JPH072848A - Morpholine and thiomorpholine derivatives - Google Patents

Abstract

PURPOSE:To obtain a new (thio)morpholine derivative which is useful as a prophylactic agent for hyperlipemia, hyperglycemia and obesity, further hypertension and osteoporosis. CONSTITUTION:A morpholine or thiomorpholine derivative of formula I [R<1> to R<5> are H, 1-5C alkyl, 1-5C alkoxy, halogen, OH, CF3; R<6> is H, 1-5C alkyl; A is O, S; B is a bond, O, S; m is 1 to 5; X is N, CH; Y is NH, O, S; Z is H, formula II (R<7> is H, 1-5C alkyl; n is 1 to 5)] or its salts, for example, 5-{4-[2-(2-(3-chlorophenyl)morpholino)propoxyl]benzyl}thiazolidine-2,4 -dione. The compound of the formula I where B is O or S is obtained by detritylation of a compound of the formula (IV) where Z<1> is trityl, resulting from the reaction of a compound of the formula (II) with a compound of the formula (III) (B<1> is O, S; Z<1> is formula II other than R<7> is H, trityl).

Description

Detailed Description of the Invention

[0001]

The present invention relates to morpholine and thiomorpholine which improve hyperlipidemia, hyperglycemia, obesity and impaired glucose tolerance, and further have aldose reductase inhibitory activity and thromboxane A ₂ synthesis inhibitory activity. Disclosed is a derivative or a salt thereof, which is useful as a prophylactic and / or therapeutic agent for hyperlipidemia, hyperglycemia and obesity, hypertension, osteoporosis and antithrombotic disease.

[0002]

[Prior art]

 1) General formula

[0003]

[Chemical 2]

(In the formula, R ¹ is a 5- or 6-membered having 1 or 2 heteroatoms selected from an alkyl group, a cycloalkyl group, a phenylalkyl group, a phenyl group, a nitrogen atom, an oxygen atom and a sulfur atom. Heterocyclic group or

[0005]

[Chemical 3]

(However, R ³ and R ⁴ are the same or different and each represents a lower alkyl group, or R ³ and R ⁴ are bonded directly or via a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. And may form a 5- or 6-membered ring with a nitrogen atom adjacent to R ³ and R ⁴ ). R ² represents a bond or a lower alkylene group. When R ¹ is an alkyl group, L ¹ and L ² are the same or different and each represents a lower alkyl group, or L ¹ and L ² may combine to form an alkylene group. When R ¹ is not an alkyl group, L ¹ and L ² may be hydrogen atoms other than the above definition. It is known that the thiazolidine derivative represented by (4) has a blood lipid- and sugar-lowering action (JP-A-55-22636).

2) The following equation

[0008]

[Chemical 4]

It is known that the morpholine compound represented by (3) reduces blood glucose lowering action and blood triglyceride but also has side effects (Chem.Pharm.Bul).
L., 30, 3580 (1982)). It is not described that these compounds have an inhibitory effect on aldose reductase that causes diabetic complications, and further have an inhibitory effect on thromboxane A ₂ synthesis that causes platelet aggregation.

3) It is known that some of the thiazolidine-2,4-dione derivatives show a blood glucose lowering action (Chem.Pharm.Bull., 30: 3580 (1982);
J. Med. Chem., 32, 421 (1989)), phenyl-substituted morpholine-thiazolidine derivatives and phenyl-substituted thiomorpholine-thiazolidine derivatives have hypoglycemic action, lipid-lowering action, aldose reductase inhibitory action and thromboxane A. ₂ It is not known to show a synthetic inhibitory action.

4) Furthermore, some oxazolidine-2,4-dione derivatives and oxadiazolidine-2,4-dione derivatives are known to have a blood glucose lowering action (J. Med. Chem. , 34, 1538 (1991), WO 9
202520-A and WO 9203425-A), phenyl-substituted morpholine-oxazolidine-2,4-dione derivatives or phenyl-substituted morpholine-oxadiazolidine-2,4
-Dione derivative or phenyl-substituted thiomorpholine-
It is not known that the oxazolidine-2,4-dione derivative or the phenyl-substituted thiomorpholine-oxadiazolidine-2,4-dione derivative exhibits blood glucose lowering action, lipid lowering action and aldose reductase inhibitory action.

[0012]

DISCLOSURE OF THE INVENTION The present inventors have aimed to develop highly safe antihyperlipidemic agents, antidiabetic agents, antiobesity agents, glucose intolerance improving agents and therapeutic agents for diabetic complications. The present invention has been completed by earnestly researching thiomorpholine derivatives.

[0013]

The present invention has the general formula (I)

[0014]

[Chemical 5]

The present invention relates to a novel morpholine and thiomorpholine derivative having or a salt thereof.

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, It represents a linear or branched alkoxy group having 1 to 5 carbon atoms, a halogen atom, a hydroxy group, or a trifluoromethyl group. R ⁶ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms. A represents an oxygen atom or a sulfur atom. B represents a bond, an oxygen atom or a sulfur atom. m represents an integer of 1 to 5. X represents a nitrogen atom or a group> CH-. Y represents an imino group, an oxygen atom or a sulfur atom.
Z is a hydrogen atom or a group _{- (CH 2) n -CO 2} R 7
(In the formula, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and n represents an integer of 1 to 5).

Where R ¹ , R ² , R ³ , R ⁴ and R
^{When 5} is the same or different and is a linear or branched alkyl group having 1 to 5 carbon atoms, it is, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2-pentyl, 3-pentyl, 2-methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl, 1,2
-Dimethylpropyl, 2,2-dimethylpropyl and the like can be mentioned. It is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Most preferably, it is a linear or branched alkyl group having 1 to 3 carbon atoms.

When R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and are straight-chain or branched alkoxy groups having 1 to 5 carbon atoms, they are, for example, methoxy, Examples thereof include ethoxy, propoxy, butoxy, pentoxy, isopropoxy, isobutoxy, t-butoxy and the like. Preferably 1 to 3 carbon atoms
It is a straight-chain or branched alkoxy group having 1 unit. Most preferably, it is a methoxy group or an ethoxy group.

When R ⁶ is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, it is, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2
-Pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and the like can be mentioned. It is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Most preferably, it is a linear or branched alkyl group having 1 to 3 carbon atoms.

When m is an integer of 1 to 5, it is preferably an integer of 1 to 3 and optimally an integer of 1 or 2.

When Z represents a group-(CH ₂ ) _n --CO ₂ R ⁷ and R ⁷ is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, it is, for example, Methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2
-Pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and the like can be mentioned. It is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Most preferably, it is a linear or branched alkyl group having 1 to 3 carbon atoms. When n is an integer of 1 to 5, it is preferably an integer of 1 to 3 and optimally an integer of 1 or 2.

The compound of the present invention represented by the general formula (I) can be converted into a salt according to a conventional method. Examples of such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium and barium; magnesium salts; aluminum salts; inorganic salts such as ammonia or methylamine, dimethylamine. , Amine salts such as dicyclohexylamine; basic amino acid salts such as lysine and arginine; and organic base salts such as. Alternatively, such salts include, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid,
Hydrohalic acid salts such as hydroiodic acid; nitrates; perchlorates; sulfates; phosphates; inorganic salts such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, etc. Salts of sulfonic acids; salts of arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; salts of amino acids such as glutamic acid and aspartic acid; fumaric acid, succinic acid, citric acid,
Examples thereof include organic acid salts such as salts of carboxylic acids such as tartaric acid, oxalic acid, and maleic acid. It is preferably a pharmacologically acceptable salt.

The compound having the general formula (I) has various isomers. That is, the formula (A)

[0024]

[Chemical 6]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , A, B, m, X, Y and Z have the same meanings as described above. ), When R ⁶ is a hydrogen atom and X is a nitrogen atom, it has at least one asymmetric carbon atom (* ¹ ), R ⁶ is a hydrogen atom,
When X is a group> CH-, it has at least two asymmetric carbon atoms (* ¹ and * ³ ), R ⁶ is an alkyl group, and when X is a nitrogen atom, asymmetric When it has at least 2 carbon atoms (* ¹ and * ² ), R ⁶ is an alkyl group, and X is a group> CH-, at least 3 asymmetric carbon atoms (* ¹ , * ²
And * ³ ) have.

In the above general formula (I), stereoisomers based on them and equal and non-equivalent mixtures of these isomers are all represented by a single formula. Therefore, the present invention includes all of these isomers and a mixture of these isomers.

In the compound represented by the general formula (I), (1) preferably, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different, and a hydrogen atom and a carbon number of 1 to 4 Straight-chain or branched-chain alkyl group having 1 carbon atom
A linear or branched alkoxy group having 1 to 3 groups, a halogen atom, a hydroxy group, or a trifluoromethyl group, and R ⁶ is a hydrogen atom or a linear or branched group having 1 to 3 carbon atoms. Represents a branched alkyl group, A represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or a sulfur atom, m represents an integer of 1 to 3, X represents a nitrogen atom or a group> CH -, Y represents an imino group, an oxygen atom or a sulfur atom, and Z
There hydrogen atom or a group - (CH ₂₎ in _n -CO ₂ R ⁷ (wherein, R ⁷ represents a straight-chain or branched alkyl group having 4 to 1 -C hydrogen or C, n represents A compound or a salt thereof, which is an integer of 1 to 4).

(2) More preferably, R ¹ , R ² and R
³ is the same or different and is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 3 carbon atoms, halogen An atom, a hydroxy group or a trifluoromethyl group, R ⁴ and R ⁵ being the same or different, a hydrogen atom, a linear or branched alkoxy group having 1 to 3 carbon atoms, and 1 to 3 carbon atoms. A linear or branched alkoxy group having a halogen atom, a hydroxy group or a trifluoromethyl group,
R ⁶ represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, A represents an oxygen atom or a sulfur atom, and B represents a bond, an oxygen atom or a sulfur atom. , m has from 1 to an integer of 3, X represents a nitrogen atom or a group> CH-, Y represents an oxygen atom or a sulfur atom, Z is a hydrogen atom or a group - (CH _2)
n —CO ₂ R ⁷ (In the formula, R ⁷ is a hydrogen atom or a carbon number 1
A linear or branched alkyl group having 4 to 4 and n represents an integer of 1 to 3. ) Is shown, or a salt thereof.

(3) More preferably, R ¹ , R ² and R
³ is the same or different and is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 3 carbon atoms, halogen An atom, a hydroxy group or a trifluoromethyl group, R ⁴ and R ⁵ being the same or different, a hydrogen atom, an alkyl group having 1 or 2 carbon atoms,
An alkoxy group having 1 to 2 carbon atoms, a fluorine atom, a chlorine atom, a hydroxy group or a trifluoromethyl group, wherein R ⁶ is a hydrogen atom or a straight chain or branched chain having 1 to 3 carbon atoms Represents an alkyl group, A
Represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or a sulfur atom, m represents an integer of 1 to 3, X represents a nitrogen atom or a group> CH-, and Y represents an oxygen atom or sulfur. Represents an atom, and Z is a hydrogen atom or a group
_{- (CH 2) n -CO 2} R 7 ( wherein, R ⁷ represents a straight-chain or branched alkyl group having 4 to 1 -C hydrogen or C, n represents 1 to 2 integer Is a compound or a salt thereof.

More preferably than (4), R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, or fluorine. An atom, a chlorine atom, a bromine atom, a hydroxy group or a trifluoromethyl group, R ² is a hydrogen atom,
An alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a fluorine atom, a chlorine atom,
A hydroxy group or a trifluoromethyl group, R ³
Represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, a fluorine atom or a chlorine atom, and R ⁴
Is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms,
An alkoxy group having 1 or 2 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group, R ⁵ is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or 1 or 2 carbon atoms. Represents an alkoxy group, a fluorine atom or a chlorine atom, R ⁶ represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, and A represents an oxygen atom or a sulfur atom. , B represents a bond, an oxygen atom or a sulfur atom,
m is an integer of 1 to 3 and X is a nitrogen atom or a group.
> Indicates CH-, Y represents an oxygen atom or a sulfur atom, Z is a hydrogen atom or a group _{- (CH 2) n -CO 2} R
⁷ (In the formula, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n
Represents an integer of 1 to 2. ) Is shown, or a salt thereof.

(5) Most preferably, R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom or a hydroxy group. Or represents a trifluoromethyl group,
R ² is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom,
Represents a chlorine atom, a hydroxy group or a trifluoromethyl group, R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, a fluorine atom or a chlorine atom, R ⁴ represents a hydrogen atom, a methyl group, a methoxy group, a hydroxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group, R ⁵ represents a hydrogen atom or a methyl group, R ⁶ represents a hydrogen atom or a methyl group, A represents an oxygen atom or a sulfur atom, B represents a bond or an oxygen atom, m represents an integer of 1 to 2,
X is a group> CH-, Y is a sulfur atom, and Z is a hydrogen atom, or a compound or salt thereof.

Specific examples of the compound having the general formula (I) of the present invention include the compounds listed in the following table.

[0033]

[Chemical 7]

[0034]

[Table 1]

[0035]

[Chemical 8]

[0036]

[Table 2]

[0037]

[Chemical 9]

[0038]

[Table 3]

[0039]

[Chemical 10]

[0040]

[Table 4] In the table, Me = methyl, Et = ethyl, Pr = propyl,
iPr = isopropyl, Bu = butyl, tBu = t-butyl, Pn = pentyl, MeO = methoxy, EtO = ethoxy, BuO = butoxy, PnO = pentyloxy, CF ₃
= Trifluoromethyl.

The compound having the above general formula (I) of the present invention can be produced by the method described below.

Manufacturing Method 1.

[0043]

[Chemical 11]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , A, m, X and Y have the same meanings as described above. B ¹ represents an oxygen atom or a sulfur atom. Z ¹ is a group
_{- (CH 2) n -CO 2} R 7 '( wherein, R ^7' a linear or .n showing a branched alkyl group is the same meaning as described above with the five 1 -C Or a trityl group. ) 1) General formula (IV) (wherein R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , A, B ¹ , m, X, Y and Z ¹ have the same meanings as described above. A compound having the general formula (II) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , A and m have the same meanings as described above. And a compound of the general formula (III) (wherein B ¹ , X, Y
And Z ¹ have the same meaning as described above. ) Is obtained by reacting with a compound having

The reaction is the usual Mitsunobu reaction (O. Mitsunobu;
Synthesis, page 1 (1981)).

That is, the reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; Ethers such as ethyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but it is usually 1 hour to several days. It is preferably carried out in the presence of a solvent for 1 hour to 1 day under ice cooling to 60 ° C.

2) Furthermore, the general formula (V) (in the formula, R ¹ and R
² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B ¹ , m, X and Y have the same meanings as described above. A compound having the general formula (IV) (wherein R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , A, B ¹ , m, X and Y have the same meanings as described above. In the compound having), Z ¹ is obtained by subjecting a compound having a trityl group to a detritylation reaction.

The reaction is carried out by a conventional method, for example, TWGreen, Protective Groups in Organic Synthesis, Jo
hnWiley & Sons ； JFWMcOmie, Protective Groups in Organic Chemistry (Protec
tive Groups in Organic Chemistry), Plenum Press;
It is carried out according to the description of.

That is, the reaction is usually carried out by reacting with an inorganic acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or These mixed solvents are preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but it is usually 1 hour to several days. It is preferably carried out in the presence of trifluoroacetic acid for 1 hour to 1 day under ice cooling to 60 ° C.

Manufacturing method 2.

[0051]

[Chemical 12]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , A, B ¹ , m, X, Y and Z ¹ have the same meanings as described above. Su represents a sulfonic acid residue such as methanesulfonyl and p-toluenesulfonyl. M represents an alkali metal. ) 1) General formula (VI) (in the formula, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , A, m and Su have the same meanings as described above. A compound having the general formula (II) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and m have the same meanings as described above. ) Is obtained by sulfonation.

The sulfonation reaction is carried out according to the usual sulfonation reaction. Examples of the sulfonating agent used include sulfonyl halides such as methanesulfonyl chloride or p-toluenesulfonyl chloride. The reaction is carried out with alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; aliphatic amines such as triethylamine; heterocyclic compounds such as pyridine; Performed in the presence or absence. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; Ethers such as ethyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Preferably used are: sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably carried out in the presence of triethylamine for 1 hour to 1 day under ice cooling to 60 ° C.

2) Next, the general formula (IV) (in the formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B ¹ , m,
X, Y and Z ¹ have the same meaning as described above. A compound having the general formula (VI) (wherein R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ , A, m and Su have the same meanings as described above. ) And a compound having the general formula (VII) (wherein B ¹ , X, Y, Z ¹ and M have the same meanings as described above). .

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. Preferably, in the presence of a solvent, for 1 hour to 1 day, under ice cooling to 6.
Performed at 0 ° C.

Manufacturing method 3.

[0057]

[Chemical 13]

1) In the compound having the general formula (I), Z is a group — (CH ₂ ) _n —CO ₂ R ⁷ (wherein n and R ⁷ have the same meanings as described above). General formula (IX) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , A, B, m, X, Y, R ⁷ and n have the same meanings as described above. A compound having the general formula (VI)
II) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
A, B, m, X and Y have the same meanings as described above. A compound having the general formula Halo ^1- (CH
₂ ) A compound having _n- CO ₂ R ⁷ (wherein R ⁷ and n have the same meanings as described above, Halo ¹ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.) It is manufactured by reacting in the presence of.

The reaction is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate; an aliphatic amine such as triethylamine; a heterocyclic compound such as pyridine;
It is carried out in the presence of a deoxidizing agent such as alkali metal alkoxides such as potassium t-butoxide. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; Ethers such as ethyl ether, tetrahydrofuran, dioxane; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; Nitriles such as acetonitrile, propionitrile Ketones such as acetone, methyl ethyl ketone, diethyl ketone; or a mixed solvent thereof is preferably used. The reaction is carried out at room temperature or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days.
It is preferably carried out in a solvent of amides or ketones for 3 hours to 3 days at room temperature to 60 ° C.

Alternatively, instead of using a deoxidizing agent in the above reaction, it can be achieved by first treating with an alkali metal hydride such as sodium hydride or potassium hydride and then reacting with the above halide.
The reaction is usually carried out in the above solvent under ice cooling or at 60 ° C.
React with alkali metal hydride for 1 hour to 3 days. Then, it is carried out by reacting with the above halide under the above reaction conditions.

2) Further, in the compound having the general formula (I), the general formula (X) in which Z is a group — (CH ₂ ) _n —CO ₂ H (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
A, B, m, X, Y, and n have the same meanings as described above. A compound having the general formula (IX) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, m,
X, Y, and n have the same meanings as described above. R ⁷ in) the compound having may be prepared by ester hydrolysis of the compound is a lower alkyl group.

The reaction is usually carried out with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate; It is carried out in the presence of a base or an inorganic acid such as hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid or hydrochloric acid. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example,
Aromatic hydrocarbons such as benzene, toluene, xylene; Aliphatic hydrocarbons such as hexane, heptane; Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride; Ethyl ether, tetrahydrofuran, dioxane Ethers such as; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile and propionitrile; water or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. Preferably in alcohols, amides, ethers, ketones or a mixed solvent of these with water for 3 hours to 3 days,
It is carried out at room temperature to 60 ° C.

Manufacturing method 4. In the compound having the general formula (II), the compound in which A is an oxygen atom is produced by the following method.

[0064]

[Chemical 14]

1) General formula (XIII) (in the formula, R ¹ and R
² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. A compound having the general formula (XI) (wherein
R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. (For example, DTCollin, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 13, pp. 674-680 (1
970), and JP-A-6-25118) and general formula (XII) (wherein Halo ² and Halo ³ represent a halogen atom such as a chlorine atom, a bromine atom or an iodine atom). Obtained by reacting with a halide.

Examples of the haloacetyl halide used in the reaction include chloroacetyl chloride, bromoacetyl chloride, bromoacetyl bromide and the like. The reaction is usually carried out in the presence of a deoxidizing agent such as alkali metal hydrides such as sodium hydride and potassium hydride; aliphatic amines such as triethylamine; heterocyclic compounds such as pyridine; and the like. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dimethylsulfoxides, sulfolane or mixtures thereof A solvent is preferably used.
The reaction is carried out under ice-cooling or under heating under reflux. The reaction time varies depending on the reaction reagents, reaction temperature, etc., but is usually
0.5 hours to 1 day. It is preferably carried out in a solvent of ethers or amides for 1 to 10 hours under ice cooling or under reflux with heating.

2) Next, the general formula (XIV) (in the formula,
R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. A compound having the general formula (XIII)
(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above) and are obtained by reduction.

The reaction is usually carried out in the presence of a reducing agent. Examples of the reducing agent used include metal hydrides such as lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran , Ethers such as dioxane; methanol, ethanol,
Alcohols such as isopropanol; or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to several days. The reaction is preferably carried out in an alcohol solvent in the presence of lithium borohydride for 1 hour to 10 hours at room temperature or under reflux, or in an ether solvent in the presence of lithium aluminum hydride for 1 hour to 1 day. It is carried out under ice cooling or under heating under reflux.

3) Next, the general formula (XVI) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and m have the same meanings as described above. R ⁸ represents a linear or branched alkyl group having 1 to 5 carbon atoms. A compound having the general formula (XIV) (wherein R ¹ ,
R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. A compound having the general formula (XV) (wherein
R ⁶ , R ⁸ and m have the same meanings as described above. H
alo ⁴ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. ) Is obtained by reacting with a compound having

The reaction is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate; an aliphatic amine such as triethylamine; a heterocyclic compound such as pyridine;
Etc. in the presence or absence of a deoxidizing agent. The reaction is usually suitably carried out in the presence of solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform and methylene chloride. , Halogenated hydrocarbons such as carbon tetrachloride, ethers such as ethyl ether, tetrahydrofuran, dioxane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl ethyl ketone; dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof is preferably used. The reaction is carried out at room temperature or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably at room temperature to 60 ° C. for 1 hour to 1 day.

4) General formula (II) (wherein R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ and m have the same meanings as described above. However, A shows an oxygen atom. A compound having the general formula (XVI) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

5) Further, in the general formula (XVII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. A compound having the general formula (XIII) (wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above) after being converted to an alkali metal salt. , General formula (XV) (wherein R
⁶ , R ⁸ , m, and Halo ⁴ have the same meanings as described above. ).

The reaction of the compound having the general formula (XIII) with an alkali metal salt is usually carried out preferably in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or These mixed solvents are preferably used. As a reagent for forming an alkyl metal salt, an alkyl-metal salt such as butyl lithium
Alkali metal compound; lithium diisopropylamide,
Alkali metal amides such as lithium amide and sodium amide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium t-butoxide;
The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably carried out in a solvent of amides using sodium hydride under ice cooling or at 50 ° C. for 1 to 10 hours.

Next, the reaction between the alkali metal salt of the compound having the general formula (XIII) and the compound having the general formula (XV) is usually suitably carried out in the presence of a solvent. As the solvent used, the above-mentioned solvent is usually used without particular limitation. The reaction is carried out in a solvent under ice cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 1 hour to several days. It is preferably under ice cooling to 60 ° C. for 1 hour to 1 day.

6) General formula (II) (in the formula, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ and m have the same meanings as described above. However, A shows an oxygen atom. A compound having the general formula (XVII) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

Manufacturing method 5. In the compound having the general formula (II), the compound in which A is a sulfur atom is produced by the following method.

[0077]

[Chemical 15]

1) General formula (XIX) (wherein R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and Su have the same meanings as described above. R ⁹ represents a linear or branched alkyl group having 1 to 5 carbon atoms. A compound having the general formula (XVIII) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ and R ⁹ have the same meanings as described above. ) And a sulfonyl halide. Examples of the sulfonyl halide used in the reaction include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like. The reaction is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate; an aliphatic amine such as triethylamine; a heterocyclic compound such as pyridine; It is preferably carried out in the presence of an agent. The reaction is usually suitably carried out in the presence of solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform and methylene chloride. , Halogenated hydrocarbons such as carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran, dioxane; nitriles such as acetonitrile, propionitrile; dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, etc. Amides; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but it is usually 1 hour to 1 day. It is preferably under ice cooling to 60 ° C. for 1 hour to 10 hours.

2) General formula (XX) (wherein R ¹ , R ² ,
R ³ , R ⁴ and R ⁵ have the same meanings as described above. A compound having the general formula (XIX) (wherein R is
¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁹ have the same meanings as described above. It is obtained by reacting a compound having a) with 2-aminoethylmercaptan or an alkali metal salt thereof.

The reaction includes alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; aliphatic amines such as triethylamine; heterocyclic compounds such as pyridine; It is carried out in the presence or absence of a deoxidizer. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran , Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof.
The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably under ice cooling to 80 ° C. for 1 hour to 1 day.

3) General formula (XXI) (wherein R ¹ ,
R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. A compound having the general formula (XX) (wherein R is
¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

4) Next, general formula (XXII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. A compound having the general formula (XXI) (wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ has the same meaning as described above. And a compound of the general formula (XV), wherein R ⁶ , R ⁸ , m and Halo
⁴ has the same meaning as described above. ) Is obtained by reacting with a compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 3).

5) General formula (II) (in the formula, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ and m have the same meanings as described above. However, A represents a sulfur atom. Is represented by the general formula (XXII) (wherein R ¹ , R ² , R ³ , R ^3
4 , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

6) Further, the compound of the general formula (XXIII) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. A compound having the general formula (XX) (wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ has the same meaning as described above. A compound of formula (XV) (in the formula, R ⁶ ,
R ⁸ , m and Halo ⁴ have the same meanings as described above. ). The reaction is the above-mentioned production method 4. It is performed according to the description in 5).

7) General formula (II) (in the formula, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ and m have the same meanings as described above. However, A represents a sulfur atom. A compound having the general formula (XXIII) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

Manufacturing Method 6. General formula (XXVIII) and general formula (XXX) (provided that in the general formula (I), A is an oxygen atom) (in the formula, R ¹ , R ² , R ³ , and R ⁴ ,
R ⁵ , R ⁶ , B, m, X, Y and Z ¹ have the same meanings as described above. The compound having) is also produced by the following method.

[0087]

[Chemical 16]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , B, m, X, Y, Z ¹ , Halo ² and Hal
o ³ has the same meaning as described above. R ⁹ represents a linear or branched alkyl group having 1 to 5 carbon atoms. ) 1) General formula (XXV) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , B, m and R ⁹ have the same meanings as described above. A compound having the general formula (XXI
V) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
B, m and R ⁹ have the same meaning as described above. Amino alcohol compound having (1) (JP-A-55-9085)
No.) and a general formula (XI) such as chloroacetyl chloride, bromoacetyl chloride or bromoacetyl bromide.
I), wherein Halo ² and Halo ³ have the same meanings as described above, and are obtained by reacting with haloacetyl halide. The reaction is the above-mentioned production method 4. It is performed according to the description in 1).

2) Next, the general formula (XXVI) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B and m have the same meanings as described above. A compound having the general formula (XXV) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5
6 , B, m and R ⁹ have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is the above-mentioned production method 4. It is performed according to the description in 2).

3) Next, the general formula (XXVII) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B and m have the same meanings as described above. Q represents a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy or a halogen atom such as chlorine atom, bromine atom or iodine atom. A compound having the general formula (XXVI) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , B and m have the same meanings as described above. Are treated with a sulfonating agent such as methanesulfonyl chloride or p-toluenesulfonyl chloride, or such as hydrogen chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide. Obtained by treating with a halogenating agent. The sulfonation reaction is carried out according to the above-mentioned production method 5. It is performed according to the description in 1).

Halogenation is carried out in the usual way, for example LFFi
eser & M.Fieser Reagents for Qrganie Synthesis, John
Wiley and Sons, Inc. It is carried out according to the description of.
That is, the reaction is usually suitably carried out in the presence of a solvent.
The solvent used is not particularly limited as long as it does not affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; ethyl ether,
Ethers such as tetrahydrofuran and dioxane;
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days.
It is preferably carried out in the presence of a solvent for 1 hour to 1 day under ice cooling to 60 ° C.

4) General formula (XXVIII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m, X, Y and Z ¹ have the same meanings as described above. A compound having the general formula (XXVII) (wherein R ¹ , R ² , R
³ , R ⁴ , R ⁵ , R ⁶ , B, m and Q have the same meanings as described above. ) And a compound represented by the general formula (XXIX)

[0093]

[Chemical 17]

(Wherein X, Y and Z ¹ have the same meanings as defined above, and M represents an alkali metal atom such as lithium, sodium or potassium). To be

The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran, Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The reaction temperature is -76 ° C or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably carried out in the presence of a solvent in an inert gas for 1 hour to 1 day at -76 ° C to room temperature.

Here, the compound having the general formula (XXIX) is represented by the general formula (XXIX) ¹

[0097]

[Chemical 18]

[0098] (wherein, X, Y and Z ¹ have the same meanings as defined above.) Alkyl such as compounds with butyllithium with - alkali metal compound; lithium diisopropylamide, lithium amide, as sodium amide Alkali metal amides; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal silazane compounds such as lithium hexamethylsilazane; and the like.

The reaction is usually carried out in the presence of a solvent in an inert gas. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran, Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The reaction temperature is from -76 ° C to under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to several days. It is preferably carried out in the presence of a solvent in an inert gas for 1 hour to 1 day at -76 ° C to room temperature. Further, the produced compound having the general formula (XXIX) can be used in the next reaction without isolation.

5) Next, the general formula (XXX) (wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m, X and Y have the same meanings as described above. A compound having the general formula (XXVIII) (wherein R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ , B, m, X and Y have the same meanings as described above. In the compound having
It is obtained by subjecting a compound in which ¹ has a trityl group to a detritylation reaction. The reaction is carried out by the above-mentioned production method 1. It is performed according to the description in 2).

Manufacturing Method 7. Alternatively, the general formula (XXXII
I) (in the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
B, m and Y have the same meanings as described above. The compound having) is also produced by the following method.

[0102]

[Chemical 19]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , B, m, Y and Q have the same meanings as described above. ) 1) General formula (XXXI) (wherein R ¹ , R ² , R ³ and R are
⁴ , R ⁵ , R ⁶ , B, m and Y have the same meanings as described above. A compound having the general formula (XXVII)
(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m
And Q have the same meanings as described above. And a compound of the general formula MN (Boc) -Y-Boc (wherein Y has the same meaning as described above. Boc is t
Represents a butoxycarbonyl group. M represents an alkali metal atom such as lithium, sodium or potassium. ) Is obtained by reacting with a compound having The reaction is the above-mentioned production method 6. It is carried out according to the description in 4).

A compound having the general formula MN (Boc) -Y-Boc (wherein Y, Boc and M have the same meanings as described above) is a compound of the general formula H-N (Boc). -Y-Boc (wherein Y and Boc have the same meanings as described above) and an alkyl-alkali metal compound such as butyllithium; an alkali such as lithium diisopropylamide, lithium amide, sodium amide. It can be obtained by treating with a base such as metal amides; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal silazane compounds such as lithium hexamethylsilazane; The reaction is the above-mentioned production method 6. It is carried out according to the description in 4).

2) Next, the general formula (XXXII) (in the formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m and Y
Has the same meaning as described above. The compound having
General formula (XXXI) (wherein R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , B, m and Y have the same meanings as described above. The compound having) is obtained by subjecting it to a de-Boc reaction. The reaction is carried out in the usual manner, for example TW Green
， Protective Groups In Organic
Synthesis (Protecfive Groups in Organic Synthesi
s), JohnWiley &Sons; JFWMcOmie, Protecfive Groups in Organic Chemistry, Plenum P
It is performed according to the description of ress.

That is, the reaction is usually carried out by contacting with an acid in the presence or absence of a solvent. Examples of the acid used include inorganic acids such as hydrochloric acid and organic acids such as trifluoroacetic acid. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. To be The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but it is usually 1 hour to several days.
It is preferably carried out in the presence of a solvent for 1 hour to 1 day under ice cooling to 60 ° C.

3) Next, general formula (XXXIII) (in the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m and Y have the same meanings as described above. A compound having the general formula (XXXII) (wherein R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , B, m and Y have the same meanings as described above. Obtained by reacting a compound having a) with chlorocarbonyl isocyanate.

The reaction is usually preferably carried out in the presence or absence of a deoxidizing agent and in the presence of a solvent. Examples of the deoxidizing agent used include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; aliphatic amines such as triethylamine; heterocyclic compounds such as pyridine. Bases such as; The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran, Ethers such as dioxane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride; nitriles such as acetonitrile and propionitrile; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Or a mixed solvent thereof is preferably used.
The reaction is performed under ice cooling or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 1 hour to several days. It is preferably carried out in the presence of a solvent for 1 hour to 1 day under ice cooling to 60 ° C.

Manufacturing Method 8.

[0110]

[Chemical 20]

Further, in the general formula (XXXI) (wherein R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , B, m and Y have the same meanings as described above. The compound having) is also produced by the following method.

1) A compound having the general formula (XXXV) (wherein B, Y and Boc have the same meanings as described above) is a compound of the general formula (XXXIV) (wherein B is as defined above). And the general formula M-
N (Boc) -Y-Boc (wherein M, Y and Boc
Has the same meaning as described above. ) Is obtained by reacting with a compound having The reaction is the above-mentioned production method 6. It is carried out according to the description in 4).

2) Next, the general formula (XXXVI) (wherein
B, Y and Boc have the same meanings as described above. )
Are represented by the general formula (XXXV) (wherein B, Y
And Boc have the same meaning as described above. A compound having a) is subjected to a debenzylation reaction. The reaction is carried out in the usual manner, for example TW Green, Protective Groups in Organic Synthesis.
(Protective Groups in Organic Synthesis), John Wi
ley &Sons; JFW McOmie, Protective Groups in Organic Chemistry (Protecti
ve Groups in Organic Chemistry), Plenum Press.

3) Next, the general formula (XXXI) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, m, Y and Boc have the same meanings as described above. A compound having the general formula (XXXVI) (wherein B, Y and Boc have the same meanings as described above) and a compound having the general formula (II) (in the formula, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , A and m have the same meanings as described above. ) With a compound having an ordinary Mitsunobu reaction (O.Mitsun
obu; Synthesis, page 1 (1981)). The reaction is carried out by the above-mentioned production method 1. It is performed according to the description in 1).

Manufacturing Method 9.

[0116]

[Chemical 21]

Further, the compound of the general formula (XXXXII) (wherein R is
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y and m have the same meanings as described above. The compound having) is also produced by the following method.

1) General formula (XXXVIII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B and m have the same meanings as described above. A compound having the general formula (XXXVII) (wherein R ¹ , R ² , R ³ , R ^3
4 , R ⁵ , R ⁶ , A, B and m have the same meanings as described above. ) And trifluoro-4-nitrobenzene in the presence of a base.

The reaction is usually suitably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethyl. Acetamide, amides such as hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used. The base used is not particularly limited as long as it does not affect the reaction, and includes sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, butyllithium, lithium diisopropylamide and the like. The reaction is performed under ice cooling or under heating.
While the reaction time varies depending on the solvent, the reaction reagent, the reaction concentration, etc., it is generally 1 hour to several days.

2) General formula (XXXIX) (wherein R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B and m have the same meanings as described above. A compound having the general formula (XXXVIII) (wherein R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , A, B and m have the same meanings as described above. ) Is obtained by reducing the compound having The reaction is accomplished by a conventional catalytic hydrogenation reaction, and by using a general reduction method, zinc-acetic acid or tin-hydrochloric acid.

3) General formula (XXXX) (in the formula, R ¹ and R
² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B and m have the same meanings as described above, Halo ⁵ represents a halogen atom such as chlorine and bromine, and R ¹⁰ has 1 to ¹⁰ carbon atoms. 5 represents a straight chain or branched chain alkyl group. A compound having the general formula (XXXIX) (wherein R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ , A, B and m have the same meanings as described above. ) To a compound having
It is obtained by carrying out an in-arylation reaction. The reaction is usually carried out according to JP-A-55-22657 and
The method of S. Oae et al. (Bull. Chem, Soc. Jpn., 53, 1065
Page (1980)).

4) General formula (XXXXII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y and m have the same meanings as described above. A compound having the general formula (XXXX) (wherein R ¹ , R ² , R ³ , R ^3
4 , R ⁵ , R ⁶ , A, B, Halo ⁵ and R ¹⁰ have the same meanings as described above. ) And a general formula
A compound having H ₂ NC (= Y) -NH ₂ (wherein Y has the same meaning as described above) is reacted to give a compound of the general formula (XXXXI) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵
, R ⁶ , A, B, Y and m have the same meanings as described above. (Compound which may be isolated and can be subjected to the next reaction without isolation.)
And is then subjected to an acid-catalyzed hydrolysis reaction. The reaction is usually performed according to the method described in JP-A-55-22657.

Manufacturing Method 10.

[0124]

[Chemical formula 22]

Production method 4. The general formula (XVI
I) (in the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁸
And m have the same meaning as described above. The compound having) can also be synthesized by the following separate production method.

1) General formula (XXXXV) (wherein R ¹ ,
^{R 2, R 3, R 4} , R 5, R 6, R 8 and m are the same meanings as described above, Si <+ represents a t- butyldimethylsilyl group. The compound is synthesized according to the method described in JP-A-6-25118. A compound having the general formula (XXXXIII) (wherein R ¹ , R ² , R
³ , R ⁴ , R ⁵ and Si <+ have the same meaning as described above. And a compound of the general formula (XXXXI
V) (wherein R ⁶ , R ⁸ and m have the same meanings as described above) and are subjected to a reductive amination reaction. The reaction is a reductive amination reaction that is usually carried out, and is carried out according to the method described in JP-A-6-25118, for example.

2) General formula (XXXXVI) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. A compound having the general formula (XXXXV) (wherein R ¹ , R ² , R ³ , R ⁴ , R
⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. Deprotection of a compound having) (desilylation reaction)
It is obtained by attaching to. The reaction is carried out in a conventional manner, for example, TW Green, Protective Groups in Organic Synthesis.
ic Synthesis), JohnWiley &Sons; JFW McOmie,
Protective Groups in Organic
Chemistry (Protective Groups in Organic Chemist
ry), Plenum Press;

3) General formula (XXXXVII) (in the formula, R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , m and H
alo ² has the same meaning as described above. A compound having the general formula (XXXXVI) (wherein R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. ) And the general formula Halo ²
-CH ₂ CO-Halo ³ (wherein, Halo ² and H
alo ³ has the same meaning as described above. ) Is obtained by reacting with a compound having Examples of the haloacetyl halide used in the reaction include chloroacetyl chloride, bromoacetyl chloride, bromoacetyl bromide and the like. The reaction is usually suitable in the presence or absence of a deoxidizing agent such as alkali metal hydrides such as sodium hydride and potassium hydride; aliphatic amines such as triethylamine; heterocyclic compounds such as pyridine; To be done. The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; chloroform, methylene chloride, Halogenated hydrocarbons such as carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dimethylsulfoxides, sulfolane or mixtures thereof. A solvent is preferably used. The reaction is carried out under ice-cooling or under heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hour to 1 day. It is preferably carried out in ether or amide in a solvent for 1 hour to 10 hours under ice cooling or under reflux with heating.

4) General formula (XVII) (in the formula, R ¹ and R
² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m have the same meanings as described above. A compound having the general formula (X
XXXVII) (wherein R ¹ , R ² , R ³ , R ⁴ , R
⁵ , R ⁶ , R ⁸ , m and Halo ² have the same meanings as described above. It is obtained by reacting a compound having The reaction is usually sodium hydride,
It is preferably carried out in the presence of a base such as an alkali metal hydride such as potassium hydride; an aliphatic amine such as triethylamine; a heterocyclic compound such as pyridine;
The reaction is usually suitably carried out in the presence of solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethyl ether, tetrahydrofuran, Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dimethylsulfoxides, sulfolane or a mixed solvent thereof is preferably used. The reaction is carried out under ice-cooling or under heating under reflux. The reaction time depends on the reaction reagent,
Although it depends on the reaction temperature and the like, it is usually 0.5 hours to 1 day. It is preferably carried out in a solvent of amides for 1 to 10 hours at room temperature or under heating under reflux.

Production Method 1. Through 10. After completion of the reaction, each compound obtained by can be purified by a conventional method, for example, column chromatography, recrystallization method, reprecipitation method or the like, if necessary. For example, a solvent is added to the reaction mixture for extraction, and the solvent is distilled off from the extract. The obtained residue can be purified by subjecting it to column chromatography using silica gel or the like to obtain a pure product of the target compound.

[0131]

The compound of the present invention having the general formula (I) or a salt thereof is effective for lowering blood glucose, improving obesity, improving glucose tolerance, suppressing gluconeogenesis in the liver, lowering lipids, and inhibiting aldose reductase. Action, thromboxane A ₂ synthesis inhibitory action, hyperglycemia, obesity, hyperlipidemia, diabetic complications such as retinopathy, nephropathy, neurosis, cataract, coronary artery disease, arteriosclerosis, and obesity It is useful as a preventive and / or therapeutic drug for hypertension, osteoporosis, thrombosis and the like. Further, the compound having the general formula (I) or a salt thereof of the present invention has extremely low toxicity, and is therefore useful as a prophylactic and / or therapeutic drug for the above-mentioned diseases.

The compounds of general formula (I) of the present invention may be administered in various forms. Examples of the dosage form include oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by injections (intravenous, intramuscular, subcutaneous), infusions, suppositories, etc. .
These various preparations are usually used in the technical field of pharmaceutical preparation such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It is possible to formulate with known auxiliary agents. The dose varies depending on symptoms, age, body weight, administration method, dosage form, etc., but usually one day for adults
0.01 mg to 2000 mg can be administered.

[0133]

EXAMPLES Next, the present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited thereto.

Example 1. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-27) 5- {4- [2- (2- (3-chlorophenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 0.89 g with ice cooling. 5 ml of trifluoroacetic acid was added below, and the mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, trifluoroacetic acid was distilled off from the reaction mixture under reduced pressure, aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value = 0.16 (silica gel thin layer chromatography; acetic acid). Ethyl: hexane = 1: 1)
0.35 g of the target compound having is obtained.

Example 2. 5- {4- [2- (2-phenylthiomorpholino) pro
Poxy] benzyl} thiazolidine-2,4-dione (eg
Compound No. 3-5) 5- {4- [2- (2-phenylthiomorpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (0.9 g) and trifluoroacetic acid (6 ml) were used, Example 1. The crude product thus obtained was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value = 0.59 (silica gel thin layer chromatography; 0.58 g of the target compound having ethyl acetate: hexane = 2: 1) was obtained.

Example 3. 5- {4- [2- (2-phenylthiomorpholino) eth
[Xy] benzyl} thiazolidine-2,4-dione (exemplification
Compound No. 3-1) Example 1 using 5- {4- [2- (2-phenylthiomorpholino) ethoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (530 mg) and trifluoroacetic acid (5 ml). ． When the reaction and post-treatment were carried out according to, the target compound (320 mg) having a softening point of 70 to 75 ° C. was obtained.

Example 4. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) butoxy] benzyl} thiazolidine-2,4-di
ON (Exemplified Compound No. 1-77) and 5- {4-
[2- (2-phenylmorpholino) butoxy] benzi
Lu} thiazolidine-2,4-dione (exemplary compound number
1-312) Reference example 15. 5- {4- [2- (2- (3-
Chlorophenyl) morpholino) butoxy] benzyl}-
2.1 g of a mixture of 3-triphenylmethylthiazolidine-2,4-dione and 5- {4- [2- (2-phenylmorpholino) butoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 2.1 g and Example 1 using 10 ml of trifluoroacetic acid. The reaction and post-treatment were carried out according to the above procedure, and the product was further purified by reverse phase chromatography (acetonitrile: water = 7: 3) to give Rf
= 0.53 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1).
(2- (3-chlorophenyl) morpholino) butoxy]
Benzyl} thiazolidine-2,4-dione 0.31 g and Rf value = 0.49 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1)
171 mg of {4- [2- (2-phenylmorpholino) butoxy] benzyl} thiazolidine-2,4-dione were obtained.

Example 5. 3-t-butoxycarbonylmethyl-5- {4- [2-
(2- (3-chlorophenyl) morpholino) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound No. 1-30) 0.27 g of sodium hydride (55% by weight) was washed with hexane and suspended in 30 ml of dimethylformamide, and then 5- {4- [2- (2- (3-chlorophenyl)). Morpholino) propoxy] benzyl} thiazolidine-2,4-dione 2.6 g of dimethylformamide 1
A 0 ml solution was added dropwise. After irradiating the reaction mixture with ultrasonic waves for 1 hour, 1.1 ml of t-butyl α-bromoacetate in 10 ml of dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give Rf value = 0.29 (silica gel thin layer). Chromatography; 1.03 g of the desired compound with hexane: ethyl acetate = 2: 1) was obtained.

Example 6. 5- {4- [2- (2- (2,5-dimethoxy-3,
4,6-Trimethylphenyl) morpholino) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-307) 5- {4- [2- (2- (2,5-dimethoxy-3,
2.0 g of 4,6-trimethylphenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione and trifluoroacetic acid
Using 10 ml, Example 1. Target compound 4 having a melting point of 95 to 99 ° C. when the reaction and post-treatment are carried out according to
80 mg was obtained.

Example 7. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) pentoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-114) and 5- {4
-[2- (2-Phenylmorpholino) pentoxy] ben
Dil} thiazolidine-2,4-dione (exemplary compound number
1-313) Reference example 22. 5- {4- [2- (2- (3-
Chlorophenyl) morpholino) pentoxy] benzyl}
2.75 g of a mixture of -3-triphenylmethylthiazolidine-2,4-dione and 5- {4- [2- (2-phenylmorpholino) pentoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione And 10 ml of trifluoroacetic acid were used, and Example 1. Reaction and post-treatment are carried out according to the procedure of Example 4. Purified according to
5- {4 with Rf value = 0.20 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1)
-[2- (2- (3-chlorophenyl) morpholino) pentoxy] benzyl} thiazolidine-2,4-dione
5 with 529 mg and Rf value = 0.15 (Id.)
-{4- [2- (2-phenylmorpholino) pentoxy] benzyl} thiazolidine-2,4-dione 186
mg was obtained.

Example 8. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) ethoxy] benzyl} thiazolidine-2,4-di
ON (Exemplified Compound No. 1-10) and 5- {4-
[2- (2-phenylmorpholino) ethoxy] benzi
Lu} thiazolidine-2,4-dione (exemplary compound number
1-1) Reference example 25. 5- {4- [2- (2- (3-
Chlorophenyl) morpholino) ethoxy] benzyl}-
2.6 g of a mixture of 3-triphenylmethylthiazolidine-2,4-dione and 5- {4- [2- (2-phenylmorpholino) ethoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 2.6 g and Example 1 using 10 ml of trifluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Purified according to
5- {4- [2 with a value = 0.22 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1)
-(2- (3-chlorophenyl) morpholino) ethoxy] benzyl} thiazolidine-2,4-dione 798
5- {4 with mg and Rf value = 0.16 (Id.)
86 mg of-[2- (2-phenylmorpholino) ethoxy] benzyl} thiazolidine-2,4-dione were obtained.

Example 9. 5- {4- [3- (2- (3-chlorophenyl) morpho]
Rhino) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-11) 5- {4- [3- (2- (3-chlorophenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 2.7 g, dichloromethane 30 ml And 3 ml of trifluoroacetic acid were used. Reaction and post-treatment are carried out according to the procedure of Example 4. Purification in accordance with the above procedure gave 1.3 g of the desired compound having a melting point of 54-59 ° C. and an Rf value = 0.32 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1).

Example 10. 5- {4- [2- (2- (3,5-dichlorophenyl)
Morpholino) propoxy] benzyl} thiazolidine-
2,4-dione (Exemplified compound number 1-250) 5- {4- [2- (2- (3,5-dichlorophenyl))
Example 1. Using 750 mg morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione and 4 ml trifluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Target compound 125 having a melting point of 75 to 79 ° C. when purified according to
mg was obtained.

Example 11. 5- {4- [2- (2- (3-methylphenyl) morpho
Rhino) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-222) 5- {4- [2- (2- (3-methylphenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 1.04 g and tri Example 1 using 6 ml of fluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Purified according to, melting point 69.5-71 ° C. and Rf value = 0.10.
196 mg of the target compound having (silica gel thin layer chromatography; benzene: ethyl acetate = 4: 1) were obtained.

Example 12. 5- {4- [2- (2- (3,5-di-t-butyl-4
-Hydroxyphenyl) morpholino) propoxy] ben
Dil} thiazolidine-2,4-dione (exemplary compound number
1-266) 5- {4- [2- (2- (3,5-di-t-butyl-4
-Hydroxyphenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4
Example 1 using 1.0 g of dione and 5 ml of trifluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Purification in accordance with to afford 500 mg of the target compound having a melting point of 103-108 ° C.

Example 13 5- {4- [2- (2- (3-bromophenyl) morpho
Rhino) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-209) 5- {4- [2- (2- (3-Bromophenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione 1.0 g and tri Example 1 using 5 ml of fluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Purified according to
350 mg of the target compound having a melting point of 65-70 ° C. are obtained.

Example 14 5- {4- [2- (2-phenylmorpholino) propoxy
[Ci] benzyl} thiazolidine-2,4-dione (exemplified
Compound number 1-5) (A) Reference example 48. 5- {4- [2- (2-
Example 1. Using 1.99 g of phenylmorpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione [(A) Polar] and 5.0 ml trifluoroacetic acid. Reaction and post-treatment are carried out according to the procedure of Example 4. Purified according to, the target compound [(A) Polar] having a melting point of 69 ° C.
76 g were obtained.

(B) 5- {4- [2- (2-phenylmorpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione [(B) Less
Polar] 0.65 g and trifluoroacetic acid 5
When treated in the same manner as above with ml, the melting point is 69-
Target compound having 71.5 ° C. [(B) LessPol]
ar] 200 mg was obtained.

Example 15. 5- {4- [2- (2- (4-hydroxy-3,5-di
Methylphenyl) morpholino) propoxy] benzyl}
Thiazolidine-2,4-dione (Exemplified compound number 1-
278) 5- {4- [2- (2- (4-benzyloxy-3,5
-Dimethylphenyl) morpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-
2.57 g dione and 20 ml trifluoroacetic acid
Example 1. Reaction and post-treatment according to
Furthermore, in Example 4. Purified according to, melting point 86-9
154 mg of the target compound having a temperature of 6 ° C. were obtained.

Example 16. 5- {4- [2- (2- (3-fluorophenyl) mol]
Holino) propoxy] benzyl} thiazolidine-2,4
-Dione (Exemplified Compound No. 1-182) 5- {4- [2- (2- (3-fluorophenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one 2.81 g (Reference Example 59. A mixture of the crude product obtained in 1.), 35% hydrochloric acid (25 ml) and water (25 ml) was heated under reflux for 6 hours. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract. The obtained residue was chromatographed on silica gel (ethyl acetate: hexane = 1: 2).
→ When purified by subjecting to 1: 1), melting point 72.1 to 7
1.12 g of the target compound having a temperature of 3.0 ° C. are obtained.

Example 17 5- {4- [2- (2- (4-chlorophenyl) morpho]
Rhino) propoxy] benzyl} thiazolidine-2,4-
Dione (Exemplified Compound No. 1-241) Reference Example 66. 5- {4- [2- (2- (4-
Chlorophenyl) morpholino) propoxy] benzyl}
-2-Iminothiazolidin-4-one [(A) Pola
r] 2.34 g, 35% hydrochloric acid 25 ml and water 2
Example 16 using 5 ml. When the reaction and post-treatment were performed according to (1), 0.71 g of the desired compound [(A) Polar] having a melting point of 74.1 to 76.0 ° C was obtained.

Similarly to the above, 5- {4- [2- (2- (4
-Chlorophenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one [(B) Le
ssPolar] 2.40 g, 35% hydrochloric acid 25 ml
And a treatment with 25 ml of water, melting point 76.
Target compound having 9 to 78.0 ° C. [(B) LessP
1.41 g was obtained.

(A) Polar and (B) Less Po
The lars were diastereomers with respect to each other.

Example 18. 5- {4- [2- (2- (3-trifluoromethylphen
Nil) morpholino) propoxy] benzyl} thiazolidi
-2,4-dione [(A) diastereomeric mixture,
(B) Polar and (C) Less Polar]
(Exemplified Compound No. 1-228) Reference Example 73. 5- {4- [2- (2- (3-
Trifluoromethylphenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one [(A) diastereomixture] 130 mg, 35% hydrochloric acid 1.2 ml and water 0.8 ml Example 1
6. When the reaction and the post-treatment are carried out according to, the melting point is 58-5.
Target compound having 9 ° C. [(A) diastereomixture]
120 mg was obtained.

Similarly to the above, 5- {4- [2- (2- (3
-Trifluoromethylphenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one [(B) Polar] 310 mg, 35% hydrochloric acid 1.
Treatment with 8 ml and 1.2 ml of water gives the desired compound [(B) Pola with a melting point of 48-50 ° C.
r] 210 mg was obtained.

Similarly, 5- {4- [2- (2- (3
-Trifluoromethylphenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one [(C) Less Polar] 500 mg, 35%
Treatment with 1.8 ml of hydrochloric acid and 1.2 ml of water gave 150 mg of the desired compound [(C) Less Polar] with a melting point of 51-52.5 ° C.

Example 19 5- {4- [2- (2- (3-chloro-4-fluorophenyl
Phenyl) morpholino) propoxy] benzyl} thiazoli
Gin-2,4-dione [(A) Polar and (B)
Less Polar] (Exemplified Compound No. 1-25
5) Reference Example 80. 5- {4- [2- (2- (3-
Chloro-4-fluorophenyl) morpholino) propoxy] benzyl} -2-iminothiazolidin-4-one [(A) Polar] 1.31 g, 35% hydrochloric acid 15
Example 16 using 15 ml of water and 15 ml of water. When the reaction and post-treatment were performed according to (1), 190 mg of the target compound [(A) Polar] having a melting point of 68.0 to 69.8 ° C was obtained.

Similarly to the above, 5- {4- [2- (2-
(3-Chloro-4-fluorophenyl) morpholino) propoxy] benzyl} -2-iminothiazolidine-4-
On [(B) Less Polar] 1.45g, 3
Treatment with 15 ml of 5% hydrochloric acid and 15 ml of water gave 175 mg of the desired compound [(B) Less Polar] with a melting point of 68.0-69.2 ° C.

Example 20. 2- {4- [2- (2- (3-chlorophenyl) morpho
Rhino) propoxy] benzyl} oxadiazolidine-
3,5-dione (Exemplified Compound No. 2-9) N- {4- [2- (2- (3-chlorophenyl) morpholino) propoxy] benzyl} hydroxylamine
0.37 g of chlorocarbonyl isocyanate was added dropwise to a solution of 1.2 g of methylene chloride in 20 ml under ice cooling. The reaction mixture was stirred at the same temperature for 1.5 hr, the solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate).
Purification by subjecting to 62 mg of the target compound having a melting point of 57-68 ° C.

Example 21. 5- {4- [2- (R)-(2- (R)-(3-chloro
Phenyl) morpholino) propoxy] benzyl} thiazo
Lysine-2,4-dione (Exemplified compound number 1-27) 5- {4- [2- (R)-(2- (R)-(3-chlorophenyl) morpholino) propoxy] benzyl} -3-
Triphenylmethylthiazolidine-2,4-dione
Example 1. Using 1.5 g, 10 ml trifluoroacetic acid and 10 ml methylene chloride. [Α] _D ²⁴ + 7.8 ° (C = 1.0)
00, CHCl ₃ ) and Rf value = 0.3 (silica gel TLC; ethyl acetate: hexane = 3: 2) 840 mg were obtained.

Reference Example 1. 2- (3-chlorophenyl) -5-oxomorpholine 2-amino-1- (3-chlorophenyl) ethanol
To 300 ml of tetrahydrofuran containing 15.5 g, 30 ml of tetrahydrofuran containing 10.2 g of chloroacetyl chloride was added dropwise under ice cooling. Next, 22.77 g of triethylamine was added to this and left overnight at room temperature. After completion of the reaction, tetrahydrofuran was distilled off from the reaction mixture, and ethyl acetate and water were added to the obtained residue. The ethyl acetate layer was separated and washed with water. The obtained ethyl acetate solution was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off. The residue obtained is purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 1) and has an Rf value = 0.34 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1). N-
15 g of [2- (3-chlorophenyl) -2-hydroxyethyl] chloroacetamide were obtained. Then
15 g of the obtained N- [2- (3-chlorophenyl) -2-hydroxyethyl] chloroacetamide was added to N, N-
It was dissolved in 300 ml of dimethylformamide, 3.9 g of sodium hydride was added, and the mixture was stirred for 2 hours and then sonicated. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, the resulting residue was subjected to silica gel column chromatography (ethyl acetate, then ethyl acetate: ethanol = 5: 1), and then recrystallized using a mixed solvent of ethyl acetate and hexane. Then, the melting point 118
7.8 g of the target compound having a .about.120.degree. C. were obtained.

Reference Example 2. 2- [2- (3-chlorophenyl) -5-oxomorpho
Rhino] ethyl propionate 2- (3-chlorophenyl) -5-oxomorpholine
N, N-dimethylformamide 50 containing 2.48 g
0.513 g of sodium hydride was added to ml under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. Then, 10 ml of N, N-dimethylformamide containing 2.56 g of ethyl α-bromopropionate was added dropwise to the reaction mixture, and the mixture was left at room temperature overnight. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate.
Ethyl acetate was distilled off from the extract. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value = 0.69.
3 g of the target compound having (silica gel thin layer chromatography; ethyl acetate; hexane = 5: 1) are obtained.

Reference Example 3. 2- (3-chlorophenyl) -4- (2-hydroxy-
20 ml of tetrahydrofuran containing 2 g of ethyl 1-methylethyl) morpholine 2- [2- (3-chlorophenyl) -5-oxomorpholino] propionate was cooled in an ice-saline bath to obtain lithium aluminum hydride (0.73 g) and tetrahydrofuran.
Dropped into 80 ml of the mixture. The reaction mixture at room temperature
Stir for 3.5 hours. After completion of the reaction, sodium sulfate decahydrate was added to the reaction mixture in excess and stirred sufficiently. The reaction mixture was then filtered through Celite. Tetrahydrofuran was distilled off from the filtrate, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification by 5: 1) gave 1.2 g of the desired compound with Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: hexane = 5: 1).

Reference Example 4. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) propoxy] benzyl} -3-triphenylmethy
Benzene containing 1.24 g of luthiazolidine-2,4- dionetriphenylphosphine
Diethyl azodicarboxylate 0.8 under cooling to 30 ml
2 g was added, and the mixture was stirred at room temperature for 0.5 hours. Then, 2.2 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione was added thereto. The reaction mixture was stirred at room temperature for 1.5 hours and then 2
-(3-chlorophenyl) -4- (2-hydroxy-1)
-Methylethyl) morpholine 1.2 g was added, stirred for 5 hours and then left overnight. After completion of the reaction, the solvent was distilled off from the reaction mixture, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give an Rf value of 0.77 (silica gel thin layer chromatography). (Graph; ethyl acetate: hexane = 4: 1)
About 0.9 g of the target compound having

Reference Example 5. Tetrahydrofuran containing 25 g of ethyl α-methanesulfoxyphenylacetate ethyl mandelate
While cooling 500 ml with an ice-brine bath, 24 g of methanesulfonyl chloride and then 22 g of triethylamine were added, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, ice and dilute hydrochloric acid were added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate.
When ethyl acetate was distilled off from the extract under reduced pressure, Rf value =
Crude product of interest having 0.25 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 5) 3.
8.2 g was obtained.

Reference Example 6. 15 g of 3-oxo-2-phenylthiomorpholine sodium hydride (55% by weight) in benzene,
Then, the mixture was washed with hexane, 500 ml of N, N-dimethylformamide was added, and 200 ml of N, N-dimethylformamide containing 20 g of 2-aminoethanethiol hydrochloride was added dropwise under cooling in an ice-saline solution bath. After the completion of dropping, the mixture was stirred at the same temperature for 1 hour. Next, N, N-containing 9 g of ethyl α-methanesulfoxyphenylacetate.
30 ml of dimethylformamide was added, and the mixture was stirred at room temperature for 1 hour, and then left for 2 days. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and 23 g of the obtained crude product was recrystallized using a mixed solvent of ethyl acetate and hexane to give a melting point of 160-
8.4 g of the target compound having a temperature of 163 ° C. were obtained.

Reference Example 7. 2- (3-oxo-2-phenylthiomorpholino) pro
100 ml of N, N-dimethylformamide containing 4 g of ethyl 3-oxo-2-phenylthiomorpholine pionate was cooled in an ice-brine bath and sodium hydride (55% by weight) was added.
9 g was added, and the mixture was stirred at room temperature for 2.5 hours. Next, 5 ml of tetrahydrofuran containing 3.8 g of ethyl α-bromopropionate was added dropwise to this, and the mixture was stirred for 3 hours and then left at room temperature for 2 days. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, brine was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give an Rf value = 0.64 (silica gel thin layer chromatography; ethyl acetate). 3.7 g of the target compound having: hexane = 1: 1) are obtained.

Reference Example 8. 4- (2-hydroxy-1-methylethyl) -2-phen
Nylthiomorpholine Ethyl 2- (3-oxo-2-phenylthiomorpholino) propionate was added to 100 ml of tetrahydrofuran containing 1.5 g of lithium aluminum hydride under ice cooling.
15 ml of tetrahydrofuran containing 3.6 g was added dropwise. The reaction mixture was stirred at the same temperature for 3 hours and then at room temperature.
It was left for 3 days. After adding 1.0 g of lithium aluminum hydride to the reaction mixture and allowing it to stand at room temperature for 1 day,
The mixture was heated under reflux for 3 hours. To the reaction mixture under cooling water 2.5
ml, then 15% aqueous sodium hydroxide solution 2.5
ml and further 8 ml of water were added, and the insoluble matter was filtered off. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give an Rf value =
1.1 g of the target compound having 0.44 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 9. 5- {4- [2- (2-phenylthiomorpholino) pro
Poxy] benzyl} -3-triphenylmethylthiazol
Gin-2,4-dione 4- (2-hydroxy-1-methylethyl) -2-phenylthiomorpholine 1.1 g, triphenylphosphine 1.1 g, diethyl azodicarboxylate 0.88 g, 5
Reference example 4. using-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (2.1 g) and benzene (50 ml). The resulting crude product was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give Rf = 0.33 (silica gel thin layer chromatography; acetic acid). About 2.5 g of the target compound having ethyl: hexane = 1: 2) was obtained.

Reference Example 10. Ethyl 3-oxo-2-phenylthiomorpholinoacetate 3-oxo-2-phenylthiomorpholine 4 g, sodium hydride 0.9 g, dimethylformamide 10
Reference example 7. using 0 ml, ethyl α-bromoacetate 3.5 g and tetrahydrofuran 5 ml. When the reaction and post-treatment are carried out according to, Rf value = 0.48 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1).
3.6 g of the target compound having 1) are obtained.

Reference Example 11. 4- (2-hydroxyethyl) -2-phenylthiomol
Folin 3-oxo-2-phenylthiomorpholino ethyl acetate
Reference Example 8 using 3.5 g, lithium aluminum hydride 2.5 g and tetrahydrofuran 115 ml.
When the reaction and post-treatment are carried out according to, the Rf value = 0.22.
690 mg of the target compound having (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 12 5- {4- [2- (2-phenylthiomorpholino) eth
[Xy] benzyl} -3-triphenylmethylthiazolidi
-2,4-dione 4- (hydroxyethyl) -2-phenylthiomorpholine 690 mg, triphenylphosphine 945 m
g, diethyl azodicarboxylate 0.57 mg, 5-
Using (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione 1.2 g and benzene 30 ml, Reference Example 4. When the reaction and post-treatment were carried out according to, 580 mg of the desired compound having an Rf value = 0.35 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1) was obtained.

Reference Example 13. 2- [2- (3-chlorophenyl) -5-oxomorpho
Rhino] ethyl butyrate 2- (3-chlorophenyl) -5-oxomorpholine
Reference example 2 using 5.58 g, sodium hydride 1.27 g, ethyl α-bromobutyrate 5.1 ml and dimethylformamide 100 ml. When the reaction and post-treatment were carried out according to (1), 6.41 g of the desired compound having an Rf value = 0.41 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1) was obtained.

Reference Example 14. 4- (1-hydroxymethylpropyl) -2- (3-ku
Lorophenyl) morpholine and 4- (1-hydroxy)
Mixture of methylpropyl) -2-phenylmorpholine 6.35 g ethyl 2- [2- (3-chlorophenyl) -5-oxomorpholine] butyrate, 2.22 g lithium aluminum hydride and 150 m tetrahydrofuran
Reference example 8. When the reaction and post-treatment were carried out according to (1), 3.79 g of the desired compound having an Rf value of 0.51 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 15. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) butoxy] benzyl} -3-triphenylmethyl
Thiazolidine-2,4-dione and 5- {4- [2-
(2-Phenylmorpholino) butoxy] benzyl} -3
Of triphenylmethylthiazolidine-2,4-dione
Mixture reference example 14. 4- (1-hydroxymethylpropyl) -2- (3-chlorophenyl) morpholine obtained in
A mixture of-(1-hydroxymethylpropyl) -2-phenylmorpholine 1.5 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,
4-dione 2.59 g, tributylphosphine 1.
Using 46 g, 1.68 g of azodicarbonyldipiperidine and 50 ml of benzene, Reference Example 4. When the reaction and post-treatment are carried out according to, Rf value = 0.44 (silica gel thin layer chromatography; hexane: ethyl acetate =
2.1 g of the title mixture with 2: 1) was obtained.

Reference Example 16. 2- (2,5-dimethoxy-3,4,6-trimethylphenyl
Example 1 ) of phenyl) -5-oxomorpholine . According to the above, first, 26.2 g of 2-amino-1- (2,5-dimethoxy-3,4,6-trimethylphenyl) ethanol, 14.9 g of chloroacetyl chloride, 13.36 g of triethylamine and 500 ml of tetrahydrofuran were used for the reaction. And work-up gave 16.7 g of N- [2- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-hydroxyethyl] chloroacetamide having a melting point of 139-141 ° C. . Then, the product obtained above, 11.56 g of sodium hydride and 500 m of dimethylformamide.
When the reaction and the post-treatment were carried out using 1 l, the melting point of 143-
8.2 g of the target compound having a temperature of 145 ° C. was obtained.

Reference Example 17: 2- [2- (2,5-dimethoxy-3,4,6-trimethyl)
Cylphenyl) -5-oxomorpholino] propionic acid
Reference Example 2 using ethyl 2- (2,5-dimethoxy-3,4,6-trimethylphenyl) -5-oxomorpholine 8.1 g, sodium hydride 1.27 g and ethyl α-bromopropionate 6.3 g. ． When the reaction and post-treatment were carried out according to (1), 7.71 g of the target compound having an Rf value = 0.43 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained.

Reference Example 18. 2- (2,5-dimethoxy-3,4,6-trimethylphenyl
Phenyl) -4- (2-droxy-1-methylethyl) mo
Ruphorin 2- [2- (2,5-dimethoxy-3,4,6-trimethylphenyl) -5-oxomorpholino] ethyl propionate 7.6 g, lithium aluminum hydride 2.
Using 28 g and 300 ml of tetrahydrofuran,
Reference example 8. 4. When the reaction and post-treatment are carried out according to, the target compound having an Rf value = 0.10 (silica gel thin layer chromatography; ethyl acetate: hexane = 5: 1).
0 g was obtained.

Reference Example 19. 5- {4- [2- (2- (2,5-dimethoxy-3,
4,6-Trimethylphenyl) morpholino) propoxy
[C] benzyl} -3-triphenylmethylthiazolidine
-2,4-dione 2- (2,5-dimethoxy-3,4,6-trimethylphenyl) -4- (2-hydroxy-1-methylethyl)
Morpholine 2.5 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-
Dione 3.6 g, tributylphosphine 1.72
g, azodicarbonyldipiperidine (1.95 g) and anhydrous benzene (50 ml) were used. When the reaction and post-treatment are carried out according to, Rf value = 0.64 (silica gel thin layer chromatography; ethyl acetate: hexane = 3:
2.0 g of the target compound having 1) were obtained.

Reference Example 20. α- [2- (3-chlorophenyl) -5-oxomorpho
Rhino] ethyl valerate 2- (3-chlorophenyl) -5-oxomorpholine
5.52 g, sodium hydride (55% by weight) 1.2
Reference example 2. Using 5 g, ethyl α-bromovalerate 5.8 ml and dimethylformamide 100 ml. The reaction and post-treatment were carried out according to the above procedure to obtain 7.97 g of the desired compound having an Rf value = 0.49 (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1).

Reference Example 21. 4- (1-hydroxymethylbutyl) -2- (3-chloro
Rophenyl) morpholine and 4- (1-hydroxyme
A mixture of tylbutyl) -2-phenylmorpholine 7.78 g ethyl 2- [2- (3-chlorophenyl) -5-oxomorpholino] valerate, 2.6 g lithium aluminum hydride and 150 ml tetrahydrofuran.
Using Reference Example 8. When the reaction and post-treatment were carried out according to, the title mixture (5.0 g) having an Rf value = 0.58 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 22. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) pentoxy] benzyl} -3-triphenylmethy
Luthiazolidine-2,4-dione and 5- {4- [2
-(2-Phenylmorpholino) pentoxy] benzyl}
-3-Triphenylmethylthiazolidine-2,4-dio
Mixture Reference Example 21 of the emissions. 4- (1-hydroxymethylbutyl) -2- (3-chlorophenyl) morpholine obtained in
1.69 g of a mixture of (1-hydroxymethylbutyl) -2-phenylmorpholine, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4
-Dione 2.77 g, tributylphosphine 1.5
6 g, azodicarbonyldipiperidine 1.80 g and benzene 50 ml were used, and Reference Example 4. When the reaction and post-treatment are carried out according to, Rf value = 0.52 (silica gel thin layer chromatography; hexane: ethyl acetate = 2:
3.1 g of the title mixture with 1) was obtained.

Reference Example 23. 2- (3-chlorophenyl) -5-oxomorpholino vinegar
Methyl acid 2- (3-chlorophenyl) -5-oxomorpholine
3.43 g, sodium hydride 0.78 g, methyl bromoacetate 2.0 ml and dimethylformamide 7
0 ml was used and Reference Example 2. When the reaction and post-treatment were carried out in accordance with the above procedure, 3.47 g of the desired compound having an Rf value = 0.45 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained.

Reference Example 24. 2- [2- (3-chlorophenyl) morpholino] ethano
And 2- (2-phenylmorpholino) ethanol
Of methyl 2- (3-chlorophenyl) -5-oxomorpholinoacetate 3.3 g, lithium aluminum hydride
Using Reference Example 8. using 1.32 g and 80 ml of tetrahydrofuran. When the reaction and post-treatment are carried out according to
The indicated mixture with f value = 0.19 (ethyl acetate)
1.31 g was obtained.

Reference Example 25. 5- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) ethoxy] benzyl} -3-triphenylmethyl
Thiazolidine-2,4-dione and 5- {4- [2-
(2-Phenylmorpholino) ethoxy] benzyl} -3
Of triphenylmethylthiazolidine-2,4-dione
Mixture reference example 24. A mixture of 2- [2- (3-chlorophenyl) morpholino] ethanol and 2- (2-phenylmorpholino) ethanol obtained in 1.3 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2. , 4-dione 2.5 g, tributylphosphine 1.4 g, azodicarbonyldipiperidine 1.6
Example 3 using 3 g and 40 ml of benzene. When the reaction and post-treatment were carried out according to, 2.9 g of the title mixture having an Rf value = 0.34 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained.

Reference Example 26. 3- [2- (3-chlorophenyl) -5-oxomorpho
Rhino] ethyl propionate 2- (3-chlorophenyl) -5-oxomorpholine
6.2 g, sodium hydride (55% by weight) 1.28
g, ethyl 3-bromopropionate 6.3 g and dimethylformamide 180 ml were used, and Reference Example 2. When the reaction and post-treatment are carried out according to, the Rf value = 0.31.
5.95 g of the target compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) are obtained.

Reference Example 27. 3- [2- (3-chlorophenyl) morpholino] propa
Ethanol 3- [2- (3-chlorophenyl) -5-oxomorpholino] propionate 5.8 g, lithium aluminum hydride 2.12 g and tetrahydrofuran
250 ml was used and Reference Example 8. The target compound having an Rf value = 0.16 (silica gel thin layer chromatography; ethyl acetate) after the reaction and post-treatment according to 1.
1 g was obtained.

Reference Example 28. 5- {4- [3- (2- (3-chlorophenyl) morpho]
Rhino) propoxy] benzyl} -3-triphenylmethy
Luthiazolidine-2,4-dione 3- [2- (3-chlorophenyl) morpholino] propanol 2.1 g, 5- (4-hydroxybenzyl)-
Reference Example 4. Using 3-triphenylmethylthiazolidine-2,4-dione 4.2 g, tributylphosphine 1.83 g, azodicarbonyldipiperidine 2.07 g and benzene 60 ml. When the reaction and post-treatment were carried out according to, the target compound (2.7 g) having an Rf value = 0.77 (silica gel thin layer chromatography; ethyl acetate: hexane = 2: 1) was obtained.

Reference Example 29. α- (3,5-dichlorophenyl) -5-oxomorpho
Phosphorus 2-amino-1- (3,5-dichlorophenyl) ethanol 5.0 g, tetrahydrofuran 55 ml, chloroacetyl chloride 2.1 ml and triethylamine.
Using 3.7 ml, Reference Example 1. N- [2- having a melting point of 68 to 70 ° C. when the reaction and post-treatment are carried out according to
3.38 g of (3,5-dichlorophenyl) -2-hydroxyethyl] chloroacetamide were obtained. Further, 1.44 g of the above product, 1.2 g of sodium hydride (55% by weight) and 72 ml of dimethylformamide.
Using Reference Example 1. Object compound 780 having a melting point of 145 to 148 ° C. when the reaction and post-treatment are carried out according to
mg was obtained.

Reference Example 30. 2- [2- (3,5-dichlorophenyl) -5-oxo
Morpholino] ethyl propionate 2- (3,5-dichlorophenyl) -5-oxomorpholine 1.1 g, sodium hydride (55% by weight)
Reference example 2 using 0.2 g, ethyl α-bromopropionate 0.6 ml and dimethylformamide 20 ml. When the reaction and the post-treatment are carried out according to, the Rf value = 0.
1.33 g of the target compound having 80 (silica gel thin layer chromatography; ethyl acetate) are obtained.

Reference Example 31. 4- (1-hydroxymethylethyl) -2- (3,5-
Dichlorophenyl) morpholine 2- [2- (3,5-dichlorophenyl) -5-oxomorpholino] ethyl propionate 1.26 g, lithium aluminum hydride (1M tetrahydrofuran solution) 7.3 ml and tetrahydrofuran 15 ml.
Using Reference Example 8. When the reaction and post-treatment were carried out according to, 937 mg of the target compound having an Rf value = 0.31 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 32. 5- {4- [2- (2- (3,5-dichlorophenyl)
Morpholino) propoxy] benzyl} -3-tripheni
Rumethylthiazolidine-2,4-dione 4- (1-hydroxymethylethyl) -2- (3,5-
Dichlorophenyl) morpholine 915 mg, 5- (4
-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 1.0 g, tributylphosphine 0.54 ml, azodicarbonyldipiperidine
Using 0.55 g and 37 ml of benzene, Reference Example 4.
When the reaction and the post-treatment are carried out according to, the Rf value = 0.27.
750 mg of the target compound having (silica gel thin layer chromatography; hexane: ethyl acetate = 2: 1) were obtained.

Reference Example 33. N- [2- (3-methylphenyl) -2-hydroxye
Cyl] chloroacetamide 2 -amino-1- (3-methylphenyl) ethanol
Using 100 mg, chloroacetyl chloride 75 mg, tetrahydrofuran 4 ml and triethylamine 67 mg, Reference Example 1. When the reaction and post-treatment are performed according to
80 mg of the desired compound with an Rf value = 0.46 (silica gel thin layer chromatography; ethyl acetate: hexane = 2: 1) was obtained.

Reference Example 34. α- [2- (3-methylphenyl) -5-oxomorpho
Ethyl Rino] propionate N- [2- (3-methylphenyl) -2-hydroxyethyl] chloroacetamide 5.0 g of a dimethylformamide 60 ml solution was mixed with sodium hydride (55% by weight) 2.9 g and dimethylformamide 200 ml. It was dripped in (reaction temperature 55-60 degreeC). The reaction mixture was stirred at room temperature for 60 minutes, 4.3 ml of ethyl α-bromopropionate was added dropwise under ice cooling, and the mixture was further stirred at room temperature for 90 minutes. After completion of the reaction, 10 ml of water was added to the reaction mixture under ice cooling, and excess water was further added, followed by extraction with benzene. The extract was dried over anhydrous sodium sulfate, then benzene was distilled off and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 2) yielded 5.1 g of the desired compound with Rf value = 0.13 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 4).

Reference Example 35. 4- (1-hydroxymethylethyl) -2- (3-methyl
Ruphenyl) morpholine ethyl 2- [2- (3-methylphenyl) -5- oxomorpholino ] propionate 5.1 g, lithium aluminum hydride 2.1 g and tetrahydrofuran 1
Using 10 ml, Reference Example 8. When the reaction and post-treatment are carried out according to, the target compound having an Rf value = 0.19 (silica gel thin layer chromatography; ethyl acetate) is obtained.
g was obtained.

Reference Example 36. 5- {4- [2- (2- (3-methylphenyl) morpho
Rhino) propoxy] benzyl} -3-triphenylmethy
Lthiazolidine-2,4-dione 4- (1-hydroxymethylethyl) -2- (3-methylphenyl) morpholine 1.0 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4 -Dione 1.65 g, tributylphosphine 0.86 g, azodicarbonyldipiperidine 1.0
Example 4 using 7 g and 60 ml of benzene. When the reaction and post-treatment were carried out according to (1), 1.04 g of the desired compound having an Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) was obtained.

Reference Example 37. N- [2- (3,5-di-t-butyl-4-hydroxy
Phenyl) -2-hydroxyethyl] chloroacetami
Using 2-amino-1- (3,5-di-t-butyl-4-hydroxyphenyl) ethanol (5.5 g), chloroacetyl chloride (2.3 g), triethylamine (2.1 g) and tetrahydrofuran (50 ml) in Reference Example 1. When the reaction and post-treatment were carried out in accordance with the above, 3.1 g of the target compound having an Rf value = 0.22 (silica gel thin layer chromatography; benzene: ethyl acetate = 4: 1) was obtained.

Example 38. 2- [2- (3,5-di-t-butyl-4-hydroxy
Phenyl) -5-oxomorpholino] ethyl propionate
Le N-[2-(3,5-di -t- butyl-4-hydroxyphenyl) -2-hydroxyethyl] chloroacetamide 1.86 g, sodium hydride (55 wt%)
1.0 g, dimethylformamide 200 ml and α
-Using 1.5 g of ethyl bromopropionate, Reference Example 34. When the reaction and post-treatment are carried out according to
Target compound having 0.39 (silica gel thin layer chromatography; benzene: ethyl acetate = 4: 1) 1.6
g was obtained.

Reference Example 39. 4- (1-hydroxymethylethyl) -2- (3,5-
Di-t-butyl-4-hydroxyphenyl) morpholine 2- [2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-oxomorpholino] ethyl propionate 1.6 g, lithium aluminum hydride 0.45g
And tetrahydrofuran 30 ml were used, and Reference Example 8. When the reaction and post-treatment are carried out according to
0.9 g of the desired compound having a temperature of ˜127 ° C. was obtained.

Reference Example 40. 5- {4- [2- (2- (3,5-di-t-butyl-4
-Hydroxyphenyl) morpholino) propoxy] ben
Zil} -3-trimethylphenyl thiazolidine-2,4
-Dione 4- (1-hydroxymethylethyl) -2- (3,5-
Di-t-butyl-4-hydroxyphenyl) morpholine 0.8 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 0.
9 g, tributylphosphine 0.85 g, azodicarbonyldipiperidine 1.1 g and benzene 70 m
Reference example 4. When the reaction and post-treatment were carried out according to (1), 1.1 g of the desired compound having an Rf value of 0.57 (silica gel thin layer chromatography; benzene: ethyl acetate = 4: 1) was obtained.

Reference Example 41. 2- (3-Bromophenyl) -5-oxomorpholine 2-amino-1- (3-bromophenyl) ethanol
Using 12 g, tetrahydrofuran 100 ml, chloroacetyl chloride 6.9 g and triethylamine 6.2 g, Reference Example 1. When the reaction and post-treatment are performed according to
N- [2 with Rf value = 0.43 (silica gel thin layer chromatography; benzene: ethyl acetate = 1: 1)
13 g of-(3-bromophenyl) -2-hydroxyethyl] chloroacetamide were obtained. Furthermore, 12 g of the above product, 9 g of sodium hydride (55% by weight) and 600 ml of dimethylformamide were used, and Reference Example 1. When the reaction and post-treatment are carried out according to
7.2 g of the target compound having a .about.145.degree. C. were obtained.

Reference Example 42. 2- [2- (3-bromophenyl) -5-oxomorpho
Rhino] ethyl propionate 2- (3-bromophenyl) -5-oxomorpholine
500 mg, sodium hydride (55% by weight) 94 m
g, 0.28 ml of α-bromopropionate and 5 ml of dimethylformamide were used, and Reference Example 2. When the reaction and post-treatment were carried out according to, 580 mg of the target compound having an Rf value = 0.33 (silica gel thin layer chromatography; benzene: ethyl acetate = 4: 1) was obtained.

Reference Example 43. 4- (1-hydroxymethylethyl) -2- (3-bro
Mophenyl) morpholine 4.2 g ethyl 2- [2- (3-bromophenyl) -5- oxomorpholino ] propionate, 1.3 g lithium aluminum hydride and tetrahydrofuran 6
0 ml was used and Reference Example 8. When the reaction and the post-treatment are carried out according to, 3.3 g of the target compound having an Rf value of 0.29 (silica gel thin layer chromatography; ethyl acetate).
was gotten.

Reference Example 44. 5- {4- [2- (2- (3-bromophenyl) morpho
Rhino) propoxy] benzyl} -3-triphenylmethy
Luthiazolidine-2,4-dione 4- (1-hydroxymethylethyl) -2- (3-bromophenyl) morpholine 3.3 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4 -Dione 4.3 g, tributylphosphine
Using 2.2 g, azodicarbonyldipiperidine 2.8 g and benzene 200 ml, Reference Example 4. Rf value = 0.66 (silica gel thin layer chromatography; benzene: ethyl acetate =)
1.0 g of the target compound having 4: 1) was obtained.

Reference Example 45. N- (2-hydroxy-2-phenylethyl) chloroa
Cetamide α-amino-1-phenylethanol 7.0 g, chloroacetyl chloride 5.65 g, tetrahydrofuran 90
ml and triethylamine 5.11 g were used, and the reference example 1. When the reaction and post-treatment are carried out according to
8.28 g of the expected compound having a temperature of 1 to 112 ° C. are obtained.

Reference Example 46. 2- (2-phenyl-5-oxomorpholino) propio
Ethyl acid salt [Diastereomer separation; (A) Polar
And (B) Less Polar] N- (2-hydroxy-2-phenylethyl) chloroacetamide 6.23 g, sodium hydride (55% by weight) 3.80 g, dimethylformamide 300 ml and ethyl α-bromopropionate 7.97 g. Using Reference Example 34. When the reaction and post-treatment are performed according to
2.73 g of the target compound [(A) Polar] with Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) and Rf value =
The target compound having 0.28 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 2) [(B)
Less Polar] 3.17 g were obtained.

Reference Example 47. 4- (1-hydroxymethylethyl) -2-phenylmo
Ruphorin [(A) Polar and (B) Less
Polar] (A) Reference Example 46. 2- (2-phenyl-5) obtained in
-Oxomorpholino) ethyl propionate [(A) Po
lar] 1.96 g, lithium aluminum hydride
Using 0.77 g and 25 ml of tetrahydrofuran, Reference Example 8. When the reaction and post-treatment are carried out according to
f value = 0.26 (silica gel thin layer chromatography;
1.25 g of the target compound [(A) Polar] having ethyl acetate: tetrahydrofuran = 10: 1) was obtained.

(B) In the same manner as above, 2- (2-phenyl-)
5-oxomorpholino) ethyl propionate [(B) L
ess Polar] 2.34 g, lithium aluminum hydroxide 0.91 g and tetrahydrofuran 3
Treated with 1 ml, the target compound [(B) Le having Rf value = 0.30 (silica gel thin layer chromatography; ethyl acetate: tetrahydrofuran = 10: 1).
1.10 g of ss Polar] was obtained.

Reference Example 48. 5- {4- [2- (2-phenylmorpholino) propoxy
[C] benzyl} -3-triphenylmethylthiazolidine
-2,4-dione [(A) Polar and (B) Le
ss Polar] (A) Reference Example 47. 4- (1-hydroxymethylethyl) -2-phenylmorpholine [(A) Pol obtained in
ar] 1.52 g, 5- (4-hydroxybenzyl)
-3-triphenylmethylthiazolidine-2,4-dione 4.84 g, tributylphosphine 2.10 g,
Reference example 4. using 2.62 g of azodicarbonylpiperidine and 100 ml of benzene. When the reaction and post-treatment were carried out according to (1), 2.53 g of the desired compound [(A) Polar] having a melting point of 75 to 78 ° C. was obtained.

(B) 4- (1-hydroxymethylethyl) -2-phenylmorpholine [(B) Le as described above]
ss Polar] 1.08 g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-
2,4-dione 1.86 g, tributylphosphine
1.00 g, azodicarbonyldipiperidine 1.24 g
And treatment with 45 ml of benzene gave 0.65 g of the desired compound [(B) Less Polar] with an Rf value = 0.29 (silica gel thin layer chromatography; ethyl acetate: benzene = 1: 6).

Reference Example 49. 2- (4-benzyloxy-3,5-dimethylphenyl
) -5-oxomorpholine 2-amino-1- (4-benzyloxy-3,5-dimethylphenyl) ethanol 1.87 g, chloroacetyl chloride 0.94 g, tetrahydrofuran 30 ml and triethylamine 0.84 g were used as a reference example. 1. When the reaction and post-treatment are carried out according to
N- [2- (4-benzyloxy-3,5 having a temperature of 8 ° C
1.26 g of -dimethylphenyl) -2-hydroxyethyl] chloroacetamide were obtained.

Further, 1.04 g of the above product, 0.65 g of sodium hydride (55% by weight) and 50 ml of dimethylformamide were used, and Reference Example 1. When the reaction and post-treatment were carried out according to (1), 0.56 g of the desired compound having a melting point of 158 to 160 ° C. was obtained.

Reference Example 50. 2- [2- (4-benzyloxy-3,5-dimethylphosphine
Ethyl) -5-oxomorpholino] propionate ethyl 2- (4-benzyloxy-3,5-dimethylphenyl) -5-oxomorpholine 0.55 g, sodium hydride (55% by weight) 93 mg, α-bromopropionic acid 0.38 g of ethyl and dimethylformamide
Using 10 ml, the reference example 2. When the reaction and the post-treatment are carried out according to (1), 0.50 g of the desired compound (diastereo mixture) having an Rf value = 0.26 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 2) is obtained. It was

Reference Example 51. 2- (4-benzyloxy-3,5-dimethylphenyl
) -4- (1-Hydroxymethylethyl) morpholine 2- [2- (4-benzyloxy-3,5-dimethylphenyl) -5-oxomorpholino] ethyl propionate 0.50 g, lithium aluminum hydride (1M Tetrahydrofuran solution) 3.6 ml and 10 ml of tetrahydrofuran were used, and Reference Example 8. When the reaction and post-treatment are carried out according to, Rf value = 0.18 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 3:
0.27 g of the target compound having 2) was obtained.

Reference Example 52. 5- {4- [2- (2- (4-benzyloxy-3,5
-Dimethylphenyl) morpholino) propoxy] benzyl
Ru} -3-triphenylmethylthiazolidine-2,4-
Dione 2- (4-benzyloxy-3,5-dimethylphenyl) -4- (1-hydroxymethylethyl) morpholine 0.25 g, 5- (4-hydroxybenzyl) -3-
Triphenylmethylthiazolidine-2,4-dione
Reference example 4. using 0.39 g, tributylphosphine 0.17 g, azodicarbonyldipiperidine 0.21 g and benzene 20 ml. When the reaction and post-treatment were carried out according to (1), 0.35 g of the desired compound having an Rf value = 0.41 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 3) was obtained.

Reference Example 53. N- [2- (3-fluorophenyl) -2-hydroxy
Ethyl] chloroacetamide 2 -amino-1- (3-fluorophenyl) ethanol 11.0 g, chloroacetyl chloride 6.7 ml, tetrahydrofuran 230 ml and triethylamine.
Using Reference Example 1. When the reaction and post-treatment were carried out according to (1), 13.7 g of the desired compound having an Rf value = 0.50 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained.

Reference Example 54. 2- [2- (3-fluorophenyl) -5-oxomol
Holino] ethyl propionate N- [2- (3-fluorophenyl) -2-hydroxyethyl] chloroacetamide 13.4 g, sodium hydride (55% by weight) 7.6 g, dimethylformamide 700 ml and ethyl α-bromopropionate.
Using Reference Example 34. When the reaction and post-treatment were carried out according to, the target product (8.02 g) having an Rf value = 0.74 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 2) was obtained.

Reference Example 55. 2- (3-fluorophenyl) -4- (1-hydroxy
Methylethyl ) morpholine Using ethyl 2- [2- (3-fluorophenyl) -5-oxomorpholino] propionate (7.42 g), lithium aluminum hydride (2.86 g) and tetrahydrofuran (100 ml) in Reference Example 8. The target compound having an Rf value = 0.37 (silica gel thin layer chromatography; ethyl acetate), when the reaction and post-treatment are performed according to
3.68 g was obtained.

Reference Example 56. 2- (3-fluorophenyl) -4- [1-methyl-2
-(4-Nitrophenoxy) ethyl] morpholine 2- (3-Fluorophenyl) -4- (1-hydroxymethylethyl) morpholine 3.10 g, 1-fluoro-4-nitrobenzene 1.45 ml into dimethylformamide 40 ml solution. 0.65 g of sodium hydride (55% by weight) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Then, after stirring at room temperature for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract. The residue obtained is purified by subjecting it to silica gel chromatography (hexane: ethyl acetate = 2: 1) and having an Rf value = 0.65 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1). 4.62 g of compound was obtained.

Reference Example 57. 4- [2- (4-aminophenoxy) -1-methylethyl
]]-2- (3-Fluorophenyl) morpholine 2- (3-Fluorophenyl) -4- [1-methyl-2
-(4-Nitrophenoxy) ethyl] morpholine 4.
50 g, methyl alcohol 120 ml, zinc 13.4
A mixture of g and acetic acid 3 ml was heated at reflux for 2 hours.
After the reaction was completed, the insoluble matter was removed using Celite, and the Celite was washed with ethyl acetate. The resulting organic layer was washed with aqueous sodium bicarbonate solution, then brine, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer, and the obtained residue was purified by subjecting it to silica gel column chromatography (ethyl acetate) to obtain the target compound having an Rf value = 0.27 (hexane: ethyl acetate = 1: 1). .8
1 g was obtained.

Reference Example 58. 2-Bromo-3- {4- [2- (2- (3-fluoro
Phenyl) morpholino) propoxy] phenyl} propio
Butyl acid salt 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-fluorophenyl) morpholine 3.
60 g, acetone 80 ml and hydrobromic acid 4.4 m
A solution of 0.83 g of sodium nitrite in 3.5 ml of water was added dropwise to the mixture of 1 under ice cooling in 10 minutes, and the mixture was stirred at the same temperature for 10 minutes. Butyl acrylate 15.6 was added to the reaction mixture.
ml was added, the temperature was slowly raised to 20 ° C., and 0.31 g of cuprous oxide (Cu ₂ O) was added little by little. The reaction mixture was then stirred at room temperature for 3 hours, then poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate.
Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel chromatography (hexane: ethyl acetate = 3:
When purified by subjecting to 1), Rf value = 0.79 (silica gel thin layer chromatography; hexane: ethyl acetate =
3.03 g of the target compound having 1: 1) was obtained.

Reference Example 59. 5- {4- [2- (2- (3-fluorophenyl) mol]
Holino) propoxy] benzyl} -2-iminothiazoli
1.79 g of butyl din- 4-one 2-bromo-3- {4- [2- (2- (3-fluorophenyl) morpholino) propoxy] phenyl} propionate, 800 mg of thiourea, 600 mg of sodium acetate and 50 ml of ethanol. The mixture was heated to reflux for 6 hours. After completion of the reaction, the reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. When ethyl acetate was distilled off from the extract, Rf
2.81 g of the expected crude product are obtained with a value = 0.08 (silica gel thin layer chromatography; ethyl acetate).

Reference Example 60. N- [2- (4-chlorophenyl) -2-hydroxye
Cyl] chloroacetamide α-amino-1- (4-chlorophenyl) ethanol
29.2 g, chloroacetyl chloride 16.4 ml, tetrahydrofuran 600 ml and triethylamine
Using 28.8 ml, Reference Example 1. When the reaction and post-treatment were carried out according to (1), 22.6 g of the desired compound having a melting point of 76.7-78.8 ° C was obtained.

Reference Example 61. 2- [2- (4-chlorophenyl) -5-oxomorpho
Ethyl lino ] propionate N- [2- (4-chlorophenyl) -2-hydroxyethyl] chloroacetamide 22.6 g, sodium hydride (55% by weight) 12.6 g, dimethylformamide 1300 ml and ethyl α-bromopropionate 17 Using 0.7 ml, Reference Example 34. Rf value = 0.52 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) when the reaction and post-treatment are carried out according to
6.46 g of the target compound [(A) Polar] having
And 8.71 g of the desired compound [(B) Less Polar] having an Rf value of 0.58 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) were obtained.

Compound (A) Polar and Compound (B) L
Ess Polar and each other were diastereomers.

Reference Example 62. 2- (4-chlorophenyl) -4- (1-hydroxyme
Tylethyl) morpholine [(A) Polar and
(B) Less Polar] Reference Example 61. Ethyl 2- [2- (4-chlorophenyl) -5-oxomorpholino] propionate [(A) Polar] 6.00 g, lithium aluminum hydride 2.30 g and tetrahydrofuran 1
Using 50 ml, Reference Example 8. When the reaction and post-treatment were carried out according to (1), 4.91 g of the desired compound [(A) Polar] having an Rf value of 0.15 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained. .

Using ethyl 2- [2- (4-chlorophenyl) -5-oxomorpholino] propionate [(B) Less Polar] 8.47 g, lithium aluminum hydride 3.20 g and tetrahydrofuran 160 ml in the same manner as above. When processed, Rf value = 0.
15 (silica gel thin layer chromatography; hexane:
The target compound [(B) Le having ethyl acetate = 1: 1)
ss Polar] 4.87 g was obtained.

Reference Example 63. 2- (4-chlorophenyl) -4- [1-methyl-2-
(4-Nitrophenoxy) ethyl] morpholine [(A)
Polar and (B) Less Polar] Reference Example 62. 2- (4-chlorophenyl) -obtained in
4- (1-hydroxymethylethyl) morpholine [(A) Polar] 3.87 g, 1-fluoro-4
-Nitrobenzene 1.64 ml, sodium hydride (55 wt%) 730 mg and dimethylformamide 60 ml were used, and Reference Example 56. When the reaction and post-treatment were carried out according to (1), 5.60 g of the desired compound [(A) Polar] having a melting point of 103.3 to 105.9 ° C was obtained.

As in the above, 2- (4-chlorophenyl)
Treated with 3.87 g of 4- (1-hydroxymethylethyl) morpholine [(B) Less Polar], 1.64 ml of 1-fluoro-4-nitrobenzene, 730 mg of sodium hydride (55% by weight) and 60 ml of dimethylformamide. Then, Rf value =
Target compound having 0.47 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) [(B)
Less Polar] 5.65 g was obtained.

Reference Example 64. 4- [2- (4-aminophenoxy) -1-methylethyl
L] -2- (4-chlorophenyl) morpholine [(A)
Polar and (B) Less Polar] Reference Example 63. 2- (4-chlorophenyl) -obtained in
4- [1-methyl-2- (4-nitrophenoxy) ethyl] morpholine [(A) Polar] 5.35 g, zinc 15.0 g, methanol 230 ml and acetic acid
Using 6.0 ml, Reference Example 57. When the reaction and post-treatment were performed according to (1), 4.60 g of the target compound [(A) Polar] having a melting point of 92 to 94 ° C was obtained.

As in the above, 2- (4-chlorophenyl)
-4- [1-Methyl-2- (4-nitrophenoxy) ethyl] morpholine [(B) Less Polar] 5.
When treated with 42 g, zinc 15.3 g, methanol 230 ml and acetic acid 5.5 ml, Rf value =
The target compound having 0.24 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) [(B)
Less Polar] 4.70 g was obtained.

Reference Example 65. 2-bromo-3- {4- [2- (2- (4-chlorophen
Nyl) morpholino) propoxy] phenyl} propion
Butylate [(A) Polar and (B) Less P
ollar] Reference Example 64. 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (4-chlorophenyl) morpholine [(A) Polar] obtained in 4.15 g, acetone 80 ml, hydrobromic acid 5.6 ml , Sodium nitrite 908 mg and water 7 ml, butyl acrylate 17.2 ml and cuprous oxide 342 mg were used, and Reference Example 58. When the reaction and post-treatment were carried out according to (1), 3.29 g of the target compound [(A) Polar] having an Rf value = 0.76 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained. .

Similarly to the above, 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (4-chlorophenyl) morpholine [(B) Less Polar]
3.03 g, acetone 60 ml, hydrobromic acid 4.0
6 ml, sodium nitrite 663 mg and water 5 m
l, further treated with 12.5 ml of butyl acrylate and 250 mg of cuprous oxide, Rf value = 0.6
Target compound [(B) Les having 1 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1)
s Polar] 2.98 g was obtained.

Reference Example 66. 5- {4- [2- (2- (4-chlorophenyl) morpho]
Rhino) propoxy] benzyl} -2-iminothiazolidi
N-4-one [(A) Polar and (B) Less
Polar] Reference Example 56. 2-Bromo-3- {4- [2-
(2- (4-Chlorophenyl) morpholino) propoxy] phenyl} butyl propionate [(A) Pola
r] 2.77 g, thiourea 1.96 g, sodium acetate 1.41 g and ethanol 100 ml were used, and Reference Example 59. When the reaction and post-treatment are performed according to
The crude product of interest [(A) Pol with Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate)]
ar] 2.52 g was obtained.

Similarly to the above, 2-bromo-3- {4- [2
Butyl- (2- (4-chlorophenyl) morpholino) propoxy] phenyl} propionate [(B) Less
Polar] 2.90 g, thiourea 1.70 g, sodium acetate 1.22 g and ethanol 60 ml.
When treated with, 2.43 g of the target compound [(B) Less Polar] having an Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Reference Example 67. N- [2-hydroxy-2- (3-trifluorophenyl)
1 ) Ethyl] chloroacetamide 2 -amino-1- (3-trifluorophenyl) ethanol 12.0 g, chloroacetyl chloride 4.6 ml,
Using 160 ml of tetrahydrofuran and 8.2 ml of triethylamine, Reference Example 1. When the reaction and post-treatment were carried out according to (1), 15.44 g of the desired compound having a melting point of 68-69 ° C. was obtained.

Reference Example 68. 2- [2- (3-trifluoromethylphenyl) -5-
Oxomorpholino] ethyl propionate [(A) dias
Tereo mixture, (B) Polar and (C) Less
Polar] N- [2-hydroxy-2- (3-trifluoromethylphenyl) ethyl] chloroacetamide 3.11 g,
Reference example 34. using sodium hydride (55% by weight) 1.44 g, dimethylformamide 160 ml and ethyl α-bromopropionate 3.08 g. When the reaction and post-treatment are carried out according to, the target compound [(A) diastereomer mixture] having Rf value = 0.43 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 3) is 2.70 g. was gotten.

As in the above, N- [2-hydroxy-2-
Crude product obtained from 10.00 g of (3-trifluoromethylphenyl) ethyl] chloroacetamide 11.
Purification by subjecting 80 g to silica gel column chromatography (hexane: ethyl acetate = 3: 1) has an Rf value = 0.53 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1). Compound [(B) Polar] 4.10 g and Rf value = 0.
3.15 g of the target compound [(C) Less Polar] having 60 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) was obtained.

Compound (B) Polar and Compound (C) L
Ess Polar and each other were diastereomers.

Reference Example 69. 4- (1-hydroxymethylethyl) -2- (3-tri
Fluoromethylphenyl) morpholine [(A) diastere
Rheo Mixture, (B) Polar and (C) Less
Polar] Reference Example 68. 2.70 g of ethyl 2- [2- (3-trifluoromethylphenyl) -5-oxomorpholino] propionate [(A) diastereomixture] obtained in 1., 0.95 g of lithium aluminum hydride and 30 ml of tetrahydrofuran were used. Reference Example 8. When the reaction and post-treatment are carried out according to, Rf value = 0.18 (silica gel thin layer chromatography; ethyl acetate: n-hexane =
1.65 g of the target compound [(A) diastereomixture] with 4: 1) were obtained.

In the same manner as above, 4.10 g of ethyl 2- (2- (3-trifluoromethylphenyl) -5-oxomorpholino] propionate [(B) Polar], 1.37 g of lithium aluminum hydride and 45 ml of tetrahydrofuran were added. When processed with Rf value = 0.2
2 (silica gel thin layer chromatography; ethyl acetate:
Target compound [(B) P having n-hexane = 4: 1]
2.31 g was obtained.

In addition, ethyl 2- [2- (3-trifluoromethylphenyl) -5-oxomorpholino] propionate [(C) Less Polar] 3.
Treated with 15 g, 1.04 g lithium aluminum hydride and 30 ml tetrahydrofuran,
1.99 g of the target compound [(C) Less Polar] having an Rf value = 0.30 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 4: 1) was obtained.

Reference Example 70. 4- [1-methyl-2- (4-nitrophenoxy) ethyl
]]-2- (3-Trifluoromethylphenyl) morpho
Phosphorus [(A) diastereo mixture, (B) Polar
And (C) Less Polar] Reference Example 69. 4- (1-hydroxymethylethyl) -2- (3-trifluoromethylphenyl) morpholine [(A) diastereomixture] obtained in 1.65 g, 1-
Fluoro-4-nitrobenzene 0.80 g, sodium hydride (55% by weight) 0.31 g and dimethylformamide 25 ml were used, and Reference Example 63. When the reaction and the post-treatment are carried out in accordance with (1), 1.98 g of the target compound [(A) diastereomer mixture] having an Rf value = 0.21 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 2: 3). was gotten.

In the same manner as described above, 4- (1-hydroxymethylethyl) -2- (3-trifluoromethylphenyl) morpholine [(B) Polar] 2.00 g, 1-fluoro-4-nitrobenzene 1.20 g, hydrogen Treatment with 0.36 g of sodium iodide (55% by weight) and 25 ml of dimethylformamide gives an Rf value = 0.31.
(Silica gel thin layer chromatography; ethyl acetate: n
-Hexane = 2: 3) target compound [(B) Po
lar] 2.50 g was obtained.

Further, as in the above, 4- (1-hydroxymethylethyl) -2- (3-trifluoromethylphenyl) morpholine [(C) Less Polar] 1.
99 g, 1-fluoro-4-nitrobenzene 1.20
g, 0.36 g of sodium hydride and 25 ml of dimethylformamide give an Rf value = 0.3
4 (silica gel thin layer chromatography; ethyl acetate:
The target compound [(C) L having n-hexane = 1: 1]
ess Polar] 2.19 g were obtained.

Reference Example 71. 4- [2- (4-aminophenoxy) -1-methylethyl
]]-2- (3-Trifluoromethylphenyl) morpho
Phosphorus [(A) diastereo mixture, (B) Polar
And (C) Less Polar] Reference Example 70. 4- [1-methyl-2- (4-
Nitrophenoxy) ethyl] -2- (3-trifluoromethylphenyl) morpholine [(A) diastereomixture] 1.98 g, 10% palladium-carbon 0.40
Hydrogen was bubbled into g and 20 ml of ethanol for 5 hours. Palladium-carbon was filtered off, the filtrate was concentrated, and the obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to give an Rf value of 0.1.
8 (silica gel thin layer chromatography; ethyl acetate:
1.03 g of the target compound [(A) diastereomer mixture] having n-hexane = 1: 1) was obtained.

Similarly to the above, 4- [1-methyl-2- (4
-Nitrophenoxy) ethyl] -2- (3-trifluoromethylphenyl) morpholine [(B) Polar]
When treated with 2.44 g, 10% palladium-carbon 0.5 g and ethanol 20 ml, Rf value =
1.58 g of the target compound [(B) Polar] having 0.25 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) was obtained.

Also, as in the above, 4- [1-methyl-2
-(4-Nitrophenoxy) ethyl] -2- (3-trifluoromethylphenyl) morpholine [(C) Less
Polar] 0.47 g, treated with 0.10 g of 10% palladium-carbon and 4 ml of ethanol for the purpose of having an Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1). Compound [(C) Less Polar] 0.31
g was obtained.

Reference Example 72. 2-Bromo-3- {4- [2- (2- (3-trifluoro
Romethylphenyl) morpholino) propoxy] pheny
Butyl propionate [(A) diastereo mixture,
(B) Polar and (C) Less Polar] Reference Example 71. 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-trifluoromethylphenyl) morpholine [(A) diastereomixture] obtained in 830 mg, acetone 8 ml, hydrobromic acid
1.89 g, sodium nitrite 179 mg and water
1 ml, further 3.2 ml of butyl acrylate and 63 mg of cuprous oxide were used, and Reference Example 58. Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate: n-hexane =)
1.02 g of the target compound [(A) diastereomixture] having 1: 3) was obtained.

As in the above, 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-trifluoromethylphenyl) morpholine [(B) Polar]
1.58 g, acetone 10 ml, hydrobromic acid 3.6
1 g, sodium nitrite 348 mg and water 1 ml,
Butyl acrylate 6.0 ml and cuprous oxide
Treated with 120 mg, the desired compound [(B) Pola with Rf value = 0.27 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3).
r] 2.04 g was obtained.

Also, as in the above, 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-trifluoromethylphenyl) morpholine [(C) Less]
Polar] 1.21 g, acetone 10 ml, hydrobromic acid 2.75 g, sodium nitrite 265 mg
And 1 ml of water, 3.7 ml of butyl acrylate
And treated with 86 mg of cuprous oxide, Rf
1.28 g of the target compound [(C) Less Polar] having a value = 0.25 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 3) were obtained.

Reference Example 73. 5- {4- [2- (2- (3-trifluoromethylphen
Nil) morpholino) propoxy] benzyl} -2-imi
Notiazolidin-4-one [(A) diastereomixed
Object, (B) Polar and (C) Less Pola
r] Reference example 72. 2-Bromo-3- {4- [2-
(2- (3-trifluoromethylphenyl) morpholino) propoxy] phenyl} butyl propionate [(A) diastereomixture] 1.25 g, thiourea 0.25 g, sodium acetate 0.25 g and methanol 7 ml were used for reference. Example 59. When the reaction and post-treatment were carried out according to (1), 0.39 g of the desired compound [(A) diastereomer mixture] having an Rf value = 0.37 (ethyl acetate: tetrahydrofuran = 20: 1) was obtained.

Similarly to the above, 2-bromo-3- {4- [2
Butyl (-(2- (3-trifluoromethylphenyl) morpholino) propoxy] phenyl} propionate [(B) Polar] 2.00 g, thiourea 0.4
1 g, sodium acetate 0.40 g and methanol
Treatment with 20 ml gave 791 mg of the desired compound [(B) Polar] with Rf value = 0.21 (ethyl acetate: tetrahydrofuran = 20: 1).

Further, as in the above, 2-bromo-3- {4
1.28 g of-(2- (2- (3-trifluoromethylphenyl) morpholino) propoxy] phenyl} propionate butyl [(C) Less Polar], thiourea 0.30 g, sodium acetate 0.29 g and methanol 7 ml. When processed using, Rf value = 0.4
0 (silica gel thin layer chromatography; ethyl acetate)
Compound having [[C] Less Polar]
610 mg was obtained.

Reference Example 74. N- [2- (3-chloro-4-fluorophenyl) -2
-Hydroxyethyl ] chloroacetamide 2 -amino-1- (3-chloro-4-fluorophenyl) ethanol 20.5 g, chloroacetyl chloride 1
Reference example 1. Using 0.1 ml, tetrahydrofuran 410 ml and triethylamine 17.6 ml. When the reaction and the post-treatment are carried out in accordance with the above, the melting point is 76.7 to 78.
25.2 g of the target compound having a temperature of 8 ° C. are obtained.

Reference Example 75. 2- [2- (3-chloro-4-fluorophenyl) -5
-Oxomorpholino] ethyl propionate [(A) Po
lar and (B) Less Polar] N- [2- (3-chloro-4-fluorophenyl) -2
-Hydroxyethyl] chloroacetamide 13.3
g, sodium hydride (55% by weight) 6.6 g, dimethylformamide 700 ml and ethyl α-bromopropionate 9.8 ml were used, and Reference Example 34. When the reaction and post-treatment are carried out according to, Rf value = 0.46 (silica gel thin layer chromatography; hexane: ethyl acetate =
Target compound having 1: 1) [(A) Polar]
The target compound [(B) Less with 3.33 g and Rf value = 0.53 (hexane: ethyl acetate = 1: 1)
Polar] was obtained.

Reference Example 76. 2- (3-chloro-4-fluorophenyl) -4- (1
-Hydroxymethylethyl) morpholine [(A) Pol
ar and (B) Less Polar] Reference Example 75. 2- [2- (3-chloro-4-) obtained in
Fluorophenyl) -5-oxomorpholino] ethyl propionate [(A) Polar] 3.16 g, lithium aluminum hydride 1.20 g and tetrahydrofuran 75 ml were used, and Reference Example 8. When the reaction and post-treatment were carried out according to, the target compound [(A) Polar] having Rf value = 0.42 (silica gel thin layer chromatography; ethyl acetate) was obtained.

Similarly to the above, 2- [2- (3-chloro-
3. (4-Fluorophenyl) -5-oxomorpholino] ethyl propionate [(B) Less Polar] 4.
When treated with 16 g, 1.50 g lithium aluminum hydride and 100 ml tetrahydrofuran,
Target compound [(B) Less having Rf value = 0.44 (silica gel thin layer chromatography; ethyl acetate)]
Polar] was obtained.

Reference Example 77. 2- (3-chloro-4-fluorophenyl) -4- [1
-Methyl-2- (4-nitrophenoxy) ethyl] mol
Holin [(A) Polar and (B) Less Po
lar] Reference Example 76. 2- (3-chloro-4-fluorophenyl) -4- (1-hydroxymethylethyl) morpholine [(A) Polar] 2.10 g, 1-fluoro-4-nitrobenzene 0.83 ml, hydrogenated 350 mg of sodium (55% by weight) and 30 ml of dimethylformamide were used, and Reference Example 63. When the reaction and post-treatment are carried out according to, Rf value = 0.55 (silica gel thin layer chromatography; hexane: ethyl acetate = 1:
The target compound having 1) [(A) Polar] 2.6
3 g was obtained.

As in the above, 2- (3-chloro-4-fluorophenyl) -4- (1-hydroxymethylethyl)
Morpholine [(B) Less Polar] 2.50
g, 1-fluoro-4-nitrobenzene 1.00m
1, 480 mg of sodium hydride (55% by weight) and 40 ml of dimethylformamide are treated with the target compound [(B which has an Rf value = 0.45 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1)). ) Less Polar] 3.25 g were obtained.

Reference Example 78. 4- [2- (4-aminophenoxy) -1-methylethyl
L] -2- (3-chloro-4-fluorophenyl) mol
Holin [(A) Polar and (B) Less Po
lar] Reference Example 77. 2- (3-Chloro-4-fluorophenyl) -4- [1-methyl-2- (4-nitrophenoxy) ethyl] morpholine [(A) Polar] obtained in
Reference Example 57. using 1.47 g, zinc 3.9 g, methanol 60 ml and acetic acid 1.5 ml. When the reaction and post-treatment are carried out according to, Rf value = 0.41 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1).
The target compound having 1) [(A) Polar] 1.2
3 g was obtained.

Similarly to the above, 2- (3-chloro-4-fluorophenyl) -4- [1-methyl-2- (4-nitrophenoxy) ethyl] morpholine [(B) Less]
Polar], the target compound having an Rf value = 0.38 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) when treated with 2.11 g, zinc 5.6 g, methanol 90 ml and acetic acid 2.2 ml. 1.81 g of [(B) Less Polar] was obtained.

Reference Example 79. 2-Bromo-3- {4- [2- (2- (3-chloro-4
-Fluorophenyl) morpholino) propoxy] pheny
Butyl propionate [(A) Polar and
(B) Less Polar] Reference Example 78. 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-chloro-4-) obtained in
Fluorophenyl) morpholine [(A) Polar]
1.21 g, acetone 30 ml, hydrobromic acid 1.5
ml, sodium nitrite 250 mg and water 2 m
1, butyl acrylate (4.8 ml) and cuprous oxide (100 mg) were used, and Reference Example 58. Rf value = 0.85 (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) when the reaction and post-treatment are carried out according to
0.89 g of the target compound having [(A) Polar]
was gotten.

Similarly to the above, 4- [2- (4-aminophenoxy) -1-methylethyl] -2- (3-chloro-4)
-Fluorophenyl) morpholine [(B) Less P
When treated with 1.77 g, acetone 40 ml, hydrobromic acid 2.4 ml, sodium nitrite 407 mg and water 6 ml, further butyl acrylate 7.1 ml and cuprous oxide 140 mg, Rf value = 0.81. 1.38 g of the target compound [(B) Less Polar] having (silica gel thin layer chromatography; hexane: ethyl acetate = 1: 1) was obtained.

Reference Example 80. 5- {4- [2- (2- (3-chloro-4-fluorophenyl
Phenyl) morpholino) propoxy] benzyl} -2-i
Minothiazolidin-4-one [(A) Polar and
(B) Less Polar] Reference Example 79. 2-Bromo-3- {4- [2-
(2- (3-chloro-4-fluorophenyl) morpholino) propoxy] phenyl} butyl propionate [(A) Polar] 0.87 g, thiourea 360
mg, sodium acetate 260 mg and ethanol 2
Using 5 ml, Reference Example 59. The target crude product having an Rf value of 0.33 (silica gel thin layer chromatography; ethyl acetate) is obtained by performing the reaction and the post-treatment according to [[A]].
Polar] 1.31 g was obtained.

Similarly to the above, 2-bromo-3- {4-
Treated with butyl [2- (2- (3-chloro-4-fluorophenyl) morpholino) propoxy] phenyl} propionate [(B) Less Polar] 1.08 g, thiourea 450 mg, sodium acetate 330 mg and ethanol 30 ml. Then, Rf value = 0.
Crude product [(B) Less Pola having 35 (silica gel thin layer chromatography; ethyl acetate).
r] 1.45 g was obtained.

Reference Example 81. N- (4-benzyloxybenzyl) -N, O-bis
( T -Butoxycarbonyl) hydroxylamine 4-benzyloxybenzyl chloride 6.98 g, N, O
-Bis (t-butoxycarbonyl) hydroxylamine To a solution of 9.1 g of dimethylformamide in 150 ml of sodium hydride under ice-cooling (55% by weight) of 1.44 g.
Was added, and the mixture was stirred at room temperature for 4 hours. Dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract. The obtained residue was purified by subjecting it to silica gel column chromatography (ethyl acetate: hexane = 1: 7) to give R
f value = 0.32 (silica gel thin layer chromatography;
12.2 g of the target compound having ethyl acetate: hexane = 1: 10) was obtained.

Reference Example 82. N- (4-hydroxybenzyl) -N, O-bis (t-
Butoxycarbonyl) hydroxylamine N- (4-benzyloxybenzyl) -N, O-bis (t-butoxycarbonyl) hydroxylamine 1
Hydrogen gas was bubbled through a mixture of 0.6 g, 10% palladium-carbon 2.1 g and methanol 300 ml at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the residue obtained by distilling methanol off from the filtrate was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4).
Rf value = 0.30 (silica gel thin layer chromatography; ethyl acetate: hexane = 1:
6.1 g of the target compound having 3) was obtained.

Reference Example 83. N- {4- [2- (2- (3-chlorophenyl) morpho]
Rhino) propoxy] benzyl} -N, O-bis (t-bu
Toxicarbonyl) hydroxylamine 2- (3-chlorophenyl) -4- (1-hydroxymethylethyl) morpholine 3.4 g, N- (4-hydroxybenzyl) -N, O-bis (t-butoxycarbonyl) hydroxylamine 4 0.5 g, tributylphosphine 2.97 g, azodicarbonyldipiperidine
A mixture of 3.36 g and 100 ml of benzene was stirred at room temperature for 6 hours. After completion of the reaction, insoluble matter was filtered off from the reaction mixture, the filtrate was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 3) yielded 2.5 g of the desired compound with Rf value = 0.62 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1).

Reference Example 84. N- {4- [2- (2- (3-chlorophenyl) morpho]
Rino] propoxy] benzyl} hydroxylamine N- {4- [2- (2- (3-chlorophenyl) morpholino) propoxy] benzyl} -N, O-bis (t-butoxycarbonyl) hydroxylamine 3 g of methylene chloride in 30 ml. Under ice-cooling, trifluoroacetic acid 4
ml was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. After ethyl acetate was distilled off from the extract, the obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give an Rf value = 0.23 (silica gel thin layer chromatography; 1.2 g of the target compound having ethyl acetate)
was gotten.

Reference Example 85. 2- (R)-[2- (R)-(3-chlorophenyl)-
2-t-butyldimethylsilyloxyethylamino]
A solution of methyl (R) -α- (t-butyldimethylsilyloxy) phenylacetaldehyde 103.5 g and D-alanine methyl ester 36.0 g in 1 liter of methanol was stirred at room temperature for 1 hour and then hydrogenated under ice cooling. Sodium cyanoborohydride (50 g) was added little by little and the mixture was left at room temperature overnight. After completion of the reaction, methanol was distilled off from the reaction mixture,
Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to give Rf value = 0.26.
54.51 g of the target compound having (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 8) were obtained.

Reference Example 86. 2- (R)-[2- (R)-(3-chlorophenyl)-
Methyl 2-hydroxyethylamino] propionate 2- (R)-[2- (R)-(3-chlorophenyl)-
300 ml of tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) was added to a solution of 44.45 g of methyl 2-t-butyldimethylsilyloxyethylamino] propionate in 400 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 45 minutes. Tetrahydrofuran was distilled off from the reaction mixture until the reaction mixture reached about 300 ml. 700 ml of 4N hydrochloric acid / dioxane solution was added to the reaction mixture under ice cooling, 200 ml of methanol was added, and the mixture was stirred at room temperature for 2.5 hours. Further, 500 ml of 4N hydrochloric acid / dioxane solution was added, and the mixture was stirred at room temperature for 1 hour,
Further, add 500 ml of 4N HCl / dioxane solution,
Stir at room temperature for 4 hours. After the reaction is completed, the reaction mixture is adjusted to about 5
The mixture was concentrated to 00 ml, adjusted to pH 8 with an aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was washed with water 3 times and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give Rf value = 0.45 (silica gel thin layer chromatography; ethyl acetate). 16.2 g of the target compound having: hexane = 3: 1) was obtained.

Reference Example 87. α- (R)-{N-chloroacetyl-N- [2- (R)
-(3-Chlorophenyl) -2-hydroxyethyl] a
Mino} methyl propionate 2- (R)-[2- (R)-(3-chlorophenyl)-
Methyl 2-hydroxyethylamino] propionate 1
To a solution of 5.95 g of tetrahydrofuran in 150 ml,
Under ice cooling, a solution of 5.91 ml of chloroacetyl chloride in 10 ml of tetrahydrofuran was added dropwise, and then 10.3 ml of triethylamine was added dropwise. The reaction mixture was stirred under ice cooling for 1 hour, poured into water and extracted with ethyl acetate. Further, salt was added to the aqueous layer and the mixture was extracted with ethyl acetate. Both extracts were combined, washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the resulting residue was subjected to silica gel chromatography (ethyl acetate: hexane =
When purified by subjecting to 1: 2 → 2: 3), the melting point is 120-
6 g of the target compound having a temperature of 121 ° C. are obtained.

Reference Example 88 2- (R)-[2- (R)-(3-chlorophenyl)-
Methyl 5-oxomorpholino] propionate 2- (R)-{N-chloroacetyl-N- [2- (R)
To a solution of 5.95 g of methyl-(3-chlorophenyl) -2-hydroxyethyl] amino} propionate in 80 ml of dimethylformamide was added 740 mg (55% by weight) of sodium hydride washed with hexane. The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. Further, salt was added to the aqueous layer and the mixture was extracted with ethyl acetate. After combining with the first extract, both extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate). 2.5 g of the target compound having: hexane = 1: 2) was obtained.

Reference Example 89 2- (R)-(3-chlorophenyl) -4- (1-
(R) -Hydroxymethylethyl) morpholine 2- (R)-[2- (R)-(3-chlorophenyl)-
Methyl 5-oxomorpholino] propionate 2.1
g, lithium aluminum hydride (1.0 M tetrahydrofuran solution) 21.2 ml and tetrahydrofuran 30 ml were used, and Reference Example 8. When the reaction and post-treatment were carried out according to (1), 1.13 g of the desired compound having an Rf value = 0.25 (silica gel thin layer chromatography; ethyl acetate: hexane = 5: 1) was obtained.

Reference Example 90 5- {4- [2- (R)-(2- (R)-(3-chloro
Phenyl) morpholino) propoxy] benzyl} -3-
Triphenylmethylthiazolidine-2,4-dione 2- (R)-(3-chlorophenyl) -4- (1-
(R) -Hydroxymethylethyl) morpholine 1.1
g, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 2.27 g,
Tributylphosphine (0.99 g), azodicarbonyldipiperidine (1.23 g) and benzene (50 ml) were used, and Reference Example 4. When the reaction and post-treatment are performed according to
[Α] _D ²⁴ -4.0 ° (C = 1.000, CHCl ₃ ).
And 1.54 g of the expected compound with Rf value = 0.41 (silica gel thin layer chromatography; ethyl acetate: hexane = 1: 1) were obtained.

[0277]

[Effects of the embodiment]

Test example 1. Hypoglycemic action The hypoglycemic action of the compound of the present invention on D-glucose-loaded hyperglycemia was measured. 3 months old K weighing 28-30g
After overnight fasting in male K mice, 1 mg / kg of the test compound was orally administered, and 60 minutes later, to induce hyperglycemia, D
-Glucose 1.2 g / kg was subcutaneously administered. Blood was collected at 60 minutes and 120 minutes after administration, and the blood glucose concentration was measured using a glucose analyzer (GL-101 (trade name), manufactured by Mitsubishi Kasei Co., Ltd.), and the blood glucose lowering rate ( R) was calculated.

R = (1− (B / A)) × 100 However, A: blood glucose level of CMC (carboxymethylcellulose) group B: blood glucose level of test compound administration group Table 5 shows the obtained results.

[0279]

[Table 5] ─────────────────────────────────── Compound dose Dose Number of mice Blood glucose reduction rate (%) ) (Mg / kg) 60 minutes 120 minutes ──────────────────────────────────── 1 of Example 1 4 30.6 39.6 Compound -------------------------------------------- [5- (4- 1 4 3.8 -2.9 Folinoethoxy) ben 10 4 -7.3 -4.9 Dil] thiazolidine-2,4-dione * ─────────────────────────── ───────── * Tab in Chem.Pharm.Bull., Volume 30, page 3580 (1982)
Compound No. 70 described in le IV. From Table 5, the compound of the present invention showed an excellent hypoglycemic action.

Test Example 2. Toxicity Male ddY mice were used as experimental animals. Three animals were used for each experiment. 300 mg / test compound for each animal
Kg body weight was administered orally. The test compound used was that of Example 1. Is a compound of. The animals were observed for 1 week after administration. Then, during that period, no abnormality caused by the test compound was observed. All animals are
I was alive. A mortality rate of 0 indicates that the compounds of the present invention are of very low toxicity in terms of real dose to each animal.

[0281]

INDUSTRIAL APPLICABILITY The compound of the present invention represented by the general formula (I) or a salt thereof is effective for lowering blood sugar, improving obesity, improving glucose tolerance, suppressing gluconeogenesis in the liver, lowering lipids, and reducing aldose. It has enzyme inhibitory action and thromboxane A ₂ synthesis inhibitory action, and has hyperglycemia, obesity, hyperlipidemia, diabetic complications such as retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, arteriosclerosis, and It is useful as a preventive and / or therapeutic drug for obesity hypertension, osteoporosis, thrombosis and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 413/12 233 263 417/10 233 263 265 271 277 279 417/12 233 263 265 277 279 // A61K 31/535 ACN ADN 9454-4C ADP 31/54 ABJ ABU 9454-4C ACB AED 9454-4C C12N 9/99 (C07D 413/10 265: 00 271: 00) (C07D 413/12 265: 00 271: 00) ) (C07D 417/10 265: 00 285: 00) (C07D 417/10 263: 00 279: 00) (C07D 417/10 279: 00 285: 00) (C07D 417/12 265: 00 279: 00) ( C07D 417/12 263: 00 265: 00) (C07D 417/12 233: 00 265: 00) (C07D 417/12 265: 00 285: 00) (C07D 417/12 263: 00 − − − − − 1 KN0 G GAA-- G,-, 86.E 7. .KE, N,-,, SD ,,,, SZ, S,-, S 91.K ,,, N, SU (72) Inventor Tsutomu Kanai Shinagawa-ku, Tokyo 1-25-2 Hiromachi Sankyo Co., Ltd. (72) Inventor Hiromi Sano 1041 Yasu, Yasu-cho, Yasu-gun, Shiga In-house (72) Inventor Horikoshi 1-chome, Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo stock company (72) Inventor Toshihiko Fujiwara 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (6)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or 1 carbon atom. A linear or branched alkoxy group having 1 to 5, a halogen atom, a hydroxy group, or a trifluoromethyl group, R ⁶ is a hydrogen atom or a linear or branched group having 1 to 5 carbon atoms. Represents a branched chain alkyl group, A represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or a sulfur atom, m represents an integer of 1 to 5, X represents a nitrogen atom or a group> CH Represents-, Y is an imino group,
Indicates an oxygen atom or a sulfur atom. Z represents a hydrogen atom or a group — (CH ₂ ) _n —CO ₂ R ⁷ (wherein R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and n Represents an integer of 1 to 5). And a thiomorpholine derivative having a) or a salt thereof. 2. The linear or branched chain according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and each has a hydrogen atom or a carbon number of 1 to 4. A linear alkyl group, a linear or branched alkoxy group having 1 to 3 carbon atoms, a halogen atom, a hydroxy group, or a trifluoromethyl group, and R ⁶ is a hydrogen atom or 1 to 3 carbon atoms. A straight chain or branched chain alkyl group having A, A represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or a sulfur atom, and m represents an integer of 1 to 3, X represents a nitrogen atom or a group> CH-, Y represents an imino group, an oxygen atom or a sulfur atom, Z is a hydrogen atom or a group _{- (CH 2) n -CO 2} R 7
(Wherein, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 4), or a salt thereof. . 3. In [Claim 1] or [Claim 2], R ¹ , R ² and R ³ are the same or different and each is a hydrogen atom,
Straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms, halogen atom, hydroxy group or trifluoromethyl group Wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a straight chain or branched chain alkoxy group having 1 to 3 carbon atoms, a straight chain or branched chain group having 1 to 3 carbon atoms A chain-like alkoxy group, a halogen atom, a hydroxy group or a trifluoromethyl group is shown, R ⁶ is a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, and A is oxygen. An atom or a sulfur atom, B is a bond, an oxygen atom or a sulfur atom, m is an integer of 1 to 3, X is a nitrogen atom or a group> CH-, Y is an oxygen atom or A sulfur atom, Z is a hydrogen atom or a group _{- (CH 2) n -CO 2} R 7
(In the formula, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 3), or a salt thereof. . 4. In [claim 1], [claim 2] or [claim 3], R ¹ , R ² and R ³ are the same or different and are hydrogen atoms,
Straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms, halogen atom, hydroxy group or trifluoromethyl group R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a fluorine atom, a chlorine atom, a hydroxy group or trifluoromethyl. R ⁶ represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, A represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or Represents a sulfur atom, m represents an integer of 1 to 3, X represents a nitrogen atom or a group> CH-, Y represents an oxygen atom or a sulfur atom, and Z represents a hydrogen atom or a group- CH _{2) n} -CO ₂ R ⁷
(Wherein, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 2), or a salt thereof. . 5. [Claim 1], [Claim 2], [Claim 3] or [Claim 4] wherein R ¹ is a hydrogen atom or a straight chain or branched chain having 1 to 4 carbon atoms. Chain alkyl group, alkoxy group having 1 or 2 carbon atoms, fluorine atom, chlorine atom, bromine atom,
A hydroxy group or a trifluoromethyl group, wherein R ² is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a fluorine atom, a chlorine atom, a hydroxy group or trifluoromethyl Represents a hydrogen atom, R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, a fluorine atom or a chlorine atom, and R 3 ⁴ represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group, and R ⁵ represents a hydrogen atom or carbon number alkyl having 1 to 2 carbon atoms, alkoxy group having two 1 -C, a fluorine atom or a chlorine atom, R ⁶ is a hydrogen atom or A linear or branched alkyl group having a prime number of 1 to 3, A represents an oxygen atom or a sulfur atom, B represents a bond, an oxygen atom or a sulfur atom, and m is 1 to 3 an integer, X represents a nitrogen atom or a group> CH-, Y represents an oxygen atom or a sulfur atom, Z is a hydrogen atom or a group _{- (CH 2) n -CO 2} R 7
(Wherein, R ⁷ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 2), or a salt thereof. . 6. In [Claim 1], [Claim 2], [Claim 3], [Claim 4] or [Claim 5], R ¹ has a hydrogen atom and 1 to 4 carbon atoms. A linear or branched alkyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group or a trifluoromethyl group is shown, and R ² is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom,
Represents a chlorine atom, a hydroxy group or a trifluoromethyl group, R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a methoxy group, a fluorine atom or a chlorine atom, R ⁴ represents a hydrogen atom, a methyl group, a methoxy group, a hydroxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group, R ⁵ represents a hydrogen atom or a methyl group, R ⁶ represents a hydrogen atom or a methyl group, A represents an oxygen atom or a sulfur atom, B represents a bond or an oxygen atom, m represents an integer of 1 to 2, X represents a group> CH-, Y represents a sulfur atom, and Z represents a hydrogen atom. Or a salt thereof.