JP3074532B2 - Oxyiminoalkanoic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel oximinoalkanoic acid derivative having a hypoglycemic effect and a hypolipidemic effect, a novel pharmaceutical composition comprising oximinoalkanoic acids, and a retinoid-related receptor function regulator. About. The novel oximinoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function regulators are useful as prophylactic / therapeutic agents for diabetes, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like. .

[0002]

2. Description of the Related Art Conventionally, as oximinoalkanoic acid derivatives, for example, intermediate compounds used in the production of β-lactam compounds or cephalosporin derivatives (for example, JP-A-58-49382, JP-A-59-167576; JP-A-62-77391, JP-A-62-192587 and JP-A-3-47186) and compounds having a leukotriene biosynthesis inhibitory activity (eg, WO96 / 02507) have been reported. However, it has not been reported that these compounds have a blood glucose and blood lipid lowering effect. On the other hand, as a preventive and / or therapeutic agent for hyperlipidemia, hyperglycemia, etc., oxime derivatives (for example,
8779, JP-A-9-323929), but the derivative is not an oximinoalkanoic acid derivative. Further, a phenylalkanoyl acid derivative having a hydroxyl group substituted at the 4-position as a peroxisome proliferator-activated receptor gamma (hereinafter sometimes abbreviated as PPARγ) agonist, which is one of retinoid-related receptor ligands (Eg, WO97 / 31907, WO97
/ 25042), but the derivative is not an oximinoalkanoic acid derivative. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily represented by steroid hormone receptors and thyroid hormone receptors.
Its expression is induced very early in adipocyte differentiation, and plays an important role in adipocyte differentiation as a master regulator. PPARγ forms a dimer with a retinoid X receptor (RXR) by binding to a ligand, and binds to a responsive site of a target gene in the nucleus to directly control (activate) transcription efficiency. In recent years, 15-deoxy- △ ^12.14 prostaglandin J ₂ , a metabolite of prostaglandin D ₂ , has been found to be an endogenous ligand of PPARγ, and furthermore, a type of insulin sensitivity enhancement represented by a thiazolidinedione derivative. It has been found that the drug has a PPARγ ligand activity, and its strength is paralleled by a hypoglycemic action or an adipocyte differentiation promoting action [Cell, 83, 803 (1995);・ Biological chemistry (The Jo
urnal of Biological Chemistry), 270, 129
53 (1995): Journal of Medicinal Chemistr
y), 39, 655 (1996)]. More recently, 1) that PPARγ is expressed in cultured cells derived from human liposarcoma and its growth is stopped by the addition of a PPARγ ligand [Proceedings of the National Academy of Sciences of the United・ States of America (Proceedings of
The National Academy of Siences of The United Sta
tes of America), 94, 237, (1997)
2) that non-steroidal anti-inflammatory drugs represented by indomethacin and fenoprofen have PPARγ ligand activity [The Journal of Biological Chemistr
y), vol. 272, p. 3406 (1997)], 3) that PPARγ is highly expressed in activated macrophages, and the transcription of genes involved in inflammation is inhibited by the addition of its ligand [Nature, 391, 7
9 (1998)], 4) PPARγ ligands are inflammatory cytokines (TNFα, IL-1β,
Suppressing the production of IL-6) [Natural
e), vol. 391, p. 82 (1998)].

[0003]

It has an excellent blood glucose lowering effect and blood lipid lowering effect, and is useful as a preventive / therapeutic agent for diabetes, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like. It is an object of the present invention to provide novel oximinoalkanoic acid derivatives and retinoid-related receptor function regulators.

[0004]

The present invention provides: 1) a compound represented by the following general formula (I-1):

Embedded image [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group which may be substituted; X represents a bond, -CO-, -CH
A group represented by (OH)-or -NR ^6- (R ⁶ is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom , -SO -, - SO ₂ - or -NR ⁷ - (provided that R ⁷
Represents a hydrogen atom or an optionally substituted alkyl group. Ring A is a benzene ring optionally having 1 to 3 substituents; p is 1 to 8
R ² is a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group; q ′ is an integer of 0 to 6; m is 0 or 1; R ³ is a hydroxy group; O
R ⁸ (R ⁸ represents an optionally substituted hydrocarbon group.)
Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group. R ⁹ and R ¹⁰ may combine to form a ring); R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or an optionally substituted hydrocarbon group, R ⁴ may combine with R ² to form a ring. Provided that R ¹ is ethoxymethyl, C _1-3 alkyl, phenyl or p-methoxyphenyl and q ′ =
When m = 0, R ³ is NR ⁹ R ¹⁰ . (Provided that [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2-iminoxypropionic acid and pyruvate methyl ester are O- [2-chloro-4- (2 -Quinolylmethoxy) phenylmethyl] oxime) or a salt thereof; 2) the compound according to the above 1), wherein R ¹ is an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group, or 3) The compound according to the above 1), wherein X is a bond or a group represented by -NR ^6- (R ⁶ is an optionally substituted alkyl group), or a salt thereof; 4) n is a salt thereof. 5) The compound according to the above 1), which is 1 or 2, or a salt thereof; 5) the compound according to the above 1), wherein Y is an oxygen atom, or a salt thereof; 6) the compound according to the above 1), wherein p is an integer of 1 to 3. Or a salt thereof; 7) R ³ is a hydrogen atom, —OR ⁸ (R ⁸ represents an optionally substituted hydrocarbon group) or —NR ^{9 ′} R ^{10 ′} (R ^{9 ′}
And R ^{10 ′} are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon group, and R ^{9 ′} and R ^{10 ′}
May combine to form a ring. 1)
8) The compound according to the above 1), wherein q ′ is an integer of 0 to 4, or a salt thereof; 9) The compound according to the above 1), wherein R ² is an optionally substituted hydrocarbon group. A compound or a salt thereof;

10) The compound according to the above 1) or a salt thereof, wherein the compound is E -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid 11) the compound is E -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyramide and E- 8- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid or a salt thereof according to 1) above; 12) R ¹ being substituted The compound or salt thereof according to the above 2), wherein the optionally substituted heterocyclic group or the optionally substituted cyclic hydrocarbon group is a group selected from the group represented by the following formula;

Embedded image 13) a ring selected from the group consisting of phenyl which may be unsubstituted or substituted, furyl which may be substituted, thienyl which may be substituted and C _1-4 alkyl which may be substituted; Or the compound according to the above 12) having two substituents or a salt thereof; 14) a group whose ring is represented by the following formula (where Ph is phenyl which may be substituted, and R ″ is hydrogen) Represents an atom or an optionally substituted C _1-6 alkyl.)
2) The compound of the above or a salt thereof;

Embedded image 15) General formula

Embedded image Wherein R ′ is an optionally substituted phenyl, furyl or thienyl group; R ″ is a hydrogen atom or an optionally substituted C _1-6 alkyl; R ^{2 ′} is a hydrogen atom, C ₁ Phenyl which may be substituted with at least one substituent selected from the group consisting of _-6 alkyl, C _1-6 alkoxy and halogen; q is an integer of 1 to 6;
R ^{3 ′} represents a hydroxy group, a C _1-6 alkoxy group or —NR ⁹
R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom,
Represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, and R ⁹ and R ¹⁰ may combine to form a ring . )] Or a salt thereof;

16) General formula (II)

Embedded image [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group which may be substituted; X represents a bond, -CO-, -CH
A group represented by (OH)-or -NR ^6- (R ⁶ is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom , -SO -, - SO ₂ - or -NR ⁷ - (provided that R ⁷
Represents a hydrogen atom or an optionally substituted alkyl group. Ring A is a benzene ring optionally having 1 to 3 substituents; p is 1 to 8
R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or a heterocyclic group; q represents an integer of 0 to 6; m represents 0 or 1; R ³ represents a hydroxy group; ⁸
(R ⁸ represents an optionally substituted hydrocarbon group.) Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group, R ⁹ and R ¹⁰ may be bonded to each other to form a ring; and R ⁴ and R ⁵ are the same or different Represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ⁴ may be bonded to R ² to form a ring. 17) a pharmaceutical composition according to the above 16), which is a prophylactic / therapeutic agent for diabetes; and 18) a prophylactic / therapeutic agent for hyperlipidemia. 19) The pharmaceutical composition according to 16), which is an agent for preventing or treating glucose intolerance; 20) The pharmaceutical composition according to 16), which is an agent for preventing or treating inflammatory diseases. 21) the pharmaceutical composition according to 16), which is an agent for preventing or treating arteriosclerosis;

22) General formula (II)

Embedded image [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group which may be substituted; X represents a bond, -CO-, -CH
A group represented by (OH)-or -NR ^6- (R ⁶ is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom , -SO -, - SO ₂ - or -NR ⁷ - (provided that R ⁷
Represents a hydrogen atom or an optionally substituted alkyl group. Ring A is a benzene ring optionally having 1 to 3 substituents; p is 1 to 8
R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or a heterocyclic group; q represents an integer of 0 to 6; m represents 0 or 1; R ³ represents a hydroxy group; ⁸
(R ⁸ represents an optionally substituted hydrocarbon group.) Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group, R ⁹ and R ¹⁰ may be bonded to each other to form a ring; and R ⁴ and R ⁵ are the same or different Represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ⁴ may be bonded to R ² to form a ring. 23) a retinoid-related receptor function modulator comprising a compound represented by the formula: or 23) the agent described in 22) above, which is a peroxisome proliferator-activated receptor ligand; and 24) a retinoid X receptor ligand. 25) The agent according to 22), which is an insulin sensitivity enhancer; 26) the agent according to 22), which is an insulin sensitizer.

(1) Definition of R ^{1 In} general formulas (I-1) and (II), the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ¹ is an aliphatic hydrocarbon Groups, alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups, araliphatic hydrocarbon groups, and aromatic hydrocarbon groups. The number of carbon atoms in these hydrocarbon groups is preferably 1 to 14. (1-1) Definition of hydrocarbon group of R ^{1 As} the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable. Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like, and a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, an alkyl group, etc.); -Propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-
Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1 -Propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5
-Unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms such as -hexynyl, 1-heptynyl and 1-octynyl (e.g.
An alkenyl group of 8, an alkadienyl group having 4 to 8 carbon atoms,
An alkenylalkynyl group having 2 to 8 carbon atoms, 4 to 8 carbon atoms
And the like). As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable. Examples of the alicyclic hydrocarbon group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
A saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cycloheptyl (eg, a cycloalkyl group); for example, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl , 3
An unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms such as -cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl (eg, cycloalkenyl group, cycloalkadienyl) And the like).

Examples of the alicyclic-aliphatic hydrocarbon group include those in which the alicyclic hydrocarbon group and the aliphatic hydrocarbon group are bonded (eg, cycloalkyl-alkyl group, cycloalkenyl-alkyl group, etc.). Among them, an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable. As the alicyclic-aliphatic hydrocarbon group, for example, cyclopropylmethyl,
Cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptyl Ethyl and the like. As the araliphatic hydrocarbon group, an araliphatic hydrocarbon group having 7 to 13 carbon atoms (eg, an aralkyl group having 7 to 13 carbon atoms, an arylalkenyl group having 8 to 13 carbon atoms) is preferable. Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; α-naphthylmethyl, α -Naphthylethyl, β-naphthylmethyl, β
-Naphthylalkyl having 11 to 13 carbon atoms such as naphthylethyl; phenylalkenyl having 8 to 10 carbon atoms such as styryl; and 12 to 13 carbon atoms such as 2- (2-naphthylvinyl)
Naphthylalkenyl and the like. As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group or the like) is preferable. Examples of the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

(1-2) Definition of heterocyclic group represented by R ^{1 In} the general formulas (I-1) and (II), the heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹ Represents 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms as ring constituent atoms.
And a 5- to 7-membered monocyclic heterocyclic group or fused heterocyclic group. As the fused heterocyclic ring, for example, these 5
And a condensed ring of a 7-membered monocyclic heterocycle and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Specific examples of the heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4- Thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazole-2-
Yl, 1,3,4-thiadiazol-2-yl, 1,
2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,2 3
-Triazol-4-yl, tetrazol-1-yl,
Tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl,
2-quinoxalyl, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1
H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-
Pyrrolo [2,3-b] pyridin-6-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 1H-imidazo [ Aromatic heterocyclic groups such as 4,5-b] pyrazin-2-yl; and 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl, thiazolidine -3-yl, imidazolidine-3-yl, 2-
Oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidine-3-
And a non-aromatic heterocyclic group such as yl. The heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl,
Benzoxazolyl or benzothiazolyl.

(1-3) Definition of substituents of hydrocarbon group and / or heterocyclic group of R ^{1 In} general formulas (I-1) and (II), hydrocarbon group and heterocyclic group represented by R ¹ Is 1 at each replaceable position
It may have up to 5, preferably 1 to 3 substituents. Examples of the substituent include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, and an optionally substituted An aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a nitro group, an optionally substituted amino group, an optionally substituted acyl group,
Examples 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 substituent represented by “optionally substituted” include a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, A C _1-6 haloalkyl group and a C _1-6 haloalkoxy group. Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group. Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-
Examples include dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Preferred examples of the alkenyl group include those having 2 carbon atoms.
Alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3
-Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like. Preferred examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-
Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like can be mentioned.

The alicyclic hydrocarbon group may have 3 to 1 carbon atoms.
And 2 saturated or unsaturated alicyclic hydrocarbon groups, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like. Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2. 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.
3.1] decyl and the like. Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1. -Yl and the like.
Preferred examples of the cycloalkadienyl group include those having 4 carbon atoms.
And 10 to 10 cycloalkadienyl groups, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Preferable examples of the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group, etc.), for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Phenyl, 1-naphthyl, 2-naphthyl and the like are preferred.

Preferred examples of the aromatic heterocyclic group include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,
A carbon atom as a ring-constituting atom such as 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl; 5 to 5 containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen
7-membered aromatic monocyclic heterocyclic group; for example, benzofuranyl,
Isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbonylyl, β-carbonilyl, γ-carbonilyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl Inyl, thianthrenyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1 , 2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like Oxygen atoms other than carbon atoms as ring constituent atoms The number of carbon atoms containing 1-5 amino acids hetero atom selected from sulfur atom and a nitrogen atom 3
And 13 condensed bicyclic or tricyclic aromatic heterocycles. Preferable examples of the non-aromatic heterocyclic group include those having 2 to 10 carbon atoms containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. For example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl,
Morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino, thiomorpholino and the like. Examples of halogen atoms include fluorine,
Chlorine, bromine and iodine are mentioned, among which fluorine and chlorine are preferred.

The amino group which may be substituted includes:
For example, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an acyl group having 1 to 13 carbon atoms (eg, An alkanoyl group having 2 to 10 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms, etc.) or 6 carbon atoms
And an amino group which may be mono- or di-substituted by an aryl group, etc. The acyl group referred to herein has the same definition as the below-mentioned acyl group which may be substituted. Examples of the substituted amino group include methylamino, dimethylamino, ethylamino, diethylamino,
Propylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like.

As the acyl group in the optionally substituted acyl group, an acyl group having 1 to 13 carbon atoms, specifically, formyl, for example, an alkyl group having 1 to 10 carbon atoms,
A cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms,
Examples thereof include a group in which a carbonyl group is bonded to an aryl group having 6 to 12 carbon atoms or an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, etc.). Preferred examples of the acyl group include, for example, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like. The acyl group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include an alkyl group having 1 to 3 carbon atoms, for example, an alkyl group having 1 to 3 carbon atoms. Examples include an alkoxy group, halogen (eg, fluorine, chlorine, iodine, etc.), nitro, hydroxy, amino and the like. Another form of the acyl group is represented by the following general formula. _{^{-COR 11, -SO 2 R 14,}} -SOR 15 or -PO ₃ R
¹⁶ R ^{17 wherein} R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are the same or different and may be substituted hydrocarbon groups. Examples of the “optionally substituted hydrocarbon group” represented by R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ include those having 1 to 1 carbon atoms.
Examples thereof include an alkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and an aryl group having 6 to 12 carbon atoms. Examples of the substituent represented by “optionally substituted” include a C _1-6 alkyl group (except when the hydrocarbon group is an alkyl group), a C _1-6 alkoxy group, and a halogen atom (eg, , Fluorine, chlorine, bromine, iodine, etc.), a nitro group, a C _1-6 haloalkyl group, and a C _1-6 haloalkoxy group.

In the optionally substituted hydroxy group, examples of the substituted hydroxy group include an optionally substituted alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group. . Preferable examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy and neopentyl. Pentyloxy, hexyloxy, heptyloxy, nonyloxy,
Cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like can be mentioned. Preferred examples of the alkenyloxy group include an alkenyloxy group having 2 to 10 carbon atoms,
For example, allyloxy, crotyloxy, 2-
Pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like can be mentioned. Preferable examples of the aralkyloxy group include an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, more preferably an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.). .
Preferable examples of the aryloxy group include those having 6 to 14 carbon atoms.
Aryloxy group, for example, phenoxy, naphthyloxy and the like. The above-mentioned alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have one or two substituents at substitutable positions. Examples of such substituents include Halogen (eg, fluorine, chlorine, bromine, etc.),
Examples thereof include an alkoxy group having 1 to 3 carbon atoms. For example, examples of the substituted aryloxy group include 4-chlorophenoxy and 2-methoxyphenoxy.

In the optionally substituted thiol group, examples of the substituted thiol group include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, heteroarylthio and the like. Preferred examples of the alkylthio group include those having 1 to 1 carbon atoms.
0 alkylthio groups such as methylthio, ethylthio,
Propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like. Preferred examples of the cycloalkylthio group include those having 3 to 1 carbon atoms.
A cycloalkylthio group such as cyclobutylthio,
Cyclopentylthio, cyclohexylthio and the like. Preferred examples of the aralkylthio group include those having 7 to 7 carbon atoms.
And 10 aralkylthio groups such as phenyl-C _1-4 alkylthio (eg, benzylthio, phenethylthio, etc.). Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, and more preferably an acylthio group having 2 to 13 carbon atoms.
And alkanoylthio groups (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) and the like. Preferred examples of the arylthio group include arylthio groups having 6 to 14 carbon atoms, such as phenylthio,
And naphthylthio. Preferable examples of the heteroarylthio group include 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like in addition to 2-pyridylthio, 3-pyridylthio and the like.

Among the carboxyl groups which may be esterified, examples of the carboxyl group which has been esterified include alkoxycarbonyl groups having 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) An aralkyloxycarbonyl group having 8 to 10 carbon atoms (eg, benzyloxycarbonyl, etc.) and 1 to 2 carbon atoms having 1 to 1 carbon atoms;
7 to 15 carbon atoms which may be substituted with an alkyl group of 3
(E.g., phenoxycarbonyl, p-tolyloxycarbonyl, etc.).

Among the carboxyl groups which may be amidated, the carboxyl groups which are amidated include:
Formula: —CON (R ¹² ) (R ¹³ ) (wherein, R ¹² and R ¹³ are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. Shown)). Here, as the hydrocarbon group in the “optionally substituted hydrocarbon group” and the heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹² and R ¹³ , the above-mentioned “R ^A hydrocarbon group in the “optionally substituted hydrocarbon group” represented by ¹ and “R ¹
The aliphatic hydrocarbon group, the alicyclic hydrocarbon group, the aromatic hydrocarbon group, and the heterocyclic group exemplified as the "heterocyclic group in the" optionally substituted heterocyclic group "represented by. The hydrocarbon group and the heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include halogen (eg, fluorine, chlorine, bromine, iodine). Etc.), an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and the like.

In the general formulas (I-1) and (II), the substituent in the hydrocarbon group and the heterocyclic group represented by R ¹ is
It is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, or an aryl group having 6 to 14 carbon atoms, and more preferably an alkyl group having 1 to 3 carbon atoms, furyl, thienyl, phenyl, and naphthyl. When the substituent in the hydrocarbon group and the heterocyclic group represented by R ¹ is an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, Each substituent may have one or more, preferably 1 to 3 suitable substituents. Examples of such a substituent include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, A cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic A heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.), an aralkyl group having 7 to 9 carbon atoms, an amino group, an alkyl group having 1 to 4 carbon atoms; Acyl group (e.g., such as an alkanoyl group) having 2 to 8 carbon atoms in the mono- or di-substituted amino group, amidino group, 2 carbon atoms
To 8 acyl groups (eg, alkanoyl groups, etc.), carbamoyl groups, carbamoyl groups mono- or di-substituted by alkyl groups having 1 to 4 carbon atoms, sulfamoyl groups, 1 carbon atoms
A sulfamoyl group mono- or di-substituted with an alkyl group having 4 to 4, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, Carbon number 3 ~
7, a cycloalkyloxy group having 7 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, and an aryloxy group having 6 to 14 carbon atoms (eg,
Phenyloxy, naphthyloxy, etc.), thiol group,
An alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.), a sulfo group, a cyano group, an azido group, a nitro group, and a nitroso group , Halogen atoms (eg, fluorine, chlorine, bromine, iodine) and the like.

(1-4) Preferred Examples of R ^{1 In} the general formulas (I-1) and (II), R ¹ is preferably an optionally substituted heterocyclic group, more preferably Pyridyl, oxazolyl, thiazolyl or triazolyl which may be substituted. R ¹ is
Particularly preferably, alkyl having 1 to 3 carbon atoms, 3 to 7 carbon atoms
Pyridyl, oxazolyl, thiazolyl or triazolyl which may have one or two substituents selected from cycloalkyl, furyl, thienyl, phenyl and naphthyl. Furyl, thienyl, phenyl and naphthyl have, as substituents, alkyl having 1 to 3 carbons, alkoxy having 1 to 3 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.) and haloalkyl having 1 to 3 carbons. You may have. The suitable optionally substituted heterocyclic group or optionally substituted cyclic hydrocarbon group for R ¹ is represented by the following structural formula.

Embedded image These rings may have one or two substituents selected from phenyl, furyl, thienyl and alkyl having 1 to 4 carbon atoms. The phenyl, furyl and thienyl are alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 1 to 6 carbons, carbon number 1
And may have a substituent selected from haloalkoxys. In addition, alkyl having 1 to 4 carbon atoms is 1 to 4 carbon atoms.
6, alkoxy, halogen (eg, fluorine, chlorine, bromine,
Iodine), nitro, haloalkyl having 1 to 6 carbon atoms,
It may have a substituent selected from haloalkoxy having 1 to 6 carbon atoms. More preferred rings of R ¹ are those represented by the following structural formulas.

Embedded image [In the formula, Ph is an optionally substituted phenyl group, R "
Represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms. Examples of the substituent of the alkyl group having 1 to 6 carbon atoms of Ph and R ″ include alkoxy having 1 to 6 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, 1 to 6 carbon atoms.
And haloalkoxy having 6 to 6 carbon atoms.

(2) Definition of X In the general formulas (I-1), (I-2) and (II), X is a bond, -CO-, -CH (OH)-or -NR ^6-.
(R ⁶ represents an alkyl group which may be substituted), and is preferably a bond, —CH (OH) — or —NR ⁶ —, and more preferably a bond or —NR ⁶ — preferable. Here, as the alkyl group in the “optionally substituted alkyl group” for R ⁶ ,
Examples thereof include an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl and the like. The alkyl group is
It may have 1 to 3 substituents at substitutable positions, and examples of such substituents include halogen (eg,
Fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy,
t.-butoxy), a hydroxy group, a nitro group, and an acyl group having 1 to 4 carbon atoms (eg, an alkanoyl group having 1 to 4 carbon atoms such as formyl, acetyl, and propionyl).

(3) Definition of n and Y In the general formulas (I-1), (I-2) and (II), n is 1
And represents an integer of 3 to 3, preferably 1 or 2. In the general formulas (I-1), (I-2) and (II), Y
, - - -O is S -, - SO -, - SO 2 - or -NR ⁷
— (R ⁷ represents an optionally substituted alkyl group)
Are illustrated, -O -, - S- or -NR ⁷ - is preferred. Here, as the "optionally substituted alkyl group" represented by R ^7, include those similar to the "optionally substituted alkyl group" represented by R ⁶ described above.

(4) Definition of Ring A In the general formulas (I-1), (I-2) and (II), ring A represents a benzene ring, and one to three further substituents are substituted at substitutable positions. It may have a group. Examples of such a substituent include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, a nitro group, and an optionally substituted amino group. In each case, those exemplified as the substituents in the hydrocarbon group and the heterocyclic group represented by R ¹ are used. The substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom. Further, the compounds represented by the general formulas (I-1), (I-2) and (I
I) Medium, partial structural formula

Embedded image It is.

(5) Definition of p In the general formulas (I-1), (I-2) and (II), p is 1
And an integer of 1 to 8, preferably an integer of 1 to 3.

[0026] (6) Definition of general formula R ² (I-1), as (I-2) and (II) in "optionally substituted hydrocarbon group" represented by R ^2, R ¹ And the "optionally substituted hydrocarbon group" represented by. As the "optionally substituted heterocyclic group" represented by R ^2, R
Include those exemplified as the "optionally substituted heterocyclic group" represented by ^1. Formulas (I-1) and (I-
In 2) and (II), R ² is preferably an optionally substituted hydrocarbon group. R ² is more preferably an aliphatic hydrocarbon group which may be substituted,
An alicyclic hydrocarbon group, an araliphatic hydrocarbon group or an aromatic hydrocarbon group, particularly preferably an alkyl group having 1 to 4 carbon atoms, each of which may be substituted;
0 is a phenylalkenyl group and an aryl group having 6 to 14 carbon atoms. The substituent which these hydrocarbon groups may have is preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms and an aromatic heterocyclic group (eg, furyl, thienyl). ).

(7) Definitions of q, q 'and m In the general formulas (I-1) and (I-2), q' represents an integer of 0 to 6, and preferably 0 to 4. m is 0 or 1. However, in the general formula (I-1), R ¹
Is ethoxymethyl, C _1-3 alkyl, phenyl or p
When it is -methoxyphenyl, q 'represents an integer of 1 to 6. In the general formula (II), q represents an integer of 0 to 6, preferably 0 to 4. m is 0 or 1.

[0028] (8) R defined R ³ of ³ hydroxy groups, -OR ⁸ (indicating the R ⁸ may be substituted hydrocarbon group.) Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same Or a different hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, and R ⁹ and R ¹⁰ are bonded to form a ring May be formed). In the general formulas (I-1), (I-2) and (II), R
As "optionally substituted hydrocarbon group" represented by ^8, those exemplified as the "optionally substituted hydrocarbon group" represented by R ^1. Preferably, R
⁸ is an "alkyl group having 1 to 4 carbon atoms" and "1 to 4 carbon atoms".
4 alkyl groups or aryl groups having 6 to 10 carbon atoms which may be substituted with halogen atoms ". here,
Examples of the alkyl group having 1 to 4 carbon atoms include methyl, ethyl, propyl, butyl, isobutyl, sec-butyl,
T-butyl is exemplified, and among them, methyl and ethyl are preferred. Examples of the halogen in the "alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with a halogen atom" include fluorine, chlorine, bromine,
And iodine. Among them, chlorine is preferred, and the number of carbon atoms is 6
Examples of the aryl group of No. 10 to No. 10 include phenyl and naphthyl. Formula (I-
In 1), (I-2) and (II), the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ⁹ and R ¹⁰ are R ¹ And the same as the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”. In the general formulas (I-1), (I-2) and (II),
As the “optionally substituted acyl group” for R ⁹ or R ¹⁰ , the “substituted or substituted hydrocarbon group” for R ¹ may be substituted. Examples of the "acyl group which may be substituted" are exemplified. Formulas (I-1), (I-2) and (II)
Wherein R ⁹ and R ¹⁰ may combine to form a 5- to 7-membered cyclic amino group, and specific examples of the cyclic amino group include 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl , 4-morpholino, 4-thiomorpholino and the like.

[0029] (9) Definition ^of R ⁴ and R ⁵ R ⁴ and R ⁵ represent the same or different, each represent a hydrogen atom, an optionally substituted hydrocarbon group, respectively, also R ⁴ is R ²
And may form a ring. Formula (I-
In 1), (I-2) and (II), the “optionally substituted hydrocarbon group” represented by R ⁴ and R ⁵ includes the aforementioned R
Include those similar to the "optionally substituted hydrocarbon group" in ^1, preferably like those similar to the "optionally substituted alkyl group" represented by R ^6. In the general formulas (I-1), (I-2) and (II), R
⁴ may combine with R ² to form a ring. Examples of the ring formed by combining R ⁴ with R ² include cycloalkanes having 5 to 11 carbon atoms and cycloalkenes having 5 to 11 carbon atoms, and specific examples thereof include cyclopentane, cyclopentene, cyclohexane, and cyclohexene. , Cycloheptane, cycloheptene, cyclooctane, cyclooctene, cyclononane, cyclononene, cyclodecane, cyclodecene, cycloundecane, cycloundecene, and the like.

(10) (E) and / or (Z) Compounds The compounds represented by the general formulas (I-1), (I-2) and (II) include the compounds (E) Body and (Z)
The body exists. The compounds include the (E) -form and the (Z) -form alone and a mixture thereof. In addition,
O- [2-Chloro-4- (2-quinolylmethoxy) phenylmethyl] oxime of [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2-iminoxypropionic acid and pyruvate methyl ester is , WO9
6/02507, and the general formula (I-1) does not include these compounds.

(11) Preferred Specific Examples Among the compounds of the general formula (I-1), preferred specific examples of the present invention include compounds represented by the following general formula.

Embedded image Wherein R ′ is alkyl having 1 to 6 carbons, 1 to 6 carbons
Phenyl optionally substituted with a substituent selected from alkoxy, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 1 to 6 carbons and haloalkoxy having 1 to 6 carbons, R "is a hydrogen atom or an optionally substituted alkyl having 1 to 6 carbon atoms (more preferably a hydrogen atom, a methyl group or an ethyl group); R2 ^' is a hydrogen atom or a 1 carbon atom. the integer q is from 1 6; 6 alkyl, of 1 to 6 carbon atoms alkoxy, at least one substituent a phenyl group which may be substituted with a group selected from the group consisting of halogen R 3 ^' is hydroxy, alkoxy of 1 to 6 carbon atoms or -NR ⁹ group represented by R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, optionally substituted Which may be a heterocyclic group, an optionally substituted acyl group or R ⁹ and R ¹⁰ bonded may form a ring); the. Ring A is optionally substituted with benzene ring respectively Or a salt thereof. Another preferred specific example of the present invention includes a compound represented by the following general formula.

Embedded image [Wherein the symbols are as defined above;] or a salt thereof.

Preferred specific examples of the compounds represented by formulas (I-1) and (II) include, for example, the following compounds (1) to (10). (1) Z- 2- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -2
-Phenylacetic acid (2) Z -4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyric acid (3) Z- 2- (4-bromophenyl) -2- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (4) Z- 2- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -2
-(4-phenoxyphenyl) acetic acid (5) Z -4- (4-fluorophenyl) -4- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (6) Z -3-methyl-2- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (7) E -4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyric acid (8) E -4- (4-fluorophenyl) -4- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (9) E -4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyramide (10) E- 8- [4- (5-methyl-2-phenyl-
4-oxazolylmethoxy) benzyloxyimino]-
8-Phenyloctanoic acid These compounds may be simply abbreviated as compound (1), compound (2) and the like.

Formula (I-1), (I-2) or (I
A compound represented by I) (hereinafter simply referred to as compound (I-1),
(I-2) or (II)) is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid , Salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Examples thereof include salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, 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 -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, etc., and preferred examples of the salt with an acidic amino acid include
For example, salts with aspartic acid, glutamic acid and the like can be mentioned. Among the above salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

(13) Formulation Compounds (I-1), (I-2) and (II) and their salts (hereinafter sometimes abbreviated simply as the compound of the present invention)
Can be used in mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, , Pigs, monkeys, etc.) as prophylactic and therapeutic agents for various diseases described below.

Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; It is blended as a solvent, a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, a soothing agent and the like in the preparation. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, and the like. Examples include pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium metasilicate aluminate. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, pregelatinized starch, sucrose, gelatin, acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, and the like.

Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like. Preferred examples of the dissolution aid include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples include sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbate and the like. Preferable examples of the colorant include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2, water-insoluble lake dyes) (Eg, the aluminum salt of the water-soluble edible tar dye, etc.), natural pigments (eg, β-carotene, chlorophyll, red pepper, etc.) Preferable examples of the sweetener include, for example, sodium saccharin, dipotassium glycyrrhizinate, Aspartame, stevia and the like.

(14) Dosage Form The dosage form of the pharmaceutical composition includes, for example, oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; Injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, Parenteral preparations such as rectal suppositories, vaginal suppositories, etc.), pellets, and drops, which can be safely orally or parenterally administered, respectively. The pharmaceutical composition can be produced by a method commonly used in the technical field of formulation, for example, a method described in the Japanese Pharmacopoeia. Hereinafter, a specific production method of the preparation will be described in detail.

For example, oral preparations include, as active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, gelatinized Starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and then, if necessary, taste masking It is manufactured by coating with a coating base by a method known per se for the purpose of enteric or sustainability.
Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base. As a sugar coating base, sucrose is used, and talc, precipitated calcium carbonate, gelatin, gum arabic,
One or two selected from pullulan, carnauba wax, etc.
More than one species may be used in combination. As the water-soluble film coating base, for example, hydroxypropyl cellulose,
Cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose and methylhydroxyethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.), polyvinylpyrrolidone; And the like.

Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L
(Trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]
And acrylic acid polymers; natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS
Acrylic polymers such as [Eudragit RS (trade name), Rohm Pharma Co., Ltd.] and ethyl acrylate / methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] .
The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.

For injections, the active ingredient is composed of a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., and a preservative (eg, methyl paraben, propyl paraben, benzyl). Alcohol, chlorobutanol, phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, dextrose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) Alternatively, it is produced by dissolving, suspending or emulsifying in an oily solvent (eg, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.). At this time, if necessary, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.

(15) Composition Another aspect of the present invention is a pharmaceutical composition containing a compound represented by the following general formula (II).

Embedded image [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group which may be substituted; X represents a bond, -CO-, -CH
A group represented by (OH)-or -NR ^6- (R ⁶ is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom , -SO -, - SO ₂ - or -NR ⁷ - (provided that R ⁷
Represents a hydrogen atom or an optionally substituted alkyl group. Ring A is a benzene ring optionally having 1 to 3 substituents; p is 1 to 8
R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or a heterocyclic group; q represents an integer of 0 to 6; m represents 0 or 1; R ³ represents a hydroxy group; ⁸
(R ⁸ represents an optionally substituted hydrocarbon group.) Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group, R ⁹ and R ¹⁰ may be bonded to each other to form a ring; and R ⁴ and R ⁵ are the same or different Represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ⁴ may be bonded to R ² to form a ring. Or a salt thereof. Each of the above substituents is the same as defined in the general formula (I-1). In particular, this pharmaceutical composition can be used for the prevention and treatment of diabetes, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like. Among these compositions, preferred ones are represented by the following general formula.

Embedded image Wherein R ′ is alkyl having 1 to 6 carbons, 1 to 6 carbons
Phenyl optionally substituted with a substituent selected from alkoxy, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, haloalkyl having 1 to 6 carbons and haloalkoxy having 1 to 6 carbons, R "is a hydrogen atom or an optionally substituted alkyl having 1 to 6 carbon atoms (more preferably a hydrogen atom, a methyl group or an ethyl group); R2 ^' is a hydrogen atom or a 1 carbon atom. the integer q is from 1 6; 6 alkyl, of 1 to 6 carbon atoms alkoxy, at least one substituent a phenyl group which may be substituted with a group selected from the group consisting of halogen R 3 ^' is hydroxy, alkoxy of 1 to 6 carbon atoms or -NR ⁹ group represented by R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, optionally substituted Which may be a heterocyclic group, an optionally substituted acyl group or R ⁹ and R ¹⁰ bonded may form a ring); the. Ring A is optionally substituted with benzene ring respectively Or a salt thereof. Another preferred specific example of the present invention includes a compound represented by the following general formula.

Embedded image [Wherein the symbols are as defined above;] or a salt thereof.

(16) Agent The compound of the present invention can be used as an insulin sensitivity enhancer, an insulin sensitizer, a retinoid-related receptor function regulator, a peroxisome proliferator-activated receptor ligand, a retinoid X receptor ligand, and the like. The function modulator herein means both an agonist and an antagonist, and is preferably an agonist. The compound of the present invention has a blood glucose lowering action, a blood lipid lowering action, a blood insulin lowering action, an insulin sensitivity enhancing action, an insulin resistance improving action, and a retinoid-related receptor function regulating activity. Here, the retinoid-related receptor is a DNA-binding transcription factor that is contained in nuclear receptors and uses a signal molecule such as a fat-soluble vitamin as a ligand. It may be either a somatic or heterodimeric receptor. Here, as the monomer type receptor, for example, a retinoid O receptor (hereinafter, referred to as a retinoid O receptor)
A (GenBank Accession)
No. L14611), RORβ (GenBank Accession No. L141)
60), RORγ (GenBank Accession No. U16997); R
ev-erb α (GenBank Accession No. M24898),
Rev-erb β (GenBank Accession No. L3178
5); ERRα (GenBank Accession No. X51416), E
RRβ (GenBank Accession No. X51417); Ftz-F
Iα (GenBank Accession No. S65876), Ftz-F
Iβ (GenBank Accession No. M81385); TIx (Ge
nBank Accession No. S77482); GCNF (GenBank Ac
cession No. U14666). As the homodimeric receptor, for example, a retinoid X receptor (hereinafter referred to as R
X (may be abbreviated as XR) α (GenBank Accession N
o. X52773), RXRβ (GenBank Accession No. M8482)
0), RXRγ (GenBank Accession No. U38480); C
OUPα (GenBank Accession No. X12795), COUP
β (GenBank Accession No. M64497), COUPγ (Gen
Bank Accession No. X12794); TR2α (GenBankAcce
ssion No. M29960), TR2β (GenBank Accession N)
o. L27586); or HNF4α (GenBank Accession N
o. X76930), HNF4γ (GenBank Accession No. Z49
826) and the like.

The heterodimeric receptor includes, for example, the above-mentioned retinoid X receptor (RXRα, RXRβ or RXRγ) and retinoid A receptor (hereinafter sometimes abbreviated as RAR) α (GenBank Accession No. X0661).
4), RARβ (GenBank Accession No. Y00291), R
ARγ (GenBank Accession No. M24857); thyroid hormone receptor (hereinafter sometimes abbreviated as TR) α (Ge
nBank Accession No. M24748), TRβ (GenBank Acce
ssion No. M26747); Vitamin D receptor (VDR) (Ge
nBank Accession No. JO3258); Peroxisome proliferator-activated receptor (hereinafter sometimes abbreviated as PPAR) α (GenBank Accession No. L02932), PPARβ
(PPARδ) (GenBank Accession No. U10375), P
PARγ (GenBank Accession No. L40904); LXRα
(GenBank Accession No. U22662), LXRβ (GenBan
k Accession No. U14534); FXR (GenBank Accessio)
n No.U18374); MB67 (GenBank Accession No. L29)
263); ONR (GenBank Accession No. X75163); and NURα (GenBank Accession No. L13740), NU
Rβ (GenBank Accession No. X75918), NURγ (Ge
nBank Accession No. U12767) and a heterodimer formed with one type of receptor.

Compound (I-1) and salts thereof include, among the above-mentioned retinoid-related receptors, retinoid X receptor (RXRα, RXRβ, RXRγ) and peroxisome proliferator-responsive receptor (PPARα, PPA).
It has excellent ligand activity for Rβ (PPARδ) and PPARγ). Further, the compound (II) and a salt thereof are used in a heterodimeric receptor formed by a retinoid X receptor and a peroxisome proliferator-activated receptor, preferably in a heterodimeric receptor formed by RXRα and PPARγ. It has excellent ligand activity for peroxisome proliferator-activated receptors. Therefore, the retinoid-related receptor ligand of the present invention is suitably used as a peroxisome proliferator-activated receptor ligand or a retinoid X receptor ligand.

(17) Diseases to be treated Therefore, the compound of the present invention and the pharmaceutical composition of the present invention include, for example, a prophylactic / therapeutic agent for diabetes (eg, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, etc.) Agents for preventing / treating hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, etc.), insulin sensitivity enhancers, insulin sensitizers, glucose intolerance (I
It can be used as a prophylactic / therapeutic agent for GT) and a transition inhibitor from glucose intolerance to diabetes. The compound of the present invention and the pharmaceutical composition of the present invention include, for example, diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, etc.), obesity, osteoporosis, cachexia (Eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, cachexia due to infectious cachexia or acquired immunodeficiency syndrome), fatty liver, Hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end stage renal disease, etc.), muscular dystrophy, myocardial infarction, angina, Cerebral infarction, insulin resistance syndrome, syndrome X, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.),
Inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgery, remission of swelling, neuralgia, laryngitis, cystitis, hepatitis, pneumonia, pancreatitis, etc.), It can also be used as a prophylactic / therapeutic agent for arteriosclerosis (eg, atherosclerosis, etc.). Further, the compound of the present invention can be used for regulating appetite and food intake and as a medicament for slimming and phagocytosis.

The dose of the compound of the present invention and the pharmaceutical composition of the present invention varies depending on the administration subject, administration route, target disease, symptoms and the like.
The compound of the present invention, which is the active ingredient, is usually used in a single dose of about 0.1%.
05-100 mg / kg body weight, preferably 0.1-10
mg / kg body weight, and it is desirable to administer this amount once to three times a day.

(18) Combination Use of Agents The compound of the present invention is used as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, and an immunotherapeutic agent. (Hereinafter abbreviated as concomitant drug). At this time, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time, or may be administered with a time lag. The dose of the concomitant drug can be appropriately determined based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast); Agents (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), or sulfonylureas ( Eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.) and other insulin secretagogues (eg, repaglinide, senaglinide, nateglinide, mitsu Rinido, GLP-1 etc.), ants Ming agonists (eg, Purarinchido etc.), phosphotyrosine phosphatase inhibitors (e.g., such as vanadate)
And the like. As a therapeutic agent for diabetic complications, aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, SK-860, CT-11)
2 etc.), neurotrophic factors (eg, NGF, NT-3, BDN)
F, etc.), PKC inhibitors (eg, LY-333531, etc.),
AGE inhibitors (eg, ALT946, pimagedine, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, tiapride, mexiletine, etc.) Is mentioned. Examples of antihyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, etc.), squalene synthase inhibitors or fibrate compounds having a triglyceride lowering action ( Examples include bezafibrate, clofibrate, simfibrate, clinofibrate, and the like. Antihypertensives include angiotensin converting enzyme inhibitors (eg, captopril, enalapril,
Delapril) or angiotensin II antagonist (eg, losartan, candesartan cilexitil, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.).

Examples of the anti-obesity agent include central anti-obesity agents (eg, dexfenfluamine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), Pancreatic lipase inhibitors (eg, orlistat etc.), β3 agonists (eg, CL
-316243, SR-58611-A, UL-TG-
307, SB-226552, AJ-9677, BMS
19685), peptidic appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-1)
5849). Examples of the diuretic include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide) , Methyclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin) And the like, plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Among them, a 5-fluorouracil derivative such as furturon or neofurturon is preferred. Examples of the immunotherapeutic agent include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( For example,
Interferon, interleukin (IL), etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.), and among others, IL-1, IL
-2 and IL-12 are preferred.

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

Preferred combinations of the prophylactic / therapeutic agents for the above-mentioned symptoms include the following. 1) insulin sensitivity enhancer, insulin preparation and biguanide; 2) insulin sensitivity enhancer, sulfonylurea and biguanide; 3) insulin sensitivity enhancer, sulfonylurea and α-glucosidase inhibitor; 4) insulin sensitivity enhancer, biguanide Agent and α
-A glucosidase inhibitor; 5) an insulin sensitivity enhancer, a hypoglycemic agent and other diabetic complication treatment agent; 6) an insulin sensitivity enhancer and two other above-mentioned agents; When used in combination with agents, the amount of each agent can be reduced within a safe range in view of the adverse effects of those agents. In particular, the dose of the insulin sensitivity enhancer, the sulfonylurea agent and the biguanide can be reduced from the usual dose. Therefore, adverse effects that may be caused by these agents can be safely prevented. In addition, diabetes complications,
The dosage of antihyperlipidemic and antihypertensive agents can be reduced, so that the adverse effects that may be caused by these agents can be effectively prevented.

(19) Production Method Hereinafter, the production method of the compound of the present invention will be described. In addition,
Since compounds (I-1) and (I-2) are included in compound (II), a method for producing compound (II) will be described. The compound (II) of the present invention can be produced by a method known per se, for example, Method A or Method B shown below or a method analogous thereto. Method A

Embedded image Wherein Z is a hydroxy group, a halogen atom or OSO
₂ R ¹⁸ (R ¹⁸ is an alkyl group having 1 to 4 carbon atoms,
6 to 10 carbon atoms which may be substituted with an alkyl group
Represents an aryl group. And the other symbols have the same meanings as described above. Here, “an alkyl group having 1 to 4 carbon atoms” represented by R ^18.
And 1 to 4 carbon atoms in "an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms".
As the alkyl group of 4, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec.-butyl, t.-
Butyl is mentioned, and methyl is preferred. Also,
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 ¹⁸ include phenyl and naphthyl. However, phenyl is preferred.

In this method, compound (III) and compound (IV)
To produce compound (II). When Z is a hydroxy group, this reaction is carried out by a method known per se, for example, the method described in Synthesis, page 1, (1981), or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophile in a solvent that does not adversely influence the reaction.
Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine. Examples of the electrophile include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperazine. The amount of the organic phosphorus compound and the electrophile to be used is preferably 1 to 5 molar equivalents relative to compound (IV). Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually-
The temperature is 50 to 150C, preferably -10 to 100C.
The reaction time is 0.5 to 20 hours.

When Z is a halogen atom or a group represented by OSO ₂ R ¹⁸ , this reaction is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction. As the base, for example, potassium hydroxide, sodium hydroxide,
Alkali metal salts such as sodium hydrogencarbonate and potassium carbonate; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; potassium hydride, hydrogen Metal hydrides such as sodium iodide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide. The amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (IV). Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; halogenated carbons such as chloroform and dichloromethane. Hydrogen; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally -50 to 150C, preferably -10 to 100C. The reaction time is usually 0.5
~ 20 hours.

Then, if desired, compound (II, R ³ =
OR ⁸ ) by subjecting the compound (I) to a hydrolysis reaction.
This hydrolysis reaction is carried out according to a conventional method in the presence of an acid or a base in a water-containing solvent. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, and hydrobromic acid. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Alternatively, the amount of the base to be used is generally an excess amount relative to compound (II).
The amount of the acid used is 2 to 50 equivalents to compound (II), and the amount of the base used is 1.2 to 5 equivalents to compound (II). Examples of the hydrated solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of one or more solvents selected from dimethyl sulfoxide and acetone with water. The reaction temperature is usually -20 to 150
° C, preferably -10 to 100 ° C. The reaction time is
Usually, it is 0.1 to 20 hours. Compounds (II) and (II ″) thus obtained can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

The compounds (III) and (IV) used as starting compounds in the above-mentioned Method A are known compounds, for example, the compound (III) wherein Z is a hydroxy group
Are described in EP-A 710659. Also,
Compound (III) is disclosed in EP-A-629624 (Japanese Unexamined Patent Publication No.
53555) and WO 98/03505. Further, compound (III) can also be produced by a method according to the methods described in these publications. On the other hand, the compound (IV) is, for example,
hemie), 311, 370 (1969); Canadian Journal of Chemistry (Canadian J
ournal of Chemistry), 48, 1948 (197
0)); Journal of Heterocyclic Chemistry, 2
5, 1283 (1988).
Compound (IV) can also be produced by a method according to the method described in these documents.

The compound (II) wherein R ² is phenyl substituted with an aliphatic hydrocarbon group or the like can also be produced by the following Method B. Method B

Embedded image [Wherein, W represents an aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group or an aromatic heterocyclic group, and other symbols have the same meanings as described above. Examples of the “aliphatic hydrocarbon group” represented by W include the hydrocarbon groups represented by R ¹ and the aliphatic hydrocarbon groups exemplified as the substituents on the heterocyclic group. As the aromatic hydrocarbon group and the aromatic heterocyclic group in the “optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group” represented by W, the hydrocarbon group and the heterocyclic group represented by R ¹ And the aromatic hydrocarbon group and the aromatic heterocyclic group exemplified as the substituents in the above. Further, as the substituents of the aromatic hydrocarbon group and the aromatic heterocyclic group, the substituents in the hydrocarbon group and the heterocyclic group represented by R ¹ are an alicyclic hydrocarbon group, an aromatic hydrocarbon group, When it is an aromatic heterocyclic group or a non-aromatic heterocyclic group, the substituents exemplified as the substituents are exemplified.

In this method, compound (II-2) is produced by reacting compound (II-1) with boric acid compound (V). This reaction is carried out in a manner known per se, for example, in a journal.
Of Chemistry (Journal of Organ
ic Chemistry), 58, 2201 (1993) or Journal of Organic Chemistry, 60, 1060.
The reaction is carried out according to the method described on page (1995) in the presence of a metal catalyst and a base in a solvent that does not adversely influence the reaction. Examples of the metal catalyst include zero-valent palladium,
Valent nickel and the like. Here, as the zero-valent palladium catalyst, for example, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium and the like, and as the zero-valent nickel catalyst, for example, 1,1′-bis (diphenylphosphino) ) Ferrocene nickel and the like. Examples of the base include alkali metal bicarbonates such as sodium bicarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal phosphates such as tripotassium phosphate. The amount of the metal catalyst used depends on the amount of the compound (II-
0.01 to 1 molar equivalent, preferably 0.0
5-0.5 molar equivalents. The amount of the base to be used is 1 to 20 molar equivalents, preferably 1 to 20 equivalents, relative to compound (II-1).
10 molar equivalents. Examples of the solvent that does not adversely affect the reaction include aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and water. These solvents may be mixed and used at an appropriate ratio. The type of the solvent is appropriately selected depending on the type of the metal catalyst. The amount of the boric acid compound (V) to be used is 1 to 7 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (II-1). The reaction temperature is usually -20
To 150 ° C, preferably 0 to 100 ° C. The reaction time is 0.1 to 24 hours.

Then, if desired, the compound (II-2, R
^The compound (II ″ -1) is produced by subjecting ³ = OR ⁸ ) to a hydrolysis reaction, which is carried out in the same manner as in the hydrolysis reaction in Method A. Compounds (II-2) and (II ″ -1) can be synthesized by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (II-1) used as a starting compound in the above method B is produced, for example, by the above method A. Compound (V) is described in, for example, Organic Synthesis, Vol. 39, p.
1959); Journal of American Chemical Societ
y), vol. 94, p. 4370 (1972) and the like. Compound (V) can also be produced by a method according to the method described in these documents.

Compound (II) can be obtained by the following [Method C] or
It can also be produced by [Method D]. [Method C]

Embedded image In this method, compound (II) is produced by reacting compound (VI) with compound (VII). This reaction is performed by a method known per se. That is, this reaction is performed in the presence of an acid or a base in a solvent that does not affect the reaction. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. Examples of the base include sodium carbonate, potassium carbonate, sodium acetate, ammonia (water) and the like. The amount of the acid or base to be used is generally 1 to 10 molar equivalents relative to compound (VI). Examples of the solvent that does not affect the reaction include ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, dimethyl sulfoxide, acetic acid, and water. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually
The temperature is from -50C to 150C, preferably from -10C to 120C. Next, if desired, the compound (II) is hydrolyzed to produce a compound (II ″). This reaction is carried out in the same manner as in the hydrolysis reaction in Method A. The compounds (II) and (II ″) is a known separation and purification means,
For example, it can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method D]

Embedded image In this method, compound (II) is produced by reacting compound (VIII) with compound (IX). This reaction is carried out in the same manner as in the reaction of compound (III) with compound (IV) in Method A. Then, if desired, compound (II) is hydrolyzed to produce compound (II ″). This reaction is carried out in the same manner as in the hydrolysis reaction in Method A. Compounds (II) and (II ″) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the compound (II), the compound wherein R ³ is NR ⁹ R ¹⁰ is produced by the following method E. [Method E]

Embedded image In this method, compound (II ″) is produced by amidating compound (II ″). This reaction is a method known per se, that is, a method of directly condensing compound (II '') with compound (X) using a condensing agent (eg, dicyclohexylcarbodiimide or the like), or a reaction of compound (II '') The reaction is carried out using a method of appropriately reacting the compound (X) with the ionic derivative. Here, as the reactive derivative of the compound (II ''), for example, acid anhydride, acid halide (acid chloride, acid bromide), imidazolide, or mixed acid anhydride (for example, anhydride with methyl carbonate, ethyl carbonate, isibutyl carbonate) And the like). For example, when an acid halide is used, the reaction is carried out in the presence of a base in a solvent that does not affect the reaction. Examples of the base include triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. Examples of the solvent that does not affect the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; ethyl acetate; and water. . These solvents may be mixed and used at an appropriate ratio. The amount of compound (X) to be used is 1 to 1 with respect to compound (II '').
It is 0 molar equivalent, preferably 1-3 molar equivalent. The reaction temperature is usually -30C to 100C, and the reaction time is 0.5 to
20 hours. When a mixed acid anhydride is used, compound (II '') and a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.)
With a base (eg, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogen carbonate,
Sodium carbonate, potassium carbonate, etc.) and further react with compound (X). The amount of compound (X) to be used is 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (II ″). The reaction temperature is usually-
30 ° C to 100 ° C, and the reaction time is 0.5 to 20 hours. Compound (II ″ ′) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like. Compound (VI) used as a starting material compound in Method C can be obtained by a method known per se, for example, Journal of Organic Chemistry (Jo
urnal of Organic Chemistry), Vol. 36, p. 3836 (1971) and the like, or a method analogous thereto. Compound (IX) used as a starting compound in Method D can be produced by the following Method F.

[Method F]

Embedded image This method is carried out in the same manner as in the reaction of compound (III) with compound (IV) in Method A. The -YH portion of compound (XI) may be protected and subjected to a condensation reaction, followed by deprotection after the reaction. As the protecting group, a benzyl group, a methoxymethyl group, a silyl group (eg, a trimethylsilyl group, a t.-butyldimethylsilyl group, and the like) are used.

[0067]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Test Examples, Reference Examples, Examples and Preparation Examples, but the present invention is not limited thereto. In the following Reference Examples and Examples,% indicates weight percent unless otherwise specified. Test Example Blood glucose and blood lipids (triglyceride) in mice
Lowering effect Test compound was added to powdered feed (CE-2, CLEA Japan) in a concentration of 0.1%.
KKA ^y mice (9-12 weeks old, 5 rats per group) mixed at a rate of 01% and used as a model for obesity and non-insulin dependent diabetes mellitus
For 4 days. During this time, water was given ad libitum. Blood was collected from the orbital venous plexus, and glucose and triglyceride were enzymatically determined using plasma using L-type Wako Glu2 (Wako Pure Chemical Industries) and Iatro-MA701T.
G kit (Yatron) or L type Wako TG
Quantification was performed using H (Wako Pure Chemical). The value of each test compound administration group is represented by a reduction rate (%) with respect to the test compound non-administration group, and is shown in [Table 1].

Table 1-------------Compound Hypoglycemic action Blood lipid-lowering action (Example number) (%) (%)- --------------------------------------------------------------------------- 1 36 35 7 42 61 61 10 36 45 11 49 82 17 17 49 59 1) 25 38 66 81 54 75 1) 106 46 65 1), 2) ------------------------- 1) Quantification using L-type Wako TG / H (Wako Pure Chemical Industries) 2 ) Dose: 0.005% As described above, the compound of the present invention has an excellent hypoglycemic effect and hypolipidemic effect, and is useful as a prophylactic / therapeutic agent for diabetes, hyperlipidemia, impaired glucose tolerance and the like. is there.

Test Example (PPARγ-RXRα Heterodimer Ligand Activity) PPARγ: RXRα: 4E obtained in Reference Example 5 described later.
After culturing RPP / CHO-K1 cells in Ham F12 medium (manufactured by Nissui Pharmaceutical) containing 10% fetal bovine serum (manufactured by Life Technologies, Inc., USA), a 96-well white plate [Corning Coaster] (Corning Coster Corporation), USA]
The cells were seeded at a density of 10 ⁴ cells / well and cultured overnight in a carbon dioxide incubator at 37 ° C. 96-well white plate was washed with PBS (Phosphate-buffered salin).
After washing in e), 90 μl of Ham's F12 medium containing 0.1% fatty acid-free bovine serum albumin (BSA) and 10 μl of a test compound were added, and the cells were cultured in a carbon dioxide incubator at 37 ° C. for 48 hours. After removing the medium, 40 μl of Vica Gene 7.5 (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and after stirring, using Lumistar (manufactured by BMG Labtechnologies GmbH, Germany), Luciferase activity was measured. When the luciferase activity of the test compound non-administration group was set to 1,
The induction ratio was calculated from the luciferase activity of each test compound. The concentration of the test compound and the value of the induction magnification were measured using a prism (PR
ISM) 2.01 [Graph Pad Software (Gra
phPad Software, Inc.), USA], to calculate the EC ₅₀ value (concentration of the compound showing 50% of the maximum induction factor) of the test compound. Table 2 shows the results.
It was shown to.

[Table 2] Thus, the compound of the present invention has excellent PPARγ-RX
Rα heterodimer ligand activity was demonstrated.

[0069]

EXAMPLES Reference Example 1 (Cloning of human PPARγ gene) Cloning of the human PPARγ gene was performed using cardiac cDN
A (manufactured by Toyobo, trade name: QUICK-Clone cDNA)
Was used as a template and reported by Greene et al. [Gene Expression (Gene Expr.), 1995, 4 (4
-5), pp. 281-299], a primer set PAG-U: 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA
GAG-3 'PAG-L: 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA
The PCR was performed using GTC-3 '. PCR reaction is Ampli
This was performed by a hot start method using Wax PCR Gem 100 (Takara Shuzo). First, 10 × L
A PCR buffer 2μl, 2.5mM dNTP solution 3μ
l, 12.5 μM of each primer solution (2.5 μl) and sterile distilled water (10 μl) were mixed to form a lower layer mixture. In addition, 1 μl of human heart cDNA (1 ng / ml) as a template and 10 × LAP
CR Buffer 3μl, 2.5mM dNTP solution 1μl, TaKa
Ra LA Taq DNA polymerase (Takara Shuzo) 0.5μ
and 24.5 μl of sterilized distilled water to obtain an upper layer mixed solution.
Add AmpliWax PCR Gem 100 to the above lower layer mixture.
(Manufactured by Takara Shuzo) and add 5 minutes at 70 ° C in ice for 5 minutes.
After treating for 1 minute, the mixed solution of the upper layer was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer, USA) and then treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes. The obtained PCR product was agarose gel (1
%) Electrophoresed, 1.4 kb D containing the PPARγ gene
After recovering the NA fragment from the gel, pT7 Blue-T vector
(Takara Shuzo) and the plasmid pTBT-hPPA
Rγ was obtained.

Reference Example 2 (Cloning of human RXRα gene)
(Manufactured by Toyobo, trade name: QUICK-Clone cDNA) as a template, and Mangersdorf D.
sdorf, DJ) et al. [Nature, 19
1990, 345 (6272), pp. 224-229], a primer set XRA-U: 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC prepared with reference to the base sequence of the RXRα gene.
CTG-3 'XRA-L: 5'-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC
It was performed by a PCR method using CTC-3 '. PCR reaction is Ampli
This was performed by a hot start method using Wax PCR Gem 100 (Takara Shuzo). First, 10 × L
A PCR buffer 2μl, 2.5mM dNTP solution 3μ
l, 12.5 μM of each primer solution (2.5 μl) and sterile distilled water (10 μl) were mixed to form a lower layer mixture. In addition, 1 μl of human kidney cDNA (1 ng / ml) as a template and 10 × LAP
CR Buffer 3μl, 2.5mM dNTP solution 1μl, TaKa
Ra LA Taq DNA polymerase (Takara Shuzo) 0.5μ
and 24.5 μl of sterilized distilled water to obtain an upper layer mixed solution.
Add AmpliWax PCR Gem 100 to the above lower layer mixture.
(Manufactured by Takara Shuzo) and add 5 minutes at 70 ° C in ice for 5 minutes.
After treating for 1 minute, the mixed solution of the upper layer was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer, USA) and then treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes. The obtained PCR product was agarose gel (1
%) Electrophoresed, 1.4 kb DN containing the RXRα gene
After recovering the A fragment from the gel, pT7 Blue-T vector
(Takara Shuzo) and the plasmid pTBT-hRXR
α was obtained.

Reference Example 3 (Preparation of plasmid for expressing human PPARγ and RXRα) Plasmid pVgRXR [Invitrogen
gen), USA] and the RXR of plasmid pTBT-hRXRα obtained in Reference Example 2.
The 0.9 kb FspI-NotI fragment containing the α gene was ligated to prepare a plasmid pVgRXR2. Next, pVgRXR
2 was digested with BstXI, and the ends were blunted by treatment with T4 DNA polymerase (Takara Shuzo). Then, KpnI
And a DNA fragment of 6.5 kb was obtained.
On the other hand, the plasmid pTBT-hPP obtained in Reference Example 1 was used.
After cutting ARγ with SalI, the ends were blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo). Then Kp
By cutting with nI, a 1.4 kb DNA fragment containing the human PPARγ gene was obtained. By ligating both DNA fragments, plasmid pVgRXR2-hPPARγ was constructed.

Reference Example 4 (Preparation of Reporter Plasmid) A DNA fragment containing the acyl-CoA oxidase PPAR-responsive element (PPRE) was prepared using the following 5′-terminal phosphorylated synthetic DNA. PPRE-U: 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-
3 'PPRE-L: 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-
3 'First, PPRE-U and PPRE-L were annealed, and then inserted into the SalI site of plasmid pBlueScript SK +. By determining the base sequence of the inserted fragment,
Plasmid pBSS- containing four PREs in tandem
PPRE4 was selected. HSV thymidine kinase
Minimum promoter (Thymidine kinase minimum p
chromosome (TK promoter) region was cloned by pRL-TK vector [Promega,
[USA] as a template, reported by Luckow, B. et al. [Nucleic Acids Research (Nucleic Acid
Res.), 1987, 15 (13), 5490], a primer set prepared with reference to the nucleotide sequence of the promoter region of the thymidine kinase gene. 'TK-L: PCR was performed using 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3'. PCR reaction is Ampli
Hot and cold using Wax PCR Gem 100 (Takara Shuzo)
Performed by the Hot Start method. First, 10 × LA
PCR Buffer 2 μl, 2.5 mM dNTP solution 3 μl, 1
2.5 μl each of 2.5 μM primer solution, sterile distilled water 10
μl was mixed to form a lower layer mixture. Also, as a template, pR
1 μl of L-TK vector [Promega, USA], 3 μl of 10 × LA PCR Buffer, 2.5 mM d
1 µl NTP solution, TaKaRa LA Taq DNA polymeras
e (manufactured by Takara Shuzo) was mixed with 0.5 μl of sterilized distilled water and 24.5 μl of sterilized distilled water to obtain an upper layer mixture.

The above lower layer mixture was added to AmpliWax PCR G
One em 100 (manufactured by Takara Shuzo) was added, and the mixture was treated at 70 ° C. for 5 minutes and in ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution. The tube containing the reaction solution was set in a thermal cycler (PerkinElmer, USA) and then treated at 95 ° C for 2 minutes. Further, after repeating a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes 35 times,
Treated at 72 ° C. for 8 minutes. The resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 140b DNA fragment containing the TK promoter was recovered from the gel.
It was inserted into e-T vector (Takara Shuzo). A fragment containing the TK promoter obtained by digesting this plasmid with the restriction enzymes BglII and NcoI was used to prepare a plasmid pGL3-
Bg of Basic vector [Promega, USA]
Plasmid pGL3-TK was prepared by ligating with the II-NcoI fragment. NheI- of the resulting plasmid pGL3-TK
XhoI fragment 4.9 kb and plasmid pBSS-PPRE4
The plasmid pGL3-4ERPP-TK was prepared by ligating the NheI-XhoI fragment 200b of the above. This plasmid pGL3-4ERPP-TK was
After cleavage with amHI (Takara Shuzo), the ends were blunted by treatment with T4 DNA polymerase (Takara Shuzo) to obtain a DNA fragment. On the other hand, pGFP-C1 (manufactured by Toyobo) was replaced with Bsu36I
After digestion with (NEB), the ends were blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo) to obtain a 1.6 kb DNA fragment. By linking both DNA fragments, a reporter plasmid pGL3-4ERPP-TK neo was constructed.

Reference Example 5 (Human PPARγ, RXRα Expression Plasmid and Reporter Plasmid CHO-K
Transfection into 1 cell and acquisition of expression cells) 10% fetal bovine serum [Life Technology
hnologies, Inc., USA] and a 750 ml tissue culture flask [Corning Costar] using Ham F12 medium (Nissui Pharmaceutical).
Corporation, USA]. 0.5 g / L trypsin-0.2 g / LEDTA (ethylenediaminetetraacetic acid) [Life Technology Co., Ltd.
Technologies, Inc.), the United States], cells were removed and treated with PBS (Phosphate-buffered saline) [Life Technologies, Inc.
USA], centrifugation (1000 rpm, 5 minutes), PB
Suspended with S. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad Laboratories, USA) under the following conditions. That is, 0.4c
In a cuvette with an m gap, 8 × 10 ⁶ cells and Reference Example 3
Plasmid pVgRXR2-hPPARγ1
0 μg of the reporter plasmid pG obtained in Reference Example 4
10 μg of L3-4ERPP-TK neo was added, and electroporation was performed under a voltage of 0.25 kV and a capacitance of 960 μF. Thereafter, the cells were transferred to Ham's F12 medium containing 10% fetal bovine serum, cultured for 24 hours, the cells were detached again and centrifuged, and then 500 μg of Geneticin (Life Technologies, Inc., USA) / Ml and Zeocin [Invitrogen
gen), USA] at 250 μg / ml in 10% fetal calf serum in Ham's F12 medium.
A 96-well plate [Corning Costar Corp.] was diluted to 10 ⁴ cells / ml.
ration), USA] and cultured in a carbon dioxide incubator at 37 ° C to produce Geneticin,
Zeocin resistant transformants were obtained. Next, the obtained transformant was cultured in a 24-well plate [Corning Costar Corporation, USA], and then added with 10 µM pioglitazone hydrochloride to induce luciferase expression, PPARγ: RXR
α: 4ERPP / CHO-K1 cells were selected.

Reference Example 6 To a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (33.42 g) in methanol (150 ml) -tetrahydrofuran (30 ml) was added sodium borohydride at 0 ° C. (4.31 g) was added slowly. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitated 4- (5-
Crystal of methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (32.85 g, 98% yield)
Was filtered. Recrystallization from ethyl acetate-diethyl ether gave pale yellow crystals. 128-129 ° C. Reference Example 7 Thionyl chloride (1.85 ml) was added to a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (5.00 g) in toluene (40 ml), and the mixture was added at room temperature for 30 minutes. Stirred. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with water,
After drying (MgSO ₄ ), the mixture was concentrated to obtain crystals of 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (5.23 g, yield 99%). Recrystallization from ethyl acetate-hexane gave colorless crystals. 108-109 ° C.

Reference Example 8 4- [2- (methyl-2-pyridylamino) ethoxy]
Benzaldehyde (15.0 g) in methanol (70 m
l) Add sodium borohydride (1.11
g) was added slowly. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4- [2- (methyl-2-pyridylamino) ethoxy] benzyl alcohol (14.3 g, yield) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). 94%) as an oil. NMR (CDCl ₃ ) δ: 3.15 (3H, s), 3.98 (2H, t, J = 5.5 Hz),
4.19 (2H, t, J = 5.5Hz), 4.61 (2H, d, J = 5.4Hz), 6.50-
6.59 (2H, m), 6.89 (2H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.
8Hz), 7.40-7.50 (1H, m), 8.13-8.18 (2H, m). Reference Example 9 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g), 3- (4-hydroxyphenyl)
Propanol (2.50 g), potassium carbonate (3.40 g)
g) and N, N-dimethylformamide (25 ml)
Was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3 parts were eluted with ethyl acetate-hexane (1: 1, volume ratio).
Crystals of-[4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propanol (4.46
g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless crystals. 70-71 ° C.

Reference Example 10 A mixture of methyl phenylglyoxylate (25.5 g), hydroxylamine hydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml) was stirred at 60 ° C. for 17 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 water, dried (MgSO ₄ ) and concentrated. The remaining crystals ethyl acetate - hexane to, E -
Colorless crystals of methyl 2-hydroxyimino-2-phenylacetate (3.58 g, 13% yield) were obtained. Melting point 151-
153 ° C. Reference Example 11 The mother liquor of Reference Example 5 was concentrated, the residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
3, v / v) Z- 2-hydroxyimino-
Methyl 2-phenylacetate (17.8 g, yield 64%) was obtained as an oil. NMR (CDCl ₃ ) δ: 3.89 (3H, s), 7.34-7.48 (3H, m), 7.52-
7.60 (2H, m), 8.51 (1H, m).

Reference Example 12 Aluminum chloride (59.0 g) and dichloromethane (5
Ethyl chloroglyoxylate (45.4 ml) was added dropwise to the mixture at 0 ° C. After stirring for 15 minutes, anisole (40.1 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. Ice the reaction mixture (500 g)
After stirring at room temperature for 1 hour, the dichloromethane layer was separated. The dichloromethane layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 4-methoxyphenylglyoxylate (43.6 g, yield 60) was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
%) As an oil. NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 3.90 (3H, s),
4.44 (2H, q, J = 7.1Hz), 6.98 (2H, d, J = 9.0Hz), 8.01 (2
H, d, J = 9.0Hz). Reference Example 13 ethyl 4-methoxyphenylglyoxylate (15.0
g), hydroxylamine hydrochloride (6.00 g), sodium acetate (8.86 g) and ethanol (150 m
The mixture of 1) was heated at reflux for 12 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 water, dried (MgSO ₄ ) and concentrated.
The residue was subjected to silica gel column chromatography,
From the ethyl acetate-hexane (1: 2, volume ratio) elution part,
Crystals of ethyl Z- 2-hydroxyimino-2- (4-methoxyphenyl) acetate (8.99 g, yield 56%) were obtained. Recrystallization from ethyl acetate-hexane gave colorless crystals. 81-82 ° C.

REFERENCE EXAMPLE 14 In Reference Example 13, crystals of ethyl E- 2-hydroxyimino-2- (4-methoxyphenyl) acetate (4.97 g, 31% yield) were obtained from the portion eluted after the Z form.
I got Recrystallization from ethyl acetate-hexane gave colorless crystals. 128-129 ° C. Reference Example 15 A mixture of ethyl pyruvate (9.50 g), hydroxylamine hydrochloride (6.82 g), sodium acetate (10.1 g) and ethanol (150 ml) was heated under reflux for 17 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 water and dried (M
After gSO ₄ ), the mixture was concentrated. The remaining crystals were eluted with ethyl acetate
Recrystallized from hexane, colorless crystals of ethyl E- 2-hydroxyiminopropionate (6.33 g, yield 59%)
I got 98-99 ° C. Reference Example 16 A mixture of methyl 3-benzoylpropionate (15.0 g), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g), and methanol (150 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
After washing with water, drying (MgSO ₄ ), and concentration. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From a hexane (1: 3, volume ratio) elution part, methyl E -4-hydroxyimino-4-phenylbutyrate (14.7 g,
(91% yield) as an oil. NMR (CDCl ₃ ) δ: 2.58-2.67 (2H, m), 3.09-3.17 (2H, m),
3.66 (3H, s), 7.35-7.44 (3H, m), 7.56-7.67 (2H, m),
8.00-8.80 (1H, br s).

Reference Example 17 In Reference Example 16, crystals of methyl Z -4-hydroxyimino-4-phenylbutyrate (1.37 g, yield 8%) were obtained from the portion eluted following the E- isomer. Recrystallization from ethyl acetate-hexane gave colorless crystals. Melting point 76-
77 ° C. Reference Example 18 ethyl 5-oxo-5-phenylpentanoate (8.00
g), hydroxylamine hydrochloride (3.03 g), sodium acetate (4.47 g) and ethanol (70 ml)
Was heated at reflux for 15 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 water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and Ethyl acetate-hexane (1: 3, volume ratio) eluted with E.
Crystals of ethyl-5-hydroxyimino-5-phenylpentanoate (7.55 g, yield 88%) were obtained. Recrystallization from hexane gave colorless crystals. 28-30 ° C.

REFERENCE EXAMPLE 19 To a solution of diethyl oxalate (26.3 g) in diethyl ether (400 ml) was added dropwise a solution of butylmagnesium chloride in tetrahydrofuran (0.90 M, 100 ml) at -78 ° C under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture was heated to 0 ° C., and 1N hydrochloric acid was added. The diethyl ether layer was separated, washed with aqueous sodium bicarbonate and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethanol (150 ml), hydroxylamine hydrochloride (7.50 g), sodium acetate (11.1.
g) was added and the mixture was refluxed for 13 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 water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and Ethyl acetate-hexane (1: 4, volume ratio) eluted with E.
Crystals of ethyl-2-hydroxyiminohexanoate (1
1.0 g, yield 71%). Recrystallization from hexane gave colorless crystals. Melting point 49-50 [deg.] C. Reference Example 20 A solution of isopropylmagnesium bromide in tetrahydrofuran (0.67 M, 100 ml) was added dropwise to a solution of diethyl oxalate (19.6 g) in diethyl ether (400 ml) at -78 ° C under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture was heated to 0 ° C., and 1N hydrochloric acid was added. The diethyl ether layer was separated, washed with aqueous sodium bicarbonate and then with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethanol (100 ml), hydroxylamine hydrochloride (5.59 g), sodium acetate (8.24)
g) was added and the mixture was heated under reflux for 15 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 water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography. From the ethyl acetate-hexane (1: 4, volume ratio) eluate, 2
-Ethyl hydroxyimino-3-methylbutyrate (a mixture of E- form and Z- form) was obtained. Recrystallization from hexane gave colorless crystals of ethyl E- 2-hydroxyimino-3-methylbutyrate (1.
91 g, 18% yield). 54-55 ° C. NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J =
7.1Hz), 3.49 (1H, sept, J = 7.0Hz), 4.29 (2H, q, J = 7.1H
z), 9.79 (1H, br s).

Reference Example 21 In Reference Example 20, the mother liquor of the E- isomer was concentrated, and E : Z =
A 2.3: 1 mixture (5.69 g, 53% yield) was obtained. Z form: NMR (CDCl ₃ ) δ: 1.17 (6H, d, J = 6.6 Hz), 1.36 (3H,
t, J = 7.1Hz), 2.80 (1H, sept, J = 6.6Hz), 4.36 (2H, q,
J = 7.1Hz), 9.75 (1H, br s). Reference Example 22 Aluminum chloride (29.3 g) and dichloromethane (2
Ethyl chloroglyoxylate (22.3 ml) was added dropwise to the mixture at 50C. After stirring for 30 minutes, diphenyl ether (63.5 ml) was added at 0 ° C for 30 minutes.
After dropwise addition over 2 minutes and stirring for 2 hours, the reaction mixture was poured into ice (250 g) and stirred at room temperature for 1 hour. The dichloromethane layer was separated, washed with saturated saline, and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
From the eluted part (10, volume ratio), ethyl 4-phenoxyphenylglyoxylate (38.0 g, yield 70%) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J =
7.1Hz), 6.98-7.13 (4H, m), 7.20-7.29 (1H, m), 7.37-7.
47 (2H, m), 8.01 (2H, d, J = 9.0Hz).

Reference Example 23 Ethyl 4-phenoxyphenylglyoxylate (37.
9g), hydroxylamine hydrochloride (11.7 g), sodium acetate (17.3 g) and ethanol (200 m
The mixture of 1) was heated at reflux for 15 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 water, dried (MgSO ₄ ) and concentrated.
The remaining crystals were recrystallized from toluene-hexane, and E-
Colorless crystals of ethyl 2-hydroxyimino-2- (4-phenoxyphenyl) acetate (11.0 g, 28% yield)
I got 131-132 ° C. Reference Example 24 In Reference Example 23, the mother liquor of the E- isomer was concentrated, and the residue was subjected to silica gel column chromatography, and Z- 2-hydroxyimino- Ethyl 2- (4-phenoxyphenyl) acetate (23.6 g, 56% yield) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J =
7.1Hz), 6.95-7.08 (4H, m), 7.11-7.20 (1H, m), 7.32-7.
42 (2H, m), 7.53 (1H, d, J = 8.8Hz), 8.42-8.49 (1H,
m).

Reference Example 25 Ethyl chloroglyoxylate (32.0 ml) was added dropwise to a mixture of aluminum chloride (41.6 g) and 1,2-dichloroethane (300 ml) at 0 ° C. After stirring for 30 minutes, 4-fluorobenzene (25.0) was added at 0 ° C.
g) was added. After stirring at 40 ° C. for 2 hours, the reaction mixture was poured into ice (300 g) and stirred at room temperature for 1 hour. The 1,2-dichloroethane layer was separated, washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethanol (300 ml), hydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g) were added, and the mixture was heated under reflux for 20 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 water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and from an eluate of ethyl acetate-hexane (1: 3, volume ratio), Z- 2-
Ethyl (4-fluorophenyl) -2-hydroxyiminoacetate (3.82 g, yield 6%) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J =
7.1Hz), 7.05-7.14 (2H, m), 7.52-7.61 (2H, m), 8.37 (1
H, s). Reference Example 26 In Reference Example 25, crystals of ethyl E- 2- (4-fluorophenyl) -2-hydroxyiminoacetate (2.45 g, yield 5%) were obtained from the portion eluted subsequently to the Z form. Was. Recrystallization from ethyl acetate-hexane gave colorless crystals. 117-118 ° C.

Reference Example 27 To a mixture of aluminum chloride (41.6 g) and 1,2-dichloroethane (300 ml) was added dropwise, at 0 ° C., monoethyl succinate chloride (40.8 ml). 3
After stirring for 0 minutes, 4-fluorobenzene (2
5.0 g) were added. After stirring at 60 ° C for 15 hours,
The reaction mixture was poured into ice (500 g) and stirred at room temperature for 1 hour. The 1,2-dichloroethane layer was separated, washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethanol (300 ml), and hydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g) were dissolved.
g) was added and the mixture was heated under reflux for 20 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 water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and Ethyl acetate-hexane (1: 4, volume ratio) eluted with E.
Ethyl-4- (4-fluorophenyl) -4-hydroxyiminobutyrate (7.45 g, yield 12%) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1 Hz), 2.56-2.65 (2H,
m), 3.05-3.14 (2H, m), 4.11 (2H, q, J = 7.1Hz), 7.01-7.
14 (2H, m), 7.56-7.66 (2H, m), 8.05-8.40 (1H, brs). Reference Example 28 3-phenoxybenzyl alcohol (25.0 g) and triethylamine (26.3 ml) in ethyl acetate (300
methanesulfonyl chloride (14.6) at 0 ° C.
ml) was added dropwise. After stirring for 1 hour, the reaction mixture was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was dissolved in acetone (300 ml), sodium iodide (37.5 g) was added, and the mixture was stirred 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 water, dried (MgSO ₄ ),
Concentrated. The residue was treated with dimethyl sulfoxide (100 m
1), sodium cyanide (7.35 g) was added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and 3 parts were eluted with ethyl acetate-hexane (1: 7, volume ratio).
-Phenoxyphenylacetonitrile (8.36 g, 32% yield) was obtained as an oil. NMR (CDCl ₃ ) δ: 3.72 (2
H, s), 6.90-7.20 (6H, m), 7.28-7.43 (3H, m).

Reference Example 29 A solution of 3-phenoxyphenylacetonitrile (8.30 g) in ethanol (15 ml) was added dropwise to a sodium ethoxide solution prepared from sodium (1.09 g) and ethanol (20 ml) at 0 ° C. Isoamyl nitrite (7.99 ml) was added dropwise. After stirring at room temperature for 15 hours, diethyl ether was added, and the mixture was washed with 1 N hydrochloric acid, aqueous sodium bicarbonate, and saturated saline in this order. The diethyl ether layer was dried (MgSO ₄ ), concentrated, and the residue was subjected to silica gel column chromatography. The crystals obtained from the ethyl acetate-hexane (1: 4, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 2-hydroxyimino-2- (3-phenoxyphenyl) acetonitrile as pale yellow crystals (4.25 g). , Yield 45%). With E- body
A mixture of Z- forms. 124-125 ° C. Reference Example 30 2-hydroxyimino-2- (3-phenoxyphenyl) acetonitrile (3.00 g), potassium hydroxide (3.40 g), ethanol (15 ml) and water (1
5 ml) was heated at reflux for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The reaction mixture was treated with methanol (30 m
l), concentrated sulfuric acid (catalytic amount) was added, and the mixture was heated under reflux for 24 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
2, volume ratio) Z- 2-hydroxyimino-
Methyl 2- (3-phenoxyphenyl) acetate (1.14
g, yield 33%) as an oil. NMR (CDCl ₃ ) δ: 3.95 (3H, s), 6.99-7.18 (4H, m), 7.21-
7.28 (2H, m), 7.31-7.41 (3H, m), 8.33 (1H, s).

[0087] Reference Example 31 Reference Example 30, from the fractions eluted following the Z-isomer, E-2-hydroxyimino-2- (3-phenoxyphenyl) methyl acetate crystalline (746 mg, yield 22
%). Recrystallization from ethyl acetate-hexane gave colorless crystals. 122-123 ° C. Reference Example 32 A solution of 4-bromophenylmagnesium bromide prepared from p-dibromobenzene (25.0 g), magnesium (2.43 g) and diethyl ether (250 ml) was added to a solution of diethyl oxalate (3
2.5 g) in diethyl ether (250 ml). After stirring for 1 hour, the reaction mixture was heated to 0 ° C., and 1N hydrochloric acid was added. Separate the diethyl ether layer,
Washed with aqueous sodium bicarbonate and then with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1:15, volume ratio). This oil was dissolved in ethanol (100 ml), hydroxylamine hydrochloride (4.17 g) and sodium acetate (6.15 g) were added, and the mixture was heated under reflux for 18 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from isopropyl ether-hexane to give colorless crystals of E- 2- (4-bromophenyl) -2-hydroxyiminoacetate (4.31 g, yield 16%). 163-164 ° C.

Reference Example 33 In Reference Example 32, ethyl Z- 2- (bromophenyl) -2-hydroxyiminoacetate (5.31 g, yield 20%) was obtained as an oil from the portion eluted subsequently to the E- isomer. Obtained. NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 4.55 (2H, q, J =
7.1Hz)), 7.43 (2H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.6H)
z), 8.47 (1H, s). Reference Example 34 Sodium (7.22 g) and ethanol (400 ml)
In a sodium ethoxide solution prepared from the above, ethyl phenylacetate (25.8 g) and diethyl oxalate (45.9) were added.
g) was added, and the mixture was stirred at 70 ° C. for 1.5 hours while distilling off ethanol. Ethyl acetate (500 m
l) and 1N hydrochloric acid (350 ml) were added, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in dimethyl sulfoxide (150 ml) -water (15 ml), sodium chloride (9.18 g) was added, and the mixture was stirred at 130 ° C for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. Ethanol (100
ml) and dissolved in hydroxylamine hydrochloride (3.34).
g) and sodium acetate (4.92 g) were added, and the mixture was heated under reflux for 17 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and from the eluate of ethyl acetate-hexane (1: 3, volume ratio), E- 2-
Crystals of ethyl hydroxyimino-3-phenylpropionate (6.94 g, 21% yield) were obtained. Ethyl acetate
Recrystallized from hexane. 54-55 ° C.

Reference Example 35 n -butyllithium (1.6 N hexane solution, 108
ml) with 3-bromopyridine (25.
-G in 7 g) of diethyl ether (400 ml).
The mixture was added dropwise at 1 ° C. over 1 hour. After stirring for further 30 minutes, a diethyl ether solution (100 ml) of diethyl oxalate (28.6 g) was added dropwise at -78 ° C over 1 hour. After stirring the reaction mixture for further 30 minutes, the temperature was raised to 0 ° C., and 1N hydrochloric acid (200 ml) was added. After stirring for 30 minutes, sodium bicarbonate was added to neutralize the reaction mixture.
The organic layer was separated, washed with saturated saline, and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and ethyl 3-pyridylglyoxylate (13.1 g, yield 45%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). . NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.1Hz), 4.48 (2H, q,
J = 7.1Hz), 7.45-7.53 (1H, m), 8.33-8.41 (1H, m), 8.
85-8.90 (1H, m), 9.26-9.29 (1H, m). Reference Example 36 A mixture of ethyl 3-pyridylglyoxylate (6.00 g), hydroxylamine hydrochloride (2.79 g), sodium acetate (4.13 g), and ethanol (80 ml) was heated to reflux for 15 hours. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The remaining crystals were recrystallized from ethyl acetate to give ethyl E- 2-hydroxyimino-2- (3-pyridyl) acetate (3.
(30 g, yield: 51%) as colorless crystals. 172-
173 ° C.

Reference Example 37 The mother liquor of Reference Example 31 was concentrated, and the residue was subjected to silica gel chromatography to give ethyl acetate-hexane (3: 2,
Crystals were obtained from the elution part (volume ratio). This was recrystallized from ethyl acetate-hexane to give Z- 2-hydroxyimino-2-
Ethyl (3-pyridyl) acetate (1.55 g, yield 24)
%) As colorless crystals. 137-138 ° C. Reference Example 38 A solution of sodium ethoxide prepared from sodium (2.51 g) and ethanol (40 ml) at 0 ° C.
(3-Bromophenyl) acetonitrile (17.8 g)
Was added dropwise, followed by dropwise addition of isoamyl nitrite (18.3 ml). After stirring at room temperature for 18 hours, diethyl ether was added, and the mixture was washed with 1N hydrochloric acid, aqueous sodium bicarbonate and saturated saline in this order. The diethyl ether layer was dried (MgSO ₄ ), concentrated, and the residue was subjected to silica gel chromatography. 2- (Hydroxyimino) acetonitrile (19.9 g, 97% yield) was obtained as an orange paste. This was recrystallized from ethyl acetate-hexane to obtain orange crystals. 91-93 ° C.

Reference Example 39 While heating a 1,2-dibromoethane solution (40 ml) of 3-methylbenzophenone (20.0 g) under reflux,
A solution of bromine (5.43 ml) in 1,2-dibromoethane (12 ml) was added dropwise over 3 hours. After heating under reflux for another 30 minutes, the mixture was concentrated. Dimethyl sulfoxide (100 ml) and sodium cyanide (7.50) were added to the residue.
g) was added thereto, and the mixture was stirred at room temperature for 2 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 3, volume ratio).
(3-benzoylphenyl) acetonitrile (13.8
g, yield 61%) as a yellow oil. NMR (CDCl ₃ ) δ: 3.84 (2H, s), 7.46-7.68 (5H, m), 7.7
3-7.83 (4H, m). Reference Example 40 A solution of sodium ethoxide prepared from sodium (1.70 g) and ethanol (40 ml) at 0 ° C.
(3-benzoylphenyl) acetonitrile (13.6
g) in ethanol (30 ml) was added dropwise and then isoamyl nitrite (12.4 ml) was added dropwise. 1 at room temperature
After stirring for 5 hours, add ethyl acetate and add 1N hydrochloric acid,
Washing was performed in the order of a saturated saline solution. The ethyl acetate layer was dried (M
gSO ₄ ), concentrate, and add 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile (1
(5.2 g, yield 99%). This was recrystallized from ethyl acetate-hexane to obtain colorless crystals of isomer 1. Melting point 175-176 [deg.] C.

Reference Example 41 The mother liquor of Reference Example 40 was concentrated, and the residue was recrystallized from ethyl acetate-hexane to give 2- (3-benzoylphenyl)-
Isomer 2 of 2- (hydroxyimino) acetonitrile was obtained as colorless crystals. 147-148 ° C. Reference Example 42 A mixture of 2- (3-bromophenyl) -2- (hydroxyimino) acetonitrile (19.0 g), an aqueous solution of 4N potassium hydroxide (100 ml) and 2-methoxyethanol (100 ml) was heated under reflux for 4 hours. . The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethanol (200 ml) and concentrated sulfuric acid (catalytic amount)
Was added. The reaction mixture was heated under reflux for 48 hours, cooled to room temperature, added with aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion with ethyl acetate-hexane (1: 3, volume ratio), ethyl Z- 2- (3-bromophenyl) -2- (hydroxyimino) acetate (3.31 g, (Yield 14%)
Was obtained as a light brown oil. NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 4.47 (2H, q,
J = 7.1Hz), 7.23-7.32 (1H, m), 7.45-7.60 (2H, m), 7.
72-7.75 (1H, m), 8.56 (1H, br s).

Reference Example 43 In Reference Example 42, ethyl E- 2- (3-bromophenyl) -2- (hydroxyimino) acetate was obtained as crystals from the portion eluted following the Z form. This was recrystallized from ethyl acetate-hexane to give colorless crystals (1.52 g,
Yield 7%). 113-114 ° C. Reference Example 44 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile (14.5 g), 4N aqueous potassium hydroxide solution (80 ml) and ethanol (80 m
The mixture of 1) was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was dissolved in ethanol (150 ml) and concentrated sulfuric acid (catalytic amount) was added.
The reaction mixture was heated at reflux for 15 hours, then cooled to room temperature,
Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluate of ethyl acetate-hexane (1: 2, volume ratio), Z
Ethyl-2- (3-benzoylphenyl) -2- (hydroxyimino) acetate (2.48 g, 14% yield) was obtained as a light brown oil. NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.1Hz), 4.45 (2H, q,
J = 7.1Hz), 7.30-7.66 (4H, m), 7.70-8.00 (5H, m), 8.
66 (1H, br s).

Reference Example 45 In Reference Example 44, ethyl E- 2- (3-benzoylphenyl) -2- (hydroxyimino) acetate was obtained as crystals from the portion eluted following the Z- isomer. This was recrystallized from ethyl acetate-hexane to give orange crystals (1.70).
g, yield 10%). 109-110 ° C. Reference Example 46 Aluminum chloride (14.7 g) and dichloromethane (1
20 ml), at 0 ° C., monoethyl succinate chloride (14.3 ml) was added dropwise. After stirring for 30 minutes, the mixture was added dropwise to a solution of diphenyl ether (34.0 g) in dichloromethane (50 ml) at 0 ° C. After stirring for 3 hours, the reaction mixture was poured into ice (200 g) and stirred at room temperature for 1 hour. The dichloromethane layer was separated, washed with brine, dried (MgSO ₄ ) and concentrated. The residue was dissolved in ethanol (150 ml), hydroxylamine hydrochloride (8.34 g) and sodium acetate (12.3 g) were added, and the mixture was heated under reflux for 15 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 (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and E -4- (hydroxyimino) -4- was extracted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
Ethyl (4-phenoxyphenyl) butyrate (10.5 g,
(34% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1Hz), 2.57-2.66 (2
H, m), 3.06-3.15 (2H, m), 4.12 (2H, q, J = 7.1Hz),
6.97-7.19 (5H, m), 7.31-7.42 (2H, m), 7.59 (2H, d,
J = 9.2Hz), 7.90-8.60 (1H, br).

Reference Example 47 A mixture of 2-chloropyrimidine (20.8 g) and 2- (methylamino) ethanol (180 ml) was heated at 120 ° C. for 15 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated. The residue was distilled under reduced pressure to give 2- (methyl-2-pyrimidylamino) ethanol (24.6 g,
(88% yield) as a colorless oil. Boiling point 130-1
32 [deg.] C / 1-1.5 mmHg. REFERENCE EXAMPLE 48 Sodium hydride (60%, oily, 4.40 g) was added to a solution of 2- (methyl-2-pyrimidylamino) ethanol (15.3 g) in N, N-dimethylformamide (400 ml) under a nitrogen atmosphere at room temperature. And stirred for 1 hour. A solution of 4-fluorobenzaldehyde (13.6 g) in N, N-dimethylformamide (100 ml) was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was added to ice (2
And then concentrated. The residue was dissolved in ethyl acetate, washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and 4- [2- (methyl-2-pyrimidylamino)) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
Ethoxy] benzaldehyde (18.4 g, yield 72
%) As crystals. This was recrystallized from ethyl acetate-hexane to obtain colorless crystals. 74-75 ° C.

Reference Example 49 4- [2- (Methyl-2-pyrimidylamino) ethoxy] benzaldehyde (16.6 g) in methanol (4
0 ml) -tetrahydrofuran (40 ml) solution.
At 0 C, sodium borohydride (1.22 g) was added slowly. After stirring for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyl alcohol (15.3 g, yield 91%) as colorless crystals. 73-74 ° C. Reference Example 50 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (5.00 g), N-hydroxyphthalimide (2.59 g), potassium carbonate (4.40 g) and N, N- After stirring the mixture of dimethylformamide (50 ml) at room temperature for 20 hours,
Water (500 ml) was added. The resulting crystals were collected by filtration and washed with water to give N- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (6.49 g, yield 93%) as colorless. Obtained as crystals. 155-156 ° C.

REFERENCE EXAMPLE 51 Sodium hydride (60%, oily, 649 mg) was treated with N, N-dimethyl 2- (5-methyl-2-phenyl-4-oxazolyl) ethanol (3.00 g) under a nitrogen atmosphere. The mixture was added to a formamide (60 ml) solution at room temperature and stirred for 1 hour. 4-fluorobenzaldehyde (2.0
A solution of 2 g) in N, N-dimethylformamide (15 ml) was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice (50 g) and concentrated. The residue was dissolved in ethyl acetate, washed with saturated saline, and dried (MgSO 4).
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). This was dissolved in tetrahydrofuran (20 ml) and methanol (20 ml),
At 0 ° C., sodium borohydride (321 mg) was added,
Stir for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in toluene (20
ml) and thionyl chloride (0.888m
l) was added and stirred for 1 hour. Concentrate the reaction mixture,
The remaining crystals were recrystallized from ethyl acetate-hexane,
-[2- (4-chloromethylphenoxy) ethyl] -5
Light yellow crystals of -methyl-2-phenyloxazole (2.51 g, yield 52%) were obtained. 93-94 ° C. Reference Example 52 Hydrazine monohydrate (1.15 ml) was added to N- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (5.22 g) in ethanol (40 ml) -tetrahydrofuran (40 m)
l) Added to the solution and heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, an aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (3.32 g, yield 90%). . 68-69 ° C.

Reference Example 53 5-chloro-2- (chloromethyl) imidazo [1,2-
a ] pyridine hydrochloride (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassium carbonate (6.1)
4 g) and N, N-dimethylformamide (30 m
After stirring the mixture of 1) at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 4- (5-
Colorless crystals of chloroimidazo [1,2- a ] pyridin-2-ylmethoxy) benzaldehyde (3.55 g, 98% yield) were obtained. 126-130 ° C. Reference Example 54 4- (5-chloroimidazo [1,2- a ] pyridine-2
-Ylmethoxy) benzaldehyde (3.52 g) in methanol (10 ml) -tetrahydrofuran (50 m
1) Add sodium borohydride (232 m
g) was added. After stirring for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate to give 4- (5-chloroimidazo [1,2- a ] pyridin-2-ylmethoxy) benzyl alcohol (2.34 g, yield 66%) as colorless crystals. Melting point 169-171 [deg.] C.

Reference Example 55 4- (5-chloroimidazo [1,2- a ] pyridine-2
-Ylmethoxy) benzyl alcohol (1.97 g),
Triethylamine (1.15 ml) and toluene (5
0 ml) at 0 ° C. with thionyl chloride (0.597).
ml) was added dropwise. After stirring for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 5-chloro-2- (4-chloromethylphenoxymethyl) imidazo [1,2- a ] pyridine (1.10 g, yield 52).
%) As colorless crystals. 114-115 ° C. Reference Example 56 To a solution of 2-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (200 ml) was added carbonyldiimidazole (7.25 g) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of tert -butyl lithiated acetate prepared from tert -butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at -78 ° C over 1 hour. did. 1
After stirring for 5 minutes, 1N hydrochloric acid (250 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). This was dissolved in tetrahydrofuran (100 ml),
Then, sodium hydride (60%, oily, 1.06 g) was added thereto, followed by stirring for 10 minutes. Further, ethyl bromoacetate (2.00 ml) was added, and the mixture was stirred at 0 ° C. for 8 hours.
0.1 N hydrochloric acid (300 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 5, volume ratio). This is added to toluene (20
0 ml) and dissolved in p -toluenesulfonic acid (2.00 ml).
g) was added and stirred at 80 ° C. for 20 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and the residue was eluted with ethyl acetate-hexane (1: 2, volume ratio).
-Ethyl oxo-4- (2-pyridyl) butyrate (1.56
g, yield 19%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.76 (2H, d,
J = 6.7Hz), 3.57 (2H, d, J = 6.7Hz), 4.16 (2H, q, J = 7.1
Hz), 7.48 (1H, dd, J = 4.8, 7.6Hz), 7.84 (1H, dt, J =
1.8, 7.6Hz), 8.05 (1H, d, J = 7.6Hz), 8.69 (1H, dd,
J = 1.8, 4.8Hz).

Reference Example 57 Oxalyl chloride (4.10 g) was added to a solution of 2-furancarboxylic acid (5.00 g) in tetrahydrofuran (50 ml) at room temperature.
47 ml) and N, N-dimethylformamide (catalytic amount)
Was added. After stirring at room temperature for 1 hour, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (20 ml) and acetic acid t was added.
ert -butyl (19.3 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 72 m
The solution was added dropwise to the tert -butyl lithiated acetic acid solution prepared in 1) at -78 ° C over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (1: 1).
(5, volume ratio) Crystals were obtained from the elution part. This was recrystallized from ethyl acetate-hexane to obtain colorless crystals of tert -butyl 3- (2-furyl) -3-oxopropionate (3.28 g, yield 35%). 74-75 ° C. Reference Example 58 3- (2-furyl) -3-oxopropionic acid tert
-Butyl (3.01 g) in tetrahydrofuran (80 m
l) Add sodium hydride (60%, oily,
629 mg) and stirred for 10 minutes. Further, ethyl bromoacetate (1.51 ml) was added, and the mixture was stirred at room temperature for 4 hours. Then, 0.1 N hydrochloric acid (200 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 5, volume ratio). This was dissolved in toluene (150 ml), trifluoroacetic acid (2.64 ml) was added, and the mixture was stirred at 90 ° C. for 6 hours.
Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and ethyl 4- (2-furyl) -4-oxobutyrate (2.22 g, yield 79%) was eluted from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). Obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1Hz), 2.74 (2H, t,
J = 6.7Hz), 3.18 (2H, t, J = 6.7Hz), 4.15 (2H, q, J = 7.1
Hz), 6.53-6.57 (1H, m), 7.23 (1H, d, J = 3.6Hz), 7.5
9 (1H, d, J = 1.8Hz).

REFERENCE EXAMPLE 59 Nicotinic acid (5.00 g) in tetrahydrofuran (10
Carbonyldiimidazole (7.25 g) was added to the solution at 0 ° C. After stirring at room temperature for 2 hours,
Tert -butyl acetate (17.5 ml) and lithium diisopropylamide (2 N tetrahydrofuran solution, 6
5 ml) was added dropwise to the solution of tert -butyl lithiated acetate prepared from the above solution at -78 ° C over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in tetrahydrofuran (100 ml), sodium hydride (60%, oily, 1.38 g) was added at 0 ° C., and the mixture was stirred for 10 minutes. Further, ethyl bromoacetate (3.33 ml) was added, and the mixture was stirred at room temperature for 3 hours.
0 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). This is dissolved in toluene (150 ml),
Add trifluoroacetic acid (7.68 ml) and add 4
Stir for hours. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (2:
From the eluted part (1, volume ratio), ethyl 4-oxo-4- (3-pyridyl) butyrate (3.39 g, yield 38%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1Hz), 2.79 (2H, t,
J = 6.6Hz), 3.33 (2H, t, J = 6.6Hz), 4.17 (2H, q, J = 7.1
Hz), 7.43 (1H, dd, J = 4.8, 8.0Hz), 8.23-8.30 (1H,
m), 8.80 (1H, dd, J = 1.6, 4.8Hz), 9.22 (1H, d, J = 2.
2Hz). Reference Example 60 To a solution of 4-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (80 ml) was added carbonyldiimidazole (7.25 g) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of tert -butyl lithiated acetate prepared from tert -butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at -78 ° C over 1 hour. did. Fifteen
After stirring for 1 minute, add 1N hydrochloric acid (250ml),
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (2: 3, volume ratio). This was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60%, oily, 1.16 g) was added at 0 ° C.
Stir for 10 minutes. Further ethyl bromoacetate (2.8
8 ml) and stirred at room temperature for 24 hours.
Normal hydrochloric acid (300 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO
₄ ) After that, the mixture was concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (1: 1, volume ratio).
An oil was obtained from the elution part. This is toluene (120m
l), trifluoroacetic acid (5.64 ml) was added, and the mixture was stirred at 90 ° C for 6 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-
From the hexane (2: 1, volume ratio) elution part, 4-oxo-
Ethyl 4- (4-pyridyl) butyrate (2.61 g, yield 3)
1%) as a pale brown oil. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 2.78 (2H, t,
J = 6.5Hz), 3.30 (2H, t, J = 6.5Hz), 4.17 (2H, q, J = 7.1
Hz), 7.76 (2H, d, J = 6.2Hz), 8.83 (2H, d, J = 6.2H
z).

Reference Example 61 To a solution of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (18.3 g) in methanol (50 ml) -tetrahydrofuran (100 ml) was added sodium borohydride at 0 ° C. (1.18 g) was added slowly. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 3- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (15.5 g, yield 84%) was obtained as colorless crystals. Melting point 101-102 [deg.] C. Reference Example 62 A mixture of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (15.0 g) and toluene (200 ml) was added to a mixture of thionyl chloride (4.
45 ml) was added dropwise. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 4- (3-chloromethylphenoxymethyl) -5-
Methyl-2-phenyloxazole (13.4 g, yield 84%) was obtained as pale yellow crystals. 79-80 ° C.

Reference Example 63 4- (3-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N , N-dimethylformamide (80 ml) was stirred at room temperature for 20 hours,
Water (800 ml) was added. The resulting crystals were collected by filtration and washed with water to give N- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (10.1 g, 90% yield). Obtained as brown crystals. 146-147 ° C. Reference Example 64 Hydrazine monohydrate (0.661 ml) was added to N- [3-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (3.00 g) in ethanol (25 ml) -tetrahydrofuran (25 m
l) Added to the solution and heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, an aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (2.04 g, yield 97%) as pale yellow crystals. . 81-82 ° C.

Reference Example 65 A mixture of 2-aminopyridine (12.5 g), 1,3-dichloro-2-propanone (17.7 g) and acetonitrile (100 ml) was heated under reflux for 2 hours, and then concentrated. Aqueous sodium bicarbonate 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 ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (3: 2, volume ratio). This was recrystallized from ethyl acetate-hexane to give 2-chloromethylimidazo [1,2
- a] pyridine was obtained (7.52 g, yield 34%) of light yellow crystals. 93-94 ° C. Reference Example 66 Oxalyl chloride (0.508 ml) and N, N-dimethylformamide (catalytic amount) were added to a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated. The residue was dissolved in ethyl acetate (25 ml), and 25% aqueous ammonia (20 ml) and ethyl acetate (2 ml) were used.
5 ml) at 0 ° C. After stirring at room temperature for 2 hours, water (200 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 6-oxo-6-phenylhexaneamide (885 mg, yield 89%) as colorless crystals. 113-114 ° C.

Reference Example 67 Sodium (9.85 g) and ethanol (300 ml)
Acetophenone (25.0 ml) and diethyl oxalate (58.3 m
1) The mixture was added, and the mixture was heated under reflux for 1 hour. After concentration, 1N hydrochloric acid (450 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. Residue is ethanol (250
of hydroxylamine hydrochloride (44.6 ml).
g) was added and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain pale brown crystals of ethyl 5-phenylisoxazole-3-carboxylate (31.5 g, yield 70%). Melting point 46-47 [deg.] C. Reference Example 68 Triethylamine (7.28 ml) was added to α-chlorobenzaldehyde oxime (4.04 g) and 2-propyne-
1-ol (1.66 ml) in tetrahydrofuran (1
30 ml) and stirred at room temperature for 4 days. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals of (3-phenyl-5-isoxazolyl) methanol (3.42 g, yield 75%). Melting point 48-49 [deg.] C.

Reference Example 69 A solution of ethyl 5-phenylisoxazole-3-carboxylate (20.0 g) in diethyl ether (50 ml) was added at 0 ° C. to lithium aluminum hydride (2.62 g).
Was added dropwise into a mixture of diethyl ether (50 ml).
After stirring for 1 hour, carefully add water to the reaction mixture,
Subsequently, 1N hydrochloric acid (200 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The remaining crystals were eluted with ethyl acetate
Recrystallization from hexane gave (5-phenyl-3-isoxazolyl) methanol (15.2 g, yield 94%) as pale brown crystals. Melting point 101-102 [deg.] C. Reference Example 70 Thionyl chloride (2.41 ml) was added to (3-phenyl-5).
-Isoxazolyl) methanol (2.89 g) in toluene (10 ml) and stirred at 60 ° C for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give light brown crystals of 5- (chloromethyl) -3-phenylisoxazole (2.75 g, 86% yield). 69-70 ° C.

Reference Example 71 Thionyl chloride (7.55 ml) was added to (5-phenyl-3).
-Isoxazolyl) methanol (12.1 g) in toluene (50 ml) and stirred at 80 ° C for 3 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. Recrystallize the remaining crystals from hexane,
Light yellow crystals of 3- (chloromethyl) -5-phenylisoxazole (11.8 g, yield 88%) were obtained. Melting point 46-47 [deg.] C. Reference Example 72 Chloromethyl methyl ether (34.2 ml) was added to 4-
A mixture of hydroxybenzaldehyde (50.0 g), potassium carbonate (84.9 g) and N, N-dimethylformamide (150 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (300 ml) and methanol (50 ml).
At 0 C, sodium borohydride (7.76 g) was added slowly. After stirring for 30 minutes, add water to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and 4-methoxymethoxybenzyl alcohol (56.7 g, yield 82%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2: 3, volume ratio). NMR (CDCl ₃ ) δ: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2
H, s), 7.03 (2H, d, J = 8.8Hz), 7.30 (2H, d, J = 8.8H
z).

Reference Example 73 Diethyl azodicarboxylate (40% toluene solution, 14
2g), 4-methoxymethoxybenzyl alcohol (50.0 g), N-hydroxyphthalimide (44.
1 g) and a solution of triphenylphosphine (83.7 g) in tetrahydrofuran (900 ml) were added dropwise at room temperature and stirred for 1 hour. After concentration of the reaction mixture, the residue was subjected to silica gel chromatography to remove triphenylphosphine oxide, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (1: 5, volume ratio). This was washed with a mixed solvent of ethyl acetate-hexane (1: 5, volume ratio), and subsequently dissolved in tetrahydrofuran (200 ml) and ethanol (50 ml). Hydrazine monohydrate (33.7 ml) was added to this solution, and the mixture was heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, an aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. Diisopropyl ether was added to the residue, and insolubles were removed by filtration. By concentrating the filtrate, 4
-Methoxymethoxybenzyloxyamine (28.9
g, yield 58%). NMR (CDCl ₃ ) δ: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2
H, s), 7.04 (2H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6H
z). Reference Example 74 4-methoxymethoxybenzyloxyamine (4.99
g), methyl 4-oxo-4-phenylbutyrate (5.71)
g), acetic acid (5.10 ml), sodium acetate (4.8)
7 g) and methanol (200 ml) was added to 15
Heated to reflux for an hour. After cooling the reaction mixture to room temperature, it was concentrated. Dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO
₄ ) After that, the mixture was concentrated. The residue was treated with tetrahydrofuran (50
ml) and methanol (5 ml). 1N hydrochloric acid (10 ml) was added to this solution, and the mixture was heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (2:
(5, volume ratio) from the elution part, methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (4.
24 g, 50% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H,
m), 3.63 (3H, s), 4.97-5.05 (1H, m), 5.14 (2H, s),
6.82 (2H, d, J = 8.8Hz), 7.25-7.38 (5H, m), 7.59-7.
65 (2H, m).

REFERENCE EXAMPLE 75 Sodium hydride (60%, oily, 2.18 g) was added to a solution of ethyl benzoylacetate (10.0 g) in N, N-dimethylformamide (100 ml) at 0 ° C., and the mixture was stirred for 30 minutes. . To this mixture was added methyl iodide (3.89 m
l) was added and stirred for 1 hour. Subsequently, sodium hydride (60%, oily, 2.18 g) was added, and the mixture was stirred for 30 minutes. Further, methyl iodide (3.89 ml) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into 0.05N hydrochloric acid (1000 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-hexane (1:20, volume ratio).
Ethyl phenylpropionate (7.37 g, yield 64)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.1Hz), 1.55 (6H, s),
4.12 (2H, q, J = 7.1Hz), 7.37-7.58 (3H, m), 7.81-7.
87 (2H, m). Reference Example 76 4-chloromethyl-5-methyl-2-phenyloxazole (15.6 g), methyl 4-hydroxyphenylacetate (12.5 g), potassium carbonate (20.8 g) and N, N-dimethylformamide (80 ml) ) Was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and 4- (5-methyl-2) was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
Crystals of methyl -phenyl-4-oxazolyylmethoxy) phenylacetate (23.8 g, 94% yield) were obtained. This was recrystallized from ethyl acetate-hexane to obtain colorless crystals. 74-75 ° C.

Reference Example 77 Methyl 4- (5-methyl-2-phenyl-4-oxazolyylmethoxy) phenylacetate (23.2 g), lithium hydroxide monohydrate (4.33 g), tetrahydrofuran (100 ml) , Water (60 ml) and methanol (4
0 ml) of the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (103 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from acetone to give 4- (5-methyl-2-phenyl-4-oxazolyylmethoxy) phenylacetic acid (21.9 g, yield 9).
(8%). Melting point 182-183 [deg.] C. Reference Example 78 Methyl 8-chloro-8-oxooctanoate (2.00
To a mixture of g) and anisole (5 ml) at 0 ° C. was added aluminum chloride (2.58 g). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice (50 g), stirred at room temperature for 1 hour, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography,
From the ethyl acetate-hexane (1: 5, volume ratio) elution part,
Methyl 8- (4-methoxyphenyl) -8-oxooctanoate (2.37 g, yield 88%) was obtained as crystals.
This was recrystallized from ethyl acetate-hexane to obtain colorless crystals. 57-58 ° C.

Reference Example 79 To a mixture of 4-hydroxybenzaldehyde (17.8 g), imidazole (19.8 g) and N, N-dimethylformamide (100 ml) was added tert -butyldimethylsilyl chloride (24.1 g). . After stirring at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was treated with tetrahydrofuran (300 m
l) and methanol (40 ml), and sodium borohydride (11.1 g) was slowly added at 0 ° C. 30
After stirring for minutes, water was added and extracted with ethyl acetate.
The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and 4- ( tert -butyldimethylsilyloxy) benzyl alcohol (27.7 g, yield 79%) was colorless from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). Obtained as an oil. NMR (CDCl ₃ ) δ: 0.19 (6H, s), 0.98 (9H, s), 4.61 (2
H, s), 6.83 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4H
z). Reference Example 80 Diethyl azodicarboxylate (40% toluene solution, 5
4.0 g) was added to a solution of 4- ( tert -butyldimethylsilyloxy) benzyl alcohol (27.5 g), N-hydroxyphthalimide (16.8 g) and triphenylphosphine (31.1 g) in tetrahydrofuran (450 ml) at room temperature. And the mixture was stirred for 18 hours.
After concentrating the reaction mixture, diisopropyl ether (200
ml) was added and the crystals were removed by filtration. After concentrating the filtrate, the residue was subjected to silica gel chromatography, and ethyl acetate-hexane-toluene (1: 10: 1).
From the eluted part (0, volume ratio), N- [4- ( tert -butyldimethylsilyloxy) benzyloxy] phthalimide (17.4 g, yield 43%) was obtained as crystals. This was recrystallized from ethyl acetate-hexane to obtain colorless crystals. Mp 76-77 ° C.

Reference Example 81 Hydrazine monohydrate (1.25 ml) was added to N- [4-
( Tert -butyldimethylsilyloxy) benzyloxy] phthalimide (5.00 g) in ethanol (10
ml) -tetrahydrofuran (40 ml) solution,
Stir at 60 ° C. for 1 hour. After cooling the reaction mixture to room temperature, an aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
O ₄₎ after, concentrated, 4-(tert - was obtained butyldimethylsilyloxy) benzyloxyamine (3.15 g, 95% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 0.19 (6H, s), 0.98 (9H, s), 4.62 (2
H, s), 5.20-5.50 (2H, br), 6.83 (2H, d, J = 8.6Hz),
7.24 (2H, d, J = 8.6Hz). Reference Example 82 4- ( tert -butyldimethylsiloxy) benzyloxyamine (3.10 g), ethyl 8-oxo-8-phenyloctanoate (6.32 g), acetic acid (2.07 m
l), a mixture of sodium acetate (1.98 g) and ethanol (80 ml) was heated at reflux for 20 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was treated with tetrahydrofuran (6
0 ml), tetrabutylammonium fluoride trihydrate (3.98 g) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from a fraction eluted with ethyl acetate-hexane (2: 7, volume ratio), ethyl E- 8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (3.5) was obtained.
(5 g, yield 77%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (11H, m), 2.18-2.27 (2H,
m), 2.69-2.78 (2H, m), 4.12 (2H, q, J = 7.1Hz), 5.13
(2H, s), 5.39 (1H, br s), 6.83 (2H, d, J = 8.4Hz),
7.25-7.38 (5H, m), 7.57-7.63 (2H, m).

Reference Example 83 A mixture of benzonitrile (26.2 g), hydroxylamine hydrochloride (17.7 g), potassium carbonate (17.6 g) and 70% ethanol (250 ml) was stirred at 80 ° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in acetone (350 ml) and potassium carbonate (1
9.0 g) was added. The mixture was cooled to 0 ° C. and chloroacetyl chloride (21.9 ml) was added dropwise. After stirring for 1 hour, the reaction mixture was concentrated. Water was added to the residue, and the resulting crystals were collected by filtration, washed with water and dissolved in ethyl acetate. This solution is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was dissolved in xylene (250 ml) and the resulting water was removed while heating at reflux. After 2 hours, the mixture was concentrated and the remaining crystals were washed with hexane to give 5
Light yellow crystals of-(chloromethyl) -3-phenyl-1,2,4-oxadiazole (25.2 g, yield 51%) were obtained. 38-39 ° C. Reference Example 84 4- ( tert -butyldimethylsilyloxy) benzyloxyamine (5.31 g), ethyl 6-oxo-6-phenylhexanoate (6.76 g), acetic acid (3.54)
ml), sodium acetate (3.38 g) and ethanol (150 ml) were heated at reflux for 18 hours.
After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was dissolved in tetrahydrofuran (100 ml), tetrabutylammonium fluoride trihydrate (10.0 g) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and ethyl E -6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (5.6) was eluted from a fraction eluted with ethyl acetate-hexane (2: 7, volume ratio).
4g, 77% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4
H, m), 2.23-2.31 (2H, m), 2.73-2.81 (2H, m), 4.09
(2H, q, J = 7.1Hz), 5.04 (1H, s), 5.13 (2H, s), 6.82
(2H, d, J = 8.2Hz), 7.25-7.38 (5H, m), 7.58-7.64 (2
H, m).

Reference Example 85 Oxalyl chloride (5.39 ml) and N, N-dimethylformamide (catalytic amount) were added to a solution of 3-benzoylpropionic acid (10.0 g) in tetrahydrofuran (100 ml) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added dropwise to 25% aqueous ammonia (100 ml) at 0 ° C. After stirring at room temperature for 30 minutes, water (1000m
l) and hexane (500 ml) were added, and the resulting crystals were collected by filtration and washed with hexane to give 4-oxo-4.
Orange crystals of -phenylbutyramide (2.67 g, 27% yield) were obtained. 126-127 ° C. Reference Example 86 A solution of 2- [2- (methoxycarbonyl) ethyl] -2-phenyl-1,3-dioxolane (5.00 g) in diethyl ether (15 ml) was added at 0 ° C. to lithium aluminum hydride (949 mg) and diethyl ether. Ether (30m
The mixture was dropped into l). After stirring for 30 minutes, water was carefully added to the reaction mixture, and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgSO ₄ ).
Concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (2: 3, volume ratio) to give 2- (3-hydroxypropyl) -2-phenyl-
1,3-Dioxolane (3.81 g, 87% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.61-1.72 (2H, m), 2.02 (2H, t, J = 6.
4Hz), 3.63 (2H, t, J = 6.3Hz), 3.74-3.87 (2H, m), 3.
95-4.08 (2H, m), 7.24-7.49 (5H, m).

Reference Example 87 2- (3-hydroxypropyl) -2-phenyl-1,
To a solution of 3-dioxolane (3.75 g) and triethylamine (5.05 ml) in ethyl acetate (100 ml),
At 0 ° C., methanesulfonyl chloride (1.81 ml) was added. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in acetone (100 ml) and sodium iodide (5.4)
0 g) and stirred at 60 ° C. for 2 hours. After concentrating the reaction mixture, 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 (MgS
After O ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 2- (3-iodopropyl) -2-
Phenyl-1,3-dioxolane (5.41 g, yield 9)
(4%) colorless crystals. 71-73 ° C. Reference Example 88 n -butyllithium (1.6 N hexane solution, 2.1
6 ml) was added to a solution of diisopropylamine (0.529 ml) in tetrahydrofuran (5 m
l) was added dropwise at -20 ° C. After further stirring for 20 minutes, the mixture was cooled to -78 ° C and methyl isobutanoate (0.39
(7 ml) in tetrahydrofuran (5 ml) was added dropwise over 30 minutes. After stirring the reaction mixture for a further 20 minutes, 2- (3-iodopropyl) -2-phenyl-
1,3-Dioxolane (1.00 g) and hexamethylphosphoramide (0.602 ml) were added. After stirring at −40 ° C. for 3 hours, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue is acetone (30 ml)
And 1N sulfuric acid (10 ml) was added, and the mixture was heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, water was added,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 7, volume ratio) to give 2,2-dimethyl-hexane.
Methyl 6-oxo-6-phenylhexanoate (350 m
g, yield 45%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.20 (6H, s), 1.55-1.80 (4H, m), 2.9
6 (2H, t, J = 6.8Hz), 3.65 (3H, s), 7.41-7.61 (3H,
m), 7.92-8.02 (2H, m).

Reference Example 89 To a solution of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (5.00 g) in methanol (30 ml) -tetrahydrofuran (30 ml) was added sodium borohydride at 0 ° C. (325 mg) was added slowly. After stirring for 1 hour, water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The crystals were recrystallized from acetone-ethyl acetate to give 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (4.17).
g, yield 83%) as colorless prisms. Melting point 1
55-156 ° C. Reference Example 90 Thionyl chloride (1.6) was added to a mixture of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (4.00 g) and toluene (60 ml) at 0 ° C.
9 g) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium bicarbonate and then with water, and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give 4- (2-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (3.5
0 g, yield 82%) as colorless needles. Melting point 10
3-104 ° C.

Reference Example 91 3,5-Dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (1
To a solution of 0.0 g) in methanol (30 ml) -tetrahydrofuran (70 ml) was slowly added sodium borohydride (540 mg) at 0 ° C. After stirring for 1 hour, water was added to the reaction mixture, and 3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (9.25 g, yield 9) was precipitated.
2%). Recrystallization from ethyl acetate-hexane gave colorless prisms. 113-114 ° C. Reference Example 92 A mixture of 3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (9.00 g) and tetrahydrofuran (50 ml) -toluene (150 ml) was added at 0 ° C. Then, thionyl chloride (3.62 g) was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then with water and dried (M
After gSO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from acetone-hexane to give 4- (4-chloromethyl-2,6).
-Dimethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (7.00 g, yield 74%) was obtained as colorless needles. 118-119 ° C.

Reference Example 93 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzaldehyde (6.
To a solution of 84 g) in methanol (50 ml) -tetrahydrofuran (50 ml) was slowly added sodium borohydride (825 mg) at 0 ° C. After stirring for one hour,
Water is added to the reaction mixture to precipitate 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-.
Methoxybenzyl alcohol (6.98 g, yield 92)
%). NMR (CDCl ₃ ) δ: 2.41 (3H, s);
88 (3H, s), 4.63 (2H, s), 5.06
(2H, s), 6.5-6.55 (1H, m), 6.8
5-6.95 (1H, m), 6.95-7.05 (3
H, m), 7.5-7.55 (1H, m). Reference Example 94 Thionyl chloride was added to a mixture of 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyl alcohol (6.30 g) and tetrahydrofuran (100 ml) at 0 ° C. (2.59 g) was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice and crystals of 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-furyl) -5-methyloxazole (5.67 g, yield 85%). NMR (CDCl ₃ ) δ: 2.40 (3H, s), 3.
88 (3H, s), 4.56 (2H, s), 5.05
(2H, s), 6.5-6.55 (2H, m), 6.9
0-7.05 (4H, m), 7.5-7.55 (1H,
m).

Reference Example 95 In the same manner as in Reference Example 93, 3-methoxy-4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (6.47 g) was reduced with sodium borohydride (760 mg) to give 3-methoxy-4- (5-
Crystals of methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (6.11 g, yield 93%) were obtained. NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.
79 (3H, s), 4.54 (2H, s), 4.96
(2H, s), 6.7-7.0 (3H, m), 7.3-
7.4 (3H, m), 7.9-8.0 (2H, m). Reference Example 96 In the same manner as in Reference Example 94, 3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (6.00 g) and thionyl chloride (1.5
8g) to give 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole crystals (5.77 g, 91% yield). NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.
79 (3H, s), 4.47 (2H, s), 4.97
(2H, s), 6.7-7.0 (3H, m), 7.3-
7.4 (3H, m), 7.9-8.0 (2H, m).

Example 1 To a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (1.32 g) in toluene (10 ml) was added thionyl chloride (0.488 ml).
And stirred at 60 ° C. for 30 minutes. The reaction mixture was concentrated, and the residue was treated with N, N-dimethylformamide (5 m
l) and mixed under a nitrogen atmosphere with a mixture of methyl Z- 2-hydroxyimino-2-phenylacetate (800 mg), sodium hydride (60%, oily, 178 mg) and N, N-dimethylformamide (5 ml). In addition, the mixture was stirred at room temperature for 1.5 hours. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This is methanol (10 ml)
Dissolve in 1N aqueous sodium hydroxide solution (7 ml)
The mixture was refluxed for 1 hour. To the reaction mixture was added 1N hydrochloric acid (7.5
ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give Z- 2- [4- (5-methyl-2-phenyl-4-).
Oxazolylmethoxy) benzyloxyimino] -2-
Colorless crystals of phenylacetic acid (1.07 g, yield 54%) were obtained. Melting point 171-172 [deg.] C (decomposition). Example 2 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propanol (1.00 g)
And a solution of triethylamine (0.866 ml) in ethyl acetate (30 ml) was added to methanesulfonyl chloride (0.47).
8ml) at 0 ° C and stirred for 1 hour. The reaction mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was treated with N, N-dimethylformamide (10 m
l) and dissolved in methyl Z- 2-hydroxyimino-2-phenylacetate (830 mg) and sodium hydride (60 mg).
%, Oily, 185 mg) and stirred at room temperature for 2 hours. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
A colorless oil was obtained from the hexane-toluene (1: 5: 5, v / v) eluate. This is treated with tetrahydrofuran (10m
1) Dissolved in methanol (5 ml), added 1N aqueous sodium hydroxide solution (5 ml), and stirred at 40 ° C. for 2 hours. After adding 1N hydrochloric acid (5.5 ml) to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and Z- 2-
[3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propoxyimino] -2-
Colorless crystals of phenylacetic acid (1.13 g, 78% yield) were obtained. 165-166 ° C (decomposition).

Example 3 4- [2- (methyl-2-pyridylamino) ethoxy]
Benzyl alcohol (1.50 g) in toluene (15 m
l) Thionyl chloride (0.636 ml) was added to the solution at 0 ° C and stirred for 30 minutes. The reaction mixture was concentrated, the residue was dissolved in N, N-dimethylformamide (10 ml), methyl Z- 2-hydroxyimino-2-phenylacetate (1.04 g) and sodium hydride (60%,
Oily, 511 mg) and added at room temperature under nitrogen atmosphere.
Stir for hours. After adding 1N hydrochloric acid (20 ml),
Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This is treated with tetrahydrofuran (20m
1) Dissolved in methanol (10 ml), added 1N aqueous sodium hydroxide solution (10 ml), and stirred at 40 ° C. for 1 hour. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate to give Z- 2- [4-
Colorless crystals of [2- (methyl-2-pyridylamino) ethoxy] benzyloxyimino] -2-phenylacetic acid (9
59 mg, yield 41%). 93-94 ° C. Example 4 4- [2- (methyl-2-pyridylamino) ethoxy]
Benzyl alcohol (1.50 g) in toluene (15 m
l) Thionyl chloride (0.636 ml) was added to the solution at 0 ° C and stirred for 30 minutes. The reaction mixture was concentrated, the residue was dissolved in N, N-dimethylformamide (10 ml), and methyl E -4-hydroxyimino-4-phenylbutyrate (1.20 g) was added.
Oily, 511 mg) and stirred at room temperature under a nitrogen atmosphere for 3 hours. After 1N hydrochloric acid (20 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
An oily substance was obtained from a portion eluted with ethyl acetate-hexane (1: 2, volume ratio). This is treated with tetrahydrofuran (20 ml)
It was dissolved in methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 4 by adding 1N hydrochloric acid,
Extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried (MgSO ₄ ), concentrated, and then subjected to E- [4- [4
-[2- (Methyl-2-pyridylamino) ethoxy] benzyloxyimino] -4-phenylbutyric acid was obtained as a colorless oil (1.04 g, yield 41%). NMR (CDCl ₃ ) δ: 2.51-2.62 (2H, m), 3.00-3.09 (2H, m),
3.13 (3H, s), 3.97 (2H, t, J = 5.6Hz), 4.19 (2H, t, J = 5.
6Hz), 5.14 (2H, s), 6.50-6.59 (2H, m), 6.87 (2H, d, J
= 8.8Hz), 7.24-7.51 (6H, m), 7.59-7.65 (2H, m), 8.13-
8.18 (1H, m).

Example 5 Sodium hydride (60%, oily, 122 mg) was mixed with methyl E- 2-hydroxyimino-2-phenylacetate (548 mg) and 4- (4-chloromethylphenoxymethyl)-under a nitrogen atmosphere. 5-Methyl-2-phenyloxazole (960 mg) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. 1
After adding normal hydrochloric acid (5 ml), aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was dissolved in methanol (5 ml) -1N aqueous sodium hydroxide solution (5 ml) and heated under reflux for 3 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-isopropyl ether to give E- 2- [4
Colorless crystals of (-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2-phenylacetic acid (948 mg, yield 70%) were obtained. Melting point 142
~ 143 [deg.] C (decomposition). Example 6 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl E- 2-hydroxyimino-3-phenylpropionate (661 mg) and 4- (4-chloromethylphenoxymethyl) -5 under a nitrogen atmosphere. The mixture was added to a solution of methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After adding 1N hydrochloric acid (5 ml), sodium bicarbonate water was added,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
An oil was obtained from the hexane (1: 3, volume ratio) elution part.
This was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), 1N aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (4.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-isopropyl ether to give E- 2- [4
Colorless crystals of-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (844 mg, yield 58%) were obtained. 143-144 ° C (decomposition).

Example 7 Sodium hydride (60%, oily, 127 mg) was mixed with methyl E -4-hydroxyimino-4-phenylbutyrate (661 mg) and 4- (4-chloromethylphenoxymethyl)-under a nitrogen atmosphere. A solution of 5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added at room temperature and stirred for 1 hour. 1
After adding normal hydrochloric acid (5 ml), aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was mixed with tetrahydrofuran (10 ml) -methanol (5 m
1) sodium hydroxide solution (5m
l) was added and the mixture was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E -4- [4- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (907 m
g, yield 60%). 126-127 ° C (decomposition). Example 8 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl E- 2-hydroxyiminohexanoate (553 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2- under a nitrogen atmosphere. N, N-dimethylformamide (10 g) of phenyloxazole (1.00 g)
ml) solution was added at room temperature and stirred for 1 hour. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). This was treated with tetrahydrofuran (10 ml) -methanol (5 ml)
And a 1N aqueous sodium hydroxide solution (5 ml) was added thereto, followed by stirring at room temperature for 30 minutes. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and colorless crystals of E- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] hexanoic acid (922 mg, yield) 68%)
I got 112-114 ° C.

Example 9 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl E- 2-hydroxyiminopropionate (418 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl under a nitrogen atmosphere. -2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 g)
ml) solution was added at room temperature and stirred for 1 hour. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was treated with tetrahydrofuran (10 ml) -methanol (5 ml)
And a 1N aqueous sodium hydroxide solution (5 ml) was added thereto, followed by stirring at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-isopropyl ether to give colorless crystals of E- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] propionic acid (849 mg,
(Yield 70%). 147-148 ° C. Example 10 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl Z- 2- (4-bromophenyl) -2-hydroxyiminoacetate (868 mg) and 4- (4-
The mixture was added to a solution of (chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was dissolved in tetrahydrofuran (5 ml) -methanol (10 ml), a 0.5 N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was heated under reflux for 1.5 hours.
1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate to give Z- 2- (4-bromophenyl)
Colorless crystals of 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.34 g, yield 81%) were obtained. Melting point 189-1
90 ° C (decomposition).

Example 11 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl Z- 2-hydroxyimino-2- (4-phenoxyphenyl) acetate (910 mg) under a nitrogen atmosphere.
(4-chloromethylphenoxymethyl) -5-methyl-
2-phenyloxazole (1.00 g) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature.
Stir for hours. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
An oil was obtained from the elution portion of ethyl acetate-hexane (1: 3, volume ratio). This is treated with tetrahydrofuran (20 ml)
It was dissolved in methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and Z- 2-
Colorless crystals of [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (4-phenoxyphenyl) acetic acid (1.51 g, yield 89)
%). 184-185 ° C (decomposition). Example 12 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl E- 2-hydroxyimino-2- (4-phenoxyphenyl) acetate (910 mg) under a nitrogen atmosphere.
(4-chloromethylphenoxymethyl) -5-methyl-
2-phenyloxazole (1.00 g) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature.
Stir for hours. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
An oil was obtained from the elution portion of ethyl acetate-hexane (1: 3, volume ratio). This is treated with tetrahydrofuran (10 ml)
It was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E- 2- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (4-phenoxyphenyl) acetic acid were obtained (1.38 g, yield 81%). 152-153 ° C (decomposition).

Example 13 Sodium hydride (60%, oily, 107 mg) was mixed with methyl Z- 2-hydroxyimino-2- (3-phenoxyphenyl) acetate (605 mg) and 4-
(4-chloromethylphenoxymethyl) -5-methyl-
2-phenyloxazole (700 mg) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature.
Stir for hours. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
An oil was obtained from the elution portion of ethyl acetate-hexane (1: 3, volume ratio). This is treated with tetrahydrofuran (10 ml)
It was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and Z- 2- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-phenoxyphenyl) acetic acid (738 mg, yield 62%) were obtained. 173-174 ° C (decomposition). Example 14 Methyl E- 2-hydroxyimino-2- (3-phenoxyphenyl) acetate (605 mg) was added to sodium hydride (60%, oily, 107 mg) under a nitrogen atmosphere.
(4-chloromethylphenoxymethyl) -5-methyl-
2-phenyloxazole (700 mg) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature.
Stir for hours. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
An oil was obtained from the elution portion of ethyl acetate-hexane (1: 3, volume ratio). This is treated with tetrahydrofuran (10 ml)
It was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E- 2- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-phenoxyphenyl) acetic acid colorless amorphous (745 mg, yield 6)
2%). 55-65 ° C. NMR (CDCl ₃ ) δ: 2.45 (3H, s), 5.10 (2H, s), 5.22 (2H,
s), 6.98-7.48 (16H, m), 7.98-8.05 (2H, m).

Example 15 Sodium hydride (60%, oily, 209 mg) was added under a nitrogen atmosphere to Z- 2- (4-fluorophenyl) -2-
Ethyl hydroxyiminoacetate (920 mg) and 4- (4
-Chloromethylphenoxymethyl) -5-methyl-2-
The mixture was added to a solution of phenyloxazole (1.37 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate to give Z- 2- (4-fluorophenyl) -2- [4- (5-methyl-2-phenyl-4).
Colorless crystals of [-oxazolylmethoxy) benzyloxyimino] acetic acid (1.66 g, 83% yield) were obtained. Melting point 1
82-183 ° C (decomposition). Example 16 Sodium hydride (60%, oily, 209 mg) was added under a nitrogen atmosphere to E- 2- (4-fluorophenyl) -2-
Ethyl hydroxyiminoacetate (920 mg) and 4- (4
-Chloromethylphenoxymethyl) -5-methyl-2-
The mixture was added to a solution of phenyloxazole (1.37 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate to give E- 2- (4-fluorophenyl) -2- [4- (5-methyl-2-phenyl-4).
Colorless crystals of (-oxazolylmethoxy) benzyloxyimino] acetic acid (1.08 g, yield 54%) were obtained. Melting point 1
50-151 ° C (decomposition).

Example 17 Sodium hydride (60%, oily, 153 mg) was added under a nitrogen atmosphere to E -4- (4-fluorophenyl) -4-
Ethyl hydroxyiminobutyrate (763 mg) and 4- (4
-Chloromethylphenoxymethyl) -5-methyl-2-
The mixture was added to a solution of phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). This was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hour.
1N hydrochloric acid (7.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E -4- (4-fluorophenyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino]
Colorless crystals of butyric acid (727 mg, 47% yield) were obtained. 139-140 ° C. Example 18 Sodium hydride (60%, oily, 153 mg) was mixed with ethyl E -5-hydroxyimino-5-phenylpentanoate (751 mg) and 4- (4-chloromethylphenoxymethyl) -5 under a nitrogen atmosphere. The mixture was added to a solution of methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After adding 1N hydrochloric acid (5 ml), sodium bicarbonate water was added,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
An oil was obtained from the hexane (1: 4, volume ratio) eluate.
This was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of E -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -5-phenylpentanoic acid ( 1.24 g, 80% yield). Melting point 129-13
0 ° C.

Example 19 Sodium hydride (60%, oily, 127 mg) was mixed with ethyl Z- 2-hydroxyimino-2- (4-methoxyphenyl) acetate (711 mg) and 4- (4
-Chloromethylphenoxymethyl) -5-methyl-2-
The mixture was added to a solution of phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and Z- 2 was eluted from an ethyl acetate-hexane (1: 2, volume ratio) elution part.
Crystals of ethyl-(4-methoxyphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.50 g, yield 9)
4%). Recrystallized from ethyl acetate-hexane.
102-103 ° C. Example 20 Sodium hydride (60%, oily, 225 mg) was mixed with ethyl 2-hydroxyimino-3-methylbutyrate ( Z : E = 2.3: 1, 1.01 g) and 4- (4 −
The mixture was added to a solution of (chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (2.00 g) in N, N-dimethylformamide (20 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (10 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane-dichloromethane (1:10:10,
Volume ratio) From the elution part, first, Z -3-methyl-2- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate was obtained as a colorless oil (640 mg, 23% yield). NMR (CDCl ₃ ) δ: 1.14 (6H, d, J = 6.8 Hz), 1.28 (3H, t, J =
7.1Hz), 2.43 (3H, s), 2.70 (1H, sept, J = 6.8Hz), 4.29
(2H, q, J = 7.1Hz), 4.99 (2H, s), 5.03 (2H, s), 6.98 (2
H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.8Hz), 7.41-7.49 (3
H, m), 7.97-8.05 (2H, m).

Example 21 In Example 20, the part eluted following the Z form was used to give E
-3-Methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino]
Ethyl butyrate was obtained as a colorless oil (1.34 g, 48%). NMR (CDCl ₃ ) δ: 1.17 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J =
7.1Hz), 2.44 (3H, s), 3.40 (1H, sept, J = 7.0Hz), 4.30
(2H, q, J = 7.1Hz), 5.00 (2H, s), 5.17 (2H, s), 7.01 (2
H, d, J = 8.8Hz), 7.32 (2H, d, J = 8.8Hz), 7.40-7.48 (3
H, m), 7.97-8.05 (2H, m). Example 22 Sodium hydride (60%, oily, 225 mg) was mixed with ethyl E- 2- (4-bromophenyl) -2-hydroxyiminoacetate (1.73 g) and 4- (4-
The mixture was added to a solution of (chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (2.00 g) in N, N-dimethylformamide (20 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (10 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and E- 2 was eluted from an ethyl acetate-hexane (1: 3, volume ratio) eluate.
-(4-bromophenyl) -2- [4- (5-methyl-
Crystals of ethyl 2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (2.54 g, yield 73)
%). Recrystallized from ethyl acetate-hexane. 105-106 ° C.

Example 23 Sodium hydride (60%, oily, 368 mg) was mixed with ethyl Z- 2- (4-bromophenyl) -2-hydroxyiminoacetate (2.50 g) and 4- (4 −
The mixture was added to a solution of (chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (3.03 g) in N, N-dimethylformamide (25 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (12 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and Z- 2 was eluted from an ethyl acetate-hexane (1: 3, volume ratio) eluted portion.
-(4-bromophenyl) -2- [4- (5-methyl-
Ethyl 2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate was obtained as a colorless oil (3.12 g, 61% yield). NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.1 Hz), 2.43 (3H, s),
4.40 (2H, q, J = 7.1Hz), 5.00 (2H, s), 5.19 (2H, s), 7.
01 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6Hz), 7.37-7.5
4 (7H, m), 7.97-8.05 (2H, m). Example 24 Z- 2- (4-methoxyphenyl) -2- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.20 g) was dissolved in tetrahydrofuran (5 ml) -methanol (10 ml), and 0.5N aqueous sodium hydroxide solution (10 m
l) was added and the mixture was heated under reflux for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate to give Z- 2- (4-methoxyphenyl) -2- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.02
g, yield 90%). 183-184 ° C (decomposition).

Example 25 Ethyl Z -3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (580 mg) was added to tetrahydrofuran (6 ml) -methanol ( 3N), 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 3 hours. 1 N hydrochloric acid (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and Z -3-
Methyl-2- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] butyric acid was obtained as colorless crystals (523 mg, yield 96%). Melting point 14
0-142 ° C. Example 26 E -3-Methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (1.27 g) was added to tetrahydrofuran (10 ml) -methanol (5 ml). ), A 1 N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and E- 3
-Methyl-2- [4- (5-methyl-2-phenyl-4
[Oxazolylmethoxy) benzyloxyimino] butyric acid was obtained as colorless crystals (1.02 g, yield 85%). Melting point 1
28-129 ° C.

Example 27 E- 2- (4-Bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate (600 mg) was added to tetrahydrofuran ( 6 ml) -methanol (3 ml), 1N aqueous sodium hydroxide solution (3 ml) was added,
Stir at 40 ° C. for 1 hour. 1 N hydrochloric acid (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The remaining crystals were recrystallized from ethyl acetate, E
Colorless crystals of -2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (561 mg, yield 9)
9%). 159-160 ° C (decomposition). Example 28 E- 2- (4-Bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate (800 mg), phenylboric acid (213 mg) , Potassium carbonate (604m
g), a mixture of toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0 value, 101 mg) was added, and the mixture was heated under reflux for 15 hours. The reaction mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was dissolved in tetrahydrofuran (6 ml) -methanol (3 ml), 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1 N hydrochloric acid (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E- 2- (4-biphenyl) -2- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (642 m
g, 85% yield). 148-149 ° C (decomposition).

Example 29 Ethyl Z- 2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.43 g) Phenyl boric acid (476 mg), potassium carbonate (1.44)
g), a mixture of toluene (30 ml), ethanol (3 ml) and water (3 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0 value, 180 mg) was added, and the mixture was refluxed for 13 hours. The reaction mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane-
An oil was obtained from a dichloromethane (1:10:10, volume ratio) elution portion. This is tetrahydrofuran (10 ml)
-Dissolved in methanol (5 ml), added 1N aqueous sodium hydroxide solution (5 ml), and stirred at 40 ° C for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining ethyl acetate crystals - was recrystallized from isopropyl ether, Z -
2- (4-biphenyl) -2- [4- (5-methyl-2
-Phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid colorless crystals (807 mg, 60% yield)
I got 193-194 [deg.] C (decomposition). Example 30 Ethyl Z- 2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (800 mg), 3-thienyl boric acid ( 224 mg), potassium carbonate (604 m
g), a mixture of toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0 value, 101 mg) was added, and the mixture was refluxed for 14 hours. The reaction mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was treated with tetrahydrofuran (10 ml) -methanol (5 ml)
And a 1N aqueous sodium hydroxide solution (5 ml) was added thereto, followed by stirring at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [4- (3-thienyl ) Phenyl] acetic acid was obtained as pale yellow crystals (442 mg, yield 58%). Melting point 20
5-206 ° C (decomposition).

Example 31 Ethyl Z- 2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (830 mg),
( E- 2-phenylethenyl) phenylboric acid (268
mg), potassium carbonate (626 mg), toluene (20
ml), ethanol (2 ml) and water (2 ml) were stirred for 30 minutes at room temperature under an argon atmosphere.
Tetrakis (triphenylphosphine) palladium (0
(105 mg), and the mixture was refluxed for 14 hours. The reaction mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This is treated with tetrahydrofuran (10
ml) -methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and Z- 2-
[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [4- ( E-
Light yellow crystals of 2-phenylethenyl) phenyl] acetic acid (634 mg, yield 77%) were obtained. Melting point 194-19
5 ° C (decomposition). Example 32 Ethyl Z- 2-hydroxyimino-2- (3-pyridyl) acetate (619 mg) and 4- (4-chloromethylphenoxymethyl) were added to sodium hydride (60%, oily, 153 mg) under a nitrogen atmosphere. A solution of -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added at room temperature and stirred for 3 hours. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 1, volume ratio), Z- 2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxyimino] -2- (3-pyridyl) acetate (1.12 g, yield 74%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1Hz), 2.44 (3H, s),
4.42 (2H, q, J = 7.1Hz), 5.00 (2H, s), 5.22 (2H,
s), 7.01 (2H, d, J = 8.8Hz), 7.25-7.37 (3H, m), 7.40-
7.48 (3H, m), 7.86-7.93 (1H, m), 7.99-8.05 (2H,
m), 8.61-8.65 (1H, m), 8.75-8.78 (1H, m).

Example 33 Sodium hydride (60%, oily, 153 mg) was mixed with ethyl E- 2-hydroxyimino-2- (3-pyridyl) acetate (619 mg) and 4- (4-chloromethyl) under a nitrogen atmosphere. (Phenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature and stirred for 3 hours. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 1, volume ratio), E- 2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Ethyl [benzyloxyimino] -2- (3-pyridyl) acetate (1.02 g, yield 68%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1Hz), 2.44 (3H, s),
4.37 (2H, q, J = 7.1Hz), 4.99 (2H, s), 5.27 (2H,
s), 7.00 (2H, d, J = 8.8Hz), 7.25-7.38 (3H, m), 7.41-
7.48 (3H, m), 7.72-7.80 (1H, m), 7.98-8.05 (2H,
m), 8.57-8.62 (1H, m), 8.66-8.70 (1H, m). Example 34 m -Chloroperoxybenzoic acid (70%, 282 mg)
Is represented by Z- 2- [4- (5-methyl-2-phenyl-4-)
Oxazolylmethoxy) benzyloxyimino] -2-
Ethyl (3-pyridyl) acetate (450 mg) was added to a solution of tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 17 hours. Saturated aqueous sodium thiosulfate solution (10 ml)
And a saturated aqueous potassium carbonate solution (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-methanol (10: 1, volume ratio). This was added to tetrahydrofuran (10 ml) -methanol (5
ml), and 1N aqueous sodium hydroxide solution (5 m
l) was added and the mixture was stirred at 40 ° C for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from acetone-diisopropyl ether to give Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (pyridine-1-oxide-3. −
Colorless crystals of yl) acetic acid (282 mg, yield 64%) were obtained. Melting point 181-182 [deg.] C (decomposition).

Example 35 Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3
-Pyridyl) ethyl acetate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml)
A normal aqueous sodium hydroxide solution (5 ml) was added, and
And stirred for 1 hour. 1N hydrochloric acid (5.5) was added to the reaction mixture.
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate to give Z- 2- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) acetic acid (321 mg, yield 66%) were obtained. 156-157 ° C (decomposition). Example 36 m -Chloroperoxybenzoic acid (70%, 282 mg)
With E- 2- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] -2-
Ethyl (3-pyridyl) acetate (450 mg) was added to a solution of tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 17 hours. Saturated aqueous sodium thiosulfate solution (10 ml)
And a saturated aqueous potassium carbonate solution (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-methanol (10: 1, volume ratio). This was added to tetrahydrofuran (10 ml) -methanol (5
ml), and 1N aqueous sodium hydroxide solution (5 m
l) was added and the mixture was stirred at 40 ° C for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (pyridine-1-oxide-3. Colorless crystals of (-yl) acetic acid (228 mg, yield 52%) were obtained. Melting point 1
61-162 ° C (decomposition).

Example 37 E- 2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3
-Pyridyl) ethyl acetate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml)
A normal aqueous sodium hydroxide solution (5 ml) was added, and
And stirred for 1 hour. 1N hydrochloric acid (5.5) was added to the reaction mixture.
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from acetone-diisopropyl ether to give E- 2- [4- (5-methyl-2-phenyl-).
4-oxazolylmethoxy) benzyloxyimino]-
2- (3-pyridyl) acetic acid (427 mg, 88% yield)
To obtain colorless crystals. 130-131 ° C (decomposition). Example 38 Sodium hydride (60%, oily, 203 mg) was added to ethyl Z- 2- (3-bromophenyl) -2-hydroxyiminoacetate (1.15 g) and 4- (4-
The mixture was added to a solution of (chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.33 g) in N, N-dimethylformamide (15 ml) at room temperature and stirred for 1 hour. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-
From the hexane (1: 4, volume ratio) elution part, Z- 2- (3
Ethyl -bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.12 g, 48% yield) was obtained as a pale yellow oil. . NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.1Hz), 2.44 (3H, s),
4.41 (2H, q, J = 7.1Hz), 5.00 (2H, s), 5.20 (2H,
s), 7.01 (2H, d, J = 8.8Hz), 7.20-7.56 (8H, m), 7.73
7.76 (1H, m), 7.99-8.06 (2H, m).

Example 39 Sodium hydride (60%, oily, 399 mg) was added under a nitrogen atmosphere to Z- 2- (3-benzoylphenyl) -2.
-Ethyl hydroxyiminoacetate (2.47 g) and 4-
(4-chloromethylphenoxymethyl) -5-methyl-
2-phenyloxazole (2.61 g) was added to a solution of N, N-dimethylformamide (15 ml) at room temperature.
Stir for hours. After adding 1N hydrochloric acid (15 ml),
Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, ethyl acetate - hexane (1: 3, volume ratio) from the fraction eluted, Z
-2- (3-benzoylphenyl) -2- [4- (5-
Ethyl methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.97 g, yield 4)
1%) as a brown oil. NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1Hz), 2.43 (3H, s),
4.40 (2H, q, J = 7.1Hz), 4.99 (2H, s), 5.20 (2H,
s), 7.00 (2H, d, J = 8.8Hz), 7.25-7.72 (11H, m), 7.76
-7.86 (3H, m), 7.96-8.05 (2H, m). Example 40, Z- 2- (3-benzoylphenyl) -2- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (800 mg)
Of tetrahydrofuran (14 ml) -methanol (7 m
l) Add 1N aqueous sodium hydroxide solution (7ml) to the solution
And stirred at 40 ° C. for 1 hour. 1N hydrochloric acid (7.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 2- (3-benzoylphenyl)-
2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (608 m
g, yield 80%). Melting point 185-18
6 ° C (decomposition).

Example 41 Potassium tert -butoxide (328 mg) was added under a nitrogen atmosphere to methyltriphenylphosphonium bromide (1.
14g) and tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 1 hour. A solution of ethyl Z- 2- (3-benzoylphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.12 g) in tetrahydrofuran (10 ml) was prepared. After dropwise addition and stirring for 3 hours, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography,
From the ethyl acetate-hexane (1: 4, volume ratio) elution part,
Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3
-(1-phenylvinyl) phenyl] ethyl acetate (88
0 mg, 79% yield) as a pale brown oil. NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1Hz), 2.43 (3H, s),
4.36 (2H, q, J = 7.1Hz), 4.99 (2H, s), 5.18 (2H,
s), 5.48 (2H, d, J = 6.4Hz), 6.99 (2H, d, J = 8.6Hz),
7.25-7.55 (14H, m), 7.99-8.05 (2H, m). Example 42 Ethyl Z- 2- (3-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (780 mg), E- styrylboronic acid (252 mg), potassium carbonate (589)
mg), toluene (20 ml), water (2 ml) and ethanol (2 ml) were stirred at room temperature under an argon atmosphere for 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (98 mg) was added thereto, and the mixture was heated under reflux for 15 hours. After cooling the reaction mixture to room temperature, the organic layer was washed with saturated saline and dried (MgSO 4).
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). Oxyimino] -2- ( E -3-styryl) acetate (610
mg, yield 75%) as a pale brown oil. NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1Hz), 2.43 (3H, s),
4.43 (2H, q, J = 7.1Hz), 5.00 (2H, s), 5.23 (2H,
s), 7.01 (2H, d, J = 8.4Hz), 7.11 (2H, s), 7.25-7.60
(13H, m), 7.69 (1H, br s), 7.99-8.05 (2H, m).

Example 43 Ethyl Z- 2- (3-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (430 mg) in tetrahydrofuran ( 10 ml) -methanol (5 ml) solution, 1N sodium hydroxide aqueous solution (5 ml) was added,
Stir at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 2- (3-bromophenyl) -2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxyimino] acetic acid (370 mg, yield 91)
%) As colorless crystals. Melting point 181-182 [deg.] C (decomposition). Example 44 Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3
-(1-phenylvinyl) phenyl] ethyl acetate (78
To a solution of 0 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a 1N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at 40 ° C for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 2- [4- (5-methyl-2).
Colorless crystals of -phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3- (1-phenylvinyl) phenyl] acetic acid (701 mg, yield 95%) were obtained. Melting point 171-172 [deg.] C.

Example 45 Z- 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- ( E
To a solution of (-3-styryl) ethyl acetate (500 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a 1N aqueous sodium hydroxide solution (5 ml),
Stir at 40 ° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 2- [4- (5-methyl-2-phenyl-4-).
Oxazolylmethoxy) benzyloxyimino] -2-
( E -3-styryl) acetic acid (474 mg, yield 95%)
To obtain colorless crystals. Melting point 178-179 [deg.] C. Example 46 Sodium hydride (60%, oily, 211 mg) was added under a nitrogen atmosphere to E -4- (hydroxyimino) -4- (4
Ethyl-phenoxyphenyl) butyrate (1.50 g) and 4
N, N- of-(4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.50 g)
To a solution of dimethylformamide (15 ml) at room temperature,
Stir for 1 hour. After adding 1N hydrochloric acid (7 ml),
Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). This was recrystallized from ethyl acetate-hexane,
E -4- [4- (5-Methyl-2-phenylo-4-xazolylmethoxy) benzyloxyimino] -4- (4
Colorless crystals of ethyl -phenoxyphenyl) butyrate (1.87 g, yield 66%) were obtained. 118-119 ° C.

Example 47 E -4- [4- (5-Methyl-2-phenylo-4-xazolylmethoxy) benzyloxyimino] -4- (4
-Phenoxyphenyl) ethyl butyrate (1.60 g) in tetrahydrofuran (20 ml) -methanol (10 m
l) Add 1N aqueous sodium hydroxide solution (10m
l) was added and the mixture was stirred at room temperature for 1 hour. 1 in the reaction mixture
Normal hydrochloric acid (10.5 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4- (5-methyl-2-phenylo-4-xazolylmethoxy) benzyloxyimino] -4- (4-phenoxyphenyl) butyric acid ( 1.50
g, yield 99%). Melting point 131-13
2 ° C. Example 48 Sodium hydride (60%, oily, 134 mg) was treated with methyl E -4- (hydroxyimino) -4-phenylbutyrate (632 mg) and 4- [2- (4-chloromethylphenoxy) under a nitrogen atmosphere. Ethyl] -5-methyl-2-phenyloxazole (1.00 g) was added to a solution of N, N-dimethylformamide (10 ml) at room temperature, and the mixture was stirred for 1 hour. After 1N hydrochloric acid (5 ml) was added, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was recrystallized from ethyl acetate-hexane to give E -4- [4
Colorless crystals of methyl [-[2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxyimino] -4-phenylbutyrate (650 mg, 43% yield) were obtained. 73-74 ° C.

Example 49 4- [2- (Methyl-2-pyrimidylamino) ethoxy] benzyl alcohol (1.50 g) in toluene (2
Thionyl chloride (0.633 ml) was added to
It was added dropwise at ° C. After stirring for 30 minutes, the mixture was concentrated. The residue was dissolved in N, N-dimethylformamide (10 ml), methyl E -4- (hydroxyimino) -4-phenylbutyrate (1.20 g) was added, and sodium hydride (60%, oily, 509 mg) was added. Was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. 1N hydrochloric acid (2
0 ml), sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from an ethyl acetate-hexane (1: 2, volume ratio) eluted portion, E -4- [4- [2- (methyl-2-
Pyrimidylamino) ethoxy] benzyloxyimino]
Methyl-4-phenylbutyrate (1.32 g, 51% yield)
Was obtained as a dark red oil. NMR (CDCl ₃ ) δ: 2.49-2.58 (2H, m), 3.00-3.09 (2H,
m), 3.30 (3H, s), 3.62 (3H, s), 4.02 (2H, t, J = 5.7
Hz), 4.21 (2H, t, J = 5.7Hz), 5.14 (2H, s), 6.48 (1H,
t, J = 4.8Hz), 6.90 (2H, d, J = 8.4Hz), 7.29-7.38 (5
H, m), 7.59-7.65 (2H, m), 8.31 (2H, d, J = 4.8Hz). Example 50 E -4- [4- [2- (5-methyl-2-phenyl-4)
-Oxazolyl) ethoxy] benzyloxyimino]-
To a solution of methyl 4-phenylbutyrate (460 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added 1
A normal aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was dissolved in ethyl acetate - hexane to, E-4-
Colorless crystals of [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxyimino] -4-phenylbutyric acid (443 mg, yield 99%) were obtained. 106-107 ° C.

Example 51 E -4- [4- [2- (Methyl-2-pyrimidylamino) ethoxy] benzyloxyimino] -4-methyl phenylbutyrate (1.22 g) in tetrahydrofuran (10
ml) -methanol (5 ml) solution, 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4- [2-
Colorless crystals of (methyl-2-pyrimidylamino) ethoxy] benzyloxyimino] -4-phenylbutyric acid (1.09 g, 92% yield) were obtained. 72-73 ° C. Example 52 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), ethyl benzoylacetate (0.612 ml), acetic acid (0.554)
ml), sodium acetate (528 mg) and ethanol (20 ml) were heated under reflux for 12 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and E -3- [4- (5-methyl-2-) was eluted from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
Ethyl phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (1.29
g, yield 83%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.1Hz), 2.44 (3H, s),
3.76 (2H, s), 4.09 (2H, q, J = 7.1Hz), 5.00 (2H, s)
s), 5.20 (2H, s), 7.01 (2H, d, J = 8.4Hz), 7.30-7.50
(8H, m), 7.61-7.67 (2H, m), 7.97-8.05 (2H, m).

Example 53 E -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate ethyl (1.16 g) in tetrahydrofuran (60 ml) Lithium hydroxide monohydrate (402 mg) was added to a water (40 ml) solution, and the mixture was stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -3- [4- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (1.08 g,
Colorless crystals having a yield of 99%) were obtained. Melting point 107-108
° C. Example 54 Sodium hydride (60%, oily, 143 mg) was added under a nitrogen atmosphere to methyl E -4- (hydroxyimino) -4-phenylbutyrate (676 mg) and 5-chloro-2- (4
-Chloromethylphenoxymethyl) imidazo [1,2-
[a ] A solution of pyridine (1.00 g) in N, N-dimethylformamide (10 ml) was added at room temperature and stirred for 1 hour. After 1N hydrochloric acid (7 ml) was added, aqueous sodium bicarbonate was added.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (2: 1, volume ratio), E -4- [4- (5
Methyl -chloroimidazo [1,2- a ] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.04 g, 67% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.60 (2H, m), 3.01-3.11 (2H,
m), 3.62 (3H, s), 5.17 (2H, s), 5.31 (2H, s), 6.90
(1H, d, J = 7.4Hz), 7.04 (2H, d, J = 8.6Hz), 7.19 (1H,
dd, J = 7.4, 8.8Hz), 7.30-7.39 (5H, m), 7.55-7.66
(3H, m), 7.85 (1H, s).

Example 55 E -4- [4- (5-Chloroimidazo [1,2- a ] pyridin-2-ylmethoxy) benzyloxyimino]-
To a solution of methyl 4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added 1
A normal aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was dissolved in ethyl acetate - hexane to, E-4-
[4- (5-chloroimidazo [1,2- a ] pyridine-
Colorless crystals of 2-ylmethoxy) benzyloxyimino] -4-phenylbutyric acid (313 mg, 78% yield) were obtained. 160-161 ° C. Example 56 E -4- [4- (5-Chloroimidazo [1,2- a ] pyridin-2-ylmethoxy) benzyloxyimino]-
Methyl 4-phenylbutyrate (550 mg), phenylboronic acid (168 mg), sodium hydrogen carbonate (348 m
g), a mixture of toluene (20 ml), water (2 ml) and methanol (2 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0) (80 mg) was added thereto,
The mixture was heated under reflux for 36 hours. After cooling the reaction mixture to room temperature, the organic layer was washed with saturated saline and dried (MgSO ₄ ).
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and from an ethyl acetate-hexane (3: 2, volume ratio) eluate, E -4- [4- (5-phenylimidazo [1,
Methyl 2- a ] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (490 mg, 82% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.49-2.58 (2H, m), 3.00-3.10 (2H,
m), 3.61 (3H, s), 5.15 (2H, s), 5.24 (2H, s), 6.75
(1H, d, J = 7.0Hz), 7.01 (2H, d, J = 8.8Hz), 7.24-7.3
7 (6H, m), 7.51-7.63 (8H, m), 7.72 (1H, s).

Example 57 E -4- [4- (5-Phenylimidazo [1,2- a ]]
Pyridin-2-ylmethoxy) benzyloxyimino]
To a solution of methyl-4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml) -methanol (5 ml),
A 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5) was added to the reaction mixture.
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethyl acetate - hexane to, E -
4- [4- (5-phenylimidazo [1,2- a ] pyridin-2-ylmethoxy) benzyloxyimino] -4
Colorless crystals of -phenylbutyric acid (365 mg, yield 94%) were obtained. 160-161 ° C. Example 58 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 6-oxo-6-phenylhexanoate (415 mg),
Acetic acid (0.276 ml), sodium acetate (264 m
A mixture of g) and ethanol (20 ml) was heated under reflux for 13 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (1: 4, volume ratio), E -6- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (620 mg, yield 73%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.73 (4
H, m), 2.28 (2H, t, J = 7.3Hz), 2.44 (3H, s), 2.78
(2H, t, J = 7.5Hz), 4.09 (2H, q, J = 7.1Hz), 5.00 (2H,
s), 5.15 (2H, s), 7.01 (2H, d, J = 8.4Hz), 7.33-7.48
(8H, m), 7.58-7.64 (2H, m), 7.99-8.05 (2H, m).

[0149] In Example 59 Example 58, from the fractions eluted following the E-form, Z -6- [4- (5- methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] -6-
Ethyl phenylhexanoate (120 mg, 14% yield)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.38-1.71 (4
H, m), 2.26 (2H, t, J = 7.3Hz), 2.43 (3H, s), 2.53
(2H, t, J = 7.5Hz), 4.09 (2H, q, J = 7.1Hz), 4.99 (2H,
s), 5.02 (2H, s), 6.97 (2H, d, J = 8.4Hz), 7.23-7.47
(10H, m), 7.97-8.05 (2H, m). Example 60 E -6- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml) -methanol (3 ml) A 1N aqueous sodium hydroxide solution (3 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -6- [4
Colorless crystals of-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (451 mg, yield 90%) were obtained. 112-113 ° C.

Example 61 Ethyl Z -6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (120 mg) in tetrahydrofuran (6 ml) -methanol (3 ml), 1N aqueous sodium hydroxide solution (3 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z -6- [4
Colorless crystals of-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (113 mg, yield 99%) were obtained. Melting point 101-102 [deg.] C. Example 62 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), 3-oxo-1-indanecarboxylic acid (284 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and a mixture of ethanol (20 ml) were heated under reflux for 18 hours, and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -1-indanecarboxylic acid (522
mg, yield 69%). Melting point 148-1
49 ° C.

Example 63 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (2-pyridyl) butyrate (367 m
g), acetic acid (0.276 ml), sodium acetate (26
4 mg) and ethanol (20 ml).
After heating under reflux for an hour, the mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (2: 7, volume ratio), E -4-
Ethyl [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2-pyridyl) butyrate (600 mg, yield 75%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1Hz), 2.44 (3H, s),
2.55-2.64 (2H, m), 3.19-3.28 (2H, m), 4.07 (2H, m
q, J = 7.1Hz), 5.00 (2H, s), 5.19 (2H, s), 7.01 (2H, s)
d, J = 8.8Hz), 7.19-7.24 (1H, m), 7.36 (2H, d, J = 8.8
Hz), 7.39-7.46 (3H, m), 7.64 (1H, dt, J = 1.8, 7.6H
z), 7.87 (1H, d, J = 8.0Hz), 7.99-8.05 (2H, m), 8.54
-8.59 (1H, m). Example 64 E -4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2
-Pyridyl) butyrate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml)
A normal aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was dissolved in ethyl acetate - hexane to, E-4-
Colorless crystals of [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2-pyridyl) butyric acid (425 mg, 87% yield) were obtained. 116-117 ° C.

Example 65 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg)
Ethyl (2-furyl) -4-oxobutyrate (347m
g), acetic acid (0.276 ml), sodium acetate (26
4 mg) and ethanol (20 ml) in 96
After heating under reflux for an hour, the mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (1: 4, volume ratio), E -4-
Ethyl (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (190 mg, yield 24%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1Hz), 2.44 (3H, s),
2.62-2.71 (2H, m), 2.95-3.04 (2H, m), 4.13 (2H,
q, J = 7.1Hz), 5.00 (2H, s), 5.14 (2H, s), 6.45-6.49
(1H, m), 7.01 (2H, d, J = 8.8Hz), 7.25-7.28 (1H, m
m), 7.34 (2H, d, J = 8.8Hz), 7.39-7.48 (4H, m), 7.99
-8.05 (2H, m). Example 66 In Example 65, a part eluted following the E- form was used to obtain Z -4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl Ethyl oxyimino] butyrate (510 mg, 65% yield)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1Hz), 2.43 (3H, s),
2.53-2.62 (2H, m), 2.89-2.98 (2H, m), 4.09 (2H, m
q, J = 7.1Hz), 5.00 (2H, s), 5.17 (2H, s), 6.43 (1H,
dd, J = 1.8, 3.2Hz), 6.68 (1H, d, J = 1.8Hz), 7.01 (2
(H, d, J = 8.8Hz), 7.34 (2H, d, J = 8.8Hz), 7.38-7.47
(4H, m), 7.97-8.05 (2H, m).

Example 67 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (3-pyridyl) butyrate (367 m
g), acetic acid (0.276 ml), sodium acetate (26
4 mg) and ethanol (20 ml).
After heating under reflux for an hour, the mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from a fraction eluted with ethyl acetate-hexane (3: 2, volume ratio), 4- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl) butyrate (590 mg, yield 73%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.16-1.30 (3H, m), 2.44 (3H, s), 2.5
1-2.64 (2H, m), 2.86 (0.4H, t, J = 6.9Hz), 3.05 (1.6
H, t, J = 7.9Hz), 4.02-4.18 (2H, m), 5.00 (2.4H, sl
ike), 5.18 (1.6H, s), 6.95-7.06 (2H, m), 7.23-7.48
(6H, m), 7.71-7.78 (0.2H, m), 7.91-8.05 (2.8H,
m), 8.53-8.61 (1H, m), 8.66-8.69 (0.2H, m), 8.85-8.
88 (0.8H, m). Example 68 Z -4- (2-furyl) -4- [4- (5-methyl-2
1N aqueous sodium hydroxide solution (5 ml) was added to a solution of ethyl -phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (460 mg) in tetrahydrofuran (10 ml) -methanol (5 ml), and the mixture was added at room temperature.
Stir for hours. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was recrystallized from ethyl acetate-hexane, and Z -4-
Colorless crystals of (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (402 mg, 93% yield) were obtained. 131-133 ° C.

Example 69 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (4-pyridyl) butyrate (367 m
g), acetic acid (0.276 ml), sodium acetate (26
4 mg) and ethanol (20 ml) in 15
After heating under reflux for an hour, the mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from a fraction eluted with ethyl acetate-hexane (3: 2, volume ratio), 4- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl) butyrate (740 mg, yield 92%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.16-1.31 (3H, m), 2.44 (3H, s), 2.4
8-4.63 (2H, m), 2.77-2.86 (0.5H, m), 3.02 (1.5H,
t, J = 7.9Hz), 4.02-4.18 (2H, m), 5.00 (2.5H, slik
e), 5.20 (1.5H, s), 6.95-7.22 (2H, m), 7.20-7.56
(7H, m), 7.99-8.05 (2H, m), 8.59-8.66 (2H, m). Example 70 Ethyl 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl) butyrate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) )) 1N aqueous sodium hydroxide solution (5 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl)
Colorless crystals of butyric acid (378 mg, 77% yield) were obtained. 158-159 ° C.

Example 71 Tetrahydrofuran (10 ml) of ethyl 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl) butyrate (670 mg) A 1 N aqueous sodium hydroxide solution (5 ml) was added to a methanol (5 ml) solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl)
Colorless crystals of butyric acid (475 mg, yield 75%) were obtained. Melting point 161-162 [deg.] C. Example 72 E -4- (2-furyl) -4- [4- (5-methyl-2)
1N sodium hydroxide aqueous solution (5 ml) was added to a solution of ethyl -phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (190 mg) in tetrahydrofuran (10 ml) -methanol (5 ml).
Stir for hours. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was dissolved in ethyl acetate - hexane to, E-4-
Colorless crystals of (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (140 mg, yield 78%) were obtained. 124-125 ° C.

Example 73 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), methyl 9-oxo-9-phenylnonanoate (464 mg), 1
A mixture of normal hydrochloric acid (3 ml), sodium acetate (264 mg) and methanol (20 ml) was heated under reflux for 72 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and an oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 6, volume ratio). This was mixed with tetrahydrofuran (10 ml) -methanol (5 m
1) sodium hydroxide solution (5m
l) was added and the mixture was stirred at room temperature for 1 hour. 1 in the reaction mixture
Normal hydrochloric acid (5.5 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -9- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -9-phenylnonanoic acid (323 mg, yield). 37
%) As colorless crystals. Mp 67-68 ° C. Example 74 3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), methyl 4-oxo-4-phenylbutyrate (371 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) were heated at reflux for 40 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 4, volume ratio), E -4- [3- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (57
0 mg, 61% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.53-2.62 (2H, m), 3.0
4-3.13 (2H, m), 3.62 (3H, s), 5.01 (2H, s), 5.22
(2H, s), 6.94-7.08 (3H, m), 7.28-7.48 (7H, m), 7.6
0-7.66 (2H, m), 7.97-8.05 (2H, m).

Example 75 3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), ethyl 6-oxo-6-phenylhexanoate (452 mg)
Acetic acid (0.331 ml), sodium acetate (317 m
A mixture of g) and ethanol (20 ml) was heated under reflux for 15 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and E -6- [3-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (590 mg, 58% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1Hz), 1.47-1.80 (4
H, m), 2.29 (2H, t, J = 7.5Hz), 2.43 (3H, s), 2.80
(2H, t, J = 7.5Hz), 4.08 (2H, q, J = 7.1Hz), 5.01 (2H,
s), 5.20 (2H, s), 6.93-7.08 (3H, m), 7.25-7.47 (7
H, m), 7.58-7.64 (2H, m), 7.97-8.05 (2H, m). Example 76 E -6- [3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) To the solution was added a 1N aqueous sodium hydroxide solution (5 ml), and the solution was added at room temperature for 1 hour.
Stir for hours. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was recrystallized from ethyl acetate-hexane to give E -6
Colorless crystals of [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (432 mg, 88% yield) were obtained.
114-115 ° C.

Example 77 E -4- [3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-methylbutyrate (500 mg) in tetrahydrofuran (10 ml) -methanol ( (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [3-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (39
(5 mg, yield: 82%) as colorless crystals. Melting point 108 ~
109 ° C. Example 78 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), ethyl 7-oxo-7-phenylheptanoate (959 mg),
Acetic acid (0.331 ml), sodium acetate (317 m
A mixture of g) and ethanol (20 ml) was heated at reflux for 18 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (1: 5, volume ratio), E- 7- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoate (800 mg, yield 77%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.08-1.70 (9H, m), 2.24 (2H, t, J = 7.
5Hz), 2.44 (3H, s), 2.76 (2H, t, J = 7.5Hz), 4.11 (2
H, q, J = 7.1Hz), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2
H, d, J = 8.8Hz), 7.33-7.48 (8H, m), 7.57-7.63 (2H,
m), 7.99-8.05 (2H, m).

Example 79 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.50 g), ethyl 8-oxo-8-phenyloctanoate (2.54 g)
Acetic acid (0.830 ml), sodium acetate (793 m
A mixture of g) and ethanol (40 ml) was heated at reflux for 18 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluate of ethyl acetate-hexane (1: 5, volume ratio), E- 8- [4-
Ethyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (2.02 g, yield 76%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.18-1.65 (11H, m), 2.25 (2H, t, J =
7.5Hz), 2.44 (3H, s), 2.75 (2H, t, J = 7.5Hz), 4.12
(2H, q, J = 7.1Hz), 5.00 (2H, s), 5.15 (2H, s), 7.01
(2H, d, J = 8.8Hz), 7.33-7.46 (8H, m), 7.58-7.64 (2
H, m), 7.99-8.05 (2H, m). In Example 80 Example 79, from the fractions eluted following the E-form, Z -8- [4- (5- methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] -8-
Ethyl phenyloctanoate (408 mg, 15% yield)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J =
7.5Hz), 2.43 (3H, s), 2.50 (2H, t, J = 7.2Hz), 4.12
(2H, q, J = 7.1Hz), 4.99 (2H, s), 5.02 (2H, s), 6.97
(2H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.6Hz), 7.27-7.48
(8H, m), 7.99-8.04 (2H, m).

Example 81 E- 8- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (660 mg) in tetrahydrofuran (10 ml) -methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added to the solution, and the solution was added at room temperature for 1 hour.
Stir for hours. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was recrystallized from ethyl acetate-hexane to give E- 8-
Colorless crystals of [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid (580 mg, yield 92%) were obtained.
116-117 ° C. Example 82 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 6-oxo-6-phenylhexaneamide (396 mg), acetic acid (0.331 ml), sodium acetate (317mg)
A mixture of and ethanol (20 ml) was heated at reflux for 18 hours and then cooled to room temperature. Water is added to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (3: 1, volume ratio). This was recrystallized from ethyl acetate-hexane to give E -6- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexaneamide (651 mg, yield 68%) was obtained as colorless crystals. 95-96 ° C.

Example 83 Ethyl 4- (chloromethyl) -2- (2-furyl) -5-methyloxazole (340 mg), ethyl E- 8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg) ), Potassium carbonate (432 mg) and N, N-dimethylformamide (7 ml) were stirred at room temperature for 18 hours. Water is added to the reaction mixture,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluate of ethyl acetate-hexane (2: 9, volume ratio), E- 8- [4- [2
Ethyl-(2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (717 mg, yield 84%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J =
7.5Hz), 2.42 (3H, s), 2.70-2.79 (2H, m), 4.11 (2H,
q, J = 7.1Hz), 5.00 (2H, s), 5.15 (2H, s), 6.51-6.5
4 (1H, m), 6.96-7.03 (3H, m), 7.31-7.40 (5H, m),
7.53-7.56 (1H, m), 7.58-7.64 (2H, m). Example 84 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), methyl 4-oxo-4-phenylbutyrate (619 mg), acetic acid (0.553 ml), A mixture of sodium acetate (528 mg) and methanol (20 ml) was heated under reflux for 19 hours, and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (2: 9, volume ratio), E -4- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.
18 g, yield 76%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.50-2.60 (2H, m), 3.0
2-3.11 (2H, m), 3.62 (3H, s), 5.01 (2H, s), 5.17
(2H, s), 7.01 (2H, d, J = 8.8Hz), 7.33-7.48 (8H, m),
7.60-7.66 (2H, m), 7.99-8.06 (2H, m).

Example 85 In Example 84, the portion eluted subsequently to the E form was converted to Z -4- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] -4-
Methyl phenylbutyrate (222 mg, 14% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.57 (2H, t, J = 7.0Hz),
2.84 (2H, t, J = 7.0Hz), 3.62 (3H, s), 5.00 (4H, s
like), 6.98 (2H, d, J = 8.8Hz), 7.26 (2H, d, J = 8.8H
z), 7.30-7.48 (8H, m), 7.99-8.05 (2H, m). Example 86 5- (chloromethyl) -3-phenylisoxazole (238 mg), methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (350 m
g), potassium carbonate (310 mg) and N, N-dimethylformamide (10 ml) were stirred at room temperature for 13 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (1: 4, volume ratio), E -4-phenyl-4- [4- (3
-Phenyl-5-isoxazolylmethoxy) benzyloxyimino] butyrate (358 mg, 62% yield)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H,
m), 3.62 (3H, s), 5.17 (2H, s), 5.22 (2H, s), 6.66
(1H, s), 6.99 (2H, d, J = 8.8Hz), 7.34-7.49 (8H,
m), 7.59-7.65 (2H, m), 7.78-7.84 (2H, m).

Example 87 E -Methyl 4-phenyl-4- [4- (3-phenyl-5-isooxosazolylmethoxy) benzyloxyimino] butyrate (326 mg) in tetrahydrofuran (6 ml)
-To a solution of water (4 ml) -methanol (2 ml) was added lithium hydroxide monohydrate (58.3 mg), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4-phenyl-4- [4- (3-phenyl-5-isooxosazolylmethoxy) benzyloxyimino] butyric acid (306 m
g, yield 97%). Melting point 96-97
° C. Example 88 3- (chloromethyl) -5-phenylisoxazole (340 mg), E -4- (4-hydroxybenzyloxyimino-4-phenylbutyrate methyl (500 mg),
A mixture of potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from the eluted portion of ethyl acetate-hexane (2: 9, volume ratio), E -4-phenyl-4- [4- (5-
Methyl phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyrate (472 mg, 63% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.59 (2H, m), 3.01-3.11 (2H,
m), 3.62 (3H, s), 5.16 (2H, s), 5.21 (2H, s), 6.66
(1H, s), 7.01 (2H, d, J = 8.8Hz), 7.34-7.53 (8H,
m), 7.57-7.65 (2H, m), 7.74-7.82 (2H, m).

Example 89 4- (Chloromethyl) -5-methyl-2-phenylthiazole (394 mg), methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg)
mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) at room temperature for 72 hours.
Stir for hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (1: 1).
From the eluted part, methyl E -4- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (570 mg,
(71% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.60 (5H, m), 3.02-3.11 (2H,
m), 3.62 (3H, s), 5.17 (2H, s), 5.18 (2H, s), 7.04
(2H, d, J = 8.6Hz), 7.33-7.51 (8H, m), 7.58-7.66 (2
H, m), 7.85-7.93 (2H, m). Example 90 Methyl E -4-phenyl-4- [4- (5-phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyrate (412 mg) in tetrahydrofuran (6 ml)
-To a solution of water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (73.5 mg), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture.
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4-phenyl-4- [4- (5-phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyric acid (320 m
g, yield 80%). Melting point 100-10
1 ° C.

Example 91 E -4- [4- (5-Methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid methyl ester (500 mg) in tetrahydrofuran (1
0 ml) -water (4 ml) -methanol (8 ml) solution, lithium hydroxide monohydrate (83.8 mg) was added,
Stir at room temperature for 2 hours. 1N hydrochloric acid (2.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4- (5-methyl-2-phenyl-4-).
Colorless crystals of thiazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (363 mg, yield 75%) were obtained. Melting point 99-100 [deg.] C. Example 92 4- (chloromethyl) -2- (2-furyl) -5-methyloxazole (348 mg), methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 3, volume ratio), E -4- [4- [2-
Methyl (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (507 mg, yield 67%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.42 (3H, s), 2.50-2.59 (2H, m), 3.0
1-3.11 (2H, m), 3.62 (3H, s), 5.00 (2H, s), 5.16
(2H, s), 6.51-6.54 (1H, m), 6.95-7.02 (3H, m), 7.2
8-7.40 (5H, m), 7.52-7.55 (1H, m), 7.59-7.66 (2H,
m).

Example 93 Methyl 4- (chloromethyl) -5-methyl-2- (2-thienyl) oxazole (376 mg), methyl E- 4-[(4-hydroxybenzyloxy) imino] -4-phenylbutyrate ( A mixture of 500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 40 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 5, volume ratio), E -4- [4-
Methyl [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (495 mg, 63% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.50-2.60 (2H, m), 3.0
2-3.11 (2H, m), 3.63 (3H, s), 4.98 (2H, s), 5.16
(2H, s), 6.99 (2H, d, J = 8.8Hz), 7.10 (1H, dd, J = 3.
6, 5.0Hz), 7.32-7.42 (6H, m), 7.59-7.66 (3H, m). Example 94 E -4- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] benzyloxyimino] -4
-Methyl phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml)
Lithium hydroxide monohydrate (76.0 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (1.9 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino]
Colorless crystals of -4-phenylbutyric acid (328 mg, yield 79%) were obtained. 124-125 ° C.

Example 95 Ethyl 4- (chloromethyl) -5-methyl-2- (2-thienyl) oxazole (368 mg), ethyl E- 8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg) ), Potassium carbonate (432mg)
And a mixture of N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluate of ethyl acetate-hexane (1: 5, volume ratio), E- 8- [4-
Ethyl [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (762 mg, yield 95%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J =
7.3Hz), 2.41 (3H, s), 2.70-2.79 (2H, m), 4.11 (2H,
q, J = 7.1Hz), 4.98 (2H, s), 5.15 (2H, s), 6.99 (2H
H, d, J = 8.8Hz), 7.07-7.12 (1H, m), 7.30-7.42 (6H,
m), 7.58-7.65 (3H, m). Example 96 Synthesis of benzyl bromide (0.209 ml), methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) The mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from a fraction eluted with ethyl acetate-hexane (1: 7, volume ratio), methyl E -4- (4-benzyloxybenzyloxyimino) -4-phenylbutyrate (400 mg, yield) 62%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H,
m), 3.62 (3H, s), 5.07 (2H, s), 5.15 (2H, s), 6.97
(2H, d, J = 8.8Hz), 7.30-7.46 (10H, m), 7.60-7.66
(2H, m).

Example 97 E -4- [4- [5-Methyl-2- (2-thienyl)-
4-oxazolylmethoxy] benzyloxyimino]-
Methyl 4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 m
l) Add lithium hydroxide monohydrate (73.6 mg) to the solution.
And stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyric acid (366 mg) , 88%). 142-143 ° C. Example 98 E -4- (4-benzyloxybenzyloxyimino)
Methyl 4-phenylbutyrate (340 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 m
l) Add lithium hydroxide monohydrate (70.7 mg) to the solution
And stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4- (4-benzyloxybenzyloxyimino) -4-phenylbutyric acid (238 mg, yield 72%).
To obtain colorless crystals. 86-87 ° C.

Example 99 2-Chloromethylimidazo [1,2- a ] pyridine (2
93 mg), a mixture of methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (3: 2, volume ratio), E -4- [4- (imidazo [1,2-
a ] Methyl pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (321 mg, yield 45)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H,
m), 3.62 (3H, s), 5.16 (2H, s), 5.30 (2H, s), 6.78
(1H, dt, J = 1.0, 6.8Hz), 7.02 (2H, d, J = 8.8Hz), 7.
13-7.40 (7H, m), 7.56-7.66 (3H, m), 8.08 (1H, d, J
= 6.8Hz). Example 100 4- (chloromethyl) -2-phenyloxazole (2
A mixture of 50 mg), methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (369 mg), potassium carbonate (325 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and E -4-phenyl-4- [4- (2-phenyl-4-oxazolylmethoxy) benzyl was eluted with ethyl acetate-hexane (2: 9, volume ratio). Oxiimino]
Methyl butyrate (320 mg, 58% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H,
m), 3.62 (3H, s), 5.10 (2H, s), 5.17 (2H, s), 7.01
(2H, d, J = 8.8Hz), 7.32-7.40 (5H, m), 7.41-7.49 (3
H, m), 7.60-7.66 (2H, m), 7.74 (1H, s), 8.03-8.09
(2H, m).

Example 101 E -4- [4- (imidazo [1,2- a ] pyridine-2
-Ylmethoxy) benzyloxyimino] -4-methyl methyl 4-phenylbutyrate (280 mg) in tetrahydrofuran (6
ml) -water (4 ml) -methanol (4 ml) solution,
Lithium hydroxide monohydrate (53.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (1.3
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was dissolved in ethyl acetate - hexane to, E -
Colorless crystals of 4- [4- (imidazo [1,2- a ] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyric acid (206 mg, yield 76%) were obtained. 180-182 ° C. Example 102: Methyl E -4-phenyl-4- [4- (2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (280 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) Lithium hydroxide monohydrate (49.9 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4-phenyl-
4- [4- (2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (237 mg, yield 8)
(7%). 144-145 ° C.

Example 103 2-Chloromethylquinoline hydrochloride (488 mg), E-
Methyl 4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (650 mg), potassium carbonate (1.
00g) and N, N-dimethylformamide (10 m
The mixture of 1) was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel chromatography, and E- 4 was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
Methyl-phenyl-4- [4- (2-quinolylmethoxy) benzyloxyimino] butyrate (655 mg, yield 70)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.49-2.58 (2H, m), 3.01-3.10 (2H,
m), 3.61 (3H, s), 5.15 (2H, s), 5.40 (2H, s), 7.02
(2H, d, J = 8.4Hz), 7.31-7.38 (5H, m), 7.50-7.85 (6
H, m), 8.09 (1H, d, J = 8.4Hz), 8.19 (1H, d, J = 8.4H
z). Example 104 Methyl E -4-phenyl-4- [4- (2-quinolylmethoxy) benzyloxyimino] butyrate (585 mg)
In a solution of tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml).
08 mg) and stirred at room temperature for 2 hours. 1N hydrochloric acid (2.6 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -4-phenyl-4- [4- (2-
Quinolylmethoxy) benzyloxyimino] butyric acid (46
(9 mg, yield 83%). Melting point 133-
134 ° C.

Example 105 4- (chloromethyl) -2-phenylthiazole (36
8 mg), a mixture of methyl E -4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was subjected to silica gel chromatography, and E -4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyl was eluted with ethyl acetate-hexane (2: 9, volume ratio). Methyl oximino] butyrate (494 mg, 63% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H,
m), 3.62 (3H, s), 5.17 (2H, s), 5.28 (2H, s), 7.02
(2H, d, J = 8.8Hz), 7.31-7.49 (9H, m), 7.59-7.65 (2
H, m), 7.93-7.99 (2H, m). Example 106 E -4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 m)
l) Add oxalyl chloride (0.156 ml) at room temperature to the solution
And N, N-dimethylformamide (catalytic amount).
After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and added dropwise at 0 ° C. to a mixture of 25% aqueous ammonia (15 ml) and ethyl acetate (20 ml). After stirring at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate to give E -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyramide (31
(5 mg, yield: 45%) as colorless crystals. Melting point 164 ~
165 ° C.

Example 107 To a solution of E -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (941 mg) in methanol (5 ml) was added sodium. Methoxide (108 mg) was added. After stirring at room temperature for 1 hour, the mixture was concentrated. The remaining crystals recrystallized from methanol - diethyl ether, E-4-
Colorless crystals of [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (456 mg, yield 46%) were obtained. 64-70 ° C. Example 108: Methyl E -4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyloxyimino] butyrate (424 mg) in tetrahydrofuran (10 ml) -water (4 ml) -methanol (4 ml) Lithium hydroxide monohydrate (54.8 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hours. 1 N hydrochloric acid (1.4 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give E -4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyloxyimino] butyric acid (369 mg, 90% yield). Colorless crystals were obtained. 104-105 ° C.

Example 109 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 2,2
-Ethyl-dimethyl-3-oxo-3-phenylpropionate (468 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml)
The mixture was heated to reflux for 5 days, and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (2: 9, volume ratio), Z -2,2-dimethyl-3- [4- (5-methyl-
Ethyl 2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (27
(3 mg, 28% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.1Hz), 1.31 (6H, s),
2.44 (3H, s), 3.96 (2H, q, J = 7.1Hz), 5.00 (2H,
s), 5.07 (2H, s), 7.00 (2H, d, J = 8.6Hz), 7.26-7.46
(10H, m), 8.00-8.06 (2H, m). Example 110 Z -2,2-dimethyl-3- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (265 m
g) tetrahydrofuran (3 ml)-water (3 ml)-
To a solution of ethanol (6 ml) was added potassium hydroxide (1.8
3 g) was added, the mixture was heated under reflux for 3 days, and then cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to give Z -2,2-dimethyl-3- [4-
Light yellow crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (130 mg, yield 52%) were obtained. 142-143 ° C (decomposition).

Example 111 E -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg), hydrochloric acid 1
A mixture of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (328 mg) and N, N-dimethylformamide (5 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous potassium carbonate solution and saturated saline in this order, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from tetrahydrofuran-hexane, and E- 3
Colorless crystals of-[4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropanamide (512 mg, yield 86%) were obtained. Melting point 164-165 [deg.] C. Example 112 E -4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 m)
l) Add oxalyl chloride (0.156 ml) at room temperature to the solution
And N, N-dimethylformamide (catalytic amount).
After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise at 0 ° C. to a mixture of 40% aqueous dimethylamine solution (20 ml) and ethyl acetate (20 ml). After stirring at room temperature for 2 hours,
Water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluate of ethyl acetate-hexane (2: 1, volume ratio), E- N, N
-Dimethyl-4- [4- (5-methyl-2-phenyl-
4-oxazolylmethoxy) benzyloxyimino]-
4-phenylbutanamide (511 mg, yield 69%)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.43-2.55 (5H, m), 2.83 (3H, s), 2.8
8 (3H, s), 3.01-3.10 (2H, m), 5.00 (2H, s), 5.17
(2H, s), 7.01 (2H, d, J = 8.6Hz), 7.30-7.48 (8H, m),
7.63-7.71 (2H, m), 7.97-8.05 (2H, m).

Example 113 E -4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 m
l) Add oxalyl chloride (0.156 ml) at room temperature to the solution
And N, N-dimethylformamide (catalytic amount).
After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of 40% aqueous methylamine solution (20 ml) and ethyl acetate (30 ml) at 0 ° C. After stirring at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane, and E -N-
Methyl-4- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxyimino] -4-
Colorless crystals of phenylbutanamide (466 mg, yield 65%) were obtained. 141-142 ° C. Example 114 Lithium hydroxide 1 was added to a solution of E -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (500 mg) in methanol (10 ml). Hydrate (44.6 mg) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated. The remaining crystals recrystallized from methanol - diethyl ether, E
Colorless crystals of lithium 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (485 mg, yield 96%) were obtained. 201-203 ° C.

Example 115 E- 7- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoic acid ethyl (730 mg) in tetrahydrofuran (10 ml) -methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added to the solution, and the mixture was added at room temperature for 1 hour.
Stir for hours. 1N hydrochloric acid (5.5 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was recrystallized from ethyl acetate-hexane to give E- 7-
Colorless crystals of [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoic acid (569 mg, yield 82%) were obtained.
84-85 ° C. Example 116 Ethyl Z- 8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (340 mg) in tetrahydrofuran (6 ml) -water (4 ml) -Methanol (4 ml)
Lithium hydroxide monohydrate (159 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (3.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 8- [4- (5-methyl-2-phenyl-4-).
Oxazolylmethoxy) benzyloxyimino] -8-
Colorless crystals of phenyloctanoic acid (293 mg, 91% yield) were obtained. 88-89 ° C.

Example 117 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 8-
A mixture of methyl (4-methoxyphenyl) -8-oxooctanoate (538 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated under reflux for 16 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from the eluted portion of ethyl acetate-hexane (2: 7, volume ratio), E- 8- (4-methoxyphenyl) -8- [4-
Methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (650
mg, yield 59%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J = 7.
5Hz), 2.44 (3H, s), 2.72 (2H, t, J = 7.7Hz), 3.65 (3
H, s), 3.82 (3H, s), 5.00 (2H, s), 5.13 (2H, s), 6.
88 (2H, d, J = 8.8Hz), 7.01 (2H, d, J = 8.8Hz), 7.35
(2H, d, J = 8.8Hz), 7.39-7.48 (3H, m), 7.56 (2H, d,
J = 8.8Hz), 7.99-8.05 (2H, m). Example 118 E- 8- (4-methoxyphenyl) -8- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (580 mg)
To a solution of the above in tetrahydrofuran (10 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (128 mg), and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (3.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8- (4-methoxyphenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (528 mg, 93% yield) colorless crystals were obtained. 69-70 ° C.

Example 119 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 8-
(4-Chlorophenyl) -8-oxooctanoic acid (54
A mixture of 6 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated under reflux for 18 hours, and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, ethyl acetate - hexane (1: 6, volume ratio) from the fraction eluted, E
Methyl -8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (828 mg, yield 75%) as a colorless oil Obtained. NMR (CDCl ₃ ) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J = 7.
5Hz), 2.44 (3H, s), 2.67-2.76 (2H, m), 3.65 (3H,
s), 5.00 (2H, s), 5.14 (2H, s), 7.01 (2H, d, J = 8.8H
z), 7.29-7.37 (4H, m), 7.40-7.47 (3H, m), 7.55 (2
H, d, J = 8.8Hz), 7.99-8.05 (2H, m). Example 120 In Example 119, the portion eluted following the E- form was used to obtain Z- 8- (4-chlorophenyl) -8- [4-
Methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (215
mg, yield 19%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (8H, m), 2.27 (2H, t, J = 7.
4Hz), 2.41-2.53 (5H, m), 3.65 (3H, s), 4.99 (2H,
s), 5.01 (2H, s), 6.98 (2H, d, J = 8.8Hz), 7.22-7.37
(6H, m), 7.40-7.46 (3H, m), 7.99-8.05 (2H, m).

Example 121 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 8-
(4-fluorophenyl) -8-oxooctanoic acid (5
A mixture of 14 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated under reflux for 18 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, ethyl acetate - hexane (1: 6, volume ratio) from the fraction eluted, E
Methyl -8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (771 mg, yield 71%) was obtained as a colorless oil. As obtained. NMR (CDCl ₃ ) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J = 7.
5Hz), 2.44 (3H, s), 2.68-2.76 (2H, m), 3.65 (3H,
s), 5.00 (2H, s), 5.14 (2H, s), 6.97-7.10 (4H, m),
7.35 (2H, d, J = 8.8Hz), 7.39-7.48 (3H, m), 7.54-7.
63 (2H, m), 7.97-8.05 (2H, m). In Example 122 Example 121, from the fractions eluted following the E-form, Z-8- (4-fluorophenyl) -8- [4-
Methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (205
mg, yield 19%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (8H, m), 2.27 (2H, t, J = 7.
5Hz), 2.43 (3H, s), 2.45-2.53 (2H, m), 3.65 (3H,
s), 4.99 (2H, s), 5.01 (2H, s), 6.95-7.09 (4H, m),
7.23-7.46 (7H, m), 7.98-8.04 (2H, m).

Example 123 E -Methyl 8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (730 mg) in tetrahydrofuran ( 10 ml) -water (4 ml) -methanol (4 ml) solution and lithium hydroxide monohydrate (1 ml).
60 mg) and stirred at room temperature for 3 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8- (4-chlorophenyl) -8.
-[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (63
(2 mg, yield 89%) as colorless crystals. Melting point 90-9
1 ° C. Example 124 Methyl Z- 8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (200 mg) in tetrahydrofuran (10 ml)- In a solution of water (4 ml) -methanol (4 ml), lithium hydroxide monohydrate (4
(3.7 mg) and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give Z- 8- (4-chlorophenyl)
Colorless crystals of -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (169 mg, yield 87%) were obtained. Melting point 5
4-57 ° C.

Example 125 E- 8- (4-Fluorophenyl) -8- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (700 mg)
To a solution of the above in tetrahydrofuran (10 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (157 mg), and the mixture was stirred at room temperature for 3 hours. 1N hydrochloric acid (3.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (608 mg, yield 89%) colorless crystals were obtained. 79-80 ° C. Example 126 Z- 8- (4-fluorophenyl) -8- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (190 mg)
To a solution of the above in tetrahydrofuran (10 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (42.8 mg), and the mixture was stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was ethyl acetate-
Recrystallization from hexane gave Z- 8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (59 mg, yield 32). %) As colorless crystals. Melting point 5
6-57 ° C.

Example 127 3-Chloromethyl-5-phenyl-1,2,4-oxadiazole (335 mg), E- 8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg) , Potassium carbonate (432 mg) and N, N-dimethylformamide (7 ml) were stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and E- 8-phenyl-8 was eluted with ethyl acetate-hexane (1: 5, volume ratio).
Ethyl-[4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octanoate (267 mg, yield 32%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.20-1.65 (11H, m), 2.24 (2H, t, J =
7.5Hz), 2.70-2.79 (2H, m), 4.11 (2H, q, J = 7.1Hz),
5.15 (2H, s), 5.26 (2H, s), 7.05 (2H, d, J = 8.8Hz),
7.30-7.40 (5H, m), 7.48-7.66 (5H, m), 8.17 (2H,
d, J = 8.2Hz). Example 128 E- 8-phenyl-8- [4- (5-phenyl-1,
In a solution of ethyl 2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octanoate (236 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml), lithium hydroxide monohydrate (54.
9 mg) and stirred at room temperature for 4 hours. 1 N hydrochloric acid (1.4 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8-phenyl-8- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octanoic acid (208 m
g, yield 93%). Melting point 76-77
° C.

Example 129 E- 8- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] benzyloxyimino] -8
-Ethyl phenyloctanoate (618 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4
ml) solution, lithium hydroxide monohydrate (143 mg)
And stirred at room temperature for 4 hours. 1N hydrochloric acid (3.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoic acid ( 523 mg, yield 90
%) As colorless crystals. 75-77 ° C. Example 130 E- 8- [4- [5-Methyl-2- (2-thienyl)-]
4-oxazolylmethoxy] benzyloxyimino]-
To a solution of ethyl 8-phenyloctanoate (682 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml), lithium hydroxide monohydrate (153 m
g) was added and the mixture was stirred at room temperature for 4 hours. 1 in the reaction mixture
Normal hydrochloric acid (3.7 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E- 8- [4- [5-methyl-2- (2-
Colorless crystals of (thienyl) -4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoic acid (567 mg, yield 87%) were obtained. 106-108 ° C.

Example 131 4-Chloromethyl-2- (2-furyl) -5-methyloxazole (368 mg), E -6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), A mixture of potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and E -6- [4- [2-] was eluted from a fraction eluted with ethyl acetate-hexane (2: 7, volume ratio).
Ethyl (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (770 mg, yield 88%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4
H, m), 2.28 (2H, t, J = 7.1Hz), 2.42 (3H, s), 2.73-
2.82 (2H, m), 4.09 (2H, q, J = 7.1Hz), 5.00 (2H, s),
5.15 (2H, s), 6.51-6.54 (1H, m), 6.95-7.03 (3H,
m), 7.30-7.39 (5H, m), 7.53-7.64 (3H, m). Example 132 E -6- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] benzyloxyimino] -6
-Ethyl phenylhexanoate (670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4
ml) solution, lithium hydroxide monohydrate (163 mg)
And stirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -6- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoic acid ( 625 mg, yield 98
%) As colorless crystals. 112-113 ° C.

Example 133 4-Chloromethyl-5-methyl-2- (2-thienyl)
A mixture of oxazole (397 mg), ethyl E -6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was added at room temperature for 18 hours. Stirred. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluted portion of ethyl acetate-hexane (1: 4, volume ratio), E -6- [4- [5-
Methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (856 mg, yield 95%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4
H, m), 2.28 (2H, t, J = 7.1Hz), 2.41 (3H, s), 2.77
(2H, t, J = 7.4Hz), 4.09 (2H, q, J = 7.1Hz), 4.98 (2H,
s), 5.15 (2H, s), 6.99 (2H, d, J = 8.8Hz), 7.09 (1H,
(dd, J = 3.6, 5.0Hz), 7.31-7.42 (6H, m), 7.58-7.65
(3H, m). Example 134 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (362 mg), ethyl E -6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and E -6-phenyl-6 was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
Ethyl-[4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoate (649 mg, yield 75%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4
H, m), 2.28 (2H, t, J = 7.2Hz), 2.77 (2H, t, J = 7.5H
z), 4.09 (2H, q, J = 7.1Hz), 5.16 (2H, s), 5.27 (2H,
s), 7.06 (2H, d, J = 8.8Hz), 7.31-7.40 (5H, m), 7.49
-7.66 (5H, m), 8.14-8.20 (2H, m).

Example 135 E -6- [4- [5-Methyl-2- (2-thienyl)-]
4-oxazolylmethoxy] benzyloxyimino]-
To a solution of ethyl 6-phenylhexanoate (747 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (177 m2).
g) was added and the mixture was stirred at room temperature for 4 hours. 1 in the reaction mixture
Normal hydrochloric acid (4.3 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -6- [4- [5-methyl-2- (2-
Colorless crystals of (thienyl) -4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoic acid (653 mg, yield 92%) were obtained. Melting point 101-102 [deg.] C. Example 136 E -6-phenyl-6- [4- (5-phenyl-1,
To a solution of ethyl 2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoate (545 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml), lithium hydroxide monohydrate (134
mg), and the mixture was stirred at room temperature for 4 hours. 1 N hydrochloric acid (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -6-phenyl-6- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoic acid (465 mg). ,
Colorless crystals having a yield of 90%) were obtained. 88-89 ° C.

Example 137 5-Chloromethyl-3-phenyl-1,2,4-oxadiazole (362 mg), E -6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg) , Potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) were stirred at room temperature for 18 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and E -6-phenyl-6 was eluted from a fraction eluted with ethyl acetate-hexane (2: 9, volume ratio).
Ethyl-[4- (3-phenyl-1,2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoate (798 mg, yield 92%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4
H, m), 2.28 (2H, t, J = 7.4Hz), 2.77 (2H, t, J = 7.4H
z), 4.09 (2H, q, J = 7.1Hz), 5.16 (2H, s), 5.36 (2H,
s), 7.02 (2H, d, J = 8.6Hz), 7.28-7.65 (10H, m), 8.0
6-8.15 (2H, m). Example 138 E -6-phenyl-6- [4- (3-phenyl-1,1
To a solution of ethyl 2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoate (790 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (194).
mg), and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid (4.7 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was recrystallized from ethyl acetate-hexane to give E -6-phenyl-6- [4- (3-phenyl-1,2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoic acid (637 mg). ,
Colorless crystals having a yield of 85%) were obtained. 91-92 ° C.

Example 139 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), 4-oxo-4-phenylbutanamide (571 mg), acetic acid (0.1 g). 553 ml), a mixture of sodium acetate (528 mg) and ethanol (20 ml) was heated under reflux for 10 hours, and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and a portion obtained subsequently to the E- form was concentrated from a portion eluted with ethyl acetate-hexane (3: 1, volume ratio) to obtain crystals. This was recrystallized from ethanol to give Z -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutanamide (120 mg, 8% yield). Colorless crystals were obtained. 110-112 ° C. Example 140 4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (467 mg), 2,2
A mixture of methyl-dimethyl-6-oxo-6-phenylhexanoate (340 mg), acetic acid (0.259 ml), sodium acetate (248 mg) and methanol (15 ml) was heated under reflux for 15 hours and then cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 5, volume ratio), E -2,2-dimethyl-6- [4- (5-methyl-
Methyl 2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (348
mg, yield 47%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.10 (6H, s), 1.35-1.65 (4H, m), 2.4
4 (3H, s), 2.73 (2H, t, J = 7.3Hz), 3.55 (3H, s), 5.
00 (2H, s), 5.15 (2H, s), 7.02 (2H, d, J = 8.8Hz),
7.33-7.48 (8H, m), 7.57-7.63 (2H, m), 7.99-8.05 (2
H, m).

Example 141 E -2,2-Dimethyl-6- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (340 m
g) of tetrahydrofuran (5 ml) -methanol (5
4N potassium hydroxide aqueous solution (5 ml)
Was added and the mixture was heated under reflux for 2 hours, and then cooled to room temperature. The reaction mixture was neutralized by adding diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and crystals were obtained from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). This was recrystallized from ethyl acetate-hexane to give E -2,2-dimethyl-6- [4-
Colorless crystals of (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (275 mg, yield 83%) were obtained. Melting point 1
11-112 ° C. Example 142 E -6- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (600 mg) in tetrahydrofuran (5 ml) was added at room temperature. Oxalyl (0.126
ml) and N, N-dimethylformamide (catalytic amount). After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in tetrahydrofuran (10 ml), and methanesulfonamide (137 mg) and N, N-dimethylaminopyridine (293 mg) were added. After stirring the reaction mixture at room temperature for 18 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel chromatography, and ethyl acetate-hexane (1: 1).
Crystals were obtained from the eluted part (1, volume ratio). This was recrystallized from ethyl acetate-hexane to give E -N-methanesulfonyl-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexaneamide ( (458 mg, yield 66%) as colorless crystals. 130-132 ° C.

Example 143 Sodium hydride (60%, oily, 200 mg) was added to E
Methyl-4-hydroxyimino-4-phenylbutyrate (9
90 mg) and 4- (2-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.5
0 g) in N , N -dimethylformamide (40 ml) was added at 0 ° C. and stirred for 2 hours. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel chromatography, and Ethyl acetate-hexane (1: 4, volume ratio) eluted with E.
Methyl-4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.65 g, 71% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.5-2.65 (2H, m), 3.0-
3.15 (2H, m), 3.61 (3H, s), 5.07 (2H, s), 5.33 (2
H, s), 6.98 (2H, dd, J = 8.5, 1.0 Hz), 7.25-7.5 (8H,
m), 7.55-7.7 (2H, m), 7.95-8.1 (2H, m). Example 144 E -Methyl 4- (2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.60 g) in tetrahydrofuran (10 ml) -methanol (5 ml) )) 1N aqueous solution of sodium hydroxide (5 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer
After washing with water, drying (MgSO ₄ ), and concentrating, E -4- [2-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (1.
(42 g, yield: 91%). Recrystallization from ethyl acetate-hexane gave colorless needles. Melting point 116-1
17 ° C.

Example 145 Sodium hydride (60%, oily, 115 mg) was added to E
Methyl-4-hydroxyimino-4-phenylbutyrate (5
85 mg) and 4- (4-chloromethyl-2,6-dimethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N , N -dimethylformamide (40 ml) at 0 ° C. Stir for 2 hours. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and from an eluate of ethyl acetate-hexane (1: 3, volume ratio), E -4- [3,5-dimethoxy-4-
Methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (970 mg, 65% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.32 (3H, s), 2.5-2.65 (2H, m), 3.05
-3.15 (2H, m), 3.63 (3H, s), 3.84 (6H, s), 4.97 (2
H, s), 5.16 (2H, s), 6.63 (2H, s), 7.3-7.5 (6H,
m), 7.6-7.7 (2H, m), 7.95-8.05 (2H, m). Example 146 E -4- [3,5-dimethoxy-4- (5-methyl-2)
-Phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (970 mg) in tetrahydrofuran (10 ml) -methanol (5 m
l) Add 1N aqueous sodium hydroxide solution (5ml) to the solution
And stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), concentrated and concentrated to E -4- [3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino]. Crystals of 4-phenylbutyric acid (880 mg, yield 93%) were obtained. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles. Melting point 89-9
0 ° C.

Example 147 Sodium hydride (60%, oily, 200 mg) was added to E
Methyl 4-hydroxyimino-4-phenylbutyrate (1.04 g) and 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-furyl) -5-methyloxazole (1.65 g) The mixture was added to a solution of N , N -dimethylformamide (20 ml) at 0 ° C. and stirred for 1 hour. The reaction mixture was poured into water, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (M
After gSO ₄ ), the mixture was concentrated. The residue was subjected to silica gel chromatography, and E -4- [4- [2- (2-furyl) -5-methyl-4-oxazolyl was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). Rumethoxy] -3-
Crystals of methyl methoxybenzyloxyimino] -4-phenylbutyrate (1.60 g, yield 64%) were obtained. Recrystallization from ethyl acetate-hexane gave pale yellow prism crystals. Mp 67-69 ° C. Example 148 E -4- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] -3-methoxybenzyloxyimino] -4-phenylbutyrate methyl (1.55 g),
A mixture of ethanol (5 ml) and a 1 N aqueous sodium hydroxide solution (5 ml) was stirred at room temperature for 2 hours.
The reaction mixture was poured into water and acidified by adding 1N hydrochloric acid.
E -4- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] -3-methoxybenzyloxyimino] -4-phenylbutyric acid (1.40 g, 93 yield)
%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. Melting point 131-1
32 ° C.

Example 149 In the same manner as in Example 147, 4- (4-chloromethyl-
By reacting 2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (1.85 g) with methyl E -4-hydroxyimino-4-phenylbutyrate (1.10 g), E -4- [3- Methoxy-4- (5-methyl-
Methyl 2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.20 g,
The crystals having a yield of 44%) were obtained. Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prism crystals. 112-114 ° C. Example 150 In the same manner as in Example 148, E -4- [3-methoxy-
Methyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.00 g) was reacted with a 1N aqueous sodium hydroxide solution to give E -4- [ 3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (790 mg, 80
%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. 134-135
° C.

Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 7 2) 10 mg of finely powdered cellulose 3) 19 mg of lactose 4) 1 mg of magnesium stearate 60 mg in total 1), 2), 3) And 4) are mixed and filled into a gelatin capsule.

Formulation Example 2 (Production of tablets) 1) 30 g of the compound of Example 7 2) lactose 50 g 3) corn starch 15 g 4) calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum, and sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder and tableted with a tableting machine. Thus, 1000 tablets each containing 30 mg of compound (7) are obtained.

[0197]

The compound of the present invention and the pharmaceutical composition of the present invention have low toxicity, for example, diabetes (eg, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, etc.).
For the prevention and treatment of hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, etc.)
It can be used as a therapeutic agent, an insulin sensitivity enhancer, an insulin sensitizer, a preventive / therapeutic agent for impaired glucose tolerance (IGT), and a transition inhibitor from impaired glucose tolerance to diabetes. The compound of the present invention and the pharmaceutical composition of the present invention include, for example, diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, etc.), obesity, osteoporosis, cachexia (Eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, cachexia due to infectious cachexia or acquired immunodeficiency syndrome), fatty liver, Hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end stage renal disease, etc.), muscular dystrophy, myocardial infarction, angina, Cerebral infarction, insulin resistance syndrome, syndrome X, impaired sensation in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), inflammatory disease (eg, rheumatoid arthritis, osteoarthritis, Deformability Flame, low back pain, gout,
Also used as a prophylactic / therapeutic agent for inflammation after surgery, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, pancreatitis, etc., arteriosclerosis (eg, atherosclerosis, etc.) Can be. Further, the compound of the present invention can be used for regulating appetite and food intake and as a medicament for slimming and phagocytosis.

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 (72) Inventor Junichi Sakamoto 1-14-14 Kamishinda, Toyonaka City, Osaka 30 Fragrance Room A103 ( 56) References WO 96/2507 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) CAPLUS (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] (1) E-4- [4- (5-methyl-2- phenyl)
Ru-4-oxazolylmethoxy) benzyloxyimi
No] -4-phenylbutyric acid or a salt thereof. 2. E-4- [4- (5-methyl-2-phenyi)
Ru-4-oxazolylmethoxy) benzyloxyimi
No. 4-Phenylbutyric acid or a salt thereof. 3. The pharmaceutical composition according to claim 2 , which is an agent for preventing or treating diabetes. 4. The pharmaceutical composition according to claim 2 , which is a preventive / therapeutic agent for hyperlipidemia. 5. which is an agent for preventing or treating impaired glucose tolerance claim 2
The pharmaceutical composition according to any one of the preceding claims. 6. which is an agent for preventing or treating inflammatory disease according to claim 2
The pharmaceutical composition according to any one of the preceding claims. 7. which is an agent for preventing or treating arterial sclerosis according to claim 2
The pharmaceutical composition according to any one of the preceding claims. 8. E-4- [4- (5-methyl-2- phenyl)
Ru-4-oxazolylmethoxy) benzyloxyimi
[No] -4-phenylbutyric acid or a salt thereof. 9. The agent according to claim 8, which is a peroxisome proliferator-activated receptor ligand. 10. The agent according to claim 8, which is a retinoid X receptor ligand. 11. An insulin sensitivity enhancer according to claim 8.
Agents as described. It is 12. insulin sensitizer claim 8
Agents as described.