JP2002348281A - Five-membered heterocyclic alkane acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide new five-membered heterocyclic alkane acid derivatives which are useful as a prophylactic and therapeutic agent against diabetes and so on. SOLUTION: Compounds represented by general formula (1) [wherein, R<1> is a five-membered heterocyclic group which may be substituted; X is a bond or the like; Q is 1-20C bivalent hydrocarbon group; Y is a bond or the like; ring A is an aromatic ring which may additionally have 1 to 3 substituents; Z is -(CH2)n-Z<1> - (wherein, n is an integer of 0 to 8 and Z<1> is a bond or the like); ring B is a five-membered heterocyclic group which may additionally have 1 to 3 substituents; W is a 1-20C saturated bivalent hydrocarbon group; and R<2> is -OH group or the like] or salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention has an excellent hypoglycemic effect and hypolipidemic effect,
The present invention relates to a novel 5-membered heterocyclic alkanoic acid derivative useful as a prophylactic / therapeutic agent for impaired glucose tolerance.

[0002]

2. Description of the Related Art As alkanoic acid derivatives, compounds described in the following documents are known. (1) WO 00/64876 includes, as a PPAR ligand receptor binding agent, a compound represented by the formula

Embedded image [Where,

Embedded image Independently, aryl or the like; A is -O- or the like; B is-
D is -O- or the like; E is a bond or an ethylene group; a, b, c and e are 0-4; d is 0-5
F is 0-6; R ₁ , R ₃ , R ₅ , R ₇ , R ₉ and R
₁₁ is independently hydrogen or the like; R ₂ , R ₄ , R ₆ , R ₈ , R ₁₀ and R ₁₂ are each independently — (CH) _q —X;
X represents hydrogen or the like; Z represents R ₂₁ O ₂ C— or the like; R ₂₁ represents hydrogen or the like]]. (2) WO 92/20350 includes substances of the formula: Mi- (Mn) n-Mt as substances capable of mimicking the action of bioactive natural polymers.
Wherein n is a number from 2 to about 50; Mi, Mn and Mt are each

Embedded image

Embedded image Independently, an aromatic carbocycle or an aromatic heterocycle;
Bi, An, Bn, At, Bt, Ti, and Tt independently represent hydrogen or a substituent; Xi and Xn independently represent a bond, etc.]. (3) Japanese Unexamined Patent Publication No. Hei 4-217668 discloses an agricultural and horticultural fungicide and an intermediate thereof, each having the formula

Embedded image [Wherein, R ₁ and R ₂ each independently represent a hydrogen atom or a C ₁ -C ₅ alkyl group;

Embedded image (X is an alkoxy group of C ₁ -C _5, a halogen atom, a nitro group, such as one or more alkyl group optionally C ₁ -C ₁₀ optionally having a substituent selected from cyano group and a trifluoromethyl group And B represents a methoxycarbonyl group or a cyano group.].

[0003] Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily represented by steroid hormone receptors and thyroid hormone receptors, and its expression is very early in adipocyte differentiation. It is induced 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 directly controls (activates) transcription efficiency by binding to a responsive site of a target gene in the nucleus. Recently, 15 which is a metabolite of prostaglandin D2
-Deoxy- △ 12.14 Prostaglandin J2 is P
It is suggested that the insulin sensitizer may be an endogenous ligand of PARγ. Further, a kind of insulin sensitivity enhancer represented by a thiazolidinedione derivative has a ligand activity of PPARγ, and its strength and hypoglycemic action or adipocyte differentiation promoting action are considered. It turned out to be parallel [Cell, 83
Volume, p. 803 (1995); The Journal of
Biological chemistry (The Journal of Biolo
gical Chemistry), 270, 12953 (199
5 years): Journal of Medicinal Chemistry, 39, 65
5 (1996)]. Furthermore, recently, 1) the fact 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 Acad)
emy of Sciences of The United States of Americ
a), 94, 237, (1997)], 2) that non-steroidal anti-inflammatory drugs represented by indomethacin and fenoprofen have PPARγ ligand activity [The Journal of Biological Chemistry ( The Journal of Biological Chemistry), 272
3406 (1997)], 3) High expression of PPARγ in activated macrophages and inhibition of transcription of genes involved in inflammation by the addition of ligand [Nature, 391, 79] Page (199
8 years)], 4) PPARγ ligand inhibits production of inflammatory cytokines (TNFα, IL-1β, IL-6) by monocytes [Nature, 391]
Vol. 82, (1998)].

[0004]

The development of novel compounds which are useful as prophylactic / therapeutic agents for diabetes, hyperlipidemia, impaired glucose tolerance, etc. and which have excellent properties as a medicament, such as having few side effects, is desired. ing.

[0005]

That is, the present invention provides: (1) a general formula

Embedded image[Wherein, R¹Represents an optionally substituted 5-membered heterocyclic group;
X is a bond, an oxygen atom, a sulfur atom, -CO-, -CS
-, -CR^Three(OR^Four)-Or -NR^Five− (R^ThreeIs hydrogen
An atom or an optionally substituted hydrocarbon group is represented by R ^FourIs
A protecting group for a hydrogen atom or a hydroxyl group is represented by R^FiveIs a hydrogen atom,
Protecting group for hydrocarbon group or amino group which may be substituted
Q is a divalent hydrocarbon having 1 to 20 carbon atoms.
A group; Y is a bond, an oxygen atom, a sulfur atom, -SO-,-
SO_Two-, -NR⁶-, -CONR⁶-Or -NR⁶CO
− (R⁶Is a hydrogen atom or an optionally substituted carbon
Ring A further has 1 to 3 substituents;
An aromatic ring which may be present at Z;_Two)_n-Z¹
-Or -Z¹− (CH_Two)_n-(N is an integer from 0 to 8
The number, Z¹Is a bond, an oxygen atom, a sulfur atom, -SO-,
-SO_Two-, -NR⁷-, -CONR⁷-Or -NR⁷C
O- (R⁷Is a hydrogen atom or an optionally substituted carbon
Ring B represents 1 to 3 substituents;
A 5-membered heterocyclic ring which may further have a substituent;
A divalent saturated hydrocarbon group of the formulas 1 to 20;^TwoIs -O
R⁸ (R⁸Is a hydrogen atom or an optionally substituted carbon
Represents a hydrogen group) or -NR⁹R^Ten (R⁹And R^TenIs
Same or different hydrogen atom, optionally substituted charcoal
A hydrogen group, an optionally substituted heterocyclic group, or an acyl group
Or R⁹And R^TenIs adjacent
Together with a nitrogen atom to form an optionally substituted ring
May be shown). Provided that ring B is a nitrogen-containing 5-membered complex
When it is a ring, the nitrogen-containing 5-membered heterocyclic ring has a ring-forming N atom
Formula:

Embedded image (Wherein, R ^1a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; Xa represents a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR ^2a (OR
^3a )-or ^-NR4a- ( ^R2a and ^R4a represent a hydrogen atom or an optionally substituted hydrocarbon group, and ^R3a represents a hydrogen atom or a protecting group for a hydroxyl group); An integer; Ya is an oxygen atom, a sulfur atom, -SO-,-
^{_{SO 2 -, - NR 5a -}} , - CONR 5a - or -NR ^5a
CO- (R ^5a represents a hydrogen atom or an optionally substituted hydrocarbon group); ring Aa represents an aromatic ring which may further have 1 to 3 substituents; na represents 1 to 8
Does not have a substituent represented by: Or a salt thereof; (2) wherein R ² is —OR ⁸ (R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted) or —NR ⁹ R
¹⁰ (R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group, or R ⁹ and R ¹⁰ are a bond (1) may form a ring together with an adjacent nitrogen atom); (3) the 5-membered heterocyclic group represented by R ¹ being a 5-membered aromatic heterocyclic group (4) The compound according to (3), wherein the 5-membered aromatic heterocyclic group is oxazolyl, thiazolyl or triazolyl; (5) X is a bond or -NR ^5- (R ⁵ is A hydrogen atom, an optionally substituted hydrocarbon group or an amino group-protecting group); (6) the compound wherein Q is C _1-6 alkylene or C _2-6 alkenylene (7) the compound according to (1); -NR ⁶ is - (R ⁶ is a hydrogen atom or a substituted also shows a good hydrocarbon group) compound of the above (1), wherein the; (8) an aromatic ring represented by ring A is a benzene ring or a pyridine ring (9) n is an integer of 0 to 3, Z ¹ is a bond, an oxygen atom, a sulfur atom, —NR ⁷ —, —CONR ⁷ — or —NR.
⁷ (CO) wherein R ⁷ is a hydrogen atom or a hydrocarbon group which may be substituted. (10) The compound according to the above (1), wherein ring B further has 1 to 3 substituents. (11) The compound according to the above (1), which is a pyrazole ring, an oxazole ring or a thiazole ring, which may be substituted; (11) the compound according to the above (1), wherein W is a divalent saturated hydrocarbon group having 1 to 6 carbon atoms; 12) The above (1) wherein R ² is —OR ⁸ (R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted).
(13) The compound according to (1), wherein the substituent which ring B may further have is a hydrocarbon group; (14) [1-methyl-3- [4- (5-methyl) -2
-Phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] acetic acid, [1-methyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy)] -3-pyridylmethoxy] -1H-
Pyrazol-4-yl] acetic acid, [1-methyl-3- [6
-(2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid, [1-benzyl-3- [6- (5-methyl-2-phenyl-4) -Oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid, [3-
[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid, [3- [6- (5-methyl-2- Phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1-phenyl-1H-pyrazole-
4-yl] acetic acid, 3- [3- [3-methoxy-4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxy] -1-phenyl-1H-pyrazole-
5- [yl] propionic acid, 3- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid, Or (3) above, which is 3- [3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid. (15) a prodrug of the compound of (1) or a salt thereof; (16) a pharmaceutical composition comprising the compound of (1) or a salt thereof or a prodrug thereof; (17) diabetes (18) The pharmaceutical composition according to the above (16), which is a prophylactic / therapeutic agent for (18);
(19) The pharmaceutical composition according to the above (1), which is an agent for preventing or treating glucose intolerance.
(20) a pharmaceutical composition according to (1), a retinoid-related receptor function modulator comprising the compound according to (1) or a salt thereof, or a prodrug thereof; (21) a peroxisome proliferator-activated receptor ligand; (22) The agent according to (2), which is a retinoid X receptor ligand.
(23) An agent for improving insulin resistance comprising the compound according to (1) or a salt thereof or a prodrug thereof; (24) a compound according to (1) or a salt thereof or a prodrug thereof. A method for preventing or treating diabetes in a mammal, which comprises administering a drug to the mammal; (25) the compound or a salt thereof according to (1) above, for producing a preventive or therapeutic agent for diabetes, or Use of the prodrug;

Embedded image [Wherein, R ¹ represents a 5-membered heterocyclic group which may be substituted,
X is a bond, an oxygen atom, a sulfur atom, -CO-, -CS
—, —CR ³ (OR ⁴ ) — or —NR ⁵ — (R ³ is a hydrogen atom or an optionally substituted hydrocarbon group, R ⁴ is a hydrogen atom or a hydroxyl-protecting group, and R ⁵ is a hydrogen atom Q represents a divalent hydrocarbon group having 1 to 20 carbon atoms; Y represents a bond, an oxygen atom, a sulfur atom, -SO -, -S
O ₂ —, —NR ⁶ —, —CONR ⁶ — or —NR ⁶ CO—
(R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group); ring A is an aromatic ring optionally having 1 to 3 substituents; Z is-(CH ₂ ) _n -Z ¹ - or -Z ¹ - a (n 0 to an integer of 8, - (CH _{2) n}
Z ¹ is a bond, an oxygen atom, a sulfur atom, —SO—, —SO ₂
^{-, - NR 7 -, -} CONR 7 - or -NR ⁷ CO-
(R ⁷ represents a hydrogen atom or an optionally substituted hydrocarbon group)); Ring B is a 5-membered heterocyclic ring which may further have 1 to 3 substituents; A divalent saturated hydrocarbon group having 1 to 20 carbon atoms; R ^{8 ′} represents an optionally substituted hydrocarbon group; Wherein the compound represented by the general formula (1) or a salt thereof is subjected to a hydrolysis reaction.

Embedded image [The symbols in the formula are as defined above. And a method for producing the compound or a salt thereof;

In the general formula (I), the “5-membered heterocyclic group” represented by R ¹ is, for example, one or more heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring constituent atoms. A 4-membered 5-membered heterocyclic group is exemplified. Preferable examples of the “5-membered heterocyclic group” include pyrrolidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), imidazolidinyl (2-imidazolidinyl, 4-imidazolidinyl), and pyrazolidinyl (2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl). 5-membered non-aromatic heterocyclic group such as furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), pyrrolyl (1-
Pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl (3-isoxazolyl) , 4-isoxazolyl, 5-isoxazolyl), isothiazolyl (3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl) , 5-oxazolyl), oxadiazolyl (1,2,4-oxadiazol-5-yl),
1,3,4-oxadiazol-2-yl), thiadiazolyl (1,3,4-thiadiazol-2-yl), triazolyl (1,2,4-triazol-1-yl),
1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2
-Yl, 1,2,3-triazol-4-yl), tetrazolyl (tetrazol-1-yl, tetrazol-5)
-Yl) and the like.

The "5-membered heterocyclic group" for R ¹ is preferably a 5-membered aromatic heterocyclic group, more preferably oxazolyl, thiazolyl, pyrazolyl or triazolyl. Of these, oxazolyl, thiazolyl and triazolyl are preferred. The “5-membered heterocyclic group” represented by R ¹ has 1 to 4, preferably 1
It may have from 3 to 3 substituents. Examples of such a substituent include “halogen atom”, “nitro group”, “optionally substituted aliphatic hydrocarbon group”,
"Optionally substituted alicyclic hydrocarbon group", "optionally substituted aromatic hydrocarbon group", "optionally substituted aromatic heterocyclic group", "optionally substituted "Non-aromatic heterocyclic group", "acyl group", "optionally substituted amino group", "optionally substituted hydroxy group", "optionally substituted thiol group", "esterification or Carboxyl group which may be amidated "and the like.

The "halogen atom" includes fluorine, chlorine, bromine and iodine, among which fluorine and chlorine are preferred. Examples of the aliphatic hydrocarbon group in the “optionally substituted aliphatic hydrocarbon group” include those having 1 carbon atom.
To 15 linear or branched aliphatic hydrocarbon groups,
For example, an alkyl group, an alkenyl group, an alkynyl group and the like can be mentioned. Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethyl Propyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl,
Examples include 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Preferred examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, -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, -Pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Examples of the substituent in the “optionally substituted aliphatic hydrocarbon group” include a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, etc.), and an aromatic heterocyclic group. Ring group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.), amino group, 1 to 4 carbon atoms
An amino group, an amidino group, an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group), a carbamoyl group, which is mono- or disubstituted with an alkyl group or an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group) A carbamoyl group or a sulfamoyl group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, a sulfamoyl group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an alkoxy group having 2 to 8 carbon atoms A carbonyl group, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (eg, , An alkenyloxy group having 2-5 carbon atoms which may be substituted by fluorine, chlorine, bromine, iodine, etc. Number 3-7 cycloalkyloxy group, aralkyloxy group having 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy, etc.), thiol group, 1 to 3
C 1 -C 6 alkylthio group, C 7 -C 9 aralkylthio group, C 6 -C 14 arylthio group which may be substituted by two halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (Eg, phenylthio,
Naphthylthio, etc.), sulfo group, cyano group, azide group,
Examples include a nitro group, a nitroso group, and a halogen atom (eg, fluorine, chlorine, bromine, iodine). The number of substituents is
For example, one to three.

The alicyclic hydrocarbon group in the “optionally substituted alicyclic hydrocarbon group” includes a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, for example, a cycloalkyl group, Examples thereof include a cycloalkenyl group and a cycloalkadienyl group. Preferred 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 cycloalkenyl groups having 3 to 10 carbon atoms, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1. -Yl and the like. Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-
Cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like can be mentioned. Preferable examples of the aromatic hydrocarbon group in the “optionally substituted aromatic hydrocarbon group” include an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group) such as phenyl, naphthyl, Anthryl, phenanthryl, acenaphthylenyl,
Biphenylyl and the like. Above all, phenyl, 1
-Naphthyl, 2-naphthyl and the like are preferred. The aromatic hydrocarbon group may be partially hydrogenated, and examples of the partially hydrogenated aromatic hydrocarbon group include tetrahydronaphthalenyl.

"Optionally substituted aromatic heterocyclic group"
Examples of the aromatic heterocyclic group in the above include, for example, a monocyclic, bicyclic or tricyclic ring containing 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring constituent atoms And an aromatic heterocyclic group. Preferable examples of the monocyclic aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl). , 1,3,4-
Oxadiazolyl), flazanil, thiadiazolyl (1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl) , Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like.
Preferred examples of the bicyclic or tricyclic aromatic heterocyclic group include benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbonilyl,
β-carbonilyl, γ-carbonilyl, acridinyl,
Phenoxazinyl, phenothiazinyl, phenazinyl,
Phenoxathiinyl, 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.

The non-aromatic heterocyclic group in the “optionally substituted non-aromatic heterocyclic group” includes, for example, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include a non-aromatic heterocyclic group having 1 to 3 carbon atoms and 2 to 10 carbon atoms. Preferred examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl,
Morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino, thiomorpholino and the like. The aforementioned “optionally substituted alicyclic hydrocarbon group”, “optionally substituted aromatic hydrocarbon group”, “optionally substituted aromatic heterocyclic group” and “optionally substituted Examples of the substituent in the “good non-aromatic heterocyclic group” include an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 3
C 2 -C 6 alkenyl group, C 3 -C 10 cycloalkyl group, C 6 -C 14 aryl group which may be substituted by two halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (Eg, phenyl, naphthyl, etc.), aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, Piperazinyl), an aralkyl group having 7 to 9 carbon atoms, an amino group, an alkyl group having 1 to 4 carbon atoms or 2 to 8 carbon atoms.
An amino group, an amidino group, mono- or di-substituted with an acyl group (eg, alkanoyl group, etc.), having 2 to 8 carbon atoms
Acyl group (eg, alkanoyl group, etc.), carbamoyl group, carbamoyl group mono- or di-substituted by alkyl group having 1 to 4 carbon atoms, sulfamoyl group, 1 carbon atom
A sulfamoyl group mono- or di-substituted with an alkyl group having 4 to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, and 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
And an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine,
A alkenyloxy group having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, an aryl having 6 to 14 carbon atoms which may be substituted by bromine, iodine, etc. Oxy groups (eg,
Phenyloxy, naphthyloxy, etc.), thiol group,
An alkylthio group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), an aralkylthio group having 7 to 9 carbon atoms, 6 to 14 carbon atoms (E.g., phenylthio, naphthylthio, etc.), sulfo group, cyano group, azide group, nitro group, nitroso group, halogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like. The number of substituents is, for example, 1 to 3.

As the "acyl group", there are 1 to 1 carbon atoms.
In addition to the acyl group of Formula 3, specifically formyl,
R ¹¹ , —SO ₂ R ¹¹ , —SOR ¹¹ or —PO ₃ R ¹¹ R ¹²
Wherein R ¹¹ and R ¹² are the same or different and each represent a hydrocarbon group which may be substituted or an aromatic heterocyclic group which may be substituted; and the like. Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” for R ¹¹ or R ¹² include, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, An araliphatic hydrocarbon group and an aromatic hydrocarbon group are exemplified. These hydrocarbon groups preferably have 1 to 15 carbon atoms. Here, an aliphatic hydrocarbon group, alicyclic hydrocarbon groups and aromatic hydrocarbon groups include those exemplified respectively as substituent in the R ^1. Examples of the alicyclic-aliphatic hydrocarbon group include those in which the alicyclic hydrocarbon group is bonded to an aliphatic hydrocarbon group (eg, a cycloalkyl-alkyl group, a cycloalkenyl-alkyl group, and the like). Of these, an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms is preferred. Alicyclic-
Preferred examples of the aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,
Cyclopentylmethyl, 2-cyclopentenylmethyl,
3-cyclopentenylmethyl, cyclohexylmethyl,
2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.

The araliphatic hydrocarbon group includes, for example, 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, etc.). No. Preferred examples of the araliphatic hydrocarbon group include benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl,
C-C9-phenylalkyl such as phenylpropyl and 3-phenylpropyl; α-naphthylmethyl,
C11-C13 naphthylalkyl such as α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl; C8-C10 phenylalkenyl such as styryl; C12-carbon such as 2- (2-naphthylvinyl)
To 13 naphthylalkenyl and the like. The hydrocarbon group is preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and 6 to 14 carbon atoms. And the like.

The aromatic heterocyclic group in the “optionally substituted aromatic heterocyclic group” for R ¹¹ or R ¹² includes, for example, an oxygen atom, a sulfur atom and a nitrogen atom other than a carbon atom as a ring-constituting atom. And a 5- to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from the above or a condensed ring group thereof. Examples of the condensed ring group include a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms (eg, pyridine), a benzene ring, and one sulfur atom And a group condensed with a 5-membered ring containing. Preferable examples of the aromatic heterocyclic group include pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl) and pyridazinyl (3-pyridinyl). Pyridazinyl, 4-pyridazinyl), pyrazinyl (2-pyrazinyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , Imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), Isothiazolyl (3-isothiazolyl, 4-iso Azolyl, 5-isothiazolyl), thiazolyl (2
-Thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5
-Oxazolyl), oxadiazolyl (1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (1,3,4-thiadiazol-2-yl), Triazolyl (1,2,4-
Triazol-1-yl, 1,2,4-triazole-
3-yl, 1,2,3-triazol-1-yl, 1,
2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (tetrazol-1
-Yl, tetrazol-5-yl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (2-quinazolyl, 4-quinazolyl), quinoxalyl (2-quinoxalyl), benzoxazolyl (2- Benzoxazolyl), benzothiazolyl (2-benzothiazolyl), benzimidazolyl (benzimidazole-
1-yl, benzimidazol-2-yl), indolyl (indol-1-yl, indol-3-yl),
Indazolyl (1H-indazol-3-yl), pyrrolopyrazinyl (1H-pyrrolo [2,3-b] pyrazine-
2-yl), pyrrolopyridinyl (1H-pyrrolo [2,3
-B] pyridin-6-yl), imidazopyridinyl (imidazo [1,2-a] pyridin-2-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4 , 5-c] pyridin-2-yl), imidazopyrazinyl (1H-imidazo [4,5-b] pyrazin-2-yl)
Yl), oxophthalazinyl (1-oxo-2 (1H)
-Phthalazinyl) and the like. Among them, thienyl, furyl, pyridyl and the like are preferable.

The hydrocarbon group or aromatic heterocyclic group represented by R ¹¹ or R ¹² may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include one to three halogen atoms (eg, fluorine,
Chlorine, C _1-6 alkyl group optionally substituted by iodine), 1 to 3 halogen atoms (e.g., good fluorine, chlorine, bromine, optionally substituted with iodine and the like) C _1-6
Examples include an alkoxy group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxy, amino and the like. 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 "optionally substituted amino group" includes, for example, an alkyl group having 1 to 10 carbon atoms,
Mono- or di-substituted with an alkenyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an acyl group having 1 to 13 carbon atoms. And an optionally substituted amino group. Examples of these groups include those exemplified above as the substituents for R ¹ . The acyl group having 1 to 13 carbon atoms is preferably an alkanoyl group having 2 to 10 carbon atoms,
To 13 arylcarbonyl groups. Preferred 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.

The “optionally substituted hydroxy group” includes, for example, one carbon atom which may be substituted.
An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, and 1 carbon atom
And a hydroxy group which may be substituted with an acyl group having 13 to 13 or an aryl group having 6 to 14 carbon atoms. Examples of the alkyl group, alkenyl group, acyl group and aryl group include those exemplified above as the substituent for R ¹ . "C7-C1
Examples of the “aralkyl group 3” include those exemplified as the hydrocarbon groups represented by R ¹¹ and R ¹² . Examples of the substituent which the above-mentioned alkyl group, alkenyl group, aralkyl group, acyl group and aryl group may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a carbon atom having 1 to 3 carbon atoms. And an alkoxy group. The number of substituents is, for example, 1 or 2. 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, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyl. Oxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy. And the like. Preferred 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.). Preferred examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy,
Butyryloxy, isobutyryloxy, etc.). Preferred examples of the aryloxy group include those having 6 carbon atoms.
To 14 aryloxy groups, 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. Such a substituent may be substituted with, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6
Examples include an alkoxy group, hydroxy, nitro, amino and the like. Examples of the substituted aryloxy group include, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like.

Examples of the optionally substituted thiol group include an alkyl group having 1 to 10 carbon atoms and a thiol group having 3 carbon atoms.
And a thiol group which may be substituted with a cycloalkyl group having 7 to 10 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an acyl group having 2 to 13 carbon atoms, an aryl group having 6 to 14 carbon atoms, or a heteroaryl group. . Examples of the alkyl group, cycloalkyl group, acyl group, and aryl group include those exemplified as the substituent for R ¹ . As the aralkyl group, R ¹¹
And those exemplified as the hydrocarbon group represented by R ^12. Preferred examples of the heteroaryl group include pyridyl (eg, 2-pyridyl, 3-pyridyl), imidazolyl (eg, 2-imidazolyl), and triazolyl (eg,
1,2,4-triazol-5-yl) and the like. Examples of the substituted thiol group include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, heteroarylthio and the like. Preferable examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neopentyl Pentylthio, hexylthio, heptylthio, nonylthio and the like can be mentioned. Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Preferred examples of the aralkylthio group include
An aralkylthio group having 7 to 10 carbon atoms, for example, phenyl-C _1-4 alkylthio (eg, benzylthio, phenethylthio, etc.) and the like can be mentioned. Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.). Preferable examples of the arylthio group include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio. Preferred examples of the heteroarylthio group include
Examples include pyridylthio (eg, 2-pyridylthio, 3-pyridylthio), imidazolylthio (eg, 2-imidazolylthio), triazolylthio (eg, 1,2,4-triazol-5-ylthio) 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); an aryloxycarbonyl group having 7 to 15 carbon atoms which may be substituted by 1 to 2 alkyl groups having 1 to 3 carbon atoms ( For example, phenoxycarbonyl, p-tolyloxycarbonyl, etc.)
And the like.

In the carboxyl group which may be amidated, the carboxyl group amidated includes:
Formula: —CON (R ¹³ ) (R ¹⁴ ) wherein R ¹³ and R ¹⁴
Represents the same or different and represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ). Here, as the “optionally substituted hydrocarbon group” represented by R ¹³ and R ¹⁴ , those exemplified as the aforementioned R ¹¹ and R ¹² can be mentioned. The heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹³ and R ¹⁴ includes R ¹
The aromatic heterocyclic group and the non-aromatic heterocyclic group exemplified as the substituent in are exemplified. The heterocyclic group may have 1 to 3 substituents at substitutable positions. Such a substituent may be substituted with, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6 alkyl group, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
A C _1-6 alkoxy group optionally substituted with nitro,
Hydroxy, amino and the like.

The substituent in R ¹ is preferably 1) 1 to 3 halogen atoms (eg, fluorine, chlorine,
1 to 3 substituents selected from C1 to C6 alkoxy groups which may be substituted by bromine and iodine, halogen atoms (eg, fluorine, chlorine, bromine and iodine), nitro, hydroxy and amino An alkyl group having 1 to 10 (preferably 1 to 4) carbon atoms which may have a group; 2) 1 to 3 halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 3 to 10 carbon atoms which may have 1 to 3 substituents selected from nitro, hydroxy and amino (preferably Is a cycloalkyl group of 3 to 7); 3) 1 to 3 halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and aryls having 6 to 14 carbon atoms which may have 1 to 3 substituents selected from nitro, hydroxy and amino. Groups (preferably phenyl, naphthyl, etc.); 4) one to three halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and an aromatic heterocyclic group which may have 1 to 3 substituents selected from nitro, hydroxy and amino (preferably Is furyl, thienyl, pyridyl, pyrazinyl and the like); The number of substituents in R ¹ is preferably 1 to 3, more preferably 1 or 2. R ¹
Is more preferably 1 to 4 carbon atoms.
Alkyl group, furyl, thienyl, phenyl, naphthyl and the like.

R ¹ is preferably 1) 1 to 3 halogen atoms (eg, fluorine, chlorine,
1 to 3 substituents selected from C1 to C6 alkoxy groups which may be substituted by bromine and iodine, halogen atoms (eg, fluorine, chlorine, bromine and iodine), nitro, hydroxy and amino An alkyl group having 1 to 10 (preferably 1 to 4) carbon atoms which may have a group; 2) 1 to 3 halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 3 to 10 carbon atoms which may have 1 to 3 substituents selected from nitro, hydroxy and amino (preferably Is a cycloalkyl group of 3 to 7); 3) 1 to 3 halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and aryls having 6 to 14 carbon atoms which may have 1 to 3 substituents selected from nitro, hydroxy and amino. Groups (preferably phenyl, naphthyl, etc.); and 4) one to three halogen atoms (eg, fluorine, chlorine,
An alkyl group having 1 to 6 carbon atoms which may be substituted by bromine, iodine, etc .; 1 carbon atom which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) To 6 alkoxy groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and an aromatic heterocyclic group which may have 1 to 3 substituents selected from nitro, hydroxy and amino (preferably Is oxazolyl, thiazolyl, pyrazolyl or triazolyl, each of which may have 1 to 3 substituents selected from furyl, thienyl, pyridyl, pyrazinyl and the like. R ¹ is more preferably 1 carbon atom
Oxazolyl, thiazolyl or triazolyl which may have 1 or 2 substituents each selected from alkyl groups having 3 to 3 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, furyl, thienyl, phenyl and naphthyl.

In the general formula (I), X is a bond, an oxygen atom,
A sulfur atom, —CO—, —CS—, —CR ³ (OR ⁴ ) — or —NR ⁵ — (R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁴ represents a hydrogen atom or a hydroxyl group; R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an amino group). X is preferably a bond or —NR ⁵ — (R ⁵ has the same meaning as described above), and more preferably a bond. As the “optionally substituted hydrocarbon group” represented by R ³ and R ⁵ , those exemplified as the aforementioned R ¹¹ and R ¹² can be mentioned. The “optionally substituted hydrocarbon group” is preferably an optionally substituted 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 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), 1-4 alkoxy groups (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, etc., hydroxy, nitro, amino, C 1-4 acyl groups (eg, formyl, acetyl, propionyl, etc.) Alkanoyl groups of the formulas 1 to 4) and the like. R ³ and R ⁵ are preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

As the protecting group for the hydroxyl group represented by R ⁴ ,
For example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, t.-butyl, etc.), phenyl, trityl, C _7-10 aralkyl (eg, benzyl, etc.), formyl, C _1-6 alkyl -Carbonyl (eg, acetyl, propionyl, etc.), benzoyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.),
2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t.-butyldimethylsilyl, t.-butyldiethylsilyl, etc.), C _2-6 alkenyl (eg, 1- Allyl, etc.). These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.), C _1-6 alkoxy (eg,
Methoxy, ethoxy, propoxy, etc.) or nitro. Examples of the protecting group for the amino group represented by R ⁵ include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _1-6
Alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t.-butoxycarbonyl, etc.), benzoyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl), C _7-14 aralkyloxy-carbonyl (eg, benzyloxy) Carbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl,
N, N-dimethylaminomethylene, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t.-butyldiethylsilyl, etc.), C _2-6 alkenyl (eg, 1-allyl, etc.)
And the like. These groups have one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_It may be substituted by _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro.

In the general formula (I), “C 1
Examples of the "-20 divalent hydrocarbon groups" include "2
Divalent acyclic hydrocarbon group "," divalent cyclic hydrocarbon group ",
Alternatively, a divalent group obtained by combining one or more “divalent acyclic hydrocarbon groups” with one or more “divalent cyclic hydrocarbon groups” may be used. Here, the “divalent acyclic hydrocarbon group” includes, for example, a group having 1 to 2 carbon atoms.
0 alkylene, 2-20 carbon alkenylene,
Examples thereof include alkynylene having 2 to 20 carbon atoms.
As the “divalent cyclic hydrocarbon group”, C 5 to C 2
0 cycloalkane, C 5-20 cycloalkene or C 6-18 aromatic hydrocarbon (eg,
Benzene, naphthalene, indene, anthracene, etc.)
And a divalent group obtained by removing any two hydrogen atoms from the above. Specific examples include 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptylene, 3-cycloheptylene, 1,4-cycloheptylene, 3-cyclohexene-1,4-ylene, 3-cyclohexene-1,2
-Ylene, 2,5-cyclohexadiene-1,4-ylene, 1,2-phenylene, 1,3-phenylene, 1,4
-Phenylene, 1,4-naphthylene, 1,6-naphthylene, 2,6-naphthylene, 2,7-naphthylene, 1,5
-Indenylene, 2,5-indenylene and the like.

[0028] Q is preferably a divalent hydrocarbon group having 1 to 6 carbon atoms, among them (1) C _1-6 alkylene _{(e.g., -CH 2 -, - (CH} 2) 2 -, -
(CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, −CH
(CH ₃ )-, -C (CH ₃ ) ₂ -,-(CH (CH ₃ )) ₂ -,-(CH ₂ ) ₂ C (CH
_{3) 2 -, - (CH} 2) 3 C (CH 3) 2 - , etc.); (2) C _2-6 alkenylene (e.g., -CH = CH -, - CH 2 -CH
= CH -, - C (CH 3) 2 -CH = CH -, - CH 2 -CH = CH-CH
_{2 -, - CH 2 -CH 2} -CH = CH -, - CH = CH-CH = CH -, - C
_{H = CH-CH 2 -CH 2} -CH 2 - , etc.); (3) C _2-6 alkynylene (e.g., -C≡C -, - CH ₂ -C≡C
_{-, - CH 2 -C≡C-CH} 2 -CH 2 - , etc.) and the like are preferable. Q is more preferably C _1-6 alkylene or C _2-6 alkenylene, and among them, -CH ₂ -,-(CH ₂ ) ₂ -,-
_{(CH 2) 3 -, -} (CH 2) 4 -, - CH = CH- , etc. are preferable. Q
Is particularly preferably _{-CH 2 -, - (CH 2} ) 2 - and the like.

In the general formula (I), Y is a bond, an oxygen atom,
Sulfur _{atom, -SO -, - SO 2 -} , - NR 6 -, - CON
R ⁶ — or —NR ⁶ CO— (R ⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted). Y is
It is preferably an oxygen atom or -NR ^6- (R ⁶ has the same meaning as described above), and more preferably an oxygen atom. As the “optionally substituted hydrocarbon group” for R ⁶ , those exemplified above for R ¹¹ and R ¹² can be mentioned. Among them, an alkyl group having 1 to 4 carbon atoms is preferable.

In the general formula (I), the “aromatic ring” in the “aromatic ring optionally having one to three substituents” represented by ring A includes, for example, a benzene ring, a condensed aromatic Examples thereof include a hydrocarbon ring, a 5- or 6-membered aromatic heterocycle, and a fused aromatic heterocycle. Here, the “condensed aromatic hydrocarbon ring” includes, for example, a condensed aromatic hydrocarbon having 9 to 14 carbon atoms. Specific examples include naphthalene, indene, fluorene, and anthracene. As the “5- or 6-membered aromatic heterocycle”, for example, 5 or 6 containing 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
And aromatic heterocycles. Specifically, thiophene, furan, pyrrole, imidazole, pyrazole,
Thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3, 4-thiadiazole,
Furazan and the like. As the "condensed aromatic heterocycle", for example, a 9 to 14-membered (preferably 9 or 10-membered) condensed aromatic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Group heterocycles and the like. Specifically, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, Examples include phthalazine, naphthyridine, quinazoline, cinnoline, carbazole, β-carboline, acridine, phenazine, phthalimide and the like. "Aromatic ring" is preferably a benzene ring,
Examples thereof include a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene and the like) and a 5- or 6-membered aromatic heterocyclic ring (preferably pyridine, oxazole, isoxazole, thiazole, oxadiazole and the like). The “aromatic ring” is more preferably a benzene ring, a pyridine ring or an isoxazole ring, and particularly preferably a benzene ring or a pyridine ring.

In the general formula (I), when the aromatic ring represented by the ring A is a benzene ring or a pyridine ring, the substituents Y and Z on the ring A are preferably in a para-configuration. That is, in the general formula (I), when the aromatic ring represented by ring A is a benzene ring,

Embedded image It is. Further, when the aromatic ring represented by ring A is a pyridine ring,

Embedded image It is.

As the “substituent” in the “aromatic ring optionally having 1 to 3 substituents” represented by ring A, an optionally substituted aliphatic hydrocarbon group (preferably alkyl Group), an optionally substituted hydroxy group, a halogen atom, an acyl group, a nitro group, and an optionally substituted amino group. As these substituents, those exemplified as the substituent for R ¹ can be used. The substituent in ring A is preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms (preferably methoxy), an aralkyloxy group having 7 to 10 carbon atoms, and a halogen atom.

In the general formula (I), Z is-(CH ₂ ) _n -Z
^1- or -Z ^1- (CH ₂ ) _n- (n is an integer of 0 to 8, and Z ¹ is a bond, an oxygen atom, a sulfur atom, -SO-,
^{_{-SO 2 -, - NR 7 -}} , - CONR 7 - or -NR ⁷ C
O- (R ⁷ represents a hydrogen atom or a hydrocarbon group which may be substituted). Here, as the “optionally substituted hydrocarbon group” for R ⁷ , those exemplified above for R ¹¹ and R ¹² can be mentioned, and preferably alkyl having 1 to 4 carbons (eg, methyl, Ethyl, propyl, etc.). R ⁷ is preferably a hydrogen atom or an alkyl having 1 to 4 carbons (eg, methyl, ethyl, propyl, etc.). n is preferably an integer of 0 to 3, and more preferably an integer of 1 to 3. Z
¹ is preferably a bond, an oxygen atom, a sulfur atom, -NR ⁷
—, —CONR ⁷ — or —NR ⁷ CO— (R ⁷ is as defined above). Here, R ⁷ is preferably a hydrogen atom or an alkyl having 1 to 4 carbon atoms. In the general formula (I), when n is an integer of 1 to 8, Z ¹ is preferably a bond, an oxygen atom, a sulfur atom, -NR ⁷ -,-
CONR ⁷ — or —NR ⁷ CO— (R ⁷ is as defined above), and when n is 0, Z ¹ is preferably an oxygen atom, a sulfur atom, —SO—, —SO ₂ — or —NR ⁷ −
(R ⁷ is as defined above). Z is preferably-
(CH ₂ ) _n -Z ^1- . Here, n is preferably 0
And an integer of 2 (preferably 1), and Z ¹ is preferably a bond, an oxygen atom or a sulfur atom (preferably an oxygen atom)
It is.

In the general formula (I), the “5-membered heterocyclic ring” represented by ring B includes, for example, 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring-constituting atoms. And a 5-membered heterocyclic ring. Preferred examples of "5-membered heterocycle" include pyrrolidine,
5-membered non-aromatic heterocycle such as imidazolidine and pyrazolidine; 5-membered aromatic heterocycle such as furan, thiophene, pyrrole, imidazole, pyrazole, isoxazole, isothiazole, thiazole, oxazole, oxadiazole, thiadiazole, triazole and tetrazole Rings. The “5-membered heterocycle” represented by ring B is preferably a 5-membered aromatic heterocycle, more preferably a 5-membered nitrogen-containing heterocycle such as an imidazole ring, a pyrazole ring, an oxazole ring, a thiazole ring, and a triazole ring. is there. Of these, a pyrazole ring, an oxazole ring, a thiazole ring and the like are preferable, and a pyrazole ring is particularly preferable. Ring B may have 1 to 3, preferably 1 to 2 substituents at substitutable positions. Examples of such a substituent include “halogen atom”, “nitro group”, “optionally substituted aliphatic hydrocarbon group”,
"Optionally substituted alicyclic hydrocarbon group", "optionally substituted aromatic hydrocarbon group", "optionally substituted aromatic heterocyclic group", "optionally substituted "Non-aromatic heterocyclic group", "acyl group", "optionally substituted amino group", "optionally substituted hydroxy group", "optionally substituted thiol group", "esterification or Carboxyl group which may be amidated "and the like. Each of these substituents is R ¹
The substituents exemplified above are used.

In the general formula (I), when ring B is a 5-membered nitrogen-containing heterocyclic ring, the 5-membered nitrogen-containing heterocyclic ring has the formula:

Embedded image (Wherein, R ^1a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; Xa represents a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR ^2a (OR
^3a )-or ^-NR4a- ( ^R2a and ^R4a represent a hydrogen atom or an optionally substituted hydrocarbon group, and ^R3a represents a hydrogen atom or a protecting group for a hydroxyl group); An integer; Ya is an oxygen atom, a sulfur atom, -SO-,-
^{_{SO 2 -, - NR 5a -}} , - CONR 5a - or -NR ^5a
CO- (R ^5a represents a hydrogen atom or an optionally substituted hydrocarbon group); ring Aa represents an aromatic ring which may further have 1 to 3 substituents; na represents 1 to 8
Does not have a substituent represented by:

The "substituent" in ring B is preferably a hydrocarbon group, more preferably 1 to 10 carbon atoms.
An alkyl group (preferably methyl or the like), an aryl group having 6 to 14 carbon atoms-an alkyl group having 1 to 10 carbon atoms (e.g., benzyl or the like), an optionally substituted hydrogen group having 6 to 14 carbon atoms (Preferably phenyl, naphthyl, tetrahydronaphthalenyl and the like).

In the general formula (I), “C 1
To 20 divalent saturated hydrocarbon groups "
Among those exemplified as above, saturated ones may be mentioned.
W is preferably a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, more preferably C _1-6 alkylene,
Particularly _{preferably, -CH 2 -, - (CH} 2) 2 - and the like.

In the general formula (I), R ² is —OR ⁸ (R ⁸ is a hydrogen atom or a hydrocarbon group which may be substituted)
Or -NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, substituted by may be a hydrocarbon group, an optionally substituted heterocyclic group, or R ⁹ or an acyl group, And R ¹⁰ may combine to form a ring together with the adjacent nitrogen atom). Examples of the “optionally substituted hydrocarbon group” for R ⁸ include the aforementioned R
Those exemplified as ¹¹ and R ¹² can be mentioned. The "optionally substituted hydrocarbon group" is preferably an "alkyl group having 1 to 4 carbon atoms". Here, examples of the "alkyl group having 1 to 4 carbon atoms" include methyl, ethyl, propyl, butyl, isobutyl, sec.-butyl, t.-butyl and the like, and among them, methyl and ethyl are preferable.

[0039] As "optionally substituted hydrocarbon group" represented by R ⁹ and R ¹⁰ include those exemplified as R ^{1 1} and R ^12. As the “optionally substituted heterocyclic group” for R ⁹ and R ¹⁰ , those exemplified as R ¹³ and R ¹⁴ can be mentioned. R ⁹ and R
^The “acyl group” represented by ^{10 includes the} “acyl group” exemplified as the substituent for R ¹ . R ⁹ and R
Examples of the ring formed by bonding with ¹⁰ and an adjacent nitrogen atom include a 5- to 7-membered nitrogen-containing heterocyclic ring. Preferred examples of the 5- to 7-membered nitrogen-containing heterocycle include pyrrolidine, piperidine, hexamethyleneimine,
Morpholine, thiomorpholine, piperazine and the like. The “ring formed by combining R ⁹ and R ¹⁰ with an adjacent nitrogen atom” is a ring optionally having 1 to 3 substituents at substitutable positions (an optionally substituted ring). ). Such a substituent may be substituted with, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6
Examples include an alkyl group, a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, hydroxy, amino and the like. R ² is preferably —OR ⁸ (the symbols have the same meanings as described above), and R ⁸ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl). R ² is particularly preferably —OH.

Preferred examples of the compound represented by the general formula (I) include the following compounds. [Compound A] wherein R ¹ is 1) 1 to 3 selected from an alkoxy group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, a halogen atom, nitro, hydroxy and amino
2) an alkyl group having 1 to 10 carbon atoms which may have a substituent; 2) an alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms; A C1-C6 alkoxy group optionally substituted by a halogen atom, a C3-C10 cyclo group optionally having 1-3 substituents selected from halogen atoms, nitro, hydroxy and amino; An alkyl group; 3) an alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, or an alkoxy group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms. , A halogen atom, a nitro, hydroxy and amino, optionally having 1 to 3 substituents, an aryl group having 6 to 14 carbon atoms (preferably
Phenyl, naphthyl, etc.); and 4) an alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, 1 to 3 carbon atoms which may be substituted by 1 to 3 halogen atoms. 6, an aromatic heterocyclic group optionally having 1 to 3 substituents selected from an alkoxy group, a halogen atom, nitro, hydroxy and amino (preferably furyl, thienyl,
Oxazolyl, thiazolyl, pyrazolyl or triazolyl optionally having 1 to 3 substituents selected from pyridyl, pyrazinyl and the like; X is a bond or —NR ⁵ —, and R ⁵ is a hydrogen atom or carbon Number 1
4 to 4 alkyl groups; Q is C _1-6 alkylene or C
_2-6 alkenylene; Y is an oxygen atom or -NR ^6- , and R ⁶ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; Ring A is an alkyl group having 1 to 4 carbon atoms, a hydroxy group, A benzene ring, a condensed aromatic group having 9 to 14 carbon atoms, which may further have 1 to 3 substituents selected from an alkoxy group having 1 to 4 atoms, an aralkyloxy group having 7 to 10 carbon atoms and a halogen atom; An aromatic hydrocarbon ring (preferably naphthalene or the like), or 5
Or 6-membered aromatic heterocycle (preferably pyridine, oxazole, isoxazole, thiazole, oxadiazole); Z is ^{_{- (CH 2) n -Z 1}} - or -Z ¹ -
(CH ₂ ) _n- , and n is an integer of 0 to 3, Z
¹ is a bond, an oxygen atom, a sulfur atom, -NR ⁷ -, - CON
R ⁷ — or —NR ⁷ CO—, wherein R ⁷ is a hydrogen atom or an alkyl having 1 to 4 carbons; Ring B is an alkyl group having 1 to 10 carbons (preferably methyl and the like), and an aryl having 6 to 14 carbons Group-selected from an alkyl group having 1 to 10 carbon atoms (eg, benzyl and the like) and an aryl group having 6 to 14 carbon atoms (preferably phenyl, naphthyl, tetrahydronaphthalenyl and the like) which may be partially hydrogenated. An imidazole ring, a pyrazole ring, an oxazole ring, a thiazole ring or a triazole ring which may further have 1 to 3 substituents;
_1-6 alkylene; a compound wherein R ² is —OR ⁸ and R ⁸ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. [Compound B] R ¹ is selected from an alkyl group having 1 to 3 carbon atoms (preferably methyl), an aryl group having 6 to 14 carbon atoms (preferably phenyl) and an aromatic heterocyclic group (preferably furyl, thienyl). Oxazolyl or thiazolyl optionally having one or two substituents selected; X is a bond; Q is C _1-6 alkylene (preferably —CH ₂ —); Y is an oxygen atom; A benzene ring or 5 or 6 each optionally substituted by an alkoxy group having 1 to 4 carbon atoms (preferably methoxy);
Membered aromatic heterocycle (preferably pyridine, isoxazole); Z is-(CH ₂ ) _n -Z ^1- and n is 0
An integer of 1 or 2 (preferably 1), Z ¹ is a bond, an oxygen atom or a sulfur atom (preferably an oxygen atom); Ring B is an alkyl group having 1 to 10 carbon atoms (preferably methyl),
Aryl group having 6 to 14 carbon atoms-1 to 10 carbon atoms
A pyrazole ring which may be substituted with an alkyl group (preferably benzyl) or an aryl group having 6 to 14 carbon atoms (preferably phenyl); W is a C _1-6 alkylene (preferably -CH ₂ -,-(CH ₂ ) _2- ); a compound wherein R ² is —OR ⁸ and R ⁸ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (preferably methyl or ethyl). [Compound C] [1-methyl-3- [4- (5-methyl-
2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] acetic acid, [1-methyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) ) -3-Pyridylmethoxy] -1H
-Pyrazol-4-yl] acetic acid, [1-methyl-3-
[6- (2-phenyl-4-thiazolylmethoxy) -3
-Pyridylmethoxy] -1H-pyrazol-4-yl]
Acetic acid, [1-benzyl-3- [6- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid, [3
-[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-
Pyrazol-4-yl] acetic acid, [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-
Pyridylmethoxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid, 3- [3- [3-methoxy-4-]
(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid, 3- [3- [4- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazole-5
-Yl] propionic acid or 3- [3- [3- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazole-5
-Yl] propionic acid.

As the salt of the compound represented by the general formula (I) (hereinafter may be abbreviated as compound (I)), a pharmacologically acceptable salt is preferable, for example, a salt with an inorganic base, Examples thereof include salts with organic bases, salts with inorganic acids, 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, sodium salt,
Alkali metal salts such as potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like can be mentioned. Preferable 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 and the like. Preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid and the like. Among the above salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. Compound (I) which is converted to (I), which is hydrolyzed by gastric acid or the like to cause compound (I)
A compound that changes to Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation, t.-butylation Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloyylated, succinyl) ,
Fumarylated, alanylated, dimethylaminomethylcarbonylated, tetrahydropyranylated compounds, etc.);
Compounds in which the carboxyl group of compound (I) is esterified and amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like). These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is available from Hirokawa Shoten 1990
Annual Development of Pharmaceuticals, Vol. 7, Molecular Design, p. 163 to 19
Under physiological conditions, as described on page 8, the compound (I
It may change to I). Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Further, the compound (I) is
It may be an anhydride or a hydrate.

Compound (I) or a salt thereof (hereinafter may be simply abbreviated as the compound of the present invention) has low toxicity and is used as it is or as a mixture with a pharmacologically acceptable carrier. By doing so, mammals (eg, humans,
Mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.) as prophylactic and / or 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 formulated 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, polyoxyethylene hydrogenated castor oil and the like.

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. Preferable examples of the preservative include, for example, p-hydroxybenzoates, 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 red Nos. 2 and 3, edible yellows 4 and 5).
Food dyes such as No. 1, Food Blue No. 1 and No. 2, water-insoluble lake dyes (eg, aluminum salts of the water-soluble edible tar dyes, etc.), and natural dyes (eg, β-carotene, chlorophyll, bengalara, etc.). It is. Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions; , Subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg,
Nasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, drops, sustained-release preparations (eg, sustained-release microcapsules, etc.), eye drops And parenteral preparations, which can be safely administered orally or parenterally, respectively.

The pharmaceutical composition can be produced by a method commonly used in the technical field of 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 A starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded, and then, if necessary, taste masking It is produced by coating with a coating base by a method known per se for the purpose of enteric coating 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-based 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.), and 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 an ethyl acrylate / methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] .
The above-mentioned coating bases may be used as a mixture of two or more kinds at an appropriate ratio. In 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 solubilizer (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.

The compound of the present invention can be used as an insulin sensitizer, an insulin sensitivity enhancer, 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. The compound of the present invention has a blood glucose lowering effect, a blood lipid lowering effect, a blood insulin lowering effect,
It has an insulin resistance improving action, an insulin sensitivity enhancing action, and a retinoid-related receptor function regulating activity. The function modulator may be a partial agonist (partial agonist) or a partial antagonist (partial antagonist). 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, retinoid O
Receptor (hereinafter sometimes abbreviated as ROR) α (GenB
ank Accession No. L14611), RORβ (GenBank Acce
ssion No. L14160), RORγ (GenBank Accession N
o. U16997); Rev-erb α (GenBank Accession
No. M24898), Rev-erb β (GenBank Accessi
on No. L31785); ERRα (GenBank Accession No. X
51416), ERRβ (GenBank Accession No. X5141)
7); Ftz-FI α (GenBank Accession No. S6587)
6), Ftz-FI β (GenBank Accession No. M8138
5); TIx (GenBank Accession No. S77482); GC
NF (GenBank Accession No. U14666). Examples of homodimeric receptors include retinoid X
Receptor (hereinafter sometimes abbreviated as RXR) α (GenB
ank Accession No. X52773), RXRβ (GenBankAcces
sion No. M84820), RXRγ (GenBank Accession No.
U38480); COUPα (GenBank Accession No. X1279)
5), COUPβ (GenBank Accession No. M64497), C
OUPγ (GenBank Accession No. X12794); TR2α
(GenBank Accession No. M29960), TR2β (GenBank
Accession No. L27586); or HNF4α (GenBank
Accession No. X76930), HNF4γ (GenBank Acces
sion No. Z49826) 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 by one type of receptor.

The compound of the present invention is a retinoid X receptor (RXR) among the above-mentioned retinoid-related receptors.
α, RXRβ, RXRγ) and peroxisome proliferator-activated receptors (PPARα, PPARβ (PPARβ)
δ), has excellent ligand activity against PPARγ), and is useful as an agonist, partial agonist (partial agonist), antagonist or partial antagonist (partial antagonist) for these receptors. Further, the compound of the present invention is a heterodimeric receptor formed by a retinoid X receptor and a peroxisome proliferator-responsive receptor (eg, a heterodimeric receptor formed by RXRα and PPARδ, RXRα and PPARγ).
Has excellent ligand activity for peroxisome proliferator-activated receptors in heterodimer-type receptors formed. 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.

The compound of the present invention is an agent for preventing or treating diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.);
Prophylactic / therapeutic agent for hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, etc.); insulin sensitizer; insulin sensitivity enhancer; glucose intolerance [ IGT (Impaired Glucose Toleran
ce)]; and a transition inhibitor from glucose intolerance to diabetes.

Regarding the criteria for judging diabetes, the Japanese Diabetes Society reported a new criteria in 1999. According to this report, diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more and a 75 g oral glucose tolerance test (75 g OGTT) 2.
Time value (glucose concentration in venous plasma) is 200 m
g / dl or more, and the blood sugar level (glucose concentration in venous plasma) at any time is 200 mg / dl or more. In addition, it does not correspond to the above-mentioned diabetes, and the fasting blood glucose level (glucose concentration in venous plasma) is 110 m
g / dl or 75 g oral glucose tolerance test (75
A state in which the (gOGTT) 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl is not "normal", and is referred to as "boundary".

The criteria for judging diabetes are as follows.
A new criterion was reported by ADA (American Diabetes Association) in 1997 and by WHO in 1998. According to these reports, diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more and a 2-hour 75 g oral glucose tolerance test (glucose concentration in venous plasma) of 200 mg / dl. dl or more. According to the above report, impaired glucose tolerance refers to a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl and a 2-hour 75 g oral glucose tolerance test (glucose concentration in venous plasma). Is 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the fasting blood glucose level (glucose concentration in venous plasma) was 11%.
IFG for the condition of 0 mg / dl or more and less than 126 mg / dl
(Impaired Fasting Glucose). On the other hand, WHO
Reports that the IFG (Impaired Fasting Gluco
se), the state in which the 2-hour value (glucose concentration in venous plasma) of the 75 g oral glucose tolerance test was less than 140 mg / dl was determined by IFG (Impaired Fasting Glycemi).
Call it a). The compound of the present invention may have diabetes, borderline type, impaired glucose tolerance, IFG determined by the above-mentioned new criteria.
(Impaired Fasting Glucose) and IFG (Impair
It is also used as a prophylactic / therapeutic agent for edFasting Glycemia). Further, the compound of the present invention has a borderline type, impaired glucose tolerance,
IFG (Impaired Fasting Glucose) or IFG
(Impaired Fasting Glycemia) can also be prevented from progressing to diabetes.

The compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder,
Osteopenia, diabetic hyperosmotic coma, infections (eg, respiratory, urinary tract, digestive, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia , Hearing loss, cerebrovascular disorder, peripheral blood circulation disorder, etc.], obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia) Quality, infectious cachexia or cachexia due to 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, cerebrovascular disorder (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia Paresthesia in sickness, Ulcer (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome, acute or chronic diarrhea, inflammatory disease (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery) Inflammation after trauma, remission of swelling, neuralgia, laryngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, etc., visceral obesity syndrome, etc. Can also be used as a prophylactic / therapeutic agent. The compound of the present invention has a total cholesterol lowering effect and has a plasma anti-atherosclerosis index [(HDL cholesterol / total cholesterol) × 10 5
0] can be used as a prophylactic / therapeutic agent for arteriosclerosis (eg, atherosclerosis, etc.). The compounds of the present invention can also be used for improving symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis and the like. Further, the compound of the present invention can be used as a therapeutic agent for slimming and phagocytosis (increase in body weight in subjects to which slimming or phagocytosis is administered) or a therapeutic agent for obesity, for example, for regulating (enhancing or suppressing) appetite. .

The compound of the present invention can also be used as a prophylactic / therapeutic agent for inflammatory diseases involving TNF-α. here,
An inflammatory disease involving TNF-α is an inflammatory disease that develops due to the presence of TNF-α and can be treated through a TNF-α inhibitory effect. Such inflammatory diseases include, for example, diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorder, etc.), rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery・ Inflammation after trauma,
Remission of swelling, neuralgia, laryngitis, cystitis, hepatitis, pneumonia,
Gastric mucosal damage (including gastric mucosal damage caused by aspirin) and the like. The compound of the present invention has an inhibitory effect on apoptosis and is also used as a prophylactic / therapeutic agent for diseases associated with promotion of apoptosis. Here, examples of the disease associated with promotion of apoptosis include viral diseases (eg, AIDS, fulminant hepatitis, etc.), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pigmented retina) Inflammation, cerebellar degeneration, etc.), myelodysplastic disease (eg, aplastic anemia, etc.), ischemic disease (eg, myocardial infarction, stroke, etc.), liver disease (eg, alcoholic hepatitis, hepatitis B, hepatitis C) Etc.), joint diseases (eg, osteoarthritis, etc.), atherosclerosis and the like. The compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary metabolism, and prevents cardiovascular complications. Treatment, prevention and treatment of heart failure complications, reduction of blood remnant, prevention of anovulation
It is also used for the treatment, prevention and treatment of hirsutism, and prevention and treatment of hyperandrogenemia. The compound of the present invention is also used for secondary prevention and suppression of progress of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction). The compound of the present invention
It can also be used in combination with midazolam, ketoconazole and the like.

The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptoms and the like. kg body weight, preferably 0.01 to 2 mg / kg body weight, more preferably 0.025 to 0.5 mg / kg body weight,
It is desirable to administer this amount once to three times a day.

The compound of the present invention can be used as an agent for treating diabetes, an agent for treating diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, etc. (Abbreviated as drug). These concomitant drugs may be low molecular compounds, high molecular proteins, polypeptides, antibodies, or vaccines. At this time, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to a subject to be administered simultaneously or at an interval. The dose of the concomitant drug can be appropriately determined based on the clinically used dose. Also,
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 genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc) A fragment or derivative of insulin (eg, INS-1, etc.), an insulin sensitizer (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, GI-26257)
0, JTT-501, MCC-555, YM-440,
KRP-297, CS-011, FK-614, etc.), α
-Glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide) , Tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide,
Glibuzole), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1
Etc.), dipeptidyl peptidase IV inhibitors (eg, NV
P-DPP-278, PT-100, etc.), β3 agonist (eg, CL-316243, SR-58611-A,
UL-TG-307, SB-226552, AJ-96
77, BMS-196085, AZ-40140, etc.),
Amylin agonists (eg, pramlintide etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid etc.),
Gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLUT (sodium-glucose cotranspo
rter) inhibitors (eg, T-1095, etc.) and the like.

Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), CT-
112), neurotrophic factors (eg, NGF, NT-3, B
DNF, etc.), neurotrophic factor production / secretion promoter, PKC inhibitor (eg, LY-333531, etc.), AGE inhibitor (eg, ALT946, pimagedin, pyratoxatin, N
-Phenacyl thiazolium bromide (ALT76
6), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), and cerebral vasodilators (eg, tiapride, mexiletine, etc.). Examples of antihyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt, etc.)), squalene Synthase inhibitors or fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.

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

Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), Pancreatic lipase inhibitors (eg, orlistat etc.), β3 agonists (eg, CL
-316243, SR-58611-A, UL-TG-
307, SB-226552, AJ-9677, BMS
1961985, AZ-40140, etc.), peptidic appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-15849, etc.) and the like. 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-based preparations (eg, chlorthalidone, mefluside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the chemotherapeutic agent include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, Mitomycin, adriamycin, etc.), 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 ( Examples include interferon, interleukin (IL) and the like, and colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin and the like). Among them, interleukins such as IL-1, IL-2 and IL-12 are exemplified. preferable.

As the concomitant drug, a drug which has been shown to improve cachexia in animal models or clinically, ie,
Cyclooxygenase inhibitors (eg, indomethacin, etc.)
[Cancer Research, 49th
Vol., 5935-5939, 1989], progesterone derivatives (eg, megestrol acetate) [Journal of C Oncology (Journal of C)
linical Oncology), Vol. 12, pp. 213-225, 1
994], carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (all references are as described above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Journal. Of Cancer (British Journal of
Cancer), 68, 314-318, 1993.
Year], growth hormone, IGF-1, or antibodies to TNF-α, LIF, IL-6, and oncostatin M, which are factors that induce cachexia.

Further, concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-853, prosaptide, etc.)
Antidepressants (eg, desipramine, amitriptyline, imipramine, etc.), antiepileptic drugs (eg, lamotrigine, etc.),
Antiarrhythmic drugs (eg, mexiletine, etc.), acetylcholine receptor ligands (eg, ABT-594, etc.), endothelin receptor antagonists (eg, ABT-627, etc.), monoamine uptake inhibitors (eg, tramadol, etc.), narcotic Analgesics (eg, morphine, etc.), GABA receptor agonists (eg, gabapentin, etc.), α
2-receptor agonist (eg, clonidine, etc.), local analgesic (eg, capsaicin, etc.), protein kinase C inhibitor (eg, LY-333531, etc.), anxiolytic (eg, benzodiazepine, etc.), phosphodiesterase inhibitor ( Eg, sildenafil (citrate), dopamine agonist (eg, apomorphine), osteoporosis treatment (eg, alphacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, disodium pamidronate, alendron) Sodium hydrate, disodium incadronate, etc.), anti-dementia agents (eg, tacrine, donepezil, rivastigmine, galantamine, etc.),
Drugs for treating incontinence and pollakiuria (eg, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride) and the like.

The combination drug is preferably an insulin preparation,
Insulin sensitizer, α-glucosidase inhibitor,
Biguanides, insulin secretagogues (preferably sulfonylurea agents) and the like. The above concomitant drugs may be used in combination of two or more at an appropriate ratio. Preferred combinations when two or more concomitant drugs are used include, for example, the following. 1) an insulin sensitizer and an insulin preparation; 2) an insulin sensitizer and an insulin secretagogue; 3) an insulin sensitizer and an α-glucosidase inhibitor; 4) an insulin sensitizer and a biguanide; 6) Insulin sensitizer, insulin preparation and insulin secretagogue; 7) insulin sensitizer, insulin preparation and α
8) an insulin sensitizer, an insulin secretagogue and a biguanide; 9) an insulin sensitizer, an insulin secretagogue and an α-glucosidase inhibitor; and 10) an insulin sensitizer, biguanide Agents and α-glucosidase inhibitors.

When the compound of the present invention is used in combination with a concomitant drug, the amount of each drug can be reduced within a safe range in consideration of the adverse effects of those drugs. In particular, the dose of the insulin sensitizer, the insulin secretagogue and the biguanide can be reduced from the usual dose. Thus, the adverse effects that would be caused by these agents can be safely prevented. In addition, diabetic 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.

Hereinafter, the method for producing the compound of the present invention will be described. Compound (I) can be produced by a method known per se, for example, Method A to Method I shown below or a method analogous thereto. In each of the following production methods, the starting compound may be used as a salt. As such a salt, those exemplified as the salt of the compound (I) are used. In the general formula (I), Z is-(CH ₂ ) _n -Z ^1a-
Compound (I-1) in which (Z ^1a is an oxygen atom, a sulfur atom, or —NR ⁷ — (R ⁷ has the same meaning as described above) and n has the same meaning as described above) is, for example, the following A It is manufactured by the method. [Method A]

Embedded image [In the formula, E represents a leaving group, and other symbols have the same meanings as described above. Here, the leaving group represented by E is, for example, a hydroxy group, a halogen atom or —OSO ₂ R ¹⁵
(R ¹⁵ represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms). An alkyl group having 1 to 4 carbon atoms in the “alkyl group having 1 to 4 carbon atoms” and 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 ¹⁵ As, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl,
Of these, methyl is preferred. 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 ¹⁵ include, for example, phenyl and naphthyl. Of these, phenyl is preferred. R ¹⁵ is particularly preferably methyl, tolyl or the like.

In this method, compound (II) and compound (III)
To produce compound (I-1). When E is a hydroxy group, this reaction is performed 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 affect the reaction. Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine. Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperazine. The amount of the organic phosphorus compound and the electrophilic agent to be used is preferably about 1 to about 5 molar equivalents relative to compound (III). Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; benzene;
Aromatic hydrocarbons such as toluene and xylene; N, N-
Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -50 to about 150C, preferably about -1.
0 to about 100 ° C. The reaction time is usually about 0.5 to
About 20 hours.

When E is a halogen atom or —OSO ₂ R ¹⁵ , this reaction is carried out in a conventional manner in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca-
Amines such as 7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide. The amount of the base to be used is preferably about 1 to about 5 relative to compound (III).
It is a molar equivalent. Examples of solvents that do not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; ketones such as acetone and 2-butanone; Halogenated hydrocarbons; amides such as N, N-dimethylformamide; and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50
To about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours.
Compound (I-1) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

The compounds (II) and (III) used as starting compounds in the above-mentioned method A are known compounds, for example, the compound (II) wherein E is a hydroxy group.
Are described in EP-A 710659. Also,
Compound (II) is disclosed in EP-A-629624 (Japanese Unexamined Patent Publication No.
53555) and WO 98/03505. Further, compound (II) can also be produced by a method according to the method described in these publications. On the other hand, compound (III) is, for example, tetrahedron (T
etrahedron), 43, 607 (1987); Chemical and Pharmaceutical Bretane (Chemica)
l & Pharmaceutical Bulletin), vol. 12, p. 176 (1964). The compound (II
I) can also be produced by a method according to the method described in these documents.

In the general formula (I), Z is -Z ^1a- (CH ₂ ) _n
-(The symbols are as defined above) (I-
2) is produced, for example, by the following method B. [Method B]

Embedded image [The symbols in the formula are as defined above. In this method, compound (I-2) is produced by reacting compound (IV-1) with compound (V). This reaction is performed in the same manner as in the reaction between compound (II) and compound (III) in the above-mentioned Method A. The amount of the organic phosphorus compound and the electrophile used when E is hydroxy is preferably about 1 to about 5 molar equivalents relative to compound (IV-1). E is a halogen atom or —OSO ₂ R ¹⁵
The amount of the base used in the case of is the compound (IV-
It is preferably about 1 to about 5 molar equivalents based on 1). The compound (I-2) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (V) used as a starting material compound in the above-mentioned Method B is a known compound, and for example, the compound (V) is described in WO 01/14372 and the like. Further, compound (V) can also be produced by a method according to the method described in these publications.

In the general formula (I), the compound (I-4) wherein R ² is --OH can also be produced, for example, by the following Method C. [Method C]

Embedded image [In the formula, R ⁸ ′ is an optionally substituted hydrocarbon group, and other symbols have the same meanings as described above. In this method, compound (I-4) is produced by subjecting compound (I-3) to a hydrolysis reaction. Where R
^{As the} “optionally substituted hydrocarbon group” represented by ^{8 ′} , those exemplified as the “optionally substituted hydrocarbon group” for R ⁸ can be mentioned. Alkyl group "and the like. Examples of the “alkyl group having 1 to 4 carbon atoms” represented by R ^{8 ′} include methyl, ethyl, propyl, butyl, isobutyl,
Examples thereof include sec-butyl and t-butyl, and among them, methyl and ethyl are preferable. This reaction is carried out in a water-containing solvent in the presence of an acid or a base according to a conventional method. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as acetic acid. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal alkoxides such as sodium methoxide; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. The amount of the acid or base to be used is generally an excess amount relative to compound (I-3). Preferably, the amount of the acid used depends on the amount of the compound (I
The equivalent amount of the base is about 2 to about 50 equivalents, and the amount of the base is about 1.2 to about 5 equivalents to the compound (I-3). Examples of the water-containing solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane, and diethyl ether; and a mixed solvent of water and one or more solvents selected from dimethyl sulfoxide, acetone, and the like. The reaction temperature is usually about-
The temperature is from 20 to about 150C, preferably from about -10 to about 100C. The reaction time is generally about 0.1 to about 20 hours. The compound (I-4) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-3) used as a starting compound in the above-mentioned Method C is produced, for example, by the above-mentioned Method A or Method B. In the general formula (I), R ² is —NR ⁹ R ¹⁰ (R ⁹
And R ¹⁰ are as defined above) (I-
5) is also produced, for example, by the following Method D. [Method D]

Embedded image [The symbols in the formula are as defined above. In this method, compound (I-5) is produced by subjecting compound (I-4) to an amidation reaction. This reaction is carried out by a method known per se, for example, compound (I-4) and compound (VII
I) is directly condensed with a condensing agent (eg, dicyclohexylcarbodiimide, etc.), or a method of appropriately reacting a reactive derivative of compound (I-4) with compound (VIII). Is Compound (I-4)
Examples of the reactive derivative include acid anhydrides, acid halides (eg, acid chloride, acid bromide), imidazolide, and mixed acid anhydrides (eg, methyl carbonate, ethyl carbonate,
An anhydride with isobutyl carbonic acid).

For example, when an acid halide is used, the reaction is as follows:
The reaction is performed in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base include amines such as triethylamine, N-methylmorpholine and N, N-dimethylaniline; and alkali metal salts such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate. Solvents that do not adversely affect the reaction include, for example, chloroform,
Halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; ethyl acetate; and water. These solvents may be mixed and used at an appropriate ratio. Compound (VII
The amount of I) to be used is 0.1 to 10 based on compound (I-4).
It is a molar equivalent, preferably 0.3 to 3 molar equivalents. The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. When a mixed acid anhydride is used, the compound (I-4) and a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) are reacted with a base (eg, triethylamine,
The reaction is carried out in the presence of an amine such as N-methylmorpholine or N, N-dimethylaniline; an alkali metal salt such as sodium hydrogencarbonate, sodium carbonate or potassium carbonate) and further reacted with the compound (VIII). Compound (VII
The amount of (I) to be used is generally 0. 1 relative to compound (I-4).
It is 1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents. The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. Compound (I-5) thus obtained can be obtained by a 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 compound (I-4) used as a starting compound in the above method D is produced, for example, by the above method A to method C. Known compounds are used as the compound (VIII).

The compound (IV-1) used as a starting compound in the method B can be produced, for example, by the following method E. [Method E]

Embedded image [The symbols in the formula are as defined above. In this method, compound (II) and compound (II) in method A described above are used.
The reaction is performed in the same manner as in the reaction with I). In this reaction,
The portion of the -Z ^1a -H of compound (X), performs a condensation reaction after protecting with a suitable protective group, after the reaction may be deprotected. Examples of such a protecting group include a benzyl group, a methoxymethyl group, a silyl group (eg, a trimethylsilyl group, a t.-butyldimethylsilyl group, and the like). Compound (IV-1) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. As the compound (IX) and the compound (X) used as the starting compounds in the above-mentioned Method E, known compounds are used.

In the general formula (I), Z _is- (CH ₂ ) _n1 -S
(O) _m- (CH ₂ ) _n2- (m is 1 or 2, n1 and n2 are the same or different and represent an integer of 0 to 8,
Compound (I-7), wherein at least one of n1 and n2 is 0), is produced, for example, by the following Method F. [Method F]

Embedded image [The symbols in the formula are as defined above. In this method, compound (I-7) is produced by subjecting compound (I-6) to an oxidation reaction. This reaction is generally performed using an oxidizing agent in a solvent that does not adversely influence the reaction. Examples of the oxidizing agent include 3-chlorophenylperbenzoic acid, sodium periodate, hydrogen peroxide, peracetic acid and the like. 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; Examples include amides such as dimethylformamide; alcohols such as ethanol and methanol. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually, it is about -50 to about 150C, preferably about -10 to about 100C. The reaction time is usually about 0.5 to about 20.
Time. Compound (I-7) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (I-6) used as a starting compound in the above method F is produced, for example, by the above method A or method B.

In the general formula (I), Z is-(CH ₂ ) _n-
(N is as defined above) (I-8)
Is manufactured, for example, by the following G method. [Method G]

Embedded image Wherein, T is an oxygen atom, a sulfur atom or -NR ⁷ -
(R ⁷ is as defined above), V is a hydrogen atom or a substituent, and other symbols are as defined above. As the substituent represented by V, those exemplified as the substituent for the ring B can be mentioned.

[Step 1] This method is carried out in the same manner as in the reaction of compound (I-4) with compound (VIII) in Method D described above. Compound (XIII) 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 (XI-1) and compound (XII) used as starting compounds in step 1 of the above-mentioned Method G are known compounds, for example, compound (XI-
1) is described in WO 99/585190 and the like. Further, compound (XI-1) can also be produced by a method according to the methods described in these publications. [Step 2] In this method, compound (I-8) is produced by subjecting compound (XIII) to a ring closure reaction. The reaction is
According to a conventional method, the reaction is performed in the presence of an ammonium salt in a solvent that does not adversely influence the reaction. Examples of the ammonium salt include ammonium acetate. 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; Examples include amides such as dimethylformamide; alcohols such as ethanol and methanol; and organic acids such as acetic acid. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually
About -50 to about 200C, preferably about -10 to about 150
° C. The reaction time is generally about 0.5 to about 20 hours. Compound (I-8) 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.

In the general formula (I), Z _is- (CH ₂ ) _n1 -C
^{_{ONR 7 - (CH 2) n2}} - ( symbol is as defined above) is a compound (I-9) is produced, for example, by the following Method H. [Method H]

Embedded image [The symbols in the formula are as defined above. This method is carried out in the same manner as in the reaction of compound (I-4) with compound (VIII) in Method D described above. Compound (I-9) thus obtained can be obtained by 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. The compound (XI-2) and the compound (XIV) used as the starting compounds in the above-mentioned Method H are known compounds. For example, the compound (XI-2) is a compound of WO 99/58.
5190. Further, the compound (XI-
2) can also be produced by a method according to the method described in these publications. On the other hand, compound (XIV)
Are described, for example, in WO 01/14372. Further, compound (XIV) can also be produced by a method according to the methods described in these publications.

In the general formula (I), Z _is- (CH ₂ ) _n1 -N
Compound (I-10), which is R ⁷ CO— (CH ₂ ) _n2 — (the symbols have the same meanings as described above), is produced, for example, by the following Method I. [Method I]

Embedded image [The symbols in the formula are as defined above. This method is carried out in the same manner as in the reaction of compound (I-4) with compound (VIII) in Method D described above. Compound (I-10) thus obtained can be obtained by a 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. Compound (IV-2) used as a starting compound in the above-mentioned Method I is produced, for example, by the above-mentioned Method E.

The compound (XV) used as a starting compound in the above-mentioned Method I is produced, for example, by the following Method J. [J method]

Embedded image [The symbols in the formula are as defined above. [Step 1] The present method is directed to compound (I-4) described in the above Method D.
And the compound (VIII). The compound (XVIII) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. As the compound (XVI) and the compound (XVII) used as the starting compound in Step 1 of the above-mentioned Method J, known compounds are used, respectively. [Step 2] This method is carried out in the same manner as in Step 2 of the above-mentioned Method G. The compound (XV) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group, a hydroxyl group or a carbonyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include those exemplified above for R ⁵ .

The carboxyl-protecting group includes, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, t.-butyl, etc., C _7-11 aralkyl (eg, benzyl etc.), phenyl, trityl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t.-butyldimethylsilyl, t.-
Butyl diethylsilyl, etc.), C _2-6 alkenyl (eg,
1-allyl, etc.). These groups are 1
Or 3 halogen atoms (eg, fluorine, chlorine, bromine,
Iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro.

As the hydroxyl-protecting group, those exemplified as the aforementioned R ⁴ can be mentioned. Examples of the carbonyl-protecting group include a cyclic acetal (eg, 1,3-dioxane, etc.) and an acyclic acetal (eg, di-C _1-6 alkylacetal, etc.). In addition, these protecting groups can be removed by a method known per se, for example, Protective Groups in Organic Synthesis, John W.
The method may be performed according to the method described in iley and Sons (1980). For example, acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method using palladium acetate, a trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.), a reduction method, and the like are used.

When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer and a rotamer, these are also contained as the compound (I), as well as a synthesis method and a separation method known per se. Each can be obtained as a single item by the method. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in compound (I). The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.

As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used. 1) Fractional recrystallization method Racemic and optically active compounds (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
A salt with phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.), separating the salt by a fractional recrystallization method, and optionally obtaining a free optical isomer through a neutralization step. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to separate the racemate or a salt thereof. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh) or CHIRAL series manufactured by Daicel,
Optical isomers can be developed by developing a solution of water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixture. Is separated. For example, in the case of gas chromatography, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences).

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

[0092]

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 percent by weight unless otherwise specified. The room temperature is 1 to 3
Indicates a temperature of 0 ° C. In the present specification, when an abbreviation is used for a base, amino acid, or the like, the
This is based on the abbreviation by Biochemical Nomenclature or the abbreviation commonly used in this field, examples of which are described below. When amino acids may have optical isomers,
Unless otherwise specified, L-form is shown.

[0093] The sequence numbers in the sequence listing in the present specification indicate the following sequences. [SEQ ID NO: 1] Primer P used in Reference Example 1a
1 shows the base sequence of ARD-U. [SEQ ID NO: 2] Primer P used in Reference Example 1a
1 shows the base sequence of ARD-L. [SEQ ID NO: 3] Primer X used in Reference Example 2a
1 shows the base sequence of RA-U. [SEQ ID NO: 4] Primer X used in Reference Example 2a
1 shows the base sequence of RA-L. [SEQ ID NO: 5] PPRE-U used in Reference Example 4a
Shows the nucleotide sequence of [SEQ ID NO: 6] PPRE-L used in Reference Example 4a
Shows the nucleotide sequence of [SEQ ID NO: 7] Primer T used in Reference Example 4a
Shows the nucleotide sequence of KU. [SEQ ID NO: 8] Primer T used in Reference Example 4a
1 shows the nucleotide sequence of KL. [SEQ ID NO: 9] Primer P used in Reference Example 6a
1 shows the nucleotide sequence of AG-U. [SEQ ID NO: 10] This shows the base sequence of primer PAG-L used in Reference Example 6a.

[0094]

EXAMPLES Test Example 1 (Blood Glucose and Blood Lipid (Triglyceride) Lowering Effect in Mice) Test compounds were added to powder feed (CE-2, CLEA Japan) in a concentration of 0.1 mg / ml.
KKA, a type 2 diabetes model
^y mice (11-12 weeks old, 5 mice per group) were fed ad libitum for 4 days. During this time, water was given ad libitum. Blood was collected from the orbital venous plexus, and glucose and triglyceride in plasma separated from the blood were separated by L-type Wako Glu2, respectively.
(Wako Pure Chemical) and L-type Wako TG · H (Wako Pure Chemical) were quantified by an enzyme method. Table 1 shows the results.
Shown in In the table, the “blood glucose lowering effect (%)” represents a reduction rate (%) of the blood glucose level of the test compound administration group when the blood glucose level of the test compound non-administration group is 100%. The “blood lipid lowering effect (%)” represents the reduction rate (%) of the blood triglyceride value of the test compound administration group when the blood triglyceride value of the test compound non-administration group is set to 100%. .

[Table 1] Thus, the compound of the present invention was found to have a strong blood sugar lowering action and a blood lipid lowering action. Therefore, the compound of the present invention is useful as an agent for preventing or treating diabetes, hyperlipidemia (particularly, hypertriglyceridemia), impaired glucose tolerance and the like.

Test Example 2 (Total cholesterol lowering action and plasma anti-atherosclerosis index raising action in mice) The test compound was added to a powdered feed (CE-2, CLEA Japan) in a concentration of 0.1%.
KKA, a type 2 diabetes model
^y mice (11-12 weeks old, 5 mice per group) were fed ad libitum for 4 days. During this time, water was given ad libitum. Blood was collected from the fundus venous plexus, and the component was measured using plasma separated from the blood. Total cholesterol was determined by L-type Wako cholesterol (Wako Pure Chemical Industries). Also, some of the plasma,
Add HDL cholesterol precipitation reagent (Wako Pure Chemicals)
Non-HDL lipoprotein was precipitated, and the cholesterol (HDL cholesterol) in the supernatant was measured. From these cholesterol values, a plasma anti-atherosclerosis index [(HDL cholesterol / total cholesterol) × 100] was calculated. The results are shown in [Table 2]. In the table, the “total cholesterol lowering effect (%)” represents the reduction rate (%) of the total cholesterol level of the test compound administration group when the total cholesterol level of the test compound non-administration group is 100%. In addition, the “plasma anti-atherosclerosis index increasing effect (%)” refers to the increase rate of the plasma anti-atherosclerosis index of the test compound administration group when the plasma anti-atherosclerosis index of the test compound non-administration group is 100% ( %).

[Table 2] Thus, it was found that the compound of the present invention has a total cholesterol lowering effect and a plasma anti-atherosclerosis index raising effect. Therefore, it can be seen that the compound of the present invention is useful as an agent for preventing or treating arteriosclerosis or the like by correcting the plasma lipoprotein profile such as hypercholesterolemia or hypoHDL cholesterolemia.

Test Example 3 (PPARδ-RXRα heterodimer ligand activity) PPARδ: RXRα: 4ERP obtained in Reference Example 5a
P / CHO-K1 cells were transformed with 10% fetal bovine serum [Life Technologies, Inc., USA]
After culturing in a Ham F12 medium (Nissui Pharmaceutical) containing
6 × white plate (Corning Coster Corporation, USA) 2 × 10
^The cells were seeded at ⁴ cells / well and cultured overnight in a carbon dioxide gas incubator at 37 ° C. A 96-well white plate was washed with PBS (Phosphate-buffered saline), and 90 μl of a Ham F12 medium containing 0.1% fatty acid-free bovine serum albumin (BSA) and a test compound 10 were added.
μl, and cultured in a carbon dioxide gas incubator at 37 ° C. for 48 hours. After removing the medium, Vicca Gene 7.
5 (manufactured by Wako Pure Chemical Industries) was added and stirred, and after stirring, Lumistar [manufactured by BMG Labtechnologies GmbH, Germany]
Was used to measure luciferase activity. The induction ratio was calculated from the luciferase activity of each test compound, assuming that the luciferase activity of the test compound non-administration group was 1. The concentration of the test compound and the value of the induction factor were determined using a prism (PRI
SM) 2.01 [Graph Pad Software (Graph
Pad Software, Inc.) manufactured by the analysis to using the US, the maximum value of The EC ₅₀ values (fold induction of the test compound 5
Compound concentration indicating 0%) was calculated. The results are shown in [Table 3].

[Table 3] As described above, the compound of the present invention has excellent PPARδ-RX
Rα was found to have heterodimeric ligand activity.

Test Example 4 (PPARγ-RXRα heterodimeric ligand activity) PPARγ: RXRα: 4ERP obtained in Reference Example 8a
P / CHO-K1 cells were transformed with 10% fetal bovine serum [Life Technologies, Inc., USA]
After culturing in a Ham F12 medium (Nissui Pharmaceutical) containing
6 × white plate (Corning Coster Corporation, USA) 2 × 10
^The cells were seeded at ⁴ cells / well and cultured overnight in a carbon dioxide gas incubator at 37 ° C. A 96-well white plate was washed with PBS (Phosphate-buffered saline), and 90 μl of a Ham F12 medium containing 0.1% fatty acid-free bovine serum albumin (BSA) and a test compound 10 were added.
μl, and cultured in a carbon dioxide gas incubator at 37 ° C. for 48 hours. After removing the medium, Vicca Gene 7.
5 (manufactured by Wako Pure Chemical Industries) was added and stirred, and after stirring, Lumistar [manufactured by BMG Labtechnologies GmbH, Germany]
Was used to measure luciferase activity. The induction ratio was calculated from the luciferase activity of each test compound, assuming that the luciferase activity of the test compound non-administration group was 1. The concentration of the test compound and the value of the induction factor were determined using a prism (PRI
SM) 2.01 [Graph Pad Software (Graph
Pad Software, Inc.) manufactured by the analysis to using the US, the maximum value of The EC ₅₀ values (fold induction of the test compound 5
Compound concentration indicating 0%) was calculated. The results are shown in [Table 4].

[Table 4] Thus, the compound of the present invention has excellent PPARγ-RX
Rα was found to have heterodimeric ligand activity.

Test Example 5 (PPARδ-RXRα Heterodimer Ligand Activity) The COS-1 cells obtained in Reference Example 9a were collected, and 0.1% fatty acid-free bovine serum albumin (BSA) (manufactured by Wako Pure Chemical Industries, Ltd.) was obtained. The cells were suspended in a DMEM medium (Nikken Institute of Biomedical Research) containing the cells, and then seeded into each well of a 96-well white plate (manufactured by Corning Incorporated, U.S.A.) at a concentration of 2 × 10 ⁴ cells / well in an amount of 80 ml.
Subsequently, 20 ml of the test compound was added, and the cells were cultured at 37 ° C. under 5% CO _{2 for} 48 hours. After removing the medium from the 96-well white plate, add 40 ml of Picker Gene LT7.5 (Wako Pure Chemical Industries), stir, and mix
label Counter) (Wallac)
Luciferase activity was measured. The induction ratio was calculated from the luciferase activity of each test compound, assuming that the luciferase activity of the test compound non-administration group was 1. The concentration of the test compound and the value of the induction ratio were determined using a prism (PRISM) 2.0.
1 [GraphPad Softwar
e, Inc., USA], to calculate the EC ₅₀ value of the test compound (the concentration of the compound showing 50% of the maximum value of the induction factor). The results are shown in [Table 5].

[Table 5] As described above, the compound of the present invention has excellent PPARδ-RX
Rα was found to have heterodimeric ligand activity.

Reference Example 1a (Cloning of Human PPARδ Gene) Cloning of the human PPARδ gene was reported by Schmidt, A. et al. (Mol Endocrinol 1992; 6: 1634) using pancreatic cDNA (manufactured by Toyobo, QUICK-Clone cDNA) as a template. -1641) P that is
Primer set PARD-U prepared with reference to the base sequence of PARδ gene; 5'-AAC GGT ACC TCA GCC ATG GAG CAG CCT CAG
GAG G-3 '(SEQ ID NO: 1) PARD-L; 5'-TAA GTC GAC CCG TTA GTA CAT GTC CTT GTA
GAT C-3 ′ (SEQ ID NO: 2) was used for the PCR method. PCR reaction is AmpliWax PCR
Hot start using Gem 100 (Takara Shuzo)
Start) method. As a lower layer mixture, 10 x LA PCR Buf
2 μl of fer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution, and 10 μl of sterile distilled water were mixed.
As the upper layer mixture, human heart cDNA (1 ng / ml) was used as a template.
1 μl, 3 μl of 10 x LAPCR Buffer, 2.5 mM dNTP solution
1 μl, TaKaRa LA Taq DNA po1ymerase (Takara Shuzo) 0.
5 μl and 24.5 μl of sterile distilled water were mixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C. for 5 minutes and on 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. In addition, 15
After 45 cycles of a 2-minute cycle at 68 ° C for 7 seconds,
Treated at 2 ° C. for 8 minutes. The resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.4 kb DN containing the PPARδ gene.
After recovering the A fragment from the gel, the plasmid pTBT-hPPA was inserted into pT7Blue-T vector (Takara Shuzo).
Rδ was prepared. Reference Example 2a (Cloning of Human RXRα Gene) Cloning of human RXRα gene
(Manufactured by Toyobo, trade name: QUICK-Clone cDNA) as a template,
Mangelsdorf, D.
J.) et al. [Nature, 1990, 3
45 (6272), pp. 224-229].
Primer set prepared with reference to the base sequence of Rα gene XRA-U: 5'-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC
CTG-3 '(SEQ ID NO: 3) XRA-L: 5'-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC
It carried out by the PCR method using CTC-3 '(SEQ ID NO: 4). PCR reaction is AmpliW
ax PCR Gem 100 (manufactured by Takara Shuzo) was carried out by a Hot Start method. First, 10 × LA PC
2 μl of R Buffer, 3 μl of 2.5 mM dNTP solution, 12.
2.5 μl each of 5 μM primer solution, 10 μl of sterile distilled water
Was mixed to form a lower layer mixed solution. Also, human kidney as template
1 μl of cDNA (1 ng / ml) and 10 × LA PCR Buf
fer 3 μl, 2.5 mM dNTP solution 1 μl, TaKaRa LA Ta
q DNA polymerase (Takara Shuzo) 0.5 μl, sterile distilled water 2
4.5 μl was mixed to obtain an upper layer mixed solution. One AmpliWax PCR Gem 100 (manufactured by Takara Shuzo) was added to the above lower layer mixture, and the mixture was treated at 70 ° C. for 5 minutes and on 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. In addition, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes is repeated for 3 cycles.
After repeating 5 times, it was treated at 72 ° C. for 8 minutes. The resulting PCR product was subjected to agarose gel (1%) electrophoresis, and RX
After a 1.4 kb DNA fragment containing the Rα gene was recovered from the gel, it was inserted into pT7 Blue-T vector (Takara Shuzo) to obtain a plasmid pTBT-hRXRα.

Reference Example 3a (Preparation of plasmid for expressing human PPARδ and RXRα) Plasmid pVgRXR [Invitrogen]
7.8 Kb FspI-NotI fragment and the RXRα gene of plasmid pTBT-hRXRα described in Reference Example 2a.
The 0.9 kb FspI-NotI fragment was ligated to prepare a plasmid pVgRXR2. Next, after cutting pVgRXR2 with BstXI, T4 DNA
The ends were blunt-ended by polymerase (Takara Shuzo) treatment. Subsequently, a DNA fragment of 6.5 kb was obtained by digestion with KpnI. On the other hand, the plasmid pTB described in Reference Example 1a
After cleaving T-hPPARδ with SalI, the ends were blunted by treatment with T4 DNA polymerase (Takara Shuzo). Then Kp
By cutting with nI, a DNA fragment containing the PPARδ gene of 1.4 kb was obtained. By ligating both DNA fragments, plasmid pVgRXR2-hPPARδ was constructed.

Reference Example 4a (Preparation of Reporter Plasmid) A DNA fragment containing the PPAR-responsive element (PPRE) of acyl CoA oxidase was prepared using the following 5′-terminal phosphorylated synthetic DNA. PPRE-U: 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-
3 '(SEQ ID NO: 5) PPRE-L: 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-
3 '(SEQ ID NO: 6) 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 by referring to the nucleotide sequence of the promoter region of the thymidine kinase gene, TK-U: 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3 '(SEQ ID NO: 7) TK-L: 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3' (SEQ ID NO: 8) PCR reaction is AmpliW
ax PCR Gem 100 (manufactured by Takara Shuzo) was carried out by a Hot Start method. First, 10 × LA PC
2 μl of R Buffer, 3 μl of 2.5 mM dNTP solution, 12.
2.5 μl each of 5 μM primer solution, 10 μl of sterile distilled water
Was mixed to form a lower layer mixed solution. In addition, pRL-
1 μm of TK vector [Promega, USA]
l, 10 x LA PCR Buffer 3 µl, 2.5 mM dNT
1 μl of the P solution, 0.5 μl of TaKaRa LA Taq DNA polymerase (manufactured by Takara Shuzo) and 24.5 μl of sterile distilled water were mixed to form an upper layer mixture. Add AmpliWax PCR Gem 1 to the above mixture
One (00) (manufactured by Takara Shuzo) was added, and the mixture was treated at 70 ° C. for 5 minutes and in ice for 5 minutes. After setting the tube containing the reaction solution in a thermal cycler (PerkinElmer, USA),
Treated at 2 ° C. for 2 minutes. Further, at 95 ° C. for 15 seconds, 68
After repeating a cycle of 2 minutes at 35 ° C. 35 times, treatment was performed at 72 ° C. for 8 minutes. The obtained PCR product was subjected to agarose gel (1%) electrophoresis, and 140b containing TK promoter was analyzed.
After recovering the DNA fragment from the gel, pT7 Blue-T v
ector (Takara Shuzo). TK obtained by digesting this plasmid with restriction enzymes BglII and NcoI
The fragment containing the promoter was replaced with the plasmid pGL3-Basic.
vector [Promega, USA] BglII-Nc
Ligation with the oI fragment produced plasmid pGL3-TK. NheI-XhoI of the resulting plasmid pGL3-TK
4.9 kb fragment and NheI of plasmid pBSS-PPRE4
The plasmid pGL3-4ERPP-TK was prepared by ligating the -XhoI fragment 200b. This plasmid pGL3-4ERPP-TK was transferred to BamHI (Takara Shuzo).
And then blunt-ended by T4 DNA polymerase (Takara Shuzo) treatment to obtain a DNA fragment. On the other hand, pG
After FP-C1 (manufactured by Toyobo) was digested with Bsu36I (NEB), the ends were blunted by treatment with T4 DNA polymerase (manufactured by Takara Shuzo) to obtain a 1.6 kb DNA fragment. Both DNA
By ligating the fragments, the reporter plasmid pG
L3-4ERPP-TK neo was constructed.

Reference Example 5a (Introduction of Human PPARδ, RXRα Expression Plasmid and Reporter Plasmid into CHO-K1 Cells and Obtaining Expression Cells) Ham F12 medium containing 10% fetal bovine serum (Lifetech Oriental) (Nissui Pharmaceutical Co., Ltd.) Grown in tissue culture flask 750 ml (Corning, USA)
After detaching the CHO-K1 cells by 0.5 g / L trypsin-0.2 g / L EDTA (Lifetech Oriental) treatment, the cells were washed with PBS.
(Lifetech Oriental) and centrifugation (1000r
pm, 5 minutes) and suspended in PBS. Next, DNA was introduced into the cells using Gene Pulser (manufactured by Bio-Rad Laboratories, USA) under the following conditions. That is, 8 × 10 ⁶ cells and 10 μg of the expression plasmid pVgRXR2- produced in Reference Example 3a were placed in a 0.4 cm gap cuvette.
hPPARδ and 10 μg of the reporter plasmid pGL3-4ERPP-TK neo prepared in Reference Example 4a were added, and electroporation was performed under a voltage of 0.25 kV and a capacitance of 960 mF.
Thereafter, the cells were transferred to Ham's F12 medium containing 10% fetal bovine serum, cultured for 24 hours, the cells were again detached and centrifuged, and then Geneticin (Lifetech Oriental) was added to 500 ml.
[mu] g / ml and Zeocin [Invitrogen (Invitrogen) Inc., USA] was suspended in Ham F12 medium containing 10% fetal calf serum was added to a 250 [mu] g / ml, diluted to 10 ⁴ cells / ml The cells were inoculated into a 96-well plate (Becton Dickinson) and cultured in a carbon dioxide incubator at 37 ° C. to obtain a geneticin- and zeocin-resistant transformant. Next, after the obtained transformant was cultured in a 24-well plate (Corning, USA), 10 mM Il
A strain in which luciferase expression was induced by adding oprost, PPARδ: RXRα: 4ERPP / CHO-K1, was selected.

Reference Example 6a (Cloning of human PPARγ gene)
(Manufactured by Toyobo, trade name: QUICK-Clone cDNA) as a template,
Greene et al. [Gene Expr., 1995, 4 (4-5), 2]
81-299], a primer set PAG-U: 5'-GTG GGT prepared with reference to the base sequence of the PPARγ gene described above.
ACC GAA ATG ACC ATG GTT GAC ACA GAG-3 '(SEQ ID NO:
9) PAG-L: 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA
The PCR was performed using CAA GTC-3 '(SEQ ID NO: 10). The PCR reaction was performed by a hot start method using AmpliWax PCR Gem 100 (Takara Shuzo). First, 2 μl of 10 × LA PCR Buffer, 2.
3 μl of a 5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution, and 10 μl of sterile distilled water were mixed to form a lower layer mixed solution. In addition, human heart cDNA (1 ng / ml) was used as a template.
1 μl, 3 μl of 10 × LA PCR Buffer, 2.5 mM
1 μl of the dNTP solution, 0.5 μl of TaKaRa LA Taq DNA polymerase (manufactured by Takara Shuzo), and 24.5 μl of sterilized distilled water were mixed to form an upper layer mixture. Add AmpliWax PCR Gem to the lower mixture
100 (manufactured by Takara Shuzo) was added, and the mixture was treated at 70 ° C. for 5 minutes and in ice for 5 minutes. After setting the tube containing the reaction solution in a thermal cycler (PerkinElmer, USA),
Treated at 2 ° C. for 2 minutes. Further, at 95 ° C. for 15 seconds, 68
After repeating a cycle of 2 minutes at 35 ° C. 35 times, treatment was performed at 72 ° C. for 8 minutes. The obtained PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.4 kb containing PPARγ gene was analyzed.
After recovering the DNA fragment from the gel, pT7 Blue-T ve
ctor (Takara Shuzo) and the plasmid pTBT-hP
PARγ was obtained.

Reference Example 7a (Preparation of plasmid for expressing human PPARγ and RXRα) Plasmid pVgRXR [Invitroge
n), 7.8 kb FspI-NotI fragment and Reference Example 2
RXR of plasmid pTBT-hRXRα obtained in a.
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). Next, KpnI
And a DNA fragment of 6.5 kb was obtained.
On the other hand, plasmid pTBT-hP obtained in Reference Example 6a
After cutting PARγ with SalI, the ends were blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo). Then
By digestion with KpnI, a 1.4 kb human PPARγ
A DNA fragment containing the gene was obtained. By ligating both DNA fragments, plasmid pVgRXR2-hPPARγ
Was built.

Reference Example 8a (Human PPARγ, RXRα Expression Plasmid and Reporter Plasmid CHO-
Introduction into K1 cells and acquisition of expression cells) 10% fetal bovine serum [Life Technology
hnologies, Inc., USA] using a Ham F12 medium (Nissui Pharmaceutical) containing 750 ml of tissue culture flask [Corning Costar Co., Ltd.
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], centrifuged (1000 rpm, 5 minutes),
Suspended in PBS. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad Laboratories, USA) under the following conditions. That is, 8 × 10 ⁶ cells and the plasmid pVgRXR2-hP obtained in Reference Example 7a were placed in a 0.4 cm gap cuvette.
10 μg of PARγ and 10 μg of the reporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 4a
And electroporated under a voltage of 0.25 kV and a capacitance of 960 μF. Then, the cells are 10%
Transfer to ham F12 medium containing fetal calf serum, culture for 24 hours, detach cells again and centrifuge, then Geneticin [Life Technologies, I.
nc.), 500 μg / ml and Zeocin [Invitrogen, USA] 250 μg / ml.
Ham1 containing 10% fetal bovine serum added to
2 medium, diluted to 10 ⁴ cells / ml, and diluted to a 96-well plate [Corning Coaster (Corn)
ing Costar Corporation), USA].
Geneticin and Zeocin resistant transformants were obtained by culturing in a carbon dioxide gas incubator at ℃. Next, the obtained transformant was placed in a 24-well plate [Corning Costar Corporation]
Luciferase expression induced by the addition of 10 μM pioglitazone hydrochloride,
PPARγ: RXRα: 4ERPP / CHO-K1 cells were selected.

Reference Example 9a (Introduction of Human PPARδ, RXRα Expression Plasmid and Reporter Plasmid into COS-1 Cells) COS-1 cells were placed in a tissue culture flask 150 cm.
² (Corning, USA) 5x10 ⁶ cells were seeded at 37 ℃
The cells were cultured for 24 hours under 5% CO ₂ . Transfection was performed using Lipofectamine (Lifetech Oriental). 125ml transfection mixture
Lipofectamine, 100ml PLUS Reagent, 2.5mg
PMCMVneo-hPPARd, 2.5 mg pMCMVneo-hRXRa, 5 mg reporter plasmid pGL3-PPRE × 4-tk-luc-neo, 5 mg p
RL-CMV (Promega, USA) with 5ml opti
It was prepared by mixing with -MEM (Life Tech Oriental). To the COS-1 cells washed with opti-MEM, add the above transfection mixture and 20 ml of opti-MEM, and 37 ° C, 5%
The cells were cultured under CO ₂ conditions for 3 hours. Then, 25 ml of DMEM medium (Nikken Biomedical Research Institute) containing 0.1% fatty acid-free bovine serum albumin (BSA) (Wako Pure Chemical Industries) was added, and 37 ° C., 5% CO 2
Culture was performed for 24 hours under _two conditions.

Reference Example 1 Methyl 5-oxo-5-phenylpentanoate (16.1)
g) in diethyl ether (100 ml) was added with bromine (4.01 ml) at room temperature over 30 minutes.
Stir for a minute. After adding an aqueous solution of sodium sulfite to the reaction mixture, the mixture was extracted with diethyl ether. The diethyl ether layer is washed with saturated saline and dried (MgSO ₄ )
Thereafter, the mixture was concentrated to obtain methyl 4-bromo-5-oxo-5-phenylpentanoate (22.1 g, yield 100%) as a pale yellow oil. _{NMR (CDCl 3) δ: 2.30-2.67} (4H, m), 3.70 (3H, s), 5.38
(1H, dd, J = 5.6, 8.2 Hz), 7.44-7.54 (2H, m), 7.56-7.
66 (1H, m), 8.00-8.06 (2H, m). Reference Example 2 A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (5.00 g), sodium formate (5.96 g) and methanol (100 ml) was refluxed for 24 hours. After removing the reaction solvent under reduced pressure, the residue was dissolved in ethyl acetate. The resulting ethyl acetate solution is treated with water, followed by
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
4 from the elution part of ethyl acetate-hexane (1: 3, volume ratio)
Methyl -hydroxy-5-oxo-5-phenylpentanoate (2.97 g, yield 76%) was obtained as a colorless oil. _{NMR (CDCl 3) δ: 1.56-1.75} (1H, m), 2.22-2.55 (2H, m),
2.63-2.81 (1H, m), 3.68-3.72 (4H, m), 5.11-5.21 (1H,
m), 7.48-7.69 (3H, m), 8.01-8.08 (2H, m).

Reference Example 3 Methyl 4-bromo-5-oxo-5-phenylpentanoate (1.00 g), diformylimide sodium salt (4
After stirring a mixture of (00 mg) and acetonitrile (5 ml) at 80 ° C. for 10 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 4-diformylimide-5-oxo-5-phenylpentanoate (485 mg, yield 50%) was colorless from a fraction eluted with ethyl acetate-hexane (2: 3, volume ratio). Obtained as an oil. NMR (CDCl ₃ ) δ: 2.10-2.40 (1H, m), 2.44 (2H, t, J = 6.8
Hz), 2.55-2.73 (1H, m), 3.71 (3H, s), 5.70-5.85 (1H,
m), 7.39-7.49 (2H, m), 7.51-7.62 (1H, m), 7.75-7.82
(2H, m), 8.86 (2H, br s). Reference Example 4 A mixture of methyl 4-diformylimide-5-oxo-5-phenylpentanoate (415 mg) and 10% hydrochloric acid in methanol (5 ml) was stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure, the resulting colorless crystals were recrystallized from diethyl ether-methanol,
Methyl 4-amino-5-oxo-5-phenylpentanoate hydrochloride (323 mg, 84% yield) was obtained. Melting point 16
5-167 ° C.

Reference Example 5 [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetic acid (1.00 g), methyl 4-hydroxy-5-oxo-5-phenylpentanoate (6
87 mg), 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide; hereinafter referred to as WSC) (711 mg), 4- (N, N-dimethylamino) pyridine (75.5 mg) and N, N
After stirring a mixture of -dimethylformamide (10 ml) at room temperature for 18 hours, the reaction mixture was poured into 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 subjected to silica gel column chromatography, and 4- [4-
Methyl (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetoxy-5-oxo-5-phenylpentanoate (1.44 g, 88% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.85-2.15 (1H, m), 2.20-2.52 (6H, m),
3.68 (5H, s like), 4.98 (2H, s), 5.92-5.99 (1H, m),
6.97 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.38-
7.50 (5H, m), 7.53-7.63 (1H, m), 7.95-8.04 (4H, m). Reference Example 6 Methyl 4-amino-5-oxo-5-phenylpentanoate hydrochloride (1.60 g), triethylamine (0.86 g)
8 ml) and N, N-dimethylformamide (15 m
After stirring the mixture of 1) at room temperature for 5 minutes, [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetic acid (2.50 g) was added to the reaction mixture.
(1.42 g) and 1-hydroxy-1H-benzotriazole hydrate (hereinafter referred to as HOBt) (1.14 g).
g) was added and the mixture was stirred at the same temperature for 18 hours.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 4- [4- (5- (5-
Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetamido-5-oxo-5-phenylpentanoate (2.67 g, 82% yield) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.60-1.80 (1H, m), 2.21-2.42 (3H, m),
2.45 (3H, s), 3.58 (2H, s), 3.67 (3H, s), 5.00 (2H, s),
5.62-5.73 (1H, m), 6.47 (1H, br d, J = 7.8 Hz), 7.02
(2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.39-7.6
6 (6H, m), 7.99-8.07 (4H, m).

Reference Example 7 3-ethoxy-5- (5-methyl-2-phenyl-4-)
Ethyl oxazolylmethoxy) benzoate (5.40 g)
Lithium aluminum hydride (540 mg) was slowly added at 0 ° C. to a tetrahydrofuran (80 ml) solution of
Stir for 1 hour. Sodium sulfate decahydrate (4.60 g) was added to the reaction mixture, and the mixture was further stirred for 30 minutes. The insolubles were removed by filtration, and the filtrate was concentrated. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give 3-ethoxy-5- (5-methyl-2-phenyl-4-oxazolylmethoxy). Colorless needles of benzyl alcohol (4.44 g, 92% yield) were obtained. Melting point 103-104
° C. Reference Example 8 3-ethoxy-5- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyl alcohol (4.38
Thionyl chloride (1.69 g) was added dropwise to a solution of g) in toluene (80 ml) at room temperature. After stirring for 90 minutes, ethyl acetate (100 ml) was added to the reaction mixture, and the mixture was washed with aqueous sodium hydrogen carbonate and then with water. The organic layer is dried (MgSO
₄ ) After that, the mixture was concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the ethyl acetate-hexane (1: 4, volume ratio) eluate were recrystallized from ethyl acetate-hexane to give 4- (3-chloromethyl-5). -Ethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (4.25 g, yield 92%) was obtained as colorless prism crystals. 86-87 ° C.

Reference Example 9 4-Chloromethyl-2- (2-furyl) -5-methylo
Xazole (10.0 g), 4-hydroxyphenyl vinegar
Methyl acid salt (8.41 g), potassium carbonate (14.0 g)
And N, N-dimethylformamide (50 ml)
The mixture was stirred at 70 ° C. for 1 hour. Pour the reaction mixture into water
And extracted with ethyl acetate. The ethyl acetate layer is
Wash with water and dry (MgSO_Four) And concentrated. Residue
After subjecting to silica gel column chromatography, ethyl acetate
[4- [2
-(2-furyl) -5-methyl-4-oxazolylmetho
Methyl [xy] phenyl] acetate (9.23 g, yield 56)
%) As a colorless oil. NMR (CDCl_Three) δ: 2.41 (3H, s), 3.57 (2H, s), 3.69 (3H,
s), 4.97 (2H, s), 6.50-6.54 (1H, m), 6.93-6.99 (3H,
m), 7.20 (2H, d, J = 8.8 Hz), 7.52-7.55 (1H, m). Reference Example 10 [4- [2- (2-furyl) -5-methyl-4-oxa
Zolylmethoxy] phenyl] methyl acetate (9.15
g), lithium hydroxide hydrate (3.52 g), tetrahi
Drofuran (60 ml), water (40 ml) and methano
(20 ml) was stirred at room temperature for 2 hours.
1N hydrochloric acid (85 ml) was added to the reaction mixture, and
Extracted. The ethyl acetate layer was washed with saturated saline and dried.
Dry (MgSO _Four), And then concentrated, [4- [2- (2-free)
) -5-methyl-4-oxazolylmethoxy] phenyl
]] Acetic acid (7.88 g, yield 90%) as colorless crystals
Obtained. Recrystallized from ethyl acetate-hexane. Melting point 13
9-140 ° C.

Reference Example 11 Methyl 4-amino-5-oxo-5-phenylpentanoate hydrochloride (822 mg), triethylamine (0.44
7 ml) and N, N-dimethylformamide (10 m
After stirring the mixture of 1) at room temperature for 5 minutes, [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetic acid (1.00 g) was added to the reaction mixture.
SC (734 mg) and HOBt (586 mg) were added, and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (3: 2, volume ratio) eluted with 4- [4- [2- (2-
Methyl [furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetamido-5-oxo-5-phenylpentanoate (1.21 g, yield 73%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 108-110 ° C. Reference Example 12 [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetic acid (1.00 g), 4-
Methyl hydroxy-5-oxo-5-phenylpentanoate (709 mg), WSC (734 mg), 4- (N,
After stirring a mixture of (N-dimethylamino) pyridine (77.9 mg) and N, N-dimethylformamide (10 ml) at room temperature for 6 hours, the reaction mixture was poured into 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 subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 3, volume ratio) eluted with 4- [4
-[2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetoxy-5-oxo-5-
Methyl phenylpentanoate (1.56 g, yield%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.90-2.52 (7H, m), 3.68 (5H, s like),
4.97 (2H, s), 5.92-5.99 (1H, m), 6.50-6.54 (1H, m),
6.92-6.99 (3H, m), 7.21 (2H, d, J = 8.8 Hz), 7.40-7.62
(4H, m), 7.95-8.00 (2H, m).

Reference Example 13 3-Hydroxy-1-methyl-1H-pyrazole-4-
Ethyl carboxylate (25.50 g), benzyl bromide (1
(7.8 ml), potassium carbonate (31.10 g) and N, N-dimethylformamide (250 ml) were stirred at 50 ° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-methyl-1H-pyrazole-4-carboxylate (31.90 g, yield) was eluted with ethyl acetate-hexane (1: 1, volume ratio). Rate 82%)
Was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 66-67 ° C. Reference Example 14 3-benzyloxy-1-methyl-1H-pyrazole-
To a solution of ethyl 4-carboxylate (18.00 g) in tetrahydrofuran (200 ml) was added lithium aluminum hydride (2.62 g) at 0 ° C., followed by stirring at room temperature for 1 hour. To the reaction mixture was added sodium sulfate decahydrate (2
After adding 2.20 g), the mixture was stirred at room temperature for 1 hour. After removing the precipitate by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (3-benzyloxy-1-methyl-1) was eluted from an ethyl acetate eluate.
H-pyrazol-4-yl) methanol (23.90
g, yield 91%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.74 (1H, t, J = 5.4 Hz), 3.72 (3H, s),
4.47 (2H, d, J = 5.4 Hz), 5.24 (2H, s), 7.17 (1H, s), 7.
28-7.47 (5H, m).

Reference Example 15 A mixture of (3-benzyloxy-1-methyl-1H-pyrazol-4-yl) methanol (18.40 g), activated manganese dioxide (40.00 g) and tetrahydrofuran (200 ml) was added at room temperature to 9 Stir for hours. After removing manganese dioxide by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-methyl-1H-pyrazole-4-carbaldehyde (14.80 g, yield) was eluted with ethyl acetate-hexane (2: 1, volume ratio). 81%)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 3.78 (3H, s), 5.32 (2H, s), 7.29-7.50
(5H, m), 7.69 (1H, s), 9.76 (1H, s). Reference Example 16 A solution of p-toluenesulfonylmethyl isocyanide (2.05 g) in dimethoxyethane (10 ml) was added to a mixture of potassium t-butoxy (2.24 g) and dimethoxyethane (10 ml) at -78 ° C, and the mixture was stirred for 5 minutes. After that, a solution of 3-benzyloxy-1-methyl-1H-pyrazole-4-carbaldehyde (2.16 g) in dimethoxyethane (10 ml) was added. After stirring at the same temperature for 1 hour, the mixture was stirred for 1 hour while heating to room temperature. Methanol (380 ml) was added to the resulting mixture, and the mixture was refluxed for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride 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-benzyloxy-1-methyl-1H-pyrazol-4-ylacetonitrile (1.86 g, yield) was eluted with ethyl acetate-hexane (1: 2, volume ratio). 82
%) As a colorless oil. NMR (CDCl ₃ ) δ: 3.43 (2H, s), 3.74 (3H, s), 5.22 (2H,
s), 7.21 (1H, s), 7.29-7.47 (5H, m).

Reference Example 17 3-benzyloxy-1-methyl-1H-pyrazole-
4-ylacetonitrile (12.0 g), 4N hydroxylation
Sodium aqueous solution (100ml), tetrahydrofuran
(100ml) and ethanol (100ml)
The material was refluxed for 21 hours. After cooling, neutralize with dilute hydrochloric acid,
Extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline
Washing and drying (MgSO _Four ) And concentrated. Residue, iodine
Methyl chloride (4.95 ml), potassium carbonate (14.7)
g) and N, N-dimethylformamide (100 m
The mixture of l) was stirred at room temperature overnight. Pour the reaction solution into water
And extracted with ethyl acetate. The ethyl acetate layer is
Wash with water and dry (MgSO _Four ) And concentrated. Residue
After subjecting to silica gel column chromatography, ethyl acetate
3-benzene from the elution part of le-hexane (1: 1, volume ratio)
Luoxy-1-methyl-1H-pyrazol-4-yl vinegar
Methylate (12.2 g, 88% yield) as a yellow oil
I got it. NMR (CDCl _Three ) δ: 3.41 (2H, s), 3.68 (3H, s), 3.73 (3H,
s), 5.22 (2H, s), 7.19 (1H, s), 7.30-7.46 (5H, m). Reference Example 18 3-benzyloxy-1-methyl-1H-pyrazole-
Methyl 4-ylacetate (12.2 g), 5% palladium-
Carbon (25.0 g), tetrahydrofuran (100 m
l) and ethanol (100 ml) in a hydrogen atmosphere.
Stir for 5 hours under ambient atmosphere. By filtration, palladium-
After removing the carbon, the filtrate was concentrated to give 3-hydroxy-1
-Methyl-1H-pyrazol-4-yl acetate
(6.33 g, 79% yield) as colorless crystals. Te
Recrystallized from trahydrofuran-hexane. Melting point 11
8-119 ° C.

Reference Example 19 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine-5-carbaldehyde (13.0
To a solution of g) in tetrahydrofuran (150 ml) -methanol (10 ml), sodium borohydride (835 mg) was gradually added at 0 ° C. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine-5-methanol. Recrystallization from acetone-isopropyl ether gave colorless prisms (12.4 g, yield 95%). 121-122 ° C. Reference Example 20 In a mixture of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine-5-methanol (12.2 g) and toluene (200 ml), thionyl chloride (5.
39 g), and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) was eluted from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). Pyridine (11.7 g, yield 90%) was obtained as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms. 86-87 ° C.

Reference Example 21 5-methyl-2-phenyl-4-oxazolylmethanol (9.46 g) of N, N-dimethylformamide (5.
Sodium hydride (60%, oily, 2.40 g) was added to the solution at 0 ° C. and stirred for 15 minutes, and then a solution of methyl 2-chloro-4-pyridinecarboxylate (8.58 g) in tetrahydrofuran (50 ml) was added. Was added. After stirring at room temperature for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) was eluted with 2- (5-methyl-2-
Methyl phenyl-4-oxazolylmethoxy) -4-pyridinecarboxylate (2190 mg, yield 14%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 106-107 ° C. Reference Example 22 methyl 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridinecarboxylate (1.95)
To a solution of g) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (228 mg) at 0 ° C., followed by stirring at room temperature for 30 minutes. Sodium sulfate decahydrate (1.93 g) was added to the reaction mixture, and the mixture was added at room temperature for 30 minutes.
Stir for a minute. After removing the precipitate by filtration, the filtrate was concentrated. The obtained colorless crystals are collected by filtration and 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4
-Pyridylmethanol (1.37 g, 77% yield) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 100
〜１０101 ° C.

Reference Example 23 A mixture of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethanol (1.19 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. After concentrating the reaction mixture, saturated 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-
4-Chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (680 mg, yield 54%) was obtained as colorless crystals from a hexane (1: 3, volume ratio) eluate. . Recrystallized from ethyl acetate-hexane. 104-105 ° C. Reference Example 24 N, N-dimethylformamide of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) (7
Sodium hydride (60%, oily, 1.40 g) was added to the solution at 0 ° C. and stirred for 15 minutes, and then 4-chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added. . After stirring at 60 ° C. for 2 hours, the reaction mixture was poured into water 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 column chromatography, and tetrahydrofuran-hexane (1: 1) was used.
(1, volume ratio) Methyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolecarboxylate (7.96 g, yield 72%) was obtained as colorless crystals from the eluted part. . Recrystallized from tetrahydrofuran-hexane. 123-124 ° C.

Reference Example 25 A solution of methyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolecarboxylate (7.86 g) in tetrahydrofuran (150 ml) was added with diisobutylaluminum hydride (150 ml). (1.0 M tetrahydrofuran solution, 60 ml) was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), concentrated, and concentrated.
(5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolylmethanol (5.93 g,
(86% yield) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 99-100 [deg.] C. Reference Example 26 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolylmethanol (2.86
Thionyl chloride (0.80 ml) was slowly added to a solution of g) in toluene (50 ml) at room temperature, followed by stirring under reflux for 30 minutes. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer
After washing with saturated saline, drying (MgSO ₄ ), and concentrating,
-Chloromethyl-3- (5-methyl-2-phenyl-4
-Oxazolylmethoxy) isoxazole (2.70
g, 89% yield) as colorless crystals. Ethyl acetate-
Recrystallized from hexane. 105-106 ° C.

Reference Example 27 Methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N, N-dimethylformamide ( After stirring the mixture at 60 ° C. for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- (2-quinolylmethoxy)-
Methyl 5-isoxazolecarboxylate (7.78 g,
(78% yield) as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 133-134 ° C. Reference Example 28 Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) was added to a solution of methyl 3- (2-quinolylmethoxy) -5-isoxazolecarboxylate (7.39 g) in tetrahydrofuran (150 ml).
After slowly adding at 0 ° C, the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Then, the mixture was concentrated to give 3- (2-quinolylmethoxy) -5-isoxazolylmethanol (4.95 g, yield 74%) as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 111-112 ° C.

Reference Example 29 3- (2-quinolylmethoxy) -5-isoxazolylmethanol (1.54 g) and thionyl chloride (5 m
The mixture of 1) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution 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, and concentrated to 2- (5-chloromethyl-3-isoxazolyloxymethyl) quinoline (1.
61 g, yield 98%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 126-127 ° C. Reference Example 30 2-phenyl-4-thiazolyl methanol (6.69
g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N, N-dimethylformamide (10 g).
Sodium hydride (60%, oily, 1.40 g) was added to the solution at 0 ° C. and stirred for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. Lithium aluminum hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0 ° C.
And then stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After removing the precipitate by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography.
-(2-Phenyl-4-thiazolylmethoxy) -5-pyridylmethanol (5.81 g, yield 56%) was obtained as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 134-135 ° C.

Reference Example 31 2- (2-phenyl-4-thiazolylmethoxy) -5
A mixture of pyridylmethanol (2.98 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue.
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2- (2-phenyl-4-
Thiazolylmethoxy) pyridine (2.40 g, yield 76)
%) As colorless crystals. Recrystallized from tetrahydrofuran-hexane. 117-118 ° C. Reference Example 32 To a mixture of 6- (5-methyl-2-phenyl-4-thiazolylmethoxy) nicotinaldehyde (4.20 g), tetrahydrofuran (50 ml) and ethanol (50 ml) was added sodium borohydride (0.51 g). ) Was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated.
-Colorless crystals of-(5-methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethanol were obtained (4.
10 g, 97% yield). Recrystallized from ethyl acetate-hexane. 70-71 ° C.

Reference Example 33 A mixture of 6- (5-methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethanol (1.56 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. After concentration under reduced pressure, ice water was added to the residue, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated.
The residue was subjected to silica gel column chromatography,
From the ethyl acetate-hexane (1: 2, volume ratio) elution part,
5-chloromethyl-2- (5-methyl-2-phenyl-
4-Thiazolylmethoxy) pyridine (1.53 g, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 78-79 [deg.] C. Reference Example 34 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] nicotinaldehyde (3.10 g), tetrahydrofuran (50 ml) and ethanol (50 m2)
l) in a mixture of sodium borohydride (0.41
g) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-pyridylmethanol. Was obtained (2.86 g, yield 92%). Recrystallized from ethyl acetate-hexane. 120-121 ° C.

Reference Example 35 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-pyridylmethanol (1.87 g)
And a mixture of thionyl chloride (15 ml) was stirred at room temperature for 1 hour. After concentration under reduced pressure, ice water was added to the residue, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2- [2- (2-furyl) -5 was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
-Methyl-4-oxazolylmethoxy] pyridine (1.
41 g, yield 71%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 95-96 ° C. Reference Example 36 A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11.53 g), benzyl bromide (18 ml), potassium carbonate (21.12 g) and N, N-dimethylformamide (300 ml) was mixed with 80 Stir at 5 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) eluted with 1-benzyl-3.
Ethyl-benzyloxy-1H-pyrazole-4-carboxylate (13.52 g, yield 95%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 71
~ 72 ° C.

Reference Example 37 To a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58.90 g) in tetrahydrofuran (500 ml) was added lithium aluminum hydride (6.64 g) at 0 ° C. After the addition, the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-3-) was eluted from the ethyl acetate elution part.
Benzyloxy-1H-pyrazol-4-yl) methanol (45.30 g, yield 88%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 79-
80 ° C. Reference Example 38 A mixture of (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl) methanol (14.70 g), activated manganese dioxide (30.00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 2 hours. . After removing manganese dioxide by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to obtain 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (13.10 g, yield 90%). Recrystallized from tetrahydrofuran-hexane. 85-86 ° C.

Reference Example 39 To a mixture of potassium t-butoxy (11.2 g) and dimethoxyethane (50 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (10.3 g) in dimethoxyethane (50 ml) at -78 ° C. After stirring for 5 minutes, a solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml) was added. 1 at the same temperature
After stirring for an hour, the mixture was stirred for 1 hour while heating to room temperature. Methanol (150 ml) was added to the resulting mixture, and the mixture was refluxed for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride 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 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetonitrile (13.1 g, yield) was eluted with ethyl acetate-hexane (1: 3, volume ratio). 8
6%) as a colorless oil. NMR (CDCl ₃ ) δ: 3.42 (2H, s), 5.11 (2H, s), 5.24 (2H,
s), 7.18-7.24 (3H, m), 7.27-7.47 (8H, m). Reference Example 40 A mixture of 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetonitrile (13.0 g), 4N aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol (100 ml) was added for 3 days. Refluxed. After cooling, neutralize with dilute hydrochloric acid,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue, ethyl iodide (5.2 ml), potassium carbonate (11.9 g)
And a mixture of N, N-dimethylformamide (100 ml) was stirred at room temperature for 3 hours. Pour the reaction into water,
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-
1-benzyl-from the hexane (1: 2, volume ratio) elution part
Ethyl 3-benzyloxy-1H-pyrazol-4-ylacetate (14.9 g, yield 99%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.2 Hz), 3.39 (2H, s),
4.12 (2H, q, J = 7.2 Hz), 5.12 (2H, s), 5.24 (2H, s), 7.
17-7.26 (3H, m), 7.28-7.49 (8H, m).

Reference Example 41 Ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetate (14.9 g), 5% palladium-carbon (15.0 g), tetrahydrofuran (150 m
A mixture of 1) and ethanol (150 ml) was stirred under a hydrogen atmosphere for 2 hours. By filtration, palladium-
After removing carbon, the filtrate was concentrated to give 1-benzyl-3-.
Ethyl hydroxy-1H-pyrazol-4-ylacetate (9.76 g, yield 88%) was obtained as colorless crystals. Recrystallized from tetrahydrofuran-hexane. Melting point 15
6-157 ° C. Reference Example 42 3-hydroxy-1-phenyl-1H-pyrazole-4
-A mixture of ethyl carboxylate (7.76 g), benzyl bromide (3.97 ml), potassium carbonate (6.91 g) and N, N-dimethylformamide (75 ml) was stirred at 50 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is diluted hydrochloric acid, followed by
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The residue was subjected to silica gel column chromatography,
Ethyl acetate-hexane (1: 1, volume ratio)
-Benzyloxy-1-phenyl-1H-pyrazole-
Ethyl 4-carboxylate (8.29 g, yield 77%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 113-114 ° C.

Reference Example 43 Lithium aluminum hydride (0.95 g) was added to a solution of ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.06 g) in tetrahydrofuran (100 ml) at 0 ° C. After the addition, the mixture was stirred at room temperature for 1 hour. After sodium sulfate decahydrate (8.06 g) was added to the reaction mixture, the mixture was stirred at room temperature for 1 hour.
After removing the precipitate by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl) methanol (5.91) was eluted with ethyl acetate.
g, yield 84%) as colorless crystals. Ethyl acetate-
Recrystallized from hexane. 93-94 ° C. Reference Example 44 To a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), ethyl diethylphosphonoacetate (9.60 ml) and N, N-dimethylformamide (200 ml), At 0 ° C. add sodium hydride (60%, oily, 1.94 g)
Stir at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is diluted hydrochloric acid, followed by
The extract was washed with saturated saline, dried (MgSO ₄ ), and concentrated.
The obtained crystals were collected by filtration, and (E) -3- (1-benzyl-
Ethyl 3-benzyloxy-1H-pyrazol-4-yl) propenoate (14.50 g, 91% yield) was obtained.
Recrystallized from ethyl acetate-hexane. Melting point 88-89
° C.

Reference Example 45 (E) -3- (1-Benzyl-3-benzyloxy-1)
Ethyl H-pyrazol-4-yl) propenoate (14.
30 g), 5% palladium-carbon (28.00 g), ethanol (150 ml) and tetrahydrofuran (1
(50 ml) was stirred under a hydrogen atmosphere at room temperature for 3 hours. After removing the palladium-carbon by filtration,
The filtrate was concentrated. The obtained crystals were collected by filtration to give ethyl 3- (1-benzyl-3-hydroxy-1H-pyrazol-4-yl) propionate (9.01 g, yield 83%). Recrystallized from ethyl acetate-hexane. Melting point 75
~ 76 ° C. Reference Example 46 A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl) methanol (5.61 g), activated manganese dioxide (15.00 g) and tetrahydrofuran (75 ml) was stirred at room temperature overnight. After removing manganese dioxide by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) eluted with 3-
Benzyloxy-1-phenyl-1H-pyrazole-4
-Carboxaldehyde (5.03 g, yield 90%) was obtained as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 153-154 ° C.

Reference Example 47 To a mixture of potassium t-butoxy (3.82 g) and dimethoxyethane (20 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (3.51 g) in dimethoxyethane (20 ml) at -78 ° C. After stirring for 5 minutes, a solution of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (4.73 g) in dimethoxyethane (80 ml) was added. 1 at the same temperature
After stirring for an hour, the mixture was stirred for 1 hour while heating to room temperature. To the resulting mixture was added methanol (100 ml) and the mixture was refluxed for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride 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-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetonitrile (3.31 g, yield) was eluted with ethyl acetate-hexane (1: 3, volume ratio). 6
7%) as colorless crystals. Recrystallized from tetrahydrofuran-hexane. 102-103 ° C. Reference Example 48 A mixture of 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetonitrile (3.01 g), a 6N aqueous sodium hydroxide solution (25 ml), tetrahydrofuran (25 ml) and ethanol (25 ml) was added for 3 days. Refluxed. After cooling, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline,
After drying (MgSO ₄ ), the mixture was concentrated to give 3-benzyloxy-
1-phenyl-1H-pyrazol-4-ylacetic acid (2.
(63 g, yield 82%) as colorless crystals. Recrystallized from acetone-hexane. 105-106 ° C.

Reference Example 49 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetic acid (2.47 g), methyl iodide (0.7%)
5 ml), potassium carbonate (2.21 g) and N, N-
A mixture of dimethylformamide (25 ml) was added at room temperature for 1 hour.
Stir for hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (Mg
After SO ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
(3, volume ratio).
(5 g, yield 99%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 74-75 ° C. Reference Example 50 Methyl 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetate (2.35 g), 5% palladium-carbon (4.00 g), tetrahydrofuran (25 m
A mixture of 1) and methanol (25 ml) was stirred under a hydrogen atmosphere for 1 hour. After removing palladium-carbon by filtration, the filtrate was concentrated to give 3-hydroxy-1-
Methyl phenyl-1H-pyrazol-4-ylacetate (1.58 g, 93% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 144-14
5 ° C.

Reference Example 51 (5-Methyl-2-phenyl-4-thiazolyl) methanol (5.00 g), 6-chloro-3-cyanopyridine (3.38 g) and N, N-dimethylformamide (100 ml) Add sodium hydride (60%,
Oily, 1.07 g) was added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 2, volume ratio). 6- (5-
Colorless crystals of methyl-5-phenyl-4-thiazolylmethoxy) nicotinonitrile were obtained (5.55 g, yield 74).
%). Recrystallized from ethyl acetate-hexane. Melting point 12
4-125 ° C. Reference Example 52 A mixture of 6- (5-methyl-5-phenyl-4-thiazolylmethoxy) nicotinonitrile (5.45 g) and anhydrous toluene (150 ml) was mixed with a hexane solution of diisobutylaluminum hydride (0.95 M, 41.0 ml)
Was added dropwise at -78 ° C. The reaction mixture was brought to room temperature over 1.5 hours with stirring. A saturated aqueous ammonium chloride solution (100 ml) was added dropwise to the mixture, and the mixture was further added at room temperature.
Stir for 0 minutes. Ethyl acetate was added to this mixture, and the mixture was stirred at room temperature for 30 minutes, and then the insoluble matter was removed by filtration. The filtrate was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated, and the obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 4, volume ratio). 6- (5-methyl-2-phenyl-4
Colorless crystals of (-thiazolylmethoxy) nicotinaldehyde were obtained (4.30 g, 78% yield). Recrystallized from ethyl acetate-hexane. 120-121 ° C.

Reference Example 53 [2- (2-furyl) -5-methyl-4-oxazolyl] methanol (5.18 g), 6-chloro-3-cyanopyridine (4.00 g) and N, N-dimethylformamide (100 ml) in a mixture of sodium hydride (60%,
(Oily, 1.27 g) was added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated, and the residue obtained was subjected to silica gel column chromatography,
From the ethyl acetate-hexane (1: 2, volume ratio) elution part,
Colorless crystals of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] nicotinonitrile were obtained (6.
97 g, 86% yield). Recrystallized from ethyl acetate-hexane. 105-106 ° C. Reference Example 54 A hexane solution of diisobutylaluminum hydride was added to a mixture of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] nicotinonitrile (6.77 g) and anhydrous toluene (150 ml) ( 0.95M, 55.8
ml) was added dropwise at -78 ° C. The reaction mixture was brought to room temperature over 1 hour with stirring. A saturated aqueous ammonium chloride solution (100 ml) was added dropwise to the mixture, and the mixture was further added at room temperature.
Stir for 0 minutes. Ethyl acetate was added to the mixture, and the mixture was stirred at room temperature for 30 minutes, and then the insoluble matter was removed by filtration. The filtrate was washed with saturated saline and dried over anhydrous magnesium sulfate.
The residue obtained by concentration was subjected to silica gel column chromatography, and 6- [2- (2-furyl) -5-methyl-4-ethyl-4-ethyl-4-hexane (1: 2, volume ratio) was eluted. Colorless crystals of [oxazolylmethoxy] nicotinaldehyde were obtained (3.25 g, 47% yield). Recrystallized from ethyl acetate-hexane. 139-140 ° C.

Reference Example 55 Phenyl chlorocarbonate (2.80 ml) was added to a mixture of methyl 4-hydroxy-5-oxo-5-phenylpentanoate (4.50 g), pyridine (1.80 ml) and tetrahydrofuran (30 ml). After slowly adding at 0 ° C., the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was dissolved in acetic acid (30 ml), and the mixture was refluxed for 3 hours after adding ammonium acetate (7.79 g). After concentrating the reaction mixture, the obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and subsequently with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 3- (2-oxo-4-phenyloxazoline-5) was eluted from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio).
Colorless crystals of methyl (-yl) propionate were obtained (3.5).
7 g, 71% yield). Recrystallized from ethyl acetate-hexane. 104-105 ° C. Reference Example 56 Methyl 3- (2-oxo-4-phenyloxazolin-5-yl) propionate (3.00 g), pyridine (0.98 ml) and phosphorus oxychloride (7.62 g)
Was stirred at 105 ° C. for 2 hours. The reaction mixture was slowly poured into ice water and extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl acetate-
From a hexane (1: 7, volume ratio) eluate, methyl 3- (2-chloro-4-phenyl-5-oxazolyl) propionate (2.40 g, yield 75%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.74 (2H, t, J = 7.6 Hz), 3.23 (2H, t, J
= 7.6 Hz), 3.69 (3H, s), 7.30-7.65 (5H, m).

Reference Example 57 3- (2-chloro-4-phenyl-5-oxazolyl)
Methyl propionate (500 mg), 4-hydroxythiophenol (475 mg), potassium carbonate (520 m
g) and N, N-dimethylformamide (10 ml)
Was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with dilute hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate.
Concentrate and concentrate 3- [2- (4-hydroxyphenylthio)-
Colorless crystals of methyl 4-phenyl-5-oxazolyl] propionate were obtained (637 mg, yield 95%). It was recrystallized from toluene-hexane. 157-158 ° C. Reference Example 58 A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (15.0 g), thiourea (3.81 g) and methanol (200 ml) was refluxed for 2 hours. After removing the reaction solvent under reduced pressure, the residue was dissolved in ethyl acetate. The resulting solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to give 3- (2
Light yellow crystals of methyl -amino-4-phenyl-5-thiazolyl) propionate (11.9 g, yield 90%) were obtained. Recrystallized from ethyl acetate-hexane. Melting point 130
~ 131 ° C.

Reference Example 59 Methyl 3- (2-amino-4-phenyl-5-thiazolyl) propionate (2.00 g), copper (II) chloride (1.
To a mixture of 54 g) and tetrahydrofuran (10 ml), t-butyl nitrite (1.51 ml) was slowly added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and methyl 3- (2-chloro-4-phenyl-5-thiazolyl) propionate (740 mg) was eluted from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). , Yield 34%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.65 (2H, t, J = 7.4 Hz), 3.23 (2H, t, J
= 7.4 Hz), 3.69 (3H, s), 7.30-7.58 (5H, m). Reference Example 60 Methyl 3- (2-chloro-4-phenyl-5-thiazolyl) propionate (380 mg), 4-hydroxythiophenol (341 mg), potassium carbonate (373 m)
A mixture of g) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, concentrated, and concentrated to give 3- [2- (4-hydroxyphenylthio) -4.
-Phenyl-5-thiazolyl] methyl propionate (4
64 mg, yield 93%) as colorless crystals. It was recrystallized from toluene-hexane. 153-155 ° C.

Reference Example 61 Methyl 4-bromo-5-oxo-5-phenylpentanoate (5.00 g), N-propylthiourea (2.01 g)
A mixture of g) and methanol (50 ml) was refluxed for 2 hours. After removing the reaction solvent under reduced pressure, the residue was dissolved in ethyl acetate. The resulting solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated, and then concentrated to give 3- [4-phenyl-2- [N- (1-propyl)].
Amino] -5-thiazolyl] propionate methyl (3.
(64 g, yield 70%) as colorless crystals. Ethyl acetate-
Recrystallized from hexane. Mp 67-68 ° C. Reference Example 62 Ethyl (2-amino-4-thiazolyl) acetate (5.00
g), a mixture of copper (II) chloride (5.41 g) and tetrahydrofuran (80 ml) was slowly added with t-butyl nitrite (5.32 ml) at 0 ° C, followed by stirring at the same temperature for 3 hours. . Pour the reaction mixture into water,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 8, volume ratio) eluted,
Ethyl (2-chloro-4-thiazolyl) acetate (880 m
g, yield 16%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 3.77 (2H, s),
4.20 (2H, q, J = 7.1 Hz), 7.13 (1H, s).

Reference Example 63 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.00 g), ethyl diethylphosphonoacetate (2.67 g) and N, N-dimethylformamide (50 ml) Sodium hydride (60%, oily, 0.52 g) was added to the mixture at 0 ° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The obtained crystals were collected by filtration to give ethyl (E) -3- (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl) propenoate (3.18 g, yield 85%). Recrystallized from ethyl acetate-hexane. Melting point 105-106
° C. Reference Example 64 (E) -3- (3-benzyloxy-1-phenyl-1)
Ethyl H-pyrazol-4-yl) propenoate (2.7
0g), a mixture of 5% palladium-carbon (3.00 g) and tetrahydrofuran (100 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hours. After removing palladium-carbon by filtration, the filtrate was concentrated. The resulting crystals were collected by filtration and 3- (3-benzyloxy-1-phenyl-1).
Ethyl H-pyrazol-4-yl) propionate (1.
78 g, 89% yield). Recrystallized from ethyl acetate-hexane. 123-124 ° C.

Reference Example 65 4-methoxymethoxymethyl-2-phenyloxazole-5-carbaldehyde (3.00 g), 4-benzyloxybenzyltriphenylphosphonium chloride (6.
58g), potassium carbonate (1.84g) and N, N-
A mixture of dimethylformamide (50 ml) was added at room temperature for 1 hour.
Stir for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). A mixture of the obtained colorless oil, 5% palladium-carbon (5.00 g) and tetrahydrofuran (200 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hours. After removing palladium-carbon by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration, and 5- [2
-(4-hydroxyphenyl) ethyl] -4-methoxymethoxymethyl-2-phenyloxazole (3.24
g, yield 79%). Recrystallized from ethyl acetate-hexane. 102-103 ° C. Reference Example 66 5- [2- (4-hydroxyphenyl) ethyl] -4-
Methoxymethoxymethyl-2-phenyloxazole (3.12 g), 4-chloromethyl-5-methyl-2-
A mixture of phenyloxazole (2.28 g), potassium carbonate (1.27 g) and N, N-dimethylformamide (50 ml) was stirred at 90 ° C. for 15 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 5- [2- [4-] was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio).
(5-Methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl] -4-methoxymethoxymethyl-2-phenyloxazole (4.70 g, yield 85)
%) As colorless crystals. Recrystallized from ethyl acetate-hexane. 124-125 ° C.

Reference Example 67 5- [2- [4- (5-methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl] -4-methoxymethoxymethyl-2-phenyloxazole (3.8
0 g), a mixture of 10% sulfuric acid (10 ml) and tetrahydrofuran (100 ml) was refluxed for 2 hours, and then concentrated. Pour ethyl acetate into the residue and wash with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2, volume ratio) eluted,
[5- [2- [4- (5-methyl-2-phenyl-4-
Oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] methanol (2.03 g, 59% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 142-143 ° C. Reference Example 68 [5- [2- [4- (5-methyl-2-phenyl-4-)
A mixture of oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] methanol (1.00 g) and thionyl chloride (2 ml) was stirred at 0 ° C for 1 hour, and then concentrated. Ethyl acetate was poured into the residue, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue, sodium cyanide (210 mg) and dimethylsulfoxide (2
(0 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2, volume ratio) was eluted with [5- [2- [4-
(5-Methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] acetonitrile (560 g, yield 56%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 97-98 ° C.

Reference Example 69 [5- [2- [4- (5-methyl-2-phenyl-4-)
A mixture of oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] methanol (0.78 g) and thionyl chloride (2 ml) was stirred at 0 ° C for 30 minutes, and then concentrated. Pour ethyl acetate into the residue,
The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. To a solution of the obtained residue in tetrahydrofuran (10 ml) was added diethyl malonate (1.
36 g), sodium hydride (60%, oily, 0.33
g) and tetrahydrofuran (30 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 15 hours and then refluxed for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl acetate-
From the hexane (1: 6, volume ratio) eluate, 2-ethoxycarbonyl-3- [5- [2- [4- (5-methyl-2
-Phenyl-4-oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] propionate (550 g, yield 53%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7.0 Hz), 2.43 (3H, s),
2.86-2.99 (6H, m), 3.82 (1H, t, J = 7.6 Hz), 4.18 (2H,
q, J = 7.0 Hz), 4.97 (2H, s), 6.92-6.97 (2H, m), 7.11-
7.15 (2H, m), 7.40-7.45 (6H, m), 7.93-8.05 (4H, m). Reference Example 70 Methyl 4-bromo-5-oxo-5-phenylpentanoate (2.00 g), N-methylthiourea (640 m
g), a mixture of sodium acetate (640 mg) and ethanol (15 ml) was heated at reflux for 30 minutes. The reaction mixture was poured into water and the precipitated methyl 3- [2- [N- (1-methyl) amino] -4-phenyl-5-thiazolyl] propionate (1.50 g, yield 77%) was obtained as colorless crystals. I filtered it. Recrystallized from ethyl acetate-isopropyl ether. 90-91 ° C.

Reference Example 71 Monoethyl succinate (22.0 g) and triethylamine (16.8 g) in tetrahydrofuran (150 g)
ml) solution, ethyl chloroformate (18.0 g) was added to -2.
It was added dropwise at 0 ° C. After stirring for 30 minutes, crushed thiosemicarbazide (13.7 g) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and extracted with chloroform. The aqueous layer was separated, sodium chloride 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 dichloromethane-ethanol to give colorless prisms (8.23 g, 25%) of ethyl 4- [2- (aminocarbothioyl) hydrazino] -4-oxobutanoate. Melting point 143-144
° C. Reference Example 72 4- [2- (aminocarbothioyl) hydrazino] -4
-Colorless prisms of ethyl oxobutanoate (8.00
g), a mixture of 28% sodium methoxide-methanol solution (1.40 g) and ethanol (30 ml) was heated under reflux for 8 hours. The reaction mixture was poured into ice water and acidified with 2N hydrochloric acid to precipitate 3- (5-mercapto-1).
Crystals of ethyl H-1,2,4-triazol-3-yl) propionate (4.27 g, 58%) were obtained. Recrystallization from ethanol-water gave colorless prisms. Melting point 1
78-179 ° C.

Reference Example 73 A solution of ethyl 3,5-dihydroxybenzoate (15.0 g) in N, N-dimethylformamide (180 ml) was added.
Sodium hydride (oily, 60%, 3.30 g) at 0 ° C
And stirred for 30 minutes. Iodoethane (1
After adding 2.9 g), the mixture was further stirred for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgS
After O ₄ ), the mixture was concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-hydroxybenzoate (6.75 g, yield 39%) was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). Was obtained. Recrystallization from diethyl ether-hexane gave colorless needles. 62-63 ° C. Reference Example 74 Ethyl 3-ethoxy-5-hydroxybenzoate (3.0
0g), 4-chloromethyl-5-methyl-2-phenyloxazole (3.26g), potassium carbonate (2.17g).
g) and N, N-dimethylformamide (60 ml)
Was stirred at 80 ° C. for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and concentrated. The obtained residue was subjected to silica gel column chromatography, and 3-ethoxy-5- (5-methyl-2) was eluted from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
Ethyl-phenyl-4-oxazolylmethoxy) benzoate (5.40 g, 99%) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7 Hz), 1.41 (3H, t, J = 7
Hz), 2.46 (3H, s), 4.05 (2H, q, J = 7 Hz), 4.36 (2H,
q, J = 7 Hz), 5.01 (2H, s), 6.77 (1H, t, J = 2 Hz), 7.22
(1H, dd, J = 2, 1 Hz), 7.30 (1H, dd, J = 2, 1 Hz), 7.4-
7.5 (3H, m), 7.95-8.05 (2H, m).

Reference Example 75 3-Hydroxy-1-phenyl-1H-pyrazole-5
-Methyl carboxylate (5.60 g), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-
A mixture of (furyl) -5-methyloxazole (9.45 g), potassium carbonate (3.55 g) and N, N-dimethylformamide (200 ml) was stirred at 90 ° C. for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The obtained colorless crystals were collected by filtration,
[4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1
Methyl -phenyl-1H-pyrazole-5-carboxylate (12.40 g, 94% yield) was obtained. Recrystallized from ethyl acetate-hexane. 146-147 ° C. Reference Example 76 3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy]
Methyl -1-phenyl-1H-pyrazole-5-carboxylate (12.10 g) in tetrahydrofuran (300 m
l) Add lithium aluminum hydride (89
(0 mg), and the mixture was stirred at room temperature for 1 hour. After sodium sulfate decahydrate (7.57 g) was added to the reaction mixture, the mixture was stirred at room temperature for 1 hour. After removing the precipitate by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration, and [3- [4- [2- (2-furyl) -5-methyl-
4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-5-yl]
Methanol (11.19 g, 98% yield) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 106-107
° C.

Reference Example 77 [3- [4- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-5-yl] methanol (9.50 g), active manganese dioxide (30.
00g) and tetrahydrofuran (300 ml) were stirred at room temperature for 15 hours. After removing manganese dioxide by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3- [4- [2-] was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
(2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-
1H-pyrazole-5-carbaldehyde (7.27
g, yield 77%) as colorless crystals. Ethyl acetate-
Recrystallized from hexane. 103-104 ° C. Reference Example 78 A solution of p-toluenesulfonylmethyl isocyanide (1.33 g) in dimethoxyethane (50 ml) was added to a mixture of potassium t-butoxy (1.46 g) and dimethoxyethane (50 ml) at -78 ° C, and the mixture was stirred for 5 minutes. After that, 3- [4- [2- (2-furyl) -5-methyl-4
-Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazole-5-carbaldehyde (3.00 g) in dimethoxyethane (50 ml)
The solution was added. The resulting mixture was stirred at the same temperature for 1 hour, and then stirred for 1 hour while warming to room temperature. To the resulting mixture was added methanol (50 ml),
Refluxed for 2 hours. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride 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- [4- [2- (2-furyl) -5-methyl-4] was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
[Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-5-yl] acetonitrile (450 mg, 15% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 141-142 ° C.

Reference Example 79 3-Hydroxy-1-phenyl-1H-pyrazole-5
Carboxylic acid (29.55 g), benzyl bromide (35 m
l), a mixture of potassium carbonate (40.99 g) and N, N-dimethylformamide (300 ml) was stirred at 90 ° C overnight. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 2, volume ratio).
Benzyl 1-phenyl-1H-pyrazole-5-carboxylate (51.33 g, 92% yield) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 5.20 (2H, s), 5.27 (2H, s), 6.49
(1H, s), 7.18-7.47 (15H, m). Reference Example 80 A mixture of benzyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (50.88 g), a 1N aqueous sodium hydroxide solution (200 ml), tetrahydrofuran (200 ml) and ethanol (200 ml) was heated at room temperature. After refluxing for 5 hours in 1N hydrochloric acid (200
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 3-benzyloxy-
1-phenyl-1H-pyrazole-5-carboxylic acid (3
(6.91 g, yield 95%). Recrystallized from acetone-isopropyl ether. 163-164 ° C.

Reference Example 81 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylic acid (33.00 g), methane iodide (8.5 ml), potassium carbonate (18.88 g) and N, N- A mixture of dimethylformamide (300 ml) was stirred at room temperature overnight. Pour the reaction mixture into dilute hydrochloric acid,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
Methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (33.48 g, yield 97%) was obtained as colorless crystals from a hexane (1: 4, volume ratio) eluate. Recrystallized from ethyl acetate-hexane. Melting point 5
3-54 ° C. Reference Example 82 Lithium aluminum hydride (1.79 g) was slowly added to a mixture of methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (14.53 g) and tetrahydrofuran (300 ml) at 0 ° C. After the addition, the mixture was stirred at room temperature for 1 hour. After sodium sulfate decahydrate (15.20 g) was slowly added to the reaction mixture at 0 ° C., the mixture was stirred at room temperature for 30 minutes. After removing insolubles by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl) methanol (11.65 g) was eluted from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). , Yield 88%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 8
7-88 ° C.

Reference Example 83 A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl) methanol (11.20 g), activated manganese dioxide (30.00 g) and tetrahydrofuran (300 ml) was added at room temperature. Stirred all night. After removing insolubles by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography.
Carboxaldehyde (10.10 g, 91% yield) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 5.31 (2H, s), 6.51 (1H, s), 7.32-
7.52 (10H, m), 9.78 (1H, s). Reference Example 84 To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carbaldehyde (6.24 g), ethyl diethylphosphonoacetate (5.55 g) and N, N-dimethylformamide (50 ml), Sodium hydride (60%, oily, 960 mg) was added at 0 ° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and (E)-
Ethyl 3- (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl) propenoate (7.33 g, yield 94%) was obtained as a pale yellow oil.

Reference Example 85 (E) -3- (3-Benzyloxy-1-phenyl-1
Ethyl H-pyrazol-5-yl) propenoate (7.3
3g), a mixture of 5% palladium-carbon (7.11 g) and tetrahydrofuran (50 ml) was stirred at room temperature under a hydrogen atmosphere overnight. After removing palladium-carbon by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- (3-hydroxy-1-phenyl-1H-pyrazol-5-yl) propionate (ethyl acetate-hexane (1: 2, volume ratio)) was eluted. (4.85 g, yield 89%) as colorless crystals. Recrystallized from acetone-hexane. 150-151 ° C.

Example 1 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetoxy-5-oxo-5
A mixture of methyl-phenylpentanoate (1.34 g), ammonium acetate (685 mg) and acetic acid (5 ml) was refluxed for 3 hours. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [2- [4- (5-methyl-2-phenyl-4-)-4-ethyl acetate-hexane (2: 5, volume ratio) eluted.
Oxazolylmethoxy) benzyl] -4-phenyl-5
Methyl [-oxazolyl] propionate (1.07 g, yield 83%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.64-2.73 (2H, m), 3.14-
3.22 (2H, m), 3.64 (3H, s), 4.06 (2H, s), 4.98 (2H, s),
6.98 (2H, d, J = 8.8 Hz), 7.22-7.47 (8H, m), 7.59-7.6
6 (2H, m), 7.98-8.04 (2H, m). Example 2 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4-phenyl-5-
Oxazolyl] propionate methyl (1.00 g), lithium hydroxide hydrate (171 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 m
The mixture of 1) was stirred at room temperature for 1 hour. 1N hydrochloric acid (5.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
O ₄ ), and then concentrated to give 3- [2- [4- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) benzyl]-
4-phenyl-5-oxazolyl] propionic acid (91
(8 mg, yield 94%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 142-143 ° C.

Example 3 4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetamido-5-oxo-
A mixture of methyl 5-phenylpentanoate (600 mg), ammonium acetate (307 mg) and acetic acid (5 ml) was refluxed for 4 hours. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [2- [4- (5-methyl-2-phenyl-4) was eluted from a fraction eluted with ethyl acetate-hexane (3: 1, volume ratio).
-Oxazolylmethoxy) benzyl] -4-phenyl-
Methyl [1H-imidazol-5-yl] propionate (358 mg, yield 62%) was obtained as colorless crystals. Recrystallized from acetone-hexane. 128-129
° C. Example 4 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4-phenyl-1H
-Imidazol-5-yl] methyl propionate (25
0 mg), a mixture of lithium hydroxide hydrate (62.0 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hour.
1N hydrochloric acid (1.5 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 to give 3- [2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Benzyl] -4-phenyl-1H-imidazole-5
[Il] propionic acid (132 mg, yield 54%) was obtained as colorless crystals. Recrystallized from acetone. Melting point 193
~ 196 ° C.

Example 5 4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetamido-5-oxo-
A mixture of methyl 5-phenylpentanoate (750 mg), phosphorus oxychloride (437 mg) and toluene (7 ml) was refluxed for 1.5 hours. After cooling, a cold saturated aqueous sodium hydrogen carbonate solution 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 3- [2- [4- (5-methyl-2-phenyl-4-)-4-ethyl acetate-hexane (2: 3, volume ratio) was eluted.
Oxazolylmethoxy) benzyl] -5-phenyl-4
Methyl [-oxazolyl] propionate (192 mg, 27% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.73-2.82 (2H, m), 3.02-
3.11 (2H, m), 3.65 (3H, s), 4.06 (2H, s), 4.97 (2H, s),
6.98 (2H, d, J = 8.4 Hz), 7.22-7.47 (8H, m), 7.52-7.5
9 (2H, m), 7.98-8.04 (2H, m). Example 6 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -5-phenyl-4-
Oxazolyl] methyl propionate (192 mg), lithium hydroxide hydrate (47.6 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 m
The mixture of 1) was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (1.2 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
gSO ₄ ), and then concentrated to give 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -5-phenyl-4-oxazolyl] propionic acid (158 mg, yield). 85%) as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 136-13
7 ° C.

Example 7 4- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] acetamido-5-oxo-
A mixture of methyl 5-phenylpentanoate (600 mg), Lawesson's reagent (530 mg) and toluene (5 ml) was refluxed for 1 hour. After cooling, the mixture was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
(Volume ratio) 3- [2- [4- (5-methyl-2)
-Phenyl-4-oxazolylmethoxy) benzyl]-
Methyl 5-phenyl-4-thiazolyl] propionate (562 mg, 94% yield) was obtained as a pale brown oil. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.74-2.83 (2H, m), 3.04-
3.12 (2H, m), 3.64 (3H, s), 4.23 (2H, s), 4.99 (2H, s),
7.00 (2H, d, J = 8.8 Hz), 7.25-7.47 (10H, m), 7.98-8.0
4 (2H, m). Example 8 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -5-phenyl-4-
Thiazolyl] methyl propionate (487 mg), lithium hydroxide hydrate (117 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml)
Was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (2.8 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
O ₄ ), and then concentrated to give 3- [2- [4- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) benzyl]-
5-phenyl-4-thiazolyl] propionic acid (434
mg, yield 92%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 119-120 ° C.

Example 9 Methyl 3- [2- (4-hydroxyphenylthio) -4-phenyl-5-oxazolyl] propionate (450
mg), 4-chloromethyl-5-methyl-2-phenyloxazole (263 mg), potassium carbonate (351 m
A mixture of g) and N, N-dimethylformamide (5 ml) was stirred at 50 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 4, volume ratio) eluted with 3- [2
Methyl-[4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-phenyl-5-oxazolyl] propionate (609 mg, yield 91)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.65 (2H, t, J = 7.7 Hz),
3.17 (2H, t, J = 7.7 Hz), 3.64 (3H, s), 5.01 (2H, s), 7.
05 (2H, d, J = 8.8 Hz), 7.28-7.48 (6H, m), 7.53-7.65 (4
H, m), 7.98-8.05 (2H, m). Example 10 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-phenyl-
[5-oxazolyl] methyl propionate (250 m
g), a mixture of lithium hydroxide hydrate (61.4 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours. 1N hydrochloric acid (1.5 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 and concentrated to 3- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-. [Phenyl-5-oxazolyl] propionic acid (200 mg, yield 82%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 136
~ 137 ° C.

Example 11 Methyl 3- [2- (4-hydroxyphenylthio) -4-phenyl-5-thiazolyl] propionate (350 m
g), 4-chloromethyl-5-methyl-2-phenyloxazole (196 mg), potassium carbonate (260 m
A mixture of g) and N, N-dimethylformamide (4 ml) was stirred at 50 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) was eluted with 3- [2
Methyl-[4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-phenyl-5-thiazolyl] propionate (400 mg, yield 78)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.56 (2H, t, J = 7.8 Hz),
3.15 (2H, t, J = 7.8 Hz), 3.63 (3H, s), 5.04 (2H, s), 7.
09 (2H, d, J = 8.8 Hz), 7.33-7.48 (6H, m), 7.54-7.67 (4
H, m), 8.00-8.06 (2H, m). Example 12 3- [2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-phenyl-
5-thiazolyl] methyl propionate (360 mg),
Lithium hydroxide hydrate (83.5 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4
ml) of the mixture was stirred 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 and dried (Mg
(SO ₄ ), and then concentrated to give 3- [2- [4- (5-methyl-
2-Phenyl-4-oxazolylmethoxy) phenylthio] -4-phenyl-5-thiazolyl] propionic acid (338 mg, yield 96%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 121-12
2 ° C.

Example 13 3- [2- (N-methylamino) -4-phenyl-5-
Thiazolyl] methyl propionate (400 mg)
Sodium hydride (60%, oily, 70 mg) was added to an N-dimethylformamide (10 ml) solution at 0 ° C,
The mixture was stirred at the same temperature for 10 minutes. After adding 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (500 mg), the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice 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 column chromatography, and ethyl acetate-hexane (1: 9, volume ratio) eluted with 3- [2- [N-
Methyl-N- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyl] amino] -4-phenyl-5-thiazolyl] propionate methyl (580m
g, yield 72%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.63 (2H, t, J = 7.5 Hz),
3.00 (3H, s), 3.13 (2H, t, J = 7.5 Hz), 3.67 (3H, s), 4.
62 (2H, s), 4.99 (2H, s), 6.99 (2H, d, J = 8.8 Hz), 7.2
-7.65 (10H, m), 7.95-8.1 (2H, m). Example 14 3- [2- [N-methyl-N- [4- (5-methyl-2
-Phenyl-4-oxazolylmethoxy) benzyl] amino] -4-phenyl-5-thiazolyl] propionate (570 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and methanol (5 ml) The mixture was stirred at room temperature for 1 hour.
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 (MgSO
₄ ) After that, the mixture was concentrated. The residue was treated with diethyl ether (40 m
l), 10% hydrochloric acid-methanol (0.5 ml)
Was added, and the precipitated solid was collected by filtration. Recrystallization from methanol-diethyl ether gave 3- [2- [N-methyl-
N- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] amino] -4-phenyl-5
[Thiazolyl] propion hydrochloride (270 mg, yield 46%) was obtained as colorless crystals. Melting point 106-108
° C.

Example 15 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (433 mg) and 3
Methyl- [4-phenyl-2- [N- (1-propyl) amino] -5-thiazolyl] propionate (400 m
g) in N, N-dimethylformamide (5 ml) at 0 ° C. in sodium hydride (60%, oily, 55.2).
mg) and stirred at the same temperature for 1 hour.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography. Rumethoxy) benzyl] -N-
Methyl (1-propyl) amino] -4-phenyl-5-thiazolyl] propionate (595 mg, 78% yield)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.55-1.75 (2H,
m), 2.43 (3H, s), 2.62 (2H, t, J = 7.7 Hz), 3.13 (2H,
t, J = 7.7 Hz), 3.27-3.36 (2H, m), 3.66 (3H, s), 4.64 (2
H, s), 4.98 (2H, s), 6.98 (2H, d, J = 8.8 Hz), 7.22-7.
48 (8H, m), 7.56-7.62 (2H, m), 7.99-8.04 (2H, m). Example 16 3- [2- [N- [4- (5-methyl-2-phenyl-
4-oxazolylmethoxy) benzyl] -N- (1-propyl) amino] -4-phenyl-5-thiazolyl] methyl propionate (537 mg), lithium hydroxide hydrate (116 mg), tetrahydrofuran (6 ml), A mixture of water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours. 1N hydrochloric acid (2.8) 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 resulting colorless oil, 10% hydrochloric acid-methanol (3
and a mixture of diethyl ether (30 ml) was stirred at room temperature for 10 minutes, and then concentrated to give 3- [2- [N
-[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -N- (1-propyl) amino] -4-phenyl-5-thiazolyl] propion hydrochloride (576 mg, yield 97%) as a colorless amorphous. NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.3 Hz), 1.65-1.85 (2H,
m), 2.55-2.63 (5H, m), 2.95 (2H, t, J = 7.2 Hz), 3.60-
3.80 (2H, m), 5.10 (2H, s), 5.40 (2H, s), 7.09 (2H, d,
J = 8.4 Hz), 7.26-7.32 (2H, m), 7.42-7.73 (8H, m), 8.
38-8.45 (2H, m).

Example 17 Ethyl 3- (5-mercapto-1H-1,2,4-triazol-3-yl) propionate (450 mg), 4
A mixture of-(4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (700 mg), potassium carbonate (370 mg) and N, N-dimethylformamide (20 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water 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 column chromatography, and ethyl acetate-hexane (3: 2, volume ratio) was eluted with 3-
[5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] -1H-1,2,4-
Crystals of ethyl [triazol-3-yl] propionate (600 mg, yield 56%) were obtained. Recrystallized from ethyl acetate-hexane. 114-115 ° C. Example 18 3- [5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] -1H-1,2,2.
Ethyl 4-triazol-3-yl] propionate (5
50 mg), 1 N aqueous sodium hydroxide solution (3 m
l), a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 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 (MgSO ₄ )
Then, the mixture was concentrated to give 3- [5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] -1.
[H-1,2,4-Triazol-3-yl] propionic acid crystals were obtained. Recrystallization from methanol-ethyl acetate gave colorless prism crystals (410 mg, yield 79%).
170-171 ° C.

Example 19 Ethyl [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-thiazolyl] acetate (330 mg), lithium hydroxide hydrate (8
9.0 mg), tetrahydrofuran (3 ml), water (2
ml) and methanol (2 ml) at room temperature for 4 hours.
Stir for hours. 1N hydrochloric acid (2.2 m) was added to the reaction mixture.
l) was added and extracted with ethyl acetate. The ethyl acetate layer
After washing with saturated saline, drying (MgSO ₄ ), and concentrating,
[2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenylthio] -4-thiazolyl] acetic acid (215 mg, yield 69%) was obtained as colorless crystals.
Recrystallized from ethyl acetate-hexane. Melting point 180-1
81 ° C. Example 20 Ethyl 3- (1-benzyl-3-hydroxy-1H-pyrazol-4-yl) propionate (900 mg), 4
A mixture of-(4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.06 g), potassium carbonate (690 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C for 5 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). A mixture of the obtained colorless oil, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added, and the mixture was extracted with ethyl acetate. did. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 3- [1-benzyl-3- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl]
Propionic acid (1.53 g, 89% yield) was obtained. Recrystallized from acetone-hexane. 125-126 melting point
° C.

Example 21 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (255 mg), 4- [2- (4-
Chloromethylphenoxy) ethyl] -5-methyl-2-
A mixture of phenyloxazole (492 mg), potassium carbonate (415 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [1-methyl-3- [4- [2- (5-methyl-
Methyl 2-phenyl-4-oxazolyl) ethoxy] benzyloxy] -1H-pyrazol-4-yl] acetate (397 mg, 57% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.38 (3H, s), 2.98 (2H, t, J = 6.8 Hz),
3.37 (2H, s), 3.66 (3H, s), 3.72 (3H, s), 4.25 (2H, t,
J = 6.8 Hz), 5.12 (2H, s), 6.89 (2H, d, J = 8.4 Hz), 7.1
7 (1H, s), 7.30-7.48 (5H, m), 7.94-8.01 (2H, m). Example 22 Methyl [1-methyl-3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxy] -1H-pyrazol-4-yl] acetate (37
9 mg), 1 N aqueous sodium hydroxide solution (2 ml),
Tetrahydrofuran (4 ml) and ethanol (4 m
After stirring the mixture of 1) at room temperature for 2 hours, 1N hydrochloric acid (2 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 obtained colorless crystals were collected by filtration, and [1-methyl-3-
[4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxy] -1H-pyrazol-4-yl] acetic acid (333 mg, yield 91%) was obtained. Recrystallized from ethanol-hexane. Melting point 148
~ 149 [deg.] C.

Example 23 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (245 mg), 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (452 mg), potassium carbonate (398 m
g) and N, N-dimethylformamide (10 ml)
Was stirred at 60 ° C. for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, volume ratio) was eluted with [1--
Methyl-3- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] methyl acetate (382 mg, 59 yield)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.39 (2H, s), 3.67 (3H,
s), 3.74 (3H, s), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2
H, d, J = 8.8 Hz), 7.19 (1H, s), 7.29-7.52 (5H, m), 7.
98-8.08 (2H, m). Example 24 [1-Methyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H
-Pyrazol-4-yl] methyl acetate (662 mg),
After stirring a mixture of 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml)
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and [1-methyl-3- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxy] -1H-pyrazol-4-yl] acetic acid (601 mg, yield 94%) was obtained. Recrystallized from ethanol-hexane. 133-134 ° C.

Example 25 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (298 mg), 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (551 mg), potassium carbonate (4
84 mg) and N, N-dimethylformamide (10
ml) of the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [1-methyl-3- [6- (5-methyl-2-phenyl-4-oxazolyl) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). Methoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] methyl acetate (67
(0 mg, 85% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.37 (2H, s), 3.67 (3H,
s), 3.73 (3H, s), 5.15 (2H, s), 5.31 (2H, s), 6.82 (1
H, d, J = 8.8 Hz), 7.18 (1H, s), 7.39-7.49 (3H, m), 7.
67 (1H, dd, J = 2.6, 8.8 Hz), 7.98-8.05 (2H, m), 8.23
(1H, d, J = 2.6 Hz). Example 26 Methyl [1-methyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetate (66
8 mg), 1 N aqueous sodium hydroxide solution (3 ml),
Tetrahydrofuran (6 ml) and ethanol (6 m
After stirring the mixture of 1) at room temperature for 2 hours, 1N hydrochloric acid (3 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 obtained colorless crystals were collected by filtration, and [1-methyl-3-
[6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid (585 mg, yield 90%) was obtained. Recrystallized from ethanol-hexane. Melting point 139
~ 140 ° C.

Example 27 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (298 mg), 4-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (551 mg), potassium carbonate (4 mg)
84 mg) and N, N-dimethylformamide (10
ml) of the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [1-methyl-3- [2- (5-methyl-2-phenyl-4-oxazolyl) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). Methoxy) -4-pyridylmethoxy] -1H-pyrazol-4-yl] methyl acetate (68
9 mg, yield 88%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.42 (2H, s), 3.69 (6H,
s), 5.20 (2H, s), 5.30 (2H, s), 6.88 (1H, s), 6.92 (1
(H, d, J = 5.2 Hz), 7.18 (1H, s), 7.39-7.49 (3H, m), 7.
98-8.05 (2H, m), 8.14 (1H, d, J = 5.2 Hz). Example 28 Methyl [1-methyl-3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethoxy] -1H-pyrazol-4-yl] acetate (68
6 mg), 1 N aqueous sodium hydroxide solution (3 ml),
Tetrahydrofuran (6 ml) and ethanol (6 m
After stirring the mixture of 1) at room temperature for 2 hours, 1N hydrochloric acid (3 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 obtained colorless crystals were collected by filtration, and [1-methyl-3-
[2- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid (471 mg, yield 71%) was obtained. Recrystallized from acetone-hexane. Melting point 126-
127 ° C.

Example 29 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (298 mg), 5-chloromethyl-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) isoxazole (533 mg), potassium carbonate (484 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 4 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and [1-methyl-3- [3- (5-methyl-2-) was eluted with ethyl acetate-hexane (2: 1, volume ratio).
Phenyl-4-oxazolylmethoxy) -5-isoxazolylmethoxy] -1H-pyrazol-4-yl] acetate (701 mg, yield 91%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.37 (2H, s), 3.69 (3H,
s), 3.70 (3H, s), 5.19 (2H, s), 5.20 (2H, s), 6.01 (1
H, s), 7.17 (1H, s), 7.42-7.49 (3H, m), 7.98-8.04 (2
H, m). Example 30 Methyl [1-methyl-3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolylmethoxy] -1H-pyrazol-4-yl] acetate ( 701 mg), 1 N aqueous sodium hydroxide solution (3 m
l), a mixture of tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals are collected by filtration, and [1-methyl-3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolylmethoxy] is obtained.
[1H-pyrazol-4-yl] acetic acid (547 mg, yield 81%) was obtained. Recrystallized from acetone-hexane. 149-150 ° C.

Example 31 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (298 mg), 2- (5-chloromethyl-3-isoxazolyloxymethyl) quinoline (481 mg), potassium carbonate (484 mg) and N, N-dimethylformamide (10 ml) in a mixture of 60. Stir at 4 ° C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [1-methyl-3] was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio).
Methyl-[3- (2-quinolylmethoxy) -5-isoxazolylmethoxy] -1H-pyrazol-4-yl] acetate (676 mg, yield 95%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 3.38 (2H, s), 3.69 (3H, s), 3.71 (3H,
s), 5.21 (2H, s), 5.57 (2H, s), 6.10 (1H, s), 7.18 (1
H, s), 7.55 (1H, ddd, J = 1.0, 6.8, 8.2 Hz), 7.61 (1H,
d, J = 8.8 Hz), 7.74 (1H, ddd, J = 1.6, 6.8, 8.4 Hz),
7.84 (1H, dd, J = 1.6, 8.2 Hz), 8.08-8.14 (1H, m), 8.2
1 (1H, d, J = 8.8 Hz). Example 32 [1-Methyl-3- [3- (2-quinolylmethoxy)-]
5-Isoxazolylmethoxy] -1H-pyrazole-
4-yl] methyl acetate (674 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 m
After stirring a mixture of 1) and ethanol (6 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals were collected by filtration, and [1-methyl-3- [3- (2-quinolylmethoxy) -5-isoxazolylmethoxy] -1H-pyrazol-4-yl] acetic acid (532 mg, yield 82%). Recrystallized from tetrahydrofuran-hexane.
124-125 ° C.

Example 33 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) A mixture of methyl acetate (255 mg), 5-chloromethyl-2- (2-phenyl-4-thiazolylmethoxy) pyridine (475 mg), potassium carbonate (415 mg) and N, N-dimethylformamide (10 ml) Was stirred at 60 ° C. for 5 hours. Pour the reaction mixture into water,
Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From the hexane (2: 1, volume ratio) elution part, [1-methyl-
3- [6- (2-phenyl-4-thiazolylmethoxy)
Methyl [-3-pyridylmethoxy] -1H-pyrazol-4-yl] acetate (581 mg, 86% yield) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 85-86 ° C. Example 34 Methyl [1-methyl-3- [6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetate (496 mg), 1 N hydroxylation A mixture of an aqueous sodium solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 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 obtained colorless crystals were collected by filtration, and [1-methyl-3- [6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid (432 m
g, yield 90%). Recrystallized from ethanol-hexane. 156-157 ° C.

Example 35 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (255 mg), 5-chloromethyl-2- (5-methyl-2-phenyl-4-thiazolylmethoxy) pyridine (496 mg), potassium carbonate (41
5 mg) and N, N-dimethylformamide (10 m
The mixture of 1) was stirred at 60 ° C. for 5 hours. The reaction mixture was poured into water 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 column chromatography,
[1-Methyl-3- [6- (5-methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy] was eluted from ethyl acetate-hexane (2: 1, volume ratio).
1H-pyrazol-4-yl] methyl acetate (501 m
g, yield 72%) as a colorless oil. NMR (CDCl ₃ ) δ: 2.57 (3H, s), 3.37 (2H, s), 3.68 (3H,
s), 3.73 (3H, s), 5.16 (2H, s), 5.45 (2H, s), 6.83 (1
(H, d, J = 8.8 Hz), 7.19 (1H, s), 7.37-7.47 (3H, m), 7.
68 (1H, dd, J = 2.2, 8.8 Hz), 7.86-7.93 (2H, m), 8.24
(1H, d, J = 2.2 Hz). Example 36 [1-Methyl-3- [6- (5-methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy]
1H-pyrazol-4-yl] methyl acetate (497 m
g) 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml)
After stirring the mixture at room temperature for 2 hours, 1N hydrochloric acid (2
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and [1-methyl-3-
[6- (5-Methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid (411 mg, yield 85%) was obtained.
Recrystallized from ethanol-hexane. Melting point 140-1
41 ° C.

Example 37 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (298 mg), 5-chloromethyl-2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] pyridine (533 mg), potassium carbonate (484 mg) and N, N -A mixture of dimethylformamide (10 ml) was stirred at 60 ° C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [3- [6- [2- (2-furyl) -5-methyl-4-oxazolyl] was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). Methoxy] -3-pyridylmethoxy] -1-methyl-1H-pyrazol-4-yl] acetate (623 mg, 81% yield) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.37 (2H, s), 3.67 (3H,
s), 3.73 (3H, s), 5.14 (2H, s), 5.28 (2H, s), 6.51 (1
H, dd, J = 1.6, 3.6 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.98
(1H, d, J = 3.6 Hz), 7.18 (1H, s), 7.52 (1H, d, J = 1.6
Hz), 7.67 (1H, dd, J = 2.4, 8.6 Hz), 8.22 (1H, d, J = 2.4
Hz). Example 38 [3- [6- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-pyridylmethoxy] -1
-Methyl-1H-pyrazol-4-yl] methyl acetate (623 mg), 1N aqueous sodium hydroxide solution (3 m
l), a mixture of tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals were collected by filtration and [3- [6
-[2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-pyridylmethoxy] -1-methyl-
[1H-pyrazol-4-yl] acetic acid (580 mg, yield 96%) was obtained. Recrystallized from ethanol-hexane. 155-156 ° C.

Example 39 (1-benzyl-3-hydroxy-1H-pyrazole-
4-yl) ethyl acetate (390 mg), 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (472 mg), potassium carbonate (414 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [1-benzyl-3- [6- (5-methyl-2-) was eluted with ethyl acetate-hexane (1: 1, volume ratio).
Phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] ethyl acetate (649 mg, yield 80%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.2 Hz), 2.48 (3H, s),
3.35 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 5.12 (2H, s),
5.17 (2H, s), 5.30 (2H, s), 6.79 (1H, d, J = 8.4Hz), 7.
17-7.47 (9H, m), 7.66 (1H, dd, J = 2.6, 8.4 Hz), 7.98-
8.08 (2H, m), 8.22 (1H, d, J = 2.6 Hz). Example 40 Ethyl [1-benzyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetate (64
8 mg), 1 N aqueous sodium hydroxide solution (3 ml),
Tetrahydrofuran (6 ml) and ethanol (6 m
After stirring the mixture of 1) at room temperature for 2 hours, 1N hydrochloric acid (3 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 obtained colorless crystals were collected by filtration and [1-benzyl-3
-[6- (5-Methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid (539 mg, yield 88%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 87-
88 ° C.

Example 41 (3-Hydroxy-1-methyl-1H-pyrazole-4
-Yl) methyl acetate (340 mg), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N, N-dimethylformamide (10 ml) ) Was stirred at 60 ° C for 5 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and [3- [3-methoxy-4- (5-methyl-2) was eluted from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio).
-Phenyl-4-oxazolylmethoxy) benzyloxy] -1-methyl-1H-pyrazol-4-yl] acetate (546 mg, yield 57%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.40 (2H, s), 3.67 (3H,
s), 3.74 (3H, s), 3.89 (3H, s), 5.06 (2H, s), 5.15 (2
H, s), 6.95 (1H, dd, J = 2.0, 8.6 Hz), 7.01 (1H, d, J =
2.0 Hz), 7.03 (1H, d, J = 8.6 Hz), 7.19 (1H, s), 7.40-
7.50 (3H, m), 7.97-8.06 (2H, m). Example 42 [3- [3-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1
-Methyl-1H-pyrazol-4-yl] methyl acetate (544 mg), 1N aqueous sodium hydroxide solution (3 m
l), a mixture of tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals were collected by filtration and [3- [3
-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-methyl-
[1H-Pyrazol-4-yl] acetic acid (482 mg, yield: 91%) was obtained. Recrystallized from acetone-hexane.
153-154 ° C.

Example 43 (1-benzyl-3-hydroxy-1H-pyrazole-
4-yl) ethyl acetate (521 mg), 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553)
mg) and N, N-dimethylformamide (10 m
The mixture of 1) was stirred at 60 ° C. for 5 hours. The reaction mixture was poured into water 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 column chromatography,
[1-benzyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1 from the eluate of ethyl acetate-hexane (1: 3, volume ratio)
[H-pyrazol-4-yl] ethyl acetate (731 mg,
(68% yield) as a colorless oil. NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.0 Hz), 2.44 (3H, s),
3.37 (2H, s), 4.12 (2H, q, J = 7.0 Hz), 5.00 (2H, s),
5.12 (2H, s), 5.17 (2H, s), 6.96-7.03 (2H, m), 7.17-7.
50 (11H, m), 7.98-8.06 (2H, m). Example 44 [1-Benzyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1
H-pyrazol-4-yl] ethyl acetate (731 m
g) 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml)
After stirring the mixture at room temperature for 2 hours, 1N hydrochloric acid (3.
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and [1-benzyl-3-
[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazole-4-
[Il] acetic acid (580 mg, yield 84%) was obtained. Recrystallized from acetone-hexane. 91-92 ° C.

Example 45 (1-benzyl-3-hydroxy-1H-pyrazole-
4-yl) ethyl acetate (521 mg), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N, N-dimethylformamide ( 10 ml) was stirred at 60 ° C. for 5 hours. The reaction mixture was poured into water 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 column chromatography, and ethyl acetate-hexane (1: 2, volume ratio) eluted with [1-benzyl-3- [3-methoxy-
Ethyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] acetate (632 mg, yield 56%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 86-87 ° C. Example 46 Ethyl [1-benzyl-3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] acetate (539 mg) 1N sodium hydroxide aqueous solution (2m
l), a mixture of tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) 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 obtained colorless crystals are collected by filtration, and [1-benzyl-3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] is obtained.
[-1H-pyrazol-4-yl] acetic acid (423 mg, yield 83%) was obtained. Recrystallized from ethanol-hexane. Melting point 99-100 [deg.] C.

Example 47 Ethyl 3- (1-benzyl-3-hydroxy-1H-pyrazol-4-yl) propionate (411 mg), 5
-Chloromethyl-2- (5-methyl-2-phenyl-4
A mixture of -oxazolylmethoxy) pyridine (472 mg), potassium carbonate (414 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 2,
Volume ratio) From the elution part, 3- [1-benzyl-3- [6-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazole-4
-Yl] ethyl propionate (748 mg, yield 91)
%) As a colorless oil. NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.45-2.53 (5H,
m), 2.60-2.68 (2H, m), 4.07 (2H, q, J = 7.2 Hz), 5.08
(2H, s), 5.16 (2H, s), 5.31 (2H, s), 6.81 (1H, d, J = 8.
4 Hz), 7.00 (1H, s), 7.14-7.22 (2H, m), 7.28-7.46 (6
H, m), 7.68 (1H, dd, J = 2.2, 8.4 Hz), 7.98-8.07 (2H,
m), 8.24 (1H, d, J = 2.2 Hz). Example 48 Ethyl 3- [1-benzyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] propionate ( 746 mg), a mixture of 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature overnight.
1N hydrochloric acid (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 obtained colorless crystals were collected by filtration,
[1-benzyl-3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] propionic acid (6
39 mg, yield 90%). Recrystallized from acetone-hexane. 130-131 ° C.

Example 49 (3-Hydroxy-1-phenyl-1H-pyrazole-
Methyl 4-yl) acetate (464 mg), 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553)
mg) and N, N-dimethylformamide (10 m
The mixture of 1) was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water 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 column chromatography,
[3- [4- (5-Methyl-2-
Methyl [phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetate (767 mg, yield 75%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 11
3-114 ° C. Example 50 [3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1
H-pyrazol-4-yl] methyl acetate (662 m
g) 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml)
After stirring the mixture at room temperature for 1 hour, 1N hydrochloric acid (3
ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazole-4-.
[Il] acetic acid (583 mg, yield 91%) was obtained. Recrystallized from acetone-hexane. 151-152 ° C.

Example 51 (3-Hydroxy-1-phenyl-1H-pyrazole-
Methyl 4-yl) acetate (406 mg), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (551 mg), potassium carbonate (484 mg) and N, N-dimethylformamide ( 10 ml) was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and dried (MgSO ₄ )
Afterwards, it was concentrated. The obtained colorless crystals were collected by filtration and [3- [3
-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-4-yl] methyl acetate (595 m
g, 55% yield). Recrystallized from ethyl acetate-hexane. 107-108 ° C. Example 52 [3- [3-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1
-Phenyl-1H-pyrazol-4-yl] methyl acetate (496 mg), 1N aqueous sodium hydroxide solution (2 m
l), a mixture of tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hour, 1N hydrochloric acid (2 ml) 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 obtained colorless crystals were collected by filtration and [3- [3
-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid (438 mg, yield 90%) was obtained. Recrystallized from ethanol-water. 147-148 ° C.

Example 53 (3-Hydroxy-1-phenyl-1H-pyrazole-
Methyl 4-yl) acetate (406 mg), 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (551 mg), potassium carbonate (484 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration and [3- [6- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
-3-Pyridylmethoxy] -1-phenyl-1H-pyrazol-4-yl] methyl acetate (690 mg, yield 77)
%). Recrystallized from ethyl acetate-hexane. 96-97 ° C. Example 54 Methyl [3- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1-phenyl-1H-pyrazol-4-yl] acetate (58
7 mg), 1 N aqueous sodium hydroxide solution (3 ml),
Tetrahydrofuran (6 ml) and ethanol (6 m
After stirring the mixture of 1) at room temperature for 1 hour, 1N hydrochloric acid (3 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 obtained colorless crystals were collected by filtration, and [3- [6- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
3-Pyridylmethoxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid (502 mg, yield 88%) was obtained. Recrystallized from ethanol-hexane. Melting point 164
１６165 ° C.

Example 55 Ethyl 3- (3-hydroxy-1-phenyl-1H-pyrazol-4-yl) propionate (0.40 g), 4
A mixture of-(4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-furyl) -5-methyloxazole (0.57 g), potassium carbonate (276 mg) and N, N-dimethylformamide (10 ml) was prepared. Stir at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and from the eluate of ethyl acetate-hexane (1: 2, volume ratio), 3- [3- [4-
Ethyl [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] propionate (420 mg, 44% yield) ) Was obtained as colorless crystals.
Recrystallized from ethyl acetate-hexane. Melting point 97-98
° C. Example 56 3- [3- [4- [2- (2-furyl) -5-methyl-
4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl]
Ethyl propionate (340 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 m
After stirring a mixture of 1) and ethanol (6 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals were collected by filtration and 3- [3- [4- [2- (2-furyl) -5-.
Methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazole-4
[-Yl] propionic acid (300 mg, yield 94%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 161
１６162 ° C.

Example 57 (2-mercapto-4-methylthiazol-5-yl)
A mixture of methyl acetate (385 mg), 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N, N-dimethylformamide (20 ml) was added at room temperature. Stir for hours. The reaction mixture was poured into water 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 column chromatography, and ethyl acetate-hexane (1: 1).
[3-methyl-2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Benzylthio] thiazol-5-yl] methyl acetate (7
(50 mg, 82% yield) as an oil. NMR (CDCl ₃ ) δ: 2.33 (3H, s), 2.43 (3H, s), 3.69 (2H,
s), 3.73 (3H, s), 4.33 (2H, s), 4.98 (2H, s), 6.96 (2
H, d, J = 8.7 Hz), 7.30 (2H, d, J = 8.7 Hz), 7.4-7.5 (3
H, m), 7.95-8.05 (2H, m). Example 58 Methyl [4-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] thiazol-5-yl] acetate (740 mg), 1N aqueous sodium hydroxide solution ( 5 ml), a mixture of tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and precipitated [4-methyl-2- [4- (5-
Crystal of methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] thiazol-5-yl] acetic acid (70
(5 mg, 98%) was collected by filtration. Recrystallization from tetrahydrofuran-ethyl acetate gave colorless prisms. Melting point 1
92-193 ° C.

Example 59 (2-mercapto-4-methylthiazol-5-yl)
Methyl acetate (385 mg), 4- (3-chloromethylf
Enoxymethyl) -5-methyl-2-phenyloxazo
(600 mg), potassium carbonate (400 mg) and
Of N and N, N-dimethylformamide (20 ml)
Was stirred at room temperature for 2 hours. Pour the reaction mixture into water and add vinegar
Extracted with ethyl acid. The ethyl acetate layer was washed with water and dried (M
gSO _Four ) And concentrated. Residue is silica gel column
After chromatograph, ethyl acetate-hexane (1:
[3-methyl-2- [3- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Benzylthio] thiazol-5-yl] acetate methyl (6
(65 mg, yield 72%) as an oil. NMR (CDCl _Three ) δ: 2.33 (3H, s), 2.44 (3H, s), 3.68 (2H,
s), 3.72 (3H, s), 4.35 (2H, s), 4.97 (2H, s), 6.9-7.1
(3H, m), 7.22 (1H, d, J = 8.1 Hz), 7.4-7.5 (3H, m), 8.
0-8.05 (2H, m). Example 60 [4-methyl-2- [3- (5-methyl-2-phenyl)
-4-oxazolylmethoxy) benzylthio] thiazoe
Ru-5-yl] methyl acetate (660 mg), 1 N hydroxyl
Sodium chloride aqueous solution (5 ml), tetrahydrofuran
(5 ml) and methanol (5 ml) at room temperature
For 2 hours. Pour the reaction mixture into water and add 2N salt
After neutralization with an acid, the mixture was extracted with 5% methanol-ethyl acetate.
The organic layer is washed with water and dried (MgSO _Four ) After that, concentrate and precipitate
[4-methyl-2- [3- (5-methyl-2-fe
Nyl-4-oxazolylmethoxy) benzylthio] thia
Crystal of (zol-5-yl) acetic acid (620 mg, 97%)
Was filtered using ethyl acetate-isopropyl ether.
Was. Recrystallized from methanol-ethyl acetate to give a colorless prism
A crystal was obtained. Melting point 154-155 [deg.] C.

Example 61 A mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzoic acid (2.00 g), N, N-dimethylformamide (0.1 ml) and tetrahydrofuran (5 ml) Oxalyl chloride (0.21m
1) was added slowly, followed by stirring at room temperature for 30 minutes. The reaction solvent was removed under reduced pressure. The obtained residue was dissolved in N, N-dimethylacetamide (10 ml),
After addition of methyl 3- (2-amino-4-phenyl-5-thiazolyl) propionate (425 mg),
Stir for hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio), 3- [2- [4
Methyl-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzamide] -4-phenyl-5-thiazolyl] propionate (609 mg, yield 68%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. 165-166 ° C. Example 62 3- [2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzamide] -4-phenyl-
5-thiazolyl] methyl propionate (440 mg),
Lithium hydroxide hydrate (100 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 m
The mixture of 1) was stirred at room temperature for 2 hours. 1N hydrochloric acid (2.4 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 (MgS
O ₄ ), and then concentrated to give 3- [2- [4- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) benzamide] -4-phenyl-5-thiazolyl] propionic acid (370 mg, yield 86%) was obtained as colorless crystals. Recrystallized from ethyl acetate. Melting point 244-245 [deg.] C.

Example 63 Ethyl 3- [2-amino-4- (5,6,7,8-tetrahydro-2-naphthyl) -5-thiazolyl] propionate (270 mg), [4- [2- (2 -Frill) -5
-Methyl-4-oxazolylmethoxy] phenyl] acetic acid (250 mg), WSC (170 mg), HOBt (1
35 mg) and N, N-dimethylformamide (10
ml) of the mixture was stirred for 3 days. 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 dissolved in ethanol (9 ml) -tetrahydrofuran (1 ml), 1N aqueous sodium hydroxide solution (2 ml) was added at 0 ° C, and the mixture was stirred at room temperature 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 (MgS
After O ₄ ), the mixture was concentrated. The residue was subjected to silica gel column chromatography, and 3- [2-[[4- [2- (2-furyl) -5-methyl-4-oxa) was eluted from acetone-hexane (3: 2, volume ratio). Zolylmethoxy] phenyl] acetylamino] -4- (5,6,7,8-tetrahydro-2-naphthyl) -5-thiazolyl] propionic acid (270 mg, 57%) was obtained as an amorphous oil. NMR (CDCl ₃ ) δ: 1.7-1.9 (4H, m), 2.40 (3H, s), 2.6-2.8
(6H, m), 3.16 (2H, t, J = 7.5 Hz), 3.66 (2H, s), 4.96
(2H, s), 6.51 (1H, dd, J = 3.5, 1.5 Hz), 6.9-7.2 (6H,
m), 7.21 (2H, d, J = 8.5 Hz), 7.5-7.55 (1H, m). Example 64 [5- [2- [4- (5-methyl-2-phenyl-4-)
Oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] acetonitrile (450 m
g) 2N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (1 ml) and ethanol (5 ml)
Was refluxed for 5 hours and then 1N hydrochloric acid (10 ml)
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and [5- [2- [4- (5-methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] acetic acid (440 mg, Yield 94%). Recrystallized from ethyl acetate-hexane. 180-181 ° C.

Example 65 2-ethoxycarbonyl-3- [5- [2- [4- (5
-Methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl] -2-phenyl-4-oxazolyl] propionate (530 mg), 4N aqueous potassium hydroxide solution (3 ml) and ethanol (5 ml)
Was refluxed for 1 hour and then 1N hydrochloric acid (15 ml)
And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The obtained residue was dissolved in pyridine (5 ml), stirred at 110 ° C. for 2 hours, and concentrated. The obtained residue was dissolved in ethyl acetate, washed sequentially with dilute hydrochloric acid and saturated saline, dried (MgSO ₄ ), and concentrated. The obtained colorless crystals were collected by filtration, and 3- [5- [2- [4- (5-methyl-2-phenyl-4-oxazolyl) methoxyphenyl] ethyl]-
2-phenyl-4-oxazolyl] propionic acid (40
0 mg, yield 91%). Recrystallized from ethyl acetate-hexane. 110-111 ° C. Example 66 Methyl 4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetamido-5-oxo-5-phenylpentanoate (900 mg),
Phosphorus oxychloride (900mg) and toluene (7m
The mixture of 1) was refluxed for 0.5 hour. After cooling, a cold saturated aqueous sodium hydrogen carbonate solution 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 column chromatography, and 3- [2- [4- [2- (2-furyl)) was extracted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio).
-5-methyl-4-oxazolylmethoxy] benzyl]
Methyl [5-phenyl-4-oxazolyl] propionate (557 mg, yield 64%) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.73-2.82 (2H, m), 3.02-
3.11 (2H, m), 3.65 (3H, s), 4.06 (2H, s), 4.97 (2H, s),
6.50-6.54 (1H, m), 6.93-7.00 (3H, m), 7.23-7.46 (5H,
m), 7.52-7.60 (3H, m).

Example 67 3- [2- [4- [2- (2-furyl) -5-methyl-
Methyl 4-oxazolylmethoxy] benzyl] -5-phenyl-4-oxazolyl] propionate (489m
g), a mixture of lithium hydroxide hydrate (127 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours. 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 ), concentrated and concentrated to 3- [2- [4- [2-
(2-Furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -5-phenyl-4-oxazolyl] propionic acid (448 mg, yield 94%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 1
54-155 ° C. Example 68 Methyl 4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] phenyl] acetoxy-5-oxo-5-phenylpentanoate (1.49 g), ammonium acetate (777 mg) and acetic acid (5 ml) were refluxed for 3 hours. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution is washed with a saturated aqueous solution of sodium bicarbonate and subsequently with a saturated saline solution, and dried (MgSO ₄ ).
Afterwards, it was concentrated. The residue was subjected to silica gel column chromatography, and 3- [2- [4- [2- (2-furyl)) was extracted from a fraction eluted with ethyl acetate-hexane (2: 3, volume ratio).
-5-methyl-4-oxazolylmethoxy] benzyl]
Methyl-4-phenyl-5-oxazolyl] propionate (1.11 g, yield 77%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.64-2.73 (2H, m), 3.14-
3.23 (2H, m), 3.64 (3H, s), 4.06 (2H, s), 4.97 (2H, s),
6.50-6.54 (1H, m), 6.93-6.99 (3H, m), 7.17-7.46 (5H,
m), 7.52-7.55 (1H, m), 7.60-7.66 (2H, m).

Example 69 3- [2- [4- [2- (2-furyl) -5-methyl-
Methyl 4-oxazolylmethoxy] benzyl] -4-phenyl-5-oxazolyl] propionate (1.01
g), a mixture of lithium hydroxide hydrate (255 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (6.1 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 and concentrated to 3- [2- [4- [2-
(2-Furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -4-phenyl-5-oxazolyl] propionic acid (881 mg, yield 92%) was obtained as colorless crystals. Recrystallized from ethyl acetate-hexane. Melting point 7
4-76 ° C. Example 70 Ethyl (2-chloro-4-thiazolyl) acetate (440 m
g), 4-hydroxythiophenol (540 mg),
A mixture of potassium carbonate (591 mg) and N, N-dimethylformamide (4 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed successively with diluted hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue, 4-
A mixture of chloromethyl-5-methyl-2-phenyloxazole (1.66 g), potassium carbonate (1.66 g) and N, N-dimethylformamide (5 ml) was added to 5
Stir at 0 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and [2- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Phenylthio] -4-thiazolyl] ethyl acetate (400
mg, yield 78%) as colorless crystals. Recrystallized from ethyl acetate-hexane. 95-96 ° C.

Example 71 (2-mercapto-4-methylthiazol-5-yl)
Methyl acetate (455 mg), 4- (3-chloromethyl-
5-ethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (800 mg), potassium carbonate (4
65 mg) and N, N-dimethylformamide (20
ml) of the mixture was stirred at room temperature 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 column chromatography, and ethyl acetate-hexane (1: 3, volume ratio) eluted with [2- [3-ethoxy-5- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) benzylthio]
-4-methylthiazol-5-yl] methyl acetate (1.
02g, 87% yield) as an oil. NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7 Hz), 2.33 (3H, s), 2.
44 (3H, s), 3.69 (2H, s), 3.72 (3H, s), 3.99 (2H, q, J
= 7 Hz), 4.30 (2H, s), 4.94 (2H, s), 6.45-6.65 (3H,
m), 7.4-7.5 (3H, m), 7.95-8.05 (2H, m). Example 72 [2- [3-Ethoxy-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] -4-
Methylthiazol-5-yl] methyl acetate (1.01
g) 1N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml) and methanol (10 ml).
ml) of the mixture was stirred at room temperature 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, dried (MgSO ₄ ), and concentrated to precipitate [2- [3-ethoxy-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzylthio] -4-. The crystals of methylthiazol-5-yl] acetic acid were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless prisms (910 mg, 93%). Melting point 11
5-116 ° C.

Example 73 (3-Hydroxy-1-phenyl-1H-pyrazole-
Methyl 4-yl) acetate (406 mg), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2
-Furyl) -5-methyloxazole (551 mg),
A mixture of potassium carbonate (484 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The obtained colorless crystals, 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4
ml) and methanol (4 ml) at room temperature for 1 hour.
After stirring for 1 hour, 1N hydrochloric acid (2 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 obtained colorless crystals were collected by filtration, and [3- [4- [2- (2-furyl) -5-
Methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazole-4
-Yl] acetic acid (748 mg, 88% yield) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 179-180
° C. Example 74 [3- [4- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (180 mg), WSC (230 mg), morpholine (100 mg) ) And N, N-dimethylformamide (10 ml) were stirred at room temperature for 15 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The obtained colorless crystals were collected by filtration, and 4- [3- [4
-[2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetylmorpholine (440 mg, 96% yield) ) Got. Recrystallized from ethyl acetate-hexane. 132-133 ° C.

Example 75 [3- [4- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (140 mg), WSC (180 mg), N-methyl A mixture of piperazine (100 mg) and N, N-dimethylformamide (20 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The obtained colorless crystals were collected by filtration,
[3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1
-Phenyl-1H-pyrazol-4-yl] acetyl-
4-Methylpiperazine (320 mg, yield 68%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 116
~ 117 ° C. Example 76 [3- [4- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (140 mg), WSC (180 mg), N-ethyl A mixture of piperazine (110 mg) and N, N-dimethylformamide (20 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried (MgS
After O ₄ ), the mixture was concentrated. The obtained colorless crystals were collected by filtration, and 4-
Ethyl-1- [3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-4-yl] Acetyl piperazine (350 mg, yield 73%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 11
2-113 ° C.

Example 77 [3- [4- [2- (2-furyl) -5-methyl-4-]
Oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-5-yl] acetonitrile (500 mg), a mixture of 2N aqueous sodium hydroxide solution (10 ml) and ethanol (10 ml) was refluxed for 4 hours. After that, 1N hydrochloric acid (20 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 obtained colorless crystals were collected by filtration and [3- [4- [2- (2-furyl))
-5-Methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1-phenyl-1H-pyrazol-5-yl] acetic acid (200 mg, yield 38%). Recrystallized from ethyl acetate-hexane. Melting point 145
１４146 ° C. (decomposition). Example 78 Ethyl 3- (3-hydroxy-1-phenyl-1H-pyrazol-5-yl) propionate (700 mg), 4
-(4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (930
mg), potassium carbonate (750 mg) and N, N-dimethylformamide (10 ml) at 60 ° C. for 4 hours.
Stir for hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and 3- [3- [3-methoxy-4- (5-methyl-2-phenyl-4-) was eluted with ethyl acetate-hexane (1: 1, volume ratio). Oxazolylmethoxy) benzyloxy] -1-phenyl-1H
-Pyrazol-5-yl] ethyl propionate (1.3
(5 g, yield 88%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.2 Hz), 2.41 (3H,
s), 2.53-2.63 (2H, m), 2.89-2.99 (2H, m), 3.88 (3
H, s), 4.11 (2H, q, J = 7.2 Hz), 5.06 (2H, s), 5.17
(2H, s), 5.70 (1H, s), 6.90-7.08 (3H, m), 7.30-7.5
0 (8H, m), 7.96-8.05 (2H, m).

Example 79 3- [3- [3-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy]
A mixture of ethyl -1-phenyl-1H-pyrazol-5-yl] propionate (1.33 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 1 hour. Thereafter, 1N hydrochloric acid (5 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 obtained colorless crystals are collected by filtration,
3- [3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy]
-1-Phenyl-1H-pyrazol-5-yl] propionic acid (1.17 g, yield 93%) was obtained. Recrystallized from tetrahydrofuran-hexane. Melting point 157-15
8 ° C. Example 80 Ethyl 3- (3-hydroxy-1-phenyl-1H-pyrazol-5-yl) propionate (500 mg), 4
A mixture of-(4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (600 mg), potassium carbonate (530 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C for 4 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) was eluted from a fraction eluted with ethyl acetate-hexane (1: 1, volume ratio). ) Benzyloxy] -1
Ethyl [-phenyl-1H-pyrazol-5-yl] propionate (980 mg, yield 95%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 2.44 (3H,
s), 2.52-2.64 (2H, m), 2.87-3.01 (2H, m), 4.12 (2
(H, q, J = 7.0 Hz), 5.01 (2H, s), 5.18 (2H, s), 5.69
(1H, s), 6.96-7.08 (2H, m), 7.30-7.52 (10H, m), 7.
98-8.06 (2H, m).

Example 81 Ethyl 3- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionate ( 950 mg), 1 N aqueous sodium hydroxide solution (4 m
l), a mixture of tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hour, 1N hydrochloric acid (4 ml) 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 obtained colorless crystals were collected by filtration, and 3- [3-
[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid (770 mg, yield 81%) was obtained. Recrystallized from acetone-hexane.
Mp 154-155 ° C. Example 82 Ethyl 3- (3-hydroxy-1-phenyl-1H-pyrazol-5-yl) propionate (460 mg), 4
A mixture of-(3-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (550 mg), potassium carbonate (350 mg) and N, N-dimethylformamide (10 ml) was stirred at 60 ° C for 4 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried (MgSO ₄ ),
Concentrated. The residue was subjected to silica gel column chromatography, and 3- [3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) was eluted with ethyl acetate-hexane (1: 1, volume ratio). ) Benzyloxy] -1
Ethyl [-phenyl-1H-pyrazol-5-yl] propionate (850 mg, yield 90%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.2 Hz), 2.44 (3H,
s), 2.54-2.62 (2H, m), 2.91-2.99 (2H, m), 4.12 (2
(H, q, J = 7.2 Hz), 5.01 (2H, s), 5.23 (2H, s), 5.70
(1H, s), 6.95-7.01 (1H, m), 7.04-7.09 (1H, m), 7.1
2-7.18 (1H, m), 7.24-7.49 (9H, m), 7.98-8.06 (2H,
m).

Example 83 Ethyl 3- [3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionate ( 830 mg), 1 N aqueous sodium hydroxide solution (3 m
l), a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) 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 obtained colorless crystals were collected by filtration, and 3- [3-
[3- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid (490 mg, yield 62%) was obtained. Recrystallized from acetone-isopropyl ether. 137-138 ° C.

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

[0193]

The compound of the present invention has low toxicity, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.).
Prophylactic / therapeutic agent; prophylactic / therapeutic agent for hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, etc.); insulin sensitivity enhancer; insulin resistance improvement Agent: Can be used as a preventive / therapeutic agent for impaired glucose tolerance (IGT) and an inhibitor for the transition from impaired glucose tolerance to diabetes. In addition, the compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infections (eg, respiratory infections) , Urinary tract infections, gastrointestinal infections,
Skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene,
Xerostomia, decreased hearing, cerebrovascular disorder, peripheral circulation disorder, etc.], obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine secretion) 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, cerebrovascular disorder (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia,
Sensory impairment in hyperinsulinemia, tumors (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteomyelitis spondylitis, deformity) Osteoarthritis, back pain, gout, inflammation after surgery trauma, remission of swelling, neuralgia, pharyngolaryngitis, cystitis,
Prevention and treatment of hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, etc., visceral obesity syndrome, arteriosclerosis (eg, atherosclerosis, etc.) It can also be used as an agent. Further, the compound of the present invention, peptic ulcer, acute or chronic gastritis, biliary dyskinesia, abdominal pain associated with cholecystitis, nausea, vomiting,
It can also be used to improve symptoms such as upper abdominal discomfort. Further, the compound of the present invention can be used as a therapeutic agent for slimming and phagocytosis (increase in body weight in subjects to which slimming or phagocytosis is administered) or a therapeutic agent for obesity, for example, for regulating (enhancing or suppressing) appetite. .

[0194]

[Sequence List] SEQUENCE LISTING <110> Takeda Chemical Industries, Ltd. <120> 5-Membered Heterocyclic Alkanoic Acid Derivatives <130> A5404 <150> JP 2001-85572 <151> 2001-03-23 <160> 10 <210 > 1 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> <400> 1 aacggtacct cagccatgga gcagcctcag gagg 34 <210> 2 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> <400> 2 taagtcgacc cgttagtaca tgtccttgta gatc 34 <210> 3 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> <400> 3 ttagaattcg acatggacac caaacatttc ctg 33 <210> 4 <211 > 33 <212> DNA <213> Artificial Sequence <220> <223> <400> 4 cccctcgagc taagtcattt ggtgcggcgc ctc 33 <210> 5 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> < 400> 5 tcgacagggg accaggacaa aggtcacgtt cgggag 36 <210> 6 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> <400> 6 tcgactcccg aacgtgacct ttgtcctggt cccctg 36 <210> 7 <211> 28 <212 > DNA <213> Artificial Sequence <220> <223> <400> 7 cccagatctc cccagcgtct tgtcattg 28 <210> 8 <211> 28 <212 > DNA <213> Artificial Sequence <220> <223> <400> 8 tcaccatggt caagctttta agcgggtc 28 <210> 9 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> <400> 9 gtgggtaccg aaatgaccat ggttgacaca gag 33 <210> 10 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> <400> 10 ggggtcgacc aggactctct gctagtacaa gtc 33

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/497 A61K 31/497 31/5377 31/5377 A61P 1/00 A61P 1/00 1/02 1 / 02 1/04 1/04 1/06 1/06 1/08 1/08 1/12 1/12 1/16 1/16 1/18 1/18 3/04 3/04 3/06 3/06 3 / 10 3/10 5/48 5/48 7/00 7/00 9/00 9/00 9/08 9/08 9/10 9/10 101 101 103 103 9/12 9/12 13/10 13 / 10 13/12 13/12 15/08 15/08 17/02 17/02 19/02 19/02 19/06 19/06 19/08 19/08 19/10 19/10 21/04 21/04 25 / 02 25/02 25/28 25/28 27/02 27/02 27/16 27/16 29/00 29/00 101 101 31/04 31/04 35/00 35/00 43/00 111 43/00 111 C07D 413/12 C07D 413/12 413/14 413/14 417/12 417/12 417/14 417/14 (72) Inventor Takeshi Maekawa 1-2-1, Gomoi, Ikaruga-cho, Ikoma-gun, Nara Prefecture (72) Inventor Hiroshi Imoto Shiga grass 6-10-10 Ichinomura 12 (72) Inventor Hiroyuki Odaka 2-12-12 Katsuragi, Kita-ku, Kobe City, Hyogo Prefecture Reference) 4C056 AA01 AB01 AC02 AD01 AE03 AF01 BA03 BA08 BA13 BB01 BC01 4C063 AA01 AA03 AA05 BB01 BB07 CC51 CC52 CC52 CC62 CC75 DD12 DD22 DD25 DD41 DD51 DD52 EE01 4C086 AA01 AA02 AA03 AA04 BC67 BC69 GA73 MA82 GA82 GA08 MA28 MA35 MA36 MA37 MA38 MA41 MA43 MA52 MA56 MA58 MA59 MA60 MA63 MA66 NA07 NA14 ZA15 ZA20 ZA33 ZA34 ZA36 ZA39 ZA40 ZA42 ZA45 ZA51 ZA66 ZA67 ZA68 ZA70 ZA71 ZA72 ZA75 ZA81 ZBC ZA37

Claims (26)

[Claims] 1. A compound of the general formula[Wherein, R¹Represents an optionally substituted 5-membered heterocyclic group;
X is a bond, an oxygen atom, a sulfur atom, -CO-, -CS
-, -CR^Three(OR^Four)-Or -NR^Five− (R^ThreeIs hydrogen
An atom or an optionally substituted hydrocarbon group is represented by R ^FourIs
A protecting group for a hydrogen atom or a hydroxyl group is represented by R^FiveIs a hydrogen atom,
Protecting group for hydrocarbon group or amino group which may be substituted
Q is a divalent hydrocarbon having 1 to 20 carbon atoms.
A group; Y is a bond, an oxygen atom, a sulfur atom, -SO-,-
SO_Two-, -NR⁶-, -CONR⁶-Or -NR⁶CO
− (R⁶Is a hydrogen atom or an optionally substituted carbon
Ring A further has 1 to 3 substituents;
An aromatic ring which may be present at Z;_Two)_n-Z¹
-Or -Z¹− (CH_Two)_n-(N is an integer from 0 to 8
The number, Z¹Is a bond, an oxygen atom, a sulfur atom, -SO-,
-SO_Two-, -NR⁷-, -CONR⁷-Or -NR⁷C
O- (R⁷Is a hydrogen atom or an optionally substituted carbon
Ring B represents 1 to 3 substituents;
A 5-membered heterocyclic ring which may further have a substituent;
A divalent saturated hydrocarbon group of the formulas 1 to 20;^TwoIs -O
R⁸ (R⁸Is a hydrogen atom or an optionally substituted carbon
Represents a hydrogen group) or -NR⁹R^Ten (R⁹And R^TenIs
Same or different hydrogen atom, optionally substituted charcoal
A hydrogen group, an optionally substituted heterocyclic group, or an acyl group
Or R⁹And R^TenIs adjacent
Together with a nitrogen atom to form an optionally substituted ring
May be shown). Provided that ring B is a nitrogen-containing 5-membered complex
When it is a ring, the nitrogen-containing 5-membered heterocyclic ring has a ring-forming N atom
In the formula:(Where R^1aIs an optionally substituted hydrocarbon group or
A heterocyclic group which may be substituted; Xa represents a bond, an oxygen atom
, Sulfur atom, -CO-, -CS-, -CR^2a(O
R^3a)-Or -NR^4a− (R^2aAnd R^4aIs hydrogen field
And the optionally substituted hydrocarbon group is represented by R^3aIs water
Ma represents 0)
Ya is an oxygen atom, a sulfur atom, -SO-,
-SO_Two-, -NR^5a-, -CONR^5a-Or -NR
^5aCO- (R^5aIs a hydrogen atom or may be substituted
Ring Aa has 1 to 3 substituents
An aromatic ring which may further have a group;
8 (indicating an integer of 8). ]
Or a salt thereof. 2. R ² is —OR ⁸ (R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon 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 acyl group; or R ⁹ and R ¹⁰ may be combined with an adjacent nitrogen atom to form a ring. The compound according to claim 1, which is 3. The compound according to claim 1, wherein the 5-membered heterocyclic group represented by R ¹ is a 5-membered aromatic heterocyclic group. 4. The compound according to claim 3, wherein the 5-membered aromatic heterocyclic group is oxazolyl, thiazolyl or triazolyl. 5. The compound according to claim 1, wherein X is a bond or —NR ⁵ — (R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an amino-protecting group). 6. The compound according to claim 1, wherein Q is C _1-6 alkylene or C _2-6 alkenylene. 7. The compound according to claim 1, wherein Y is an oxygen atom or —NR ⁶ — (R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group). 8. The compound according to claim 1, wherein the aromatic ring represented by ring A is a benzene ring or a pyridine ring. 9. n is an integer of 0 to 3, Z ¹ is a bond,
Oxygen atom, a sulfur ^{atom, -NR 7 -, - CONR 7} - or -NR ⁷ CO- (R ⁷ is a hydrogen atom or an optionally substituted hydrocarbon group) A compound according to claim 1 wherein the. 10. The compound according to claim 1, wherein ring B is a pyrazole ring, an oxazole ring or a thiazole ring which may further have 1 to 3 substituents. 11. The compound according to claim 1, wherein W is a divalent saturated hydrocarbon group having 1 to 6 carbon atoms. 12. The compound according to claim 1, wherein R ² is —OR ⁸ (R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group). 13. The compound according to claim 1, wherein the substituent which ring B may further have is a hydrocarbon group. 14. [1-methyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] acetic acid, [1
-Methyl-3- [6- (5-methyl-2-phenyl-4
-Oxazolylmethoxy) -3-pyridylmethoxy]-
1H-pyrazol-4-yl] acetic acid, [1-methyl-3
-[6- (2-phenyl-4-thiazolylmethoxy)-
3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid, [1-benzyl-3- [6- (5-methyl-
2-phenyl-4-oxazolylmethoxy) -3-pyridylmethoxy] -1H-pyrazol-4-yl] acetic acid,
[3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1
H-pyrazol-4-yl] acetic acid, [3- [6- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
3-pyridylmethoxy] -1-phenyl-1H-pyrazol-4-yl] acetic acid, 3- [3- [3-methoxy-4]
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1-phenyl-1H-pyrazol-5-yl] propionic acid, 3- [3- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxy] -1-phenyl-1H-pyrazole-
5-yl] propionic acid or 3- [3- [3- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
[Benzyloxy] -1-phenyl-1H-pyrazole-
5-yl] propionic acid. 15. A prodrug of the compound of claim 1 or a salt thereof. 16. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof or a prodrug thereof. 17. The method according to claim 1, which is a prophylactic / therapeutic agent for diabetes.
7. The pharmaceutical composition according to 6. 18. The pharmaceutical composition according to claim 16, which is an agent for preventing or treating hyperlipidemia. 19. The pharmaceutical composition according to claim 16, which is a preventive or therapeutic agent for impaired glucose tolerance. 20. A retinoid-related receptor function modulator comprising the compound according to claim 1 or a salt thereof or a prodrug thereof. 21. The agent according to claim 20, which is a peroxisome proliferator-activated receptor ligand. 22. The agent according to claim 20, which is a retinoid X receptor ligand. 23. An insulin sensitizer comprising the compound according to claim 1 or a salt thereof or a prodrug thereof. 24. A method for preventing or treating diabetes in a mammal, comprising administering the compound according to claim 1 or a salt thereof or a prodrug thereof to the mammal. 25. Use of the compound according to claim 1, a salt thereof, or a prodrug thereof for producing a prophylactic / therapeutic agent for diabetes. 26. A compound of the general formula [Wherein, R ¹ represents a 5-membered heterocyclic group which may be substituted,
X is a bond, an oxygen atom, a sulfur atom, -CO-, -CS
—, —CR ³ (OR ⁴ ) — or —NR ⁵ — (R ³ is a hydrogen atom or an optionally substituted hydrocarbon group, R ⁴ is a hydrogen atom or a hydroxyl-protecting group, and R ⁵ is a hydrogen atom Q represents a divalent hydrocarbon group having 1 to 20 carbon atoms; Y represents a bond, an oxygen atom, a sulfur atom, -SO -, -S
O ₂ —, —NR ⁶ —, —CONR ⁶ — or —NR ⁶ CO—
(R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group); ring A is an aromatic ring optionally having 1 to 3 substituents; Z is-(CH ₂ ) _n -Z ¹ - or -Z ¹ - a (n 0 to an integer of 8, - (CH _{2) n}
Z ¹ is a bond, an oxygen atom, a sulfur atom, —SO—, —SO ₂
^{-, - NR 7 -, -} CONR 7 - or -NR ⁷ CO-
(R ⁷ represents a hydrogen atom or an optionally substituted hydrocarbon group)); Ring B is a 5-membered heterocyclic ring which may further have 1 to 3 substituents; A divalent saturated hydrocarbon group having 1 to 20 carbon atoms; R ^{8 ′} represents an optionally substituted hydrocarbon group; Wherein the compound represented by the general formula (1) or a salt thereof is subjected to a hydrolysis reaction. [The symbols in the formula are as defined above. ] Or a salt thereof.