JP2002212171A - Isoxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an isoxazole derivative having excellent insulin secretion promoting action and hypoglycemic action and low toxicity and, accordingly, useful as pharmaceuticals, especially agent for the treatment of diabetes and diabetic complications and provide a compound useful as the agent. SOLUTION: The objective compound is expressed by general formula (I) [one of R1 and R2 is H or a substituent and the other one is a (substituted) cyclic group; W is a bond or a bivalent aliphatic hydrocarbon group; Y is a group expressed by OR3 (R3 is H, a (substituted) hydrocarbon group, a (substituted) heterocyclic group or a (substituted) acyl group) or a carboxy group which may be esterified or amidated]. The present invention further discloses salts or prodrugs of the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive / therapeutic agent for diabetes, impaired glucose tolerance or diabetic complications, comprising an isoxazole derivative.

[0002] The present invention also relates to an insulin secretagogue comprising an isoxazole derivative.

Further, the present invention relates to a novel isoxazole derivative which has an excellent blood glucose lowering effect and is useful as a prophylactic / therapeutic agent for diabetes, impaired glucose tolerance, diabetic complications, and the like. The present invention relates to a method for preventing and treating diabetes or diabetic complications comprising administering to an animal, and use of the novel isoxazole derivative for the manufacture of a preventive or therapeutic agent for diabetes or a diabetic complication.

[0004]

2. Description of the Related Art Currently, sulfonylurea agents, biguanides, α-glucosidase inhibitors and the like are used as therapeutic agents for diabetes. However, sulfonylurea agents have a potent hypoglycemic effect, but often cause severe hypoglycemia and require careful use. Biguanides tend to cause relatively severe lactic acidosis as a side effect. In addition, α-glucosidase inhibitors delay the digestion and absorption of carbohydrates in the gastrointestinal tract and suppress an increase in blood glucose after eating, but have side effects such as bloating or diarrhea (JOSLIN'S DIABETES MELLITU
S 13Th Edition 521-522).

On the other hand, as isoxazole derivatives,
For example, the following compounds are known. (1) In Japanese Patent Publication No. 44-29656, the formula

[0006]

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[Wherein, R is a phenyl group, R 'is a hydrogen or lower alkyl group, A is a linear or branched divalent hydrocarbon group having 2 to 5 carbon atoms, Q' is a hydroxy group, an amino group or Which shows an acylamino group] is described as having an analgesic action, an antitussive action, an antipyretic action and an anti-inflammatory action. (2) In Table 9-509951, the formula

[0008]

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Wherein ^one of R ^{1 and} R ² is 3,5-
R ¹ or R ² is pyridyl or the like; A is a double bond or the like; R ⁴ is a hydrogen atom or the like; R ³ is a hydrogen atom, (C ₁ -C ₄ )- Alkyl or hydroxy- (C ₁ -C ₄ ) -alkyl] is described as being useful for the treatment of inflammation, asthma, rheumatic diseases and autoimmune diseases. (3) WO00 / 08001 has the formula

[0010]

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Wherein R ¹ and R ³ represent optionally substituted lower alkyl, aryl and the like, and R ² represents a hydrogen atom and the like. It is stated that there is. (4) WO98 / 28282 has the formula

[0012]

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[Ring M may contain 0 to 2 N atoms in addition to J; J is O or S; D is CN or the like; E is phenyl or the like; G is absent or NHCH ₂ Z is C _1-4 alkylene or the like; R ^1a and R ^1b are independently absent, or — (CH ₂ ) _r —R1 ′ (r is 0, 1, 2 or 3; R1 ′ Represents a hydrogen atom, etc.); A represents C
_3-10 etc. carbocyclic residue; B a is C _3-10, such as carbocyclic residue; s is described that the compound represented by] 0, 1 or 2 are useful as factor Xa inhibitors Have been.

However, it has not been known that the above-mentioned isoxazole derivatives are useful as a preventive / therapeutic agent for diabetes or impaired glucose tolerance, an insulin secretagogue or the like.

[0015]

An object of the present invention is to provide an isoxazole derivative which has an excellent insulin secretion promoting action and a hypoglycemic action, is useful as a therapeutic agent for diabetes, etc. and has low toxicity. .

[0016]

Means for Solving the Problems The present inventors provide a compound of the formula: -WY [W is a bond or 2 at the 4-position of the isoxazole ring.
Y is a group represented by the formula: -OR ³ (R ³ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted An acyl group) or a carboxyl group which may be esterified or amidated. General formula (Ia) having a structural feature at the point where the group represented by

[0017]

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[In the formula, ^one of R ¹ and R ² represents a hydrogen atom or a substituent, and the other represents a cyclic group which may be substituted;
W and Y are as defined above. However, when R ¹ or R ² is 3,5-ditert-butyl-4-hydroxyphenyl and W is C _1-4 alkylene, Y is not OH. Has unexpectedly excellent insulin secretion-promoting action and hypoglycemic action based on its characteristic chemical structure, and is effective in preventing diabetes, impaired glucose tolerance, diabetic complications, etc. It was found for the first time that it was useful as a therapeutic agent, and the present invention was completed based on this finding.

That is, the present invention provides: 1) a prophylactic / therapeutic agent for diabetes comprising a compound represented by the general formula (Ia) or a salt thereof or a prodrug thereof; 2) a general formula (I)

[0020]

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[In the formula, ^one of R ¹ and R ² represents a hydrogen atom or a substituent, and the other represents a cyclic group which may be substituted;
W is a bond or a divalent aliphatic hydrocarbon group;
—OR ³ (R ³ represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted); Shows a carboxyl group which may be amidated. 3) a prophylactic / therapeutic agent for impaired glucose tolerance comprising a compound represented by the formula (I) or a salt thereof or a prodrug thereof; 3) containing a compound represented by the general formula (I) or a salt thereof or a prodrug thereof; 4) a prophylactic / therapeutic agent for diabetic complication comprising a compound represented by the general formula (I) or a salt thereof or a prodrug thereof; 5) a diabetic complication is a neurological disorder. A prophylactic / therapeutic agent according to 4) above; 6) a general formula (II)

[0022]

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Wherein one of R ^1a and R ^2a is a hydrogen atom, the other is a cyclic group which may be substituted; Wa is a divalent aliphatic hydrocarbon group; and Y is a group represented by the formula: —OR ³ (R ³ represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an acyl group which may be substituted) or a group which is esterified or amidated Represents a carboxyl group which may be substituted. Where W
When a is C _1-3 alkylene and Y is a group represented by the formula: —OR ³ (R ³ has the same meaning as described above) or a carboxyl group which may be methylesterified, R ^1a represents hydrogen The atom R ^2a is an ^optionally substituted cyclic group]
(However, excluding 5-phenyl-4-isoxazolylmethanol and 5-phenyl-4-isoxazolylacetic acid) or a salt thereof; 7) a compound represented by R ^1a or R ^2a The compound according to the above 6), wherein the good cyclic group is an optionally substituted aromatic group; 8) the compound according to the above 6), wherein R ^1a is a hydrogen atom and R ^2a is an ^optionally substituted cyclic group; 9) The compound according to the above 8), wherein R ^2a is an ^optionally substituted aromatic group; 10) the compound according to the above 6), wherein Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms; 11) The compound according to the above 6), wherein Y is a carboxyl group which may be amidated; 12) a prodrug of the compound according to the above 6); 13) 3- [5- (3,4-dichlorophenyl) -4 −
Isoxazolyl] propan-1-ol; 3- [5-
(3,4-dichlorophenyl) -4-isoxazolyl] propionic acid or a salt thereof; 3- [5- (4-chlorophenyl) -4-isoxazolyl] propane-1
-Ol; 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid or a salt thereof;
[5- (3,4-difluorophenyl) -4-isoxazolyl] propan-1-ol; 3- [5- (3,4
-Difluorophenyl) -4-isoxazolyl] propionic acid or a salt thereof; N- [4- (diethylphosphonomethyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide; N- [4- (diethyl Phosphonomethyl) phenyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide; N- [4- (dimethylphosphonomethyl) phenyl] -3- (5-phenyl-4-isoxazolyl ) Propionamide; N- {4-[(2-oxide-1,3,3;
2-dioxaphosphinan-2-yl) methyl] phenyl} -3- (5-phenyl-4-isoxazolyl) propionamide; N-benzyl-N- [2- (dimethylamino) ethyl] -3- [5 -(4-fluorophenyl) -4
-Isoxazolyl] propionamide; or N-benzyl-N- (1-benzyl-3-pyrrolidinyl) -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
14) The compound according to the above 6), which is propionamide; 14) A medicine comprising the compound according to the above 6) or a prodrug thereof; 15) A glucose-dependent insulin secretagogue comprising an isoxazole derivative; 16) A method for preventing diabetes in a mammal, comprising administering to the mammal an effective amount of the compound represented by formula (Ia), a salt thereof, or a prodrug thereof.
17) A method for preventing and treating diabetic complications in a mammal, which comprises administering an effective amount of the compound represented by the general formula (I), a salt thereof, or a prodrug thereof to the mammal. 18) A method for preventing or treating impaired glucose tolerance in a mammal, which comprises administering to the mammal an effective amount of the compound represented by the general formula (I), a salt thereof, or a prodrug thereof. 19) A method for promoting insulin secretion in a mammal, which comprises administering to the mammal an effective amount of the compound represented by the general formula (I), a salt thereof, or a prodrug thereof. 20) Formula (I) for producing a prophylactic / therapeutic agent for diabetes
Use of the compound represented by a) or a salt thereof or a prodrug thereof; 21) The compound represented by the general formula (I) or a salt thereof or a prodrug thereof for production of a prophylactic / therapeutic agent for diabetic complications 22) Use of a compound represented by the general formula (I) or a salt thereof or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for glucose intolerance; Use of the compound represented by the formula (I) or a salt thereof or a prodrug thereof; 24) The preventive / therapeutic agent for diabetes according to the above 1), and the agent can be used or should be used for the prevention / treatment of diabetes 25) A prophylactic / therapeutic agent for glucose intolerance as described in 2) above, and the agent can be used for the prevention / treatment of glucose intolerance. Or a commercial package containing documents stating that it should be used; 26) The insulin secretagogue according to 3) above, and that the agent can or should be used to promote insulin secretion 27) A prophylactic / therapeutic agent for diabetic complications described in 4) above, and that the agent can or should be used for the prophylaxis / treatment of diabetic complications described in 4) above. Commercial package containing written documents;

Hereinafter, the compound represented by formula (I), (Ia) or (II) will be described in detail. (1) Definition of R ¹ and R ^{2 In} the general formulas (I) and (Ia), the “cyclic group” in the “optionally substituted cyclic group” represented by R ¹ or R ²
Examples thereof include an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, and the like.

The alicyclic hydrocarbon group may have 3 to 1 carbon atoms.
And two saturated or unsaturated alicyclic hydrocarbon groups, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like.

Preferred examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, cyclooctyl, bicyclo [2.2.
1] Heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2]
Nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like can be mentioned.

Preferred examples of the cycloalkenyl group include:
A cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like can be mentioned.

Preferred examples of the cycloalkadienyl group include cycloalkadienyl groups having 4 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

Examples of the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group, etc.). Preferable examples of the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like, among which phenyl, 1-naphthyl and 2-naphthyl are preferable. The aromatic hydrocarbon group may be partially saturated. Examples of the partially saturated aromatic hydrocarbon group (aryl group having 6 to 14 carbon atoms) include dihydroindenyl and the like. .

Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-cyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. Examples include an aromatic heterocyclic group or a fused non-aromatic heterocyclic group. Examples of the non-aromatic condensed heterocyclic group include a 5- to 7-membered monocyclic non-aromatic heterocyclic group and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a condensed 5-membered ring.

Preferable examples of the non-aromatic heterocyclic group include pyrrolidinyl (eg, 1-pyrrolidinyl), piperidinyl (eg, piperidino), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, , 1-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidin-3-yl), thiazolidinyl (eg, thiazolidine-3-yl), imidazolidinyl (eg, imidazolidine) -3-yl), oxoimidazolidinyl (eg, 2-oxoimidazolidin-1-
Yl), dioxoimidazolidinyl (eg, 2,4-dioxoimidazolidin-3-yl), dioxooxazolidinyl (eg, 2,4-dioxooxazolidin-3-yl), dioxothia Zolidinyl (eg, 2,4-dioxothiazolidine-3-yl), tetrahydrofuranyl, azepanyl, tetrahydropyridinyl (eg, 1,2,3,
6-tetrahydropyridin-1-yl) and the like.

Examples of the aromatic heterocyclic group include, for example, those containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms.
And a 7-membered monocyclic aromatic heterocyclic group or a fused aromatic heterocyclic group. The condensed aromatic heterocyclic group includes, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a group condensed with a 5-membered ring.

Preferred examples of the aromatic heterocyclic group include furyl (eg, 2-furyl, 3-furyl) and thienyl (eg, 2
-Thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (eg, 3
-Pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) 5-imidazolyl), pyrazolyl (eg, 1-
Pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl, thiazolyl (eg, 2-
Thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl), oxadiazolyl (eg, 1,2,
4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,
3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,2
4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,
1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), quinolyl (eg, 2-quinolyl, 3-quinolyl,
-Quinolyl), quinazolyl (eg, 2-quinazolyl, 4-
Quinazolyl), quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl), benzothienyl (eg, 2-benzothienyl),
3-benzothienyl), benzooxazolyl (eg, 2-
Benzoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl), indolyl (eg, indol-1-yl, indol-3-yl) ), 1H-indazolyl (eg, 1H-indazol-3-yl), 1H-pyrrolo [2,3-b]
Pyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl), 1H-pyrrolopyridinyl (eg, 1H-pyrrolo [2,3-b] pyridin-6-yl), 1H-imidazopyridinyl (Example: 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl), 1H-imidazopyrazinyl (Example 1
H-imidazo [4,5-b] pyrazin-2-yl), triazinyl, isoquinolyl, benzothiadiazolyl and the like.

The aromatic heterocyclic group is preferably a 5- or 6-membered aromatic heterocyclic group which is optionally condensed with a benzene ring (preferably furyl, thienyl, pyridyl, pyrimidinyl,
Pyrazinyl, oxazolyl, thiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, quinolyl) and the like. The “cyclic group” is preferably an aromatic group such as an aromatic hydrocarbon group and an aromatic heterocyclic group, and more preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group or the like). . Particularly, phenyl is preferable.

In the general formulas (I) and (Ia), the “cyclic group” represented by R ¹ or R ^{2 represents} 1-5, preferably 1-3, at substitutable positions on the cyclic group. It may have a substituent. Examples of such a substituent include “halogen atom”, “nitro group”, “cyano group”, “C _1-3
"Alkylenedioxy group", "optionally substituted aliphatic hydrocarbon group", "optionally substituted alicyclic hydrocarbon group", "optionally substituted aromatic hydrocarbon group",
"Optionally substituted heterocyclic group", "optionally substituted acyl group", "optionally substituted amino group", "optionally substituted hydroxy group", "optionally substituted And a carboxyl group which may be esterified or amidated.

The "halogen atom" includes fluorine, chlorine, bromine and iodine, among which fluorine and chlorine are preferred.

The "C _1-3 alkylenedioxy group" includes, for example, methylenedioxy and ethylenedioxy.

As the aliphatic hydrocarbon group in the “optionally substituted aliphatic hydrocarbon group”, the aliphatic hydrocarbon group may have 1 to 1 carbon atoms.
And 5 straight-chain or branched aliphatic hydrocarbon groups, such as an alkyl group, an alkenyl group, and an alkynyl group.

Preferred examples of the alkyl group include those having 1 carbon atom.
Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl,
Examples include 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

Preferred examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

Preferred examples of the alkynyl group include those having 2 carbon atoms.
Alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. .

Examples of the substituent in the “optionally substituted aliphatic hydrocarbon group” include a cycloalkyl group having 3 to 10 carbon atoms and an aryl group having 6 to 14 carbon atoms (eg,
Phenyl, naphthyl, etc.), aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.) An aralkyl group having 7 to 13 carbon atoms, an amino group, an amino group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.), an amidino group, Carbon number 2
To 8 acyl groups (eg, alkanoyl groups, etc.), carbamoyl groups, carbamoyl groups mono- or di-substituted by alkyl groups having 1 to 4 carbon atoms, sulfamoyl groups, 1 carbon atoms
A sulfamoyl group mono- or di-substituted with an alkyl group of 4 to 4, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, and 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) An alkoxy group having 1 to 6 carbon atoms which may be substituted with an alkenyloxy having 2 to 5 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Group, cycloalkyloxy group having 3 to 7 carbon atoms, 7 carbon atoms
To 13 aralkyloxy groups, 6 to 14 carbon atom aryloxy groups (eg, phenyloxy, naphthyloxy, etc.), thiol groups, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) An optionally substituted alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 13 carbon atoms, an arylthio group having 6 to 14 carbon atoms (eg,
Phenylthio, naphthylthio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen atom (eg, fluorine, chlorine, bromine, iodine) and the like. The number of substituents is, for example, 1 to 3.

"Optionally substituted alicyclic hydrocarbon group" and "optionally substituted aromatic hydrocarbon group"
Examples of the alicyclic hydrocarbon group and aromatic hydrocarbon group in are those exemplified as the “cyclic group” represented by R ¹ or R ² .

Examples of the heterocyclic group in the “optionally substituted heterocyclic group” include the aromatic heterocyclic group and the non-aromatic heterocyclic group exemplified as the “cyclic group” for R ¹ or R ^2. Can be

The substituents in the aforementioned “optionally substituted alicyclic hydrocarbon group”, “optionally substituted aromatic hydrocarbon group” and “optionally substituted heterocyclic group” include: For example, an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, chlorine, An alkenyl group having 2 to 6 carbon atoms, which may be substituted with bromine, iodine, etc .;
A cycloalkyl group of 0, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), a non-aromatic heterocyclic group ( Examples, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.), an aralkyl group having 7 to 13 carbon atoms, an amino group, an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (eg, Alkanoyl group) mono- or di-substituted amino group, amidino group, C 2-8 acyl group (eg, alkanoyl group, etc.), carbamoyl group, C 1-4 alkyl group. A carbamoyl group, a sulfamoyl group, a sulfamoyl group mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms, Hexyl group, 2 carbon atoms
8 alkoxycarbonyl groups, hydroxy groups, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) which may be substituted with 1 to 6 carbon atoms, 1 to 3 halogen atoms 2 to 5 carbon atoms which may be substituted by an atom (eg, fluorine, chlorine, bromine, iodine, etc.)
An alkenyloxy group, a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 13 carbon atoms, an aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy,
Naphthyloxy), a thiol group, an alkylthio group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and an aralkyl having 7 to 13 carbon atoms A thio group, an arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.),
Sulfo group, cyano group, azide group, nitro group, nitroso group, halogen atom (eg, fluorine, chlorine, bromine, iodine)
And the like. The number of substituents is, for example, 1 to 3.

As the acyl group in the "optionally substituted acyl group", an acyl group having 1 to 13 carbon atoms, specifically, formyl, a compound represented by the formula: -COR ⁴ , -SO ₂ R ⁴ ,-
SOR ⁴ or -PO ₃ of R ⁴ R ⁵ [wherein, R ⁴ and R
⁵ is the same or different and represents a hydrocarbon group or an aromatic heterocyclic group. R ⁴ and R ⁵ may form a heterocyclic ring together with an adjacent oxo-substituted phosphorus atom and two oxygen atoms].

Examples of the hydrocarbon group represented by R ⁴ or R ⁵ include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and an araliphatic hydrocarbon group.

As the aliphatic hydrocarbon group, for example, R ¹
Or the "aliphatic hydrocarbon group" in the "optionally substituted aliphatic hydrocarbon group" exemplified as the substituent in the "cyclic group" for R ² .

The alicyclic hydrocarbon group and aromatic hydrocarbon group include, for example, a “cyclic group” represented by R ¹ or R ²
Are exemplified.

Examples of the araliphatic hydrocarbon group include araliphatic hydrocarbon groups having 7 to 13 carbon atoms, such as aralkyl groups and arylalkenyl groups.

Preferable examples of the aralkyl group include aralkyl groups having 7 to 13 carbon atoms, such as benzyl, phenethyl, naphthylmethyl, and benzhydryl.

Preferable examples of the arylalkenyl group include an arylalkenyl group having 8 to 13 carbon atoms, such as styryl.

The hydrocarbon group preferably has 1 to 10 carbon atoms.
Alkyl group, alkenyl group having 2 to 10 carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbon atoms, aryl group having 6 to 12 carbon atoms, 7 carbon atoms
To 13 aralkyl groups.

As the aromatic heterocyclic group represented by R ⁴ or R ⁵ , for example, those exemplified as the “cyclic group” represented by R ¹ or R ² can be mentioned. Among them, for example, thienyl, furyl, pyridyl and the like are preferable.

The heterocyclic ring formed by R ⁴ and R ⁵ together with an adjacent oxo-substituted phosphorus atom and two oxygen atoms includes, for example, an oxo-substituted phosphorus atom and two oxygen atoms in addition to a carbon atom as a ring-constituting atom. And a 4- to 7-membered heterocyclic ring which may contain 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Specific examples of such a heterocyclic ring include 2-oxide-1,3,2-dioxaphosphinane;
2-oxide-1,3,2-dioxaphospholane and the like.

Preferred examples of the acyl group include those having 2 to 2 carbon atoms.
10 alkanoyl groups (eg, acetyl, propionyl,
Butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl), an alkenoyl group having 3 to 10 carbon atoms (eg, crotonyl), a cycloalkanoyl group having 4 to 10 carbon atoms (eg, cyclobutanecarbonyl, cyclopentanecarbonyl, Cyclohexanecarbonyl, cycloheptanecarbonyl), a cycloalkanoyl group having 4 to 10 carbon atoms (eg, 2
-Cyclohexenecarbonyl), an arylcarbonyl group having 7 to 13 carbon atoms (eg, benzoyl), an aromatic heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl), an alkylsulfinyl group having 1 to 10 carbon atoms (eg, methylsulfinyl, ethylsulfinyl) ), An alkylsulfonyl group having 1 to 10 carbon atoms (eg, methylsulfonyl, ethylsulfonyl), and a phosphono group which may form a ring (mono- or di-alkyl having 1 to 10 carbon atoms) (eg,
Dimethylphosphono; Diethylphosphono; Diisopropylphosphono; Dibutylphosphono; 2-Oxide-1,3,2
-Dioxaphosphinyl) and the like.

The acyl group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include 1 to 3 halogen atoms (eg, fluorine, chlorine , Iodine, etc.) which may be substituted with a C _1-6 alkyl group (eg, methyl, ethyl, etc.), which is substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) And C _1-6 alkoxy groups (eg, methoxy, ethoxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxy, amino and the like.

The "optionally substituted amino group" includes, for example, an alkyl group having 1 to 10 carbon atoms,
0 alkenyl group, C3-C10 cycloalkyl group, C3-C10 cycloalkenyl group, C6-C6
And an amino group which may be mono- or di-substituted with an aryl group having 14, an acyl group having 1 to 13 carbon atoms, or the like.

Here, as the alkyl group having 1 to 10 carbon atoms and the alkenyl group having 2 to 10 carbon atoms, those exemplified as the substituents in the “cyclic group” represented by R ¹ or R ² can be mentioned.

A cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms and 6 to 14 carbon atoms
Examples of the aryl group include those exemplified as the “cyclic group” represented by R ¹ or R ² .

Examples of the acyl group having 1 to 13 carbon atoms include those exemplified as the acyl group in the above-mentioned "optionally substituted acyl group", and preferably 2 to 13 carbon atoms.
0, an alkanoyl group, an arylcarbonyl group having 7 to 13 carbon atoms, and the like.

Examples of the substituted amino group include mono- or di-C _1-10 alkylamino (eg, methylamino, dimethylamino, ethylamino, diethylamino,
Ethylmethylamino, propylamino, dibutylamino), mono- or di-C _2-10 alkenylamino (eg,
Diallylamino), mono- or di-C _3-10 cycloalkylamino (eg, cyclohexylamino), mono- or di-C _2-10 alkanoylamino (eg, acetylamino, propionylamino), having 7 to 13 carbon atoms Arylcarbonylamino group (eg, benzoylamino), arylamino having 6 to 14 carbon atoms (eg, phenylamino), N
—C _1-10 alkyl- _{NC 6-14} arylamino (eg, N
-Methyl-N-phenylamino) and the like.

Examples of the “optionally substituted hydroxy group” include “optionally substituted alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, and “3 Cycloalkyl group having 10 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbon atoms,
4 aryl groups "," aralkyl having 7 to 13 carbon atoms ",
A hydroxy group which may be substituted by "an acyl group having 1 to 13 carbon atoms" or "heteroaryl group" is exemplified.

Here, “an alkyl group having 1 to 10 carbon atoms”, “an alkenyl group having 2 to 10 carbon atoms”, and “an alkyl group having 1 to 10 carbon atoms”
Examples of the “acyl group to ^No. 13” include those exemplified as the substituents in the “cyclic group” represented by R ¹ or R ² .

"Cycloalkyl group having 3 to 10 carbon atoms",
Examples of the “cycloalkenyl group having 3 to 10 carbon atoms” and “aryl group having 6 to 14 carbon atoms” include those exemplified as the “cyclic group” represented by R ¹ or R ² .

Examples of the "aralkyl having 7 to 13 carbon atoms" include benzyl, phenethyl, naphthylmethyl, naphthylethyl and the like.

These “alkyl groups having 1 to 10 carbon atoms”,
"Alkenyl groups having 2 to 10 carbon atoms", "3 to 10 carbon atoms"
A cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aralkyl having 7 to 13 carbon atoms, and an acyl group having 1 to 13 carbon atoms May have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (Eg, methoxy, ethoxy, etc.).

As the “heteroaryl group”, for example, R
“Optionally substituted cyclic group” represented by ¹ or R ²
And the aromatic heterocyclic groups exemplified above. Of these, pyridyl, imidazolyl, triazolyl and the like are preferred.

Examples of the substituted hydroxy group include an optionally substituted alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group,
Examples include an acyloxy group and a heteroaryloxy group.

Preferred examples of the alkoxy group include alkoxy groups having 1 to 10 carbon atoms, such as methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy,
Examples include isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, and the like.

Preferred examples of the alkenyloxy group include:
An alkenyloxy group having 2 to 10 carbon atoms, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like can be mentioned.

Preferable examples of the cycloalkyloxy group include a cycloalkyloxy group having 3 to 10 carbon atoms, for example, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 3 to 10 carbon atoms, for example, 2-cyclopentenyloxy, 2-cyclohexenyloxy and the like.

Preferred examples of the aryloxy group include aryloxy groups having 6 to 14 carbon atoms, for example, phenoxy,
Naphthyloxy and the like.

Preferred examples of the aralkyloxy group include:
An aralkyloxy group having 7 to 13 carbon atoms, for example, benzyloxy, phenethyloxy, naphthylmethyloxy and the like can be mentioned.

Preferable examples of the acyloxy group include acyloxy groups having 2 to 13 carbon atoms, such as alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.). Can be

Preferred examples of the heteroaryloxy group include a 5- to 7-membered monocyclic heteroaryloxy group such as 2-pyridyloxy, 3-pyridyloxy, 2-imidazolyloxy, 1,2,4-triazole -5-yloxy and the like.

The above-mentioned alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group, acyloxy group and heteroaryloxy group have one or two substituents at substitutable positions. Such a substituent may be, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) And the like, and a C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.) optionally substituted with hydroxy, nitro, amino and the like. For example, substituted aryloxy groups include, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like.

Examples of the thiol group which may be substituted include “an alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”, “ A cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, and a
And a thiol group which may be substituted with "13 aralkyl", "1 to 13 carbon acyl group" or "heteroaryl group".

Here, “an alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, “3 carbon atoms”
A cycloalkyl group having 10 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms,
As the “aralkyl having 7 to 13 carbon atoms”, the “acyl group having 1 to 13 carbon atoms” and the “heteroaryl group”, those exemplified in the aforementioned “optionally substituted hydroxy group” can be exemplified.

Examples of the substituted thiol group include alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, aralkylthio,
Acylthio, heteroarylthio and the like.

Preferable examples of the alkylthio group include alkylthio groups having 1 to 10 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentyl Luthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like.

Preferable examples of the alkenylthio group include alkenylthio groups having 2 to 10 carbon atoms, for example, allyl
l) thio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like.

Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

Preferable examples of the cycloalkenylthio group include a cycloalkenylthio group having 3 to 10 carbon atoms, for example, 2-cyclopentenylthio, 2-cyclohexenylthio and the like.

Preferred examples of the arylthio group include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.

Preferable examples of the aralkylthio group include aralkylthio groups having 7 to 13 carbon atoms, such as benzylthio, phenethylthio, and naphthylmethylthio.

Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, for example, an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio,
Butyrylthio, isobutyrylthio, etc.).

Preferred examples of the heteroarylthio group include a 5- to 7-membered monocyclic heteroarylthio group such as 2
-Pyridylthio, 3-pyridylthio, 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like.

In the carboxyl group which may be esterified, examples of the carboxyl group which has been esterified include alkoxycarbonyl groups having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) An aralkyloxycarbonyl group having 8 to 14 carbon atoms (eg, benzyloxycarbonyl, etc.) and 1 to 2 carbon atoms having 1 to 1 carbon atoms;
7 to 15 carbon atoms which may be substituted with an alkyl group of 3
(E.g., phenoxycarbonyl, p-tolyloxycarbonyl, etc.).

In the carboxyl group which may be amidated, the amidated carboxyl group includes
Formula: —CON (R ⁶ ) (R ⁷ ) (wherein R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group) R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic ring which may be substituted together with an adjacent nitrogen atom).

Here, examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁶ and R ⁷ include the hydrocarbon groups exemplified as the aforementioned R ⁴ .
The hydrocarbon group is preferably an alkyl group having 1 to 10 carbon atoms (preferably methyl, ethyl, propyl, butyl,
tert-butyl, pentyl, 1-ethylpropyl, 2,2
-Dimethylpropyl); an alkynyl group having 2 to 10 carbon atoms (preferably 2-propynyl); a cycloalkyl group having 3 to 10 carbon atoms (preferably cyclopropyl, cyclohexyl) which may be condensed with a benzene ring; 3 to 1
An aryl group having 6 to 14 carbon atoms (preferably phenyl, dihydroindenyl, biphenylyl) which may be condensed with 0 cycloalkane (preferably cyclopentane);
An aralkyl group having 7 to 13 carbon atoms (preferably benzyl,
Phenethyl, phenylpropyl, naphthylmethyl, benzhydryl) and the like.

The heterocyclic group in the “optionally substituted heterocyclic group” represented by R ⁶ and R ⁷ includes R
^The aromatic heterocyclic group and the non-aromatic heterocyclic group exemplified as the “cyclic group” represented by ¹ or R ² are exemplified. The heterocyclic group is preferably thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl,
Pyrazinyl, triazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl and the like.

The hydrocarbon group and the heterocyclic group may have 1 to 4 (preferably 1 to 3) substituents at substitutable positions. Examples of such substituents include Halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.);
A C _1-6 alkyl group (eg, methyl, trifluoromethyl, etc.) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.); 1 to 3 halogen atoms (Eg, fluorine, chlorine, bromine, iodine, etc.)
A C _1-6 alkoxy group optionally substituted with (eg, methoxy, isopropoxy, trifluoromethoxy, etc.);
Nitro; hydroxy; amino; carbamoyl group; (optionally form a ring mono- - or di -C _1-6 alkyl -
Phosphono) -C _1-6 alkyl group [eg, dimethylphosphonomethyl, diethylphosphonomethyl, diisopropylphosphonomethyl, dibutylphosphonomethyl, diethylphosphonoethyl, (2-oxide-1,3,2-dioxa (Phosphinanyl) methyl, (methyl-2-oxide-1,3,2)
-Dioxaphosphinyl) methyl, (dimethyl-2-
Oxide-1,3,2-dioxaphosphinanyl) methyl, (diethyl-2-oxide-1,3,2-dioxaphosphinanyl) methyl, (5-butyl-5-ethyl-2)
-Oxide-1,3,2-dioxaphosphinanyl) methyl, (5-ethyl-5-methyl-2-oxide-1,3,
2-dioxaphosphinanyl) methyl and the like]; phosphono-C _1-6 alkyl group (eg, phosphonomethyl and the like); C _2-5
An alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.); a C _2-5 alkoxycarbonyl-C _1-6 alkyl group (eg, ethoxycarbonylmethyl, etc.); 1 to 3 halogen atoms (eg, fluorine, chlorine, Bromine, iodine, etc.), C _6-10 aryl group optionally substituted by C _1-6 alkoxy group or carbamoyl group (eg,
Phenyl, etc.); C _1-6 alkyl group (eg, methyl, etc.)
Or a heterocyclic group optionally substituted with an oxo group (eg,
Indolyl, imidazolyl, pyridyl, morpholino, furyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.); C _1-6 alkyl-heterocycle-
A C _1-6 alkoxy group (eg, ethyltriazolylethoxy); a hydroxy group, a C _6-10 aryl group (eg, phenyl) or a C _1-6 alkyl-C _6-10 aryl group (eg, methylphenyl) Mono- or di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, N-methyl-N-phenylamino, di-hydroxyethyl-) A C _6-10 arylamino group (eg, phenylamino); a C _3-10 cycloalkyl group (eg, cyclohexyl); a C _1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy) 1 to 3 halogen atoms (eg, fluorine, chlorine,
A C _1-6 alkylthio group (eg, methylthio, etc.) optionally substituted with bromine or iodine; a C _7-13 aralkyl group (eg, benzyl, etc.); an aromatic heterocyclic group optionally substituted with a nitro group ring amino group (e.g., such as pyridylamino); C _6-10 aryloxy group (e.g., phenoxy); mono - or di -C _1-6 alkyl - phosphono group (e.g., a diethylphosphono); C _2-5 A mono- or di- (mono- or di-C _1-6 alkyl-phosphono) -C _2-6 alkenyl group optionally substituted with an alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.) [eg, bis (Diethylphosphono) ethenyl, 2
Bis (mono- or di-C _1-6 alkylamino) -phosphoryl-C _1-6 alkyl group [eg, bis (ethylamino) phosphorylmethyl and the like]; Oxo group and the like.

The nitrogen-containing heterocyclic ring formed by R ⁶ and R ⁷ together with an adjacent nitrogen atom includes, for example, at least one nitrogen atom other than a carbon atom as a ring-constituting atom, and further includes an oxygen atom, a sulfur atom and a nitrogen atom And a 5- to 8-membered (preferably 5- to 7-membered) nitrogen-containing (preferably saturated) heterocyclic group which may contain one or two heteroatoms selected from Preferred examples of the nitrogen-containing heterocyclic group include 1-pyrrolidinyl, 1-imidazolidinyl,
Pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, 1-azocanyl and the like. In addition, the nitrogen-containing heterocyclic group may form a condensed ring group with a benzene ring or a C _3-10 cycloalkane (eg, cyclohexane). -Yl, decahydroisoquinolin-2-yl and the like.

The nitrogen-containing heterocyclic group has 1
It may have up to 2 substituents. Examples of such a substituent include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, a C _2-7 alkoxycarbonyl group (eg, ethoxycarbonyl) or 5
To 6-membered nitrogen-containing Hajime Tamaki (e.g., pyrrolidinyl, etc.) which may be C _1-6 alkyl group (e.g. substituted by methyl,
Ethyl, etc.); a C _7-14 aralkyl group optionally substituted by a C _1-3 alkylenedioxy group (eg, methylenedioxy) (eg, benzyl, diphenylmethyl, benzhydryl, etc.); Halogen atom (eg, fluorine,
C which may be substituted with chlorine, bromine, iodine, etc.)
_1-6 alkyl group (eg, methyl, trifluoromethyl, etc.), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.) or C _2-10 alkanoyl group (eg, such as acetyl) which may C _6-14 aryl group optionally substituted with (e.g., phenyl, etc.); C _6-14 aryl -C _2-6 alkenyl group (e.g., phenyl propenyl); C _{1 A} C _6-14 arylamino-C _1-6 alkyl group (eg, phenylaminomethyl, etc.) which may be substituted with a _-6 alkyl group (eg, methyl, etc.); a cyano group; an oxo group;
A mono- or di-C _2-10 alkanoylamino which may be substituted by three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) or a C _1-6 alkyl group (eg, methyl, ethyl, etc.) Group (eg, acetylamino, trifluoroacetylamino, propionylamino, N-acetyl-N-ethylamino, etc.); C _2-7 alkoxycarbonylamino group (eg, tert-butoxycarbonylamino, etc.); nitrogen Hajime Tamaki (e.g., pyridyl, piperidinyl, pyrimidinyl, pyrrolidinyl, etc.); aromatic heterocyclic carbonyl group (e.g., such as furoyl); a carbamoyl group; C _2-10 alkanoyl group (eg acetyl, etc.);
And C _2-7 alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, etc.).

The “substituent” in the “optionally substituted cyclic group” for R ¹ or R ² is preferably 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); 1 to 6 carbon atoms which may be substituted with up to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
3) 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
4) an alkoxy group (e.g., methoxy, trifluoromethoxy, etc.); 4) having 1-6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.)
5) nitro group; 6) cyano group; 7) C _1-3 alkylenedioxy group (eg, methylenedioxy); 8) aryl group having 6 to 14 carbon atoms (e.g. 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methylsulfinyl); 10) an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methylsulfonyl). The number of substituents is preferably 1 to 3, more preferably 1 or 2.

The “substituent” is more preferably 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); 2) 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) 1 to 6 carbon atoms which may be substituted
3) 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
4) a nitro group; 5) a cyano group; and the like.

The “optionally substituted cyclic group” for R ¹ or R ² is preferably an optionally substituted aromatic group, and more preferably 1) a halogen atom (eg, fluorine, chlorine , Bromine, iodine); 2) an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, trifluoro) which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine) 3) an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, trifluoromethoxy) which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 4) an alkylthio group having 1 to 6 carbon atoms (eg, methylthio) which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 5) a nitro group; 6) a cyano group ; 7) C _1-3 Al A dioxy group (eg, methylenedioxy); 8) an aryl group having 6 to 14 carbon atoms (eg, phenyl); 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methylsulfinyl); and 10) a carbon number An aromatic hydrocarbon group (preferably phenyl or naphthyl) or an aromatic heterocyclic group (optionally having 1 to 3 substituents selected from 1 to 6 alkylsulfonyl groups (eg, methylsulfonyl)) ( Preferably it is furyl, thienyl, pyridyl, quinolyl, more preferably thienyl, pyridyl).

The "optionally substituted cyclic group" for R ¹ or R ² is particularly preferably C 1 -C 3 optionally containing a halogen atom (preferably fluorine, chlorine or bromine). _{It is a 6-14} aryl group (preferably phenyl).

[0102] In the general formula (I) and (Ia), as the "substituent" represented by R ¹ or R ^2, "substituted in the" optionally substituted cyclic group "represented by R ¹ or R ² Examples of the “group” include those exemplified above.

The substituent is preferably 1) an alkyl group having 1 to 6 carbon atoms (for example, methyl, 2) a hydroxy group; 3) an aryl group having 6 to 14 carbon atoms (eg, phenyl);

In the general formulas (I) and (Ia), R ¹ is preferably a hydrogen atom or a substituent, and R ² is preferably an optionally substituted cyclic group. Further, it is preferable that R ¹ is a hydrogen atom and R ² is an optionally substituted cyclic group.

(2) Definition of R ^1a and R ^{2a In} the general formula (II), the “optionally substituted cyclic group” represented by R ^1a or R ^2a includes the general formulas (I) and (Ia) And those exemplified as R ¹ or R ^{2 in the} above.

In the general formula (II), R ^1a is a hydrogen atom,
R ^2a is preferably an ^optionally substituted cyclic group. Further, R ^2a is preferably an aromatic group which may be substituted, especially a C _6-14 aryl group which may have 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine). (Preferably phenyl).

(3) Definition of W and Wa In the general formulas (I), (Ia) and (II), W or Wa
The “divalent aliphatic hydrocarbon group” represented by may be linear or branched, and may be saturated or unsaturated.

The “divalent aliphatic hydrocarbon group” is preferably a divalent aliphatic hydrocarbon group having 1 to 8 carbon atoms, and specific examples thereof include (1) C _1-8 alkylene ( For _{example, -CH 2 -, - (CH} 2) 2 -, -
(CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, − (C
_{H 2) 7 -, - (} CH 2) 8 -, - CH (CH 3) -, - C (CH 3) 2 -, - (C
_{H (CH 3)) 2 -} , - (CH 2) 2 C (CH 3) 2 -, - (CH 2) 3 C (CH 3) 2 - , etc.); (2) C _2-8 alkenylene (e.g., _{-CH = CH -, - CH 2} -CH
= CH -, - C (CH 3) 2 -CH = CH -, - CH 2 -CH = CH-CH
_{2 -, - CH 2 -CH 2} -CH = CH -, - CH = CH-CH = CH -, - C
H = CH—CH ₂ —CH ₂ —CH ₂ —) and the like.

The “divalent aliphatic hydrocarbon group” is more preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and is more preferably saturated. Above all,-
CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) _4- and the like are preferable, and especially-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,- (CH ₂ ) ₄
-And the like are preferable.

In the general formulas (I) and (Ia), W is “2”
A compound that is a “valent aliphatic hydrocarbon group” has an excellent blood glucose lowering effect as compared with a compound in which W is a bond. Therefore, W is preferably a divalent aliphatic hydrocarbon group.

W and Wa are preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, more preferably -CH
_{2 -, - (CH 2)} 2 -, - (CH 2) 3 -, - (CH 2) 4 - a. Among _{them, - (CH 2) 2 -} , - (CH 2) 3 -, - (CH 2) 4 - , etc. are preferable.

In the general formulas (I), (Ia) and (II),
Y has the formula: If -OR ³ (R ³ is as defined above) is a group represented by, W and Wa are particularly preferably - (C
H ₂ ) ₃ −.

The compounds of the general formulas (I), (Ia) and (I
During I), optionally Y is a carboxyl group which may be esterified or amidated, W and Wa are particularly preferably - (CH _{2) 2} - it is. (4) Definition of Y In the general formulas (I), (Ia) and (II), Y is a group represented by the formula:-
A group represented by OR ³ (R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group), or esterification or amide Shows a carboxyl group which may be converted.

[0113] Here, as the "optionally substituted heterocyclic group" and "optionally substituted acyl group" represented by R ^3, it is "substituted represented by R ¹ or R ² Examples of the “substituent” in the “good cyclic group” include those exemplified above.

Here, the “optionally substituted hydrocarbon group” represented by R ³ is exemplified by the “substituent” in the “optionally substituted cyclic group” represented by R ¹ or R ^2. "Optionally substituted aliphatic hydrocarbon group", "optionally substituted alicyclic hydrocarbon group" and "optionally substituted aromatic hydrocarbon group".

R ³ is preferably a hydrogen atom, carbon number 1
And 10 to 10 alkyl groups, among which a hydrogen atom is preferable.

The “carboxyl group which may be esterified or amidated” represented by Y is exemplified as the “substituent” in the “optionally substituted cyclic group” represented by R ¹ or R ² . Things.

Specific examples of the “carboxyl group which may be esterified or amidated” include: 1) a carboxyl group; 2) an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.) ; 3) C _1-6 mono substituted by an alkyl group also heterocyclic group with one to two optionally having C _1-6 alkyl group -
Or a carbamoyl group which may be di-substituted (eg,
Carbamoyl, ethylcarbamoyl, indolylethylcarbamoyl, methylpyrazylmethylcarbamoyl, etc.); 4) (mono- or di-C _1-6 alkyl) -phosphono-
A C _1-6 alkyl group; a C _2-5 alkoxycarbonyl group; a carbamoyl group; a C _2-5 alkoxycarbonyl-C _1-6 alkyl group; a heterocyclic group; and a C _1-6 alkyl group. A heterocyclic-C _1-6 alkoxy group; a C _6-10 aryl-carbamoyl group optionally having one or two substituents selected from the group _{consisting of, for} example, diethylphosphonomethylphenylcarbamoyl, methoxycarbonylphenylcarbamoyl, carbamoyl Phenylcarbamoyl, ethoxycarbonylmethylphenylcarbamoyl, imidazolylphenylcarbamoyl, morpholinophenylcarbamoyl,
5) a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.); and C _1-6 An alkoxy-C _7-13 aralkyl group;
C _7-13 which may have 1 to 2 substituent (s) selected from
An aralkyl-carbamoyl group (eg, trifluoromethylbenzylcarbamoyl, methoxyphenylethylcarbamoyl, etc.); 6) C ₆ optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) _A heterocyclic carbamoyl group optionally having one or two substituents selected from a _-10 aryl group; a C _1-6 alkyl; and a heterocyclic group optionally substituted with a C _1-6 alkyl (eg, , 4- (4
-Chlorophenyl) thiazol-2-yl-carbamoyl, 5-methyl-3-phenylthiazol-2-yl-
Carbamoyl, quinolylcarbamoyl, pyridylcarbamoyl, (2-methyl-1-imidazolyl) pyridylcarbamoyl, pyrazylcarbamoyl, morpholinopyridylcarbamoyl, etc.); 7) C _7-14 aralkyl-nitrogen-containing (preferably saturated) heterocyclic carbonyl group (Eg, 4-diphenylmethylpiperazin-1-ylcarbonyl and the like) and the like.

Of these, a carboxyl group; an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.) is preferred.

Y is preferably “even if it is amidated
Good carboxyl group ", more preferably
"Amidated carboxyl group" such as a) to g)
It is. a) C_1-6Alkoxy group (eg, methoxy, isopropoxy)
C); C_1-6An alkyl group (eg, methyl, etc.) or
A heterocyclic group which may be substituted with an oxo group (eg, India
Ril, imidazolyl, pyridyl, morpholino, furyl,
Tetrahydrofuranyl, pyrrolidinyl, piperidinyl,
Piperazinyl, etc.); C_1-6Alkylthio group (eg, methyl
Ruthio etc.); hydroxy group, C_6-10Aryl group (eg,
Phenyl etc.) or C_1-6Alkyl-C_6-10Aryl
May be substituted with a group (eg, methylphenyl, etc.)
Mono- or di-C_1-6Alkylamino group (eg, dimethyl
Ruamino, diethylamino, ethylmethylamino, dii
Isopropylamino, N-methyl-N-phenylamino,
Di-hydroxyethyl-amino, etc.); C_6-10Aryl
Amino group (eg, phenylamino); substituted with nitro group
Optionally substituted aromatic heterocyclic amino group (eg, pyridyl
Amino or the like); mono- or di-C_1-6Alkyl-phos
A hono group (eg, diethylphosphono, etc.);
C which may have 1 to 2 substituents_1-6Aliphatic hydrocarbon
Groups [eg, alkyl groups (eg, methyl, ethyl, propyl,
Butyl, tert-butyl, 1-ethylpropyl, 2,2-
Dimethylpropyl), C_2-6Alkynyl group (eg,
Ropinyl, etc.)]
Good carbamoyl group. b) halogen atom (eg, fluorine, chlorine, bromine, iodine
1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
C which may be substituted with_1-6Archi
Group (eg, methyl, trifluoromethyl);
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy groups (eg, meth
(Xy, trifluoromethoxy); carbamoyl group; (ring
Mono- or di-C which may form_1-6Alkyl
-Phosphono) -C_1-6Alkyl group [eg, methylphosphono
Methyl, ethyl phosphonomethyl, dimethyl phosphonomethyl
, Diethylphosphonomethyl, ethylmethylphosphonome
Chill, diisopropylphosphonomethyl, dibutylphospho
Nomethyl, diethylphosphonoethyl, (2-oxide-
1,3,2-dioxaphosphinanyl) methyl, (methyl
-2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, (dimethyl-2-oxide-1,3,2-dioxy
Saphosphinanyl) methyl, (diethyl-2-oxide)
-1,3,2-dioxaphosphinanyl) methyl, (5-
Butyl-5-ethyl-2-oxide-1,3,2-dioxy
Saphosphinanyl) methyl, (5-ethyl-5-methyl
-2-oxide-1,3,2-dioxaphosphinanyl)
Methyl and the like]; phosphono-C_1-6Alkyl group (eg, phos
Honomethyl etc.); C_2-5Alkoxycarbonyl group
(Eg, methoxycarbonyl, ethoxycarbonyl
Etc.); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylmethyl, etc.); heterocyclic group
(Eg, imidazolyl, morpholino); C_1-6Alkyl group
(Eg, methyl, ethyl)
-C_1-6An alkoxy group (eg, triazolylethoxy);
C_{1 -3}Alkylenedioxy group (eg, methylenedioxy,
Ethylenedioxy, etc.); C _7-14Aralkyl groups (eg,
Nil); C_6-10Aryloxy group (eg, phenoxy
Etc.); mono- or di-C_1-6Alkyl-phosphono group
(Eg, diethylphosphono, etc.); C_2-5Alkoxycal
Bonyl group (eg, methoxycarbonyl, ethoxycarbonyl
Mono- or di-
No- or di-C _1-6Alkyl-phosphono) -C_2-6Al
Kenyl group [eg, bis (diethylphosphono) ethenyl, 2
-Diethylphosphono-2-ethoxycarbonylethenyl
Etc.]; may have 1 to 2 substituents selected from
C_3-10Cycloalkane (eg, cyclopentane)
C that may be combined_6-14Aryl-carbamoyl group
(E.g., phenylcarbamoyl, naphthylcarbamoyl,
Dihydroindenylcarbamoyl, biphenylylcarba
Moyle). c) 1-2 C_1-6Substitute with an alkyl group (eg, methyl)
Which may be condensed with a benzene ring
_3-10Cycloalkyl-carbamoyl group (eg, cyclopro
Pyrcarbamoyl, cyclohexylcarbamoyl, dihi
Droindenylcarbamoyl). d) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor
Or mono- or di-C)_1-6Archi
C optionally substituted with ruamino_1-6Alkyl group
(Eg, methyl, trifluoromethyl, dimethylamino
Tyl, diethylaminoethyl); C_1-6Alkoxy group
(Eg, methoxy); C_1-3Alkylenedioxy group (eg,
Methylenedioxy, etc.); C_6-14Aryl group (eg,
Nyl); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylethyl);
C optionally having 1 to 2 groups_7-13Aralkyl-cal
Bamoyl group (eg, benzylcarbamoyl, phenethylca
Rubamoyl, phenylpropylcarbamoyl, benzhi
Drill carbamoyl). e) C_3-10Cycloalkyl-C_1-6Alkyl-carbamo
An yl group (eg, cyclohexylmethylcarbamoyl). f) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor
C which may be substituted with_6-10Ally
Group (eg, phenyl, etc.); 1-3 halogen atoms
(Eg, fluorine, chlorine, bromine, iodine, etc.)
May be C_1-6Alkyl (eg, methyl); C_1-6Archi
Heterocyclic group which may be substituted with a methyl group (eg, methyl)
(Eg, imidazolyl, morpholino); C_7-14Aralkyl
Group (eg, benzyl); oxo group;
Complexes which may have 1 to 4 (preferably 1 to 2)
Cyclic carbamoyl groups (eg, piperidinylcarbamoyl,
Zepanylcarbamoyl, pyrrolidinylcarbamoyl, e
Xazolylcarbamoyl, thiazolylcarbamoyl, pi
Lysylcarbamoyl, triazinylcarbamoyl, quino
Rilcarbamoyl, isoquinolylcarbamoyl, benzo
Thiazolylcarbamoyl, pyrazolylcarbamoyl, pi
Perazinylcarbamoyl, benzothiadiazolylcarba
Moyl, pyrazinylcarbamoyl). g) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor
Iodine), hydroxy group, C_2-7Alkoxyka
Rubonyl group (eg, ethoxycarbonyl) or 5 to
Substituted with a 6-membered nitrogen-containing heterocyclic group (eg, pyrrolidinyl, etc.)
C that may be_{1- 6}Alkyl (eg, methyl, ethyl
Etc.); C_1-3Alkylenedioxy group (eg, methylenedioxy
C) optionally substituted with_7-14Aralkyl group
(Eg, benzyl, benzhydryl, etc.);
With a logen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
Optionally substituted C_1-6Alkyl groups (eg, methyl,
Trifluoromethyl, etc.), halogen atoms (eg,
Element, chlorine, bromine, iodine, etc.), C _1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.) or C_2-10Alkano
C which may be substituted with an yl group (eg, acetyl, etc.)
_6-14Aryl group (eg, phenyl, etc.); C_6-14Aryl
-C_2-6Alkenyl groups (eg, phenylpropenyl
Etc.); C_1-6Substituted with an alkyl group (eg, methyl)
May be C_6-14Arylamino-C_1-6Alkyl group
(Eg, phenylaminomethyl, etc.); cyano group; oxo
Group; hydroxy group; 1 to 3 halogen atoms (eg, fluorine)
Element, chlorine, bromine, iodine, etc.) or C_1-6Alkyl group
(Eg, methyl, ethyl, etc.)
No- or di-C_2-10Alkanoylamino group (eg,
Cylamino, trifluoroacetylamino, propioni
Ruamino, N-acetyl-N-ethylamino, etc.); C
_2-7Alkoxycarbonylamino group (eg, tert-butoxy
5- or 6-membered nitrogen-containing heterocyclic group
(Eg, pyridyl, piperidinyl, pyrimidinyl, pyrrolidyl
Aromatic heterocyclic carbonyl group (eg, floy
Carbamoyl group; C_2-10Alkanoyl group
(Eg, acetyl, etc.); C_2-7Alkoxycarbonyl group
(Eg, methoxycarbonyl, ethoxycarbonyl
And the like may have 1 to 2 substituents selected from
Benzene ring or C_3-10Cycloalkanes (eg,
Nitrogen-containing heterocyclic ring which may be condensed with
Rubonyl group (eg, piperidinylcarbonyl, pyrrolidini
Carbonyl, morpholinocarbonyl, thiomorpholino
Carbonyl, piperazinylcarbonyl, tetrahydroi
Soquinoline carbonyl, decahydroisoquinoline carb
Nil, azepanylcarbonyl, azocancarbonyl, 1,
2,3,6-tetrahydropyridinecarbonyl).

Among these, b), d) and f) are preferred. In particular, (mono- or di-C _1-6 alkyl-phosphono) which may form a ring-C _1-6 alkyl group [eg, dimethylphosphonomethyl, diethylphosphonomethyl, diisopropylphosphonomethyl, dibutyl Phosphonomethyl, diethylphosphonoethyl, (2-oxide-
1,3,2-dioxaphosphinanyl) methyl, (methyl-2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, (dimethyl-2-oxide-1,3,2-dioxaphosphinanyl) methyl, (diethyl-2-oxide-1,3,2-dioxaphosphinanyl) methyl, (5-
Butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinanyl) methyl, (5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinanyl)
_C6-14 aryl- which may be substituted
Carbamoyl group (preferably phenylcarbamoyl)
Is preferred.

(5) Preferred Compounds Among the compounds represented by the general formula (I) or salts thereof, the compounds represented by the general formula (II) (provided that 5-phenyl-
4-isoxazolylmethanol and 5-phenyl-
(Except 4-isoxazolylacetic acid) or a salt thereof is a novel compound.

Preferred examples of the compound represented by the general formula (II) include the following compounds (A), (B) and (C).

Compound (A) R ^1a is a hydrogen atom; R ^2a is 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine); 2) 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, An alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, trifluoromethyl) which may be substituted with iodine); 3) 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Optionally substituted alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, trifluoromethoxy); 4) substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) An alkylthio group having 1 to 6 carbon atoms (eg, methylthio); 5) a nitro group; 6) a cyano group; 7) a C _1-3 alkylenedioxy group (eg, methylenedioxy); To 14 aryl groups (eg, phenyl 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methylsulfinyl); and 10) 1 to 3 substituents selected from an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methylsulfonyl). An aromatic hydrocarbon group (preferably phenyl, naphthyl) or an aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, quinolyl, more preferably thienyl, pyridyl) which may have each; 4 in 2
Valent aliphatic hydrocarbon group (preferably _{-CH 2 -, - (CH 2} ) 2
_{-, - (CH 2) 3} -, - (CH 2) 4 -; more preferably - (C
_{H 2) 2 -, - (} CH 2) 3 -, - (CH 2) 4 -; particularly preferably - (C
H ₂ ) _3- ); a compound wherein Y is a group represented by the formula: —OR ³ and R ³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

Compound (B) R ^1a is a hydrogen atom; R ^2a is 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine); 2) 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, An alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, trifluoromethyl) which may be substituted by iodine); 3) 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Optionally substituted alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, trifluoromethoxy); 4) substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) An alkylthio group having 1 to 6 carbon atoms (eg, methylthio); 5) a nitro group; 6) a cyano group; 7) a C _1-3 alkylenedioxy group (eg, methylenedioxy); To 14 aryl groups (eg, phenyl 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methylsulfinyl); and 10) 1 to 3 substituents selected from an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methylsulfonyl). An aromatic hydrocarbon group (preferably phenyl, naphthyl) or an aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, quinolyl, more preferably thienyl, pyridyl) which may have each; 4 in 2
Valent aliphatic hydrocarbon group (preferably _{-CH 2 -, - (CH 2} ) 2
_{-, - (CH 2) 3} -, - (CH 2) 4 -; more preferably - (C
_{H 2) 2 -, - (} CH 2) 3 -, - (CH 2) 4 -; particularly preferably - (C
H _{2) 2} -); Y is an alkoxycarbonyl group (e.g. having 2 to 5 carboxyl groups or C, methoxycarbonyl, ethoxycarbonyl, etc.), compound.

Compound (C) R^1aIs a hydrogen atom; R^2a1) Halogen atom (eg, fluorine, chlorine, bromine, iodine
2) 1 to 5 halogen atoms (eg, fluorine, chlorine, odor)
A) having 1 to 6 carbon atoms which may be substituted
Alkyl group (eg, methyl, ethyl, trifluoromethyl
3) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
A) having 1 to 6 carbon atoms which may be substituted
Lucoxy group (eg, methoxy, ethoxy, trifluoromethyl
4) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
A) having 1 to 6 carbon atoms which may be substituted
Alkylthio group (eg, methylthio); 5) nitro group; 6) cyano group;_1-3Alkylenedioxy group (eg, methylenedioxy
8) an aryl group having 6 to 14 carbon atoms (eg, phenyl); 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methyl)
10) an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methyl
Rusulfonyl)
Aromatic hydrocarbon groups (preferably
Nyl, naphthyl) or an aromatic heterocyclic group (preferably
Ryl, thienyl, pyridyl, quinolyl, more preferably
Is thienyl, pyridyl); Wa is 2-4 carbon atoms.
Aliphatic hydrocarbon group (preferably -CH_Two−, − (CH_Two)_Two
−, − (CH_Two)_Three−, − (CH_Two)_Four-; More preferably-(C
H_Two)_Two−, − (CH_Two)_Three−, − (CH_Two)_Four-; Particularly preferably-(C
H_Two)_Two-); Y is a) C_1-6Alkoxy groups (eg, methoxy
C, isopropoxy, etc.); C_1-6Alkyl groups (eg,
Or a hetero group optionally substituted with an oxo group
Ring groups (eg, indolyl, imidazolyl, pyridyl,
Holino, furyl, tetrahydrofuranyl, pyrrolidini
, Piperidinyl, piperazinyl, etc.); C_1-6Archi
Ruthio group (eg, methylthio, etc.); hydroxy group, C
_6-10Aryl group (eg, phenyl, etc.) or C_1-6Al
Kill-C_6-10With an aryl group (eg, methylphenyl, etc.)
Optionally substituted mono- or di-C_1-6Alkyl
Amino group (eg, dimethylamino, diethylamino,
Methylamino, diisopropylamino, N-methyl-
N-phenylamino, di-hydroxyethyl-amino
Etc.); C_6-10Arylamino group (eg, phenylamino
Etc.); an aromatic heterocyclic ring which may be substituted by a nitro group;
A mino group (eg, pyridylamino, etc.); mono- or di-
C_1-6Alkyl-phosphono group (eg, diethylphosphono group)
And the like may have 1 to 2 substituents selected from
C_1-6Aliphatic hydrocarbon group [eg, alkyl group (eg, methyl
, Ethyl, propyl, butyl, tert-butyl, 1-e
Propyl, 2,2-dimethylpropyl, etc.), C_2-6
Alkynyl group (eg, propynyl, etc.)]
A carbamoyl group which may be di-substituted; b) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
C which may be substituted with_1-6Archi
Group (eg, methyl, trifluoromethyl);
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy groups (eg, meth
(Xy, trifluoromethoxy); carbamoyl group; (ring
Mono- or di-C which may form_1-6Alkyl
-Phosphono) -C_1-6Alkyl group [eg, methylphosphono
Methyl, ethyl phosphonomethyl, dimethyl phosphonomethyl
, Diethylphosphonomethyl, ethylmethylphosphonome
Chill, diisopropylphosphonomethyl, dibutylphospho
Nomethyl, diethylphosphonoethyl, (2-oxide-
1,3,2-dioxaphosphinanyl) methyl, (methyl
-2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, (dimethyl-2-oxide-1,3,2-dioxy
Saphosphinanyl) methyl, (diethyl-2-oxide)
-1,3,2-dioxaphosphinanyl) methyl, (5-
Butyl-5-ethyl-2-oxide-1,3,2-dioxy
Saphosphinanyl) methyl, (5-ethyl-5-methyl
-2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, etc.]; C_2-5Alkoxycarbonyl group (eg,
C, ethoxycarbonyl, ethoxycarbonyl, etc.);_2-5
Alkoxycarbonyl-C_1-6Alkyl group (eg, ethoxy
Phosphono-C)_1-6Alkyl
Groups (eg, phosphonomethyl, etc.); heterocyclic groups (eg, imida
Zolyl, morpholino); C_1-6Alkyl group (eg, methyl
, Ethyl)_1-6A
Lucoxy group (eg, triazolylethoxy); C_{1 -3}Al
Killenedioxy groups (eg, methylenedioxy, ethylenedi
Oxy, etc.); C _7-14An aralkyl group (eg, benzyl);
C_6-10Aryloxy group (eg, phenoxy, etc.); mono
-Or di-C_1-6Alkyl-phosphono group (eg, diethyl
Lephosphono, etc.); C_2-5Alkoxycarbonyl group
(Eg, methoxycarbonyl, ethoxycarbonyl, etc.)
Mono- or di- (mono- or
Is Di-C _1-6Alkyl-phosphono) -C_2-6Alkenyl group
[Examples: bis (diethylphosphono) ethenyl, 2-diethyl
Ruphosphono-2-ethoxycarbonylethenyl and the like];
May have one or two substituents selected from
_3-10Condensed with cycloalkane (eg, cyclopentane)
May be C_6-14Aryl-carbamoyl group (eg,
Nilcarbamoyl, naphthylcarbamoyl, dihydroi
C) 1-2 C_1-6Substitute with an alkyl group (eg, methyl)
Which may be condensed with a benzene ring
_3-10Cycloalkyl-carbamoyl group (eg, cyclopro
Pyrcarbamoyl, cyclohexylcarbamoyl, dihi
D) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Or mono- or di-C)_1-6Archi
C optionally substituted with ruamino_1-6Alkyl group
(Eg, methyl, trifluoromethyl, dimethylamino
Tyl, diethylaminoethyl); C_1-6Alkoxy group
(Eg, methoxy); C_1-3Alkylenedioxy group (eg,
Methylenedioxy, etc.); C_6-14Aryl group (eg,
Nyl); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylethyl);
C optionally having 1 to 2 groups_7-13Aralkyl-cal
Bamoyl group (eg, benzylcarbamoyl, phenethylca
Rubamoyl, phenylpropylcarbamoyl, benzhi
Drillcarbamoyl); e) C_3-10Cycloalkyl-C_1-6Alkyl-carbamo
Yl group (eg, cyclohexylmethylcarbamoyl); f) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor
C which may be substituted with_6-10Ally
Group (eg, phenyl, etc.); 1-3 halogen atoms
(Eg, fluorine, chlorine, bromine, iodine, etc.)
May be C_1-6Alkyl (eg, methyl); C_1-6Archi
Heterocyclic group which may be substituted with a methyl group (eg, methyl)
(Eg, imidazolyl, morpholino); C_7-14Aralkyl
Group (eg, benzyl); oxo group;
Complexes which may have 1 to 4 (preferably 1 to 2)
Cyclic carbamoyl groups (eg, piperidinylcarbamoyl,
Zepanylcarbamoyl, pyrrolidinylcarbamoyl, e
Xazolylcarbamoyl, thiazolylcarbamoyl, pi
Lysylcarbamoyl, triazinylcarbamoyl, quino
Rilcarbamoyl, isoquinolylcarbamoyl, benzo
Thiazolylcarbamoyl, pyrazolylcarbamoyl, pi
Perazinylcarbamoyl, benzothiadiazolylcarba
Moyl, pyrazinylcarbamoyl); or g) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Iodine), hydroxy group, C_2-7Alkoxyka
Rubonyl group (eg, ethoxycarbonyl) or 5 to
Substituted with a 6-membered nitrogen-containing heterocyclic group (eg, pyrrolidinyl, etc.)
C that may be_{1- 6}Alkyl (eg, methyl, ethyl
Etc.); C_1-3Alkylenedioxy group (eg, methylenedioxy
C) optionally substituted with_7-14Aralkyl group
(Eg, benzyl, benzhydryl, etc.);
With a logen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
Optionally substituted C_1-6Alkyl groups (eg, methyl,
Trifluoromethyl, etc.), halogen atoms (eg,
Element, chlorine, bromine, iodine, etc.), C _1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.) or C_2-10Alkano
C which may be substituted with an yl group (eg, acetyl, etc.)
_6-14Aryl group (eg, phenyl, etc.); C_6-14Aryl
-C_2-6Alkenyl groups (eg, phenylpropenyl
Etc.); C_1-6Substituted with an alkyl group (eg, methyl)
May be C_6-14Arylamino-C_1-6Alkyl group
(Eg, phenylaminomethyl, etc.); cyano group; oxo
Group; hydroxy group; 1 to 3 halogen atoms (eg, fluorine)
Element, chlorine, bromine, iodine, etc.) or C_1-6Alkyl group
(Eg, methyl, ethyl, etc.)
No- or di-C_2-10Alkanoylamino group (eg,
Cylamino, trifluoroacetylamino, propioni
Ruamino, N-acetyl-N-ethylamino, etc.); C
_2-7Alkoxycarbonylamino group (eg, tert-butoxy
5- or 6-membered nitrogen-containing heterocyclic group
(Eg, pyridyl, piperidinyl, pyrimidinyl, pyrrolidyl
Aromatic heterocyclic carbonyl group (eg, floy
Carbamoyl group; C_2-10Alkanoyl group
(Eg, acetyl, etc.); C_2-7Alkoxycarbonyl group
(Eg, methoxycarbonyl, ethoxycarbonyl
And the like may have 1 to 2 substituents selected from
Benzene ring or C_3-10Cycloalkanes (eg,
Nitrogen-containing heterocyclic ring which may be condensed with
Rubonyl group (eg, piperidinylcarbonyl, pyrrolidini
Carbonyl, morpholinocarbonyl, thiomorpholino
Carbonyl, piperazinylcarbonyl, tetrahydroi
Soquinoline carbonyl, decahydroisoquinoline carb
Nil, azepanylcarbonyl, azocancarbonyl, 1,
2,3,6-tetrahydropyridinecarbonyl and the like);
A compound that is

Among the above compounds (A), (B) and (C), the following compounds are particularly preferable. 3-
[5- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol; 3- [5- (3,4-
Dichlorophenyl) -4-isoxazolyl] propionic acid; 3- [5- (4-chlorophenyl) -4-isoxazolyl] propan-1-ol; 3- [5- (4-
Chlorophenyl) -4-isoxazolyl] propionic acid; 3- [5- (3,4-difluorophenyl) -4-
Isoxazolyl] propan-1-ol; 3- [5-
(3,4-difluorophenyl) -4-isoxazolyl] propionic acid; N- [4- (diethylphosphonomethyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide; N- [4- ( Diethylphosphonomethyl) phenyl] -3- [5- (4-fluorophenyl)
-4-isoxazolyl] propionamide; N- [4-
(Dimethylphosphonomethyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide; N-
{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- (5-phenyl-4-isoxazolyl) propionamide; N-benzyl-N- [ 2- (dimethylamino) ethyl] -3- [5
-(4-fluorophenyl) -4-isoxazolyl] propionamide; N-benzyl-N- (1-benzyl-
3-pyrrolidinyl) -3- [5- (4-fluorophenyl)
-4-isoxazolyl] propionamide.

(6) Salt A compound represented by formula (I), (Ia) or (II) (hereinafter referred to as compound (I), (Ia) or (II), respectively)
) Are preferably pharmacologically acceptable salts. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, and organic salts. Examples thereof include salts with acids, salts with basic or acidic amino acids, and the like.

Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.

Preferred examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.

Preferable examples of the salt with an inorganic acid include hydrochloric acid,
Salts with hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.

Preferable examples of the salt with an organic acid include formic acid,
Examples thereof include salts with acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like.

Preferred examples of the salt with an acidic amino acid include:
Salts with aspartic acid, glutamic acid and the like can be mentioned.

Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

(7) Prodrugs and the like Prodrugs of compound (I) are compounds that are converted to compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in vivo, that is, enzymatically oxidize, reduce or hydrolyze. A compound that changes to the compound (I) by causing decomposition or the like, and a compound that changes to the compound (I) by causing hydrolysis or the like by gastric acid or the like. Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of the compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of the compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Compound, dimethylaminomethylcarbonylated compound, etc.); the carboxyl group of compound (I) is an ester Amidated compounds (eg, the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified) Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like). These compounds can be produced from compound (I) by a method known per se.

The prodrug of compound (I) is described in “Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol. 7, Molecular Design 1
Compounds that change to compound (I) under physiological conditions as described on pages 63 to 198 may be used.

The prodrugs of the compounds (Ia) and (II) include the same prodrugs as the above-mentioned prodrugs of the compound (I).

Compounds (I), (Ia) and compound (II) are isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.)
It may be labeled with, for example.

Further, the compounds (I), (Ia) and (II) may be anhydrous or hydrate.

(8) Formulation Compounds (I), (Ia), (II) and their salts (hereinafter sometimes abbreviated simply as the compound of the present invention) have low toxicity and are used as such or pharmacologically. By mixing with an acceptable carrier or the like to form a pharmaceutical composition, it can be used for mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.) to It can be used as a prophylactic / therapeutic agent for diseases.

Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; It is blended as a solvent, a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, a soothing agent and the like in the preparation. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can also be used.

Preferred examples of the excipient include lactose, sucrose,
D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, aluminum metasilicate Magnesium acid and the like.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, and hydroxypropyl. Cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned.

Preferable examples of the disintegrant include lactose, sucrose,
Examples include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.

Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,
Trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glyceryl monostearate; Hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil and the like.

Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.

Preferable examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Preferred examples of the antioxidant include sulfite,
Ascorbate and the like.

Preferred examples of the coloring agent include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5 and edible blues 1 and 2);
Water-insoluble lake dyes (eg, the aluminum salt of the water-soluble edible tar dye, etc.), natural dyes (eg, β-carotene,
Chlorophyll, bengalara, etc.).

Preferred examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like. (9) Administration Form The pharmaceutical composition may be in the form of, for example, tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions, and other oral preparations; and injections. (Eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, transnasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppository) Preparations, vaginal suppositories, etc.), pellets, drops, sustained release preparations (eg, sustained release microcapsules, etc.) and the like, which can be safely administered orally or parenterally, respectively. .

The pharmaceutical composition can be produced by a method commonly used in the technical field of pharmaceutical preparations, for example, a method described in the Japanese Pharmacopoeia. Hereinafter, a specific production method of the preparation will be described in detail. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, and the like, but is, for example, about 0.1 to 100% by weight.

For example, oral preparations include, as an active ingredient, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, calcium carboxymethylcellulose), binders (eg, pregelatinized starch). , Gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and compression-molded, and if necessary, taste masking, It is produced by coating with a coating base by a method known per se for the purpose of enteric solubility or durability.

Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained release film coating base and the like.

As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E
[Eudragit E (trade name), ROHM PHARMA],
Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan;

Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L
(Trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]
And acrylic acid polymers; natural products such as shellac.

Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS
Acrylic polymers such as [Eudragit RS (trade name), Rohm Pharma Co., Ltd.] and ethyl acrylate / methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] .

The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.

Injectables are prepared by dispersing the active ingredient into a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc., polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), a preservative (eg, methyl paraben, propyl paraben, benzyl alcohol). ,
Chlorobutanol, phenol, etc.), tonicity agent (eg,
Sodium chloride, glycerin, D-mannitol, D-
Dissolved in aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) or oily solvents (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.) It is manufactured by turbidity or emulsification. At this time, if necessary, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used. (10) Target disease The compound of the present invention and the medicament of the present invention are, for example, agents for preventing or treating diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, Prevention and treatment of hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, etc .; prevention and treatment of arteriosclerosis; prevention and prevention of impaired glucose tolerance [IGT (Impaired Glucose Tolerance)]
It can be used as a therapeutic agent; an insulin secretagogue; and a transition inhibitor from glucose intolerance to diabetes.

Regarding the criterion of diabetes, a new criterion was reported by the Japanese Diabetes Association in 1999.

According to this report, diabetes means that the fasting blood glucose level (glucose concentration in venous plasma) is 126 mg.
/ Dl or more, 75g oral glucose tolerance test (75gOG
TT) A state in which the 2-hour value (glucose concentration in venous plasma) is 200 mg / dl or more, and the blood sugar level (glucose concentration in venous plasma) is 200 mg / dl or more. In addition, it does not correspond to the diabetes, and
"A state in which the fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or the 75-hour oral glucose tolerance test (75 g OGTT) 2-hour value (glucose concentration in venous plasma) is less than 140 mg / dl" (normal type) The state is called "boundary type".

The criteria for judging diabetes are as follows.
A new criterion was reported by ADA (American Diabetes Association) in 1997 and by WHO in 1998.

According to these reports, diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126.
mg / dl or more, and the 75-hour oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 2
It is a state showing 00 mg / dl or more.

According to the above report, impaired glucose tolerance refers to fasting blood glucose level (glucose concentration in venous plasma).
Is less than 126 mg / dl, and the 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the fasting blood glucose level (glucose concentration in venous plasma) was 110 m
g / dl or more and less than 126 mg / dl is defined as IFG (Im
paired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose)
Among them, the state in which the 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is less than 140 mg / dl is called IFG (Impaired Fasting Glycemia).

The compound of the present invention and the medicament of the present invention can be used for diabetes, borderline type,
Prevention of impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia)
It is also used as a therapeutic. Furthermore, the compound of the present invention and the pharmaceutical composition of the present invention can be used in a borderline form, impaired glucose tolerance,
(Impaired Fasting Glucose) or IFG (Impaired Fasting Glucose)
ed Fasting Glycemia) can be prevented from progressing to diabetes.

The compound of the present invention and the medicament of the present invention include, for example, diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infectious disease ( Respiratory infections, urinary tract infections, digestive tract infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, decreased hearing, cerebrovascular disorders, peripheral blood circulation disorders, etc.],
Obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome) Fluid), fatty liver, hypertension, polycystic ovary syndrome,
Kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease, etc.), muscular dystrophy, myocardial infarction, angina, cerebrovascular disorder (eg, cerebral infarction) , Stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, paresthesia in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome, acute or chronic diarrhea , Inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgical trauma, remission of swelling, neuralgia, laryngitis, cystitis, hepatitis (non-alcoholic fatty Prevention and treatment of pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin), visceral obesity syndrome, etc. It can also be used as agent.

The compound of the present invention and the medicament of the present invention reduce visceral fat, suppress visceral fat accumulation, improve glucose metabolism, improve lipid metabolism, suppress oxidized LDL production, improve lipoprotein metabolism,
Improvement of coronary artery metabolism, prevention and treatment of cardiovascular complications, prevention and treatment of heart failure complications, reduction of blood remnant, prevention and treatment of anovulation, prevention and treatment of hirsutism, prevention and treatment of hyperandrogenemia, etc. It is also used for

The compound of the present invention and the medicament of the present invention are also used for secondary prevention and suppression of progress of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction).

In particular, the compound of the present invention and the medicament of the present invention can be administered in the presence of a high concentration of glucose (for example, a fasting blood glucose level of 126 mg / dl or more or a 75 g oral glucose tolerance test (75 g OGTT) and a 2-hour value of 140 mg / dl).
This is useful as a glucose-dependent insulin secretagogue that selectively exerts an insulin secretagogue action only in patients with the above. Therefore, the compound of the present invention and the medicament of the present invention are particularly useful as a safe and preventive or therapeutic agent for diabetes, which has a low risk of vascular complications and hypoglycemia induction, which are the adverse effects of insulin.

The dose of the compound of the present invention and the medicament of the present invention varies depending on the administration subject, administration route, target disease, symptoms and the like. For example, when orally administered to an adult diabetic patient, the compound of the present invention as an active ingredient Is usually about 0.01 to 100 mg / kg body weight, preferably 0.0
5 to 30 mg / kg body weight, more preferably 0.1 to 2
mg / kg body weight, and it is desirable to administer this amount once to three times a day.

(11) Concomitant Use of Drugs The compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, It can be used in combination with a drug such as an antithrombotic agent, a therapeutic agent for osteoporosis, an anti-dementia agent, an erectile dysfunction improving agent, a therapeutic agent for urinary incontinence and pollakiuria (hereinafter abbreviated as concomitant drug). At this time, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to a subject at the same time or may be administered at a time interval. The dose of the concomitant drug can be appropriately determined based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

[0177] Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically synthesized using Escherichia coli and yeast; insulin zinc; protamine insulin). Zinc; a fragment or derivative of insulin (eg, INS-1 etc.), an insulin sensitizer (eg, pioglitazone hydrochloride, rosiglitazone (maleate), GI-262570, JTT-501, MC
C-555, YM-440, KRP-297, CS-0
11, FK-614, compounds described in WO 99/58510 (for example, (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid) , NN-622, AR-H
-039242, BMS-298585, EML-16
336), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylureas (eg, tolbutamide, glibenclamide,
Gliclazide, chlorpropamide, tolazamide, acetohexamide, gliclopyramide, glimepiride, glipizide, glybuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate etc.], GLP-1 receptor agonist [eg, GL
P-1, NN-2211, AC-2993 (exendin-4), BI
M-51077, Aib (8,35) hGLP-1 (7,37) NH ₂
Amylin agonists (eg, pramlintide etc.),
Phosphotyrosine phosphatase inhibitors (eg, vanadic acid etc.), dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32
/ 98 etc.), β3 agonists (eg, CL-31624)
3, SR-58611-A, UL-TG-307, SB
-226552, AJ-9677, BMS-19608
5, AZ40140, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLT (sodi
um-glucose cotransporter) inhibitor (eg, T-109
5 etc.).

As the therapeutic agent for diabetic complications, aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidalestat, SNK-860, CT-1)
12 etc.), neurotrophic factor and its increasing drug (eg, NG
F, NT-3, BDNF, the neurotrophin production / secretion enhancers described in WO 01/14372 (for example,
(E.g., (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole), nerve regeneration promoters (eg,
Y-128 etc.), PKC inhibitors (eg, LY-33353)
1), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (E.g.,
Thiapride, mexiletine and the like).

Examples of antihyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin,
Atorvastatin, fluvastatin, itavastatin or a salt thereof (eg, sodium salt), a squalene synthase inhibitor (eg, a compound described in WO 97/10224, such as N-[[(3R, 5S) -1- ( 3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-yl] acetyl] piperidine-4-acetic acid or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).

Examples of antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.) and angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan,
Tasosartan, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like.

Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), Pancreatic lipase inhibitors (eg, orlistat etc.), β3 agonists (eg, CL
-316243, SR-58611-A, UL-TG-
307, SB-226552, AJ-9677, BMS
19685, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-15849, etc.) and the like.

Examples of diuretics include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, Penflutide, polythiazide, methyclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), Azosemide, isosorbide,
Examples include ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin) And the like, plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Of these, furtulon or neofurturon, which is a 5-fluorouracil derivative, is preferred.

Examples of the immunotherapeutic agent include a microorganism or bacterial component (eg, muramyl dipeptide derivative, picibanil, etc.), a polysaccharide having an immunopotentiating activity (eg, lentinan,
Schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.). 1, IL-2 and IL-12 are preferred.

Examples of the antithrombotic agent include heparin (eg,
Heparin sodium, heparin calcium, dalteparin sodium, etc., warfarin (eg, warfarin potassium, etc.), antithrombin drugs (eg, argatroban, etc.), thrombolytic drugs (eg, urokinase, tisokinase) (tiso
kinase), alteplase, altenplase (n
ateplase), monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine hydrochloride), cilostazol, icosapentate ethyl, beraprost sodium (beraprost sodium), sarpogrelate hydrochloride (sarpogrelate hydrochloride) ) Etc.).

Examples of the osteoporosis therapeutic agent include alfacalcidol, calcitriol (ca)
lcitriol), elcaltonin (elcaltonin), salmon calcitonin (calcitonin salmon), estriol (es)
triol), ipriflavone, pamidronate disodium, alendronate sodium hydra
te), disodium incadronate (incadronate dis
odium) and the like.

Examples of anti-dementia agents include tacrine (tacr)
ine), donepezil, rivastigmine (ri)
vastigmine) and galantamine (galantamine).

Examples of erectile dysfunction ameliorating agents include apomorphine and sildenafil citrate
denafil citrate).

Examples of the therapeutic agents for urinary incontinence and pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

Furthermore, drugs that have been shown to improve cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin etc.) [Cancer Research, Vol. 49, 5935-59.
39, 1989], progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncolog
y), Vol. 12, pp. 213-225, 1994], carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (all references are as described above), fat metabolism improvers ( For example, eicosapentaenoic acid, etc.) [British Journal of Cancer, No. 68
314-318, 1993], growth hormone,
IGF-1 or TN, a factor that induces cachexia
Antibodies against F-α, LIF, IL-6, and oncostatin M can also be used in combination with the compound of the present invention.

The concomitant drug is preferably an insulin preparation,
Insulin sensitizer, α-glucosidase inhibitor,
Biguanides, insulin secretagogues (preferably sulfonylurea agents) and the like.

The above concomitant drugs may be used in combination of two or more kinds at an appropriate ratio. Preferred combinations when two or more concomitant drugs are used include, for example, the following. 1) insulin secretagogue (preferably sulfonylurea) and α-glucosidase inhibitor; 2) insulin secretagogue (preferably sulfonylurea) and biguanide; 3) insulin secretagogue (preferably sulfonylurea), biguanide And α-glucosidase inhibitors; 4) insulin sensitizers and α-glucosidase inhibitors; 5) insulin sensitizers and biguanides; 6) insulin sensitizers, biguanides and α.
-Glucosidase inhibitors.

When the compound of the present invention or the medicament of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the adverse effects of those agents. In particular, the dose of an insulin sensitizer, an insulin secretagogue (preferably a sulfonylurea) and a biguanide can be reduced from the usual dose. Therefore, adverse effects that may be caused by these agents can be safely prevented. In addition, diabetes complications,
The dosage of antihyperlipidemic and antihypertensive agents can be reduced, so that the adverse effects that may be caused by these agents can be effectively prevented. (12) Production Method Hereinafter, a method for producing the compound of the present invention will be described. In addition,
Since compounds (Ia) and (II) are included in compound (I), a method for producing compound (I) will be described.

Compound (I) can be produced by a method known per se, for example, the following Method A to Method I or a method analogous thereto.

In the general formula (I), the compound (I-2) wherein Y is a carboxyl group can be produced, for example, by the following method A. [Method A]

[0196]

Embedded image

[Wherein, R ^3a represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and other symbols have the same meanings as described above. Show. A “optionally substituted hydrocarbon group” for R ^3a ,
As the “optionally substituted heterocyclic group” and the “optionally substituted acyl group”, those exemplified as R ³ can be mentioned.

In this method, compound (I-2) is produced by subjecting compound (I-1) to a hydrolysis reaction.

This hydrolysis reaction is carried out in a water-containing solvent in the presence of an acid or a base according to a conventional method.

Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like.

Examples of the base include alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate;
Alkaline earth metal carbonates such as barium carbonate and calcium carbonate; alkali metal alkoxides such as sodium methoxide; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; barium hydroxide;
And alkaline earth metal hydroxides such as calcium hydroxide.

The amount of the acid or base to be used is generally an excess with respect to compound (I-1). Preferably, the amount of the acid to be used is about 2 to about 50 equivalents, relative to compound (I-1),
The amount of the base to be used is about 1.2 to about compound (I-1).
About 5 equivalents.

Examples of the water-containing solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; mixed solvents of at least one solvent selected from dimethyl sulfoxide and acetone with water. Can be When the reaction is performed under acidic conditions, an excess acid may be used as a solvent.

The reaction temperature is usually about -20 to about 150.
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.1 to about 20 hours.

Compound (I-2) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-1) used as a starting compound in the above-mentioned Method A can be obtained, for example, from the Journal of Heteroc chemistry.
yclic Chemistry), 28, 453 (1991)
Year); Journal of Organic Chemistry, 49, 4419
P. (1984); Tetrah Letters
edron Letters), vol. 34, p. 485 (1993), or a method analogous thereto.

In the general formula (I), the compound (I-3) in which Y is an amidated carboxyl group is represented by, for example, the following B
It is manufactured by the method. [Method B]

[0209]

Embedded image

[The symbols in the formula are as defined above. In this method, compound (I-3) is produced by subjecting compound (I-2) to an amidation reaction. This reaction is carried out by a method known per se, for example, compound (I-2) and compound (VI)
And a method of appropriately reacting the compound (VI) with a reactive derivative of the compound (I-2). Examples of the condensing agent include carbodiimide condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride; phosphoric acid condensing reagents such as diethyl cyanophosphate and diphenylphosphoryl azide Generally known condensing agents such as carbonyldiimidazole and 2-chloro-1,3-dimethylimidazolium tetrafluoroborate.

Examples of the solvent used in the reaction using the condensing agent include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; benzene, toluene and the like. Aromatic hydrocarbons; ethers such as tetrahydrofuran, dioxane and diethyl ether; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.

The amount of compound (VI) to be used is as follows:
0.1 to 10 molar equivalents, preferably 0.
3 to 3 molar equivalents.

The amount of the condensing agent to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-2).

As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-
When using a carbodiimide-based condensation reagent such as 3-dimethylaminopropylcarbodiimide and its hydrochloride, a suitable condensation accelerator (eg, 1-hydroxy-7
-Azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.) can improve the reaction efficiency. When a phosphate condensing reagent such as diethyl cyanophosphate or diphenylphosphoryl azide is used as the condensing agent, the reaction efficiency can be generally improved by adding an organic amine base such as triethylamine.

The amount of the above-mentioned condensation promoter and organic amine base to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-2).

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is generally 0.5 to 60 hours.

In the method using the reactive derivative of the compound (I-2), the reactive derivative of the compound (I-2) includes, for example, an acid anhydride, an acid halide (an acid chloride, an acid bromide), an imidazolide, or a mixture thereof. Acid anhydrides (for example, anhydrides with methyl carbonate, ethyl carbonate, and isobutyl carbonate) and the like.

For example, when an acid anhydride or an acid halide is used, the reaction is usually performed in the presence of a base in a solvent that does not affect the reaction.

As the base, for example, triethylamine,
Examples include pyridine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.

Solvents which do not affect the reaction include:
For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran;
Ethers such as dioxane and diethyl ether; and ethyl acetate and water. These solvents may be mixed and used at an appropriate ratio. When the amides are used as a solvent that does not affect the reaction, the reaction can be performed in the absence of a base.

The amount of compound (VI) to be used may be the same as that of compound (I-
0.1 to 10 molar equivalents, preferably 0.
3 to 3 molar equivalents. The amount of the base used is the same as that of the compound (I-
0.1 to 10 molar equivalents, preferably 0.
3 to 3 molar equivalents.

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is generally 0.5 to 20 hours.

When a mixed acid anhydride is used, the compound (I-2) and a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are used as bases (eg, triethylamine, aniline, N- Methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate,
Reaction in the presence of potassium carbonate, cesium carbonate, etc.)
It is further reacted with compound (VI).

The amount of compound (VI) to be used is as follows:
It is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, based on 2).

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is usually 0.5 to 20 hours.

Compound (I-3) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-2) used as a starting compound in the above method B is produced, for example, by the above method A.

Compound (VI) used as a starting compound in the above-mentioned Method B can be produced by a method known per se.

In the general formula (I), the compound (I-4) wherein Y is a hydroxy group is produced, for example, by the following Method C. [Method C]

[0233]

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[Wherein Wb represents a bond or a divalent aliphatic hydrocarbon group, and the other symbols have the same meanings as described above. As the “divalent aliphatic hydrocarbon group” represented by Wb,
Examples of the above W are exemplified.

In this method, compound (I-4) is produced by subjecting compound (I-1) to a reduction reaction.

This reaction is carried out according to a method known per se in the presence of a reducing agent in a solvent that does not affect the reaction.

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, borane and a complex thereof (eg, borane). -Tetrahydrofuran, pyridineborane, borane-dimethylsulfide, etc.).

The amount of the reducing agent to be used is preferably about 0.5 to about 10 molar equivalents relative to compound (I-1).

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; tetrahydrofuran, dioxane and the like.
Ethers such as diethyl ether; water, methanol,
Examples include alcohols such as ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is generally about 0.5 to about 20 hours.

Compound (I-4) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), Y represents the formula: —OCOR ⁴
Compound (I-5) which is a group represented by (R ⁴ has the same meaning as described above) is produced, for example, by the following Method D. [Method D]

[0244]

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[The symbols in the formula are as defined above. In this method, compound (I-5) is produced by subjecting compound (I-4) to an acylation reaction. This reaction can be performed by a method known per se. As such a method, for example, a method of directly condensing a compound (I-4) and a carboxylic acid derivative (R ⁴ CO ₂ H) using a condensing agent, or a method of preparing a carboxylic acid derivative (R ⁴ CO ₂ H) A method of appropriately reacting the reactive derivative with the compound (I-4) is exemplified. Here, the method of directly condensing compound (I-4) with a carboxylic acid derivative (R ⁴ CO ₂ H) using a condensing agent is described in the above “Condensing compound (I-2) with compound (VI)”. Method of Direct Condensation Using Agent ".

In the method using the reactive derivative of the carboxylic acid derivative, examples of the reactive derivative of the carboxylic acid derivative include an acid anhydride, an acid halide (acid chloride, acid bromide), imidazolide, or a mixed acid anhydride (for example, Methyl carbonate, ethyl carbonate, anhydrides with isobutyl carbonate, etc.).

For example, when an acid anhydride or an acid halide is used, the reaction is usually performed in the presence of a base in a solvent that does not affect the reaction.

As the base, for example, triethylamine,
Examples include pyridine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.

Solvents that do not affect the reaction include:
For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran;
Ethers such as dioxane and diethyl ether; and ethyl acetate and water. These solvents may be mixed and used at an appropriate ratio. When the amides are used as a solvent that does not affect the reaction, the reaction can be performed in the absence of a base.

The amount of the reactive derivative of the carboxylic acid to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-4). The amount of the base to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-4).

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is usually 0.5 to 20 hours.

When a mixed acid anhydride is used, a carboxylic acid derivative (R ⁴ CO ₂ H) and a chlorocarbonate (eg,
Methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc. are converted into bases (eg, triethylamine, aniline, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, hydroxide) The reaction is carried out in the presence of potassium, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and further reacted with compound (I-4).

The amount of the carboxylic acid derivative used is determined by the amount of the compound (I
Based on -4), it is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents.

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is usually 0.5 to 20 hours.

Compound (I-5) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-4) used as a starting compound in the above method D is produced, for example, by the above method C.

In the general formula (I), Y is a group represented by the formula: —OR ^3a
Compound (I-6), which is a group represented by (R ^3a has the same meaning as described above), can also be produced, for example, by the following Method E and Method F. [Method E]

[0260]

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[Wherein X is a hydroxy group, a halogen atom or a formula: -OSO ₂ R ⁸ (R ⁸ may be substituted with an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms) And the other symbols have the same meanings as described above. Here, the “alkyl group having 1 to 4 carbon atoms” represented by R ⁸
And "1-6 carbon atoms in the aryl group having 6-10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms".
As the alkyl group of 4, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec.-butyl, t.-
Butyl and the like, among which methyl is preferable.

Examples of the aryl group having 6 to 10 carbon atoms in the “aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms” represented by R ⁸ include phenyl and naphthyl. And the like, among which phenyl is preferred.

In this method, compound (I-4) and compound (VI
Compound (I-6) is produced by reaction with I).

When X is a hydroxy group, the reaction is as follows:
It is carried out by a method known per se, for example, the method described in Synthesis, page 1, (1981) or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophile in a solvent that does not adversely influence the reaction.

As the organic phosphorus compound, for example, triphenylphosphine, tributylphosphine and the like can be mentioned.

Examples of the electrophile include diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperidine and the like.

The amount of the organic phosphorus compound and the electrophile to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-4).

Examples of the solvent which does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. Amides such as N, N-dimethylformamide; and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

X is a halogen atom or a formula: —OSO ₂ R ⁸
When R ⁸ is a group represented by the above definition, this reaction is carried out in a conventional manner in the presence of a base in a solvent that does not adversely influence the reaction.

Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide;
Alkaline earth metal salts such as calcium hydroxide; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Amines such as ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t.-butoxide.

The amount of the base to be used is as defined in Compound (I-4).
Is preferably about 1 to about 5 molar equivalents.

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone; Halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

Compound (I-6) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. [Method F]

[0278]

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[Wherein E is a halogen atom or a formula: -O
A group represented by SO ₂ R ⁸ (R ⁸ has the same meaning as described above), and other symbols have the same meanings as described above. In this method, compound (I-6) is produced by reacting compound (III-1) with compound (VIII).

This reaction is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction.

As the base, for example, alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, hydroxide Alkaline earth metal salts such as calcium; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; potassium hydride, sodium hydride and the like Metal hydrides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide and the like.

The amount of these bases to be used is as defined in Compound (III-
It is preferably about 1 to about 5 molar equivalents based on 1).

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone; Halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is generally about 0.5 to about 20 hours.

Compound (I-6) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), Y is an esterified carboxyl group, and W is —CH ＝ CH— or — (C
The compound [Compound (I-9) or (I-10), respectively] which is H ₂ ) ₂ — can also be produced by the following Method G. [Method G]

[0288]

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[The symbols in the formula are as defined above. (Step 1) Reduction Reaction This reaction is performed in a conventional manner in the presence of a reducing agent in a solvent that does not affect the reaction.

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, borane and a complex thereof (eg, borane). -Tetrahydrofuran, pyridineborane, borane-dimethylsulfide, etc.).

The amount of the reducing agent to be used is preferably about 0.5 to about 10 molar equivalents relative to compound (I-7).

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; tetrahydrofuran, dioxane, and the like.
Ethers such as diethyl ether; water, methanol,
Examples include alcohols such as ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is generally about 0.5 to about 20 hours.

Compound (I-8) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-7) used as a starting material compound in Step 1 of the above-mentioned Method G may be, for example, a compound of the journal of heterocyclic chemistry (Journal).
nal of Heterocyclic Chemistry), 28, 453 (1991); Journal of Organic Chemistry, 49
4419 (1984); Tetrahedron Letters, 34, 485 (199)
3 years) or a method similar thereto.

(Step 2) Oxidation reaction This reaction is carried out according to a conventional method in the presence of an oxidizing agent in a solvent that does not affect the reaction.

Examples of the oxidizing agent include manganese dioxide,
Metal oxidizing agents such as pyridinium chlorochromate, pyridinium dichromate, and ruthenium oxide are exemplified.

The amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound (I-8).

Solvents which do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. And the like.
These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is generally about 0.5 to about 20 hours.

Compound (IV) can be prepared by adding compound (I-8) to a sulfur trioxide pyridine complex or oxalyl chloride in a mixed solvent of a sulfoxide such as dimethyl sulfoxide and a halogenated hydrocarbon such as chloroform and dichloromethane. The reaction can be also carried out by adding a reaction reagent such as above and further reacting with an organic base such as triethylamine or N-methylmorpholine.

The amount of the reaction reagent to be used is preferably about 1 to about 10 molar equivalents relative to compound (I-8).

The amount of the organic base to be used is preferably about 1 to about 10 molar equivalents relative to compound (I-8).

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

The compound (IV) thus obtained is
Isolation and purification can be performed by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 3) Carbon Increase Reaction In this reaction, an organic phosphorus reagent and a compound (IV) are added in the presence of a base.
To produce compound (I-9).

This method is carried out in a conventional manner in the presence of a base in a solvent that does not affect the reaction.

Examples of the organic phosphorus reagent include methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, and ethyl dimethylphosphonoacetate.

The amount of the organic phosphorus reagent to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).

Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like; barium carbonate, calcium carbonate,
Alkaline earth metal salts such as barium hydroxide and calcium hydroxide; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; hydrogenation Metal hydrides such as potassium and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide.

The amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (IV).

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. Amides such as N, N-dimethylformamide; and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

Compound (I-9) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 4) Hydrogenation reaction This method is carried out in a conventional manner under a hydrogen atmosphere or a hydrogen source such as formic acid and a metal catalyst in a solvent that does not affect the reaction.

Examples of the metal catalyst include transition metal catalysts such as palladium-carbon, palladium-barium carbonate, palladium black, platinum oxide, platinum-carbon, Raney nickel, Wilkinson catalyst and the like.

The amount of the transition metal catalyst to be used is preferably about 0.01 to about 10 molar equivalents relative to compound (I-9).

Solvents which do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. Amides such as N, N-dimethylformamide; alcohols such as methanol, ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

The compound thus obtained (I-1)
0) is a known separation and purification means, for example, concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), the compound (I-11) wherein Y is a carboxyl group and W is-(CH ₂ ) ₂ -is
It is also manufactured by the following H method. [Method H]

[0327]

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[The symbols in the formula are as defined above. (Step 1) Carburization Reaction In this method, compound (V) is produced by subjecting compound (III-2) to a two-carbon carburization reaction using malonic acid diester.

This reaction is carried out according to a conventional method in the presence of a malonic acid diester and a base in a solvent that does not adversely influence the reaction.

Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide;
Alkaline earth metal salts such as calcium hydroxide; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Amines such as ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t.-butoxide.

Examples of the malonate diester include diethyl malonate, dimethyl malonate, dipropyl malonate, dibutyl malonate and the like.

The amount of the base and malonic diester used is preferably about 1 to about compound (III-2).
About 5 molar equivalents.

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -50 to about 150
° C, preferably about -10 to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

The compound (V) thus obtained is
Isolation and purification can be performed by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 2) Decarboxylation reaction In this method, compound (I-11) is produced by subjecting compound (V) to a decarboxylation reaction.

The present decarboxylation reaction is carried out under an acidic condition or a basic condition according to a conventional method.

When the reaction is carried out under acidic conditions, this method is carried out in a conventional manner in a solvent that does not affect the reaction.

As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like can be mentioned.

The amount of the acid to be used is generally an excess amount relative to compound (V). Preferably, the amount is about 2 to about 50 equivalents relative to compound (V).

The solvent which does not affect the reaction includes
For example, a mixed solvent of water and one or more solvents selected from alcohols such as methanol and ethanol; ketones such as acetone and 2-butanone. Also,
Excess acid may be used as the solvent.

When the reaction is carried out under basic conditions, the compound (V) is converted into a dicarboxylic acid by hydrolysis and then thermally decomposed to produce a compound (I-11) according to a conventional method.

The hydrolysis reaction is carried out in the presence of a base according to a conventional method in a water-containing solvent which does not affect the reaction.

Examples of the base include alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate; and alkali metals such as barium carbonate, calcium carbonate, barium hydroxide and calcium hydroxide. Earth metal salts; and alkali metal alkoxides such as sodium methoxide.

The amount of the base to be used is generally an excess amount relative to compound (V). Preferably, for compound (V),
From about 2.5 to about 20 equivalents.

Examples of the water-containing solvent that does not affect the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; one or more solvents selected from dimethyl sulfoxide and acetone. Examples thereof include a mixed solvent with water.

The reaction temperature is usually about -20 to about 150.
° C, preferably about -10 to about 100 ° C.

The reaction time is generally about 0.1 to about 20 hours.

This thermal decomposition reaction is carried out according to a conventional method in a solvent that does not affect the reaction.

Solvents which do not affect the reaction include:
For example, pyridine, quinoline, collidine and the like can be mentioned.

The reaction temperature is usually about -20 to about 250
° C, preferably from about 50 to about 200 ° C.

The reaction time is usually about 0.1 to about 20 hours.

The compound thus obtained (I-1)
1) is a known separation and purification means, for example, concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Of the compounds (III-1) used as starting compounds in Method F, those wherein E is a halogen atom or a group represented by the formula: —OSO ₂ R ⁸ (R ⁸ has the same meaning as described above) Can be produced, for example, by the following Method I. Compound (III-1) is compound (III-2) used as a starting compound in Method H
including. [Method I]

[0356]

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[Wherein the symbols have the same meanings as described above. Compound (III-1) wherein E is a halogen atom is produced, for example, by reacting compound (I-4) with a halogenating agent.

This method is carried out according to a conventional method, in the presence of a halogenating agent, in a solvent that does not affect the reaction.

Examples of the halogenating agent include thionyl chloride and phosphorus tribromide.

The amount of the halogenating agent to be used may be the same as that of the compound (I-
It is preferably about 1 to about 20 molar equivalents with respect to 4).

Examples of the solvent which does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane. And the like.
These solvents may be mixed and used at an appropriate ratio.
Further, an excess halogenating agent may be used as a solvent.

The reaction temperature is usually about -20 to about 150
° C, preferably from about 0 to about 100 ° C.

The reaction time is usually about 0.1 to about 20 hours.

Compound (III-1) wherein E is a group represented by the formula: —OSO ₂ R ⁸ (R ⁸ is as defined above)
Is produced, for example, by reacting compound (I-4) with a sulfonylating agent in the presence of a suitable base.

This method is carried out according to a conventional method, in the presence of a sulfonylating agent, in a solvent that does not affect the reaction.

Examples of the sulfonylating agent include mesyl chloride, tosyl chloride, benzenesulfonyl chloride and the like. In this case, a compound (I-1) in which E is mesyloxy, tosyloxy and benzenesulfonyloxy, respectively, is produced.

The amounts of the sulfonylating agent and the base to be used are preferably about 1 to about 2 molar equivalents relative to compound (I-4).

Solvents which do not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; N, N-dimethylformamide, N, N Amides such as dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; ethyl acetate, acetone and the like. These solvents may be mixed and used at an appropriate ratio.

The reaction temperature is usually about -20 to about 150
° C, preferably from about 0 to about 100 ° C.

The reaction time is usually about 0.1 to about 20 hours.

The compound (III-
1) is a known separation and purification means, for example, concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In each of the above reactions, when the starting compound has amino, carboxy, hydroxy, or carbonyl as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. After the reaction, the desired compound can be obtained by removing the protecting group as necessary.

Examples of the amino-protecting group include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.) and C _1-6 alkoxy-carbonyl (eg,
Methoxycarbonyl, ethoxycarbonyl, tert-
Butoxycarbonyl, benzoyl, C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl), C
_7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert) - butyldimethylsilyl, tert- butyldiethylsilyl, etc.), C _2-6 alkenyl (e.g., 1-allyl) and the like. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.)
Or it may be substituted by nitro or the like.

As the protecting group for carboxy, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C _7-13 aralkyl (eg, benzyl, etc.), phenyl, trityl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenyl) Silyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), _C2-6 alkenyl (eg, 1-allyl, etc.) and the like. These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro. .

Examples of the hydroxy protecting group include, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl,
Trityl, C _7-13 aralkyl (eg, benzyl, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl,
Propionyl, etc.), benzoyl, C _7-13 aralkyl-
Carbonyl (eg, benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, t
ert- butyldiethylsilyl, etc.), C _2-6 alkenyl (e.g., 1-allyl) and the like. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.), C _1-6 alkoxy (eg,
Methoxy, ethoxy, propoxy, etc.) or nitro.

Examples of the carbonyl protecting group include a cyclic acetal (eg, 1,3-dioxane) and an acyclic acetal (eg, di-C _1-6 alkyl acetal).
And the like.

[0377] These protective groups can be removed by a method known per se, for example, Protective Groups in Organic Synthesis.
Organic Synthesis), published by John Wiley and Sons (19
80), and the like. For example,
Acid, base, ultraviolet light, hydrazine, phenylhydrazine,
Sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide,
Trimethylsilyl bromide, etc.)
A reduction method or the like is used.

In each of the above reactions, when the starting compound can form a salt, the compound may be used as a salt. As such salts, for example, those exemplified as the salt of compound (I) are used.

When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotamers, these are also included as compound (I), as well as synthetic methods and separation methods known per se. Each can be obtained as a single item by the method. For example, when the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I).

The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.

As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used.

1) Fractional recrystallization method Racemic and optically active compounds (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
A salt with phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.), separating the salt by a fractional recrystallization method, and optionally obtaining a free optical isomer through a neutralization step.

2) Chiral column method A method of separating a racemate or a salt thereof by applying it to a column for separating optical isomers (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh) or CHIRAL series manufactured by Daicel,
Optical isomers can be developed by developing a solution of water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixture. Is separated. For example, in the case of gas chromatography, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences).

3) Diastereomer Method The mixture of the racemate is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and the mixture is subjected to ordinary separation means (eg, fractional recrystallization, chromatography, etc.). A method of obtaining an optical isomer by separating an optically active reagent site by a chemical treatment such as a hydrolysis reaction after forming a single substance. For example, when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]),
(-)-Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound is subjected to a condensation reaction with an optically active amine or an alcohol reagent to obtain an amide or ester diastereomer, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

The present invention further relates to a glucose-dependent insulin secretagogue comprising an isoxazole derivative.

The isoxazole derivative is not particularly limited as long as it is a compound having an isoxazole skeleton. Examples of the isoxazole derivative include a compound having a group represented by the formula: -W-Y (W and Y have the same meanings as described above) at the 4-position of the isoxazole skeleton.

The isoxazole derivative is preferably compound (I) or a salt thereof or a prodrug thereof, and more preferably compound (II) or a salt thereof or a prodrug thereof.

A glucose-dependent insulin secretagogue is defined as having a fasting blood glucose level of 126 mg / dl or more or a 75 g oral glucose tolerance test (75 g OGTT) and a 2-hour value of 140 mg / dl or more in the presence of high-concentration glucose. Patients, etc.) and selectively exert an insulin secretion promoting action. Therefore, the glucose-dependent insulin secretagogue of the present invention is useful as a safe and preventive or therapeutic agent for diabetes, which has a low risk of vascular complications and hypoglycemia induction, which are the adverse effects of insulin.

[0389] The glucose-dependent insulin secretagogue of the present invention can be produced in the same manner as in the above-mentioned pharmaceutical composition. , Pigs, monkeys, etc.).

The dose and administration method of the glucose-dependent insulin secretagogue of the present invention are the same as those of the compound of the present invention described above. Furthermore, the glucose-dependent insulin secretagogue of the present invention can be used in combination with the above-mentioned concomitant drug.

Hereinafter, the present invention will be described in more detail with reference to Test Examples, Reference Examples, Examples and Formulation Examples, but the present invention is not limited thereto.

[0392]

EXAMPLES In the following Reference Examples and Examples,
% Indicates weight percent unless otherwise specified. Further, the room temperature indicates a temperature of 1 to 30 ° C.

In Examples, HPLC was measured under the following conditions. Measuring instrument: Shimadzu LC-10Avp system Column: CAPSEL PAK C18UG120 S-3 μm, 2.0 X 50
mm Solvent: Liquid A; water containing 0.1% trifluoroacetic acid, B
Solution; acetonitrile containing 0.1% trifluoroacetic acid Gradient cycle: 0.00 min (solution A / solution B = 90/10), 4.
00 minutes (A / B solution = 5/95), 5.50 minutes (A / B solution = 5/95), 5.5
1 minute (solution A / B = 90/10), 8.00 minutes (solution A / B = 90/10) Injection volume: 2 μl, flow rate: 0.5 ml / min, detection method: UV 220
nm In Examples, the mass spectrum (MS) was measured under the following conditions. Measurement equipment: Micromass Platform II, Waters ZQ, or Waters ZMD Ionization: Atmospheric pressure chemical ionization (Atmospheric Pre-
ssure Chemical Ionization (APCI) or electron impact ionization (Electron
Spray Ionization: ESI) Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep ODS-A S-5 μm, 50 × 20
mmm solvent: solution A; water containing 0.1% trifluoroacetic acid, B
Solution; acetonitrile containing 0.1% trifluoroacetic acid Gradient cycle: 0.00 min (solution A / solution B = 90/10), 1.
20 minutes (Solution A / B = 90/10), 4.75 minutes (Solution A / B = 0/100),
7.30 minutes (A / B solution = 0/100), 7.40 minutes (A / B solution = 90/1)
0), 7.50 min (A / B solution = 90/10) Flow rate: 25 ml / min, Detection method: UV 220nm

Test Example 1 Hypoglycemic Action in Rats Male SD rats (7 weeks old, 5 rats per group) were fasted overnight, and blood was collected from the tail vein to measure the blood sugar level before administration of the test compound. The test compound suspended in 0.5% methylcellulose (30 mg / kg body weight / 10 mL (Examples 8, 1
6, 66, 68, 79, 94, 123) or 50 mg / kg body weight / 10 mL (compounds of Examples 58 and 70)) were orally administered using a gastric tube, and 60 minutes later, an oral glucose tolerance (2 g) was obtained. / kg body weight / 10 mL). Blood was collected 30 minutes after the glucose load, and the blood glucose level was measured. The blood glucose level was measured using an automatic measuring device (Hitachi 7070). The blood glucose level of the test compound group was expressed as a relative value (%) to the control group, and is shown in [Table 1].

[0395]

[Table 1]

As described above, the compound of the present invention has an excellent blood glucose (blood glucose) lowering effect, and is therefore useful as a preventive / therapeutic agent for diabetes.

Test Example 2 Insulin Secretion-Promoting Activity in Rat Pancreatic Islet of Pancreas The pancreas of an 8-week-old male SD rat was treated with collagenase, and isolated in a 24-well culture plate at 2.8 mmol / ml.
After preincubation for 1 hour in a medium containing L glucose (KRB), KRB containing 100 μmol / L test compound (see Table 2) and 7.5 mmol / L glucose (the control group does not contain the test compound) Incubated for 1 hour. The medium was collected, and the amount of secreted insulin was measured using a radioimmunoassay kit (trade name: Shionoria Insulin Kit (manufactured by Shionogi & Co., Ltd.)). Lajishima measured the amount of DNA after sonication, and corrected the insulin level in the medium according to the measured value. The insulin secretion amount of the test compound group was expressed as a relative value (%) to the control group, and is shown in [Table 2].

[0398]

[Table 2]

As described above, the compound of the present invention has an excellent insulin secretion promoting action, and thus is useful as an agent for preventing and treating diabetes.

Reference Example 1 4'-trifluoromethoxyacetophenone (6.30)
g), sodium hydride (60%, oily, 1.22 g)
And a mixture of diethyl carbonate (70 ml) at 80 ° C. for 1 hour.
Stir for hours. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (5.54 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (120 ml). To the obtained solution, hydroxylamine hydrochloride (4.29 g) was added, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
From the eluted part (volume ratio), ethyl 5- (4-trifluoromethoxyphenyl) isoxazole-4-carboxylate (6.60 g, yield 71%) was obtained as a yellow oil.
NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.0 Hz), 4.36 (2H, q, J
= 7.0 Hz), 7.35 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8
Hz), 8.64 (1H, s). Reference Example 2 In a solution of ethyl 5- (4-trifluoromethoxyphenyl) isoxazole-4-carboxylate (6.60 g) in tetrahydrofuran (80 ml), diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 55
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
gSO ₄ ), concentrate, and add 5- (4-trifluoromethoxyphenyl) -4-isoxazolyl methanol (5.
(70 g, yield 99%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 45-46 ° C.

Reference Example 3 4'-trifluoromethylacetophenone (10.0
g), sodium hydride (60%, oily, 2.13 g)
And diethyl carbonate (80 ml) at 80 ° C. for 9 hours.
Stir for 0 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3 parts were eluted with ethyl acetate-hexane (1: 9, volume ratio).
Ethyl-oxo-3- (4-trifluoromethylphenyl) propionate was obtained as an oil. A mixture of this oil and N, N-dimethylformamide dimethyl acetal (9.50 g) was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). The resulting solution was added with hydroxylamine hydrochloride (7.3).
9 g) was added and the mixture was refluxed for 2 hours. Concentrate the reaction mixture,
Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 9, volume ratio) eluate were recrystallized from hexane to give 5- (4
-Trifluoromethylphenyl) isoxazole-4
-Ethyl carboxylate (8.42 g, yield 56%) was obtained as colorless prism crystals. 53-54 ° C. Reference Example 4 N-methoxy-N-methylamine hydrochloride (9.28
g), triethylamine (14 ml) and N, N-dimethylformamide (500 ml) at room temperature for 3 hours.
After stirring for 0 minutes, 5-phenylisoxazole-
4-carboxylic acid (14.95 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (14.
08g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18.00g) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N-methoxy-N-methyl- (5-phenyl-4-isoxazolyl) carbamide (13.9) was eluted with ethyl acetate-hexane (1: 4, volume ratio).
(5 g, yield 76%) as a colorless oil. NMR (CDCl
₃ ) δ: 3.36 (3H, s), 3,57 (3H, s), 7.44-7.56 (3H, m),
7.86-7.98 (2H, m), 8.52 (1H, s).

Reference Example 5 A solution of N-methoxy-N-methyl- (5-phenyl-4-isoxazolyl) carbamide (13.01 g) in tetrahydrofuran (200 ml) was charged with diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 1 ml).
20 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5-phenylisoxazole-4-carbaldehyde (8.54 g, yield 88) was eluted with ethyl acetate-hexane (1: 4, volume ratio).
%) As a colorless oil. NMR (CDCl ₃ ) δ: 7.53-7.6
6 (3H, m), 7.87-7.96 (2H, m), 8.72 (1H, s), 10.10 (1H,
s). Reference Example 6 Methyl 4'-fluorobenzoylacetate (10.02 g)
And a mixture of N, N-dimethylformamide dimethyl acetal (8.63 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was ethanol (150 ml).
Was dissolved. Hydroxylamine hydrochloride (6.75 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4,
From the eluted part (volume ratio), methyl 5- (4-fluorophenyl) isoxazole-4-carboxylate (9.75 g, yield 91%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 92-93 ° C.

Reference Example 7 5- (4-fluorophenyl) isoxazole-4-
To a solution of methyl carboxylate (7.06 g) in tetrahydrofuran (50 ml) was added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0 ° C.
, And stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (4-fluorophenyl) -4-isoxazolylmethanol (6.35 g, yield 90%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 41-42 ° C. Reference Example 8 3 ', 4'-Difluoroacetophenone (10.27
g), sodium hydride (60%, oily, 2.60 g)
And a mixture of diethyl carbonate (150 ml) at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (11.80 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml). To the obtained solution, hydroxylamine hydrochloride (9.18 g) was added, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
Volume ratio) Ethyl 5- (3,4-difluorophenyl) isoxazole-4-carboxylate (11.
(60 g, yield 70%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 64-65 ° C.

Reference Example 9 In a solution of ethyl 5- (3,4-difluorophenyl) isoxazole-4-carboxylate (6.68 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 75 ml).
1) was added slowly at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
SO ₄ ), and then concentrated.
(92% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 72-73 ° C. Reference Example 10 A mixture of 4′-bromoacetophenone (9.00 g), sodium hydride (60%, oily, 1.80 g) and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (8.10 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (150 ml). To the obtained solution, hydroxylamine hydrochloride (6.33 g) was added, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the eluate of ethyl acetate-hexane (1: 9, volume ratio)
Ethyl-(4-bromophenyl) isoxazole-4-carboxylate (10.17 g, yield 76%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 47-48 [deg.] C.

Reference Example 11 To a solution of ethyl 5- (4-bromophenyl) isoxazole-4-carboxylate (9.50 g) in tetrahydrofuran (70 ml) was added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) in 0 ml. ° C
, And stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Thereafter, the mixture was concentrated to give 5- (4-bromophenyl) -4-isoxazolylmethanol (8.03 g, yield 98%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 104-105 ° C. Reference Example 12 A mixture of ethyl 4'-nitrobenzoyl acetate (10.61 g) and N, N-dimethylformamide dimethyl acetal (8.06 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml). To the obtained solution, hydroxylamine hydrochloride (6.33 g) was added, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4,
From the eluted part (volume ratio), ethyl 5- (4-nitrophenyl) isoxazole-4-carboxylate (9.78 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 78-79 [deg.] C.

Reference Example 13 To a solution of ethyl 5- (4-nitrophenyl) isoxazole-4-carboxylate (9.06 g) in tetrahydrofuran (50 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 80 ml). ° C
, And stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (4-nitrophenyl) -4-isoxazolylmethanol (7.16 g, yield 94%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 170-171 ° C. Reference Example 14 A mixture of 3′-chloroacetophenone (7.00 g), sodium hydride (60%, oily, 1.80 g) and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (8.15 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). Hydroxylamine hydrochloride (6.30 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the eluate of ethyl acetate-hexane (1: 9, volume ratio)
Ethyl- (3-chlorophenyl) isoxazole-4-carboxylate (9.13 g, yield 80%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 77-78 ° C.

Reference Example 15 To a solution of ethyl 5- (3-chlorophenyl) isoxazole-4-carboxylate (8.50 g) in tetrahydrofuran (80 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 80 ml) at 0 ° C.
, And stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (3-chlorophenyl) -4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 80-81 ° C. Reference Example 16 5-acetyl-1,3-benzodioxole (7.45
g), sodium hydride (60%, oily, 1.80 g)
And a mixture of diethyl carbonate (100 ml) at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (8.30 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). To the obtained solution, hydroxylamine hydrochloride (6.33 g) was added, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
From the eluted part (volume ratio), ethyl 5- (1,3-benzodioxol-5-yl) isoxazole-4-carboxylate (9.49 g, yield 80%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 73-74 melting point
° C.

Reference Example 17 In a solution of ethyl 5- (1,3-benzodioxol-5-yl) isoxazole-4-carboxylate (8.56 g) in tetrahydrofuran (70 ml), diisobutylaluminum hydride (1. 0 M tetrahydrofuran solution,
(70 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated to 5- (1,3-benzodioxol-5-yl) -4-isoxazolyl methanol (6.97 g, (97% yield) as colorless crystals.
Recrystallized from ethyl acetate-hexane. Melting point 92-93
° C. Reference Example 18 3'-chloro-4'-fluoroacetophenone (9.54
g), sodium hydride (60%, oily, 2.15 g)
And a mixture of diethyl carbonate (100 ml) at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (9.63 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). Hydroxylamine hydrochloride (7.47 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
Volume ratio) From the elution part, ethyl 5- (3-chloro-4-fluorophenyl) isoxazole-4-carboxylate (1
0.33 g, yield 71%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 106-107
° C.

Reference Example 19 To a solution of ethyl 5- (3-chloro-4-fluorophenyl) isoxazole-4-carboxylate (9.50 g) in tetrahydrofuran (75 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 75
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
gSO ₄ ), then concentrate and concentrate on 5- (3-chloro-4-fluorophenyl) -4-isoxazolylmethanol (7.
(58 g, yield 95%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 106-107 ° C. Reference Example 20 3 ', 4'-dimethoxyacetophenone (9.20 g),
A mixture of sodium hydride (60%, oily, 1.99 g) and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. Residue and N, N-
Dimethylformamide dimethyl acetal (8.95
The mixture of g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). To the resulting solution was added hydroxylamine hydrochloride (6.98 g).
Was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (3,4-dimethoxyphenyl) isoxazole-4-carboxylate (10.81 g, yield) was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). Rate 78
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 113-114 ° C.

Reference Example 21 In a solution of ethyl 5- (3,4-dimethoxyphenyl) isoxazole-4-carboxylate (8.40 g) in tetrahydrofuran (100 ml), diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 m
1) was added slowly at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
(SO ₄ ), and concentrated.
(96% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 83-84 ° C. Reference Example 22 4'-chloro-3'-fluoroacetophenone (12.5
0g), sodium hydride (60%, oily, 2.88)
g) and diethyl carbonate (150 ml)
Stirred at ℃ for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (12.99 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was ethanol (150 ml).
Was dissolved. Hydroxylamine hydrochloride (10.10 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
From the eluted part, ethyl 5- (4-chloro-3-fluorophenyl) isoxazole-4-carboxylate (1
(4.86 g, yield 76%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Mp 76-77 ° C.

Reference Example 23 In a solution of ethyl 5- (4-chloro-3-fluorophenyl) isoxazole-4-carboxylate (12.00 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran,
100 ml) at 0 ° C. slowly and then at room temperature for 30 minutes.
Stir for a minute. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated, and then concentrated to give 5- (4-chloro-3-
Fluorophenyl) -4-isoxazolylmethanol (9.73 g, 96% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 87-88
° C. Reference Example 24 A mixture of 4′-methoxyacetophenone (7.52 g), sodium hydride (60%, oily, 2.00 g) and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (8.93 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). Hydroxylamine hydrochloride (6.97 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the eluate of ethyl acetate-hexane (1: 9, volume ratio)
Ethyl-(4-methoxyphenyl) isoxazole-4-carboxylate (9.48 g, yield 77%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 54-55 ° C.

Reference Example 25 5- (4-methoxyphenyl) isoxazole-4-
To a solution of ethyl carboxylate (8.56 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 80 ml) in 0 ml.
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (4-methoxyphenyl) -4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 57-58 ° C. Reference Example 26 3'-bromo-4'-fluoroacetophenone (12.4
6g), sodium hydride (60%, oily, 2.30)
g) and diethyl carbonate (100 ml)
Stirred at ℃ for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (10.29 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was ethanol (150 ml).
Was dissolved. Hydroxylamine hydrochloride (12.06 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
Ethyl 5- (3-bromo-4-fluorophenyl) isoxazole-4-carboxylate (1
(3.55 g, yield: 75%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 111-112
° C.

Reference Example 27 5- (3-bromo-4-fluorophenyl) isoxa
Tet of ethyl sol-4-carboxylate (10.01 g)
In a solution of lahydrofuran (70 ml), add
Aluminum (1.0 M tetrahydrofuran solution, 7
0 ml) slowly at 0 ° C. and then at room temperature for 30 minutes
Stirred. Pour the reaction mixture into diluted hydrochloric acid and add ethyl acetate.
Extracted. The ethyl acetate layer is washed with saturated saline and dried
(MgSO _Four), And then concentrated to give 5- (3-bromo-4-f
Fluorophenyl) -4-isoxazolyl methanol
(8.26 g, yield 95%) as colorless crystals. vinegar
It was recrystallized from ethyl acetate-hexane. 134-13 melting point
5 ° C. Reference Example 28 3'-bromo-4'-chloroacetophenone (6.27
g), sodium hydride (60%, oily, 1.06 g)
And a mixture of diethyl carbonate (90 ml) at 80 ° C. for 1 hour.
Stir for hours. Water is added to the reaction mixture, and the aqueous layer is diluted with diluted hydrochloric acid.
After stirring for 30 minutes at room temperature, followed by acetic acid.
Extracted with ethyl. Wash the ethyl acetate layer with saturated saline
Purification, drying (MgSO_Four) And concentrated. Residue and
N, N-dimethylformamide dimethyl acetal
(4.84 g) was refluxed for 1.5 hours. Reaction mixture
The mixture was concentrated, and the residue was dissolved in ethanol (100 ml).
I understand. To the resulting solution, add hydroxylamine hydrochloride.
(3.75 g) was added and the mixture was refluxed for 5 hours. The reaction mixture
Concentrate, add diluted hydrochloric acid to the residue, extract with ethyl acetate.
Was. The ethyl acetate layer was washed with saturated saline and dried (MgS
O_Four) And concentrated. The residue is purified by silica gel column chromatography.
The mixture was subjected to chromatography, and ethyl acetate-hexane (1: 9,
(Volume ratio) From the elution part, 5- (3-bromo-4-chlorophene)
Ethyl) isoxazole-4-carboxylate (6.
(25 g, yield 70%) as colorless crystals. Diethyl
Recrystallized from ether-hexane. Melting point 109-11
0 ° C.

Reference Example 29 To a solution of ethyl 5- (3-bromo-4-chlorophenyl) isoxazole-4-carboxylate (6.19 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 40 ml).
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
gSO ₄ ), then concentrate and concentrate on 5- (3-bromo-4-chlorophenyl) -4-isoxazolylmethanol (5.1
0 g, 94% yield) as a colorless oil. NMR (CDCl
₃ ) δ: 4.73 (2H, d, J = 4.8 Hz), 7.59 (1H, d, J = 8.4 H
z), 7.72 (1H, dd, J = 2.2, 8.4 Hz), 8.10 (1H, d, J = 2.2
Hz), 8.37 (1H, s). Reference Example 30 A solution of 3- (5-phenyl-4-isoxazolyl) propan-1-ol (15.00 g) and triethylamine (21.0 ml) in ethyl acetate (500 ml) was prepared.
After methanesulfonyl chloride (9.0 ml) was slowly added at 0 ° C., the mixture was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue, sodium cyanide (7.33 g), sodium iodide (13.48 g) and N, N-dimethylformamide (150 ml) was stirred at 70 ° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
From the eluted part, 4- (5-phenyl-4-isoxazolyl) butyronitrile (13.47 g, yield 86)
%) As a colorless oil. NMR (CDCl ₃₎ δ: 1.91-2.0
9 (2H, m), 2.36-2.46 (2H, m), 2.78-2.94 (2H, m), 7.44
-7.58 (3H, m), 7.64-7.74 (2H, m), 8.22 (1H, s).

Reference Example 31 2 ′, 4′-Dichloroacetophenone (17.01 g)
A mixture of sodium hydride (60%, oily, 3.58 g) and diethyl carbonate (200 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. Residue and N, N-
Dimethylformamide dimethyl acetal (16.2
The mixture of 3 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml).
To the resulting solution was added hydroxylamine hydrochloride (12.53
g) was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (2,4-dichlorophenyl) isoxazole-4-carboxylate (17.51 g, yield) was eluted with ethyl acetate-hexane (1: 9, volume ratio). 68
%) As a pale yellow oil. NMR (CDCl ₃ ) δ: 1.24 (3
H, t, J = 7.0 Hz), 4.25 (2H, q, J = 7.0 Hz), 7.39 (1H, d
d, J = 1.8, 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.56 (1H,
d, J = 1.8 Hz), 8.67 (1H, s). Reference Example 32 5- (2,4-dichlorophenyl) isoxazole-
Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 ml) was slowly added to a solution of ethyl 4-carboxylate (8.60 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated to give 5- (2,4-dichlorophenyl)-
4-isoxazolyl methanol (7.09 g, yield 9)
6%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Mp 76-77 ° C.

Reference Example 33 A mixture of 3 ′, 4′-dichloroacetophenone (8.64 g), sodium hydride (60%, oily, 1.83 g) and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue and N, N-dimethylformamide dimethyl acetal (8.15
The mixture of g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (100 ml). To the resulting solution was added hydroxylamine hydrochloride (6.51 g).
Was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (3,4-dichlorophenyl) isoxazole-4-carboxylate (10.33 g, yield) was eluted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). 79%)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 117-118 ° C. Reference Example 34 5- (3,4-dichlorophenyl) isoxazole-
Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 ml) was slowly added to a solution of ethyl 4-carboxylate (8.60 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
O ₄ ), after which it was concentrated and 5- (3,4-dichlorophenyl)-
4-isoxazolyl methanol (6.97 g, yield 9)
5%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 101-102 [deg.] C.

Reference Example 35 3 ′, 5′-Dichloroacetophenone (12.80 g),
A mixture of sodium hydride (60%, oily, 2.71 g) and diethyl carbonate (150 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. Residue and N, N-
Dimethylformamide dimethyl acetal (12.1
The mixture of 8 g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml).
To the resulting solution was added hydroxylamine hydrochloride (9.49).
g) was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (3,5-dichlorophenyl) isoxazole-4-carboxylate (12.48 g, yield) was eluted with ethyl acetate-hexane (1: 9, volume ratio). 64
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 50-51 [deg.] C. Reference Example 36 5- (3,5-dichlorophenyl) isoxazole-
To a solution of ethyl 4-carboxylate (10.82 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 100 ml).
1) was added slowly at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
SO ₄ ), and then concentrated to give 5- (3,5-dichlorophenyl)
4-Isoxazolyl methanol (10.28 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 104-105 ° C.

Reference Example 37 A mixture of 4′-phenylacetophenone (10.00 g), sodium hydride (60%, oily, 1.96 g) and diethyl carbonate (150 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue and N, N-dimethylformamide dimethyl acetal (8.89
The mixture of g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml). To the resulting solution was added hydroxylamine hydrochloride (6.88 g).
Was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5- (4-phenylphenyl) isoxazole-4 was extracted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio).
-Ethyl carboxylate (10.98 g, yield 76%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 73-75 ° C. Reference Example 38 5- (4-phenylphenyl) isoxazole-4-
To a solution of ethyl carboxylate (10.68 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 83.7 m).
1) was added slowly at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
SO ₄ ), and then concentrated to give 5- (4-phenylphenyl)-
4-isoxazolyl methanol (7.55 g, yield 8)
3%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 108-110 ° C.

Reference Example 39 A solution of pyrrolidine (6.4 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (7.50 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. A solution of 3,4-dichloro-N-hydroxybenzenecarboximidoyl chloride (11.40 g) in tetrahydrofuran (100 ml) was added to the resulting mixture at 0 ° C., and then triethylamine (15 ml) in tetrahydrofuran (10 m
l) The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
Ethyl 3- (3,4-dichlorophenyl) isoxazole-4-carboxylate (12.9, volume ratio)
(26 g, yield: 84%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 129-130 ° C. Reference Example 40 3- (3,4-dichlorophenyl) isoxazole-
Diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 60 ml) was slowly added to a solution of ethyl 4-carboxylate (7.80 g) in tetrahydrofuran (60 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
O ₄ ), and then concentrated to give 3- (3,4-dichlorophenyl)
-4-Isoxazolyl methanol (6.43 g, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 103-104 ° C.

Reference Example 41 A solution of pyrrolidine (6.4 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (7.51 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. A solution of 3-chloro-4-fluoro-N-hydroxybenzenecarboximidoyl chloride (10.20 g) in tetrahydrofuran (100 ml) was added to the obtained mixture at 0 ° C., and then triethylamine (15 ml) in tetrahydrofuran (10 ml) was added. ) The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted from 3- (3-chloro-4).
Ethyl- (fluorophenyl) isoxazole-4-carboxylate (10.93 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 1
08-109 ° C. Reference Example 42 Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) was added to a solution of ethyl 3- (3-chloro-4-fluorophenyl) isoxazole-4-carboxylate (9.70 g) in tetrahydrofuran (50 ml).
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
gSO ₄ ), then concentrate and concentrate on 3- (3-chloro-4-fluorophenyl) -4-isoxazolylmethanol (7.
91 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 87-88 ° C.

Reference Example 43 A solution of pyrrolidine (7.4 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (8.61 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. A solution of 4-chloro-3-fluoro-N-hydroxybenzenecarboximidoyl chloride (11.70 g) in tetrahydrofuran (100 ml) was added to the obtained mixture at 0 ° C., and then triethylamine (16 ml) in tetrahydrofuran (10 ml) was added. ) The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and 3- (4-chloro-3) was eluted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio).
Ethyl- (fluorophenyl) isoxazole-4-carboxylate (12.63 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 7
7-78 ° C. Reference Example 44 In a solution of ethyl 3- (4-chloro-3-fluorophenyl) isoxazole-4-carboxylate (12.00 g) in tetrahydrofuran (100 ml), diisobutylaluminum hydride (1.0 M tetrahydrofuran solution,
100 ml) at 0 ° C. slowly and then at room temperature for 30 minutes.
Stir for a minute. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated, and then concentrated to give 3- (4-chloro-3-
Fluorophenyl) -4-isoxazolylmethanol (9.75 g, 96% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 124-12
5 ° C.

Reference Example 45 A solution of pyrrolidine (5.2 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. To the obtained mixture, a solution of 3-bromo-4-fluoro-N-hydroxybenzenecarboximidoyl chloride (10.10 g) in tetrahydrofuran (100 ml) was added at 0 ° C., and then triethylamine (11.5 ml) in tetrahydrofuran was added. (10 ml) solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- (3-bromo-4-fluorophenyl) isoxazole-4-carboxylate (13.96 g) was eluted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). , Yield 71%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 96-97 ° C. Reference Example 46 A solution of diisobutylaluminum hydride (1.0 M tetrahydrofuran solution,
(75 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated, and then 3- (3-bromo-4-fluorophenyl) -4-isoxazolylmethanol (9.75 g, yield 96%). ) Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 93-94
° C.

Reference Example 47 N-methoxy-N-methylamine hydrochloride (4.53
g), triethylamine (7.0 ml) and N, N-
A mixture of dimethylformamide (15 ml) was added at room temperature for 3 hours.
After stirring for 0 minutes, 3-methyl-5-phenylisoxazole-4-carboxylic acid (8.26 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (6.58 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.33 g)
And stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer contains diluted hydrochloric acid,
Washed with saturated aqueous sodium bicarbonate and then with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4,
(Volume ratio) N-methoxy-N-methyl- (3-
Methyl-5-phenyl-4-isoxazolyl) carbamide (13.95 g, yield 76%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 2.36 (3H, s), 3.20-3.60 (6H,
m), 7.42-7.52 (3H, m), 7.72-7.84 (2H, m). Reference Example 48 N-methoxy-N-methyl- (3-methyl-5-phenyl-4-isoxazolyl) carbamide (7.51)
To a solution of g) in tetrahydrofuran (150 ml), diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. Pour the reaction mixture into dilute hydrochloric acid,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
3-Methyl-5 from hexane (1: 4, volume ratio) elution part
-Phenylisoxazole-4-carbaldehyde (5.39 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 87-88
° C.

Reference Example 49 A solution of pyrrolidine (4.3 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (5.01 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. To the obtained mixture, a solution of 4-phenyl-N-hydroxybenzenecarboximidoyl chloride (9.28 g) in tetrahydrofuran (100 ml) was added at 0 ° C, and then triethylamine (12.0 ml) in tetrahydrofuran (10 m2) was added.
l) The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
9, (volume ratio) 3- (4-phenylphenyl)
Ethyl isoxazole-4-carboxylate (13.04
g, yield 87%) as colorless crystals. Ethyl acetate
Recrystallized from hexane. 81-82 ° C. Reference Example 50 3- (4-phenylphenyl) isoxazole-4-
Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) was slowly added to a solution of ethyl carboxylate (10.00 g) in tetrahydrofuran (100 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
O ₄ ), and then concentrated to give 3- (4-phenylphenyl) -4
-Isoxazolyl methanol (8.32 g, yield 97)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 138-139 ° C.

Reference Example 51 3- (4-phenylphenyl) -4-isoxazolylmethanol (4.16 g) and thionyl chloride (10.
(0 ml) was stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration and 4-chloromethyl-3- (4-phenylphenyl)
Isoxazole (3.84 g, yield 92%) was obtained.
Recrystallized from ethyl acetate-hexane. Melting point 102-1
03 ° C. Reference Example 52 A solution of pyrrolidine (4.3 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (5.00 g) in tetrahydrofuran (50 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. To the obtained mixture, a solution of 4-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (7.50 g) in tetrahydrofuran (100 ml) was added at 0 ° C., and then triethylamine (10.0 ml) in tetrahydrofuran (10 ml) was added. ) The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- (4-trifluoromethylphenyl) isoxazole-4-carboxylate (8.09 g, yield) was extracted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). 85%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 4.32 (2H,
q, J = 7.0 Hz), 7.70-7.78 (2H, m), 7.88-7.97 (2H, m),
9.05 (1H, s).

Reference Example 53 A solution of ethyl 3- (4-trifluoromethylphenyl) isoxazole-4-carboxylate (8.00 g) in tetrahydrofuran (150 ml) was added with diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 60 ml).
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
gSO ₄ ), concentrate, and add 3- (4-trifluoromethylphenyl) -4-isoxazolyl methanol (6.4).
(6 g, 95% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 70-71 ° C. Reference Example 54 A mixture of 3- (4-trifluoromethylphenyl) -4-isoxazolyl methanol (6.00 g) and thionyl chloride (10.0 ml) was stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 4-chloromethyl-3- (4-trifluoromethylphenyl) isoxazole (6.16 g,
(95% yield). Recrystallized from ethyl acetate-hexane. 84-85 ° C.

Reference Example 55 Methyl acetoacetate (8.88 g) and 4-chloro-N
To a solution of -hydroxybenzenecarboximidoyl chloride (9.65 g) in tetrahydrofuran (100 ml), a solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil, tetrahydrofuran (100
ml) solution into a solution of diisobutylaluminum hydride (1.
(0 M tetrahydrofuran solution, 110 ml) was slowly added at 0 ° C, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated and concentrated to 3- (4-chlorophenyl) -5-methyl-4-.
Isoxazolyl methanol (7.69 g, yield 68)
%) As colorless crystals. Recrystallized from ethanol. 94-95 ° C. Reference Example 56 A mixture of 3- (4-chlorophenyl) -5-methyl-4-isoxazolylmethanol (2.23 g) and thionyl chloride (5.0 ml) was stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 4-chloromethyl-3- (4-chlorophenyl) -5-methylisoxazole (2.20 g,
Yield 91%). Recrystallized from diisopropyl ether. 91-92 ° C.

Reference Example 57 Methyl acetoacetate (8.88 g) and 4-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (11.35 g) in tetrahydrofuran (1
00 ml) solution, a solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 110 ml) was slowly added to a solution of the obtained colorless oil in tetrahydrofuran (100 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated to give 5-methyl-3- (4-trifluoromethylphenyl) -4-isoxazolylmethanol (7.86 g, yield 60%) as colorless crystals. It was recrystallized from diisopropyl ether-hexane. 72-73 ° C. Reference Example 58 5-methyl-3- (4-trifluoromethylphenyl)
A mixture of -4-isoxazolyl methanol (1.75 g) and thionyl chloride (5.0 ml) was stirred at 0 ° C for 30 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration to obtain 4-chloromethyl-5-methyl-3- (4-trifluoromethylphenyl) isoxazole (1.50 g, yield 80%). Recrystallized from diisopropyl ether. 91-92 ° C.

Reference Example 59 In a solution of ethyl 5- (4-trifluoromethylphenyl) isoxazole-4-carboxylate (7.63 g) in tetrahydrofuran (100 ml), diisobutylaluminum hydride (1.0 M hexane solution, 59 ml) was added. To 0
After slowly adding the mixture at ° C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (4-trifluoromethylphenyl)
4-Isoxazolyl methanol (6.29 g, 97% yield) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms. Melting point 106-1
07 ° C. Reference Example 60 A mixture of 5- (4-trifluoromethylphenyl) -4-isoxazolyl methanol (5.65 g), tetrahydrofuran (20 ml) and toluene (80 ml) was mixed with thionyl chloride (4.15 g) at 0 ° C. And stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5- (4-trifluoromethylphenyl) isoxazole (4.70 g,
(Yield 77%) as colorless prisms. Melting point 99 ~
100 ° C.

Reference Example 61 2 ′, 4′-Difluoroacetophenone (9.50 g)
A mixture of sodium hydride (60%, oily, 2.44 g) and diethyl carbonate (80 ml) was stirred at 80 ° C. for 1.5 hours. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (7.25 g) was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (60 ml). To the obtained solution, hydroxylamine hydrochloride (6.
34 g) was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (2,4-difluorophenyl) isoxazole-4-carboxylate (3.85 g, yield) was extracted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). Rate 3
5%) as an oil. NMR (CDCl ₃ ) δ: 1.29 (3H,
t, J = 7.0 Hz), 4.29 (2H, q, J = 7.0 Hz), 6.9-7.1 (2H,
m), 7.6-7.75 (1H, m), 8.66 (1H, s). Reference Example 62 Diisobutylaluminum hydride (1.0 M hexane solution, 33 ml) was added to a solution of ethyl 5- (2,4-difluorophenyl) isoxazole-4-carboxylate (3.85 g) in tetrahydrofuran (60 ml) at 0 ° C. And then stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5- (2,4-difluorophenyl) -4-isoxazolylmethanol (2.70 g, (84% yield) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms. Melting point 60-61 [deg.] C.

Reference Example 63 5- (2,4-difluorophenyl) -4-isoxazolylmethanol (2.50 g) in toluene (50 m
l) Thionyl chloride (2.11 g) was added dropwise to the solution at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5- (2,4-difluorophenyl) isoxazole (2.20 g, yield) was eluted with ethyl acetate-hexane (1: 5, volume ratio). 81%) as an oil. NMR (CDCl ₃ ) δ: 4.53 (2
H, s), 6.95-7.15 (2H, m), 7.6-7.75 (1H, m), 8.43 (1H,
s). Reference Example 64 2-acetyl-5-chlorothiophene (10.0 g),
A mixture of sodium hydride (60%, oily, 2.49 g) and diethyl carbonate (80 ml) was stirred at 80 ° C. for 30 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 5, volume ratio) eluate, 3- (5
Ethyl -chloro-2-thienyl) -3-oxopropionate was obtained as an oil. This oil and N, N-dimethylformamide dimethyl acetal (11.1
The mixture of g) was refluxed for 1 hour. Concentrate the reaction mixture,
The residue was dissolved in ethanol (80ml). To the obtained solution, hydroxylamine hydrochloride (8.65 g) was added, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 5, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 5-
(5-chloro-2-thienyl) isoxazole-4-
Ethyl carboxylate (9.34 g, yield 58%) was obtained as colorless prism crystals. 74-75 ° C.

Reference Example 65 5- (5-chloro-2-thienyl) isoxazole-
Diisobutylaluminum hydride (1.5 M toluene solution, 52 ml) was slowly added to a solution of ethyl 4-carboxylate (9.00 g) in tetrahydrofuran (100 ml) at 0 ° C., followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into dilute hydrochloric acid to precipitate 5- (5-chloro-2).
-Thienyl) -4-isoxazolylmethanol (7.
(00 g, yield 93%). Recrystallization from ethyl acetate-hexane gave colorless needles. Melting point 80-81
° C. Reference Example 66 Thionyl chloride (5.41 g) was added to a mixture of 5- (5-chloro-2-thienyl) -4-isoxazolylmethanol (6.54 g), tetrahydrofuran (20 ml) and toluene (100 ml) in a mixture of 0 and 0. C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5- (5-chloro-2-thienyl) isoxazole (6.98 g, yield) was eluted with ethyl acetate-hexane (1: 5, volume ratio). (98%). Recrystallization from ethyl acetate-hexane gave a colorless prism. 70-71 ° C.

Reference Example 67 4'-chloro-3'-methylacetophenone (10.0
g), sodium hydride (60%, oily, 2.38 g)
And diethyl carbonate (80 ml) at 80 ° C. for 9 hours.
Stir for 0 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3 parts were eluted with ethyl acetate-hexane (1: 9, volume ratio).
Ethyl-(4-chloro-3-methylphenyl) -3-oxopropionate was obtained as an oil. A mixture of this oil and N, N-dimethylformamide dimethyl acetal (10.6 g) was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). The resulting solution was added to hydroxylamine hydrochloride (8.2
4 g) was added and refluxed for 2 hours. Concentrate the reaction mixture,
Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5- (4-chloro-3-methylphenyl) isoxazole-4-carboxylate (9.26 g) was eluted from a fraction eluted with ethyl acetate-hexane (1: 5, volume ratio). , Yield 5
9%). Recrystallization from hexane gave colorless prisms. Melting point 50-51 [deg.] C. Reference Example 68 Diisobutylaluminum hydride (1.5 M toluene solution, 47 ml) was added to a solution of ethyl 5- (4-chloro-3-methylphenyl) isoxazole-4-carboxylate (8.50 g) in tetrahydrofuran (100 ml). 0
After slowly adding the mixture at ° C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 5- (4-chloro-3-methylphenyl)
4-Isoxazolyl methanol (6.13 g, 86% yield) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless needles. 92-93 ° C.

Reference Example 69 To a mixture of 5- (4-chloro-3-methylphenyl) -4-isoxazolylmethanol (5.80 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added thionyl chloride (4. 63 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5- (4-chloro-
3-methylphenyl) isoxazole (5.47 g,
(87% yield) as colorless prisms. Melting point 84-
85 ° C. Reference Example 70 A mixture of 2 ′, 5′-dichloroacetophenone (10.0 g), sodium hydride (60%, oily, 2.12 g) and diethyl carbonate (80 ml) was stirred at 80 ° C. for 20 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 9, volume ratio).
Ethyl (2,5-dichlorophenyl) -3-oxopropionate was obtained as an oil. This oil and N, N
-Dimethylformamide dimethyl acetal (9.4
The mixture of 6 g) was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). Hydroxylamine hydrochloride (7.35 g) was added to the obtained solution, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 5, volume ratio) was eluted with 5-
(2,5-dichlorophenyl) isoxazole-4-
Ethyl carboxylate (6.40 g, 42% yield) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7 Hz), 4.2
5 (2H, q, J = 7 Hz), 7.4-7.6 (3H, m), 8.68 (1H, s).

Reference Example 71 5- (2,5-dichlorophenyl) isoxazole-
To a solution of ethyl 4-carboxylate (6.40 g) in tetrahydrofuran (100 ml) was slowly added diisobutylaluminum hydride (1.5 M toluene solution, 33 ml) at 0 ° C, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5- (2,5-dichlorophenyl) -4-isoxazolylmethanol (3.86 g, yield) was eluted with ethyl acetate-hexane (1: 1, volume ratio). (71%) as colorless crystals. Recrystallization from isopropyl ether-hexane gave colorless prisms. Melting point 51-52
° C. Reference Example 72 5- (2,5-dichlorophenyl) -4-isoxazolyl methanol (3.80 g) in toluene (60 ml)
To the solution, thionyl chloride (2.78 g) was added dropwise at 0 ° C.
Stir at room temperature for 2 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5- (2,5-dichlorophenyl) isoxazole (2.15 g, yield) was eluted with ethyl acetate-hexane (1: 9, volume ratio). 53%)
Was obtained as an oil. NMR (CDCl ₃ ) δ: 4.45 (2H, s), 7.4
-7.55 (3H, m), 8.48 (1H, s).

Reference Example 73 A mixture of 4′-methylthioacetophenone (20.0 g), sodium hydride (60%, oily, 4.81 g) and diethyl carbonate (120 ml) was stirred at 80 ° C. for 1.5 hours. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 9, volume ratio) eluate, 3- (4
-Methylthiophenyl) -3-oxopropionate was obtained as an oil. This oil and N, N-dimethylformamide dimethyl acetal (21.5 g)
Was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution, hydroxylamine hydrochloride (16.7 g) was added, and 2
Refluxed for hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 5, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 5- (4-
Crystals of ethyl methylthiophenyl) isoxazole-4-carboxylate (18.9 g, yield 60%) were obtained. Melting point 59-60 [deg.] C. Reference Example 74 5- (4-methylthiophenyl) isoxazole-4
-To a solution of ethyl carboxylate (10.0 g) in tetrahydrofuran (100 ml) was slowly added diisobutylaluminum hydride (0.95 M hexane solution, 92 ml) at 0 ° C, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give 5- (4-methylthiophenyl)-
4-isoxazolyl methanol (7.50 g, yield 8)
9%) as colorless prisms. Melting point 102-10
3 ° C.

Reference Example 75 5- (4-methylthiophenyl) -4-isoxazolylmethanol (7.35 g), tetrahydrofuran (2
Thionyl chloride (5.93 g) was added dropwise to a mixture of 0 ml) and toluene (80 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4-ethyl acetate-hexane (1: 3, volume ratio) eluted.
Chloromethyl-5- (4-methylthiophenyl) isoxazole (7.70 g, yield 97%) was obtained as crystals. Recrystallization from diethyl ether-hexane gave colorless prisms. 73-74 ° C. Reference Example 76 A mixture of 4′-methylacetophenone (15.4 g), sodium hydride (60%, oily, 4.59 g) and diethyl carbonate (80 ml) was stirred at 80 ° C. for 30 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethyl acetal (20.5 g) was refluxed for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (120 ml). To the obtained solution, hydroxylamine hydrochloride (16.
0 g) was added and the mixture was refluxed for 2 hours. Concentrate the reaction mixture,
Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5- (4-methylphenyl) isoxazole-4 was extracted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio).
-Colorless crystals of ethyl carboxylate (17.2 g, yield 65%) were obtained. Recrystallization from hexane gave colorless prisms. 45-46 ° C.

Reference Example 77 Diisobutylaluminum hydride (1.0 M toluene solution, 83 ml) was added to a solution of ethyl 5- (4-methylphenyl) isoxazole-4-carboxylate (7.70 g) in tetrahydrofuran (100 ml). After slowly adding at 0 ° C, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in toluene (100 ml), and thionyl chloride (5.94 g) was added dropwise at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5- (4-methylphenyl) isoxazole (6.49 g, yield 94) was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). %) As an oil.
NMR (CDCl ₃ ) δ: 2.44 (3H, s), 4.62 (2H, s), 7.34 (2H,
d, J = 8 Hz), 7.67 (2H, d, J = 8 Hz), 8.35 (1H, s). Reference Example 78 2-acetyl-4,5-dichlorothiophene (6.10
g), sodium hydride (60%, oily, 1.25 g)
And a mixture of diethyl carbonate (60 ml) at 80 ° C. for 3 hours.
Stir for 0 minutes. Water was added to the reaction mixture, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a mixture of an oil obtained from an ethyl acetate-hexane (1: 9, volume ratio) eluate and N, N-dimethylformamide dimethyl acetal (5.60 g) was added for 1 hour. Refluxed. The reaction mixture was concentrated, and the residue was treated with ethanol (80 m
l). Hydroxylamine hydrochloride (4.35 g) was added to the obtained solution, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
9, (volume ratio) from the elution part to 5- (4,5-dichloro-2-
Colorless crystals of ethyl (thienyl) isoxazole-4-carboxylate (3.42 g, yield 37%) were obtained. Recrystallization from ethyl acetate gave pale yellow prism crystals. Melting point 12
0-121 ° C.

Reference Example 79 To a solution of ethyl 5- (4,5-dichloro-2-thienyl) isoxazole-4-carboxylate (3.30 g) in tetrahydrofuran (60 ml) was added diisobutylaluminum hydride (0.95 M hexane solution). , 29.7 ml)
Was slowly added at 0 ° C., followed by stirring at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was dissolved in toluene (60 ml), and thionyl chloride (2.02 g) was added dropwise at 0 ° C.
Stir at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography.
2-thienyl) isoxazole (2.41 g, yield 7)
9%) as crystals. Recrystallization from hexane gave colorless prisms. Melting point 60-61 [deg.] C. Reference Example 80 A mixture of 4-nitrobenzyl bromide (15.0 g) and triisopropyl phosphite (15.9 g) was stirred for 3 hours while heating under reflux. The reaction mixture was subjected to silica gel column chromatography, and diisopropyl 4-nitrobenzylphosphonate (19.5 g) was obtained as an oil from a fraction eluted with ethyl acetate-chloroform (1: 1, v / v). This oil, 5% palladium on carbon (2.3
A mixture of g) and ethanol (130 ml) was stirred under a hydrogen atmosphere at room temperature for 6 hours. Filter off the catalyst,
The filtrate (ethanol solution) was concentrated and diisopropyl 4-aminobenzylphosphonate (17.2 g, yield 98)
%) As a yellow oil. NMR (CDCl ₃ ) δ: 1.17 (6H,
d, J = 7 Hz), 1.27 (6H, d, J = 7 Hz), 2.92 (2H, br
s), 3.25 (2H, d, J = 22Hz), 4.55-4.65 (2H, m), 6.
64 (2H, d, J = 8 Hz), 7.09 (2H, dd, J = 3/9 Hz). The following compounds were synthesized as in Reference Example 1.

Reference Example 81 dibutyl 4-aminobenzyl phosphonate 98% yield (yellow oil) NMR (CDCl ₃ ) δ: 0.90 (6H, t, J = 7 Hz), 1.25-1.45 (4H,
m), 1.5-1.65 (4H, m), 2.87 (2H, brs), 3.04 (2H, d,
J = 22Hz), 3.9-4.05 (4 H, m), 6.66 (2H, d, J = 8 Hz),
7.08 (2H, dd, J = 3 / 9Hz). Reference Example 82 diethyl 4-amino-3-methylbenzylphosphonate 97% yield (yellow oil) NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7 Hz), 2.16 (3H, s),
3.03 (2H, d, J = 21 Hz), 3.18 (2H, s), 3.95-4.05 (4
H, m), 6.66 (2H, d, J = 8 Hz), 6.95-7.0 (2H, m).

Reference Example 83 A mixture of titanium tetrachloride (20.0 g) and tetrahydrofuran (100 ml) was added to 4-nitrobenzaldehyde (8.00 g) and ethyl diethylphosphonoacetate (11.0 g).
9 g) was added under ice-cooling, N-methylmorpholine (21.4 g) was further added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated to give 4-[(E) -2- (diethylphosphono) -2.
[-Ethoxycarbonylethenyl] nitrobenzene was obtained as crystals (15.7 g, yield 83%). Dichloromethane-
Recrystallization from isopropyl ether gave colorless prisms (14.0 g). Melting point 60-61 [deg.] C. A mixture of this compound (5.00 g), iron (3.13 g), concentrated hydrochloric acid (7 ml) and ethanol (30 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated, the residue was subjected to silica gel column chromatography, and 4-[(E) -2- (diethylphosphono) -2) was extracted from an ethyl acetate-hexane (2: 1, v / v) eluate. [-Ethoxycarbonylethenyl] aniline (2.40 g, yield 52%) was obtained as crystals. Recrystallization from acetone-isopropyl ether gave pale yellow needles (1.75 g). Mp 79-80 ° C. Elemental analysis: Calculated _{(C 15 H 22 NO 5 P} ) C, 55.04; H, 6.77; N, 4.29. Found C, 55.07; H, 6.92; N, 4.25.

Example 1 5- (4-trifluoromethoxyphenyl) -4-isoxazolylmethanol (5.60 g) in toluene (1
00 ml) solution at 0 ° C. in thionyl chloride (2.36 m
After l) was added dropwise, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and diethyl malonate (6.
92g), sodium hydride (60%, oily, 1.72)
g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (70 ml) and acetic acid (70 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (4-trifluoromethoxyphenyl) -4-isoxazolyl] propionic acid (3.7
7 g, 58% yield). Recrystallized from acetone-hexane. Melting point 116-118 [deg.] C. Example 2 3- [5- (4-trifluoromethoxyphenyl) -4
A mixture of [-isoxazolyl] propionic acid (3.30 g), concentrated sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[5- (4-trifluoromethoxyphenyl) -4-
Isoxazolyl] methyl propionate (2.80 g,
(81% yield) as a colorless oil. NMR (CDCl ₃ ) δ:
2.66 (2H, t, J = 7.4 Hz), 2.99 (2H, q, J = 7.4 Hz), 3.69
(3H, s), 7.35 (2H, dd, J = 1.0, 9.2 Hz), 7.76 (2H, d, J
= 9.2 Hz), 8.24 (1H, s).

Example 3 3- [5- (4-trifluoromethoxyphenyl) -4
-Isoxazolyl] methyl propionate (1.63
g) in tetrahydrofuran (25 ml)
Diisobutylaluminum (1.0 M hexane solution, 1
3.2 ml) at 0 ° C. slowly and then at room temperature for 1 hour.
Stirred. The reaction mixture was poured into dilute hydrochloric acid, and ethyl acetate was added.
Extracted. The ethyl acetate layer is washed with saturated saline and dried
(MgSO _Four) And concentrated. Silica gel residue
Chromatography, and ethyl acetate-hexane
(2: 1, volume ratio) 3- [5- (4-trif) from the elution part
Fluoromethoxyphenyl) -4-isoxazolyl] p
Lopan-1-ol (1.36 g, 92% yield) was colorless.
Obtained as crystals. Recrystallized from ethyl acetate-hexane
Was. Melting point 50-51 [deg.] C. Example 4 3- [5- (4-bromophenyl) -4-isoxazo
Ril] propan-1-ol (1.10 g), cyanation
Copper (1.41 g), Tris (dibenzylideneacetone)
Dipalladium (130 mg), 1,1'-bis (dife
Nylphosphino) ferrocene (314 mg), cyanide
Tetraethylammonium (553 mg) and 1,4
Reflux the mixture of dioxane (20 ml) for 3.5 hours
Was. Water was added to the reaction mixture, and extracted with ethyl acetate. vinegar
The ethyl acid layer is washed with saturated saline and dried (MgSO 4)._Four)
Afterwards, it was concentrated. The residue is purified by silica gel column chromatography.
And then added ethyl acetate-hexane (1: 3, volume
Ratio) 3- [5- (4-cyanophenyl) -4
-Isoxazolyl] propan-1-ol (418 m
g, yield 52%) as pale yellow crystals. Ethyl acetate
-Recrystallized from hexane. 82-83 ° C.

Example 5 A solution of pyrrolidine (5.2 ml) in tetrahydrofuran (5 ml) was slowly added to a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml) at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Was. To the obtained mixture, a solution of 4-chloro-N-hydroxybenzenecarboximidoyl chloride (7.60 g) in tetrahydrofuran (100 ml) was added at 0 ° C, and then triethylamine (11.5 ml) in tetrahydrofuran (10 ml).
The solution was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
(Volume ratio) A colorless oil was obtained from the elution part. To a solution of the obtained colorless oil in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M hexane solution,
(85 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. Thionyl chloride (4.50 ml) was added dropwise to a solution of the obtained colorless oil in toluene (100 ml) at 0 ° C.
Stir for hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
Dissolve the residue in tetrahydrofuran (100 ml)
To a mixture of diethyl malonate (12.81 g), sodium hydride (60%, oily, 3.20 g) and tetrahydrofuran (50 ml) at 0 ° C., stir at 0 ° C. for 1 hour, then stir at room temperature overnight. Was. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). Colorless oil obtained, 6
A mixture of normal hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (4-
[Chlorophenyl) -4-isoxazolyl] propionic acid (4.93 g, yield 49%) was obtained. Recrystallized from isopropyl ether. 149-150 ° C. Example 6 5- (3-bromo-4-chlorophenyl) -4-isoxazolylmethanol (5.09 g) in toluene (10
0 ml) solution at 0 ° C. in thionyl chloride (1.93 ml).
After dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (50 ml) and treated with diethyl malonate (5.64).
g), sodium hydride (60%, oily, 1.41 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (3-bromo-4-chlorophenyl)
-4-isoxazolyl] propionic acid (3.24 g,
Yield 56%). Recrystallized from diethyl ether-hexane. Melting point 177-180 [deg.] C.

Example 7 Ethyl benzoyl acetate (12.65 g) and N, N-
Dimethylformamide dimethyl acetal (11.80
The mixture of g) was refluxed for 1.5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethanol (200 ml). To the resulting solution was added hydroxylamine hydrochloride (9.18 g).
Was added and refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a yellow oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). To a solution of the obtained yellow oil in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 100 ml) in 0 ml.
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. Thionyl chloride (5.0 ml) was added dropwise to a solution of the residue in toluene (100 ml) at 0 ° C.
Stir at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added to a mixture of diethyl malonate (13.50 g), sodium hydride (60%, oily, 3.33 g) and tetrahydrofuran (30 ml) at 0 ° C.
Stirred at C for 1 hour, then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3,
A colorless oil was obtained from the elution part (volume ratio). The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of 1) was refluxed for 5 hours. Concentrate the reaction mixture,
Water was added to the residue. The obtained colorless crystals were collected by filtration,
(5-Phenyl-4-isoxazolyl) propionic acid (9.14 g, yield 64%) was obtained. Recrystallized from isopropyl ether. 90-91 ° C. Example 8 A mixture of 4′-chloroacetophenone (10.47 g), sodium hydride (60%, oily, 2.71 g) and diethyl carbonate (150 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the aqueous layer was neutralized with dilute hydrochloric acid, followed by stirring at room temperature for 30 minutes, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. Residue and N, N-dimethylformamide dimethyl acetal (12.18 g)
Was refluxed for 1.5 hours. Concentrate the reaction mixture,
The residue was dissolved in ethanol (200ml). Hydroxylamine hydrochloride (9.49 g) was added to the obtained solution, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
A yellow oil was obtained from the elution portion of ethyl acetate-hexane (1: 2, volume ratio). Diisobutylaluminum hydride (1.0 M hexane solution, 100 ml) was slowly added to a solution of the obtained yellow oil in tetrahydrofuran (100 ml) at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. To a solution of the residue in toluene (100 ml) was added 0
After dropwise addition of thionyl chloride (2.7 ml) at ℃, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added to a mixture of diethyl malonate (7.96 g), sodium hydride (60%, oily, 1.95 g) and tetrahydrofuran (30 ml) at 0 ° C., and then 0 ° C. At 1
Stirred for an hour, then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [5-
(4-Chlorophenyl) -4-isoxazolyl] propionic acid (7.84 g, 46% yield) was obtained. Recrystallized from isopropyl ether. 155-154 ° C.

Example 9 3- [5- (3-bromo-4-chlorophenyl) -4-
Isoxazolyl] methyl propionate (1.00 g)
In a solution of diisobutylaluminum hydride (1.0 M in hexane, 6.5).
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [5- (3-bromo-4-)
Chlorophenyl) -4-isoxazolyl] propane-
1-ol (0.85 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 7
5-76 ° C. Example 10 To a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml) was slowly added sodium hydride (60%, oily, 1.07 g) at 0 ° C. After stirring for 10 minutes, a solution of 4-chloromethyl-5- (4-trifluoromethylphenyl) isoxazole (3.50 g) in tetrahydrofuran (40 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hours.
The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 3
Colorless prism crystals of-[5- (4-trifluoromethylphenyl) -4-isoxazolyl] propionic acid (3.
00g, 79% yield). Melting point 171-172 [deg.] C.

Example 11 5- (4-fluorophenyl) -4-isoxazolyl
Methanol (5.84 g) in toluene (50 ml)
At 0 ° C., thionyl chloride (3 ml) was added dropwise at room temperature.
And stirred for 3 hours. Concentrate the reaction mixture and saturate the residue.
Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. Ethyl acetate layer
Is washed with saturated saline and dried (MgSO _Four) And then concentrate
Was. Dissolve the residue in tetrahydrofuran (100 ml)
And diethyl malonate (6.92 g), sodium hydride
(60%, oily, 1.70 g) and tetrahydroph
After adding to the mixture of the runs (50 ml) at 0 ° C.,
Stirred for an hour, then at room temperature overnight. Dilute the reaction mixture
After acidifying with hydrochloric acid, the mixture was extracted with ethyl acetate. Acetic acid
The ethyl layer is washed with a saturated saline solution and dried (MgSO 4)._Four)
Afterwards, it was concentrated. The residue is purified by silica gel column chromatography.
And then added ethyl acetate-hexane (1: 3, volume
Ratio) A colorless oil was obtained from the elution part. Colorless oil obtained
Product, 6N hydrochloric acid (30 ml) and acetic acid (50 ml)
The mixture was refluxed for 5 hours. The reaction mixture is concentrated and the residue
Was added to water. The obtained colorless crystals were collected by filtration, and 3- [5-
(4-Fluorophenyl) -4-isoxazolyl] p
Lopionic acid (4.53 g, yield 78%) was obtained. Isop
Recrystallized from propyl ether. 126-127
° C. Example 12 Tetrahydrofuran of diethyl malonate (11.0 g)
(60ml) solution in sodium hydride (60%, oil
, 2.50 g) was slowly added at 0 ° C. Persimmon for 10 minutes
After mixing, 4-chloromethyl-5- (4-methylphenyl
I) tetrahydrofuran of isoxazole (6.48 g)
A run (80 ml) solution was added dropwise at 0 ° C., and at room temperature for 15 hours.
Stirred. After pouring the reaction mixture into 2N hydrochloric acid, acetic acid was added.
Extracted with ethyl. After concentrating the ethyl acetate layer, the residue
Mixture of normal hydrochloric acid (80ml) and acetic acid (120ml)
And heated to reflux for 8 hours. Concentrate the reaction mixture
And water was added to the residue. The obtained colorless crystals are collected by filtration,
After drying, it was recrystallized from ethyl acetate-hexane to give 3- [5
-(4-methylphenyl) -4-isoxazolyl] p
Colorless prism crystals of ropionic acid (5.03 g, yield 70)
%). 121-122 ° C.

Example 13 Thionyl chloride (3.3 ml) was added dropwise at 0 ° C. to a solution of 5- (4-methoxyphenyl) -4-isoxazolyl methanol (6.09 g) in toluene (100 ml). Stir at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was treated with tetrahydrofuran (100 m
l) and added to a mixture of diethyl malonate (9.51 g), sodium hydride (60%, oily, 2.32 g) and tetrahydrofuran (50 ml) at 0 ° C., followed by 1 hour at 0 ° C. And stirred overnight at room temperature. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(3, volume ratio) A colorless oil was obtained from the elution part. The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50
ml) of the mixture was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals are collected by filtration,
3- [5- (4-Methoxyphenyl) -4-isoxazolyl] propionic acid (5.16 g, yield 70%) was obtained. Recrystallized from isopropyl ether-diethyl ether. Melting point 101-102 [deg.] C. Example 14 Diethyl 4-aminobenzylphosphonate (0.37
g), 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.25 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.33 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-diethylphosphonomethylphenyl) -3- [5- (4-chlorophenyl) -4 was extracted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). -Isoxazolyl] propionamide (0.61 g, yield 9)
2%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 138-139 ° C.

Example 15 3- [5- (4-Chlorophenyl) -4-isoxazolyl] propionic acid (6.57 g), concentrated sulfuric acid (0.5 m
A mixture of 1) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-
Methyl [chlorophenyl) -4-isoxazolyl] propionate (6.51 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 51
~ 52 ° C. Example 16 Diisobutylaluminum hydride (1.0 M hexane solution, 50 ml) was added to a solution of methyl 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionate (6.00 g) in tetrahydrofuran (100 ml) at 0 ° C.
And then stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-chlorophenyl) -4-isoxazolyl] propan-1-ol (4.89 g) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). , 91%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 58-59 ° C.

Example 17 Diethyl 4-aminobenzylphosphonate (0.76
g), 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.66 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.41 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-diethylphosphonomethylphenyl) -3- [3- (4-chlorophenyl) -4 was extracted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). -Isoxazolyl] propionamide (1.14 g, yield 9)
1%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 88-90 ° C. Example 18 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionic acid (1.28 g), triethylamine (1.1 ml) and tetrahydrofuran (100 m
l) at -30 ° C with ethyl chlorocarbonate (0.6 m
After adding l), the mixture was stirred at -20 ° C for 1 hour. Aqueous ammonia (15 ml) was added to the obtained mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated to give 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionamide (0. 91 g, yield 71
%) As colorless crystals. Recrystallized from acetone-hexane. 158-159 ° C.

Example 19 3- [3- (4-Chlorophenyl) -4-isoxazolyl] propionic acid (4.05 g), concentrated sulfuric acid (0.1 m
A mixture of 1) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) was eluted with 3- [3- (4-
Methyl [chlorophenyl) -4-isoxazolyl] propionate (3.93 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 56
~ 57 ° C. Example 20 3-trifluoromethylbenzylamine (0.75 m
l), 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.82 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.03 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (3-trifluoromethylbenzyl) -3- [3- (4-chlorophenyl) -4- was obtained from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). Isoxazolyl] propionamide (1.27 g, yield 87)
%) As colorless crystals. Recrystallized from isopropyl ether-hexane. 80-81 ° C.

Example 21 Diethyl 4-aminobenzylphosphonate (1.25
g), 3- (5-phenyl-4-isoxazolyl) propionic acid (1.00 g), 1-hydroxy-1H-
1,2,3-benzotriazole hydrate (0.80
g), a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.08 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer consists of diluted hydrochloric acid, saturated aqueous sodium bicarbonate,
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 1, volume ratio)
-(4-diethylphosphonomethylphenyl) -3- (5
-Phenyl-4-isoxazolyl) propionamide (1.89 g, yield 93%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 139-14
0 ° C. Example 22 3- (5-phenyl-4-isoxazolyl) propionic acid (1.08 g), triethylamine (1.1 ml)
And a mixture of tetrahydrofuran (100 ml)
After adding ethyl chlorocarbonate (0.6 ml) at 30 ° C.
Stir at -20 ° C for 1 hour. Aqueous ammonia (20 ml) was added to the obtained mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated to give 3- (5-
Phenyl-4-isoxazolyl) propionamide (0.82 g, yield 78%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 151-15
2 ° C.

Example 23 3- (5-Phenyl-4-isoxazolyl) propionic acid (1.00 g), triethylamine (1.0 ml)
And a mixture of tetrahydrofuran (50 ml)
After adding ethyl chlorocarbonate (0.5 ml) at 0 ° C,
Stir at 20 ° C. for 1 hour. Ethylamine aqueous solution (10 ml) was added to the obtained mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated in N-ethyl-3- (5-phenyl-4-isoxazolyl) propionamide (0. 93 g, yield 83%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 75-76 ° C. Example 24 (E) -3- (5-Phenyl-4-isoxazolyl)
Ethyl propenoate (4.89 g), 2N hydrochloric acid (50 m
A mixture of 1) and acetic acid (50 ml) was refluxed for 3 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and (E) -3- (5-phenyl-4)
-Isoxazolyl) propenoic acid (4.02 g, yield 9)
3%). Recrystallized from acetone-hexane. Melting point 197-199 [deg.] C.

Example 25 (E) -3- (5-Phenyl-4-isoxazolyl)
Propenoic acid (0.97 g), triethylamine (1 m
To a mixture of 1) and tetrahydrofuran (60 ml) was added ethyl chlorocarbonate (0.5 ml) at -30 ° C, followed by stirring at -20 ° C for 1 hour. In the resulting mixture,
Aqueous ammonia (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated (E) -3.
-(5-Phenyl-4-isoxazolyl) propenamide (0.86 g, 89% yield) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 194 ~
196 ° C. Example 26 Diethyl 4-aminobenzylphosphonate (0.83
g), (E) -3- (5-phenyl-4-isoxazolyl) propenoic acid (0.69 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (0.5
4g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.65 g) and N, N-
A mixture of dimethylformamide (30 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and (E) -N- (4-diethylphosphonomethylphenyl) -3- (5-phenyl-4) was eluted with ethyl acetate-hexane (1: 1, volume ratio). -Isoxazolyl) propenamide (0.86 g, 61% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 173-174 ° C.

Example 27 (E) -3- (5-Phenyl-4-isoxazolyl)
Propenoic acid (0.76 g), triethylamine (0.8
mixture of tetrahydrofuran (50 ml)
Ethyl chlorocarbonate (0.4 ml) was added to the mixture at -30 ° C.
Thereafter, the mixture was stirred at -20 ° C for 1 hour. In the resulting mixture,
Ethylamine aqueous solution (1 ml) was added, and the mixture was added at room temperature for 1 hour.
I mixed. Pour the reaction mixture into water and extract with ethyl acetate.
Was. The ethyl acetate layer consists of diluted hydrochloric acid, saturated aqueous sodium bicarbonate,
Wash with sodium chloride solution and dry (MgSO _Four) And then concentrate,
(E) -N-ethyl-3- (5-phenyl-4-isothio)
Xazolyl) propenamide (0.78 g, yield 91)
%) As colorless crystals. Acetone-hexane
Crystallized. 156-157 ° C. Example 28 3- (3-methyl-5-phenyl-4-isoxazolyl
R) propionic acid (0.95 g), triethylamine
(1.0 ml) and tetrahydrofuran (50 ml)
Ethyl chlorocarbonate (0.5ml) at -30 ° C
Was added thereto, followed by stirring at −20 ° C. for 1 hour. The resulting blend
Aqueous ammonia (5 ml) was added to the mixture, and the mixture was allowed to stand at room temperature for 1 hour.
Stirred. Pour the reaction mixture into water and extract with ethyl acetate
did. The ethyl acetate layer consists of diluted hydrochloric acid, saturated aqueous sodium bicarbonate,
Wash with saturated saline and dry (MgSO _Four) After that, concentrate
-(3-methyl-5-phenyl-4-isoxazolyl
G) without propionamide (0.86 g, 91% yield)
Obtained as colored crystals. Recrystallized from ethyl acetate-hexane
Was. Melting point 149-151 [deg.] C.

Example 29 Methyl 4-aminobenzoate (0.47 g), 3- (3-
Methyl-5-phenyl-4-isoxazolyl) propionic acid (0.60 g), 1-hydroxy-1H-1,
2,3-benzotriazole hydrate (0.50 g),
1-ethyl-3- (3-dimethylaminopropyl) hydrochloride
A mixture of carbodiimide (0.61 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- (4) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-Methoxycarbonylphenyl) -3- (3-methyl-
5-Phenyl-4-isoxazolyl) propionamide (0.75 g, yield 79%) was obtained as colorless crystals.
Recrystallized from ethyl acetate-hexane. Melting point 140-1
41 ° C. Example 30 N-diphenylmethylpiperazine (0.85 g), 3-
(5-phenyl-4-isoxazolyl) propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-
Benzotriazole hydrate (0.55 g), hydrochloric acid 1-
A mixture of ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.69 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N-diphenylmethyl-N ′-[3- (5-phenyl-4-isoxazolyl) propionyl] piperazine (from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio)) 1.35 g, yield 9
3%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.26-
2.42 (4H, m), 2.50-2.64 (2H, m), 2.94-3.08 (2H, m),
3.32-3.44 (2H, m), 3.56-3.68 (2H, m), 4.22 (1H, s),
7.12-7.54 (13H, m), 7.66-7.86 (2H, m), 8.21 (1H, s).

Example 31 2-amino-4- (4-chlorophenyl) thiazole (0.75 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.72 g), 1-hydroxy-1H-1 A mixture of 2,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.70 g) and N, N-dimethylformamide (15 ml) was prepared. Stir at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- [4- (4-chlorophenyl) -2 was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-Thiazolyl] -3- (5-phenyl-4-isoxazolyl) propionamide (0.58 g, 43% yield)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 172-173 ° C. Example 32 Methyl 4-aminobenzoate (0.46 g), 3- (5-
Phenyl-4-isoxazolyl) propionic acid (0.
60g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.48 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.61 g) and N, A mixture of N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-methoxycarbonylphenyl) -3- (5-phenyl-4-isoxazolyl) propionamide (eluent) was eluted with ethyl acetate-hexane (1: 1, volume ratio). 0.86 g, yield 89
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 111-112 ° C.

Example 33 2-amino-5-methyl-4-phenylthiazole (0.95 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (1.01 g), 1-hydroxy-1H-1 A mixture of 2,2,3-benzotriazole hydrate (0.78 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.97 g) and N, N-dimethylformamide (20 ml) was prepared. Stir at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (5-methyl-4-phenyl-2-phenyl) was eluted from an ethyl acetate-hexane (1: 1, volume ratio) eluate.
Thiazolyl) -3- (5-phenyl-4-isoxazolyl) propionamide (1.74 g, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 150-151 ° C. Example 34 2-Aminoquinoline (0.55 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.82
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3 hydrochloride
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.91 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (2-quinolyl) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-3- (5-Phenyl-4-isoxazolyl) propionamide (1.09 g, yield 84%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 1
12-113 ° C.

Example 35 4-Aminobenzamide (0.55 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.8%)
7g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl hydrochloride-
A mixture of 3- (3-dimethylaminopropyl) carbodiimide (0.88 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-carbamoylphenyl) -3- (5-phenyl-4-isoxazolyl) propionamide (0%) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). .95 g, yield 71%) as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 250-251 ° C. Example 36 3- (2-aminoethyl) indole hydrochloride (0.4
6g), triethylamine (0.6 ml) and N, N
A mixture of -dimethylformamide (20 ml) was stirred at room temperature for 1 hour. To the obtained mixture, 3- (5-phenyl-4-isoxazolyl) propionic acid (0.42
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.45 g) were added, Stir at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- [2- (3-indolyl) ethyl] -3- (5-phenyl-4-isoxazolyl) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). Propionamide (0.63 g, yield 91)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.32-2.4
4 (2H, m), 2.88-3.04 (4H, m), 3.54-3.66 (2H, m), 5.45
(1H, br s), 6.93 (1H, d, J = 2.2 Hz), 7.04-7.28 (2H,
m), 7.32-7.62 (5H, m), 7.64-7.74 (2H, m), 8.05 (1H, b
rs), 8.17 (1H, s).

Example 37 Diethyl 4-aminobenzylphosphonate (1.20
g), 5-phenyl-4-isoxazolylacetic acid (0.
84g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.97 g) and N, A mixture of N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-diethylphosphonomethylphenyl) -5-phenyl-4-isoxazolylacetamide (from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio)) 1.58 g, 89% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 132-133 ° C. Example 38 2-Amino-4- (4-chlorophenyl) thiazole (0.65 g), 5-phenyl-4-isoxazolylacetic acid (0.60 g), 1-hydroxy-1H-1,2,2,3.
A mixture of 3-benzotriazole hydrate (0.51 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.59 g) and N, N-dimethylformamide (15 ml) was added at room temperature overnight. Stirred. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- [4-
(4-Chlorophenyl) -2-thiazolyl] -5-phenyl-4-isoxazolylacetamide (0.92
g, yield 79%) as colorless crystals. Ethyl acetate
Recrystallized from hexane. Melting point 210-211C.

Example 39 Ethyl 4-aminophenylacetate (0.32 g), 3-
[5- (4-Chlorophenyl) -4-isoxazolyl] propionic acid (0.37 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (0.2
8g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g) and N, N-
A mixture of dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- (4-ethoxycarbonylmethylphenyl) -3 was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-[5- (4-Chlorophenyl) -4-isoxazolyl] propionamide (0.56 g, yield 93%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 117-118 ° C. Example 40 3-aminopyridine (0.18 g), 3- [5- (4-
Chlorophenyl) -4-isoxazolyl] propionic acid (0.50 g), 1-hydroxy-1H-1,2,3
-Benzotriazole hydrate (0.35 g), hydrochloric acid 1
A mixture of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.45 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
N- (3-pyridyl) -3- [5- (4-chlorophenyl) -4-isoxazolyl] propionamide (0.60 g, yield 9) was eluted from a hexane (1: 1, volume ratio) elution part.
6%) as colorless crystals. Recrystallized from acetone-hexane. 197-198 ° C.

Example 41 5-amino-2- (2-methyl-1-imidazolyl) pyridine (0.40 g), 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.58 g)
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g), 1-ethyl-3 hydrochloride
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.54 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- [6- (2-methyl-1-imidazolyl) -3-pyridyl) -3- [5 was obtained from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). −
(4-Chlorophenyl) -4-isoxazolyl] propionamide (0.59 g, yield 63%) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 1
93-194 ° C. Example 42 1- (3-methoxyphenyl) ethylamine (0.32
g), 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.33 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.40 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- [1- (3-methoxyphenyl) ethyl] -3- [5- (4-chlorophenyl) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). -4-isoxazolyl] propionamide (0.61 g, yield 8
8%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 89-90 ° C.

Example 43 2-Aminomethyl-5-methylpyrazine (0.25 m
l), 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.40 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (5-methyl-2-pyrazinylmethyl) -3- [5- (4-chlorophenyl) -4 was extracted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). -Isoxazolyl] propionamide (0.58 g, yield 90
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 124-125 ° C. Example 44 4- (1-Imidazolyl) aniline (0.51 g), 3
-(5-phenyl-4-isoxazolyl) propionic acid (0.70 g), 1-hydroxy-1H-1,2,3
-Benzotriazole hydrate (0.60 g), hydrochloric acid 1
A mixture of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.75 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From the hexane (1: 1, volume ratio) elution part, N- [4- (1
-Imidazolyl) phenyl] -3- (5-phenyl-4
-Isoxazolyl) propionamide (0.95 g,
(83% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 176-177 [deg.] C.

Example 45 6-Aminoquinoline (0.38 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.56 g)
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3 hydrochloride
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.60 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (6-quinolyl) was eluted from an ethyl acetate-hexane (1: 1, volume ratio) eluate.
-3- (5-Phenyl-4-isoxazolyl) propionamide (0.79 g, yield 89%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 1
70-171 ° C. Example 46 2-Aminopyrazine (0.26 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.58
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3 hydrochloride
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.60 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- (2-pyrazinyl) -3- (5-phenyl-4-isoxazolyl) propionamide (0. 1) was eluted with ethyl acetate-hexane (1: 1, volume ratio). (46 g, 58% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 163-164 ° C.

Example 47 4- (1-morpholino) aniline (0.90 g),
(5-phenyl-4-isoxazolyl) propionic acid (1.07 g), 1-hydroxy-1H-1,2,3-
Benzotriazole hydrate (0.90 g), hydrochloric acid 1-
A mixture of ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.15 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- [4- (1- (1-
Morpholino) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide (1.23 g, yield 66%) was obtained as colorless crystals. Recrystallized from acetone-hexane. 197-198 ° C. Example 48 5-Amino-2- (1-morpholino) pyridine (0.8
5g), 3- (5-phenyl-4-isoxazolyl)
Propionic acid (1.01 g), 1-hydroxy-1H-
1,2,3-benzotriazole hydrate (0.85
g), a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.09 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer consists of diluted hydrochloric acid, saturated aqueous sodium bicarbonate,
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 1, volume ratio)
-[6- (1-morpholino) -3-pyridyl] -3-
(5-Phenyl-4-isoxazolyl) propionamide (0.86 g, yield 49%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 146
１４147 ° C.

Example 49 4- (1-Imidazolyl) aniline (0.85 g), 4
-(5-phenyl-4-isoxazolyl) butanoic acid (1.21 g), 1-hydroxy-1H-1,2,3-
Benzotriazole hydrate (0.95 g), hydrochloric acid 1-
A mixture of ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.20 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- [4- (1- (1-
Imidazolyl) phenyl] -4- (5-phenyl-4-
Isoxazolyl) butanamide (1.68 g, yield 8)
6%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 132-133 ° C. Example 50 A mixture of 3- (5-phenyl-4-isoxazolyl) propionic acid (18.62 g), concentrated sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(3, volume ratio) From the elution part, methyl 3- (5-phenyl-4-isoxazolyl) propionate (19.03 g, yield 96%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.
59-2.71 (2H, m), 2.95-3.06 (2H, m), 3.68 (3H, s), 7.4
2-7.56 (3H, m), 7.64-7.74 (2H, m), 8.22 (1H, s).

Example 51 Methyl 3- (5-phenyl-4-isoxazolyl) propionate (18.13 g) in tetrahydrofuran (3
(00 ml) solution, diisobutylaluminum hydride (1.0 M hexane solution, 160 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- (5-phenyl-4-isoxazolyl) propan-1-ol (15.72 g, yield 99) was eluted with ethyl acetate-hexane (2: 1, volume ratio). %) As a colorless oil. NMR (CDCl ₃ ) δ: 1.82-2.00 (2H, m), 2.
72-2.88 (2H, m), 3.66-3.78 (2H, m), 7.41-7.56 (3H,
m), 7.68-7.78 (2H, m), 8.21 (1H, s). Example 52 A mixture of 4- (5-phenyl-4-isoxazolyl) butyronitrile (12.83 g) and concentrated hydrochloric acid (100 ml) was refluxed overnight. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
4- (5-phenyl-4-isoxazolyl) butanoic acid (13.03 g, 93% yield)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Mp 67-68 ° C.

Example 53: Diethyl 4-aminobenzylphosphonate (1.74)
g), 4- (5-phenyl-4-isoxazolyl) butanoic acid (1.38 g), 1-hydroxy-1H-1,
2,3-benzotriazole hydrate (1.08 g),
1-ethyl-3- (3-dimethylaminopropyl) hydrochloride
A mixture of carbodiimide (1.38 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and N- (4) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-Diethylphosphonomethylphenyl) -4- (5-phenyl-4-isoxazolyl) butanamide (2.56
g, yield 94%) as colorless crystals. Ethyl acetate
Recrystallized from hexane. 128-129 ° C. Example 54 4- [2- (3-Ethyl-4H-triazol-4-yl) ethoxy] aniline (1.12 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (1.0
4g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.89 g), 1-ethyl hydrochloride
A mixture of 3- (3-dimethylaminopropyl) carbodiimide (1.11 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- [4- [2- (3
-Ethyl-4H-triazol-4-yl) ethoxy]
[Phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide (1.58 g, yield 76%) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 167-168 [deg.] C.

Example 55 4- [2- (3-Ethyl-4H-triazol-4-yl) ethoxy] aniline (0.51 g), 4- (5-phenyl-4-isoxazolyl) butanoic acid (0.51 g)
g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.40 g), 1-ethyl-3 hydrochloride
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.50 g) and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and N- [4- [2- (3
-Ethyl-4H-triazol-4-yl) ethoxy]
[Phenyl] -4- (5-phenyl-4-isoxazolyl) butanamide (0.83 g, yield 84%) was obtained as colorless crystals. Recrystallized from acetone-hexane. 125-126 ° C. Example 56 5-phenylisoxazole-4-carbaldehyde (7.18 g), ethyl diethylphosphonoacetate (9.3)
5 g) and N, N-dimethylformamide (150 m
To the mixture of 1), sodium hydride (60%, oily, 1.65 g) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E) -3- (5-phenyl-4-isoxazolyl) propenoate (8.88 g, yield) was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). Rate 8
8%) as a yellow oil. NMR (CDCl ₃ ) δ: 1.33 (3
H, t, J = 7.2 Hz), 4.27 (2H, q, J = 7.2 Hz), 6.34 (1H,
d, J = 15.4 Hz), 7.48-7.82 (6H, m), 8.52 (1H, s).

Example 57 4-Chloromethyl-3- (4-phenylphenyl) isoxazole (3.20 g) in tetrahydrofuran (1
00 ml) solution with diethyl malonate (5.70 g),
A mixture of sodium hydride (60%, oily, 1.40 g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight.
The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (4-phenylphenyl) -4-isoxazolyl] propionic acid (2.89 g, yield 83%).
I got Recrystallized from acetone-hexane. Melting point 16
9-170 ° C. Example 58 Diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) was added to a solution of methyl 3- [5- (4-fluorophenyl) -4-isoxazolyl] propionate (3.21 g) in tetrahydrofuran (30 ml). ° C
And then stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-fluorophenyl) -4-isoxazolyl] propan-1-ol (2. 48g,
(87% yield) as a pale yellow oil. NMR (CDCl ₃ )
δ: 1.38 (1H, br s), 1.82-2.02 (2H, m), 2.70-2.84 (2
H, m), 3.64-3.80 (2H, m), 7.10-7.26 (2H, m), 7.64-7.
80 (2H, m), 8.21 (1H, s).

Example 59 To a solution of diethyl malonate (3.38 g) in tetrahydrofuran (40 ml), sodium hydride (60%, oily, 770 mg) was gradually added at 0 ° C. After stirring for 10 minutes, a solution of 4-chloromethyl-5- (2,4-difluorophenyl) isoxazole (2.20 g) in tetrahydrofuran (40 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 2N hydrochloric acid to make it acidic, and then extracted with ethyl acetate. After concentrating the ethyl acetate layer, the residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml), and the mixture was heated under reflux for 8 hours.
The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, dried, and recrystallized from ethyl acetate-hexane to give 3- [5- (2,4-difluorophenyl)-.
Colorless prism crystals of [4-isoxazolyl] propionic acid (2.10 g, yield 87%) were obtained. 125 to 12
6 ° C. Example 60 3- [5- (4-trifluoromethylphenyl) -4-
Isoxazolyl] propionic acid (2.20 g) in methanol (50 ml) was added with concentrated sulfuric acid (1 ml),
Heated to reflux for an hour. The reaction mixture was concentrated, ice water was poured into the residue, and precipitated crystals of methyl 3- [5- (4-trifluoromethylphenyl) -4-isoxazolyl] propionate (1.70 g, yield 74%) were collected by filtration. I took it. Recrystallization from ethyl acetate-hexane gave colorless prisms. 68-69 ° C.

Example 61 Concentrated sulfuric acid (1 ml) was added to a solution of 3- [5- (2,4-difluorophenyl) -4-isoxazolyl] propionic acid (1.25 g) in methanol (40 ml), and the mixture was heated under reflux for 1 hour. did. The reaction mixture was concentrated, ice water was poured into the residue, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 1, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 3- [5- (2,4). -Difluorophenyl) -4-isoxazolyl] colorless prisms of methyl propionate (1.15 g, yield 87)
%). Melting point 40-41 [deg.] C. Example 62 3- [5- (4-trifluoromethylphenyl) -4-
Isoxazolyl] methyl propionate (1.40 g)
In a tetrahydrofuran (80 ml) solution of diisobutylaluminum hydride (1.0 M hexane solution, 10.
3 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, concentrated, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 3- [5- (4-trifluoromethylphenyl)-.
4-isoxazolyl] propan-1-ol (970
mg, yield 76%) as colorless needles. Melting point 85
~ 86 ° C.

Example 63 To a solution of methyl 3- [5- (2,4-difluorophenyl) -4-isoxazolyl] propionate (1.05 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution). , 8.7m
1) was added slowly at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1,
From the eluted part, 3- [5- (2,4-difluorophenyl) -4-isoxazolyl] propan-1-ol (640 mg, yield 68%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.29 (1H, brs), 1.75-1.95 (2H,
m), 2.55-2.65 (2H, m), 3.6-3.75 (2H, m), 6.9-7.1 (2H,
m), 7.5-7.65 (1H, m), 8.25 (1H, s). Example 64 To a solution of diethyl malonate (10.1 g) in tetrahydrofuran (60 ml) was slowly added sodium hydride (60%, oily, 2.29 g) at 0 ° C. After stirring for 10 minutes, 4-chloromethyl-5- (5-chloro-2-
A solution of (thienyl) isoxazole (6.70 g) in tetrahydrofuran (60 ml) was added dropwise at 0 ° C.
Stir for 5 hours. The reaction mixture was poured into 2N hydrochloric acid to make it acidic, and then extracted with ethyl acetate. After concentrating the ethyl acetate layer, the residue was treated with 6N hydrochloric acid (80 ml) and acetic acid (1 ml).
20 ml) and heated under reflux for 8 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 3-
Colorless prism crystals of [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionic acid (4.95 g,
Yield 67%). 138-139 ° C.

Example 65 Concentrated sulfuric acid (1 ml) was added to a solution of 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionic acid (2.20 g) in methanol (50 ml), and the mixture was heated for 1 hour. Refluxed. The reaction mixture was concentrated, ice water was poured into the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of methyl 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionate were obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). (3.80 g, 86% yield). Recrystallization from diethyl ether-isopropyl ether gave colorless prisms. 34-35 ° C. Example 66 To a solution of methyl 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionate (3.10 g) in tetrahydrofuran (80 ml) was added diisobutylaluminum hydride (1.5 M toluene solution, 17 ml). ) Was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propan-1-ol was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). (2.02 g, 73% yield) as a colorless oil.
NMR (CDCl ₃ ) δ: 1.41 (1H, brt, J = 5 Hz), 1.8-2.0 (2H,
m), 2.73 (2H, t, J = 8 Hz), 3.73 (2H, td, J = 6, 5 Hz),
6.98 (1H, d, J = 4 Hz), 7.29 (1H, d, J = 4 Hz), 8.17 (1H,
s).

Example 67 To a solution of methyl 3- [5- (2,4-dichlorophenyl) -4-isoxazolyl] propionate (2.00 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 15 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (2,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol (1) was eluted with ethyl acetate-hexane (2: 1, volume ratio). .67 g, 92% yield) as a colorless oil.
NMR (CDCl ₃ ) δ: 1.20-1.32 (1H, brt), 1.70-1.88 (2H,
m), 2.44-2.60 (2H, m), 3.56-3.70 (2H, m), 7.35-7.39 (2
H, m), 7.53-7.57 (1H, m), 8.27 (1H, s). Example 68 Diisobutylaluminum hydride (1.0 M hexane solution, 13 ml) was added to a solution of methyl 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propionate (1.63 g) in tetrahydrofuran (25 ml). After slowly adding at 0 ° C., the mixture was stirred at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol (1) was eluted with ethyl acetate-hexane (2: 1, volume ratio). 0.53 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 66-67
° C.

Example 69 5- (2,4-Dichlorophenyl) -4-isoxazolylmethanol (5.15 g) in toluene (100 m
l) Thionyl chloride (2.00 ml) was added dropwise to the solution at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00 ml) and diethyl malonate (5.89).
g), sodium hydride (60%, oily, 1.45 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (2,4-dichlorophenyl) -4-.
Isoxazolyl] propionic acid (3.85 g, yield 7)
2%). Recrystallized from acetone-hexane. 106-107 ° C. Example 70 5- (3,4-Dichlorophenyl) -4-isoxazolylmethanol (6.50 g) in toluene (100 m
l) Thionyl chloride (3.0 ml) was added dropwise to the solution at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00ml) and diethyl malonate (8.53).
g), sodium hydride (60%, oily, 2.01 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (3,4-dichlorophenyl) -4-.
Isoxazolyl] propionic acid (5.96 g, yield 7)
8%). Recrystallized from acetone-hexane. Melting point 171-172 [deg.] C.

Example 71 3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionic acid (3.68 g), concentrated sulfuric acid (0.0
5 ml) and methanol (100 ml).
Refluxed for hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) eluted with 3- [5-
Methyl (4-fluorophenyl) -4-isoxazolyl] propionate (3.50 g, 90% yield) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 2.65 (2H, t, J = 7.4
Hz), 2.98 (2H, t, J = 7.4 Hz), 3.69 (3H, s), 7.12-7.28
(2H, m), 7.64-7.78 (2H, m), 8.22 (1H, s). Example 72 A mixture of 3- [5- (2,4-dichlorophenyl) -4-isoxazolyl] propionic acid (3.00 g), concentrated sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) was eluted with 3- [5
Methyl-(2,4-dichlorophenyl) -4-isoxazolyl] propionate (2.96 g, 94% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.46-2.58 (2H,
m), 2.71-2.81 (2H, m), 3.66 (3H, s), 7.35-7.42 (2H,
m), 7.54-7.58 (1H, m), 8.28 (1H, s).

Example 73 A mixture of 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propionic acid (3.20 g), concentrated sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4 hours. . The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) was eluted with 3- [5
Methyl-(3,4-dichlorophenyl) -4-isoxazolyl] propionate (3.26 g, 97% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 74-75 ° C. Example 74 5- (3,5-Dichlorophenyl) -4-isoxazolylmethanol (6.06 g) in toluene (100 m
l) Thionyl chloride (2.7 ml) was added dropwise to the solution at 0 ° C, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00 ml) and diethyl malonate (7.96).
g), sodium hydride (60%, oily, 1.95 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (3,5-dichlorophenyl) -4-.
Isoxazolyl] propionic acid (5.96 g, yield 8)
4%). Recrystallized from acetone-hexane. 143-144 ° C.

Example 75 A mixture of 3- [5- (3,5-dichlorophenyl) -4-isoxazolyl] propionic acid (3.50 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. . The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with 3-
Methyl [5- (3,5-dichlorophenyl) -4-isoxazolyl] propionate (3.49 g, yield 99)
%) As a pale yellow oil. NMR (CDCl ₃ ) δ: 2.62-
2.72 (2H, m), 2.92-3.02 (2H, m), 3.70 (3H, s), 7.45 (1
H, t, J = 1.8 Hz), 7.60 (1H, d, J = 1.8 Hz), 8.24 (1H,
s). Example 76 Diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) was added to a solution of methyl 3- [5- (3,5-dichlorophenyl) -4-isoxazolyl] propionate (2.25 g) in tetrahydrofuran (30 ml). After slowly adding at 0 ° C., the mixture was stirred at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (3,5-dichlorophenyl) -4-isoxazolyl] propan-1-ol (1) was eluted with ethyl acetate-hexane (2: 1, volume ratio). .65 g, 81% yield) as a colorless oil.
NMR (CDCl ₃ ) δ: 1.83-2.00 (2H, m), 2.72-2.86 (2H, m),
3.68-3.80 (2H, m), 7.43 (1H, t, J = 1.8 Hz), 7.64 (2H, m
d, J = 1.8 Hz), 8.24 (1H, s).

Example 77 5- (3,4-Difluorophenyl) -4-isoxazolyl methanol (4.80 g) in toluene (100 m
l) Thionyl chloride (2.5 ml) was added dropwise to the solution at 0 ° C, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00 ml) and diethyl malonate (7.26).
g), sodium hydride (60%, oily, 1.79 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (3,4-difluorophenyl) -4.
[Isoxazolyl] propionic acid (4.98 g, yield 87%) was obtained. Recrystallized from ethyl acetate-hexane. 102-103 ° C. Example 78 A mixture of 3- [5- (3,4-difluorophenyl) -4-isoxazolyl] propionic acid (3.45 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with 3-
Methyl [5- (3,4-difluorophenyl) -4-isoxazolyl] propionate (3.56 g, yield 98)
%) As a pale yellow oil. NMR (CDCl ₃ ) δ: 2.60-
2.71 (2H, m), 2.92-3.03 (2H, m), 3.69 (3H, s), 7.22-
7.65 (3H, m), 8.23 (1H, s).

Example 79 To a solution of methyl 3- [5- (3,4-difluorophenyl) -4-isoxazolyl] propionate (2.20 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution). , 20ml)
Was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1,
From the eluted part, 3- [5- (3,4-difluorophenyl) -4-isoxazolyl] propan-1-ol (1.88 g, yield 95%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.38 (1H, br s), 1.82-2.00 (2H,
m), 2.72-2.84 (2H, m), 3.66-3.82 (2H, m), 7.21-7.38 (1
H, m), 7.44-7.66 (2H, m), 8.22 (1H, s). Example 80 Thionyl chloride (3.3 ml) was added dropwise to a solution of 5- (4-nitrophenyl) -4-isoxazolylmethanol (6.56 g) in toluene (100 ml) at 0 ° C.
Stir at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml), added to a mixture of diethyl malonate (9.56 g), sodium hydride (60%, oily, 2.35 g) and tetrahydrofuran (50 ml) at 0 ° C.
For 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate.
The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3,
A colorless oil was obtained from the elution part (volume ratio). The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of 1) was refluxed for 5 hours. Concentrate the reaction mixture,
Water was added to the residue. The obtained colorless crystals were collected by filtration,
[5- (4-Nitrophenyl) -4-isoxazolyl] propionic acid (6.19 g, 79% yield) was obtained.
Recrystallized from acetone-hexane. Melting point 204-20
5 ° C.

Example 81 3- [5- (4-Nitrophenyl) -4-isoxazolyl] propionic acid (5.28 g), concentrated sulfuric acid (0.1 m
A mixture of 1) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-
Methyl [nitrophenyl) -4-isoxazolyl] propionate (5.45 g, 98% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 11
8-119 ° C. Example 82 Diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) was added to a solution of methyl 3- [5- (4-nitrophenyl) -4-isoxazolyl] propionate (1.60 g) in tetrahydrofuran (20 ml). After slowly adding the mixture at ° C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-nitrophenyl) -4-isoxazolyl] propan-1-ol (1.x) was eluted with ethyl acetate-hexane (2: 1, volume ratio). (36 g, 95% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 132-133 ° C.

Example 83 5- (4-Bromophenyl) -4-isoxazolylme
Solution of toluene (7.55 g) in toluene (50 ml)
After dropwise addition of thionyl chloride (3.3 ml) at 0 ° C,
Stir at room temperature for 3 hours. The reaction mixture is concentrated and the residue
To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. Ethyl acetate
Layer is washed with saturated saline and dried (MgSO_Four) After, dark
Shrunk. Residue in tetrahydrofuran (100ml)
Dissolved, diethyl malonate (9.58 g), sodium hydride
Lithium (60%, oily, 2.36 g) and tetrahydride
After adding to a mixture of lofuran (50 ml) at 0 ° C,
For 1 hour and then overnight at room temperature. Reaction mixture
Was acidified with diluted hydrochloric acid, and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline and dried (MgS
O _Four) And concentrated. The residue is purified by silica gel column chromatography.
The mixture was subjected to chromatography, and ethyl acetate-hexane (1: 3,
A colorless oil was obtained from the elution part (volume ratio). Colorless obtained
Oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of 1) was refluxed for 5 hours. Concentrate the reaction mixture,
Water was added to the residue. The obtained colorless crystals were collected by filtration,
[5- (4-bromophenyl) -4-isoxazolyl
[Propionic acid] (6.18 g, yield 70%).
Recrystallized from ethyl acetate-hexane. Melting point 164-1
65 ° C. Example 84: 3- [5- (4-bromophenyl) -4-isoxazo
Lyl] propionic acid (5.00 g), concentrated sulfuric acid (0.1 m
l) and a mixture of methanol (100 ml) for 4 hours
Refluxed. Concentrate the reaction mixture, add water to the residue, add vinegar
Extracted with ethyl acid. Wash the ethyl acetate layer with saturated saline
Purification, drying (MgSO_Four) And concentrated. Silica residue
The mixture was subjected to gel column chromatography,
From the elution part of xanthane (1: 3, volume ratio), 3- [5- (4-
Bromophenyl) -4-isoxazolyl] propion
Methyl (5.03 g, 96% yield) as colorless crystals
Obtained. Recrystallized from ethyl acetate-hexane. Melting point 58
~ 59 ° C.

Example 85 Diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) was added to a solution of methyl 3- [5- (4-bromophenyl) -4-isoxazolyl] propionate (4.06 g) in tetrahydrofuran (30 ml). ) Was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-bromophenyl) -4-isoxazolyl] propan-1-ol (3.1) was eluted with ethyl acetate-hexane (2: 1, volume ratio). (58 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 72-73 ° C. Example 86 Thionyl chloride (3.6 ml) was added dropwise to a solution of 5- (3-chlorophenyl) -4-isoxazolyl methanol (6.80 g) in toluene (100 ml) at 0 ° C.
Stir at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added at 0 ° C. to a mixture of diethyl malonate (10.38 g), sodium hydride (60%, oily, 2.56 g) and tetrahydrofuran (50 ml).
Stirred at C for 1 hour, then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3,
A colorless oil was obtained from the elution part (volume ratio). The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of 1) was refluxed for 5 hours. Concentrate the reaction mixture,
Water was added to the residue. The obtained colorless crystals were collected by filtration,
[5- (3-Chlorophenyl) -4-isoxazolyl] propionic acid (5.95 g, yield 73%) was obtained.
Recrystallized from acetone-hexane. Melting point 110-11
1 ° C.

Example 87 3- [5- (3-Chlorophenyl) -4-isoxazolyl] propionic acid (3.10 g), concentrated sulfuric acid (0.1 m
A mixture of 1) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (3- (3-
Chlorophenyl) -4-isoxazolyl] propionate (3.06 g, 93% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.59-2.71 (2H, m), 2.93-3.05
(2H, m), 3.69 (3H, s), 7.36-7.50 (2H, m), 7.54-7.65
(1H, m), 7.69-7.73 (1H, m), 8.23 (1H, s). Example 88 Diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) was added to a solution of methyl 3- [5- (3-chlorophenyl) -4-isoxazolyl] propionate (2.50 g) in tetrahydrofuran (30 ml) at 0 ° C. And then stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (3-chlorophenyl) -4-isoxazolyl] propan-1-ol (2.38 g) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). , 95% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 1.39
(1H, br s), 1.84-2.00 (2H, m), 2.72-2.86 (2H, m), 3.
66-3.80 (2H, m), 7.38-7.49 (2H, m), 7.56-7.68 (1H,
m), 7.70-7.77 (1H, m), 8.23 (1H, s).

Example 89 5- (1,3-benzodioxol-5-yl) -4-
Isoxazolyl methanol (7.90 g) in toluene
(150 ml) solution at 0 ° C. with thionyl chloride (4.0 m
After l) was added dropwise, the mixture was stirred at room temperature for 3 hours. Reaction mixing
The residue was concentrated, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was
Extracted. The ethyl acetate layer is washed with saturated saline and dried
(MgSO_Four) And concentrated. The residue was
Dissolve in orchid (200 ml) and add diethyl malonate (1
1.55 g), sodium hydride (60%, oily, 2.
85g) and tetrahydrofuran (50ml)
At 0 ° C for 1 hour, followed by ending at room temperature.
Stirred at night. The reaction mixture was acidified with dilute hydrochloric acid
Then, the mixture was extracted with ethyl acetate. The ethyl acetate layer is
Wash with water and dry (MgSO_Four) And concentrated. Residue
After subjecting to silica gel column chromatography, ethyl acetate
Colorless oil from the eluate of le-hexane (1: 3, volume ratio)
I got something. The obtained colorless oil, 6N hydrochloric acid (50 m
l) and a mixture of acetic acid (50 ml) was refluxed for 5 hours.
Was. The reaction mixture was concentrated, and water was added to the residue. Obtained
The colorless crystals were collected by filtration, and 3- [5- (1,3-benzodioxide) was collected.
Xol-5-yl) -4-isoxazolyl] propi
Ononic acid (7.36 g, 78% yield) was obtained. Acetone-
Recrystallized from hexane. 150-151 ° C. Example 90 3- [5- (1,3-benzodioxol-5-yl)
-4-isoxazolyl] propionic acid (4.19
g), concentrated sulfuric acid (0.1 ml) and methanol (100
ml) of the mixture was refluxed for 4 hours. Concentrate the reaction mixture
Then, water was added to the residue, and the mixture was extracted with ethyl acetate. Acetic acid
The chill layer is washed with a saturated saline solution and dried (MgSO 4). _Four)rear,
Concentrated. Silica gel column chromatography of the residue
And dissolve in ethyl acetate-hexane (1: 3, volume ratio)
From the head, 3- [5- (1,3-benzodioxol-5)
-Yl) -4-isoxazolyl] methyl propionate
(4.26 g, yield 97%) was obtained as colorless crystals. vinegar
It was recrystallized from ethyl acetate-hexane. Melting point 84-85
° C.

Example 91 3- [5- (1,3-benzodioxol-5-yl)
-4-isoxazolyl] methyl propionate (2.7
0 g) in tetrahydrofuran (30 ml) solution.
Diisobutylaluminum chloride (1.0 M hexane solution,
25 ml) slowly at 0 ° C. and then at room temperature for 1 hour
Stirred. Pour the reaction mixture into diluted hydrochloric acid and add ethyl acetate.
Extracted. The ethyl acetate layer is washed with saturated saline and dried
(MgSO _Four) And concentrated. Silica gel residue
Chromatography, and ethyl acetate-hexane
(2: 1, volume ratio) 3- [5- (1,3-b
Nzodioxol-5-yl) -4-isoxazoly
Ru] propan-1-ol (2.33 g, 96% yield)
Was obtained as colorless crystals. Recombined from ethyl acetate-hexane
Crystallized. 45-46 ° C. Example 92 5- (3-chloro-4-fluorophenyl) -4-iso
Oxazolyl methanol (7.01 g) in toluene (1
Thionyl chloride (3.5 ml) at 0 ° C.
After dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture
Concentrate, add saturated aqueous sodium bicarbonate to the residue, and extract with ethyl acetate
did. The ethyl acetate layer was washed with saturated saline and dried (Mg
SO_Four) And concentrated. Residue in tetrahydrofuran
(100 ml) and diethyl malonate (9.89).
g), sodium hydride (60%, oily, 2.43 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
, And stirred at 0 ° C for 1 hour, followed by stirring at room temperature overnight.
I did. After acidifying the reaction mixture with dilute hydrochloric acid,
Extracted with chill. The ethyl acetate layer was washed with saturated saline,
Dry (MgSO_Four) And concentrated. Silica gel residue
After column chromatography,
A colorless oil was obtained from the elution portion of the solvent (1: 3, volume ratio).
The obtained colorless oil, 6N hydrochloric acid (50 ml) and vinegar
The mixture of acids (50 ml) was refluxed for 5 hours. Reaction mixture
Was concentrated, and water was added to the residue. Filter the obtained colorless crystals.
To give 3- [5- (3-chloro-4-fluorophenyl)
) -4-isoxazolyl] propionic acid (6.68)
g, 80% yield). Reconstituted from acetone-hexane
Crystallized. 118-119 ° C.

Example 93 3- [5- (3-Chloro-4-fluorophenyl) -4
A mixture of [-isoxazolyl] propionic acid (3.10 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[5- (3-chloro-4-fluorophenyl) -4-
Isoxazolyl] methyl propionate (3.18 g,
(97% yield) as a pale yellow oil. NMR (CDCl ₃ )
δ: 2.60-2.72 (2H, m), 2.91-3.03 (2H, m), 3.69 (3H,
s), 7.22-7.33 (1H, m), 7.52-7.66 (1H, m), 7.74-7.82
(1H, m), 8.23 (1H, s). Example 94: 3- [5- (3-Chloro-4-fluorophenyl) -4
-Isoxazolyl] methyl propionate (3.00
g) in tetrahydrofuran (25 ml) was added to diisobutylaluminum hydride (1.0 M hexane solution, 2 ml).
5 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [5- (3-chloro-4-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (2.59 g, yield 95%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.40 (1H, br s), 1.82-
2.00 (2H, m), 2.70-2.84 (2H, m), 3.66-3.78 (2H, m),
7.20-7.32 (1H, m), 7.55-7.67 (1H, m), 7.76-7.84 (1H, m
m), 8.22 (1H, s).

Example 95 To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml) was slowly added sodium hydride (60%, oily, 1.32 g) at 0 ° C. After stirring for 10 minutes, 4-chloromethyl-5- (4-chloro-3-
A solution of (methylphenyl) isoxazole (4.00 g) in tetrahydrofuran (40 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hours.
The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 3
Colorless prism crystals of-[5- (4-chloro-3-methylphenyl) -4-isoxazolyl] propionic acid (2.
(56 g, yield 58%). 158-159 ° C. Example 96 3- [5- (4-Chloro-3-methylphenyl) -4-
Isoxazolyl] propionic acid (1.80 g) in methanol (50 ml) was added with concentrated sulfuric acid (1 ml),
Heated to reflux for an hour. The reaction mixture was concentrated, ice water was poured into the residue, and precipitated crystals of methyl 3- [5- (4-chloro-3-methylphenyl) -4-isoxazolyl] propionate were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless needles (1.72 g, 91% yield). Melting point 60-61 [deg.] C.

Example 97 3- [5- (4-Chloro-3-methylphenyl) -4-
Isoxazolyl] methyl propionate (1.20 g)
To a solution of diisobutylaluminum hydride (1.0 M in toluene, 9.5).
ml) was slowly added at 0 ° C., followed by stirring at room temperature for 3 hours. Water was carefully added to the reaction mixture, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 1, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 3-
Colorless needles of [5- (4-chloro-3-methylphenyl) -4-isoxazolyl] propan-1-ol (780 mg, yield 72%) were obtained. Melting point 50-51 [deg.] C. Example 98 To a solution of diethyl malonate (2.89 g) in tetrahydrofuran (40 ml) was slowly added sodium hydride (60%, oily, 655 mg) at 0 ° C. After stirring for 10 minutes, a solution of 4-chloromethyl-5- (2,5-dichlorophenyl) isoxazole (2.15 g) in tetrahydrofuran (40 ml) was added dropwise at 0 ° C.
Stir for 5 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was treated with 6N hydrochloric acid (40 ml) and acetic acid (60
ml) and heated to reflux for 8 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 3- [5
Colorless prism crystals of (-(2,5-dichlorophenyl) -4-isoxazolyl] propionic acid (1.35 g, yield 58%) were obtained. 103-104 ° C.

Example 99 To a solution of 3- [5- (2,5-dichlorophenyl) -4-isoxazolyl] propionic acid (800 mg) in methanol (30 ml) was added concentrated sulfuric acid (1 ml), and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, ice water was poured into the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio), 3- [5
Methyl-(2,5-dichlorophenyl) -4-isoxazolyl] propionate was obtained as a colorless oil (500 mg, yield 60%). NMR (CDCl ₃ ) δ: 2.5-2.85 (4H,
m), 3.66 (3H, s), 7.35-7.5 (3H, m), 8.28 (1H, s). Example 100 5- (3,4-Dimethoxyphenyl) -4-isoxazolylmethanol (6.65 g) in toluene (100 m
l) Thionyl chloride (3.1 ml) was added dropwise to the solution at 0 ° C, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00 ml) and diethyl malonate (9.10).
g), sodium hydride (60%, oily, 2.25 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [5- (3,4-dimethoxyphenyl) -4.
[Isoxazolyl] propionic acid (7.36 g, 78% yield) was obtained. Recrystallized from acetone-hexane.
Melting point 169-170 [deg.] C.

Example 101 A mixture of 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] propionic acid (2.53 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. did. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with 3-
Methyl [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] propionate (2.58 g, yield 97)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 68-69 ° C. Example 102 Diisobutylaluminum hydride (1.0 M hexane solution, 15 ml) in a solution of methyl 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] propionate (1.70 g) in tetrahydrofuran (20 ml)
Was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1,
From the eluted part, 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] propan-1-ol (1.26 g, yield 82%) was obtained as colorless crystals.
Recrystallized from ethyl acetate-hexane. 55-56 melting point
° C.

Example 103: Tetrahydrofuran of diethyl malonate (10.3 g)
(80 ml) solution in sodium hydride (60%, oil
2.34 g) was added slowly at 0 ° C. Persimmon for 10 minutes
After mixing, 4-chloromethyl-5- (4-methylthiophene
Enyl) isoxazole (7.00 g)
A solution of lofuran (70 ml) was added dropwise at 0 ° C., and at room temperature for 8 hours
Stirred. Pour the reaction mixture into water and acidify with 2N hydrochloric acid.
After being made acidic, it was extracted with ethyl acetate. The ethyl acetate layer
Wash with saturated saline and dry (MgSO _Four) And concentrated.
The residue was treated with 6N hydrochloric acid (50 ml) and acetic acid (100 m
The mixture was dissolved in the mixture of 1) and heated under reflux for 5 hours. Reaction mixing
The product was concentrated, water was added to the residue, and 3- [5- (4-methyl
Ruthiophenyl) -4-isoxazolyl] propion
Colorless crystals of the acid (4.68 g, 61% yield) were obtained. Acetic acid
Recrystallized from ethyl-isopropyl ether to give
Zum crystals were obtained. 124-125 ° C. Example 104 3- [5- (4-methylthiophenyl) -4-isooxo
Sazolyl] propionic acid (3.70 g) in methanol
(100 ml) solution, add concentrated sulfuric acid (1 ml) and add 1 hour
Heated to reflux. Concentrate the reaction mixture and pour ice water into the residue.
3- [5- (4-methylthiophenyl)-
The crystals of methyl 4-isoxazolyl] propionate are filtered.
I took it. Recrystallized from ethyl acetate-isopropyl ether
To obtain colorless prism crystals (3.60 g, yield 92%).
Was. 57-58 ° C.

Example 105 To a solution of methyl 3- [5- (4-methylthiophenyl) -4-isoxazolyl] propionate (1.60 g) in tetrahydrofuran (60 ml) was added diisobutylaluminum hydride (0.95 M toluene solution, 15 ml). .2m
1) was added slowly at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the acetone-hexane (1: 1, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 3- [5- (4-methylthiophene). Phenyl) -4-isoxazolyl] propan-1-ol was obtained as colorless prism crystals (1.36 g, yield 95%). 54-55 ° C. Example 106 To a solution of 3- [5- (4-methylthiophenyl) -4-isoxazolyl] propan-1-ol (500 mg) in tetrahydrofuran (30 ml), m-chloroperbenzoic acid (870 mg) was gradually added at 0 ° C. After adding, 1 at room temperature
Stir for hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and crystals of 3- [5- (4-methylsulfonylphenyl) -4-isoxazolyl] propan-1-ol were eluted with acetone-hexane (1: 1, volume ratio). (480 mg, yield 85%) was obtained. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles. 125-126 ° C.

Example 107 To a solution of 3- [5- (4-methylthiophenyl) -4-isoxazolyl] propan-1-ol (900 mg) in acetonitrile (20 ml) was added m-chloroperbenzoic acid (750 mg) at 0 ° C. And then stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and acetone-hexane (2:
From the eluted part (1, volume ratio), crystals of 3- [5- (4-methylsulfinylphenyl) -4-isoxazolyl] propan-1-ol (390 mg, yield 41%) were obtained. Recrystallization from ethyl acetate-diethyl ether gave colorless prisms. 73-74 ° C. Example 108 5- (4-Chloro-3-fluorophenyl) -4-isoxazolylmethanol (7.80 g) in toluene (1
50 ml) solution at 0 ° C. in thionyl chloride (4.0 ml).
After dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (150 ml) and diethyl malonate (10.9
8g), sodium hydride (60%, oily, 2.71)
g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [5- (4-chloro-3-fluorophenyl) -4-isoxazolyl] propionic acid (7.2
0 g, 78% yield). Recrystallized from acetone-hexane. 139-140 ° C.

Example 109 3- [5- (4-Chloro-3-fluorophenyl) -4
A mixture of -isoxazolyl] propionic acid (5.08 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[5- (4-chloro-3-fluorophenyl) -4-
Isoxazolyl] methyl propionate (5.25 g,
(98% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 53-54 ° C. Example 110 3- [5- (4-chloro-3-fluorophenyl) -4
-Isoxazolyl] methyl propionate (3.30
g) in tetrahydrofuran (30 ml) was added to diisobutylaluminum hydride (1.0 M hexane solution, 2 ml).
5 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [5- (4-chloro-3-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (2.79 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 51-52 [deg.] C.

Example 111 3- (3,4-Dichlorophenyl) -4-isoxazolyl methanol (5.50 g) in toluene (50 ml)
Thionyl chloride (2.5 ml) was added dropwise to the solution at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was treated with tetrahydrofuran (100 m
1) and added to a mixture of diethyl malonate (7.21 g), sodium hydride (60%, oily, 1.79 g) and tetrahydrofuran (50 ml) at 0 ° C., followed by 1 hour at 0 ° C. And stirred overnight at room temperature. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(3, volume ratio) A colorless oil was obtained from the elution part. The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50
ml) of the mixture was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals are collected by filtration,
3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionic acid (5.09 g, 79% yield)
I got Recrystallized from acetone-hexane. Melting point 18
1-182 ° C. Example 112 A mixture of 3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionic acid (3.03 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with 3-
Methyl [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionate (3.15 g, yield 99)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 87-88 ° C.

Example 113 To a solution of methyl 3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionate (2.40 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol (2) was eluted with ethyl acetate-hexane (2: 1, volume ratio). 0.06 g, yield 95%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 62-63
° C. Example 114 3- (3-Chloro-4-fluorophenyl) -4-isoxazolylmethanol (6.60 g) in toluene (7
Thionyl chloride (3.5 ml) was added dropwise to the solution (5 ml) at 0 ° C., followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00 ml) and diethyl malonate (9.31).
g), sodium hydride (60%, oily, 2.30 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (3-chloro-4-fluorophenyl) -4-isoxazolyl] propionic acid (5.71).
g, yield 73%). Recrystallized from acetone-hexane. 140-141 ° C.

Example 115 3- [3- (3-Chloro-4-fluorophenyl) -4
A mixture of [-isoxazolyl] propionic acid (4.34 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[3- (3-chloro-4-fluorophenyl) -4-
Isoxazolyl] methyl propionate (4.39 g,
(96% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 39-40 [deg.] C. Example 116 3- [3- (3-chloro-4-fluorophenyl) -4
-Isoxazolyl] methyl propionate (3.50
g) in tetrahydrofuran (50 ml) solution, diisobutylaluminum hydride (1.0 M hexane solution, 3
(0 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [3- (3-chloro-4-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (2.89 g, yield 92%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ 1.30 (1H, t, J = 5.2 Hz), 1.7
4-1.94 (2H, m), 2.62-2.74 (2H, m), 3.64-3.76 (2H, m),
7.18-7.31 (1H, m), 7.50-7.60 (1H, m), 7.74 (1H, dd,
J = 2.2, 7.0 Hz), 8.29 (1H, s).

Example 117 3- (4-Chloro-3-fluorophenyl) -4-isoxazolylmethanol (9.04 g) in toluene (1
00 ml) solution at 0 ° C. in thionyl chloride (4.5 ml).
After dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and diethyl malonate (12.7).
5g), sodium hydride (60%, oily, 3.15)
g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (4-chloro-3-fluorophenyl) -4-isoxazolyl] propionic acid (7.7) was used.
2 g, yield 72%). Recrystallized from acetone-hexane. 148-149 ° C. Example 118 3- [3- (4-chloro-3-fluorophenyl) -4
[Isoxazolyl] propionic acid (5.00 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) were refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[3- (4-chloro-3-fluorophenyl) -4-
Isoxazolyl] methyl propionate (5.01 g,
(96% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 57-58 ° C.

Example 119 3- [3- (4-Chloro-3-fluorophenyl) -4
-Isoxazolyl] methyl propionate (3.69
g) in tetrahydrofuran (30 ml) was added to diisobutylaluminum hydride (1.0 M hexane solution, 3
(0 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [3- (4-chloro-3-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (3.06 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 54-55 ° C. Example 120 3- [5- (4-Methoxyphenyl) -4-isoxazolyl] propionic acid (2.75 g), concentrated sulfuric acid (0.1
ml) and methanol (100 ml) were refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From the hexane (1: 3, volume ratio) elution part, 3- [5- (4
-Methoxyphenyl) -4-isoxazolyl] propionate (2.76 g, yield 95%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.58-2.70 (2H, m), 2.92-3.
04 (2H, m), 3.68 (3H, s), 3.87 (3H, s), 6.96-7.06 (2H,
m), 7.59-7.69 (2H, m), 8.18 (1H, s).

Example 121 To a solution of methyl 3- [5- (4-methoxyphenyl) -4-isoxazolyl] propionate (2.50 g) in tetrahydrofuran (20 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml). ) At 0 ° C
And then stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-methoxyphenyl) -4-isoxazolyl] propan-1-ol (2. 1) was eluted with ethyl acetate-hexane (2: 1, volume ratio). 03g,
(91% yield) as a colorless oil. NMR (CDCl ₃ ) δ:
1.82-1.98 (2H, m), 2.70-2.82 (2H, m), 3.66-3.78 (2H, m
m), 3.86 (3H, s), 6.95-7.06 (2H, m), 7.62-7.73 (2H,
m), 8.18 (1H, s). Example 122 3- [5- (4-Methylphenyl) -4-isoxazolyl] propionic acid (4.00 g), concentrated sulfuric acid (2 ml)
And a mixture of methanol (80 ml) was refluxed for 1 hour. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- [5- (4-methylphenyl) -4-isoxazolyl] propionate (3.35 g, (79% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.63 (2H, t, J = 7.5 H
z), 2.99 (2H, t, J = 7.5 Hz), 3.68 (3H, s), 7.30 (2H, d,
J = 8 Hz), 7.59 (2H, d, J = 8 Hz), 8.20 (1H, s).

Example 123 To a solution of diethyl malonate (3.55 g) in tetrahydrofuran (50 ml) was slowly added sodium hydride (60%, oily, 710 mg) at 0 ° C. After stirring for 10 minutes, a solution of 4-chloromethyl-5- (4,5-dichloro-2-thienyl) isoxazole (2.38 g) in tetrahydrofuran (50 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 15 hours. . The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (60 ml) and acetic acid (90 ml) and heated under reflux for 8 hours.
The reaction mixture was concentrated, water was added to the residue, and 3- [5-
Colorless crystals of (4,5-dichloro-2-thienyl) -4-isoxazolyl] propionic acid (2.04 g, yield 7)
9%). Recrystallization from ethyl acetate-hexane gave colorless prisms. 142-143 ° C. Example 124 3- [5- (4,5-dichloro-2-thienyl) -4-
Isoxazolyl] propionic acid (1.60 g) in methanol (30 ml) was added with concentrated sulfuric acid (1 ml),
Heated to reflux for an hour. The reaction mixture was concentrated, ice water was poured into the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 7, volume ratio) was eluted with 3-
Crystals of methyl [5- (4,5-dichloro-2-thienyl) -4-isoxazolyl] propionate (1.34
g, 80% yield). Recrystallization from diethyl ether-hexane gave colorless needles. Melting point 49-50 [deg.] C.

Example 125 3- (3-Bromo-4-fluorophenyl) -4-isoxazolylmethanol (6.79 g) in toluene (5
0 ml) solution was added dropwise with thionyl chloride (3.0 ml) at 0 ° C., followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (1
00ml) and diethyl malonate (8.11).
g), sodium hydride (60%, oily, 2.00 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [3- (3-bromo-4-fluorophenyl) -4-isoxazolyl] propionic acid (6.33).
g, yield 81%). Recrystallized from acetone-hexane. 151-152 ° C.

Example 126 3- [3- (3-Bromo-4-fluorophenyl) -4
A mixture of [-isoxazolyl] propionic acid (3.15 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[3- (3-Bromo-4-fluorophenyl) -4-
Isoxazolyl] methyl propionate (3.11 g,
(95% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. 57-58 ° C. Example 127 3- [3- (3-bromo-4-fluorophenyl) -4
-Isoxazolyl] methyl propionate (1.68
g) in tetrahydrofuran (20 ml) was added to diisobutylaluminum hydride (1.0 M hexane solution, 1
5 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- (3- (3-bromo-4-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (1.49 g, yield 97%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 40-41 [deg.] C. Example 128 5- (3-Bromo-4-fluorophenyl) -4-isoxazolylmethanol (6.49 g) in toluene (1
Thionyl chloride (2.6 ml) at 0 ° C.
After dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and treated with diethyl malonate (7.65).
g), sodium hydride (60%, oily, 1.87 g)
0 ° C. in a mixture of and tetrahydrofuran (50 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [5- (3-bromo-4-fluorophenyl) -4-isoxazolyl] propionic acid (5.06) was used.
g, yield 67%). Recrystallized from acetone-hexane. 136-137 ° C.

Example 129 3- [5- (3-Bromo-4-fluorophenyl) -4
A mixture of [-isoxazolyl] propionic acid (2.38 g), concentrated sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio)
-[5- (3-bromo-4-fluorophenyl) -4-
Isoxazolyl] methyl propionate (2.39 g,
(96% yield) as a colorless oil. NMR (CDCl ₃ ) δ:
2.60-2.71 (2H, m), 2.91-3.03 (2H, m), 3.69 (3H, s),
7.18-7.32 (1H, m), 7.60-7.70 (1H, m), 7.94 (1H, dd, J =
2.2, 6.2 Hz), 8.23 (1H, s). Example 130 3- [5- (3-Bromo-4-fluorophenyl) -4
-Isoxazolyl] methyl propionate (1.43
g) in tetrahydrofuran (20 ml) was added to diisobutylaluminum hydride (1.0 M hexane solution, 1
(0 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
3- [5- (3-bromo-4-)
Fluorophenyl) -4-isoxazolyl] propan-1-ol (1.11 g, yield 85%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 57-58 ° C.

Example 131 Thionyl chloride (3.10 ml) was added dropwise to a solution of 5- (4-phenylphenyl) -4-isoxazolyl methanol (7.11 g) in toluene (200 ml) at 0 ° C. Stir at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was treated with tetrahydrofuran (100 m
1) and added to a mixture of diethyl malonate (9.07 g), sodium hydride (60%, oily, 2.22 g) and tetrahydrofuran (50 ml) at 0 ° C., followed by 1 hour at 0 ° C. And stirred overnight at room temperature. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(3, volume ratio) A colorless oil was obtained from the elution part. The resulting colorless oil, 6N hydrochloric acid (70 ml) and acetic acid (70
ml) of the mixture was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals are collected by filtration,
3- [5- (4-Phenylphenyl) -4-isoxazolyl] propionic acid (6.30 g, yield 76%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 94 ~
95 ° C. Example 132 3- [5- (4-Phenylphenyl) -4-isoxazolyl] propionic acid (6.00 g), concentrated sulfuric acid (0.1
ml) and methanol (100 ml) were refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From the hexane (1: 3, volume ratio) elution part, 3- [5- (4
[Phenylphenyl) -4-isoxazolyl] propionate (5.91 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 103-104 ° C.

Example 133 To a solution of methyl 3- [5- (4-phenylphenyl) -4-isoxazolyl] propionate (1.00 g) in tetrahydrofuran (25 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 8 M). .0 ml) to 0
After slowly adding the mixture at ° C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-phenylphenyl)-) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio).
4-isoxazolyl] propan-1-ol (0.6
(56 g, yield 72%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 94-95 ° C. Example 134 3- [5- (3-bromo-4-chlorophenyl) -4-
A mixture of isoxazolyl] propionic acid (2.74 g), concentrated sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with 3-
Methyl [5- (3-bromo-4-chlorophenyl) -4-isoxazolyl] propionate (2.22 g, yield 78%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 54-55 ° C.

Example 135 Diethyl 4-aminobenzylphosphonate (0.58
g), 3- (3-methyl-5-phenyl-4-isoxazolyl) propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and N- (4-diethylphosphonomethylphenyl) -3- (3-methyl-5-phenyl-4) was eluted from an ethyl acetate-hexane (1: 1, volume ratio) eluate. -Isoxazolyl) propionamide (0.87 g, yield 88)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 114-115 ° C. Example 136 To a mixture of 3-methyl-5-phenylisoxazole-4-carbaldehyde (4.94 g), ethyl diethylphosphonoacetate (6.53 g) and N, N-dimethylformamide (70 ml) at 0 ° C. Sodium hydride (60%, oily, 1.13 g) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(4, volume ratio) A yellow oil was obtained from the elution part. The obtained yellow oil, 2N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of 1) was refluxed for 3 hours. Concentrate the reaction mixture,
Water was added to the residue. The obtained colorless crystals are collected by filtration,
(E) -3- (3-Methyl-5-phenyl-4-isoxazolyl) propenoic acid (4.02 g, yield 93%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 17
3-174 ° C.

Example 137 Methyl 4-aminobenzoate (0.30 g), (E) -3
-(3-methyl-5-phenyl-4-isoxazolyl) propenoic acid (0.35 g), 1-hydroxy-1H
-1,2,3-benzotriazole hydrate (0.27
g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g) and N, N-dimethylformamide (15 ml) were stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer consists of diluted hydrochloric acid, saturated aqueous sodium bicarbonate,
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
From the elution part of ethyl acetate-hexane (1: 1, volume ratio), (E) -N- (4-methoxycarbonylphenyl) -3
-(3-Methyl-5-phenyl-4-isoxazolyl) propenamide (0.51 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 174-175 [deg.] C. Example 138 Ethyl 4-aminophenylacetate (1.11 g), (E)
-3- (3-Methyl-5-phenyl-4-isoxazolyl) propenoic acid (0.95 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (0.7
5g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.91 g) and N, N-
A mixture of dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and (E) -N- (4-ethoxycarbonylmethylphenyl) -3- (3-methyl-5) was eluted with ethyl acetate-hexane (1: 1, volume ratio). Phenyl-4-isoxazolyl) propenamide (1.82 g, 97% yield)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 164-165 [deg.] C.

Example 139 Diethyl 4-aminobenzylphosphonate (0.43
g), (E) -3- (3-methyl-5-phenyl-4-
(Isoxazolyl) propenoic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.38 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 0.45 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried (MgSO ₄ ).
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and (E) -N- (4-diethylphosphonomethylphenyl) -3- (3-methyl-5) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). -Phenyl-4
-Isoxazolyl) propenamide (0.71 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 155-156 ° C. Example 140 A solution of 4-chloromethyl-3- (4-trifluoromethylphenyl) isoxazole (2.90 g) in tetrahydrofuran (100 ml) was added to diethyl malonate (5.
35 g), sodium hydride (60%, oily, 1.30)
g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration and 3- [3- (4-trifluoromethylphenyl) -4-isoxazolyl] propionic acid (2.49)
g, yield 79%). Recrystallized from ethyl acetate-hexane. 173-174 ° C.

Example 141 4-Chloromethyl-3- (4-chlorophenyl) -5
Methyl isoxazole (1.21 g) was dissolved in tetrahydrofuran (50 ml), and diethyl malonate (1.
20 g), sodium hydride (60%, oily, 0.21
g) and tetrahydrofuran (20 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (4-chlorophenyl) -5-methyl-4-isoxazolyl] propionic acid (1.20).
g, yield 90%). Recrystallized from ethanol.
187-188 ° C. Example 142 Methyl propionyl acetate (9.95 g) and 4-chloro-N-hydroxybenzenecarboximidoyl chloride (9.65 g) in tetrahydrofuran (100 m2)
1) To the solution was slowly added a solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil, tetrahydrofuran (1
(00 ml) solution, diisobutylaluminum hydride (1.0 M hexane solution, 110 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. A mixture of the obtained colorless oil and thionyl chloride (10.0 ml) was stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. The obtained colorless oil was dissolved in tetrahydrofuran (100 ml), and diethyl malonate (2.40) was dissolved.
g), sodium hydride (60%, oily, 0.42 g)
0 ° C to a mixture of and tetrahydrofuran (20 ml)
Then, the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (4-chlorophenyl) -5-ethyl-4-isoxazolyl] propionic acid (4.33 g,
Yield 30%). Recrystallized from ethanol. Melting point 164-165 [deg.] C.

Example 143 To a solution of ethyl benzoyl acetate (5.76 g) and sodium hydride (60%, oily, 0.12 g) in tetrahydrofuran (60 ml) was added methyl acrylate (3.2 m).
l) was added slowly at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated saline solution and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
(Volume ratio) A colorless oil was obtained from the elution part. A mixture of the obtained colorless oil, hydroxylamine hydrochloride (1.68 g) and isopropyl alcohol (65 ml) was refluxed for 16 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. A mixture of the obtained colorless oil, 2N sodium hydroxide (20 ml) and methanol (30 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 3- [5-hydroxy-3-phenyl-4
[Isoxazolyl] propionic acid (2.49 g, yield 36%) was obtained. Recrystallized from ethanol. Melting point 18
3-184 ° C. Example 144 A solution of 4-chloromethyl-5-methyl-3- (4-trifluoromethylphenyl) isoxazole (1.37 g) in tetrahydrofuran (50 ml) was added to diethyl malonate (1.20 g), sodium hydride ( 60%, oily, 0.21 g) and tetrahydrofuran (20 m
1) was added to the mixture at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [5-methyl-3
-(4-Trifluoromethylphenyl) -4-isoxazolyl] propionic acid (1.25 g, yield 84%) was obtained. Recrystallized from ethanol-hexane. Melting point 13
8-139 ° C.

Example 145 Methyl acetoacetate (8.88 g) and 3-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (11.35 g) in tetrahydrofuran (1
00 ml) solution, triethylamine (15 ml) in tetrahydrofuran (10 ml) was added slowly at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil, tetrahydrofuran (1
(00 ml) solution, diisobutylaluminum hydride (1.0 M hexane solution, 110 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. A mixture of the obtained colorless oil and thionyl chloride (5.0 ml) was stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A solution of the obtained colorless oil in tetrahydrofuran (100 ml) was added to a mixture of diethyl malonate (12.20 g), sodium hydride (60%, oily, 3.05 g) and tetrahydrofuran (50 ml) at 0 ° C. At 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [5-
Methyl-3- (3-trifluoromethylphenyl) -4
[Isoxazolyl] propionic acid (6.54 g, yield 43%) was obtained. Recrystallized from ethanol-water. 63-64 ° C.

Example 146 Dibenzoylmethane (4.48 g), methyl acrylate (1.8 ml), potassium t-butoxide (0.23 g)
g) and N, N-dimethylformamide (40 ml)
After stirring the mixture at room temperature overnight, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). A mixture of the obtained colorless oil, hydroxylamine hydrochloride (1.00 g) and isopropyl alcohol (50 ml) was refluxed for 6 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. The obtained colorless oil, 2N sodium hydroxide (20 ml) and methanol (30 m
The mixture of 1) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, it was concentrated. The obtained colorless crystals were collected by filtration, and 3- [3,
[5-Diphenyl-4-isoxazolyl] propionic acid (1.91 g, yield 33%) was obtained. Recrystallized from ethanol. 152-153 ° C. Example 147 methyl acetoacetate (8.88g) and 2-chloro-N
To a solution of -hydroxybenzenecarboximidoyl chloride (9.65 g) in tetrahydrofuran (100 ml), a solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added at 0 ° C. After stirring at room temperature overnight, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil, tetrahydrofuran (100
ml) solution into a solution of diisobutylaluminum hydride (1.
(0M hexane solution, 110 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated to give a colorless oil. A mixture of the obtained colorless oil and thionyl chloride (5.0 ml) was stirred at 0 ° C. for 30 minutes.
The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. A solution of the obtained colorless oil in tetrahydrofuran (100 ml) was treated with diethyl malonate (12.20 g) and sodium hydride (6.
A mixture of 0%, oily, 3.05 g) and tetrahydrofuran (50 ml) was added at 0 ° C., followed by stirring at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. The reaction mixture was acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). Colorless oil obtained, 6
A mixture of normal hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 5 hours. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were collected by filtration, and 3- [3- (2-
Chlorophenyl) -5-methyl-4-isoxazolyl] propionic acid (5.40 g, yield 40%) was obtained.
Recrystallized from ethyl acetate-hexane. Melting point 79-81
° C.

Example 148 To a solution of methyl 3- [5- (4-methylphenyl) -4-isoxazolyl] propionate (2.00 g) in tetrahydrofuran (50 ml) was added diisobutylaluminum hydride (0.95 M hexane solution, 21 (0.5 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 1 hour.
Sodium sulfate decahydrate (6.57 g) was added to the reaction mixture.
After stirring for 2 hours, insoluble materials were filtered off. The filtrate was concentrated, the residue was subjected to silica gel column chromatography, and 3- [5- (4-methylphenyl) -4-isoxazolyl] propane- 1-ol (1.53 g, 86% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.
25-1.35 (1H, m), 1.8-2.0 (2H, m), 2.41 (3H, s), 2.7-
2.85 (2H, m), 3.65-3.8 (2H, m), 7.29 (2H, d, J = 8 H
z), 7.62 (2H, d, J = 8Hz), 8.19 (1H, s). Example 149 3- [5- (4,5-dichloro-2-thienyl) -4-
Isoxazolyl] methyl propionate (1.30 g)
In tetrahydrofuran (40 ml) was added diisobutylaluminum hydride (0.95 M hexane solution, 1
1.2 ml) was slowly added at room temperature and then stirred for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
3- (5- (4,5-dichloro-2-thienyl) -4-isoxazolyl] propane-
1-ol (1.05 g, yield 89%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.35-1.5 (1H, m), 1.8-2.0
(2H, m), 2.65-2.8 (2H, m), 3.65-4.0 (2H, m), 7.29 (1
H, s), 8.19 (1H, s). Example 150 Diisobutylaluminum hydride (1.0 M toluene solution, 4.2 ml) in a solution of methyl 3- [5- (2,5-dichlorophenyl) -4-isoxazolyl] propionate (500 mg) in tetrahydrofuran (30 ml).
Was slowly added at room temperature, followed by stirring for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (2,5-dichlorophenyl) -4-
-Isoxazolyl] propan-1-ol (420 m
g, yield 93%) as a colorless oil. NMR (CDCl ₃ )
δ: 1.28 (1H, t, J = 5 Hz), 1.7-1.9 (2H, m), 2.5-2.6
(2H, m), 3.65 (2H, td, J = 6, 5 Hz), 7.35-7.5 (3H,
m), 8.27 (1H, s).

Example 151 Diethyl 4-aminobenzylphosphonate (0.73
g), 3- [5- (4-fluorophenyl) -4-isoxazolyl] propionic acid (0.49 g), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAT) (0 .40 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSCI) (0.4 g).
45 g) and N, N-dimethylformamide (5 m
The mixture of l) was stirred at room temperature overnight. Reaction mixture 1
The mixture was poured into a normal aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a 10% aqueous potassium carbonate solution, then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to give N- [4
-(Diethylphosphonomethyl) phenyl] -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide (0.67 g, yield 70%) was obtained as colorless prism crystals. 134-135 ° C. Elementary analysis: Calculated _{(C 23 H 26 FN 2 O} 5 P) C, 60.00; H, 5.69; N, 6.08. Found C, 59.83; H, 5.52; N, 6.03. HPLC analysis: purity 100% (retention time: 3.735 min) MS (ESI +): 461 (M + H) NMR (CDCl 3) δ: 1.23 (6H, t, J = 7Hz), 2.69 (2H, t , J
= 7Hz), 3.0-3.2 (4H, m), 3.9-4.1 (4H, m), 7.1-7.3 (4
H, m), 7.38 (2H, d, J = 8.5Hz), 7.7-7.8 (2H, m), 8.1
3 (1H, br s), 8.26 (1H, s). Example 152 Diethyl 4-aminobenzylphosphonate (72.9 m
g), 3- [5- (4-trifluoromethylphenyl)-
4-Isoxazolyl] propionic acid (57 mg), 1
-Hydroxy-7-aza-1H-1,2,3-benzotriazole (40 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (45 mg) and N, N-dimethylformamide (0.3 ml) Was stirred overnight at room temperature. Direct preparative HPLC of the reaction solution
To obtain N- [4- (diethylphosphonomethyl) phenyl] -3- [5- (4-trifluoromethylphenyl) -4-isoxazolyl] propionamide. Yield: 40 mg (71% yield) HPLC analysis: 100% purity (retention time: 3.858 minutes) MS (ESI +): 511 (M + H) The following compounds were synthesized as in Example 152.

Example 153 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (4-Methylthiophenyl) -4-isoxazolyl] propionamide Yield: 80 mg (yield: 82%) HPLC analysis: 100% purity (retention time: 3.713)
Min) MS (ESI +): 489 (M + H) NMR (CDCl 3) δ: 1.23 (6H, t, J = 7Hz), 2.53 (3H, s),
2.68 (2H, t, J = 7Hz), 3.0-3.1 (4H, m), 3.9-4.05 (4H,
m), 7.1-7.2 (2H, m), 7.3-7.4 (4H, m), 7.66 (2H, d, J
= 8.5Hz), 8.08 (1H, br s), 8.24 (1H, s). Example 154 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (2,4-difluorophenyl) -4-isoxazolyl] propionamide Yield: 35 mg (yield: 74%) HPLC analysis: 100% purity (retention time: 3.554)
Min) MS (ESI +): 479 (M + H).

Example 155 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (5-Chloro-2-thienyl) -4-isoxazolyl] propionamide Yield: 71 mg (yield: 73%) HPLC analysis: 100% purity (retention time: 3.779)
MS) (ESI +): 483 (M + H) Example 156 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (4-Trifluoromethoxyphenyl) -4-isoxazolyl] propionamide Yield: 82 mg (yield: 78%) HPLC analysis: 100% purity (retention time: 3.914 minutes) MS (ESI +): 527 (M + H) NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7 Hz), 2.71 (2H, t, J
= 7Hz), 3.0-3.1 (4H, m), 3.9-4.05 (4H, m), 7.1-7.2 (2
H, m), 7.3-7.4 (4H, m), 7.79 (2H, d, J = 8.5Hz), 8.2
9 (1H, s).

Example 157 N- [4- (Diethylphosphonomethyl) phenyl] -3-
[5- (3-Bromo-4-chlorophenyl) -4-isoxazolyl] propionamide Yield: 53 mg (Yield: 48%) HPLC analysis: Purity 99.6% (Retention time: 3.985)
MS) (ESI +): 555 (M + H), 557 Example 158 N- [4- (diethylphosphonomethyl) phenyl] -3-
A mixture of [5- (4-methylthiophenyl) -4-isoxazolyl] propionamide (98 mg), m-chloroperbenzoic acid (60 mg), and tetrahydrofuran (5 ml) was stirred at room temperature for 4 hours. 10% in the reaction mixture
An aqueous sodium sulfite solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 10% aqueous potassium carbonate solution, then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was purified by preparative HPLC to give N- [4- (diethylphosphonomethyl) phenyl] -3- [5- (4-methylsulfinylphenyl) -4-isoxazolyl] propionamide. Yield: 16 mg (yield: 16%) HPLC analysis: 95.1% purity (retention time: 2.903)
Min) MS (ESI +): 505 (M + H)

Example 159 In the experiment of Example 158, N- [4- (diethylphosphonomethyl) phenyl] -3- [5- (4-methylsulfonylphenyl) was obtained from the fraction eluted later by preparative HPLC. -4-isoxazolyl] propionamide was obtained. Yield: 14 mg (yield: 13%) HPLC analysis: purity 93.0% (retention time: 3.163)
MS) (ESI +): 521 (M + H) Example 160 4-Hydroxypiperidine (10 mg), 3- [5- (3
A mixture of -chlorophenyl) -4-isoxazolyl] propionic acid (25 mg), Argonaute PS-carbodiimide (100 mg) and dichloromethane (1 ml) was stirred overnight at room temperature. Filtering the reaction mixture,
The filtrate was concentrated. The obtained residue was purified by preparative HPLC to give 1- {3- [5- (3-chlorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinol. Yield: 15 mg (yield: 46%) HPLC analysis: 98.1% purity (retention time: 3.084)
MS) (APCI +): 335 (M + H) The following compounds were synthesized as in Example 160.

Example 161 3- [5- (3-Chlorophenyl) -4-isoxazolyl] -N-methyl-N- (1-methyl-4-piperidinyl) propionamide trifluoroacetate Yield: 36 mg (yield: HPLC analysis: 98.9% purity (retention time: 2.697)
MS) (APCI +): 362 (M + H) Example 162 N-((3S) -1- {3- [5- (3-chlorophenyl)-
4-Isoxazolyl] propanoyl} pyrrolidine-3-
Yl) -2,2,2-trifluoroacetamide Yield: 22 mg (yield: 53%) HPLC analysis: purity 97.5% (retention time: 3.572)
Min) MS (APCI +): 416 (M + H)

Example 163 tert-butyl (3S) -1- {3- [5- (3-chlorophenyl) -4-isoxazolyl] propanoyl} pyrrolidin-3-ylcarbamate Yield: 37 mg (89% yield) HPLC Analysis: 96.7% purity (retention time: 3.771)
MS) (APCI-): 418 (MH) Example 164 4- {3- [5- (3-Chlorophenyl) -4-isoxazolyl] propanoyl} thiomorpholine 1,1'-
Dioxide yield: 2 mg (yield: 7%) HPLC analysis: purity 95.8% (retention time: 3.308)
Min) MS (APCI +): 369 (M + H).

Example 165 diethyl 4-aminobenzylphosphonate (36 mg)
3- [5- (3-chloro-4-fluorophenyl) -4-
Isoxazolyl] propionic acid (27 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (30 mg) and N, A mixture of N-dimethylformamide (0.5 ml) was stirred at room temperature overnight. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the obtained solid was purified by preparative HPLC to give 3- [5-
(3-Chloro-4-fluorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide was obtained. Yield: 39 mg (yield: 79%) HPLC analysis: purity 99.5% (retention time: 3.875)
Min) MS (ESI +): 495 (M + H) The following compound was synthesized as in Example 165. Example 166 3- [5- (4-bromophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 36 mg (yield: 69%) HPLC analysis: purity 99 0.6% (retention time: 3.897
Min) MS (ESI +): 521 (M + H), 523.

Example 167 N-((3S) -1- {3- [5- (3-chloro-4-fluorophenyl) -4-isoxazolyl] propanoyl} pyrrolidin-3-yl) -2,2,2 -Trifluoroacetamide yield: 26 mg (yield: 60%) HPLC analysis: purity 99.8% (retention time: 3.764)
MS) (ESI +): 434 (M + H) Example 168 N-((3S) -1- {3- [5- (4-bromophenyl)-
4-Isoxazolyl] propanoyl} pyrrolidine-3-
Yl) -2,2,2-trifluoroacetamide Yield: 33 mg (yield: 72%) HPLC analysis: 93.6% purity (retention time: 3.768)
Min) MS (ESI +): 460 (M + H), 462.

Example 169 N-((3S) -1- {3- [5- (4-fluorophenyl)
-4-isoxazolyl] propanoyl} pyrrolidine-3
-Yl) -2,2,2-trifluoroacetamide Yield: 25 mg (yield: 74%) HPLC analysis: 98.3% purity (retention time: 3.480)
MS) (ESI +): 400 (M + H) Example 170 3- [5- (3-Chloro-4-fluorophenyl) -4-
Isoxazolyl] -N-methyl-N- (1-methyl-4
-Piperidinyl) propionamide trifluoroacetate Yield: 36 mg (69% yield) HPLC analysis: 99.7% purity (retention time: 2.910)
Min) MS (ESI +): 380 (M + H)

Example 171 3- [5- (4-Bromophenyl) -4-isoxazolyl] -N-methyl-N- (1-methyl-4-piperidinyl) propionamide trifluoroacetate Yield: 20 mg (yield: 20 mg) : 38%) HPLC analysis: 99.2% purity (retention time: 2.925)
MS) (ESI +): 406 (M + H), 408 Example 172 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N-methyl-N- (1-methyl-4-piperidinyl) ) Propionamide trifluoroacetate Yield: 23 mg (yield: 49%) HPLC analysis: 97.5% purity (retention time: 2.654)
Min) MS (ESI +): 346 (M + H)

Example 173 1- {3- [5- (3-Chloro-4-fluorophenyl)-
4-Isoxazolyl] propanoyl} -4-piperidinol Yield: 34 mg (Yield: 96%) HPLC analysis: 95.5% purity (Retention time: 3.255)
MS) (ESI +): 353 (M + H) Example 174 1- {3- [5- (4-bromophenyl) -4-isoxazolyl] propanoyl} -4-piperidinol Yield: 11 mg (yield: 28) %) HPLC analysis: 98.5% purity (retention time: 3.264)
MS) (ESI +): 379 (M + H), 381

Example 175 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinol Yield: 22 mg (68% yield) HPLC analysis: 89.5% purity ( Retention time: 2.952
MS) (ESI +): 319 (M + H) EXAMPLE 176 1- {3- [5- (3-chloro-4-fluorophenyl)-
4-Isoxazolyl] propanoyl} -4- (2-furoyl) piperazine Yield: 32 mg (Yield: 75%) HPLC analysis: 95.9% purity (Retention time: 3.634)
MS) (ESI +): 432 (M + H) Example 177 1- {3- [5- (4-bromophenyl) -4-isoxazolyl] propanoyl} -4- (2-furoyl) piperazine Yield: 41 mg (Yield: 89%) HPLC analysis: purity 96.1% (retention time: 3.637)
MS) (ESI +): 458 (M + H), 460 Example 178 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-furoyl) piperazine Yield. : 20 mg (yield: 50%) HPLC analysis: 98.9% purity (retention time: 3.352)
Min) MS (ESI +): 398 (M + H)

Example 179 1- {3- [5- (3-Chloro-4-fluorophenyl)-
4-Isoxazolyl] propanoyl} -4-methylpiperazine trifluoroacetate Yield: 40 mg (Yield: 85%) HPLC analysis: 96.6% purity (Retention time: 2.857)
MS) (ESI +): 352 (M + H) Example 180 1- {3- [5- (4-Bromophenyl) -4-isoxazolyl] propanoyl} -4-methylpiperazine trifluoroacetate Yield: 43 mg (Yield: 87%) HPLC analysis: purity 95.7% (retention time: 2.852)
Min) MS (ESI +): 378 (M + H), 380

Example 181 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-methylpiperazine trifluoroacetate Yield: 32 mg (Yield: 74%) HPLC analysis: Purity 93.4% (retention time: 2.574
MS) (ESI +): 318 (M + H) Example 182 N'-benzyl-N, N-dimethylethylenediamine (27 mg), 3- [5- (4-fluorophenyl) -4
-Isoxazolyl] propionic acid (24 mg), 1-
Hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (23 mg) and N, N-dimethylformamide (0.3 ml) The mixture was stirred at room temperature overnight. The reaction solution was directly introduced into preparative HPLC for purification, and N-benzyl-N- [2- (dimethylamino) ethyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Fluoroacetate was obtained. Yield: 47 mg (92% yield) HPLC analysis: 93.8% purity (retention time: 2.481)
Min) MS (APCI +): 396 (M + H) The following compounds were synthesized as in Example 182.

Example 183 N-butyl-3- [5- (4-fluorophenyl) -4-
Isoxazolyl] propionamide Yield: 21 mg (71% yield) HPLC analysis: 97.9% purity (retention time: 3.463)
MS) (APCI +): 291 (M + H) Example 184 N- (cyclohexylmethyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 23 mg (71% yield) ) HPLC analysis: 95.2% purity (retention time: 3.870)
Min) MS (APCI +): 331 (M + H) NMR (CDCl 3) δ: 0.8-1.8 (11H, m), 2.46 (2H, t, J = 7H
z), 2.95-3.1 (4H, m), 5.40 (1H, br s), 7.15-7.25 (2H,
m), 7.7-7.8 (2H, m), 8.21 (1H, s).

Example 185 N-cyclopropyl-3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 20 mg (73% yield) HPLC analysis: 97.0% purity (retention time: 3.031
MS) (APCI +): 275 (M + H) Example 186 N-benzyl-3- [5- (4-fluorophenyl) -4
-Isoxazolyl] propionamide Yield: 23 mg (71% yield) HPLC analysis: 95.4% purity (retention time: 3.566)
Min) MS (APCI +): 325 (M + H)

Example 187 N- (1,3-benzodioxol-5-ylmethyl)-
3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 27 mg (73% yield) HPLC analysis: 97.2% purity (retention time: 3.507)
MS) (APCI +): 369 (M + H) Example 188 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-phenylethyl) propionamide Yield: 25 mg (Yield) HPLC analysis: 98.4% purity (retention time: 3.680)
Min) MS (APCI +): 339 (M + H)

Example 189 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (3-phenylpropyl) propionamide Yield: 25 mg (71% yield) HPLC analysis: 98.9% purity (Retention time: 3.822
MS) (APCI +): 353 (M + H) Example 190 N-benzhydryl-3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 23 mg (57% yield) HPLC analysis : Purity 98.4% (retention time: 4.051)
Min) MS (APCI +): 401 (M + H)

Example 191 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-methoxyethyl) propionamide Yield: 21 mg (yield 72%) HPLC analysis: purity 99.4% (Retention time: 2.904
MS) (APCI +): 293 (M + H) Example 192 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (methylsulfanyl) propyl] propionamide Yield: 23 mg (Yield 70%) HPLC analysis: purity 97.9% (retention time: 3.345)
Min) MS (APCI +): 323 (M + H)

Example 193 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (tetrahydro-2-furanylmethyl) propionamide Yield: 21 mg (65% yield) HPLC analysis: purity 98.1 % (Retention time: 3.057
MS) (APCI +): 319 (M + H) Example 194 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (1H-indol-3-yl) ethyl] Propionamide yield: 34 mg (89% yield) HPLC analysis: 99.7% purity (retention time: 3.657)
Min) MS (APCI +): 378 (M + H)

Example 195 N- (2-ethylpropyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 22 mg (71% yield) HPLC analysis: 98.8% purity (Retention time: 3.566
MS) (APCI +): 305 (M + H) Example 196 N- (tert-butyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 23 mg (80) %) HPLC analysis: 98.7% purity (retention time: 3.548)
Min) MS (APCI +): 291 (M + H)

Example 197 N-cyclohexyl-3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 24 mg (76% yield) HPLC analysis: 96.8% purity (retention time: 3) .672
MS) (APCI +): 317 (M + H) Example 198 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-propynyl) propionamide Yield: 20 mg (Yield 72) %) HPLC analysis: 99.2% purity (retention time: 3.092)
Min) MS (APCI +): 273 (M + H)

Example 199 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [4- (trifluoromethyl) benzyl] propionamide Yield: 28 mg (73% yield) HPLC analysis: Purity 99.2% (retention time: 3.913
Min) MS (APCI +): 393 (M + H) NMR (CDCl 3) δ: 2.54 (2H, t, J = 7Hz), 3.04 (2H, t, J
= 7Hz), 4.47 (2H, d, J = 7Hz), 5.82 (1H, br s), 7.1-
7.4 (4H, m), 7.57 (2H, d, J = 8Hz), 7.65-7.8 (2H, m),
8.20 (1H, s). Example 200 N- [2- (3,4-dimethoxyphenyl) ethyl] -3
-[5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 29 mg (73% yield) HPLC analysis: 99.1% purity (retention time: 3.454)
Min) MS (APCI +): 399 (M + H)

Example 201 N- (3,3-diphenylpropyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 30 mg (70% yield) HPLC analysis: Purity 99. 4% (retention time: 4.173
MS) (APCI +): 429 (M + H) Example 202 N- (2,3-dihydro-1H-inden-2-yl)-
3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 26 mg (75% yield) HPLC analysis: 98.9% purity (retention time: 3.763)
Min) MS (APCI +): 351 (M + H)

Example 203 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (3-isopropoxypropyl) propionamide Yield: 24 mg (71% yield) HPLC analysis: purity 99.4 % (Retention time: 3.375
MS) (APCI-): 333 (MH) Example 204 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-oxo-3-azepanyl) propionamide Yield: 25 mg (Yield: 72%) HPLC analysis: 97.5% purity (retention time: 2.953)
Min) MS (APCI +): 346 (M + H)

Example 205 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-furylmethyl) propionamide Yield: 23 mg (73% yield) HPLC analysis: 99.4% purity (Retention time: 3.364
MS) (APCI-): 313 (MH) Example 206 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (2-oxo-1-pyrrolidinyl) propyl] Propionamide Yield: 29 mg (80% yield) HPLC analysis: 99.5% purity (retention time: 2.847)
Min) MS (APCI +): 360 (M + H)

Example 207 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N-methyl-N- (1-naphthylmethyl) propionamide Yield: 24 mg (62% yield) HPLC analysis: Purity 99.8% (retention time: 4.165)
MS) (APCI +): 389 (M + H) Example 208 N- [2- (3,4-dimethoxyphenyl) ethyl] -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
-N-methylpropionamide Yield: 25 mg (61% yield) HPLC analysis: 98.1% purity (retention time: 3.626)
Min) MS (ESI +): 413 (M + H).

Example 209 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N, N-bis (2-methoxyethyl) propionamide Yield: 23 mg (66% yield) HPLC analysis: Purity 99 0.6% (retention time: 3.353
MS) (ESI +): 351 (M + H) Example 210 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} piperidine Yield: 29 mg (96% yield) HPLC analysis: purity 99 0.6% (retention time: 3.566
Min) MS (APCI +): 303 (M + H)

Example 211 4- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -2,6-dimethylmorpholine Yield: 31 mg (93% yield) HPLC analysis: purity 99.7 % (Retention time: 3.423
Min) MS (APCI +): 333 (M + H) NMR (CDCl 3) δ: 1.18 (6H, t, J = 7Hz), 2.25-2.4 (1H,
m), 2.5-2.8 (3H, m), 3.02 (2H, t, J = 7Hz), 3.4-3.6
(3H, m), 4.4-4.5 (1H, m), 7.15-7.25 (2H, m), 7.7-7.8
(2H, m), 8.24 (1H, s). Example 212 2- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -1,2,3,4-tetrahydroisoquinoline yield: 26 mg (75% yield) HPLC analysis: purity 99. 0% (retention time: 3.902
MS) (APCI +): 351 (M + H) Example 213 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinecarboxamide Yield: 39 mg (90% yield) HPLC analysis: purity 99.5% (retention time: 2.792
MS) (APCI +): 346 (M + H) Example 214 2- (1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinyl) ethanol Yield: 27 mg (Yield) HPLC analysis: 96.2% purity (retention time: 3.086)
MS) (APCI +): 347 (M + H) Example 215 4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} thiomorpholine Yield: 23 mg (72% yield) HPLC analysis: Purity 99.4% (retention time: 3.496
MS) (APCI +): 321 (M + H) Example 216 4-benzyl-1- {3- [5- (4-fluorophenyl)
-4-Isoxazolyl] propanoyl} piperidine Yield: 8 mg (21% yield) HPLC analysis: 99.8% purity (retention time: 4.273)
Min) MS (APCI +): 393 (M + H)

Example 217 3-acetamido-1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} pyrrolidine Yield: 28 mg (80% yield) HPLC analysis: 99.7% purity ( Retention time: 2.779
MS) (APCI +): 346 (M + H) Example 218 N-cyclohexyl-3- [5- (4-fluorophenyl) -4-isoxazolyl] -N-methylpropionamide Yield: 19 mg (58% yield) HPLC Analysis: 99.5% purity (retention time: 3.966)
Min) MS (APCI +): 331 (M + H).

Example 219 N-benzyl-3- [5- (4-fluorophenyl) -4
-Isoxazolyl] -N-methylpropionamide Yield: 28 mg (83% yield) HPLC analysis: 99.5% purity (retention time: 3.837)
Min) MS (APCI +): 339 (M + H) Example 220 N-benzyl-N- [2- (ethoxycarbonyl) ethyl]
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 25 mg (60% yield) HPLC analysis: 98.8% purity (retention time: 4.068)
Min) MS (APCI +): 425 (M + H)

Example 221 N-ethyl-3- [5- (4-fluorophenyl) -4-
Isoxazolyl] -N- (2-methoxyethyl) propionamide Yield: 34 mg (90% yield) HPLC analysis: 99.5% purity (retention time: 3.410
MS) (APCI-): 319 (MH) Example 222 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} morpholine Yield: 47 mg (90% yield) HPLC analysis : Purity 97.0% (retention time: 3.070)
Min) MS (APCI +): 305 (M + H) NMR (CDCl 3) δ: 2.60 (2H, t, J = 7Hz), 3.03 (2H, t, J
= 7Hz), 3.35-3.45 (2H, m), 3.55-3.7 (6H, m), 7.15-7.2
5 (2H, m), 7.7-7.8 (2H, m), 8.23 (1H, s).

Example 223 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -3,5-dimethylpiperidine Yield: 44 mg (90% yield) HPLC analysis: purity 99.5 % (Retention time: 4.029
Min) MS (APCI +): 331 (M + H) NMR (CDCl 3) δ: 0.7-0.9 (6H, m), 1.3-1.5 (1H, m), 1.7-
2.0 (2H, m), 2.35-2.65 (3H, m), 2.9-3.1 (3H, m), 3.3-
3.8 (2H, m), 4.5-4.7 (1H, m), 7.1-7.25 (2H, m), 7.65-
7.8 (2H, m), 8.23 (1H, s). Example 224 2- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} decahydroisoquinoline yield: 28 mg (78% yield) HPLC analysis: 90.1% purity (retention time: 2. 861
Min) MS (APCI +): 357 (M + H)

Example 225 4- (ethoxycarbonyl) -1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}
Piperidine Yield: 33 mg (88% yield) HPLC analysis: 99.1% purity (retention time: 3.614)
MS) (APCI +): 375 (M + H) Example 226 N- (2,6-dimethylphenyl) -N-[((2S) -1-
{3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} pyrrolidinyl) methyl] amine Yield: 7 mg (18% yield) HPLC analysis: Purity 97.8% (Retention time: 3.186)
Min) MS (APCI +): 422 (M + H)

Example 227 4- (4-chlorophenyl) -1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}
-4-Piperidinol Yield: 9 mg (21% yield) HPLC analysis: 99.7% purity (retention time: 3.817)
MS) (APCI-): 427 (M-H) Example 228 3- (N-acetyl-N-ethylamino) -1- {3- [5
-(4-Fluorophenyl) -4-isoxazolyl] propanoyl} pyrrolidine Yield: 14 mg (36% yield) HPLC analysis: 97.0% purity (retention time: 3.055)
Min) MS (APCI +): 374 (M + H)

Example 229 N- [2- (Dimethylamino) ethyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] -N-methylpropionamide trifluoroacetate Yield: 39 mg (yield: 39 mg) HPLC analysis: 99.8% purity (retention time: 2.481)
MS) (APCI-): 318 (MH) Example 230 N- (1-benzyl-3-pyrrolidinyl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] -N-methylpropionamide trifluoroacetate Yield: 49 mg (93% yield) HPLC analysis: 94.5% purity (retention time: 2.980)
Min) MS (APCI +): 408 (M + H)

Example 231 N-ethyl-3- [5- (4-fluorophenyl) -4-
Isoxazolyl] -N- (4-pyridinylmethyl) propionamide trifluoroacetate Yield: 43 mg (91% yield) HPLC analysis: 99.5% purity (retention time: 2.637
MS) (APCI +): 354 (M + H) Example 232 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N, N-bis (3-pyridinylmethyl) propionamide 2-trifluoroacetate Yield: 57 mg (90% yield) HPLC analysis: 99.7% purity (retention time: 2.193)
Min) MS (APCI +): 417 (M + H)

Example 233 1-ethyl-4- {3- [5- (4-fluorophenyl)-
4-Isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 42 mg (93% yield) HPLC analysis: 99.6% purity (retention time: 2.473)
MS) (APCI +): 332 (M + H) Example 234 1- (ethoxycarbonylmethyl) -4- {3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 43 mg (86% yield) HPLC analysis: 99.7% purity (retention time: 2.627
Min) MS (APCI +): 390 (M + H)

Example 235 1-benzyl-4- {3- [5- (4-fluorophenyl)
-4-Isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 41 mg (80% yield) HPLC analysis: 98.6% purity (retention time: 2.834)
MS) (APCI +): 394 (M + H) Example 236 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-pyridinyl) piperazine trifluoroacetate Yield: 47 mg (96% yield) HPLC analysis: 99.6% purity (retention time: 2.598)
Min) MS (APCI +): 381 (M + H)

Example 237 1-Benzhydryl-4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 59 mg (96% yield) HPLC analysis: Purity 99 0.2% (retention time: 3.220
MS) (APCI-): 468 (MH) Example 238 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-phenylpiperazine trifluoroacetate Yield: 40 mg (Yield 81%) HPLC analysis: purity 98.5% (retention time: 3.456)
Min) MS (APCI +): 380 (M + H)

Example 239 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-methoxyphenyl)
Piperazine trifluoroacetate yield: 47 mg (89% yield) HPLC analysis: purity 99.5% (retention time: 3.140)
Min) MS (APCI +): 410 (M + H)

Example 240 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (1-piperidinyl) piperidine trifluoroacetate Yield: 48 mg (96% yield) HPLC Analysis: 99.2% purity (retention time: 2.578)
Min) MS (APCI +): 386 (M + H)

Example 241 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N-methyl-N- (1-methyl-3-pyrrolidinyl) propionamide trifluoroacetate Yield: 40 mg (yield: 40 mg) HPLC analysis: 99.4% purity (retention time: 2.494)
MS) (APCI +): 332 (M + H) Example 242 N-benzyl-N- (1-benzyl-3-pyrrolidinyl)
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate yield:
54 mg (yield 90%) HPLC analysis: purity 97.0% (retention time: 3.378)
Min) MS (APCI +): 484 (M + H)

Example 243 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N, N-bis (2-pyridinylmethyl) propionamide 2-trifluoroacetate Yield: 48 mg (80% yield) HPLC Analysis: 99.0% purity (retention time: 2.606)
Min) MS (APCI +): 417 (M + H) EXAMPLE 244 1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-hydroxyethyl).
Piperazine trifluoroacetate yield: 36 mg (79% yield) HPLC analysis: 99.6% purity (retention time: 2.390)
Min) MS (APCI +): 348 (M + H)

Example 245 1- (1,3-benzodioxol-5-ylmethyl)-
4- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 58 mg (95% yield) HPLC analysis: 98.4% purity (retention time: 2.864)
MS) (APCI +): 438 (M + H) Example 246 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-pyrimidinyl) piperazine trifluoroacetate Yield: 43 mg (86% yield) HPLC analysis: 99.1% purity (retention time: 3.054)
Min) MS (APCI +): 382 (M + H)

Example 247 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-[(E) -3-phenyl-
2-Propenyl] piperazine trifluoroacetate Yield: 48 mg (91% yield) HPLC analysis: 96.9% purity (retention time: 3.064)
MS) (APCI +): 420 (M + H) Example 248 (2S) -1- {3- [5- (4-fluorophenyl) -4-
Isoxazolyl] propanoyl} -2- (1-pyrrolidinylmethyl) pyrrolidine trifluoroacetate Yield: 44 mg (91% yield) HPLC analysis: 99.5% purity (retention time: 2.701)
Min) MS (APCI +): 372 (M + H)

Example 249 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (1-pyrrolidinyl) piperidine trifluoroacetate Yield: 44 mg (91% yield) HPLC Analysis: 99.4% purity (retention time: 2.530
MS) (APCI +): 372 (M + H) Example 250 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- [3- (trifluoromethyl) phenyl] piperazine tri Fluoroacetate yield: 34 mg (61% yield) HPLC analysis: 99.6% purity (retention time: 4.229)
Min) MS (APCI +): 448 (M + H)

Example 251 1- (4-Acetylphenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 35 mg (65% yield) HPLC analysis: 100% purity (retention time: 3.619
MS) (APCI +): 422 (M + H) Example 252 1- (2-Chlorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}
Piperazine trifluoroacetate yield: 37 mg (71% yield) HPLC analysis: 99.1% purity (retention time: 4.176)
Min) MS (APCI +): 414 (M + H)

Example 253 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (3-methoxyphenyl)
Piperazine trifluoroacetate Yield: 52 mg (98% yield) HPLC analysis: 99.6% purity (retention time: 3.625)
MS) (APCI +): 410 (M + H) Example 254 1- (3-Chlorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}.
Piperazine trifluoroacetate Yield: 27 mg (51% yield) HPLC analysis: 98.8% purity (retention time: 4.149)
Min) MS (APCI +): 414 (M + H)

Example 255 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-methylphenyl) piperazine trifluoroacetate Yield: 11 mg (22% yield) HPLC analysis: 97.7% purity (retention time: 4.004)
MS) (APCI +): 394 (M + H) Example 256 1- (2-Ethoxyphenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield : 40 mg (yield 75%) HPLC analysis: purity 99.2% (retention time: 3.336)
Min) MS (APCI +): 424 (M + H)

Example 257 1- (2-Fluorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield: 34 mg (67% yield) HPLC analysis: purity 99.4% (retention time: 3.956
MS) (APCI +): 398 (M + H) EXAMPLE 258 1- (4-Chlorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}.
Piperazine trifluoroacetate Yield: 28 mg (53% yield) HPLC analysis: 99.5% purity (retention time: 4.084)
Min) MS (APCI +): 414 (M + H)

Example 259 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (4-methoxyphenyl)
Piperazine trifluoroacetate Yield: 24 mg (45% yield) HPLC analysis: 99.2% purity (retention time: 3.085)
MS) (APCI +): 410 (M + H) Example 260 1- (4-Fluorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate Yield : 30 mg (58% yield) HPLC analysis: 99.0% purity (retention time: 3.643)
Min) MS (APCI +): 398 (M + H) NMR (CDCl 3) δ: 2.66 (2H, t, J = 7Hz), 3.0-3.1 (6H,
m), 3.57 (2H, m, J = 5Hz), 3.79 (2H, m, J = 5Hz), 6.
85-7.0 (4H, m), 7.15-7.25 (2H, m), 7.7-7.8 (2H, m),
8.25 (1H, s).

Example 261 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4- (3-methylphenyl) piperazine trifluoroacetate Yield: 32 mg (63% yield) HPLC analysis: purity 89.6% (retention time: 3.545)
Min) MS (APCI +): 394 (M + H) Example 262 2-Ethyl-1- {3- [5- (4-fluorophenyl)-
4-Isoxazolyl] propanoyl} piperidine Yield: 27 mg (80% yield) HPLC analysis: 98.9% purity (retention time: 3.916)
Min) MS (APCI +): 331 (M + H).

Example 263 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -3-piperidinecarboxamide Yield: 30 mg (86% yield) HPLC analysis: 99.1% purity (Retention time: 2.860
MS) (APCI +): 346 (M + H) Example 264 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-phenyl-4-piperidinol Yield: 32 mg (82 yield) %) HPLC analysis: 99.3% purity (retention time: 3.541)
Min) MS (APCI-): 393 (M-H)

Example 265 4- (4-Bromophenyl) -1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}
-4-Piperidinol Yield: 37 mg (79% yield) HPLC analysis: 99.2% purity (retention time: 3.867)
MS) (APCI-): 471 (MH), 473 Example 266 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} azepan Yield: 25 mg (79% yield) HPLC analysis: purity 99.0% (retention time: 3.709
Min) MS (APCI +): 317 (M + H).

Example 267 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} azocan Yield: 27 mg (81% yield) HPLC analysis: 99.2% purity (retention time: 3) .881
MS) (APCI +): 331 (M + H) Example 268 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} decahydroquinoline Yield: 30 mg (84% yield) HPLC analysis: Purity 98.9% (retention time: 4.166)
Min) MS (APCI +): 357 (M + H)

Example 269 1- {3- [5- (4-Fluorophenyl) -4-isoxazolyl] propanoyl} -4-phenyl-4-piperidinecarbonitrile Yield: 35 mg (86% yield) HPLC analysis: Purity 98.9% (retention time: 3.929)
MS) (APCI +): 404 (M + H) Example 270 4-Acetyl-1- {3- [5- (4-fluorophenyl)
-4-Isoxazolyl] propanoyl} -4-phenylpiperidine Yield: 17 mg (41% yield) HPLC analysis: 99.0% purity (retention time: 3.898)
Min) MS (APCI +): 421 (M + H)

Example 271 2-ethoxycarbonyl-1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperidine Yield: 23 mg (64% yield) HPLC analysis: 98.3% purity (Retention time: 3.693
MS) (APCI +): 361 (M + H) Example 272 N- [2- (dimethylamino) ethyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 20 mg (47% yield) HPLC analysis: 99.9% purity (retention time: 2.516)
Min) MS (ESI +): 306 (M + H).

Example 273 N- [3- (Diethylamino) propyl] -3- [5- (4-
Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 34 mg (75% yield) HPLC analysis: 99.8% purity (retention time: 2.567)
MS) (ESI +): 348 (M + H) Example 274 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (1-piperidinyl) ethyl] propionamide trifluoroacetate Yield : 34 mg (yield 73%) HPLC analysis: purity 99.8% (retention time: 2.621)
MS) (ESI +): 346 (M + H) Example 275 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (4-morpholinyl) ethyl] propionamide trifluoroacetate Yield : 33 mg (yield 71%) HPLC analysis: purity 99.7% (retention time: 2.499)
MS) (ESI +): 348 (M + H) Example 276 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (4-methyl-1-piperazinyl) propyl] propionamide 2 Trifluoroacetic acid salt Yield: 27 mg (Yield 45%) HPLC analysis: Purity 99.7% (Retention time: 2.282)
Min) MS (ESI +): 375 (M + H) NMR (CDCl 3) δ: 1.6-1.75 (2H, m), 2.45 (2H, t, J = 7H
z), 2.79 (3H, s), 2.8-2.9 (4H, m), 3.0-3.1 (4H, m),
7.35-7.45 (2H, m), 7.75-7.85 (2H, m), 8.02 (1H, br
s), 8.52 (1H, s).

Example 277 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (methylanilino) propyl] propionamide trifluoroacetate Yield: 39 mg (78% yield) HPLC analysis : Purity 99.8% (retention time: 2.842)
MS) (ESI +): 382 (M + H) Example 278 N- (1-benzyl-4-piperazinyl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 39 mg (74% yield) HPLC analysis: 99.9% purity (retention time: 2.863)
Min) MS (ESI +): 408 (M + H).

Example 279 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2,2,6,6-tetramethyl-4-piperidinyl) propionamide trifluoroacetate Yield: 23 mg (Yield 48%) HPLC analysis: 100% purity (retention time: 2.661)
Min) MS (ESI +): 374 (M + H) NMR (CDCl 3) δ: 1.25-1.4 (12H, m), 1.7-1.9 (2H, m), 2.
43 (2H, t, J = 7Hz), 2.86 (2H, t, J = 7Hz), 3.55-3.6
5 (2H, m), 4.0-4.1 (1H, m), 7.35-7.45 (2H, m), 7.7-7.8
(1H, m), 7.75-7.85 (2H, m), 7.95-8.05 (1H, m), 8.51
(1H, s), 8.5-8.6 (1H, m). Example 280 N- (2-anilinoethyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 35 mg (76% yield) HPLC analysis: 99.7% purity (Retention time: 3.002
Min) MS (ESI +): 354 (M + H).

Example 281 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-pyridinylmethyl) propionamide trifluoroacetate Yield: 27 mg (yield 62%) HPLC analysis: purity 99 9.9% (retention time: 2.497)
MS) (ESI +): 326 (M + H) Example 282 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (4-pyridinyl) ethyl] propionamide trifluoroacetate Yield : 32 mg (yield 72%) HPLC analysis: purity 99.9% (retention time: 2.454)
Min) MS (ESI +): 340 (M + H)

Example 283 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (1-imidazolyl) propyl] propionamide trifluoroacetate Yield: 31 mg (68% yield) HPLC analysis: purity 99.9% (retention time: 2.496
MS) (ESI +): 343 (M + H) Example 284 N- [2- (diisopropylamino) ethyl] -3- [5-
(4-Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 33 mg (69% yield) HPLC analysis: 99.8% purity (retention time: 2.733)
Min) MS (ESI +): 362 (M + H).

Example 285 N- [3- (dimethylamino) -2,2-dimethylpropyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 32. 1 mg (70% yield) HPLC analysis: 99.9% purity (retention time: 2.570)
MS) (ESI +): 348 (M + H) Example 286 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (2-methyl-1-piperidinyl) propyl] propionamide tri. Fluoroacetate yield: 35 mg (71% yield) HPLC analysis: 100% purity (retention time: 2.696)
Min) MS (ESI +): 374 (M + H).

Example 287 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (4-morpholinyl) propyl] propionamide trifluoroacetate Yield: 35 mg (74% yield) HPLC analysis: 100% purity (retention time: 2.512
MS) (ESI +): 362 (M + H) Example 288 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (1-pyrrolidinyl) ethyl] propionamide trifluoroacetate Yield : 31 mg (yield 69%) HPLC analysis: purity 99.9% (retention time: 2.542)
Min) MS (ESI +): 332 (M + H).

Example 289 N- [2- (ethyl-3-methylanilino) ethyl] -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
Propionamide trifluoroacetate Yield: 39 mg (77% yield) HPLC analysis: 99.5% purity (retention time: 3.054)
MS) (ESI +): 396 (M + H) Example 290 N- (1-benzyl-3-pyrrolidinyl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 38 mg (74% yield) HPLC analysis: 99.7% purity (retention time: 2.922)
Min) MS (ESI +): 394 (M + H).

Example 291 N- {3- [bis (2-hydroxyethyl) amino] propyl} -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 34 mg ( HPLC analysis: purity 99.9% (retention time: 2.417)
MS) (ESI +): 380 (M + H) Example 292 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (4-pyridinylmethyl) propionamide trifluoroacetate Yield: 46 mg (Yield) HPLC analysis: 100% purity (retention time: 2.466)
Min) MS (ESI +): 326 (M + H).

Example 293 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (3-pyridinylmethyl) propionamide trifluoroacetate Yield: 31 mg (71% yield) HPLC analysis: purity 99 0.9% (retention time: 2.456
MS) (ESI +): 326 (M + H) Example 294 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (3-pyridinyl) ethyl] propionamide trifluoroacetate Yield : 35 mg (78% yield) HPLC analysis: 100% purity (retention time: 2.489)
Min) MS (ESI +): 340 (M + H)

Example 295 N- [2- (dimethylamino) ethyl] -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 5 mg (20% yield) HPLC analysis: 100% purity (retention time: 2.931)
MS) (ESI +): 356 (M + H) Example 296 N- [3- (methylanilino) propyl] -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 3 mg (10% yield) HPLC analysis: 92.9% purity (retention time: 3.212
Min) MS (ESI +): 432 (M + H)

Example 297 N- (1-benzyl-4-piperidinyl) -3- {5- [4
-(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 11 mg (39% yield) HPLC analysis: 100% purity (retention time: 3.213
MS) (ESI +): 458 (M + H) Example 298 N- (2,2,6,6-tetramethyl-4-piperidinyl) -3- {5- [4- (trifluoromethyl) phenyl]-
4-Isoxazolyl} propionamide trifluoroacetate Yield: 8 mg (28% yield) HPLC analysis: 100% purity (retention time: 3.069)
Min) MS (ESI +): 424 (M + H).

Example 299 N- (2-anilinoethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 7 mg (13% yield) HPLC Analysis: 92.2% purity (retention time: 3.387)
MS) (ESI +): 404 (M + H) Example 300 N- (2-pyridinylmethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 11 mg (48% yield) HPLC analysis: 99.9% purity (retention time: 2.949)
Min) MS (ESI +): 376 (M + H).

Example 301 N- [2- (4-pyridinyl) ethyl] -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 10 mg (41% yield) HPLC analysis: 100% purity (retention time: 2.899
MS) (ESI +): 390 (M + H) Example 302 N- [3- (1-Imidazolyl) propyl] -3- {5- [4
-(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 13 mg (50% yield) HPLC analysis: 100% purity (retention time: 2.928
Min) MS (ESI +): 393 (M + H).

Example 303 N- [3- (Dimethylamino) -2,2-dimethylpropyl] -3- {5- [4- (trifluoromethyl) phenyl]-
4-Isoxazolyl} propionamide trifluoroacetate Yield: 12 mg (45% yield) HPLC analysis: 100% purity (retention time: 3.020)
MS) (ESI +): 398 (M + H) Example 304 N- [3- (2-Methyl-1-piperidinyl) propyl]-
3- {5- [4- (trifluoromethyl) phenyl] -4-
Isoxazolyl} propionamide trifluoroacetate Yield: 5 mg (20% yield) HPLC analysis: 100% purity (retention time: 3.088)
Min) MS (ESI +): 424 (M + H).

Example 305 N- [2- (ethyl-3-methylanilino) ethyl] -3-
{5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 4 mg (14% yield) HPLC analysis: 98.9% purity (retention time: 3.411)
MS) (ESI +): 446 (M + H) Example 306 N- (1-benzyl-3-pyrrolidinyl) -3- {5- [4
-(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 10 mg (34% yield) HPLC analysis: 100% purity (retention time: 3.275
Min) MS (ESI +): 444 (M + H)

Example 307 N- {3- [bis (2-hydroxyethyl) amino] propyl} -3- {5- [4- (trifluoromethyl) phenyl]-
4-Isoxazolyl} propionamide trifluoroacetate Yield: 7 mg (25% yield) HPLC analysis: 100% purity (retention time: 2.854)
MS) (ESI +): 430 (M + H) Example 308 N- {2-[(5-nitro-2-pyridinyl) amino] ethyl} -3- {5- [4- (trifluoromethyl) phenyl]-
4-Isoxazolyl} propionamide trifluoroacetate Yield: 15 mg (52% yield) HPLC analysis: 98.1% purity (retention time: 3.732)
Min) MS (ESI +): 450 (M + H)

Example 309 N- (4-pyridinylmethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 8 mg (yield 31%) HPLC Analysis: 100% purity (retention time: 2.907
MS) (ESI +): 376 (M + H) Example 310 N- (3-pyridinylmethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 13 mg (yield 51%) HPLC analysis: 100% purity (retention time: 2.901
Min) MS (ESI +): 376 (M + H).

Example 311 N- [2- (3-pyridinyl) ethyl] -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 13 mg (53% yield) HPLC analysis: 100% purity (retention time: 2.916
MS) (ESI +): 390 (M + H) Example 312 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N-phenylpropionamide Yield: 25 mg (79% yield) HPLC analysis: Purity 100 % (Retention time: 3.728
Min) MS (ESI +): 311 (M + H).

Example 313 N- (2,3-dihydro-5-indenyl) -3- [5-
(4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 27 mg (78% yield) HPLC analysis: Purity 99.1% (Retention time: 4.100)
MS) (ESI +): 351 (M + H) Example 314 N- (3,5-dimethoxyphenyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 31 mg (84 yield) %) HPLC analysis: purity 99.5% (retention time: 3.784)
Min) MS (ESI +): 371 (M + H).

Example 315 N- (4-benzylphenyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 17 mg (43% yield) HPLC analysis: 99.6% purity (Retention time: 4.307
MS) (ESI +): 401 (M + H) Example 316 N- (1,1'-biphenyl-3-yl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 34 mg (87% yield) HPLC analysis: 97.7% purity (retention time: 4.300)
Min) MS (ESI +): 387 (M + H).

Example 317 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-thiazolyl) propionamide Yield: 34 mg (90% yield) HPLC analysis: 97.2% purity ( Retention time: 3.346
MS) (ESI +): 318 (M + H) Example 318 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (4-pyridinyl) propionamide trifluoroacetate Yield: 27 mg (Yield) HPLC analysis: purity 98.8% (retention time: 2.646)
Min) MS (ESI +): 312 (M + H).

Example 319 N- (5,6-Dimethyl-1,2,4-triazine-3
-Yl) -3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 20 mg (59% yield) HPLC analysis: 98.4% purity (retention time: 3.081)
MS) (ESI +): 342 (M + H) Example 320 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (6-quinolinyl) propionamide trifluoroacetate Yield: 40 mg (Yield) HPLC analysis: 99.7% purity (retention time: 2.756)
Min) MS (ESI +): 362 (M + H).

Example 321 N- (2-benzothiazolyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 22 mg (61% yield) HPLC analysis: 98.7% purity ( Retention time: 3.908
MS) (ESI +): 368 (M + H) Example 322 N- (2-Fluorophenyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 26 mg (78% yield) HPLC analysis: purity 99.5% (retention time: 3.735)
Min) MS (ESI +): 329 (M + H).

Example 323 N- (2,3-dihydro-1,4-benzodioxin-
6-yl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 30 mg (80% yield) HPLC analysis: 100% purity (retention time: 3.608)
MS) (ESI +): 369 (M + H) Example 324 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [4- (trifluoromethyl) phenyl] propionamide Yield: 33 mg (yield) HPLC analysis: 100% purity (retention time: 4.170)
Min) MS (ESI +): 395 (M + H)

Example 325 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-phenoxyphenyl) propionamide Yield: 38 mg (93% yield) HPLC analysis: 99.1% purity (Retention time: 4.258
MS) (ESI +): 403 (M + H) Example 326 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (1-phenyl-5-pyrazolyl) propionamide Yield: 19 mg (Yield) HPLC analysis: 99.5% purity (retention time: 3.490)
Min) MS (ESI +): 377 (M + H).

Example 327 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (5-methyl-3-isoxazolyl) propionamide Yield: 10 mg (33% yield) HPLC analysis: Purity 99 0.5% (retention time: 3.427)
MS) (ESI +): 316 (M + H) Example 328 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (3-quinolinyl) propionamide trifluoroacetate Yield: 44 mg (Yield) HPLC analysis: 100% purity (retention time: 2.959)
Min) MS (ESI +): 362 (M + H).

Example 329 N-phenyl-3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 6 mg (35% yield) HPLC analysis: 98.5% purity ( Retention time: 4.174
MS) (ESI +): 361 (M + H) Example 330 N- (2,3-dihydro-5-indenyl) -3- {5-
[4- (Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 7 mg (34% yield) HPLC analysis: 98.3% purity (retention time: 4.511)
Min) MS (ESI +): 401 (M + H).

Example 331 N- (3,4-Dichlorophenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl}
Propionamide yield: 12 mg (55% yield) HPLC analysis: 99.5% purity (retention time: 4.672)
MS) (ESI +): 429 (M + H) Example 332 N- (3,5-dimethoxyphenyl) -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 12 mg (55% yield) HPLC analysis: 99.5% purity (retention time: 4.195)
Min) MS (ESI +): 421 (M + H).

Example 333 N- (4-benzylphenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 12 mg (55% yield) HPLC analysis: Purity 96.7% (retention time: 4.698)
MS) (ESI +): 451 (M + H) Example 334 N- (1,1'-biphenyl-3-yl) -3- {5- [4
-(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 10 mg (46% yield) HPLC analysis: 98.2% purity (retention time: 4.660)
Min) MS (ESI +): 437 (M + H)

Example 335 N- (2-Thiazolyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 3 mg (14% yield) HPLC analysis: purity 97 0.5% (retention time: 3.816
MS) (ESI +): 368 (M + H) Example 336 N- (4-pyridinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: HPLC analysis: 80.0% purity (retention time: 3.114)
Min) MS (ESI +): 362 (M + H).

Example 337 N- (5,6-Dimethyl-1,2,4-triazine-3
-Yl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 5 mg (24% yield) HPLC analysis: 97.4% purity (retention time: 3.634)
MS) (ESI +): 392 (M + H) Example 338 N- (6-quinolinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: HPLC analysis: 98.9% purity (retention time: 3.189)
Min) MS (ESI +): 412 (M + H).

Example 339 N- (2-benzothiazolyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 6 mg (yield 28%) HPLC analysis: purity 99 0.1% (retention time: 4.316)
MS) (ESI +): 418 (M + H) Example 340 N- (2-fluorophenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 8 mg (yield) HPLC analysis: purity 99.4% (retention time: 4.200)
Min) MS (ESI +): 379 (M + H).

Example 341 N- (2,3-dihydro-1,4-benzodioxin-
6-yl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 10 mg (47% yield) HPLC analysis: 100% purity (retention time: 4.056)
Min) MS (ESI +): 419 (M + H) Example 342 N- [3,5-bis (trifluoromethyl) phenyl] -3.
-{5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 13 mg (52% yield) HPLC analysis: 99.1% purity (retention time: 4.859)
Min) MS (ESI +): 497 (M + H).

Example 343 N- [4- (trifluoromethoxy) phenyl] -3- {5
-[4- (Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 9 mg (41% yield) HPLC analysis: 99.2% purity (retention time: 4.566)
MS) (ESI +): 445 (M + H) Example 344 N- (2-phenoxyphenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 11 mg (yield) HPLC analysis: 99.3% purity (retention time: 4.680)
Min) MS (ESI +): 453 (M + H)

Example 345 N- (1-Phenyl-5-pyrazolyl) -3- {5- [4-
(Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 11 mg (52% yield) HPLC analysis: 100% purity (retention time: 3.952
MS) (ESI +): 427 (M + H) Example 346 N- (5-methyl-3-isoxazolyl) -3- {5-
[4- (Trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 7 mg (40% yield) HPLC analysis: 99.5% purity (retention time: 3.921)
Min) MS (ESI +): 366 (M + H).

Example 347 N- (3-pyridinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 10 mg (41% yield) HPLC Analysis: purity 86.0% (retention time: 3.046)
MS) (ESI +): 362 (M + H) Example 348 N- (2-pyrazinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 7 mg (Yield) HPLC analysis: purity 99.0% (retention time: 3.650)
Min) MS (ESI +): 363 (M + H).

Example 349 N- (3-quinolinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 14 mg (yield 68%) HPLC analysis: purity 99 0.2% (retention time: 3.395
MS) (ESI +): 412 (M + H) Example 350 N- (2,1,3-benzothiadiazol-4-yl)-
3- {5- [4- (trifluoromethyl) phenyl] -4-
Isoxazolyl} propionamide Yield: 11 mg (52% yield) HPLC analysis: 100% purity (retention time: 4.334)
Min) MS (ESI +): 419 (M + H).

Example 351 N- [4- (Diethylphosphono) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide Yield: 36 mg (84% yield) HPLC analysis: Purity 99.6% ( Retention time: 4.208
MS) (ESI +): 429 (M + H) Example 352 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Chlorophenyl) -4-isoxazolyl] propionamide Yield: 38 mg (83% yield) HPLC analysis: 100% purity (retention time: 4.431)
Min) MS (ESI +): 463 (M + H).

Example 353 N- [4- (Diethylphosphono) phenyl] -2- (5-phenyl-4-isoxazolyl) acetamide Yield: 38 mg (91% yield) HPLC analysis: 94.1% purity (retention) Time: 4.136
MS) (ESI +): 415 (M + H) Example 354 N- [4- (diethylphosphono) phenyl] -4- (5-phenyl-4-isoxazolyl) butanamide Yield: 34 mg (77% yield) HPLC analysis : Purity 100% (retention time: 4.258)
Min) MS (ESI +): 443 (M + H).

Example 355 N- {4-[(2-Oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- (5-phenyl-4-isoxazolyl) propionamide Yield: 35 mg (82% yield) HPLC analysis: 100% purity (retention time: 3.796)
MS) (ESI +): 427 (M + H) Example 356 3- [5- (4-Chlorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphos. Finnan-2-yl) methyl] phenyl} propionamide Yield: 17 mg (36% yield) HPLC analysis: 100% purity (retention time: 4.035)
Min) MS (ESI +): 461 (M + H).

Example 357 N- {4-[(2-Oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -2- (5-phenyl-4-isoxazolyl) acetamide Yield : 23 mg (55% yield) HPLC analysis: 100% purity (retention time: 3.718)
MS) (ESI +): 413 (M + H) Example 358 N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -4- (5- (Phenyl-4-isoxazolyl) butanamide yield: 40 mg (92% yield) HPLC analysis: 99.1% purity (retention time: 3.862)
Min) MS (ESI +): 441 (M + H).

Example 359 N- [4- (dimethylphosphonomethyl) phenyl] -3-
(5-phenyl-4-isoxazolyl) propionamide Yield: 26 mg (63% yield) HPLC analysis: 100% purity (retention time: 3.897)
MS) (ESI +): 415 (M + H) Example 360 N- [4- (dimethylphosphonomethyl) phenyl] -3-
[5- (4-Chlorophenyl) -4-isoxazolyl] propionamide Yield: 27 mg (59% yield) HPLC analysis: 100% purity (retention time: 4.135)
Min) MS (ESI +): 449 (M + H).

Example 361 N- [4- (dimethylphosphonomethyl) phenyl] -2-
(5-Phenyl-4-isoxazolyl) acetamide Yield: 26 mg (64% yield) HPLC analysis: 100% purity (retention time: 3.826)
MS) (ESI +): 401 (M + H) Example 362 N- [4- (dimethylphosphonomethyl) phenyl] -4-.
(5-phenyl-4-isoxazolyl) butanamide yield: 26 mg (61% yield) HPLC analysis: 100% purity (retention time: 3.960)
Min) MS (ESI +): 429 (M + H).

Example 363 N- [4- (dimethylphosphonomethyl) phenyl] -3-
(3,5-diphenyl-4-isoxazolyl) propionamide Yield: 31 mg (64% yield) HPLC analysis: 99.9% purity (retention time: 4.417)
Min) MS (ESI +): 491 (M + H) Example 364 N- [4- (dimethylphosphonomethyl) phenyl] -3-.
[5- (4-Methylphenyl) -4-isoxazolyl] propionamide Yield: 30 mg (70% yield) HPLC analysis: 100% purity (retention time: 4.074)
Min) MS (ESI +): 429 (M + H).

Example 365 N- [4- (dimethylphosphonomethyl) phenyl] -3-
(3-Methyl-5-phenyl-4-isoxazolyl) propionamide Yield: 35 mg (82% yield) HPLC analysis: 100% purity (retention time: 3.934)
Min) MS (ESI +): 429 (M + H) Example 366 N- [4- (dimethylphosphonomethyl) phenyl] -3-.
[5- (4-methoxyphenyl) -4-isoxazolyl]
Propionamide yield: 32 mg (73% yield) HPLC analysis: 100% purity (retention time: 3.914)
Min) MS (ESI +): 445 (M + H).

Example 367 N- [4- (dimethylphosphonomethyl) phenyl] -3-
{5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 30 mg (63% yield) HPLC analysis: 99.9% purity (retention time: 4.293)
MS) (ESI +): 483 (M + H) Example 368 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxa Phosphinan-2-yl) methyl] phenyl} propionamide Yield: 27 mg (44% yield) HPLC analysis: 97.0% purity (retention time: 3.274)
Min) MS (ESI +): 445 (M + H) NMR (CDCl 3) δ: 1.8-2.0 (2H, m), 2.70 (2H, t, J = 7H
z), 3.07 (2H, t, J = 7Hz), 3.19 (2H, d, J = 21Hz),
4.1-4.2 (2H, m), 4.3-4.5 (2H, m), 7.1-7.25 (4H, m),
7.35-7.45 (2H, m), 7.7-7.8 (2H, m), 8.11 (1H, br s),
8.23 (1H, s).

Example 369 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (4-Nitrophenyl) -4-isoxazolyl] propionamide Yield: 44 mg (71% yield) HPLC analysis: 99.4% purity (retention time: 3.730)
Min) MS (ESI +): 488 (M + H) NMR (CDCl 3) δ: 1.24 (6H, t, J = 7Hz), 2.75 (2H, t, J
= 7Hz), 3.09 (2H, d, J = 22Hz), 3.15 (2H, d, J = 7H
z), 3.9-4.05 (4H, m), 7.1-7.2 (2H, m), 7.36 (2H, d, J
= 8.5Hz), 7.97 (2H, d, J = 8.5Hz), 8.22 (1H, br s),
8.35-8.4 (3H, m). Example 370 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (3,4-Dimethoxyphenyl) -4-isoxazolyl] propionamide Yield: 57 mg (90% yield) HPLC analysis: 99.9% purity (retention time: 3.502
Min) MS (ESI +): 503 (M + H)

Example 371 3- [5- (3-Bromo-4-fluorophenyl) -4-
Isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 51 mg (75% yield) HPLC analysis: 99.9% purity (retention time: 3.979)
MS) (ESI +): 539 (M + H), 541 Example 372 3- [5- (4-Chloro-3-fluorophenyl) -4-
Isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 48 mg (77% yield) HPLC analysis: 100% purity (retention time: 3.990
Min) MS (ESI +): 495 (M + H)

Example 373 3- [5- (3,5-Dichlorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 53 mg (82% yield) HPLC analysis : Purity 99.6% (retention time: 4.180)
Min) MS (ESI +): 511 (M + H) Example 374 N- [4- (diethylphosphonomethyl) phenyl] -3-.
[5- (3,4-Difluorophenyl) -4-isoxazolyl] propionamide Yield: 37 mg (63% yield) HPLC analysis: 100% purity (retention time: 3.822)
Min) MS (ESI +): 479 (M + H).

Example 375 N- [4- (dimethylphosphonomethyl) phenyl] -3-
[5- (4-Nitrophenyl) -4-isoxazolyl] propionamide Yield: 10 mg (17% yield) HPLC analysis: 98.7% purity (retention time: 3.476)
MS) (ESI +): 460 (M + H) Example 376 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide Yield: 43 mg (yield 72%) HPLC analysis: purity 99.8% (retention time: 3.237)
Min) MS (ESI +): 475 (M + H) NMR (CDCl 3) δ: 2.67 (2H, t, J = 7Hz), 3.11 (2H, t, J
= 7Hz), 3.14 (2H, d, J = 22Hz), 3.64 (3H, s), 3.69 (3
H, s), 3.94 (3H, s), 3.95 (3H, s), 6.97 (1H, d, J = 9H
z), 7.35-7.55 (4H, m), 7.42 (2H, d, J = 8.5Hz), 7.56
(1H, br s), 8.24 (1H, s).

Example 377 3- [5- (3-Bromo-4-fluorophenyl) -4-
Isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide Yield: 34 mg (53% yield) HPLC analysis: 100.% purity (retention time: 3.732
MS) (ESI +): 511 (M + H), 513 Example 378 3- [5- (4-Chloro-3-fluorophenyl) -4-
Isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide Yield: 37 mg (63% yield) HPLC analysis: 100% purity (retention time: 3.739
Min) MS (ESI +): 467 (M + H).

Example 379 3- [5- (3,5-Dichlorophenyl) -4-isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide Yield: 38 mg (64% yield) HPLC analysis : Purity 99.8% (retention time: 3.909)
MS) (ESI +): 483 (M + H) Example 380 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 40 mg (64% yield) HPLC analysis: 99.6% purity (retention time: 3.680)
Min) MS (ESI +): 447 (M + H).

Example 381 3- [5- (3,4-Difluorophenyl) -4-isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide Yield: 31 mg (56% yield) HPLC Analysis: 99.8% purity (retention time: 3.565)
MS) (ESI +): 451 (M + H) Example 382 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Nitrophenyl) -4-isoxazolyl] propionamide Yield: 49 mg (83% yield) HPLC analysis: 100% purity (retention time: 3.746)
Min) MS (ESI +): 474 (M + H).

Example 383 N- [4- (Diethylphosphono) phenyl] -3- [5-
(3,4-dimethoxyphenyl) -4-isoxazolyl]
Propionamide yield: 51 mg (83% yield) HPLC analysis: 99.8% purity (retention time: 3.528)
Min) MS (ESI +): 489 (M + H) Example 384 3- [5- (3-Bromo-4-fluorophenyl) -4-.
Isoxazolyl] -N- [4- (diethylphosphono) phenyl] propionamide Yield: 52 mg (79% yield) HPLC analysis: 99.7% purity (retention time: 4.011)
Min) MS (ESI +): 525 (M + H), 527

Example 385 3- [5- (4-Chloro-3-fluorophenyl) -4-
Isoxazolyl] -N- [4- (diethylphosphono) phenyl] propionamide Yield: 51 mg (84% yield) HPLC analysis: 99.9% purity (retention time: 4.019)
Min) MS (ESI +): 481 (M + H) NMR (CDCl 3) δ: 1.32 (6H, t, J = 7Hz), 2.73 (2H, t, J
= 7Hz), 3.10 (2H, t, J = 7Hz), 4.0-4.2 (4H, m), 7.5-
7.8 (8H, m), 8.27 (1H, s). Example 386 3- [5- (3,5-Dichlorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphono) phenyl] propionamide Yield: 53 mg (85% yield) HPLC analysis: purity 99. 8% (retention time: 4.215
Min) MS (ESI +): 497 (M + H).

Example 387 N- [4- (dimethylphosphonomethyl) phenyl] -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
Propionamide yield: 25 mg (42% yield) HPLC analysis: 97.9% purity (retention time: 3.375)
Min) MS (ESI +): 433 (M + H) NMR (CDCl 3) δ: 2.69 (2H, t, J = 7Hz), 3.08 (2H, t, J
= 7Hz), 3.10 (2H, d, J = 21Hz), 3.62 (3H, s), 3.66 (3
H, s), 7.1-7.2 (4H, m), 7.38 (2H, d, J = 8.5Hz), 7.7
-7.75 (2H, m), 8.01 (1H, br s), 8.26 (1H, s). Example 388 N- [4- (diethylphosphono) phenyl] -3- [5-
(3,4-difluorophenyl) -4-isoxazolyl]
Propionamide yield: 36 mg (62% yield) HPLC analysis: 100% purity (retention time: 3.849)
Min) MS (ESI +): 465 (M + H).

Example 389 3- [5- (4-Nitrophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl ] Phenyl} propionamide Yield: 19 mg (33% yield) HPLC analysis: 100% purity (retention time: 3.375
MS) (ESI +): 472 (M + H) Example 390 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2- Dioxaphosphinan-2-yl) methyl] phenyl} propionamide Yield: 24 mg (40% yield) HPLC analysis: 100% purity (retention time: 3.136)
Min) MS (ESI +): 487 (M + H).

Example 391 3- [5- (3-Bromo-4-fluorophenyl) -4-
Isoxazolyl] -N- {4-[(2-oxide-1,3,
2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide Yield: 24 mg (37% yield) HPLC analysis: 99.9% purity (retention time: 3.637)
MS) (ESI +): 523 (M + H), 525 Example 392 3- [5- (4-Chloro-3-fluorophenyl) -4-
Isoxazolyl] -N- {4-[(2-oxide-1,3,
2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide Yield: 22 mg (37% yield) HPLC analysis: 100% purity (retention time: 3.634)
Min) MS (ESI +): 479 (M + H).

Example 393 3- [5- (3,5-Dichlorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) Methyl] phenyl} propionamide Yield: 28 mg (44% yield) HPLC analysis: 100% purity (retention time: 3.809)
Min) MS (ESI +): 495 (M + H) Example 394 N-benzyl-N- [2- (diethylamino) ethyl] -3.
-[5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 33 mg (57% yield) HPLC analysis: 98.3% purity (retention time: 3.184)
Min) MS (ESI +): 424 (M + H).

Example 395 3- [5- (3,4-Difluorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl ) Methyl] phenyl} propionamide Yield: 20 mg (35% yield) HPLC analysis: 100% purity (retention time: 3.462)
MS) (ESI +): 463 (M + H) Example 396 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(5-methyl-2-oxide-1,3,
2-Dioxaphosphinan-2-yl) methyl] phenyl} propionamide Yield: 33 mg (52% yield) HPLC analysis: 97.6% purity (retention time: 3.419)
Min) MS (ESI +): 459 (M + H) NMR (CDCl 3) δ: 0.84 (3H, t, J = 7Hz), 2.0-2.4 (1H,
m), 2.68 (2H, t, J = 7Hz), 3.08 (2H, t, J = 7Hz), 3.
1-3.25 (2H, m), 3.75-3.85 (1H, m), 4.0-4.2 (2H, m),
4.25-4.4 (1H, m), 7.1-7.2 (4H, m), 7.35-7.45 (2H, m),
7.7-7.8 (2H, m), 7.95 (1H, br s), 8.27 (1H, s).

Example 397 N- {4-[(5,5-dimethyl-2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 33 mg (50% yield) HPLC analysis: 95.8% purity (retention time: 3.546)
Min) MS (ESI +): 473 (M + H) NMR (CDCl 3) δ: 1.23 (6H, t, J = 7Hz), 2.69 (2H, t, J
= 7Hz), 3.0-3.2 (4H, m), 4.3-4.8 (4H, m), 7.1-7.25 (4
H, m), 7.3-7.4 (2H, m), 7.7-7.8 (2H, m), 7.8-7.9 (1
H, m), 8.28 (1H, s). Example 398 N- {4-[(5,5-diethyl-2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 35 mg (50% yield) HPLC analysis: 100% purity (retention time: 3.805)
Min) MS (ESI +): 501 (M + H).

Example 399 N- {4-[(4,6-dimethyl-2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 34 mg (52% yield) HPLC analysis: 97.6% purity (retention time: 3.505)
MS) (ESI +): 473 (M + H) Example 400 N- {4-[(5-butyl-5-ethyl-2-oxide-
1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 32 mg (44% yield) HPLC analysis: Purity 98.9% (retention time: 4.130)
Min) MS (ESI +): 529 (M + H) NMR (CDCl 3) δ: 0.7-0.95 (6H, m), 1.0-1.4 (8H, m), 2.6
8 (2H, t, J = 7Hz), 3.07 (2H, t, J = 7Hz), 3.18 (2H,
d, J = 21Hz), 3.75-3.9 (2H, m), 4.05-4.2 (2H, m), 7.1
-7.25 (4H, m), 7.35-7.45 (2H, m), 7.7-7.8 (2H, m), 7.
9-8.0 (1H, m), 8.27 (1H, s).

Example 401 N- {4- [2,2-bis (diethylphosphono) ethenyl] phenyl} -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 31 mg (yield HPLC analysis: 100% purity (retention time: 3.730)
MS) (ESI +): 609 (M + H) Example 402 N- (4-{[bis (ethylamino) phosphoryl] methyl} phenyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propion Amide yield: 13 mg (yield 21%) HPLC analysis: purity 97.3% (retention time: 3.362)
Min) MS (ESI +): 459 (M + H).

Example 403 N- [4- (Diethylphosphonomethyl) -2-methylphenyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 37 mg (56% yield) ) HPLC analysis: 98.1% purity (retention time: 3.615)
Min) MS (ESI +): 475 (M + H) Example 404 N- [3- (diethylphosphonomethyl) phenyl] -3-.
[5- (4-fluorophenyl) -4-isoxazolyl]
Propionamide yield: 34 mg (53% yield) HPLC analysis: 99.7% purity (retention time: 3.668)
Min) MS (ESI +): 461 (M + H).

Example 405 N- [2- (diethylphosphonomethyl) phenyl] -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
Propionamide yield: 44 mg (69% yield) HPLC analysis: 96.4% purity (retention time: 3.789)
MS) (ESI +): 461 (M + H) Example 406 N- {4-[(5-ethyl-5-methyl-2-oxide-
1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 30 mg (44% yield) HPLC analysis: 98.4% purity (retention time: 3.672)
Min) MS (ESI +): 487 (M + H).

Example 407 N- [4- (dibutylphosphonomethyl) phenyl] -3-
[5- (4-fluorophenyl) -4-isoxazolyl]
Propionamide yield: 44 mg (61% yield) HPLC analysis: 100% purity (retention time: 4.299)
Min) MS (ESI +): 517 (M + H) Example 408 N- [4- (diisopropylphosphonomethyl) phenyl]-.
3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 48 mg (70% yield) HPLC analysis: 100% purity (retention time: 3.906
Min) MS (ESI +): 489 (M + H).

Example 409 N- {4- [2- (diethylphosphono) ethyl] phenyl}-
3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 37 mg (57% yield) HPLC analysis: 100% purity (retention time: 3.725
MS) (ESI +): 475 (M + H) Example 410 N- {4-[(E) -2- (diethylphosphono) -2- (ethoxycarbonyl) ethenyl] phenyl} -3- [5- (4 -Fluorophenyl) -4-isoxazolyl] propionamide Yield: 9 mg (12% yield) HPLC analysis: 88.0% purity (retention time: 3.972)
Min) MS (ESI +): 545 (M + H)

Example 411 N- [2- (diethylphosphono) ethyl] -3- [5- (4-
[Fluorophenyl) -4-isoxazolyl] propionamide Yield: 1.2 mg (10% yield) HPLC analysis: 91.6% purity (retention time: 3.211)
MS) (ESI +): 399 (M + H) Example 412 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (diethylphosphono) propyl] propionamide Yield: 10 mg (yield) HPLC analysis: 97.4% purity (retention time: 3.182)
Min) MS (ESI +): 413 (M + H).

Example 413 N- [4- (diethylphosphonomethyl) phenyl] -3-
(5-phenyl-4-isoxazolyl) propionamide (221 mg), trimethylsilyl bromide (0.17 m
A mixture of 1) and acetonitrile (10 ml) was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC, and N- [4- (ethylphosphonomethyl) phenyl] -3-
(5-Phenyl-4-isoxazolyl) propionamide (139 mg, 67%) was obtained. 80-82 ° C. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7 Hz), 2.64 (2H, t, J
= 7Hz), 3.0-3.2 (4H, m), 3.9-4.1 (2H, m), 7.1-7.2 (3
H, m), 7.3-7.4 (2H, m), 7.4-7.6 (4H, m), 7.6-7.7 (2H,
m), 8.21 (1H, s). MS (ESI +): 415 (M + H) As a by-product in the preparative HPLC operation, 3- (5-
Phenyl-4-isoxazolyl) -N- [4- (phosphonomethyl) phenyl] propionamide was obtained. Yield: 39 mg (20% yield) Melting point: 162-164 ° C NMR (DMSO) δ: 2.67 (2H, t, J = 7 Hz), 2.88 (2H, t, J =
21Hz), 2.96 (2H, t, J = 7Hz), 7.15 (2H, dd, J = 8.5 /
2Hz), 7.45 (2H, d, J = 8.5Hz), 7.5-7.65 (3H, m), 7.76
(2H, dd, J = 8.5 / 2Hz), 8.56 (1H, s), 9.90 (1H, s). MS (ESI +): 387 (M + H)

[0646] Formulation Example 1 (production of capsule) 1) compound 30 mg 2) finely powdered cellulose 10 mg 3 of Example 68) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) And 4) are mixed and filled into a gelatin capsule. Formulation Example 2 (production of tablets) 1) 30 g of the compound of Example 68 2) 50 g of lactose 3) 15 g of corn starch 4) 44 g of calcium carboxymethylcellulose 5) 1 g of magnesium stearate 1000 tablets Total 140 g 1), The total amount of 2), 3) and 30 g of 4) are kneaded with water, dried under vacuum, and sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder and tableted with a tableting machine. Thus, the compound 3 of Example 68 per tablet
1000 tablets containing 0 mg are obtained.

[0647]

Industrial Applicability The compounds (I), (Ia) and (II) of the present invention have excellent insulin secretion promoting action and hypoglycemic action and are low toxic, so that they are preventive and therapeutic agents for diabetes, etc. Can be used as Further, the isoxazole derivative of the present invention selectively exerts an insulin secretion promoting action only in the presence of high concentration glucose,
It can be used as a glucose-dependent insulin secretagogue. Therefore, the isoxazole derivative is useful as an agent for safely preventing and treating diabetes, which has a low risk of vascular complications and hypoglycemia induction, which are adverse effects of insulin.

────────────────────────────────────────────────── ─── of the front page continued (51) Int.Cl. ⁷ identification mark FI theme Court Bu (reference) A61P 3/10 A61P 3/10 25/00 25/00 C07D 413/12 C07D 413/12 417/12 417 / 12 F term (reference) 4C056 AA01 AB01 AC01 AD01 AE03 FA08 FA16 FB01 FC01 4C063 AA01 AA03 BB09 CC51 CC62 DD03 DD14 DD41 DD61 EE01 4C086 AA01 AA02 AA03 BC67 GA07 GA10 GA12 MA04 MA52 MA55 NA14 ZA01 ZC35

Claims (27)

[Claims] 1. A compound of the general formula (Ia) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. However, when R ¹ or R ² is 3,5-ditert-butyl-4-hydroxyphenyl and W is C _1-4 alkylene, Y is not OH. Or a salt or prodrug thereof, for preventing or treating diabetes. 2. A compound of the general formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. Or a salt thereof or a prodrug thereof, for preventing or treating glucose intolerance. 3. A compound of the general formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. And a salt thereof or a prodrug thereof. 4. A compound of the general formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. Or a salt thereof or a prodrug thereof, for preventing or treating diabetic complications. 5. The preventive / therapeutic agent according to claim 4, wherein the diabetic complication is a neuropathy. 6. A compound of the general formula (II) [Wherein, one is a hydrogen atom R ^1a and R ^2a, the other is a cyclic group which may be substituted; Wa is a divalent aliphatic hydrocarbon group; Y is the formula: -OR ³ (R ³ Represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) or an esterified or amidated group Shows good carboxyl groups. However, when Wa is a C _1-3 alkylene and Y is a group represented by the formula: —OR ³ (R ³ has the same meaning as described above) or a carboxyl group which may be methylesterified, R ^1a Is a hydrogen atom, R
^2a is a cyclic group which may be substituted], except for 5-phenyl-4-isoxazolylmethanol and 5-phenyl-4-isoxazolylacetic acid, or a salt thereof. 7. The compound according to claim 6, wherein the optionally substituted cyclic group represented by R ^1a or R ^2a is an optionally substituted aromatic group. 8. R ^1a is a hydrogen atom, a compound of claim 6 wherein R ^2a is a cyclic group which may be substituted. 9. The compound according to claim 8, wherein R ^2a is an ^optionally substituted aromatic group. 10. The compound according to claim 6, wherein Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms. 11. The compound according to claim 6, wherein Y is a carboxyl group which may be amidated. 12. A prodrug of the compound according to claim 6. 13. [3- (5- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol;
3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propionic acid or a salt thereof;
(4-chlorophenyl) -4-isoxazolyl] propan-1-ol; 3- [5- (4-chlorophenyl)
-4-isoxazolyl] propionic acid or a salt thereof; 3- [5- (3,4-difluorophenyl) -4-
Isoxazolyl] propan-1-ol; 3- [5-
(3,4-difluorophenyl) -4-isoxazolyl] propionic acid or a salt thereof; N- [4- (diethylphosphonomethyl) phenyl] -3- (5-phenyl-
4-isoxazolyl) propionamide; N- [4-
(Diethylphosphonomethyl) phenyl] -3- [5-
(4-fluorophenyl) -4-isoxazolyl] propionamide; N- [4- (dimethylphosphonomethyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide; N- {4-[(2 -Oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- (5-phenyl-4-isoxazolyl) propionamide; N-benzyl-N- [2
-(Dimethylamino) ethyl] -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide; or N-benzyl-N- (1-benzyl-3-
Pyrrolidinyl) -3- [5- (4-fluorophenyl)
-4-isoxazolyl] propionamide. 14. A medicament comprising the compound according to claim 6 or a prodrug thereof. 15. A glucose-dependent insulin secretagogue comprising an isoxazole derivative. 16. A compound represented by the general formula (Ia): [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. However, when R ¹ or R ² is 3,5-ditert-butyl-4-hydroxyphenyl and W is C _1-4 alkylene, Y is not OH. Or a salt thereof or a prodrug thereof is administered in an effective amount. 17. A method for treating a mammal with the formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. And / or a salt thereof or a prodrug thereof is administered in an effective amount. 18. A method for treating a mammal with the formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. And / or a salt thereof or a prodrug thereof is administered in an effective amount, thereby preventing or treating glucose intolerance in the mammal. 19. A compound represented by the general formula (I): [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. A method for promoting insulin secretion in said mammal, which comprises administering an effective amount of the compound represented by the formula (I) or a salt thereof or a prodrug thereof. 20. A method for producing a prophylactic / therapeutic agent for diabetes mellitus,
Formula (Ia) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. However, when R ¹ or R ² is 3,5-ditert-butyl-4-hydroxyphenyl and W is C _1-4 alkylene, Y is not OH. Or a salt thereof or a prodrug thereof. 21. A compound of the general formula (I) for the manufacture of a prophylactic / therapeutic agent for diabetic complications. [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. Or a salt thereof or a prodrug thereof. 22. A compound of the general formula (I) for producing a prophylactic / therapeutic agent for impaired glucose tolerance. [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. Or a salt thereof or a prodrug thereof. 23. A method for producing an insulin secretagogue,
General formula (I) [Wherein, ^one of R ¹ and R ² is a hydrogen atom or a substituent, the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; -OR
³ (R ³ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) group represented by or esterified or amidated Represents a carboxyl group which may be substituted. Or a salt thereof or a prodrug thereof. 24. A commercial package comprising the agent for preventing or treating diabetes according to claim 1, and a document stating that the agent can or should be used for the prevention or treatment of diabetes. 25. A commercial package comprising a preventive / therapeutic agent for glucose intolerance according to claim 2 and a document stating that the agent can or should be used for the prevention / treatment of glucose intolerance. . 26. A commercial package comprising the insulin secretagogue of claim 3 and a document stating that the agent can or should be used to promote insulin secretion. 27. The method for preventing and treating diabetic complications according to claim 4.
A commercial package containing a therapeutic agent and documentation stating that the agent can or should be used in the prevention and treatment of diabetic complications.