JP2011136905A - Benzene compound, and pharmaceutical application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel benzene compound exhibiting an excellent immunosuppressing action, an excellent rejection inhibiting action and the like, with a reduced risk of side effects such as bradycardia. <P>SOLUTION: The compound is represented by formula (I), (II-1), (II-2), (III-1), or (III-2). In the formula, each symbol has a specific definition. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a benzene compound and its use as a medicine.

  In recent years, calcineurin inhibitors such as cyclosporine and FK506 have been used to suppress rejection in patients who have undergone organ transplantation. However, certain calcineurin inhibitors, such as cyclosporine, can cause adverse side effects such as nephrotoxicity, hepatotoxicity, and neurotoxicity. For this reason, development of safer and more effective drugs is being promoted to suppress rejection in transplant patients.

  Patent Documents 1 to 3 describe 2-aminopropane useful as an inhibitor of (acute or chronic) rejection in organ or bone marrow transplantation, and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases. -1,3-diol compounds are disclosed.

  One of these compounds, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride (hereinafter sometimes referred to as FTY720) is rejected in renal transplantation. It is a compound currently in clinical development as a reaction inhibitor and a therapeutic agent for multiple sclerosis. FTY720 is phosphorylated by sphingosine kinase in vivo and may be referred to as FTY720 [hereinafter referred to as FTY720-P]. For example, 2-amino-2-phosphoryloxymethyl-4- (4-octylphenyl) butanol is included]. FTY720-P is one of four types of S1P receptors (S1P2) among five types of sphingosine-1-phosphate (hereinafter also referred to as S1P) receptors (hereinafter also referred to as S1P1 to 5, respectively). Other than the above) (Non-patent Document 1).

  Recently, it was reported that S1P1 in the S1P receptor is essential for the export of mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an S1P1 agonist, thereby down-regulating S1P1 on lymphocytes. As a result, the migration of mature lymphocytes from the thymus and secondary lymphoid tissues is inhibited, and it is suggested that the immunosuppressive effect is exhibited by isolating circulating mature lymphocytes in the blood in the secondary lymphoid tissues. (Non-Patent Document 2).

  On the other hand, in the conventional 2-aminopropane-1,3-diol compound, transient bradycardia is concerned as a side effect, and in order to solve this problem, 2-aminopropane-1,3-diol Many novel compounds obtained by chemical structural modification of diol compounds have been reported. Among them, as a compound in which a substituent is added to the benzene ring of FTY720, Patent Document 4 is an aminopropanol derivative as a S1P receptor modulator with a phosphate group, and Patent Documents 5 and 6 are both S1P acceptors. Although aminopropanol derivatives as body regulators are disclosed, trihaloalkyl groups such as trifluoromethyl groups are not disclosed as substituents on the benzene ring. Recently published Patent Document 7 discloses that the bradycardia of a compound in which the substituent on the benzene ring of FTY720 is a trihaloalkyl group or a cyano group is weak. However, those compounds disclosed therein contain only alkyloxy or alkylthio having 6 to 9 carbon atoms as substituents on the benzene ring bonded to the ortho position of the trihaloalkyl group or cyano group, A compound having a substituent in the alkyl group or a compound having an unsaturated bond in the alkyl group is not shown. In addition, there is no report as promising as an immunomodulator with reduced side effects such as bradycardia for compounds in which the polar part of the compound in which the substituent on the benzene ring of FTY720 is a trihaloalkyl group or a cyano group is modified.

International publication pamphlet WO94 / 08943 International pamphlet WO96 / 06068 International Publication Pamphlet WO 98/45429 International Publication Pamphlet WO02 / 076995 International publication pamphlet WO2004 / 096752 International publication pamphlet WO2004 / 110979 International Publication Pamphlet WO2007 / 069712 Science, 2002, No. 296, pages 346-349 Nature, 2004, 427, 355-360.

  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.

  As a result of further studies taking the above circumstances into consideration, the present inventors have found that a benzene compound having a specific structural formula as described below can achieve the intended purpose, and completed the present invention. .

  That is, the gist of the present invention is as follows.

  (1) The following general formula (I)

(Wherein 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 alkyl having 1 to 4 carbon atoms,
A _I represents straight-chain alkyl having 5 to 9 carbon atoms, and A _I has 1 to 6 functional groups selected from any of the following four groups a to d. a, alkyl having 1 to 6 carbon atoms; When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms. b, a halogen atom. c, a double bond, a triple bond, an oxygen atom, a sulfur atom, or a cycloalkyl having 3 to 6 carbon atoms in the chain. d, double bond and triple bond at the chain end. Indicates. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

  (2) The following general formula (II-1) or (II-2)

(Wherein 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 a linear alkyl having 5 to 9 carbon atoms, and A _II-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
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 aryl atom having 1 to 2 nitrogen atoms, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
A _II-2 is a hydrogen atom, P (═O) (OH) ₂ , O—P (═O) (OH) ₂ , COOH, SO ₃ H, 1H-tetrazol-5-yl, OH, or C 1 -C 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. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

  (3) The following general formula (III-1) or (III-2)

(Wherein 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 a linear alkyl having 5 to 9 carbon atoms, and A _III-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
Y _III-2 is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
A _III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
A _III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms,
B _III represents an alkyl having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group or may be substituted with a halogen atom, B _III is bonded to A _III-2, and Y _III-1 , X _III-2 , A _III-2 , B _III and a carbon atom to which the amino group is bonded contain a 4- to 7-membered cycloalkane or a nitrogen atom having 4 to 7 member atoms Heterocycloalkanes may be formed,
X _III-1 represents an oxygen atom or a sulfur atom,
XIII _-2 is a methine or nitrogen atom,
Y _III-1 represents alkylene having 1 to 2 carbon atoms or C═O. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

  (4) The following general formula (IV-1) or (IV-2)

(Wherein 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 1 to 20 carbon atoms, or a substituent that is eliminated in vivo.
R _IV-3 is a hydrogen atom, P (═O) (OH) ₂ , P (═O) (OR _IV-5 ) (OR _IV-6 ), (R _IV-5 and R _IV-6 are phosphate groups. Or a substituent that is eliminated in vivo)
R _IV-4 may be substituted with a hydroxyl group or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom,
A _IV-1 represents linear alkyl having 5 to 9 carbon atoms, and A _IV-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, 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 they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
Y _IV is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
A _IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted 1 to 2 nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
X _IV represents an oxygen atom or a sulfur atom. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(5) The compound according to (1), wherein R _I-3 and R _I-4 are both hydrogen atoms in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof Or a solvate.

(6) The compound according to any one of (1) and (5), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein X _I is an oxygen atom in the general formula (I) Or a solvate.

(7) In the general formula (I), _{Y I} is _CH 2 CH ₂ (1) or (5) a compound, or an acid addition salt acceptable pharmaceutically according to any one of the - (6), or Their hydrates or solvates.

(8) In the general formula (I), A _I represents a linear alkyl having 5 to 9 carbon atoms, and hereinafter, any one functional group of a to d (a, alkyl having 1 to 6 carbon atoms; b, (1) or any one of (5) to (7) having a fluorine atom, c, a double bond or a triple bond in the chain, d, a double bond or a triple bond at the chain end. Compound, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(9) The compound according to any one of (1) or (5) to (8), wherein R _I-1 is trifluoromethyl in general formula (I), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.

(10) The compound according to any one of (1) or (5) to (9), wherein R _I-2 is hydroxymethyl in general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or Their hydrates or solvates.

(11) The compound according to any one of (1) or (5) to (10), wherein R _I is a hydrogen atom in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof Hydrates or solvates.

(12) The compound according to (2), wherein R _II-3 is a hydrogen atom in general formula (II-1) or (II-2), or a pharmaceutically acceptable acid addition salt thereof, or water thereof Japanese solvate or solvate.

(13) In formula (II-1) or (II-2) _{in, X II} is an oxygen atom (2) or (12) a compound according to any, or acid addition a pharmaceutically acceptable salt thereof, Or a hydrate or a solvate thereof.

(14) In the general formula (II-1) or (II-2), Y _II-1 is CH ₂ CH ₂ (2) or the compound according to any one of (12) to (13), or a compound thereof Pharmaceutically acceptable acid addition salts, or hydrates or solvates thereof.

(15) In the general formula (II-1), even if A _II-1 is a linear alkyl having 5 to 9 carbon atoms or A _II-3 is substituted in the general formula (II-2) A good aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 9 ring atoms containing 1 to 2 sulfur atoms or oxygen atoms which may be substituted as ring atoms (2) or The compound according to any one of (12) to (14), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(16) In Formula (II-2), when A _II-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent is the same or different. Each selected from alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; halogen atom; aryl having 6 to 10 carbon atoms Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The compound according to any one of (2) and (12) to (15),

(17) In the general formula (II-2), A _II-3 is

(In the formula, R _II-4 and R _II-5 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof, represented by (2) or (12) to (16): Or a hydrate or a solvate thereof.

(18) In the general formula (II-2), Y _II-2 is trimethylene, the amine compound according to any one of (2) or (12) to (17), or a pharmaceutically acceptable acid addition thereof Salts, or hydrates or solvates thereof.

(19) The compound according to any one of (2) or (12) to (18), wherein R _II-1 is trifluoromethyl in general formula (II-1) or (II-2), or a pharmaceutical product thereof A top acceptable acid addition salt, or a hydrate or solvate thereof.

(20) The compound according to any one of (2) or (12) to (19), or a pharmaceutical product thereof, wherein R _II-2 is hydroxymethyl in the general formula (II-1) or (II-2) Acceptable acid addition salts, or hydrates or solvates thereof.

(21) In general formula (II-1) or (II-2), A _II-2 is a hydrogen atom, P (═O) (OH) ₂ , O—P (═O) (OH) ₂ or COOH. The compound according to any one of (2) or (12) to (20), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(22) In the general formula (II-1) or _{(II-2), Z II} is a single bond or alkyl of 1 to 4 carbon atoms according to any one of (2) or (12) - (21) Compound, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(23) The compound according to (3), wherein X _III-1 is an oxygen atom in general formula (III-1) or (III-2), or a pharmaceutically acceptable acid addition salt thereof, or water thereof Japanese solvate or solvate.

(24) In general formula (III-1), A _III-1 is a linear alkyl having 5 to 9 carbon atoms, or A _III-3 is substituted in general formula (III-2). A good aryl having 6 to 10 carbon atoms, or a heteroaryl having 5 to 9 ring atoms containing 1 to 2 sulfur atoms or oxygen atoms which may be substituted as ring atoms (3) or (23) The compound according to any one of the above, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(25) In General Formula (III-2), when A _III-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent is the same or different. Each selected from alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; halogen atom; aryl having 6 to 10 carbon atoms Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The compound according to any one of (3) and (23) to (24),

(26) In the general formula (III-2), A _III-3 is

(In the formula, R _III-3 and R _III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or an amine compound according to any one of (3) and (23) to (25), or a pharmaceutically acceptable acid addition salt thereof. Or a hydrate or solvate thereof.

(27) The compound according to any one of (3) or (23) to (26), wherein Y _III-2 is trimethylene in general formula (III-2), or a pharmaceutically acceptable acid addition salt thereof, Or a hydrate or a solvate thereof.

(28) The compound according to any one of (3) or (23) to (27), wherein R _III-1 is trifluoromethyl in general formula (III-1) or (III-2), or a pharmaceutical product thereof A top acceptable acid addition salt, or a hydrate or solvate thereof.

(29) In the general formula (III-1) or (III-2), when X _III-2 is methine, Y _III-1 is methylene, and A _III-2 and B _III are both 1 to 3 carbon atoms. The compound according to any one of (3) and (23) to (28), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(30) In formula (III-1) or _{(III-2), X III} -2 are _{methine, B III} combines with _{A III-2, Y III-} 1, X III-2, A III- ₂ , the carbon atom to which B _III and the amino group are bonded forms cyclopentyl (3) or the compound according to any one of (23) to (29), or a pharmaceutically acceptable acid addition salt thereof, or Their hydrates or solvates.

(31) In the general formula (III-1) or (III-2), when X _III-2 is a nitrogen atom, Y _III-1 is C═O and B _III is a hydrogen atom or methyl (3) Or the compound according to any one of (23) to (28), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(32) The compound according to any one of (3) or (23) to (31), or a pharmaceutical product thereof, wherein R _III-2 is a hydrogen atom in the general formula (III-1) or (III-2) Acceptable acid addition salts, or hydrates or solvates thereof.

(33) The compound according to (4), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein _XIV is an oxygen atom in general formula (IV-1) or (IV-2) Or a solvate.

(34) In general formula (IV-1), AIV _-1 is a linear alkyl having 5 to 9 carbon atoms, or in formula (IV-2), _AIV-2 is substituted. A good aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 9 ring atoms containing 1 to 2 sulfur atoms or oxygen atoms which may be substituted as ring atoms (4) or (33) The compound according to any one of the above, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(35) In general formula (IV-2), when A _IV-2 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent is the same or different. Each selected from alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; halogen atom; aryl having 6 to 10 carbon atoms Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof, which is a substituent of (4) or (33) to (34).

(36) In the general formula (IV-2), A _IV-2 is

(In the formula, R _IV-7 and R _IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof, represented by (4) or (33) to (35): Or a hydrate or a solvate thereof.

(37) The compound according to any one of (4) and (33) to (36), wherein Y _IV is trimethylene in general formula (IV-2), or a pharmaceutically acceptable acid addition salt thereof, or Their hydrates or solvates.

(38) The compound according to any one of (4) or (33) to (37), or a pharmaceutical product thereof, wherein RIV _-1 is trifluoromethyl in the general formula (IV-1) or (IV-2) A top acceptable acid addition salt, or a hydrate or solvate thereof.

(39) In the general formula (IV-1) or (IV-2), R _IV-2 is a substituent capable of leaving in vivo, and R _IV-3 is a hydrogen atom (4) or (33) to (33) 38), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof.

(40) In general formula (IV-1) or (IV-2), _RIV-2 is a hydrogen atom, _RIV-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), or a pharmaceutically acceptable acid addition thereof according to any one of (4) and (33) to (38) Salts, or hydrates or solvates thereof.

  (41) The compound according to any one of (1) to (40), wherein the compound of general formula (I) is any of the following a to f, or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof: Hydrates or solvates.

a. 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of b. 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate c. 2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of d. 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate e. 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of f. 2-amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate g. [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or solvate h. [1-Amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof i. Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese (42) A pharmaceutical composition comprising the compound of any one of (1) to (41) and a pharmaceutically acceptable carrier.

  (43) Treatment or prevention of autoimmune disease; resistance to organ or tissue transplantation or prevention or suppression of acute rejection or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; allergic disease The pharmaceutical composition according to (42), which is used for treatment or prevention.

  (44) The pharmaceutical composition according to (42), wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes.

  (45) The pharmaceutical composition according to (42), wherein the allergic disease is atopic dermatitis, allergic rhinitis, or asthma.

  According to the present invention, it is possible to provide a novel compound having an excellent peripheral blood lymphocyte-reducing action and reduced side effects such as bradycardia.

  Details of the present invention will be described below.

  The compounds of the present invention are represented by the following general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1), and (IV-2).

(In the formula, R _I is a hydrogen atom or P (═O) (OH) ₂ , X _I is an oxygen atom or sulfur atom, Y _I is CH ₂ CH ₂ or CH═CH, and R _I-1 is substituted with a halogen atom. C 1 -C 4 alkyl or cyano, R _I-2 may be substituted with a hydroxyl group or may be substituted with a halogen atom, C 1 -C 4 alkyl, R _I-3 and R _I-4 may be the same or different, each represent a hydrogen atom or an alkyl of 1 to 4 carbon atoms, a _I represents a straight-chain alkyl of 5-9 carbon atoms, a _I is listed below in a~d It has 1 to 6 functional groups selected from any combination of four groups: a, alkyl having 1 to 6 carbon atoms, and two alkyl groups substituted on the same carbon atom. Two alkyl groups and the carbon atom to which they are bonded are C3-C6 B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, double chain end Bond, triple bond.)

(In the formula, R _II-1 is alkyl or cyano having 1 to 4 carbon atoms substituted with a halogen atom, and R _II-2 is substituted with either a hydroxyl group, alkoxy having 1 to 4 carbon atoms or a halogen atom. The alkyl having 1 to 4 carbon atoms, R _II-3 represents a hydrogen atom or alkyl having 1 to 4 carbon atoms, A _II-1 represents a linear alkyl having 5 to 9 carbon atoms, and A _II-1 represents And may have 1 to 6 functional groups selected from any of the four groups a to d (a, an alkyl having 1 to 6 carbon atoms, and two alkyl groups having the same carbon atom) When substituted, the two alkyl groups and the carbon atom to which they are attached can also form a cycloalkyl having 3 to 6 carbon atoms, b, a halogen atom, c, double in the chain Bond, triple bond, oxygen atom, sulfur atom, carbon 3-6 cycloalkyl .d, the double bond of the chain ends, triple _{bond), Y II-2} is alkylene of 1 to 5 carbon atoms, an alkynylene having 2 to 5 alkenylene carbon atoms or 2 to 5 carbon atoms A _II-3 represents an aryl group having 6 to 10 carbon atoms that may be substituted, a ring structure that contains 1 to 2 nitrogen atoms, oxygen atoms, or sulfur atoms that may be substituted as ring atoms. A heteroaryl having 5 to 10 atoms, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 alkyl A heterocycloalkyl having a ring atom number of 5 to 7 and containing a nitrogen atom or an oxygen atom as a ring atom, A _II-2 represents a hydrogen atom or P (═O) (OH) ₂ , O—P ( _{= O) (OH) 2,} COOH SO ₃ H, 1H-tetrazol-5-yl, OH, alkoxy having 1 to 4 carbon _{atoms, X II} is an oxygen atom or a sulfur _{atom, Y II-1} is _CH 2 CH ₂ or CH = _{CH, Z II} is a single bond Or an alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms.

(Wherein R _III-1 is alkyl or cyano having 1 to 4 carbon atoms substituted with a halogen atom, R _III-2 is a hydrogen atom or P (═O) (OH) ₂ , and A _III-1 is the number of carbon atoms. 5 to 9 linear alkyl, A _III-1 may have 1 to 6 functional groups selected from the following four groups a to d in any combination (a, Alkyl having 1 to 6 carbon atoms, and when two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded form a cycloalkyl having 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, double bond at the end of the chain, triple bond) , Y _III-2 is alkylene having 1 to 5 carbon atoms, 2 carbon atoms -5 alkenylene or alkynylene having 2 to 5 carbon atoms, A _III-3 is optionally substituted aryl having 6 to 10 carbon atoms, optionally substituted 1 to 2 nitrogen atoms, oxygen atom Alternatively, a heteroaryl having 5 to 10 ring atoms containing a sulfur atom as a ring constituting atom, or an optionally substituted cyclohexane having 3 to 7 carbon atoms which may be condensed with an optionally substituted benzene Alkyl or an optionally substituted 1 to 2 nitrogen atom or oxygen atom as a constituent atom of the ring represents a heterocycloalkyl having 5 to 7 ring atoms, and A _III-2 represents a hydrogen atom or carbon number 1-3 alkyl, B _III represents an alkyl hydrogen atom or a hydroxyl group carbon atoms which may be substituted with a substituted or even if it or a halogen atom at 1 to 4, B _III is a Binds to _{II-2, Y III-1} , X III-2, A III-2, B III and bonded to carbon atom is 4-7 membered ring cycloalkane amino group, or constituting atoms of ring May form a heterocycloalkane containing one nitrogen atom of 4 to 7, X _III-1 is an oxygen atom or sulfur atom, X _III-2 is a methine or nitrogen atom, and Y _III-1 is a carbon number. 1-2 alkylene or C = O.)

(Wherein R _IV-1 is alkyl or cyano having 1 to 4 carbon atoms 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 1 to 20 carbon atoms, or a substituent that is eliminated in vivo, R _IV-3 is a hydrogen atom, P (═O) (OH) ₂ , P (═O) (OR _IV-5 ) (OR _IV-6 ), (R _IV-5 and R _IV-6 represent a protecting group for a phosphate group or a substituent capable of leaving in vivo), R _IV-4 may be substituted with a hydroxyl group, or C 1-4 alkyl optionally substituted with a halogen atom, A _IV-1 represents a linear alkyl having 5-9 carbon atoms, and A _IV-1 represents the following four groups a to d: May have 1 to 6 functional groups selected from any combination of a, alkyl having 1 to 6 carbon atoms, and when two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded form a cycloalkyl having 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, double bond at the end of the chain, triple Bond), 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, and AIV _-2 represents aryl having 6 to 10 carbon atoms which may be substituted. A heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms which may be substituted as ring atoms, and benzene which may be substituted; May be replaced An optionally substituted cycloalkyl having 3 to 7 carbon atoms or an optionally substituted heterocycloalkyl having 1 to 2 nitrogen atoms or oxygen atoms as a ring constituting atom and having 5 to 7 ring atoms. shown, the X _IV compound represented by the oxygen atom or a sulfur atom. showing a.), or a pharmaceutically acceptable acid addition salts, or their hydrate or solvate.

  In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a fluorine atom can be mentioned as a preferred example.

  C1-C3 alkyl means linear or branched C1-C3 alkyl, for example, methyl, ethyl, n-propyl, isopropyl etc. can be mentioned.

  A C1-C4 alkyl means a linear or branched C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl And tertiary butyl (hereinafter, “tertiary” may be expressed as t- or tert-).

  The alkyl having 1 to 6 carbons means straight or branched alkyl having 1 to 6 carbons, 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.

  C5-C9 linear alkyl is n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl.

  Examples of the cycloalkyl having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

  Examples of the 4- to 7-membered cycloalkane and the 4- to 7-membered heterocycloalkane containing one nitrogen atom include cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, and homopiperidine. 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 halogen atoms having 1 to 5 carbon atoms as described above. For example, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoro n-propyl, trifluoro n-propyl, pentafluoro n- In addition to propyl, fluoroisopropyl, difluoroisopropyl, fluoro n-butyl, trifluoro n-butyl, pentafluoro n-butyl, etc., some or all of the fluorine atoms of the substituents exemplified here are substituted with other halogen atoms. Can be mentioned.

  The alkyl having 1 to 4 carbon atoms in the case of being substituted with a hydroxyl group means an 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.

  C1-C4 alkoxy means linear or branched C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, t-butoxy, etc. can be mentioned. The C1-C4 alkyl substituted by the C1-C4 alkoxy is the above-mentioned C1-C4 alkoxy is the above-mentioned C1 -4, and methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, n-propoxyethyl, isobutoxypropyl, t-butoxybutyl and the like.

  The acyl having 1 to 20 carbon atoms is a linear or branched alkyl having 1 to 19 carbon atoms bonded to carbonyl, and examples thereof include acetyl, propionyl, myristoyl, palmitoyl, stearoyl and the like. .

  The alkoxy group having 1 to 20 carbon atoms is a straight chain or branched alkoxy group 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.

When A _I , A _II-1 , A _III-1 , A _IV-1 is substituted by 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 C 1-6 alkyls 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 and 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.

When A _I , A _II-1 , A _III-1 and A _IV-1 are substituted with a halogen atom, specific examples of A _I , A _II-1 , A _III-1 and A _IV-1 Is 5-fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, trifluoro n-pentyl, trifluoro n-hexyl, trifluoro n-heptyl, trifluoro n-octyl , Trifluoro n-nonyl, pentafluoro n-pentyl, pentafluoro n-hexyl, pentafluoro n-heptyl, pentafluoro n-octyl, pentafluoro n-nonyl, 1-fluoroheptyl, 2-fluoroheptyl, 3-fluoro Heptyl, 4-fluoroheptyl, 5-fluoroheptyl, 6-fluoroheptyl, 1- In addition to lurooctyl, 2-fluorooctyl, 3-fluorooctyl, 4-fluorooctyl, 5-fluorooctyl, 6-fluorooctyl, 7-fluorooctyl, etc., some or all of the fluorine atoms of the substituents exemplified here Examples thereof include those substituted with other halogen atoms.

When A _I , A _II-1 , A _III-1 , A _IV-1 has a double bond, a triple bond, or a C 3-6 cycloalkyl in the chain or at the chain end, A _I , Specific examples of A _II-1 , A _III-1 , A _IV-1 include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-hexynyl, n-heptynyl, n-octynyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, 2-pentylcyclopropan-1-yl, (2-butylcyclopropan-1-yl) methyl, (2-ethylcyclopropan-1-yl) propyl, 3- (3-methylcyclohexane-1-yl) propyl, 4- (4-methylcyclohexane-1-yl) butyl and the like can be mentioned.

When an oxygen atom or a sulfur atom is inserted in the chain of A _I , A _II-1 , A _III-1 , A _IV-1 , A _I , A _II-1 , A _III-1 , A _IV- Specific examples of ₁ include butoxyethyl, propoxypropyl, ethoxybutyl, butylthioethyl, propylthiopropyl, ethylthiobutyl and the like.

  Examples of the aryl having 6 to 10 carbon atoms include phenyl, 1-naphthyl, 2-naphthyl and the like.

  Heteroaryl having 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring constituent atoms and having 5 to 10 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.

  Examples of the heterocycloalkyl having 5 to 7 ring atoms containing 1 to 2 nitrogen atoms or oxygen atoms as ring atoms include piperidyl, piperazinyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl and the like. be able to.

  C1-C2 alkylene is a methylene and ethylene.

  Examples of the alkylene having 1 to 4 carbon atoms which may be substituted with 1 to 2 fluorine atoms include, for example, methylene, ethylene, trimethylene, tetramethylene, propylene, cyclopropylene, fluoromethylene, difluoromethylene, fluoroethylene and difluoroethylene. , Fluorotrimethylene, difluorotrimethylene, fluorotetramethylene, difluorotetramethylene and the like.

  Examples of alkylene having 1 to 5 carbon atoms include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propylene, ethylethylene, methyltrimethylene, dimethyltrimethylene, cyclopropylidene, cyclopropylene, (cyclopropylidene) ethylene, And cyclopropylene-methylene.

  Examples of the alkenylene having 2 to 5 carbon atoms include vinylene, propenylene, butenylene, pentenylene, methylvinylene, dimethylvinylene, ethylvinylene, methylpropenylene, dimethylpropenylene and the like.

  Examples of the alkynylene having 2 to 5 carbon atoms include ethynylene, propynylene, butynylene, pentynylene, methylpropynylene, dimethylpropynylene and the like.

  “C6-C10 aryl”, “Heteroaryl having 5 to 10 ring atoms containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as ring atoms”, “C3-C3 The number of substituents that the "7 cycloalkyl" and the "heterocycloalkyl having 5 to 7 ring atoms containing one or two nitrogen atoms or oxygen atoms as ring atoms" may have 1 to 5, preferably 1 or 2. Examples of the substituent include alkyl having 1 to 4 carbon atoms which may be substituted with the aforementioned halogen atom; alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; Alkylthio; alkyl sulfinyl having 1 to 4 carbon atoms; alkyl sulfonyl having 1 to 4 carbon atoms; alkyl carbonyl having 2 to 5 carbon atoms; halogen atom described above; cyano; nitro; cycloalkyl having 3 to 7 carbon atoms described above An aryl having 6 to 10 carbon atoms; an aralkyloxy having 7 to 14 carbon atoms; and an aryloxy having 6 to 10 carbon atoms; and two of them substituted together with an oxo or halogen atom; Alkylene having 3 to 4 carbon atoms which may be substituted; alkyleneoxy having 2 to 3 carbon atoms which may be substituted with oxo or halogen atom; and oxo or Substituted with androgenic atoms can be mentioned alkylenedioxy good having 1 to 2 carbon atoms also.

  The alkoxy having 1 to 4 carbon atoms when substituted with a halogen atom means that the aforementioned alkoxy having 1 to 4 carbon atoms is substituted with 1 to 5 halogen atoms. For example, fluoromethoxy, Such as 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 alkyl having 1 to 4 carbon atoms as described above, for example, , 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 is the aforementioned alkoxy having 1 to 4 carbon atoms substituted with the aforementioned aryl having 6 to 10 carbon atoms, for example, 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 aryl having 6 to 10 carbon atoms described above, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.

Examples of the alkylene having 3 to 4 carbon atoms include trimethylene, tetramethylene, methyltrimethylene and the like. The alkylene having 3 to 4 carbon atoms when substituted with oxo is, for example, —C (═O) —CH ₂ —CH ₂ —, —CH ₂ —C (═O) —CH ₂ —, —C _{(= O) -CH 2 -CH 2} -CH 2 -, - CH 2 -C (= O) -CH 2 -CH 2 - and the like. The alkylene having 3 to 4 carbon atoms in the case of being substituted with a halogen atom is one in which part or all of the hydrogen atoms in the aforementioned alkylene having 3 to 4 carbon atoms are substituted with a halogen atom.

Examples of the alkyleneoxy having 2 to 3 carbon atoms include ethyleneoxy, trimethyleneoxy, propyleneoxy and the like. The alkyleneoxy having 2 to 3 carbon atoms when substituted with oxo 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 in the case of being substituted with a halogen atom is one in which part or all of the hydrogen atoms in the aforementioned alkyleneoxy having 2 to 3 carbon atoms are substituted with a halogen atom.

Examples of the alkylenedioxy having 1 to 2 carbon atoms include methylenedioxy and ethylenedioxy. The alkylenedioxy having 1 to 2 carbon atoms when substituted with oxo is, for example, —O—C (═O) —O—, —O—CH ₂ —C (═O) —O— or 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 protecting group for the phosphate group of R _IV-5 and R _IV-6 include alkyl such as methyl, ethyl and t-butyl, substituted ethyl such as cyanoethyl and pyridylethyl, aralkyl such as benzyl, phenyl, phenylamino and the like. Can be mentioned.

The substituent that RIV _-5 and _RIV-6 are eliminated in vivo is a substituent that is chemically or enzymatically eliminated after the compound is administered or absorbed in vivo. Examples include alkyl such as isopropyl, t-butyl, hexadecyl and octadecyl, alkyloxyalkyl such as hexadecyloxypropyl and octadecyloxyethyl, acyloxyalkyl such as pivaloyloxymethyl, methoxycarbonyloxymethyl and isopropoxycarbonyloxy Alkyloxycarbonyloxyalkyl such as methyl, S-acylthioethyl such as acetylthioethyl and pivaloylthioethyl, substituted phenyl, substituted benzyl, or the following structure

(R ′ represents a side chain of a natural amino acid such as glycine, alanine, valine, R ″ represents a hydrogen atom or an alkyl having 1 to 4 carbon atoms), and P (═O) ( OR _IV-5 ) (OR _IV-6 ) can also form the following structure. In this case, the phenyl group may be further substituted.

Preferable examples of R ₁ in the general formula (I) include a hydrogen atom.

A preferred example of X _I is an oxygen atom, and a preferred example of Y _I is CH ₂ CH ₂ .

Preferred examples of R _I-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyano. More preferable examples include trifluoromethyl and cyano. An even more preferred example is fluoromethyl.

Preferred examples of R _I-2 include methyl, ethyl, hydroxymethyl, hydroxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl, and more preferred. Examples include methyl, ethyl, and hydroxymethyl, and more preferable examples include hydroxymethyl.

Preferable examples of R _I-3 and R _I-4 are the same or different and include a hydrogen atom, methyl, and ethyl, and more preferable examples include a hydrogen atom.

Preferred examples of A _I is substituted heptyl, substituted octyl, mention may be made of n- octenyl.

Taking preferred examples of A _I more specifically, may be mentioned 6-methyl heptyl, 3,7-dimethyl octyl, 8-fluoro-octyl, 7-octenyl.

Preferred examples of X _{II in} the general formulas (II-1) and (II-2) include an oxygen atom, and preferred examples of Y _II-1 include CH ₂ CH ₂ .

Preferred examples of R _II-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano, and more preferred examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.

A preferred example of R _II-3 is a hydrogen atom.

Preferred examples of R _II-2 include methyl, ethyl, hydroxymethyl, hydroxyethyl, fluoromethyl, fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and more preferred. Examples include methyl, ethyl, and hydroxymethyl, and more preferable examples include hydroxymethyl.

Preferable examples of A _II-2 include P (═O) (OH) ₂ , O—P (═O) (OH) ₂ , COOH, and OH.

Preferred examples of Z _II include alkylene having 1 to 4 carbon atoms.

Preferable examples of A _II-1 in the general formula (II-1) include n-heptyl and n-octyl.

Preferred examples of Y _II-2 in the general formula (II-2) include trimethylene or propenylene.

As a more preferred example, trimethylene can be cited as a more preferred 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 1 or 2 sulfur atom or oxygen atom as a ring constituting atom. A heteroaryl having 5 to 9 atoms can be mentioned, and a phenyl which may be substituted can be mentioned as a more preferable example. Preferred examples of the substituent when A _II-3 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, be mentioned 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.

Preferable examples of R _{III-2 in} the general formulas (III-1) and (III-2) include a hydrogen atom.

Preferable examples of _XIII-1 include an oxygen atom.

Preferable examples of R _III-1 include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyano. More preferable examples include trifluoromethyl or cyano. An even more preferred example is fluoromethyl.

When X _III-2 is methine, preferred examples of Y _III-1 , A _III-2 and B _III are

Can be mentioned.
When X _III-2 is a nitrogen atom, preferred examples of Y _III-1 , A _III-2 and B _III are

Or

Can be mentioned.

Preferable examples of A _III-1 in formula (III-1) include n-heptyl and n-octyl.

Preferred examples of Y _III-2 in the general formula (III-2) include trimethylene or propenylene.

As a more preferred example, trimethylene can be cited as a more preferred 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 1 or 2 sulfur atom or oxygen atom as a ring constituting atom. A heteroaryl having 5 to 9 atoms can be mentioned, and a phenyl which may be substituted can be mentioned as a more preferable example. 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 , a chlorine atom, a bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, _{trimethylene, -C (= O) -CH 2} -CH 2 -, ethyleneoxy, methylenedioxy, cited difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, difluoromethylenedioxy. Can be exemplified, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom.

More specifically, preferred examples of A _III-3 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.

Preferable examples of _{XIV in} the general formulas (IV-1) and (IV-2) include an oxygen atom.

Preferred examples of R _IV-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.

Preferable examples of R _IV-2 include a hydrogen atom or an acyl having 1 to 20 carbon atoms.

A preferred example of R _IV-3 when R _IV-2 is an acyl or alkoxycarbonyl having 1 to 20 carbon atoms includes 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 capable of leaving 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.

Preferred examples of A _IV-1 in formula (IV-1) include n-heptyl and n-octyl.

Preferred examples of Y _{IV in} the general formula (IV-1) include trimethylene or propenylene.

As a more preferred example, trimethylene can be cited as a more preferred example.

A preferred example of A _IV-2 is a ring structure containing an optionally substituted aryl having 6 to 10 carbon atoms or an optionally substituted 1 or 2 sulfur atom or oxygen atom as a ring constituting atom. A heteroaryl having 5 to 9 atoms can be mentioned, and a phenyl which may be substituted can be mentioned as a more preferable example. 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 , a chlorine atom, a bromine atom, cyano, nitro, cyclopropyl, phenyl, benzyloxy, phenoxy, _{trimethylene, -C (= O) -CH 2} -CH 2 -, ethyleneoxy, methylenedioxy, cited difluoromethylenedioxy More preferred examples are methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine atom, chlorine atom, bromine atom, cyclopropyl, phenyl, trimethylene, ethyleneoxy, methylenedioxy, difluoromethylenedioxy You can gel, methyl, trifluoromethyl, trifluoromethoxy, fluorine atom, still more preferable examples of the chlorine atom.

More specifically, preferred examples of A _IV-2 include methylphenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, chlorophenyl, dichlorophenyl, and fluoro (trifluoromethyl) phenyl.

  Examples of the pharmaceutically acceptable acid addition salt of the compound of the present invention include inorganic acid salts, organic acid salts, alkali metal salts, alkaline earth metal salts and the like. The compounds of the present invention include those represented by the general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1) and (IV-2). In addition to the compounds and their pharmaceutically acceptable acid addition salts, their geometric isomers, optically active forms, hydrates, and solvates are also included.

Synthesis method of the compound of the present invention Examples of the synthesis method of the compound of the present invention include the following methods.

1) Among the inventive compounds, 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 (I-I-1) is synthesized by the following scheme (I-II).

(In the formula, R _I-1 , R _I-2 and A _I are as defined in the general formula (I), R _I ^a , R _I ^b , R _I ^c are protecting groups, and X _I ^a is a leaving group. The leaving group, X _I ^b represents a leaving group or a hydroxyl group, and PB _I represents a leaving group containing phosphorus.)
R _I ^a in the formula is not particularly limited as long as it protects the phenolic hydroxyl group. For example, alkyl (specifically methyl, ethyl etc.), aralkyl (benzyl etc.) and the like can be mentioned. R _I ^b in the formula is not particularly limited as long as it protects the hydroxyl group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), trialkylsilyl (specifically trimethylsilyl etc.), benzyl or a substituent that forms an acetal compound (specifically methoxy) Methyl, tetrahydropyranyl, etc.). When R _I-2 has a hydroxyl group, the hydroxyl group may be protected with a suitable protecting group, and specific examples of the protecting group R _I ^d include the same as R _I ^b . Further, R _I ^b and R _I ^d can be bonded to form a cyclic acetal. (The same shall apply hereinafter.) The protecting group represented by R _I ^c in the formula is not particularly limited as long as it protects the amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned. Leaving group represented by X _I ^a is desorbed upon reaction intermediates (I-II-1) with the phosphorus compound, it does not inhibit the reaction upon reaction with subsequent aldehyde (I-II-3) If there is no particular limitation. For example, halogen atoms (specifically iodine atom, bromine atom, chlorine atom, etc.), methanesulfonyloxy, toluenesulfonyloxy and the like can be mentioned. The leaving group containing phosphorus represented by _{PB I, (P (C 6} H 5 in _{particular) 3)} triaryl phosphonium or ^{_{P (O) (OR I e}} ) 2 (R I e is 1 carbon atoms -4 is shown, and the same shall apply hereinafter). If X _I ^b is a leaving group, examples of the leaving group leaves upon alkylation of a phenolic hydroxyl group is not particularly limited as long as it does not inhibit the reaction. For example, a halogen atom (specifically an iodine atom, a bromine atom, a chlorine atom, etc.) and the like can be mentioned.

The first step is to react a compound (I-II-1) having ^a leaving group X _I ^a synthesized by a known method (WO 2007/069712 pages 23-28) with a phosphorus compound to leave the phosphorus-containing leaving group. it is a reaction to obtain intermediates having a PB _I to (I-II-2). If PB _I is triarylphosphonium, intermediate (I-II-2) can be obtained by reacting triarylphosphine with a compound (I-II-1). Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB _I is P (O) (OR _I ^e ) ₂ , intermediate (I-II-2) can be obtained by an Arbuzov reaction of compound (I-II-1) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. In addition, when PB _I is P (O) (OR _I ^e ) ₂ , 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 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). 69 (2004) 7765-7768) by condensing aldehyde (I-II-3), and subsequently reducing the resulting olefin, followed by deprotection of protecting group R _I ^a , A reaction to obtain a phenolic intermediate (I-II-4). If PB _I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, in an ether solvent such as tetrahydrofuran, a base such as sodium hydride or potassium t-butoxide is used, and it can be about 30 minutes to 12 hours at −30 ° C. to reflux. 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 improved method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB _I is P _(O) of the ^_(OR I _{e) 2,} the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can obtain E form preferentially. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting group R _I ^a are not particularly limited as long as they are used for the usual deprotecting of the protecting group. For example, if R _I ^a is methyl, it can be used in a methylene chloride solvent. A method using a Lewis acid such as boron tribromide, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water if acyl such as acetyl, methoxymethyl or tetrahydropyranyl, Examples of ether-based protecting groups such as t-butyl include a method using an acid such as hydrochloric acid or trifluoroacetic acid. In the case of using benzyl R _I ^a, hydrogenolysis, such as substituted benzyl, or benzyloxymethyl, a protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R _I ^a is above double bonds It can also be performed at the same time as the reduction.

The third step alkylates the phenolic hydroxyl group of intermediate (I-II-4) with intermediate (I-II-5) 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 (I-I-1) of the present invention. Examples of intermediates (I-II-5) used for alkylation include commercially available halides and alcohols, those obtained by halogen exchange of halides, those obtained by exchanging hydroxyl groups of alcohols with leaving groups X _I ^b , and commercially available carboxylic acids. Alcohol or the like obtained by reducing can be used. For example, X is obtained by fluorinating a bromoalkyl alcohol with a generally known fluorinating reagent to form a fluoroalkyl alcohol, and then converting the alcohol moiety 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. Intermediate The reagents used in the alkylation of (I-II-4) phenolic hydroxyl groups of, if X _I ^b is a leaving group, intermediate (I-II-5) and potassium carbonate or hydride The combination of inorganic bases, such as sodium, is mentioned. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran under ice-cooling at about 80 ° C. for about 30 minutes to 12 hours. Further, when X _I ^b represents a hydroxyl group, the alkylation of the phenolic hydroxyl group of intermediate (I-II-4) has the azocarboxylic acid derivative such as a phosphine compound and azodicarboxylic acid diisopropyl ester such as triphenyl phosphine The Mitsunobu reaction used can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal and R _I ^c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

2) Among the compounds of the present invention, compounds represented by general formula (I) in which R _I , R _I-3 and R _I-4 are all hydrogen atoms and R _I-2 is ω-fluoroalkyl (II -3) is also synthesized by the following scheme (I-III).

(Wherein, X _I , Y _I , R _I-1 and A _I have the same meaning as the symbols in general formula (I).)
The first step is the general formula (I) _{R I} is a hydrogen atom _{in, by R I-2} protects ω- hydroxyalkyl, compound of (I-I-2), oxazoline body (I-III-1 ). In this step, the reaction can be carried out using orthoacetate as a reagent in a polar solvent such as acetonitrile or N, N-dimethylformamide, a halogen-based solvent such as methylene chloride, or a hydrocarbon solvent such as toluene. For the purpose of promoting the reaction, a base such as N, N-diisopropylethylamine or an acid such as p-toluenesulfonic acid can be added. The reaction conditions include room temperature to reflux and 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). Examples of the fluorinating agent include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI). In this step, the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane. The reaction conditions include -78 ° C to room temperature for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Moreover, this process can also be performed by the method of making a fluoride ion act after converting the hydroxyl group of compound (I-III-1) into a corresponding sulfonate body. For example, when p-toluenesulfonyl fluoride and tetrabutylammonium fluoride (TBAF) are used, the reaction is carried out in an ether solvent such as tetrahydrofuran at room temperature to 80 ° C. for about 1 hour to 24 hours. A dehydrating agent such as molecular sieves can be added to this reaction. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

  In the third step, compound (I-I-3) of the present invention is prepared by deprotecting compound (I-III-2). This step can be performed using a normal deprotection reaction. Specifically, it can be performed using an acid such as hydrochloric acid or trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol or a mixed solvent thereof and water at room temperature to 100 ° C. for about 30 minutes to 12 hours. The reaction solution can be purified by a conventional method to obtain the desired product.

3) R _I , R _I-3 , and R _{I-4 in the} general formula (I) are all hydrogen atoms, and A _I has 5 to 9 carbon atoms that do not have a triple bond as a functional group in the chain or at the chain end. Compound (II-4) in which alkyl and R _I-1 are trifluoromethyl or cyano is synthesized by the following scheme (I-IV).

(Wherein R _I-1 ′ is trifluoromethyl or cyano, A _I ′ is alkyl having 5 to 9 carbon atoms having no triple bond as a functional group in the chain or at the chain end, R _I ^b , R _I ^c Represents a protecting group, X _I ^c and X _I ^d represent a leaving group, and R _I-2 , X _I and Y _I have the same meanings as those in the general formula (I).
R _I ^b and R _I ^c in the formula are as defined above. Examples of the leaving group represented by X _I ^c not particularly limited as long as it can desorbed activated by the catalyst during Sonogashira reaction. For example, a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyloxy and the like can be mentioned. The leaving group represented by X _I ^d is not particularly limited as long as it is eliminated during the substitution reaction with alkoxide or thiol anion. For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned.

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 performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of the reaction conditions are about 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) (for example, Tetrahedron, Vol. 57 (2001) pages 6531-6538, Chemical and Pharmaceutical Intermediate (I-IV-4) synthesized by Chemical and Pharmaceutical Bulletin 53 (2005) pages 100-102) is condensed by Sonogashira reaction to produce an intermediate (I -IV-5) is obtained. Examples of the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II). In order to accelerate the reaction, an organic base such as triethylamine, an inorganic base such as ammonia, a copper compound such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl It is also possible to add additives such as phosphine compounds. As reaction conditions, in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene, ice cooling to reflux is performed for about 30 minutes to about 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 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 that does not contain a double bond in the chain or at the chain end, may be used for reducing an ordinary unsaturated carbon bond. Although it will not be limited if it is a reagent used, for example, a homogeneous catalyst such as a heterogeneous catalyst rhodium complex (chlorotris (triphenylphosphine) rhodium (I), etc.) such as palladium carbon, Raney nickel, palladium carbon ethylenediamine complex was used. Catalytic hydrogenation can be mentioned. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product. On the other hand, the reaction used when Y _I is —CH═CH— or A _I ′ is an alkyl having 5 to 9 carbon atoms including a double bond includes a Lindlar catalyst, a nickel-graphite-ethylenediamine complex, a diene compound and a phosphine compound, and Catalytic hydrogenation carried out in the presence of a catalyst with regulated activity such as various rhodium complexes. 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 (I-IV-6). When R _I ^b , R _I ^c and R _I-2 have a hydroxyl group, the deprotection of the protecting group R _I ^d protecting the hydroxyl group is not particularly limited as long as it is used for deprotecting a normal protecting group. All the protecting groups can be deprotected at once or stepwise. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal, and R _I ^c is a t-butyloxycarbonyl group, the cyclic acetal is deprotected with a catalytic amount of acid, followed by stronger 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. Meanwhile The conditions for the deprotection of R _I ^c which is performed subsequent to the deprotection of the acetal, with inorganic acids or trifluoroacetic acid such as hydrochloric acid in equivalent amount or more, ether solvents such as alcoholic solvents and tetrahydrofuran ethanol , Water, or a mixed solvent thereof for about 10 minutes to 12 hours at 80 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

4) In the general formula (I), R _I , R _I-3 and R _I-4 are all hydrogen atoms, X _I is a sulfur atom, Y _I is —CH ₂ CH ₂ —, and A _I is in the chain or 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 as a functional group is synthesized by the following scheme (IV).

(Wherein, the R I f a hydrogen atom or a protecting group, R I b, R I c is a protecting group, X I a, X I e is a leaving group, A I '' double in the chain or chain end C 5-9 alkyl having no bond or triple bond, PB I represents a leaving group containing phosphorus, and R I-1 and R I-2 have the same meaning as each symbol in formula (I). .)
In the formula, R I b , R I c , X I a , and PB I are as defined above. R I f in the formula is not particularly limited as long as it protects a hydrogen atom or a carboxyl group. For example, alkyl (specifically methyl, ethyl etc.), aralkyl (benzyl etc.) and the like can be mentioned. The leaving group represented by X I e is not particularly limited as long as it is eliminated during the substitution reaction with the alkylthioion A I ″ S — . For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned.

The first step is to introduce the fused by 4-position alkylthio benzoic acid derivatives with a leaving group X _I ^e at the 4-position (I-V-1) and thiol (I-V-2), intermediate ( Reaction to obtain IV-3). This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as potassium carbonate or sodium hydride or an organic base such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene can be used. Examples of the reaction conditions include about -30 to 80 ° C and about 10 minutes to 10 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

  The second step is a reaction in which the carboxyl group of the intermediate (IV-3) is reduced to obtain an intermediate (IV-4) having a hydroxyl group. The reagent used for the reduction is not particularly limited as long as it is usually used, but alkali metals such as sodium and alkaline earth metals, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and hydrogenation. Examples thereof include metal hydrogen complex compounds such as sodium boron, boron compounds such as diborane, and catalytic hydrogenation using a homogeneous or heterogeneous catalyst. As the reaction conditions, a temperature and time appropriate for the reducing reagent to be used are selected. Specific examples include reduction in diborane, lithium aluminum hydride, lithium borohydride, ethanol-based alcohol solvents or alcohols in an ether solvent such as tetrahydrofuran at −30 ° C. to reflux for about 10 minutes to 12 hours. Reduction with sodium borohydride or calcium borohydride performed in a mixed solvent of a system solvent and an ether solvent such as tetrahydrofuran under ice-cooling to reflux for about 30 minutes to 24 hours can be mentioned. 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 X _I ^a is used when the halogen N- chlorosuccinimide, N- bromosuccinimide, carbon tetrachloride and their triphenylphosphine, a combination of a reaction auxiliary agent such as a base, hydrochloric, hydrobromic, hydroiodic Examples thereof include inorganic acids such as hydrogen acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, thionyl halide, α-haloenamine, and the like. The reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at −30 ° C. to 130 ° C. for about 10 minutes to 6 hours. In addition, when an inorganic acid is used, a reaction in an aqueous solution or an organic solvent such as toluene and water in a two-layer system can also be performed. As ^a reagent used when X _I ^a is a sulfonyloxy group, a combination of a sulfonyl chloride such as methanesulfonyl chloride or toluenesulfonyl chloride and an organic base such as triethylamine or pyridine is used. Examples of the reaction conditions include an organic solvent such as a halogen-based solvent such as methylene chloride and an ether-based solvent such as tetrahydrofuran at −30 ° C. to 50 ° C. for about 5 minutes to 3 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

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. If PB _I is triarylphosphonium, intermediate (I-V-6) can be obtained by reacting the intermediate (I-V-5) with triarylphosphine. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB _I is P (O) (OR _I ^e ) ₂ , intermediate (IV-6) can be obtained by Arbuzov reaction of intermediate (IV-5) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. When PB _I is P (O) (OR _I ^e ) ₂ , intermediate (IV-6) is intermediate (IV-5) in the presence of an additive such as tetraalkylammonium or cesium carbonate. It can also be obtained by reacting phosphonic acid diester. The reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

In the fifth step, an intermediate (IV-6) containing phosphorus and an aldehyde (I-II-3) separately synthesized are condensed, and then the resulting olefin is reduced to give an intermediate ( I-V-7) is obtained. If PB _I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, in an ether solvent such as tetrahydrofuran, a base such as sodium hydride or potassium t-butoxide is used, and it can be about 30 minutes to 12 hours at −30 ° C. to reflux. 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 improved method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB _I is P _(O) of the ^_(OR I _{e) 2,} the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can obtain E form preferentially. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent reduction of the double bond is not limited as long as it is a reagent used for normal olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenyl Catalytic hydrogenation using a homogeneous catalyst such as (phosphine) rhodium (I)). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

In the sixth step, when R _I ^b , R _I ^c and R _I-2 of the intermediate (IV-7) have a hydroxyl group, the protecting group R _I ^d protecting it is ^removed to remove the present invention. This is a reaction to obtain compound (II-5). The deprotection of the intermediate (IV-7) is not particularly limited as long as it is used for the deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal and R _I ^c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

5) A compound (II-6) in which R _I , R _I-3 and R _{I-4 in} general formula (I) are each a hydrogen atom and X is a sulfur atom is represented by the following scheme (I-VI ).

(Wherein R _I ^b and R _I ^c represent a protecting group, X _I ^f represents a hydroxyl-activating group, and Y _I , R _I-1 , R _I-2 and A represent each of the general formula (I) (It is synonymous with symbol.)
R _I ^b and R _I ^c in the formula are as defined above. The activation group for a hydroxyl group represented by X _I ^f, a sulfonyl such as trifluoromethanesulfonyl and toluenesulfonyl.

The first step is a compound (I-VI-1) synthesized by a known method (WO 2007/069712 pages 37-38) and a thiol (I-VI-2) obtained by a generally known synthesis method. In this reaction, an intermediate (I-VI-3) is obtained by condensation of A _I -SH. This step can be carried out in the presence of a palladium catalyst in an ether solvent such as dioxane or a hydrocarbon solvent such as toluene. Examples of the palladium catalyst include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), and the like. In this reaction, a phosphine compound or a base can be added as a reaction auxiliary agent. Examples of the phosphine compound include triphenylphosphine and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene. On the other hand, examples of the base include inorganic bases such as cesium carbonate and organic bases such as N, N-diisopropylethylamine. Examples of the reaction conditions include room temperature to reflux and 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

In the second step, when R _I ^b , R _I ^c and R _I-2 of the intermediate (I-VI-3) have a hydroxyl group, the protecting group R _I ^d protecting it is removed, thereby protecting the compound of the present invention. This is a reaction to obtain (I-I-6). The deprotection of the intermediate (I-VI-3) is not particularly limited as long as it is used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. it can. For example, when R _I ^b is a protecting group that can be deprotected 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.

Table Of both formulas (either of _{R I-3} and _{R I-4} in I) or _{R I-3} and _{R I-4} is an alkyl of 1 to 4 carbon atoms 6) Compound of the present invention Compound (II-7) to be synthesized is synthesized by the following scheme (I-VII).

(In the formula, either R _I-3 ′ or R _I-4 ′ represents 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).)
In this step, the compound (I-7) of the present invention is synthesized by alkylating the amino group of the compound (I-VII-1) having a primary amino group among the compounds of the present invention. For this synthesis, a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used. When the reductive amination reaction is used, an aldehyde having the same carbon number as R _I-3 ′ or R _I-4 ′ and the compound (I-VII-1) are mixed with an alcohol solvent such as methanol or dichloroethane. The target product can be obtained by reacting in a halogen-based solvent using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide. In this reaction, the generation of a Schiff base and the reduction reaction can also be sequentially performed. In this reductive amination reaction, an acid such as acetic acid can be added as a reaction accelerator. Examples of the reaction conditions include about 30 minutes to 10 hours at about 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R _I-3 ′ and R _I-4 ′ are methyl, it is also possible to use an Eschweiler-Clarke methylation reaction using a reducing agent such as formic acid and formaldehyde, or formaldehyde and sodium cyanoborohydride.

7) Among the compounds of the present invention, R ₁ , R _I-3 and R _{I-4 in} the general formula (I) are all hydrogen atoms, and Y _I is represented by —CH═CH— (I—I— 8) is synthesized by the following scheme (I-VIII).

(Wherein R _I ^b and R _I ^c are protecting groups, R _I ^g is a protecting group or —A _I , X _I ^a is a leaving group, X _I ^g is a leaving group or hydroxyl group, and PB _I contains phosphorus. A leaving group is shown, and X _I , R _I-1 , R _I-2 and A _I have the same meanings as symbols in the general formula (I).
In the formula, R _I ^b , R _I ^c , X _I ^a , and PB _I are as defined above. If X _I ^g is a leaving group, examples of the leaving group leaves upon alkylation of a phenolic hydroxyl group or thiol group, is not particularly limited as long as it does not inhibit the reaction. For example, a halogen atom (specifically an iodine atom, a bromine atom, a chlorine atom, etc.) and the like can be mentioned. If R _I ^g in the formula is a protecting group, R _I ^g is not particularly limited as long as it protects a phenol group or a thiol group. Examples of R _I ^g, X is when an oxygen atom alkyl (such as methyl), aralkyl (4-methoxybenzyl, etc.), or the like protecting group forming acetal (methoxymethyl and ethoxyethyl) can be mentioned. In addition, when X _I is a sulfur atom, examples include alkyl (such as methyl), aralkyl (such as 4-methoxybenzyl), and a protecting group that forms thioacetal (such as methoxymethyl, phenylthiomethyl, and acetamidemethyl).

In the first step, a compound having ^a leaving group X _I ^a (I-VIII-1) synthesized by a known method (WO 2007/069712, pages 41-43) is reacted with a phosphorus compound to leave a phosphorus-containing leaving group. This is a reaction to obtain an intermediate (I-VIII-2) having PB _I. If PB _I is triarylphosphonium, intermediate (I-VIII-2) is the presence additive such as tetraalkylammonium carbonate or cesium carbonate, intermediates (I-VIII-1) by reacting triarylphosphine Obtainable. Examples of the reaction conditions include room temperature to reflux for about 30 minutes to 12 hours in an inert solvent such as diethyl ether, benzene, and toluene. After the reaction, if necessary, the target product can be obtained by distilling off the solvent, cooling, adding a hardly soluble solvent such as diisopropyl ether or hexane, and collecting the precipitated solid by filtration. When PB _I is P (O) (OR _I ^e ) ₂ , intermediate (I-VIII-2) can be obtained by Arbuzov reaction of intermediate (I-VIII-1) and phosphite triester. The reaction conditions include no solvent or in an inert solvent such as xylene at 50 ° C. to 170 ° C. for about 30 minutes to 12 hours. After the reaction, the desired product can be obtained by distilling off or distilling excess phosphorous acid triester. When PB _I is P (O) (OR _I ^e ) ₂ , intermediate (I-VIII-2) can also be obtained by reaction of intermediate (I-VIII-1) with phosphonic acid diester. The reaction conditions include an inert solvent such as tetrahydrofuran and xylene, or a polar solvent such as N, N-dimethylformamide, and ice-cooled to 50 ° C. for 30 minutes to 6 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

By the second step of condensation of intermediates containing phosphorus (I-VIII-2) separately synthesized aldehyde (I-II-3), deprotecting the protecting group R _I ^g of the resulting olefin body , A reaction to obtain a phenolic intermediate or a thiol intermediate (I-VIII-3). If PB _I is triarylphosphonium, the conditions of normal Wittig reaction are used. For example, in an ether solvent such as tetrahydrofuran, a base such as sodium hydride or potassium t-butoxide is used, and it can be about 30 minutes to 12 hours at −30 ° C. to reflux. 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 improved method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. If PB _I is P _(O) of the ^_(OR I _{e) 2,} the conditions of normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can obtain E form preferentially. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The conditions used for the deprotection of the protecting group R _I ^g performed subsequently, is not particularly limited insofar as the conditions that alkenylene wear and tear, for example, when R _I ^g is 4-methoxybenzyl, 2,3-dichloro -5 6- the oxidation reaction with dicyano-1,4-benzoquinone (DDQ) or the like, R if _I ^g is silyl such as trialkylsilyl, deprotection with fluorine compound of an inorganic acid or tetrabutylammonium fluoride and the like such as hydrochloric acid Can be mentioned. In the case of using the -A _I is a partial structure of the invention compound as ^{_{R I g (I-I-}} 8) is not necessary to deprotect R _I ^g, alkyl phenol or thiol in the next step Can also be omitted.

In the third step, the phenolic hydroxyl group or thiol group of the intermediate (I-VIII-3) is alkylated, and when R _I ^b , R _I ^c and R _I-2 have a hydroxyl group, a protecting group for protecting it. In this reaction, R _I ^d (R _I ^d is as defined above) is deprotected to give the compound of the present invention (I-8). The reagents used in the alkylation of a phenolic hydroxyl group or thiol hydroxyl intermediate (I-VIII-3) _{having, if X} ^{I g} is a leaving group, intermediates (I-VIII-4) carbonate Examples include combinations of inorganic bases such as potassium and sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran under ice-cooling at about 80 ° C. for about 30 minutes to 12 hours. Further, X _I ^g is a hydroxyl group, the alkylation in the case of Intermediate (I-VIII-3) having a phenolic hydroxyl group, phosphine compounds such as triphenylphosphine and azocarboxylic acid derivative such as diisopropyl azodicarboxylate Mitsunobu reaction using can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal and R _I ^c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

8) In general formula (I), R _I , R _I-3 and R _I-4 are all hydrogen atoms, and R _I-1 is represented by difluoromethyl (I-9) having the following scheme ( I-IX).

(Wherein R _I ^b , R _I ^c and R _I ^h represent a protecting group, X _I ^g represents a leaving group or a hydroxyl group, and X _I , Y _I , R _I-2 and A _I represent the general formula (I) It is synonymous with each symbol in.)
Specific examples of R _I ^b , R _I ^c and X _I ^{g in} the formula are as defined above. The protecting group represented by R _I ^h in the formula is not particularly limited as long as it protects a phenol group or a thiol group. Examples of R _I ^h include alkyl (such as methyl), aralkyl (such as 4-methoxybenzyl), a protecting group (eg, methoxymethyl and ethoxyethyl) that forms an acetal when X _I is an oxygen atom. In addition, when X _I is a sulfur atom, examples include alkyl (such as methyl), aralkyl (such as 4-methoxybenzyl), and a protecting group that forms thioacetal (such as methoxymethyl, phenylthiomethyl, and acetamidemethyl).

The first step is to remove 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 45-48), thereby producing a phenolic intermediate. Or a thiol intermediate (I-IX-2). When R _I ^h is benzyl, the hydrogenolysis reaction using a homogeneous catalyst such as palladium carbon or Raney nickel is used, and in the case of 4-methoxybenzyl, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone In the case of a silyl group such as trialkylsilyl, the oxidation reaction by (DDQ) or the like can include deprotection with an inorganic acid such as hydrochloric acid or a fluorine compound such as tetrabutylammonium fluoride. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

In the second step, the phenolic hydroxyl group or thiol group of the intermediate (I-IX-2) is alkylated, and when R _I ^b , R _I ^c and R _I-2 have a hydroxyl group, a protecting group for protecting it. In this reaction, R _I ^d (R _I ^d is as defined above) is deprotected to give the compound (I-I-9) of the present invention. The reagents used in the alkylation of a phenolic hydroxyl group or thiol hydroxyl intermediate (I-IX-2) _{having, if X} ^{I g} is a leaving group, intermediates (I-VIII-4) carbonate Examples include combinations of inorganic bases such as potassium and sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran under ice-cooling at about 80 ° C. for about 30 minutes to 12 hours. Further, X _I ^g is a hydroxyl group, the alkylation in the case of Intermediate (I-IX-2) having a phenolic hydroxyl group, phosphine compounds such as triphenylphosphine and azocarboxylic acid derivative such as diisopropyl azodicarboxylate Mitsunobu reaction using can also be used. The reaction conditions at this time include, for example, about 10 minutes to 6 hours at 50 ° C. under ice cooling in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent deprotection is not particularly limited as long as it can be used for deprotection of ordinary protecting groups, and all protecting groups can be deprotected at once or stepwise. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal and R _I ^c is t-butyloxycarbonyl, they can be simultaneously deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

9) A compound (I-10) in which R _I , R _I-3 and R _{I-4 in} general formula (I) are all hydrogen atoms and R _I-1 is fluoromethyl is represented by the following scheme ( I-X).

(Wherein R _I ^b , R _I ^c and R _I ⁱ represent a protecting group, X _I ^c and X _I ^d represent a leaving group, and A _I ″ represents a double bond or a triple bond in the chain or at the chain end. (C 5 -C 9 alkyl, X _I , and Y _I having no meaning are the same 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 (I-X-3) by condensation of the raw materials with a leaving group ^{_{X I d (I-X-}} 1) and the alcohol or thiol (I-X-2). This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of the reaction conditions include about 30 minutes to 24 hours at about 80 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In addition, it is also possible to use a compound (I-X-1) having a leaving group X _I ^d of a phenolic hydroxyl group or thiol as a raw material, and in this case, the first step is a phenolic hydroxyl group or thiol. Is alkylated. Examples of the reagent used for this alkylation include a combination of an alkylating agent such as an alkyl halide and an inorganic base such as potassium carbonate or sodium hydride. The reaction conditions include a polar solvent such as N, N-dimethylformamide and an ether solvent such as tetrahydrofuran and a temperature of about 80 minutes to 80 ° C. under ice cooling for about 10 minutes to 12 hours. Moreover, Mitsunobu reaction can also be used for alkylation of a phenolic hydroxyl group.

The second step is a reaction in which the formyl group of the intermediate (I-X-3) is reduced to hydroxymethyl and then the protective group R _I ⁱ is introduced. The reagent used for the reduction of the formyl group is not particularly limited as long as it is usually used, but metal hydrides such as diisobutylaluminum hydride, metal hydride complex compounds such as lithium aluminum hydride and sodium borohydride. And catalytic hydrogenation using a homogeneous or heterogeneous catalyst. As the reaction conditions, a temperature and time appropriate for the reducing reagent to be used are selected. Specific examples include lithium aluminum hydride, reduction with lithium borohydride, ethanol-based alcoholic solvents or alcoholic solvents, which are carried out at −30 ° C. to room temperature for about 10 minutes to 3 hours in an ether-based solvent such as tetrahydrofuran. And reduction with sodium borohydride or calcium borohydride performed in a mixed solvent of an ether solvent such as tetrahydrofuran and the like under ice cooling to room temperature for about 10 minutes to 3 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. For introducing the protecting group R _I ^i, a conventional protecting group introduction reaction is used. When a trialkylsilyl group is used for R _I ⁱ , a silylating agent such as t-butyldimethylchlorosilane is used as a reagent, and a base such as imidazole or triethylamine can be added as a reaction accelerator. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

  The third step is a reaction in which intermediate (I-X-4) and intermediate (I-IV-4) are condensed by Sonogashira reaction to obtain intermediate (I-X-5) containing a triple bond. . Examples of the catalyst used include palladium compounds such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II). In order to accelerate the reaction, an organic base such as triethylamine, an inorganic base such as ammonia, a copper compound such as copper iodide and copper bromide, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl It is also possible to add additives such as phosphine compounds. As reaction conditions, in an ether solvent such as tetrahydrofuran and dioxane, a polar solvent such as acetonitrile and dimethylformamide, or a hydrocarbon solvent such as benzene, ice cooling to reflux is performed for about 30 minutes to about 24 hours. 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 in which intermediate (IX-6) is obtained by reducing the triple bond of intermediate (IX-5). Y _I is -CH 2 _CH 2 _- Examples of the reagent used when, but not limited as long as the reagents used in the reduction of the usual unsaturated carbon bond, such as palladium carbon or Raney nickel, etc. palladium-carbon ethylenediamine complex non Examples thereof include catalytic hydrogenation using a homogeneous catalyst such as a homogeneous catalyst rhodium complex (chlorotris (triphenylphosphine) rhodium (I) and the like). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification or the like can be performed by a usual method to obtain the target product. On the other hand, the reaction in which Y _I is used when -CH = CH-, Lindlar catalyst, nickel - Graphite - ethylenediamine complexes, catalytic hydrogenation carried out in the presence of a catalyst of modulating the activity and various complexes of diene and 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.

In the fifth step, R _I ⁱ of the compound (IX-6) is deprotected, and the hydroxyl group of the obtained compound is fluorinated to synthesize a fluorinated substance (IX-7). . Deprotection of the protecting group R _I ⁱ can be carried out using a conventional deprotection reaction. As a reagent used when R _I ⁱ is trialkylsilyl, a fluorine compound such as tetrabutylammonium fluoride can be used. As conditions for this reaction, ice-cooling to reflux for about 30 minutes to 24 hours may be mentioned in an ether solvent such as tetrahydrofuran. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Examples of the reagent used for the subsequent fluorination include diethylaminosulfur trifluoride (DAST) and 2,2-difluoro-1,3-dimethylimidazolidine (DFI). In this step, the reaction can be carried out in a halogen solvent such as methylene chloride or a hydrocarbon solvent such as hexane. The reaction conditions include -78 ° C to room temperature for about 30 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Moreover, this process can also be performed by the method of making a fluoride ion act after converting a hydroxyl group into a corresponding sulfonate body. For example, when p-toluenesulfonyl fluoride and tetrabutylammonium fluoride (TBAF) are used, the reaction is carried out in an ether solvent such as tetrahydrofuran at room temperature to 80 ° C. for about 1 hour to 24 hours. A dehydrating agent such as molecular sieves can be added to this reaction. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R _I ⁱ is trialkylsilyl, fluorination can be performed without deprotecting R _I ⁱ .

The sixth step is a reaction for obtaining the compound (II-10) of the present invention by deprotecting the intermediate (IX-7). When R _I ^b , R _I ^c and R _I-2 have a hydroxyl group, deprotection of the protecting group R _I ^d protecting R _I ^d (R _I ^d is as defined above) includes the usual protecting group. It will not specifically limit if it is used for deprotection, All the protecting groups can be deprotected at once or in steps. For example, when R _I ^b and R _I ^d combine to form a cyclic acetal, and R _I ^c is t-butyloxycarbonyl, the cyclic acetal is deprotected with a catalytic amount of acid, followed by stronger acidic conditions. By using it, R _I ^c can be deprotected. The conditions used for the deprotection of the acetal at this time include a catalytic amount of hydrochloric acid or toluenesulfonic acid in an alcoholic solvent such as methanol, or a mixed solution of an alcoholic solvent and another organic solvent. Examples include about 30 minutes to 12 hours at ° C. On the other hand, the conditions for the deprotection of R _I ^c which is performed subsequent to the deprotection of the acetal, with inorganic acids or trifluoroacetic acid such as hydrochloric acid in equivalent amount or more, ethers such as alcoholic solvent or tetrahydrofuran such as ethanol-based In a solvent, water, or a mixed solvent thereof, for about 10 minutes to 5 hours may be mentioned under ice cooling to room temperature. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Moreover, the target object which precipitates by adding a low solubility solvent, such as diisopropyl ether, to the reaction solution can also be filtered.

10) Among the compounds of the present invention, the compound (I) in which R _I in the general formula (II) is P (═O) (OH) ₂ , R _I-3 and R _I-4 are all represented by hydrogen atoms -I-11) is synthesized according to the following scheme (I-XI).

(In the formula, X _I , Y _I , R _I-1 , R _I-2 and A _I have the same _{meanings as those} in the general formula (I).)
In this step, the compound (I-I-11) of the present invention is obtained by a known synthesis method (WO2007 / 069712, pp. 53-56). The phosphorylated form (I-I-11) can be synthesized from the alcohol form (I-XI-1) in three steps using the above-mentioned known synthesis method.

11) Among the compounds of the present invention, R _I in the general formula (I) is represented by P (═O) (OH) ₂ , R _I-3 and R _I-4 are both alkyl having 1 to 4 carbon atoms. Instead of (I-XI-1) as a raw material, the compound is

(In the formula, 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 are represented by the general formula (It is synonymous with each symbol in (I).)
Can be synthesized by the same method, omitting the protection of the amino group or amino group and hydroxyl group in the first step of scheme (I-XI).

12) Among the compounds of the present invention, the general formula _{(II-1) R II-} 3 is hydrogen atom _{in, X II} is an oxygen _{atom, Y II-1} are _{-CH 2 CH 2 -, A II} -1 is n- Compound (II-I-1) represented by 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). .

(In the formula, n is 0 to 2, R _II-1 and R _II-2 are as defined in the general formula (II-1), R _II ^a is a protecting group, and R _II ^b is 1 to 4 represents alkyl.)
Protecting group represented by R _II ^a in the formula is not particularly limited as long as it protects an amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned.

When R _II-2 has a hydroxyl group, the hydroxyl group may be protected with a suitable protecting group, and the protecting group R _II ^c is specifically acyl (preferably having about 2 to 4 carbon atoms, Specific examples include acetyl), trialkylsilyl (specifically trimethylsilyl, etc.), benzyl or a substituent that forms an acetal compound (specifically methoxymethyl, tetrahydropyranyl, etc.).

The first step is to synthesize the amino group protected form (II-II-2) by protecting the amino group of the compound (II-II-1) synthesized by a known method (WO 2007/069712, pages 8-13). To do. 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-layer system of an alcohol such as methanol, or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture. Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

  In the second step, the hydroxyl group of the protected amino group (II-II-2) is oxidized to synthesize the aldehyde (II-II-3). This step can be performed using an oxidation reaction of a normal alcohol to an aldehyde. Specifically, the purpose is 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). You can get things. The reaction conditions include -78 ° C to 50 ° C 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.

In the third step, an intermediate (II-II-4) is synthesized by condensing a commercially available phosphorus reagent containing aldehyde (II-II-3) and R _II ^b . When a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C ₆ H ₅ ) ₃ ), normal Wittig reaction conditions are used. For example, in an ether solvent such as tetrahydrofuran, a base such as sodium hydride or potassium t-butoxide is used, and it can be about 30 minutes to 12 hours at −30 ° C. to reflux. 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 improved method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When a commercially available phosphorus reagent contains P (O) (OR _II ^d ) ₂ (R _II ^d represents an alkyl having 1 to 4 carbon atoms, the same shall apply hereinafter), the conditions of normal Horner-Wadsworth-Emmons reaction are used. It is done. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can obtain E form preferentially. 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 deprotecting the protecting group R _II ^a after reducing the olefin part of the intermediate (II-II-4).
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. And hydrogenation using a homogeneous catalyst. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting group R _II ^a are not particularly limited as long as they can be used for the deprotection of ordinary protecting groups. For example, if R _II ^a is acyl such as acetyl, an alcohol type A method using an inorganic base such as sodium hydroxide in a mixed solvent of a solvent and water, or a method using an acid such as hydrochloric acid or trifluoroacetic acid as long as it is a protecting group such as t-butyloxycarbonyl. . In the case of using benzyl R _II ^a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R _II ^a is a reduction of the double bond of the above It can be done at the same time. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), Z _II is alkylene having 2 to 4 carbon atoms, A _II-2 is alkoxy having 1 to 4 carbon atoms, Y _II- Other compounds in which ₁ is —CH ₂ CH ₂ — can also be synthesized by the same method.

13) Among the compounds of the present invention, the general formula _{(II-1) R II-} 3 is hydrogen atom _{in, X II} is an oxygen _{atom, Y II-1} are _{-CH 2 CH 2 -, A II} -1 is n- _{heptyl, compound Z II} is _{methylene, a II-2} is represented by COOH (III-2) is synthesized by the following scheme (II-III).

(In the formula, R _II-1 and R _II-2 have the same meanings as symbols in the general formula (II-1), and R _II ^a represents a protecting group.)
Specific examples of R _II ^{a in} the formula are as defined above.

The first step is an acid treatment of compound (II-III-1) in which n is 0 and R _II ^b is methyl in intermediate (II-II-4) in scheme (II-II), followed by aldehyde The carboxylic acid compound (II-III-2) is synthesized by oxidation. Examples of the acid treatment include a method using an acid such as hydrochloric acid, and the reaction conditions include concentrated hydrochloric acid in water and about 30 minutes to 2 hours at 60 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Subsequent oxidation of the aldehyde to the carboxylic acid can be carried out by using a general method. Specifically, a target product can be obtained by oxidation or pernication using permanganate, chromic acid, oxygen, hydrogen peroxide, or organic peroxide. The reaction conditions include -78 ° C to 50 ° C 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.

Second step by deprotecting the protecting group _{R II} ^a carboxylic acid derivative (II-III-2), is a reaction to obtain the present compound (III-2). The deprotection conditions are not particularly limited as long as they are used for the deprotection of ordinary protecting groups. For example, when R _II ^a is acyl such as acetyl, it is used in a mixed solvent of an alcohol solvent and water. Method using an inorganic base such as sodium hydroxide, t-butyloxycarbonyl or the like, method using an acid such as hydrochloric acid or trifluoroacetic acid, or hydrogenation if it is a protecting group such as benzyl or benzyloxycarbonyl The method using decomposition and 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. Among the formula (II-1) and the compound represented by _{(II-2), Z} II is _{methylene, can} be _{A II-2} is synthesized by other similar methods are also compounds is COOH.

14) Among the compounds of the present invention, the general formula _{(II-1) R II-} 3 is hydrogen atom _{in, X II} is an oxygen _{atom, Y II-1} are _{-CH 2 CH 2 -, A II} -1 is n- A 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).

(In the formula, R _II-1 and R _II-2 have the same meanings as symbols in the general formula (II-1), and R _II ^a represents a protecting group.)
Specific examples of R _II ^{a in} the formula are as defined above.

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 give the desired product using the same method as in Scheme (II-III). Of the compounds represented by the general formulas (II-1) and (II-2), other compounds in which Z _II is a single bond and A _II-2 is COOH can also be synthesized by the same method. .

15) Among the compounds of the present invention, the general formula _{(II-1) R II-} 3 is hydrogen atom _{in, X II} is an oxygen _{atom, Y II-1} are _{-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).

(Wherein R _II-1 and R _II-2 have the same meanings as the symbols in general 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.

By _{(the R II} ^e that described above) the first step is aldehyde (II-II-3) with a commercially available _R ^II e O-C = O condensing phosphorus reagent containing intermediate (II-V- 1) is synthesized. When a commercially available phosphorus reagent contains triarylphosphonium (specifically, P (C ₆ H ₅ ) ₃ ), normal Wittig reaction conditions are used. For example, in an ether solvent such as tetrahydrofuran, a base such as sodium hydride or potassium t-butoxide is used, and it can be about 30 minutes to 12 hours at −30 ° C. to reflux. 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 improved method. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When a commercially available phosphorus-containing reagent contains P (O) (OR _II ^d ) ₂ , normal Horner-Wadsworth-Emmons reaction conditions are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. Olefin can obtain E form preferentially. 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. And hydrogenation using a homogeneous catalyst. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product. The conditions for the subsequent deprotection of the protecting groups R _II ^a and R _II ^e are not particularly limited as long as they are used for the deprotection of ordinary protecting groups. For example, if 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, hydrochloric acid And a method using an acid such as trifluoroacetic acid. In the case of using benzyl R _II ^a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R _II ^a is a reduction of the double bond of the above It can be done at the same time. The conditions for deprotection by hydrolysis of R _II ^e are the same as those for R _II ^a. A method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solvent and water, hydrochloric acid or trifluoro Examples include a method using an acid such as acetic acid. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the general formulas (II-1) and the compound represented by _{(II-2), Z} II is _{ethylene, A II-2} is _{COOH, Y II-1} are _-CH 2 CH ₂ - in which the other Compounds can also be synthesized by similar methods.

16) Among the compounds of the present invention, R _II-3 in the general formula (II-1) is a hydrogen atom, X _II is an oxygen atom, Y _II-1 is —CH ₂ CH ₂ —, and A _II-1 is n—. Compound (II-I-5) in which heptyl, Z _II is alkylene having 1 to 3 carbon atoms, and A _II-2 is OH is synthesized by the following scheme (II-VI).

(In the formula, m is 0 to 2, R _II-1 and R _II-2 are synonymous with symbols in the general formula (II-1), and R _II ^a represents a protecting group.)
Specific examples of R _II ^{a in} the formula are as defined above.

In this step, the carboxylic acid compound (II-VI-1) synthesized in Scheme (II-III), Scheme (II-IV) and Scheme (II-V) is reduced to give an alcohol, and then the protecting group R _II ^In this reaction, the compound (II-I-5) of the present invention is obtained by deprotecting a. Reduction of carboxylic acid to alcohol can be performed by using a general method. Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like. The reaction conditions include -78 ° C to 50 ° C 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 conditions for the subsequent deprotection of the protecting group R _II ^a are not particularly limited as long as they can be used for the deprotection of ordinary protecting groups. For example, if R _II ^a is acyl such as acetyl, an alcohol type A method using an inorganic base such as sodium hydroxide in a mixed solvent of a solvent and water, or a method using an acid such as hydrochloric acid or trifluoroacetic acid as long as it is a protecting group such as t-butyloxycarbonyl. . In the case of using benzyl R _II ^a, hydrogenolysis, such as benzyloxycarbonyl, the protecting group which can be deprotected by catalytic hydrogenation conditions, the deprotection of R _II ^a is a reduction of the double bond of the above It can be done at the same time. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at ice-cooled to 80 ° C. for about 10 minutes to 12 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), other compounds in which Z _II is alkylene having 1 to 3 carbon atoms and A _II-2 is OH are also produced in the same manner. Can be synthesized.

17) Among the compounds of the present invention, the general formula _{(II-1) R II-} 3 is hydrogen atom _{in, X II} is an oxygen _{atom, Y II-1} are _{-CH 2 CH 2 -, A II} -1 is n- Compound (II-I-6) represented by heptyl, Z _II is alkylene having 1 to 4 carbon atoms, and A _II-2 is P (═O) (OH) ₂ is synthesized by the following scheme (II-VII). Is done.

(In the formula, q is 1 to 4, R _II-1 and R _II-2 are as defined in the general formula (II-1), R _II ^a is a protecting group, and R _II ^f is 1 to 1 carbon atoms. 4 represents an alkyl group.)
Specific examples of R _II ^{a in} the formula are as defined above.

In the first step, a phosphorus reagent (for example, tetraethyl methylenediphosphonate) containing aldehyde (II-II-3) and commercially available P (═O) (OR _II ^f ) ₂ (R _II ^f is as described above) is used. After the condensation to form a phosphorus compound, the intermediate (II-VII-1) is synthesized by reducing the olefin moiety. For the condensation, the conditions of a normal Horner-Wadsworth-Emmons reaction are used. For example, in a hydrocarbon solvent such as benzene or an ether solvent such as tetrahydrofuran, a base such as sodium hydride, potassium t-butoxide, or lithium hexamethyldisilazane is used, and the temperature is about −20 ° C. to reflux for about 30 minutes to 12 hours. Can be mentioned. After the reaction, purification or the like can be performed by a usual method to obtain the target product. The reagent used for the subsequent olefin reduction is not limited as long as it is a reagent used for ordinary olefin reduction. For example, a heterogeneous catalyst such as palladium carbon or Raney nickel or a rhodium complex (chlorotris (triphenylphosphine) And catalytic hydrogenation using a homogeneous catalyst such as rhodium (I). The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as dioxane, or a hydrocarbon solvent such as toluene, under a hydrogen pressure of 1 to 20 atm, under ice cooling to reflux for 30 minutes to 1 week. Can be mentioned. An acid such as acetic acid or a base such as triethylamine can be added to the reaction solution depending on the reaction rate and the stability of the compound. After the reaction, purification and the like can be performed to obtain the target product.

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 long as it is a protecting group such as t-butyloxycarbonyl. Incidentally, benzyl R _II ^a, hydrogenolysis, such as benzyloxycarbonyl, when using the deprotection can be protected group by catalytic hydrogenation conditions, the deprotection of R _II ^a is a double bond in the first step It can be performed simultaneously with the reduction. R _II ^f can be deprotected using a Lewis acid such as trimethylsilyl bromide. Moreover, as reaction conditions, it is about 10 minutes-about 24 hours at 80 degreeC under ice-cooling in halogenated solvents, such as a methylene chloride. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (II-1) and (II-2), Z _II is alkylene having 1 to 4 carbon atoms, A _II-2 is P (═O) (OH) ₂ , Y Other compounds in which _II-1 is —CH ₂ CH ₂ — can also be synthesized by the same method.

18) Among the compounds of the present invention, a compound represented by formula (II-1) wherein R _II-3 is a hydrogen atom, Z _II is methylene, and A _II-2 is OP (═O) (OH) ₂ II-I-7) is synthesized according to the following scheme (II-VIII).

(In formula, _XII , YII _-1 , _RII-1 , _RII-2 and _AII-1 are synonymous with each symbol in General formula (II-1).)
In this step, the compound (II-I-7) of the present invention is obtained by a known synthesis method (WO 2007/069712, pages 53-56). The phosphorylated form (II-I-7) can be synthesized in three steps from the alcohol form (II-VIII-1) using the above 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 in the same manner. Can do.

19) Among the compounds of the present invention, R _III-2 in the general formula (III-1) is a hydrogen atom, X _III-1 is an oxygen atom, Y _III-1 is methylene, X _III-2 is methine, A _{III- 1} is n-heptyl, A _III-2 is methylene, B _III is methylene, B _III is bonded to A _III-2, and Y _III-1 , X _III-2 and a carbon atom to which an amino group is bonded. Compound (III-I-1) forming cyclopentyl is synthesized by the following scheme (III-II).

(Wherein X _III ^a and X _III ^b represent a leaving group, Y _III represents an activating group at the time of the condensation reaction, and R _III-1 has the same meaning as the symbol in general formula (III-1).)
Leaving group represented by _{X III} ^a in the formula is an alkoxide ion _{(CH 3 (CH 2) 7} -O -) is not particularly limited as long as it departs during a substitution reaction by. For example, a halogen atom (specifically a fluorine atom, etc.), toluenesulfonyloxy and the like can be mentioned. The leaving group represented by X _III ^b in the formula is not particularly limited as long as it is eliminated during the introduction reaction or condensation reaction of the activating group Y _III . For example, a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyloxy and the like can be mentioned. The activating group represented by Y _III substituent containing metal such as lithium or magnesium, or a substituted group containing a silicon or non-metallic elements such as boron and the like. The above leaving group and activating group are used in an appropriate combination depending on the type of condensation reaction.

The first step is to introduce the 4-position leaving group _{X III} ^a marked with a benzoic acid derivative (III-II-1) and n- heptanol condensation by 4-position n- heptyloxy group, intermediate (III- II-2) is obtained. This step can be performed in the presence of a base in a polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran. As the base, an inorganic base such as sodium hydride, potassium hydroxide or potassium carbonate, an alkoxide such as potassium t-butoxide, or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene is used. Can be done. Examples of the 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 can be reacted in the presence of a base and a palladium catalyst. As the base, an organic base such as potassium acetate or diisopropylethylamine, or an inorganic base such as cesium carbonate or tripotassium phosphate can be used. As the palladium catalyst, palladium complexes such as dichlorobis (tricyclohexylphosphine) palladium (II) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) can be used. Further, a palladium compound such as palladium acetate and a reaction aid such as tri-t-butylphosphine can be used in combination. As the boric acid reagent, diboron compounds such as bis (neopentyl glycolate) diboron and bispinacolato diboron can be used. Examples of the reaction conditions include room temperature to reflux and 30 minutes to 24 hours. After the reaction, the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.

The fourth step is a reaction to convert the intermediate having cyclopentanone intermediate (III-II-4) having an activating group _{Y III} to (III-II-5). As the conditions of this step, when Y _III is a borate ester, general conjugate addition reaction conditions can be used. Specifically, ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran, hydrocarbon solvents such as toluene, highly polar solvents such as N, N-dimethylformamide, bases such as cesium carbonate and tripotassium phosphate, and palladium The reaction can be carried out in the presence of a catalyst. Also, the reaction is carried out in a hydrous or two-layer solvent such as tetrahydrofuran and water, 1,2-dimethoxyethane and water in the presence of a base such as sodium hydroxide, sodium carbonate, thallium hydroxide and a palladium catalyst. You can also. Furthermore, reaction aids such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl and 2- (di-t-butylphosphino) biphenyl can be added according to circumstances. Examples of the reaction conditions include room temperature to reflux and 30 minutes to 24 hours. After the reaction, the desired product can be obtained by performing extraction, washing, drying, solvent removal, etc. by a usual method, and purifying by silica gel column chromatography, recrystallization, etc. as necessary.

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 acids, and then the amino acid is obtained by reduction of the carboxylic acid. The reaction conditions for the step of converting to hydantoin include about 30 minutes to 48 hours at 0 ° C to 60 ° C. 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 to 120 ° C. for 30 minutes to 48 hours. The subsequent reduction from carboxylic acid to alcohol can be carried out by using a general method. Specific examples include metal hydrides such as diisobutylaluminum hydride, reduction with metal hydride complex compounds such as lithium aluminum hydride, reduction with diborane and substituted borane, and the like. The reaction conditions include -78 ° C to 100 ° C for about 30 minutes to 24 hours. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Of the compounds represented by the general formulas (III-1) and (III-2), R _III-2 is a hydrogen atom, X _III-1 is an oxygen atom, Y _III-1 is methylene, X _III-2 Is methine, A _III-2 is methylene, B _III is methylene, B _III is bonded to A _III-2 to form cyclopentane with Y _III , X _III-2 and the carbon atom to which the amino group is bonded. Other compounds can also be synthesized by the same method.

20) Among the compounds of the present invention, compound (III-I-2) wherein R _III-2 in general formula (III-1) is P (═O) (OH) ₂ is represented by the following scheme (III-III) Is synthesized.

(In the formula, _XIII-1 , _XIII-2 , YIII _-1 , _AIII-1 , _AIII-2 , _BIII and _RIII-1 have the same meanings as the symbols in general formula (III-1). .)
In this step, the compound (III-I-2) of the present invention is obtained by a known synthesis method (WO2007 / 069712, pages 53-56). The phosphorylated form (III-I-2) can be synthesized in three steps from the alcohol form (III-III-1) using the above known synthesis method. A compound in which R _{III-2 in} General Formula (III-2) is P (═O) (OH) ₂ can also be synthesized by the same method.

21) Among the compounds of the present invention, R _IV-3 in the general formula (IV-1) is a hydrogen atom, R _IV-2 is alkyl having 1 to 4 carbons, acyl having 1 to 20 carbons or alkoxycarbonyl. Compound (IV-I-1) to be synthesized is synthesized by the following scheme (IV-II).

(In the formula, R _IV-1 , R _IV-4 , X _IV and A _IV-1 have the same meanings as symbols 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 1 to 20 carbon atoms.)
In this step, the compound (IV-I-1) of the compound (IV-II-1) having a primary amino group is alkylated, acylated or alkoxycarbonylated. To get. For the alkylation of the amino group, a reductive amination reaction or an amine alkylation reaction using an alkyl halide and a base can be used. When a reductive amination reaction is used, an aldehyde having the same number of carbon atoms as R _IV ^a and the compound (IV-II-1) in an alcohol solvent such as methanol or a halogen solvent such as dichloroethane is borohydride. The target product can be obtained by reacting with a reducing agent such as sodium, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The reduction can also be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide. In this reaction, the generation of a Schiff base and the reduction reaction can also be sequentially performed. In this reductive amination reaction, an acid such as acetic acid can be added as a reaction accelerator. Examples of the reaction conditions include about 30 minutes to 10 hours at about 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. When R _IV ^a is methyl, it is also possible to use an Eschweiler-Clarke methylation reaction using a reducing agent such as formic acid and formaldehyde or formaldehyde and sodium cyanoborohydride. 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-layer system or a mixed solution of water and an organic solvent such as ethyl acetate or chloroform. Examples of the reagent used include acid chlorides such as acetyl chloride, stearoyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. In general formula (IV-2), R _IV-3 is a hydrogen atom, R _IV-2 is alkyl having 1 to 4 carbons, acyl having 1 to 20 carbons, or alkoxycarbonyl having 1 to 20 carbons. The compounds represented can also be synthesized by the same method.

22) Among the compounds of the present invention, compound (IV-I-2) in which R _IV-2 in general formula (IV-1) is a hydrogen atom is synthesized according to the following scheme (IV-III).

(In the formula, X _IV , A _IV-1 , R _IV-1 , R _IV-3 and R _IV-4 have the same meanings as those in the general formula (IV-1), and R _IV ^b represents a protecting group. .)
The protecting group represented by R _IV ^b in the formula is not particularly limited as long as it protects the amino group. For example, acyl (preferably having about 2 to 4 carbon atoms, specifically acetyl etc.), carbamate (specifically t-butyloxycarbonyl, benzyloxycarbonyl etc.) and the like can be mentioned.

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-layer system of an alcohol such as methanol, or water and an organic solvent such as ethyl acetate or chloroform. It can be carried out in a mixture. Examples of the reagent used include acid chlorides such as acetyl chloride and benzyloxycarbonyl chloride, and acid anhydrides such as acetic anhydride and di-t-butyl dicarbonate. In this reaction, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate can be added as a reaction accelerator. The reaction conditions may include about 30 minutes to 24 hours at 50 ° C. under ice cooling. After the reaction, purification or the like can be performed by a usual method to obtain the target product. Further, when R _IV-4 contains a hydroxyl group, the hydroxyl group can also be protected with an appropriate protecting group such as acyl, alkoxycarbonyl, benzyl and the like.

The second step is to convert the hydroxyl group of the protected amino group (IV-III-1) into a substituent R _IV-3 containing phosphorus. In this step, appropriate reagents and conditions are selected depending on the type of _RIV-3 . For example, when R _IV-3 is a bis (pivaloyloxymethyl) phosphoryl group, a combination of bis (pivaloyloxymethyl) phosphoryl chloride and triethylamine can be used, and R _IV-3 can be bis (S-acetyl). In the case of 2-thioethyl) phosphoryl group, mention is made of a method in which bis (S-acetyl-2-thioethyl) -N, N-diisopropyl phosphoramidite and 1H-tetrazole are reacted and then oxidized with metachloroperbenzoic acid. Can do. After the reaction, purification or the like can be performed by a usual method to obtain the target product.

The third step is a reaction for obtaining the compound (IV-I-2) of the present invention by deprotecting the protecting group of the intermediate (IV-III-2). The deprotection conditions are not particularly limited as long as they are used for deprotection of ordinary protecting groups. For example, when 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 a protective group such as t-butyloxycarbonyl is hydrochloric acid. And a method using an acid such as trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof at about 80 minutes at 80 ° C. under ice cooling 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. In addition, among the compounds represented by the general formula (IV-2), a compound in which R _IV-2 is a hydrogen atom can also be synthesized by the same method.

  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.).

  The compound of the present invention can treat or prevent autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes, etc.); human, dog, cat 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.).

  In the present invention, “prevention” means an act of administering the compound of the present invention or a pharmaceutical composition containing the same 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”.

  When the compound of the present invention is used as a pharmaceutical, the compound of the present invention is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, solubilizer, etc.) It can be administered orally or parenterally in the form of the resulting pharmaceutical composition or formulation (oral, injection, etc.). The pharmaceutical composition can be formulated according to a usual method.

  In this specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (transdermal administration, ophthalmic administration, transpulmonary / bronchial administration, nasal administration) Administration or rectal administration, etc.).

  The content of the compound of the present invention that can be combined with a carrier can vary depending on the individual to be treated and the particular dosage form. However, the specific dose for a specific patient will be determined according to various factors including age, weight, general health, sex, diet, administration time, method of administration, excretion rate and degree of specific disease being treated.

  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 subcutaneously, intravenously, intramuscularly, percutaneously, ophthalmically, pulmonary / bronchially, nasally or rectally, about 0.01-50 mg / person / day, orally about 0.01 to 150 mg / person / day is administered.

  In order to describe the present invention in more detail, examples are given below, but the present invention is not limited to these examples.

Example 1
2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (1-1) Synthesis of 8-fluorooctanol ( Compound 1-1)

  To a tetrahydrofuran (30 ml) solution of 8-bromooctanol (3.00 g) was added a 1 mol / l tetrahydrofuran solution (71.7 ml) of tetrabutylammonium fluoride, and the mixture was refluxed for 7 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.95 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.23 (1H, brs), 1.32-1.44 (8H, m), 1.54-1.61 (2H, m), 63-1.69 (1H, m), 1.69-1.76 (1H, m), 3.64 (2H, t, J = 6.5 Hz), 4.43 (2H, dt, J = 47) .2, 6.2 Hz).

  (1-2) Synthesis of 1-fluoro-8-iodooctane (Compound 1-2)

  Compound 1-1 (1.93 g) was dissolved in methylene chloride (40 ml), triethylamine (1.98 ml) and methanesulfonyl chloride (1.06 ml) were added under ice cooling, and the mixture was stirred as such for 40 minutes under ice cooling. The reaction mixture was diluted with methylene chloride (60 ml), the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Sodium iodide (2.15 g) was added to a solution of the obtained residue in 2-butanone (80 ml), and the mixture was refluxed for 3 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product (3.16 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.32-1.44 (8H, m), 1.62-1.69 (1H, m), 1.69-1.75 (1H, m ), 1.82 (2H, quint, J = 7.1 Hz), 3.19 (2H, t, J = 7.0 Hz), 4.44 (2H, dt, J = 47.1, 6.2 Hz) .

  (1-3) (5- {2- [4- (8-Fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (compound 1-3)

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane- synthesized by a known method (for example, WO2007 / 069712, pp. 58-62) 5-yl} carbamic acid t-butyl ester (500 mg) was dissolved in N, N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 1-2 (349 mg) were added, and the mixture was heated at 80 ° C. for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (440 mg) as a white solid.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.30-1.42 (6H, m), 1.42-1.53 (2H, m), 1.43 (3H, s), 44 (3H, s), 1.47 (9H, s), 1.62-1.69 (1H, m), 1.69-1.77 (1H, m), 1.77-1.83 ( 2H, m), 1.92-1.98 (2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 ( 2H, d, J = 11.7 Hz), 4.00 (2H, t, J = 6.3 Hz), 4.44 (2H, dt, J = 47.2, J = 6.2 Hz), 5.00 (1H, brs), 6.88 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.35 (1H, d, J = 1.6 Hz) .

  (1-4) Synthesis of 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 1-4) )

  Compound 1-3 (440 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (330 mg) as a white powder.

MS (ESI) m / z: 410 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.25-1.51 (8H, m), 1.55-1.80 (6H, m), 2.58-2.63 (2H) M), 3.52 (4H, d, J = 4.8 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.42 (2H, dt, J = 47.6, 6. 2Hz), 5.41 (2H, t, J = 5.1 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.86 ( 3H, brs).

Example 2
(Z) -2-amino-2- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (2-1) (Z) -2 Synthesis of -amino-2- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 2-1)

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), cis-4-hepten-1-ol (0.404 ml) and {5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography, and (Z)-(5- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3- Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (430 mg) as a white powder.

MS (ESI) m / z: 376 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 7.5 Hz), 1.71-1.80 (4H, m), 1.94-2.02 (2H, m), 2.14-2.21 (2H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.05 (2H, t, J = 5.9 Hz), 5.33-5.42 (4H, m), 7.17 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.85 (3H, brs).

Example 3
(E) -2-amino-2- {2- [4- (2-heptenyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (3-1) (E) -2- Synthesis of amino-2- {2- [4- (2-heptenyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (Compound 3-1)

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), trans-2-hepten-1-ol (0.409 ml) and {5- [2 -(4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography, and (E)-(5- {2- [4- (2-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3- Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.

MS (ESI) m / z: 376 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.87 (3H, t, J = 7.1 Hz), 1.23-1.37 (4H, m), 1.74-1.78 (2H, m), 2.02-2.08 (2H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.40 (2H, t, J = 5.1 Hz), 5.63 (1H, dt, J = 15.3, 5.6 Hz), 5.85 ( 1H, dt, J = 15.3, 6.8 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.86 (3H, brs) ).

Example 4
2-amino-2- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (4-1) 2-amino-2- {2- Synthesis of [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 4-1)

  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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a pale yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was concentrated, and the residue was washed with diethyl ether to obtain a white powder. The white powder was purified by HPLC, and hydrogen chloride-containing ether (1 mol / l, 15 ml) was added to the resulting residue to form a hydrochloride. The precipitate was collected by filtration and dried to give the desired product (420 mg) as a white powder. Obtained.

MS (ESI) m / z: 376 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.38-1.49 (4H, m), 1.68-1.80 (4H, m), 2.00-2.07 (2H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.94 (1H, d, J = 10.2 Hz), 5.00 (1H, dd, J = 17.2, 1.5 Hz), 5.40 (2H, t, J = 5.0 Hz), 5.80 ( 1H, ddt, J = 17.2, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.84 (3H, brs).

Example 5
2-Amino-2- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (5-1) Synthesis of 7-fluoroheptanol (Compound 5-1)

  To a tetrahydrofuran (50 ml) solution of 7-bromoheptanol (3.00 g) was added a 1 mol / l tetrahydrofuran solution (67.8 ml) of tetrabutylammonium fluoride, and the mixture was refluxed for 5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.97 g) as a pale-brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (1H, brs), 1.32-1.46 (6H, m), 1.55-1.61 (2H, m), 62-1.69 (1H, m), 1.69-1.76 (1H, m), 3.62-3.68 (2H, m), 4.44 (2H, dt, J = 47.6) 6.2 Hz).

  (5-2) Synthesis of 1-fluoro-7-iodoheptane (Compound 5-2)

  Compound 5-1 (1.97 g) was dissolved in methylene chloride (30 ml), triethylamine (2.64 ml) and methanesulfonyl chloride (1.25 ml) were added under ice cooling, and the mixture was stirred as it was under ice cooling for 4 hours. The reaction mixture was diluted with methylene chloride (60 ml), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Sodium iodide (2.43 g) was added to a solution of the obtained residue in 2-butanone (60 ml), and the mixture was refluxed for 3 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (3.31 g) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.32-1.46 (6H, m), 1.63-1.69 (1H, m), 1.69-1.75 (1H, m ) 1.76-1.87 (2H, m), 3.19 (2H, t, J = 7.0 Hz), 4.44 (2H, dt, J = 47.5, 6.2 Hz).

  (5-3) (5- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (compound 5-3)

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added to N, N. -Dissolved in dimethylformamide (10 ml), potassium carbonate (593 mg) and compound 5-2 (465 mg) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (630 mg) as a white solid.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 to 1.52 (6H, m), 1.43 (3H, s), 1.44 (3H, s), 1.47 (9H, s), 1.64-1.70 (1H, m), 1.70-1.78 (1H, m), 1.78-1.84 (2H, m), 1.92-1.98 ( 2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 (2H, d, J = 11.7 Hz), 4. 00 (2H, t, J = 6.3 Hz), 4.44 (2H, dt, J = 47.3, J = 6.1 Hz), 5.00 (1H, brs), 6.88 (1H, d , J = 8.4 Hz), 7.28 (1H, brs), 7.35 (1H, d, J = 1.9 Hz).

  (5-4) Synthesis of 2-amino-2- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 5-4 )

  Compound 5-3 (630 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (300 mg) as a white powder.

MS (ESI) m / z: 396 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.34-1.38 (4H, m), 1.38-1.48 (2H, m), 1.55-1.63 (2H) M), 1.63-1.79 (4H, m), 2.59-2.64 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.06 (2H) , T, J = 6.1 Hz), 4.43 (2H, dt, J = 47.4, 6.1 Hz), 5.41 (2H, t, J = 5.0 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.44-7.46 (2H, m), 7.89 (3H, brs).

Example 6
2-Amino-2- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (6-1) 2-amino-2- {2- Synthesis of [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 6-1)

  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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (330 mg) as a white powder.

MS (ESI) m / z: 374 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.90 (3H, t, J = 7.2 Hz), 1.36 to 1.46 (2H, m), 1.73-1.80 (2H, m), 2.07-2.12 (2H, m), 2.57-2.64 (4H, m), 3.52 (4H, d, J = 4.8 Hz), 4.13 (2H, t, J = 6.6 Hz), 5.40 (2H, t, J = 5.0 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.44-7.47 ( 2H, m), 7.87 (3H, brs).

Example 7
2-amino-2- {2- [4- (5-hexenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (7-1) 2-amino-2- {2 Synthesis of — [4- (5-hexenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 7-1)

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N. -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and 6-bromo-1-hexene (0.201 ml) were added, and the mixture was stirred at 80 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 560 mg of a colorless oil. The colorless oil (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.

MS (ESI) m / z: 362 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.46-1.54 (2H, m), 1.68-1.80 (4H, m), 2.05-2.11 (2H) M), 2.58-2.63 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.07 (2H, t, J = 6.2 Hz), 4.96. (1H, d, J = 10.2 Hz), 5.03 (1H, brd, J = 17.1 Hz), 5.39 (2H, t, J = 5.0 Hz), 5.81 (1H, ddt, J = 17.1, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.82 (3H, brs) ).

Example 8
2-amino-2- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (8-1) 2-amino-2- {2- Synthesis of [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 8-1)

  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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a pale yellow oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.

MS (ESI) m / z: 374 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.83 (3H, t, J = 7.2 Hz), 1.25-1.32 (2H, m), 1.33-1.42 (2H, m), 1.74-1.79 (2H, m), 2.19-2.23 (2H, m), 2.59-2.65 (2H, m), 3.52 (4H , D, J = 4.8 Hz), 4.90 (2H, s), 5.41 (2H, t, J = 5.1 Hz), 7.25 (1H, d, J = 9.2 Hz), 7 .47-7.49 (2H, m), 7.87 (3H, brs).

Example 9
2-Amino-2- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (9-1) Synthesis of 6-heptyn-1-ol (Compound 9-1)

  6-Heptynoic acid (2.00 g) was dissolved in 1,2-dichloroethane (30 ml), and catalytic amounts of N, N-dimethylformamide and oxalyl chloride (3.30 ml) were added at 0 ° C., and 2 at room temperature. Stir for hours. The temperature was returned again to 0 ° C., methanol (20 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then the solvent was concentrated. Diethyl ether and water were added to the resulting residue, extracted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oil. It was. The oil was dissolved in tetrahydrofuran (40 ml), 1 mol / l diisobutylaluminum hydride / toluene solution (36.9 ml) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 2 hours. (+)-Potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred while warming to room temperature, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (1.31 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.24 (1H, brs), 1.46-1.54 (2H, m), 1.54-1.63 (4H, m), 95 (1H, t, J = 2.6 Hz), 2.19-2.23 (2H, m), 3.63-3.69 (2H, m).

  (9-2) Synthesis of 2-amino-2- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 9-2)

  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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added and stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (6-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane-5 Yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (500 mg) as a white powder.

MS (ESI) m / z: 374 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.48-1.52 (4H, m), 1.69-1.78 (4H, m), 2.14-2.19 (2H) M), 2.56-2.63 (2H, m), 2.75 (1H, t, J = 2.4 Hz), 3.51 (4H, d, J = 4.6 Hz), 4.06 (2H, t, J = 6.2 Hz), 5.39 (2H, t, J = 5.0 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.43-7.45 ( 2H, m), 7.79 (3H, brs).

Example 10
2-amino-2- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (10-1) Synthesis of 6-fluorohexanol ( Compound 10-1)

  To a solution of 6-bromohexanol (3.00 g) in tetrahydrofuran (50 ml), a 1 mol / l tetrahydrofuran solution (78.5 ml) of tetrabutylammonium fluoride was added and refluxed for 5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.16 g) as a brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.24 (1H, brs), 1.36-1.49 (4H, m), 1.53-1.64 (2H, m), 64-1.71 (1H, m), 1.71-1.77 (1H, m), 3.63-3.67 (2H, m), 4.45 (2H, dt, J = 47.1) 6.2 Hz).

  (10-2) Synthesis of 1-fluoro-6-iodohexane (Compound 10-2)

  Compound 10-1 (1.16 g) was dissolved in methylene chloride (20 ml), triethylamine (1.76 ml) and methanesulfonyl chloride (0.896 ml) were added under ice cooling, and the mixture was stirred as it was under ice cooling for 3 hours. The reaction mixture was diluted with methylene chloride (20 ml), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Sodium iodide (1.74 g) was added to a solution of the obtained residue in 2-butanone (60 ml), and the mixture was refluxed for 6 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (1.76 g) as a pale-brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.40-1.52 (4H, m), 1.64-1.71 (1H, m), 1.71-1.79 (1H, m ), 1.80-1.89 (2H, m), 3.20 (2H, t, J = 6.8 Hz), 4.45 (2H, dt, J = 47.5, 6.1 Hz).

  (10-3) (5- {2- [4- (6-Fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxan-5-yl) carbamic acid Synthesis of t-butyl ester (Compound 10-3)

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added to N, N. -Dissolved in dimethylformamide (10 ml), potassium carbonate (593 mg) and compound 10-2 (416 mg) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (500 mg) as a white solid.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42-1.60 (4H, m), 1.43 (3H, s), 1.44 (3H, s), 1.47 (9H, s), 1.66-1.74 (1H, m), 1.74-1.79 (1H, m), 1.79-1.85 (2H, m), 1.94-1.99 ( 2H, m), 2.51-2.56 (2H, m), 3.69 (2H, d, J = 11.7 Hz), 3.89 (2H, d, J = 11.7 Hz), 4. 01 (2H, t, J = 6.2 Hz), 4.45 (2H, dt, J = 47.5, J = 6.1 Hz), 4.99 (1H, brs), 6.88 (1H, d , J = 8.4 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.35 (1H, d, J = 1.6 Hz).

  (10-4) Synthesis of 2-amino-2- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 10-4) )

  Compound 10-3 (500 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (370 mg) as a white powder.

MS (ESI) m / z: 382 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.38-1.49 (4H, m), 1.58-1.64 (1H, m), 1.64-1.79 (5H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.7 Hz), 4.07 (2H, t, J = 6.2 Hz), 4.43 (2H, dt, J = 47.5, 6.1 Hz), 5.40 (2H, t, J = 5.0 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.43− 7.46 (2H, m), 7.83 (3H, brs).

Example 11
2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (11-1) 2-amino-2- { Synthesis of 2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 11-1)

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N. -Dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and 8-bromo-1-octene (0.247 ml) were added, and the mixture was stirred at 80 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 610 mg of a pale yellow oil. The pale yellow oil (610 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (440 mg) as a white powder.

MS (ESI) m / z: 390 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.29-1.46 (6H, m), 1.66-1.79 (4H, m), 1.98-2.05 (2H) M), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.8 Hz), 4.06 (2H, t, J = 6.2 Hz), 4.93. (1H, d, J = 10.2 Hz), 5.03 (1H, dd, J = 17.2, 1.9 Hz), 5.40 (2H, t, J = 5.1 Hz), 5.80 ( 1H, ddt, J = 17.2, 10.2, 6.7 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.85 (3H, brs).

Example 12
2-Amino-2- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (12- 1) 2-amino-2- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride Synthesis (Compound 12-1)

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 4,4,5,5,5-pentafluoropentanol (0.406 ml) and {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added at room temperature. For 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} -2,2 -Dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester was obtained as a colorless oily substance, and concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml) at 80 ° C. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (590 mg) as a white powder.

MS (ESI) m / z: 440 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.72-1.79 (2H, m), 1.93-2.02 (2H, m), 2.30-2.45 (2H) M), 2.58-2.67 (2H, m), 3.51 (4H, d, J = 4.6 Hz), 4.18 (2H, t, J = 5.9 Hz), 5.39. (2H, t, J = 4.9 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.45-7.48 (2H, m), 7.77 (3H, brs).

Example 13
2-amino-2- {2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (13-1) 2-amino-2- { Synthesis of 2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 13-1)

  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 stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (5- {2- [4- (1-ethylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2,2-dimethyl-1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (460 mg) as a white powder.

MS (ESI) m / z: 406 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 6.9 Hz), 0.88 (3H, t, J = 7.4 Hz), 1.19-1 .39 (8H, m), 1.54-1.69 (4H, m), 1.73-1.79 (2H, m), 2.57-2.62 (2H, m), 3.52 (4H, d, J = 4.8 Hz), 4.42-4.48 (1H, m), 5.41 (2H, t, J = 5.1 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.44 (1H, brs), 7.86 (3H, brs).

Example 14
(R) -2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (14-1) (R) Synthesis of 2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 14-1)

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml), 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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain (R)-(2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1, 3-Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (520 mg) as a white powder.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (3H, t, J = 6.8 Hz), 1.22 (3H, d, J = 6.1 Hz), 1.22-1 .31 (6H, m), 1.31-1.43 (2H, m), 1.52-1.66 (2H, m), 1.74-1.78 (2H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.55-4.62 (1H, m), 5.40 (2H, t, J = 5. 1 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.41-7.44 (2H, m), 7.83 (3H, brs).

Example 15
(S) -2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (15-1) (S) Synthesis of 2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 15-1)

  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-dioxan-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain (S)-(2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1, 3-Dioxane-5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (510 mg) as a white powder.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (3H, t, J = 6.9 Hz), 1.22 (3H, d, J = 5.9 Hz), 1.22-1 .31 (6H, m), 1.31-1.43 (2H, m), 1.52-1.67 (2H, m), 1.73-1.78 (2H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.7 Hz), 4.55-4.62 (1H, m), 5.39 (2H, t, J = 5. 1 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.41-7.44 (2H, m), 7.83 (3H, brs).

Example 16
2-amino-2- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (16-1) 2-amino-2- { Synthesis of 2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 16-1)

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (40 ml) and diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 2-octanol (0.469 ml) and {5- [2- (4-hydroxy- 3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a white solid. Concentrated hydrochloric acid (1.5 ml) was added to the solid ethanol (15 ml) solution, and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (470 mg) as a white powder.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.84 (3H, t, J = 6.9 Hz), 1.22 (3H, d, J = 6.0 Hz), 1.22-1 .31 (6H, m), 1.32-1.43 (2H, m), 1.52-1.67 (2H, m), 1.73-1.78 (2H, m), 2.56 -2.61 (2H, m), 3.51 (4H, d, J = 4.8 Hz), 4.55-4.61 (1H, m), 5.39 (2H, t, J = 5. 0 Hz), 7.20 (1H, d, J = 8.5 Hz), 7.40-7.44 (2H, m), 7.79 (3H, brs).

Example 17
(R) -2-amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (17-1) ( Synthesis of R) -2-amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 17-1 )

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N. -It dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and (R)-(-)-citronellyl bromide (0.291 ml) were added, and it stirred at 80 degreeC for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 680 mg of a white solid. The white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium carbon (200 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (420 mg) as a white powder.

MS (ESI) m / z: 420 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.84 (6H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.4 Hz), 1.10-1 .20 (3H, m), 1.21-1.36 (3H, m), 1.45-1.54 (2H, m), 1.60-1.70 (1H, m), 1.71 -1.79 (3H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.6 Hz), 4.04-4.14 (2H, m) 5.40 (2H, t, J = 5.0 Hz), 7.20 (1H, d, J = 8.7 Hz), 7.43-7.46 (2H, m), 7.83 (3H, brs).

Example 18
(S) -2-amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (18-1) ( Synthesis of S) -2-amino-2- {2- [4- (3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 18-1) )

  {5- [2- (4-Hydroxy-3-trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added to N, N. -It dissolved in dimethylformamide (10 ml), potassium carbonate (494 mg) and (S)-(+)-citronellyl bromide (0.291 ml) were added, and it stirred at 80 degreeC for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 740 mg of a white solid. The white solid (680 mg) was dissolved in ethyl acetate (20 ml), 10% palladium on carbon (400 mg) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (490 mg) as a white powder.

MS (ESI) m / z: 420 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.84 (6H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.5 Hz), 1.09-1 .20 (3H, m), 1.21-1.35 (3H, m), 1.45-1.54 (2H, m), 1.61-1.71 (1H, m), 1.72 -1.79 (3H, m), 2.58-2.63 (2H, m), 3.52 (4H, d, J = 4.9 Hz), 4.05-4.13 (2H, m) 5.40 (2H, t, J = 5.0 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.43-7.46 (2H, m), 7.83 (3H, brs).

Example 19
2-Amino-2- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (19-1) 2-methyl-1-heptanol Synthesis of Compound 19-1

  2-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (50 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice-cooling. The mixture was further stirred at room temperature for 20 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (1.73 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 to 1.44 (7H, m), 1.05-1.14 (1H, m), 1.20 to 1.42 (6H, m ), 1.57-1.66 (2H, m), 3.39-3.43 (1H, m), 3.48-3.53 (1H, m).

  (19-2) Synthesis of 2-amino-2- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 19-2) )

  Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.27 ml), compound 19-1 (0.310 ml) and {5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (500 mg) was added, and the mixture was stirred at room temperature for 4 and a half hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (290 mg) as a white powder.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.16-1 .39 (7H, m), 1.41-1.51 (1H, m), 1.73-1.78 (2H, m), 1.82-1.91 (1H, m), 2.57 -2.62 (2H, m), 3.51 (4H, d, J = 4.5 Hz), 3.82-3.86 (1H, m), 3.90-3.94 (1H, m) 5.39 (2H, t, J = 4.9 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.42-7.46 (2H, m), 7.76 (3H, brs).

Example 20
2-Amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (20-1) 6-methyl-1-heptanol (Compound 20-1)

  6-Methylheptanoic acid (2.00 g) was dissolved in tetrahydrofuran (60 ml), and a tetrahydrofuran-borane / tetrahydrofuran solution (1 mol / l, 17.7 ml) was added dropwise under ice cooling. The mixture was further stirred at room temperature for 4 hours. Water, 1 mol / l hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (1.72 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 1.14-1.25 (3H, m), 1.25-1.37 (4H) M), 1.48-1.60 (3H, m), 3.64 (2H, brs).

  (20-2) Synthesis of 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol hydrochloride (Compound 20-2) )

  Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), compound 20-1 (0.372 ml) and {5- [2- (4-hydroxy -3-Trifluoromethylphenyl) ethyl] -2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid t-butyl ester (600 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (2,2-dimethyl-5- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -1,3-dioxane- 5-yl) carbamic acid t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of the oily substance in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (530 mg) as a white powder.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (6H, d, J = 6.7 Hz), 1.12-1.18 (2H, m), 1.27-1.36 (2H, m), 1.36-1.43 (2H, m), 1.46-1.55 (1H, m), 1.67-1.79 (4H, m), 2.58-2 .63 (2H, m), 3.52 (4H, d, J = 4.6 Hz), 4.06 (2H, t, J = 6.2 Hz), 5.42 (2H, t, J = 5. 0 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.43-7.46 (2H, m), 7.84 (3H, brs).

Example 21
2-Amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (21-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 4- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 21-1)

  N, N-Diisopropylethylamine (0.302 ml) and trimethyl orthoacetate (0.142 ml) were added to a solution of compound 1-4 (250 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 280 mg of a brown oil. To a solution of the brown oil (280 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (78 mg) and di-t-butyldiethylphosphoramidite (0.335 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.336 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (340 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.35 to 1.45 (6H, m), 1.48 (18H, s), 1.49 to 1.55 (2H, m), 1 .60-1.72 (2H, m), 1.73-1.89 (4H, m), 2.01 (3H, s), 2.52-2.70 (2H, m), 3.87 −3.93 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.40 (2H, dt, J = 47.6, 6.2 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8) .6 Hz), 7.40 (1H, brs).

  (21-2) Synthesis of 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 21-2)

  Compound 21-1 (340 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (200 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 490 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.35 to 1.46 (6H, m), 1.46 to 1.56 (2H, m), 1.61 to 1.68 (1H, m), 1.68-1.74 (1H, m), 1.75-1.82 (2H, m), 1.92-1.98 (2H, m), 2.63-2.72 ( 2H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.05 (2H, t, J = 6.2 Hz), 4.40 (2H, dt, J = 47.5, 6.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m).

Example 22
(Z) -2-amino-4- {4- (4-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (22-1) (Z) -4-di (t- Synthesis of (butyl) phosphoryloxymethyl-4- {2- [4- (4-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 22-1)

  To a solution of compound 2-1 (340 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.445 ml) and trimethyl orthoacetate (0.210 ml) were added and stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 370 mg of a brown oil. To a solution of the brown oil (370 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (116 mg) and di-t-butyldiethylphosphoramidite (0.497 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.498 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (300 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 7.5 Hz), 1.48 (18H, s), 1.79-1.90 (4H, m) 2.00-2.07 (2H, m), 2.01 (3H, s), 2.22-2.28 (2H, m), 2.52-2.70 (2H, m), 3 .87-3.94 (2H, m), 4.03 (2H, t, J = 6.0 Hz), 4.19 (1H, d, J = 9.0 Hz), 4.33 (1H, d, J = 9.0 Hz), 5.31-5.47 (2H, m), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.41 (1H, brs).

  (22-2) Synthesis of (Z) -2-amino-4- {4- (4-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 22-2)

  Compound 22-1 (300 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (300 mg ) Was obtained as a white solid.

MS (ESI) m / z: 456 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 7.5 Hz), 1.78-1.86 (2H, m), 1.91-2.00 ( 2H, m), 2.00-2.06 (2H, m), 2.22-2.28 (2H, m), 2.61-2.76 (2H, m), 3.70 (2H, brs), 3.94-4.01 (2H, m), 4.04 (2H, t, J = 5.9 Hz), 5.31-5.46 (2H, m), 7.06 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.46 (1H, brs).

Example 23
(E) -2-Amino-4- {4- (2-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (23-1) (E) -4-di (t- Synthesis of (butyl) phosphoryloxymethyl-4- {2- [4- (2-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 23-1)

  N, N-diisopropylethylamine (0.512 ml) and trimethyl orthoacetate (0.221 ml) were added to a solution of compound 3-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 380 mg of a brown oil. To a solution of the brown oil (380 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (133 mg) and di-t-butyldiethylphosphoramidite (0.569 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.570 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (530 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.90 (3H, t, J = 7.0 Hz), 1.28-1.40 (4H, m), 1.48 (18H, s) 1.79-1.89 (2H, m), 2.01 (3H, s), 2.06-2.12 (2H, m), 2.52-2.70 (2H, m), 3 .87-3.94 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.56 (2H, d, J = 5.5 Hz), 5.64 (1H, dt, J = 15.4, 5.5 Hz), 5.86 (1H, dt, J = 15.4, 6.9 Hz), 7.06 (1H , D, J = 8.5 Hz), 7.38 (1H, d, J = 8.5 Hz), 7.41 (1H, brs).

  (23-2) Synthesis of (E) -2-amino-4- {4- (2-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 23-2)

  Compound 23-1 (530 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (210 mg ) Was obtained as a white solid.

MS (ESI) m / z: 456 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.90 (3H, t, J = 7.0 Hz), 1.29-1.42 (4H, m), 1.91-2.00 ( 2H, m), 2.05-2.12 (2H, m), 2.61-2.74 (2H, m), 3.70 (2H, brs), 3.96-4.02 (2H, m), 4.57 (2H, d, J = 15.5 Hz), 5.65 (1H, dt, J = 15.4, 5.5 Hz), 5.86 (1H, dt, J = 15.4) 6.8 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.46 (1H, brs).

Example 24
2-Amino-4- {4- (6-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (24-1) 4-di (t-butyl) phosphoryloxymethyl-4- Synthesis of {2- [4- (6-heptenyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 24-1)

  To a solution of compound 4-1 (330 mg) in N, N-dimethylformamide (10 ml) was added N, N-diisopropylethylamine (0.431 ml) and trimethyl orthoacetate (0.203 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 350 mg of a brown oil. To a solution of the brown oil (350 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (112 mg) and di-t-butyldiethylphosphoramidite (0.479 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.480 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (430 mg) as an orange oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.44 to 1.54 (4H, m), 1.48 (18H, s), 1.75 to 1.87 (4H, m), 2 .01 (3H, s), 2.06-2.11 (2H, m), 2.52-2.70 (2H, m), 3.87-3.92 (2H, m), 4.04 (2H, t, J = 6.1 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 4.92 (1H, d, J = 10.4 Hz), 5.00 (1 H, dd, J = 17.1, 1.5 Hz), 5.82 (1 H, ddt, J = 17.1, 10.4, 6.5 Hz), 7 .05 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).

  (24-2) Synthesis of 2-amino-4- {4- (6-heptenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 24-2)

  Compound 24-1 (430 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (272 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 456 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.41-1.56 (4H, m), 1.75-1.83 (2H, m), 1.92-1.99 (2H, m), 2.05-2.11 (2H, m), 2.61-2.72 (2H, m), 3.70 (2H, brs), 3.94-4.01 (2H, m) 4.04 (2H, t, J = 6.2 Hz), 4.92 (1H, d, J = 10.4 Hz), 4.99 (1H, dd, J = 17.0, 1.5 Hz), 5.82 (1H, ddt, J = 17.0, 10.4, 6.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m) .

Example 25
2-Amino-4- {4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (25-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 4- {2- [4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 25-1)

  N, N-Diisopropylethylamine (0.312 ml) and trimethyl orthoacetate (0.147 ml) were added to a solution of compound 5-4 (250 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 280 mg of a brown oil. To a solution of the brown oil (230 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (77 mg) and di-t-butyldiethylphosphoramidite (0.329 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.330 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.35 to 1.45 (4H, m), 1.48 (18H, s), 1.48 to 1.55 (2H, m), 1 .63-1.68 (1H, m), 1.68-1.74 (1H, m), 1.75-1.89 (4H, m), 2.01 (3H, s), 2.52 -2.70 (2H, m), 3.87-3.93 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9. 2Hz), 4.32 (1H, d, J = 9.2 Hz), 4.41 (2H, dt, J = 47.6, 6.2 Hz), 7.06 (1H, d, J = 8.6 Hz) ), 7.39 (1H, d, J = 8.6 Hz), 7.41 (1H, brs).

  (25-2) Synthesis of 2-amino-4- {4- (7-fluoroheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 25-2)

  Compound 25-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (160 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 476 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.39-1.46 (4H, m), 1.47-1.56 (2H, m), 1.62-1.68 (1H, m), 1.68-1.74 (1H, m), 1.74-1.82 (2H, m), 1.92-1.98 (2H, m), 2.63-2.72 ( 2H, m), 3.70 (2H, brs), 3.94-4.03 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 4.41 (2H, dt, J = 47.5, 6.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.42-7.45 (2H, m).

Example 26
2-Amino-4- {4- (3-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (26-1) 4-di (t-butyl) phosphoryloxymethyl-4- Synthesis of {2- [4- (3-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 26-1)

  To a solution of compound 6-1 (260 mg) in N, N-dimethylformamide (10 ml) was added N, N-diisopropylethylamine (0.342 ml) and trimethyl orthoacetate (0.159 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 240 mg of a brown oil. To a solution of the brown oil (240 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (85 mg) and di-t-butyldiethylphosphoramidite (0.360 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.360 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.96 (3H, t, J = 7.4 Hz), 1.43-1.53 (2H, m), 1.48 (18H, s) 1.80-1.90 (2H, m), 2.01 (3H, s), 2.08-2.14 (2H, m), 2.53-2.70 (4H, m), 3 .88-3.92 (2H, m), 4.11 (2H, t, J = 6.9 Hz), 4.18 (1H, d, J = 9.2 Hz), 4.32 (1H, d, J = 9.2 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.39-7.42 (2H, m).

  (26-2) Synthesis of 2-amino-4- {4- (3-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 26-2)

  Compound 26-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (180 mg ) Was obtained as a white solid.

MS (ESI) m / z: 454 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.96 (3H, brt, J = 7.3 Hz), 1.40-1.53 (2H, m), 1.90-2.02 ( 2H, m), 2.05-2.17 (2H, m), 2.58-2.78 (4H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.12 (2H, brt, J = 6.4 Hz), 7.10 (1H, brd, J = 8.4 Hz), 7.43-7.46 (2H, m).

Example 27
2-Amino-4- {4- (2-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (27-1) 4-di (t-butyl) phosphoryloxymethyl-4- Synthesis of {2- [4- (2-heptynyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 27-1)

  N, N-diisopropylethylamine (0.499 ml) and trimethyl orthoacetate (0.235 ml) were added to a solution of compound 8-1 (380 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 380 mg of a brown oil. To a solution of the brown oil (380 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (130 mg) and di-t-butyldiethylphosphoramidite (0.557 ml), and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.558 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.87 (3H, t, J = 7.3 Hz), 1.30-1.40 (2H, m), 1.40-1.54 ( 2H, m), 1.48 (18H, s), 1.82-1.90 (2H, m), 2.01 (3H, s), 2.18-2.22 (2H, m), 2 .53-2.70 (2H, m), 3.89-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.78 (2H, brs), 7.19 (1H, d, J = 8.4 Hz), 7.39-7.43 (2H, m).

  (27-2) Synthesis of 2-amino-4- {4- (2-heptynyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 27-2)

  Compound 27-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (345 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 454 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.88 (3H, t, J = 7.1 Hz), 1.28-1.41 (2H, m), 1.42-1.48 ( 2H, m), 1.91-2.05 (2H, m), 2.19-2.25 (2H, m), 2.60-2.78 (2H, m), 3.70 (2H, brs), 3.94-4.02 (2H, m), 4.79 (2H, brs), 7.20 (1H, d, J = 8.4 Hz), 7.44-7.47 (2H, m).

Example 28
2-Amino-4- {4- (6-fluorohexyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (28-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 4- {2- [4- (6-fluorohexyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2-oxazoline (Compound 28-1)

  N, N-diisopropylethylamine (0.373 ml) and trimethyl orthoacetate (0.174 ml) were added to a solution of compound 10-4 (290 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 310 mg of a brown oil. To a solution of the brown oil (310 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (97 mg) and di-t-butyldiethylphosphoramidite (0.413 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.414 ml) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (390 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.45 to 1.58 (4H, m), 1.48 (18H, s), 1.63-1.68 (1H, m), 1 .68-1.74 (1H, m), 1.75-1.89 (4H, m), 2.01 (3H, s), 2.53-2.69 (2H, m), 3.88 −3.92 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 4.42 (2H, dt, J = 47.4, 6.0 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.37-7.41 (2H, m) ).

  (28-2) Synthesis of 2-amino-4- {4- (6-fluorohexyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 28-2)

  Compound 28-1 (390 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (260 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 462 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.44 to 1.60 (4H, m), 1.62-1.70 (1H, m), 1.70-1.79 (1H, m) 1.79-1.85 (2H, m), 1.87-2.01 (2H, m), 2.60-2.76 (2H, m), 3.70 (2H, brs) 3.94-4.03 (2H, m), 4.03-4.10 (2H, m), 4.42 (2H, dt, J = 47.5, 6.0 Hz), 7.07 ( 1H, d, J = 8.2 Hz), 7.42-7.45 (2H, m).

Example 29
2-Amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (29-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 2-methyl-4- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 29-1)

  N, N-Diisopropylethylamine (0.379 ml) and trimethyl orthoacetate (0.177 ml) were added to a solution of compound 11-1 (300 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 300 mg of a brown oil. To a solution of the brown oil (300 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (98 mg) and di-t-butyldiethylphosphoramidite (0.419 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.420 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (370 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.35 to 1.45 (4H, m), 1.48 (18H, s), 1.48 to 1.54 (2H, m), 1 .74-1.80 (2H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.02-2.09 (2H, m), 2.52 -2.69 (2H, m), 3.88-3.91 (2H, m), 4.04 (2H, t, J = 6.2 Hz), 4.18 (1H, d, J = 9. 0 Hz), 4.32 (1 H, d, J = 9.0 Hz), 4.91 (1 H, d, J = 10.3 Hz), 4.99 (1 H, dd, J = 17.2, 1.4 Hz) ), 5.82 (1H, ddt, J = 17.2, 10.3, 6.9 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.38-7.41 (2H, brs).

  (29-2) Synthesis of 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 29-2)

  Compound 29-1 (370 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (220 mg ) Was obtained as a pale yellow solid.

MS (ESI) m / z: 470 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.33-1.45 (4H, m), 1.45-1.54 (2H, m), 1.74-1.81 (2H, m), 1.89-2.02 (2H, m), 2.03-2.10 (2H, m), 2.60-2.74 (2H, m), 3.70 (2H, brs) 3.94-4.01 (2H, m), 4.01-4.06 (2H, m), 4.87-4.92 (1H, m), 4.98 (1H, brd, J = 17.1 Hz), 5.81 (1H, ddt, J = 17.1, 10.2, 6.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.41-7.45 (2H, m).

Example 30
2-Amino-4- {4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (30-1) 4-di (T-Butyl) phosphoryloxymethyl-4- {2- [4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl] ethyl} -2-methyl-2- Synthesis of oxazoline (Compound 30-1)

  N, N-diisopropylethylamine (0.521 ml) and trimethyl orthoacetate (0.245 ml) were added to a solution of compound 12-1 (460 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 530 mg of a brown oil. To a solution of the brown oil (530 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (136 mg) and di-t-butyldiethylphosphoramidite (0.581 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.582 ml) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (630 mg) as a yellow solid.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.48 (18H, s), 1.82-1.88 (2H, m), 2.01 (3H, s), 2.03-2 .11 (2H, m), 2.28-2.40 (2H, m), 2.53-2.71 (2H, m), 3.88-3.92 (2H, m), 4.15 (2H, t, J = 5.8 Hz), 4.18 (1H, d, J = 9.2 Hz), 4.32 (1H, d, J = 9.2 Hz), 7.09 (1H, d, J = 8.5 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.43 (1H, brs).

  (30-2) Synthesis of 2-amino-4- {4- (4,4,5,5,5-pentafluoropentyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol ( Compound 30-2)

  Compound 30-1 (630 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with ethyl acetate, diethyl ether and methanol to obtain the desired product. (395 mg) was obtained as a pale yellow solid.

MS (ESI) m / z: 520 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 1.90-2.03 (2H, m), 2.04-2.19 (2H, m), 2.29-2.48 (2H, m) 2.62-2.81 (2H, m), 3.70 (2H, brs), 3.92-4.05 (2H, m), 4.14-4.19 (2H, m) 7.10 (1H, d, J = 8.4 Hz), 7.43-7.48 (2H, m).

Example 31
2-Amino-4- {4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (31-1) 4-di (t-butyl) Synthesis of phosphoryloxymethyl-2-methyl-4- {2- [4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 31-1)

  N, N-Diisopropylethylamine (0.491 ml) and trimethyl orthoacetate (0.230 ml) were added to a solution of compound 14-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 390 mg of a brown oil. To a solution of the brown oil (390 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) were added 1H-tetrazole (127 mg) and di-t-butyldiethylphosphoramidite (0.545 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.546 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.27 (3H, d, J = 5.8 Hz), 1.27-1. 36 (6H, m), 1.47-1.53 (2H, m), 1.49 (18H, s), 1.54-1.66 (1H, m), 1.67-1.74 ( 1H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.49-4.55 (1H, m), 7.06 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).

(31-2) Synthesis of 2-amino-4- {4-((1R) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 31-2)

  Compound 31-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, isopropyl alcohol (5 ml) and acetonitrile (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with acetonitrile to obtain the desired product (150 mg) as a pale yellow solid.

MS (ESI) m / z: 472 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.37 (6H, m), 1.27 (3H, d, J = 5.9 Hz), 1.37-1.54 (2H, m), 1.56-1.67 (1H, m), 1.68-1.76 (1H, m), 1.91- 1.99 (2H, m), 2.60-2.74 (2H, m), 3.70 (2H, brs), 3.94-4.03 (2H, m), 4.50-4. 89 (1H, m), 7.07 (1H, d, J = 8.5 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.44 (1H, brs).

Example 32
2-Amino-4- {4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (32-1) 4-di (t-butyl) Synthesis of phosphoryloxymethyl-2-methyl-4- {2- [4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 32-1)

  N, N-Diisopropylethylamine (0.491 ml) and trimethyl orthoacetate (0.230 ml) were added to a solution of compound 15-1 (390 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 400 mg of a brown oil. To a solution of the brown oil (400 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (127 mg) and di-t-butyldiethylphosphoramidite (0.545 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.546 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (570 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 6.7 Hz), 1.26-1.35 (6H, m), 1.27 (3H, d, J = 6.0 Hz), 1.47-1.52 (2H, m), 1.48 (18H, s), 1.55-1.66 (1H, m), 1.67-1.75 ( 1H, m), 1.81-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 4.49-4.55 (1H, m), 7.06 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).

(32-2) Synthesis of 2-amino-4- {4-((1S) -1-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 32-2)

  Compound 32-1 (570 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, isopropyl alcohol (5 ml) and acetonitrile (5 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with acetonitrile to obtain the desired product (200 mg) as a pale yellow solid.

MS (ESI) m / z: 472 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.37 (6H, m), 1.27 (3H, d, J = 5.9 Hz), 1.37-1.50 (2H, m), 1.56-1.66 (1H, m), 1.67-1.75 (1H, m), 1.92- 1.99 (2H, m), 2.60-2.73 (2H, m), 3.71 (2H, brs), 3.95-4.04 (2H, m), 4.51-4. 57 (1H, m), 7.07 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.44 (1H, brs).

Example 33
2-Amino-4- {4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (33-1) 4-di (t- Synthesis of (butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 33) -1)

  N, N-diisopropylethylamine (0.390 ml) and trimethyl orthoacetate (0.182 ml) were added to a solution of compound 17-1 (330 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 320 mg of a brown oil. To a solution of the brown oil (320 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (101 mg) and di-t-butyldiethylphosphoramidite (0.431 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.432 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (310 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.8 Hz), 1.10-1. 20 (3H, m), 1.26-1.39 (3H, m), 1.47-1.57 (2H, m), 1.48 (18H, s), 1.70-1.78 ( 1H, m), 1.79-1.90 (3H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.03-4.12 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 7.07 ( 1H, d, J = 8.3 Hz), 7.37-7.41 (2H, m).

(33-2) Synthesis of 2-amino-4- {4-((3R) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (compound 33- 2)

  Compound 33-1 (310 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (180 mg ) Was obtained as a white solid.

MS (ESI) m / z: 500 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.88 (6H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.5 Hz), 1.14-1. 22 (3H, m), 1.23-1.41 (3H, m), 1.48-1.60 (2H, m), 1.68-1.78 (1H, m), 1.79- 1.87 (1H, m), 1.92-1.99 (2H, m), 2.60-2.75 (2H, m), 3.70 (2H, brs), 3.95-4. 04 (2H, m), 4.05-4.15 (2H, m), 7.08 (1H, d, J = 8.3 Hz), 7.42-7.45 (2H, m).

Example 34
2-Amino-4- {4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (34-1) 4-di (t- Synthesis of (butyl) phosphoryloxymethyl-2-methyl-4- {2- [4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 34) -1)

  N, N-Diisopropylethylamine (0.426 ml) and trimethyl orthoacetate (0.200 ml) were added to a solution of compound 18-1 (360 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 340 mg of a brown oil. To a solution of the brown oil (340 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (108 mg) and di-t-butyldiethylphosphoramidite (0.461 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.462 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (330 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.87 (6H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.8 Hz), 1.10-1. 21 (3H, m), 1.26-1.39 (3H, m), 1.47-1.59 (2H, m), 1.48 (18H, s), 1.70-1.77 ( 1H, m), 1.78-1.90 (3H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.88-3.92 (2H, m), 4.03-4.12 (2H, m), 4.18 (1H, d, J = 9.0 Hz), 4.32 (1H, d, J = 9.0 Hz), 7.08 ( 1H, d, J = 8.2 Hz), 7.38-7.41 (2H, m).

(34-2) Synthesis of 2-amino-4- {4-((3S) -3,7-dimethyloctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 34- 2)

  Compound 34-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (170 mg ) Was obtained as a white solid.

MS (ESI) m / z: 500 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.88 (6H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.4 Hz), 1.13-1. 21 (3H, m), 1.22-1.41 (3H, m), 1.48-1.60 (2H, m), 1.68-1.78 (1H, m), 1.78- 1.87 (1H, m), 1.91-1.99 (2H, m), 2.60-2.72 (2H, m), 3.70 (2H, brs), 3.94-4. 04 (2H, m), 4.05-4.13 (2H, m), 7.08 (1H, d, J = 8.3 Hz), 7.42-7.45 (2H, m).

Example 35
2-Amino-4- {4- (2-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (35-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 2-methyl-4- {2- [4- (2-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 35-1)

  N, N-Diisopropylethylamine (0.302 ml) and trimethyl orthoacetate (0.146 ml) were added to a solution of compound 19-2 (240 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at 120 ° C. for 5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 230 mg of a brown oil. To a solution of the brown oil (230 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (77 mg) and di-t-butyldiethylphosphoramidite (0.329 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.330 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (240 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.90 (3H, t, J = 6.8 Hz), 1.03 (3H, d, J = 6.7 Hz), 1.22-1. 41 (7H, m), 1.48 (18H, s), 1.48-1.57 (1H, m), 1.80-1.88 (2H, m), 1.88-1.96 ( 1H, m), 2.09 (3H, s), 2.52-2.69 (2H, m), 3.80-3.92 (4H, m), 4.18 (1H, d, J = 8.9 Hz), 4.32 (1H, d, J = 8.9 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.40 (1H, brs).

(35-2) Synthesis of 2-amino-4- {4- (2-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 35-2)

  Compound 35-1 (240 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 50 ° C. for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (125 mg ) Was obtained as a white solid.

MS (ESI) m / z: 472 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.90 (3H, t, J = 6.9 Hz), 1.04 (3H, d, J = 6.8 Hz), 1.21-1. 45 (7H, m), 1.50-1.60 (1H, m), 1.88-1.99 (3H, m), 2.60-2.72 (2H, m), 3.70 ( 2H, brs), 3.82-3.92 (2H, m), 3.94-4.03 (2H, m), 7.06 (1H, d, J = 8.4 Hz), 7.42- 7.45 (2H, m).

Example 36
2-Amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (36-1) 4-di (t-butyl) phosphoryloxymethyl- Synthesis of 2-methyl-4- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} -2-oxazoline (Compound 36-1)

  To a solution of compound 20-2 (420 mg) in N, N-dimethylformamide (10 ml), N, N-diisopropylethylamine (0.528 ml) and trimethyl orthoacetate (0.248 ml) were added and stirred at 120 ° C. for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2450 mg of a brown oil. To a solution of the brown oil (450 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (137 mg) and di-t-butyldiethylphosphoramidite (0.586 ml), and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.588 ml) was added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (520 mg) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (6H, d, J = 6.4 Hz), 1.18-1.23 (2H, m), 1.33-1.40 ( 2H, m), 1.45-1.57 (3H, m), 1.48 (18H, s), 1.73-1.80 (2H, m), 1.80-1.90 (2H, m), 2.01 (3H, s), 2.52-2.69 (2H, m), 3.85-3.92 (2H, m), 4.04 (2H, t, J = 6. 2 Hz), 4.18 (1H, d, J = 9.1 Hz), 4.32 (1H, d, J = 9.1 Hz), 7.05 (1H, d, J = 8.4 Hz), 7. 37-7.40 (2H, m).

(36-2) Synthesis of 2-amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol (Compound 36-2)

  Compound 36-1 (520 mg) was dissolved in ethanol (6 ml), concentrated hydrochloric acid (1.2 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. The solvent was concentrated under reduced pressure, methanol (5 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to obtain the desired product (285 mg ) Was obtained as a white solid.

MS (ESI) m / z: 472 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (6H, d, J = 6.6 Hz), 1.16 to 1.26 (2H, m), 1.32-1.42 ( 2H, m), 1.42-1.60 (3H, m), 1.72-1.85 (2H, m), 1.89-2.02 (2H, m), 2.60-2. 78 (2H, m), 3.70 (2H, brs), 3.82-3.99 (2H, m), 3.98-4.05 (2H, m), 7.07 (1H, d, J = 8.0 Hz), 7.42-7.45 (2H, m).

Example 37
[3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester (37-1) [3- (4-heptyloxy-3- Synthesis of (trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester (compound 37-1)

  2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride synthesized by a known method (for example, WO2007 / 069712, pages 58-63) Triethylamine (3.06 ml) and di-t-butyl dicarbonate (3.16 g) were added to a methanol (50 ml) solution of (3.00 g), and the mixture was stirred at room temperature for 22 hours. Furthermore, di-t-butyl dicarbonate (1.58 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Of the obtained residue, 590 mg was purified by silica gel column chromatography to obtain the desired product (440 mg) as a colorless oil.

MS (ESI) m / z: 378 [M-100 + H]
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.40 (6H, m), 1.41-1.50 (2H) , M), 1.46 (9H, s), 1.75-1.82 (2H, m), 1.83-1.89 (2H, m), 2.56-2.61 (2H, m) ), 3.31 (2H, brs), 3.62-3.67 (2H, m), 3.86-3.90 (2H, m), 4.00 (2H, t, J = 6.4 Hz) ), 5.03 (1H, brs), 6.89 (1H, d, J = 8.5 Hz), 7.26-7.29 (1H, m), 7.36 (1H, d, J = 1) .9 Hz).

Example 38
N- [3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] octadecanamide (38-1) N- [3- (4-heptyloxy-3-tri Synthesis of (fluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] octadecanamide (Compound 38-1)

  Chloroform (50 ml) of 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (1.00 g) and saturated aqueous sodium hydrogencarbonate ( 50 ml), stearoyl chloride (0.98 ml) was added with stirring under ice cooling, and the mixture was stirred under ice cooling for 2 hours and further at room temperature for 5 hours. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane (40 ml) was added to the residue and the precipitated solid was collected by filtration to obtain the desired product (1.21 g) as a white solid.

MS (ESI) m / z: 685 [M + CH ₃ CN + H]
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (3H, t, J = 6.6 Hz), 0.89 (3H, t, J = 6.6 Hz), 1.23-1.39 (34H, m), 1.42-1.50 (2H, m), 1.56-1.63 (2H, m), 1.80 (2H, quint, J = 6.9 Hz), 1.91 -1.95 (2H, m), 2.19 (2H, t, J = 7.6 Hz), 2.59-2.63 (2H, m), 3.61-3.67 (4H, m) 3.83-3.88 (2H, m), 4.00 (2H, t, J = 6.3 Hz), 5.90 (1H, brs), 6.90 (1H, d, J = 8. 5 Hz), 7.28 (1H, dd, J = 8.5, 2.0 Hz), 7.36 (1H, d, J = 2.0 Hz).

Example 39
2-Amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butanol tosylate (39-1) {3- (4-heptyloxy-3-trifluoro Synthesis of methylphenyl) -1-hydroxymethyl-1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39-1)

  To a solution of compound 37-1 (3.87 g) in methylene chloride (50 ml) was added N, N-diisopropylethylamine (1.95 ml) and methoxymethyl chloride (0.716 ml) under ice-cooling, and the mixture was cooled for 10 minutes under ice-cooling. The mixture was further stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain the desired product (1.94 g) and the raw material [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl). ) Propyl] carbamic acid t-butyl ester (1.44 g) was obtained as a colorless oil. To the methylene chloride (20 ml) solution of [3- (4-heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid t-butyl ester recovered above, N, N-Diisopropylethylamine (0.964 ml) and methoxymethyl chloride (0.353 ml) were added, and the mixture was stirred for 5 minutes under ice cooling and further for 14 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (990 mg) as a colorless oil. Combined with the target product obtained in the first reaction, the total amount of the target product was 2.93 g.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.40-1.49 (2H M), 1.45 (9H, s), 1.75-1.82 (2H, m), 1.82-1.90 (1H, m), 2.00-2.09 (1H, m ), 2.49-1.57 (1H, m), 2.61-2.77 (1H, m), 3.39 (3H, s), 3.50 (1H, d, J = 9.6 Hz) ), 3.72-3.78 (4H, m), 4.00 (2H, t, J = 6.3 Hz), 4.65 (2H, s), 5.17 (1H, brs), 6. 88 (1H, d, J = 8.4 Hz), 7.26-7.29 (1H, m), 7.36 (1H, d, J = 1.6 Hz).

  (39-2) Synthesis of {1-formyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39-2) )

  Compound 39-1 (1.94 g) was dissolved in dimethyl sulfoxide (50 ml), triethylamine (3.40 ml) and sulfur trioxide pyridine complex (1.78 g) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (1.77 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.40-1.49 (2H M), 1.47 (9H, s), 1.75-1.82 (2H, m), 2.00-2.06 (1H, m), 2.38-2.41 (2H, m ), 2.53-2.59 (1H, m), 3.32 (3H, s), 3.82 (1H, d, J = 10.1 Hz), 3.98-4.02 (3H, m) ), 4.59 (2H, s), 5.48 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7.22 (1H, dd, J = 8.5, 1 .9 Hz), 7.31 (1H, brs), 9.42 (1H, s).

  (39-3) Synthesis of {3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyethyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid t-butyl ester (Compound 39-3)

  (Methoxymethyl) triphenylphosphonium chloride (658 mg) was dissolved in tetrahydrofuran (30 ml), potassium t-butoxide (215 mg) was added, and the mixture was stirred for 10 minutes. A solution of compound 39-2 (500 mg) in tetrahydrofuran (10 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (methoxymethoxy) methyl-1- (2-methoxyvinyl) propyl] carbamic acid t- 290 mg of butyl ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (10 ml), 10% palladium carbon (100 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (240 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H) M), 1.44 (9H, s), 1.75-1.82 (2H, m), 1.90-2.20 (2H, m), 2.21-2.13 (2H, m) ), 2.55-2.60 (2H, m), 3.33 (3H, s), 3.38 (3H, s), 3.48-3.57 (2H, m), 3.69 ( 2H, brs), 4.00 (2H, t, J = 6.4 Hz), 4.63 (2H, s), 5.17 (1H, brs), 6.88 (1H, d, J = 8. 4 Hz), 7.26-7.29 (1 H, m), 7.36 (1 H, d, J = 1.9 Hz).

  (39-4) Synthesis of 2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butanol tosylate (Compound 39-4)

  Compound 39-3 (240 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was concentrated, ethyl acetate (5 ml) and methanol (5 ml) were added, p-toluenesulfonic acid monohydrate (84 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain the desired product (220 mg) as a white powder.

MS (ESI) m / z: 406 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.45 (2H, m), 1.65-1.72 (2H, m), 1.72-1.80 (2H, m), 1.85 (2H, t, J = 6.4 Hz), 2.29 (3H, s), 2.56-2.61 (2H, m), 3.25 (3H, s), 3.44-3.51 (4H, m), 4.06 (2H, t, J = 6.2 Hz), 5.50 (1H, brs), 7.11 (2H, d, J = 7.9 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.42-7 .48 (4H, m), 7.66 (3H, brs).

Example 40
2-Amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] pentane-1,5-dioltosylate (40-1) 4- (t-butoxy) carbonylamino-6 Synthesis of-(4-heptyloxy-3-trifluoromethylphenyl) -4-[(methoxymethoxy) methyl] hexanoic acid ethyl ester (Compound 40-1)

  Triethyl phosphonoacetate (518 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min. A solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and ethyl 4-t-butoxycarbonylamino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4-[(methoxymethoxy) methyl] -2-hexenoate 450 mg of the ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (15 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (450 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H, m), 1.45 (9H, s), 1.75-1.83 (2H, m), 1.84-1.95 (1H) M), 1.95-2.06 (2H, m), 2.11-2.19 (1H, m), 2.38 (2H, t, J = 8.0 Hz), 2.57 (2H) , T, J = 8.6 Hz), 3.38 (3H, s), 3.55-3.62 (2H, m), 4.00 (2H, t, J = 6.4 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.63 (2H, s), 4.76 (1H, brs), 6.88 (1H, d, J = 8.4 Hz), 7.26-7 .28 (1H, m), 7.35 ( H, d, J = 1.9Hz).

  (40-2) Synthesis of 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] pentane-1,5-dioltosylate (Compound 40-2)

  To a solution of compound 40-1 (450 mg) in ethanol (15 ml) was added sodium borohydride (61.0 mg) under ice cooling, and the mixture was stirred for 1 hour under ice cooling and further at room temperature for 15 hours. Again, the mixture was returned to ice-cooling, sodium borohydride (120 mg) was added, and the mixture was stirred under ice-cooling for 1 hour and further at room temperature for 22 hours. 1M Hydrochloric acid (100 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and {3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (3-hydroxypropyl) -1-[(methoxymethoxy) methyl] propyl} carbamic acid 370 mg of t-butyl ester was obtained as a colorless oil. Concentrated hydrochloric acid (1.5 ml) was added to a solution of this colorless oil (370 mg) in ethanol (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated, chloroform (5 ml) and methanol (5 ml) were added, p-toluenesulfonic acid monohydrate (127 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to obtain the desired product (355 mg) as a white powder.

MS (ESI) m / z: 406 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.49 (4H, m), 1.57-1.62 (2H, m), 1.68-1.78 (4H, m), 2.29 (3H, s), 2.54-2.59 (2H) M), 3.38-3.51 (5H, m), 4.06 (2H, t, J = 6.2 Hz), 5.50 (1H, brt, J = 4.5 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.42-7.48 (4H, m), 7.72 (3H, brs).

Example 41
3-Amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentanoic acid (41-1) [1-benzyloxymethyl-1-hydroxymethyl-3- (4- Synthesis of heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester (Compound 41-1)

  [3- (4-Heptyloxy-3-trifluoromethylphenyl) -1,1-bis (hydroxymethyl) propyl] carbamic acid benzyl ester synthesized by a known method (for example, WO2007 / 069712, pages 63-64) Benzyl bromide (0.513 ml) and silver oxide (1.48 g) were added to a toluene (30 ml) solution of 1.34 g), and the mixture was stirred at room temperature for 15 hours. The solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the desired product (1.05 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.38 (6H, m), 1.42-1.49 (2H) M), 1.75-1.82 (2H, m), 1.82-1.89 (1H, m), 2.01-2.10 (1H, m), 2.40-2.48. (1H, m), 2.52-2.61 (1H, m), 3.43 (1H, d, J = 9.1 Hz), 3.69 (1H, d, J = 9.1 Hz), 3 .70-3.76 (2H, m), 3.99 (2H, t, J = 6.4 Hz), 4.47-4.55 (2H, m), 4.71 (1H, d, J = 5.8Hz), 5.08 (2H, s), 5.48 (1H, brs), 6.86 (1H, d, J = 8.5Hz), 7.21 (1H, brd, J = 8. 2Hz), 7.26-7.36 11H, m).

  (41-2) Synthesis of [1-benzyloxymethyl-1-formyl-3- (4-heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester (Compound 41-2)

  To a mixed solution of compound 41-1 (1.05 g) and sodium bromide (198 mg) in toluene (10 ml), ethyl acetate (10 ml) and water (1 ml), 2,2,6,6-tetramethyl was added under ice cooling. Piperidine 1-oxyl and free radical (5.5 mg) were added, and then a 10% aqueous sodium hypochlorite solution (1.45 ml) and a solution of sodium hydrogen carbonate (425 mg) in water (5 ml) were added dropwise over 30 minutes. . The mixture was further stirred for 2 hours under ice cooling. The organic layer was separated and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (910 mg) as a pale brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.25-1.39 (6H, m), 1.41-1.49 (2H) M), 1.74-1.82 (2H, m), 1.98-2.08 (1H, m), 2.26-2.52 (3H, m), 3.75 (1H, d). , J = 9.8 Hz), 3.92 (1H, d, J = 9.8 Hz), 3.98 (2H, t, J = 6.3 Hz), 4.42-4.52 (2H, m) 5.10 (2H, s), 5.76 (1H, brs), 6.84 (1H, d, J = 8.5 Hz), 7.15 (1H, brd, J = 8.3 Hz), 7 .22-7.38 (11H, m), 9.39 (1H, s).

  (41-3) Synthesis of 3-benzyloxycarbonylamino-3-benzyloxymethyl-5- (4-heptyloxy-3-trifluoromethylphenyl) pentanoic acid (Compound 41-3)

  (Methoxymethyl) triphenylphosphonium chloride (1.56 g) was dissolved in tetrahydrofuran (30 ml), potassium t-butoxide (556 mg) was added, and the mixture was stirred for 10 minutes. A solution of compound 41-2 (910 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [1-benzyloxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyvinyl) propyl] carbamic acid benzyl ester was palely purified. 470 mg was obtained as a yellow oil. This pale yellow oil was dissolved in tetrahydrofuran (10 ml), concentrated hydrochloric acid (3 ml) and water (3 ml) were added, and the mixture was stirred at 60 ° C. for 2 hr. Saturated brine and ethyl acetate were added to the reaction solution, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [1-benzyloxymethyl-1- (formylmethyl) -3- (4-heptyloxy-3-trifluoromethylphenyl) propyl] carbamic acid benzyl ester was pale yellow oily. 210 mg was obtained as a product. This pale yellow oil was dissolved in t-butyl alcohol (8 ml) and water (2 ml), sodium dihydrogen phosphate (103 mg) and sodium chlorite (115 mg) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. . A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (220 mg) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.39 (6H, m), 1.42-1.50 (2H) M), 1.75-1.82 (2H, m), 2.05-2.19 (2H, m), 2.48-2.53 (2H, m), 2.80 (1H, d). , J = 14.7 Hz), 2.94 (1H, d, J = 14.7 Hz), 3.63-3.70 (2H, m), 3.99 (2H, t, J = 6.4 Hz) 4.51 (2H, s), 5.08 (2H, s), 5.49 (1H, brs), 6.85 (1H, d, J = 8.5 Hz), 7.19 (1H, brd) , J = 8.4 Hz), 7.26-7.38 (11H, m).

  (41-4) Synthesis of 3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentanoic acid (Compound 41-4)

  Compound 41-3 (220 mg) was dissolved in ethyl acetate (10 ml), 10% palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (45 mg) as a pale-brown oil.

MS (ESI) m / z: 406 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.8 Hz), 1.22-1.36 (6H, m), 1.37-1.46 (2H, m), 1.68-1.75 (2H, m), 1.75-1.88 (2H, m), 2.30-2.37 (2H, m), 2.54-2 .62 (2H, m), 3.30-3.70 (4H, brm), 4.05 (2H, t, J = 6.2 Hz), 7.17 (1H, d, J = 8.3 Hz) 7.39-7.42 (2H, m).

Example 42
Phosphoric acid mono [2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butyl] ester (42-1) [1-di (t-butyl) phosphoryl Synthesis of Oxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) -1- (2-methoxyethyl) propyl] carbamic acid t-butyl ester (Compound 42-1)

  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 solution, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 210 mg of a colorless oil. To a solution of the colorless oil (210 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) was added 1H-tetrazole (46 mg) and di-t-butyldiethylphosphoramidite (0.197 ml), and the mixture was stirred at room temperature for 2 hours. Half stirred. The reaction solution was ice-cooled, t-butyl hydroperoxide-containing decane solution (5-6 mol / l, 0.198 ml) was added, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (210 mg) as a colorless oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.28-1.40 (6H, m), 1.43 (9H, s) 1.47-1.52 (2H, m), 1.50 (18H, s), 1.72-1.81 (2H, m), 1.84-1.91 (1H, m), .96-2.08 (3H, m), 2.56-2.62 (2H, m), 3.33 (3H, s), 3.48-3.57 (2H, m), 4.03 (2H, t, J = 6.2 Hz), 4.10-4.16 (2H, m), 7.04 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.38 (1H, brs).

  (42-2) Synthesis of phosphoric acid mono [2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (2-methoxyethyl) butyl] ester (Compound 42-2)

  Compound 42-1 (210 mg) was dissolved in methylene chloride (6 ml), hydrogen chloride-containing dioxane (4 mol / l, 3 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The solvent was concentrated under reduced pressure, methanol (3 ml), diethyl ether (2 ml) and propylene oxide (5 ml) were added to the residue. The precipitated powder was collected by filtration and washed with ethyl acetate and diethyl ether to give the desired product (25 mg ) Was obtained as a white solid.

MS (ESI) m / z: 486 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.27 to 1.42 (6H, m), 1.44 to 1.53 ( 2H, m), 1.73-1.82 (2H, m), 1.89-2.09 (4H, m), 2.62 (1H, td, J = 12.9, 4.7 Hz), 2.73 (1H, td, J = 12.9, 4.7 Hz), 3.37 (3H, s), 3.61-3.65 (2H, m), 3.97 (2H, d, J = 5.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 7.07 (1H, d, J = 8.2 Hz), 7.42-7.44 (2H, m).

Example 43
2-Amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (hydroxymethyl) butanoic acid (43-1) 2-t-butyloxycarbonylamino-4- (4-heptyloxy- Synthesis of 3-trifluoromethylphenyl) -2-[(methoxymethoxy) methyl] butanoic acid (Compound 43-1)

  Compound 39-2 (400 mg) was dissolved in t-butyl alcohol (16 ml) and water (4 ml), sodium dihydrogen phosphate (230 mg) and sodium chlorite (265 mg) were added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Stir. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (480 mg) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.24-1.39 (6H, m), 1.40-1.49 (2H) M), 1.47 (9H, s), 1.75-1.82 (2H, m), 2.08-2.12 (2H, m), 2.44-2.50 (1H, m ), 2.59-2.65 (1H, m), 3.36 (3H, s), 3.86 (1H, d, J = 9.8 Hz), 4.00 (2H, t, J = 6) .3 Hz), 4.09-4.13 (1H, m), 4.62-4.66 (2H, m), 5.67 (1H, brs), 6.88 (1H, d, J = 8). 0.5 Hz), 7.23-7.26 (1H, m), 7.33 (1H, brs).

  (43-2) Synthesis of 2-amino-4- (4-heptyloxy-3-trifluoromethylphenyl) -2- (hydroxymethyl) butanoic acid (Compound 43-2)

  Concentrated hydrochloric acid (1.5 ml) was added to a solution of compound 43-1 (480 mg) in dioxane (15 ml), and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction solution is concentrated, ethyl acetate (20 ml) is added, 1 mol / l aqueous sodium hydroxide solution is added until the pH is 7-8, and the precipitated powder is collected by filtration and washed with water and diethyl ether. Gave the desired product (250 mg) as a white solid.

MS (ESI) m / z: 392 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.22-1.36 (6H, m), 1.37-1.45 (2H, m), 1.68-1.75 (2H, m), 1.75-1.89 (2H, m), 2.45 (1H, td, J = 12.9, 4.8 Hz) 2.67 (1H, td, J = 12.9, 4.8 Hz), 3.30-3.50 (1H, brm), 3.52 (1H, d, J = 11.0 Hz), 3. 60 (1H, d, J = 11.0 Hz), 4.05 (2H, t, J = 6.2 Hz), 5.35 (1H, brs), 7.13-7.16 (1H, m), 7.36 (2H, brs).

Example 44
4-Amino-6- (4-heptyloxy-3-trifluoromethylphenyl) -4- (hydroxymethyl) hexanoic acid (44-1) 4-amino-6- (4-heptyloxy-3-trifluoromethyl) Synthesis of (phenyl) -4- (hydroxymethyl) hexanoic acid (Compound 44-1)

  Concentrated hydrochloric acid (1.5 ml) was added to a solution of compound 40-1 (260 mg) in dioxane (10 ml), and the mixture was stirred at 80 ° C. for 3 hours. Furthermore, water (1 ml) and concentrated hydrochloric acid (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated, ethyl acetate (20 ml) was added, 1 mol / l aqueous sodium hydroxide solution was added until the pH reached 7-8, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to obtain the desired product (110 mg) as a white solid.

MS (ESI) m / z: 420 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.9 Hz), 1.21-1.36 (6H, m), 1.37-1.44 (2H, m), 1.68-1.76 (4H, m), 1.82-1.88 (2H, m), 2.33-3.39 (2H, m), 2.56-2 .62 (2H, m), 3.30-3.50 (1H, brm), 3.47 (2H, brs), 4.06 (2H, t, J = 6.2 Hz), 5.54 (1H) , Brs), 7.18 (1H, d, J = 8.4 Hz), 7.45-7.48 (2H, m).

Example 45
[3-Amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid (45-1) {3- (t-butoxy) carbonylamino-5- ( Synthesis of 4-heptyloxy-3-trifluoromethylphenyl) -3-[(methoxymethoxy) methyl] pentyl} phosphonic acid diethyl ester (Compound 45-1)

  Tetraethyl methylene diphosphonate (663 mg) was dissolved in tetrahydrofuran (20 ml), sodium hydride (92 mg) was added, and the mixture was stirred for 30 min. A solution of compound 39-2 (600 mg) in tetrahydrofuran (20 ml) was added dropwise to the mixed solution under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and [3-t-butoxycarbonylamino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (methoxymethoxy) methyl-1-pentenyl] phosphonic acid 730 mg of diethyl ester was obtained as a colorless oil. This colorless oil was dissolved in ethyl acetate (15 ml), 10% palladium carbon (300 mg) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (650 mg) as a colorless oil.

¹ H-NMR (CD ₃ OD) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), 1.26-1.39 (6H, m), 1.32 (6H, t, J = 7.0 Hz), 1.42-1.50 (2H, m), 1.44 (9H, s), 1.73-1.82 (4H, m), 1.83-2.13 ( 4H, m), 2.54-2.59 (2H, m), 3.39 (3H, s), 3.58 (2H, brs), 4.00 (2H, t, J = 6.4 Hz) 4.05-4.13 (4H, m), 4.63 (2H, s), 4.71 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7.25. −7.27 (1H, m), 7.34 (1H, d, J = 1.5 Hz).

  (45-2) Synthesis of [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid (Compound 45-2)

  Compound 45-1 (650 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The solvent was concentrated under reduced pressure, trimethylsilyl bromide (2.67 ml) was added to a solution of the residue in methylene chloride (10 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, methanol (20 ml) was added, and the mixture was allowed to stand at room temperature for 24 hours, and then concentrated under reduced pressure. Methanol (10 ml), diethyl ether (2 ml) and propylene oxide (10 ml) were added to the residue, and the precipitated powder was collected by filtration and washed with methanol to obtain the desired product (435 mg) as a white solid.

MS (ESI) m / z: 456 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.91 (3H, t, J = 6.8 Hz), 1.28-1.42 (6H, m), 1.44 to 1.53 ( 2H, m), 1.57-1.68 (2H, m), 1.76-1.82 (2H, m), 1.83-1.99 (4H, m), 2.58-2. 72 (2H, m), 3.62 (2H, brs), 4.04 (2H, t, J = 6.2 Hz), 7.06 (1H, d, J = 8.3 Hz), 7.42− 7.45 (2H, m).

Example 46
[1-Amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol hydrochloride (46-1) Synthesis of 4-amino-1-heptyloxy-2-trifluoromethylbenzene hydrochloride ( Compound 46-1)

  4-heptyloxy-3-trifluoromethylbenzoic acid (50.0 g), diphenylphosphoric acid azide (49.7 g) and triethylamine (33.2 g) which can be synthesized by a known method (for example, WO2007 / 069712, pages 108-109). ) In t-butyl alcohol (360 ml) was heated to reflux for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residual brown oil (67.2 g) was dissolved in hydrogen chloride-containing dioxane (4 mol / l, 200 ml) and stirred at room temperature for 2 hours. Diisopropyl ether (300 ml) was added dropwise to the reaction solution and stirred for 30 minutes. The precipitated solid was collected by filtration to obtain the desired product (41.3 g) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.6 Hz), 1.27-1.44 (8H, m), 1.70-1.74 (2H, m), 4.11 (2H, t, J = 6.0 Hz), 7.35 (1H, d, J = 8.7 Hz), 7.50-7.60 (2H, m), 10 .11 (3H, brs).

  (46-2) Synthesis of 4-heptyloxy-1-iodo-3-trifluoromethylbenzene (Compound 46-2)

  Concentrated hydrochloric acid (70 ml) was added to a suspension of compound 46-1 (41.3 g) in water (620 ml), and a solution of sodium nitrite (9.56 g) in water (35 ml) was added dropwise under ice cooling and stirred for 30 minutes. . Further, a solution of potassium iodide (23.0 g) in water (35 ml) was added dropwise over 20 minutes, and then the temperature was gradually raised to room temperature (foaming started vigorously from an internal temperature of 13 ° C.). Further, the mixture was gradually heated to 80 ° C. while foaming slowly and stirred for 30 minutes. The reaction mixture was ice-cooled, 2% aqueous sodium sulfite solution (500 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the object product (29.2 g) as a red-brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.9 Hz), 1.30-1.56 (8H, m), 1.75-1.84 (2H M), 4.00 (2H, t, J = 6.3 Hz), 6.74 (1H, d, J = 8.7 Hz), 7.71-7.82 (2H, m).

  (46-3) Synthesis of 4-heptyloxy-3-trifluoromethylphenylboric acid (Compound 46-3)

  An n-butyllithium / hexane solution (1.57 mol / l, 21.0 ml) was added dropwise to a solution of compound 46-2 (11.6 g) in anhydrous tetrahydrofuran (160 ml) at −80 ° C. over 20 minutes, followed by stirring for 30 minutes. did. Trimethyl borate (15.6 g) was added all at once at the same temperature, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was ice-cooled to 0 ° C., 6 mol / l aqueous hydrochloric acid solution (110 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2 to 1: 1) to obtain the desired product (5.07 g) as a brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 6.6 Hz), 1.26 to 1.51 (8H, m), 1.83 to 1.88 (2H) M), 4.11 (2H, t, J = 6.3 Hz), 7.06 (1H, d, J = 8.4 Hz), 8.25 (1H, d, J = 8.4 Hz), 8 .31 (1H, s).

  (46-4) Synthesis of 4- (cyclopentanone-3-yl) -1-heptyloxy-2-trifluoromethylbenzene (Compound 46-4)

  To a solution of compound 46-3 (5.07 g), 2-cyclopenten-1-one (1.37 g) and sodium acetate (2.74 g) in acetic acid (150 ml), palladium acetate (375 mg) and antimony (III) chloride ( 381 mg) was added and stirred for 30 minutes. Trimethyl borate (15.6 g) was added at the same temperature, and the mixture was stirred at room temperature for 2 days. The reaction mixture was ice-cooled to 0 ° C., 6 mol / l hydrochloric acid aqueous solution (110 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (450 ml), diethyl ether (200 ml) was added, and the mixture was stirred for a while and filtered through celite. After the filtrate was separated, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 4) to obtain the desired product (3.29 g) as a brown oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 6.7 Hz), 1.30-1.58 (8H, m), 1.78-1.83 (2H M), 1.88-2.04 (1H, m), 2.12-2.54 (4H, m), 2.58-2.64 (1H, m), 3.30-3.48. (1H, m), 4.03 (2H, t, J = 6.2 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.34 (1H, dd, J = 2.1, 8.4 Hz), 7.44 (1H, d, J = 2.1 Hz).

  (46-5) Synthesis of [1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol hydrochloride (Compound 46-5)

  A suspension of compound 46-4 (3.29 g), sodium cyanide (0.94 g) and ammonium chloride (1.03 g) in 28% aqueous ammonia (20 ml) was stirred at room temperature for 2 days. The reaction solution was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and a mixed solution of the residual brown oil (3.49 g) in concentrated hydrochloric acid (60 ml) and ethanol (90 ml) was stirred at 80 ° C. for 43 hours. The solvent was distilled off under reduced pressure, ethanol (50 ml) and 2 mol / l aqueous lithium hydroxide solution (10 ml) were added to the residue, and the mixture was stirred at 80 ° C. for 4 hours. The solvent was distilled off under reduced pressure and concentrated to dryness. A borane-tetrahydrofuran complex / tetrahydrofuran solution (0.96 mol / l, 30 ml) of the obtained brown powder (3.67 g) was heated to reflux for 4 hours. The reaction solution was cooled, carefully added with 1 mol / l hydrochloric acid aqueous solution (40 ml), and heated under reflux for 30 minutes. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol = 100: 0 to 90:10), and further purified by HPLC to obtain 694 mg of the desired free base as a colorless oil. Got as. Among them, 470 mg was dissolved in diethyl ether (20 ml), and hydrogen chloride-containing dioxane (4 mol / l, 2.0 ml) was added. The solvent was distilled off under reduced pressure to obtain the desired product (296 mg) as a light brown solid. The target product obtained in this operation was a nearly 1: 1 geometric isomer mixture of cis and trans isomers.

MS (ESI) m / z: 373 [M + H]
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 6.7 Hz), 1.22-1.36 (6H, m), 1.39-1.44 (2H, m), 1.58-1.80 (4.5H, m), 1.89-1.99 (2H, m), 2.03-2.13 (1.5H, m), 2 .28 (0.5H, dd, J = 7.4, 13.2 Hz), 3.06-3.12 (0.5H, m), 3.34 (1H, brs), 3.42-3. 55 (2.5H, m), 4.07 (2H, t, J = 6.2 Hz), 5.58 (1H, m), 7.18 (0.5H, d, J = 8.6 Hz), 7.20 (0.5H, d, J = 8.6 Hz), 7.40 (0.5H, d, J = 1.4 Hz), 7.47 (0.5H, d, J = 8.6 Hz) 7.51 (0.5H, s), 7.54 0.5H, d, J = 8.6Hz), 8.15,8.18 (3H, brs × 2).

Example 47
Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester (47-1) [3- (4-heptyloxy-3-trifluoromethylphenyl) Synthesis of -1- (hydroxymethyl) cyclopentyl] carbamic acid t-butyl ester (Compound 47-1)

  Diisopropylethylamine (155 mg) and di-t-butyl dicarbonate (196 mg) were added to a methanol solution (18 ml) of compound 46-5 (224 mg), and the mixture was stirred at room temperature for 1 day. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 3) to obtain the desired product (256 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 7.2 Hz), 1.22-1.54 (7H, m), 1.45 (9H, s), 1.56-2.24 (8H, m), 2.35 (0.5H, dd, J = 7.4, 13.6 Hz), 2.47 (0.5H, dd, J = 7.5, 13.2 Hz), 3.02-3.14 (0.5 H, m), 3.25-3.37 (0.5 H, m), 3.62-3.82 (2 H, m), 3. 89 (1H, brs), 4.01 (2H, t, J = 6.3 Hz), 4.91 (0.5H, s), 4.95 (0.5H, s), 6.90 (1H, d, J = 8.4 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.40 (1H, dd, J = 1.8, 5.4 Hz).

  (47-2) Synthesis of [1- (di-t-butyl) phosphoryloxymethyl-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] carbamic acid t-butyl ester (Compound 47-2)

  Di-t-butyldiisopropyl phosphoramidite (177 mg) and 1H-tetrazole (45 mg) were added to a solution of compound 47-1 (256 mg) in methylene chloride (5 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C., m-chloroperbenzoic acid (25% hydrate, 112 mg) was added, and the mixture was stirred at room temperature for 2 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 9 to 2: 3) to give the object product (280 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.6 Hz), 1.16-2.25 (33H, m), 1.30 (9H, s), 2.30-2.52 (1H, m), 2.95-3.14 (0.5H, m), 3.29-3.52 (0.5H, m), 3.62-3.82 (0.5H, m), 3.94-4.10 (2.5H, m), 4.01 (2H, t, J = 6.3 Hz), 4.90-5.15 (1H, m) 6.90 (1H, d, J = 8.4 Hz), 7.29-7.42 (2H, m).

  (47-3) Synthesis of phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester (Compound 47-3)

  Compound 47-2 (280 mg) was dissolved in ethanol (10 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (50 ml) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water and diethyl ether to obtain the desired product (66 mg) as a white solid. The target product obtained in this operation was a nearly 1: 1 geometric isomer mixture of cis and trans isomers.

MS (ESI) m / z: 453 [M + H]
¹ H-NMR (CD ₃ OD) δ (ppm): 0.91 (3H, t, J = 6.7 Hz), 1.29-1.40 (6H, m), 1.47-1.52 ( 2H, m), 1.69 (0.5H, t, J = 12.8 Hz), 1.76-1.83 (3H, m), 1.89-2.03 (2H, m), 2. 15-2.30 (2H, m), 2.54 (0.5H, dd, J = 7.4, 13.2 Hz), 3.06-3.12 (0.5H, m), 3.18 -3.26 (0.5H, m), 3.87-3.98 (2H, m), 4.05 (2H, t, J = 6.1 Hz), 7.087 (0.5H, d, J = 8.5 Hz), 7.095 (0.5 H, d, J = 8.6 Hz), 7.44-7.49 (2 H, m).

Experimental Example 1: Evaluation of mouse peripheral blood lymphocyte count reducing action The compound of the present invention was dissolved or suspended in 20% cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and dosed from 0.001 to 10 mg / kg body weight. It was intraperitoneally administered to 10-week-old male BALB / c mice (Nippon Charles River). Three or 24 hours after administration of the compound of the present invention, peripheral blood was collected from the posterior vena cava of mice under ether anesthesia using a tuberculin syringe (Terumo) treated with sodium heparin (Novo Nordisk). About 0.3 ml was collected. After 0.1 ml of blood was hemolyzed using an automatic hemolyzer (TQ-Prep, manufactured by Beckman Coulter), a known number of standard particles were used using a flow cytometer (CYTOMICS FC 500, manufactured by Beckman Coulter). The number of lymphocytes was measured by a gating method using Flow-Count ^™ Fluorospheres (manufactured by Beckman Coulter, Inc.) as an internal standard and using forward and side scatter of laser light as an index. When the number of lymphocytes in the vehicle group was taken as 100%, the dose at which the lymphocyte count was reduced by 50% was calculated and taken as the ED ₅₀ value (mg / kg body weight). The ED ₅₀ values of the mouse peripheral blood lymphocyte count reducing activity 24 hours after administration of Compound 1-4, Compound 11-1, and Compound 20-2 are 0.07, 0.08, and 0.15 mg / kg body weight, respectively. there were. The ED ₅₀ value of the mouse peripheral blood lymphocyte count reducing effect 3 hours after administration of Compound 45-2 was 0.17 mg / kg body weight.

Experimental Example 2: Effect on heart rate of anesthetized rat Anesthesia was performed by intraperitoneally administering Nembutal (Dainippon Sumitomo Pharma Co., Ltd.) to male Sprague-Dawley (IGS) rats, and then fixed to the dorsal position. Electrodes were attached to the limbs, and an electrocardiogram was measured by a standard limb II induction method using an electrocardiogram amplifier (AC-601G, manufactured by Nihon Kohden). Heart rate was counted from an instantaneous heart rate monitor unit (AT-601G, manufactured by Nihon Kohden Co., Ltd.) using an electrocardiogram wave as a trigger. The compound of the present invention was dissolved in 20% cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and administered intravenously at a dose of 0.001 to 10 mg / kg body weight over 30 seconds. Heart rate was measured before administration, 1, 2, 3, 4, 5, 10 and 15 minutes after administration. Compound 29-2 and Compound 45-2, which are phosphates of Compound 11-1, did not decrease the heart rate of rats by 20% or more compared to the pre-dose value up to a dose of 0.03 mg / kg body weight. .

  From the results of Experimental Example 1 above, the compound of the present invention has an excellent peripheral blood lymphocyte depletion action, and therefore can be expected to show an excellent immunosuppressive action, rejection inhibitory action, and allergy inhibitory action. Treatment or prevention of immune diseases; resistance to organ or tissue transplantation or prevention or suppression of acute rejection or chronic rejection; treatment or prevention of graft-versus-host (GvH) disease by bone marrow transplantation; for treatment or prevention of allergic diseases It is considered effective. Furthermore, it is considered that the compound of the present invention is a compound in which side effects such as bradycardia are reduced based on the results of Experimental Example 2 described above.

Claims (45)

The following general formula (I)

(Wherein 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 alkyl having 1 to 4 carbon atoms,
A _I represents straight-chain alkyl having 5 to 9 carbon atoms, and A _I has 1 to 6 functional groups selected from any of the following four groups a to d. a, alkyl having 1 to 6 carbon atoms; When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded can also form a cycloalkyl having 3 to 6 carbon atoms. b, a halogen atom. c, a double bond, a triple bond, an oxygen atom, a sulfur atom, or a cycloalkyl having 3 to 6 carbon atoms in the chain. d, double bond and triple bond at the chain end. Indicates. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The following general formula (II-1) or (II-2)

(Wherein 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 a linear alkyl having 5 to 9 carbon atoms, and A _II-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
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 aryl atom having 1 to 2 nitrogen atoms, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
A _II-2 is a hydrogen atom, P (═O) (OH) ₂ , O—P (═O) (OH) ₂ , COOH, SO ₃ H, 1H-tetrazol-5-yl, OH, or C 1 -C 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. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The following general formula (III-1) or (III-2)

(Wherein 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 a linear alkyl having 5 to 9 carbon atoms, and A _III-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, an alkyl having 1 to 6 carbon atoms. When two alkyl groups are substituted on the same carbon atom, the two alkyl groups and the carbon atom to which they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
Y _III-2 is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
A _III-3 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
A _III-2 is a hydrogen atom or alkyl having 1 to 3 carbon atoms,
B _III represents an alkyl having 1 to 4 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group or may be substituted with a halogen atom, B _III is bonded to A _III-2, and Y _III-1 , X _III-2 , A _III-2 , B _III and a carbon atom to which the amino group is bonded contain a 4- to 7-membered cycloalkane or a nitrogen atom having 4 to 7 member atoms Heterocycloalkanes may be formed,
X _III-1 represents an oxygen atom or a sulfur atom,
XIII _-2 is a methine or nitrogen atom,
Y _III-1 represents alkylene having 1 to 2 carbon atoms or C═O. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The following general formula (IV-1) or (IV-2)

(Wherein 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 1 to 20 carbon atoms, or a substituent that is eliminated in vivo.
R _IV-3 is a hydrogen atom, P (═O) (OH) ₂ , P (═O) (OR _IV-5 ) (OR _IV-6 ), (R _IV-5 and R _IV-6 are phosphate groups. Or a substituent that is eliminated in vivo)
R _IV-4 may be substituted with a hydroxyl group or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom,
A _IV-1 represents linear alkyl having 5 to 9 carbon atoms, and A _IV-1 has ₁ to 6 functional groups selected from any of the following four groups a to d: (A, 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 they are bonded have 3 to 6 carbon atoms. B, halogen atom, c, double bond, triple bond, oxygen atom, sulfur atom, cycloalkyl having 3 to 6 carbon atoms in the chain, d, at the end of the chain Double bond, triple bond),
Y _IV is alkylene having 1 to 5 carbons, alkenylene having 2 to 5 carbons, or alkynylene having 2 to 5 carbons,
A _IV-2 is an optionally substituted aryl having 6 to 10 carbon atoms, an optionally substituted 1 to 2 nitrogen atom, an oxygen atom or a sulfur atom as a ring constituting atom. Is a heteroaryl having 5-10, an optionally substituted benzene that may be condensed with an optionally substituted benzene, an optionally substituted cycloalkyl having 3 to 7 carbon atoms, or an optionally substituted 1-2 nitrogen atom Or a heterocycloalkyl having 5 to 7 ring atoms containing an oxygen atom as a ring atom;
X _IV represents an oxygen atom or a sulfur atom. )
Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. The compound according to claim 1, wherein R _I-3 and R _I-4 are both hydrogen atoms in the general formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese products. In general formula (I), _XI is an oxygen atom, The compound of any one of Claim 1 or 5, or its pharmaceutically acceptable acid addition salt, those hydrates, or solvation object. In the general formula (I), Y _I is CH ₂ CH compound according to any one of _2. It claim 1 or 5-6, or a pharmaceutically acceptable acid addition salt or a hydrate thereof, Or a solvate. In the general formula (I), _{A I} represents a straight-chain alkyl of 5-9 carbon atoms, following one of the functional groups (a in to d, alkyl .b 1 to 6 carbon atoms, a fluorine atom. c, a double bond or a triple bond in the chain, d, a double bond or a triple bond at the chain end), or a pharmaceutical thereof. A top acceptable acid addition salt, or a hydrate or solvate thereof. In formula (I), R _I-1 is trifluoromethyl, the compound according to any one of claims 1 or 5 to 8, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate. In the general formula (I), R _I-2 is hydroxymethyl, the compound according to any one of claims 1 or 5 to 9, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate. In general formula (I), R _<I> is a hydrogen atom, The compound of any one of Claim 1 or 5-10, its pharmaceutically acceptable acid addition salt, or those hydrates, or Solvate. In the general formula (II-1) or (II-2), R _II-3 is a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or a solvate. In the general formula (II-1) or _(II-2), X II is a compound according to 1, wherein any one of claims 2 or 12 is an oxygen atom, or an acid addition salt acceptable pharmaceutically, or their Hydrates or solvates. In the general formula (II-1) or _(II-2), compound according to any one of claims 2 or 12 to 13 _{Y II-1} is _CH 2 CH _2, or acceptable pharmaceutically Acid addition salts, or hydrates or solvates thereof. In General Formula (II-1), A _II-1 is a linear alkyl having 5 to 9 carbon atoms, or in General Formula (II-2), A _II-3 may be substituted. The heteroaryl having 6 to 9 aryl or 5 to 9 ring atoms containing 1 to 2 sulfur atoms or oxygen atoms, which may be substituted, as a ring constituting atom. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (II-2), when A _II-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different. A C1-C4 alkyl optionally substituted with a halogen atom; a C1-C4 alkoxy optionally substituted with a halogen atom; a halogen atom; a substitution selected from aryl having 6-10 carbons The compound according to claim 2 or any one of claims 12 to 15, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (II-2), A _II-3 is

(In the formula, R _II-4 and R _II-5 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable acid addition salt thereof, Hydrate or solvate of In general formula (II-2), YII _-2 is trimethylene, The amine compound of any one of Claim 2 or 12-17, its pharmaceutically acceptable acid addition salt, or those water Japanese solvate or solvate. In the general formula (II-1) or (II-2), R _II-1 is trifluoromethyl, or the compound according to any one of claims 2 or 12 to 18, or a pharmaceutically acceptable acid thereof. Addition salts, or hydrates or solvates thereof. In general formula (II-1) or (II-2), RII _-2 is hydroxymethyl, The compound of any one of Claim 2 or 12-19, or its pharmaceutically acceptable acid addition Salts, or hydrates or solvates thereof. In general formula (II-1) or (II-2), A _II-2 is a hydrogen atom, P (═O) (OH) ₂ , O—P (═O) (OH) ₂ or COOH. 21. The compound according to any one of 2 or 12 to 20, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In formula (II-1) or _(II-2), compound according to any one of claims 2 or 12 to 21 _{Z II} is a single bond or alkyl of 1 to 4 carbon atoms, or a pharmaceutically A top acceptable acid addition salt, or a hydrate or solvate thereof. In the general formula (III-1) or (III-2), _XIII-1 is an oxygen atom, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or a solvate. In general formula (III-1), A _III-1 is a linear alkyl having 5 to 9 carbon atoms, or in general formula (III-2), A _III-3 may be substituted. The aryl of 6 to 10 or the heteroaryl having 5 to 9 atoms in the ring containing 1 to 2 sulfur atoms or oxygen atoms which may be substituted as the atoms constituting the ring. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (III-2), when A _III-3 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different. A C1-C4 alkyl optionally substituted with a halogen atom; a C1-C4 alkoxy optionally substituted with a halogen atom; a halogen atom; a substitution selected from aryl having 6-10 carbons 25. The compound according to any one of claims 3 and 23 to 24, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (III-2), A _III-3 is

(In the formula, R _III-3 and R _III-4 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof, or an amine compound according to any one of claims 3 to 23-25, Their hydrates or solvates. In general formula (III-2), YIII _-2 is trimethylene, The compound of any one of Claim 3 or 23-26, or its pharmaceutically acceptable acid addition salt, or those hydration Or solvate. In the general formula (III-1) or (III-2), R _III-1 is trifluoromethyl, or the compound according to any one of claims 3 or 23 to 27, or a pharmaceutically acceptable acid thereof. Addition salts, or hydrates or solvates thereof. In the general formula (III-1) or (III-2), when XIII _-2 is methine, YIII _-1 is methylene, and _AIII-2 and _BIII are both alkyl having 1 to 3 carbon atoms. 29. A compound according to any one of claims 3 or 23 to 28, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (III-1) or _(III-2), it is methine _{X III-2, B III} combines with _{A III-2, Y III-} 1, X III-2, A III-2, B The compound according to any one of claims 3 to 23 to 29, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein the carbon atom to which _III and the amino group are bonded forms cyclopentyl. Or a solvate. In general formula (III-1) or (III-2), when _XIII-2 is a nitrogen atom, _YIII-1 is C = O and _BIII is a hydrogen atom or methyl. 28. The compound according to any one of 28, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. 32. The compound according to any one of claims 3 and 23 to 31, or a pharmaceutically acceptable acid addition thereof, wherein R _III-2 is a hydrogen atom in the general formula (III-1) or (III-2). Salts, or hydrates or solvates thereof. The compound according to claim 4, wherein _XIV is an oxygen atom in the general formula (IV-1) or (IV-2), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese products. In general formula (IV-1), A _IV-1 is a linear alkyl having 5 to 9 carbon atoms, or in general formula (IV-2), the number of carbon atoms with which A _IV-2 may be substituted. The aryl of 6 to 10 or the heteroaryl having 5 to 9 ring atoms containing 1 to 2 sulfur atoms or oxygen atoms which may be substituted as ring atoms. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (IV-2), when A _IV-2 is unsubstituted or has a substituent, the number of substituents is 1 to 3, and each substituent may be the same or different. A C1-C4 alkyl optionally substituted with a halogen atom; a C1-C4 alkoxy optionally substituted with a halogen atom; a halogen atom; a substitution selected from aryl having 6-10 carbons 35. The compound according to any one of claims 4 or 33 to 34, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (IV-2), A _IV-2 is

(In the formula, R _IV-7 and R _IV-8 may be the same or different, and each of them may be substituted with a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof, or a pharmaceutically acceptable acid addition salt thereof, represented by: Hydrate or solvate of The compound according to any one of claims 4 and 33 to 36, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, wherein in formula (IV-2), Y _IV is trimethylene. Or a solvate. In general formula (IV-1) or (IV-2), RIV _-1 is trifluoromethyl, The compound of any one of Claim 4 or 33-37, or its pharmaceutically acceptable acid Addition salts, or hydrates or solvates thereof. In general formula (IV-1) or (IV-2), RIV _-2 is a substituent which is eliminated in vivo, and RIV _-3 is a hydrogen atom. Or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof. In general formula (IV-1) or (IV-2), R _IV-2 is a hydrogen atom, R _IV-3 is P (═O) (OR _IV-5 ) (OR _IV-6 ) (R _IV-5 And R _IV-6 represents a substituent capable of leaving in vivo), the compound according to any one of claims 4 and 33 to 38, or a pharmaceutically acceptable acid addition salt thereof, or a compound thereof. Hydrates or solvates. The compound of general formula (I) is any of the following a to f: The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof. Or a solvate.
a. 2-amino-2- {2- [4- (8-fluorooctyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of b. 2-amino-4- {4- (8-fluorooctyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate c. 2-amino-2- {2- [4- (7-octenyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of d. 2-amino-4- {4- (7-octenyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate e. 2-amino-2- {2- [4- (6-methylheptyloxy) -3-trifluoromethylphenyl] ethyl} propane-1,3-diol, or a pharmaceutically acceptable acid addition salt thereof, or thereof Hydrate or solvate of f. 2-amino-4- {4- (6-methylheptyloxy) -3-trifluoromethylphenyl} -2- (phosphoryloxymethyl) butanol, or a pharmaceutically acceptable acid addition salt thereof, or hydration thereof Or solvate g. [3-amino-5- (4-heptyloxy-3-trifluoromethylphenyl) -3- (hydroxymethyl) pentyl] phosphonic acid, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, Or solvate h. [1-Amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methanol, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate thereof i. Phosphoric acid mono {[1-amino-3- (4-heptyloxy-3-trifluoromethylphenyl) cyclopentyl] methyl} ester, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvent thereof Japanese 42. A pharmaceutical composition comprising the compound of any one of claims 1-41 and a pharmaceutically acceptable carrier. 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; treatment or prevention of allergic disease 43. The pharmaceutical composition according to claim 42, used for the purpose of. 43. The pharmaceutical composition according to claim 42, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, type I diabetes. 43. The pharmaceutical composition according to claim 42, wherein the allergic disease is atopic dermatitis, allergic rhinitis, or asthma.