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WO2009119858A1 - Composé benzénique et son utilisation à des fins médicales - Google Patents

Composé benzénique et son utilisation à des fins médicales 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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Prior art keywords
carbon atoms
atom
atoms
iii
pharmaceutically acceptable
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English (en)
Japanese (ja)
Inventor
薫 田代
正壽 城内
真以子 濱田
邦夫 菅原
弘 坂下
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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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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    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
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    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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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

Cette invention concerne un nouveau composé benzénique qui a une excellente activité immunodépressive, un excellent effet inhibiteur de rejet et autres, et a des effets secondaires défavorables réduits comprenant la bradycardie. Un composé représenté par la formule générale (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2) ou (V) est spécifiquement décrit.
PCT/JP2009/056400 2008-03-27 2009-03-27 Composé benzénique et son utilisation à des fins médicales Ceased WO2009119858A1 (fr)

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JP2008083017A JP2011136905A (ja) 2008-03-27 2008-03-27 ベンゼン化合物及びその医薬用途
JP2008-083017 2008-03-27

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120136063A1 (en) * 2010-11-29 2012-05-31 The Ohio State University Research Foundation Fty720-derived anticancer agents
US20150045341A1 (en) * 2013-08-08 2015-02-12 Allergan, Inc. Disubstituted aryl azetidine derivatives as sphingosine-1 phosphate receptors modulators
CN105085299A (zh) * 2015-08-20 2015-11-25 上海交通大学 塑化剂邻苯二甲酸二乙酯半抗原及其制备方法
US9802954B2 (en) 2011-08-24 2017-10-31 Boehringer Ingelheim International Gmbh Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma
US10752575B2 (en) 2016-07-29 2020-08-25 Mitsubishi Tanabe Pharma Corporation 4-alkoxy-3-(trifluoromethyl)benzyl alcohol production method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007069712A1 (fr) * 2005-12-15 2007-06-21 Mitsubishi Tanabe Pharma Corporation Compose amine et utilisation de celui-ci pour des applications medicales
WO2008153159A1 (fr) * 2007-06-14 2008-12-18 Mitsubishi Tanabe Pharma Corporation Composé aminé et son utilisation pharmaceutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007069712A1 (fr) * 2005-12-15 2007-06-21 Mitsubishi Tanabe Pharma Corporation Compose amine et utilisation de celui-ci pour des applications medicales
WO2008153159A1 (fr) * 2007-06-14 2008-12-18 Mitsubishi Tanabe Pharma Corporation Composé aminé et son utilisation pharmaceutique

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120136063A1 (en) * 2010-11-29 2012-05-31 The Ohio State University Research Foundation Fty720-derived anticancer agents
US8309768B2 (en) * 2010-11-29 2012-11-13 The Ohio State University Research Foundation FTY720-derived anticancer agents
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 (zh) * 2015-08-20 2015-11-25 上海交通大学 塑化剂邻苯二甲酸二乙酯半抗原及其制备方法
US10752575B2 (en) 2016-07-29 2020-08-25 Mitsubishi Tanabe Pharma Corporation 4-alkoxy-3-(trifluoromethyl)benzyl alcohol production method

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