( 2H, m), 2.00-2.06 (2H, m), 2.22-2.28 (2H, m), 2.61-2.76 (2H, m), 3.70 (2H, brs), 3.94-4.01 (2H, m), 4.04 (2H, t, J = 5.9 Hz), 5.31-5.46 (2H, m), 7.06 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.46 (1H, brs).
　実施例２３
（Ｅ）－２－アミノ－４－｛４－（２－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 23
(E) -2-Amino-4- {4- (2-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２３－１）（Ｅ）－４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（２－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２３－１） (23-1) (E) -4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (2-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2 -Synthesis of Oxazoline (Compound 23-1)
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　化合物３－１（３９０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．５１２ｍｌ）、オルト酢酸トリメチル（０．２２１ｍｌ）を加え、１２０℃にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３８０ｍｇ得た。その褐色油状物（３８０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１３３ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５６９ｍｌ）を加え、室温で３時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５７０ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（５３０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、１．２８－１．４０（４Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．７９－１．８９（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．０６－２．１２（２Ｈ、ｍ）、２．５２－２．７０（２Ｈ、ｍ）、３．８７－３．９４（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．５６（２Ｈ、ｄ、Ｊ＝５．５Ｈｚ）、５．６４（１Ｈ、ｄｔ、Ｊ＝１５．４、５．５Ｈｚ）、５．８６（１Ｈ、ｄｔ、Ｊ＝１５．４、６．９Ｈｚ）、７．０６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４１（１Ｈ、ｂｒｓ）。 N, N-diisopropylethylamine (0.512 ml) and trimethyl orthoacetate (0.221 ml) were added to a solution of compound 3-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 380 mg of a brown oil. To a solution of the brown oil (380 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (133 mg) and di-t-butyldiethylphosphoramidite (0.569 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.570 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (530 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.90 (3H, t, J = 7.0 Hz), 1.28-1.40 (4H, m), 1.48 (18H, s) 1.79-1.89 (2H, m), 2.01 (3H, s), 2.06-2.12 (2H, m), 2.52-2.70 (2H, m), 3 .87-3.94 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.56 (2H, d, J = 5.5 Hz), 5.64 (1H, dt, J = 15.4, 5.5 Hz), 5.86 (1H, dt, J = 15.4, 6.9 Hz), 7.06 (1H , D, J = 8.5 Hz), 7.38 (1H, d, J = 8.5 Hz), 7.41 (1H, brs).
　（２３－２）（Ｅ）－２－アミノ－４－｛４－（２－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２３－２） (23-2) Synthesis of (E) -2-amino-4- {4- (2-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 23-2)
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　化合物２３－１（５３０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２１０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、１．２９－１．４２（４Ｈ、ｍ）、１．９１－２．００（２Ｈ、ｍ）、２．０５－２．１２（２Ｈ、ｍ）、２．６１－２．７４（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９６－４．０２（２Ｈ、ｍ）、４．５７（２Ｈ、ｄ、Ｊ＝５．５Ｈｚ）、５．６５（１Ｈ、ｄｔ、Ｊ＝１５．４、５．５Ｈｚ）、５．８６（１Ｈ、ｄｔ、Ｊ＝１５．４、６．８Ｈｚ）、７．０８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４３（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４６（１Ｈ、ｂｒｓ）。 Compound 23-1 (530 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (210 mg ) Was obtained as a white solid.
MS (ESI) m / z: 456 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.90 (3H, t, J = 7.0 Hz), 1.29-1.42 (4H, m), 1.91-2.00 ( 2H, m), 2.05-2.12 (2H, m), 2.61-2.74 (2H, m), 3.70 (2H, brs), 3.96-4.02 (2H, m), 4.57 (2H, d, J = 15.5 Hz), 5.65 (1H, dt, J = 15.4, 5.5 Hz), 5.86 (1H, dt, J = 15.4) 6.8 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.46 (1H, brs).
　実施例２４
２－アミノ－４－｛４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 24
2-Amino-4- {4- (6-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２４－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２４－１） (24-1) Synthesis of 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 24-1)
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　化合物４－１（３３０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４３１ｍｌ）、オルト酢酸トリメチル（０．２０３ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３５０ｍｇ得た。その褐色油状物（３５０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１１２ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４７９ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４８０ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（４３０ｍｇ）を橙色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．４４－１．５４（４Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．７５－１．８７（４Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．０６－２．１１（２Ｈ、ｍ）、２．５２－２．７０（２Ｈ、ｍ）、３．８７－３．９２（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、４．９２（１Ｈ、ｄ、Ｊ＝１０．４Ｈｚ）、５．００（１Ｈ、ｄｄ、Ｊ＝１７．１、１．５Ｈｚ）、５．８２（１Ｈ、ｄｄｔ、Ｊ＝１７．１、１０．４、６．５Ｈｚ）、７．０５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４０（１Ｈ、ｂｒｓ）。 N, N-Diisopropylethylamine (0.431 ml) and trimethyl orthoacetate (0.203 ml) were added to a solution of compound 4-1 (330 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 350 mg of a brown oil. To a solution of the brown oil (350 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (112 mg) and di-t-butyldiethylphosphoramidite (0.479 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.480 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (430 mg) as an orange oil.
1 H-NMR (CD 3 OD) δ (ppm): 1.44 to 1.54 (4H, m), 1.48 (18H, s), 1.75 to 1.87 (4H, m), 2 .01 (3H, s), 2.06-2.11 (2H, m), 2.52-2.70 (2H, m), 3.87-3.92 (2H, m), 4.04 (2H, t, J = 6.1 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 4.92 (1H, d, J = 10.4 Hz), 5.00 (1 H, dd, J = 17.1, 1.5 Hz), 5.82 (1 H, ddt, J = 17.1, 10.4, 6.5 Hz), 7 .05 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).
　（２４－２）２－アミノ－４－｛４－（６－ヘプテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２４－２） (24-2) Synthesis of 2-amino-4- {4- (6-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 24-2)
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　化合物２４－１（４３０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２７２ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．４１－１．５６（４Ｈ、ｍ）、１．７５－１．８３（２Ｈ、ｍ）、１．９２－１．９９（２Ｈ、ｍ）、２．０５－２．１１（２Ｈ、ｍ）、２．６１－２．７２（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０１（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．９２（１Ｈ、ｄ、Ｊ＝１０．４Ｈｚ）、４．９９（１Ｈ、ｄｄ、Ｊ＝１７．０、１．５Ｈｚ）、５．８２（１Ｈ、ｄｄｔ、Ｊ＝１７．０、１０．４、６．６Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 24-1 (430 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (272 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 456 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 1.41-1.56 (4H, m), 1.75-1.83 (2H, m), 1.92-1.99 (2H, m), 2.05-2.11 (2H, m), 2.61-2.72 (2H, m), 3.70 (2H, brs), 3.94-4.01 (2H, m) 4.04 (2H, t, J = 6.2 Hz), 4.92 (1H, d, J = 10.4 Hz), 4.99 (1H, dd, J = 17.0, 1.5 Hz), 5.82 (1H, ddt, J = 17.0, 10.4, 6.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m) .
　実施例２５
２－アミノ－４－｛４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 25
2-Amino-4- {4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２５－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２５－１） (25-1) 4-Di (t-butyl) phosphoryloxymethyl-4- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline Synthesis of Compound (Compound 25-1)
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　化合物５－４（２５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３１２ｍｌ）、オルト酢酸トリメチル（０．１４７ｍｌ）を加え、１２０℃にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を２８０ｍｇ得た。その褐色油状物（２３０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（７７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．３２９ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．３３０ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３３０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３５－１．４５（４Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．４８－１．５５（２Ｈ、ｍ）、１．６３－１．６８（１Ｈ、ｍ）、１．６８－１．７４（１Ｈ、ｍ）、１．７５－１．８９（４Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．７０（２Ｈ、ｍ）、３．８７－３．９３（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、４．４１（２Ｈ、ｄｔ、Ｊ＝４７．６、６．２Ｈｚ）、７．０６（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．３９（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４１（１Ｈ、ｂｒｓ）。 N, N-Diisopropylethylamine (0.312 ml) and trimethyl orthoacetate (0.147 ml) were added to a solution of compound 5-4 (250 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 280 mg of a brown oil. To a solution of the brown oil (230 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (77 mg) and di-t-butyldiethylphosphoramidite (0.329 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.330 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 1.35 to 1.45 (4H, m), 1.48 (18H, s), 1.48 to 1.55 (2H, m), 1 .63-1.68 (1H, m), 1.68-1.74 (1H, m), 1.75-1.89 (4H, m), 2.01 (3H, s), 2.52 -2.70 (2H, m), 3.87-3.93 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9. 2Hz), 4.32 (1H, d, J = 9.2 Hz), 4.41 (2H, dt, J = 47.6, 6.2 Hz), 7.06 (1H, d, J = 8.6 Hz) ), 7.39 (1H, d, J = 8.6 Hz), 7.41 (1H, brs).
　（２５－２）２－アミノ－４－｛４－（７－フルオロヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２５－２） (25-2) Synthesis of 2-amino-4- {4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 25-2)
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　化合物２５－１（３３０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（１６０ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３９－１．４６（４Ｈ、ｍ）、１．４７－１．５６（２Ｈ、ｍ）、１．６２－１．６８（１Ｈ、ｍ）、１．６８－１．７４（１Ｈ、ｍ）、１．７４－１．８２（２Ｈ、ｍ）、１．９２－１．９８（２Ｈ、ｍ）、２．６３－２．７２（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０３（２Ｈ、ｍ）、４．０５（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．４１（２Ｈ、ｄｔ、Ｊ＝４７．５、６．１Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 25-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (160 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 476 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 1.39-1.46 (4H, m), 1.47-1.56 (2H, m), 1.62-1.68 (1H, m), 1.68-1.74 (1H, m), 1.74-1.82 (2H, m), 1.92-1.98 (2H, m), 2.63-2.72 ( 2H, m), 3.70 (2H, brs), 3.94-4.03 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 4.41 (2H, dt, J = 47.5, 6.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m).
　実施例２６
２－アミノ－４－｛４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 26
2-Amino-4- {4- (3-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２６－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２６－１） (26-1) Synthesis of 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 26-1)
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　化合物６－１（２６０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３４２ｍｌ）、オルト酢酸トリメチル（０．１５９ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を２４０ｍｇ得た。その褐色油状物（２４０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（８５ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．３６０ｍｌ）を加え、室温で３時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．３６０ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３３０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９６（３Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、１．４３－１．５３（２Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．８０－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．０８－２．１４（２Ｈ、ｍ）、２．５３－２．７０（４Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．１１（２Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、７．０８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．３９－７．４２（２Ｈ、ｍ）。 N, N-Diisopropylethylamine (0.342 ml) and trimethyl orthoacetate (0.159 ml) were added to a solution of compound 6-1 (260 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 240 mg of a brown oil. To a solution of the brown oil (240 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (85 mg) and di-t-butyldiethylphosphoramidite (0.360 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.360 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.96 (3H, t, J = 7.4 Hz), 1.43-1.53 (2H, m), 1.48 (18H, s) 1.80-1.90 (2H, m), 2.01 (3H, s), 2.08-2.14 (2H, m), 2.53-2.70 (4H, m), 3 .88-3.92 (2H, m), 4.11 (2H, t, J = 6.9 Hz), 4.18 (1H, d, J = 9.2 Hz), 4.32 (1H, d, J = 9.2 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.39-7.42 (2H, m).
　（２６－２）２－アミノ－４－｛４－（３－ヘプチニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２６－２） (26-2) Synthesis of 2-amino-4- {4- (3-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 26-2)
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　化合物２６－１（３３０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（１８０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９６（３Ｈ、ｂｒｔ、Ｊ＝７．３Ｈｚ）、１．４０－１．５３（２Ｈ、ｍ）、１．９０－２．０２（２Ｈ、ｍ）、２．０５－２．１７（２Ｈ、ｍ）、２．５８－２．７８（４Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０２（２Ｈ、ｍ）、４．１２（２Ｈ、ｂｒｔ、Ｊ＝６．４Ｈｚ）、７．１０（１Ｈ、ｂｒｄ、Ｊ＝８．４Ｈｚ）、７．４３－７．４６（２Ｈ、ｍ）。 Compound 26-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (180 mg ) Was obtained as a white solid.
MS (ESI) m / z: 454 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.96 (3H, brt, J = 7.3 Hz), 1.40-1.53 (2H, m), 1.90-2.02 ( 2H, m), 2.05-2.17 (2H, m), 2.58-2.78 (4H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.12 (2H, brt, J = 6.4 Hz), 7.10 (1H, brd, J = 8.4 Hz), 7.43-7.46 (2H, m).
　実施例２７
２－アミノ－４－｛４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 27
2-Amino-4- {4- (2-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２７－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２７－１） (27-1) Synthesis of 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 27-1)
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　化合物８－１（３８０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４９９ｍｌ）、オルト酢酸トリメチル（０．２３５ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３８０ｍｇ得た。その褐色油状物（３８０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１３０ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５５７ｍｌ）を加え、室温で３時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５５８ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（５２０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８７（３Ｈ、ｔ、Ｊ＝７．３Ｈｚ）、１．３０－１．４０（２Ｈ、ｍ）、１．４０－１．５４（２Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．８２－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．１８－２．２２（２Ｈ、ｍ）、２．５３－２．７０（２Ｈ、ｍ）、３．８９－３．９２（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．７８（２Ｈ、ｂｒｓ）、７．１９（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．３９－７．４３（２Ｈ、ｍ）。 To a solution of compound 8-1 (380 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.499 ml) and trimethyl orthoacetate (0.235 ml) were added and stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 380 mg of a brown oil. To a solution of the brown oil (380 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (130 mg) and di-t-butyldiethylphosphoramidite (0.557 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.558 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.87 (3H, t, J = 7.3 Hz), 1.30-1.40 (2H, m), 1.40-1.54 ( 2H, m), 1.48 (18H, s), 1.82-1.90 (2H, m), 2.01 (3H, s), 2.18-2.22 (2H, m), 2 .53-2.70 (2H, m), 3.89-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.78 (2H, brs), 7.19 (1H, d, J = 8.4 Hz), 7.39-7.43 (2H, m).
　（２７－２）２－アミノ－４－｛４－（２－ヘプチニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２７－２） (27-2) Synthesis of 2-amino-4- {4- (2-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 27-2)
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　化合物２７－１（５２０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（３４５ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８８（３Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．２８－１．４１（２Ｈ、ｍ）、１．４２－１．４８（２Ｈ、ｍ）、１．９１－２．０５（２Ｈ、ｍ）、２．１９－２．２５（２Ｈ、ｍ）、２．６０－２．７８（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０２（２Ｈ、ｍ）、４．７９（２Ｈ、ｂｒｓ）、７．２０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４４－７．４７（２Ｈ、ｍ）。 Compound 27-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (345 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 454 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.88 (3H, t, J = 7.1 Hz), 1.28-1.41 (2H, m), 1.42-1.48 ( 2H, m), 1.91-2.05 (2H, m), 2.19-2.25 (2H, m), 2.60-2.78 (2H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.79 (2H, brs), 7.20 (1H, d, J = 8.4 Hz), 7.44-7.47 (2H, m).
　実施例２８
２－アミノ－４－｛４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 28
2-Amino-4- {4- (6-fluorohexyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２８－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物２８－１） (28-1) 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline Synthesis of Compound (Compound 28-1)
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
　化合物１０－４（２９０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３７３ｍｌ）、オルト酢酸トリメチル（０．１７４ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３１０ｍｇ得た。その褐色油状物（３１０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（９７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４１３ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４１４ｍｌ）を加え、室温で２０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３９０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．４５－１．５８（４Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．６３－１．６８（１Ｈ、ｍ）、１．６８－１．７４（１Ｈ、ｍ）、１．７５－１．８９（４Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５３－２．６９（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．０５（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、４．４２（２Ｈ、ｄｔ、Ｊ＝４７．４、６．０Ｈｚ）、７．０６（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．３７－７．４１（２Ｈ、ｍ）。 N, N-diisopropylethylamine (0.373 ml) and trimethyl orthoacetate (0.174 ml) were added to a solution of compound 10-4 (290 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 310 mg of a brown oil. To a solution of the brown oil (310 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (97 mg) and di-t-butyldiethylphosphoramidite (0.413 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.414 ml) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (390 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 1.45 to 1.58 (4H, m), 1.48 (18H, s), 1.63-1.68 (1H, m), 1 .68-1.74 (1H, m), 1.75-1.89 (4H, m), 2.01 (3H, s), 2.53-2.69 (2H, m), 3.88 −3.92 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 4.42 (2H, dt, J = 47.4, 6.0 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.37-7.41 (2H, m ).
　（２８－２）２－アミノ－４－｛４－（６－フルオロヘキシルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２８－２） (28-2) Synthesis of 2-amino-4- {4- (6-fluorohexyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 28-2)
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
　化合物２８－１（３９０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２６０ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４６２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．４４－１．６０（４Ｈ、ｍ）、１．６２－１．７０（１Ｈ、ｍ）、１．７０－１．７９（１Ｈ、ｍ）、１．７９－１．８５（２Ｈ、ｍ）、１．８７－２．０１（２Ｈ、ｍ）、２．６０－２．７６（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０３（２Ｈ、ｍ）、４．０３－４．１０（２Ｈ、ｍ）、４．４２（２Ｈ、ｄｔ、Ｊ＝４７．５、６．０Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 28-1 (390 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (260 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 462 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 1.44 to 1.60 (4H, m), 1.62-1.70 (1H, m), 1.70-1.79 (1H, m) 1.79-1.85 (2H, m), 1.87-2.01 (2H, m), 2.60-2.76 (2H, m), 3.70 (2H, brs) 3.94-4.03 (2H, m), 4.03-4.10 (2H, m), 4.42 (2H, dt, J = 47.5, 6.0 Hz), 7.07 ( 1H, d, J = 8.2 Hz), 7.42-7.45 (2H, m).
　実施例２９
２－アミノ－４－｛４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 29
2-Amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（２９－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物２９－１） (29-1) 4-Di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline Synthesis of Compound 29-1
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　化合物１１－１（３００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３７９ｍｌ）、オルト酢酸トリメチル（０．１７７ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３００ｍｇ得た。その褐色油状物（３００ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（９８ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４１９ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４２０ｍｌ）を加え、室温で１０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３７０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３５－１．４５（４Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．４８－１．５４（２Ｈ、ｍ）、１．７４－１．８０（２Ｈ、ｍ）、１．８１－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．０２－２．０９（２Ｈ、ｍ）、２．５２－２．６９（２Ｈ、ｍ）、３．８８－３．９１（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．９１（１Ｈ、ｄ、Ｊ＝１０．３Ｈｚ）、４．９９（１Ｈ、ｄｄ、Ｊ＝１７．２、１．４Ｈｚ）、５．８２（１Ｈ、ｄｄｔ、Ｊ＝１７．２、１０．３、６．９Ｈｚ）、７．０５（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．３８－７．４１（２Ｈ、ｂｒｓ）。 N, N-Diisopropylethylamine (0.379 ml) and trimethyl orthoacetate (0.177 ml) were added to a solution of compound 11-1 (300 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 300 mg of a brown oil. To a solution of the brown oil (300 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (98 mg) and di-t-butyldiethylphosphoramidite (0.419 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.420 ml) was added, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (370 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 1.35 to 1.45 (4H, m), 1.48 (18H, s), 1.48 to 1.54 (2H, m), 1 .74-1.80 (2H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.02-2.09 (2H, m), 2.52 -2.69 (2H, m), 3.88-3.91 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9. 0 Hz), 4.32 (1 H, d, J = 9.0 Hz), 4.91 (1 H, d, J = 10.3 Hz), 4.99 (1 H, dd, J = 17.2, 1.4 Hz) ), 5.82 (1H, ddt, J = 17.2, 10.3, 6.9 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.38-7.41 (2H, brs).
　（２９－２）２－アミノ－４－｛４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物２９－２） (29-2) Synthesis of 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 29-2)
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
　化合物２９－１（３７０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２２０ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．３３－１．４５（４Ｈ、ｍ）、１．４５－１．５４（２Ｈ、ｍ）、１．７４－１．８１（２Ｈ、ｍ）、１．８９－２．０２（２Ｈ、ｍ）、２．０３－２．１０（２Ｈ、ｍ）、２．６０－２．７４（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０１（２Ｈ、ｍ）、４．０１－４．０６（２Ｈ、ｍ）、４．８７－４．９２（１Ｈ、ｍ）、４．９８（１Ｈ、ｂｒｄ、Ｊ＝１７．１Ｈｚ）、５．８１（１Ｈ、ｄｄｔ、Ｊ＝１７．１、１０．２、６．６Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４１－７．４５（２Ｈ、ｍ）。 Compound 29-1 (370 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (220 mg ) Was obtained as a pale yellow solid.
MS (ESI) m / z: 470 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 1.33-1.45 (4H, m), 1.45-1.54 (2H, m), 1.74-1.81 (2H, m), 1.89-2.02 (2H, m), 2.03-2.10 (2H, m), 2.60-2.74 (2H, m), 3.70 (2H, brs) 3.94-4.01 (2H, m), 4.01-4.06 (2H, m), 4.87-4.92 (1H, m), 4.98 (1H, brd, J = 17.1 Hz), 5.81 (1H, ddt, J = 17.1, 10.2, 6.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.41-7.45 (2H, m).
　実施例３０
２－アミノ－４－｛４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 30
2-Amino-4- {4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３０－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－４－｛２－［４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－メチル－２－オキサゾリンの合成（化合物３０－１） (30-1) 4-di (t-butyl) phosphoryloxymethyl-4- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl } Synthesis of 2-methyl-2-oxazoline (Compound 30-1)
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　化合物１２－１（４６０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．５２１ｍｌ）、オルト酢酸トリメチル（０．２４５ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を５３０ｍｇ得た。その褐色油状物（５３０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１３６ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５８１ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５８２ｍｌ）を加え、室温で２０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（６３０ｍｇ）を黄色固体として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．４８（１８Ｈ、ｓ）、１．８２－１．８８（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．０３－２．１１（２Ｈ、ｍ）、２．２８－２．４０（２Ｈ、ｍ）、２．５３－２．７１（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．１５（２Ｈ、ｔ、Ｊ＝５．８Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．２Ｈｚ）、７．０９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４２（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４３（1Ｈ、ｂｒｓ）。 N, N-diisopropylethylamine (0.521 ml) and trimethyl orthoacetate (0.245 ml) were added to a solution of compound 12-1 (460 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 530 mg of a brown oil. To a solution of the brown oil (530 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (136 mg) and di-t-butyldiethylphosphoramidite (0.581 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.582 ml) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (630 mg) as a yellow solid.
1 H-NMR (CD 3 OD) δ (ppm): 1.48 (18H, s), 1.82-1.88 (2H, m), 2.01 (3H, s), 2.03-2 .11 (2H, m), 2.28-2.40 (2H, m), 2.53-2.71 (2H, m), 3.88-3.92 (2H, m), 4.15 (2H, t, J = 5.8 Hz), 4.18 (1H, d, J = 9.2 Hz), 4.32 (1H, d, J = 9.2 Hz), 7.09 (1H, d, J = 8.5 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.43 (1H, brs).
　（３０－２）２－アミノ－４－｛４－（４，４，５，５，５－ペンタフルオロペンチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３０－２） (30-2) Synthesis of 2-amino-4- {4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol ( Compound 30-2)
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
　化合物３０－１（６３０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルそしてメタノールで洗浄することにより、目的物（３９５ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５２０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：１．９０－２．０３（２Ｈ、ｍ）、２．０４－２．１９（２Ｈ、ｍ）、２．２９－２．４８（２Ｈ、ｍ）、２．６２－２．８１（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９２－４．０５（２Ｈ、ｍ）、４．１４－４．１９（２Ｈ、ｍ）、７．１０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４３－７．４８（２Ｈ、ｍ）。 Compound 30-1 (630 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with ethyl acetate, diethyl ether and methanol to obtain the desired product. (395 mg) was obtained as a pale yellow solid.
MS (ESI) m / z: 520 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 1.90-2.03 (2H, m), 2.04-2.19 (2H, m), 2.29-2.48 (2H, m) 2.62-2.81 (2H, m), 3.70 (2H, brs), 3.92-4.05 (2H, m), 4.14-4.19 (2H, m) 7.10 (1H, d, J = 8.4 Hz), 7.43-7.48 (2H, m).
　実施例３１
２－アミノ－４－｛４－（（１Ｒ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 31
2-Amino-4- {4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３１－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（（１Ｒ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３１－１） (31-1) 4-di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} Synthesis of -2-oxazoline (Compound 31-1)
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　化合物１４－１（３９０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４９１ｍｌ）、オルト酢酸トリメチル（０．２３０ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３９０ｍｇ得た。その褐色油状物（３９０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１２７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５４５ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５４６ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（５２０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２７（３Ｈ、ｄ、Ｊ＝５．８Ｈｚ）、１．２７－１．３６（６Ｈ、ｍ）、１．４７－１．５３（２Ｈ、ｍ）、１．４９（１８Ｈ、ｓ）、１．５４－１．６６（１Ｈ、ｍ）、１．６７－１．７４（１Ｈ、ｍ）、１．８１－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．４９－４．５５（１Ｈ、ｍ）、７．０６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３７（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４０（１Ｈ、ｂｒｓ）。 To a solution of compound 14-1 (390 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.491 ml) and trimethyl orthoacetate (0.230 ml) were added and stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 390 mg of a brown oil. To a solution of the brown oil (390 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (127 mg) and di-t-butyldiethylphosphoramidite (0.545 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.546 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.27 (3H, d, J = 5.8 Hz), 1.27-1. 36 (6H, m), 1.47-1.53 (2H, m), 1.49 (18H, s), 1.54-1.66 (1H, m), 1.67-1.74 ( 1H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.49-4.55 (1H, m), 7.06 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).
　（３１－２）２－アミノ－４－｛４－（（１Ｒ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３１－２） (31-2) Synthesis of 2-amino-4- {4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 31-2)
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
　化合物３１－１（５２０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にイソプロピルアルコール（５ｍｌ）、アセトニトリル（５ｍｌ）を加え、析出した粉末を濾取し、アセトニトリルで洗浄することにより、目的物（１５０ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３７（６Ｈ、ｍ）、１．２７（３Ｈ、ｄ、Ｊ＝５．９Ｈｚ）、１．３７－１．５４（２Ｈ、ｍ）、１．５６－１．６７（１Ｈ、ｍ）、１．６８－１．７６（１Ｈ、ｍ）、１．９１－１．９９（２Ｈ、ｍ）、２．６０－２．７４（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０３（２Ｈ、ｍ）、４．５０－４．８９（１Ｈ、ｍ）、７．０７（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４２（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４４（１Ｈ、ｂｒｓ）。 Compound 31-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hr. The solvent was concentrated under reduced pressure, isopropyl alcohol (5 ml) and acetonitrile (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with acetonitrile to obtain the desired product (150 mg) as a pale yellow solid.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.37 (6H, m), 1.27 (3H, d, J = 5.9 Hz), 1.37-1.54 (2H, m), 1.56-1.67 (1H, m), 1.68-1.76 (1H, m), 1.91- 1.99 (2H, m), 2.60-2.74 (2H, m), 3.70 (2H, brs), 3.94-4.03 (2H, m), 4.50-4. 89 (1H, m), 7.07 (1H, d, J = 8.5 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.44 (1H, brs).
　実施例３２
２－アミノ－４－｛４－（（１Ｓ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 32
2-Amino-4- {4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３２－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（（１Ｓ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３２－１） (32-1) 4-di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} Synthesis of -2-oxazoline (Compound 32-1)
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　化合物１５－１（３９０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４９１ｍｌ）、オルト酢酸トリメチル（０．２３０ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を４００ｍｇ得た。その褐色油状物（４００ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１２７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５４５ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５４６ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（５７０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．２６－１．３５（６Ｈ、ｍ）、１．２７（３Ｈ、ｄ、Ｊ＝６．０Ｈｚ）、１．４７－１．５２（２Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．５５－１．６６（１Ｈ、ｍ）、１．６７－１．７５（１Ｈ、ｍ）、１．８１－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．４９－４．５５（１Ｈ、ｍ）、７．０６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３７（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４０（１Ｈ、ｂｒｓ）。 N, N-Diisopropylethylamine (0.491 ml) and trimethyl orthoacetate (0.230 ml) were added to a solution of compound 15-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 400 mg of a brown oil. To a solution of the brown oil (400 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (127 mg) and di-t-butyldiethylphosphoramidite (0.545 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.546 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (570 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 6.7 Hz), 1.26-1.35 (6H, m), 1.27 (3H, d, J = 6.0 Hz), 1.47-1.52 (2H, m), 1.48 (18H, s), 1.55-1.66 (1H, m), 1.67-1.75 ( 1H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.49-4.55 (1H, m), 7.06 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).
　（３２－２）２－アミノ－４－｛４－（（１Ｓ）－１－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３２－２） (32-2) Synthesis of 2-amino-4- {4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 32-2)
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
　化合物３２－１（５７０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にイソプロピルアルコール（５ｍｌ）、アセトニトリル（５ｍｌ）を加え、析出した粉末を濾取し、アセトニトリルで洗浄することにより、目的物（２００ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３７（６Ｈ、ｍ）、１．２７（３Ｈ、ｄ、Ｊ＝５．９Ｈｚ）、１．３７－１．５０（２Ｈ、ｍ）、１．５６－１．６６（１Ｈ、ｍ）、１．６７－１．７５（１Ｈ、ｍ）、１．９２－１．９９（２Ｈ、ｍ）、２．６０－２．７３（２Ｈ、ｍ）、３．７１（２Ｈ、ｂｒｓ）、３．９５－４．０４（２Ｈ、ｍ）、４．５１－４．５７（１Ｈ、ｍ）、７．０７（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４２（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４４（１Ｈ、ｂｒｓ）。 Compound 32-1 (570 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, isopropyl alcohol (5 ml) and acetonitrile (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with acetonitrile to obtain the desired product (200 mg) as a pale yellow solid.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.37 (6H, m), 1.27 (3H, d, J = 5.9 Hz), 1.37-1.50 (2H, m), 1.56-1.66 (1H, m), 1.67-1.75 (1H, m), 1.92- 1.99 (2H, m), 2.60-2.73 (2H, m), 3.71 (2H, brs), 3.95-4.04 (2H, m), 4.51-4. 57 (1H, m), 7.07 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.44 (1H, brs).
　実施例３３
２－アミノ－４－｛４－（（３Ｒ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 33
2-Amino-4- {4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３３－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（（３Ｒ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３３－１） (33-1) 4-Di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] Synthesis of ethyl} -2-oxazoline (Compound 33-1)
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　化合物１７－１（３３０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３９０ｍｌ）、オルト酢酸トリメチル（０．１８２ｍｌ）を加え、１２０℃にて４時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３２０ｍｇ得た。その褐色油状物（３２０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１０１ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４３１ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４３２ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３１０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８７（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、０．９４（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）、１．１０－１．２０（３Ｈ、ｍ）、１．２６－１．３９（３Ｈ、ｍ）、１．４７－１．５７（２Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．７０－１．７８（１Ｈ、ｍ）、１．７９－１．９０（３Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．０３－４．１２（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．３７－７．４１（２Ｈ、ｍ）。 N, N-diisopropylethylamine (0.390 ml) and trimethyl orthoacetate (0.182 ml) were added to a solution of compound 17-1 (330 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 320 mg of a brown oil. To a solution of the brown oil (320 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (101 mg) and di-t-butyldiethylphosphoramidite (0.431 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.432 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (310 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.8 Hz), 1.10-1. 20 (3H, m), 1.26-1.39 (3H, m), 1.47-1.57 (2H, m), 1.48 (18H, s), 1.70-1.78 ( 1H, m), 1.79-1.90 (3H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.03-4.12 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 7.07 ( 1H, d, J = 8.3 Hz), 7.37-7.41 (2H, m).
　（３３－２）２－アミノ－４－｛４－（（３Ｒ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３３－２） (33-2) Synthesis of 2-amino-4- {4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (compound 33- 2)
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　化合物３３－１（３１０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（５ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（１８０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５００［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８８（６Ｈ、ｄ、Ｊ＝６．７Ｈｚ）、０．９４（３Ｈ、ｄ、Ｊ＝６．５Ｈｚ）、１．１４－１．２２（３Ｈ、ｍ）、１．２３－１．４１（３Ｈ、ｍ）、１．４８－１．６０（２Ｈ、ｍ）、１．６８－１．７８（１Ｈ、ｍ）、１．７９－１．８７（１Ｈ、ｍ）、１．９２－１．９９（２Ｈ、ｍ）、２．６０－２．７５（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９５－４．０４（２Ｈ、ｍ）、４．０５－４．１５（２Ｈ、ｍ）、７．０８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 33-1 (310 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (180 mg ) Was obtained as a white solid.
MS (ESI) m / z: 500 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.88 (6H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.5 Hz), 1.14-1. 22 (3H, m), 1.23-1.41 (3H, m), 1.48-1.60 (2H, m), 1.68-1.78 (1H, m), 1.79- 1.87 (1H, m), 1.92-1.99 (2H, m), 2.60-2.75 (2H, m), 3.70 (2H, brs), 3.95-4. 04 (2H, m), 4.05-4.15 (2H, m), 7.08 (1H, d, J = 8.3 Hz), 7.42-7.45 (2H, m).
　実施例３４
２－アミノ－４－｛４－（（３Ｓ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 34
2-Amino-4- {4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３４－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（（３Ｓ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３４－１） (34-1) 4-Di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] Synthesis of ethyl} -2-oxazoline (Compound 34-1)
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　化合物１８－１（３６０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４２６ｍｌ）、オルト酢酸トリメチル（０．２００ｍｌ）を加え、１２０℃にて２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を３４０ｍｇ得た。その褐色油状物（３４０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１０８ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．４６１ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．４６２ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３３０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８７（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、０．９４（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）、１．１０－１．２１（３Ｈ、ｍ）、１．２６－１．３９（３Ｈ、ｍ）、１．４７－１．５９（２Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．７０－１．７７（１Ｈ、ｍ）、１．７８－１．９０（３Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８８－３．９２（２Ｈ、ｍ）、４．０３－４．１２（２Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、７．０８（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．３８－７．４１（２Ｈ、ｍ）。 To a solution of compound 18-1 (360 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.426 ml) and trimethyl orthoacetate (0.200 ml) were added and stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 340 mg of a brown oil. To a solution of the brown oil (340 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (108 mg) and di-t-butyldiethylphosphoramidite (0.461 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.462 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.8 Hz), 1.10-1. 21 (3H, m), 1.26-1.39 (3H, m), 1.47-1.59 (2H, m), 1.48 (18H, s), 1.70-1.77 ( 1H, m), 1.78-1.90 (3H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.03-4.12 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 7.08 ( 1H, d, J = 8.2 Hz), 7.38-7.41 (2H, m).
　（３４－２）２－アミノ－４－｛４－（（３Ｓ）－３，７－ジメチルオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３４－２） (34-2) Synthesis of 2-amino-4- {4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 34- 2)
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　化合物３４－１（３３０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（５ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（１７０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５００［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８８（６Ｈ、ｄ、Ｊ＝６．７Ｈｚ）、０．９４（３Ｈ、ｄ、Ｊ＝６．４Ｈｚ）、１．１３－１．２１（３Ｈ、ｍ）、１．２２－１．４１（３Ｈ、ｍ）、１．４８－１．６０（２Ｈ、ｍ）、１．６８－１．７８（１Ｈ、ｍ）、１．７８－１．８７（１Ｈ、ｍ）、１．９１－１．９９（２Ｈ、ｍ）、２．６０－２．７２（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．９４－４．０４（２Ｈ、ｍ）、４．０５－４．１３（２Ｈ、ｍ）、７．０８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 34-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (170 mg ) Was obtained as a white solid.
MS (ESI) m / z: 500 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.88 (6H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.4 Hz), 1.13-1. 21 (3H, m), 1.22-1.41 (3H, m), 1.48-1.60 (2H, m), 1.68-1.78 (1H, m), 1.78- 1.87 (1H, m), 1.91-1.99 (2H, m), 2.60-2.72 (2H, m), 3.70 (2H, brs), 3.94-4. 04 (2H, m), 4.05-4.13 (2H, m), 7.08 (1H, d, J = 8.3 Hz), 7.42-7.45 (2H, m).
　実施例３５
２－アミノ－４－｛４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 35
2-Amino-4- {4- (2-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３５－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３５－１） (35-1) 4-Di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline Synthesis of Compound 35-1
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　化合物１９－２（２４０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．３０２ｍｌ）、オルト酢酸トリメチル（０．１４６ｍｌ）を加え、１２０℃にて５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を２３０ｍｇ得た。その褐色油状物（２３０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（７７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．３２９ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．３３０ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（２４０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．０３（３Ｈ、ｄ、Ｊ＝６．７Ｈｚ）、１．２２－１．４１（７Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．４８－１．５７（１Ｈ、ｍ）、１．８０－１．８８（２Ｈ、ｍ）、１．８８－１．９６（１Ｈ、ｍ）、２．０９（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８０－３．９２（４Ｈ、ｍ）、４．１８（１Ｈ、ｄ、Ｊ＝８．９Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝８．９Ｈｚ）、７．０４（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．４０（１Ｈ、ｂｒｓ）。 N, N-diisopropylethylamine (0.302 ml) and trimethyl orthoacetate (0.146 ml) were added to a solution of compound 19-2 (240 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 230 mg of a brown oil. To a solution of the brown oil (230 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (77 mg) and di-t-butyldiethylphosphoramidite (0.329 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.330 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (240 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.90 (3H, t, J = 6.8 Hz), 1.03 (3H, d, J = 6.7 Hz), 1.22-1. 41 (7H, m), 1.48 (18H, s), 1.48-1.57 (1H, m), 1.80-1.88 (2H, m), 1.88-1.96 ( 1H, m), 2.09 (3H, s), 2.52-2.69 (2H, m), 3.80-3.92 (4H, m), 4.18 (1H, d, J = 8.9 Hz), 4.32 (1H, d, J = 8.9 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).
　（３５－２）２－アミノ－４－｛４－（２－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール
の合成（化合物３５－２） (35-2) Synthesis of 2-amino-4- {4- (2-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 35-2)
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　化合物３５－１（２４０ｍｇ）をエタノール（５ｍｌ）に溶解させ、濃塩酸（１ｍｌ）を加え、５０℃にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（５ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（１２５ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．０４（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）、１．２１－１．４５（７Ｈ、ｍ）、１．５０－１．６０（１Ｈ、ｍ）、１．８８－１．９９（３Ｈ、ｍ）、２．６０－２．７２（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．８２－３．９２（２Ｈ、ｍ）、３．９４－４．０３（２Ｈ、ｍ）、７．０６（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 35-1 (240 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (125 mg ) Was obtained as a white solid.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.90 (3H, t, J = 6.9 Hz), 1.04 (3H, d, J = 6.8 Hz), 1.21-1. 45 (7H, m), 1.50-1.60 (1H, m), 1.88-1.99 (3H, m), 2.60-2.72 (2H, m), 3.70 ( 2H, brs), 3.82-3.92 (2H, m), 3.94-4.03 (2H, m), 7.06 (1H, d, J = 8.4 Hz), 7.42- 7.45 (2H, m).
　実施例３６
２－アミノ－４－｛４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール Example 36
2-Amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol
　（３６－１）４－ジ（ｔ－ブチル）ホスホリルオキシメチル－２－メチル－４－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝－２－オキサゾリンの合成（化合物３６－１） (36-1) 4-di (t-butyl) phosphoryloxymethyl-2-methyl-4- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline Synthesis of Compound 36-1
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　化合物２０－２（４２０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．５２８ｍｌ）、オルト酢酸トリメチル（０．２４８ｍｌ）を加え、１２０℃にて４時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって、褐色油状物を２４５０ｍｇ得た。その褐色油状物（４５０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（１３７ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．５８６ｍｌ）を加え、室温で２時間攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．５８８ｍｌ）を加え、室温で３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（５２０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（６Ｈ、ｄ、Ｊ＝６．４Ｈｚ）、１．１８－１．２３（２Ｈ、ｍ）、１．３３－１．４０（２Ｈ、ｍ）、１．４５－１．５７（３Ｈ、ｍ）、１．４８（１８Ｈ、ｓ）、１．７３－１．８０（２Ｈ、ｍ）、１．８０－１．９０（２Ｈ、ｍ）、２．０１（３Ｈ、ｓ）、２．５２－２．６９（２Ｈ、ｍ）、３．８５－３．９２（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１８（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、４．３２（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、７．０５（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．３７－７．４０（２Ｈ、ｍ）。 N, N-diisopropylethylamine (0.528 ml) and trimethyl orthoacetate (0.248 ml) were added to a solution of compound 20-2 (420 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2450 mg of a brown oil. To a solution of the brown oil (450 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (137 mg) and di-t-butyldiethylphosphoramidite (0.586 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.588 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (6H, d, J = 6.4 Hz), 1.18-1.23 (2H, m), 1.33-1.40 ( 2H, m), 1.45-1.57 (3H, m), 1.48 (18H, s), 1.73-1.80 (2H, m), 1.80-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.85-3.92 (2H, m), 4.04 (2H, t, J = 6. 2 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 7.05 (1H, d, J = 8.4 Hz), 7. 37-7.40 (2H, m).
　（３６－２）２－アミノ－４－｛４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノールの合成（化合物３６－２） (36-2) Synthesis of 2-amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 36-2)
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　化合物３６－１（５２０ｍｇ）をエタノール（６ｍｌ）に溶解させ、濃塩酸（１．２ｍｌ）を加え、５０℃にて３時間攪拌した。溶媒を減圧濃縮し、残渣にメタノール（５ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２８５ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（６Ｈ、ｄ、Ｊ＝６．６Ｈｚ）、１．１６－１．２６（２Ｈ、ｍ）、１．３２－１．４２（２Ｈ、ｍ）、１．４２－１．６０（３Ｈ、ｍ）、１．７２－１．８５（２Ｈ、ｍ）、１．８９－２．０２（２Ｈ、ｍ）、２．６０－２．７８（２Ｈ、ｍ）、３．７０（２Ｈ、ｂｒｓ）、３．８２－３．９９（２Ｈ、ｍ）、３．９８－４．０５（２Ｈ、ｍ）、７．０７（１Ｈ、ｄ、Ｊ＝８．０Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 36-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to obtain the desired product (285 mg ) Was obtained as a white solid.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (6H, d, J = 6.6 Hz), 1.16-1.26 (2H, m), 1.32-1.42 ( 2H, m), 1.42-1.60 (3H, m), 1.72-1.85 (2H, m), 1.89-2.02 (2H, m), 2.60-2. 78 (2H, m), 3.70 (2H, brs), 3.82-3.99 (2H, m), 3.98-4.05 (2H, m), 7.07 (1H, d, J = 8.0 Hz), 7.42-7.45 (2H, m).
　実施例３７
［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］カルバミン酸ｔ－ブチルエステル Example 37
[3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester
　（３７－１）［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］カルバミン酸ｔ－ブチルエステルの合成（化合物３７－１） (37-1) Synthesis of [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester (Compound 37-1)
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　公知の方法（例えば、ＷＯ２００７／０６９７１２号公報、５８～６３ページ）により合成した２－アミノ－２－［２－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）エチル］プロパン－１，３－ジオール塩酸塩（３．００ｇ）のメタノール（５０ｍｌ）溶液にトリエチルアミン（３．０６ｍｌ）とジ－ｔ－ブチルジカルボナート（３．１６ｇ）を加え、室温で２２時間攪拌した。さらに、反応液にジ－ｔ－ブチルジカルボナート（１．５８ｇ）を加え、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣のうち５９０ｍｇをシリカゲルカラムクロマトグラフィーで精製することにより、目的物（４４０ｍｇ）を無色油状物として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７８［Ｍ－１００＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．４０（６Ｈ、ｍ）、１．４１－１．５０（２Ｈ、ｍ）、１．４６（９Ｈ、ｓ）、１．７５－１．８２（２Ｈ、ｍ）、１．８３－１．８９（２Ｈ、ｍ）、２．５６－２．６１（２Ｈ、ｍ）、３．３１（２Ｈ、ｂｒｓ）、３．６２－３．６７（２Ｈ、ｍ）、３．８６－３．９０（２Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、５．０３（１Ｈ、ｂｒｓ）、６．８９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２６－７．２９（１Ｈ、ｍ）、７．３６（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-synthesized by a known method (for example, WO2007 / 069712, pp. 58-63) Triethylamine (3.06 ml) and di-t-butyl dicarbonate (3.16 g) were added to a methanol (50 ml) solution of diol hydrochloride (3.00 g), and the mixture was stirred at room temperature for 22 hours. Further, di-t-butyl dicarbonate (1.58 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Of the obtained residue, 590 mg was purified by silica gel column chromatography to obtain the desired product (440 mg) as a colorless oil.
MS (ESI) m / z: 378 [M-100 + H]
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.40 (6H, m), 1.41-1.50 (2H) M), 1.46 (9H, s), 1.75-1.82 (2H, m), 1.83-1.89 (2H, m), 2.56-2.61 (2H, m) ), 3.31 (2H, brs), 3.62-3.67 (2H, m), 3.86-3.90 (2H, m), 4.00 (2H, t, J = 6.4 Hz) ), 5.03 (1H, brs), 6.89 (1H, d, J = 8.5 Hz), 7.26-7.29 (1H, m), 7.36 (1H, d, J = 1) .9 Hz).
　実施例３８
Ｎ－［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］オクタデカナミド Example 38
N- [3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] octadecanamide
　（３８－１）Ｎ－［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］オクタデカナミドの合成（化合物３８－１） (38-1) Synthesis of N- [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] octadecanamide (Compound 38-1)
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
　２－アミノ－２－［２－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）エチル］プロパン－１，３－ジオール塩酸塩（１．００ｇ）のクロロホルム（５０ｍｌ）と飽和炭酸水素ナトリウム水溶液（５０ｍｌ）の混合物に氷冷下撹拌しながら塩化ステアロイル（０．９８ｍｌ）を加え、氷冷下２時間さらに室温で５時間撹拌した。有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した．残渣にヘキサン（４０ｍｌ）を加え析出した固体を濾取することによって、目的物（１．２１ｇ）を白色の固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：６８５［Ｍ＋ＣＨ３ＣＮ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８８（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、０．８９（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、１．２３－１．３９（３４Ｈ、ｍ）、１．４２－１．５０（２Ｈ、ｍ）、１．５６－１．６３（２Ｈ、ｍ）、１．８０（２Ｈ、ｑｕｉｎｔ、Ｊ＝６．９Ｈｚ）、１．９１－１．９５（２Ｈ、ｍ）、２．１９（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．５９－２．６３（２Ｈ、ｍ）、３．６１－３．６７（４Ｈ、ｍ）、３．８３－３．８８（２Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、５．９０（１Ｈ、ｂｒｓ）、６．９０（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２８（１Ｈ、ｄｄ、Ｊ＝８．５、２．０Ｈｚ）、７．３６（１Ｈ、ｄ、Ｊ＝２．０Ｈｚ）。 2-Amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (1.00 g) in chloroform (50 ml) and saturated aqueous sodium bicarbonate solution ( 50 ml), stearoyl chloride (0.98 ml) was added with stirring under ice cooling, and the mixture was stirred under ice cooling for 2 hours and further at room temperature for 5 hours. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane (40 ml) was added to the residue and the precipitated solid was collected by filtration to obtain the desired product (1.21 g) as a white solid.
MS (ESI) m / z: 685 [M + CH 3 CN + H]
1 H-NMR (CDCl 3 ) δ (ppm): 0.88 (3H, t, J = 6.6 Hz), 0.89 (3H, t, J = 6.6 Hz), 1.23-1.39 (34H, m), 1.42-1.50 (2H, m), 1.56-1.63 (2H, m), 1.80 (2H, quint, J = 6.9 Hz), 1.91 -1.95 (2H, m), 2.19 (2H, t, J = 7.6 Hz), 2.59-2.63 (2H, m), 3.61-3.67 (4H, m) 3.83-3.88 (2H, m), 4.00 (2H, t, J = 6.3 Hz), 5.90 (1H, brs), 6.90 (1H, d, J = 8. 5 Hz), 7.28 (1H, dd, J = 8.5, 2.0 Hz), 7.36 (1H, d, J = 2.0 Hz).
　実施例３９
２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（２－メトキシエチル）ブタノールトシル酸塩 Example 39
2-Amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butanol tosylate
　（３９－１）｛３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－ヒドロキシメチル－１－［（メトキシメトキシ）メチル］プロピル｝カルバミン酸ｔ－ブチルエステルの合成（化合物３９－１） (39-1) Synthesis of {3- (4-heptyloxy-3-trifluoromethylphenyl) -1-hydroxymethyl-1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39- 1)
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
　化合物３７－１（３．８７ｇ）の塩化メチレン（５０ｍｌ）溶液に、氷冷下Ｎ，Ｎ－ジイソプロピルエチルアミン（１．９５ｍｌ）及びメトキシメチルクロリド（０．７１６ｍｌ）を加え、氷冷下で１０分さらに室温で６時間攪拌した。反応液に水を加え、塩化メチレンで抽出後、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（１．９４ｇ）と、原料の［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］カルバミン酸ｔ－ブチルエステル（１．４４ｇ）をそれぞれ無色油状物として得た。上記で回収された［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］カルバミン酸ｔ－ブチルエステルの塩化メチレン（２０ｍｌ）溶液に、氷冷下Ｎ，Ｎ－ジイソプロピルエチルアミン（０．９６４ｍｌ）及びメトキシメチルクロリド（０．３５３ｍｌ）を加え、氷冷下で５分さらに室温で１４時間攪拌した。反応液に水を加え、塩化メチレンで抽出後、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（９９０ｍｇ）を無色油状物として得た。一回目の反応で得られた目的物と合わせて、目的物の総量は２．９３ｇであった。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４０－１．４９（２Ｈ、ｍ）、１．４５（９Ｈ、ｓ）、１．７５－１．８２（２Ｈ、ｍ）、１．８２－１．９０（１Ｈ、ｍ）、２．００－２．０９（１Ｈ、ｍ）、２．４９－２．５７（１Ｈ、ｍ）、２．６１－２．７７（１Ｈ、ｍ）、３．３９（３Ｈ、ｓ）、３．５０（１Ｈ、ｄ、Ｊ＝９．６Ｈｚ）、３．７２－３．７８（４Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．６５（２Ｈ、ｓ）、５．１７（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２６－７．２９（１Ｈ、ｍ）、７．３６（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 To a solution of compound 37-1 (3.87 g) in methylene chloride (50 ml) was added N, N-diisopropylethylamine (1.95 ml) and methoxymethyl chloride (0.716 ml) under ice-cooling, and the mixture was cooled under ice-cooling for 10 minutes. The mixture was further stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain the desired product (1.94 g) and the raw material [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl). ) Propyl] carbamic acid t-butyl ester (1.44 g) was obtained as a colorless oil. To the solution of [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester collected above in methylene chloride (20 ml), N, N-Diisopropylethylamine (0.964 ml) and methoxymethyl chloride (0.353 ml) were added, and the mixture was stirred for 5 minutes under ice cooling and further for 14 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (990 mg) as a colorless oil. Combined with the target product obtained in the first reaction, the total amount of the target product was 2.93 g.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.40-1.49 (2H M), 1.45 (9H, s), 1.75-1.82 (2H, m), 1.82-1.90 (1H, m), 2.00-2.09 (1H, m) ), 2.49-1.57 (1H, m), 2.61-2.77 (1H, m), 3.39 (3H, s), 3.50 (1H, d, J = 9.6 Hz) ), 3.72-3.78 (4H, m), 4.00 (2H, t, J = 6.3 Hz), 4.65 (2H, s), 5.17 (1H, brs), 6. 88 (1H, d, J = 8.4 Hz), 7.26-7.29 (1H, m), 7.36 (1H, d, J = 1.6 Hz).
　（３９－２）｛１－ホルミル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－［（メトキシメトキシ）メチル］プロピル｝カルバミン酸ｔ－ブチルエステルの合成（化合物３９－２） (39-2) Synthesis of {1-formyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39-2) )
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
　化合物３９－１（１.９４ｇ）をジメチルスルホキシド（５０ｍｌ）に溶解させ、トリエチルアミン（３．４０ｍｌ）、三酸化硫黄ピリジン錯体（１．７８ｇ）を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製することによって、目的物（１．７７ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４０－１．４９（２Ｈ、ｍ）、１．４７（９Ｈ、ｓ）、１．７５－１．８２（２Ｈ、ｍ）、２．００－２．０６（１Ｈ、ｍ）、２．３８－２．４１（２Ｈ、ｍ）、２．５３－２．５９（１Ｈ、ｍ）、３．３２（３Ｈ、ｓ）、３．８２（１Ｈ、ｄ、Ｊ＝１０．１Ｈｚ）、３．９８－４．０２（３Ｈ、ｍ）、４．５９（２Ｈ、ｓ）、５．４８（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２２（１Ｈ、ｄｄ、Ｊ＝８．５、１．９Ｈｚ）、７．３１（１Ｈ、ｂｒｓ）、９．４２（１Ｈ、ｓ）。 Compound 39-1 (1.94 g) was dissolved in dimethyl sulfoxide (50 ml), triethylamine (3.40 ml) and sulfur trioxide pyridine complex (1.78 g) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (1.77 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.40-1.49 (2H M), 1.47 (9H, s), 1.75-1.82 (2H, m), 2.00-2.06 (1H, m), 2.38-2.41 (2H, m) ), 2.53-2.59 (1H, m), 3.32 (3H, s), 3.82 (1H, d, J = 10.1 Hz), 3.98-4.02 (3H, m ), 4.59 (2H, s), 5.48 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7.22 (1H, dd, J = 8.5, 1 .9 Hz), 7.31 (1H, brs), 9.42 (1H, s).
　（３９－３）｛３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（２－メトキシエチル）－１－［（メトキシメトキシ）メチル］プロピル｝カルバミン酸ｔ－ブチルエステルの合成（化合物３９－３） (39-3) Synthesis of {3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyethyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39-3)
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
　（メトキシメチル）トリフェニルホスホニウムクロリド（６５８ｍｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、カリウムｔ-ブトキシド（２１５ｍｇ）を加え、１０分間攪拌した。その混合溶液に化合物３９－２（５００ｍｇ）のテトラヒドロフラン（１０ｍｌ）溶液を氷冷下滴下した後、室温で２時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（メトキシメトキシ）メチル－１－（２－メトキシビニル）プロピル］カルバミン酸ｔ－ブチルエステルを無色油状物として２９０ｍｇ得た。この無色油状物を酢酸エチル（１０ｍｌ）に溶解させ、１０％パラジウム炭素（１００ｍｇ）を加え、水素雰囲気下、室温で４時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（２４０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４１－１．４９（２Ｈ、ｍ）、１．４４（９Ｈ、ｓ）、１．７５－１．８２（２Ｈ、ｍ）、１．９０－２．２０（２Ｈ、ｍ）、２．２１－２．１３（２Ｈ、ｍ）、２．５５－２．６０（２Ｈ、ｍ）、３．３３（３Ｈ、ｓ）、３．３８（３Ｈ、ｓ）、３．４８－３．５７（２Ｈ、ｍ）、３．６９（２Ｈ、ｂｒｓ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．６３（２Ｈ、ｓ）、５．１７（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２６－７．２９（１Ｈ、ｍ）、７．３６（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 (Methoxymethyl) triphenylphosphonium chloride (658 mg) was dissolved in tetrahydrofuran (30 ml), potassium t-butoxide (215 mg) was added, and the mixture was stirred for 10 minutes. A solution of compound 39-2 (500 mg) in tetrahydrofuran (10 ml) was added dropwise to the mixed solution under ice-cooling, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (methoxymethoxy) methyl-1- (2-methoxyvinyl) propyl] carbamic acid t- 290 mg of butyl ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (10 ml), 10% palladium carbon (100 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (240 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H) M), 1.44 (9H, s), 1.75-1.82 (2H, m), 1.90-2.20 (2H, m), 2.21-2.13 (2H, m) ), 2.55-2.60 (2H, m), 3.33 (3H, s), 3.38 (3H, s), 3.48-3.57 (2H, m), 3.69 ( 2H, brs), 4.00 (2H, t, J = 6.4 Hz), 4.63 (2H, s), 5.17 (1H, brs), 6.88 (1H, d, J = 8. 4 Hz), 7.26-7.29 (1 H, m), 7.36 (1 H, d, J = 1.9 Hz).
　（３９－４）２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（２－メトキシエチル）ブタノールトシル酸塩の合成（化合物３９－４） (39-4) Synthesis of 2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butanol tosylate (Compound 39-4)
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
　化合物３９－３（２４０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、酢酸エチル（５ｍｌ）とメタノール（５ｍｌ）を加えた後、ｐ－トルエンスルホン酸一水和物（８４ｍｇ）を加え、室温で１時間攪拌した。反応液を濃縮し、残渣をジエチルエーテルにて洗浄し、目的物（２２０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２２－１．３６（６Ｈ、ｍ）、１．３７－１．４５（２Ｈ、ｍ）、１．６５－１．７２（２Ｈ、ｍ）、１．７２－１．８０（２Ｈ、ｍ）、１．８５（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、２．２９（３Ｈ、ｓ）、２．５６－２．６１（２Ｈ、ｍ）、３．２５（３Ｈ、ｓ）、３．４４－３．５１（４Ｈ、ｍ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．５０（１Ｈ、ｂｒｓ）、７．１１（２Ｈ、ｄ、Ｊ＝７．９Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４２－７．４８（４Ｈ、ｍ）、７．６６（３Ｈ、ｂｒｓ）。 Compound 39-3 (240 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, ethyl acetate (5 ml) and methanol (5 ml) were added, p-toluenesulfonic acid monohydrate (84 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (220 mg) as a white powder.
MS (ESI) m / z: 406 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.45 (2H, m), 1.65-1.72 (2H, m), 1.72-1.80 (2H, m), 1.85 (2H, t, J = 6.4 Hz), 2.29 (3H, s), 2.56-2.61 (2H, m), 3.25 (3H, s), 3.44-3.51 (4H, m), 4.06 (2H, t, J = 6.2 Hz), 5.50 (1H, brs), 7.11 (2H, d, J = 7.9 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.42-7 .48 (4H, m), 7.66 (3H, brs).
　実施例４０
２－アミノ－２－［２－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）エチル］ペンタン－１，５－ジオールトシル酸塩 Example 40
2-Amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] pentane-1,5-diol tosylate
　（４０－１）４－（ｔ－ブトキシ）カルボニルアミノ－６－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－４－［（メトキシメトキシ）メチル］ヘキサン酸エチルエステルの合成（化合物４０－１） (40-1) Synthesis of 4- (t-butoxy) carbonylamino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4-[(methoxymethoxy) methyl] hexanoic acid ethyl ester (Compound 40- 1)
Figure JPOXMLDOC01-appb-C000149
 　
Figure JPOXMLDOC01-appb-C000149
 　
　ホスホノ酢酸トリエチル（５１８ｍｇ）をテトラヒドロフラン（２０ｍｌ）に溶解させ、水素化ナトリウム（９２ｍｇ）を加え、３０分間攪拌した。その混合溶液に化合物３９－２（６００ｍｇ）のテトラヒドロフラン（２０ｍｌ）溶液を氷冷下滴下した後、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、４－ｔ－ブトキシカルボニルアミノ－６－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－４－［（メトキシメトキシ）メチル］－２－ヘキセン酸エチルエステルを無色油状物として４５０ｍｇ得た。この無色油状物を酢酸エチル（１５ｍｌ）に溶解させ、１０％パラジウム炭素（１５０ｍｇ）を加え、水素雰囲気下、室温で４時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮し、目的物（４５０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５（３Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４１－１．４９（２Ｈ、ｍ）、１．４５（９Ｈ、ｓ）、１．７５－１．８３（２Ｈ、ｍ）、１．８４－１．９５（１Ｈ、ｍ）、１．９５－２．０６（２Ｈ、ｍ）、２．１１－２．１９（１Ｈ、ｍ）、２．３８（２Ｈ、ｔ、Ｊ＝８．０Ｈｚ）、２．５７（２Ｈ、ｔ、Ｊ＝８．６Ｈｚ）、３．３８（３Ｈ、ｓ）、３．５５－３．６２（２Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．１３（２Ｈ、ｑ、Ｊ＝７．１Ｈｚ）、４．６３（２Ｈ、ｓ）、４．７６（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２６－７．２８（１Ｈ、ｍ）、７．３５（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 Triethyl phosphonoacetate (518 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min. A solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and ethyl 4-t-butoxycarbonylamino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4-[(methoxymethoxy) methyl] -2-hexenoate 450 mg of the ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (15 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (450 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H, m), 1.45 (9H, s), 1.75-1.83 (2H, m), 1.84-1.95 (1H M), 1.95-2.06 (2H, m), 2.11-2.19 (1H, m), 2.38 (2H, t, J = 8.0 Hz), 2.57 (2H) , T, J = 8.6 Hz), 3.38 (3H, s), 3.55-3.62 (2H, m), 4.00 (2H, t, J = 6.4 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.63 (2H, s), 4.76 (1H, brs), 6.88 (1H, d, J = 8.4 Hz), 7.26-7 .28 (1H, m), 7.35 ( H, d, J = 1.9Hz).
　（４０－２）２－アミノ－２－［２－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）エチル］ペンタン－１，５－ジオールトシル酸塩の合成（化合物４０－２） (40-2) Synthesis of 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] pentane-1,5-diol tosylate (Compound 40-2)
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
　化合物４０－１（４５０ｍｇ）のエタノール（１５ｍｌ）溶液に、氷冷下水素化ホウ素ナトリウム（６１．０ｍｇ）を加え、氷冷下で１時間、さらに室温で１５時間攪拌した。再度、氷冷下に戻し水素化ホウ素ナトリウム（１２０ｍｇ）を加え、氷冷下で１時間、さらに室温で２２時間攪拌した。反応液に１Ｍ塩酸（１００ｍｌ）を加え、減圧で濃縮後、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液そして飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、｛３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（３－ヒドロキシプロピル）－１－［（メトキシメトキシ）メチル］プロピル｝カルバミン酸ｔ－ブチルエステルを無色油状物として３７０ｍｇ得た。この無色油状物（３７０ｍｇ）のエタノール（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、クロロホルム（５ｍｌ）とメタノール（５ｍｌ）を加えた後、ｐ－トルエンスルホン酸一水和物（１２７ｍｇ）を加え、室温で１時間攪拌した。反応液を濃縮し、残渣をジイソプロピルエーテルにて洗浄し、目的物（３５５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２２－１．３６（６Ｈ、ｍ）、１．３７－１．４９（４Ｈ、ｍ）、１．５７－１．６２（２Ｈ、ｍ）、１．６８－１．７８（４Ｈ、ｍ）、２．２９（３Ｈ、ｓ）、２．５４－２．５９（２Ｈ、ｍ）、３．３８－３．５１（５Ｈ、ｍ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．５０（１Ｈ、ｂｒｔ、Ｊ＝４．５Ｈｚ）、７．１１（２Ｈ、ｄ、Ｊ＝７．９Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４２－７．４８（４Ｈ、ｍ）、７．７２（３Ｈ、ｂｒｓ）。 To a solution of compound 40-1 (450 mg) in ethanol (15 ml) was added sodium borohydride (61.0 mg) under ice cooling, and the mixture was stirred for 1 hour under ice cooling and further at room temperature for 15 hours. Again, the mixture was returned to ice-cooling, sodium borohydride (120 mg) was added, and the mixture was stirred under ice-cooling for 1 hour and further at room temperature for 22 hours. 1M Hydrochloric acid (100 ml) was added to the reaction mixture, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain {3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (3-hydroxypropyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid 370 mg of t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of this colorless oil (370 mg) in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, chloroform (5 ml) and methanol (5 ml) were added, p-toluenesulfonic acid monohydrate (127 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (355 mg) as a white powder.
MS (ESI) m / z: 406 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.49 (4H, m), 1.57-1.62 (2H, m), 1.68-1.78 (4H, m), 2.29 (3H, s), 2.54-2.59 (2H) M), 3.38-3.51 (5H, m), 4.06 (2H, t, J = 6.2 Hz), 5.50 (1H, brt, J = 4.5 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.42-7.48 (4H, m), 7.72 (3H, brs).
　実施例４１
３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンタン酸 Example 41
3-Amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentanoic acid
　（４１－１）［１－ベンジルオキシメチル－１－ヒドロキシメチル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）プロピル］カルバミン酸ベンジルエステルの合成（化合物４１－１） (41-1) Synthesis of [1-benzyloxymethyl-1-hydroxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester (Compound 41-1)
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
　公知の方法（例えば、ＷＯ２００７／０６９７１２号公報、６３～６４ページ）により合成した［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１，１－ビス（ヒドロキシメチル）プロピル］カルバミン酸ベンジルエステル（１．３４ｇ）のトルエン（３０ｍｌ）溶液に、ベンジルブロミド（０．５１３ｍｌ）と酸化銀（１．４８ｇ）を加え、室温で１５時間攪拌した。溶液を濾過し、濾液を濃縮し、残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（１．０５ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２６－１．３８（６Ｈ、ｍ）、１．４２－１．４９（２Ｈ、ｍ）、１．７５－１．８２（２Ｈ、ｍ）、１．８２－１．８９（１Ｈ、ｍ）、２．０１－２．１０（１Ｈ、ｍ）、２．４０－２．４８（１Ｈ、ｍ）、２．５２－２．６１（１Ｈ、ｍ）、３．４３（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、３．６９（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、３．７０－３．７６（２Ｈ、ｍ）、３．９９（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．４７－４．５５（２Ｈ、ｍ）、４．７１（１Ｈ、ｄ、Ｊ＝５．８Ｈｚ）、５．０８（２Ｈ、ｓ）、５．４８（１Ｈ、ｂｒｓ）、６．８６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２１（１Ｈ、ｂｒｄ、Ｊ＝８．２Ｈｚ）、７．２６－７．３６（１１Ｈ、ｍ）。 [3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid synthesized by a known method (for example, WO2007 / 069712, pp. 63-64) Benzyl bromide (0.513 ml) and silver oxide (1.48 g) were added to a toluene (30 ml) solution of benzyl ester (1.34 g), and the mixture was stirred at room temperature for 15 hours. The solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the desired product (1.05 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.38 (6H, m), 1.42-1.49 (2H) M) 1.75-1.82 (2H, m), 1.82-1.89 (1H, m), 2.01-2.10 (1H, m), 2.40-2.48 (1H, m), 2.52-2.61 (1H, m), 3.43 (1H, d, J = 9.1 Hz), 3.69 (1H, d, J = 9.1 Hz), 3 .70-3.76 (2H, m), 3.99 (2H, t, J = 6.4 Hz), 4.47-4.55 (2H, m), 4.71 (1H, d, J = 5.8Hz), 5.08 (2H, s), 5.48 (1H, brs), 6.86 (1H, d, J = 8.5Hz), 7.21 (1H, brd, J = 8. 2Hz), 7.26-7.36 11H, m).
　（４１－２）［１－ベンジルオキシメチル－１－ホルミル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）プロピル］カルバミン酸ベンジルエステルの合成（化合物４１－２） (41-2) Synthesis of [1-benzyloxymethyl-1-formyl-3- (4-heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester (Compound 41-2)
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
　化合物４１－１（１．０５ｇ）と臭化ナトリウム（１９８ｍｇ）のトルエン（１０ｍｌ）、酢酸エチル（１０ｍｌ）、水（１ｍｌ）の混合溶液に、氷冷下２，２，６，６－テトラメチルピペリジン　１－オキシル，フリーラジカル（５．５ｍｇ）を加え、次に１０％次亜塩素酸ナトリウム水溶液（１．４５ｍｌ）及び炭酸水素ナトリウム（４２５ｍｇ）の水（５ｍｌ）溶液を３０分かけて滴下した。さらに氷冷下で２時間攪拌した。有機層を分液し酢酸エチル（２００ｍｌ）で希釈後、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（９１０ｍｇ）を淡褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４１－１．４９（２Ｈ、ｍ）、１．７４－１．８２（２Ｈ、ｍ）、１．９８－２．０８（１Ｈ、ｍ）、２．２６－２．５２（３Ｈ、ｍ）、３．７５（１Ｈ、ｄ、Ｊ＝９．８Ｈｚ）、３．９２（１Ｈ、ｄ、Ｊ＝９．８Ｈｚ）、３．９８（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．４２－４．５２（２Ｈ、ｍ）、５．１０（２Ｈ、ｓ）、５．７６（１Ｈ、ｂｒｓ）、６．８４（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１５（１Ｈ、ｂｒｄ、Ｊ＝８．３Ｈｚ）、７．２２－７．３８（１１Ｈ、ｍ）、９．３９（１Ｈ、ｓ）。 To a mixed solution of compound 41-1 (1.05 g) and sodium bromide (198 mg) in toluene (10 ml), ethyl acetate (10 ml) and water (1 ml), 2,2,6,6-tetramethyl was added under ice cooling. Piperidine 1-oxyl and free radical (5.5 mg) were added, and then a 10% aqueous sodium hypochlorite solution (1.45 ml) and a solution of sodium hydrogen carbonate (425 mg) in water (5 ml) were added dropwise over 30 minutes. . The mixture was further stirred for 2 hours under ice cooling. The organic layer was separated and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (910 mg) as a pale brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H) M), 1.74-1.82 (2H, m), 1.98-2.08 (1H, m), 2.26-2.52 (3H, m), 3.75 (1H, d) , J = 9.8 Hz), 3.92 (1H, d, J = 9.8 Hz), 3.98 (2H, t, J = 6.3 Hz), 4.42-4.52 (2H, m) 5.10 (2H, s), 5.76 (1H, brs), 6.84 (1H, d, J = 8.5 Hz), 7.15 (1H, brd, J = 8.3 Hz), 7 .22-7.38 (11H, m), 9.39 (1H, s).
　（４１－３）３－ベンジルオキシカルボニルアミノ－３－ベンジルオキシメチル－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）ペンタン酸の合成（化合物４１－３） (41-3) Synthesis of 3-benzyloxycarbonylamino-3-benzyloxymethyl-5- (4-heptyloxy-3-trifluoromethylphenyl) pentanoic acid (Compound 41-3)
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
　（メトキシメチル）トリフェニルホスホニウムクロリド（１．５６ｇ）をテトラヒドロフラン（３０ｍｌ）に溶解させ、カリウムｔ-ブトキシド（５５６ｍｇ）を加え、１０分間攪拌した。その混合溶液に化合物４１－２（９１０ｍｇ）のテトラヒドロフラン（２０ｍｌ）溶液を氷冷下滴下した後、室温で４時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、［１－ベンジルオキシメチル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（２－メトキシビニル）プロピル］カルバミン酸ベンジルエステルを淡黄色油状物として４７０ｍｇ得た。この淡黄色油状物をテトラヒドロフラン（１０ｍｌ）に溶解させ、濃塩酸（３ｍｌ）と水（３ｍｌ）を加え、６０℃で２時間攪拌した。反応液に飽和食塩水と酢酸エチルを加え、有機層を水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、［１－ベンジルオキシメチル－１－（ホルミルメチル）－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）プロピル］カルバミン酸ベンジルエステルを淡黄色油状物として２１０ｍｇ得た。この淡黄色油状物をｔ－ブチルアルコール（８ｍｌ）と水（２ｍｌ）に溶解し、氷冷下リン酸二水素ナトリウム（１０３ｍｇ）と亜塩素酸ナトリウム（１１５ｍｇ）を加え、室温で５時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去し、目的物（２２０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２６－１．３９（６Ｈ、ｍ）、１．４２－１．５０（２Ｈ、ｍ）、１．７５－１．８２（２Ｈ、ｍ）、２．０５－２．１９（２Ｈ、ｍ）、２．４８－２．５３（２Ｈ、ｍ）、２．８０（１Ｈ、ｄ、Ｊ＝１４．７Ｈｚ）、２．９４（１Ｈ、ｄ、Ｊ＝１４．７Ｈｚ）、３．６３－３．７０（２Ｈ、ｍ）、３．９９（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．５１（２Ｈ、ｓ）、５．０８（２Ｈ、ｓ）、５．４９（１Ｈ、ｂｒｓ）、６．８５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１９（１Ｈ、ｂｒｄ、Ｊ＝８．４Ｈｚ）、７．２６－７．３８（１１Ｈ、ｍ）。 (Methoxymethyl) triphenylphosphonium chloride (1.56 g) was dissolved in tetrahydrofuran (30 ml), potassium t-butoxide (556 mg) was added, and the mixture was stirred for 10 minutes. A solution of compound 41-2 (910 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [1-benzyloxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyvinyl) propyl] carbamic acid benzyl ester 470 mg was obtained as a yellow oil. This pale yellow oil was dissolved in tetrahydrofuran (10 ml), concentrated hydrochloric acid (3 ml) and water (3 ml) were added, and the mixture was stirred at 60 ° C. for 2 hr. Saturated brine and ethyl acetate were added to the reaction solution, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [1-benzyloxymethyl-1- (formylmethyl) -3- (4-heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester was obtained as a pale yellow oil. 210 mg was obtained as a product. This pale yellow oil was dissolved in t-butyl alcohol (8 ml) and water (2 ml), sodium dihydrogen phosphate (103 mg) and sodium chlorite (115 mg) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. . A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (220 mg) as a yellow oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.39 (6H, m), 1.42-1.50 (2H) , M), 1.75-1.82 (2H, m), 2.05-2.19 (2H, m), 2.48-2.53 (2H, m), 2.80 (1H, d) , J = 14.7 Hz), 2.94 (1H, d, J = 14.7 Hz), 3.63-3.70 (2H, m), 3.99 (2H, t, J = 6.4 Hz) 4.51 (2H, s), 5.08 (2H, s), 5.49 (1H, brs), 6.85 (1H, d, J = 8.5 Hz), 7.19 (1H, brd) , J = 8.4 Hz), 7.26-7.38 (11H, m).
　（４１－４）３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンタン酸の合成（化合物４１－４） (41-4) Synthesis of 3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentanoic acid (Compound 41-4)
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
　化合物４１－３（２２０ｍｇ）を酢酸エチル（１０ｍｌ）に溶解させ、１０％パラジウム炭素（１００ｍｇ）を加え、水素雰囲気下、室温で２４時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮し、目的物（４５ｍｇ）を淡褐色油状物として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２２－１．３６（６Ｈ、ｍ）、１．３７－１．４６（２Ｈ、ｍ）、１．６８－１．７５（２Ｈ、ｍ）、１．７５－１．８８（２Ｈ、ｍ）、２．３０－２．３７（２Ｈ、ｍ）、２．５４－２．６２（２Ｈ、ｍ）、３．３０－３．７０（４Ｈ、ｂｒｍ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．１７（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．３９－７．４２（２Ｈ、ｍ）。 Compound 41-3 (220 mg) was dissolved in ethyl acetate (10 ml), 10% palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (45 mg) as a pale-brown oil.
MS (ESI) m / z: 406 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.46 (2H, m), 1.68-1.75 (2H, m), 1.75-1.88 (2H, m), 2.30-2.37 (2H, m), 2.54-2 .62 (2H, m), 3.30-3.70 (4H, brm), 4.05 (2H, t, J = 6.2 Hz), 7.17 (1H, d, J = 8.3 Hz) 7.39-7.42 (2H, m).
　実施例４２
リン酸　モノ［２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（２－メトキシエチル）ブチル］エステル Example 42
Phosphoric acid mono [2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butyl] ester
　（４２－１）［１－ジ（ｔ－ブチル）ホスホリルオキシメチル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（２－メトキシエチル）プロピル］カルバミン酸ｔ－ブチルエステルの合成（化合物４２－１） (42-1) [1-Di (t-butyl) phosphoryloxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyethyl) propyl] carbamic acid t-butyl ester Synthesis of Compound 42-1
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
　化合物３９－４（１９０ｍｇ）のメタノール（１０ｍｌ）溶液にトリエチルアミン（０．１３９ｍｌ）とジ－ｔ－ブチルジカルボナート（１４４ｍｇ）を加え、室温で１８時間攪拌した。さらに反応液にジ－ｔ－ブチルジカルボナート（１００ｍｇ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去し無色油状物を２１０ｍｇ得た。その無色油状物（２１０ｍｇ）の塩化メチレン（５ｍｌ）とアセトニトリル（２ｍｌ）の溶液に、１Ｈ－テトラゾール（４６ｍｇ）、ジ－ｔ－ブチルジエチルホスホルアミダイト（０．１９７ｍｌ）を加え、室温で２時間半攪拌した。反応溶液を氷冷し、ｔ－ブチルヒドロペルオキシド含有デカン溶液（５－６ｍｏｌ／ｌ、０．１９８ｍｌ）を加え、室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（２１０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９１（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２８－１．４０（６Ｈ、ｍ）、１．４３（９Ｈ、ｓ）、１．４７－１．５２（２Ｈ、ｍ）、１．５０（１８Ｈ、ｓ）、１．７２－１．８１（２Ｈ、ｍ）、１．８４－１．９１（１Ｈ、ｍ）、１．９６－２．０８（３Ｈ、ｍ）、２．５６－２．６２（２Ｈ、ｍ）、３．３３（３Ｈ、ｓ）、３．４８－３．５７（２Ｈ、ｍ）、４．０３（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１０－４．１６（２Ｈ、ｍ）、７．０４（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３８（１Ｈ、ｂｒｓ）。 Triethylamine (0.139 ml) and di-t-butyl dicarbonate (144 mg) were added to a solution of compound 39-4 (190 mg) in methanol (10 ml), and the mixture was stirred at room temperature for 18 hours. Further, di-t-butyl dicarbonate (100 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 210 mg of a colorless oil. To a solution of the colorless oil (210 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (46 mg) and di-t-butyldiethylphosphoramidite (0.197 ml), and the mixture was stirred at room temperature for 2 hours. Half stirred. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.198 ml) was added, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (210 mg) as a colorless oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.28-1.40 (6H, m), 1.43 (9H, s) 1.47-1.52 (2H, m), 1.50 (18H, s), 1.72-1.81 (2H, m), 1.84-1.91 (1H, m), 1 .96-2.08 (3H, m), 2.56-2.62 (2H, m), 3.33 (3H, s), 3.48-3.57 (2H, m), 4.03 (2H, t, J = 6.2 Hz), 4.10-4.16 (2H, m), 7.04 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.38 (1H, brs).
　（４２－２）リン酸　モノ［２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（２－メトキシエチル）ブチル］エステルの合成（化合物４２－２） (42-2) Synthesis of mono [2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butyl] ester (compound 42-2) phosphoric acid
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
　化合物４２－１（２１０ｍｇ）を塩化メチレン（６ｍｌ）に溶解させ、塩化水素含有ジオキサン（４ｍｏｌ／ｌ、３ｍｌ）を加え、室温にて３時間半攪拌した。溶媒を減圧濃縮し、残渣にメタノール（３ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（５ｍｌ）を加え、析出した粉末を濾取し、酢酸エチルとジエチルエーテルで洗浄することにより、目的物（２５ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４８６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９１（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２７－１．４２（６Ｈ、ｍ）、１．４４－１．５３（２Ｈ、ｍ）、１．７３－１．８２（２Ｈ、ｍ）、１．８９－２．０９（４Ｈ、ｍ）、２．６２（１Ｈ、ｔｄ、Ｊ＝１２．９、４．７Ｈｚ）、２．７３（１Ｈ、ｔｄ、Ｊ＝１２．９、４．７Ｈｚ）、３．３７（３Ｈ、ｓ）、３．６１－３．６５（２Ｈ、ｍ）、３．９７（２Ｈ、ｄ、Ｊ＝５．４Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．０７（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．４２－７．４４（２Ｈ、ｍ）。 Compound 42-1 (210 mg) was dissolved in methylene chloride (6 ml), hydrogen chloride-containing dioxane (4 mol / l, 3 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (25 mg ) Was obtained as a white solid.
MS (ESI) m / z: 486 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.27 to 1.42 (6H, m), 1.44 to 1.53 ( 2H, m), 1.73-1.82 (2H, m), 1.89-2.09 (4H, m), 2.62 (1H, td, J = 12.9, 4.7 Hz), 2.73 (1H, td, J = 12.9, 4.7 Hz), 3.37 (3H, s), 3.61-3.65 (2H, m), 3.97 (2H, d, J = 5.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 7.07 (1H, d, J = 8.2 Hz), 7.42-7.44 (2H, m).
　実施例４３
２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（ヒドロキシメチル）ブタン酸 Example 43
2-Amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (hydroxymethyl) butanoic acid
　（４３－１）２－ｔ－ブチルオキシカルボニルアミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－［（メトキシメトキシ）メチル］ブタン酸の合成（化合物４３－１） (43-1) Synthesis of 2-t-butyloxycarbonylamino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2-[(methoxymethoxy) methyl] butanoic acid (Compound 43-1)
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
　化合物３９－２（４００ｍｇ）をｔ－ブチルアルコール（１６ｍｌ）と水（４ｍｌ）に溶解し、氷冷下リン酸二水素ナトリウム（２３０ｍｇ）と亜塩素酸ナトリウム（２６５ｍｇ）を加え、室温で４時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去し、目的物（４８０ｍｇ）を黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２４－１．３９（６Ｈ、ｍ）、１．４０－１．４９（２Ｈ、ｍ）、１．４７（９Ｈ、ｓ）、１．７５－１．８２（２Ｈ、ｍ）、２．０８－２．１２（２Ｈ、ｍ）、２．４４－２．５０（１Ｈ、ｍ）、２．５９－２．６５（１Ｈ、ｍ）、３．３６（３Ｈ、ｓ）、３．８６（１Ｈ、ｄ、Ｊ＝９．８Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．０９－４．１３（１Ｈ、ｍ）、４．６２－４．６６（２Ｈ、ｍ）、５．６７（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２３－７．２６（１Ｈ、ｍ）、７．３３（１Ｈ、ｂｒｓ）。 Compound 39-2 (400 mg) was dissolved in t-butyl alcohol (16 ml) and water (4 ml), sodium dihydrogen phosphate (230 mg) and sodium chlorite (265 mg) were added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Stir. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (480 mg) as a yellow oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.24-1.39 (6H, m), 1.40-1.49 (2H M), 1.47 (9H, s), 1.75-1.82 (2H, m), 2.08-2.12 (2H, m), 2.44-2.50 (1H, m) ), 2.59-2.65 (1H, m), 3.36 (3H, s), 3.86 (1H, d, J = 9.8 Hz), 4.00 (2H, t, J = 6) .3 Hz), 4.09-4.13 (1H, m), 4.62-4.66 (2H, m), 5.67 (1H, brs), 6.88 (1H, d, J = 8) .5 Hz), 7.23-7.26 (1H, m), 7.33 (1H, brs).
　（４３－２）２－アミノ－４－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－２－（ヒドロキシメチル）ブタン酸の合成（化合物４３－２） (43-2) Synthesis of 2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (hydroxymethyl) butanoic acid (Compound 43-2)
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
　化合物４３－１（４８０ｍｇ）のジオキサン（１５ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。反応液を濃縮し、酢酸エチル（２０ｍｌ）を加えた後、１ｍｏｌ／ｌ水酸化ナトリウム水溶液をｐＨが７～８になるまで加え、析出した粉末を濾取し、水とジエチルエーテルで洗浄することにより、目的物（２５０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２２－１．３６（６Ｈ、ｍ）、１．３７－１．４５（２Ｈ、ｍ）、１．６８－１．７５（２Ｈ、ｍ）、１．７５－１．８９（２Ｈ、ｍ）、２．４５（１Ｈ、ｔｄ、Ｊ＝１２．９、４．８Ｈｚ）、２．６７（１Ｈ、ｔｄ、Ｊ＝１２．９、４．８Ｈｚ）、３．３０－３．５０（１Ｈ、ｂｒｍ）、３．５２（１Ｈ、ｄ、Ｊ＝１１．０Ｈｚ）、３．６０（１Ｈ、ｄ、Ｊ＝１１．０Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．３５（１Ｈ、ｂｒｓ）、７．１３－７．１６（１Ｈ、ｍ）、７．３６（２Ｈ、ｂｒｓ）。 Concentrated hydrochloric acid (1.5 ml) was added to a solution of compound 43-1 (480 mg) in dioxane (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture is concentrated, ethyl acetate (20 ml) is added, 1 mol / l aqueous sodium hydroxide solution is added until the pH is 7-8, and the precipitated powder is collected by filtration and washed with water and diethyl ether. Gave the desired product (250 mg) as a white solid.
MS (ESI) m / z: 392 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.22-1.36 (6H, m), 1.37-1.45 (2H, m), 1.68-1.75 (2H, m), 1.75-1.89 (2H, m), 2.45 (1H, td, J = 12.9, 4.8 Hz) 2.67 (1H, td, J = 12.9, 4.8 Hz), 3.30-3.50 (1H, brm), 3.52 (1H, d, J = 11.0 Hz), 3. 60 (1H, d, J = 11.0 Hz), 4.05 (2H, t, J = 6.2 Hz), 5.35 (1H, brs), 7.13-7.16 (1H, m), 7.36 (2H, brs).
　実施例４４
４－アミノ－６－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－４－（ヒドロキシメチル）ヘキサン酸 Example 44
4-Amino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4- (hydroxymethyl) hexanoic acid
　（４４－１）４－アミノ－６－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－４－（ヒドロキシメチル）ヘキサン酸の合成（化合物４４－１） (44-1) Synthesis of 4-amino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4- (hydroxymethyl) hexanoic acid (Compound 44-1)
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
　化合物４０－１（２６０ｍｇ）のジオキサン（１０ｍｌ）溶液に、濃塩酸（１．５ｍｌ）を加え、８０℃にて３時間攪拌した。さらに、反応液に水（１ｍｌ）と濃塩酸（１ｍｌ）を加え、８０℃にて４時間攪拌した。反応液を濃縮し、酢酸エチル（２０ｍｌ）を加え、１ｍｏｌ／ｌ水酸化ナトリウム水溶液をｐＨが７～８になるまで加えた後、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をジエチルエーテルにて洗浄し、目的物（１１０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４２０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２１－１．３６（６Ｈ、ｍ）、１．３７－１．４４（２Ｈ、ｍ）、１．６８－１．７６（４Ｈ、ｍ）、１．８２－１．８８（２Ｈ、ｍ）、２．３３－２．３９（２Ｈ、ｍ）、２．５６－２．６２（２Ｈ、ｍ）、３．３０－３．５０（１Ｈ、ｂｒｍ）、３．４７（２Ｈ、ｂｒｓ）、４．０６（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．５４（１Ｈ、ｂｒｓ）、７．１８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４５－７．４８（２Ｈ、ｍ）。 Concentrated hydrochloric acid (1.5 ml) was added to a solution of compound 40-1 (260 mg) in dioxane (10 ml), and the mixture was stirred at 80 ° C. for 3 hours. Furthermore, water (1 ml) and concentrated hydrochloric acid (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated, ethyl acetate (20 ml) was added, 1 mol / l aqueous sodium hydroxide solution was added until the pH reached 7-8, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to obtain the desired product (110 mg) as a white solid.
MS (ESI) m / z: 420 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.21-1.36 (6H, m), 1.37-1.44 (2H, m), 1.68-1.76 (4H, m), 1.82-1.88 (2H, m), 2.33-3.39 (2H, m), 2.56-2 .62 (2H, m), 3.30-3.50 (1H, brm), 3.47 (2H, brs), 4.06 (2H, t, J = 6.2 Hz), 5.54 (1H , Brs), 7.18 (1H, d, J = 8.4 Hz), 7.45-7.48 (2H, m).
　実施例４５
［３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンチル］ホスホン酸 Example 45
[3-Amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid
　（４５－１）｛３－（ｔ－ブトキシ）カルボニルアミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－［（メトキシメトキシ）メチル］ペンチル｝ホスホン酸ジエチルエステルの合成（化合物４５－１） (45-1) Synthesis of {3- (t-butoxy) carbonylamino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3-[(methoxymethoxy) methyl] pentyl} phosphonic acid diethyl ester ( Compound 45-1)
Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160
　メチレンジホスホン酸テトラエチル（６６３ｍｇ）をテトラヒドロフラン（２０ｍｌ）に溶解させ、水素化ナトリウム（９２ｍｇ）を加え、３０分間攪拌した。その混合溶液に化合物３９－２（６００ｍｇ）のテトラヒドロフラン（２０ｍｌ）溶液を氷冷下滴下した後、室温で５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、［３－ｔ－ブトキシカルボニルアミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（メトキシメトキシ）メチル－１－ペンテニル］ホスホン酸ジエチルエステルを無色油状物として７３０ｍｇ得た。この無色油状物を酢酸エチル（１５ｍｌ）に溶解させ、１０％パラジウム炭素（３００ｍｇ）を加え、水素雰囲気下、室温で６時間撹拌した。反応容器内を窒素置換した後に溶液を濾過し、濾液を濃縮し、目的物（６５０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２６－１．３９（６Ｈ、ｍ）、１．３２（６Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、１．４２－１．５０（２Ｈ、ｍ）、１．４４（９Ｈ、ｓ）、１．７３－１．８２（４Ｈ、ｍ）、１．８３－２．１３（４Ｈ、ｍ）、２．５４－２．５９（２Ｈ、ｍ）、３．３９（３Ｈ、ｓ）、３．５８（２Ｈ、ｂｒｓ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．０５－４．１３（４Ｈ、ｍ）、４．６３（２Ｈ、ｓ）、４．７１（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２５－７．２７（１Ｈ、ｍ）、７．３４（１Ｈ、ｄ、Ｊ＝１．５Ｈｚ）。 Tetraethyl methylene diphosphonate (663 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min. A solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [3-t-butoxycarbonylamino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (methoxymethoxy) methyl-1-pentenyl] phosphonic acid 730 mg of diethyl ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (15 ml), 10% palladium carbon (300 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (650 mg) as a colorless oil.
1 H-NMR (CD 3 OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.39 (6H, m), 1.32 (6H, t, J = 7.0 Hz), 1.42-1.50 (2H, m), 1.44 (9H, s), 1.73-1.82 (4H, m), 1.83-2.13 ( 4H, m), 2.54-2.59 (2H, m), 3.39 (3H, s), 3.58 (2H, brs), 4.00 (2H, t, J = 6.4 Hz) 4.05-4.13 (4H, m), 4.63 (2H, s), 4.71 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7.25 -7.27 (1H, m), 7.34 (1H, d, J = 1.5 Hz).
　（４５－２）［３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンチル］ホスホン酸の合成（化合物４５－２） (45-2) Synthesis of [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid (Compound 45-2)
Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161
　化合物４５－１（６５０ｍｇ）をエタノール（１５ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて１時間半攪拌した。溶媒を減圧濃縮し、残渣の塩化メチレン（１０ｍｌ）溶液に、臭化トリメチルシリル（２．６７ｍｌ）を加え、室温で２４時間撹拌した。反応液を減圧濃縮し、メタノール（２０ｍｌ）を加え、室温で２４時間放置した後、減圧濃縮した。残渣にメタノール（１０ｍｌ）、ジエチルエーテル（２ｍｌ）、プロピレンオキシド（１０ｍｌ）を加え、析出した粉末を濾取し、メタノールで洗浄することにより、目的物（４３５ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９１（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２８－１．４２（６Ｈ、ｍ）、１．４４－１．５３（２Ｈ、ｍ）、１．５７－１．６８（２Ｈ、ｍ）、１．７６－１．８２（２Ｈ、ｍ）、１．８３－１．９９（４Ｈ、ｍ）、２．５８－２．７２（２Ｈ、ｍ）、３．６２（２Ｈ、ｂｒｓ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．０６（１Ｈ、ｄ、Ｊ＝８．３Ｈｚ）、７．４２－７．４５（２Ｈ、ｍ）。 Compound 45-1 (650 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The solvent was concentrated under reduced pressure, trimethylsilyl bromide (2.67 ml) was added to a solution of the residue in methylene chloride (10 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, methanol (20 ml) was added, and the mixture was allowed to stand at room temperature for 24 hours, and then concentrated under reduced pressure. Methanol (10 ml), diethyl ether (2 ml) and propylene oxide (10 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with methanol to obtain the desired product (435 mg) as a white solid.
MS (ESI) m / z: 456 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.28-1.42 (6H, m), 1.44 to 1.53 ( 2H, m), 1.57-1.68 (2H, m), 1.76-1.82 (2H, m), 1.83-1.99 (4H, m), 2.58-2. 72 (2H, m), 3.62 (2H, brs), 4.04 (2H, t, J = 6.2 Hz), 7.06 (1H, d, J = 8.3 Hz), 7.42- 7.45 (2H, m).
　実施例４６
［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メタノール塩酸塩 Example 46
[1-Amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol hydrochloride
　（４６－１）４－アミノ－１－ヘプチルオキシ－２－トリフルオロメチルベンゼン塩酸塩の合成（化合物４６－１） (46-1) Synthesis of 4-amino-1-heptyloxy-2-trifluoromethylbenzene hydrochloride (Compound 46-1)
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
　公知の方法（例えば、ＷＯ２００７／０６９７１２号公報、１０８～１０９ページ）により合成できる４－ヘプチルオキシ－３－トリフルオロメチル安息香酸（５０．０ｇ）、ジフェニルリン酸アジド（４９．７ｇ）及びトリエチルアミン（３３．２ｇ）のｔ－ブチルアルコール（３６０ｍｌ）溶液を１．５時間加熱還流した。溶媒を減圧留去し残渣に水を加えた後、ジエチルエーテルにて抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣の褐色油状物（６７．２ｇ）を塩化水素含有ジオキサン（４ｍｏｌ／ｌ、２００ｍｌ）に溶解し室温で２時間攪拌した。反応液にジイソプロピルエーテル（３００ｍｌ）を滴下し３０分攪拌した。析出した固体を濾取することにより、目的物（４１．３ｇ）を白色粉末として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、１．２７－１．４４（８Ｈ、ｍ）、１．７０－１．７４（２Ｈ、ｍ）、４．１１（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、７．３５（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．５０－７．６０（２Ｈ、ｍ）、１０．１１（３Ｈ、ｂｒｓ）。 4-heptyloxy-3-trifluoromethylbenzoic acid (50.0 g), diphenylphosphoric acid azide (49.7 g) and triethylamine (which can be synthesized by a known method (for example, WO 2007/069712, pages 108 to 109) A solution of 33.2 g) in t-butyl alcohol (360 ml) was heated to reflux for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residual brown oil (67.2 g) was dissolved in hydrogen chloride-containing dioxane (4 mol / l, 200 ml) and stirred at room temperature for 2 hours. Diisopropyl ether (300 ml) was added dropwise to the reaction solution and stirred for 30 minutes. The precipitated solid was collected by filtration to obtain the desired product (41.3 g) as a white powder.
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.6 Hz), 1.27-1.44 (8H, m), 1.70-1.74 (2H, m), 4.11 (2H, t, J = 6.0 Hz), 7.35 (1H, d, J = 8.7 Hz), 7.50-7.60 (2H, m), 10 .11 (3H, brs).
　（４６－２）４－ヘプチルオキシ－１－ヨード－３－トリフルオロメチルベンゼンの合成（化合物４６－２） (46-2) Synthesis of 4-heptyloxy-1-iodo-3-trifluoromethylbenzene (Compound 46-2)
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
　化合物４６－１（４１．３ｇ）の水（６２０ｍｌ）懸濁液に濃塩酸（７０ｍｌ）を加え、氷冷下亜硝酸ナトリウム（９．５６ｇ）の水（３５ｍｌ）溶液を滴下後３０分攪拌した。さらにヨウ化カリウム（２３．０ｇ）の水（３５ｍｌ）溶液を２０分かけて滴下後室温まで徐々に昇温した（内温１３℃より激しく発泡し出した）。さらにゆっくりと発泡させながら徐々に８０℃まで昇温し３０分攪拌した。反応液を氷冷後、２％亜硫酸ナトリウム水溶液（５００ｍｌ）を加え酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン）で精製することにより、目的物（２９．２ｇ）を赤褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．３０－１．５６（８Ｈ、ｍ）、１．７５－１．８４（２Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．７４（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．７１－７．８２（２Ｈ、ｍ）。 Concentrated hydrochloric acid (70 ml) was added to a suspension of compound 46-1 (41.3 g) in water (620 ml), and a solution of sodium nitrite (9.56 g) in water (35 ml) was added dropwise under ice cooling and stirred for 30 minutes. . Further, a solution of potassium iodide (23.0 g) in water (35 ml) was added dropwise over 20 minutes, and then the temperature was gradually raised to room temperature (foaming started vigorously from an internal temperature of 13 ° C.). Further, the mixture was gradually heated to 80 ° C. while foaming slowly and stirred for 30 minutes. The reaction mixture was ice-cooled, 2% aqueous sodium sulfite solution (500 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the object product (29.2 g) as a red-brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.9 Hz), 1.30-1.56 (8H, m), 1.75-1.84 (2H M), 4.00 (2H, t, J = 6.3 Hz), 6.74 (1H, d, J = 8.7 Hz), 7.71-7.82 (2H, m).
　（４６－３）４－ヘプチルオキシ－３－トリフルオロメチルフェニルホウ酸の合成（化合物４６－３） (46-3) Synthesis of 4-heptyloxy-3-trifluoromethylphenylboric acid (Compound 46-3)
Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164
　化合物４６－２（１１．６ｇ）の無水テトラヒドロフラン（１６０ｍｌ）溶液に－８０℃にてｎ－ブチルリチウム／ヘキサン溶液（１．５７ｍｏｌ／ｌ、２１．０ｍｌ）を２０分かけて滴下後３０分攪拌した。同温度でホウ酸トリメチル（１５．６ｇ）を一気に加え室温に昇温後３０分攪拌した。反応液を０℃に氷冷後６ｍｏｌ／ｌ塩酸水溶液（１１０ｍｌ）を滴下し、室温で１時間攪拌した。反応液を酢酸エチルで抽出後、有機層を水及び飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１：２～１：１）で精製することにより、目的物（５．０７ｇ）を褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．９２（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、１．２６－１．５１（８Ｈ、ｍ）、１．８３－１．８８（２Ｈ、ｍ）、４．１１（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．０６（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、８．２５（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、８．３１（１Ｈ、ｓ）。 An n-butyllithium / hexane solution (1.57 mol / l, 21.0 ml) was added dropwise to a solution of compound 46-2 (11.6 g) in anhydrous tetrahydrofuran (160 ml) at −80 ° C. over 20 minutes, followed by stirring for 30 minutes. did. Trimethyl borate (15.6 g) was added all at once at the same temperature, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was ice-cooled to 0 ° C., 6 mol / l aqueous hydrochloric acid solution (110 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2 to 1: 1) to obtain the desired product (5.07 g) as a brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.92 (3H, t, J = 6.6 Hz), 1.26-1.51 (8H, m), 1.83 to 1.88 (2H) M), 4.11 (2H, t, J = 6.3 Hz), 7.06 (1H, d, J = 8.4 Hz), 8.25 (1H, d, J = 8.4 Hz), 8 .31 (1H, s).
　（４６－４）４－（シクロペンタノン－３－イル）－１－ヘプチルオキシ－２－トリフルオロメチルベンゼンの合成（化合物４６－４） (46-4) Synthesis of 4- (cyclopentanone-3-yl) -1-heptyloxy-2-trifluoromethylbenzene (Compound 46-4)
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
　化合物４６－３（５．０７ｇ）、２－シクロペンテン－１－オン（１．３７ｇ）及び酢酸ナトリウム（２．７４ｇ）の酢酸（１５０ｍｌ）溶液に、酢酸パラジウム（３７５ｍｇ）及び塩化アンチモン（ＩＩＩ）（３８１ｍｇ）を加えて３０分攪拌した。同温度でホウ酸トリメチル（１５．６ｇ）を加え室温にて２日間攪拌した。反応液を０℃に氷冷後６ｍｏｌ／ｌの塩酸水溶液（１１０ｍｌ）を滴下し、室温で１時間攪拌した。反応液を水（４５０ｍｌ）にあけ、ジエチルエーテル（２００ｍｌ）を加えしばらく攪拌後セライト濾過した。濾液を分液後、有機層を水、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１：４）で精製することにより、目的物（３．２９ｇ）を褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．３０－１．５８（８Ｈ、ｍ）、１．７８－１．８３（２Ｈ、ｍ）、１．８８－２．０４（１Ｈ、ｍ）、２．１２－２．５４（４Ｈ、ｍ）、２．５８－２．６４（１Ｈ、ｍ）、３．３０－３．４８（１Ｈ、ｍ）、４．０３（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、６．９５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３４（１Ｈ、ｄｄ、Ｊ＝２．１、８．４Ｈｚ）、７．４４（１Ｈ、ｄ、Ｊ＝２．１Ｈｚ）。 To a solution of compound 46-3 (5.07 g), 2-cyclopenten-1-one (1.37 g) and sodium acetate (2.74 g) in acetic acid (150 ml), palladium acetate (375 mg) and antimony (III) chloride ( 381 mg) was added and stirred for 30 minutes. Trimethyl borate (15.6 g) was added at the same temperature, and the mixture was stirred at room temperature for 2 days. The reaction mixture was ice-cooled to 0 ° C., 6 mol / l hydrochloric acid aqueous solution (110 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (450 ml), diethyl ether (200 ml) was added, and the mixture was stirred for a while and filtered through celite. After the filtrate was separated, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 4) to obtain the desired product (3.29 g) as a brown oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.90 (3H, t, J = 6.7 Hz), 1.30-1.58 (8H, m), 1.78-1.83 (2H M), 1.88-2.04 (1H, m), 2.12-2.54 (4H, m), 2.58-2.64 (1H, m), 3.30-3.48 (1H, m), 4.03 (2H, t, J = 6.2 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.34 (1H, dd, J = 2.1, 8.4 Hz), 7.44 (1H, d, J = 2.1 Hz).
　（４６－５）［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メタノール塩酸塩の合成（化合物４６－５） (46-5) Synthesis of [1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol hydrochloride (Compound 46-5)
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
　化合物４６－４（３．２９ｇ）、シアン化ナトリウム（０．９４ｇ）及び塩化アンモニウム（１．０３ｇ）の２８％アンモニア水（２０ｍｌ）懸濁液を室温で２日間攪拌した。反応液を塩化メチレンで抽出後、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣の褐色油状物（３．４９ｇ）の濃塩酸（６０ｍｌ）及びエタノール（９０ｍｌ）混合液を８０℃にて４３時間攪拌した。溶媒を減圧留去し、残渣にエタノール（５０ｍｌ）及び２ｍｏｌ／ｌの水酸化リチウム水溶液（１０ｍｌ）を加え８０℃にて４時間攪拌した。溶媒を減圧留去し濃縮乾固した。得られた褐色粉末（３．６７ｇ）のボラン－テトラヒドロフラン錯体／テトラヒドロフラン溶液（０．９６ｍｏｌ／ｌ、３０ｍｌ）を４時間加熱還流した。反応液を冷却後１ｍｏｌ／ｌの塩酸水溶液（４０ｍｌ）を注意深く加え、３０分加熱還流した。反応液を冷却後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール＝１００：０～９０：１０）で精製し、さらにＨＰＬＣで精製することにより、目的物のフリーベース体６９４ｍｇを無色油状物として得た。その内４７０ｍｇをジエチルエーテル（２０ｍｌ）に溶解し、塩化水素含有ジオキサン（４ｍｏｌ／ｌ、２．０ｍｌ）を加えた。溶媒を減圧留去することにより、目的物（２９６ｍｇ）を薄褐色固体として得た。なお、本操作で取得した目的物は、シス体とトランス体のほぼ１：１の幾何異性体混合物であった。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７３［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．２２－１．３６（６Ｈ、ｍ）、１．３９－１．４４（２Ｈ、ｍ）、１．５８－１．８０（４．５Ｈ、ｍ）、１．８９－１．９９（２Ｈ、ｍ）、２．０３－２．１３（１．５Ｈ、ｍ）、２．２８（０．５Ｈ、ｄｄ、Ｊ＝７．４、１３．２Ｈｚ）、３．０６－３．１２（０．５Ｈ、ｍ）、３．３４（１Ｈ、ｂｒｓ）、３．４２－３．５５（２．５Ｈ、ｍ）、４．０７（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、５．５８（１Ｈ、ｍ）、７．１８（０．５Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．２０（０．５Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４０（０．５Ｈ、ｄ、Ｊ＝１．４Ｈｚ）、７．４７（０．５Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．５１（０．５Ｈ、ｓ）、７．５４（０．５Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、８．１５、８．１８（３Ｈ、ｂｒｓ×２）。 A suspension of compound 46-4 (3.29 g), sodium cyanide (0.94 g) and ammonium chloride (1.03 g) in 28% aqueous ammonia (20 ml) was stirred at room temperature for 2 days. The reaction solution was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and a mixed solution of the residual brown oil (3.49 g) in concentrated hydrochloric acid (60 ml) and ethanol (90 ml) was stirred at 80 ° C. for 43 hours. The solvent was distilled off under reduced pressure, ethanol (50 ml) and 2 mol / l aqueous lithium hydroxide solution (10 ml) were added to the residue, and the mixture was stirred at 80 ° C. for 4 hours. The solvent was distilled off under reduced pressure and concentrated to dryness. A borane-tetrahydrofuran complex / tetrahydrofuran solution (0.96 mol / l, 30 ml) of the obtained brown powder (3.67 g) was heated to reflux for 4 hours. The reaction solution was cooled, carefully added with 1 mol / l hydrochloric acid aqueous solution (40 ml), and heated under reflux for 30 minutes. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol = 100: 0 to 90:10) and further purified by HPLC to obtain 694 mg of the desired free base as a colorless oil. Got as. Among them, 470 mg was dissolved in diethyl ether (20 ml), and hydrogen chloride-containing dioxane (4 mol / l, 2.0 ml) was added. The solvent was distilled off under reduced pressure to obtain the desired product (296 mg) as a light brown solid. The target product obtained in this operation was a nearly 1: 1 geometric isomer mixture of cis and trans isomers.
MS (ESI) m / z: 373 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.7 Hz), 1.22-1.36 (6H, m), 1.39-1.44 (2H, m), 1.58-1.80 (4.5H, m), 1.89-1.99 (2H, m), 2.03-2.13 (1.5H, m), 2 .28 (0.5H, dd, J = 7.4, 13.2 Hz), 3.06-3.12 (0.5H, m), 3.34 (1H, brs), 3.42-3. 55 (2.5H, m), 4.07 (2H, t, J = 6.2 Hz), 5.58 (1H, m), 7.18 (0.5H, d, J = 8.6 Hz), 7.20 (0.5H, d, J = 8.6 Hz), 7.40 (0.5H, d, J = 1.4 Hz), 7.47 (0.5H, d, J = 8.6 Hz) 7.51 (0.5H, s), 7.54 0.5H, d, J = 8.6Hz), 8.15,8.18 (3H, brs × 2).
　実施例４７
リン酸モノ｛［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メチル｝エステル Example 47
Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester
　（４７－１）［３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－１－（ヒドロキシメチル）シクロペンチル］カルバミン酸　ｔ－ブチルエステルの合成（化合物４７－１） (47-1) Synthesis of [3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (hydroxymethyl) cyclopentyl] carbamic acid t-butyl ester (Compound 47-1)
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
　化合物４６－５（２２４ｍｇ）のメタノール溶液（１８ｍｌ）にジイソプロピルエチルアミン（１５５ｍｇ）及びジ－ｔ－ブチルジカルボナート（１９６ｍｇ）を加え、室温で１日攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１：３）で精製することにより、目的物（２５６ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．２２－１．５４（７Ｈ、ｍ）、１．４５（９Ｈ、ｓ）、１．５６－２．２４（８Ｈ、ｍ）、２．３５（０．５Ｈ、ｄｄ、Ｊ＝７．４、１３．６Ｈｚ）、２．４７（０．５Ｈ、ｄｄ、Ｊ＝７．５、１３．２Ｈｚ）、３．０２－３．１４（０．５Ｈ、ｍ）、３．２５－３．３７（０．５Ｈ、ｍ）、３．６２－３．８２（２Ｈ、ｍ）、３．８９（１Ｈ、ｂｒｓ）、４．０１（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．９１（０．５Ｈ、ｓ）、４．９５（０．５Ｈ、ｓ）、６．９０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．３２（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．４０（１Ｈ、ｄｄ、Ｊ＝１．８、５．４Ｈｚ）。 Diisopropylethylamine (155 mg) and di-t-butyl dicarbonate (196 mg) were added to a methanol solution (18 ml) of compound 46-5 (224 mg), and the mixture was stirred at room temperature for 1 day. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 3) to obtain the desired product (256 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 7.2 Hz), 1.22-1.54 (7H, m), 1.45 (9H, s), 1.56-2.24 (8H, m), 2.35 (0.5H, dd, J = 7.4, 13.6 Hz), 2.47 (0.5H, dd, J = 7.5, 13.2 Hz), 3.02-3.14 (0.5 H, m), 3.25-3.37 (0.5 H, m), 3.62-3.82 (2 H, m), 3. 89 (1H, brs), 4.01 (2H, t, J = 6.3 Hz), 4.91 (0.5H, s), 4.95 (0.5H, s), 6.90 (1H, d, J = 8.4 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.40 (1H, dd, J = 1.8, 5.4 Hz).
　（４７－２）［１－（ジ－ｔ－ブチル）ホスホリルオキシメチル－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］カルバミン酸　ｔ－ブチルエステルの合成（化合物４７－２） (47-2) Synthesis of [1- (di-t-butyl) phosphoryloxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] carbamic acid t-butyl ester (Compound 47-2)
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
　化合物４７－１（２５６ｍｇ）の塩化メチレン（５ｍｌ）溶液に０℃にてジ－ｔ－ブチルジイソプロピルホスホルアミダイト（１７７ｍｇ）及び１Ｈ－テトラゾール（４５ｍｇ）を加え、室温にて２時間攪拌した。反応液を０℃に冷却後、ｍ－クロロ過安息香酸（２５％含水物、１１２ｍｇ）を加え、室温にて２時間攪拌した。反応液に炭酸水素ナトリウム水溶液を加え、塩化メチレンで抽出後、飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１：９～２：３）で精製することにより、目的物（２８０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、１．１６－２．２５（３３Ｈ、ｍ）、１．３０（９Ｈ、ｓ）、２．３０－２．５２（１Ｈ、ｍ）、２．９５－３．１４（０．５Ｈ、ｍ）、３．２９－３．５２（０．５Ｈ、ｍ）、３．６２－３．８２（０．５Ｈ、ｍ）、３．９４－４．１０（２．５Ｈ、ｍ）、４．０１（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．９０―５．１５（１Ｈ、ｍ）、６．９０（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．２９－７．４２（２Ｈ、ｍ）。 Di-t-butyldiisopropylphosphoramidite (177 mg) and 1H-tetrazole (45 mg) were added to a solution of compound 47-1 (256 mg) in methylene chloride (5 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C., m-chloroperbenzoic acid (25% hydrate, 112 mg) was added, and the mixture was stirred at room temperature for 2 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 9-2: 3) to give the object product (280 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.6 Hz), 1.16-2.25 (33H, m), 1.30 (9H, s), 2.30-2.52 (1H, m), 2.95-3.14 (0.5H, m), 3.29-3.52 (0.5H, m), 3.62-3.82 (0.5H, m), 3.94-4.10 (2.5H, m), 4.01 (2H, t, J = 6.3 Hz), 4.90-5.15 (1H, m) 6.90 (1H, d, J = 8.4 Hz), 7.29-7.42 (2H, m).
　（４７－３）リン酸モノ｛［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メチル｝エステルの合成（化合物４７－３） (47-3) Synthesis of phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester (Compound 47-3)
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
　化合物４７－２（２８０ｍｇ）をエタノール（１０ｍｌ）に溶解させ、濃塩酸（３ｍｌ）を加え、５０℃にて３時間攪拌した。反応液に水（５０ｍｌ）を加え、析出する固体を濾取し、水及びジエチルエーテルで洗浄することによって、目的物（６６ｍｇ）を白色固体として得た。なお、本操作で取得した目的物は、シス体とトランス体のほぼ１：１の幾何異性体混合物であった。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５３［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）： ０．９１（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．２９－１．４０（６Ｈ、ｍ）、１．４７－１．５２（２Ｈ、ｍ）、１．６９（０．５Ｈ、ｔ、Ｊ＝１２．８Ｈｚ）、１．７６－１．８３（３Ｈ、ｍ）、１．８９－２．０３（２Ｈ、ｍ）、２．１５－２．３０（２Ｈ、ｍ）、２．５４（０．５Ｈ、ｄｄ、Ｊ＝７．４、１３．２Ｈｚ）、３．０６－３．１２（０．５Ｈ、ｍ）、３．１８－３．２６（０．５Ｈ、ｍ）、３．８７－３．９８（２Ｈ、ｍ）、４．０５（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．０８７（０．５Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．０９５（０．５Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．４４－７．４９（２Ｈ、ｍ）。 Compound 47-2 (280 mg) was dissolved in ethanol (10 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (50 ml) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water and diethyl ether to obtain the desired product (66 mg) as a white solid. The target product obtained in this operation was a nearly 1: 1 geometric isomer mixture of cis and trans isomers.
MS (ESI) m / z: 453 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.91 (3H, t, J = 6.7 Hz), 1.29-1.40 (6H, m), 1.47-1.52 ( 2H, m), 1.69 (0.5H, t, J = 12.8 Hz), 1.76-1.83 (3H, m), 1.89-2.03 (2H, m), 2. 15-2.30 (2H, m), 2.54 (0.5H, dd, J = 7.4, 13.2 Hz), 3.06-3.12 (0.5H, m), 3.18 -3.26 (0.5H, m), 3.87-3.98 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 7.087 (0.5H, d, J = 8.5 Hz), 7.095 (0.5 H, d, J = 8.6 Hz), 7.44-7.49 (2 H, m).
　参考例１
４－ヒドロキシ－３－トリフルオロメチルベンズアルデヒド Reference example 1
4-hydroxy-3-trifluoromethylbenzaldehyde
　（参考例１－１）４－ヒドロキシ－３－（トリフルオロメチル）ベンゾニトリルの合成（参考例化合物１－１） (Reference Example 1-1) Synthesis of 4-hydroxy-3- (trifluoromethyl) benzonitrile (Reference Example Compound 1-1)
Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170
　窒素雰囲気下、３－トリフルオロメチル－４－フルオロベンゾニトリル（４８．８ｇ）、２－ヒドロキシエチルメチルスルホン（４８．０ｇ）のＮ，Ｎ－ジメチルホルムアミド（４５０ｍｌ）溶液を氷冷下に冷却した。この溶液に６０％水素化ナトリウム（１８．５ｇ）を少量ずつ加えた。全量加えた後、反応溶液を室温にて２時間攪拌した。反応液を氷水に開け、反応を停止した。反応液に６Ｍ塩酸水溶液（６０ｍｌ）を加え、酢酸エチルにて抽出し、有機層を水、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することによって目的物（６０ｇ）を得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）d（ｐｐｍ）：７．１６（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、７．９２（１Ｈ、ｄｄ、Ｊ＝３．０Ｈｚ、９．１Ｈｚ）、８．０５（１Ｈ、ｄ、Ｊ＝３．０Ｈｚ）、１１．９０（１Ｈ、ｓ）。 Under a nitrogen atmosphere, a solution of 3-trifluoromethyl-4-fluorobenzonitrile (48.8 g) and 2-hydroxyethylmethylsulfone (48.0 g) in N, N-dimethylformamide (450 ml) was cooled under ice cooling. . To this solution 60% sodium hydride (18.5 g) was added in small portions. After the total amount was added, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was opened in ice water to stop the reaction. A 6M aqueous hydrochloric acid solution (60 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (60 g).
1 H-NMR (CDCl 3 ) d (ppm): 7.16 (1H, d, J = 9.1 Hz), 7.92 (1H, dd, J = 3.0 Hz, 9.1 Hz), 8.05 (1H, d, J = 3.0 Hz), 11.90 (1H, s).
　（参考例１－２）４－ヒドロキシ－３－（トリフルオロメチル）ベンズアルデヒドの合成（参考例化合物１－２） (Reference Example 1-2) Synthesis of 4-hydroxy-3- (trifluoromethyl) benzaldehyde (Reference Example Compound 1-2)
Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171
　窒素雰囲気下、参考例化合物１－１（４７．０ｇ）のテトラヒドロフラン溶液（３００ｍｌ）を－７８℃に冷却し、ジイソブチルアルミニウムヒドリドのヘキサン溶液（１．０Ｍ溶液、５００ｍｌ）を加えた後、２時間掛けて昇温し、室温にて１時間半攪拌した。反応液を氷冷下に冷却し、飽和塩化アンモニウム水溶液（２００ｍｌ）をゆっくり加えた後、室温にて撹拌し、さらにｐＨが４付近になるまで飽和塩化アンモニウム水溶液を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水にて洗浄した。有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去し、得られた残渣を酢酸エチル－イソプロピルエーテル混合溶媒により洗浄し、さらにシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３３．９ｇ）を淡黄色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：１８９［Ｍ－Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）d（ｐｐｍ）：７．１９（１Ｈ、ｄ、Ｊ＝７．９Ｈｚ）、８．０１（１Ｈ、ｄｄ、Ｊ＝１．８Ｈｚ、７．９Ｈｚ）、８．０９（１Ｈ、ｄ、Ｊ＝１．８Ｈｚ）、９．８８（１Ｈ、ｓ）、１１．８５（１Ｈ、ｂｒ　ｓ）。 Under a nitrogen atmosphere, a tetrahydrofuran solution (300 ml) of Reference Example compound 1-1 (47.0 g) was cooled to −78 ° C., and a hexane solution (1.0 M solution, 500 ml) of diisobutylaluminum hydride was added thereto for 2 hours. The mixture was heated up and stirred at room temperature for 1 hour and a half. The reaction solution was cooled under ice-cooling, and a saturated aqueous ammonium chloride solution (200 ml) was slowly added, followed by stirring at room temperature, and a saturated aqueous ammonium chloride solution was further added until the pH reached about 4. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was washed with a mixed solvent of ethyl acetate-isopropyl ether, and further purified by silica gel column chromatography to obtain the desired product (33. 9 g) was obtained as a pale yellow powder.
MS (ESI) m / z: 189 [MH]
1 H-NMR (CDCl 3 ) d (ppm): 7.19 (1H, d, J = 7.9 Hz), 8.01 (1H, dd, J = 1.8 Hz, 7.9 Hz), 8.09 (1H, d, J = 1.8 Hz), 9.88 (1H, s), 11.85 (1H, br s).
　実施例４８
４－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸 Example 48
4-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} butyric acid
　（４８－１）４－ヘプチルオキシ－３－（トリフルオロメチル）ベンズアルデヒドの合成（化合物４８－１） (48-1) Synthesis of 4-heptyloxy-3- (trifluoromethyl) benzaldehyde (Compound 48-1)
Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172
　４－ヘプチルオキシ－３－トリフルオロメチルベンジルアルコール（ＷＯ２００７０６９７１２号公報、１０８～１０９ページ）の化合物２８－２、（７．２ｇ）、臭化ナトリウム（２．５５ｇ）、トルエン（５０ｍｌ）、酢酸エチル（５０ｍｌ）、水（１１ｍｌ）および２，２，６，６－テトラメチル－１－ピペリジニルオキシ（８０ｍｇ）の混合物に、氷冷下撹拌しながら１０％次亜塩素酸ナトリウム水溶液（２０．９ｇ）、炭酸水素ナトリウム（６．２１ｇ）および水（７０ｍｌ）の混合物を１時間かけて滴下した。氷冷下で１時間撹拌後、再び１０％次亜塩素酸ナトリウム水溶液（２０．９ｇ）、炭酸水素ナトリウム（６．２１ｇ）および水（７０ｍｌ）の混合物を１時間かけて滴下した。有機層を分離し、食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（６．２１ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．９０（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．２９－１．４０（６Ｈ、ｍ）、１．４５－１．５２（２Ｈ、ｍ）、１．８２－１．８９（２Ｈ、ｍ）、４．１５（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１１（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、８．０３（１Ｈ、ｄｄ、Ｊ＝８．６、１．８Ｈｚ）、８．１１（１Ｈ、ｄ、Ｊ＝１．８Ｈｚ）、９．９２（１Ｈ、ｓ）。 Compound 28-2 of 4-heptyloxy-3-trifluoromethylbenzyl alcohol (WO2007069712, pages 108 to 109), (7.2 g), sodium bromide (2.55 g), toluene (50 ml), ethyl acetate (50 ml), water (11 ml) and 2,2,6,6-tetramethyl-1-piperidinyloxy (80 mg) were mixed with a 10% aqueous sodium hypochlorite solution (20. 9 g), a mixture of sodium bicarbonate (6.21 g) and water (70 ml) was added dropwise over 1 hour. After stirring for 1 hour under ice cooling, a mixture of 10% aqueous sodium hypochlorite (20.9 g), sodium hydrogen carbonate (6.21 g) and water (70 ml) was added dropwise over 1 hour. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (6.21 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.90 (3H, t, J = 6.7 Hz), 1.29-1.40 (6H, m), 1.45 to 1.52 (2H) M), 1.82-1.89 (2H, m), 4.15 (2H, t, J = 6.3 Hz), 7.11 (1H, d, J = 8.6 Hz), 8.03 (1H, dd, J = 8.6, 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz), 9.92 (1H, s).
　（４８－２）４－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸の合成（化合物４８－２） (48-2) Synthesis of 4-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} butyric acid (Compound 48-2)
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
　化合物４８－１（５００ｍｇ）と４－アミノ酪酸（１７８ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で２４時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、中和し、析出物を濾取、乾燥することにより、目的物（３５０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２１－１．３８（６Ｈ、ｍ）、１．３９－１．４６（２Ｈ、ｍ）、１．６８－１．７３（２Ｈ、ｍ）、１．７５－１．８１（２Ｈ、ｍ）、２．３２（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、２．８１（２Ｈ、ｔ、Ｊ＝７．３Ｈｚ）、３．００－３．７０（１Ｈ、ｂｒｍ）、４．０１（２Ｈ、ｂｒｓ）、４．１１（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．２８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．６９（１Ｈ、ｄｄ、Ｊ＝８．６、１．２Ｈｚ）、７．７５（１Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and 4-aminobutyric acid (178 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC and then neutralized. The precipitate was collected by filtration and dried to obtain the desired product (350 mg) as a white powder.
MS (ESI) m / z: 376 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.21-1.38 (6H, m), 1.39-1.46 (2H, m), 1.68-1.73 (2H, m), 1.75-1.81 (2H, m), 2.32 (2H, t, J = 7.1 Hz), 2.81 (2H, t, J = 7.3 Hz), 3.00-3.70 (1H, brm), 4.01 (2H, brs), 4.11 (2H, t, J = 6.2 Hz), 7 .28 (1H, d, J = 8.6 Hz), 7.69 (1H, dd, J = 8.6, 1.2 Hz), 7.75 (1H, brs).
　実施例４９
３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピオン酸 Example 49
3-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} propionic acid
　（４９－１）３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピオン酸の合成（化合物４９－１） (49-1) Synthesis of 3-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} propionic acid (Compound 49-1)
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
　化合物４８－１（５００ｍｇ）とβ－アラニン（１５４ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で２時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で２２時間攪拌した。反応液に水を加え、析出物を濾取、乾燥することにより、目的物（３２３ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３６２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２０－１．３６（６Ｈ、ｍ）、１．３７－１．４５（２Ｈ、ｍ）、１．６７－１．７６（２Ｈ、ｍ）、２．３１（２Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、２．７３（２Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、３．２０－３．９０（１Ｈ、ｂｒｍ）、３．７７（２Ｈ、ｂｒｓ）、４．０８（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．２１（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．５６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．６０（１Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and β-alanine (154 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and dried to obtain the desired product (323 mg) as a white powder.
MS (ESI) m / z: 362 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.20-1.36 (6H, m), 1.37-1.45 (2H, m), 1.67-1.76 (2H, m), 2.31 (2H, t, J = 6.8 Hz), 2.73 (2H, t, J = 6.7 Hz), 3 .20-3.90 (1H, brm), 3.77 (2H, brs), 4.08 (2H, t, J = 6.2 Hz), 7.21 (1H, d, J = 8.5 Hz) 7.56 (1H, d, J = 8.5 Hz), 7.60 (1H, brs).
　実施例５０
１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸 Example 50
1- [4-Heptyloxy-3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid
　（５０－１）１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸の合成（化合物５０－１） (50-1) Synthesis of 1- [4-heptyloxy-3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid (Compound 50-1)
Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175
　化合物４８－１（５００ｍｇ）とアゼチジン－３－カルボン酸（１７８ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で１時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で１７時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水にて洗浄後、析出物を濾取、乾燥することにより、目的物（２５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３７４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２３－１．３６（６Ｈ、ｍ）、１．３７－１．４５（２Ｈ、ｍ）、１．６７－１．７５（２Ｈ、ｍ）、３．００－３．７０（１Ｈ、ｂｒｍ）、３．２０－３．６５（５Ｈ、ｂｒｍ）、３．６９（２Ｈ、ｂｒｓ）、４．０７（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝９．０Ｈｚ）、７．５０－７．５５（２Ｈ、ｂｒｍ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and azetidine-3-carboxylic acid (178 mg), and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and the precipitate was collected by filtration and dried to obtain the desired product (25 mg) as a white powder.
MS (ESI) m / z: 374 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.23-1.36 (6H, m), 1.37-1.45 (2H, m), 1.67-1.75 (2H, m), 3.00-3.70 (1H, brm), 3.20-3.65 (5H, brm), 3.69 (2H) , Brs), 4.07 (2H, t, J = 6.2 Hz), 7.20 (1H, d, J = 9.0 Hz), 7.50-7.55 (2H, brm).
　実施例５１
４－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝ブタン－１－オール塩酸塩 Example 51
4-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} butan-1-ol hydrochloride
　（５１－１）［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－（４－ヒドロキシブチル）カルバミン酸ｔ－ブチルエステルの合成（化合物５１－１） (51-1) Synthesis of [4-heptyloxy-3- (trifluoromethyl) benzyl]-(4-hydroxybutyl) carbamic acid t-butyl ester (Compound 51-1)
Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176
　化合物４９－１（２８０ｍｇ）のメタノール（１０ｍｌ）溶液に、トリエチルアミン（０．３１４ｍｌ）とジ－ｔ－ブチルジカルボナート（３２７ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去することにより、無色油状物を得た。その油状物（３５０ｍｇ）をテトラヒドロフラン（１０ｍｌ）に溶解させ、氷冷下でテトラヒドロフラン－ボラン・テトラヒドロフラン溶液（１Ｍ、０．９６ｍｌ）を滴下した後、氷冷下３０分、さらに室温で１６時間攪拌した。反応液に水、１Ｍ塩酸水溶液を加え、酢酸エチルで抽出後、水、飽和炭酸水素ナトリウム水溶液そして飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物（３２０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．３９（６Ｈ、ｍ）、１．４０－１．７０（６Ｈ、ｍ）、１．４７（９Ｈ、ｓ）、１．７６－１．８４（２Ｈ、ｍ）、２．３５（１Ｈ、ｂｒｓ）、３．２２（２Ｈ、ｂｒｓ）、３．６５（２Ｈ、ｂｒｔ、Ｊ＝５．７Ｈｚ）、４．０２（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．３６（２Ｈ、ｂｒｓ）、６．９３（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．３２（１Ｈ、ｂｒｓ）、７．４３（１Ｈ、ｂｒｓ）。 Triethylamine (0.314 ml) and di-t-butyldicarbonate (327 mg) were added to a solution of compound 49-1 (280 mg) in methanol (10 ml), and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH reached about 7, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil. Got. The oil (350 mg) was dissolved in tetrahydrofuran (10 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1M, 0.96 ml) was added dropwise under ice cooling, followed by stirring for 30 minutes under ice cooling and further at room temperature for 16 hours. . Water, 1M aqueous hydrochloric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (320 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.40-1.70 (6H) M), 1.47 (9H, s), 1.76-1.84 (2H, m), 2.35 (1H, brs), 3.22 (2H, brs), 3.65 (2H, brt, J = 5.7 Hz), 4.02 (2H, t, J = 6.3 Hz), 4.36 (2H, brs), 6.93 (1H, d, J = 8.5 Hz), 7. 32 (1H, brs), 7.43 (1H, brs).
　（５１－２）４－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝ブタン－１－オール塩酸塩の合成（化合物５１－２） (51-2) Synthesis of 4-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} butan-1-ol hydrochloride (Compound 51-2)
Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177
　化合物５１－１（３２０ｍｇ）を塩化メチレン（１０ｍｌ）に溶解させ、塩化水素含有ジオキサン（４Ｍ、５ｍｌ）を加え、室温にて４時間攪拌した。反応液を濃縮し、残渣をイソプロピルエーテルにて洗浄し、目的物（２４０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３６２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２４－１．３８（６Ｈ、ｍ）、１．３９－１．４９（４Ｈ、ｍ）、１．６５－１．７６（４Ｈ、ｍ）、２．８７（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、３．４０（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１０－４．１４（４Ｈ、ｍ）、４．５８（１Ｈ、ｂｒｓ）、７．３０（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．７９（１Ｈ、ｄｄ、Ｊ＝８．６、１．７Ｈｚ）、７．８５（１Ｈ、ｄ、Ｊ＝１．７Ｈｚ）、９．１７（２Ｈ、ｂｒｓ）。 Compound 51-1 (320 mg) was dissolved in methylene chloride (10 ml), hydrogen chloride-containing dioxane (4M, 5 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was washed with isopropyl ether to obtain the desired product (240 mg) as a white powder.
MS (ESI) m / z: 362 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.24-1.38 (6H, m), 1.39-1.49 (4H) M), 1.65-1.76 (4H, m), 2.87 (2H, t, J = 7.8 Hz), 3.40 (2H, t, J = 6.2 Hz), 4.10 -4.14 (4H, m), 4.58 (1H, brs), 7.30 (1H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 8.6, 1. 7 Hz), 7.85 (1H, d, J = 1.7 Hz), 9.17 (2H, brs).
　実施例５２
３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロパン－１－オール塩酸塩 Example 52
3-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} propan-1-ol hydrochloride
　（５２－１）３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロパン－１－オール塩酸塩の合成（化合物５２－１） (52-1) Synthesis of 3-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} propan-1-ol hydrochloride (Compound 52-1)
Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178
　化合物４８－１（５００ｍｇ）と３－アミノ－１－プロパノール（０．１４１ｍｌ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去し白色固体を得た。その白色固体を、ＨＰＬＣで精製した後、得られた残渣に塩化水素含有エーテル（１Ｍ、１５ｍｌ）を加え塩酸塩とした後、析出物を濾取、乾燥し目的物（２７０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３４８［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．７Ｈｚ）、１．２６－１．３８（６Ｈ、ｍ）、１．３９－１．４５（２Ｈ、ｍ）、１．６９－１．８２（３Ｈ、ｍ）、２．０８－２．１５（１Ｈ、ｍ）、２．９０－３．０１（２Ｈ、ｍ）、３．４７（２Ｈ、ｂｒｔ、Ｊ＝５．７Ｈｚ）、４．１０－４．１５（４Ｈ、ｍ）、４．４６（１Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．７６（１Ｈ、ｂｒｓ）、７．３１（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．７５－７．８２（１Ｈ、ｍ）、７．８５（１Ｈ、ｂｒｓ）、９．０５（２Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and 3-amino-1-propanol (0.141 ml), and the mixture was stirred at room temperature for 30 minutes. . Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The white solid was purified by HPLC, and hydrogen chloride-containing ether (1M, 15 ml) was added to the resulting residue to form a hydrochloride. The precipitate was collected by filtration and dried to give the desired product (270 mg) as a white powder. Obtained.
MS (ESI) m / z: 348 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 0.86 (3H, t, J = 6.7 Hz), 1.26-1.38 (6H, m), 1.39-1.45 (2H M), 1.69-1.82 (3H, m), 2.08-2.15 (1H, m), 2.90-3.01 (2H, m), 3.47 (2H, brt) , J = 5.7 Hz), 4.10-4.15 (4H, m), 4.46 (1H, t, J = 6.1 Hz), 4.76 (1H, brs), 7.31 (1H , D, J = 8.2 Hz), 7.75-7.82 (1H, m), 7.85 (1H, brs), 9.05 (2H, brs).
　実施例５３
２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エタノール塩酸塩 Example 53
2-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} ethanol hydrochloride
　（５３－１）２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エタノール塩酸塩の合成（化合物５３－１） (53-1) Synthesis of 2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethanol hydrochloride (Compound 53-1)
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
　化合物４８－１（５００ｍｇ）とエタノールアミン（０．１０５ｍｌ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去し白色固体を得た。その白色固体を、ＨＰＬＣで精製した後、得られた残渣に塩化水素含有エーテル（１Ｍ、１５ｍｌ）を加え塩酸塩とした後、析出物を濾取、乾燥し目的物（３９５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３３４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２４－１．３６（６Ｈ、ｍ）、１．３７－１．４５（２Ｈ、ｍ）、１．６８－１．７６（２Ｈ、ｍ）、２．９４（２Ｈ、ｔ、Ｊ＝５．３Ｈｚ）、３．６４－３．６８（２Ｈ、ｍ）、４．１２（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１５（２Ｈ、ｂｒｓ）、５．２４（１Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、７．３０（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．７７（１Ｈ、ｄｄ、Ｊ＝８．６、１．７Ｈｚ）、７．８４（１Ｈ、ｄ、Ｊ＝１．７Ｈｚ）、９．０３（２Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and ethanolamine (0.105 ml), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The white solid was purified by HPLC, and then hydrogen chloride-containing ether (1M, 15 ml) was added to the resulting residue to obtain a hydrochloride. The precipitate was collected by filtration and dried to give the desired product (395 mg) as a white powder. Obtained.
MS (ESI) m / z: 334 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.24-1.36 (6H, m), 1.37-1.45 (2H M), 1.68-1.76 (2H, m), 2.94 (2H, t, J = 5.3 Hz), 3.64-3.68 (2H, m), 4.12 (2H) , T, J = 6.2 Hz), 4.15 (2H, brs), 5.24 (1H, t, J = 5.0 Hz), 7.30 (1H, d, J = 8.6 Hz), 7 .77 (1H, dd, J = 8.6, 1.7 Hz), 7.84 (1H, d, J = 1.7 Hz), 9.03 (2H, brs).
　実施例５４
（３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピル）ホスホン酸 Example 54
(3-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} propyl) phosphonic acid
　（５４－１）（３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピル）ホスホン酸の合成（化合物５４－１） (54-1) Synthesis of 3-{[4-Heptyloxy-3- (trifluoromethyl) benzyl] amino} propyl) phosphonic acid (Compound 54-1)
Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180
　化合物４８－１（５００ｍｇ）と３－アミノプロピルホスホン酸（２４３ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で１時間、５０℃で２時間攪拌した。室温でナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、５０℃で２０時間攪拌した。反応液に水を加え、析出物を濾取、乾燥することにより、目的物（４８０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４１２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．７３（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．１０－１．２６（６Ｈ、ｍ）、１．２８－１．３９（２Ｈ、ｍ）、１．４７－１．５５（２Ｈ、ｍ）、１．５９－１．６５（２Ｈ、ｍ）、１．７３－１．８３（２Ｈ、ｍ）、２．９０－２．９４（２Ｈ、ｍ）、３．９１－３．９５（４Ｈ、ｍ）、７．０４（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．５２（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．５５（１Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and 3-aminopropylphosphonic acid (243 mg). Stir for hours. Sodium triacetoxyborohydride (550 mg) was added at room temperature, and the mixture was stirred at 50 ° C. for 20 hr. Water was added to the reaction solution, and the precipitate was collected by filtration and dried to obtain the desired product (480 mg) as a white powder.
MS (ESI) m / z: 412 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.73 (3H, t, J = 6.8 Hz), 1.10-1.26 (6H, m), 1.28-1.39 ( 2H, m), 1.47-1.55 (2H, m), 1.59-1.65 (2H, m), 1.73-1.83 (2H, m), 2.90-2. 94 (2H, m), 3.91-3.95 (4H, m), 7.04 (1H, d, J = 8.6 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.55 (1H, brs).
　実施例５５
リン酸モノ（２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エチル）エステル Example 55
Phosphoric acid mono (2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethyl) ester
　（５５－１）リン酸モノ（２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エチル）エステルの合成（化合物５５－１） (55-1) Synthesis of mono (2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethyl) ester of phosphoric acid (Compound 55-1)
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181
　化合物４８－１（５００ｍｇ）とＯ－ホスホリルエタノールアミン（２４９ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で２時間攪拌した。反応液に、さらにテトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で２時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５５０ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え、析出物を濾取、乾燥することにより、目的物（５５０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４１４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤ３ＯＤ）δ（ｐｐｍ）：０．９１（３Ｈ、ｔ、Ｊ＝６．６Ｈｚ）、１．２８－１．４２（６Ｈ、ｍ）、１．４３－１．５６（２Ｈ、ｍ）、１．７８－１．８６（２Ｈ、ｍ）、３．２２－３．２６（２Ｈ、ｍ）、４．１０－４．１４（４Ｈ、ｍ）、４．２０（２Ｈ、ｂｒｓ）、７．２３（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．７１（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．７６（１Ｈ、ｂｒｓ）。 Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to compound 48-1 (500 mg) and O-phosphorylethanolamine (249 mg), and the mixture was stirred at room temperature for 2 hours. Tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) was further added to the reaction solution, followed by stirring at room temperature for 2 hours. Sodium triacetoxyborohydride (550 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and dried to obtain the desired product (550 mg) as a white powder.
MS (ESI) m / z: 414 [M + H]
1 H-NMR (CD 3 OD) δ (ppm): 0.91 (3H, t, J = 6.6 Hz), 1.28-1.42 (6H, m), 1.43-1.56 ( 2H, m), 1.78-1.86 (2H, m), 3.22-3.26 (2H, m), 4.10-4.14 (4H, m), 4.20 (2H, brs), 7.23 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.76 (1H, brs).
　実施例５６
１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－Ｌ－プロリン Example 56
1- [4-Heptyloxy-3- (trifluoromethyl) benzyl] -L-proline
　（５６－１）１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－Ｌ－プロリンの合成（化合物５６－１） (56-1) Synthesis of 1- [4-heptyloxy-3- (trifluoromethyl) benzyl] -L-proline (Compound 56-1)
Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182
　化合物４８－１（２８８ｍｇ）のメタノール（１０ｍＬ）溶液にＬ－プロリン（１７３ｍｇ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（３１８ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが６付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去し白色固体を得た。その白色固体に酢酸エチルを加え室温にて攪拌した。不溶の粉末を濾取して目的物（１１２ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３８８［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．１８－１．４９（８Ｈ、ｍ）、１．６０－１．９４（５Ｈ、ｍ）、２．０４－２．１７（１Ｈ、ｍ）、２．５３－２．６６（１Ｈ、ｍ）、３．０２－３．１４（１Ｈ、ｍ）、３．３０－３．４０（１Ｈ、ｍ）、３．７７（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、３．９８－４．１５（３Ｈ、ｍ）、６．６０（１Ｈ、ｂｒｓ）、７．２１（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．６１（１Ｈ、ｄｄ、Ｊ＝８．５、１．８Ｈｚ）、７．６４（１Ｈ、ｄ、Ｊ＝１．８Ｈｚ）。 To a solution of compound 48-1 (288 mg) in methanol (10 mL) was added L-proline (173 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (318 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 6. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. Ethyl acetate was added to the white solid and stirred at room temperature. The insoluble powder was collected by filtration to obtain the desired product (112 mg) as a white powder.
MS (ESI) m / z: 388 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.18-1.49 (8H, m), 1.60-1.94 (5H, m), 2.04-2.17 (1H, m), 2.53-2.66 (1H, m), 3.02-3.14 (1H, m), 3.30-3 .40 (1H, m), 3.77 (1H, d, J = 13 Hz), 3.98-4.15 (3H, m), 6.60 (1H, brs), 7.21 (1H, d , J = 8.5 Hz), 7.61 (1H, dd, J = 8.5, 1.8 Hz), 7.64 (1H, d, J = 1.8 Hz).
　実施例５７
（４Ｒ）－１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－４－ヒドロキシ－Ｌ－プロリン Example 57
(4R) -1- [4-Heptyloxy-3- (trifluoromethyl) benzyl] -4-hydroxy-L-proline
　（５７－１）（４Ｒ）－１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－４－ヒドロキシ－Ｌ－プロリンの合成（化合物５７－１） Synthesis of (57-1) (4R) -1- [4-heptyloxy-3- (trifluoromethyl) benzyl] -4-hydroxy-L-proline (Compound 57-1)
Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183
　化合物４８－１（２８８ｍｇ）のメタノール（１０ｍＬ）溶液に４－ヒドロキシ－Ｌ－プロリン（１９７ｍｇ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．２ｍｌ）を加え、室温で３時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（３１８ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し白色固体を得た。その白色固体に酢酸エチルを加え室温にて攪拌した。不溶の粉末を濾取して目的物（５４ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、１．１９－１．４８（８Ｈ、ｍ）、１．６６－１．７７（２Ｈ、ｍ）、１．８９－２．０４（２Ｈ、ｍ）、２．３６－２．４６（１Ｈ、ｍ）、３．０７－３．２０（１Ｈ、ｍ）、３．３４－３．５４（１Ｈ、ｍ）、４．００（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、４．０８（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１４－４．２６（１Ｈ、ｍ）、５．０６（１Ｈ、ｂｒｓ）、７．２０（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．５７（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．５９（１Ｈ、ｓ）。 4-hydroxy-L-proline (197 mg) and tetrabutylammonium hydroxide (37% methanol solution, 0.2 ml) were added to a solution of compound 48-1 (288 mg) in methanol (10 mL), and the mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (318 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. Ethyl acetate was added to the white solid and stirred at room temperature. The insoluble powder was collected by filtration to obtain the desired product (54 mg) as a white powder.
MS (ESI) m / z: 404 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 7.0 Hz), 1.19-1.48 (8H, m), 1.66-1.77 (2H, m), 1.89-2.04 (2H, m), 2.36-2.46 (1H, m), 3.07-3.20 (1H, m), 3.34-3 .54 (1H, m), 4.00 (1H, d, J = 13 Hz), 4.08 (2H, t, J = 6.2 Hz), 4.14-4.26 (1H, m), 5 0.06 (1H, brs), 7.20 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.59 (1H, s).
　実施例５８
（４Ｓ）－１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－４－ヒドロキシ－Ｌ－プロリン Example 58
(4S) -1- [4-Heptyloxy-3- (trifluoromethyl) benzyl] -4-hydroxy-L-proline
　（５８－１）（４Ｓ）－１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－４－ヒドロキシ－Ｌ－プロリンの合成（化合物５８－１） Synthesis of (58-1) (4S) -1- [4-heptyloxy-3- (trifluoromethyl) benzyl] -4-hydroxy-L-proline (Compound 58-1)
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184
　化合物４８－１（２８８ｍｇ）のメタノール（１０ｍＬ）溶液にｃｉｓ－４－ヒドロキシ－Ｌ－プロリン（１９７ｍｇ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．６ｍｌ）を加え、室温で３時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（３１８ｍｇ）を加え、室温で２時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣に酢酸エチルを加え攪拌した。析出した粉末を濾取して目的物（８３ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．２０－１．４９（８Ｈ、ｍ）、１．６５－１．７２（３Ｈ、ｍ）、２．３１－２．４２（１Ｈ、ｍ）、２．５６－２．６４（１Ｈ、ｍ）、２．８２－２．８８（１Ｈ、ｍ）、３．１９－３．２９（１Ｈ、ｍ）、３．５９（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、３．９６（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、４．０８（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１７－４．２４（１Ｈ、ｍ）、７．２０（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．５８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．６０（１Ｈ、ｓ）。 Add cis-4-hydroxy-L-proline (197 mg) and tetrabutylammonium hydroxide (37% methanol solution, 0.6 ml) to a solution of compound 48-1 (288 mg) in methanol (10 mL) and stir at room temperature for 3 hours. did. Sodium triacetoxyborohydride (318 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue and stirred. The precipitated powder was collected by filtration to obtain the desired product (83 mg) as a white powder.
MS (ESI) m / z: 404 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.20-1.49 (8H, m), 1.65-1.72 (3H, m), 2.31-2.42 (1H, m), 2.56-2.64 (1H, m), 2.82-2.88 (1H, m), 3.19-3 .29 (1H, m), 3.59 (1H, d, J = 13 Hz), 3.96 (1H, d, J = 13 Hz), 4.08 (2H, t, J = 6.2 Hz), 4 .17-4.24 (1H, m), 7.20 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.60 (1H, s) .
　実施例５９
１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－Ｄ－プロリン Example 59
1- [4-Heptyloxy-3- (trifluoromethyl) benzyl] -D-proline
　（５９－１）１－［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］－Ｄ－プロリンの合成（化合物５９－１） (59-1) Synthesis of 1- [4-heptyloxy-3- (trifluoromethyl) benzyl] -D-proline (Compound 59-1)
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185
　化合物４８－１（２８８ｍｇ）のメタノール（１０ｍＬ）溶液にＤ－プロリン（１７３ｍｇ）を加え、室温で３０分間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（３１８ｍｇ）を加え、室温で１８時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し白色固体を得た。その白色固体に酢酸エチルを加え室温にて攪拌した。不溶の粉末を濾取して目的物（１４３ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３８８［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、１．１９－１．４９（８Ｈ、ｍ）、１．６４－１．９５（５Ｈ、ｍ）、２．０５－２．１８（１Ｈ、ｍ）、２．５４－２．６７（１Ｈ、ｍ）、３．０４－３．１４（１Ｈ、ｍ）、３．２６－３．４８（１Ｈ、ｍ）、３．７９（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、４．０４（１Ｈ、ｄ、Ｊ＝１３Ｈｚ）、４．０８（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．２２（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．６１（１Ｈ、ｄｄ、Ｊ＝８．５、１．８Ｈｚ）、７．６５（１Ｈ、ｄ、Ｊ＝１．８Ｈｚ）。 To a solution of compound 48-1 (288 mg) in methanol (10 mL) was added D-proline (173 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (318 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. Ethyl acetate was added to the white solid and stirred at room temperature. Insoluble powder was collected by filtration to obtain the desired product (143 mg) as a white powder.
MS (ESI) m / z: 388 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.19-1.49 (8H, m), 1.64-1.95 (5H, m), 2.05-2.18 (1H, m), 2.54-2.67 (1H, m), 3.04-3.14 (1H, m), 3.26-3 .48 (1H, m), 3.79 (1H, d, J = 13 Hz), 4.04 (1H, d, J = 13 Hz), 4.08 (2H, t, J = 6.2 Hz), 7 .22 (1H, d, J = 8.5 Hz), 7.61 (1H, dd, J = 8.5, 1.8 Hz), 7.65 (1H, d, J = 1.8 Hz).
　実施例６０
３－［４－ヘプチルオキシ－３－（トリフルオロメチル）フェニル］プロピオン酸メチル Example 60
Methyl 3- [4-heptyloxy-3- (trifluoromethyl) phenyl] propionate
　（６０－１）（２Ｅ）－３－［４－ヘプチルオキシ－３－（トリフルオロメチル）フェニル］アクリル酸メチルの合成（化合物６０－１） Synthesis of methyl (60-1) (2E) -3- [4-heptyloxy-3- (trifluoromethyl) phenyl] acrylate (Compound 60-1)
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186
　ホスホノ酢酸ジエチルメチル（６４９ｍｇ）をテトラヒドロフラン（１０ｍｌ）に溶解させ、６０％水素化ナトリウム（１３９ｍｇ）を加え、１５分間攪拌した。その混合溶液に化合物４８－１（５００ｍｇ）のテトラヒドロフラン（１０ｍｌ）溶液を氷冷下滴下した後、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（６３０ｍｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２５－１．４０（６Ｈ、ｍ）、１．４２－１．５１（２Ｈ、ｍ）、１．７９－１．８６（２Ｈ、ｍ）、３．８１（３Ｈ、ｓ）、４．０８（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．３５（１Ｈ、ｄ、Ｊ＝１５．８Ｈｚ）、６．９９（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．６１－７．６６（２Ｈ、ｍ）、７．７３（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 Diethyl methyl phosphonoacetate (649 mg) was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride (139 mg) was added, and the mixture was stirred for 15 min. A solution of compound 48-1 (500 mg) in tetrahydrofuran (10 ml) was added dropwise to the mixed solution under ice-cooling, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (630 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.40 (6H, m), 1.42-1.51 (2H) M), 1.79-1.86 (2H, m), 3.81 (3H, s), 4.08 (2H, t, J = 6.3 Hz), 6.35 (1H, d, J = 15.8 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.61-7.66 (2H, m), 7.73 (1H, d, J = 1.9 Hz).
　（６０－２）３－［４－ヘプチルオキシ－３－（トリフルオロメチル）フェニル］プロピオン酸メチルの合成（化合物６０－２） (60-2) Synthesis of methyl 3- [4-heptyloxy-3- (trifluoromethyl) phenyl] propionate (Compound 60-2)
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187
　化合物６０－１（６３０ｍｇ）の酢酸エチル（５ｍｌ）とメタノール（５ｍｌ）溶液に、１０％パラジウム炭素（３００ｍｇ）を加え、水素雰囲気下室温で２時間半攪拌した。反応液をセライトで濾過後濃縮することによって、目的物（６３０ｍｇ）を薄黄色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２４－１．４０（６Ｈ、ｍ）、１．４１－１．５０（２Ｈ、ｍ）、１．７５－１．８３（２Ｈ、ｍ）、２．６０（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．９１（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．６７（３Ｈ、ｓ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．８９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．２９（１Ｈ、ｄｄ、Ｊ＝８．５、１．９Ｈｚ）、７．３７（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 To a solution of compound 60-1 (630 mg) in ethyl acetate (5 ml) and methanol (5 ml) was added 10% palladium carbon (300 mg), and the mixture was stirred at room temperature for 2 hours and a half in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to give the object product (630 mg) as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.24-1.40 (6H, m), 1.41-1.50 (2H) M), 1.75-1.83 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6 Hz), 3.67. (3H, s), 4.00 (2H, t, J = 6.3 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.29 (1H, dd, J = 8.5, 1.9 Hz), 7.37 (1H, d, J = 1.9 Hz).
　実施例６１
３－［４－ヘプチルオキシ－３－（トリフルオロメチル）フェニル］プロピオン酸 Example 61
3- [4-Heptyloxy-3- (trifluoromethyl) phenyl] propionic acid
　（６１－１）３－［４－ヘプチルオキシ－３－（トリフルオロメチル）フェニル］プロピオン酸の合成（化合物６１－１） (61-1) Synthesis of 3- [4-heptyloxy-3- (trifluoromethyl) phenyl] propionic acid (Compound 61-1)
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188
　化合物６０－２（６３０ｍｇ）を１，４－ジオキサン（１５ｍｌ）と水（１ｍｌ）に溶解させ、濃塩酸（１．５ｍｌ）を加え、８０℃にて２時間攪拌した。反応液に１Ｍ塩酸（１０ｍｌ）を加え、８０℃にて２時間攪拌した。反応液を濃縮し、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をエタノールと水にて洗浄し、目的物（５４７ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３３３［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２０－１．３４（６Ｈ、ｍ）、１．３５－１．４５（２Ｈ、ｍ）、１．６６－１．７４（２Ｈ、ｍ）、２．５０－２．５４（２Ｈ、ｍ）、２．８１（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．１５（１Ｈ、ｄ、Ｊ＝９．１Ｈｚ）、７．４３－７．４８（２Ｈ、ｍ）、１２．２（１Ｈ、ｂｒｓ）。 Compound 60-2 (630 mg) was dissolved in 1,4-dioxane (15 ml) and water (1 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 2 hr. 1M Hydrochloric acid (10 ml) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 2 hr. The reaction mixture was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethanol and water to obtain the desired product (547 mg) as a white powder.
MS (ESI) m / z: 333 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.20-1.34 (6H, m), 1.35 to 1.45 (2H, m), 1.66-1.74 (2H, m), 2.50-2.54 (2H, m), 2.81 (2H, t, J = 7.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 7.15 (1H, d, J = 9.1 Hz), 7.43-7.48 (2H, m), 12.2 (1H, brs).
　実施例６２
４－｛［４－オクチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩 Example 62
4-{[4-Octyloxy-3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate
　（６２－１）４－｛［４－オクチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩の合成（化合物６２－１） (62-1) Synthesis of 4-{[4-octyloxy-3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate (Compound 62-1)
Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、１－ブロモオクタン（０．３３０ｍｌ）を加え、室温にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（９６ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．５６ｍｌ）を加え、室温で一昼夜攪拌した。氷冷下、ナトリウムトリアセトキシボロヒドリド（２９６ｍｇ）を加え、室温で７時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、析出物を濾取、乾燥することにより、目的物（７０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：０．８６（３Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、１．２２－１．３８（８Ｈ、ｍ）、１．３９－１．４５（２Ｈ、ｍ）、１．６８－１．７６（２Ｈ、ｍ）、１．７８－１．８６（２Ｈ、ｍ）、２．３５（２Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．９４（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．３０－３．４５（１Ｈ、ｂｒｍ）、４．１２（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１４（２Ｈ、ｓ）、７．３２（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．７０（１Ｈ、ｄｄ、Ｊ＝８．６、１．６Ｈｚ）、７．７９（１Ｈ、ｂｒｄ、Ｊ＝１．６Ｈｚ）。 Reference Example compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (10 ml), potassium carbonate (654 mg) and 1-bromooctane (0.330 ml) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 0.56 ml) were added to the resulting residue and 4-aminobutyric acid (96 mg), and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (296 mg) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC, and the precipitate was collected by filtration and dried to give the object product (70 mg) as a white powder.
MS (ESI) m / z: 390 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.38 (8H, m), 1.39-1.45 (2H, m), 1.68-1.76 (2H, m), 1.78-1.86 (2H, m), 2.35 (2H, t, J = 7.2 Hz), 2.94 (2H, t, J = 7.7 Hz), 3.30-3.45 (1H, brm), 4.12 (2H, t, J = 6.2 Hz), 4.14 (2H, s), 7 .32 (1H, d, J = 8.6 Hz), 7.70 (1H, dd, J = 8.6, 1.6 Hz), 7.79 (1H, brd, J = 1.6 Hz).
　実施例６３
４－｛［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸 Example 63
4-{[4- (3-Phenylpropoxy) -3- (trifluoromethyl) benzyl] amino} butyric acid
　（６３－１）４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）ベンズアルデヒドの合成（化合物６３－１） (63-1) Synthesis of 4- (3-phenylpropoxy) -3- (trifluoromethyl) benzaldehyde (Compound 63-1)
Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190
　参考例化合物１－２（１．５ｇ）をＮ，Ｎ－ジメチルホルムアミド（３０ｍｌ）に溶解させ、炭酸カリウム（１．９６ｇ）、１－ブロモ－３－フェニルプロパン（１．８９ｇ）を加え、８０℃にて１．５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣にヘキサンを加えると粉末が析出した。上澄みを除き、乾燥することにより目的物（２．１６ｇ）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：２．１３－２．２６（２Ｈ、ｍ）、２．８６（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、４．１２（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、７．０５（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．１４－７．５５（５Ｈ、ｍ）、８．０１（１Ｈ、ｄｄ、Ｊ＝８．５、１．９Ｈｚ）、８．１３（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）、９．９２（１Ｈ、ｓ）。 Reference Example Compound 1-2 (1.5 g) was dissolved in N, N-dimethylformamide (30 ml), potassium carbonate (1.96 g) and 1-bromo-3-phenylpropane (1.89 g) were added, and 80 Stir at 1.5 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. When hexane was added to the obtained residue, a powder precipitated. The supernatant was removed and dried to obtain the desired product (2.16 g) as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ (ppm): 2.13-2.26 (2H, m), 2.86 (2H, t, J = 7.6 Hz), 4.12 (2H, t, J = 6.0 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.14-7.55 (5H, m), 8.01 (1H, dd, J = 8.5, 1. 9 Hz), 8.13 (1H, d, J = 1.9 Hz), 9.92 (1H, s).
　（６３－２）４－｛［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸の合成（化合物６３－２） (63-2) Synthesis of 4-{[4- (3-phenylpropoxy) -3- (trifluoromethyl) benzyl] amino} butyric acid (Compound 63-2)
Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191
　化合物６３－１（４０７ｍｇ）のメタノール（１０ｍＬ）溶液に４－アミノ酪酸（２０４ｍｇ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．５ｍｌ）を加え、室温で２時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（４２０ｍｇ）を加え、室温で２４時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが６付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し淡黄色固体を得た。この淡黄色固体に酢酸エチルを加え室温にて攪拌した。不溶の粉末を濾取して目的物（２３５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．６０－１．７１（２Ｈ、ｍ）、１．９５－２．０９（２Ｈ、ｍ）、２．２６（２Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、２．６０（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、２．７５（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、３．７６（２Ｈ、ｓ）、４．０６（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１５－７．２２（４Ｈ、ｍ）、７．２４－７．３３（２Ｈ、ｍ）、７．５６（１Ｈ、ｄｄ、Ｊ＝８．５、１．８Ｈｚ）、７．６３（１Ｈ、ｄ、Ｊ＝１．８Ｈｚ）。 4-Aminobutyric acid (204 mg) and tetrabutylammonium hydroxide (37% methanol solution, 0.5 ml) were added to a solution of compound 63-1 (407 mg) in methanol (10 mL), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (420 mg) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 6. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow solid. Ethyl acetate was added to the pale yellow solid and stirred at room temperature. Insoluble powder was collected by filtration to obtain the desired product (235 mg) as a white powder.
MS (ESI) m / z: 396 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.60-1.71 (2H, m), 1.95-2.09 (2H, m), 2.26 (2H, t, J = 6.8 Hz), 2.60 (2H, t, J = 6.4 Hz), 2.75 (2H, t, J = 7.8 Hz), 3.76 (2H, s), 4.06 (2H) , T, J = 6.1 Hz), 7.15-7.22 (4H, m), 7.24-7.33 (2H, m), 7.56 (1H, dd, J = 8.5, 1.8 Hz), 7.63 (1H, d, J = 1.8 Hz).
　実施例６４
１－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸 Example 64
1- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid
　（６４－１）１－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸の合成（化合物６４－１） Synthesis of (64-1) 1- [4- (3-phenylpropoxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid (Compound 64-1)
Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192
　化合物６３－１（５００ｍｇ）のメタノール（５ｍＬ）溶液に３－アゼチジンカルボン酸（７６ｍｇ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．１ｍｌ）を加え、室温で１８時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（１５９ｍｇ）を加え、室温で３時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し白色固体を得た。この白色固体に酢酸エチルを加え室温にて攪拌した。不溶の粉末を濾取して目的物（１７２ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：３９４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．９７－２．０８（２Ｈ、ｍ）、２．７４（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、３．１５－３．８０（５Ｈ、ｍ）、４．０６（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１４－７．２２（４Ｈ、ｍ）、７．２４－７．３２（２Ｈ、ｍ）、７．４８－７．６３（２Ｈ、ｍ）。 3-azetidinecarboxylic acid (76 mg) and tetrabutylammonium hydroxide (37% methanol solution, 0.1 ml) were added to a solution of compound 63-1 (500 mg) in methanol (5 mL), and the mixture was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (159 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. Ethyl acetate was added to the white solid and stirred at room temperature. The insoluble powder was collected by filtration to obtain the desired product (172 mg) as a white powder.
MS (ESI) m / z: 394 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.97-2.08 (2H, m), 2.74 (2H, t, J = 7.9 Hz), 3.15-3.80 (5H, m), 4.06 (2H, t, J = 6.1 Hz), 7.14-7.22 (4H, m), 7.24-7.32 (2H, m), 7.48 -7.63 (2H, m).
　実施例６５
３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸エチル Example 65
Ethyl 3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionate
　（６５－１）（２Ｅ）－３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］アクリル酸エチル及び（２Ｚ）－３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］アクリル酸エチルの合成（化合物６５－１－Ｅ及び化合物６５－１－Ｚ） (65-1) (2E) -3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] ethyl acrylate and (2Z) -3- [4- (3-phenylpropoxy)- Synthesis of ethyl 3- (trifluoromethyl) phenyl] acrylate (compound 65-1-E and compound 65-1-Z)
Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193
　臭化（エトキシカルボニルメチル）トリフェニルホスホニウム（４．５０ｇ）のエタノール（３０ｍｌ）溶液に氷冷下ナトリウムエトキシド（０．５７１ｇ）を加え、室温にて３０分間攪拌した。反応液に化合物６３－１（２．１６ｇ）を加え、さらに室温にて２時間攪拌した。反応溶媒を減圧留去し、残渣に水を加え、酢酸エチルで抽出した。有機層を１Ｍ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、硫酸マグネシウムにて乾燥した。有機層の溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物のＥ体とＺ体が約４：１の混合物（２．４２ｇ）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２７（０．６Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．３４（２．４Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．１０－２．１９（２Ｈ、ｍ）、２．８４（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、４．０２－４．０８（２Ｈ、ｍ）、４．１９（０．４Ｈ、ｑ、Ｊ＝７．１Ｈｚ）、４．２６（１．６Ｈ、ｑ、Ｊ＝７．２Ｈｚ）、５．９１（０．２Ｈ、ｄ、Ｊ＝１３Ｈｚ）、６．３５（０．８Ｈ、ｄ、Ｊ＝１６Ｈｚ）、６．８４（０．２Ｈ、ｄ、Ｊ＝１３Ｈｚ）、６．８８－６．９６（１Ｈ、ｍ）、７．１６－７．３２（５Ｈ、ｍ）、７．５８－７．６７（１．６Ｈ、ｍ）、７．７６（０．８Ｈ、ｄ、Ｊ＝２．０Ｈｚ）、７．８５－７．９２（０．４Ｈ、ｍ）。 Sodium ethoxide (0.571 g) was added to an ethanol (30 ml) solution of (ethoxycarbonylmethyl) triphenylphosphonium bromide (4.50 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Compound 63-1 (2.16 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a mixture (2.42 g) of the objective E-form and Z-form of about 4: 1 as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.27 (0.6 H, t, J = 7.2 Hz), 1.34 (2.4 H, t, J = 7.2 Hz), 2.10 -2.19 (2H, m), 2.84 (2H, t, J = 7.6 Hz), 4.02-4.08 (2H, m), 4.19 (0.4H, q, J = 7.1 Hz), 4.26 (1.6 H, q, J = 7.2 Hz), 5.91 (0.2 H, d, J = 13 Hz), 6.35 (0.8 H, d, J = 16 Hz) ), 6.84 (0.2H, d, J = 13 Hz), 6.88-6.96 (1H, m), 7.16-7.32 (5H, m), 7.58-7.67. (1.6H, m), 7.76 (0.8H, d, J = 2.0 Hz), 7.85-7.92 (0.4H, m).
　（６５－２）３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸エチルの合成（化合物６５－２） (65-2) Synthesis of ethyl 3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionate (Compound 65-2)
Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194
　化合物６５－１（Ｅ体とＺ体が約４：１の混合物、２．２４ｇ）のエタノール（１００ｍｌ）溶液に、１０％パラジウム炭素（１ｇ）を加え、水素雰囲気下室温で７時間攪拌した。反応液をセライトで濾過後濃縮することによって、目的物（２．１５ｍｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２３（３Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．０５－２．１６（２Ｈ、ｍ）、２．５９（２Ｈ、ｔ、７．５Ｈｚ）、２．８３（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．９９（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、４．１２（２Ｈ、ｑ、Ｊ＝７．２Ｈｚ）、６．８５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１６－７．２２（３Ｈ、ｍ）、７．２４－７．３２（３Ｈ、ｍ）、７．４０（１Ｈ、ｄ、Ｊ＝２．１Ｈｚ）。 To a solution of compound 65-1 (a mixture of E and Z forms of about 4: 1, 2.24 g) in ethanol (100 ml) was added 10% palladium carbon (1 g), and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to give the object product (2.15 mg) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.23 (3H, t, J = 7.2 Hz), 2.05-2.16 (2H, m), 2.59 (2H, t, 7 .5 Hz), 2.83 (2H, t, J = 7.7 Hz), 2.92 (2H, t, J = 7.7 Hz), 3.99 (2H, t, J = 6.0 Hz), 4 .12 (2H, q, J = 7.2 Hz), 6.85 (1H, d, J = 8.5 Hz), 7.16-7.22 (3H, m), 7.24-7.32 ( 3H, m), 7.40 (1H, d, J = 2.1 Hz).
　実施例６６
３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸 Example 66
3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionic acid
　（６６－１）３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸の合成（化合物６６－１） (66-1) Synthesis of 3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionic acid (Compound 66-1)
Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195
　化合物６５－２（２．１５ｇ）の１，４－ジオキサン（２０ｍｌ）溶液に、濃塩酸（１０ｍｌ）を加え、８０℃にて４時間攪拌した。さらに反応液に濃塩酸（１０ｍｌ）を加え、８０℃にて１時間攪拌した。反応液を濃縮し、酢酸エチルで抽出後、飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をヘキサンにて洗浄し、目的物（１．７０ｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．９２－２．１０（２Ｈ、ｍ）、２．５３（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．７４（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．８１（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、４．０４（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１３（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１５－７．２２（３Ｈ、ｍ）、７．２５－７．３１（２Ｈ、ｍ）、７．４３－７．４９（２Ｈ、ｍ）、１２．１４（１Ｈ、ｂｒｓ）。 Concentrated hydrochloric acid (10 ml) was added to a solution of compound 65-2 (2.15 g) in 1,4-dioxane (20 ml), and the mixture was stirred at 80 ° C. for 4 hours. Further, concentrated hydrochloric acid (10 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the desired product (1.70 g) as a white solid.
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.92-2.10 (2H, m), 2.53 (2H, t, J = 7.4 Hz), 2.74 (2H, t , J = 7.8 Hz), 2.81 (2H, t, J = 7.4 Hz), 4.04 (2H, t, J = 6.1 Hz), 7.13 (1H, d, J = 8. 5Hz), 7.15-7.22 (3H, m), 7.25-7.31 (2H, m), 7.43-7.49 (2H, m), 12.14 (1H, brs) .
　実施例６７
３－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸エチル Example 67
3-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) ethyl benzoate
　（６７－１）３－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸エチルの合成（化合物６７－１） Synthesis of (67-1) 3-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) ethyl benzoate (Compound 67-1)
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
　化合物６６－１（３５２ｍｇ）のジクロロメタン（１０ｍｌ）溶液に氷冷下オキサリルクロリド（０．１２８ｍｌ）、ＤＭＦ（２滴）を加え室温にて１８時間攪拌した。次いで反応液を減圧下濃縮し黄色油状物を得た。この油状物にジクロロメタン（１０ｍｌ）、３－アミノ安息香酸エチル（２４８ｍｇ）、トリエチルアミン（０．４１６ｍｌ）を順次加え、室温にて１８時間攪拌した。反応液に１Ｍ塩酸を加え、酢酸エチルで抽出し、有機層を１Ｍ塩酸、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物の化合物（２９６ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５００［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２６（０．９Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．３９（２．１Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．０８－２．１７（２Ｈ、ｍ）、２．６２－２．７０（２Ｈ、ｍ）、２．８３（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、２．９３（０．６Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．０４（１．４Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、３．９９（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、４．１２（０．６Ｈ、ｑ、Ｊ＝７．１Ｈｚ）、４．３７（１．４Ｈ、ｑ、Ｊ＝７．１Ｈｚ）、６．８５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１６－７．２３（４Ｈ、ｍ）、７．２４－７．３６（３Ｈ、ｍ）、７．３６－７．４７（２Ｈ、ｍ）、７．７９（１Ｈ、ｄ、Ｊ＝７．７Ｈｚ）、７．８７（１Ｈ、ｄ、Ｊ＝８．０Ｈｚ）、７．９４（１Ｈ、ｓ）。 Oxalyl chloride (0.128 ml) and DMF (2 drops) were added to a solution of compound 66-1 (352 mg) in dichloromethane (10 ml) under ice cooling, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. Dichloromethane (10 ml), ethyl 3-aminobenzoate (248 mg) and triethylamine (0.416 ml) were successively added to the oil, and the mixture was stirred at room temperature for 18 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired compound (296 mg) as a white solid.
MS (ESI) m / z: 500 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 1.26 (0.9 H, t, J = 7.1 Hz), 1.39 (2.1 H, t, J = 7.2 Hz), 2.08 -2.17 (2H, m), 2.62-2.70 (2H, m), 2.83 (2H, t, J = 7.9 Hz), 2.93 (0.6H, t, J = 7.7 Hz), 3.04 (1.4 H, t, J = 7.5 Hz), 3.99 (2 H, t, J = 6.0 Hz), 4.12 (0.6 H, q, J = 7) .1 Hz), 4.37 (1.4 H, q, J = 7.1 Hz), 6.85 (1 H, d, J = 8.5 Hz), 7.16-7.23 (4 H, m), 7 .24-7.36 (3H, m), 7.36-7.47 (2H, m), 7.79 (1H, d, J = 7.7 Hz), 7.87 (1H, d, J = 8.0 Hz), 7.94 (1H, s).
　実施例６８
３－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸 Example 68
3-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzoic acid
　（６８－１）３－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸の合成（化合物６８－１） Synthesis of (68-1) 3-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzoic acid (Compound 68-1)
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
　化合物６７－１（２４５ｍｇ）のエタノール（１０ｍｌ）溶液に１Ｍ水酸化ナトリウム水溶液（０．７４ｍｌ）を加え室温で１８時間攪拌した。さらに１Ｍ水酸化ナトリウム水溶液（０．７４ｍｌ）を加え室温にて１８時間攪拌した後、反応液に１Ｍ塩酸（２ｍｌ）加え、減圧下濃縮した。残渣に水を加え酢酸エチルで抽出し有機層を無水硫酸マグネシウムで乾燥した。有機層の溶媒を減圧下留去し、得た固体をエーテルで洗浄して目的物（８３ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．９２－２．０７（２Ｈ、ｍ）、２．６３（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．７３（２Ｈ、ｔ、Ｊ＝８．０Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、４．０３（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１１－７．２３（４Ｈ、ｍ）、７．２４－７．３２（２Ｈ、ｍ）、７．４１（１Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、７．４７（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．５１（１Ｈ、ｓ）、７．６０（１Ｈ、ｄｔ、Ｊ＝７．８，１．１Ｈｚ），７．７９（１Ｈ、ｄｄ、Ｊ＝８．１、２．１Ｈｚ）、８．１９（１Ｈ、ｔ、Ｊ＝１．７Ｈｚ）、１０．０９（１Ｈ、ｓ）、１２．９５（１Ｈ、ｂｒｓ）。 To a solution of compound 67-1 (245 mg) in ethanol (10 ml) was added 1M aqueous sodium hydroxide solution (0.74 ml), and the mixture was stirred at room temperature for 18 hours. Further, 1M aqueous sodium hydroxide solution (0.74 ml) was added and stirred at room temperature for 18 hours, and then 1M hydrochloric acid (2 ml) was added to the reaction mixture, followed by concentration under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the obtained solid was washed with ether to obtain the desired product (83 mg) as a white powder.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.92-2.07 (2H, m), 2.63 (2H, t, J = 7.4 Hz), 2.73 (2H, t , J = 8.0 Hz), 2.92 (2H, t, J = 7.5 Hz), 4.03 (2H, t, J = 6.1 Hz), 7.11-7.23 (4H, m) 7.24-7.32 (2H, m), 7.41 (1H, t, J = 7.9 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.51 (1H, s), 7.60 (1H, dt, J = 7.8, 1.1 Hz), 7.79 (1H, dd, J = 8.1, 2.1 Hz), 8.19 (1H, t, J = 1.7 Hz), 10.09 (1H, s), 12.95 (1H, brs).
　実施例６９
５－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸ジメチル Example 69
5-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) dimethyl isophthalate
　（６９－１）５－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸ジメチルの合成（化合物６９－１） Synthesis of (69-1) 5-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid dimethyl (Compound 69-1)
Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198
　化合物６６－１（３５２ｍｇ）のジクロロメタン（１０ｍｌ）溶液に氷冷下オキサリルクロリド（０．１２８ｍｌ）、ＤＭＦ（２滴）を加え室温にて３日間攪拌した。次いで反応液を減圧下濃縮し残渣にジクロロメタン（１０ｍｌ）、５－アミノイソフタル酸ジメチル（３１４ｍｇ）、トリエチルアミン（０．４１６ｍｌ）、ＤＭＦ（０．２ｍｌ）を順次加え、室温にて１８時間攪拌した。反応液に１Ｍ塩酸を加え、酢酸エチルで抽出し、有機層を１Ｍ塩酸、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製することにより、目的物の化合物（１４０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５４４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：２．０５－２．１６（２Ｈ、ｍ）、２．６８（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．８３（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．０４（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、３．９３（６Ｈ、ｓ）、３．９９（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、６．８６（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１５－７．２２（３Ｈ、ｍ）、７．２４－７．３７（４Ｈ、ｍ）、７．４４（１Ｈ、ｓ）、８．３４（２Ｈ、ｓ）、８．４３（１Ｈ、ｓ）。 Oxalyl chloride (0.128 ml) and DMF (2 drops) were added to a solution of compound 66-1 (352 mg) in dichloromethane (10 ml) under ice cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was then concentrated under reduced pressure, and dichloromethane (10 ml), dimethyl 5-aminoisophthalate (314 mg), triethylamine (0.416 ml), and DMF (0.2 ml) were successively added to the residue, followed by stirring at room temperature for 18 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired compound (140 mg) as a white powder.
MS (ESI) m / z: 544 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 2.05-2.16 (2H, m), 2.68 (2H, t, J = 7.4 Hz), 2.83 (2H, t, J = 7.7 Hz), 3.04 (2H, t, J = 7.5 Hz), 3.93 (6H, s), 3.99 (2H, t, J = 6.0 Hz), 6.86 (1H) , D, J = 8.5 Hz), 7.15-7.22 (3H, m), 7.24-7.37 (4H, m), 7.44 (1H, s), 8.34 (2H) , S), 8.43 (1H, s).
　実施例７０
５－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸 Example 70
5-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid
　（７０－１）５－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸の合成（化合物７０－１） Synthesis of (70-1) 5-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid (Compound 70-1)
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
　化合物６９－１（１０２ｍｇ）のＴＨＦ（５ｍｌ）溶液に１Ｍ水酸化ナトリウム水溶液（０．８ｍｌ）を加え室温で２日間攪拌した後、１Ｍ塩酸（２ｍＬ）を加え、減圧下濃縮した。残渣に水を加え酢酸エチルで抽出し有機層を無水硫酸マグネシウムで乾燥した。有機層の溶媒を減圧下留去し、得た固体をエーテルで洗浄して目的物（２５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５１６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．９３－２．０８（２Ｈ、ｍ）、２．６５（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．７３（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、２．９３（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、４．０３（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、７．１１－７．２２（４Ｈ、ｍ）、７．２４－７．３２（２Ｈ、ｍ）、７．４４－７．５４（２Ｈ、ｍ）、８．１４（１Ｈ、ｔ、Ｊ＝１．５Ｈｚ）、８．４１（２Ｈ、ｄ、Ｊ＝１．５Ｈｚ）、１０．２８（１Ｈ、ｓ）。 To a solution of compound 69-1 (102 mg) in THF (5 ml) was added 1M aqueous sodium hydroxide solution (0.8 ml), and the mixture was stirred at room temperature for 2 days. 1M hydrochloric acid (2 mL) was added, and the mixture was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the obtained solid was washed with ether to obtain the desired product (25 mg) as a white powder.
MS (ESI) m / z: 516 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.93-2.08 (2H, m), 2.65 (2H, t, J = 7.4 Hz), 2.73 (2H, t , J = 7.9 Hz), 2.93 (2H, t, J = 7.4 Hz), 4.03 (2H, t, J = 6.0 Hz), 7.11-7.22 (4H, m) 7.24-7.32 (2H, m), 7.44-7.54 (2H, m), 8.14 (1H, t, J = 1.5 Hz), 8.41 (2H, d, J = 1.5 Hz), 10.28 (1H, s).
　実施例７１
４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸ジエチル Example 71
4-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) diethyl phthalate
　（７１－１）４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸ジエチルの合成（化合物７１－１） Synthesis of (71-1) 4-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) diethyl phthalate (Compound 71-1)
Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200
　化合物６６－１（３５２ｍｇ）及び４－アミノフタル酸ジエチル（３５６ｍｇ）を用い、実施例６９と同様に行ない無色透明油状の目的物（４７０ｍｇ）を得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２８－１．４１（６Ｈ、ｍ）、２．０５－２．１７（２Ｈ、ｍ）、２．６５（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．８３（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．０２（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．９９（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．２５－４．３９（４Ｈ、ｍ）、６．８５（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１６－７．２２（３Ｈ、ｍ）、７．２３－７．３４（３Ｈ、ｍ）、７．３７（１Ｈ、ｓ）、７．４３（１Ｈ、ｄ、Ｊ＝２．０Ｈｚ）、７．６７（１Ｈ、ｄ、Ｊ＝２．０Ｈｚ）、７．７２（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．７６（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）。 Using Compound 66-1 (352 mg) and diethyl 4-aminophthalate (356 mg) in the same manner as in Example 69, the desired product (470 mg) was obtained as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.28-1.41 (6H, m), 2.05-2.17 (2H, m), 2.65 (2H, t, J = 7) .4 Hz), 2.83 (2H, t, J = 7.7 Hz), 3.02 (2H, t, J = 7.6 Hz), 3.99 (2H, t, J = 6.1 Hz), 4 .25-4.39 (4H, m), 6.85 (1H, d, J = 8.5 Hz), 7.16-7.22 (3H, m), 7.23-7.34 (3H, m), 7.37 (1H, s), 7.43 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 8.4 Hz).
　実施例７２
４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸 Example 72
4-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) phthalic acid
　（７２－１）４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸の合成（化合物７２－１） Synthesis of (72-1) 4-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) phthalic acid (Compound 72-1)
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
　化合物７１－１（４７０ｍｇ）を用い、実施例６８と同様に行い、目的物（２４２ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５１６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．９４－２．０５（２Ｈ、ｍ）、２．６６（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．７４（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、４．０３（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１０－７．２２（４Ｈ、ｍ）、７．２４－７．３１（２Ｈ、ｍ）、７．４４－７．５４（２Ｈ、ｍ）、７．６７－７．７４（２Ｈ、ｍ）、７．８５（１Ｈ、ｓ）、１０．２７（１Ｈ、ｓ）。 Using Compound 71-1 (470 mg), the same operation as in Example 68 was carried out to obtain the desired product (242 mg) as a white powder.
MS (ESI) m / z: 516 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.94-2.05 (2H, m), 2.66 (2H, t, J = 7.4 Hz), 2.74 (2H, t , J = 7.9 Hz), 2.92 (2H, t, J = 7.6 Hz), 4.03 (2H, t, J = 6.1 Hz), 7.10-7.22 (4H, m) 7.24-7.31 (2H, m), 7.44-7.54 (2H, m), 7.67-7.74 (2H, m), 7.85 (1H, s), 10 .27 (1H, s).
　実施例７３
４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸メチル Example 73
4-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) methyl butyrate
　（７３－１）４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸メチルの合成（化合物７３－１） (73-1) Synthesis of 4-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) methyl butyrate (Compound 73-1)
Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202
　化合物６６－１（３５２ｍｇ）のジクロロメタン（５ｍｌ）溶液に１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（２８８ｍｇ）、１－ヒドロキシベンゾトリアゾール水和物（２０３ｍｇ）、４－アミノ酪酸（２３０ｍｇ）を順次加え、室温にて１８時間攪拌した。反応液に１Ｍ塩酸を加え酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。有機層の溶媒を減圧下留去し残渣をシリカゲルカラムクロマトグラフィーで精製して、無色透明油状の目的化合物（３３０ｍｇ）を得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．７３－１．８３（２Ｈ、ｍ）、２．０６－２．１８（２Ｈ、ｍ）、２．３０（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、２．４２（２Ｈ、ｔ、Ｊ＝７．３Ｈｚ）、２．８３（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、２．９３（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．２２－３．３１（２Ｈ、ｍ）、３．６６（３Ｈ、ｓ）、３．９９（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、５．５８－５．６９（１Ｈ、ｍ）、６．８４（１Ｈ、ｄ、Ｊ＝６．４Ｈｚ）、７．１６－７．２２（３Ｈ、ｍ）、７．２５－７．３２（３Ｈ、ｍ）、７．３９（１Ｈ、ｄ、Ｊ＝１．５Ｈｚ）。 To a solution of compound 66-1 (352 mg) in dichloromethane (5 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg), 1-hydroxybenzotriazole hydrate (203 mg), 4-aminobutyric acid (230 mg) was sequentially added and stirred at room temperature for 18 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound (330 mg) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.73-1.83 (2H, m), 2.06-2.18 (2H, m), 2.30 (2H, t, J = 7 .1 Hz), 2.42 (2H, t, J = 7.3 Hz), 2.83 (2H, t, J = 7.7 Hz), 2.93 (2H, t, J = 7.6 Hz), 3 .22-3.31 (2H, m), 3.66 (3H, s), 3.99 (2H, t, J = 6.1 Hz), 5.58-5.69 (1H, m), 6 .84 (1H, d, J = 6.4 Hz), 7.16-7.22 (3H, m), 7.25-7.32 (3H, m), 7.39 (1H, d, J = 1.5 Hz).
　実施例７４
４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸 Example 74
4-({3- [4- (3-Phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) butyric acid
　（７４－１）４－（｛３－［４－（３－フェニルプロポキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸の合成（化合物７４－１） (74-1) Synthesis of 4-({3- [4- (3-phenylpropoxy) -3- (trifluoromethyl) phenyl] propionyl} amino) butyric acid (Compound 74-1)
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
　化合物７３－１（３３０ｍｇ）を用い、実施例７０と同様に行ない、白色粉末の目的物（２０４ｍｇ）を得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４３８［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．５１－１．６１（２Ｈ、ｍ）、１．９５－２．１６（２Ｈ、ｍ）、２．１４（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．３４（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．７４（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、２．８０（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、３．０２（２Ｈ、ｑ、Ｊ＝５．９Ｈｚ）、４．０３（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、７．１０（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１４－７．２２（３Ｈ、ｍ）、７．２５－７．３２（２Ｈ、ｍ）、７．３７－７．４６（２Ｈ、ｍ）、７．８１（１Ｈ、ｔ、Ｊ＝５．６Ｈｚ）、１２．０１（１Ｈ、ｂｒｓ）。 Using Compound 73-1 (330 mg), the same operation as in Example 70 was performed to obtain the desired product (204 mg) as a white powder.
MS (ESI) m / z: 438 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.51-1.61 (2H, m), 1.95-2.16 (2H, m), 2.14 (2H, t, J = 7.4 Hz), 2.34 (2H, t, J = 7.4 Hz), 2.74 (2H, t, J = 7.9 Hz), 2.80 (2H, t, J = 7.5 Hz) 3.02 (2H, q, J = 5.9 Hz), 4.03 (2H, t, J = 6.1 Hz), 7.10 (1H, d, J = 8.5 Hz), 7.14- 7.22 (3H, m), 7.25-7.32 (2H, m), 7.37-7.46 (2H, m), 7.81 (1H, t, J = 5.6 Hz), 12.01 (1H, brs).
　実施例７５
４－｛［４－（４－フェニルブトキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸 Example 75
4-{[4- (4-Phenylbutoxy) -3- (trifluoromethyl) benzyl] amino} butyric acid
　（７５－１）４－（４－フェニルブトキシ）－３－（トリフルオロメチル）ベンズアルデヒドの合成（化合物７５－１） (75-1) Synthesis of 4- (4-phenylbutoxy) -3- (trifluoromethyl) benzaldehyde (Compound 75-1)
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
　参考例化合物１－２（３００ｍｇ）及び１－ブロモ－４－フェニルブタン（４０５ｍｇ）を用い、実施例６３－１と同様に行ない目的物（４５０ｍｇ）を淡黄色固体として得た。
　１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．８１－１．９８（４Ｈ、ｍ）、２．７０（２Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、４．１５（２Ｈ、ｔ、Ｊ＝５．９Ｈｚ）、７．０８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．１６－７．２３（３Ｈ、ｍ）、７．２５－７．３３（２Ｈ、ｍ）、８．０２（１Ｈ、ｄｄ、Ｊ＝８．６、１．９Ｈｚ）、８．１１（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）、９．９２（１Ｈ、ｓ）。 Reference Example Compound 1-2 (300 mg) and 1-bromo-4-phenylbutane (405 mg) were used in the same manner as Example 63-1 to obtain the target product (450 mg) as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.81-1.98 (4H, m), 2.70 (2H, t, J = 6.9 Hz), 4.15 (2H, t, J = 5.9 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.16-7.23 (3H, m), 7.25-7.33 (2H, m), 8.02 (1H, dd, J = 8.6, 1.9 Hz), 8.11 (1H, d, J = 1.9 Hz), 9.92 (1H, s).
　（７５－２）４－｛［４－（４－フェニルブトキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸（化合物７５－２） (75-2) 4-{[4- (4-Phenylbutoxy) -3- (trifluoromethyl) benzyl] amino} butyric acid (Compound 75-2)
Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205
　化合物７５－１（４５０ｍｇ）及び４－アミノ酪酸（２１６ｍｇ）を用い、実施例６３－２と同様に行ない、目的の化合物（２２９ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４１０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．５１－１．８１（６Ｈ、ｍ）、２．２８（２Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、２．５９－２．７２（４Ｈ、ｍ）、３．８４（１Ｈ、ｓ）、４．０７－４．１９（１Ｈ、ｍ）、７．１４－７．３２（６Ｈ、ｍ）、７．６０（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．６４（１Ｈ、ｓ）。 Using Compound 75-1 (450 mg) and 4-aminobutyric acid (216 mg) in the same manner as in Example 63-2, the target compound (229 mg) was obtained as a white powder.
MS (ESI) m / z: 410 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.51-1.81 (6H, m), 2.28 (2H, t, J = 6.8 Hz), 2.59-2.72 (4H, m), 3.84 (1H, s), 4.07-4.19 (1H, m), 7.14-7.32 (6H, m), 7.60 (1H, d, J = 8.6 Hz), 7.64 (1H, s).
　実施例７６
４－｛［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩 Example 76
4-{[4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate
　（７６－１）４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンズアルデヒドの合成（化合物７６－１） (76-1) Synthesis of 4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzaldehyde (Compound 76-1)
Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、１－ブロモ－５－フェニルペンタン（０．４４５ｍｌ）を加え、室温にて４時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、目的物（７０ｍｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．５０－１．６１（２Ｈ、ｍ）、１．６７－１．７８（２Ｈ、ｍ）、１．８２－１．９４（２Ｈ、ｍ）、２．６５（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、４．１４（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．０９（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．１４－７．２４（３Ｈ、ｍ）、７．２４－７．３３（２Ｈ、ｍ）、８．０２（１Ｈ、ｄｄ、Ｊ＝８．６、２．０Ｈｚ）、８．１１（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）、９．９２（１Ｈ、ｓ）。 Reference Example Compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (10 ml), potassium carbonate (654 mg) and 1-bromo-5-phenylpentane (0.445 ml) were added, and the mixture was stirred at room temperature for 4 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired product (70 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.50-1.61 (2H, m), 1.67-1.78 (2H, m), 1.82-1.94 (2H, m ), 2.65 (2H, t, J = 7.7 Hz), 4.14 (2H, t, J = 6.3 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.14 -7.24 (3H, m), 7.24-7.33 (2H, m), 8.02 (1H, dd, J = 8.6, 2.0 Hz), 8.11 (1H, d, J = 1.9 Hz), 9.92 (1H, s).
　（７６－２）４－｛［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩の合成（化合物７６－２） (76-2) Synthesis of 4-{[4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate (Compound 76-2)
Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207
　化合物７６－１（７０ｍｇ）と４－アミノ酪酸（２１ｍｇ）にメタノール（５ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．２５ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（６７ｍｇ）を加え、室温で２４時間攪拌した。反応液に水、１Ｍ塩酸水溶液をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、析出物を濾取、乾燥することにより、目的物（４７ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４２４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．４０－１．４９（２Ｈ、ｍ）、１．５８－１．６７（２Ｈ、ｍ）、１．７２－１．８５（４Ｈ、ｍ）、２．３５（２Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．５８（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．９４（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．３０－３．６５（１Ｈ、ｂｒｍ）、４．１０－４．１５（４Ｈ、ｍ）、７．１４－７．２０（３Ｈ、ｍ）、７．２４－７．３２（３Ｈ、ｍ）、７．６９（１Ｈ、ｄｄ、Ｊ＝８．６、１．６Ｈｚ）、７．７８（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 Methanol (5 ml) and tetrabutylammonium hydroxide (37% methanol solution, 0.25 ml) were added to compound 76-1 (70 mg) and 4-aminobutyric acid (21 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (67 mg) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water and 1M aqueous hydrochloric acid solution were added to the reaction solution until the pH reached about 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC, and the precipitate was collected by filtration and dried to give the object product (47 mg) as a white powder.
MS (ESI) m / z: 424 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.40-1.49 (2H, m), 1.58-1.67 (2H, m), 1.72-1.85 (4H) M), 2.35 (2H, t, J = 7.2 Hz), 2.58 (2H, t, J = 7.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 3 .30-3.65 (1H, brm), 4.10-4.15 (4H, m), 7.14-7.20 (3H, m), 7.24-7.32 (3H, m) 7.69 (1H, dd, J = 8.6, 1.6 Hz), 7.78 (1H, d, J = 1.6 Hz).
　実施例７７
１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸 Example 77
1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid
　（７７－１）１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸の合成（化合物７７－１） (77-1) Synthesis of 1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid (Compound 77-1)
Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208
　化合物７６－１（１６８ｍｇ）のメタノール（５ｍｌ）溶液に３－アゼチジンカルボン酸（７６ｍｇ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、０．１ｍｌ）を加え、室温で１８時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（１５９ｍｇ）を加え、室温で４時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた固体をエーテルで洗浄して、目的物（３８ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４２２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４９（２Ｈ、ｍ）、１．５７－１．６７（２Ｈ、ｍ）、１．７０－１．７９（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．１０－３．７０（７Ｈ、ｍ）、４．０６（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１３－７．２１（４Ｈ、ｍ）、７．２３－７．２９（２Ｈ、ｍ）、７．４４－７．５０（２Ｈ、ｍ）。 To a solution of compound 76-1 (168 mg) in methanol (5 ml) were added 3-azetidinecarboxylic acid (76 mg) and tetrabutylammonium hydroxide (37% methanol solution, 0.1 ml), and the mixture was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (159 mg) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ether to obtain the desired product (38 mg) as a white powder.
MS (ESI) m / z: 422 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.49 (2H, m), 1.57-1.67 (2H, m), 1.70-1.79 (2H) M), 2.58 (2H, t, J = 7.7 Hz), 3.10-3.70 (7H, m), 4.06 (2H, t, J = 6.3 Hz), 7.13 -7.21 (4H, m), 7.23-7.29 (2H, m), 7.44-7.50 (2H, m).
　実施例７８
Ｎ－メチルスルホニル－１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミド Example 78
N-methylsulfonyl-1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide
　（７８－１）Ｎ－メチルスルホニル－１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミドの合成（化合物７８－１） (78-1) Synthesis of N-methylsulfonyl-1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide (Compound 78-1)
Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209
　化合物７７－１（４６４ｍｇ）のＴＨＦ（１０ｍｌ）溶液にＮ，Ｎ’－カルボニルジイミダゾール（２８６ｍｇ）を加え８０℃で１時間攪拌した。反応液にメタンスルホンアミド（１１５ｍｇ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（１８１ｍｌ）を順次加え、徐々に室温まで冷却した。２時間攪拌後減圧下濃縮し酢酸エチルを加えた。１Ｍ塩酸を加え水層を中性にした後、分液操作で水層を除いた。有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥した。有機層の溶媒を減圧下留去し、残渣をＨＰＬＣ精製して目的化合物のトリフルオロ酢酸塩を得た。この塩に１Ｍ水酸化ナトリウム水溶液を加え中性にした後、クロロホルム及び酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。有機層の溶媒を減圧下留去して目的物（２１０ｍｇ）を白色無定形固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４９９［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４９（２Ｈ、ｍ）、１．５７－１．６７（２Ｈ、ｍ）、１．７１－１．８０（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．００（３Ｈ、ｓ）、３．２０－３．６０（１Ｈ、ｍ）、３．７６－３．９２（４Ｈ、ｍ）、４．０６－４．１９（４Ｈ、ｍ）、７．１２－７．２１（３Ｈ、ｍ）、７．２３－７．３０（３Ｈ、ｍ）、７．６５－７．７４（２Ｈ、ｍ）。 N, N′-carbonyldiimidazole (286 mg) was added to a solution of compound 77-1 (464 mg) in THF (10 ml), and the mixture was stirred at 80 ° C. for 1 hour. Methanesulfonamide (115 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (181 ml) were sequentially added to the reaction mixture, and the mixture was gradually cooled to room temperature. After stirring for 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate was added. 1M Hydrochloric acid was added to neutralize the aqueous layer, and the aqueous layer was removed by liquid separation. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by HPLC to obtain the trifluoroacetate salt of the target compound. The salt was neutralized with 1M aqueous sodium hydroxide solution, extracted with chloroform and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent of the organic layer was distilled off under reduced pressure to obtain the desired product (210 mg) as a white amorphous solid.
MS (ESI) m / z: 499 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.49 (2H, m), 1.57-1.67 (2H, m), 1.71-1.80 (2H) M), 2.58 (2H, t, J = 7.7 Hz), 3.00 (3H, s), 3.20-3.60 (1H, m), 3.76-3.92 (4H) M), 4.06-4.19 (4H, m), 7.12-7.21 (3H, m), 7.23-7.30 (3H, m), 7.65-7.74. (2H, m).
　実施例７９
Ｎ－フェニルスルホニル－１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミド Example 79
N-phenylsulfonyl-1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide
　（７９－１）Ｎ－フェニルスルホニル－１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミドの合成（化合物７９－１） (79-1) Synthesis of N-phenylsulfonyl-1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide (Compound 79-1)
Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210
　化合物７７－１（３００ｍｇ）及びベンゼンスルホンアミド（１２３ｍｇ）を用い、実施例７８と同様に行ない、目的物（９４ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５６０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４９（２Ｈ、ｍ）、１．５８－１．６６（２Ｈ、ｍ）、１．７０－１．８０（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．１３－３．３０（１Ｈ、ｍ）、３．７５－３．８８（２Ｈ、ｍ）、３．８８－３．９９（２Ｈ、ｍ）、４．１０（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．１３－４．２５（２Ｈ、ｍ）、７．１３－７．２０（３Ｈ、ｍ）、７．２３－７．３０（３Ｈ、ｍ）、７．３８－７．４８（３Ｈ、ｍ）、７．６２－７．７２（２Ｈ、ｍ）、７．７５－７．８１（２Ｈ、ｍ）。 Using Compound 77-1 (300 mg) and benzenesulfonamide (123 mg), the same operation as in Example 78 was performed to obtain the desired product (94 mg) as a white powder.
MS (ESI) m / z: 560 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.49 (2H, m), 1.58-1.66 (2H, m), 1.70-1.80 (2H) M), 2.58 (2H, t, J = 7.7 Hz), 3.13-3.30 (1H, m), 3.75-3.88 (2H, m), 3.88-3 .99 (2H, m), 4.10 (2H, t, J = 6.3 Hz), 4.13-4.25 (2H, m), 7.13-7.20 (3H, m), 7 .23-7.30 (3H, m), 7.38-7.48 (3H, m), 7.62-7.72 (2H, m), 7.75-7.81 (2H, m) .
　実施例８０
３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸エチル Example 80
Ethyl 3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionate
　（８０－１）（２Ｅ）－３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］アクリル酸エチル及び（２Ｚ）－３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］アクリル酸エチルの合成（化合物８０－１－Ｅ及び化合物８０－１－Ｚ） (80-1) (2E) -3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] ethyl acrylate and (2Z) -3- [4- (5-phenylpentyloxy) ) Synthesis of ethyl 3- (trifluoromethyl) phenyl] acrylate (Compound 80-1-E and Compound 80-1-Z)
Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211
　化合物７６－１（６．４８ｇ）と臭化（エトキシカルボニルメチル）トリフェニルホスホニウム（１２．４ｇ）を用い、実施例６５－１と同様に行ない、目的物のＥ体とＺ体が約４：１の混合物（７．１３ｇ）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２７（０．６Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．３３（２．４Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．４８－１．５９（２Ｈ、ｍ）、１．６４－１．７４（２Ｈ、ｍ）、１．８１－１．９１（２Ｈ、ｍ）、２．６４（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、４．０４－４．１０（２Ｈ、ｍ）、４．１９（０．４Ｈ、ｑ、Ｊ＝７．２Ｈｚ）、４．２６（１．６Ｈ、ｑ、Ｊ＝７．１Ｈｚ）、５．９０（０．２Ｈ、ｄ、Ｊ＝１３Ｈｚ）、６．３５（０．８Ｈ、ｄ、Ｊ＝１６Ｈｚ）、６．８３（０．２Ｈ、ｄ、Ｊ＝１３Ｈｚ）、６．９１－６．９９（１Ｈ、ｍ）、７．１５－７．３１（５Ｈ、ｍ）、７．５９－７．６６（１．６Ｈ、ｍ）、７．７３（０．８Ｈ、ｄ、Ｊ＝２．０Ｈｚ）、７．８６－７．９０（０．４Ｈ、ｍ）。 Using compound 76-1 (6.48 g) and (ethoxycarbonylmethyl) triphenylphosphonium bromide (12.4 g) in the same manner as in Example 65-1, the target E form and Z form were about 4: 1 mixture (7.13 g) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ (ppm): 1.27 (0.6 H, t, J = 7.2 Hz), 1.33 (2.4 H, t, J = 7.1 Hz), 1.48 -1.59 (2H, m), 1.64-1.74 (2H, m), 1.81-1.91 (2H, m), 2.64 (2H, t, J = 7.8 Hz) 4.04-4.10 (2H, m), 4.19 (0.4H, q, J = 7.2 Hz), 4.26 (1.6H, q, J = 7.1 Hz), 5. 90 (0.2 H, d, J = 13 Hz), 6.35 (0.8 H, d, J = 16 Hz), 6.83 (0.2 H, d, J = 13 Hz), 6.91-6.99 (1H, m), 7.15-7.31 (5H, m), 7.59-7.66 (1.6H, m), 7.73 (0.8H, d, J = 2.0 Hz) 7.86-7.90 (0.4H m).
　（８０－２）３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸エチル（化合物８０－２） (80-2) Ethyl 3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionate (Compound 80-2)
Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212
　化合物８０－１（Ｅ体とＺ体が約４：１の混合物、７．１３ｇ）を用い実施例６５－２と同様に行ない、目的物（７．０１ｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．２３（３Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、１．４８－１．６１（２Ｈ、ｍ）、１．６４－１．７３（２Ｈ、ｍ）、１．７９－１．９０（２Ｈ、ｍ）、２．５９（２Ｈ、ｔ、７．５Ｈｚ）、２．６２（２Ｈ、ｔ、Ｊ＝４．１Ｈｚ）、２．９１（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．１２（２Ｈ、ｑ、Ｊ＝４．１Ｈｚ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１４－７．２０（３Ｈ、ｍ）、７．２４－７．３１（３Ｈ、ｍ）、７．３７－７．４０（１Ｈ、ｍ）。 The same procedure as in Example 65-2 was carried out using compound 80-1 (a mixture of E and Z isomers of about 4: 1, 7.13 g) to obtain the desired product (7.01 g) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.23 (3H, t, J = 7.1 Hz), 1.48-1.61 (2H, m), 1.64-1.73 (2H M), 1.79-1.90 (2H, m), 2.59 (2H, t, 7.5 Hz), 2.62 (2H, t, J = 4.1 Hz), 2.91 (2H) , T, J = 7.7 Hz), 4.00 (2H, t, J = 6.3 Hz), 4.12 (2H, q, J = 4.1 Hz), 6.88 (1H, d, J = 8.5 Hz), 7.14-7.20 (3H, m), 7.24-7.31 (3H, m), 7.37-7.40 (1H, m).
　実施例８１
３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸 Example 81
3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionic acid
　（８１－１）３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオン酸の合成（化合物８１－１） (81-1) Synthesis of 3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionic acid (Compound 81-1)
Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213
　化合物８０－２（７．０１ｇ）を用い実施例６６と同様に行ない、目的物（５．９１ｇ）を白色固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．４０－１．５０（２Ｈ、ｍ）、１．５７－１．７９（２Ｈ、ｍ）、１．７９－１．８１（２Ｈ、ｍ）、２．４９－２．６２（４Ｈ、ｍ）、２．８０（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．１２－７．２１（４Ｈ、ｍ）、７．２３－７．２９（２Ｈ、ｍ）、７．４２－７．４７（２Ｈ、ｍ）、１２．００（１Ｈ、ｂｒｓ）。 Using compound 80-2 (7.01 g) in the same manner as in Example 66, the target product (5.91 g) was obtained as a white solid.
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.40-1.50 (2H, m), 1.57-1.79 (2H, m), 1.79-1.81 (2H) M), 2.49-2.62 (4H, m), 2.80 (2H, t, J = 7.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 7.12 -7.21 (4H, m), 7.23-7.29 (2H, m), 7.42-7.47 (2H, m), 12.00 (1H, brs).
　実施例８２
３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸エチル Example 82
3-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) ethyl benzoate
　（８２－１）３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸エチルの合成（化合物８２－１） Synthesis of (82-1) 3-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) ethyl benzoate (Compound 82-1)
Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214
　化合物８１－１（７６１ｍｇ）及び３－アミノ安息香酸エチル（４９６ｍｇ）を用い実施例６７と同様に行ない目的物（９６０ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５２８［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３９（３Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、１．４６－１．６０（２Ｈ、ｍ）、１．６３－１．７３（２Ｈ、ｍ）、１．７９－１．８８（２Ｈ、ｍ）、２．５９－２．６９（２Ｈ、ｍ）、３．０３（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．３７（２Ｈ、ｑ、Ｊ＝７．２Ｈｚ）、６．８９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１０－７．４６（９Ｈ、ｍ）、７．７９（１Ｈ、ｄ、Ｊ＝７．８Ｈｚ）、７．８７（１Ｈ、ｄ、Ｊ＝７．８Ｈｚ）、７．９３（１Ｈ、ｓ）。 Using Compound 81-1 (761 mg) and ethyl 3-aminobenzoate (496 mg) in the same manner as in Example 67, the target product (960 mg) was obtained as a white solid.
MS (ESI) m / z: 528 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 1.39 (3H, t, J = 7.2 Hz), 1.46-1.60 (2H, m), 1.63-1.73 (2H M), 1.79-1.88 (2H, m), 2.59-2.69 (2H, m), 3.03 (2H, t, J = 7.5 Hz), 4.00 (2H) , T, J = 6.4 Hz), 4.37 (2H, q, J = 7.2 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.10-7.46 (9H, m), 7.79 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.93 (1H, s).
　実施例８３
３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸 Example 83
3-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzoic acid
　（８３－１）３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）安息香酸の合成（化合物８３－１） (83-1) Synthesis of 3-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzoic acid (Compound 83-1)
Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215
　化合物８２－１（９１０ｍｇ）を用い、実施例６８と同様に行ない目的化合物（２９６ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５００［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３８－１．５０（２Ｈ、ｍ）、１．５６－１．６８（２Ｈ、ｍ）、１．６８－１．８０（２Ｈ、ｍ）、２．５７（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、２．６２（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．９１（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１２－７．２０（４Ｈ、ｍ）、７．２１－７．２９（２Ｈ、ｍ）、７．３６－７．５０（３Ｈ、ｍ）、７．５９（１Ｈ、ｄ、Ｊ＝７．８Ｈｚ）、７．７８（１Ｈ、ｄ、Ｊ＝８．１Ｈｚ），８．１７（１Ｈ、ｓ）、１０．０７（１Ｈ、ｓ）。 The target compound (296 mg) was obtained as a white solid by using the compound 82-1 (910 mg) in the same manner as in Example 68.
MS (ESI) m / z: 500 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.38-1.50 (2H, m), 1.56-1.68 (2H, m), 1.68-1.80 (2H) M), 2.57 (2H, t, J = 7.7 Hz), 2.62 (2H, t, J = 7.4 Hz), 2.91 (2H, t, J = 7.6 Hz), 4 .05 (2H, t, J = 6.3 Hz), 7.12-7.20 (4H, m), 7.21-7.29 (2H, m), 7.36-7.50 (3H, m), 7.59 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 8.1 Hz), 8.17 (1H, s), 10.07 (1H, s) .
　実施例８４
Ｎ－メチルスルホニル－３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）ベンズアミド Example 84
N-methylsulfonyl-3-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzamide
　（８４－１）Ｎ－メチルスルホニル－３－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）ベンズアミドの合成（化合物８４－１） Synthesis of (84-1) N-methylsulfonyl-3-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) benzamide (Compound 84-1)
Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216
　化合物８３－１（１９４ｍｇ）及びメタンスルホンアミド（４１ｍｇ）を用い、実施例７８と同様に行ない、目的物（８２ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５７７［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４９（２Ｈ、ｍ）、１．５５－１．７８（２Ｈ、ｍ）、１．７８－１．８１（２Ｈ、ｍ）、２．５７（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．６４（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．３５（３Ｈ、ｓ）、４．０５（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１２－７．２０（４Ｈ、ｍ）、７．２２－７．２９（２Ｈ、ｍ）、７．４０－７．５１（３Ｈ、ｍ）、７．５９（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７．７９（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ），８．１３（１Ｈ、ｓ）、１０．１２（１Ｈ、ｓ）、１２．１３（１Ｈ、ｂｒｓ）。 The same procedure was carried out as in Example 78 using Compound 83-1 (194 mg) and methanesulfonamide (41 mg) to obtain the desired product (82 mg) as a white powder.
MS (ESI) m / z: 577 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.49 (2H, m), 1.55-1.78 (2H, m), 1.78-1.81 (2H) M), 2.57 (2H, t, J = 7.8 Hz), 2.64 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.6 Hz), 3 .35 (3H, s), 4.05 (2H, t, J = 6.3 Hz), 7.12-7.20 (4H, m), 7.22-7.29 (2H, m), 7 .40-7.51 (3H, m), 7.59 (1H, d, J = 8.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 8.13 (1H, s) 10.12 (1H, s), 12.13 (1H, brs).
　実施例８５
５－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸ジメチル Example 85
5-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) dimethyl isophthalate
　（８５－１）５－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸ジメチルの合成（化合物８５－１） Synthesis of (85-1) 5-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid dimethyl (Compound 85-1)
Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217
　化合物８１－１（３８０ｍｇ）及び５－アミノイソフタル酸ジメチル（３１４ｍｇ）を用い、実施例６９と同様に行ない、目的物（５１１ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４５－１．６０（２Ｈ、ｍ）、１．６２－１．７３（２Ｈ、ｍ）、１．７７－１．８８（２Ｈ、ｍ）、２．６０－２．７２（４Ｈ、ｍ）、３．０４（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、３．９４（６Ｈ、ｓ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．８９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１４－７．３８（７Ｈ、ｍ）、７．４２（１Ｈ、ｓ）、８．３３（２Ｈ、ｓ）、８．４３（１Ｈ、ｓ）。 Using compound 81-1 (380 mg) and dimethyl 5-aminoisophthalate (314 mg), the same operation as in Example 69 was performed to obtain the desired product (511 mg) as a white powder.
MS (ESI) m / z: 572 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 1.45 to 1.60 (2H, m), 1.62-1.73 (2H, m), 1.77-1.88 (2H, m ), 2.60-2.72 (4H, m), 3.04 (2H, t, J = 7.5 Hz), 3.94 (6H, s), 4.00 (2H, t, J = 6) .3 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.14-7.38 (7H, m), 7.42 (1H, s), 8.33 (2H, s), 8.43 (1H, s).
　実施例８６
５－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸 Example 86
5-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid
　（８６－１）５－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）イソフタル酸の合成（化合物８６－１） (86-1) Synthesis of 5-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) isophthalic acid (Compound 86-1)
Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218
　化合物８５－１（４７１ｍｇ）を用い、実施例７０と同様に行ない、目的物（２６２ｍｇ）を白色粉末として得た。
　ＭＳ（ＥＳＩ）ｍ／ｚ：５４４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３７－１．５５（２Ｈ、ｍ）、１．５６－１．６７（２Ｈ、ｍ）、１．６７－１．８０（２Ｈ、ｍ）、２．５７（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．６５（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、４．０５（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１２－７．２０（４Ｈ、ｍ）、７．２２－７．３８（２Ｈ、ｍ）、７．４４－７．５０（２Ｈ、ｍ）、８．１４（１Ｈ、ｔ、Ｊ＝１．５Ｈｚ）、８．４０（２Ｈ、ｄ、Ｊ＝１．５Ｈｚ）、１０．２６（１Ｈ、ｓ）、１３．２１（１Ｈ、ｂｒｓ）。 Compound 85-1 (471 mg) was used in the same manner as in Example 70 to obtain the desired product (262 mg) as a white powder.
MS (ESI) m / z: 544 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.37-1.55 (2H, m), 1.56-1.67 (2H, m), 1.67-1.80 (2H) M), 2.57 (2H, t, J = 7.8 Hz), 2.65 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.5 Hz), 4 .05 (2H, t, J = 6.3 Hz), 7.12-7.20 (4H, m), 7.22-7.38 (2H, m), 7.44-7.50 (2H, m), 8.14 (1H, t, J = 1.5 Hz), 8.40 (2H, d, J = 1.5 Hz), 10.26 (1H, s), 13.21 (1H, brs) .
　実施例８７
４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸ジエチル Example 87
4-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) diethyl phthalate
　（８７－１）４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸ジエチルの合成（化合物８７－１） Synthesis of (87-1) 4-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) diethyl phthalate (Compound 87-1)
Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219
　化合物８１－１（３８０ｍｇ）及び４－アミノフタル酸ジエチル（３５６ｍｇ）を用い、実施例６９と同様に行ない、目的物（４４０ｍｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３０－１．４１（６Ｈ、ｍ）、１．４９－１．６０（２Ｈ、ｍ）、１．６２－１．７２（２Ｈ、ｍ）、１．７９－１．８９（２Ｈ、ｍ）２．６０－２．６８（４Ｈ、ｍ）、３．０１（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、４．２９－４．３９（４Ｈ、ｍ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１４－７．４３（７Ｈ、ｍ）、７．６６－７．８０（３Ｈ、ｍ）。 Using compound 81-1 (380 mg) and diethyl 4-aminophthalate (356 mg), the same operation as in Example 69 was carried out to obtain the desired product (440 mg) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.30-1.41 (6H, m), 1.49-1.60 (2H, m), 1.62-1.72 (2H, m ) 1.79-1.89 (2H, m) 2.60-2.68 (4H, m), 3.01 (2H, t, J = 7.6 Hz), 4.00 (2H, t, J = 6.4 Hz), 4.29-4.39 (4H, m), 6.88 (1H, d, J = 8.5 Hz), 7.14-7.43 (7H, m), 7. 66-7.80 (3H, m).
　実施例８８
４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸 Example 88
4-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) phthalic acid
　（８８－１）４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）フタル酸の合成（化合物８８－１） Synthesis of (88-1) 4-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) phthalic acid (Compound 88-1)
Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220
　化合物８７－１（４４０ｍｇ）を用い、実施例６８と同様に行ない、目的物（１８５ｍｇ）を淡黄色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：５４４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３８－１．４９（２Ｈ、ｍ）、１．５６－１．６７（２Ｈ、ｍ）、１．６８－１．７８（２Ｈ、ｍ）、２．５７（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、２．６５（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．９１（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、４．０４（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１２－７．２１（４Ｈ、ｍ）、７．２３－７．２９（２Ｈ、ｍ）、７．４３－７．５０（２Ｈ、ｍ）、７．７０（２Ｈ、ｄ、Ｊ＝１．１Ｈｚ）、７．８４（１Ｈ、ｓ）、１０．２８（１Ｈ、ｓ）。 The compound 87-1 (440 mg) was used in the same manner as in Example 68, and the target product (185 mg) was obtained as a pale yellow solid.
MS (ESI) m / z: 544 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.38-1.49 (2H, m), 1.56-1.67 (2H, m), 1.68-1.78 (2H) M), 2.57 (2H, t, J = 7.7 Hz), 2.65 (2H, t, J = 7.4 Hz), 2.91 (2H, t, J = 7.5 Hz), 4 .04 (2H, t, J = 6.3 Hz), 7.12-7.21 (4H, m), 7.23-7.29 (2H, m), 7.43-7.50 (2H, m), 7.70 (2H, d, J = 1.1 Hz), 7.84 (1H, s), 10.28 (1H, s).
　実施例８９
４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸メチル Example 89
4-({3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) methyl butyrate
　（８９－１）４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸メチルの合成（化合物８９－１） (89-1) Synthesis of 4-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) methyl butyrate (Compound 89-1)
Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221
　化合物８１－１（３８０ｍｇ）及び４－アミノ酪酸（２３０ｍｇ）を用い、実施例７３と同様に行ない、目的物（４３０ｍｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４９－１．９０（８Ｈ、ｍ）、２．２９（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、２．４２（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．６４（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．９３（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．２６（２Ｈ、ｑ、Ｊ＝６．０Ｈｚ）、３．６６（３Ｈ、ｓ）、４．００（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、５．６３（１Ｈ、ｂｒｓ）、６．８８（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１５－７．２０（３Ｈ、ｍ）、７．２４－７．３２（３Ｈ、ｍ）、７．３５－７．３８（１Ｈ、ｍ）。 Using Compound 81-1 (380 mg) and 4-aminobutyric acid (230 mg), the same operation as in Example 73 was carried out to obtain the desired product (430 mg) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.49-1.90 (8H, m), 2.29 (2H, t, J = 7.1 Hz), 2.42 (2H, t, J = 7.4 Hz), 2.64 (2H, t, J = 7.8 Hz), 2.93 (2H, t, J = 7.6 Hz), 3.26 (2H, q, J = 6.0 Hz) 3.66 (3H, s), 4.00 (2H, t, J = 6.3 Hz), 5.63 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7 .15-7.20 (3H, m), 7.24-7.32 (3H, m), 7.35-7.38 (1H, m).
　実施例９０
４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸ナトリウム Example 90
4-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) butyric acid sodium salt
　（９０－１）４－（｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピオニル｝アミノ）酪酸ナトリウムの合成（化合物９０－１） (90-1) Synthesis of 4-({3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propionyl} amino) butyric acid sodium (Compound 90-1)
Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222
　化合物８９－１（４３０ｍｇ）のＴＨＦ（１０ｍｌ）溶液に１Ｍ水酸化ナトリウム水溶液（６ｍｌ）を加え、室温にて１８時間攪拌した。反応液に１Ｍ塩酸（１０ｍｌ）を加えた後減圧下濃縮した。残渣に酢酸エチルを加え、水層を分液操作で除いた。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣にエタノール（１０ｍｌ）、次いで１Ｍ水酸化ナトリウム水溶液（０．５３１ｍｌ）を加え攪拌後、減圧下濃縮し、白色固体を得た。この固体をエーテルで洗浄して目的物（２４９ｍｇ）を白色固体として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４６６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．７８（１０Ｈ、ｍ）、１．８６（２Ｈ、ｔ、Ｊ＝７．０Ｈｚ）、２．３０（２Ｈ、ｔ、Ｊ＝７．３Ｈｚ）、２．５６（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、２．７７（２Ｈ、ｔ、Ｊ＝７．９Ｈｚ）、２．９５（２Ｈ、ｑ、Ｊ＝５．２Ｈｚ）、４．０３（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．０９－７．２０（４Ｈ、ｍ）、７．２１－７．２８（２Ｈ、ｍ）、７．３６－７．４２（２Ｈ、ｍ）、８．２９（１Ｈ、ｔ、Ｊ＝５．０Ｈｚ）。 To a solution of compound 89-1 (430 mg) in THF (10 ml) was added 1M aqueous sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature for 18 hours. 1M Hydrochloric acid (10 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the aqueous layer was removed by a liquid separation operation. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (10 ml) and then 1M aqueous sodium hydroxide solution (0.531 ml) were added to the residue, and the mixture was stirred and concentrated under reduced pressure to give a white solid. This solid was washed with ether to obtain the desired product (249 mg) as a white solid.
MS (ESI) m / z: 466 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.78 (10H, m), 1.86 (2H, t, J = 7.0 Hz), 2.30 (2H, t , J = 7.3 Hz), 2.56 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.9 Hz), 2.95 (2H, q, J = 5. 2 Hz), 4.03 (2H, t, J = 6.2 Hz), 7.09-7.20 (4H, m), 7.21-7.28 (2H, m), 7.36-7. 42 (2H, m), 8.29 (1H, t, J = 5.0 Hz).
　実施例９１
３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロパン－１－オール Example 91
3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propan-1-ol
　（９１－１）３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロパン－１－オールの合成（化合物９１－１） (91-1) Synthesis of 3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propan-1-ol (Compound 91-1)
Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223
　化合物８１－１（３．３７ｇ）のＴＨＦ（２０ｍｌ）溶液に氷冷下テトラヒドロフラン－ボラン・テトラヒドロフラン溶液（０．９Ｍ、１２．８ｍｌ）を加え室温で６時間攪拌した。反応液に１Ｎ塩酸（４０ｍｌ）を加え６０℃で３０分間攪拌後、減圧下濃縮した。残渣に酢酸エチルを加え、水層を分液操作で除いた。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。有機層を減圧下濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製することにより目的物（２．９２ｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．３３（１Ｈ、ｂｒｓ）、１．４７－１．７４（４Ｈ、ｍ）、１．７６－１．９２（４Ｈ、ｍ）、２．６１－２．７２（４Ｈ、ｍ）、３．６４－３．７２（２Ｈ、ｍ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、６．８８（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．１４－７．２１（３Ｈ、ｍ）、７．２４－７．３１（３Ｈ、ｍ）、７．３８（１Ｈ、ｄ、Ｊ＝２．０Ｈｚ）。 To a solution of compound 81-1 (3.37 g) in THF (20 ml) was added tetrahydrofuran-borane-tetrahydrofuran solution (0.9 M, 12.8 ml) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. 1N Hydrochloric acid (40 ml) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 30 min and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the aqueous layer was removed by a liquid separation operation. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (2.92 g) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.33 (1H, brs), 1.47-1.74 (4H, m), 1.76-1.92 (4H, m), 2. 61-2.72 (4H, m), 3.64-3.72 (2H, m), 4.00 (2H, t, J = 6.4 Hz), 6.88 (1H, d, J = 8) .4 Hz), 7.14-7.21 (3H, m), 7.24-7.31 (3H, m), 7.38 (1 H, d, J = 2.0 Hz).
　実施例９２
１－｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピル｝アゼチジン－３－カルボン酸 Example 92
1- {3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propyl} azetidine-3-carboxylic acid
　（９２－１）３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロパナールの合成（化合物９２－１） (92-1) Synthesis of 3- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) phenyl] propanal (Compound 92-1)
Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224
　化合物９１－１（２．８３ｇ）の酢酸エチル（３９ｍｌ）溶液に２，２，６，６－テトラメチル－１－ピペリジニルオキシ（１２ｍｇ）、臭化ナトリウム（９３ｍｇ）を加えた。反応液氷冷下、炭酸水素ナトリウム（１．１６ｇ）の１．９％次亜塩素酸ナトリウム水溶液（２４ｍｌ）を加え、氷冷下１時間攪拌した。さらに１２％次亜塩素酸ナトリウム水溶液（１ｍｌ）加え氷冷下１時間攪拌した後、分液操作で水層を除いた。有機層を亜硫酸ナトリウム水溶液、水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。有機層を減圧下濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製して目的物（１．５３ｇ）を無色透明油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４８－１．６０（２Ｈ、ｍ）、１．６２－１．７４（２Ｈ、ｍ）、１．７８－１．８９（２Ｈ、ｍ）、２．６４（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．７７（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、２．９２（２Ｈ、ｔ、Ｊ＝７．４Ｈｚ）、４．００（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、６．８９（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１４－７．２１（３Ｈ、ｍ）、７．２４－７．３１（３Ｈ、ｍ）、７．３７（１Ｈ、ｄ、Ｊ＝２．０Ｈｚ）、９．８１（１Ｈ、ｓ）。 2,2,6,6-Tetramethyl-1-piperidinyloxy (12 mg) and sodium bromide (93 mg) were added to a solution of compound 91-1 (2.83 g) in ethyl acetate (39 ml). Under ice-cooling of the reaction solution, 1.9% sodium hypochlorite aqueous solution (24 ml) of sodium hydrogen carbonate (1.16 g) was added, and the mixture was stirred for 1 hour under ice-cooling. Further, 12% sodium hypochlorite aqueous solution (1 ml) was added and stirred for 1 hour under ice cooling, and then the aqueous layer was removed by a liquid separation operation. The organic layer was washed successively with aqueous sodium sulfite solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.53 g) as a colorless transparent oil.
1 H-NMR (CDCl 3 ) δ (ppm): 1.48-1.60 (2H, m), 1.62-1.74 (2H, m), 1.78-1.89 (2H, m ), 2.64 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.4 Hz), 4.00 (2H, t, J = 6.4 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.14-7.21 (3H, m), 7.24-7.31 (3H, m), 7.37 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
　（９２－２）１－｛３－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）フェニル］プロピル｝アゼチジン－３－カルボン酸　トリフルオロ酢酸塩の合成（化合物９２－２） (92-2) 1- {3- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) phenyl] propyl} azetidine-3-carboxylic acid Synthesis of trifluoroacetate (Compound 92-2)
Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225
　化合物９２－１（７２９ｍｇ）及び３－アゼチジンカルボン酸（３０３ｍｇ）を用い、実施例７７と同様に行ない、目的物（２３１ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４５０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３７－１．４８（２Ｈ、ｍ）、１．５５－１．７８（６Ｈ、ｍ）、２．５０－２．６５（４Ｈ、ｍ）、３．０４－３．１３（２Ｈ、ｍ）、４．０４（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．０６－４．２４（４Ｈ、ｍ）、７．１２－７．１９（４Ｈ、ｍ）、７．２１－７．２８（２Ｈ、ｍ）、７．３９－７．４５（２Ｈ、ｍ）。 Using Compound 92-1 (729 mg) and 3-azetidinecarboxylic acid (303 mg), the same operation as in Example 77 was performed to obtain the desired product (231 mg) as a white powder.
MS (ESI) m / z: 450 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.37-1.48 (2H, m), 1.55-1.78 (6H, m), 2.50-2.65 (4H) M), 3.04-3.13 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.06-4.24 (4H, m), 7.12-7 .19 (4H, m), 7.21-7.28 (2H, m), 7.39-7.45 (2H, m).
　実施例９３
１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボニトリル Example 93
1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carbonitrile
　（９３－１）１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボニトリルの合成（化合物９３－１） (93-1) Synthesis of 1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carbonitrile (Compound 93-1)
Figure JPOXMLDOC01-appb-C000226
Figure JPOXMLDOC01-appb-C000226
　１－（ｔ－ブトキシカルボニル）－３－シアノアゼチジン（１ｇ）の酢酸エチル（４ｍｌ）溶液に４Ｍ塩酸酢酸エチル溶液を加え、室温にて１８時間攪拌した。反応液中に粉末が析出した。上澄みを除き乾燥させることにより、白色粉末を得た。この白色粉末を、化合物７６－１（１．１１ｇ）のＴＨＦ（５ｍｌ）溶液中に加え、室温で２時間攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（１．０５ｇ）を加え、室温で１８時間攪拌した。反応液に水、次いで飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製して、目的物（６２０ｍｇ）を無色透明油状物として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４０３［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４９－１．６０（２Ｈ、ｍ）、１．６０－１．７４（２Ｈ、ｍ）、１．８０－１．９０（２Ｈ、ｍ）、２．６４（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、３．２２－３．４６（３Ｈ、ｍ）、３．５２－３．６２（４Ｈ、ｍ）、４．０２（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．９１（１Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．１５－７．２１（３Ｈ、ｍ）、７．２４－７．３１（２Ｈ、ｍ）、７．３５（１Ｈ、ｄｄ、Ｊ＝８．５、１．９Ｈｚ）、７．４５（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 To a solution of 1- (t-butoxycarbonyl) -3-cyanoazetidine (1 g) in ethyl acetate (4 ml) was added 4M hydrochloric acid ethyl acetate solution, and the mixture was stirred at room temperature for 18 hours. A powder precipitated in the reaction solution. A white powder was obtained by drying the supernatant. This white powder was added to a solution of compound 76-1 (1.11 g) in THF (5 ml) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1.05 g) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and then saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (620 mg) as a colorless transparent oil.
MS (ESI) m / z: 403 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 1.49-1.60 (2H, m), 1.60-1.74 (2H, m), 1.80-1.90 (2H, m ), 2.64 (2H, t, J = 7.8 Hz), 3.22-3.46 (3H, m), 3.52-3.62 (4H, m), 4.02 (2H, t) , J = 6.3 Hz), 6.91 (1H, d, J = 8.5 Hz), 7.15-7.21 (3H, m), 7.24-7.31 (2H, m), 7 .35 (1H, dd, J = 8.5, 1.9 Hz), 7.45 (1H, d, J = 1.9 Hz).
　実施例９４
１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミド　オキシム Example 94
1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide oxime
　（９４－１）１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボキサミド　オキシムの合成（化合物９４－１） (94-1) 1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxamide Synthesis of oxime (Compound 94-1)
Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227
　化合物９３－１（５８３ｍｇ）のエタノール（２５ｍｌ）溶液に塩化ヒドロキシルアンモニウム（１０１ｍｇ）、酢酸アンモニウム（２３８ｍｇ）、水（５ｍｌ）を加え８５℃で２時間攪拌した。さらに反応液に塩化ヒドロキシルアンモニウム（２０２ｍｇ）、酢酸アンモニウム（４７６ｍｇ）を加え、８５℃で３時間攪拌した。反応液を濃縮し残渣に水を加えクロロホルムで抽出した。有機層の溶媒を減圧下留去し残渣をシリカゲルカラムクロマトグラフィーで精製して目的物（４２７ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４３６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４９（２Ｈ、ｍ）、１．５７－１．６７（２Ｈ、ｍ）、１．７０－１．７９（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝７．８Ｈｚ）、２．９４－３．０４（１Ｈ、ｍ）、３．１１（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、３．２５－３．４０（２Ｈ、ｍ）、３．５１（２Ｈ、ｓ）、４．０６（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、５．３８（２Ｈ、ｂｒｓ）、７．１２－７．２１（４Ｈ、ｍ）、７．２２－７．２９（２Ｈ、ｍ）、７．４３－７．４９（２Ｈ、ｍ）、８．９４（１Ｈ、ｓ）。 To a solution of compound 93-1 (583 mg) in ethanol (25 ml) was added hydroxylammonium chloride (101 mg), ammonium acetate (238 mg) and water (5 ml), and the mixture was stirred at 85 ° C. for 2 hr. Furthermore, hydroxylammonium chloride (202 mg) and ammonium acetate (476 mg) were added to the reaction solution, and the mixture was stirred at 85 ° C. for 3 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (427 mg) as a white powder.
MS (ESI) m / z: 436 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.49 (2H, m), 1.57-1.67 (2H, m), 1.70-1.79 (2H) M), 2.58 (2H, t, J = 7.8 Hz), 2.94-3.04 (1H, m), 3.11 (2H, t, J = 7.1 Hz), 3.25 -3.40 (2H, m), 3.51 (2H, s), 4.06 (2H, t, J = 6.3 Hz), 5.38 (2H, brs), 7.12-7.21 (4H, m), 7.22-7.29 (2H, m), 7.43-7.49 (2H, m), 8.94 (1H, s).
　実施例９５
３－｛１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－イル｝－１，２，４－オキサジアゾール－５（４Ｈ）－オン　トリフルオロ酢酸塩 Example 95
3- {1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidin-3-yl} -1,2,4-oxadiazol-5 (4H) -one trifluoro Acetate
　（９５－１）３－｛１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－イル｝－１，２，４－オキサジアゾール－５（４Ｈ）－オン　トリフルオロ酢酸塩の合成（化合物９５－１） (95-1) 3- {1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidin-3-yl} -1,2,4-oxadiazole-5 (4H ) -On synthesis of trifluoroacetate (Compound 95-1)
Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228
　化合物９４－１（３７６ｍｇ）のＴＨＦ（５ｍｌ）溶液に１，１’－カルボニルジイミダゾール（２１０ｍｇ）を加え、２時間加熱還流した。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製後、ＨＰＬＣでさらに精製して目的物（１０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４６２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．４８（２Ｈ、ｍ）、１．５８－１．６８（２Ｈ、ｍ）、１．７１－１．８２（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝８．０Ｈｚ）、３．９４－４．０５（１Ｈ、ｍ）、４．１２（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、４．１６－４．４０（６Ｈ、ｍ）、７．１３－７．２１（３Ｈ、ｓ）、７．２４－７．２９（２Ｈ、ｍ）、７．３２（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．６９（１Ｈ、ｄｄ、Ｊ＝８．６、１．８Ｈｚ）、７．７５（１Ｈ、ｄ、Ｊ＝１．４Ｈｚ）。 1,1′-carbonyldiimidazole (210 mg) was added to a solution of compound 94-1 (376 mg) in THF (5 ml), and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography and further purified by HPLC to obtain the desired product (10 mg) as a white powder.
MS (ESI) m / z: 462 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.48 (2H, m), 1.58-1.68 (2H, m), 1.71-1.82 (2H) M), 2.58 (2H, t, J = 8.0 Hz), 3.94-4.05 (1H, m), 4.12 (2H, t, J = 6.3 Hz), 4.16 -4.40 (6H, m), 7.13-7.21 (3H, s), 7.24-7.29 (2H, m), 7.32 (1H, d, J = 8.6 Hz) 7.69 (1H, dd, J = 8.6, 1.8 Hz), 7.75 (1H, d, J = 1.4 Hz).
　実施例９６
１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－カルボニトリル Example 96
1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidine-4-carbonitrile
　（９６－１）１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－カルボニトリルの合成（化合物９６－１） (96-1) Synthesis of 1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidine-4-carbonitrile (Compound 96-1)
Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229
　１－（ｔ－ブトキシカルボニル）－４－シアノピペリジン（３６４ｍｇ）及び化合物７６－１（６７３ｍｇ）を用い、実施例９３と同様に行ない、目的物（５０１ｍｇ）を無色透明油状物として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４３１［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：１．４９－１．６４（２Ｈ、ｍ）、１．６４－１．７４（２Ｈ、ｍ）、１．８０－１．９８（６Ｈ、ｍ）、２．２２－２．４０（２Ｈ、ｍ）、２．５７－２．７１（５Ｈ、ｍ）、３．４４（２Ｈ、ｓ）、４．０２（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、６．９１（１Ｈ、ｄ、Ｊ＝８．４Ｈｚ）、７．１５－７．２１（３Ｈ、ｍ）、７．２４－７．３１（２Ｈ、ｍ）、７．３８（１Ｈ、ｄｄ、Ｊ＝８．４、１．９Ｈｚ）、７．４８（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）。 1- (t-Butoxycarbonyl) -4-cyanopiperidine (364 mg) and compound 76-1 (673 mg) were used in the same manner as in Example 93 to obtain the desired product (501 mg) as a colorless transparent oil.
MS (ESI) m / z: 431 [M + H]
1 H-NMR (CDCl 3 ) δ (ppm): 1.49-1.64 (2H, m), 1.64-1.74 (2H, m), 1.80-1.98 (6H, m ), 2.22-2.40 (2H, m), 2.57-2.71 (5H, m), 3.44 (2H, s), 4.02 (2H, t, J = 6.3 Hz) ), 6.91 (1H, d, J = 8.4 Hz), 7.15-7.21 (3H, m), 7.24-7.31 (2H, m), 7.38 (1H, dd) , J = 8.4, 1.9 Hz), 7.48 (1H, d, J = 1.9 Hz).
　実施例９７
１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－カルボキサミド　オキシム Example 97
1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidine-4-carboxamide oxime
　（９７－１）１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－カルボキサミド　オキシムの合成（化合物９７－１） (97-1) 1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidine-4-carboxamide Synthesis of oxime (Compound 97-1)
Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230
　化合物９６－１（５０１ｍｇ）を用い、実施例９４と同様に行ない、目的物（７３ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４６４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３９－１．５０（２Ｈ、ｍ）、１．５０－１．７０（６Ｈ、ｍ）、１．７０－１．８１（２Ｈ、ｍ）、１．８２－１．８９（２Ｈ、ｍ）、２．５８（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、２．７６－２．８３（２Ｈ、ｍ）、３．２５－３．４０（１Ｈ、ｍ）、３．４２（２Ｈ、ｓ）、４．０７（（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、５．２７（２Ｈ、ｂｒｓ）、７．１３－７．２１（４Ｈ、ｍ）、７．２３－７．２９（２Ｈ、ｍ）、７．４５－７．５２（２Ｈ、ｍ）、８．７５（１Ｈ、ｓ）。 Compound 96-1 (501 mg) was used in the same manner as in Example 94 to obtain the desired product (73 mg) as a white powder.
MS (ESI) m / z: 464 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.39-1.50 (2H, m), 1.50-1.70 (6H, m), 1.70-1.81 (2H) M), 1.82-1.89 (2H, m), 2.58 (2H, t, J = 7.5 Hz), 2.76-2.83 (2H, m), 3.25-3 .40 (1H, m), 3.42 (2H, s), 4.07 ((2H, t, J = 6.3 Hz), 5.27 (2H, brs), 7.13-7.21 ( 4H, m), 7.23-7.29 (2H, m), 7.45-7.52 (2H, m), 8.75 (1H, s).
　実施例９８
３－｛１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－イル｝－１，２，４－オキサジアゾール－５（４Ｈ）－オン Example 98
3- {1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidin-4-yl} -1,2,4-oxadiazol-5 (4H) -one
　（９８－１）３－｛１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］ピペリジン－４－イル｝－１，２，４－オキサジアゾール－５（４Ｈ）－オンの合成（化合物９８－１） (98-1) 3- {1- [4- (5-Phenylpentyloxy) -3- (trifluoromethyl) benzyl] piperidin-4-yl} -1,2,4-oxadiazole-5 (4H ) -One synthesis (compound 98-1)
Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231
　化合物９７－１（６０ｍｇ）のＴＨＦ（５ｍｌ）溶液に１，１’－カルボニルジイミダゾール（３１ｍｇ）を加え、４時間加熱還流した。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィーで精製して、白色粉末の目的化合物（１８ｍｇ）を得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４９０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．４０－１．４９（２Ｈ、ｍ）、１．５６－１．６８（４Ｈ、ｍ）、１．７０－１．８８（４Ｈ、ｍ）、１．９９－２．０９（２Ｈ、ｍ）、２．４９－２．６２（３Ｈ、ｍ）、２．７６－２．８５（２Ｈ、ｍ）、３．４７（２Ｈ、ｓ）、４．０８（２Ｈ、ｔ、Ｊ＝６．３Ｈｚ）、７．１３－７．２２（４Ｈ、ｓ）、７．２３－７．２９（２Ｈ、ｍ）、７．４７－７．５３（２Ｈ、ｍ）。 1,1′-carbonyldiimidazole (31 mg) was added to a solution of compound 97-1 (60 mg) in THF (5 ml), and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain the target compound (18 mg) as a white powder.
MS (ESI) m / z: 490 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.40-1.49 (2H, m), 1.56-1.68 (4H, m), 1.70-1.88 (4H) M), 1.99-2.09 (2H, m), 2.49-2.62 (3H, m), 2.76-2.85 (2H, m), 3.47 (2H, s) ), 4.08 (2H, t, J = 6.3 Hz), 7.13-7.22 (4H, s), 7.23-7.29 (2H, m), 7.47-7.53 (2H, m).
　実施例９９
４－｛［４－（６－フェニルヘキシルオキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩 Example 99
4-{[4- (6-Phenylhexyloxy) -3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate
　（９９－１）４－｛［４－（６－フェニルヘキシルオキシ）－３－（トリフルオロメチル）ベンジル］アミノ｝酪酸トリフルオロ酢酸塩の合成（化合物９９－１） (99-1) Synthesis of 4-{[4- (6-phenylhexyloxy) -3- (trifluoromethyl) benzyl] amino} butyric acid trifluoroacetate (Compound 99-1)
Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232
　参考例化合物１－２（６９６ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（２０ｍｌ）に溶解させ、炭酸カリウム（１．５２ｇ）、１－ブロモ－６－フェニルヘキサン（１．０６ｇ）を加え、室温にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥した。有機層の溶媒を減圧留去し、黄色油状物（１．２６ｇ）を得た。この油状物（６５０ｍｇ）と４－アミノ酪酸（１９１ｍｇ）にメタノール（２０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムアセトキシボロヒドリド（５９１ｍｇ）を加え、室温で１２時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、析出物を濾取、乾燥することにより、目的物（２９０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４３８［Ｍ＋Ｈ］    
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．３０－１．３８（２Ｈ、ｍ）、１．４２－１．４９（２Ｈ、ｍ）、１．５３－１．６１（２Ｈ、ｍ）、１．６８－１．７４（２Ｈ、ｍ）、１．７９－１．８６（２Ｈ、ｍ）、２．３５（２Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．５７（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．９５（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．３０－３．４５（１Ｈ、ｂｒｍ）、４．１１（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、４．１５（２Ｈ、ｓ）、７．１４－７．１９（３Ｈ、ｍ）、７．２４－７．３２（３Ｈ、ｍ）、７．７０（１Ｈ、ｄｄ、Ｊ＝８．３、１．６Ｈｚ）、７．７９（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 Reference Example Compound 1-2 (696 mg) was dissolved in N, N-dimethylformamide (20 ml), potassium carbonate (1.52 g) and 1-bromo-6-phenylhexane (1.06 g) were added, and at room temperature. Stir for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent of the organic layer was distilled off under reduced pressure to obtain a yellow oil (1.26 g). To this oil (650 mg) and 4-aminobutyric acid (191 mg) were added methanol (20 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml), and the mixture was stirred at room temperature for 30 minutes. Sodium acetoxyborohydride (591 mg) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC, and the precipitate was collected by filtration and dried to give the object product (290 mg) as a white powder.
MS (ESI) m / z: 438 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.30-1.38 (2H, m), 1.42-1.49 (2H, m), 1.53-1.61 (2H) M), 1.68-1.74 (2H, m), 1.79-1.86 (2H, m), 2.35 (2H, t, J = 7.2 Hz), 2.57 (2H) , T, J = 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), 3.30-3.45 (1H, brm), 4.11 (2H, t, J = 6. 2 Hz), 4.15 (2H, s), 7.14-7.19 (3H, m), 7.24-7.32 (3H, m), 7.70 (1H, dd, J = 8. 3, 1.6 Hz), 7.79 (1H, d, J = 1.6 Hz).
　実施例１００
１－［４－（６－フェニルヘキシルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸 Example 100
1- [4- (6-Phenylhexyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid
　（１００－１）１－［４－（６－フェニルヘキシルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸の合成（化合物１００－１） (100-1) Synthesis of 1- [4- (6-phenylhexyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid (Compound 100-1)
Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233
　実施例９９で中間体として得た黄色油状物（１．２６ｇ）のうち６１０ｍｇと、３－アゼチジンカルボン酸（２６４ｍｇ）を用い実施例７７と同様に行ない、目的物（８１ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４３６［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．２８－１．３８（２Ｈ、ｍ）、１．４０－１．５０（２Ｈ、ｍ）、１．５２－１．６２（２Ｈ、ｍ）、１．６６－１．７６（２Ｈ、ｍ）、２．５６（２Ｈ、ｔ、Ｊ＝７．７Ｈｚ）、３．１５－３．９５（７Ｈ、ｍ）、４．０８（２Ｈ、ｔ、Ｊ＝６．２Ｈｚ）、７．１３－７．２９（６Ｈ、ｍ）、７．３６－７．６５（２Ｈ、ｍ）。 The same procedure as in Example 77 was performed using 610 mg of the yellow oil (1.26 g) obtained as an intermediate in Example 99 and 3-azetidinecarboxylic acid (264 mg), and the target product (81 mg) was obtained as a white powder. Obtained.
MS (ESI) m / z: 436 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.28-1.38 (2H, m), 1.40-1.50 (2H, m), 1.52-1.62 (2H) M), 1.66-1.76 (2H, m), 2.56 (2H, t, J = 7.7 Hz), 3.15-3.95 (7H, m), 4.08 (2H) , T, J = 6.2 Hz), 7.13-7.29 (6H, m), 7.36-7.65 (2H, m).
　実施例１０１
４－（｛４－［３－（３－メチルフェニル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸 Example 101
4-({4- [3- (3-Methylphenyl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid
　（１０１－１）４－（｛４－［３－（３－メチルフェニル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸の合成（化合物１０１－１） Synthesis of (101-1) 4-({4- [3- (3-methylphenyl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid (Compound 101-1)
Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、公知の方法（例えば、ＷＯ２００８／１５３１５９号公報、８７～８８ページ）により合成した１－（３－ブロモプロピル）－３－メチルベンゼン（４０５ｍｇ）を加え、室温にて１５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（１５４ｍｇ）にメタノール（２０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（４７５ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去し、白色固体を得た。その白色固体を酢酸エチルにて洗浄し、乾燥することにより、目的物（４５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４１０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．７９－１．８５（２Ｈ、ｍ）、１．９８－２．０５（２Ｈ、ｍ）、２．３４（２Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．７１（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、２．８９（２Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、３．００－３．８０（１Ｈ、ｂｒｓ）、４．０９－４．１１（４Ｈ、ｍ）、６．９６－７．０３（３Ｈ、ｍ）、７．１６（１Ｈ、ｔ、Ｊ＝７．５Ｈｚ）、７．２８（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．７２（１Ｈ、ｄｄ、Ｊ＝８．６、１．６Ｈｚ）、７．８２（１Ｈ、ｄ、Ｊ＝１．６Ｈｚ）。 Reference Example Compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (10 ml) and synthesized by potassium carbonate (654 mg) by a known method (for example, WO 2008/153159, pages 87 to 88) -(3-Bromopropyl) -3-methylbenzene (405 mg) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (20 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to the resulting residue and 4-aminobutyric acid (154 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (475 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The white solid was washed with ethyl acetate and dried to obtain the desired product (45 mg) as a white powder.
MS (ESI) m / z: 410 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.79-1.85 (2H, m), 1.98-2.05 (2H, m), 2.34 (2H, t, J = 7.2 Hz), 2.71 (2H, t, J = 7.5 Hz), 2.89 (2H, t, J = 7.5 Hz), 3.00-3.80 (1H, brs), 4 0.09-4.11 (4H, m), 6.96-7.03 (3H, m), 7.16 (1H, t, J = 7.5 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.72 (1H, dd, J = 8.6, 1.6 Hz), 7.82 (1H, d, J = 1.6 Hz).
　実施例１０２
４－（｛４－［３－（ビフェニル－４－イル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸 Example 102
4-({4- [3- (biphenyl-4-yl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid
　（１０２－１）４－（｛４－［３－（ビフェニル－４－イル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸の合成（化合物１０２－１） Synthesis of (102-1) 4-({4- [3- (biphenyl-4-yl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid (Compound 102-1)
Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、公知の方法（例えば、ＷＯ２００８／１５３１５９号公報、２４２～２４４ページ）により合成した４－（３－ブロモプロピル）ビフェニル（５２３ｍｇ）を加え、室温にて１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（１６３ｍｇ）にメタノール（２０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５０２ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、酢酸エチルを加え、析出物を濾取、乾燥し、目的物（１７５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］    
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．６０－１．６７（２Ｈ、ｍ）、２．０２－２．１０（２Ｈ、ｍ）、２．２５（２Ｈ、ｔ、Ｊ＝６．９Ｈｚ）、２．５６（２Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、２．８０（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．３０－３．９０（３Ｈ、ｂｒｍ）、４．０９（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ）、７．２０（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．２８－７．３６（３Ｈ、ｍ）、７．４５（２Ｈ、ｄ、Ｊ＝７．６Ｈｚ）、７．５３－７．６５（６Ｈ、ｍ）。 Reference Example Compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (10 ml) and synthesized by potassium carbonate (654 mg) by a known method (for example, WO 2008/153159, pages 242 to 244). -(3-Bromopropyl) biphenyl (523 mg) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (20 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to the resulting residue and 4-aminobutyric acid (163 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (502 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and ethyl acetate were added to the reaction solution, and the precipitate was collected by filtration and dried to obtain the desired product (175 mg) as a white powder.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.60-1.67 (2H, m), 2.02-2.10 (2H, m), 2.25 (2H, t, J = 6.9 Hz), 2.56 (2H, t, J = 6.4 Hz), 2.80 (2H, t, J = 7.6 Hz), 3.30-3.90 (3H, brm), 4 .09 (2H, t, J = 6.0 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.28-7.36 (3H, m), 7.45 (2H, d, J = 7.6 Hz), 7.53-7.65 (6H, m).
　実施例１０３
４－（｛４－［３－（ビフェニル－３－イル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸トリフルオロ酢酸塩 Example 103
4-({4- [3- (biphenyl-3-yl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid trifluoroacetate
　（１０３－１）４－（｛４－［３－（ビフェニル－３－イル）プロポキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸トリフルオロ酢酸塩の合成（化合物１０３－１） Synthesis of (103-1) 4-({4- [3- (biphenyl-3-yl) propoxy] -3- (trifluoromethyl) benzyl} amino) butyric acid trifluoroacetate (Compound 103-1)
Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（２０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、公知の方法（例えば、ＷＯ２００８／１５３１５９号公報、２４６～２４８ページ）により合成した３－（３－ブロモプロピル）ビフェニル（５２３ｍｇ）を加え、室温にて１５時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（１６３ｍｇ）にメタノール（２０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５０２ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、析出物を濾取、乾燥することにより、目的物（２５５ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７２［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．７８－１．８６（２Ｈ、ｍ）、２．０７－２．１４（２Ｈ、ｍ）、２．３５（２Ｈ、ｔ、Ｊ＝７．２Ｈｚ）、２．８３（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．９５（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、３．１０－３．６０（１Ｈ、ｂｒｍ）、４．１３（２Ｈ、ｔ、Ｊ＝６．１Ｈｚ）、４．１６（２Ｈ、ｓ）、７．２０（１Ｈ、ｄ、Ｊ＝７．５Ｈｚ）、７．２９－７．４９（７Ｈ、ｍ）、７．５８－７．６２（２Ｈ、ｍ）、７．７０（１Ｈ、ｄｄ、Ｊ＝８．６、１．５Ｈｚ）、７．８３（１Ｈ、ｄ、Ｊ＝１．５Ｈｚ）。 Reference Example Compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (20 ml) and synthesized by potassium carbonate (654 mg) by a known method (for example, WO 2008/153159, pages 246 to 248) 3 -(3-Bromopropyl) biphenyl (523 mg) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (20 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to the resulting residue and 4-aminobutyric acid (163 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (502 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC, and the precipitate was collected by filtration and dried to give the object product (255 mg) as a white powder.
MS (ESI) m / z: 472 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.78-1.86 (2H, m), 2.07-2.14 (2H, m), 2.35 (2H, t, J = 7.2 Hz), 2.83 (2H, t, J = 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), 3.10-3.60 (1H, brm), 4 .13 (2H, t, J = 6.1 Hz), 4.16 (2H, s), 7.20 (1H, d, J = 7.5 Hz), 7.29-7.49 (7H, m) 7.58-7.62 (2H, m), 7.70 (1H, dd, J = 8.6, 1.5 Hz), 7.83 (1H, d, J = 1.5 Hz).
　実施例１０４
４－（｛４－［３－（３－フェノキシフェニル）ベンジルオキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸トリフルオロ酢酸塩 Example 104
4-({4- [3- (3-phenoxyphenyl) benzyloxy] -3- (trifluoromethyl) benzyl} amino) butyric acid trifluoroacetate
　（１０４－１）４－（｛４－［３－（３－フェノキシフェニル）ベンジルオキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸トリフルオロ酢酸塩の合成（化合物１０４－１） Synthesis of (104-1) 4-({4- [3- (3-phenoxyphenyl) benzyloxy] -3- (trifluoromethyl) benzyl} amino) butyric acid trifluoroacetate (Compound 104-1)
Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（２０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、３－フェノキシベンジルクロリド（０．３７１ｍｌ）を加え、室温にて１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（１２８ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（３９４ｍｇ）を加え、室温で２０時間攪拌した。反応液に水、１Ｍ塩酸をｐＨが７付近になるまで加えた。酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣を、ＨＰＬＣで精製した後、析出物を水で洗浄し、乾燥することにより、目的物（８０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４６０［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．７２－１．７９（２Ｈ、ｍ）、２．３２（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、２．８１（２Ｈ、ｔ、Ｊ＝７．１Ｈｚ）、３．２０－３．８０（１Ｈ、ｂｒｍ）、３．９９（２Ｈ、ｓ）、５．２９（２Ｈ、ｓ）、６．９７（１Ｈ、ｄｄ、Ｊ＝８．１、２．２Ｈｚ）、７．０２（２Ｈ、ｄ、Ｊ＝７．６Ｈｚ）、７．０７（１Ｈ、ｂｒｓ）、７．１４－７．２０（２Ｈ、ｍ）、７．３４（１Ｈ、ｄ、Ｊ＝８．６Ｈｚ）、７．３８－７．４４（２Ｈ、ｍ）、７．６５（１Ｈ、ｄｄ、Ｊ＝８．６、１．５Ｈｚ）、７．７４（１Ｈ、ｄ、Ｊ＝１．５Ｈｚ）。 Reference Example compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (20 ml), potassium carbonate (654 mg) and 3-phenoxybenzyl chloride (0.371 ml) were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to the resulting residue and 4-aminobutyric acid (128 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (394 mg) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. Water and 1M hydrochloric acid were added to the reaction solution until the pH was around 7. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC, and then the precipitate was washed with water and dried to obtain the desired product (80 mg) as a white powder.
MS (ESI) m / z: 460 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.72-1.79 (2H, m), 2.32 (2H, t, J = 7.1 Hz), 2.81 (2H, t , J = 7.1 Hz), 3.20-3.80 (1H, brm), 3.99 (2H, s), 5.29 (2H, s), 6.97 (1H, dd, J = 8) .1, 2.2 Hz), 7.02 (2H, d, J = 7.6 Hz), 7.07 (1H, brs), 7.14-7.20 (2H, m), 7.34 (1H , D, J = 8.6 Hz), 7.38-7.44 (2H, m), 7.65 (1H, dd, J = 8.6, 1.5 Hz), 7.74 (1H, d, J = 1.5 Hz).
　実施例１０５
４－（｛４－［３－（３－ベンジルオキシフェニル）ベンジルオキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸 Example 105
4-({4- [3- (3-Benzyloxyphenyl) benzyloxy] -3- (trifluoromethyl) benzyl} amino) butyric acid
　（１０５－１）４－（｛４－［３－（３－ベンジルオキシフェニル）ベンジルオキシ］－３－（トリフルオロメチル）ベンジル｝アミノ）酪酸の合成（化合物１０５－１） Synthesis of (105-1) 4-({4- [3- (3-benzyloxyphenyl) benzyloxy] -3- (trifluoromethyl) benzyl} amino) butyric acid (Compound 105-1)
Figure JPOXMLDOC01-appb-C000238
Figure JPOXMLDOC01-appb-C000238
　参考例化合物１－２（３００ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、炭酸カリウム（６５４ｍｇ）、公知の方法（例えば、ＷＯ２００８／１５３１５９号公報、７０～７１ページ）により合成した３－ベンジルオキシベンジルブロミド（５４３ｍｇ）を加え、室温にて１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、水、飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。得られた残渣と４－アミノ酪酸（１６３ｍｇ）にメタノール（１０ｍｌ）、テトラブチルアンモニウムヒドロキシド（３７％メタノール溶液、１．１２ｍｌ）を加え、室温で３０分攪拌した。氷冷下ナトリウムトリアセトキシボロヒドリド（５０２ｍｇ）を加え、室温で１８時間攪拌した。反応液に水、析出物を濾取し、その析出物を酢酸エチルで洗浄し、乾燥することにより、目的物（５５０ｍｇ）を白色粉末として得た。
ＭＳ（ＥＳＩ）ｍ／ｚ：４７４［Ｍ＋Ｈ］
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：１．６０－１．６８（２Ｈ、ｍ）、２．２６（２Ｈ、ｔ、Ｊ＝６．８Ｈｚ）、２．５６（２Ｈ、ｔ、Ｊ＝６．５Ｈｚ）、３．４０－４．２０（３Ｈ、ｂｒｍ）、５．１０（２Ｈ、ｓ）、５．２４（２Ｈ、ｓ）、６．９７（１Ｈ、ｄｄ、Ｊ＝８．３、２．３Ｈｚ）、７．０２（１Ｈ、ｄ、Ｊ＝７．６Ｈｚ）、７．０９（１Ｈ、ｂｒｓ）、７．２５－７．３５（３Ｈ、ｍ）、７．３７－７．４６（４Ｈ、ｍ）、７．５６（１Ｈ、ｄｄ、Ｊ＝８．６、１．３Ｈｚ）、７．６３（１Ｈ、ｄ、Ｊ＝１．３Ｈｚ）。 Reference Example Compound 1-2 (300 mg) was dissolved in N, N-dimethylformamide (10 ml) and synthesized by potassium carbonate (654 mg) by a known method (for example, WO 2008/153159, pages 70 to 71) 3 -Benzyloxybenzyl bromide (543 mg) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Methanol (10 ml) and tetrabutylammonium hydroxide (37% methanol solution, 1.12 ml) were added to the resulting residue and 4-aminobutyric acid (163 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (502 mg) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water and a precipitate were collected by filtration in the reaction solution, and the precipitate was washed with ethyl acetate and dried to obtain the desired product (550 mg) as a white powder.
MS (ESI) m / z: 474 [M + H]
1 H-NMR (DMSO-d 6 ) δ (ppm): 1.60-1.68 (2H, m), 2.26 (2H, t, J = 6.8 Hz), 2.56 (2H, t , J = 6.5 Hz), 3.40-4.20 (3H, brm), 5.10 (2H, s), 5.24 (2H, s), 6.97 (1H, dd, J = 8) .3, 2.3 Hz), 7.02 (1H, d, J = 7.6 Hz), 7.09 (1H, brs), 7.25-7.35 (3H, m), 7.37-7 .46 (4H, m), 7.56 (1H, dd, J = 8.6, 1.3 Hz), 7.63 (1H, d, J = 1.3 Hz).
　実験例１：マウス末梢血リンパ球数減少作用の評価
　本発明化合物を２０％シクロデキストリン（日本食品化工社製）に溶解又は懸濁させて、０．００１～１０ｍｇ／ｋｇ体重の用量で、７～１０週齢の雄性ＢＡＬＢ／ｃマウス（日本チャールス・リバー）に腹腔内投与した。本発明化合物の投与３又は２４時間後に、エーテル麻酔下にマウスの後大静脈から、ヘパリンナトリウム（ノボ・ノルディスク社製）で処理したツベルクリン用シリンジ（テルモ社製）を用いて、末梢血を約０．３ｍｌ採取した。０．１ｍｌの血液を自動溶血処理装置（ＴＱ－Ｐｒｅｐ、ベックマン・コールター社製）を用いて溶血した後、フローサイトメーター（ＣＹＴＯＭＩＣＳ ＦＣ　５００、ベックマン・コールター社製）を用い、既知数の標準粒子であるＦｌｏｗ－ＣｏｕｎｔＴＭＦｌｕｏｒｏｓｐｈｅｒｅｓ（ベックマン・コールター社製）を内部標準として、レーザー光の前方及び側方散乱を指標としたゲーティング法でリンパ球数を測定した。ビークル群のリンパ球数を１００％としたときに、それを５０％低下させる用量を算出し、ＥＤ５０値（ｍｇ／ｋｇ体重）とした。化合物１－４、化合物１１－１、化合物２０－２の投与２４時間後におけるマウス末梢血リンパ球数減少作用のＥＤ５０値は、それぞれ０．０７、０．０８、０．１５ｍｇ／ｋｇ体重であった。化合物４５－２、化合物５３－１、化合物５４－１、化合物７７－１の投与３時間後におけるマウス末梢血リンパ球数減少作用のＥＤ５０値は、０．１７、０．４７、０．０９、０．６７ｍｇ／ｋｇ体重であった。 Experimental Example 1: Evaluation of mouse peripheral blood lymphocyte count reducing action The compound of the present invention was dissolved or suspended in 20% cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and dosed from 0.001 to 10 mg / kg body weight The mice were intraperitoneally administered to male BALB / c mice (Charles River Japan) ˜10 weeks old. 3 or 24 hours after administration of the compound of the present invention, peripheral blood was collected from the posterior vena cava of mice under ether anesthesia using a tuberculin syringe (Terumo) treated with heparin sodium (Novo Nordisk). About 0.3 ml was collected. After 0.1 ml of blood was lysed using an automatic hemolyzer (TQ-Prep, manufactured by Beckman Coulter), a known number of standard particles were used using a flow cytometer (CYTOMICS FC 500, manufactured by Beckman Coulter). The number of lymphocytes was measured by a gating method using Flow-Count ™ Fluorospheres (manufactured by Beckman Coulter, Inc.) as an internal standard and using forward and side scatter of laser light as an index. When the number of lymphocytes in the vehicle group was taken as 100%, the dose that reduced it by 50% was calculated and taken as the ED 50 value (mg / kg body weight). The ED 50 values of the mouse peripheral blood lymphocyte count reducing activity 24 hours after administration of Compound 1-4, Compound 11-1, and Compound 20-2 are 0.07, 0.08, and 0.15 mg / kg body weight, respectively. there were. The ED 50 values of the mouse peripheral blood lymphocyte count reducing activity 3 hours after administration of Compound 45-2, Compound 53-1, Compound 54-1, and Compound 77-1 were 0.17, 0.47, 0.09. 0.67 mg / kg body weight.
　実験例２：麻酔下ラットの心拍数に対する作用
　雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ（ＩＧＳ）ラットにネンブタール（大日本住友製薬社製）を腹腔内投与することで麻酔した後、背位に固定した。四肢に電極を装着し、心電図アンプ（ＡＣ－６０１Ｇ、日本光電社製）を用いて標準四肢第ＩＩ誘導法にて心電図を計測した。心電図波をトリガーとして瞬時心拍計ユニット（ＡＴ－６０１Ｇ、日本光電社製）より心拍数を計数した。本発明化合物は、２０％シクロデキストリン（日本食品化工社製）に溶解させて、０．００１～１０ｍｇ／ｋｇ体重の用量で、３０秒間かけて静脈内投与した。心拍数は、投与前、投与後１、２、３、４、５、１０及び１５分に測定した。化合物１１－１のリン酸体である化合物２９－２、及び化合物４５－２は、投与量０．０３ｍｇ／ｋｇ体重まで投与前値と比較してラットの心拍数を２０％以上低下させなかった。化合物７７－１は、投与量０．３ｍｇ／ｋｇ体重まで投与前値と比較してラットの心拍数を２０％以上低下させなかった。
　上記の実験例１の結果より、本発明化合物は優れた末梢血リンパ球減少作用を有しているので、優れた免疫抑制作用、拒絶反応抑制作用、アレルギー抑制作用を示すことが期待でき、自己免疫疾患の治療又は予防；器官又は組織の移植に対する抵抗又は急性拒絶反応若しくは慢性拒絶反応の予防又は抑制；骨髄移植による移植片対宿主（ＧｖＨ）病の治療又は予防；アレルギー性疾患治療又は予防に有効であると考えられる。さらに、上記の実験例２の結果により本発明化合物は徐脈等の副作用が軽減された化合物であると考えられる。 Experimental Example 2: Effect on Heart Rate of Anesthetized Rats Anesthetized by intraperitoneal administration of Nembutal (Dainippon Sumitomo Pharma Co., Ltd.) to male Sprague-Dawley (IGS) rats, and then fixed to the dorsal position. Electrodes were attached to the limbs, and an electrocardiogram was measured by a standard limb lead II method using an electrocardiogram amplifier (AC-601G, manufactured by Nihon Kohden). Heart rate was counted from an instantaneous heart rate monitor unit (AT-601G, manufactured by Nihon Kohden Co., Ltd.) using an electrocardiogram as a trigger. The compound of the present invention was dissolved in 20% cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and administered intravenously over 30 seconds at a dose of 0.001 to 10 mg / kg body weight. Heart rate was measured before administration, 1, 2, 3, 4, 5, 10 and 15 minutes after administration. Compound 29-2 and Compound 45-2, which are phosphates of Compound 11-1, did not reduce the heart rate of rats by 20% or more compared to the pre-dose value up to a dose of 0.03 mg / kg body weight. . Compound 77-1 did not reduce the heart rate of rats by more than 20% compared to the pre-dose value up to a dose of 0.3 mg / kg body weight.
From the results of Experimental Example 1 above, the compound of the present invention has an excellent peripheral blood lymphocyte depletion action, and therefore can be expected to show an excellent immunosuppressive action, rejection inhibitory action, and allergy inhibitory action. Treatment or prevention of immune diseases; resistance to organ or tissue transplantation or prevention or suppression of acute rejection or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; for treatment or prevention of allergic diseases It is considered effective. Furthermore, it is considered that the compound of the present invention is a compound in which side effects such as bradycardia are reduced based on the results of Experimental Example 2 described above.
　本発明化合物は、優れた末梢血リンパ球減少作用を有し、自己免疫疾患、組織の移植に対する抵抗又は急性拒絶反応若しくは慢性拒絶反応の予防又は抑制、骨髄移植による移植片対宿主（ＧｖＨ）病、又はアレルギー性疾患等の予防又は治療に有効な医薬となり得る。 The compound of the present invention has an excellent peripheral blood lymphocyte reduction action, autoimmune disease, resistance to tissue transplantation or prevention or suppression of acute rejection or chronic rejection, graft-versus-host (GvH) disease by bone marrow transplantation Or, it can be an effective drug for preventing or treating allergic diseases.
　本願は、日本で出願された特願２００８－０８３０１７を基礎としており、その内容は本明細書にすべて包含されるものである。
  This application is based on patent application No. 2008-083017 filed in Japan, the contents of which are incorporated in full herein.

Claims (52)

  1. 　下記一般式（ＩＩ－１）又は（ＩＩ－２）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    ＲＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
    ＲＩＩ－２は水酸基、炭素数１～４のアルコキシ又はハロゲン原子のいずれかで置換されていても良い炭素数１～４のアルキル、
    ＲＩＩ－３は水素原子又は炭素数１～４のアルキル、
    ＡＩＩ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
    （ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
    ｂ、ハロゲン原子。
    ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
    ｄ、当該鎖端の二重結合、三重結合。）、
    ＹＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
    ＡＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキル、
    ＡＩＩ－２は水素原子、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２、ＣＯＯＨ、ＳＯ３Ｈ、１Ｈ－テトラゾール－５－イル、ＯＨ又は炭素数１～４のアルコキシ、
    ＸＩＩは酸素原子又は硫黄原子、
    ＹＩＩ－１はＣＨ２ＣＨ２又はＣＨ＝ＣＨ、及び
    ＺＩＩは単結合又は１～２個のフッ素原子で置換されていてもよい炭素数１～４のアルキレンを示す。］
    で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     The following general formula (II-1) or (II-2)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    R II-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
    R II-2 is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, or an alkyl having 1 to 4 carbon atoms which may be substituted with any of halogen atoms,
    R II-3 is a hydrogen atom or alkyl having 1 to 4 carbon atoms,
    A II-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A II-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
    b, a halogen atom.
    c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
    Y II-2 is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
    A II-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
    A II-2 is a hydrogen atom, P (═O) (OH) 2 , O—P (═O) (OH) 2 , COOH, SO 3 H, 1H-tetrazol-5-yl, OH, or 1 to 4 alkoxy,
    XII is an oxygen atom or a sulfur atom,
    Y II-1 represents CH 2 CH 2 or CH═CH, and Z II represents a single bond or alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms. ]
    Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  2. 　下記一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000002
    ［式中、
    ＲＩは水素原子又はＰ（＝Ｏ）（ＯＨ）２、
    ＸＩは酸素原子又は硫黄原子、
    ＹＩはＣＨ２ＣＨ２又はＣＨ＝ＣＨ、
    ＲＩ-１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
    ＲＩ-２は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
    ＲＩ-３及びＲＩ-４は同一又は異なっていても良く、それぞれ水素原子又は炭素数１～４のアルキル、及び
    ＡＩは炭素数５～９の直鎖のアルキルを示し、ＡＩは次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有している。
    ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換されている場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
    ｂ、ハロゲン原子。
    ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
    ｄ、当該鎖端の二重結合、三重結合。を示す。］
    で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     The following general formula (I)
    Figure JPOXMLDOC01-appb-C000002
    [Where:
    R I is a hydrogen atom or P (═O) (OH) 2 ,
    X I is an oxygen atom or a sulfur atom,
    Y I is CH 2 CH 2 or CH═CH,
    R I-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
    R I-2 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
    R I-3 and R I-4 may be the same or different, and each represents a hydrogen atom or alkyl having 1 to 4 carbon atoms, and A I represents a straight alkyl having 5 to 9 carbon atoms, and A I represents It has 1 to 6 functional groups selected from any of the following four groups a to d.
    a, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms.
    b, a halogen atom.
    c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. Indicates. ]
    Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  3. 　下記一般式（ＩＩＩ－１）又は（ＩＩＩ－２）
    Figure JPOXMLDOC01-appb-C000003
    ［式中、
    ＲＩＩＩ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
    ＲＩＩＩ－２は水素原子又はＰ（＝Ｏ）（ＯＨ）２、
    ＡＩＩＩ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＩＩ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
    （ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
    ｂ、ハロゲン原子。
    ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
    ｄ、当該鎖端の二重結合、三重結合。）、
    ＹＩＩＩ－２は炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
    ＡＩＩＩ－３は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキル、
    ＡＩＩＩ－２は水素原子又は炭素数１～３のアルキル、
    ＢＩＩＩは水素原子又は水酸基で置換されていても良いか若しくはハロゲン原子で置換されていても良い炭素数１～４のアルキルを示し、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ－２、ＢＩＩＩ及びアミノ基の結合している炭素原子が４～７員環のシクロアルカン、若しくは環の構成原子数が４～７の窒素原子を一つ含んだヘテロシクロアルカンを形成しても良く、
    ＸＩＩＩ－１は酸素原子又は硫黄原子、
    ＸＩＩＩ－２はメチン又は窒素原子、及び
    ＹＩＩＩ－１は炭素数１～２のアルキレン又はＣ＝Ｏを示す。］
    で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     The following general formula (III-1) or (III-2)
    Figure JPOXMLDOC01-appb-C000003
    [Where:
    R III-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
    R III-2 is a hydrogen atom or P (═O) (OH) 2 ,
    A III-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A III-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
    b, a halogen atom.
    c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
    Y III-2 represents alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
    A III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom,
    A III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms,
    B III represents an alkyl having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group, or may be substituted with a halogen atom, and B III is bonded to A III-2 and Y III-1 , X III-2 , A III-2 , B III and the amino group to which the carbon atom is bonded include a 4- to 7-membered cycloalkane or a nitrogen atom having 4 to 7 member atoms Heterocycloalkanes may be formed,
    X III-1 represents an oxygen atom or a sulfur atom,
    X III-2 represents a methine or nitrogen atom, and Y III-1 represents an alkylene having 1 to 2 carbon atoms or C═O. ]
    Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  4. 　下記一般式（ＩＶ－１）又は（ＩＶ－２）
    Figure JPOXMLDOC01-appb-C000004
    ［式中、
    ＲＩＶ－１は、ハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
    ＲＩＶ－２は水素原子、炭素数１～４のアルキル、炭素数１～２０のアシル、炭素数２～２１のアルコキシカルボニル、又は生体内で脱離する置換基、
    ＲＩＶ－３は水素原子、Ｐ（＝Ｏ）（ＯＨ）２又はＰ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）（ＲＩＶ－５及びＲＩＶ－６はリン酸基の保護基若しくは生体内で脱離する置換基を示す。）、
    ＲＩＶ－４は水酸基で置換されていても良いか又はハロゲン原子で置換されていても良い炭素数１～４のアルキル、
    ＡＩＶ－１は炭素数５～９の直鎖のアルキルを示し、ＡＩＶ－１は次にあげるａ～ｄの４つのグループから任意の組み合わせで選ばれる１～６個の官能基を有していても良く
    （ａ、炭素数１～６のアルキル。同じ炭素原子に２つのアルキル基が置換している場合、それら２つのアルキル基とそれらが結合している炭素原子は炭素数３～６のシクロアルキルを形成することもできる。
    ｂ、ハロゲン原子。
    ｃ、当該鎖中の、二重結合、三重結合、酸素原子、硫黄原子、炭素数３～６のシクロアルキル。及び
    ｄ、当該鎖端の二重結合、三重結合。）、
    ＹＩＶは炭素数１～５のアルキレン、炭素数２～５のアルケニレン又は炭素数２～５のアルキニレン、
    ＡＩＶ－２は置換されていても良い炭素数６～１０のアリール、置換されていても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、置換されていても良いベンゼンと縮合していても良い置換されていても良い炭素数３～７のシクロアルキル又は置換されていても良い１～２個の窒素原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～７のヘテロシクロアルキルを示し、及び
    ＸＩＶは酸素原子又は硫黄原子を示す。］
    で表される化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     The following general formula (IV-1) or (IV-2)
    Figure JPOXMLDOC01-appb-C000004
    [Where:
    R IV-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
    R IV-2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, acyl having 1 to 20 carbon atoms, alkoxycarbonyl having 2 to 21 carbon atoms, or a substituent capable of leaving in vivo.
    R IV-3 is a hydrogen atom, P (═O) (OH) 2 or P (═O) (OR IV-5 ) (OR IV-6 ) (R IV-5 and R IV-6 are phosphoric acid groups A protecting group or a substituent that is eliminated in vivo).
    R IV-4 is an alkyl having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or may be substituted with a halogen atom,
    A IV-1 represents straight-chain alkyl having 5 to 9 carbon atoms, and A IV-1 has 1 to 6 functional groups selected from any of the following four groups a to d: (A, alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which the two alkyl groups are bonded have 3 to 6 carbon atoms. Can also be formed.
    b, a halogen atom.
    c, a double bond, triple bond, oxygen atom, sulfur atom or cycloalkyl having 3 to 6 carbon atoms in the chain. And d, a double bond and a triple bond at the chain end. ),
    Y IV is alkylene having 1 to 5 carbon atoms, alkenylene having 2 to 5 carbon atoms, or alkynylene having 2 to 5 carbon atoms,
    A IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl of 5 to 10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, or an optionally substituted cycloalkyl of 3 to 7 carbon atoms or an optionally substituted nitrogen atom of 1 to 2 Alternatively, it represents a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom, and XIV represents an oxygen atom or a sulfur atom. ]
    Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  5. 　下記一般式（Ｖ）
    Figure JPOXMLDOC01-appb-C000005
    ［式中、
    ＲＶ－１はハロゲン原子で置換された炭素数１～４のアルキル又はシアノ、
    ＸＶは単結合、
    酸素原子、
    硫黄原子、
    －ＳＯ－、
    －ＳＯ２－、
    カルボニル、
    －ＮＲＶ－２－（ここで、ＲＶ－２は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、又は
    下記一般式
    Figure JPOXMLDOC01-appb-C000006
    （ここで、ＲＶ－３は置換基を有していても良い炭素数１～２０のアルキル、置換基を有していても良い炭素数２～２０のアルケニル、置換基を有していても良い炭素数２～２０のアルキニル又は置換基を有していても良い炭素数１～２０のアルコキシを示す。）で表される基を示し、
    ＡＶは水素原子、
    置換基を有していても良い炭素数１～２０のアルキル｛当該鎖中に二重結合、三重結合、酸素原子、硫黄原子、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－４－（ここで、ＲＶ－４は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、カルボニル、置換基を有していても良い炭素数６～１０のアリーレン、置換基を有していても良い炭素数３～７のシクロアルキレン、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを有していてもよく、また、当該鎖端に二重結合、三重結合、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを有していてもよい｝、
    置換基を有していても良い炭素数６～１０のアリール、
    置換基を有していても良い炭素数３～７のシクロアルキル、
    置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール、又は
    置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示し、
    ＶＶは単結合又は置換基を有していても良い炭素数１～６のアルキレンを示し、
    ＹＶは単結合、酸素原子、硫黄原子、－ＣＯ－、－ＳＯ－、－ＳＯ２－、－ＮＲＶ－５－、－ＮＲＶ－５ＣＯ－、－ＣＯＮＲＶ－５－、－ＮＲＶ－５ＳＯ２－又は－ＳＯ２ＮＲＶ－５－を示し（ここで、ＲＶ－５は水素原子、置換基を有していても良い炭素数１～６のアルキル、置換基を有していても良い炭素数１～７のアシル又は炭素数２～７のアルコキシカルボニルを示す。）、
    さらにＶＶが置換基を有していても良い炭素数１～６のアルキレンを示す場合には、ＹＶは二重結合又は三重結合であってもよく、
    ｎＶは０～３、但しＹＶが二重結合又は三重結合の場合にはｎＶは１～３を示し、
    ＺＶは置換基を有していても良い炭素数１～６のアルキレン、
    置換基を有していても良い炭素数６～１０のアリーレン、
    置換基を有していても良い炭素数３～７のシクロアルキレン、又は
    置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリーレン、又は
    置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレン
    （但し、ＹＶが二重結合の場合には、
    置換基を有していても良い炭素数１～６のアルキレン、
    置換基を有していても良い炭素数３～７のシクロアルキレン又は
    置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンを示し、
    ＹＶが三重結合の場合には、
    置換基を有していても良い炭素数１～６のアルキレンを示し、
    さらに、ｎＶが２又は３の場合、ＺＶは同一であっても又は異なっていても良い。）
    を示し、及び
    ＢＶは水素原子、
    ＣＯＯＲＶ－６（ここで、ＲＶ－６は水素原子又は炭素数１～４のアルキル若しくは生体内で脱離する置換基を示す。）、
    ＳＯ３ＲＶ－６（ここで、ＲＶ－６は上記と同義を示す。）、
    Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）、
    Ｏ－Ｐ（＝Ｏ）（ＯＲＶ－７）（ＯＲＶ－８）（ここで、ＲＶ－７及びＲＶ－８は水素原子、リン酸基の保護基、又は生体内で脱離する置換基を示す。）、
    シアノ、
    －ＣＯ－ＮＨ－ＳＯ２－ＲＶ－９（ここで、ＲＶ－９は置換基を有しても良い炭素数１～６のアルキル、置換基を有していても良い炭素数６～１０のアリール、置換基を有していても良い炭素数３～７のシクロアルキル、置換基を有していても良い１～２個の窒素原子、酸素原子又は硫黄原子を環の構成原子として含む環の構成原子数が５～１０のヘテロアリール又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキルを示す。）、
    ＯＨ、又は
    下記式
    Figure JPOXMLDOC01-appb-C000007
    で表される基を示す。］
    で表される化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。     The following general formula (V)
    Figure JPOXMLDOC01-appb-C000005
    [Where:
    R V-1 is alkyl having 1 to 4 carbon atoms or cyano substituted with a halogen atom,
    XV is a single bond,
    Oxygen atom,
    Sulfur atom,
    -SO-,
    -SO 2- ,
    Carbonyl,
    —NR V-2 — (wherein R V-2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or an alkyl having 1 to 7 carbon atoms which may have a substituent. Acyl or C2-C7 alkoxycarbonyl), or the following general formula
    Figure JPOXMLDOC01-appb-C000006
    (Here, R V-3 has an optionally substituted alkyl having 1 to 20 carbon atoms, an optionally substituted alkenyl having 2 to 20 carbon atoms, and a substituent. Or a alkynyl group having 2 to 20 carbon atoms or an alkoxy group having 1 to 20 carbon atoms which may have a substituent.
    A V is a hydrogen atom,
    Optionally substituted alkyl having 1 to 20 carbon atoms {double bond, triple bond, oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR V-4 — ( Here, R V-4 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, an acyl having 1 to 7 carbon atoms which may have a substituent, or 2 to 7 carbon atoms. A carbonyl, an arylene having 6 to 10 carbon atoms which may have a substituent, a cycloalkylene having 3 to 7 carbon atoms which may have a substituent, and a substituent. A heteroarylene having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 ring constituent atoms, or optionally having 1 to 2 substituents A ring containing one nitrogen atom, oxygen atom or sulfur atom as a constituent atom of the ring It may have a heterocycloalkylene having 3 to 7 member atoms, and may have a double bond, a triple bond or a substituent at the chain end. A ring-constituting atom containing an optionally substituted cycloalkyl having 3 to 7 carbon atoms, an optionally substituted nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. Heteroaryl having a number of 5 to 10 or a hetero atom having 3 to 7 ring atoms containing 1 to 2 optionally substituted nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms May have cycloalkyl},
    Aryl having 6 to 10 carbon atoms which may have a substituent,
    A cycloalkyl having 3 to 7 carbon atoms which may have a substituent,
    A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as a ring constituting atom, or a substituent Or a heterocycloalkyl having 3 to 7 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms,
    V V represents a single bond or an alkylene having 1 to 6 carbon atoms which may have a substituent,
    Y V is a single bond, oxygen atom, sulfur atom, —CO—, —SO—, —SO 2 —, —NR V-5 —, —NR V-5 CO—, —CONR V-5 —, —NR V -5 SO 2 -or -SO 2 NR V-5- (wherein R V-5 has a hydrogen atom, an alkyl having 1 to 6 carbon atoms which may have a substituent, or a substituent. An optionally substituted acyl having 1 to 7 carbon atoms or alkoxycarbonyl having 2 to 7 carbon atoms).
    In addition, when V V represents an optionally substituted alkylene having 1 to 6 carbon atoms, Y V may be a double bond or a triple bond,
    n V is 0-3, provided that n V when Y V is a double bond or triple bond represents a 1-3,
    Z V is an alkylene having 1 to 6 carbon atoms which may have a substituent,
    Arylene having 6 to 10 carbon atoms which may have a substituent,
    A cycloalkylene having 3 to 7 carbon atoms which may have a substituent, or a ring which contains 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent as ring constituent atoms. Heteroarylene having 5 to 10 member atoms, or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 to 7 ring atoms heterocycloalkylene (however, if Y V is a double bond,
    Alkylene having 1 to 6 carbons which may have a substituent,
    Ring structure containing optionally substituted cycloalkylene having 3 to 7 carbon atoms or optionally having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent. Represents heterocycloalkylene having 3 to 7 atoms,
    If Y V is a triple bond,
    An alkylene having 1 to 6 carbon atoms which may have a substituent;
    Further, n V if 2 or 3, Z V may be the be identical or different. )
    And B V is a hydrogen atom,
    COOR V-6 (wherein R V-6 represents a hydrogen atom, an alkyl having 1 to 4 carbon atoms, or a substituent capable of leaving in vivo),
    SO 3 R V-6 (where R V-6 has the same meaning as above),
    P (= O) (OR V-7 ) (OR V-8 ),
    OP (= O) (OR V-7 ) (OR V-8 ) (where R V-7 and R V-8 are hydrogen atoms, phosphate protecting groups, or are eliminated in vivo. Represents a substituent).
    Cyano,
    —CO—NH—SO 2 —R V-9 (where R V-9 is an alkyl having 1 to 6 carbon atoms which may have a substituent, and 6 to 6 carbon atoms which may have a substituent) 10 aryls, optionally substituted cycloalkyl having 3 to 7 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms A ring containing 5 to 10 heteroaryl atoms or 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may have a substituent, and 3 ring atoms Represents a heterocycloalkyl of ˜7),
    OH or the following formula
    Figure JPOXMLDOC01-appb-C000007
    The group represented by these is shown. ]
    Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  6. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-３が水素原子である請求項１に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to claim 1, wherein R II-3 is a hydrogen atom in general formula (II-1) or (II-2), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate.
  7. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＸＩＩが酸素原子である請求項１又は６いずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (II-1) or (II-2), XII is an oxygen atom, or the compound according to any one of claims 1 and 6, or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof. Hydrates or solvates.
  8. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＹＩＩ－１がＣＨ２ＣＨ２である請求項１又は６～７のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (II-1) or (II-2), Y II-1 is CH 2 CH 2 or the compound according to any one of claims 1 or 6 to 7, or a pharmaceutically acceptable salt thereof. Acid addition salts, or hydrates or solvates thereof.
  9. 　一般式（ＩＩ－１）中、
    ＡＩＩ－１が炭素数５～９の直鎖のアルキルであるか、
    一般式（ＩＩ－２）中、
    ＡＩＩ－３が置換されていても良い炭素数６～１０のアリール又は
    置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリール
    である請求項１又は６～８のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (II-1),
    A II-1 is straight-chain alkyl having 5 to 9 carbon atoms,
    In general formula (II-2),
    A II-3 is an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted 1 to 2 sulfur atom or oxygen atom as a ring constituting atom, 9. The compound according to claim 1, which is 9 heteroaryls, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  10. 　一般式（ＩＩ－２）中、
    ＡＩＩ－３は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；
    ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
    ハロゲン原子；
    炭素数６～１０のアリールから選択される置換基である
    請求項１又は６～９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (II-2),
    When A II-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different, and each may be substituted with a halogen atom. Good alkyl of 1 to 4 carbons;
    Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
    A halogen atom;
    The compound according to any one of claims 1 or 6 to 9, which is a substituent selected from aryl having 6 to 10 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate.
  11. 　一般式（ＩＩ－２）中、ＡＩＩ－３が下記一般式
    Figure JPOXMLDOC01-appb-C000008
    （式中、
    ＲＩＩ－４及びＲＩＩ－５は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、
    ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ、又は
    ハロゲン原子を示す。）
    で表される基である請求項１又は６～１０のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (II-2), A II-3 represents the following general formula
    Figure JPOXMLDOC01-appb-C000008
    (Where
    R II-4 and R II-5 may be the same or different and each is a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom,
    An alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a halogen atom is shown. )
    11. The compound according to claim 1 or any one of claims 6 to 10, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  12. 　一般式（ＩＩ－２）中、ＹＩＩ－２がトリメチレンである請求項１又は６～１１のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (II-2), Y II-2 is trimethylene, the compound according to any one of claims 1 or 6 to 11, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof. Or solvate.
  13. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-１がトリフルオロメチルである請求項１又は６～１２のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 1 and 6 to 12, or a pharmaceutically acceptable acid thereof, wherein R II-1 is trifluoromethyl in the general formula (II-1) or (II-2) Addition salts, or hydrates or solvates thereof.
  14. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＲＩＩ-２がヒドロキシメチルである請求項１又は６～１３のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 14. The compound according to claim 1, wherein R II-2 is hydroxymethyl in the general formula (II-1) or (II-2), or a pharmaceutically acceptable acid addition thereof. Salts, or hydrates or solvates thereof.
  15. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＡＩＩ－２が水素原子、Ｐ（＝Ｏ）（ＯＨ）２、Ｏ－Ｐ（＝Ｏ）（ＯＨ）２又はＣＯＯＨである請求項１又は６～１４のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (II-1) or (II-2), A II-2 is a hydrogen atom, P (═O) (OH) 2 , O—P (═O) (OH) 2 or COOH. 15. The compound according to 1 or any one of 6 to 14, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  16. 　一般式（ＩＩ－１）又は（ＩＩ－２）中、ＺＩＩが単結合又は炭素数１～４のアルキルである請求項１又は６～１５のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (II-1) or (II-2), Z II is a single bond or an alkyl having 1 to 4 carbon atoms, or a compound thereof, or a pharmaceutical thereof A top acceptable acid addition salt, or a hydrate or solvate thereof.
  17. 　一般式（Ｉ）中、ＲＩ-３及びＲＩ-４がともに水素原子である請求項２に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to claim 2, wherein R I-3 and R I-4 are both hydrogen atoms in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese products.
  18. 　一般式（Ｉ）中、ＸＩが酸素原子である請求項２又は１７のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 2 and 17, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof, wherein in formula (I), XI is an oxygen atom object.
  19. 　一般式（Ｉ）中、ＹＩがＣＨ２ＣＨ２である請求項２又は１７～１８のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (I), Y I is CH 2 CH 2 or the compound according to any one of claims 2 or 17 to 18, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate.
  20. 　一般式（Ｉ）中、
    ＡＩは炭素数５～９の直鎖のアルキルを示し、以下ａ～ｄのいずれか１つの官能基
    （ａ、炭素数１～６のアルキル。
    ｂ、フッ素原子。
    ｃ、当該鎖中の、二重結合、三重結合。又は
    ｄ、当該鎖端の二重結合、三重結合。）
    を有する請求項２又は１７～１９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (I),
    A I represents straight-chain alkyl having 5 to 9 carbon atoms, and any one of functional groups a to d below (a, alkyl having 1 to 6 carbon atoms.
    b, a fluorine atom.
    c, a double bond or a triple bond in the chain. Or d, a double bond or a triple bond at the chain end. )
    The compound according to claim 2 or any one of claims 17 to 19, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  21. 　一般式（Ｉ）中、ＲＩ-１がトリフルオロメチルである請求項２又は１７～２０のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (I), R I-1 is trifluoromethyl, or a compound according to any one of claims 2 or 17 to 20, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof. Or solvate.
  22. 　一般式（Ｉ）中、ＲＩ-２がヒドロキシメチルである請求項２又は１７～２１のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 2 and 17 to 21, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein in formula (I), R I-2 is hydroxymethyl. Or a solvate.
  23. 　一般式（Ｉ）中、ＲＩが水素原子である請求項２又は１７～２２のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (I), R I is a hydrogen atom, the compound according to any one of claims 2 or 17 to 22, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or Solvate.
  24. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ－１が酸素原子である請求項３に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (III-1) or (III-2), XIII-1 is an oxygen atom, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or a solvate.
  25. 　一般式（ＩＩＩ－１）中、ＡＩＩＩ－１が炭素数５～９の直鎖のアルキルであるか、一般式（ＩＩＩ－２）中、ＡＩＩＩ－３が置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールである請求項３又は２４のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (III-1), A III-1 is straight-chain alkyl having 5 to 9 carbon atoms, or in general formula (III-2), A III-3 may be substituted. The aryl of 6 to 10 or heteroaryl having 5 to 9 ring atoms containing 1 to 2 optionally substituted sulfur atoms or oxygen atoms as ring atoms. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  26. 　一般式（ＩＩＩ－２）中、ＡＩＩＩ－３は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；ハロゲン原子；炭素数６～１０のアリールから選択される置換基である請求項３又は２４～２５のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (III-2), when A III-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different. Each selected from alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; halogen atom; aryl having 6 to 10 carbon atoms The compound according to any one of claims 3 and 24 to 25, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof, which is a group.
  27. 　一般式（ＩＩＩ－２）中、ＡＩＩＩ－３が下記一般式
    Figure JPOXMLDOC01-appb-C000009
    （式中、ＲＩＩＩ－３及びＲＩＩＩ－４は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基である請求項３又は２４～２６のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (III-2), A III-3 represents the following general formula
    Figure JPOXMLDOC01-appb-C000009
    (In the formula, R III-3 and R III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof. 27. A compound represented by any one of claims 3 to 24 to 26, or a pharmaceutically acceptable acid addition salt thereof: Or a hydrate or solvate thereof.
  28. 　一般式（ＩＩＩ－２）中、ＹＩＩＩ－２がトリメチレンである請求項３又は２４～２７のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (III-2), Y III-2 is trimethylene, the compound according to any one of claims 3 or 24 to 27, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof. Or solvate.
  29. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＲＩＩＩ-１がトリフルオロメチルである請求項３又は２４～２８のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (III-1) or (III-2), R III-1 is trifluoromethyl, or the compound according to any one of claims 3 to 24 to 28, or a pharmaceutically acceptable acid thereof. Addition salts, or hydrates or solvates thereof.
  30. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２がメチンである場合、ＹＩＩＩ-１がメチレンで、ＡＩＩＩ-２及びＢＩＩＩがともに炭素数１～３のアルキルである請求項３又は２４～２９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (III-1) or (III-2), when X III-2 is methine, Y III-1 is methylene, and A III-2 and B III are both alkyl having 1 to 3 carbon atoms. A compound according to any one of claims 3 or 24 to 29, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  31. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２がメチンで、ＢＩＩＩがＡＩＩＩ－２と結合し、ＹＩＩＩ－１、ＸＩＩＩ－２、ＡＩＩＩ-２、ＢＩＩＩ及びアミノ基が結合している炭素原子がシクロペンチルを形成する請求項３又は２４～２９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (III-1) or (III-2), X III-2 is methine, B III is bonded to A III-2, and Y III-1 , X III-2 , A III-2 , B The compound according to any one of claims 3 to 24 to 29, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein the carbon atom to which III and the amino group are bonded forms cyclopentyl. Or a solvate.
  32. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＸＩＩＩ-２が窒素原子である場合、ＹＩＩＩ-１がＣ＝Ｏ、ＢＩＩＩが水素原子又はメチルである請求項３又は２４～２９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (III-1) or (III-2), when X III-2 is a nitrogen atom, Y III-1 is C═O and B III is a hydrogen atom or methyl. 30. The compound according to any one of 29, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  33. 　一般式（ＩＩＩ－１）又は（ＩＩＩ－２）中、ＲＩＩＩ－２が水素原子である請求項３又は２４～３２のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 3 and 24-32, or a pharmaceutically acceptable acid addition thereof, wherein R III-2 is a hydrogen atom in the general formula (III-1) or (III-2) Salts, or hydrates or solvates thereof.
  34. 　一般式（ＩＶ－１）又は（ＩＶ－２）中、ＸＩＶが酸素原子である請求項４に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to claim 4, wherein XIV is an oxygen atom in general formula (IV-1) or (IV-2), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese products.
  35. 　一般式（ＩＶ－１）中、ＡＩＶ－１が炭素数５～９の直鎖のアルキルであるか、
    一般式（ＩＶ－２）中、ＡＩＶ－２が置換されていても良い炭素数６～１０のアリール又は置換されていても良い１～２個の硫黄原子若しくは酸素原子を環の構成原子として含む環の構成原子数が５～９のヘテロアリールである請求項４又は３４のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In the general formula (IV-1), A IV-1 is straight-chain alkyl having 5 to 9 carbon atoms,
    In general formula (IV-2), A IV-2 may be substituted aryl having 6 to 10 carbon atoms or optionally substituted 1 or 2 sulfur atoms or oxygen atoms as ring constituent atoms. 35. The compound according to any one of claims 4 and 34, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof, wherein the ring contains a heteroaryl having 5 to 9 atoms. Japanese products.
  36. 　一般式（ＩＶ－２）中、ＡＩＶ－２は無置換であるか又は置換基を有する場合、置換基の数は１～３であり、それぞれの置換基は同一又は異なっていても良く、それぞれハロゲン原子で置換されていても良い炭素数１～４のアルキル；
    ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ；
    ハロゲン原子；
    炭素数６～１０のアリール
    から選択される置換基である請求項４又は３４～３５のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (IV-2), when A IV-2 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different. Alkyl having 1 to 4 carbon atoms each optionally substituted with a halogen atom;
    Alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom;
    A halogen atom;
    The compound according to any one of claims 4 and 34 to 35, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, which is a substituent selected from aryl having 6 to 10 carbon atoms, Or a solvate.
  37. 　一般式（ＩＶ－２）中、ＡＩＶ－２が下記一般式
    Figure JPOXMLDOC01-appb-C000010
    （式中、ＲＩＶ－７及びＲＩＶ－８は同一又は異なっていても良く、それぞれ水素原子、ハロゲン原子で置換されていても良い炭素数１～４のアルキル、ハロゲン原子で置換されていても良い炭素数１～４のアルコキシ又はハロゲン原子を示す。）で表される基である請求項４又は３４～３６のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。     In general formula (IV-2), A IV-2 represents the following general formula
    Figure JPOXMLDOC01-appb-C000010
    (In the formula, R IV-7 and R IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof. 37. A compound represented by any one of claims 4 to 34-36, or a pharmaceutically acceptable acid addition salt thereof: Or a hydrate or solvate thereof.
  38. 　一般式（ＩＶ－２）中、ＹＩＶがトリメチレンである、請求項４又は３４～３７のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (IV-2), Y IV is trimethylene, claim 4 or a compound according to any one of 34-37, or a pharmaceutically acceptable acid addition salt or a hydrate thereof, Or a solvate.
  39. 　一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－１がトリフルオロメチルである請求項４又は３４～３８のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 4 and 34 to 38, or a pharmaceutically acceptable acid thereof, wherein R IV-1 is trifluoromethyl in the general formula (IV-1) or (IV-2) Addition salts, or hydrates or solvates thereof.
  40. 　一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－２が生体内で脱離する置換基、ＲＩＶ－３が水素原子である請求項４又は３４～３９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (IV-1) or (IV-2), R IV-2 is a substituent capable of leaving in vivo, and R IV-3 is a hydrogen atom. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.
  41. 　一般式（ＩＶ－１）又は（ＩＶ－２）中、ＲＩＶ－２が水素原子、ＲＩＶ－３がＰ（＝Ｏ）（ＯＲＩＶ－５）（ＯＲＩＶ－６）（ＲＩＶ－５及びＲＩＶ－６は生体内で脱離する置換基を示す）である請求項４又は３４～３９のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (IV-1) or (IV-2), R IV-2 is a hydrogen atom, R IV-3 is P (═O) (OR IV-5 ) (OR IV-6 ) (R IV-5 And R IV-6 represents a substituent capable of leaving in vivo), or the compound according to any one of claims 4 or 34 to 39, or a pharmaceutically acceptable acid addition salt thereof, or a Hydrates or solvates.
  42. 　一般式（Ｖ）中、ＢｖがＣＯＯＲｖ－６、Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）、Ｏ－Ｐ（＝Ｏ）（ＯＲｖ－７）（ＯＲｖ－８）又はＯＨである請求項５に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 In general formula (V), B v is COOR v-6 , P (= O) (OR v-7 ) (OR v-8 ), OP (= O) (OR v-7 ) (OR v− The compound according to claim 5, which is 8 ) or OH, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  43. 　一般式（Ｖ）中、Ｙｖが単結合、－ＮＲｖ－５－、－ＮＲｖ－５ＣＯ－又は－ＣＯＮＲｖ－５－である請求項５又は４２のいずれか１項に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 5 and 42, wherein, in the general formula (V), Y v is a single bond, -NR v-5- , -NR v -5 CO- or -CONR v-5- . Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  44. 　一般式（Ｖ）中、Ｚｖが置換基を有していても良い炭素数１～６のアルキレン、置換基を有していても良い炭素数６～１０のアリーレン又は置換基を有していても良い１～２個の窒素原子、酸素原子若しくは硫黄原子を環の構成原子として含む環の構成原子数が３～７のヘテロシクロアルキレンである請求項５又は４２～４３のいずれか１項に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 In the general formula (V), Z v are have an arylene or a substituent of the alkylene, carbon atoms which may have a substituent 6-10 good 1-6 carbon atoms which may have a substituent 44. The heterocycloalkylene having from 3 to 7 ring atoms, which may contain 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring-constituting atoms. Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  45. 　一般式（Ｖ）中、ｎｖが１である請求項５又は４２～４４のいずれか１項に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 5 and 42 to 44, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein n v is 1 in the general formula (V) .
  46. 　一般式（Ｖ）中、Ｒｖ－１がトリフルオロメチル又はシアノである請求項５又は４２～４５のいずれか１項に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 The compound according to any one of claims 5 or 42 to 45, or a pharmaceutically acceptable salt thereof, or a hydration thereof, wherein in general formula (V), R v-1 is trifluoromethyl or cyano. Or solvate.
  47. 　一般式（Ｖ）中、Ｘｖが単結合、酸素原子、硫黄原子、カルボニル又は－ＮＲｖ－２－である請求項５又は４２～４６のいずれか１項に記載の化合物、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。 47. In the general formula (V), X v is a single bond, an oxygen atom, a sulfur atom, carbonyl or —NR v-2 —, or a pharmaceutically acceptable compound thereof An acceptable salt, or a hydrate or solvate thereof.
  48. 　以下のａ～ｍのいずれかである請求項１～４７のいずれか１項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
    　ａ．２－アミノ－２－｛２－［４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｂ．２－アミノ－４－｛４－（８－フルオロオクチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｃ．２－アミノ－２－｛２－［４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｄ．２－アミノ－４－｛４－（７－オクテニルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｅ．２－アミノ－２－｛２－［４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル］エチル｝プロパン－１，３－ジオール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｆ．２－アミノ－４－｛４－（６－メチルヘプチルオキシ）－３－トリフルオロメチルフェニル｝－２－（ホスホリルオキシメチル）ブタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｇ．［３－アミノ－５－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）－３－（ヒドロキシメチル）ペンチル］ホスホン酸、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｈ．［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メタノール、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｉ．リン酸モノ｛［１－アミノ－３－（４－ヘプチルオキシ－３－トリフルオロメチルフェニル）シクロペンチル］メチル｝エステル、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物、
    　ｊ．２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エタノール、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
    　ｋ．リン酸モノ（２－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝エチル）エステル、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
    　ｌ．（３－｛［４－ヘプチルオキシ－３－（トリフルオロメチル）ベンジル］アミノ｝プロピル）ホスホン酸、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物、
    　ｍ．１－［４－（５－フェニルペンチルオキシ）－３－（トリフルオロメチル）ベンジル］アゼチジン－３－カルボン酸、若しくはその製薬上許容しうる塩、又はそれらの水和物、若しくは溶媒和物。     The compound according to any one of claims 1 to 47, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof, which is any of the following a to m:
    a. 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrates or solvates of
    b. 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Product, or solvate,
    c. 2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrates or solvates of
    d. 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Product, or solvate,
    e. 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or Hydrates or solvates of
    f. 2-Amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydration thereof Product, or solvate,
    g. [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or a solvate,
    h. [1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof,
    i. Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese,
    j. 2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethanol, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof,
    k. Phosphoric acid mono (2-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} ethyl) ester, or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof,
    l. (3-{[4-heptyloxy-3- (trifluoromethyl) benzyl] amino} propyl) phosphonic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof,
    m. 1- [4- (5-phenylpentyloxy) -3- (trifluoromethyl) benzyl] azetidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  49. 　請求項１～４８のいずれか１項に記載の化合物及び製薬上許容しうる担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 48 and a pharmaceutically acceptable carrier.
  50. 　自己免疫疾患の治療又は予防；器官又は組織の移植に対する抵抗又は急性拒絶反応若しくは慢性拒絶反応の予防又は抑制；骨髄移植による移植片対宿主（ＧｖＨ）病の治療又は予防；及び／又はアレルギー性疾患治療又は予防のために用いられる請求項４９に記載の医薬組成物。 Treatment or prevention of autoimmune diseases; resistance to organ or tissue transplantation or prevention or suppression of acute or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; and / or allergic diseases The pharmaceutical composition according to claim 49, which is used for treatment or prevention.
  51. 　自己免疫疾患が関節リウマチ、多発性硬化症、脳脊髄炎、全身性エリテマトーデス、ループス腎炎、ネフローゼ症候群、乾癬及び／又はＩ型糖尿病である請求項５０に記載の医薬組成物。 51. The pharmaceutical composition according to claim 50, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis and / or type I diabetes.
  52. 　アレルギー性疾患がアトピー性皮膚炎、アレルギー性鼻炎及び／又は喘息である請求項５０に記載の医薬組成物。 51. The pharmaceutical composition according to claim 50, wherein the allergic disease is atopic dermatitis, allergic rhinitis and / or asthma.
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US20120136063A1 (en) * 2010-11-29 2012-05-31 The Ohio State University Research Foundation Fty720-derived anticancer agents
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US9802954B2 (en) 2011-08-24 2017-10-31 Boehringer Ingelheim International Gmbh Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma
US10745411B2 (en) 2011-08-24 2020-08-18 Boehringer Ingelheim International Gmbh Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma
US20150045341A1 (en) * 2013-08-08 2015-02-12 Allergan, Inc. Disubstituted aryl azetidine derivatives as sphingosine-1 phosphate receptors modulators
CN105085299A (en) * 2015-08-20 2015-11-25 上海交通大学 Plasticizing agent diethyl phthalate hapten and preparation method thereof
US10752575B2 (en) 2016-07-29 2020-08-25 Mitsubishi Tanabe Pharma Corporation 4-alkoxy-3-(trifluoromethyl)benzyl alcohol production method

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