JP2003261545A - Neurotrophic factor production/secretion accelerator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a neurotrophic factor production/secretion accelerator having excellent activity and low toxicity. <P>SOLUTION: The neurotrophic factor production/secretion accelerator contains a compound expressed by general formula (I) [one of R<SP>1</SP>and R<SP>2</SP>is H or a substituent and the other is a (substituted)cyclic group; W is a bond or a bivalent aliphatic hydrocarbon group; and Y is a group of formula OR<SP>3</SP>(R<SP>3</SP>is H, a (substituted)hydrocarbon group, a (substituted)heterocyclic group or a (substituted)acyl group)], its salt or its prodrug. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a neurotrophic factor production / secretion promoter containing an isoxazole derivative. The present invention also relates to an agent for improving neuropathic pain (excluding low back pain and neuralgia), which comprises an isoxazole derivative. Furthermore, the present invention relates to a method for producing a model animal for neuropathic pain, which is useful for screening a neuropathic pain improving substance.

[0002]

2. Description of the Related Art The following compounds are known as isoxazole derivatives. Formula (1)

[Chemical 9] [Wherein R is a phenyl group, R'is hydrogen or a lower alkyl group, A is a linear or branched divalent hydrocarbon group having 2 to 5 carbon atoms, and Q'is a hydroxy group, an amino group or an acylamino group. The compound represented by [shown] has an analgesic effect, an antitussive effect,
It has been reported to have antipyretic action and anti-inflammatory action (see Patent Document 1). Formula (2)

[Chemical 10] [In the formula, one R ¹ or R ² is 3,5-dimethyl-4
-Hydroxyphenyl, the other R ¹ or R ² is pyridinyl or the like; A is a double bond or the like; R ⁴ is a hydrogen atom or the like; R
³ represents a hydrogen atom, (C ₁ -C ₄ ) -alkyl or hydroxy- (C ₁ -C ₄ ) -alkyl] for the treatment of inflammation, asthma, rheumatic diseases and autoimmune diseases. It is reported to be useful (see Patent Document 2). Formula (3)

[Chemical 11] [Wherein R ¹ and R ³ represent optionally substituted lower alkyl, aryl, etc., and R ² represents a hydrogen atom, etc.] are useful as estrogen receptor modulators. It has been reported (see Patent Document 3). Formula (4)

[Chemical 12] [Ring M may contain 0-2 N atoms in addition to J;
J is O or S; D is CN and the like; E is phenyl and the like; G is absent or NHCH _{2 and the} like; Z is C _1-4 alkylene and the like; R ^1a and R ^1b are independently present Or not
- a _{(CH 2) r -R1 '(} r is 0, 1, 2 or 3, R
1'represents a hydrogen atom or the like); A is a C _3-10 carbocyclic residue or the like; B is a C _3-10 carbocyclic residue or the like; s is 0, 1 or 2
Are shown to be useful as factor Xa inhibitors (see Patent Document 4). However, it is not known that the above isoxazole derivative is useful as a neurotrophic factor production / secretion promoter. By the way, an excellent animal model of experimental disease is necessary to evaluate the efficacy of therapeutic agents for neuropathic pain. In recent years, one of the causes of rapid progress in research on neuropathic pain is
The rat model that can reproduce the pain close to the neuropathic pain seen in the clinic has been developed. As typical examples thereof, a chronic constriction injury model (see Non-Patent Document 1), a partial sciatic nerve injury model
(See Non-Patent Document 2), spinal nerve ligation model
(See Non-Patent Document 3) and the like. Recently, a rat model (spared nerve injury model; SNI model) in which surgery is relatively easy and pain behavior can be observed more clearly has been reported (see Non-Patent Document 4). The model is created by ligating and injuring the common peroneal and tibial nerves, leaving the sural nerve among the three terminal branches of the sciatic nerve.

[0003]

[Patent Document 1] Japanese Patent Publication No. 44-9656

[Patent Document 2] Japanese Patent Publication No. 9-509951

[Patent Document 3] International Publication No. WO00 / 08001 Pamphlet

[Patent Document 4] International Publication No. WO98 / 28282 Pamphlet

[Non-Patent Document 1] GJ Bennett and YK Xie, Pain, 3
3: 87-107 (1988)

[Non-Patent Document 2] Z. Seltzer et al., Pain, 43: 205-2.
18 (1990)

[Non-Patent Document 3] SH Kim and JM Chung, Pain, 50:
355-363 (1992)

[Non-Patent Document 4] I. Decosterd and CJ Woolf, Pain,
87: 149-158 (2000)

[0004]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a neurotrophic factor production / secretion promoter having excellent action and low toxicity. Another object of the present invention is to provide an agent for improving neuropathic pain (excluding low back pain and neuralgia), which has excellent effects and is low in toxicity. Further, the present invention provides
It is intended to provide a method for producing a model animal for neuropathic pain, which is useful for screening a neuropathic pain improving substance.

[0005]

The present inventors have found that the formula: -W-Y [W is a bond or a divalent aliphatic hydrocarbon group on the isoxazole ring; and 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. Represents a carboxyl group which may be present. ] Having a structural characteristic in that the group represented by

[Chemical 13] [Wherein ^one of R ¹ and R ² is a hydrogen atom or a substituent, and the other is an optionally substituted cyclic group; W and Y
Has the same meaning as above. ] The compound represented by the above is unexpectedly found to be useful as a neurotrophic factor production / secretion promoter based on its characteristic chemical structure,
The present invention has been completed based on this finding. In addition, the present inventors surprisingly surprisingly ligate and cut the rat peroneal nerve, thereby mechanically stimulating allodynia (mechanical allodyni) with a lower pain threshold than that of a conventionally known SNI model.
It was found that a) can be caused.

That is, the present invention provides: 1) production of a neurotrophic factor comprising a compound represented by the general formula (I), a salt thereof or a prodrug thereof.
Secretion enhancer; 2) a compound represented by the general formula (I) is represented by the formula (Ia)

[Chemical 14] The agent according to 1) above, which is a compound represented by: 3) The agent according to 1) above, wherein the optionally substituted cyclic group represented by R ¹ or R ² is an optionally substituted aromatic group. 4) The agent according to 1) above, wherein R ¹ is a hydrogen atom, and R ² is an optionally substituted cyclic group; 5) The agent according to 4) above, wherein R ² is an optionally substituted aromatic group Agent; 6) The agent according to 1) above, wherein W is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms; 7) The agent according to 1) above, wherein Y is an optionally amidated carboxyl group. 8) General formula (I-3)

[Chemical 15] [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] An agent for improving neuropathic pain (excluding low back pain and neuralgia) comprising the compound represented by the formula or a salt thereof or a prodrug thereof; 9) The above 8), wherein the neuropathic pain is carpal tunnel syndrome. Agents: 10) Use of a compound represented by the general formula (I), a salt thereof or a prodrug thereof for producing a neurotrophic factor production / secretion promoter; 11) A mammal represented by the general formula (I) A method for promoting production and secretion of neurotrophic factor in the mammal, which comprises administering an effective amount of a compound or a salt thereof or a prodrug thereof; 12) Improvement of neuropathic pain (excluding low back pain and neuralgia) Use of a compound represented by the general formula (I-3) or a salt thereof or a prodrug thereof for producing an agent; 13) A compound represented by the general formula (I-3) or a salt thereof in a mammal; Which comprises administering an effective amount of a prodrug thereof, a method for improving the neuropathic pain in the mammal (excluding back pain, neuralgia); 14) the general formula (I-3a)

[Chemical 16] [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] Or a salt thereof; 15) A method for producing a model animal for neuropathic pain, characterized by cleaving the common peroneal nerve of a non-human mammal; 16) The non-human mammal is a rat 17) The method described in 15) above; 17) The model animal for neuropathic pain obtained by the method described in 15) above; 18) The model animal described in 17) above is used for screening for a neuropathic pain improving substance. Method: 19) A neuropathic pain ameliorating agent comprising the neuropathic pain ameliorating substance obtained by the method according to 18) above; 20) Effectiveness of the neuropathic pain ameliorating substance obtained by the method according to 18) above. 21) A method for improving neuropathic pain in a mammal, which comprises administering an amount to the mammal;
8) Use of a neuropathic pain improving substance obtained by the method described above;

The compound represented by formula (I) is described in detail below. In the general formula (I), the “cyclic group” in the “optionally substituted cyclic group” represented by R ¹ or R ² is, for example, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or an aromatic heterocyclic group. Examples thereof include a ring group and a non-aromatic heterocyclic group. Examples of the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group. Preferable 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 etc. are mentioned. Preferable examples of the cycloalkenyl group include cycloalkenyl groups having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexene-1. -Ill and the like.
A preferred example of the cycloalkadienyl group has 4 carbon atoms.
Cycloalkadienyl groups of 10 to 10, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadiene-1-yl, and 2,5-cyclohexadiene-1-yl.

Examples of the aromatic hydrocarbon group include aromatic hydrocarbon groups having 6 to 14 carbon atoms (eg, aryl group). Preferable examples of the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like, among which phenyl, 1-naphthyl, 2-naphthyl and the like are preferable. The aromatic hydrocarbon group may be partially saturated, and 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-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring-constituting atoms. Examples thereof include aromatic heterocyclic groups and condensed non-aromatic heterocyclic groups. Examples of the non-aromatic condensed heterocyclic group include a 5-membered to 7-membered monocyclic non-aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. And a group condensed with a 5-membered ring. Preferred 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, thiazolidin-3-yl), imidazolidinyl (eg, imidazolidin-3-yl) Yl), oxoimidazolidinyl (eg, 2-oxoimidazolidine-1-
Yl), dioxoimidazolidinyl (eg, 2,4-dioxoimidazolidin-3-yl), dioxooxazolidinyl (eg, 2,4-dioxooxazolidin-3-yl), dioxothia Zolidinyl (eg, 2,4-dioxothiazolidin-3-yl), tetrahydrofuranyl, azepanyl, tetrahydropyridinyl (eg, 1,2,3
6-tetrahydropyridin-1-yl) and the like.

The aromatic heterocyclic group contains, for example, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring-constituting atoms.
To 7-membered monocyclic aromatic heterocyclic groups or condensed aromatic heterocyclic groups. The fused 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 1 sulfur atom. Examples thereof include a group condensed with a 5-membered ring.
Preferred examples of the aromatic heterocyclic group include furyl (eg, 2-
Furyl, 3-furyl), thienyl (eg, 2-thienyl,
3-thienyl), pyridinyl (eg, 2-pyridinyl, 3
-Pyridinyl, 4-pyridinyl), 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-oxadiazole-2)
-Yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-)
Triazol-1-yl, 1,2,4-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, 4-quinolyl),
Quinazolyl (eg, 2-quinazolyl, 4-quinazolyl),
Quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazoli) ), Benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazole-
1-yl, benzimidazol-2-yl), indolyl (eg, indol-1-yl, indol-3-yl), 1H-indazolyl (eg, 1H-indazole-
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 (eg, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl) 1H-imidazopyrazinyl (eg, 1H-
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 may be condensed with a benzene ring (preferably furyl, thienyl, pyridinyl, 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). . Phenyl is especially preferred.

In the general formula (I), the "cyclic group" represented by R ¹ or R ² is 1 to 5 at a substitutable position on the cyclic group.
It may have one, preferably 1 to 3 substituents.
Examples of such a substituent include a "halogen atom",
"Nitro group", "cyano group", "C _1-3 alkylenedioxy group", "optionally substituted aliphatic hydrocarbon group", "optionally substituted alicyclic hydrocarbon group",
"Aromatic hydrocarbon group which may be substituted", "heterocyclic group which may be substituted", "acyl group which may be substituted", "amino group which may be substituted", "substitution" Examples thereof include a hydroxy group which may be substituted, a thiol group which may be substituted, and a carboxyl group which may be esterified or amidated. Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine, and among them, fluorine and chlorine are preferable.
Examples of the “C _1-3 alkylenedioxy group” include methylenedioxy and ethylenedioxy.

The aliphatic hydrocarbon group in the "optionally substituted aliphatic hydrocarbon group" has 1 to 1 carbon atoms.
The linear or branched aliphatic hydrocarbon group of 5, for example, an alkyl group, an alkenyl group, an alkynyl group and the like can be mentioned. Preferable examples of the alkyl group include alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethyl. Examples thereof include propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl and decyl. Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl and 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 can be mentioned. Preferable examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms such as ethynyl and 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, pyridinyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (eg, tetrahydrofuryl,
Morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl), 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, carbon number 2
To acyl groups (eg, alkanoyl groups), carbamoyl groups, carbamoyl groups mono- or di-substituted with alkyl groups having 1 to 4 carbon atoms, sulfamoyl groups, and 1 carbon atoms
To a mono- or di-substituted sulfamoyl group, 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). Group, cycloalkyloxy group having 3 to 7 carbon atoms, 7 carbon atoms
To 13 aralkyloxy groups, C6 to C14 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.

"Alicyclic hydrocarbon group which may be substituted" and "aromatic hydrocarbon group which may be substituted"
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 groups and non-aromatic heterocyclic groups exemplified as the "cyclic group" for R ¹ or R ² .

The substituents in the above-mentioned "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., or 3 to 1 carbon atoms
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, pyridinyl, oxazolyl,
Thiazolyl, etc.), non-aromatic heterocyclic groups (eg, 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 amino group mono- or di-substituted with an acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.) Group, amidino group, acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.), carbamoyl group, carbamoyl group mono- or di-substituted with alkyl group having 1 to 4 carbon atoms, sulfamoyl group, 1 to 4 carbon atoms Mono- or di-substituted sulfamoyl group, carboxyl group, carbon number 2 to
8 alkoxycarbonyl group, hydroxy group, 1-3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), optionally substituted C 1-6 alkoxy group, 1-3 halogen 2 to 5 carbon atoms that may be substituted with atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
Alkenyloxy group, C3-7 cycloalkyloxy group, C7-13 aralkyloxy group, C6-14 aryloxy group (eg, phenyloxy,
Naphthyloxy, etc.), thiol group, alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 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, azido group, nitro group, nitroso group, halogen atom (eg, fluorine, chlorine, bromine, iodine)
And so on. The number of substituents is, for example, 1 to 3.

Examples of the acyl group in the "acyl group which may be substituted" include an acyl group having 1 to 13 carbon atoms, specifically formyl, as well as a compound represented by the formula: -COR ⁴ , -SO ₂ R ⁴ ,-.
SOR ⁴ or —PO ₃ R ⁴ R ⁵ [wherein R ⁴ and R ^4
5 are the same or different and each represents a hydrocarbon group or an aromatic heterocyclic group. R ⁴ and R ⁵ may form a heterocycle with the 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. Examples of the aliphatic hydrocarbon group include "aliphatic hydrocarbon group" in "optionally substituted aliphatic hydrocarbon group" exemplified as the substituent in "cyclic group" represented by R ¹ or R ^2.
Is mentioned. Examples of the alicyclic hydrocarbon group and aromatic hydrocarbon group include those exemplified as the "cyclic group" represented by R ¹ or R ² . Examples of the araliphatic hydrocarbon group include an araliphatic hydrocarbon group having 7 to 13 carbon atoms, such as an aralkyl group and an arylalkenyl group. Preferable examples of the aralkyl group include an aralkyl group having a carbon number of 7 to 13, 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 is preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or 3 to 10 carbon atoms.
Examples thereof include a cycloalkenyl group having 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, and an aralkyl group having 7 to 13 carbon atoms.

Examples of the aromatic heterocyclic group represented by R ⁴ or R ⁵ include those exemplified as the “cyclic group” represented by R ¹ or R ² . Among them, for example, thienyl, furyl, pyridinyl and the like are preferable.

The heterocycle formed by R ⁴ and R ⁵ together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms includes, for example, an oxo-substituted phosphorus atom and two oxygen atoms other than carbon atoms as ring-constituting atoms. Further, a 4- to 7-membered heterocycle optionally containing 1 or 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, and the like can be mentioned. Specific examples of such a heterocycle include 2-oxide-1,3,2-dioxaphosphinane;
2-oxide-1,3,2-dioxaphosphorane and the like can be mentioned.

Preferable 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 ring-forming (mono- or di-alkyl having 1 to 10 carbon atoms) phosphosno group (eg,
Dimethylphosphono; Diethylphosphono; Diisopropylphosphono; Dibutylphosphono; 2-Oxide-1,3,2
-Dioxaphosphinanyl) and the like.

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

The "optionally substituted amino group" is, for example, an alkyl group having 1 to 10 carbon atoms or 2-1 to 2 carbon atoms.
0 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-
Examples thereof include an aryl group having 14 carbon atoms, an acyl group having 1 to 13 carbon atoms, and an amino group which may be mono- or di-substituted with the like. Here, examples of the alkyl group having 1 to 10 carbon atoms and the alkenyl group having 2 to 10 carbon atoms include those exemplified as the substituents in the “cyclic group” represented by R ¹ or R ² . Examples of the cycloalkyl group having 3 to 10 carbon atoms, the cycloalkenyl group having 3 to 10 carbon atoms, and the aryl group having 6 to 14 carbon atoms include those exemplified as the "cyclic group" represented by R ¹ or R ^2. To be Examples of the acyl group having 1 to 13 carbon atoms include those exemplified as the acyl group in the above-mentioned "acyl group which may be substituted", and preferably an alkanoyl group having 2 to 10 carbon atoms and 7 to 13 carbon atoms. An arylcarbonyl group 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-N—C _6-14 arylamino (eg, N
-Methyl-N-phenylamino) and the like.

The "optionally substituted hydroxy group" is, for example, an optionally substituted "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms" and "3 carbon atoms". -10 cycloalkyl group "," C3-C10 cycloalkenyl group "," C6-1 "
4 aryl group "," aralkyl having 7 to 13 carbon atoms ",
Examples thereof include a hydroxy group which may be substituted with an "acyl group having 1 to 13 carbon atoms" or a "heteroaryl group". Here, the "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", and "acyl group having 1 to 13 carbon atoms" are "cyclic groups" represented by R ¹ or R ^2. Each of those exemplified as the substituent in is mentioned. "Cycloalkyl group having 3 to 10 carbon atoms", "Cycloalkenyl group having 3 to 10 carbon atoms" and "6 to 1 carbon atoms"
Examples of the "4 aryl group" include those exemplified as the "cyclic group" for 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",
"C2-C10 alkenyl group", "C3-C10
Of "cycloalkyl group", "cycloalkenyl group having 3 to 10 carbon atoms", "aryl group having 6 to 14 carbon atoms", "aralkyl having 7 to 13 carbon atoms" and "acyl group having 1 to 13 carbon atoms" It may have 1 to 2 substituents at substitutable positions, and examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and a carbon number of 1 to 3. Alkoxy groups (eg, methoxy, ethoxy, etc.) and the like.

Examples of the "heteroaryl group" include R
“An optionally substituted cyclic group” represented by ¹ or R ²
The aromatic heterocyclic group exemplified as is mentioned. Of these, pyridinyl, imidazolyl, triazolyl and the like are preferable.

The substituted hydroxy group is, for example, an optionally substituted alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group,
Examples thereof include an acyloxy group and a heteroaryloxy group. Preferable examples of the alkoxy group have 1 to 10 carbon atoms.
Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-
Examples include butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy and the like. Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy and 3-hexenyloxy. Preferable examples of the cycloalkyloxy group include cycloalkyloxy groups having 3 to 10 carbon atoms, such as cyclobutoxy, cyclopentyloxy and cyclohexyloxy. Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy.
Preferable examples of the aryloxy group include C6 to C14.
Aryloxy groups such as phenoxy and naphthyloxy. Preferable examples of the aralkyloxy group include an aralkyloxy group having a carbon number of 7 to 13, such as benzyloxy, phenethyloxy, naphthylmethyloxy and the like. Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, for example, 2 carbon atoms.
To alkanoyloxy (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) and the like. Preferred examples of the heteroaryloxy group include a 5- to 7-membered monocyclic heteroaryloxy group such as 2-pyridinyloxy, 3-pyridinyloxy, 2-imidazolyloxy, 1,2,4-triazol-5-yloxy and the like. Is mentioned.

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

Examples of the thiol group which may be substituted are "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", ""C3-C10 cycloalkenyl group", "C6-14 aryl group", "C7-
Thirteen groups that may be substituted with “13 aralkyl”, “acyl group having 1 to 13 carbon atoms”, “heteroaryl group” and the like. Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms",
"C3-C10 cycloalkyl group", "C3-C3
As the “10 cycloalkenyl group”, the “aryl group having 6 to 14 carbon atoms”, the “aralkyl group having 7 to 13 carbon atoms”, the “acyl group having 1 to 13 carbon atoms” and the “heteroaryl group”, the above-mentioned “substituted Each of those exemplified as the “optionally-substituted hydroxy group” can be mentioned.

Examples of the substituted thiol group include alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, aralkylthio,
Acylthio, heteroarylthio and the like can be mentioned. Preferable examples of the alkylthio group include alkylthio groups having 1 to 10 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neo. Pentylthio, hexylthio, heptylthio, nonylthio and the like can be mentioned. Preferable examples of the alkenylthio group include alkenylthio groups having 2 to 10 carbon atoms, such as allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like. Preferable examples of the cycloalkylthio group include cycloalkylthio groups having 3 to 10 carbon atoms, such as cyclobutylthio, cyclopentylthio and cyclohexylthio. Preferable examples of the cycloalkenylthio group include cycloalkenylthio groups having 3 to 10 carbon atoms, such as 2-cyclopentenylthio and 2-cyclohexenylthio. Preferable examples of the arylthio group include arylthio groups 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.) and the like. Suitable examples of the heteroarylthio group include a 5- to 7-membered monocyclic heteroarylthio group, for example, 2-pyridinylthio, 3-pyridinylthio,
2-imidazolylthio, 1,2,4-triazole-5
-Ilthio and the like can be mentioned.

In the optionally esterified carboxyl group, examples of the esterified carboxyl group include an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), Aralkyloxycarbonyl group having 8 to 14 carbon atoms (eg, benzyloxycarbonyl etc.), 1 to 2 carbon atoms having 1 to 2 carbon atoms
7 to 15 carbon atoms which may be substituted with an alkyl group of 3
Aryloxycarbonyl group (eg, phenoxycarbonyl, p-tolyloxycarbonyl, etc.) and the like.

In the carboxyl group which may be amidated, the amidated carboxyl group is
^{Formula: -CON (R 6) (R} 7) ( wherein, R ⁶ and R ⁷ are the same or different, a hydrogen atom, a hydrocarbon may be substituted hydrogen group or an optionally substituted heterocyclic group Show.
R ⁶ and R ⁷ together with the adjacent nitrogen atom may form an optionally substituted nitrogen-containing heterocycle. ) The group represented by is mentioned.

Here, as the hydrocarbon group in the “hydrocarbon group which may be substituted” represented by R ⁶ and R ⁷ , the hydrocarbon groups exemplified as the above R ⁴ can be mentioned.
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); alkynyl group having 2 to 10 carbon atoms (preferably 2-propynyl); cycloalkyl group having 3 to 10 carbon atoms which may be condensed with a benzene ring (preferably cyclopropyl, cyclohexyl); carbon number 3-1
An aryl group having 6 to 14 carbon atoms which may be condensed with a cycloalkane of 0 (preferably cyclopentane) (preferably phenyl, dihydroindenyl, biphenylyl);
Aralkyl groups 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 is R
^The aromatic heterocyclic group and the non-aromatic heterocyclic group exemplified as the “cyclic group” represented by ¹ or R ² can be mentioned. The heterocyclic group is preferably thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrazinyl, triazinyl, benzoxazolyl,
Benzothiazolyl, benzothiadiazolyl, quinolyl,
Examples include isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanyl.

The hydrocarbon group and the heterocyclic group can be substituted
Have 1 to 4 (preferably 1 to 3) substituents at
Such substituents include, for example,
Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.);
1-3 halogen atoms (eg, fluorine, chlorine, bromine, yo
C which may be substituted with_1-6Alkyl group
(Eg, methyl, trifluoromethyl, etc.); 1-3
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, isopropoxy, trifluoromethoxy, etc.);
Nitro; hydroxy; amino; carbamoyl group;
Optionally formed mono- or di-C_{1- 6}Alkyl-
Phosphono) -C_1-6Alkyl group [eg, dimethylphosphono
Methyl, diethylphosphonomethyl, diisopropylphos
Honomethyl, dibutylphosphonomethyl, diethylphospho
Noethyl, (2-oxide-1,3,2-dioxaphosphine
Inanyl) methyl, (methyl-2-oxide-1,3,2
-Dioxaphosphinanyl) methyl, (dimethyl-2-
Oxide-1,3,2-dioxaphosphinanyl) meth
(Diethyl-2-oxide-1,3,2-dioxapho
Sufinanyl) methyl, (5-butyl-5-ethyl-2)
-Oxide-1,3,2-dioxaphosphinanyl) methyi
, (5-ethyl-5-methyl-2-oxide-1,3,
2-dioxaphosphinanyl) methyl etc.]; phosphono
-C_1-6Alkyl group (eg, phosphonomethyl, etc.); C_2-5
Alkoxycarbonyl group (eg, methoxycarbonyl, ether
Toxycarbonyl etc.); C_2-5Alkoxy carbonyl
-C_1-6Alkyl group (eg, ethoxycarbonylmethyl
Etc.); 1-3 halogen atoms (eg, fluorine, chlorine, odor)
Element, iodine, etc.), C_1-6Alkoxy group or carbamo
C optionally substituted with an yl group_6-10Aryl groups (eg,
Phenyl, etc.); C_1-6Alkyl group (eg, methyl, etc.)
Or a heterocyclic group optionally substituted with an oxo group (eg,
Indolyl, imidazolyl, pyridinyl, morpholino,
Furyl, tetrahydrofuranyl, pyrrolidinyl, piperi
Dinyl, piperazinyl, etc.); C_1-6Alkyl group (eg,
Methyl, etc.) or a compound which may be substituted with an oxo group
Elementary ring-C_1-6Alkyl groups (eg dioxothiazolidinyl
Methyl, dioxooxazolidinylmethyl, tetrazoli
Rumethyl, triazolylmethyl, pyrazolylmethyl,
Cyl-imidazolylmethyl, dioxoimidazolidinyl
Methyl, methyl-dioxoimidazolidinylmethyl
DO); C_1-6Alkyl-heterocycle-C_1-6Alkoxy group
(Eg, ethyltriazolylethoxy, etc.); hydroxy
Base, C_6-10Aryl group (eg, phenyl, etc.) or C
_1-6Alkyl-C_6-10Aryl group (eg, methylphenyl
Etc.) optionally substituted with mono- or di-C_1-6
Alkylamino group (eg, dimethylamino, diethylami
No, ethylmethylamino, diisopropylamino, N-
Methyl-N-phenylamino, di-hydroxyethyl-
Amino etc.); C_6-10Arylamino group (eg, phenyl
Amino etc.); C_3-10Cycloalkyl groups (eg cyclohexyl
Xyl)); C _1-3Alkylenedioxy group (eg, methyl
Rangeoxy, ethylenedioxy, etc.); 1-3 c
Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C which may be substituted_1-6Alkylthio group (eg, methyl
Lucio etc.); C_7-13Aralkyl groups (eg benzyl
Etc.); aromatic heterocycles optionally substituted with nitro groups
Mino group (eg, pyridinylamino etc.); C_6-10Aryl
An oxy group (eg, phenoxy etc.); mono- or di-C
_1-6An alkyl-phosphono group (eg, diethylphosphono
DO); C_2-5Alkoxycarbonyl group (eg methoxyca
Substituted with carbonyl, ethoxycarbonyl, etc.)
Good mono- or di- (mono- or di-C_1-6Al
Kill-phosphono) -C_2-6Alkenyl group [eg bis (di
Ethylphosphono) ethenyl, 2-diethylphosphono-2
-Ethoxycarbonylethenyl, etc.]; bis (mono-or
Or J-C_1-6Alkylamino) -phosphoryl-C_1-6A
Rukyl group [eg, bis (ethylamino) phosphorylmethyl
Etc.]; oxo group; C_1-6Substituted with an alkyl group
Good heterocyclic sulfamoyl group (eg, (4,6-dimethyl)
Lupyrimidin-2-yl) sulfamoyl and the like.
Be done.

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

The nitrogen-containing heterocyclic group has 1 at the substitutable position.
It may have 2 to 2 substituents. Such substituents
Is, for example, 1 to 3 halogen atoms (eg, fluorine, salt
Element, bromine, iodine), hydroxy group, C_2-7Arco
Xycarbonyl group (eg, ethoxycarbonyl) or 5
To 6-membered nitrogen-containing heterocyclic groups (eg, pyrrolidinyl, etc.)
C which may be substituted_1-6Alkyl group (eg, methyl,
Ethyl etc.); C_1-3Alkylenedioxy group (eg, methyl
C optionally substituted with (dioxy, etc.)_7-14Ara
Rukyl group (eg benzyl, diphenylmethyl, benzhi
1 to 3 halogen atoms (eg, fluorine,
C optionally substituted with chlorine, bromine, iodine, etc.)
_1-6Alkyl groups (eg methyl, trifluoromethyl etc.
Etc.), halogen atom (eg, fluorine, chlorine, bromine, iodine)
Etc.), C_1-6Alkoxy group (eg, methoxy, ethoxy
Etc.) or C_2-10Alkanoyl groups (eg acetyl
C) which may be substituted with_6-14Aryl groups (eg,
C); C_6-14Aryl-C_{2- 6}Alkenyl group
(Eg, phenylpropenyl etc.); C_1-6Alkyl group
C optionally substituted with (eg, methyl, etc.)_6-14Ants
Amino-C_1-6Alkyl group (eg phenylaminometh
Chill group); cyano group; oxo group; hydroxy group;
3 halogen atoms (eg fluorine, chlorine, bromine, iodine)
Etc.) or C_1-6Alkyl group (eg, methyl, ethyl
Etc.) mono- or di-C optionally substituted with_2-10A
Lucanoylamino group (eg, acetylamino, trifluor
Roacetylamino, propionylamino, N-acetyl
-N-ethylamino etc.); C_2-7Alkoxy Carboni
Ruamino group (eg, tert-butoxycarbonylamino
Etc.); 5- to 6-membered nitrogen-containing heterocyclic group (eg, pyridinyl,
Piperidinyl, pyrimidinyl, pyrrolidinyl, etc.);
Aromatic heterocyclic carbonyl group (eg, furoyl, etc.); carba
Moyl group; C _2-10Alkanoyl groups (eg acetyl
DO); C_2-7Alkoxycarbonyl group (eg methoxyca
Such as rubonyl, ethoxycarbonyl, etc.)
It

The "substituent" in the "optionally substituted cyclic group" represented by R ¹ or R ² is preferably 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); 2) 1 1 to 6 carbon atoms which may be substituted with 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
An alkyl group (eg, methyl, trifluoromethyl, etc.); 3) 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
An alkoxy group (eg, methoxy, trifluoromethoxy, etc.); 4) 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
Alkylthio group (eg, methylthio, etc.); 5) nitro group; 6) cyano group; 7) C _1-3 alkylenedioxy group (eg, methylenedioxy); 8) aryl group having 6 to 14 carbon atoms ( 9) Alkylsulfinyl group having 1 to 6 carbon atoms (eg, methylsulfinyl); 10) Alkylsulfonyl group having 1 to 6 carbons (eg, methylsulfonyl). The number of substituents is preferably 1 to 3, and 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 with
An alkyl group (eg, methyl, trifluoromethyl, etc.); 3) 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
4) nitro group; 5) cyano group; and the like.

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

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

[0041] In the formula (I), "substituent" represented by R ¹ or R ² is exemplified as the "substituent" in the "optionally substituted cyclic group" represented by R ¹ or R ² The ones that have been done are listed.

The substituent is preferably 1) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg, methyl, Ethyl, trifluoromethyl); 2) hydroxy group; 3) aryl group having 6 to 14 carbon atoms (eg, phenyl); and the like.

In the general formula (I), 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.

In the general formula (I), the "divalent aliphatic hydrocarbon group" represented by W 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.
A valent aliphatic hydrocarbon group, 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 - , etc.) and the like. "2
The "valent aliphatic hydrocarbon group" is more preferably one having 1 carbon atom.
To 4 divalent aliphatic hydrocarbon groups (eg, alkylene,
Alkenylene). Among _{them, -CH 2 -, - (CH} 2) 2
_{-, - (CH 2) 3} -, - (CH 2) 4 -, - is preferable, CH = CH-, _{especially, - (CH 2) 2 -} , - (CH 2) 3 -, - CH = CH- Are preferred.

In the general formula (I), W is preferably a divalent aliphatic hydrocarbon group. W preferably has 1 carbon atom
To 4 divalent aliphatic hydrocarbon groups (eg, alkylene,
Alkenylene), more preferably _{-CH 2 -, - (CH 2} ) 2
_{-, - (CH 2) 3} -, - (CH 2) 4 -, - CH = CH- , and the like.
Among _{them, - (CH 2) 2 -} , - (CH 2) 3 -, - CH = CH- , etc. are preferable. In the general formula (I), when Y is a group represented by the formula: —OR ³ (R ³ has the same meaning as described above), W is particularly preferably — (CH ₂ ) ₃ —. In general formula (I),
When Y is a carboxyl group which may be esterified or amidated, W is preferably - (CH _{2) 2} - or a -CH = CH-, particularly preferably - (CH _{2) 2} - is .

In the general formula (I), Y is represented by 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. It shows a good carboxyl group. Here, the "optionally substituted heterocyclic group" and "optionally substituted acyl group" represented by R ^3, the "optionally substituted cyclic group represented by R ¹ or R ² Examples of the "substituent" in "" are mentioned. Here, as the "optionally substituted hydrocarbon group" represented by R ^3, the "substituent" in the "optionally substituted cyclic group" represented by R ¹ or R ²
Examples of the “optionally substituted aliphatic hydrocarbon group”, the “optionally substituted alicyclic hydrocarbon group” and the “optionally substituted aromatic hydrocarbon group”. R ³ is preferably a hydrogen atom or a carbon number of 1 to 10.
And an hydrogen atom is preferable.

"Esterification or amide" represented by Y
As the “optionally converted carboxyl group”, R is¹Well
Or R²To the “optionally substituted cyclic group”
What was illustrated as the "substituent" in the above is mentioned. The
“Carbohydrate which may be esterified or amidated
As a specific example of the “xyl group”, 1) carboxyl group; 2) an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, meth
Xycarbonyl, ethoxycarbonyl, etc.); 3) C_1-6Alkoxy group (eg methoxy, isopropoxy
C etc .; C_1-6Alkyl group (eg, methyl) or
Heterocyclic group optionally substituted by oxo group (eg, indo
Ril, imidazolyl, pyridinyl, morpholino, furi
Le, tetrahydrofuranyl, pyrrolidinyl, piperidinyl
Le, piperazinyl, etc.); C_1-6Alkylthio group (eg,
Methylthio etc.); Hydroxy group, C_6-10Aryl group
(Eg phenyl etc.) or C_1-6Alkyl-C_6-10A
Substituted with a reel group (eg, methylphenyl, etc.)
Moyo Mono- or Di-C_1-6Alkylamino group (eg,
Dimethylamino, diethylamino, ethylmethylami
No, diisopropylamino, N-methyl-N-phenyl
Amino, di-hydroxyethyl-amino, etc.); C_6-10
Arylamino group (eg, phenylamino, etc.); Nitro
An aromatic heterocyclic amino group which may be substituted with a group (eg,
Pyridinylamino etc.); mono- or di-C_1-6Al
From a kill-phosphono group (eg, diethylphosphono, etc.);
C optionally having 1 or 2 substituents selected_1-6fat
Group hydrocarbon group [eg, alkyl group (eg, methyl, ethyl,
Propyl, butyl, tert-butyl, 1-ethyl propyl
L, 2,2-dimethylpropyl, etc.), C_2-6Alkynyl
Groups (eg, propynyl, etc.)] mono- or di-substituted
A carbamoyl group which may be substituted; 4) Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
Etc.); 1-3 halogen atoms (eg, fluorine, chlorine, odor)
C, which may be substituted with hydrogen, iodine, etc.)_1-6Archi
Group (eg, methyl, trifluoromethyl); 1-3 groups
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, trifluoromethoxy); carbamoyl group; (ring
Optionally forming mono- or di-C_1-6Alkyl
-Phosphono) -C_1-6Alkyl group [eg, methylphosphono
Methyl, ethylphosphonomethyl, dimethylphosphonomethy
L, 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-dioki
Saphosphinanyl) methyl, (5-ethyl-5-methyl
2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, etc.]; Phosphono-C_1-6Alkyl groups (eg phos
Honomethyl etc.); C_2-5Alkoxycarbonyl group
(Eg methoxycarbonyl, ethoxycarbonyl
DO); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylmethyl, etc.); Heterocyclic group
(Eg, imidazolyl, morpholino); C_1-6Alkyl group
(Eg, methyl, etc.) or even if substituted with an oxo group
Good heterocycle-C_1-6Alkyl group (eg, dioxothiazoli
Dinylmethyl, dioxooxazolidinylmethyl, tet
Razolylmethyl, triazolylmethyl, pyrazolylmethyl
, Methyl-imidazolylmethyl, dioxoimidazole
Dinylmethyl, methyl-dioxoimidazolidinylmethyi
C); C_1-6With an alkyl group (eg methyl, ethyl)
Optionally substituted heterocycle-C_1-6Alkoxy group
(Eg, triazolyl ethoxy); C_1-3Alkylene geo
Xy groups (eg methylenedioxy, ethylenedioxy
DO); C_7-14Aralkyl group (eg, benzyl); C_6-10A
A reeloxy group (eg, phenoxy, etc.); mono- or
The-C_1-6Alkyl-phosphono group (eg, diethyl phospho
No)); C_2-5Alkoxycarbonyl group (eg, methoki
Carbonyl, ethoxycarbonyl, etc.)
May be mono- or di- (mono- or di-C_1-6
Alkyl-phosphono) -C_2-6Alkenyl group [eg bis
(Diethylphosphono) ethenyl, 2-diethylphosphono
-2-Ethoxycarbonylethenyl, etc.]; C_1-6Al
Heterocyclic sulfamoyl group optionally substituted by a kill group
(Eg, (4,6-dimethylpyrimidin-2-yl) sulfate
Even if it has 1 or 2 substituents selected from
Well, C_3-10With cycloalkanes (eg cyclopentane)
C which may be condensed_6-14Aryl-carbamoyl group
(Eg, phenylcarbamoyl, naphthylcarbamoyl,
Dihydroindenylcarbamoyl, biphenylylcarba
Moyle); 5) 1-2 C_1-6Substitute with an alkyl group (eg, methyl)
C, optionally condensed with a benzene ring
_3-10A cycloalkyl-carbamoyl group (eg, cyclopropyl
Pyrcarbamoyl, cyclohexylcarbamoyl, Jihi
Droindenylcarbamoyl); 6) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Elemental, iodine, etc.) or mono- or di-C_1-6Archi
C optionally substituted with luamino_1-6Alkyl group
(Eg, methyl, trifluoromethyl, dimethylaminoe
Cyl, diethylaminoethyl); C_1-6Alkoxy group
(Eg methoxy); C_1-3Alkylenedioxy group (eg,
Methylenedioxy etc.); C_6-14Aryl groups (eg,
Nil); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylethyl); substitution selected from
C which may have 1 or 2 groups_7-13Aralkyl-Cal
Vamoyl group (eg, benzylcarbamoyl, phenethylca)
Luvamoyl, phenylpropylcarbamoyl, benzhi
Drill carbamoyl); 7) C_3-10Cycloalkyl-C_1-6Alkyl-carbamo
An yl group (eg, cyclohexylmethylcarbamoyl); 8) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
C, which may be substituted with hydrogen, iodine, etc.)_6-10Ally
Group (eg, phenyl, etc.); 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine, etc.)
May be C_1-6Alkyl (eg, methyl); C_1-6Archi
Heterocyclic group optionally substituted with a phenyl group (eg, methyl)
(Eg, imidazolyl, morpholino); C_7-14Aralkyl
A substituent selected from a group (eg, benzyl); an oxo group;
Complex that may have 1 to 4 (preferably 1 to 2)
A cyclic carbamoyl group (eg, piperidinylcarbamoyl, a
Zepanylcarbamoyl, pyrrolidinylcarbamoyl, o
Xazolylcarbamoyl, thiazolylcarbamoyl, pi
Lysinylcarbamoyl, triazinylcarbamoyl, ki
Norylcarbamoyl, Isoquinolylcarbamoyl, Ben
Zothiazolylcarbamoyl, pyrazolylcarbamoyl,
Piperazinylcarbamoyl, benzothiadiazolylcar
Vamoyl, pyrazinylcarbamoyl); 9) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Element, iodine, etc.), hydroxy group, C_2-7Alkoxyca
Rubonyl group (eg ethoxycarbonyl) or 5 to
Substituted with a 6-membered nitrogen-containing heterocyclic group (eg, pyrrolidinyl, etc.)
May be C_{1- 6}Alkyl (eg methyl, ethyl
DO); C_1-3Alkylenedioxy group (eg, methylenedio
C optionally substituted with xy)_7-14Aralkyl group
(Eg, benzyl, benzhydryl, etc.); 1-3 c
Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C which may be substituted_1-6Alkyl group (eg, methyl,
Trifluoromethyl, etc.), halogen atom (eg, fluorine
Elemental, chlorine, bromine, iodine, etc.), C _1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.) or C_2-10Alkano
C optionally substituted with an yl group (eg, acetyl, etc.)
_6-14Aryl group (eg, phenyl, etc.); C_6-14Aryl
-C_2-6Alkenyl groups (eg phenylpropenyl
DO); C_1-6Substituted with an alkyl group (eg, methyl, etc.)
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 group)
Elemental, chlorine, bromine, iodine, etc.) or C_1-6Alkyl group
(Eg, methyl, ethyl, etc.)
No or di-C_2-10Alkanoylamino groups (eg ace
Cylamino, trifluoroacetylamino, propioni
Luamino, N-acetyl-N-ethylamino, etc.); C
_2-7Alkoxycarbonylamino group (eg, tert-butoxy
Carbonylamino, etc.); 5- or 6-membered nitrogen-containing heterocyclic group
(Eg pyridinyl, piperidinyl, pyrimidinyl, pyro
Ridinyl, etc.); aromatic heterocyclic carbonyl group (eg, furo)
And the like); carbamoyl group; C_2-10Alkanoyl group
(Eg, acetyl, etc.); C_{2- 7}Alkoxycarbonyl group
(Eg methoxycarbonyl, ethoxycarbonyl
Etc.); may have 1 or 2 substituents selected from
Benzene ring or C_3-10Cycloalkanes (eg shiku)
Nitrogen-containing heterocyclic ring which may be condensed with
Rubonyl group (eg piperidinylcarbonyl, pyrrolidini
Lecarbonyl, morpholinocarbonyl, thiomorpholino
Carbonyl, piperazinyl carbonyl, tetrahydro
Soquinoline carbonyl, decahydroisoquinoline carbo
Nyl, azepancarbonyl, azocancarbonyl, 1,
2,3,6-tetrahydropyridinecarbonyl etc.);
Etc.

Y is preferably "even if amidated
A good carboxyl group, and more preferably
“Amidated carboxyl group” such as a) to g) of
Is. a) C_1-6Alkoxy group (eg methoxy, isopropoxy
C etc .; C_1-6Alkyl group (eg, methyl) or
Heterocyclic group optionally substituted by oxo group (eg, indo
Ril, imidazolyl, pyridinyl, morpholino, furi
Le, tetrahydrofuranyl, pyrrolidinyl, piperidinyl
Le, piperazinyl, etc.); C_1-6Alkylthio group (eg,
Methylthio etc.); Hydroxy group, C_6-10Aryl group
(Eg phenyl etc.) or C_1-6Alkyl-C_6-10A
Substituted with a reel group (eg, methylphenyl, etc.)
Moyo Mono- or Di-C_1-6Alkylamino group (eg,
Dimethylamino, diethylamino, ethylmethylami
No, diisopropylamino, N-methyl-N-phenyl
Amino, di-hydroxyethyl-amino, etc.); C_6-10
Arylamino group (eg, phenylamino, etc.); Nitro
An aromatic heterocyclic amino group which may be substituted with a group (eg,
Pyridinylamino etc.); mono- or di-C_1-6Al
From a kill-phosphono group (eg, diethylphosphono, etc.);
C optionally having 1 or 2 substituents selected_1-6fat
Group hydrocarbon group [eg, alkyl group (eg, methyl, ethyl,
Propyl, butyl, tert-butyl, 1-ethyl propyl
L, 2,2-dimethylpropyl, etc.), C_2-6Alkynyl
Groups (eg, propynyl, etc.)] mono- or di-substituted
A carbamoyl group which may be present. b) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
Etc.); 1-3 halogen atoms (eg, fluorine, chlorine, odor)
C, which may be substituted with hydrogen, iodine, etc.)_1-6Archi
Group (eg, methyl, trifluoromethyl); 1-3 groups
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, trifluoromethoxy); carbamoyl group; (ring
Optionally forming mono- or di-C_1-6Alkyl
-Phosphono) -C_1-6Alkyl group [eg, methylphosphono
Methyl, ethylphosphonomethyl, dimethylphosphonomethy
L, 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-dioki
Saphosphinanyl) methyl, (5-ethyl-5-methyl
2-oxide-1,3,2-dioxaphosphinanyl)
Methyl, etc.]; Phosphono-C_1-6Alkyl groups (eg phos
Honomethyl etc.); C_2-5Alkoxycarbonyl group
(Eg methoxycarbonyl, ethoxycarbonyl
DO); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylmethyl, etc.); Heterocyclic group
(Eg, imidazolyl, morpholino); C_1-6Alkyl group
(Eg, methyl, etc.) or even if substituted with an oxo group
Good heterocycle-C_1-6Alkyl group (eg, dioxothiazoli
Dinylmethyl, dioxooxazolidinylmethyl, tet
Razolylmethyl, triazolylmethyl, pyrazolylmethyl
, Methyl-imidazolylmethyl, dioxoimidazole
Dinylmethyl, methyl-dioxoimidazolidinylmethyi
C); C_1-6With an alkyl group (eg methyl, ethyl)
Optionally substituted heterocycle-C_1-6Alkoxy group
(Eg, triazolyl ethoxy); C_1-3Alkylene geo
Xy groups (eg methylenedioxy, ethylenedioxy
DO); C_7-14Aralkyl group (eg, benzyl); C_6-10A
A reeloxy group (eg, phenoxy, etc.); mono- or
The-C_1-6Alkyl-phosphono group (eg, diethyl phospho
No)); C_2-5Alkoxycarbonyl group (eg, methoki
Carbonyl, ethoxycarbonyl, etc.)
May be mono- or di- (mono- or di-C_1-6
Alkyl-phosphono) -C_2-6Alkenyl group [eg bis
(Diethylphosphono) ethenyl, 2-diethylphosphono
-2-Ethoxycarbonylethenyl, etc.]; C_1-6Al
Heterocyclic sulfamoyl group optionally substituted by a kill group
(Eg, (4,6-dimethylpyrimidin-2-yl) sulfate
Even if it has 1 or 2 substituents selected from
Well, C_3-10With cycloalkanes (eg cyclopentane)
C which may be condensed_6-14Aryl-carbamoyl group
(Eg, phenylcarbamoyl, naphthylcarbamoyl,
Dihydroindenylcarbamoyl, biphenylylcarba
Moyle). c) 1-2 C_1-6Substitute with an alkyl group (eg, methyl)
C, optionally condensed with a benzene ring
_3-10A cycloalkyl-carbamoyl group (eg, cyclopropyl
Pyrcarbamoyl, cyclohexylcarbamoyl, Jihi
Doloindenylcarbamoyl). d) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Elemental, iodine, etc.) or mono- or di-C_1-6Archi
C optionally substituted with luamino_1-6Alkyl group
(Eg, methyl, trifluoromethyl, dimethylaminoe
Cyl, diethylaminoethyl); C_1-6Alkoxy group
(Eg methoxy); C_1-3Alkylenedioxy group (eg,
Methylenedioxy etc.); C_6-14Aryl groups (eg,
Nil); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylethyl); substitution selected from
C which may have 1 or 2 groups_7-13Aralkyl-Cal
Vamoyl group (eg, benzylcarbamoyl, phenethylca)
Luvamoyl, 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 hydrogen, iodine, etc.)_6-10Ally
Group (eg, phenyl, etc.); 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine, etc.)
May be C_1-6Alkyl (eg, methyl); C_1-6Archi
Heterocyclic group optionally substituted with a phenyl group (eg, methyl)
(Eg, imidazolyl, morpholino); C_7-14Aralkyl
A substituent selected from a group (eg, benzyl); an oxo group;
Complex that may have 1 to 4 (preferably 1 to 2)
A cyclic carbamoyl group (eg, piperidinylcarbamoyl, a
Zepanylcarbamoyl, pyrrolidinylcarbamoyl, o
Xazolylcarbamoyl, thiazolylcarbamoyl, pi
Lysinylcarbamoyl, triazinylcarbamoyl, ki
Norylcarbamoyl, Isoquinolylcarbamoyl, Ben
Zothiazolylcarbamoyl, pyrazolylcarbamoyl,
Piperazinylcarbamoyl, benzothiadiazolylcar
Vamoyl, pyrazinylcarbamoyl). g) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Element, iodine, etc.), hydroxy group, C_2-7Alkoxyca
Rubonyl group (eg ethoxycarbonyl) or 5 to
Substituted with a 6-membered nitrogen-containing heterocyclic group (eg, pyrrolidinyl, etc.)
May be C_{1- 6}Alkyl (eg methyl, ethyl
DO); C_1-3Alkylenedioxy group (eg, methylenedio
C optionally substituted with xy)_7-14Aralkyl group
(Eg, benzyl, benzhydryl, etc.); 1-3 c
Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C which may be substituted_1-6Alkyl group (eg, methyl,
Trifluoromethyl, etc.), halogen atom (eg, fluorine
Elemental, chlorine, bromine, iodine, etc.), C _1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.) or C_2-10Alkano
C optionally substituted with an yl group (eg, acetyl, etc.)
_6-14Aryl group (eg, phenyl, etc.); C_6-14Aryl
-C_2-6Alkenyl groups (eg phenylpropenyl
DO); C_1-6Substituted with an alkyl group (eg, methyl, etc.)
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 group)
Elemental, chlorine, bromine, iodine, etc.) or C_1-6Alkyl group
(Eg, methyl, ethyl, etc.)
No or di-C_2-10Alkanoylamino groups (eg ace
Cylamino, trifluoroacetylamino, propioni
Luamino, N-acetyl-N-ethylamino, etc.); C
_2-7Alkoxycarbonylamino group (eg, tert-butoxy
Carbonylamino, etc.); 5- or 6-membered nitrogen-containing heterocyclic group
(Eg pyridinyl, piperidinyl, pyrimidinyl, pyro
Ridinyl, etc.); aromatic heterocyclic carbonyl group (eg, furo)
And the like); carbamoyl group; C_2-10Alkanoyl group
(Eg, acetyl, etc.); C_{2- 7}Alkoxycarbonyl group
(Eg methoxycarbonyl, ethoxycarbonyl
Etc.); may have 1 or 2 substituents selected from
Benzene ring or C_3-10Cycloalkanes (eg shiku)
Nitrogen-containing heterocyclic ring which may be condensed with
Rubonyl group (eg piperidinylcarbonyl, pyrrolidini
Lecarbonyl, morpholinocarbonyl, thiomorpholino
Carbonyl, piperazinyl carbonyl, tetrahydro
Soquinoline carbonyl, decahydroisoquinoline carbo
Nyl, azepancarbonyl, azocancarbonyl, 1,
2,3,6-Tetrahydropyridine carbonyl etc.).

Of these, b), d) and f) are preferred. In particular (mono- or di-C _1-6 alkyl-phosphono optionally forming 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)
C _6-14 aryl-, which may be substituted with methyl, etc.
Carbamoyl group (preferably phenylcarbamoyl)
Is preferred.

In the general formula (I), R ¹ , R ² and --W--Y
[Symbols have the same meaning as defined above] may be substituted at any of the 3-position, 4-position or 5-position on the isoxazole ring. Among the compounds represented by the general formula (I), R ¹ , R ² and -WY [symbols have the same meanings as defined above] are present at the 3-position, 5-position and 4-position on the isoxazole ring, respectively. Substituting the formula (Ia)

[Chemical 17] Compounds represented by are preferred.

Suitable examples of the compound represented by formula (I)
Examples of the compound include the following compound (A). Compound (A) R¹Is a hydrogen atom; R²But 1) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Bare); 2) 1 to 5 halogen atoms (eg, fluorine, chlorine, odor)
(Chemical, iodine) C1-C6 optionally substituted by
Rukyl group (eg methyl, ethyl, trifluoromethyi
Le); 3) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
(Chemical, iodine) C1-C6 optionally substituted by
Lucoxy group (eg, methoxy, ethoxy, trifluorome
Toxi); 4) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
(Chemical, iodine) C1-C6 optionally substituted by
A ruquilthio group (eg, methylthio); 5) nitro group; 6) cyano group; 7) C_1-3Alkylenedioxy groups (eg methylene dioxy)
Shi); 8) an aryl group having 6 to 14 carbon atoms (eg, phenyl); 9) an alkylsulfinyl group having 1 to 6 carbon atoms (eg, methyl
Rusulfinyl); and 10) an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methyl
1 to 3 substituents each selected from
Aromatic hydrocarbon group which may have
Nyl, naphthyl) or an aromatic heterocyclic group (preferably phenyl).
Ryl, thienyl, pyridinyl, quinolyl, more preferred
Ku-thienyl, pyridinyl); W has 1 to 4 carbon atoms.
Divalent aliphatic hydrocarbon group (preferably -CH₂−, − (CH ₂)
₂−, − (CH₂)₃−, − (CH₂)_Four-, -CH = CH-; more preferable
Masu-ha- (CH₂)₂−, − (CH₂)₃−, − (CH₂)_Four-, -CH =
CH-; particularly preferably-(CH₂)₂-, -CH = CH-); Y is
a) C_1-6Alkoxy group (eg methoxy, isopropoxy
C etc .; C_1-6Alkyl group (eg, methyl) or
Heterocyclic group optionally substituted by oxo group (eg, indo
Ril, imidazolyl, pyridinyl, morpholino, furi
Le, tetrahydrofuranyl, pyrrolidinyl, piperidinyl
Le, piperazinyl, etc.); C_1-6Alkylthio group (eg,
Methylthio etc.); Hydroxy group, C_6-10Aryl group
(Eg phenyl etc.) or C_1-6Alkyl-C_6-10A
Substituted with a reel group (eg, methylphenyl, etc.)
Moyo Mono- or Di-C_1-6Alkylamino group (eg,
Dimethylamino, diethylamino, ethylmethylami
No, diisopropylamino, N-methyl-N-phenyl
Amino, di-hydroxyethyl-amino, etc.); C_6-10
Arylamino group (eg, phenylamino, etc.); Nitro
An aromatic heterocyclic amino group which may be substituted with a group (eg,
Pyridinylamino etc.); mono- or di-C_{1- 6}Al
From a kill-phosphono group (eg, diethylphosphono, etc.);
C optionally having 1 or 2 substituents selected_1-6fat
Group hydrocarbon group [eg, alkyl group (eg, methyl, ethyl,
Propyl, butyl, tert-butyl, 1-ethyl propyl
L, 2,2-dimethylpropyl, etc.), C_2-6Alkynyl
Groups (eg, propynyl, etc.)] mono- or di-substituted
A carbamoyl group which may be substituted; b) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
Etc.); 1-3 halogen atoms (eg, fluorine, chlorine, odor)
C, which may be substituted with hydrogen, iodine, etc.)_1-6Archi
Group (eg, methyl, trifluoromethyl); 1-3 groups
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, trifluoromethoxy); carbamoyl group; (ring
Optionally forming mono- or di-C_1-6Alkyl
-Phosphono) -C_1-6Alkyl group [eg, methylphosphono
Methyl, ethylphosphonomethyl, dimethylphosphonomethy
L, 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-dioki
Saphosphinanyl) methyl, (5-ethyl-5-methyl
2-oxide-1,3,2-dioxaphosphinanyl)
Methyl etc.]; C_2-5Alkoxycarbonyl group (eg,
Toxycarbonyl, ethoxycarbonyl, etc.); C_2-5
Alkoxycarbonyl-C_1-6Alkyl group (eg Etoki
Cycarbonylmethyl); Phosphono-C_1-6Alkyl
Groups (eg, phosphonomethyl, etc.); heterocyclic groups (eg, imida
Zolyl, morpholino); C_1-6Alkyl group (eg, methyl
Or the like) or a heterocycle optionally substituted with an oxo group-
C_1-6Alkyl groups (eg dioxothiazolidinylmethyi)
, Dioxooxazolidinylmethyl, tetrazolylme
Chill, triazolylmethyl, pyrazolylmethyl, methyl
-Imidazolylmethyl, dioxoimidazolidinylmethyi
, Methyl-dioxoimidazolidinylmethyl, etc.);
C_1-6Substituted with an alkyl group (eg methyl, ethyl)
Heterocycle-C_1-6Alkoxy group (eg triazo
Rylethoxy); C_1-3Alkylenedioxy group (eg,
Tolylenedioxy, ethylenedioxy, etc.); C_7-14Ara
Rualkyl group (eg, benzyl); C_6-10Aryloxy group
(Eg, phenoxy, etc.); mono- or di-C_1-6Al
Kill-phosphono group (eg, diethylphosphono etc.); C
_2-5Alkoxycarbonyl group (eg, methoxycarbonyl
, Ethoxycarbonyl, etc.)
Mono- or di- (mono- or di-C_1-6Alkyl-
Phosphono) -C_2-6Alkenyl group [eg, bis (diethyl
Phosphono) ethenyl, 2-diethylphosphono-2-eth
Xycarbonylethenyl, etc.]; C_1-6Place with an alkyl group
Optionally substituted heterocyclic sulfamoyl group (eg,
(4,6-Dimethylpyrimidin-2-yl) sulfamoy
Optionally have 1 to 2 substituents selected from
C_3-10Condensed with cycloalkanes (eg cyclopentane)
May be C_6-14An aryl-carbamoyl group (eg,
Phenylcarbamoyl, naphthylcarbamoyl, dihydro
Indenylcarbamoyl, biphenylylcarbamoy
Le); c) 1-2 C_1-6Substitute with an alkyl group (eg, methyl)
C, optionally condensed with a benzene ring
_3-10A cycloalkyl-carbamoyl group (eg, cyclopropyl
Pyrcarbamoyl, cyclohexylcarbamoyl, Jihi
Droindenylcarbamoyl); d) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Elemental, iodine, etc.) or mono- or di-C_1-6Archi
C optionally substituted with luamino_1-6Alkyl group
(Eg, methyl, trifluoromethyl, dimethylaminoe
Cyl, diethylaminoethyl); C_1-6Alkoxy group
(Eg methoxy); C_1-3Alkylenedioxy group (eg,
Methylenedioxy etc.); C_6-14Aryl groups (eg,
Nil); C_2-5Alkoxycarbonyl-C_1-6Alkyl group
(Eg, ethoxycarbonylethyl); substitution selected from
C which may have 1 or 2 groups_7-13Aralkyl-Cal
Vamoyl group (eg, benzylcarbamoyl, phenethylca)
Luvamoyl, 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 hydrogen, iodine, etc.)_6-10Ally
Group (eg, phenyl, etc.); 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine, etc.)
May be C_1-6Alkyl (eg, methyl); C_1-6Archi
Heterocyclic group optionally substituted with a phenyl group (eg, methyl)
(Eg, imidazolyl, morpholino); C_7-14Aralkyl
A substituent selected from a group (eg, benzyl); an oxo group;
Complex that may have 1 to 4 (preferably 1 to 2)
A cyclic carbamoyl group (eg, piperidinylcarbamoyl, a
Zepanylcarbamoyl, pyrrolidinylcarbamoyl, o
Xazolylcarbamoyl, thiazolylcarbamoyl, pi
Lysinylcarbamoyl, triazinylcarbamoyl, ki
Norylcarbamoyl, Isoquinolylcarbamoyl, Ben
Zothiazolylcarbamoyl, pyrazolylcarbamoyl,
Piperazinylcarbamoyl, benzothiadiazolylcar
Vamoyl, pyrazinylcarbamoyl); or g) 1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
Element, iodine, etc.), hydroxy group, C_2-7Alkoxyca
Rubonyl group (eg ethoxycarbonyl) or 5 to
Substituted with a 6-membered nitrogen-containing heterocyclic group (eg, pyrrolidinyl, etc.)
May be C_{1- 6}Alkyl (eg methyl, ethyl
DO); C_1-3Alkylenedioxy group (eg, methylenedio
C optionally substituted with xy)_7-14Aralkyl group
(Eg, benzyl, benzhydryl, etc.); 1-3 c
Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
C which may be substituted_1-6Alkyl group (eg, methyl,
Trifluoromethyl, etc.), halogen atom (eg, fluorine
Elemental, chlorine, bromine, iodine, etc.), C _1-6Alkoxy group
(Eg, methoxy, ethoxy, etc.) or C_2-10Alkano
C optionally substituted with an yl group (eg, acetyl, etc.)
_6-14Aryl group (eg, phenyl, etc.); C_6-14Aryl
-C_2-6Alkenyl groups (eg phenylpropenyl
DO); C_1-6Substituted with an alkyl group (eg, methyl, etc.)
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 group)
Elemental, chlorine, bromine, iodine, etc.) or C_1-6Alkyl group
(Eg, methyl, ethyl, etc.)
No or di-C_2-10Alkanoylamino groups (eg ace
Cylamino, trifluoroacetylamino, propioni
Luamino, N-acetyl-N-ethylamino, etc.); C
_2-7Alkoxycarbonylamino group (eg, tert-butoxy
Carbonylamino, etc.); 5- or 6-membered nitrogen-containing heterocyclic group
(Eg pyridinyl, piperidinyl, pyrimidinyl, pyro
Ridinyl, etc.); aromatic heterocyclic carbonyl group (eg, furo)
And the like); carbamoyl group; C_2-10Alkanoyl group
(Eg, acetyl, etc.); C_{2- 7}Alkoxycarbonyl group
(Eg methoxycarbonyl, ethoxycarbonyl
Etc.); may have 1 or 2 substituents selected from
Benzene ring or C_3-10Cycloalkanes (eg shiku)
Nitrogen-containing heterocyclic ring which may be condensed with
Rubonyl group (eg piperidinylcarbonyl, pyrrolidini
Lecarbonyl, morpholinocarbonyl, thiomorpholino
Carbonyl, piperazinyl carbonyl, tetrahydro
Soquinoline carbonyl, decahydroisoquinoline carbo
Nyl, azepancarbonyl, azocancarbonyl, 1,
2,3,6-tetrahydropyridinecarbonyl etc.);
And R¹, R²And -W-Y [symbols have the same meaning as above.
Are present on the isoxazole ring at positions 3 and 5, respectively.
Compounds substituted at position 4 and position 4.

Among the above-mentioned compounds (A), the following compounds are particularly preferable. 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.

As the salt of the compound represented by the general formula (I) (hereinafter sometimes abbreviated as compound (I)), a pharmacologically acceptable salt is preferable. Examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic 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;
Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts; as well as aluminum salts and ammonium salts. Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline,
Examples thereof include salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like. Suitable examples of salts with acidic amino acids include aspartic acid,
Examples thereof include salts with glutamic acid and the like. Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, a compound which is enzymatically oxidized, reduced or hydrolyzed. Compound which changes to (I), Compound (I) which is hydrolyzed by stomach acid etc.
A compound that changes to. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); The hydroxyl group of compound (I) is acylated, alkylated,
Phosphorylated or borated compounds (eg, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); The carboxyl group of compound (I) is esterified,
Amidated compound (eg, 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 compounds and the like); and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is available from Hirokawa Shoten 1
It may be a compound (I) which is changed under physiological conditions as described in “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pages 163 to 198, 1990. The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like. Further, the compound (I) is
It may be an anhydride or a hydrate.

Compound (I) and salts thereof (hereinafter sometimes simply abbreviated as the compound of the present invention) have low toxicity and are used as they are or as a pharmaceutical composition by mixing with a pharmacologically acceptable carrier or the like. A mammal (eg, human,
Mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.), it can be used as a neurotrophic factor production / secretion promoter. Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation , A solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. Also, if necessary, a preservative,
Pharmaceutical additives such as antioxidants, coloring agents and sweeteners can also be used.

Preferable examples of excipients include lactose, sucrose,
D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, alumino metasilicate. Magnesium acid etc. are mentioned. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Suitable examples of binders include pregelatinized starch,
Sucrose, gelatin, gum arabic, methyl cellulose,
Examples thereof include carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and the like. Preferable 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. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. And so on. Suitable examples of suspending agents include stearyl triethanolamine, sodium lauryl sulfate,
Surfactants such as laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; hydrophilic such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose Polymers: polysorbates, polyoxyethylene hydrogenated castor oil and the like. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbate and the like. Suitable examples of colorants include water-soluble food tar dyes (eg, food red Nos. 2 and 3, food yellow Nos. 4 and 5, food blue Nos. 1 and 2 and the like, water-insoluble lake dyes ( Examples thereof include aluminum salts of the above water-soluble food tar pigments), natural pigments (eg, β-carotene, chlorophyll, red iron oxide, etc.), etc. Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, and aspartame. , Stevia, etc.

Examples of the dosage form of the above-mentioned pharmaceutical composition include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions; and injections (eg. , Subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), external preparation (eg,
Nasal administration preparations, transdermal preparations, ointments etc.), suppositories (eg rectal suppositories, vaginal suppositories etc.), pellets, drops, sustained release preparations (eg sustained release microcapsules etc.) Parenteral agents can be mentioned, and these can be safely administered orally or parenterally, respectively. The pharmaceutical composition can be produced by a method conventionally used in the technical field of formulation, such as the method described in the Japanese Pharmacopoeia. Below, the concrete manufacturing method of a formulation is explained in full detail. Although 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, etc.,
For example, it is about 0.1 to 100% by weight.

For example, an oral preparation includes an active ingredient as an active ingredient, an excipient (eg, lactose, sucrose, starch, D-mannitol, etc.), a disintegrant (eg, carboxymethylcellulose calcium), a binder (eg, pregelatinized starch). , Gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. are added for compression molding, 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 property or sustainability.

Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained release film coating base and the like. Saccharose is used as the sugar coating base, and talc, precipitated calcium carbonate, gelatin,
You may use together 1 type (s) or 2 or more types selected from gum arabic, pullulan, a carnauba wax, etc. As the water-soluble film coating base, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
Cellulose polymers such as hydroxyethyl cellulose and methyl hydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co.], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan And so on. Examples of enteric film coating bases 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.], methacrylic acid copolymer S [Eudragit S]
(Trade name), Rohm Pharma Co., Ltd., and the like; acrylic acid-based 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 [Eudragit RS (trade name), Rohm Pharma Co.], ethyl acrylate / methyl methacrylate copolymer suspension. Suspended liquid [Eudragit NE
(Trade name), ROHM Pharma Co., Ltd., and the like. The coating base described above,
You may mix and use 2 or more types in an appropriate ratio. Further, at the time of coating, a light shielding agent such as titanium oxide, iron sesquioxide, etc. may be used.

Injectables are prepared by dispersing active ingredients (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol). ，
Chlorobutanol, phenol, etc., tonicity agent (eg,
Sodium chloride, glycerin, D-mannitol, D-
Soluble and suspended in an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution, etc.) or an oily solvent (eg, olive oil, sesame oil, cottonseed oil, vegetable oil such as corn oil, propylene glycol, etc.) together with sorbitol, glucose, etc. It is produced by turbidity or emulsification. At this time, if desired, additives such as solubilizing agents (eg, sodium salicylate, sodium acetate, etc.), stabilizers (eg, human serum albumin, etc.), soothing agents (eg, benzyl alcohol, etc.) may be used.

The compound of the present invention has an excellent neurotrophic factor production / secretion promoting action. Examples of the neurotrophic factor include neurotrophin, TGF-β superfamily, neurokine family, growth factor and the like. Neurotrophin is a nerve growth factor (nerve
Growth factor (NGF) gene family, which is a protein that plays an important role in differentiation and function maintenance of central and peripheral nervous system cells, synapse formation, regeneration upon damage, and repair. Specific examples of neurotrophins include:
NGF, BDNF (brain-derived neurotrophic factor, brain-derived neuron
trophic factor), NT-3 (neurotrophin-3, neur
otrophin-3), NT-4 / 5 (neurotrophin-4 / 5, neur
otrophin-4 / 5), NT-6 (Neurotrophin-6, neurot
rophin-6) and so on. Neurotrophins
Preferred are NGF, BDNF, NT-3 and the like. The TGF-β superfamily means a group of proteins known to exert various actions on various cells and tissues, which has a characteristic structure in which cysteine is arranged in a mature molecule. Specific examples include TGF-β1, TGF-β2, TGF-
β3, BMP (bone morphogenetic protein, Bone Morphogenetic Protein)
-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-
8A, BMP-8B, BMP-14 (GDF-5), GDNF (Glial cell line-derived neurotroph
ic factor), neurturin, artemin, persephin, GDF−
1, GDF-8, GDF (Growth / differentiat, Growth / differentiat
ion factor) −15, inhibit α, inhibit β, DAF (dauer
formation) 7 and the like. The TGF-β superfamily is preferably GDNF, GDF-15 and the like. Examples of the neurokine family include ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6).
Examples of growth factors include insulin-like growth factor 1 (ins
ulin growth factor-1: IGF-1), basic fibroblast growth factor, and the like. The neurotrophic factor is preferably neurotrophin,
The TGF-β superfamily and the like are more preferable, and NGF, BDNF, NT-3, GDNF, GDF-15 and the like are more preferable. Further, the compound of the present invention has a nerve function improving action and a neuroprotective action. Furthermore, the compound of the present invention has an action of improving conduction velocity of motor nerve and sensory nerve, and an action of improving neuropathic pain.

The neurotrophic factor production / secretion promoter of the present invention is, for example, a neurodegenerative disease (eg, Alzheimer-type senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), Down syndrome). ); Neuropathy (eg, peripheral neuropathy such as diabetic neuropathy, neuropathy due to cancer treatment); diabetic cardiomyopathy; peripheral nerve injury; spinal cord injury; multiple sclerosis; cerebral ischemic disease; epilepsy; depression Disease; inflammatory bowel disease (eg, inflammatory bowel disease); chronic pain (eg, cancer pain); problematic behavior associated with dementia (eg, loitering, aggressive behavior); anxiety; numbness due to wounds Pain; autonomic dysfunction (eg, diabetic autonomic neuropathy, subconscious hypoglycemia, gastroparesis, neurogenic diarrhea and constipation, erectile dysfunction, orthostatic hypotension, arrhythmia, heart failure, painless myocardial infarction, abnormal sweating , Neurogenic胱 etc.); bladder dysfunction (eg, such as bladder reflection disorder); hearing impairment; diabetic foot;
It is useful as a prophylactic / therapeutic agent for bone diseases (eg, osteoporosis, etc.); joint diseases (eg, Charcot joint, osteoarthritis, rheumatism, etc.); Hirschsprung disease, etc. In addition, the neurotrophic factor production of the present invention
Secretagogues are diabetic (eg, type 1 diabetes, type 2 diabetes,
Gestational diabetes, etc., glucose intolerance [IGT (Impaired Gluc
ose Tolerance)], hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, etc.), hyperinsulinemia, obesity, bulimia, hypertension, cardiovascular disease It is also useful as a prophylactic / therapeutic drug for diseases such as (eg, atherosclerosis, etc.); or syndromes having some of these diseases (eg, syndrome X, visceral obesity syndrome, etc.). Furthermore, the neurotrophic factor production / secretion promoter of the present invention is used for secondary prevention and suppression of progression of various diseases described above (eg, neuropathy such as diabetic neuropathy, myocardial infarction, etc.) (eg, glucose intolerance to diabetes). It is also used for restraining the progress to. Further, the neurotrophic factor production / secretion promoting agent of the present invention is an agent for improving neurological disorders or cerebral metabolic disorders; an agent for promoting healing of metabolic or endocrine system diseases such as diabetes and skin damage due to trauma; It is also useful as a drug for renal regeneration (a drug for restoring renal function); a drug for improving or suppressing neuropathic pain; a drug for preventing leg amputation; a drug for preventing sudden death.

The dose of the neurotrophic factor production / secretion promoter of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. In the case of oral administration, the compound of the present invention, which is an active ingredient, is usually used in a single dose of about 0.01-100.
mg / kg body weight, preferably 0.05-30 mg / kg
The body weight is more preferably 0.1 to 2 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

The neurotrophic factor production / secretion promoter of the present invention is a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antiepileptic drug, an antidepressant, an opioid agonist, an antihyperlipidemic agent, an antihypertensive agent, and an antihypertensive agent. Antiarrhythmic drug, antiobesity agent, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, osteoporosis therapeutic agent, antidementia agent, erectile dysfunction improving agent, urinary incontinence / frequency treatment agent, nonsteroidal anti-inflammatory drug, topical It can be used in combination with drugs such as anesthetics and vitamins (hereinafter abbreviated as concomitant drugs). These concomitant drugs may be low molecular weight compounds, high molecular weight proteins, polypeptides, antibodies, or vaccines. At this time, the administration timing of the neurotrophic factor production / secretion promoter and the concomitant drug of the present invention is not limited, and these may be administered to the administration subject at the same time or at a staggered time. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the neurotrophic factor production of the present invention
The mixing ratio of the secretagogue 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, for 1 part by weight of the neurotrophic factor production / secretion promoter of the present invention,
The concomitant drug may be used in an amount of 0.01 to 100 parts by weight.

As the antidiabetic agent, an insulin preparation (eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically synthesized using Escherichia coli or yeast; insulin zinc; protamine insulin) Zinc; fragments or derivatives of insulin (eg, INS-1 etc.), insulin sensitizers (eg, pioglitazone hydrochloride, rosiglitazone (maleic acid), GI-262570, reglixane (Reglixa)
ne) (JTT-501), netoglitazone
(MCC-555), YM-440, KRP-297, C
S-011, FK-614, the compound described in WO99 / 58510 (for example, (E) -4- [4- (5-methyl-
2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid), Ragaglitazar (NN-622), AR-H-039.
242, BMS-298585, EML-16336,
DRF-2593, BM-13.1258, Tesaglitaz
ar) (AZ-242), ONO-5816, LM-4156, MBX-102, LY-51
9818, MX-6054, LY-510929, etc.), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanide agent (eg, phenformin, metformin, buformin, etc.), insulin secretagogue [sulfonylurea Agent (eg, tolbutamide,
Glibenclamide, gliclazide, chlorpropamide,
Trazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, etc.], GLP-1 receptor agonist [eg, GLP-1, NN-2211] , AC-2993
(Exendin-4), BIM-51077, Aib (8,35) hG
LP-1 (7,37) NH ₂ etc.], amylin agonist (eg,
Pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), dipeptidyl peptidase IV inhibitor (eg, NVP-DPP-278, PT
-100, P32 / 98, LAF237 etc.), β3 agonist (eg CL-316243, SR-58611-A, U
L-TG-307, SB-226552, AJ-967
7, BMS-196085, AZ40140, etc., gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.), SGLT (sodium-glucose cotransporter)
Inhibitors (eg, T-1095 etc.) and the like can be mentioned.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-1).
12, etc.), neurotrophic factors and their increasing drugs (eg, NG)
F, NT-3, BDNF, the neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4-
(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole, etc.), a nerve regeneration promoter (eg,
Y-128), PKC inhibitor (eg, LY-33353)
1), AGE inhibitors (eg, ALT946, pimagegedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (Eg,
Tiapride, mexiletine, etc.) and the like.

Examples of the antiepileptic drug include gabapentin, carbamazepine and the like. Examples of the antidepressant include amitriptyline, imipramine and the like. Examples of the opioid agonist include morphine and the like. Antihyperlipidemic agents include statin compounds that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin,
Atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt), squalene synthase inhibitors (eg, compounds described in WO97 / 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, etc.) or fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), antioxidants (eg, lipoic acid, probucol), etc. Is mentioned. Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists Examples thereof include agents (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like. Examples of the antiarrhythmic drug include mexiletine. Examples of the anti-obesity agent include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc .; MCH receptor antagonist). Drugs (eg SB-568849; SNAP-7941; WO01 / 82925 and WO
Compounds contained in 01/87834); neuropeptide Y antagonists (eg, CP-422935 etc.); cannabinoid receptor antagonists (eg, SR-141716, SR-147778 etc.); ghrelin antagonists;
11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498 etc.), pancreatic lipase inhibitors (eg, orlistat, ALT-962 etc.), β3 agonists (eg CL
-316243, SR-58611-A, UL-TG-
307, SB-226552, AJ-9677, BMS
-196085, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (ciliary nerve trophic factor), etc.), cholecystokinin agonists (eg, lint trypto, FPL-15849 etc.) and the like.

Examples of the diuretics include xanthine derivatives (eg sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide type preparations (eg ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, Penfluthizide, polythiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), Azosemide, isosorbide,
Ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Examples include plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Among them, 5-fluorouracil derivative such as furtulon or neofurtulon is preferable. Immunotherapeutic agents include, for example, microbial or bacterial components (eg, muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Example,
Interferon, interleukin (IL), etc., colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like. Among them, IL-1, I
Interleukins such as L-2 and IL-12 are preferred.

Examples of antithrombotic agents include heparin (eg,
Heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, aragatroban, etc.), thrombolytic drug (eg, urokinase, thisokinase) (tiso
kinase), alteplase, nateplase (n
ateplase), monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) ) Etc.) and the like. Examples of therapeutic agents for osteoporosis include alfacalcidol (alfacalcidol) and calcitriol (calcit).
riol), elcatonin, salmon calcitonin salmon, estriol
l), ipriflavone, disodium pamidronate, alendronate sodium hydrate, incadronate disodium and the like. Examples of anti-dementia agents include tacrine (ta
crine), donepezil (donepezil), rivastigmine (rivastigmine), galantamine (galantamine) and the like. Examples of erectile dysfunction improving agents include apomorphine and sildenafil citrate (sil
denafil citrate) and the like. Examples of therapeutic agents for urinary incontinence and frequent urination include flavoxate hydrochloride.
drochloride), oxybutynin hyd
rochloride), propiverine hydroc
hloride) and the like. Examples of the nonsteroidal anti-inflammatory drug include aspirin, acetaminophen, indomethacin and the like. Examples of local anesthetics include lidocaine and capsaicin. Examples of vitamins include vitamin B1 and vitamin B12.

Further, drugs which have been shown to have an effect of improving cachexia in animal models and clinically, that is, 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], glucosteroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (both documents are the same as above), fat metabolism improving agents ( (Eg, eicosapentaenoic acid) [British Journal of Cancer, No. 68
Vol., 314-318, 1993], growth hormone,
IGF-1, or TN, a factor that induces cachexia
Antibodies against F-α, LIF, IL-6, oncostatin M and the like 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 sulfonylureas), aldose reductase inhibitors, PKC
Inhibitors, antiepileptic drugs, antidepressants, antiarrhythmic drugs, opioid agonists, antioxidants, non-steroidal anti-inflammatory drugs and the like.

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

When the neurotrophic factor production / secretion promoter of the present invention is used in combination with a concomitant drug, the amounts of both components can be reduced within a safe range in consideration of the opposite effects of those components. In particular, insulin sensitizers, insulin secretagogues (preferably sulfonylureas), biguanides, aldose reductase inhibitors, PKC inhibitors,
Concomitant drugs such as antiepileptic drugs, antidepressants, antiarrhythmic drugs, opioid agonists, antioxidants, and nonsteroidal anti-inflammatory drugs can be used at lower doses than usual. Therefore, the adverse effects that would be caused by these drugs can be safely prevented. The neurotrophic factor production / secretion promoter of the present invention is
It may be used in combination with treatment methods by non-pharmacological means such as spinal cord electrical stimulation and acupuncture.

The present invention further provides an agent for improving neuropathic pain (excluding low back pain and neuralgia) (prevention / treatment) which comprises a compound represented by the general formula (I-3) or a salt thereof or a prodrug thereof. Agent). Here, the general formula (I-
The compound represented by 3) is a compound in which Y is an amidated carboxyl group [—CON (R ⁶ ) (R ⁷ )] in the general formula (I). In the present specification, neuropathic pain (Neuropathi
c Pain) means pain caused by structural abnormality of the nerve itself. In the neuropathic pain, pain occurs without noxious stimuli. Specific examples of the neuropathic pain include carpal tunnel syndrome, painful neuropathy, phantom limb pain, spinal cord injury, multiple sclerosis, back pain, postherpetic neuralgia,
Examples include trigeminal neuralgia. Suitable specific examples of neuropathic pain (excluding low back pain and neuralgia) include carpal tunnel syndrome,
Examples include painful neuropathy, phantom limb pain, spinal cord injury, multiple sclerosis, back pain (not including back pain). Of these, carpal tunnel syndrome is preferred. The agent for improving neuropathic pain (excluding lower back pain and neuralgia) of the present invention can accept the compound (I-3) as it is or pharmacologically as in the above-mentioned neurotrophic factor production / secretion promoter. By mixing with a carrier or the like to form a pharmaceutical composition, a mammal (eg, human,
Mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.). The dose of the agent for improving neuropathic pain (excluding low back pain and neuralgia) of the present invention is
The dose is the same as the dose of the neurotrophic factor production / secretion promoter described above. Further, the agent for improving neuropathic pain (excluding back pain and neuralgia) of the present invention can be used in combination with the same concomitant drug as in the case of the neurotrophic factor production / secretion promoter.

The present invention further relates to a compound represented by the general formula (I-3a) or a salt thereof. Here, the compound represented by the general formula (I-3a) is represented by the general formula (I-3).
^{Among, -W-CON (R 6)} (R 7), R 1 and R ² [symbol is as defined above], respectively 3-position on the isoxazole ring, substituted at the 4-position and 5-position It is a compound.
The compound represented by the general formula (I-3a) is preferably the following compound (B) and the like. Compound (B) R ¹ is a hydrogen atom; R ² is 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine); and 2) 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine). An alkyl group having 1 to 6 carbon atoms which may be substituted with (eg, methyl, ethyl, trifluoromethyl)
An aromatic hydrocarbon group optionally having 1 to 3 substituents selected from the group (preferably phenyl); W is a bond or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms (preferably _{-CH 2 -, - (CH 2} ) 2 -, - (CH 2) 3 -, - (CH 2) 4 -,
-CH = CH-; more preferably _{- (CH 2) 2 -,} - CH = CH
-); R ⁶ and R ⁷ are the same or different; a) a hydrogen atom; b) a C _1-6 aliphatic hydrocarbon group [eg, an alkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl, 1-
Ethylpropyl, 2,2-dimethylpropyl, etc.)];
Or c) (mono- or di-C _1-6 which may form a ring)
Alkyl-phosphono) -C _1-6 alkyl group [eg, methylphosphonomethyl, ethylphosphonomethyl, dimethylphosphonomethyl, diethylphosphonomethyl, ethylmethylphosphonomethyl, diisopropylphosphonomethyl, dibutylphosphonomethyl, 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) methyl and the like], phosphono-C _1-6 alkyl group (eg, phosphonomethyl and the like) and mono- or di-C
C which may have 1 to 2 substituents selected from _1-6 alkyl-phosphono groups (eg, diethylphosphono etc.)
_6-14 aryl group (eg phenyl, naphthyl);

Compound (I-3a) is similar to compound (I-3a) similar to the above-mentioned neurotrophic factor production / secretion promoter.
, Or by mixing with a pharmacologically acceptable carrier or the like to give a pharmaceutical composition, a mammal (eg,
Human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.). The dose of the compound (I-3a) is the same as the dose of the neurotrophic factor production / secretion promoter described above. In addition, the compound (I
-3a) can be used in combination with the same concomitant drug as in the case of the neurotrophic factor production / secretion promoter. In addition, the compound (I-3a) produces neurotrophic factor
It is useful as a secretagogue, a neuropathic pain ameliorator, etc.

The production method of the compound of the present invention will be described below. Compound (I) [Compound (I-3) and (I-3
including a)] is a method known per se, for example, A shown below.
It can be manufactured by the method to the method I or a method similar thereto.

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

[Chemical 18] [In the formula, R ^3a represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and the other symbols have the same meanings as described above. ] “A hydrocarbon group which may be substituted” represented by R ^3a ,
Examples of the “optionally substituted heterocyclic group” and the “optionally substituted acyl group” include those exemplified as R ³ .

In this method, compound (I-2) is produced by subjecting compound (I-1) to hydrolysis. This hydrolysis reaction is carried out according to a conventional method in the presence of an acid or a base,
It is carried out in a water-containing solvent. 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; potassium hydroxide and sodium hydroxide. Alkali metal hydroxides such as lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide. The amount of the acid or base used is usually an excess amount with respect to compound (I-1). Preferably, the amount of the acid used is the compound (I-1)
On the other hand, about 2 to about 50 equivalents, and the amount of the base used are about 1.2 to about 5 equivalents relative to compound (I-1). Examples of the water-containing solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; a mixed solvent of water and one or more solvents selected from dimethyl sulfoxide and acetone. When the reaction is carried out under acidic conditions, excess acid may be used as a solvent. The reaction temperature is generally about −20 to about 150 ° C., preferably about −10.
Is about 100 ° C. The reaction time is usually about 0.1 to about 20 hours. The compound (I-
2) is a known separation / purification means such as concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-1) used as the starting material compound in the above Method A is, for example, the compound of the Journal of Heteroc Chemistry.
yclic Chemistry), 28, 453 (1991)
Year); Journal of Organic Chemistry, Volume 49, 4419
Page (1984); Tetrahedron Letters (Tetrah
edron Letters), Volume 34, page 485 (1993), or the like, or a method analogous thereto.

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

[Chemical 19] [The symbols in the formulas have the same meanings as described above. In this method, compound (I-3) is produced by subjecting compound (I-2) to an amidation reaction. This reaction is a method known per se, for example, compound (I-2) and compound (VI)
And a method in which the reactive derivative of the compound (I-2) and the compound (VI) are appropriately reacted with each other. Examples of the condensing agent include carbodiimide-based condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride; phosphoric acid-based condensation reagents such as diethyl cyanophosphate and diphenylphosphoryl azide. And a commonly known condensing agent 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 and toluene. 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) used is
The amount is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-2). The amount of the condensing agent used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-2). When a carbodiimide-based condensation reagent such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride is used as the condensation agent, a suitable condensation accelerator (eg, 1-hydroxy- The reaction efficiency can be improved by using 7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide and the like. When a phosphoric acid type condensation reagent such as diethyl cyanophosphate or diphenylphosphoryl azide is used as the condensing agent, the reaction efficiency can be improved by adding an organic amine base such as triethylamine.
The amount of the above-mentioned condensation accelerator or organic amine base 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
The temperature is -30 ° C to 100 ° C. The reaction time is usually 0.5
~ 60 hours.

In the method using the reactive derivative of the compound (I-2), examples of the reactive derivative of the compound (I-2) include acid anhydride, acid halide (acid chloride, acid bromide), imidazolide, or a mixture thereof. Examples thereof include acid anhydrides (eg, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, etc.). For example, when using an acid anhydride or an acid halide, the reaction is usually performed in the presence of a base in a solvent that does not influence the reaction. Examples of the base include triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate,
Examples thereof include potassium carbonate and cesium carbonate. Examples of the solvent that does not influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatics such as benzene and toluene. Hydrocarbons; ethers such as tetrahydrofuran, dioxane, diethyl ether; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio. When the above amides are used as the solvent that does not affect the reaction, the reaction can be performed in the absence of a base. The amount of compound (VI) used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-2). The amount of the base 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 -3.
It is 0 ° C to 100 ° C. The reaction time is usually 0.5 to 2
It's 0 hours.

When a mixed acid anhydride is used, compound (I-2) and a chlorocarbonic acid ester (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) are combined with a base (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.,
Further, it is reacted with compound (VI). The amount of compound (VI) to be used is generally 0.1-10 molar equivalents, preferably 0.3-3 molar equivalents, relative to compound (I-2). The reaction temperature is usually -30 ° C to 100 ° C. The reaction time is
Usually, it is 0.5 to 20 hours. The compound (I-3) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-2) used as the starting compound in the above method B is produced, for example, by the above method A. Further, the compound (VI) used as the starting compound in the above Method B can be produced by a method known per se.

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

[Chemical 20] [In the formula, Wb represents a bond or a divalent aliphatic hydrocarbon group, and other symbols have the same meanings as described above. ] As the "divalent aliphatic hydrocarbon group" represented by Wb,
What was illustrated as said W is mentioned.

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 influence the reaction. As a reducing agent,
For example, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, borane and its complex (eg, borane).
-Tetrahydrofuran, pyridine borane, borane-dimethyl sulfide, etc.) and the like. The amount of the reducing agent used is preferably about 0.5 to about 10 molar equivalents relative to compound (I-1). Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; ethers such as tetrahydrofuran, dioxane and diethyl ether; water, Examples thereof include alcohols such as methanol, ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally 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 (I-4) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), Y is the formula: -OCOR ⁴
The 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. [D method]

[Chemical 21] [The symbols in the formulas have the same meanings as described above. In this method, compound (I-5) is produced by subjecting compound (I-4) to an acylation reaction. This reaction can be carried out by a method known per se. As such a method, for example, a method of directly condensing the compound (I-4) and a carboxylic acid derivative (R ⁴ CO ₂ H) using a condensing agent, or a carboxylic acid derivative (R ⁴ CO ₂ H) Examples thereof include a method of appropriately reacting the reactive derivative with the compound (I-4). Here, the method of directly condensing the compound (I-4) and the carboxylic acid derivative (R ⁴ CO ₂ H) using a condensing agent is the condensation of the above-mentioned “compound (I-2) and compound (VI)”. The method of directly condensing using an agent "is performed.

In the method using the reactive derivative of the carboxylic acid derivative, examples of the reactive derivative of the carboxylic acid derivative include acid anhydrides, acid halides (acid chlorides and bromides), imidazolides, and mixed acid anhydrides (for example, Methyl carbonate, ethyl carbonate, an anhydride with isobutyl carbonate, etc.) and the like. When using, for example, an acid anhydride or an acid halide, the reaction is usually carried out in the presence of a base, in a solvent that does not influence the reaction. Examples of the base include triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate,
Examples thereof include potassium carbonate and cesium carbonate. Examples of the solvent that does not influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatics such as benzene and toluene. Hydrocarbons; ethers such as tetrahydrofuran, dioxane, diethyl ether; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio. When the above amides are used as the 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 carboxylic acid 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 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 -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 chlorocarbonic acid ester (eg,
Methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) is used as a base (eg, triethylamine, aniline, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodium hydroxide, hydroxide). Potassium, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), and further reacted with compound (I-4). The amount of the carboxylic acid derivative used is the compound (I-
It is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, based on 4). The reaction temperature is usually -30.
The temperature is from 100 ° C to 100 ° C. The reaction time is usually 0.5 to 20.
It's time. Compound (I-5) thus obtained
Can be isolated and purified by known separation / purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (I-4) used as a raw material compound in the above Method D is produced, for example, by the above Method C.

In the general formula (I), Y is represented by the formula: -OR ^3a
The 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. [E method]

[Chemical formula 22] [In the formula, X is a hydroxy group, a halogen atom or a formula:-
A group represented by OSO ₂ R ⁸ (R ⁸ represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms), Symbol has the same meaning as described above. ] Here, "alkyl group having 1 to 4 carbon atoms" represented by R ⁸
And "1 to 4 carbon atoms in the" 6 to 10 carbon aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms "
The alkyl group of 4 includes methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec.-butyl, t.-
Butyl and the like can be mentioned, of 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. Among them, phenyl is preferable.

In this method, compound (I-4) and compound (VI
Compound (I-6) is produced by reaction with I). When X is a hydroxy group, this reaction can be carried out by a method known per se,
For example, Synthesis, page 1 (1981)
The method described in 1) or a method similar thereto is used. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely influence the reaction. Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine. Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperidine. The amount of the organic phosphorus compound and electrophilic agent used is preferably about 1 to about 5 molar equivalents relative to compound (I-4). Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane;
Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; 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 generally 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
In the case of a group represented by (R ⁸ has the same meaning as described above), 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. Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and cesium carbonate; alkaline earth salts such as barium carbonate, calcium carbonate, barium hydroxide and calcium hydroxide. Metal salts; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.
0] amines such as undeca-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide and the like. The amount of these bases used is based on the compound (I-4).
It is preferably about 1 to about 5 molar equivalents. Examples of the solvent that does not adversely influence 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; chloroform and dichloromethane. Halogenated hydrocarbons such as;
Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about −50 to about 150 ° C., preferably about −10 to about 100 ° C. The reaction time is usually
It is about 0.5 to about 20 hours. The compound (I-6) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
[F method]

[Chemical formula 23] [In the formula, E is a halogen atom or a formula: -OSO 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 (III-1) and compound (V
Compound (I-6) is produced by the reaction with III). 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. Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like. Alkaline earth metal salts; pyridine, triethylamine,
Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride;
Examples thereof include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide. The amount of these bases used is the compound (III-
It is preferably about 1 to about 5 molar equivalents relative to 1). Examples of the solvent that 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;
Examples thereof include sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally 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 (I-6) thus obtained can be isolated and purified by a known separation and purification means such as 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.dbd.CH-- or-(C
H _{2) 2} -, compound [respectively compound (I-9) or (I-10)] are also prepared by the following Method G. [G method]

[Chemical formula 24] [The symbols in the formulas have the same meanings as described above. ]

(Step 1) Reduction Reaction This reaction is carried out according to a conventional method in the presence of a reducing agent, in a solvent that does not influence the reaction. Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, borane and its complex (eg, borane-tetrahydrofuran, Pyridine borane, borane-dimethyl sulfide, etc.) and the like. The amount of reducing agent used is
It is preferably about 0.5 to about 10 relative to compound (I-7).
It is a molar equivalent. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; ethers such as tetrahydrofuran, dioxane and diethyl ether; water, Examples thereof include 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 1.
The temperature is 50 ° C, preferably about -10 to about 100 ° C. The reaction time is usually about 0.5 to about 20 hours. The compound (I-8) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

The compound (I-7) used as a starting compound in Step 1 of Method G is, for example, a compound of the Journal of Heterocyclic Chemistry (Jour).
nalof Heterocyclic Chemistry, 28, 453 (1991); Journal of Organic Chemistry, 49,
4419 p. (1984); Tetrahedron Letters, 34, 485 (199).
3 years) or the like, 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 metal oxidizing agents such as manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, and ruthenium oxide. The amount of the oxidizing agent used is the compound (I-
It is preferably about 1 to about 10 molar equivalents relative to 8).
Examples of the solvent that does not adversely influence 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. To be These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
It 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.
It's time.

Compound (IV) is prepared by adding sulfur trioxide pyridine complex or oxalyl chloride to compound (I-8) in a mixed solvent of sulfoxides such as dimethyl sulfoxide and halogenated hydrocarbons such as chloroform and dichloromethane. It can also be produced by adding a reaction reagent such as and reacting with an organic base such as triethylamine and N-methylmorpholine. The amount of the reaction reagent used is preferably about 1 to the compound (I-8).
It is about 10 molar equivalents. The amount of the organic base used is preferably about 1 to about 10 molar equivalents relative to compound (I-8). The reaction temperature is generally 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 can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 3) Carburizing reaction In this reaction, an organic phosphorus reagent and compound (IV) are added in the presence of a base.
Compound (I-9) is produced by the reaction with. This method is performed according to a conventional method in the presence of a base in a solvent that does not influence the reaction. Examples of the organic phosphorus reagent include methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, and dimethylphosphonoethyl acetate.
The amount of the organic phosphorus reagent 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 and potassium carbonate; alkaline earth metal salts such as barium carbonate, calcium carbonate, barium hydroxide and calcium hydroxide; pyridine, triethylamine, Amines such as N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide,
Examples include alkali metal alkoxides such as potassium t.-butoxide. The amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (IV).
Examples of the solvent that does not adversely influence 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; N, Examples thereof include amides such as N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50 to
The temperature is about 150 ° C, preferably about -10 to about 100 ° C.
The reaction time is usually about 0.5 to about 20 hours. The compound (I-9) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 4) Hydrogenation Reaction This method is carried out according to a conventional method in a hydrogen atmosphere or in the presence of 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, and Wilkinson catalyst. The amount of these transition metal catalysts used is preferably about 0.01 to about 10 molar equivalents relative to compound (I-9). Examples of the solvent that does not adversely influence 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; N, Amides such as N-dimethylformamide; alcohols such as methanol, ethanol, isopropanol, and the like. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
It 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.
It's time. The compound (I-1) thus obtained
0) is a known separation and purification means such as 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) in which Y is a carboxyl group and W is — (CH ₂ ) ₂ — is
It is also produced by the following H method. [H method]

[Chemical 25] [The symbols in the formulas have the same meanings as described above. ]

(Step 1) Carburization Reaction In this method, compound (III-2) is subjected to a 2-carbon charcoal reaction using malonic acid diester to produce compound (V). This reaction is carried out according to a conventional method in the presence of 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; alkaline earth salts such as barium carbonate, calcium carbonate, barium hydroxide and calcium hydroxide. Metal salts; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca
Examples include amines such as 7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide. Examples of the malonic acid diester include diethyl malonate, dimethyl malonate, dipropyl malonate, dibutyl malonate and the like. The amount of the base and malonic acid diester used is preferably about 1 with respect to the compound (III-2).
~ About 5 molar equivalents. Examples of the solvent that does not adversely influence 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; N,
Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
It 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.
It's time. The compound (V) thus obtained is
It can be isolated and purified by known separation and purification means such as 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. This decarboxylation reaction is
According to a conventional method, it is carried out under acidic conditions or basic conditions. When carried out under acidic conditions, this method follows conventional methods
It is carried out in a solvent that does not affect the reaction. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like. The amount of the acid used is usually an excess amount with respect to the compound (V). Preferably, it is about 2 to about 50 equivalents relative to compound (V). Examples of the solvent that does not affect the reaction include alcohols such as methanol and ethanol; a mixed solvent of water and one or more solvents selected from ketones such as acetone and 2-butanone.
Also, excess acid may be used as a solvent.

In the case where the method is carried out under basic conditions, according to a conventional method, the compound (V) is converted into the dicarboxylic acid by hydrolysis and then thermally decomposed to produce the compound (I-11).
The hydrolysis reaction is carried out in the presence of a base according to a conventional method in a water-containing solvent that does not affect the reaction. As a base,
For example, alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate; barium carbonate, calcium carbonate,
Examples thereof include alkaline earth metal salts such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as sodium methoxide. The amount of the base used is usually an excess amount with respect to compound (V). It is preferably about 2.5 to about 20 equivalents relative to compound (V). 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;
Examples thereof include a mixed solvent of water and one or more solvents selected from dimethyl sulfoxide, acetone and the like. The reaction temperature is generally 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. This thermal decomposition reaction is carried out according to a conventional method,
It is carried out in a solvent that does not affect the reaction. Examples of the solvent that does not influence the reaction include pyridine, quinoline, collidine and the like. The reaction temperature is usually
About -20 to about 250 ° C, preferably about 50 to about 200 ° C
Is. The reaction time is usually about 0.1 to about 20 hours. The compound (I-11) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

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

[Chemical formula 26] [In the formula, each symbol has the same meaning as described above. The compound (III-1) in which E is a halogen atom is produced, for example, by reacting the compound (I-4) with a halogenating agent. This method is performed according to a conventional method in the presence of a halogenating agent, in a solvent that does not influence the reaction.
Examples of the halogenating agent include thionyl chloride and phosphorus tribromide. The amount of halogenating agent used is
It is preferably about 1 to about 20 molar equivalents relative to compound (I-4). Examples of the solvent that does not adversely influence 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. To be
These solvents may be mixed and used at an appropriate ratio.
Also, an excess halogenating agent may be used as a solvent.
The reaction temperature is generally about -20 to about 150 ° C, preferably about 0 to about 100 ° C. The reaction time is usually about 0.1
~ About 20 hours.

A compound (III-1) in which E is a group represented by the formula: -OSO ₂ R ⁸ (R ⁸ has the same meaning as defined above).
Can be produced, for example, by reacting compound (I-4) with a sulfonylating agent in the presence of an appropriate base.
This method is performed according to a conventional method in the presence of a sulfonylating agent, in a solvent that does not influence 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 is produced. The amount of the sulfonylating agent and the base used is preferably about 1 to about 2 molar equivalents relative to compound (I-4). Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane;
Examples thereof include ethyl acetate and acetone. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually about -20 to about 150 ° C, preferably about 0 to about 10
It is 0 ° C. The reaction time is usually about 0.1 to about 20 hours. Compound (III-1) thus obtained
Can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, 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 target compound can be obtained by removing the protective group if necessary.

Examples of the amino-protecting group include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _1-6 alkoxy-carbonyl (eg,
Methoxycarbonyl, ethoxycarbonyl, tert-
Butoxycarbonyl, etc.), benzoyl, C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), 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 (eg, 1-allyl etc.) and the like. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.)
Alternatively, it may be substituted with nitro or the like.

Examples of the protecting group for carboxy include 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.), C _2-6 alkenyl (eg, 1-allyl etc.) and the like. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy etc.) or nitro etc. .

Examples of the hydroxy protecting group include 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, etc.), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, t
ert-butyldiethylsilyl, etc.), C _2-6 alkenyl (eg, 1-allyl etc.) and the like. These groups include 1 to 3 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 and the like) or nitro and the like.

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

The method for removing these protecting groups is a method known per se, for example, Protective Groups in Organic Synthesis (Protective Groups in
Organic Synthesis), 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 salt, those exemplified as the salt of compound (I) are used.

When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also included as the compound (I), and a synthetic method known per se and a separation method are known. 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 racemate of the final product 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 can be used. 1) Fractional recrystallization method racemate and optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
Phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, and this is separated by a fractional recrystallization method, and if desired, a free optical isomer is obtained through a neutralization step. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separating optical isomers (chiral column) for separation. 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 Corporation) or CHIRAL series manufactured by Daicel Corporation,
Optical isomers by developing water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as single or mixed solutions To separate. In the case of gas chromatography, for example, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences Inc.). 3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this mixture is subjected to usual separation means (eg, fractional recrystallization, chromatography method, etc.) to obtain a single substance. Then, a method of obtaining an optical isomer by cleaving the optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, when the compound (I) has hydroxy or 1,2 amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid],
(−)-Menthoxyacetic acid and the like) and the like are subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound and the optically active amine or alcohol reagent are subjected to a condensation reaction 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 also provides a novel model animal for neuropathic pain (hereinafter sometimes referred to as the model animal of the present invention) and a method for producing the same. The animal that is the source of the model animal of the present invention is not particularly limited as long as it is a mammal other than human, and examples thereof include mice, rats, guinea pigs, hamsters, rabbits, dogs, cats, monkeys, and the like. Is rat or mouse, more preferably rat. In addition, it is desirable that a closed colony animal that has been mated / maintained while maintaining a constant number of inbred strains with fixed genetic traits or a new individual from the outside, for example, in the case of rats, Sprague Dawley ( SD) rat, Wistar rat, Donryu rat, F344 rat, Lewis
s Rats and the like. The animals used may be those raised in conventional conditions, but SP
It is more preferable to use SPF-ized animals in the animal species for which F technology is established. The sex of the animal is not particularly limited. The age and weight are also not particularly limited, but it is preferable that they are grown so that the surgical procedure can be easily performed. For example, a rat weighs about 70 to about 70
Those of 0 g, about 1 to about 8 months of age can be preferably used.

The model animal of the present invention can be produced by cutting only the common peroneal nerve among the peripheral nerves. The cutting method is not particularly limited, and examples thereof include a method in which after anesthetizing the animal, the knee is incised to expose the common peroneal nerve, and this is ligated with a silk thread, and then the distal portion is cut. . The range of incision is not particularly limited as long as it is a range sufficient to expose the common peroneal nerve, but it is preferable to perform it in the minimum range necessary to expose only the common peroneal nerve. Not only can the time required for incision and suturing be shortened, but by minimizing the damage to muscles, the reaction of the animal becomes clearer, and at the same time, the reaction can be regarded as hyperalgesia due to nerve damage (hypersensitivity due to muscle damage). The reaction can be ignored). After the nerve is cut, the muscle layer and the skin may be sutured one after another by a conventional method, and the skin may be disinfected and antibiotics may be administered if necessary. The model animal of the present invention obtained as described above has a markedly lower pain sensation threshold as compared with the conventionally known SNI model, and is more suitable for the search for a neuropathic pain improving substance (preventive / therapeutic substance). There is.
The onset of hyperalgesia is recognized within 24 hours after the operation, and the degree of hyperalgesia becomes maximum within about 1 week after the operation, and at least 2 weeks or more, preferably about 1 month or more, more preferably about 3 months or more, It preferably lasts about 6 months or longer.

In addition, the model animal of the present invention, for example, 1) ligates only the common peroneal nerve, so that the operation is easy and can be performed in a short time, and the risk of damaging other nerves is extremely low. ) The muscle damage can be minimized so that the reaction of the animal can be judged as hyperalgesia due to net nerve damage, and 3) the hyperalgesia test test stimulates the middle of the foot. It is easy to identify the place to give the stimulus (for example, in the method of Woolf et al. Mentioned above, a clear pain behavior is not observed because the tibial nerve that controls the central sense is cut. ) And the like, it is superior to conventionally known neuropathic pain model animals.

The present invention also provides a method for screening a neuropathic pain improving substance using the model animal of the present invention. Specifically, the present screening method, after administering the test substance to the model animal of the present invention, the body surface portion near the site controlled by the common peroneal nerve, for example, the sole of the foot, preferably the middle of the sole of the foot. The mechanical stimulation (eg, von Frey hair, etc.) or thermal stimulation is given to the patient, and the degree of stimulation (ie, pain threshold) that indicates positive pain behavior (for example, quick withdrawal of the foot when stimulating the sole of the foot), Comparison with that in another model animal of the present invention before or without administration of the test substance. For example, von Frey hair
When a hypersensitivity reaction was only exerted on a weight greater than that before administration of the test substance when the test substance was applied to the middle part of the sole of the model animal of the present invention, the test substance was treated for neuropathic pain. It can be selected as a substance candidate. Alternatively, after pre-administering a test substance to an animal before surgery, a common peroneal nerve is cut to obtain a model animal of the present invention, and a pain threshold is measured by stimulation in the same manner as above, and the test substance is administered. By comparing with that in another model animal of the present invention which is not present, a substance having a preventive effect on neuropathic pain can be searched for. That is, in this screening method,
A substance that increases the pain threshold in a model animal can be selected as a candidate for a neuropathic pain preventive substance.

Examples of test substances include peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, etc. These substances may be novel substances or known substances. . As the administration route of the test substance,
Examples include, but are not limited to, intraperitoneal administration, intrathecal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration and the like. Further, the dose of the test substance can be appropriately changed depending on the type of model animal, body weight, age, drug acceptability and the like, administration route, administration form, etc. It can be selected from the range of 100 mg / kg body weight.

The present invention also provides a neuropathic pain improving agent comprising the neuropathic pain improving substance obtained by the above screening method. The neuropathic pain improving agent is a pharmaceutical composition in the same manner as the above-mentioned neurotrophic factor production / secretion promoting agent, a neuropathic pain improving substance as it is or in a mixture with a pharmacologically acceptable carrier or the like. By
Mammals (eg, human, mouse, rat, rabbit, dog,
(Cat, cow, horse, pig, monkey, etc.). The dose of the neuropathic pain ameliorating agent varies depending on the administration subject, administration route, target disease, symptom and the like, but when administered orally to an adult patient, for example, the neuropathic pain ameliorating substance which is an active ingredient is usually 1 About 0.01
-100 mg / kg body weight, preferably 0.05-30 m
g / kg body weight, more preferably 0.1-2 mg / kg
It is the body weight, and it is desirable to administer this amount once to three times a day. Further, the neuropathic pain ameliorating agent can be used in combination with the same concomitant drug as the above-mentioned neurotrophic factor production / secretion promoting agent.

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.

EXAMPLES In the following reference examples and examples,
Unless otherwise specified,% means weight percent. In addition, room temperature refers to a temperature of 1 to 30 ° C.

In the examples, HPLC was measured under the following conditions. Measuring equipment: Shimadzu LC-10Avp system column: CAPSEL PAK C18UG120 S-3 μm, 2.0 X 50mm Gradient cycle: 0.00 minutes (Solution A / Solution B = 90/10), 4.
00 minutes (Solution A / B = 5/95), 5.50 minutes (Solution A / B = 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 220n
m In the examples, mass spectra (MS) were measured under the following conditions. Measuring equipment: Micromass Platform II, Waters ZQ, or Waters ZMD Ionization method: Atmospheric pressure chemical ionization method (Atmospheric Pres)
sure Chemical Ionization (APCI) or Electron Impact Ionization (ESI) Preparative HPLC Equipment: Gilson High Throughput Purification System Column: YMC Combiprep ODS-A S-5 μm, 50 X 20 mm Gradient cycle: 0.00 minutes (Solution A / Solution B = 90/10), 1.
20 minutes (A / B solution = 90/10), 4.75 minutes (A / B solution = 0/100),
7.30 minutes (Solution A / B = 0/100), 7.40 minutes (Solution A / B = 90/1
0), 7.50 minutes (Solution A / Solution B = 90/10) Flow rate: 25 ml / min, Detection method: UV 220nm

Test Example 1 Male 6-week-old SD rats were intravenously injected with 70 mg / kg body weight streptozotocin (STZ) by tail injection to prepare a diabetic neuropathy model. Then, after raising the rats for 4 weeks, 0.5% methylcellulose aqueous suspension of the compound of Example 21 was orally administered for 4 weeks so that the dose of the compound would be 3 mg / kg body weight / day, and hyperalgesia and nerve conduction. The speed was evaluated. The control group was administered with a 0.5% aqueous methylcellulose suspension containing no compound. Analgesy-Meter assessment of hyperalgesia
(Ugobasil Co., Ltd.) was used in principle to determine the response threshold to pressure stimulation for the left hind limb.
Nerve conduction velocity is evaluated by evoked potential measuring device (Neuropack
2, Nihon Kohden) was used to determine the motor nerve conduction velocity between the hip and ankle. After evaluation of hyperalgesia and nerve conduction velocity, sciatic nerve was collected from the rat. On the collected sciatic nerve, 20 times as much wet weight of sciatic nerve as crushing buffer (1 M sodium chloride, 2% BSA, 2 mM EDTA, 80
0.1 M Tris-HCl buffer containing trypsin unit / L aprotinin, pH 7.6) was added and ultrasonically disrupted, and the disrupted liquid was centrifuged (15,000 rpm, 60 minutes), and then G
The content of DNF and BDNF was measured. GDNF content is anti-GDNF
It was measured by a sandwich ELISA method using an antibody (AF-212, R & D) and its biotinylated GDNF antibody (BAF-212, R & D). BDNF content depends on the anti-BDNF antibody (MAB248, R & D
) And biotinylated anti-BDNF antibody (G1641, Promega)
Was measured by the sandwich ELISA method using. As a result, the pain threshold was 49% in the compound-administered group compared to the control group.
%, Nerve conduction velocity was 22%, sciatic nerve GDNF content was 40%, and sciatic nerve BDNF content was 16%.

Example 1A Preparation of Neuropathic Pain Model Six-week-old male SD rats (CLEA Japan, Inc.) (n = 34) were subjected to hypersensitivity reaction to tactile stimulation by von Frey hairs method ( Allodynia) was tested. That is, 8 filaments (grams of forc
e / label; 0.4 / 3.61, 0.7 / 3.84, 1.2 / 4.08, 2.0 / 4.31,
4.0 / 4.56, 6.0 / 4.74, 9.0 / 4.93, 15 / 5.18),
4.56 up-down method from filament (Chaplan, SR et al., J NeurocsiMethods 1994 53 : 55-63)
According to the above, the middle part of the right sole of the rat was stimulated, and the 50% threshold value (g) was calculated from the avoidance response. If there is no reaction in the thickest filament, the fixed value is
15g was taken as the 50% threshold. The preoperative values were measured three times on different days in total, and the ones showing the approximate values at least the last two times were selected and sorted into five groups of group A to group E by the reaction threshold of the third time. Regarding 4 groups from A group to D group, under the anesthesia of pentobarbital (50 mg / kg, ip), after stabilizing the rat to the right positioning, the skin and muscle layers were incised and attached to the common sciatic nerve. Three nerves [sural nerv
e), tibial nerve, common pero nerve
[neal nerve)] was exposed. The tibial nerve (group A) or the common peroneal nerve (group B) were ligated with silk thread (4-0) alone, and both nerves were ligated with silk thread (4-0) (C Then, the ligated nerve was cut at the distal portion. Thereafter, the muscle layer was sutured with silk thread, and the skin was adhered using a stapler and Aron Alpha (trade name, manufactured by Toagosei Co., Ltd.) to produce a neuropathic pain model rat. Moreover, after exposing the three nerves associated with the common sciatic nerve, sham-operated rats (D
Group). In order to prevent the infection of each rat of the above groups A to D, an antibiotic (sulvenicillin sodium) was intramuscularly injected into the left hind leg of the rat.

Test Example 2 Assay of Hypersensitivity Reaction (Allodynia) to Tactile Stimulation For each rat of groups A to D obtained in Example 1A and each group of unoperated group (Group E), the same procedure as in Example 1A was conducted. Hypersensitivity reaction (allodynia) to tactile stimulus was assayed. The measurement was performed on days 1, 2, 6 and 13 after surgery. The results are shown in Table 1. The numerical values in the table indicate the 50% threshold value (g) (mean value ± standard error) (n = 6 to 7). [Table 1] Group A Group B Group C Group D Group E Before surgery 10.4 ± 5.7 10.0 ± 5.5 10.8 ± 5.5 9.9 ± 5.7 10.0 ± 5.5 1 day after surgery 11.6 ± 1.7 5.6 ± 2.5 10.3 ± 2.5 10.3 ± 2.5 9.0 ± 2.0 2 days after surgery 9.1 ± 2.4 3.9 ± 1.6 7.9 ± 2.0 9.9 ± 2.3 10.0 ± 2.1 6 days after surgery 6.8 ± 2.0 3.5 ± 2.0 8.0 ± 2.0 9.8 ± 2.5 8.0 ± 2.2 13 days after surgery 6.8 ± 2.1 4.0 ± 1.9 10.5 ± 2.5 7.4 ± 2.8 9.8 ± 2.4 Table As shown in 1, a group (A
Group) and a group in which both the tibial nerve and the common peroneal nerve were dissected (C group), whereas a clear decrease in the reaction threshold was not observed, whereas a group in which only the common peroneal nerve was dissected (B group) was operated. One day after that, a decrease in the reaction threshold was already observed, and allodynia was stably maintained after the second day.

Test Example 3 Neuropathic pain ameliorating action of the compound of the present invention The compound described in Example 21 (3 mg / kg body weight /
After the oral administration of 0.5% aqueous solution of 0.5% methylcellulose (15 days) from the model preparation, the 50% threshold value of the rat was measured in the same manner as in Test Example 2 (F group). In addition, Example 1A
A 0.5% methylcellulose aqueous suspension containing no compound described in Example 21 was administered to a neuropathic pain model rat produced in the same manner as in Group B, and this was used as a control group (Group G).
Furthermore, a sham-operated rat produced in the same manner as in the group D of Example 1A was orally administered with a 0.5% aqueous methylcellulose suspension containing no compound described in Example 21 for 15 days, and then Test Example 2 was used.
The 50% threshold of the rat was measured in the same manner as in (H
group). As a result, 50% threshold (g) (mean ± standard error)
(N = 8) is 11.43 ± 1.95 in F group, 3.81 ± 1.18 in G group,
It was 13.74 ± 1.01 in the H group. Moreover, as a result of performing a t-test on the F group and the H group, the p value was less than 0.01. That is, the reaction threshold of the control group (G group) is the sham operation group.
Although it was significantly lower than that in the (H group), the reaction threshold of the compound administration group described in Example 21 was improved to about 76% of that in the sham operation group (H group). This revealed that the compound of the present invention has an excellent neuropathic pain improving effect.

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
Stir for hours. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (5.54 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (120 ml). Hydroxylamine hydrochloride (4.29 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
Ethyl 5- (4-trifluoromethoxyphenyl) isoxazole-4-carboxylate (6.60 g, yield 71%) was obtained as a yellow oil from the elution part (volume ratio). 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 A solution of ethyl 5- (4-trifluoromethoxyphenyl) isoxazole-4-carboxylate (6.60 g) in tetrahydrofuran (80 ml) was charged with diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 55).
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. 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 ) and then concentrated to give 5- (4-trifluoromethoxyphenyl) -4-isoxazolylmethanol (5.
70 g, yield 99%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 45-46 [deg.] C.

Reference Example 3 4'-trifluoromethylacetophenone (10.0
g), sodium hydride (60%, oily, 2.13 g)
And a mixture of diethyl carbonate (80 ml) at 80 ° C for 9
Stir for 0 minutes. Water was added to the reaction mixture, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio) from the eluate to 3
Ethyl -oxo-3- (4-trifluoromethylphenyl) propionate was obtained as an oil. A mixture of this oil and N, N-dimethylformamide dimethylacetal (9.50 g) was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethanol (80 ml). Hydroxylamine hydrochloride (7.3
9 g) was added and the mixture was refluxed for 2 hours. The reaction mixture is concentrated,
Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the eluate of ethyl acetate-hexane (1: 9, volume ratio) were recrystallized from hexane to give 5- (4
-Trifluoromethylphenyl) isoxazole-4
-Ethyl carboxylate (8.42 g, yield 56%) was obtained as colorless prism crystals. Melting point 53-54 [deg.] C. Reference Example 4 N-methoxy-N-methylamine hydrochloride (9.28)
g), triethylamine (14 ml) and N, N-dimethylformamide (500 ml) at room temperature.
After stirring for 0 minutes, 5-phenylisoxazole-
4-carboxylic acid (14.95 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (14.
08 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18.00 g) 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, 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 collected from the ethyl acetate-hexane (1: 4, volume ratio) eluate.
5 g, yield 76%) was obtained 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) carboxamide (13.01 g) in tetrahydrofuran (200 ml) was charged with diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 1
(20 ml) was slowly added at 0 ° C., and then the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 4, volume ratio).
%) As a colorless oil. NMR (CDCl ₃ ) δ: 7.53-7.66 (3H, m), 7.87-7.96 (2H, m),
8.72 (1H, s), 10.10 (1H, s). Reference Example 6 Methyl 4′-fluorobenzoyl acetate (10.02 g)
And a mixture of N, N-dimethylformamide dimethylacetal (8.63 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was ethanol (150 ml)
Dissolved in. Hydroxylamine hydrochloride (6.75 g) was added to the resulting 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 4,
(Volume ratio) From the eluate, methyl 5- (4-fluorophenyl) isoxazole-4-carboxylate (9.75 g, yield 91%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 92-93 [deg.] 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.
Was slowly added, and 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, the mixture was concentrated to obtain 5- (4-fluorophenyl) -4-isoxazolylmethanol (6.35 g, yield 90%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 41-42 ° C. Reference Example 8 3 ′, 4′-difluoroacetophenone (10.27)
g), sodium hydride (60%, oily, 2.60 g)
A mixture of and diethyl carbonate (150 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (11.80 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (200 ml). Hydroxylamine hydrochloride (9.18 g) was added to the resulting 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 was washed with saturated saline and dried (MgS
After O ₄ ) it 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%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 64-65 ° C.

Reference Example 9 A solution of ethyl 5- (3,4-difluorophenyl) isoxazole-4-carboxylate (6.68 g) in tetrahydrofuran (100 ml) was charged with diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 75 m).
1) was slowly added at 0 ° C., and then 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 was washed with saturated saline and dried (Mg
SO ₄ ) and then concentrated to give 5- (3,4-difluorophenyl) -4-isoxazolylmethanol (6.68 g,
Yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 72-73 [deg.] 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ) it was concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (8.10 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (150 ml). Hydroxylamine hydrochloride (6.33 g) was added to the resulting 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 saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the elution part 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. Melting point 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 solution in tetrahydrofuran, 70 ml). ℃
Was slowly added, and 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, it was concentrated to obtain 5- (4-bromophenyl) -4-isoxazolylmethanol (8.03 g, yield 98%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 104-105 [deg.] 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). Hydroxylamine hydrochloride (6.33 g) was added to the resulting 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 4,
Ethyl 5- (4-nitrophenyl) isoxazole-4-carboxylate (9.78 g, yield 83%) was obtained as colorless crystals from the eluate (volume ratio). 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 tetrahydrofuran solution, 80 ml). ℃
Was slowly added, and 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, the mixture was concentrated to obtain 5- (4-nitrophenyl) -4-isoxazolylmethanol (7.16 g, yield 94%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 170-171 [deg.] 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 hr. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ) it was concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the elution part 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. Melting point 77-78 [deg.] 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 tetrahydrofuran solution, 80 ml) at 0 ° C.
Was slowly added, and 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, the mixture was concentrated to obtain 5- (3-chlorophenyl) -4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 80-81 [deg.] C. Reference Example 16 5-acetyl-1,3-benzodioxole (7.45
g), sodium hydride (60%, oily, 1.80 g)
A mixture of and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (8.30 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (100 ml). Hydroxylamine hydrochloride (6.33 g) was added to the resulting 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
Ethyl 5- (1,3-benzodioxol-5-yl) isoxazole-4-carboxylate (9.49 g, yield 80%) was obtained as colorless crystals from the eluate (volume ratio). Recrystallized from ethyl acetate-hexane. Melting point 73-74
° C.

Reference Example 17 A solution of ethyl 5- (1,3-benzodioxol-5-yl) isoxazole-4-carboxylate (8.56 g) in tetrahydrofuran (70 ml) was charged with diisobutylaluminum hydride (1. 0M tetrahydrofuran solution,
70 ml) was slowly added at 0 ° C., and then 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 was washed with saturated brine, dried (MgSO ₄ ), and concentrated to give 5- (1,3-benzodioxol-5-yl) -4-isoxazolylmethanol (6.97 g, Yield 97%) was obtained 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)
A mixture of and diethyl carbonate (100 ml) was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (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 resulting 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 was washed with saturated saline and dried (MgS
After O ₄ ) it 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%) was obtained 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., and the mixture was stirred at room temperature for 30 min. 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 ) and then concentrated to give 5- (3-chloro-4-fluorophenyl) -4-isoxazolylmethanol (7.
58 g, yield 95%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 106-107 [deg.] 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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). Hydroxylamine hydrochloride (6.98 g) was added to the resulting solution.
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 brine, 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 the ethyl acetate-hexane (1: 9, volume ratio) eluate. Rate 78
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 113-114 [deg.] C.

Reference Example 21 To a solution of ethyl 5- (3,4-dimethoxyphenyl) isoxazole-4-carboxylate (8.40 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 65 m).
1) was slowly added at 0 ° C., and then 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 was washed with saturated saline and dried (Mg
SO ₄ ) and then concentrated to give 5- (3,4-dimethoxyphenyl) -4-isoxazolylmethanol (6.85 g,
Yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 83-84 [deg.] C. Reference Example 22 4'-chloro-3'-fluoroacetophenone (12.5
0 g), sodium hydride (60%, oily, 2.88)
80 g of a mixture of g) and diethyl carbonate (150 ml)
Stir at ℃ for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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)
Dissolved in. 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 was washed with saturated saline and dried (MgS
After O ₄ ) it 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- (4-chloro-3-fluorophenyl) isoxazole-4-carboxylate (1
4.86 g, yield 76%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 76-77 [deg.] C.

Reference Example 23 To 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) was slowly added at 0 ° C., and then 30 minutes at room temperature.
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 brine, dried (MgSO ₄ ), concentrated, and 5- (4-chloro-3-).
Fluorophenyl) -4-isoxazolylmethanol (9.73 g, yield 96%) 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ) it was concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (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 resulting 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 saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
5 from the elution part 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. Melting point 54-55 [deg.] 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 tetrahydrofuran solution, 80 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, the mixture was concentrated to give 5- (4-methoxyphenyl) -4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 57-58 [deg.] C. Reference Example 26 3'-Bromo-4'-fluoroacetophenone (12.4
6 g), sodium hydride (60%, oily, 2.30)
80 g of a mixture of g) and diethyl carbonate (100 ml).
Stir at ℃ for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. A mixture of the residue and N, N-dimethylformamide dimethylacetal (10.29 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was ethanol (150 ml)
Dissolved in. 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 was washed with saturated saline and dried (MgS
After O ₄ ) it 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-bromo-4-fluorophenyl) isoxazole-4-carboxylate (1
(3.55 g, yield 75%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 111-112
° C.

Reference Example 27 5- (3-bromo-4-fluorophenyl) isooxa
Tet of ethyl sol-4-carboxylate (10.01 g)
Lahydrofuran (70 ml) solution was charged with hydrogenated diisobutyrate.
Lualuminum (1.0 M tetrahydrofuran solution, 7
(0 ml) was slowly added at 0 ° C, and then at room temperature for 30 minutes.
Stir it. Pour the reaction mixture into dilute hydrochloric acid and wash with ethyl acetate.
Extracted. The ethyl acetate layer is washed with saturated saline and dried.
(MgSO 4 _Four) And then concentrated to give 5- (3-bromo-4-phenyl).
Luorophenyl) -4-isoxazolylmethanol
(8.26 g, yield 95%) was obtained as colorless crystals. vinegar
Recrystallized from ethyl acetate-hexane. Melting point 134-13
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
Stir for hours. Water was added to the reaction mixture, and the aqueous layer was diluted with dilute hydrochloric acid.
After neutralizing, stir for 30 minutes at room temperature, then
Extracted with ethyl. Wash the ethyl acetate layer with saturated saline.
Clean and dry (MgSO4_Four) And then concentrated. Residue and
N, N-dimethylformamide dimethyl acetal
The mixture of (4.84 g) was refluxed for 1.5 hours. Reaction mixture
Concentrate the mixture and dissolve the residue in ethanol (100 ml).
I understand. Hydroxylamine hydrochloride was added to the resulting solution.
(3.75 g) was added and the mixture was refluxed for 5 hours. The reaction mixture
Concentrate, add dilute hydrochloric acid to the residue, and extract with ethyl acetate.
It was The ethyl acetate layer was washed with saturated saline and dried (MgS
O_Four) And then concentrated. The residue is chromatographed on a silica gel column.
Subject to chromatography, ethyl acetate-hexane (1: 9,
Volume ratio) From the elution part, 5- (3-bromo-4-chlorophene)
Ethyl nyl) isoxazole-4-carboxylate (6.
25 g, yield 70%) was obtained 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 tetrahydrofuran solution, 40).
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. 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 ) and then concentrated to give 5- (3-bromo-4-chlorophenyl) -4-isoxazolylmethanol (5.1
0 g, yield 94%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 4.73 (2H, d, J = 4.8 Hz), 7.59 (1H, d, J
= 8.4 Hz), 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 added,
Methanesulfonyl chloride (9.0 ml) was slowly added at 0 ° C., and then 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 brine, 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
(Volume ratio) 4- (5-phenyl-4-isoxazolyl) butyronitrile (13.47 g, yield 86 from the elution part)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 1.91-2.09 (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, 3.58g) and diethyl carbonate (200ml) was stirred at 80 ° C for 1 hour. Water was added to the reaction mixture, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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).
Hydroxylamine hydrochloride (12.53) was added to the resulting solution.
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 was washed with saturated brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 9, volume ratio). 68
%) As a pale yellow oil. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 4.25 (2H, q, J
= 7.0 Hz), 7.39 (1H, dd, 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., and then the mixture was stirred at room temperature for 30 min. 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 (MgS
After O ₄ ) and then concentrated, 5- (2,4-dichlorophenyl)-
4-isoxazolylmethanol (7.09 g, yield 9
6%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 76-77 [deg.] 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. 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). Hydroxylamine hydrochloride (6.51 g) was added to the resulting solution.
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 brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 9, volume ratio). 79%)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 117-118 [deg.] 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., and then the mixture was stirred at room temperature for 30 min. 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 (MgS
After O ₄ ), it was concentrated to give 5- (3,4-dichlorophenyl)-
4-isoxazolylmethanol (6.97 g, yield 9
5%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 101-102 ° 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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).
Hydroxylamine hydrochloride (9.49) was added to the resulting solution.
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 was washed with saturated brine, 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 obtained from the elution part of 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-
A solution of ethyl 4-carboxylate (10.82 g) in tetrahydrofuran (100 ml) was charged with diisobutylaluminum hydride (1.0 M solution in tetrahydrofuran, 100 m).
1) was slowly added at 0 ° C., and then 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 was washed with saturated saline and dried (Mg
SO ₄ ), then concentrated to 5- (3,5-dichlorophenyl)
-4-isoxazolylmethanol (10.28 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 104-105 [deg.] 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. 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). Hydroxylamine hydrochloride (6.88 g) was added to the resulting solution.
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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted with 5- (4-phenylphenyl) isoxazole-4.
-Ethyl carboxylate (10.98 g, yield 76%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 73-75 [deg.] C. Reference Example 38 5- (4-phenylphenyl) isoxazole-4-
A solution of ethyl carboxylate (10.68 g) in tetrahydrofuran (100 ml) was added with diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 83.7 m).
1) was slowly added at 0 ° C., and then 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 was washed with saturated saline and dried (Mg
SO ₄ ), then concentrated to give 5- (4-phenylphenyl)-
4-isoxazolylmethanol (7.55 g, yield 8
3%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 108-110 [deg.] C.

Reference Example 39 To a solution of ethyl propiolate (7.50 g) in tetrahydrofuran (50 ml) was slowly added a solution of pyrrolidine (6.4 ml) in tetrahydrofuran (5 ml) at 0 ° C., and then the mixture was stirred at 0 ° C. for 30 min. It was A solution of 3,4-dichloro-N-hydroxybenzenecarboximidoyl chloride (11.40 g) in tetrahydrofuran (100 ml) was added to the obtained mixed solution at 0 ° C, and then triethylamine (15 ml) in tetrahydrofuran (10 m) was added.
l) The solution was added slowly at 0 ° C. After stirring overnight at room temperature, 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
(9, volume ratio) From the elution part, ethyl 3- (3,4-dichlorophenyl) isoxazole-4-carboxylate (12.
26 g, yield 84%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 129-130 [deg.] C. Reference Example 40 3- (3,4-dichlorophenyl) isoxazole-
Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) was slowly added to a solution of ethyl 4-carboxylate (7.80 g) in tetrahydrofuran (60 ml) at 0 ° C., and then the mixture was stirred at room temperature for 30 min. 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 (MgS
O ₄ ) and then concentrated to 3- (3,4-dichlorophenyl)
-4-isoxazolylmethanol (6.43 g, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 103-104 [deg.] 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., and the mixture was stirred at 0 ° C. for 30 min. It was A solution of 3-chloro-4-fluoro-N-hydroxybenzenecarboximidoyl chloride (10.20 g) in tetrahydrofuran (100 ml) was added to the obtained mixed solution at 0 ° C., and then triethylamine (15 ml) in tetrahydrofuran (10 ml) was added. ) The solution was added slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted with 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 In a tetrahydrofuran (50 ml) solution of ethyl 3- (3-chloro-4-fluorophenyl) isoxazole-4-carboxylate (9.70 g), diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. 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
MgSO ₄₎ after, and concentrated to give 3- (3-chloro-4-fluorophenyl) -4-isoxazolyl methanol (7.
91 g, yield 97%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 87-88 [deg.] C.

Reference Example 43 To a solution of ethyl propiolate (8.61 g) in tetrahydrofuran (50 ml) was slowly added a solution of pyrrolidine (7.4 ml) in tetrahydrofuran (5 ml) at 0 ° C, and then the mixture was stirred at 0 ° C for 30 minutes. It 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). ) The solution was added slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted with 3- (4-chloro-3).
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 To a solution of ethyl 3- (4-chloro-3-fluorophenyl) isoxazole-4-carboxylate (12.00 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution,
100 ml) was slowly added at 0 ° C., and then 30 minutes at room temperature.
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 brine, dried (MgSO _4), concentrated, 3- (4-chloro-3-
Fluorophenyl) -4-isoxazolylmethanol (9.75 g, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 124-12
5 ° C.

Reference Example 45 To a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml) was slowly added a solution of pyrrolidine (5.2 ml) in tetrahydrofuran (5 ml) at 0 ° C., and then the mixture was stirred at 0 ° C. for 30 min. It was A solution of 3-bromo-4-fluoro-N-hydroxybenzenecarboximidoyl chloride (10.10 g) in tetrahydrofuran (100 ml) was added to the obtained mixed solution at 0 ° C., and then triethylamine (11.5 ml) in tetrahydrofuran. (10 ml) solution was added slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 9, volume ratio). , Yield 71%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 96-97 [deg.] C. Reference Example 46 A solution of ethyl 3- (3-bromo-4-fluorophenyl) isoxazole-4-carboxylate (10.47 g) in tetrahydrofuran (100 ml) was charged with diisobutylaluminum hydride (1.0 M tetrahydrofuran solution,
(75 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO ₄₎ after, and concentrated to give 3- (3-bromo-4-fluorophenyl) -4-isoxazolyl methanol (9.75 g, 96% yield ) 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-
Add a mixture of dimethylformamide (15 ml) at room temperature for 3 times.
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)
Was added and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is diluted hydrochloric acid,
Wash with saturated aqueous sodium hydrogen carbonate, then saturated saline, and dry (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 4,
(Volume ratio) From the elution part, N-methoxy-N-methyl- (3-
Methyl-5-phenyl-4-isoxazolyl) carboxamide (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) carboxamide (7.51
Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) was slowly added to a tetrahydrofuran (150 ml) solution of g) at 0 ° C., and then the mixture was stirred at room temperature for 30 min. Pour the reaction mixture into dilute hydrochloric acid,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
3-Methyl-5 from the elution part of hexane (1: 4, volume ratio)
-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 To a solution of ethyl propiolate (5.01 g) in tetrahydrofuran (50 ml) was slowly added a solution of pyrrolidine (4.3 ml) in tetrahydrofuran (5 ml) at 0 ° C, and the mixture was stirred at 0 ° C for 30 min. It was A solution of 4-phenyl-N-hydroxybenzenecarboximidoyl chloride (9.28 g) in tetrahydrofuran (100 ml) was added to the obtained mixed solution at 0 ° C., and then triethylamine (12.0 ml) in tetrahydrofuran (10 m) was added.
l) The solution was added slowly at 0 ° C. After stirring overnight at room temperature, 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
9, volume ratio) from the elution part to 3- (4-phenylphenyl)
Ethyl isoxazole-4-carboxylate (13.04
g, yield 87%) was obtained as colorless crystals. Ethyl acetate-
Recrystallized from hexane. Melting point 81-82 [deg.] 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., and then the mixture was stirred at room temperature for 30 min. 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 (MgS
After O ₄ ), it was concentrated to give 3- (4-phenylphenyl) -4.
-Isoxazolylmethanol (8.32 g, yield 97)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 138-139 [deg.] C.

Reference Example 51 3- (4-phenylphenyl) -4-isoxazolylmethanol (4.16 g) and thionyl chloride (10.
0 ml) of the mixture 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 brine, 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 To a solution of ethyl propiolate (5.00 g) in tetrahydrofuran (50 ml) was slowly added a solution of pyrrolidine (4.3 ml) in tetrahydrofuran (5 ml) at 0 ° C, and then the mixture was stirred at 0 ° C for 30 min. A solution of 4-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (7.50 g) in tetrahydrofuran (100 ml) was added to the obtained mixture at 0 ° C., and then triethylamine (10.0 ml) in tetrahydrofuran (10 ml). ) The solution was added slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 9, volume ratio). (85%) was obtained 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 To a solution of ethyl 3- (4-trifluoromethylphenyl) isoxazole-4-carboxylate (8.00 g) in tetrahydrofuran (150 ml) was added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60).
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. 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 ) and then concentrated to give 3- (4-trifluoromethylphenyl) -4-isoxazolylmethanol (6.4
6 g, yield 95%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 70-71 ° C. Reference Example 54 A mixture of 3- (4-trifluoromethylphenyl) -4-isoxazolylmethanol (6.00 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,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration and 4-chloromethyl-3- (4-trifluoromethylphenyl) isoxazole (6.16 g,
Yield 95%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 84-85 [deg.] C.

Reference Example 55 Methyl acetoacetate (8.88 g) and 4-chloro-N
To a solution of hydroxybenzenecarboximidoyl chloride (9.65g) in tetrahydrofuran (100ml) was added a solution of triethylamine (15ml) in tetrahydrofuran (10ml) slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil of tetrahydrofuran (100
diisobutylaluminum hydride (1.
After slowly adding 0 M tetrahydrofuran solution (110 ml) 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 was washed with saturated brine, dried (MgSO ₄ ), concentrated, and 3- (4-chlorophenyl) -5-methyl-4-.
Isoxazolylmethanol (7.69 g, yield 68)
%) As colorless crystals. Recrystallized from ethanol. Melting point 94-95 [deg.] 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, saturated aqueous sodium hydrogen carbonate was added to the residue,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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%) was obtained. Recrystallized from diisopropyl ether. Melting point 91-92 [deg.] C.

Reference Example 57 Methyl acetoacetate (8.88 g) and 4-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (11.35 g) in tetrahydrofuran (1
A solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added to the solution (00 ml) at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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., and the mixture was stirred at room temperature for 30 min. 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 (MgS
O ₄₎ after, and concentrated to give 5-methyl-3- (4-trifluoromethylphenyl) -4-isoxazolyl methanol (7.86 g, 60% yield) as colorless crystals. Recrystallized from diisopropyl ether-hexane. Melting point 72-73 [deg.] C. Reference Example 58 5-Methyl-3- (4-trifluoromethylphenyl)
A mixture of -4-isoxazolylmethanol (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 brine, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 4-chloromethyl-5-methyl-3- (4-trifluoromethylphenyl) isoxazole (1.50 g, yield 80%). Recrystallized from diisopropyl ether. Melting point 91-92 [deg.] C.

Reference Example 59 To a solution of ethyl 5- (4-trifluoromethylphenyl) isoxazole-4-carboxylate (7.63 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 59 ml). 0
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 1 hr. 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 (MgSO ₄ ).
After that, concentrate to give 5- (4-trifluoromethylphenyl)
-4-isoxazolylmethanol (6.29 g, yield 97%) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 106-1
07 ° C. Reference Example 60 A mixture of 5- (4-trifluoromethylphenyl) -4-isoxazolylmethanol (5.65 g), tetrahydrofuran (20 ml) and toluene (80 ml) was charged with thionyl chloride (4.15 g) at 0 ° C. It was dripped at 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 brine, 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%) was obtained as colorless prism crystals. 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, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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). 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 brine, 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 obtained from the elution part of 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 To a solution of ethyl 5- (2,4-difluorophenyl) isoxazole-4-carboxylate (3.85 g) in tetrahydrofuran (60 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 33 ml) at 0 ° C. After slowly adding with, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and 5- (2,4-difluorophenyl) -4-isoxazolylmethanol (2.70 g, from the ethyl acetate-hexane (1: 1, volume ratio) eluate. Yield 84%) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. 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 hr. 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 (MgSO ₄ ).
After that, 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 obtained from the elution part of ethyl acetate-hexane (1: 5, volume ratio). 81%) as an oil. NMR (CDCl ₃ ) δ: 4.53 (2H, 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, 2.49g) and diethyl carbonate (80ml) was stirred at 80 ° C for 30 minutes. Water was added to the reaction mixture, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 5, volume ratio) to give 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. The reaction mixture is concentrated,
The residue was dissolved in ethanol (80 ml). Hydroxylamine hydrochloride (8.65 g) was added to the resulting 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the elution part of ethyl acetate-hexane (1: 5, volume ratio) 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. Melting point 74-75 [deg.] 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., and then the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into dilute hydrochloric acid and precipitated 5- (5-chloro-2
-Thienyl) -4-isoxazolylmethanol (7.
(00 g, yield 93%) was collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. Melting point 80-81
° C. Reference Example 66 To a mixture of 5- (5-chloro-2-thienyl) -4-isoxazolylmethanol (6.54 g), tetrahydrofuran (20 ml) and toluene (100 ml), thionyl chloride (5.41 g) was added. The mixture was added dropwise 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 brine, 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 obtained from the elution part of ethyl acetate-hexane (1: 5, volume ratio). A crystal with a rate of 98%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 70-71 ° C.

Reference Example 67 4'-chloro-3'-methylacetophenone (10.0
g), sodium hydride (60%, oily, 2.38 g)
And a mixture of diethyl carbonate (80 ml) at 80 ° C for 9
Stir for 0 minutes. Water was added to the reaction mixture, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio) from the eluate to 3
Ethyl-(4-chloro-3-methylphenyl) -3-oxopropionate was obtained as an oil. A mixture of this oily substance and N, N-dimethylformamide dimethylacetal (10.6 g) was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethanol (80 ml). Hydroxylamine hydrochloride (8.2
4 g) was added and the mixture was refluxed for 2 hours. The reaction mixture is concentrated,
Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 collected from the ethyl acetate-hexane (1: 5, volume ratio) eluate. , Yield 5
9%) crystals were obtained. Recrystallization from hexane gave colorless prism crystals. Melting point 50-51 [deg.] C. Reference Example 68 To a solution of ethyl 5- (4-chloro-3-methylphenyl) isoxazole-4-carboxylate (8.50 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.5 M toluene solution, 47 ml). 0
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 1 hr. 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 (MgSO ₄ ).
After that, concentrate and 5- (4-chloro-3-methylphenyl)
-4-isoxazolylmethanol (6.13 g, yield 86%) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. Melting point 92-93 [deg.] C.

Reference Example 69 5- (4-chloro-3-methylphenyl) -4-isoxazolylmethanol (5.80 g), tetrahydrofuran (20 ml) and toluene (80 ml) were mixed with thionyl chloride (4. 63 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hr. 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 brine, 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,
Yield 87%) was obtained as colorless prism crystals. 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, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio) to give 3-
Ethyl (2,5-dichlorophenyl) -3-oxopropionate was obtained as an oil. This oil and N, N
-Dimethylformamide dimethylacetal (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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 5, volume ratio) 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), 4.25 (2H, q, J = 7
Hz), 7.4-7.6 (3H, m), 8.68 (1H, s).

Reference Example 71 5- (2,5-dichlorophenyl) isoxazole-
Diisobutylaluminum hydride (1.5 M toluene solution, 33 ml) was slowly added to a solution of ethyl 4-carboxylate (6.40 g) in tetrahydrofuran (100 ml) at 0 ° C., and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 collected from the ethyl acetate-hexane (1: 1, volume ratio) eluate. Yield 71%) as colorless crystals. Recrystallization from isopropyl ether-hexane gave colorless prism crystals. Melting point 51-52
° C. Reference Example 72 5- (2,5-Dichlorophenyl) -4-isoxazolylmethanol (3.80 g) in toluene (60 ml)
Thionyl chloride (2.78 g) was added dropwise to the solution 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 brine, 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 obtained from the elution part of 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 (1
H, 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, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio) to give 3- (4
Ethyl -methylthiophenyl) -3-oxopropionate was obtained as an oil. This oil and N, N-dimethylformamide dimethylacetal (21.5 g)
The mixture was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethanol (80 ml). Hydroxylamine hydrochloride (16.7 g) was added to the resulting solution, and 2
Reflux 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the eluate of ethyl acetate-hexane (1: 5, volume ratio) 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
-Diisobutylaluminum hydride (0.95M hexane solution, 92 ml) was slowly added to a solution of ethyl carboxylate (10.0 g) in tetrahydrofuran (100 ml) at 0 ° C, and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give 5- (4-methylthiophenyl)-
4-isoxazolylmethanol (7.50 g, yield 8
9%) was obtained as colorless prism crystals. 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 hr. 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 3, volume ratio) to give 4-
Chloromethyl-5- (4-methylthiophenyl) isoxazole (7.70 g, yield 97%) was obtained as crystals. Recrystallization from diethyl ether-hexane gave colorless prism crystals. Melting point 73-74 [deg.] 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, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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). Hydroxylamine hydrochloride (16.
0 g) was added and the mixture was refluxed for 2 hours. The reaction mixture is concentrated,
Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted portion with 5- (4-methylphenyl) isoxazole-4.
-Either colorless crystals of ethyl carboxylate (17.2 g, yield 65%) were obtained. Recrystallization from hexane gave colorless prism crystals. Melting point 45-46 [deg.] C.

Reference Example 77 To a solution of ethyl 5- (4-methylphenyl) isoxazole-4-carboxylate (7.70 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M toluene solution, 83 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 brine, dried (MgSO _4), and concentrated. The residue was dissolved in toluene (100 ml), thionyl chloride (5.94 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 brine, 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 the elution part of 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
Stir for 0 minutes. Water was added to the reaction mixture, the mixture was neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a mixture of an oily substance obtained from an ethyl acetate-hexane (1: 9, volume ratio) eluate and N, N-dimethylformamide dimethylacetal (5.60 g) for 1 hour. Refluxed. The reaction mixture was concentrated and the residue was washed with ethanol (80 m
It was dissolved in 1). Hydroxylamine hydrochloride (4.35 g) was added to the resulting 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
9, volume ratio) From the elution part, 5- (4,5-dichloro-2-
Ethyl thienyl) isoxazole-4-carboxylate (3.42 g, yield 37%) was obtained as colorless crystals. Recrystallization from ethyl acetate gave pale yellow prism crystals. Melting point 12
0-121 ° C.

Reference Example 79 A solution of ethyl 5- (4,5-dichloro-2-thienyl) isoxazole-4-carboxylate (3.30 g) in tetrahydrofuran (60 ml) was charged with diisobutylaluminum hydride (0.95M hexane solution). , 29.7 ml)
Was slowly added at 0 ° C., and then 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 and dried (MgS
After O ₄ ) it was concentrated. The residue was dissolved in toluene (60 ml), 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl hexane-hexane (1: 9, volume ratio) eluate gave 4-chloromethyl-5- (4,5-dichloro-).
2-Thienyl) isoxazole (2.41 g, yield 7)
9%) was obtained as crystals. Recrystallization from hexane gave colorless prism crystals. 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 with heating under reflux for 3 hours. 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-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 to diisopropyl 4-aminobenzylphosphonate (17.2 g, yield 98).
%) As a yellow oil. NMR (CDCl ₃ ) δ: 1.17 (6H, d, J = 7Hz), 1.27 (6H, d,
J = 7Hz), 2.92 (2H, brs), 3.25 (2H, d, J = 22Hz),
4.55-4.65 (2 H, m), 6.64 (2 H, d, J = 8 Hz), 7.09 (2
H, dd, J = 3 / 9Hz). The following compounds were synthesized as in Reference Example 80.

Reference Example 81 Dibutyl 4-aminobenzylphosphonate yield 98% (yellow oily matter) NMR (CDCl ₃ ) δ: 0.90 (6H, t, J = 7Hz), 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 yield 97% (yellow oily matter) NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7Hz), 2.16 (3H, s),
3.03 (2H, d, J = 21Hz), 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 diethylphosphonoethyl acetate (11.
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 hr. 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.
Crystals of -ethoxycarbonylethenyl] nitrobenzene were obtained (15.7 g, yield 83%). Dichloromethane-
Recrystallization from isopropyl ether gave colorless prism crystals (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 the ethyl acetate-hexane (2: 1, v / v) eluate. Crystals of -ethoxycarbonylethenyl] aniline (2.40 g, 52% yield) were obtained. Recrystallization from acetone-isopropyl ether gave pale yellow needle crystals (1.75 g). Melting point 79-80 ° C Elemental analysis: Theoretical value (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. to 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 brine, dried (MgSO _4), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and diethyl malonate (6.
92 g), sodium hydride (60%, oily, 1.72)
g) and tetrahydrofuran (50 ml) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [5- (4-trifluoromethoxyphenyl) -4-isoxazolyl] propionic acid (3.7
7 g, yield 58%) was obtained. 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[5- (4-trifluoromethoxyphenyl) -4-
Methyl isoxazolyl] propionate (2.80 g,
Yield 81%) was obtained 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
hydrogenation to a solution of g) in tetrahydrofuran (25 ml).
Diisobutylaluminum (1.0M hexane solution, 1
3.2 ml) was slowly added at 0 ° C., and then at room temperature for 1 hour.
Stir it. The reaction mixture was poured into dilute hydrochloric acid, ethyl acetate
It was extracted with. The ethyl acetate layer is washed with saturated saline and dried.
(MgSO 4 _Four) And then concentrated. Silica gel color residue
Chromatography, ethyl acetate-hexane
(2: 1, volume ratio) 3- [5- (4-trif
Luoromethoxyphenyl) -4-isoxazolyl] pre
Lopan-1-ol (1.36 g, yield 92%) is colorless
Obtained as crystals. Recrystallized from ethyl acetate-hexane
It was Melting point 50-51 [deg.] C. Example 4 3- [5- (4-bromophenyl) -4-isoxazo
Ryl] propan-1-ol (1.10 g), cyanide
Copper (1.41g), Tris (dibenzylideneacetone)
Dipalladium (130 mg), 1,1'-bis (dife
Nylphosphino) ferrocene (314 mg), cyanide
Tetraethylammonium (553 mg) and 1,4
-Reflux a mixture of dioxane (20 ml) for 3.5 hours
It was Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. vinegar
The ethyl acid layer was washed with saturated saline and dried (MgSO4)._Four)
After that, it was concentrated. Silica gel column chromatograph
Then, add ethyl acetate-hexane (1: 3, volume
Ratio) From the elution part, 3- [5- (4-cyanophenyl) -4
-Isoxazolyl] propan-1-ol (418m
g, yield 52%) was obtained as pale yellow crystals. Ethyl acetate
Recrystallized from hexane. Melting point 82-83 [deg.] C.

Example 5 To a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml) was slowly added a solution of pyrrolidine (5.2 ml) in tetrahydrofuran (5 ml) at 0 ° C, and then the mixture was stirred at 0 ° C for 30 minutes. It was A solution of 4-chloro-N-hydroxybenzenecarboximidoyl chloride (7.60 g) in tetrahydrofuran (100 ml) was added to the obtained mixed solution at 0 ° C, and then triethylamine (11.5 ml) in tetrahydrofuran (10 ml).
The solution was added slowly at 0 ° C. After stirring overnight at room temperature, 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
(Volume ratio) A colorless oily substance 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., and then the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ) and concentrated to give a colorless oil. Thionyl chloride (4.50 ml) was added dropwise to a toluene (100 ml) solution of the obtained colorless oil at 0 ° C., and then the mixture was stirred at room temperature for 3 hours.
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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
Dissolve the residue in tetrahydrofuran (100 ml),
Add to a mixture of diethyl malonate (12.81 g), sodium hydride (60%, oily, 3.20 g) and tetrahydrofuran (50 ml) at 0 ° C., then stir at 0 ° C. for 1 hour, then at room temperature overnight. It was The reaction mixture was acidified with diluted hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). The 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. Melting point 149-150 [deg.] C. Example 6 5- (3-Bromo-4-chlorophenyl) -4-isoxazolylmethanol (5.09 g) in toluene (10
0 ml) solution at 0 ° C. to thionyl chloride (1.93 ml)
After dripping, 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 ) it was concentrated. The residue was dissolved in tetrahydrofuran (50 ml) and diethyl malonate (5.64) was added.
g), sodium hydride (60%, oily, 1.41 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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%) was obtained. 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). Hydroxylamine hydrochloride (9.18 g) was added to the resulting solution.
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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a yellow oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). To a solution of the obtained yellow oily substance in tetrahydrofuran (100 ml) was added 0 parts of diisobutylaluminum hydride (1.0 M hexane solution, 100 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, it was concentrated. Thionyl chloride (5.0 ml) was added dropwise to a toluene (100 ml) solution of the residue 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 brine, 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., then 0
Stir at 1 ° 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 3,
A colorless oily substance was obtained from the elution part (volume ratio). The resulting colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of l) was refluxed for 5 hours. The reaction mixture is concentrated,
Water was added to the residue. The colorless crystals obtained were collected by filtration, and 3-
(5-Phenyl-4-isoxazolyl) propionic acid (9.14 g, yield 64%) was obtained. Recrystallized from isopropyl ether. Melting point 90-91 [deg.] 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, the aqueous layer was neutralized with diluted hydrochloric acid, the mixture was stirred at room temperature for 30 min, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ) it was concentrated. Residue and N, N-dimethylformamide dimethyl acetal (12.18 g)
The mixture was refluxed for 1.5 hours. The reaction mixture is concentrated,
The residue was dissolved in ethanol (200 ml). 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
A yellow oily substance was obtained from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). Diisobutylaluminum hydride (1.0 M hexane solution, 100 ml) was slowly added to a tetrahydrofuran (100 ml) solution of the obtained yellow oily substance at 0 ° C., and then 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 was washed with saturated brine, dried (MgSO ₄ ),
Concentrated. To a solution of the residue in toluene (100 ml),
Thionyl chloride (2.7 ml) was added dropwise at ° C, and the mixture was stirred at room temperature for 3 hr. 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 brine, 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 at 0 ° C. In 1
Stir for hours followed by 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 and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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, yield 46%) was obtained. Recrystallized from isopropyl ether. Melting point 155-154 [deg.] C.

Example 9 3- [5- (3-Bromo-4-chlorophenyl) -4-
Methyl isoxazolyl] propionate (1.00 g)
In tetrahydrofuran (30 ml) of diisobutylaluminum hydride (1.0 M hexane solution, 6.5
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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 to 76 ° C. Example 10 Sodium hydride (60%, oily, 1.07 g) was gradually added to a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml) 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 brine, dried (MgSO ₄ ),
Concentrated. 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 colorless crystals obtained 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, yield 79%) was obtained. Melting point 171-172 [deg.] C.

Example 11 5- (4-fluorophenyl) -4-isoxazolyl
Methanol (5.84g) in toluene (50ml) solution
Thionyl chloride (3 ml) was added dropwise at 0 ° C to room temperature.
Stir for 3 hours. The reaction mixture is concentrated and saturated with residue.
Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. Ethyl acetate layer
Washed with saturated saline and dried (MgSO4 _Four), Then concentrate
It was Dissolve the residue in tetrahydrofuran (100 ml)
And diethyl malonate (6.92g), hydrogenated sodium
(60%, oily, 1.70 g) and tetrahydrof
Add to a mixture of orchids (50 ml) at 0 ° C, then add 1 at 0 ° C.
Stir for hours followed by room temperature overnight. Dilute the reaction mixture
After acidifying with hydrochloric acid, it was extracted with ethyl acetate. Acetic acid
The ethyl layer was washed with saturated saline and dried (MgSO4)._Four)
After that, it was concentrated. Silica gel column chromatograph
Then, add ethyl acetate-hexane (1: 3, volume
A colorless oily substance was obtained from the elution part. Colorless oil obtained
Of 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 water. The obtained colorless crystals were collected by filtration, and 3- [5-
(4-Fluorophenyl) -4-isoxazolyl] p
Ropionic acid (4.53 g, yield 78%) was obtained. Aesop
Recrystallized from ropyl ether. Melting point 126-127
° C. Example 12 Tetrahydrofuran of diethyl malonate (11.0 g)
(60 ml) solution, sodium hydride (60%, oil
, 2.50 g) was added slowly at 0 ° C. Oyster for 10 minutes
After mixing, 4-chloromethyl-5- (4-methylphenyl)
) Tetrahydrofuran of isoxazole (6.48 g)
Orchid (80 ml) solution was added dropwise at 0 ° C, and then at room temperature for 15 hours.
Stir it. After pouring the reaction mixture into 2N hydrochloric acid, acetic acid was added.
Extracted with ethyl. After concentrating the ethyl acetate layer, the residue was washed with 6
Normal hydrochloric acid (80 ml) and acetic acid (120 ml) mixed
It was dissolved in the product and heated under reflux for 8 hours. Concentrate the reaction mixture
Then, water was added to the residue. The obtained colorless crystals were 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
%) Was obtained. Melting point 121-122 [deg.] C.

Example 13 Thionyl chloride (3.3 ml) was added dropwise to a solution of 5- (4-methoxyphenyl) -4-isoxazolylmethanol (6.09 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 and dried (MgSO ₄ ).
After that, it was concentrated. Tetrahydrofuran (100 m
l) and dissolved in diethyl malonate (9.51 g), sodium hydride (60%, oily, 2.32 g) and tetrahydrofuran (50 ml) at 0 ° C., then at 0 ° C. for 1 h, then And stirred 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 and dried (M
After gSO ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
A colorless oily substance was obtained from the elution part. The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50
The mixture of (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,
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 ° 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [4- (diethylphosphonomethyl) phenyl] -3- [5- (4-chlorophenyl). -4-Isoxazolyl] propionamide (0.61 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 138-139 [deg.] C.

Example 15 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionic acid (6.57 g), concentrated sulfuric acid (0.5 m)
A mixture of l) 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 brine, 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- [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 To a solution of methyl 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionate (6.00 g) in tetrahydrofuran (100 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 50 ml) at 0 ° C.
After slowly adding with, 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 brine, 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 collected from the elution part of ethyl acetate-hexane (2: 1, volume ratio). , Yield 91%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 58-59 [deg.] 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [4- (diethylphosphonomethyl) phenyl] -3- [3- (4-chlorophenyl). -4-Isoxazolyl] propionamide (1.14 g, yield 91%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 88-90 [deg.] C. Example 18 3- [3- (4-Chlorophenyl) -4-isoxazolyl] propionic acid (1.28 g), triethylamine (1.1 ml) and tetrahydrofuran (100 m).
1) to a mixture of ethyl chlorocarbonate (0.6 m
l) was added, and the mixture was stirred at -20 ° C for 1 hr. Aqueous ammonia (15 ml) was added to the obtained mixed liquid, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine, dried (MgSO ₄ ), and concentrated to give 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionamide (0. 91 g, yield 71
%) As colorless crystals. Recrystallized from acetone-hexane. Melting point 158-159 [deg.] C.

Example 19 3- [3- (4-chlorophenyl) -4-isoxazolyl] propionic acid (4.05 g), concentrated sulfuric acid (0.1 m)
A mixture of l) 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 brine, 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- [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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and N- [3- (trifluoromethyl) benzyl] -3- [3- (4-chlorophenyl)-was extracted from an ethyl acetate-hexane (1: 1, volume ratio) eluate. 4-isoxazolyl] propionamide (1.27 g, yield 87
%) As colorless crystals. Recrystallized from isopropyl ether-hexane. Melting point 80-81 [deg.] 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 overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then,
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 1, volume ratio) eluate to N
-[4- (Diethylphosphonomethyl) phenyl] -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 mixed liquid, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine, dried (MgSO ₄ ), 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) -3
After adding ethyl chlorocarbonate (0.5 ml) at 0 ° C.,
Stir at 20 ° C. for 1 hour. An ethylamine aqueous solution (10 ml) was added to the obtained mixed liquid, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated to give N-ethyl-3- (5-phenyl-4-isoxazolyl) propionamide (0. 93 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 75-76 [deg.] C. Example 24 Ethyl (2E) -3- (5-phenyl-4-isoxazolyl) propenoate (4.89 g), 2N hydrochloric acid (5
A mixture of 0 ml) 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 (2E) -3- (5-phenyl-
4-isoxazolyl) propenoic acid (4.02 g, yield 93%) was obtained. Recrystallized from acetone-hexane.
Melting point 197-199 [deg.] C.

Example 25 (2E) -3- (5-phenyl-4-isoxazolyl) propenoic acid (0.97 g), triethylamine (1
ml) and tetrahydrofuran (60 ml) were added with ethyl chlorocarbonate (0.5 ml) at -30 ° C, and then the mixture was stirred at -20 ° C for 1 hr. In the obtained mixed liquid,
Aqueous ammonia (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine, dried (MgSO ₄ ), and concentrated to give (2E)-
3- (5-Phenyl-4-isoxazolyl) acrylamide (0.86 g, yield 89%) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 194-
196 ° C. Example 26 Diethyl 4-aminobenzylphosphonate (0.83
g), (2E) -3- (5-phenyl-4-isoxazolyl) propenoic acid (0.69 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (0.5
4 g), 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and (2E) -N- (4-diethylphosphonomethylphenyl) -3- (5-phenyl-4) was extracted from an ethyl acetate-hexane (1: 1, volume ratio) eluate. -Isoxazolyl) acrylamide (0.86 g, yield 61%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 173-174 [deg.] C.

Example 27 (2E) -3- (5-phenyl-4-isoxazolyl)
Propenoic acid (0.76 g), triethylamine (0.8
ml) and tetrahydrofuran (50 ml) mixture
Ethyl chlorocarbonate (0.4 ml) was added to the mixture at -30 ° C.
Then, the mixture was stirred at -20 ° C for 1 hour. In the obtained mixed liquid,
Aqueous ethylamine solution (1 ml) was added for 1 hour at room temperature.
Mixed The reaction mixture was poured into water and extracted with ethyl acetate.
It was The ethyl acetate layer was diluted with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated.
Washed with Japanese salt water and dried (MgSO _Four) And then concentrate to (2
E) -N-Ethyl-3- (5-phenyl-4-isooxa
Zolyl) acrylamide (0.78 g, 91% yield)
Obtained as colorless crystals. Recrystallized from acetone-hexane
It was Melting point 156-157 [deg.] C. Example 28 3- (3-methyl-5-phenyl-4-isoxazoli
Le) propionic acid (0.95 g), triethylamine
(1.0 ml) and tetrahydrofuran (50 ml)
Ethyl chlorocarbonate (0.5 ml) at -30 ° C.
After adding, the mixture was stirred at -20 ° C for 1 hour. The resulting mixture
Ammonia water (5 ml) was added to the mixture, and the mixture was kept at room temperature for 1 hour.
Stir it. Pour the reaction mixture into water and extract with ethyl acetate.
did. The ethyl acetate layer was diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then,
Wash with saturated saline and dry (MgSO 4 _Four) And then concentrate to 3
-(3-Methyl-5-phenyl-4-isoxazoli
No) Propionamide (0.86 g, 91% yield)
Obtained as colored crystals. Recrystallized from ethyl acetate-hexane
It 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),
Hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl)
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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to give N- [4
-(Methoxycarbonyl) phenyl] -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
~ 141 ° 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 1- (diphenylmethyl) -4- [3- (5-phenyl-4-isoxazolyl) propanoyl] piperazine was extracted from the elution part of ethyl acetate-hexane (1: 1, volume ratio). (1.35 g, yield 93%) was obtained 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. , 2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.70 g) and N, N-dimethylformamide (15 ml) were added to a mixture. Stir overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to give N- [4- (4-chlorophenyl) -2.
-Thiazolyl] -3- (5-phenyl-4-isoxazolyl) propionamide (0.58 g, yield 43%)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 172-173 [deg.] C. Example 32 Methyl 4-aminobenzoate (0.46 g), 3- (5-
Phenyl-4-isoxazolyl) propionic acid (0.
60 g), 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with N- [4- (methoxycarbonyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propion. Amide (0.86 g, yield 89
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 111-112 [deg.] 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. , 2,3-benzotriazole hydrate (0.78 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.97 g) and N, N-dimethylformamide (20 ml) as a mixture. Stir overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- (5-methyl-4-phenyl-2-).
Thiazolyl) -3- (5-phenyl-4-isoxazolyl) propionamide (1.74 g, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 150-151 [deg.] 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 (0.91g) and N, N-dimethylformamide (15ml) 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- (2-quinolyl).
-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
7 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), hydrochloric acid 1-ethyl-
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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with N- [4- (carbamoyl) phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide. (0.95 g, yield 71%) was obtained as colorless crystals. Recrystallized from tetrahydrofuran-hexane. Melting point 250-251 ° C. Example 36 3- (2-Aminoethyl) indole hydrochloride (0.4
6 g), triethylamine (0.6 ml) and N, N
A mixture of dimethylformamide (20 ml) was stirred at room temperature for 1 hour. The resulting mixture was added with 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 overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and eluate from ethyl acetate-hexane (1: 1, volume ratio) eluted with N- [2- (3-indolyl) ethyl] -3- (5-phenyl-4-isoxazolyl). Propionamide (0.63 g, yield 91
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.32-2.44 (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, br s), 8.17 (1H, s).

Example 37 Diethyl 4-aminobenzylphosphonate (1.20
g), 5-phenyl-4-isoxazolylacetic acid (0.
84 g), 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 overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [4- (diethylphosphonomethyl) phenyl] -2- (5-phenyl-4-isoxazolyl). ) Acetamide (1.58 g, yield 89)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 132-133 [deg.] 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.
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) at room temperature overnight. Stir it. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with N- [4-
(4-Chlorophenyl) -2-thiazolyl] -2- [5
-Phenyl-4-isoxazolyl] acetamide (0.92 g, yield 79%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 210-21
1 ° C.

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
8 g), 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [4- (ethoxycarbonylmethyl) phenyl] -3.
-[5- (4-Chlorophenyl) -4-isoxazolyl] propionamide (0.56 g, yield 93%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 117-118 [deg.] 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 (0.35g), hydrochloric acid 1
A mixture of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.45g) and N, N-dimethylformamide (15ml) 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
Colorless crystals of N- (3-pyridinyl) -3- [5- (4-chlorophenyl) -4-isoxazolyl] propionamide (0.60 g, 96% yield) were obtained from the eluate of hexane (1: 1, volume ratio). Got as. Recrystallized from acetone-hexane. Melting point 197-198 [deg.] 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), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g), hydrochloric acid 1-ethyl-3
A mixture of-(3-dimethylaminopropyl) carbodiimide (0.54g) and N, N-dimethylformamide (15ml) 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and N- [6- (2-methyl-1H-imidazol-1-yl) -3-pyridinyl)-was obtained from the elution part of ethyl acetate-hexane (1: 1, volume ratio). 3- [5- (4-chlorophenyl) -4-isoxazolyl] propionamide (0.59 g, 63% yield)
%) As colorless crystals. Recrystallized from acetone-hexane. Melting point 193-194 [deg.] 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 overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [1- (3-methoxyphenyl) ethyl] -3- [5- (4-chlorophenyl). -4-isoxazolyl] propionamide (0.61 g, yield 8
8%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N-[(5-methyl-2-pyrazinyl).
Methyl] -3- [5- (4-chlorophenyl) -4-isoxazolyl] propionamide (0.58 g, yield 90%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 124-125 [deg.] 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 (0.75g) and N, N-dimethylformamide (20ml) was stirred overnight at room temperature.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
From the elution part of hexane (1: 1, volume ratio), N- [4- (1
H-imidazol-1-yl) phenyl] -3- (5-
Phenyl-4-isoxazolyl) propionamide (0.95 g, yield 83%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 176-17
7 ° C.

Example 45 6-Aminoquinoline (0.38 g), 3- (5-phenyl-4-isoxazolyl) propionic acid (0.56)
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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to give N- (6-quinolyl).
-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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine,
After being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and N- (2-pyrazinyl) -3- (5-phenyl-4-isoxazolyl) propionamide (0. 46 g, yield 58%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 163-164 [deg.] C.

Example 47 4- (4-morpholinyl) aniline (0.90 g), 3
-(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 (1.15g) and N, N-dimethylformamide (20ml) 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
From the elution part of hexane (1: 1, volume ratio), N- [4- (4
-Morpholinyl) phenyl] -3- (5-phenyl-4)
-Isoxazolyl) propionamide (1.23 g,
Yield 66%) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 197-198 [deg.] C. Example 48 5-amino-2- (1-morpholino) pyridine (0.8
5 g), 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 overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then,
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 1, volume ratio) eluate to N
-[6- (4-morpholinyl) -3-pyridinyl] -3
-(5-Phenyl-4-isoxazolyl) propionamide (0.86 g, yield 49%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 146
~ 147 ° 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) from N- [4- (1H
-Imidazol-1-yl) phenyl] -4- (5-phenyl-4-isoxazolyl) butanamide (1.6
8 g, yield 86%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 132-133 [deg.] C. Example 50 A mixture of 3- (5-phenyl-4-isoxazolyl) propionic acid (18.62g), concentrated sulfuric acid (0.2ml) and methanol (100ml) 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (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), 7.42-7.56 (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., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 obtained from the elution part of 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 (12.83g) and concentrated hydrochloric acid (100ml) 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
(1, volume ratio) 4- (5-phenyl-4-isoxazolyl) butanoic acid (13.03 g, yield 93%) from the elution part
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 67-68 [deg.] 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),
Hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl)
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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to give N- [4
-(Diethylphosphonomethyl) phenyl] -4- (5-phenyl-4-isoxazolyl) butanamide (2.5
6 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 128-129 [deg.] C. Example 54 4- [2- (3-Ethyl-4H-1,2,4-triazol-4-yl) ethoxy] aniline (1.12g),
3- (5-phenyl-4-isoxazolyl) propionic acid (1.04 g), 1-hydroxy-1H-1,2,
A mixture of 3-benzotriazole hydrate (0.89 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.11 g) and N, N-dimethylformamide (20 ml) at room temperature overnight. Stir it. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with N- [4-
[2- (3-Ethyl-4H-1,2,4-triazol-4-yl) ethoxy] phenyl] -3- (5-phenyl-4-isoxazolyl) propionamide (1.5
8 g, yield 76%) was obtained as colorless crystals. Acetone-
Recrystallized from hexane. Melting point 167-168 [deg.] C.

Example 55 4- [2- (3-Ethyl-4H-1,2,4-triazol-4-yl) ethoxy] aniline (0.51 g),
4- (5-phenyl-4-isoxazolyl) butanoic acid (0.51 g), 1-hydroxy-1H-1,2,3-
Benzotriazole hydrate (0.40 g), hydrochloric acid 1-
A mixture of ethyl-3- (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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) from N- [4- [2-
(3-Ethyl-4H-1,2,4-triazole-4-
Iyl) ethoxy] phenyl] -4- (5-phenyl-4)
-Isoxazolyl) butanamide (0.83 g, yield 84%) was obtained as colorless crystals. Recrystallized from acetone-hexane. Melting point 125-126 [deg.] C. Example 56 5-Phenylisoxazole-4-carbaldehyde (7.18 g), ethyl diethylphosphonoacetate (9.3
5 g) and N, N-dimethylformamide (150 m
Sodium hydride (60%, oily, 1.65 g) was added to the mixture of l) at 0 ° C., and the mixture was stirred at room temperature for 3 hr. 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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) eluted from (2E)))-3- (5-phenyl-4).
Ethyl -isoxazolyl) propenoate (8.88 g,
Yield 88%) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.33 (3H, 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 A solution of 4-chloromethyl-3- (1,1`-biphenyl-4-yl) isoxazole (3.20 g) in tetrahydrofuran (100 ml) was added to diethyl malonate (5.7).
0 g), sodium hydride (60%, oily, 1.40)
g) and tetrahydrofuran (50 ml) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, 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 brine, dried (MgSO <sub>4),</sub> and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [3- (1,1`-biphenyl-4-yl) -4-isoxazolyl] propionic acid (2.89).
g, yield 83%) was obtained. Recrystallized from acetone-hexane. Melting point 169-170 [deg.] C. Example 58 To a solution of methyl 3- [5- (4-fluorophenyl) -4-isoxazolyl] propionate (3.21 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml). ℃
After slowly adding with, 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 brine, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with 3- [5- (4-fluorophenyl) -4-isoxazolyl] propan-1-ol (2. 48g,
Yield 87%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.38 (1H, br s), 1.82-2.02 (2H, m), 2.
70-2.84 (2H, 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. The ethyl acetate layer was concentrated, 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 hrs.
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)-.
A colorless prism crystal of 4-isoxazolyl] propionic acid (2.10 g, yield 87%) was obtained. Melting point 125-12
6 ° C. Example 60 3- [5- (4-trifluoromethylphenyl) -4-
Concentrated sulfuric acid (1 ml) was added to a solution of isoxazolyl] propionic acid (2.20 g) in methanol (50 ml), and 1
Heated to reflux for hours. The reaction mixture was concentrated, ice water was poured into the residue, and the precipitated crystal of methyl 3- [5- (4-trifluoromethylphenyl) -4-isoxazolyl] propionate (1.70 g, yield 74%) was filtered. I took it. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 68-69 [deg.] C.

Example 61 To a solution of 3- [5- (2,4-difluorophenyl) -4-isoxazolyl] propionic acid (1.25 g) in methanol (40 ml) was added concentrated sulfuric acid (1 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 elution part of ethyl acetate-hexane (1: 1, volume ratio) were recrystallized from ethyl acetate-hexane to give 3- [5- (2,4 -Difluorophenyl) -4-isoxazolyl] colorless prism crystals of methyl propionate (1.15 g, yield 87)
%) Was obtained. Melting point 40-41 [deg.] C. Example 62 3- [5- (4-trifluoromethylphenyl) -4-
Methyl isoxazolyl] propionate (1.40 g)
In tetrahydrofuran (80 ml) of diisobutylaluminum hydride (1.0 M hexane solution, 10.
(3 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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%) was obtained as colorless needle crystals. 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
l) was slowly added at 0 ° C., and then the mixture was stirred at room temperature for 1 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1,
3- [5- (2,4-difluorophenyl) -4-isoxazolyl] propan-1-ol (640 mg, yield 68%) was obtained as a colorless oily substance from the elution part (volume ratio). NMR (CDCl ₃ ) δ: 1.29 (1H, br s), 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), sodium hydride (60%, oily, 2.29 g) was gradually added 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, and the mixture was stirred at room temperature for 1 hour.
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 added with 6N hydrochloric acid (80 ml) and acetic acid (1
20 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 to give 3-
Colorless prism crystals of [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionic acid (4.95 g,
Yield 67%) was obtained. Melting point 138-139 [deg.] C.

Example 65 To a solution of 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propionic acid (2.20 g) in methanol (50 ml) was added concentrated sulfuric acid (1 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 then 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 the elution part of ethyl acetate-hexane (1: 3, volume ratio). (3.80 g, yield 86%) was obtained. Recrystallization from diethyl ether-isopropyl ether gave colorless prism crystals. Melting point 34-35 [deg.] 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., and the mixture was stirred at room temperature for 1 hr.
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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with 3- [5- (5-chloro-2-thienyl) -4-isoxazolyl] propan-1-ol. (2.02 g, yield 73%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.41 (1H, br t, 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., and then the mixture was stirred at room temperature for 1 hr.
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 (MgSO ₄ ).
After that, 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 obtained from the elution part of ethyl acetate-hexane (2: 1, volume ratio). 0.67 g, yield 92%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.32 (1H, br t), 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 To a solution of methyl 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propionate (1.63 g) in tetrahydrofuran (25 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 13 ml). After slowly adding at 0 ° C, the mixture was stirred at room temperature for 1 hr.
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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol (1 0.53 g, yield 97%) was obtained 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 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
It was dissolved in diethyl malonate (5.89 ml).
g), sodium hydride (60%, oily, 1.45 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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%) was obtained. Recrystallized from acetone-hexane. Melting point 106-107 [deg.] 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 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
It was dissolved in 100 ml of diethyl malonate (8.53
g), sodium hydride (60%, oily, 2.01 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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) in a mixture of 4
Reflux 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 brine, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 4, volume ratio) from 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 4, volume ratio) from 3- [5
Methyl-(3,4-dichlorophenyl) -4-isoxazolyl] propionate (3.26 g, yield 97%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 74-75 [deg.] 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., and the mixture was stirred at room temperature for 3 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
It was dissolved in diethyl malonate (7.96 ml).
g), sodium hydride (60%, oily, 1.95 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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. Melting point 143-144 [deg.] 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 brine, 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 (1H, t, J = 1.8 Hz), 7.60 (1H, d, J =
1.8 Hz), 8.24 (1H, s). Example 76 To a solution of methyl 3- [5- (3,5-dichlorophenyl) -4-isoxazolyl] propionate (2.25 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml). After slowly adding at 0 ° C, the mixture was stirred at room temperature for 1 hr.
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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3- [5- (3,5-dichlorophenyl) -4-isoxazolyl] propan-1-ol (1 .65 g, yield 81%) was obtained 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,
d, J = 1.8 Hz), 8.24 (1H, s).

Example 77 5- (3,4-difluorophenyl) -4-isoxazolylmethanol (4.80 g) in toluene (100 m)
l) Thionyl chloride (2.5 ml) was added dropwise to the solution at 0 ° C., and the mixture was stirred at room temperature for 3 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
(00 ml) and dissolved in diethyl malonate (7.26
g), sodium hydride (60%, oily, 1.79 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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, 87% yield) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 102-103 [deg.] 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 brine, 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). , 20 ml)
Was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1,
(Volume ratio) From the elution 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 (1H,
m), 7.44-7.66 (2H, m), 8.22 (1H, s). Example 80 To a solution of 5- (4-nitrophenyl) -4-isoxazolylmethanol (6.56 g) in toluene (100 ml) was added dropwise thionyl chloride (3.3 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 brine, dried (MgSO _4), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added to a mixture of diethyl malonate (9.56 g), sodium hydride (60%, oily, 2.35 g) and tetrahydrofuran (50 ml) at 0 ° C. and then 0 ° C.
Stirred for 1 hour at room temperature, then 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 3,
A colorless oily substance was obtained from the elution part (volume ratio). The resulting colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of l) was refluxed for 5 hours. The reaction mixture is concentrated,
Water was added to the residue. The colorless crystals obtained were collected by filtration, and 3-
[5- (4-Nitrophenyl) -4-isoxazolyl] propionic acid (6.19 g, yield 79%) 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 l) 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 brine, 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- [5- (4-
Methyl nitrophenyl-4-isoxazolyl] propionate (5.45 g, yield 98%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 11
8 to 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 at 0 ° C, the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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. 1 was obtained from the elution part of ethyl acetate-hexane (2: 1, volume ratio). 36 g, yield 95%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 132-133 [deg.] C.

Example 83 5- (4-bromophenyl) -4-isoxazolylme
A solution of tonol (7.55 g) in toluene (50 ml)
Thionyl chloride (3.3 ml) was added dropwise thereto at 0 ° C.,
Stir at room temperature for 3 hours. The reaction mixture is concentrated and the residue
Saturated aqueous sodium hydrogen carbonate was added to and extracted with ethyl acetate. Ethyl acetate
The layer is washed with saturated saline and dried (MgSO 4_Four) After that,
Contracted. The residue is taken up in tetrahydrofuran (100 ml)
Dissolve, diethyl malonate (9.58g), hydrogenated sodium
Lithium (60%, oily, 2.36 g) and tetrahydr
Add to a mixture of lofran (50 ml) at 0 ° C, then add 0 ° C
Stirred for 1 hour at room temperature, 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 then concentrated. The residue is chromatographed on a silica gel column.
Subject to chromatography, ethyl acetate-hexane (1: 3,
A colorless oily substance was obtained from the elution part (volume ratio). Colorless obtained
Oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of l) was refluxed for 5 hours. The reaction mixture is concentrated,
Water was added to the residue. The colorless crystals obtained were collected by filtration, and 3-
[5- (4-bromophenyl) -4-isoxazoli
Lu] propionic acid (6.18 g, yield 70%) was obtained.
Recrystallized from ethyl acetate-hexane. Melting point 164-1
65 ° C. Example 84 3- [5- (4-bromophenyl) -4-isoxazo
Lil] propionic acid (5.00 g), concentrated sulfuric acid (0.1 m
1) and methanol (100 ml) for 4 hours
Refluxed. The reaction mixture is concentrated, water is added to the residue and vinegar is added.
It was extracted with ethyl acidate. Wash the ethyl acetate layer with saturated saline.
Clean and dry (MgSO4_Four) And then concentrated. Silica residue
Subject to gel column chromatography using ethyl acetate-
3- [5- (4-
Bromophenyl) -4-isoxazolyl] propion
Methyl acidate (5.03 g, yield 96%) as colorless crystals
Obtained. Recrystallized from ethyl acetate-hexane. Melting point 58
~ 59 ° C.

Example 85 To a solution of methyl 3- [5- (4-bromophenyl) -4-isoxazolyl] propionate (4.06 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml). ) Was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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. 58 g, yield 97%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 72-73 [deg.] C. Example 86 To a solution of 5- (3-chlorophenyl) -4-isoxazolylmethanol (6.80 g) in toluene (100 ml) was added dropwise thionyl chloride (3.6 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 brine, dried (MgSO _4), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added to a mixture of diethyl malonate (10.38 g), sodium hydride (60%, oily, 2.56 g) and tetrahydrofuran (50 ml) at 0 ° C., then 0
Stir at 1 ° 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 was washed with saturated saline and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 3,
A colorless oily substance was obtained from the elution part (volume ratio). The resulting colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of l) was refluxed for 5 hours. The reaction mixture is concentrated,
Water was added to the residue. The colorless crystals obtained were collected by filtration, and 3-
[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 l) 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 brine, 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- (3-
Methyl chlorophenyl) -4-isoxazolyl] propionate (3.06 g, yield 93%) 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 To a solution of methyl 3- [5- (3-chlorophenyl) -4-isoxazolyl] propionate (2.50 g) in tetrahydrofuran (30 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) at 0 ° C. After slowly adding with, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3- [5- (3-chlorophenyl) -4-isoxazolyl] propan-1-ol (2.38 g). , Yield 95%) was obtained 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-
Toluene of isoxazolylmethanol (7.90 g)
(150 ml) solution, thionyl chloride (4.0 m
After l) was added dropwise, the mixture was stirred at room temperature for 3 hours. Reaction mixture
The product was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was washed with ethyl acetate.
Extracted. The ethyl acetate layer is washed with saturated saline and dried.
(MgSO 4_Four) And then concentrated. Tetrahydrofuran
Dissolve in orchid (200 ml) and use diethyl malonate (1
1.55 g), sodium hydride (60%, oily, 2.
85 g) and tetrahydrofuran (50 ml)
Add to the mixture at 0 ° C, then at 0 ° C for 1 hour, then finish at room temperature.
I stirred it at night. The reaction mixture was acidified with dilute hydrochloric acid
Then, it was extracted with ethyl acetate. The ethyl acetate layer is saturated salt
Wash with water and dry (MgSO_Four) And then concentrated. Residue
Subjected to silica gel column chromatography, ethyl acetate
A colorless oil from the elution part of ru-hexane (1: 3, volume ratio)
I got a thing. The obtained colorless oily substance, 6N hydrochloric acid (50 m
Reflux a mixture of l) and acetic acid (50 ml) for 5 hours.
It 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-benzodio
Xyl-5-yl) -4-isoxazolyl] propyi
On-acid (7.36 g, yield 78%) was obtained. Acetone-
Recrystallized from hexane. Melting point 150-151 [deg.] 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) was refluxed for 4 hours. Concentrate the reaction mixture
Then, water was added to the residue, and the mixture was extracted with ethyl acetate. Acetate
The chill layer was washed with saturated saline and dried (MgSO4). _Four)rear,
Concentrated. Silica gel column chromatography of the residue
And dissolve in ethyl acetate-hexane (1: 3, volume ratio).
From the beginning, 3- [5- (1,3-benzodioxole-5)
-Yl) -4-isoxazolyl] methyl propionate
(4.26 g, yield 97%) was obtained as colorless crystals. vinegar
Recrystallized from ethyl acetate-hexane. Melting point 84-85
° C.

Example 91 3- [5- (1,3-benzodioxol-5-yl)
Methyl-4-isoxazolyl] propionate (2.7
0 g) in tetrahydrofuran (30 ml) solution, hydrogen
Diisobutylaluminium chloride (1.0M hexane solution,
25 ml) was slowly added at 0 ° C., and then at room temperature for 1 hour.
Stir it. Pour the reaction mixture into dilute hydrochloric acid and wash with ethyl acetate.
Extracted. The ethyl acetate layer is washed with saturated saline and dried.
(MgSO 4 _Four) And then concentrated. Silica gel color residue
Chromatography, ethyl acetate-hexane
(2: 1, volume ratio) 3- [5- (1,3-
Nazodioxol-5-yl) -4-isoxazoli
Lu] propan-1-ol (2.33 g, yield 96%)
Was obtained as colorless crystals. Reconstitute from ethyl acetate-hexane
Crystallized Melting point 45-46 [deg.] C. Example 92 5- (3-chloro-4-fluorophenyl) -4-iso
Oxazolylmethanol (7.01 g) in toluene (1
(00 ml) solution at 0 ° C. with thionyl chloride (3.5 ml)
After dripping, the mixture was stirred at room temperature for 3 hours. The reaction mixture
Concentrate, add saturated aqueous sodium hydrogen carbonate to the residue, and extract with ethyl acetate.
did. The ethyl acetate layer was washed with saturated saline and dried (Mg
SO_Four) And then concentrated. Tetrahydrofuran
Dissolve in 100 ml of diethyl malonate (9.89
g), sodium hydride (60%, oily, 2.43 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
After 1 hour, stir at 0 ° C for 1 hour and then at room temperature overnight.
I got it. The reaction mixture was acidified with dilute hydrochloric acid and then treated with acetic acid.
Extracted with chill. The ethyl acetate layer was washed with saturated saline,
Dry (MgSO4_Four) And then concentrated. Silica gel residue
Subjected to column chromatography, ethyl acetate-hexa
A colorless oily substance was obtained from the elution part of the solvent (1: 3, volume ratio).
Obtained colorless oil, 6N hydrochloric acid (50 ml) and vinegar
A mixture of acids (50 ml) was refluxed for 5 hours. Reaction mixture
Was concentrated and water was added to the residue. The colorless crystals obtained are filtered
Then, 3- [5- (3-chloro-4-fluorophenyl)
L) -4-isoxazolyl] propionic acid (6.68)
g, yield 80%) was obtained. Reconstitute from acetone-hexane
Crystallized Melting point 118-119 [deg.] 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[5- (3-chloro-4-fluorophenyl) -4-
Methyl isoxazolyl] propionate (3.18 g,
Yield 97%) was obtained 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), diisobutylaluminum hydride (1.0 M hexane solution, 2
(5 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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), 8.22 (1H,
s).

Example 95 To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml), sodium hydride (60%, oily, 1.32 g) was gradually added 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 hr. 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 brine, dried (MgSO ₄ ),
Concentrated. 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 colorless crystals obtained 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%) was obtained. Melting point 158-159 [deg.] C. Example 96 3- [5- (4-chloro-3-methylphenyl) -4-
Concentrated sulfuric acid (1 ml) was added to a solution of isoxazolyl] propionic acid (1.80 g) in methanol (50 ml), and 1
Heated to reflux for hours. The reaction mixture was concentrated, ice water was poured into the residue, and the precipitated crystals of methyl 3- [5- (4-chloro-3-methylphenyl) -4-isoxazolyl] propionate were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless needle crystals (1.72 g, yield 91%). Melting point 60-61 [deg.] C.

Example 97 3- [5- (4-chloro-3-methylphenyl) -4-
Methyl isoxazolyl] propionate (1.20 g)
In a tetrahydrofuran (40 ml) solution of diisobutylaluminum hydride (1.0 M toluene solution, 9.5
(ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 3 hr. Water was carefully added to the reaction mixture, acidified with diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the eluate of ethyl acetate-hexane (1: 1, volume ratio) were recrystallized from ethyl acetate-hexane to give 3-.
Colorless needle crystals 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), sodium hydride (60%, oily, 655 mg) was gradually added 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, and the mixture was stirred at room temperature for 1 hour.
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 brine, dried (MgSO _4), and concentrated. The residue was mixed with 6N hydrochloric acid (40 ml) and acetic acid (60
ml) and heated at 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
A colorless prism crystal (1.35 g, yield 58%) of-(2,5-dichlorophenyl) -4-isoxazolyl] propionic acid was obtained. Melting point 103-104 [deg.] C.

Example 99 Concentrated sulfuric acid (1 ml) was added to a solution of 3- [5- (2,5-dichlorophenyl) -4-isoxazolyl] propionic acid (800 mg) in methanol (30 ml), and the mixture was heated under reflux for 1 hr. 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio) to give 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., and the mixture was stirred at room temperature for 3 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
(00 ml) and dissolved in diethyl malonate (9.10
g), sodium hydride (60%, oily, 2.25 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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, yield 78%) 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 brine, 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, 97% yield)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 68-69 [deg.] C. Example 102 To a solution of methyl 3- [5- (3,4-dimethoxyphenyl) -4-isoxazolyl] propionate (1.70 g) in tetrahydrofuran (20 ml) was added diisobutylaluminum hydride (1.0 M hexane solution, 15 ml).
Was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1,
(Volume ratio) From the elution 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. Melting point 55-56
° C.

Example 103 Tetrahydrofuran of diethyl malonate (10.3g)
(80 ml) solution, sodium hydride (60%, oil
2.34 g) was gradually added at 0 ° C. Oyster for 10 minutes
After mixing, 4-chloromethyl-5- (4-methylthiof
Tetrahydr of (phenyl) isoxazole (7.00 g)
Lofuran (70 ml) solution was added dropwise at 0 ° C, and at room temperature 8:00
Stir it. The reaction mixture was poured into water and acidified with 2N hydrochloric acid.
After having been rendered sexual, it was extracted with ethyl acetate. The ethyl acetate layer is
Wash with saturated saline and dry (MgSO 4 _Four) And then concentrated.
The residue was mixed with 6N hydrochloric acid (50 ml) and acetic acid (100 m
It was dissolved in the mixture of 1) and heated under reflux for 5 hours. Reaction mixture
The product was concentrated, water was added to the residue, and 3- [5- (4-meth
Luthiophenyl) -4-isoxazolyl] propion
Colorless crystals of acid (4.68 g, yield 61%) were obtained. Acetic acid
Recrystallize from ethyl-isopropyl ether to give colorless
I got Zum crystal. Melting point 124-125 [deg.] C. Example 104 3- [5- (4-methylthiophenyl) -4-isooxy
Sazolyl] propionic acid (3.70 g) in methanol
Concentrated sulfuric acid (1 ml) was added to the (100 ml) solution for 1 hour.
Heated to reflux. The reaction mixture was concentrated and ice water was poured into the residue.
And precipitated 3- [5- (4-methylthiophenyl)-
The crystals of methyl 4-isoxazolyl] propionate were filtered off.
I took it. Recrystallized from ethyl acetate-isopropyl ether
To obtain colorless prism crystals (3.60 g, yield 92%).
It was Melting point 57-58 [deg.] 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 (0.95M toluene solution, 15). .2m
l) was slowly added at 0 ° C., and then the mixture was stirred at room temperature for 1 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the eluate from acetone-hexane (1: 1, volume ratio) were recrystallized from ethyl acetate-hexane to give 3- [5- (4-methylthio). Phenyl) -4-isoxazolyl] propan-1-ol was obtained as colorless prism crystals (1.36 g, yield 95%). Melting point 54-55 [deg.] C. Example 106 A solution of 3- [5- (4-methylthiophenyl) -4-isoxazolyl] propan-1-ol (500 mg) in tetrahydrofuran (30 ml) was gradually added m-chloroperbenzoic acid (870 mg) at 0 ° C. 1 at room temperature after adding
Stir for hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a crystal of 3- [5- (4-methylsulfonylphenyl) -4-isoxazolyl] propan-1-ol was obtained from the elution part of acetone-hexane (1: 1, volume ratio). (480 mg, yield 85%) was obtained. Recrystallization from ethyl acetate-isopropyl ether gave colorless needle crystals. Melting point 125-126 [deg.] C.

Example 107 m-Chloroperbenzoic acid (750 mg) was added to a solution of 3- [5- (4-methylthiophenyl) -4-isoxazolyl] propan-1-ol (900 mg) in acetonitrile (20 ml) at 0 ° C. Then, the mixture was stirred for 1 hour at room temperature. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and acetone-hexane (2:
(1, volume ratio) From the elution part, 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 prism crystals. Melting point 73-74 [deg.] C. Example 108 5- (4-chloro-3-fluorophenyl) -4-isoxazolylmethanol (7.80 g) in toluene (1
50 ml) solution at 0 ° C with thionyl chloride (4.0 ml).
After dripping, 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 ) it was concentrated. The residue was dissolved in tetrahydrofuran (150 ml) and diethyl malonate (10.9
8 g), sodium hydride (60%, oily, 2.71)
g) and tetrahydrofuran (50 ml) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [5- (4-chloro-3-fluorophenyl) -4-isoxazolyl] propionic acid (7.2
0 g, yield 78%) was obtained. Recrystallized from acetone-hexane. Melting point 139-140 [deg.] C.

Example 109 3- [5- (4-chloro-3-fluorophenyl) -4
A mixture of -isoxazolyl] propionic acid (5.08g), concentrated sulfuric acid (0.1ml) and methanol (100ml) 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[5- (4-chloro-3-fluorophenyl) -4-
Methyl isoxazolyl] propionate (5.25 g,
Yield 98%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 53-54 [deg.] C. Example 110 3- [5- (4-chloro-3-fluorophenyl) -4
Methyl -isoxazolyl] propionate (3.30
g) in tetrahydrofuran (30 ml), diisobutylaluminum hydride (1.0 M hexane solution, 2
(5 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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-isoxazolylmethanol (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 hr. 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 (MgSO ₄ ).
After that, it was concentrated. Tetrahydrofuran (100 m
1) dissolved in diethyl malonate (7.21 g), sodium hydride (60%, oily, 1.79 g) and tetrahydrofuran (50 ml) at 0 ° C., then at 0 ° C. for 1 h, then And stirred 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 and dried (M
After gSO ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
A colorless oily substance was obtained from the elution part. The obtained colorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50
The mixture of (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,
3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionic acid (5.09 g, 79% yield)
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 brine, 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. Melting point 87-88 [deg.] C.

Example 113 A solution of methyl 3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propionate (2.40 g) in tetrahydrofuran (30 ml) was dissolved in diisobutylaluminum hydride (1.0 M hexane solution, (20 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr.
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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3- [3- (3,4-dichlorophenyl) -4-isoxazolyl] propan-1-ol (2. 0.06 g, yield 95%) was obtained 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., and the mixture was stirred at room temperature for 3 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
It was dissolved in 00 ml) and diethyl malonate (9.31) was added.
g), sodium hydride (60%, oily, 2.30 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [3- (3-chloro-4-fluorophenyl) -4-isoxazolyl] propionic acid (5.71).
g, yield 73%). Recrystallized from acetone-hexane. Melting point 140-141 [deg.] 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[3- (3-chloro-4-fluorophenyl) -4-
Methyl isoxazolyl] propionate (4.39 g,
Yield 96%) was obtained 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), diisobutylaluminum hydride (1.0 M hexane solution, 3
(0 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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), 1.74-1.94 (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. with thionyl chloride (4.5 ml)
After dripping, 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 ) it was concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and diethyl malonate (12.7
5 g), sodium hydride (60%, oily, 3.15)
g) and tetrahydrofuran (50 ml) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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
2 g, yield 72%) was obtained. Recrystallized from acetone-hexane. Melting point 148-149 [deg.] C. Example 118 3- [3- (4-chloro-3-fluorophenyl) -4
A mixture of -isoxazolyl] propionic acid (5.00 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[3- (4-chloro-3-fluorophenyl) -4-
Methyl isoxazolyl] propionate (5.01 g,
Yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 57-58 [deg.] C.

Example 119 3- [3- (4-chloro-3-fluorophenyl) -4
Methyl-isoxazolyl] propionate (3.69
g) in tetrahydrofuran (30 ml), diisobutylaluminum hydride (1.0 M hexane solution, 3
(0 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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. Melting point 54-55 [deg.] C. Example 120 3- [5- (4-methoxyphenyl) -4-isoxazolyl] propionic acid (2.75 g), concentrated sulfuric acid (0.1
A mixture of (ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
From the elution part of hexane (1: 3, volume ratio), 3- [5- (4
Methyl -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
After slowly adding with, 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 brine, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (4-methoxyphenyl) -4-isoxazolyl] propan-1-ol (2. 03g,
Yield 91%) was obtained 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), 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 brine, 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, from the ethyl acetate-hexane (1: 7, volume ratio) eluate part. Yield 79%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.63 (2H, t, J = 7.5 Hz),
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), sodium hydride (60%, oily, 710 mg) was gradually added 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 brine, dried (MgSO ₄ ),
Concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (60 ml) and acetic acid (90 ml), and the mixture was 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%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 142-143 [deg.] C. Example 124 3- [5- (4,5-dichloro-2-thienyl) -4-
Concentrated sulfuric acid (1 ml) was added to a solution of isoxazolyl] propionic acid (1.60 g) in methanol (30 ml), and 1
Heated to reflux for hours. 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 7, volume ratio) eluted with 3-
Crystals of methyl [5- (4,5-dichloro-2-thienyl) -4-isoxazolyl] propionate (1.34
g, yield 80%) was obtained. Recrystallization from diethyl ether-hexane gave colorless needle crystals. Melting point 49-50 [deg.] C.

Example 125 3- (3-Bromo-4-fluorophenyl) -4-isoxazolylmethanol (6.79 g) in toluene (5
Thionyl chloride (3.0 ml) was added dropwise to the solution (0 ml) at 0 ° C., and the mixture was stirred at room temperature for 3 hr. 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 (MgS
After O ₄ ) it was concentrated. The residue was converted to tetrahydrofuran (1
It was dissolved in 100 ml of diethyl malonate (8.11).
g), sodium hydride (60%, oily, 2.00 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [3- (3-bromo-4-fluorophenyl) -4-isoxazolyl] propionic acid (6.33).
g, yield 81%). Recrystallized from acetone-hexane. Melting point 151-152 [deg.] 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[3- (3-Bromo-4-fluorophenyl) -4-
Methyl isoxazolyl] propionate (3.11 g,
Yield 95%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 57-58 [deg.] C. Example 127 3- [3- (3-Bromo-4-fluorophenyl) -4
-Isoxazolyl] methyl propionate (1.68
g) in tetrahydrofuran (20 ml), diisobutylaluminum hydride (1.0 M hexane solution, 1
(5 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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
(00 ml) solution at 0 ° C with thionyl chloride (2.6 ml).
After dripping, 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 ) it was concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and diethyl malonate (7.65) was added.
g), sodium hydride (60%, oily, 1.87 g)
And a mixture of tetrahydrofuran (50 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [5- (3-bromo-4-fluorophenyl) -4-isoxazolyl] propionic acid (5.06).
g, yield 67%). Recrystallized from acetone-hexane. Melting point 136-137 [deg.] 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 is
Washed with saturated brine, dried (MgSO _4), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 3, volume ratio) 3 from the elution part
-[5- (3-Bromo-4-fluorophenyl) -4-
Methyl isoxazolyl] propionate (2.39 g,
Yield 96%) was obtained 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), diisobutylaluminum hydride (1.0 M hexane solution, 1
(0 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2:
1, volume ratio) From the elution part, 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. Melting point 57-58 [deg.] C.

Example 131 Thionyl chloride (3.10 ml) was added dropwise to a solution of 5- (4-phenylphenyl) -4-isoxazolylmethanol (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 was washed with saturated saline and dried (MgSO ₄ ).
After that, it was concentrated. Tetrahydrofuran (100 m
l) and dissolved in diethyl malonate (9.07 g), sodium hydride (60%, oily, 2.22 g) and tetrahydrofuran (50 ml) at 0 ° C. and then at 0 ° C. for 1 h, then And stirred 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 and dried (M
After gSO ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
A colorless oily substance was obtained from the elution part. The resulting colorless oil, 6N hydrochloric acid (70 ml) and acetic acid (70
The mixture of (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,
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
A mixture of (ml) and methanol (100 ml) was refluxed for 4 hours. The reaction mixture was concentrated, water was added to the residue,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, ethyl acetate-
From the elution part of hexane (1: 3, volume ratio), 3- [5- (4
Methyl -phenylphenyl) -4-isoxazolyl] propionate (5.91 g, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 103-104 [deg.] 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). 0.0 ml) to 0
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 1 hr. 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 (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3- [5- (4-phenylphenyl)-.
4-isoxazolyl] propan-1-ol (0.6
56 g, yield 72%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 94-95 [deg.] 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 brine, 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. Melting point 54-55 [deg.] 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, volume ratio) to obtain N- [4- (diethylphosphonomethyl) phenyl] -3- (3-methyl-5-phenyl). -4-isoxazolyl) propionamide (0.87 g, yield 8)
8%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 114-115 [deg.] C. Example 136 A mixture of 3-methyl-5-phenylisoxazole-4-carbaldehyde (4.94g), ethyl diethylphosphonoacetate (6.53g) and N, N-dimethylformamide (70ml) at 0 ° C. Sodium hydride (60%, oily, 1.13 g) was added, and the mixture was stirred at room temperature for 3 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
(4, volume ratio) A yellow oily substance was obtained from the elution part. The obtained yellow oily substance, 2N hydrochloric acid (50 ml) and acetic acid (50 m
The mixture of l) was refluxed for 3 hours. The reaction mixture is concentrated,
Water was added to the residue. The obtained colorless crystals were collected by filtration, (2
E) -3- (3-Methyl-5-phenyl-4-isoxazolyl) propenoic acid (4.02 g, yield 93%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 173
~ 174 ° C.

Example 137 Methyl 4-aminobenzoate (0.30 g), (2E)-
3- (3-Methyl-5-phenyl-4-isoxazolyl) propenoic acid (0.35 g), 1-hydroxy-1H
-1,2,3-benzotriazole hydrate (0.27
g), a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then,
Washed with saturated brine, 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), (2E) -N- [4- (methoxycarbonyl) phenyl]-
3- (3-Methyl-5-phenyl-4-isoxazolyl) acrylamide (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), (2
E) -3- (3-Methyl-5-phenyl-4-isoxazolyl) propenoic acid (0.95 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.91 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 diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and from the elution part of ethyl acetate-hexane (1: 1, volume ratio), (2E) -N- [4- (ethoxycarbonylmethyl) phenyl] -3- (3-methyl- 5-phenyl-4-isoxazolyl) acrylamide (1.82)
g, yield 97%) was obtained as colorless crystals. Ethyl acetate-
Recrystallized from hexane. Melting point 164-165 [deg.] C.

Example 139 Diethyl 4-aminobenzylphosphonate (0.43
g), (2E) -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 a mixture of N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. Pour the reaction mixture into water,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated saline, and dried (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1,
(Volume ratio) From (2E) -N- [4- (diethylphosphonomethyl) phenyl] -3- (3-methyl-5-phenyl-4-isoxazolyl) acrylamide (0.71)
g, yield 83%) was obtained as colorless crystals. Ethyl acetate-
Recrystallized from hexane. Melting point 155-156 [deg.] 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) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [3- (4-trifluoromethylphenyl) -4-isoxazolyl] propionic acid (2.49).
g, yield 79%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 173-174 [deg.] C.

Example 141 4-chloromethyl-3- (4-chlorophenyl) -5-
Methylisoxazole (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) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to give 3- [3- (4-chlorophenyl) -5-methyl-4-isoxazolyl] propionic acid (1.20).
g, yield 90%) was obtained. Recrystallized from ethanol.
Melting point 187-188 [deg.] C. Example 142 Methyl propionyl acetate (9.95 g) and 4-chloro-N-hydroxybenzenecarboximidoyl chloride (9.65 g) in tetrahydrofuran (100 m
1) To the solution, a solution of triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The colorless oil obtained was tetrahydrofuran (1
(00 ml), diisobutylaluminum hydride (1.0 M hexane solution, 110 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 brine, dried (MgSO ₄ ) and concentrated to give a colorless oil. The obtained colorless oily substance was dissolved in tetrahydrofuran (100 ml), and diethyl malonate (2.40) was added.
g), sodium hydride (60%, oily, 0.42 g)
And a mixture of tetrahydrofuran (20 ml) at 0 ° C.
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 being dried (MgSO ₄ ), it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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%) was obtained. Recrystallized from ethanol. Melting point 164-165 [deg.] C.

Example 143 A solution of ethyl benzoyl acetate (5.76 g) and sodium hydride (60%, oily, 0.12 g) in tetrahydrofuran (60 ml) was added with methyl acrylate (3.2 m).
1) was added slowly at room temperature. After stirring overnight at room temperature, 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 (MgS
After O ₄ ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 9,
(Volume ratio) A colorless oily substance was obtained from the elution part. A mixture of the resulting 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 brine, dried (MgSO ₄ ) and concentrated to give a colorless oil. A mixture of the obtained colorless oily substance, 2N sodium hydroxide (20 ml) and methanol (30 ml) was stirred at room temperature for 1 hr. The reaction mixture was acidified with diluted hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration, and 3- [5-hydroxy-3-phenyl-4 was used.
-Isoxazolyl] propionic acid (2.49 g, yield 36%) was obtained. Recrystallized from ethanol. Melting point 18
3 to 184 ° C. Example 144 A solution of 4-chloromethyl-5-methyl-3- (4-trifluoromethylphenyl) isoxazole (1.37 g) in tetrahydrofuran (50 ml) was added with diethyl malonate (1.20 g) and sodium hydride ( 60%, oily, 0.21 g) and tetrahydrofuran (20 m
After being added to the mixture of l) at 0 ° C., the mixture was stirred at 0 ° C. for 1 hr 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 brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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 to 139 ° C.

Example 145 Methyl acetoacetate (8.88 g) and 3-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride (11.35 g) in tetrahydrofuran (1
To a (00 ml) solution, triethylamine (15 ml) in tetrahydrofuran (10 ml) was slowly added at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The colorless oil obtained was tetrahydrofuran (1
(00 ml), diisobutylaluminum hydride (1.0 M hexane solution, 110 ml) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 brine, 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. 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 and dried (MgSO ₄ ).
After that, it was concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the 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, 43% yield) was obtained. Recrystallized from ethanol-water. Melting point 63-64 [deg.] C.

Example 146 Dibenzoylmethane (4.48 g), methyl acrylate (1.8 ml), potassium t-butoxide (0.23)
g) and N, N-dimethylformamide (40 ml)
The mixture was stirred overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). A mixture of the resulting 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 brine, 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 l) 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 was washed with saturated saline and dried (MgSO ₄ ).
After that, 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. Melting point 152-153 [deg.] C. Example 147 Methyl acetoacetate (8.88 g) and 2-chloro-N
To a solution of hydroxybenzenecarboximidoyl chloride (9.65g) in tetrahydrofuran (100ml) was added a solution of triethylamine (15ml) in tetrahydrofuran (10ml) slowly at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). The resulting colorless oil of tetrahydrofuran (100
diisobutylaluminum hydride (1.
0 M hexane solution (110 ml) was slowly added at 0 ° C., and then the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, 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 brine, 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., and the mixture was stirred at 0 ° C. for 1 hr 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 brine, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). The 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 (0.95M hexane solution, 21). 0.5 ml) was slowly added at 0 ° C., and then the mixture was stirred at room temperature for 1 hr.
Sodium sulfate decahydrate (6.57 g) in the reaction mixture
Was added and the mixture was stirred for 2 hours, and then the insoluble matter was filtered off. The filtrate was concentrated, the residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, volume ratio) eluted with 3- [5- (4-methylphenyl) -4-isoxazolyl] propane-. 1-ol (1.53 g, yield 86%) 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 Hz), 7.62 (2H, d, J = 8 Hz), 8.19 (1H,
s). Example 149 3- [5- (4,5-dichloro-2-thienyl) -4-
Methyl isoxazolyl] propionate (1.30 g)
In tetrahydrofuran (40 ml) of diisobutylaluminum hydride (0.95M hexane solution, 1
(1.2 ml) was slowly added at room temperature, and the mixture was stirred for 1 hr. 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 ) it was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
1, volume ratio) from the elution part to 3- [5- (4,5-dichloro-2-thienyl) -4-isoxazolyl] propane-
1-ol (1.05 g, 89% yield) 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 (1H, s), 8.19
(1H, s). Example 150 Diisobutylaluminum hydride (1.0M toluene solution, 4.2 ml) was added to a solution of methyl 3- [5- (2,5-dichlorophenyl) -4-isoxazolyl] propionate (500 mg) in tetrahydrofuran (30 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 brine, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [5- (2,5-dichlorophenyl) -4 was extracted from the elution part of ethyl acetate-hexane (1: 1, volume ratio).
-Isoxazolyl] propan-1-ol (420m
g, yield 93%) was obtained 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.
45 g) and N, N-dimethylformamide (5 m
The mixture of l) was stirred at room temperature overnight. 1 reaction mixture
It was poured into a normal hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, then with saturated saline, 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. Melting point 134-135 [deg.] C. Elemental analysis: Theoretical value (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, 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) The mixture was stirred at room temperature overnight. Direct preparative HPLC of reaction liquid
Was introduced into and purified 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 in the same manner as in Example 152.

Example 153 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (4-Methylthiophenyl) -4-isoxazolyl] propionamide Yield: 80 mg (Yield: 82%) HPLC analysis: Purity 100% (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, 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: Purity 100% (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: Purity 100% (Retention time: 3.779)
Min) 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: Purity 100% (Retention time: 3.914 minutes) MS (ESI +): 527 (M + H) NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7Hz), 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)
Min) 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 reaction mixture
Aqueous sodium sulfite solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, then with saturated saline, 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: Purity 95.1% (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 fractions eluting later in preparative HPLC. -4-isoxazolyl] propionamide was obtained. Yield: 14 mg (yield: 13%) HPLC analysis: Purity 93.0% (retention time: 3.163)
Min) 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. The reaction mixture is filtered,
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: Purity 98.1% (Retention time: 3.084
Min) MS (APCI +): 335 (M + H) In the same manner as in Example 160, the following compounds were synthesized.

Example 161 3- [5- (3-chlorophenyl) -4-isoxazolyl] -N-methyl-N- (1-methyl-4-piperidinyl) propionamide trifluoroacetate Yield: 36 mg (Yield: 75%) HPLC analysis: Purity 98.9% (retention time: 2.697)
Min) MS (APCI +): 362 (M + H) Example 162 N-((3S) -1- {3- [5- (3-chlorophenyl)-
4-isoxazolyl] propanoyl} pyrrolidine-3-
Yield) -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 (yield: 89%) HPLC Analysis: Purity 96.7% (retention time: 3.771
Min) 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 overnight at room temperature. 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) In the same manner as in Example 165, the following compounds were synthesized. Example 166 3- [5- (4-Bromophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 36 mg (Yield: 69%) HPLC analysis: Purity 99 0.6% (holding 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)
Min) MS (ESI +): 434 (M + H) Example 168 N-((3S) -1- {3- [5- (4-bromophenyl)-
4-isoxazolyl] propanoyl} pyrrolidine-3-
Yield) -2,2,2-trifluoroacetamide Yield: 33 mg (Yield: 72%) HPLC analysis: Purity 93.6% (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: Purity 98.3% (Retention time: 3.480)
Min) 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 (Yield: 69%) HPLC analysis: Purity 99.7% (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 : 38%) HPLC analysis: Purity 99.2% (retention time: 2.925)
Min) 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: Purity 97.5% (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: Purity 95.5% (Retention time: 3.255)
Min) MS (ESI +): 353 (M + H) Example 174 1- {3- [5- (4-bromophenyl) -4-isoxazolyl] propanoyl} -4-piperidinol Yield: 11 mg (yield: 28 %) HPLC analysis: Purity 98.5% (retention time: 3.264)
Min) MS (ESI +): 379 (M + H), 381

Example 175 1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinol Yield: 22 mg (Yield: 68%) HPLC analysis: Purity 89.5% ( Retention time: 2.952
Min) 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: Purity 95.9% (Retention time: 3.634)
Min) 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)
Min) 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: Purity 98.9% (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: Purity 96.6% (Retention time: 2.857)
Min) 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% (holding time: 2.574
Min) 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 tri A fluoroacetate salt was obtained. Yield: 47 mg (yield 92%) HPLC analysis: Purity 93.8% (retention time: 2.481)
Min) MS (APCI +): 396 (M + H) In the same manner as in Example 182, the following compounds were synthesized.

Example 183 N-butyl-3- [5- (4-fluorophenyl) -4-
Isoxazolyl] propionamide yield: 21 mg (71% yield) HPLC analysis: Purity 97.9% (retention time: 3.463)
Min) MS (APCI +): 291 (M + H) Example 184 N- (cyclohexylmethyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 23 mg (71% yield) ) HPLC analysis: Purity 95.2% (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: Purity 97.0% (retention time: 3.031
Min) MS (APCI +): 275 (M + H) Example 186 N-benzyl-3- [5- (4-fluorophenyl) -4.
-Isoxazolyl] propionamide yield: 23 mg (71% yield) HPLC analysis: Purity 95.4% (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: Purity 97.2% (retention time: 3.507)
Min) MS (APCI +): 369 (M + H) Example 188 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-phenylethyl) propionamide Yield: 25 mg (yield 74%) HPLC analysis: Purity 98.4% (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: Purity 98.9% (Retention time: 3.822
Min) 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 (72% yield) HPLC analysis: Purity 99.4% (Retention time: 2.904
Min) 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 % (Holding time: 3.057
Min) 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: Purity 99.7% (retention time: 3.657)
Min) MS (APCI +): 378 (M + H)

Example 195 N- (1-Ethylpropyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 22 mg (71% yield) HPLC analysis: Purity 98.8% (Retention time: 3.566
Min) MS (APCI +): 305 (M + H) Example 196 N- (tert-butyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 23 mg (yield 80 %) HPLC analysis: Purity 98.7% (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: Purity 96.8% (retention time: 3 .672
Min) MS (APCI +): 317 (M + H) Example 198 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (2-propynyl) propionamide Yield: 20 mg (yield 72 %) HPLC analysis: Purity 99.2% (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% (holding 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: Purity 99.1% (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% (holding time: 4.173
Min) 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: Purity 98.9% (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 % (Holding time: 3.375
Min) 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: Purity 97.5% (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: Purity 99.4% (Retention time: 3.364
Min) 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: Purity 99.5% (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% (holding time: 4.165
Min) 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: Purity 98.1% (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% (holding time: 3.353
Min) 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 .6% (holding 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 % (Holding 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% (holding time: 3.902
Min) 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
Min) MS (APCI +): 346 (M + H) Example 214 2- (1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4-piperidinyl) ethanol Yield: 27 mg (yield 77%) HPLC analysis: Purity 96.2% (retention time: 3.086
Min) 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% (holding time: 3.496
Min) 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: Purity 99.8% (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: Purity 99.7% ( Retention time: 2.779
Min) MS (APCI +): 346 (M + H) Example 218 N-cyclohexyl-3- [5- (4-fluorophenyl) -4-isoxazolyl] -N-methylpropionamide Yield: 19 mg (58% yield) HPLC Analysis: Purity 99.5% (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: Purity 99.5% (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: Purity 98.8% (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 (yield 90%) HPLC analysis: Purity 99.5% (retention time: 3.410).
Min) MS (APCI-): 319 (M-H) Example 222 4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} morpholine Yield: 47 mg (yield 90%) HPLC analysis : Purity 97.0% (holding 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 % (Holding 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: Purity 90.1% (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: Purity 99.1% (retention time: 3.614)
Min) 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 (yield 18%) 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: Purity 99.7% (retention time: 3.817)
Min) MS (APCI-): 427 (MH) Example 228 3- (N-acetyl-N-ethylamino) -1- {3- [5
-(4-Fluorophenyl) -4-isoxazolyl] propanoyl} pyrrolidine Yield: 14 mg (36% yield) HPLC analysis: Purity 97.0% (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 89%) HPLC analysis: Purity 99.8% (retention time: 2.481)
Min) 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: Purity 94.5% (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: Purity 99.5% (retention time: 2.637
Min) MS (APCI +): 354 (M + H) Example 232 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N, N-bis (3-pyridinylmethyl) propionamide 2 trifluoroacetate Yield: 57 mg (yield 90%) HPLC analysis: Purity 99.7% (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 (yield 93%) HPLC analysis: purity 99.6% (retention time: 2.473).
Min) 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: Purity 99.7% (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: Purity 98.6% (retention time: 2.834)
Min) 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: Purity 99.6% (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% (holding time: 3.202
Min) 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 (yield 89%) 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: Purity 99.2% (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 90%) HPLC analysis: Purity 99.4% (retention time: 2.494)
Min) 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 (90% yield) 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: Purity 99.0% (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: Purity 99.6% (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: Purity 98.4% (retention time: 2.864)
Min) MS (APCI +): 438 (M + H) Example 246 1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4- (2-pyrimidinyl) piperazine trifluoroacetate Yield: 43 mg (yield 86%) HPLC analysis: Purity 99.1% (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: Purity 96.9% (retention time: 3.064
Min) 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: Purity 99.5% (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 (yield 91%) HPLC Analysis: Purity 99.4% (retention time: 2.530
Min) 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: Purity 99.6% (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: Purity 100% (retention time: 3.619
Min) 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: Purity 99.1% (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 (yield 98%) HPLC analysis: Purity 99.6% (retention time: 3.625)
Min) 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: Purity 98.8% (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: Purity 97.7% (retention time: 4.004
Min) 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)
Min) 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: Purity 99.5% (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: Purity 99.2% (retention time: 3.085
Min) MS (APCI +): 410 (M + H) Example 260 1- (4-fluorophenyl) -4- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} piperazine trifluoroacetate yield : 30 mg (yield 58%) HPLC analysis: Purity 99.0% (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 (yield 80%) HPLC analysis: Purity 98.9% (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: Purity 99.1% (Retention time: 2.860
Min) MS (APCI +): 346 (M + H) Example 264 1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl} -4-phenyl-4-piperidinol Yield: 32 mg (yield 82 %) HPLC analysis: Purity 99.3% (retention time: 3.541
Min) MS (APCI-): 393 (MH)

Example 265 4- (4-bromophenyl) -1- {3- [5- (4-fluorophenyl) -4-isoxazolyl] propanoyl}
-4-Piperidinol yield: 37 mg (79% yield) HPLC analysis: Purity 99.2% (retention time: 3.867)
Min) 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: Purity 99.2% (retention time: 3 .881
Min) 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% (holding time: 3.929
Min) 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: Purity 99.0% (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 (yield 64%) HPLC analysis: Purity 98.3% (Retention time: 3.693
Min) 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: Purity 99.9% (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: Purity 99.8% (retention time: 2.567)
Min) 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)
Min) 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)
Min) MS (ESI +): 348 (M + H) Example 276 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (4-methyl-1-piperazinyl) propyl] propionamide 2 Trifluoroacetate yield: 27 mg (45% yield) 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
Min) MS (ESI +): 382 (M + H) Example 278 N- (1-benzyl-4-piperidinyl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide trifluoroacetate Yield: 39 mg (74% yield) HPLC analysis: Purity 99.9% (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: Purity 100% (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: Purity 99.7% (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 (62% yield) HPLC analysis: Purity 99 .9% (holding time: 2.497
Min) 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
Min) 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: Purity 99.8% (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: Purity 99.9% (retention time: 2.570)
Min) 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: Purity 100% (retention time: 2.512
Min) MS (ESI +): 362 (M + H) Example 288 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (1-pyrrolidinyl) ethyl] propionamide trifluoroacetate Yield : 31 mg (69% yield) 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: Purity 99.5% (retention time: 3.054
Min) 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: Purity 99.7% (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 ( Yield 68%) HPLC analysis: Purity 99.9% (retention time: 2.417)
Min) MS (ESI +): 380 (M + H) Example 292 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (4-pyridinylmethyl) propionamide trifluoroacetate Yield: 46 mg (yield 95%) 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 .9% (holding time: 2.456
Min) MS (ESI +): 326 (M + H) Example 294 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [2- (3-pyridinyl) ethyl] propionamide trifluoroacetate Yield : 35 mg (yield 78%) HPLC analysis: Purity 100% (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)
Min) 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: Purity 92.9% (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: Purity 100% (Retention time: 3.213
Min) 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 (yield 28%) HPLC analysis: Purity 100% (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: Purity 92.2% (retention time: 3.387)
Min) MS (ESI +): 404 (M + H) Example 300 N- (2-pyridinylmethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 11 mg (yield 48%) HPLC analysis: Purity 99.9% (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 (Yield 41%) HPLC analysis: Purity 100% (Retention time: 2.899
Min) 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 (yield 45%) HPLC analysis: Purity 100% (retention time: 3.020
Min) 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: Purity 98.9% (retention time: 3.411)
Min) 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 (yield 25%) HPLC analysis: Purity 100% (retention time: 2.854
Min) 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: Purity 98.1% (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 (31% yield) HPLC Analysis: 100% purity (retention time: 2.907
Min) MS (ESI +): 376 (M + H) Example 310 N- (3-pyridinylmethyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 13 mg (51% yield) 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)
Min) MS (ESI +): 390 (M + H) Example 312 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N-phenylpropionamide Yield: 25 mg (79% yield) HPLC analysis: Purity 100 % (Holding 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)
Min) MS (ESI +): 351 (M + H) Example 314 N- (3,5-dimethoxyphenyl) -3- [5- (4-fluorophenyl) -4-isoxazolyl] propionamide Yield: 31 mg (yield 84 %) 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: Purity 99.6% (Retention time: 4.307
Min) MS (ESI +): 401 (M + H) Example 316 N- (1,1'-biphenyl-3-yl) -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide Yield: 34 mg (Yield 87%) HPLC analysis: Purity 97.7% (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 (Yield 90%) HPLC analysis: Purity 97.2% ( Retention time: 3.346
Min) MS (ESI +): 318 (M + H) Example 318 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (4-pyridinyl) propionamide trifluoroacetate Yield: 27 mg (yield 63%) 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: Purity 98.4% (retention time: 3.081
Min) MS (ESI +): 342 (M + H) Example 320 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (6-quinolinyl) propionamide trifluoroacetate Yield: 40 mg (yield 80%) HPLC analysis: Purity 99.7% (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: Purity 98.7% ( Retention time: 3.908
Min) 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)
Min) MS (ESI +): 369 (M + H) Example 324 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [4- (trifluoromethoxy) phenyl] propionamide Yield: 33 mg (yield 84%) 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: Purity 99.1% (Retention time: 4.258
Min) MS (ESI +): 403 (M + H) Example 326 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (1-phenyl-5-pyrazolyl) propionamide Yield: 19 mg (yield 51%) HPLC analysis: Purity 99.5% (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% (holding time: 3.427
Min) MS (ESI +): 316 (M + H) Example 328 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- (3-quinolinyl) propionamide trifluoroacetate Yield: 44 mg (yield 85%) 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: Purity 98.5% ( Retention time: 4.174
Min) 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: Purity 98.3% (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: Purity 99.5% (retention time: 4.672)
Min) 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: Purity 99.5% (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% (holding time: 4.698
Min) 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: Purity 98.2% (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% (holding time: 3.816
Min) MS (ESI +): 368 (M + H) Example 336 N- (4-pyridinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 12 mg (52% yield) HPLC analysis: Purity 80.0% (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: Purity 97.4% (retention time: 3.634)
Min) MS (ESI +): 392 (M + H) Example 338 N- (6-quinolinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide trifluoroacetate Yield: 12 mg (yield 60%) HPLC analysis: Purity 98.9% (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 (28% yield) HPLC analysis: Purity 99 0.1% (holding time: 4.316
Min) MS (ESI +): 418 (M + H) Example 340 N- (2-fluorophenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 8 mg (yield 44%) 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 (Yield 47%) HPLC analysis: Purity 100% (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 (yield 52%) HPLC analysis: Purity 99.1% (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 (Yield 41%) HPLC analysis: Purity 99.2% (Retention time: 4.566
Min) MS (ESI +): 445 (M + H) Example 344 N- (2-phenoxyphenyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 11 mg (yield 48%) HPLC analysis: Purity 99.3% (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)
Min) 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: Purity 99.5% (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
Min) MS (ESI +): 362 (M + H) Example 348 N- (2-pyrazinyl) -3- {5- [4- (trifluoromethyl) phenyl] -4-isoxazolyl} propionamide Yield: 7 mg (yield 36%) 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 (68% yield) HPLC analysis: Purity 99 0.2% (holding time: 3.395
Min) 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
Min) MS (ESI +): 429 (M + H) Example 352 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Chlorophenyl) -4-isoxazolyl] propionamide yield: 38 mg (yield 83%) HPLC analysis: purity 100% (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: Purity 94.1% (retention) Time: 4.136
Min) MS (ESI +): 415 (M + H) Example 354 N- [4- (diethylphosphono) phenyl] -4- (5-phenyl-4-isoxazolyl) butanamide Yield: 34 mg (77% yield) HPLC analysis : 100% purity (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 (yield 82%) HPLC analysis: Purity 100% (retention time: 3.796
Min) MS (ESI +): 427 (M + H) Example 356 3- [5- (4-chlorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphos. Finan-2-yl) methyl] phenyl} propionamide Yield: 17 mg (36% yield) HPLC analysis: Purity 100% (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)
Min) 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 (yield 92%) HPLC analysis: Purity 99.1% (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)
Min) 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: Purity 100% (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 (Yield 64%) HPLC analysis: Purity 100% (Retention time: 3.826
Min) MS (ESI +): 401 (M + H) Example 362 N- [4- (dimethylphosphonomethyl) phenyl] -4-.
(5-Phenyl-4-isoxazolyl) butanamide Yield: 26 mg (61% yield) HPLC analysis: Purity 100% (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 (Yield 64%) HPLC analysis: Purity 99.9% (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: Purity 100% (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 (yield 82%) HPLC analysis: Purity 100% (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: Purity 100% (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: Purity 99.9% (retention time: 4.293)
Min) 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: Purity 97.0% (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: Purity 99.4% (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: Purity 99.9% (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: Purity 99.9% (retention time: 3.979)
Min) 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: Purity 100% (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% (holding 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 (Yield 63%) HPLC analysis: Purity 100% (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: Purity 98.7% (retention time: 3.476)
Min) 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, 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: Purity 100.% (retention time: 3.732)
Min) 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: Purity 100% (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% (holding time: 3.909
Min) MS (ESI +): 483 (M + H) Example 380 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Fluorophenyl) -4-isoxazolyl] propionamide yield: 40 mg (yield 64%) HPLC analysis: Purity 99.6% (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: Purity 99.8% (retention time: 3.565
Min) MS (ESI +): 451 (M + H) Example 382 N- [4- (diethylphosphono) phenyl] -3- [5- (4
-Nitrophenyl) -4-isoxazolyl] propionamide yield: 49 mg (yield 83%) HPLC analysis: Purity 100% (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: Purity 99.8% (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: Purity 99.7% (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: Purity 99.9% (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% (holding 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: Purity 97.9% (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 (yield 33%) HPLC analysis: Purity 100% (retention time: 3.375)
Min) 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 (Yield 40%) HPLC analysis: Purity 100% (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: Purity 99.9% (retention time: 3.637)
Min) 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 (Yield 44%) HPLC analysis: Purity 100% (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 (yield 57%) HPLC analysis: Purity 98.3% (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)
Min) 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: Purity 97.6% (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: Purity 95.8% (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 (Yield 50%) HPLC analysis: Purity 100% (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: Purity 97.6% (retention time: 3.505)
Min) 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 37%) HPLC analysis: 100% purity (retention time: 3.730)
Min) 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 (21% yield) 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: Purity 98.1% (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: Purity 99.7% (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)
Min) 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: Purity 98.4% (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 (yield 57%) HPLC analysis: Purity 100% (retention time: 3.725)
Min) 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 (yield 12%) HPLC analysis: Purity 80.0% (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: Purity 91.6% (retention time: 3.211)
Min) MS (ESI +): 399 (M + H) Example 412 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- [3- (diethylphosphono) propyl] propionamide Yield: 10 mg (yield 18%) HPLC analysis: Purity 97.4% (retention time: 3.182)
Min) MS (ESI +): 413 (M + H)

Example 413 N- {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenyl} -3- (5-phenyl-4)
-Isoxazolyl) propionamide HPLC analysis: Purity 99.7% (retention time: 3.688)
Min) MS (ESI +): 422 (M + H) Example 414 3- (5-phenyl-4-isoxazolyl) -N-{[4
-(1H-Tetrazol-5-yl) methyl] phenyl} propionamide HPLC analysis: Purity 100% (retention time: 3.326
Min) MS (ESI +): 375 (M + H) Example 415 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] -N- {4-[(1H-1,2,4-triazole-1. -Yl) methyl] phenyl} propionamide HPLC analysis: Purity 99.7% (retention time: 3.689)
Min) MS (ESI +): 442 (M + H) Example 416 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] -N- {4-[(1H-pyrazol-1-yl).
Methyl] phenyl} propionamide HPLC analysis: Purity 97.0% (retention time: 4.092
Min) MS (ESI +): 441 (M + H)

Example 417 3- [5- (3,4-Dichlorophenyl) -4-isoxazolyl] -N- {4-[(2-methyl-1H-imidazol-1-yl) methyl] phenyl} propionamide HPLC Analysis: Purity 97.5% (retention time: 3.377
Min) MS (ESI +): 455 (M + H) Example 418 N- {4-[(2,5-dioxoimidazolidin-1-yl) methyl] phenyl} -3- [5- (3,4-dichlorophenyl). ) -4-Isoxazolyl] propionamide HP
LC analysis: Purity 93.0% (retention time: 3.747 min) MS (ESI +): 473 (M + H) Example 419 3- [5- (3,4-dichlorophenyl) -4-isoxazolyl] -N- { 4-[(2,4-Dioxo-1,3-thiazolidin-3-yl) methyl] phenyl} propionamide HPLC analysis: Purity 98.2% (retention time: 4.235).
Min) MS (ESI +): 490 (M + H) Example 420 3- [5- (3,4-Dichlorophenyl) -4-isoxazolyl] -N- {4-[(1H-1,2,4-triazole-4. -Yl) methyl] phenyl} propionamide HPLC analysis: Purity 89.0% (retention time: 3.418)
Min) MS (ESI +): 442 (M + H)

Example 421 3- [5- (4-fluorophenyl) -4-isoxazolyl] -N- {4-[(1H-1,2,4-triazole-
1-yl) methyl] phenyl} propionamide HPLC analysis: Purity 98.7% (retention time: 3.101
Min) MS (ESI +): 392 (M + H) Example 422 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(1H-pyrazol-1-yl) methyl] phenyl}. Propionamide HPLC analysis: Purity 97.0% (retention time: 3.683)
Min) MS (ESI +): 391 (M + H) Example 423 3- [5- (4-fluorophenyl) -4-isoxazolyl] -N- {4-[(2-methyl-1H-imidazole-
1-yl) methyl] phenyl} propionamide HPLC analysis: Purity 99.7% (retention time: 3.003
Min) MS (ESI +): 405 (M + H) Example 424 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(2,5-dioxoimidazolidine-
1-yl) methyl] phenyl} propionamide HPLC analysis: Purity 97.1% (retention time: 3.323)
Min) MS (ESI +): 423 (M + H)

Example 425 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(3-methyl-2,5-dioxoimidazolidin-1-yl) methyl] phenyl} Propionamide HPLC analysis: Purity 98.0% (retention time: 3.474)
Min) MS (ESI +): 437 (M + H) Example 426 N- {4-[(2,4-dioxo-1,3-thiazolidin-3-yl) methyl] phenyl} -3- [5- (4- Fluorophenyl) -4-isoxazolyl] propionamide HPLC analysis: Purity 98.3% (retention time: 3.857)
Min) MS (ESI +): 440 (M + H) Example 427 N- {4-[(2,4-dioxo-1,3-oxazolidin-3-yl) methyl] phenyl} -3- [5- (4- Fluorophenyl) -4-isoxazolyl] propionamide HPLC analysis: Purity 98.6% (retention time: 3.74)
5 min) MS (ESI +): 424 (M + H) Example 428 3- [5- (4-Fluorophenyl) -4-isoxazolyl] -N- {4-[(1H-1,2,4-triazole-
4-yl) methyl] phenyl} propionamide HPLC analysis: Purity 99.2% (retention time: 3.010
Min) MS (ESI +): 392 (M + H)

Example 429 (2E) -3- (5-phenyl-4-isoxazolyl)-
N- {4-[(1H-tetrazol-5-yl) methyl] phenyl} acrylamide HPLC analysis: Purity 88.0% (retention time: 3.506
Min) MS (ESI +): 373 Example 430 (2E) -N- {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenyl} -3- (5-phenyl- 4-Isoxazolyl) acrylamide HPLC analysis: Purity 96.7% (retention time: 3.874)
Min) MS (ESI +): 420 (M + H) Example 431 (2E) -N- {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenyl} -3- (3 -Methyl-5-phenyl-4-isoxazolyl) acrylamide HPLC analysis: Purity 99.2% (retention time: 3.965).
Min) MS (ESI +): 434 (M + H) Example 432 3- [5- (4-chlorophenyl) -4-isoxazolyl]]-N- (4-{[(4,6-dimethylpyrimidine-2-
Iyl) amino] sulfonyl} phenyl) propionamide HPLC analysis: Purity 100% (retention time: 3.781)
Min) MS (ESI +): 512 (M + H)

Example 433 N- {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenyl} -3- [5- (4-fluorophenyl) -4-isoxazolyl] Propionamide HPLC analysis: Purity 100% (retention time: 3.753
Min) MS (ESI +): 440 (M + H) Example 434 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N-ethylpropionamide HPLC analysis: Purity 100% (retention time: 3.529).
Min) MS (ESI +): 279 (M + H) Example 435 3- [5- (4-chlorophenyl) -3-isoxazolyl] propionamide HPLC analysis: 100% purity (retention time: 3.261).
Min) MS (ESI +): 251 (M + H) Example 436 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide HPLC analysis: Purity 100. % (Holding time: 3.962
Min) MS (ESI +): 477 (M + H)

Example 437 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide HPLC analysis: Purity 99.8% (retention time: 3 .719
Min) MS (ESI +): 449 (M + H) Example 438 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N- [4- (diethylphosphono) phenyl] propionamide HPLC analysis: Purity 100%. (Retention time: 4.019
Min) MS (ESI +): 463 (M + H) Example 439 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphos. Finan-2-yl) methyl] phenyl} propionamide HPLC analysis: Purity 99.2% (retention time: 3.620)
Min) MS (ESI +): 461 (M + H) Example 440 3- [5- (4-chlorophenyl) -3-isoxazolyl] carboxamide HPLC analysis: Purity 92.3% (retention time: 3.444).
Min) MS (ESI +): 223 (M + H)

Example 441 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N-ethylcarboxamide HPLC analysis: Purity 97.9% (retention time: 3.849).
Min) MS (ESI +): 251 (M + H) Example 442 3- [5- (4-chlorophenyl) -3-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] carboxamide HPLC analysis: Purity 99. 0.7% (holding time: 4.229
Min) MS (ESI +): 449 (M + H) Example 443 3- {5- [4- (trifluoromethyl) phenyl] -3-
Isoxazolyl} -N-methoxy-N-methylcarboxamide HPLC analysis: Purity 100% (retention time: 4.015)
Min) Example 444 N- {4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] phenyl} -3- [4- (4-fluorophenyl) -5-isoxazolyl] propion Amide HPLC analysis: 100% purity (retention time: 3.753)
Min) MS (ESI +): 440 (M + H)

Example 445 3- [4- (4-Fluorophenyl) -5-isoxazolyl] -N- {4-[(1H-tetrazol-5-yl) methyl] phenyl} propionamide HPLC analysis: 100% pure. (Retention time: 3.396
Min) MS (ESI +): 393 (M + H) Example 446 N- [4- (diethylphosphonomethyl) phenyl] -3-
[4- (4-fluorophenyl) -5-isoxazolyl]
Propionamide HPLC analysis: 100% purity (retention time: 3.727
Min) MS (ESI +): 461 (M + H) Example 447 N- [4- (dimethylphosphonomethyl) phenyl] -3-
[4- (4-fluorophenyl) -5-isoxazolyl]
Propionamide HPLC analysis: Purity 97.9% (retention time: 3.471)
Min) MS (ESI +): 433 (M + H) Example 448 3- [5- (3,4-Dichlorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide HPLC analysis: Purity 99.6% (retention time: 4.132
Min) MS (ESI +): 511 (M + H)

Example 449 3- [5- (3,4-Dichlorophenyl) -4-isoxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide HPLC analysis: Purity 100% (retention time: 3 .883
Min) MS (ESI +): 483 (M + H) Example 450 3- [5- (3,4-Dichlorophenyl) -4-isoxazolyl] -N- {4-[(2-oxide-1,3,2-di). Oxaphosphinan-2-yl) methyl] phenyl} propionamide HPLC analysis: Purity 99.9% (retention time: 3.776).
Min) MS (ESI +): 495 (M + H) Example 451 3- [5- (3-chlorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide HPLC analysis: Purity 91 0.7% (holding time: 4.091
Min) MS (ESI +): 475 (M + H) Example 452 N- [4- (diethylphosphonomethyl) phenyl] -3-
[5- (2-fluorophenyl) -4-isoxazolyl]
Propionamide HPLC analysis: Purity 99.4% (retention time: 3.650)
Min) MS (ESI +): 461 (M + H)

Example 453 N- [4- (dimethylphosphonomethyl) phenyl] -3-
[5- (2-fluorophenyl) -4-isoxazolyl]
Propionamide HPLC analysis: Purity 99.5% (retention time: 3.391)
Min) MS (ESI +): 433 (M + H) Example 454 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (4-Fluorophenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 97.6% (retention time: 3.910)
Min) MS (ESI +): 459 (M + H) Example 455 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (4-Methoxyphenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 99.6% (retention time: 3.863)
Min) MS (ESI +): 471 (M + H) Example 456 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (3,4-Dimethoxyphenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 96.5% (retention time: 3.691)
Min) MS (ESI +): 501 (M + H)

Example 457 (2E) -N- [4- (diethylphosphonomethyl) phenyl]
-3- [5- (2-Fluorophenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 99.0% (retention time: 3.809
Min) MS (ESI +): 459 (M + H) Example 458 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (3-Fluorophenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 99.1% (retention time: 3.913)
Min) MS (ESI +): 459 (M + H) Example 459 (2E) -3- [5- (4-chlorophenyl) -4-isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] acrylamide HPLC analysis : Purity 94.4% (Retention time: 4.119
Min) MS (ESI +): 475 (M + H) Example 460 (2E) -3- [5- (3,4-dichlorophenyl) -4-
Isoxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] acrylamide HPLC analysis: Purity 85.8% (retention time: 4.341)
Min) MS (ESI +): 509 (M + H)

Example 461 (2E) -N- [4- (diethylphosphonomethyl) phenyl]
-3- {5- [3,4- (methylenedioxy) phenyl]-
4-Isoxazolyl} acrylamide HPLC analysis: Purity 99.8% (retention time: 3.810)
Min) MS (ESI +): 485 (M + H) Example 462 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (4-Methylphenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 99.9% (retention time: 4.026
Min) MS (ESI +): 455 (M + H) Example 463 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- [5- (3,4-Difluorophenyl) -4-isoxazolyl] acrylamide HPLC analysis: Purity 96.3% (retention time: 3.982)
Min) MS (ESI +): 477 (M + H) Example 464 (2E) -N- [4- (diethylphosphonomethyl) phenyl].
-3- (4-phenyl-5-isoxazolyl) acrylamide HPLC analysis: Purity 98.7% (retention time: 3.903)
Min) MS (ESI +): 441 (M + H)

Example 465 (2E) -N- [4- (dimethylphosphonomethyl) phenyl]
-3- (4-phenyl-5-isoxazolyl) acrylamide HPLC analysis: Purity 97.9% (retention time: 3.635).
Min) MS (ESI +): 413 (M + H) Example 466 N- [4- (diethylphosphonomethyl) phenyl] -3-
(4-Phenyl-5-isoxazolyl) propionamide HPLC analysis: Purity 97.7% (retention time: 3.683)
Min) MS (ESI +): 443 (M + H) Example 467 N- [4- (dimethylphosphonomethyl) phenyl] -3-
(4-Phenyl-5-isoxazolyl) propionamide HPLC analysis: Purity 98.3% (retention time: 3.409)
Min) MS (ESI +): 415 (M + H) Example 468 N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} -3- (4- Phenyl-5-isoxazolyl) acrylamide HPLC analysis: Purity 99.5% (retention time: 3.302)
Min) MS (ESI +): 427 (M + H)

Example 469 Mitsunobu reaction of 3- [5- (3,4-difluorophenyl) -4-isoxazolyl] propanol with diethyl 4-hydroxybenzylphosphonate (1,1- (azodicarbonyl) dipiperidine, tributyl) Phosphine, tetrahydrofuran) to give 4- {3-
[4- (diethylphosphonomethyl) phenoxy] propyl}
-5- (3,4-Difluorophenyl) isoxazole was prepared. HPLC analysis: Purity 100% (retention time: 4.312
Min) MS (ESI +): 466 (M + H) Example 470 In analogy to Example 469, 5- (3,4-dichlorophenyl) -4- {3- [4- (diethylphosphonomethyl) phenoxy] propyl}. Isoxazole was synthesized. HPLC analysis: Purity 99.6% (retention time: 4.673
Min) MS (ESI +): 498 (M + H)

Example 471 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. Melting point 80-82 ° C. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7Hz), 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 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 = 7Hz), 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)

Formulation Example 1 (Production of Capsule) 1) Compound of Example 68 30 mg 2) Fine powder cellulose 10 mg 3) 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) Compound of Example 68 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets Total 140 g 1), The whole amount of 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder, and the mixture is compressed with a tableting machine. Thus, per tablet, compound 3 of Example 68
1000 tablets containing 0 mg are obtained.

[0390]

The neurotrophic factor production / secretion promoting agent of the present invention has an excellent neurotrophic factor production / secretion promoting action, and has low toxicity. Further, the agent for improving neuropathic pain (excluding low back pain and neuralgia) of the present invention has an excellent effect of improving neuropathic pain and has low toxicity. Furthermore, the method for producing a model animal for neuropathic pain of the present invention is useful for screening a neuropathic pain improving substance.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4439 A61K 31/4439 31/4709 31/4709 31/4725 31/4725 31/496 31/496 31 / 497 31/497 31/506 31/506 31/53 31/53 31/5377 31/5377 31/541 31/541 31/55 31/55 31/662 31/662 A61P 1/04 A61P 1/04 1 / 10 1/10 1/12 1/12 1/18 1/18 3/00 3/00 3/04 3/04 3/06 3/06 3/10 3/10 5/00 5/00 9/00 9/00 9/02 9/02 9/04 9/04 9/06 9/06 9/10 9/10 9/12 9/12 9/14 9/14 13/10 13/10 13/12 13 / 12 15/10 15/10 17/00 17/00 17/02 17/02 19/00 19/00 19/02 19/02 19/10 19/10 25/00 25/00 25/02 25/02 101 101 103 103 25/04 25/04 25/08 25/08 25/14 25/14 25/16 25/16 25/22 25/22 25/24 25/24 25/28 25/28 29/00 29 / 00 101 101 35/00 35/00 41/00 41/00 43/00 107 43/00 107 111 111 111 123 123 07D 413/04 C07D 413/04 413/06 413/06 413/12 413/12 413/14 413/14 417/12 417/12 C07F 9/653 C07F 9/653 9/6574 9/6574 Z G01N 33 / 15 G01N 33/15 Z 33/48 33/48 N 33/50 33/50 Z // C07M 7:00 C07M 7:00 (72) Inventor Nozomi Sakai 5-3-12 Matsumoto-dori, Hyogo-ku, Hyogo Prefecture No. (72) Inventor Takeshi Maekawa 1-22-1 Gohyoi, Ikaruga-cho, Ikoma-gun, Nara (72) Inventor Yu Momose 2-8-7 Sumiregaoka, Takarazuka, Hyogo Prefecture (72) Toru Kawamura, Nishinomiya-shi, Hyogo Prefecture 7-510 Hinoikecho No. 7-510 F Term (reference) 2G045 AA29 4C056 AA01 AB01 AC01 AD01 AE03 FA04 FA07 FA08 FA16 FA17 FC01 4C063 AA01 AA03 BB01 BB04 BB09 CC51 CC67 CC73 CC75 CC81 CC82 DD06 DD10 DD12 DD14 DD15 DD19 DD19 DD19 DD44 DD47 DD54 EE01 4C086 AA01 AA02 AA03 BC67 BC73 BC82 BC84 BC85 BC88 DA34 GA02 GA04 GA07 GA08 GA09 GA10 GA12 GA16 MA01 MA04 NA07 NA14 NA15 ZA01 ZA02 ZA04 ZA05 ZA06 ZA08 ZA12 ZA15 ZA16 ZA20 ZA24 ZA21 ZA21 4 ZA36 ZA42 ZA43 ZA45 ZA66 ZA68 ZA70 ZA72 ZA73 ZA81 ZA89 ZA96 ZA97 ZB15 ZB22 ZB26 ZC02 ZC21 ZC33 ZC35 ZC54 4H050 AA01 AA03 AB21

Claims (21)

[Claims] 1. 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; Y is a 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 esterification or amidation Indicates a carboxyl group which may be incorporated. ] A neurotrophic factor production / secretion promoter comprising the compound represented by the formula or a salt thereof or a prodrug thereof. 2. A compound represented by the general formula (I) is represented by the formula (I
a) [Chemical 2] The agent according to claim 1, which is a compound represented by: 3. The agent according to claim ^{1, wherein the} optionally substituted cyclic group represented by R ¹ or R ² is an optionally substituted aromatic group. 4. The agent according to claim ¹ , wherein R ¹ is a hydrogen atom and R ² is an optionally substituted cyclic group. 5. The agent according to claim 4, wherein R ² is an aromatic group which may be substituted. 6. The agent according to claim 1, wherein W is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms. 7. The agent according to claim 1, wherein Y is a carboxyl group which may be amidated. 8. A compound represented by the general formula (I-3): [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] An agent for improving neuropathic pain (excluding low back pain and neuralgia), which comprises a compound represented by the formula or a salt thereof or a prodrug thereof. 9. The agent according to claim 8, wherein the neuropathic pain is carpal tunnel syndrome. 10. A compound of general formula (I) for producing a neurotrophic factor production / secretion promoter. [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; Y is a 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 esterification or amidation Indicates a carboxyl group which may be incorporated. ] Use of the compound represented by these, its salt, or its prodrug. 11. A mammal 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; Y is a 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 esterification or amidation Indicates a carboxyl group which may be incorporated. ] A method for promoting production / secretion of a neurotrophic factor in the mammal, which comprises administering an effective amount of the compound represented by the formula or a salt thereof or a prodrug thereof. 12. A compound of the general formula (I-3): for producing a remedy for neuropathic pain (excluding low back pain and neuralgia). [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] Use of the compound represented by these, its salt, or its prodrug. 13. A mammal of the general formula (I-3): [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] A method for improving neuropathic pain (excluding low back pain and neuralgia) in the mammal, which comprises administering an effective amount of the compound represented by the formula or a salt thereof or a prodrug thereof. 14. A compound represented by the general formula (I-3a): [Wherein ^one of R ¹ and R ² represents a hydrogen atom or a substituent, the other represents an optionally substituted cyclic group; W represents a bond or a divalent aliphatic hydrocarbon group; R ⁶ and R ⁷ is the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁶ and R ⁷ are substituted with an adjacent nitrogen atom. Optionally forms a nitrogen-containing heterocycle. ] The compound or its salt represented by these. 15. A method for producing a model animal for neuropathic pain, which comprises cutting only the common peroneal nerve of a non-human mammal. 16. The non-human mammal is a rat.
The method according to 5. 17. A model animal for neuropathic pain obtained by the method according to claim 15. 18. A method for screening a neuropathic pain improving substance, which comprises using the model animal according to claim 17. 19. A neuropathic pain ameliorating agent comprising the neuropathic pain ameliorating substance obtained by the method according to claim 18. 20. A method for improving neuropathic pain in a mammal, which comprises administering an effective amount of the neuropathic pain improving substance obtained by the method according to claim 18 to the mammal. 21. A method for producing a neuropathic pain ameliorating agent,
Use of a neuropathic pain improving substance obtained by the method according to claim 18.