JP2000302680A - Brain protective agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic and therapeutic agent for brain edema, cerebrovascular disease or cephalopathy having low toxicity, brain protecting action, excellent safety, brain transfer, metabolic stability by making the prophylactic and therapeutic agent include a specific 1,3-azole compound. SOLUTION: This prophylactic and therapeutic agent comprises a 1,3-azole compound of the formula [R1 is H, a (substituted) hydrocarbon, a (substituted) heterocyclic group, a (substituted) amino or an acyl; one of R2 and R3 is H, a (substituted) pyridyl or a (substituted) aromatic hydrocarbon and the other is a (substituted) pyridyl; X is S, O, NR4 (R4 is H, a hydrocarbon, an acyl, or the like)] which is substituted with a pyridyl group that may contain a substituent at least at one of the 4-position and the 5-position and may be N- oxidized, such as N-[4-(4methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide. A daily dose of 1,3-azole compound is preferably 1-20 mg/kg body weight as an injection.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive / therapeutic agent for cerebral edema, cerebrovascular disorder or head injury characterized by containing a 1,3-azole compound.

[0002]

2. Description of the Related Art In cerebrovascular disorders (cerebral hemorrhage, cerebral infarction, etc.) and head trauma, it is difficult to restore the function of damaged central nervous tissue, and the treatment is focused on preventing secondary disorders. Is squeezed. In particular, when cerebral edema that occurs during cerebrovascular disorder or head trauma is remarkable, it causes cerebral hernia due to increased intracranial pressure and threatens life. Although it is very difficult to treat cerebral edema, it is first attempted to eliminate the cause (eg, surgical removal of hematoma in cerebral hemorrhage), and at the same time, try to remove D-mannnitol or glycerol (gl).
osmotherapy with ycerol) is applied. A diuretic such as furosemide may be used in combination with these. However, these drugs also have a limited therapeutic effect because they only physically drain water from the brain. Others may use glucocorticoids, but their effects are no better than hyperosmolars. Recently, it has been reported that cerebral hypothermia is effective for the treatment of acute cerebrovascular disease and head trauma.However, due to the difficulty of maintenance and risk of infection, etc. It is a difficult situation to do. Thus, there has not yet been found a revolutionary method for the preventive treatment of cerebral edema, cerebrovascular disorder or head trauma from both a surgical aspect and a drug aspect.

On the other hand, the following compounds are known as thiazole compounds. 1) analgesic, antipyretic, anti-inflammatory, anti-ulcer, thromboxane A ₂
(TXA ₂ ) has a synthetase inhibitory action and a platelet aggregation inhibitory action,
formula

Embedded image [In the formula, R ¹ is a cycloalkyl group, a cyclic amino group, an amino group optionally having one or two lower alkyl, phenyl, acetyl or lower alkoxycarbonylacetyl as a substituent, a hydroxyl, carboxyl or a substituent as a substituent. As an alkyl group or a substituent which may have a lower alkoxycarbonyl, carboxyl, 2-
A phenyl group optionally having carboxyethenyl or 2-carboxy-1-propenyl, R ² represents a pyridyl group optionally having lower alkyl as a substituent,
R ³ represents a phenyl group which may have lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy as a substituent. 1,3-thiazole derivative or a salt thereof (JP-A-60-58981). 2) analgesic, antipyretic, anti-inflammatory, anti-ulcer, TXA ₂ synthase inhibition,
Formula having platelet aggregation inhibitory action

Embedded image [Wherein, R ¹ is an alkyl group which may have a substituent,
An alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group having a carbon bond or an amino group,
R ² represents a pyridyl group which may be substituted with an alkyl group, and R ³ represents a phenyl group which may have a substituent. 1,3-thiazole derivatives or salts thereof (JP-A-61-10580). 3) analgesic, antipyretic, anti-inflammatory, anti-ulcer, TXA ₂ synthase inhibition,
Formula having platelet aggregation inhibitory action

Embedded image [Wherein, R ¹ is an alkyl group which may have a substituent,
An alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group having a carbon bond or an amino group,
R ² represents a pyridyl group which may be substituted with an alkyl group, and R ³ represents an aryl group which may have a substituent. 1,3-thiazole derivative or a salt thereof (USP 4,612,321). 4) As having gastric acid secretion inhibitory action,

Embedded image Wherein R ¹ is phenyl which may be substituted, R ² is C
_1-6 alkyl or (CH ₂ ) _n Ar, n is 0 to 2, Ar is optionally substituted phenyl, R ³ is hydrogen or C _1-4 alkyl, R ⁴ is hydrogen, C _1-4 alkyl, etc. , R ⁵ is hydrogen or C
_1-4 alkyl and R ⁶ represent hydrogen, C _1-4 alkyl and the like. ]
Or a salt thereof (Japanese Patent Application Laid-Open No. 7-503023)
No. WO93 / 15071). 5) Formulas that are anti-inflammatory and anti-allergic agents

Embedded image[Wherein, R¹Is pyridyl, R^TwoIs phenyl, R^Threeas well as
R^FourIs hydrogen or methyl, R ^FiveIs methyl, R⁶Is hydrogen,
Indicates chill or the like. Or a salt thereof (DE-
A-3601411). 6) Having anti-inflammatory, antipyretic, analgesic and anti-allergic effects
Then the formula

Embedded image [Wherein R ¹ is lower alkyl substituted with halogen, R ²
Represents pyridyl or the like, and R ³ represents phenyl or the like. Or a salt thereof (JP-A-5-70446).

[0004]

Problems to be Solved by the Invention As a preventive / therapeutic agent for cerebral edema, cerebrovascular disorder or head trauma, it has been found that the agent has satisfactory effects, safety, brain localization, metabolic stability and the like. Absent. Therefore, an effective prophylactic and / or therapeutic agent for cerebral edema, cerebrovascular disorder or head injury is eagerly desired.

[0005]

As a result of various studies, the present inventors have found that at least one of the 4- and 5-positions of 1,3-azole is substituted with a pyridyl group which may have a substituent. However, 1,3-azole compounds having the features of chemical structures (hereinafter, sometimes abbreviated as compound (I)) may be, for example, a compound of the formula (I) which may be N-oxidized.
a)

Embedded image [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an amino group or an acyl group which may have a substituent. , R ² and R ³
One of a hydrogen atom, a pyridyl group which may have a substituent or an aromatic hydrocarbon group which may have a substituent,
The other is a pyridyl group which may have a substituent, and X is a sulfur atom, an oxygen atom or a formula NR ⁴ which may be oxidized.
(Wherein, R ⁴ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group). ]
Including a compound represented by the following or a salt thereof (hereinafter, also sometimes abbreviated as compound (Ia)), has an unexpectedly excellent brain protection effect on cerebral edema, cerebrovascular disorder, head trauma, etc. In addition, they have excellent properties as pharmaceuticals such as stability, and have found for the first time that they are sufficiently satisfactory as pharmaceuticals, and based on these findings, completed the present invention.

That is, the present invention provides (1) a prophylactic / therapeutic agent for cerebral edema, cerebrovascular disorder or head injury characterized by containing compound (I), and (2) a 1,3-azole compound comprising The prophylactic / therapeutic agent according to the above (1), which is (Ia), (3) R
¹ is (i) a hydrogen atom, (ii) C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _optionally having 1 to 5 substituents,
A C _3-6 cycloalkyl, a C _6-14 aryl or a C _7-16 aralkyl group; (iii) _optionally having 1 to 5 substituents, from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom 5 to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected; (iv) (a) C _1-6 alkyl _optionally having 1 to 5 substituents, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C
_7-16 aralkyl, (b) C _1-6 alkylidene optionally having 1 to 5 substituents, (c) 1 to 5 substituents
A 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, which may have a carbon atom, and (d) a formula:-(C =
^{O) -R 5, - (C} = O) -OR 5, - (C = O) -NR
⁵ R ⁶ , — (C ＝ S) —NHR ⁵ or —SO ₂ —R ⁷ (where R ⁵ is a hydrogen atom, a hydrocarbon group which may have a substituent or a A heterocyclic group, R ⁶ represents a hydrogen atom or C _1-6 alkyl, and R ⁷ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.) (V) C _1-6 alkyl, C _6-14 aryl, C _1-6 alkyl-carbonyl, 5 to 10 amino groups which may have one or two substituents selected from acyl represented by 1 to 4 substituents selected from nitrogen, sulfur and oxygen other than carbon and at least one nitrogen which may have 1 to 3 substituents selected from membered aromatic heterocyclic groups and oxo. A 5- to 7-membered non-aromatic cyclic amino group optionally containing two heteroatoms, or (vi) a compound of the formula:-(C = O) -R ^{5, - (C = O)} -OR 5, -
^{(C = O) -NR 5 R} 6, - (C = S) -NHR 5 or -S
An acyl group represented by O ₂ —R ⁷ (wherein each symbol is as defined above); one of R ² and R ³ is (i) a hydrogen atom,
(Ii) a pyridyl group optionally having 1 to 5 substituents or (iii) a C _6-14 aryl group _optionally having 1 to 5 substituents (when two adjacent substituents are Combined 4
Or a 7-membered non-aromatic carbocyclic ring); the other is a pyridyl group optionally having 1 to 5 substituents; and a sulfur atom, oxygen atom or A group represented by the formula NR ⁴ , wherein R ⁴ is (i) a hydrogen atom,
(Ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl optionally having 1 to 5 substituents,
C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, or (iii) formula: — (C ＝ O) —R ⁵ , — (CＣO)
^{-OR 5, - (C = O} ) -NR 5 R 6, - (C = S) -NHR
⁵ or —SO ₂ —R ⁷ (wherein each symbol has the same meaning as described above) (R ¹ , R ² , R ³ , R ⁴ , R
^{When the} groups represented by ⁵ , R ⁶ and R ⁷ have a substituent, the substituent may be (1) a halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, (4) ) Cyano, (5) optionally halogenated C _1-6 alkyl, (6) optionally halogenated C _2-6 alkenyl, (7) carboxy C _2-6 alkenyl, (8) halogenated _Optionally substituted C _2-6 alkynyl, (9) optionally halogenated C
_3-6 cycloalkyl, (10) C _6-14 aryl, (11) optionally halogenated C _1-8 alkoxy, (12) C
_1-6 alkoxy-carbonyl-C _1-6 alkoxy, (13)
Hydroxy, (14) C _6-14 aryloxy, (15) C
_7-16 aralkyloxy, (16) mercapto, (17) optionally halogenated C _1-6 alkylthio, (18) C
_6-14 arylthio, (19) _C7-16 aralkylthio, (2
0) amino, (21) mono-C _1-6 alkylamino, (22)
Mono-C _6-14 arylamino, (23) di-C _1-6 alkylamino, (24) di-C _6-14 arylamino, (25) formyl, (26) carboxy, (27) C _1-6 Alkyl-carbonyl, (28) C _3-6 cycloalkyl-carbonyl,
(29) C _1-6 alkoxy-carbonyl, (30) C _6-14 aryl-carbonyl, (31) C _7-16 aralkyl-carbonyl, (32) C _6-14 aryloxy-carbonyl, (3
3) C _7-16 aralkyloxy-carbonyl, (34) 5- or 6-membered heterocyclic carbonyl, (35) carbamoyl or thiocarbamoyl, (36) mono-C _1-6 alkyl-carbamoyl, (37) di-C _{1 -6} alkyl-carbamoyl, (3
8) mono- or di-C _6-14 aryl-carbamoyl, (3
9) mono- or di-5 or 6 membered heterocyclic carbamoyl, (4
0) C _1-6 alkylsulfonyl, (41) C _6-14 arylsulfonyl, (42) formylamino, (43) C _1-6 alkyl-carbonylamino, (44) C _6-14 aryl-carbonylamino, ( 45) C _1-6 alkoxy-carbonylamino, (46) C _1-6 alkylsulfonylamino, (47) C
_6-14 arylsulfonylamino, (48) C _1-6 alkyl - carbonyloxy, (49) C _6-14 aryl - carbonyloxy, (50) C _1-6 alkoxy - carbonyloxy, (51) mono -C _{1 -6} alkyl - carbamoyloxy, (52) di -C _1-6 alkyl - carbamoyloxy,
(53) mono- or di-C _6-14 aryl-carbamoyloxy, (54) nicotinoyloxy, (55) C _1-6 alkyl, C _6-14 aryl, C _1-6 alkyl-carbonyl, 5
A 5- to 7-membered saturated cyclic amino optionally having 1 to 3 substituents selected from a to 10-membered aromatic heterocyclic group and oxo, (56) a 5- to 10-membered aromatic heterocyclic group and (57) (4) R ⁵ is (i) a hydrogen atom, and (ii) C _1-6 which may have 1 to 5 substituents, respectively. Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl or (iii) _optionally having 1 to 5 substituents, A 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom; R ⁶ is a hydrogen atom or C _1-6 alkyl; and R ⁷ is (i C) C _1-6 alkyl, C _2-6 alkenyl _optionally having 1 to 5 substituents, _2-6 alkynyl,
C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl or (ii) _optionally having 1 to 5 substituents, selected from nitrogen, sulfur and oxygen other than carbon atoms 5 to 1 containing 1 to 4 heteroatoms
The prophylactic / therapeutic agent according to the above (3), which is a 4-membered heterocyclic group,
(5) The prophylactic / therapeutic agent according to the above (2), wherein R ¹ is an amino group which may have a substituent, (6) R ¹ is a compound represented by the formula:-(C =
^{O) -R 5, - (C} = O) -OR 5, - (C = O) -NR
⁵ R ⁶ , — (C ＝ S) —NHR ^5, or —SO ₂ —R ⁷ (wherein the symbols have the same meanings as in the above (3)). The prophylactic / therapeutic agent according to the above (3), which is an amino group; (7) R ¹ is a group represented by the formula:-(C = O)
-R ⁵ or - at ^{(C = O) -NR 5 R} 6 acyl of 1 or 2 optionally having an amino group (the symbols in the formula above (3) and the same meaning) represented by there wherein (3), wherein the prophylactic treatment agent, (8) X is the sulfur atom (2) wherein the preventive treatment agent, (9) the R ² is a pyridyl group which may have a substituent (2) the prophylactic / therapeutic agent according to (10) R
(3) wherein ³ is a C _6-14 aryl group which may have a substituent, (11) R ¹ is a group represented by the formula:-(C
ＯO) —R ⁵ or — (C ＝ O) —NR ⁵ R ⁶ (the symbols in the formula have the same meanings as in the above (3)), and may have one or two acyl groups. An amino group; R ² is C _1-6 alkyl,
Pyridyl group optionally having 1 to 5 substituents selected from hydroxy and C _1-6 alkyl-carbonyloxy; R ³ is a halogen atom, optionally halogenated C _1-6 alkyl, halogenated The preventive treatment according to the above (3), wherein X is a sulfur atom, and a C _6-14 aryl group optionally having 1 to 5 substituents selected from C _1-6 alkoxy and carboxy; Agent, (12) R ¹
Is (i) a halogen atom, an optionally halogenated C
_1-6 alkyl, carboxy C _2-6 alkenyl, optionally halogenated C _1-6 alkoxy, C _1-6 alkoxy-
Carbonyl-C _1-6 alkoxy, hydroxy, amino,
Mono- or di-C _1-6 alkylamino, carboxy, C
C _1-8 alkyl optionally having 1 to 5 substituents each selected from _1-6 alkoxy-carbonyl, mono- or di-C _1-6 alkyl-carbamoyl and C _6-14 aryl-carbonylamino A C _3-6 cycloalkyl group or a C _6-10 aryl group, (ii) a 5-membered heterocyclic group, (iii)
(1) C _1-6 alkyl, (2) C _6-14 aryl, (3) C
_7-16 aralkyl, (4) a 6-membered heterocyclic group and (5) a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, carboxy and C _1-6 alkoxy-carbonyl, 1 to 3 C _1-6 alkyl-carbonyl, C _3-6 cycloalkyl-carbonyl, C
_6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-6 alkyl-carbamoyl or 5 or 6
An amino group optionally having one or two substituents selected from membered heterocyclic carbonyl or (6) di-C _1-6 alkylamino-C _1-6 alkylidene, (iv) C _1-6 alkyl −
5 or 6 optionally substituted by carbonyl or oxo
Membered non-aromatic cyclic amino group or (v) carboxy group; R ² may have 1 to 3 substituents selected from C _1-6 alkyl, hydroxy and C _1-6 alkyl-carbonyloxy Pyridyl group; R ³ is a halogen atom, C _1-3 alkylenedioxy, optionally halogenated C _1-6
Alkyl, carboxy C _2-6 alkenyl, optionally halogenated C _1-8 alkoxy, hydroxy, C _7-16
A C _6-10 aryl group _optionally having 1 to 3 substituents selected from aralkyloxy and C _1-6 alkyl-carbonyloxy (a 5-membered group wherein two adjacent alkyl groups are bonded as a substituent; Or a non-aromatic carbon ring); and X is a sulfur atom.

In the present specification, examples of the “acyl group” include those represented by the formulas: — (C ＝ O) —R ⁵ , — (C ＝ O) —OR ⁵ , and — (C =
^{O) -NR 5 R 6, -} (C = S) -NHR 5 or -SO ₂ -R
⁷ (wherein, R ⁵ is a hydrogen atom, which may have a hydrocarbon may have a substituent hydrogen group or an optionally substituted heterocyclic group, R ⁶
_{Represents a} hydrogen atom or C _1-6 alkyl, and R ⁷ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. And the like. In the above formula, examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ⁵ include a chain or cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, Cycloalkyl, aryl, aralkyl and the like). Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable. “Alkyl” includes, for example, C _1-6 alkyl (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. “Alkenyl” includes, for example, C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2
-Propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.) and the like. "Alkynyl"
As C _2-6 alkynyl (eg, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-
Butynyl, 1-hexynyl, etc.) and the like. As the “cycloalkyl”, for example, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is preferable. “Aryl” includes, for example, C _6-14 aryl (eg, phenyl, 1
-Naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like). “Aralkyl” includes, for example, C _7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
2,2-diphenylethyl, 3-phenylpropyl, 4
-Phenylbutyl, 5-phenylpentyl and the like).

The “substituent” of the “optionally substituted hydrocarbon group” represented by R ⁵ includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 Alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _2-6
Alkenyl, carboxy C _2-6 alkenyl (eg, 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.), optionally halogenated C _2-6 alkynyl, optionally halogenated C _{3- 6} cycloalkyl, C _6-14 aryl (eg, phenyl, 1-naphthyl, 2
-Naphthyl, 2-biphenylyl, 3-biphenylyl, 4
-Biphenylyl, 2-anthryl, etc.), optionally halogenated C _1-8 alkoxy, C _1-6 alkoxy-carbonyl-C _1-6 alkoxy (eg, ethoxycarbonylmethyloxy, etc.), hydroxy, C _{6- 14} aryloxy (eg, phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.), C _7-16 aralkyloxy (eg, benzyloxy, phenethyloxy, etc.), mercapto, optionally halogenated C _{1- 6} alkylthio, C _6-14
Arylthio (eg, phenylthio, 1-naphthylthio,
2-naphthylthio, etc.), C _7-16 aralkylthio (eg, benzylthio, phenethylthio, etc.), amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, etc.), mono-C _6-14 aryl Amino (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, etc.), di-C
_6-14 arylamino (eg, diphenylamino, etc.), formyl, carboxy, C _1-6 alkyl-carbonyl (eg,
Acetyl, propionyl, etc.), C _3-6 cycloalkyl-
Carbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C
_1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert
-Butoxycarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _7-16 aralkyl-carbonyl (eg, phenylacetyl, 3-phenylpropionyl, etc.), C _{6 -14} aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _7-16 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, tenoyl) , Furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di- C _1-6 alkyl - Cal Moil (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), mono - or di -C _6-14 aryl - carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), mono -
Or a di-5 or 6 membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-
Thienylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C
_6-14 arylsulfonyl (eg, phenylsulfonyl, 1
-Naphthylsulfonyl, 2-naphthylsulfonyl and the like),
Formylamino, C _1-6 alkyl-carbonylamino (eg, acetylamino, etc.), C _6-14 aryl-carbonylamino (eg, benzoylamino, naphthoylamino, etc.), C _1-6 alkoxy-carbonylamino (eg, Methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _6-14
Arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), mono- or di-C _1-6 alkyl-
Carbonyloxy (eg, acetoxy, propionyloxy, etc.), C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), C _1-6
Alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-
C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-
C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.),
C _6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
Nicotinoyloxy, an optionally substituted 5- to 7-membered saturated cyclic amino, 5- to 10-membered aromatic heterocyclic group (eg, 2-thienyl, 3-thienyl, 2-pyridyl,
-Pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-
Isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,
5-isoquinolyl, 1-indolyl, 2-indolyl,
3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl and the like, and sulfo. The “hydrocarbon group” may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions. When the number of the substituents is 2 or more, each substituent is They may be the same or different.

The above-mentioned “optionally halogenated C _1-6”
The “alkyl” includes, for example, C _1-6 alkyl (eg, methyl, ethyl) which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoro Propyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6- Trifluorohexyl and the like. The “optionally halogenated C _2-6 alkenyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Good C
_2-6 alkenyl (eg, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl) and the like. The “optionally halogenated C _2-6 alkynyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkynyl (eg, 2-butyne-
1-yl, 4-pentyn-1-yl, 5-hexyne-1
-Yl and the like). The “optionally halogenated C _3-6 cycloalkyl” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like. The “optionally halogenated C _1-8 alkoxy” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-8 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
Hexyloxy) and the like. As a specific example,
For example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4
4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
The “optionally halogenated C _1-6 alkylthio” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.). Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
4,4,4-trifluorobutylthio, pentylthio,
Hexylthio and the like.

The "5- to 7-membered saturated cyclic amino" of the "5- to 7-membered saturated cyclic amino optionally having substituent (s)" includes, for example, a nitrogen atom other than one nitrogen atom and a carbon atom. , A sulfur atom and an oxygen atom, selected from the group consisting of one or two, and a 5- to 7-membered saturated cyclic amino which may contain 1 to 4 heteroatoms. Specific examples thereof include pyrrolidin-1-yl, piperidino , Piperazine-
Examples thereof include 1-yl, morpholino, thiomorpholino, and tetrahydroazepin-1-yl. Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, etc.),
C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.) ) 5- to 10-membered aromatic heterocyclic group (eg, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl and the like, and 1 to 3 oxo.

The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” for R ⁵ is, for example, one or more selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. 2 to 5 to 14 membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 heteroatoms, preferably (i) 5 to 14 membered (preferably 5 to 10 membered) aromatic heterocyclic And a monovalent group formed by removing any one hydrogen atom from a ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring, or (iii) a 7- to 10-membered bridged heterocyclic ring. Examples of the above “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle” include, for example, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benziso Thiazole, naphtho [2,3-b] thiophene,
Furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,
Isoindole, 1H-indazole, purine, 4H-
Quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
Carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,
An aromatic heterocyclic ring such as phenothiazine, isoxazole, furazane, phenoxazine, or one or more (preferably one or two) aromatic rings (preferably one or two) of these rings (preferably one or two); And a ring formed by condensation. The above “5- to 10-membered non-aromatic heterocycle”
Examples thereof include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like. The above “7 to 10
As the "membered heterocyclic ring", for example, quinuclidine, 7-
Azabicyclo [2.2.1] heptane and the like.

The "heterocyclic group" is preferably a 5- to 14-membered member containing one or two, preferably one to four, heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. It is preferably a 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group. Specifically, for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2- Imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2
Aromatic heterocyclic groups such as indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl and 3-benzo [b] furanyl; For example, 1-pyrrolidinyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-
Pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2
-Piperidyl, 3-piperidyl, 4-piperidyl, 1-
Non-aromatic heterocyclic groups such as piperazinyl, 2-piperazinyl, morpholino and thiomorpholino. Among them, for example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom is more preferable. Specifically, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
Pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-
Pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-
Isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4- Piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like. As the "substituent" of the "heterocyclic group which may have a substituent", for example, the represented by R ⁵ in the "optionally substituted hydrocarbon group" as "substituent" The same thing is mentioned. The “heterocyclic group” may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions. When the number of substituents is 2 or more, each substituent is They may be the same or different.

The "C _1-6 alkyl" represented by R ⁶ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, hexyl and the like can be mentioned. As "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ^7, for example wherein R
⁵ "optionally substituted hydrocarbon group"
And "heterocyclic group optionally having substituent (s)", respectively. “1,3” of “1,3-azole compound in which at least one of the 4-position and 5-position is substituted with an optionally substituted pyridyl group” in the compound (I)
Examples of the “azole compound” include 1,3-thiazole, 1,3-oxazole, 1,3-imidazole and the like. The “1,3 wherein at least one of the 4-position and 5-position is substituted with a pyridyl group optionally having substituent (s)”.
As the “substituent” of the “pyridyl optionally having substituent (s)” of the “-azole compound”, for example, the “substituent of the“ optionally substituted hydrocarbon group ”represented by R ⁵ ].

The "pyridyl group" may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions, and when the number of the substituents is 2 or more,
Each substituent may be the same or different. Further, the nitrogen atom in the ring of the “pyridyl group” may be N-oxidized. The above “1,3 wherein at least one of the 4-position and 5-position is substituted with an optionally substituted pyridyl group.
The “-azole compound” may further have 1 to 4, preferably 1 to 3 substituents. When the number of substituents is two or more, each substituent may be the same or different. Examples of the “substituent” include a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, an amino group optionally having a substituent, an acyl group, and the like. Is mentioned.

[0015] As the "optionally substituted hydrocarbon group" and "an optionally substituted heterocyclic group" may have a "substituent represented by R ⁵ Hydrocarbon group "and" heterocyclic group optionally having substituent (s) "
Respectively. The “amino group optionally having substituent (s)” includes (1) an amino group optionally having one or two substituents and (2) a cyclic amino optionally having substituent (s). Groups. Examples of the “substituent” of the “amino group optionally having one or two substituents” in the above (1) include, for example, a hydrocarbon group optionally having a substituent, And an optionally substituted heterocyclic group, an acyl group, and an optionally substituted alkylidene group. Examples of the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” include the “optionally substituted hydrocarbon group” for R ^5. The same groups as the “hydrogen group” and “heterocyclic group optionally having substituent (s)” can be exemplified. Examples of the “alkylidene group” of the “alkylidene group optionally having substituent (s)” include, for example, C _1-6 alkylidene (eg, methylidene,
Ethylidene, propylidene, etc.). "Substituent" of the "alkylidene group optionally having substituent (s)"
Examples of the substituent include 1 to 5, preferably 1 to 3, the same as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ⁵ . When the number of the “substituents” in the “amino group optionally having one or two substituents” is two, the respective substituents may be the same or different. The “cyclic amino group” of the “optionally substituted cyclic amino group” in the above (2) is selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atom. One or two or more 5- to 7-membered non-aromatic cyclic amino groups which may contain 1 to 4 heteroatoms, and specific examples thereof include pyrrolidin-1-yl, piperidino, piperazin-1-yl Morpholino, thiomorpholino, tetrahydroazepin-1-yl, imidazolidine-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1 (2H) -pyrimidinyl, 3,6-dihydro-1 (2H) -pyrimidinyl,
3,4-dihydro-1 (2H) -pyrimidinyl and the like. As the "substituent" of the "cyclic amino group which may have a substituent", for example, as a "substituent" of the "optionally substituted hydrocarbon group" represented by R ⁵ One to three of the same “substituents” as the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” described above may be mentioned. Specific examples of the 5- to 7-membered non-aromatic cyclic amino group having one oxo include 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1 (2H) -pyrimidinyl, 2-oxo-3,6
-Dihydro-1 (2H) -pyrimidinyl, 2-oxo-
3,4-dihydro-1 (2H) -pyrimidinyl and the like.

Preferred examples of compound (I) include compound (Ia). The nitrogen atom as a constituent atom of 1,3-azole in compound (Ia) may be N-oxidized. “Optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group” and “optionally substituted amino group” represented by R ¹
Are a "hydrocarbon group optionally having substituent (s)", a "heterocyclic group optionally having substituent (s)" and "substituent" which the compound (I) may have as a substituent. And the same as the "amino group optionally having".
R ¹ is preferably an amino group which may have a substituent. More preferably, the formula ^{:-( C = O) -R 5,} - (C
^{= O) -OR 5, - (} C = O) -NR 5 R 6, - (C = S) -N
HR ⁵ or —SO ₂ —R ⁷ wherein each symbol is as defined above. An amino group which may have one or two acyl groups represented by the formula: Particularly preferably, the formula:-(C =
O) -R ⁵ or ^{- (C = O) -NR 5} R 6 wherein each symbol is as defined above. An amino group which may have one or two acyl groups represented by the formula:

As the "pyridyl group optionally having substituent (s)" for R ² or R ³ , the "pyridyl group optionally having substituent (s)" which the compound (I) has And the same as "pyridyl group". The “aromatic hydrocarbon group” of the “aromatic hydrocarbon group optionally having substituent (s)” for R ² or R ³ includes, for example, a monocyclic or condensed polycyclic group having 6 to 14 carbon atoms. An aromatic hydrocarbon group of the formula (bicyclic or tricyclic) is exemplified. Specific examples thereof include C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl and 2-anthryl. Examples of the “substituent” of the “optionally substituted aromatic hydrocarbon group” include the “substituent” of the “optionally substituted hydrocarbon group” represented by the aforementioned R ^5. And 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different. Two adjacent substituents are 4 to 7
It may form a membered non-aromatic carbon ring. Preferably it is a 5-membered non-aromatic carbocyclic ring.

One of R ² and R ³ may be a pyridyl group which may have a substituent or an aromatic hydrocarbon group which may have a substituent, and the other may have a substituent. Preference is given to a pyridyl group. R ² is preferably an optionally substituted pyridyl group. R ³ is preferably an optionally substituted C _6-14 aryl (preferably a C _6-10 aryl such as phenyl). The “optionally oxidized sulfur atom” represented by X includes S, S
O, SO ₂ . Examples of the “optionally substituted hydrocarbon group” represented by R ⁴ include the same as the “optionally substituted hydrocarbon group” represented by R ^5. . X is preferably a sulfur atom which may be oxidized. More preferably, it is S.

The compounds (I), R ¹ to the amino group which may have a substituent, preferably monoacylamino group; R ²
And one of R ³ and R ^{3 is} a pyridyl group optionally having a substituent or an aromatic hydrocarbon group optionally having a substituent, and the other is a pyridyl group optionally having a substituent; Is preferred. More preferably, R ¹ is of the formula:-(C =
O) -R ⁵ or ^{- (C = O) -NR 5} R 6 wherein each symbol is as defined above. An amino group optionally having 1 or 2 acyl groups represented by the formula: wherein R ² has 1 to 5 substituents selected from C _1-6 alkyl, hydroxy and C _1-6 alkyl-carbonyloxy; A pyridyl group which may be substituted; wherein R ³ is a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy and carboxy;
Pieces have good C _6-14 aryl group; and X is a compound such as an S. R ¹ is (i) a halogen atom, an optionally halogenated C _1-6 alkyl, carboxy C _2-6 alkenyl, an optionally halogenated C _1-6 alkoxy, C _1-6 alkoxy- Carbonyl-C _1-6 alkoxy, hydroxy, amino, mono- or di-C _1-6 alkylamino, carboxy, C _1-6 alkoxy-carbonyl, mono- or di-C _1-6 alkyl-carbamoyl and C _6- C _1-8 alkyl, C _3-6 cycloalkyl or C _6-14 aryl (preferably C _6-10 aryl) _optionally having 1 to 5 substituents selected from ₁₄ aryl-carbonylamino,

(Ii) a 5-membered heterocyclic group, (iii) (1) C _1-6
Alkyl, (2) C _6-14 aryl, (3) C _7-16 aralkyl, (4) 6-membered heterocyclic group and (5) halogen atom, C _1-6
C _1-6 alkyl-carbonyl, C _3-6 cycloalkyl-carbonyl optionally having 1 to 3 substituents each selected from alkyl, C _1-6 alkoxy, carboxy and C _1-6 alkoxy-carbonyl , C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C
1 or 2 substituents selected from _1-6 alkyl-carbamoyl or 5- or 6-membered heterocyclic carbonyl or (6)
An amino group optionally having di-C _1-6 alkylamino-C _1-6 alkylidene, (iv) a 5- or 6-membered non-aromatic optionally substituted by C _1-6 alkyl-carbonyl or oxo cyclic amino group or (v) carboxy group; R ² is C _1-6 alkyl, hydroxy and C _1-6 alkyl - 1 substituent selected from carbonyloxy it also pyridyl group have had three; R ³ is a halogen atom, C _1-3 alkylenedioxy, optionally halogenated C _1-6 alkyl, carboxy C _2-6 alkenyl, optionally halogenated C _1-8 alkoxy, hydroxy, C ₇ C may have 1 to 3 substituents selected from _-16 aralkyloxy and C _1-6 alkyl-carbonyloxy.
_6-10 aryl groups (two adjacent alkyl groups may be bonded as a substituent to form a 5-membered non-aromatic carbocyclic ring); and compounds wherein X is a sulfur atom are also preferred.

Preferred specific examples of compound (I) include:
N- [4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3-thiazol-2-yl] acetamide (Reference Example 10), N- [4- (4-methoxyphenyl)
-5- (4-pyridyl) -1,3-thiazol-2-yl] acetamide (Reference Example 23-64), N- [4-
(4-methoxyphenyl) -5- (4-pyridyl)-
1,3-thiazol-2-yl] propionamide (Reference Examples 23-37), N- [4- (4-methoxyphenyl) -5- (4-pyridyl) -1,3-thiazol-2
-Yl] -2-methylpropionamide (Reference Example 23-
105), N- [4- (4-methoxyphenyl) -5
(4-pyridyl) -1,3-thiazol-2-yl] butylamide, N- [4- (4-methoxyphenyl) -5
-(4-pyridyl) -1,3-thiazol-2-yl]
Benzamide (Reference Examples 23-38), N- [4- (4-
Methoxyphenyl) -5- (4-pyridyl) -1,3-
Thiazol-2-yl] nicotinamide (Reference Example 23-
101), N- [4- (4-methoxyphenyl) -5
(4-pyridyl) -1,3-thiazol-2-yl]-
N'-ethylurea (Reference Examples 23-156), N- [4
-(4-methoxyphenyl) -5- (4-pyridyl)-
1,3-thiazol-2-yl] -N'-propylurea (Reference Example 23-108), 4- (4-methoxyphenyl) -2- (2-oxoimidazolidin-1-yl)-
5- (4-pyridyl) -1,3-thiazole (Reference Example 2)
3-222), 4- (4-methoxyphenyl) -2-
(2-oxo-2,3-dihydro-1H-imidazol-1-yl) -5- (4-pyridyl) -1,3-thiazole, 4- (4-methoxyphenyl) -2- [2-oxotetrahydro -1 (2H) -pyrimidinyl] -5-
(4-pyridyl) -1,3-thiazole, 4- (4-methoxyphenyl) -2- (2-oxopyrrolidine-1-
Yl) -5- (4-pyridyl) -1,3-thiazole (Reference Examples 23-115), N- [4- (4-ethylphenyl) -5- (4-pyridyl) -1,3-thiazole-
2-yl] acetamide (Reference Examples 23-110), N-
[4- (4-ethylphenyl) -5- (4-pyridyl)
-1,3-thiazol-2-yl] propionamide,
N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (3-pyridyl) -1,3-thiazole-2
-Yl] acetamide (Reference Example 23-172), N-
[4- [4- (1,1-dimethylethyl) phenyl]-
5- (4-pyridyl) -1,3-thiazol-2-yl] acetamide (Reference Examples 23-137), N- [4-
[4- (1,1-dimethylethyl) phenyl] -5-
(4-pyridyl) -1,3-thiazol-2-yl] propionamide (Reference Example 23-163), N- [4-
[4- (1,1-dimethylethyl) phenyl] -5-
(4-pyridyl) -1,3-thiazol-2-yl]-
2-methylpropionamide (Reference Examples 23 to 138),
N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazole-2
-Yl] butylamide, N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl)-
1,3-thiazol-2-yl] cyclopentanecarboxamide (Reference Example 23-168), N- [4- [4-
(1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] benzamide (Reference Example 23-164), N- [4- [4- (1,1
-Dimethylethyl) phenyl] -5- (4-pyridyl)
-1,3-thiazol-2-yl] nicotinamide (Reference Example 23-165), N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,
3-thiazol-2-yl] -N'-ethylurea (Reference Example 23-169), N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,
3-thiazol-2-yl] -N'-propylurea (Reference Example 23-170), 4- [4- (1,1-dimethylethyl) phenyl] -2- (2-oxoimidazolidin-1-yl ) -5- (4-Pyridyl) -1,3-thiazole, 4- [4- (1,1-dimethylethyl) phenyl] -2- (2-oxo-2,3-dihydro-1H-imidazole-1 -Yl) -5- (4-pyridyl) -1,
3-thiazole,

4- [4- (1,1-dimethylethyl) phenyl] -2- [2-oxotetrahydro-1 (2H)
-Pyrimidinyl] -5- (4-pyridyl) -1,3-thiazole, 4- [4- (1,1-dimethylethyl) phenyl] -2- (2-oxopyrrolidin-1-yl) -5
-(4-pyridyl) -1,3-thiazole, N- [4-
(3,5-dimethylphenyl) -5- (3-pyridyl)
-1,3-thiazol-2-yl] acetamide (Reference Example 23-205), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazole-
2-yl] acetamide (Reference Examples 23-128), N-
[4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] propionamide (Reference Example 23-194), N- [4- (3,5- Dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -2-methylpropionamide (Reference Example 23-195), N- [4- (3,5-dimethylphenyl)- 5- (4-pyridyl) -1,3-thiazol-2-yl] butylamide, N- [4- (3,5-
Dimethylphenyl) -5- (4-pyridyl) -1,3-
Thiazol-2-yl] cyclopentanecarboxamide (Reference Example 23-198), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] benzamide (Reference Examples 23-19
7), N- [4- (3,5-dimethylphenyl) -5-
(4-pyridyl) -1,3-thiazol-2-yl] nicotinamide (Reference Example 23-199), N- [4-
(3,5-dimethylphenyl) -5- (4-pyridyl)
-1,3-thiazol-2-yl] -N′-ethylurea (Reference Example 23-201), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3- Thiazol-2-yl] -N'-propylurea (Reference Example 2
3-202), 4- (3,5-dimethylphenyl) -2
-(2-oxoimidazolidin-1-yl) -5- (4
-Pyridyl) -1,3-thiazole, 4- (3,5-dimethylphenyl) -2- (2-oxo-2,3-dihydro-1H-imidazol-1-yl) -5- (4-pyridyl) -1,3-thiazole, 4- (3,5-dimethylphenyl) -2- [2-oxotetrahydro-1 (2
H) -Pyrimidinyl] -5- (4-pyridyl) -1,3
-Thiazole, 4- (3,5-dimethylphenyl) -2
-(2-oxopyrrolidin-1-yl) -5- (4-pyridyl) -1,3-thiazole, N- [5- (4-pyridyl) -4- (4-trifluoromethylphenyl)-
1,3-thiazol-2-yl] acetamide (Reference Example 23-184), N- [5- (4-pyridyl) -4-
(4-trifluoromethylphenyl) -1,3-thiazol-2-yl] propionamide (Reference Examples 23-18)
5), N- [5- (4-pyridyl) -4- (4-trifluoromethylphenyl) -1,3-thiazol-2-yl] -2-methylpropionamide (Reference Examples 23-18)
6), N- [5- (4-pyridyl) -4- (4-trifluoromethylphenyl) -1,3-thiazol-2-yl] benzamide (Reference Example 23-188), N- [5-
(4-pyridyl) -4- (4-trifluoromethylphenyl) -1,3-thiazol-2-yl] nicotinamide (Reference Examples 23-190), N- [5- (4-pyridyl) -4- (4-trifluoromethylphenyl) -1,
3-thiazol-2-yl] -N'-ethylurea (Reference Example 23-192), N- [5- (4-pyridyl) -4
-(4-trifluoromethylphenyl) -1,3-thiazol-2-yl] -N'-propylurea (Reference Example 2
3-193) or salts thereof. In particular, N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazole-
2-yl] benzamide (Reference Examples 23-164), N-
[4- [4- (1,1-dimethylethyl) phenyl]-
5- (4-pyridyl) -1,3-thiazol-2-yl] nicotinamide (Reference Example 23-165), N- [4
-[4- (1,1-dimethylethyl) phenyl] -5-
(4-pyridyl) -1,3-thiazol-2-yl] cyclopentanecarboxamide (Reference Examples 23-168),
N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazole-2
-Yl] cyclohexanecarboxamide, N- [4-
(3,5-dimethylphenyl) -5- (4-pyridyl)
-1,3-thiazol-2-yl] acetamide (Reference Example 23-128), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazole-
2-yl] propionamide (Reference Examples 23-194),
2-methyl-N- [4- (3,5-dimethylphenyl)
-5- (4-pyridyl) -1,3-thiazol-2-yl] propionamide (Reference Examples 23-195), N-
[4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] butylamide, N- [4- (3,5-dimethylphenyl) -5-
(4-pyridyl) -1,3-thiazol-2-yl] pentanamide, N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazole-2
-Yl] hexaneamide, N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] benzamide (Reference Examples 23-19)
7), N- [4- (3,5-dimethylphenyl) -5-
(4-pyridyl) -1,3-thiazol-2-yl] nicotinamide (Reference Example 23-199), N- [4-
(3,5-dimethylphenyl) -5- (4-pyridyl)
-1,3-thiazol-2-yl] isonicotinamide (Reference Example 23-200), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazole- 2-yl] pyrazinecarboxamide (Reference Example 23
-246), N- [4- (3,5-dimethylphenyl)
-5- (4-Pyridyl) -1,3-thiazol-2-yl] cyclopentanecarboxamide (Reference Examples 23-19
8), N- [4- (3,5-dimethylphenyl) -5-
(4-pyridyl) -1,3-thiazol-2-yl] cyclohexanecarboxamide, 2-phenyl-N- [4
-(3,5-Dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] acetamide (Reference Example 23-196), N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -N'-ethylurea (Reference Example 23-
201), N- [4- (3,5-dimethylphenyl)-
5- (4-pyridyl) -1,3-thiazol-2-yl] -N′-propylurea (Reference Example 23-202) or a salt thereof is preferred.

The salts of compounds (I) and (Ia) include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like. Is mentioned. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,
Salts with ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, 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. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acid, p-
Salts with toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an alkali metal salt (eg, sodium salt,
Inorganic salts such as potassium salts, etc., alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc., and when the compound has a basic functional group, for example, bromide Hydrochloric acid, nitric acid, sulfuric acid, salts with inorganic acids such as phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like And salts with organic acids.

The method for producing compound (I) (including compound (Ia)) is described below. Compound (I) can be obtained by a method represented by the following reaction formulas 1 to 3, or a method analogous thereto, and for example, when compound (I) is 1,3-
In the case of oxazoles, the method described in WO 95/13067 or a method analogous thereto, and in the case of 1,3-imidazoles, USP 3,940,486, WO
88/01169, WO 93/14081, WO 95
In the case of 1,3-thiazoles, the method described in US Pat.
No. 10580, Japanese Patent Application Laid-Open No. 7-503023, W
O 93/15071, DE-A-3601411, JP-A-5-70446, or the like, or a method analogous thereto. Each symbol of the compounds in the following Reaction Formulas 1 to 3 has the same meaning as described above. The compound in the reaction formula includes a case in which a salt is formed.
For example, those similar to the salt of compound (I) and the like can be mentioned.

[0025]

Embedded image

Compounds (II), (III), (V), (VI
When I), (XI), (XIII) and (XIV) are commercially available, commercially available products can be used as they are, or they can be produced according to a method known per se or a method analogous thereto. Compound (IV) is compound (II) and compound (III)
By condensation in the presence of a base. In the compound (III), R ⁸ is, for example, C _1-6 alkoxy (eg,
Methoxy, ethoxy, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), NC
_6-10 aryl-N-C _1-6 alkylamino (eg, N-phenyl-N-methylamino and the like), C _6-10 aryl and / or C _1-6 alkyl _optionally substituted with 3 to And 7-membered cyclic amino (eg, pyrrolidino, morpholino, methylaziridin-1-yl and the like) and the like. Compound (III)
Is used in an amount of about 0.5 to about 3.0 mol, preferably about 0.8 to about 2.0 mol, per 1 mol of compound (II). The amount of the base to be used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (II). Examples of the "base" include basic salts such as sodium carbonate, potassium carbonate and cesium carbonate; inorganic bases such as sodium hydroxide and potassium hydroxide; aromatic amines such as pyridine and lutidine; triethylamine and tripropyl. Tertiary amines such as amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, hydrogenation Examples include alkali metal hydrides such as potassium, metal amides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, water, or a mixture of two or more thereof Are used. The reaction temperature is usually about -5 to about 200C, preferably about 5 to about 150C. The reaction time is usually about 5 minutes to about 7
2 hours, preferably about 0.5 to about 30 hours.
The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (VIII) can be obtained by treating compound (IV) with an acid. The amount of the acid used depends on the amount of the compound (I
V) The amount is about 1.0 to about 100 mol, preferably about 1.0 to about 30 mol, per 1 mol. As the "acid", for example, mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are used. This reaction is performed in the presence of a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds, but for example, water, a mixture of water and amides, a mixture of water and alcohols, and the like are used. The reaction temperature is generally 20 to about 200 ° C, preferably about 60 to about 150 ° C. The reaction time is generally about 30 minutes to about 72 hours, preferably about 1 to about 30 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (VIII) can also be obtained by condensing compound (VI) obtained by treating compound (V) with a base and compound (VII). In the compound (VI), M
Represents an alkali metal such as lithium, sodium and potassium. In compound (VII), examples of R ⁹ include the same as those described above for R ⁸ . The amount of base used is
About 1.0 to about 30 mol, per 1 mol of compound (V),
Preferably it is from about 1.0 to about 10 moles. Examples of the "base" include metal amides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more thereof are used. The reaction temperature is generally about -78 to about 60 ° C, preferably about -78.
To about 20 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (IX) can be obtained by treating compound (VIII) with a halogen. This reaction is carried out in the presence of a base or a basic salt, if desired. The amount of the halogen to be used is about 1.0-about 5.0 mol, preferably about 1.0-about 2.0 mol, per 1 mol of compound (VIII). Examples of the "halogens" include bromine, chlorine, iodine and the like. The amount of the base to be used is about 1.0 to about 10.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (VIII). As the "base",
For example, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine,
Tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like. The amount of the basic salt to be used is about 1.0 to about 1 to 1 mol of compound (VIII).
0.0 mole, preferably about 1.0 to about 3.0 mole. Examples of the “basic salt” include sodium carbonate,
Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate and the like can be mentioned. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, ethers, aromatic hydrocarbons,
Aliphatic hydrocarbons, amides, halogenated hydrocarbons,
Nitriles, sulfoxides, organic acids, aromatic amines or a mixture of two or more of these are used. The reaction temperature is about -20 to about 150C, preferably about 0 to about 100C. The reaction time is usually from 5 minutes to about 2 minutes.
4 hours, preferably about 10 minutes to about 5 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (Ia) is obtained by condensing compound (IX) with compound (X). This reaction is performed in the presence of a base, if desired. Hal in compound (IX)
Represents a halogen. When the compound (X) is commercially available, a commercially available product may be used as it is, or it may be obtained by a method known per se or a method analogous thereto, or a method represented by the following reaction formula 2, or the like. Can be The amount of compound (X) to be used is about 0.5 to about 3.0 mol, preferably about 0.8 to about 2.0 mol, per 1 mol of compound (IX). The amount of the base to be used is 1 mol of compound (IX),
It is about 1.0 to about 30 moles, preferably about 1.0 to about 10 moles. Examples of the "base" include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, and the like. -Dimethylaminopyridine, N, N-dimethylaniline, N
Tertiary amines such as -methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine; This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles, or two or more thereof And the like are used. The reaction temperature ranges from about -5 to about 20
0 ° C., preferably about 5 to about 150 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 hour.
5 to about 30 hours. The product can be used in the next reaction as a reaction solution or as a crude product,
It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

[0031]

Embedded image Compound (XII) is obtained by condensing compound (XI) with an amine represented by formula R ¹¹ H. R ¹¹ represents the “optionally substituted amino” represented by the aforementioned R ¹
Is shown. In compound (XI), R ¹⁰ represents alkoxy.
Examples of the “alkoxy” include C _1-6 such as methoxy, ethoxy, propoxy, isopropoxy and butoxy.
Alkoxy and the like. The amount of the “amine” to be used is about 1.0 to about 30 to 1 mol of compound (XI).
Mole, preferably from about 1.0 to about 10 moles. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles, ketones or these A mixture of two or more kinds is used. The reaction temperature is about -5 to about 200C, preferably about 5 to about 120C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (X) can be obtained by hydrolyzing compound (XII) using an acid or a base. The amount of the acid and base to be used is about 0.1 to about 50 mol, preferably about 1 to about 2 mol, per 1 mol of compound (XII), respectively.
0 mol. Examples of the `` acid '' include hydrochloric acid, hydrobromic acid, mineral acids such as sulfuric acid, boron trichloride, Lewis acids such as boron tribromide, a combination use of Lewis acid with thiols or sulfides, trifluoroacetic acid, Organic acids such as p-toluenesulfonic acid and the like are used. Examples of the "base" include metal hydroxides such as sodium hydroxide, potassium hydroxide and barium hydroxide, basic salts such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert-butoxide. And organic bases such as triethylamine, imidazole and formamidine. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water or two or more of these A mixture or the like is used. The reaction time is generally about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 200 ° C, preferably about 20 to about 120 ° C.

Compound (X) can also be obtained by treating compound (XIII) with hydrogen sulfide in the presence of a base.
The amount of hydrogen sulfide to be used is about 1 mol-about 30 mol per 1 mol of compound (XIII). The amount of the base to be used is about 1.0 to about 30 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (XIII). Examples of the "base" include pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine,
Tributylamine, cyclohexyldimethylamine, 4
-Dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N
And tertiary amines such as -methylmorpholine. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines or a mixture of two or more thereof Used. This reaction is performed under normal pressure or under pressure. The reaction temperature is generally about -20 to about 80C, preferably about-
10 to about 30 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (X) can also be obtained by treating compound (XIV) with phosphorus pentasulfide or Lawesson's reagent. The amount of the phosphorus pentasulfide or Lawesson reagent to be used is about 0.5 to about 1 to 1 mol of compound (XIV).
0 moles, preferably about 0.5 to about 3 moles. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, or a mixture of two or more of these are used. The reaction time is generally about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 150
° C, preferably about 20 to about 120 ° C. The product (X) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is separated by separation means such as recrystallization, distillation, and chromatography. It can be easily purified.

When the compound (Ia) is an acylamino compound, the target compound can be obtained by subjecting the corresponding amine compound to an acylation reaction known per se. For example, compound (Ia)
Wherein the compound in which R ¹ is an acylamino optionally having substituent (s) is obtained by reacting the corresponding 2-thiazolamine with an acylating agent in the presence of a base or an acid, if desired. The amount of the acylating agent used depends on the amount of the compound (I
a) It is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol. As the “acylating agent”, for example, a carboxylic acid or a reactive derivative thereof (eg, acid halide,
Acid anhydrides, esters, etc.). The amount of the base or acid to be used is about 0.8-about 5.0 mol, preferably about 1.0-about 2.0 mol, per 1 mol of compound (Ia). Examples of the “base” include triethylamine,
Pyridine, 4-dimethylaminopyridine and the like can be mentioned. Examples of the “acid” include methanesulfonic acid and p-
Toluenesulfonic acid, camphorsulfonic acid and the like can be mentioned. This reaction is advantageously carried out without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic amines Alternatively, a mixture of two or more of these may be used. The reaction temperature is about -20 to about 150C, preferably about 0 to about 100C. The reaction time is usually about 5 minutes to about 2 minutes.
4 hours, preferably about 10 minutes to about 5 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.

Compound (Ib) can also be obtained by the method shown in Reaction Scheme 3 or a method analogous thereto.

Embedded image Compound (Ib) is obtained by treating compound (I) with an organic peracid. The amount of the organic peracid used is the amount of compound (I) 1
It is about 0.8 to about 10 mol, preferably about 1.0 to about 3.0 mol, per mol. Examples of the "organic peracid" include peracetic acid, pertrifluoroacetic acid, and metachloroperbenzoic acid. This reaction is advantageously performed without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitrile , Ketones or a mixture of two or more of these. The reaction temperature is about -20 ° C to about 130 ° C, preferably about 0 ° C to about 100 ° C. The reaction time is generally about 5 minutes to about 72 minutes.
Hours, preferably about 0.5 to about 12 hours. Compound (Ib) can also be obtained by treating compound (I) with hydrogen peroxide or an alkyl hydroperoxide, if desired, in the presence of a base, acid or metal oxide. The amount of hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to about 1 to 1 mol of compound (I).
0 mole, preferably about 1.0 to about 3.0 mole. Examples of the “alkyl hydroperoxide” include tert-butyl hydroperoxide, cumene hydroperoxide and the like. The amount of the base, acid or metal oxide to be used is about 0.1 to about 3 to 1 mol of compound (I).
0 mol, preferably about 0.8 to about 5 mol. Examples of the “base” include inorganic bases such as sodium hydroxide and potassium hydroxide, and basic salts such as sodium carbonate and potassium carbonate. Examples of the "acid" include mineral acids such as hydrochloric acid, sulfuric acid, and perchloric acid, and Lewis acids such as boron trifluoride, aluminum chloride, and titanium tetrachloride;
Organic acids such as formic acid and acetic acid are exemplified. Examples of the “metal oxide” include vanadium oxide (V ₂ O ₅ ), osmium tetroxide (OsO ₄ ), and tungsten oxide (W
O ₃ ), molybdenum oxide (MoO ₃ ), selenium dioxide (S
eO ₂ ) and chromium oxide (CrO ₃ ). This reaction is advantageously performed without a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitrile , Ketones or a mixture of two or more of these. The reaction temperature is about -20 ° C to about 130 ° C, preferably about 0 ° C to about 100 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. it can.

In each of the above reactions, when the starting compound has amino, carboxy, or hydroxy as a substituent,
These groups may be those into which a protecting group generally used in peptide chemistry or the like has been introduced, and the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include formyl and C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.) each having a substituent, phenylcarbonyl, C _1-6 alkoxy-carbonyl (eg, methoxy Carbonyl, ethoxycarbonyl and the like), phenyloxycarbonyl, _C7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl and the like), trityl, phthaloyl and the like are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), nitro and the like are used. Is one to three.
As the carboxy protecting group, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. Can be These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butylcarbonyl, etc.), nitro, C _1-6 alkyl (Eg, methyl, ethyl, tert-butyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.) and the like, and the number of substituents is 1 to 3. Examples of the hydroxy-protecting group include, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C
_7-11 aralkyl (eg benzyl etc.), formyl, C
_1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenyloxycarbonyl, C _7-11 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, ter
t-butyl, etc., C _7-11 aralkyl (eg, benzyl etc.), C _6-10 aryl (eg, phenyl, naphthyl etc.), nitro and the like, and the number of substituents is 1 to 4. In addition, as a method for removing the protecting group, a method known per se or a method analogous thereto is used. A treatment method or a reduction reaction is used. In any case, if desired, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, and substituent exchange reaction may be used alone or in combination with each other. Compound (I) can be synthesized by performing a combination of two or more. For these reactions, for example, a method described in New Experimental Chemistry Course 14, 15, 1977 (Maruzen Publishing) or the like is adopted.

As the above-mentioned "alcohols", for example,
Examples include methanol, ethanol, propanol, isopropanol, tert-butanol and the like. Examples of the “ethers” include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like. Examples of the “halogenated hydrocarbons” include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Examples of the “aliphatic hydrocarbons” include hexane, pentane, cyclohexane and the like. The "aromatic hydrocarbons"
Examples thereof include benzene, toluene, xylene, chlorobenzene and the like. The above "aromatic amines"
Examples include pyridine, lutidine, quinoline and the like. Examples of the “amides” include N,
N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like can be mentioned. Examples of the "ketones" include acetone,
Methyl ethyl ketone and the like can be mentioned. Examples of the “sulfoxides” include dimethyl sulfoxide. Examples of the “nitrile” include acetonitrile, propionitrile and the like. Examples of the “organic acids” include acetic acid, propionic acid,
Trifluoroacetic acid and the like.

When the desired product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. It can also be converted. Compound (I) (including compounds (Ia) and (Ib)) thus obtained can be isolated from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like. Release,
It can be purified. When the compound (I) exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, each can be isolated by the above separation and purification means, if desired. When compound (I) is a racemate, it can be separated into an S-form and an R-form by ordinary optical resolution means. When the compound (I) has a stereoisomer, the case where the isomer is used alone and the case where the isomer is a mixture thereof are also included in the present invention. Compound (I)
May be hydrated or non-hydrated.

The compound (I) has an excellent cerebral protective action (preventive treatment for cerebral edema, cerebrovascular disorder or head injury), has low toxicity and has few side effects, and is therefore useful as a safe pharmaceutical. is there. The preparation of the present invention containing compound (I) has an excellent cerebral protective effect on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Showing, translocation into the brain,
Because of its excellent metabolic stability, it can be used as a prophylactic / therapeutic agent for cerebral edema, a prophylactic / therapeutic agent for cerebrovascular disorders (especially in the acute phase of cerebrovascular disease), a therapeutic agent for head trauma, or a prophylactic / therapeutic agent for brain tumors. it can.

The preparations of the present invention containing compound (I) have low toxicity, and can be prepared by treating compound (I) as it is or pharmacologically according to a method known per se which is generally used in the production of pharmaceutical preparations. Mixed with an acceptable carrier such as tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules, (including soft capsules),
It can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as a pharmaceutical preparation such as a solution, injection, suppository, sustained release agent and the like. The content of compound (I) in the preparation of the present invention is about 0.01 to about 100% by weight of the whole preparation. The dose is based on the administration subject, administration route, disease,
Although it depends on the symptoms, etc., as a therapeutic agent for cerebral edema (anti-cerebral edema drug), for example, for a patient with cerebral edema (body weight about 60 kg), about 0 as an active ingredient [compound (I)] per day as an injection. 0.01 to about 30 mg / kg body weight, preferably about 0.1 to about 20 mg / kg body weight, more preferably about 1 to about 20 mg / kg body weight, may be administered once or several times a day. Compound (I) may also be used in combination with other anti-cerebral edema drugs (eg, low molecular weight dextran,
High osmotic agents such as D-mannitol, diuretics such as furosemide, corticosteroids such as prednisolone and dexamethasone, etc., and thrombolytic agents (eg, t-PA (tissue plasminogen activator), urokinase, etc.) You can also.

The pharmacologically acceptable carriers which may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients and solids in solid preparations. Sachets, binders and disintegrants, or solvents in liquid formulations, solubilizers, suspending agents,
Examples include tonicity agents, buffers, and soothing agents. Further, if necessary, normal preservatives, antioxidants, coloring agents, sweeteners,
Additives such as adsorbents and wetting agents can be used in appropriate amounts. Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose,
And light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples include hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

[0043]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following Reference Examples, Examples, Formulation Examples and Experimental Examples.
These examples are merely implementations, do not limit the present invention, and may be changed without departing from the scope of the present invention. “Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. "%" Indicates percent by weight unless otherwise specified. However, the yield indicates mol / mol%. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double double
t) dt: double triplet br: broad J: coupling constant Hz: Hertz CDCl ₃ : deuterated chloroform ¹ H-NMR: proton nuclear magnetic resonance Me: methyl

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EXAMPLES Reference Example 1 1- (4-Methoxyphenyl) -2- (3-pyridyl) ethanone A solution of diisopropylamine (33.2 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to -78 ° C, and stirred.
1.6 M n-butyllithium hexane solution (148 mL) was added dropwise. Stir at the same temperature for 10 minutes after dropping, then
Picolin (20 g) was added dropwise. After raising the temperature to -10 to 0 ° C and stirring for 20 minutes, ethyl p-anisate (19.4
g) in anhydrous tetrahydrofuran (40 mL) was added dropwise.
After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, and water (100 mL) was added. The organic solvent was distilled off under reduced pressure, and the oily product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off.
The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (20.8 g, yield 85%). Mp 71-72 ° C.

Reference Example 2 In accordance with the above Reference Example 1, ethyl benzoate, ethyl 3,4-dimethoxybenzoate, 3,4,5-
Ethyl trimethoxybenzoate, ethyl 4- (methoxymethoxy) benzoate, ethyl 4-fluorobenzoate, ethyl 4-ethylbenzoate, ethyl 3,4-methylenedioxybenzoate,
Methyl 5-indanylcarboxylate, 5,6,7,8-tetrahydro
The following Reference Examples Compounds 2-1 to 2-11 were synthesized using methyl 2-naphthoate, methyl 1,4-benzodioxane-6-carboxylate, and methyl 2-naphthoate, respectively. Reference Example Compound 2-1: 1-phenyl-2- (3-pyridyl) ethanone Melting point: 44.5-45.5 ° C. Reference Example Compound 2-2: 1- (3,4-dimethoxyphenyl) -2-
(3-pyridyl) ethanone melting point 114-115 ° C. Reference Example Compound 2-3: 2- (3-pyridyl) -1- (3,4,5-trimethoxyphenyl) ethanone Melting point 104-105 ° C. Reference Example Compound 2-4: 1- (4-methoxymethoxyphenyl)
2- (3-pyridyl) ethanone melting point 43-44 ° C. Reference Example Compound 2-5: 1- (4-fluorophenyl) -2- (3-pyridyl) ethanone oil. Reference example compound 2-6: 1- (4-ethylphenyl) -2- (3-pyridyl) ethanone Melting point 80-81 ° C. Reference Example Compound 2-7: 1- (3,4-methylenedioxyphenyl) -2- (3-pyridyl) ethanone Melting point 98-99 ° C. Reference Example Compound 2-8: 1- (5-Indanyl) -2- (3-pyridyl) ethanone Melting point 55-56 ° C. Reference Example Compound 2-9: 2- (3-pyridyl) -1- (5,6,7,8-tetrahydro-2-naphthyl) ethanone Melting point 65-66 ° C. Reference Example Compound 2-10: 1- (1,4-benzodioxan-6-yl) -2- (3-pyridyl) ethanone Melting point 89-90 ° C. Reference Example Compound 2-11: 1- (2-naphthyl) -2- (3-pyridyl) ethanone Melting point 69-70 ° C. Reference Example 3 According to Reference Example 2 above, α-picoline, γ-picoline, and 3,5-lutidine were used instead of β-picoline, respectively.
The following Reference Example Compounds 3-1 to 3-5 were synthesized. Reference Example Compound 3-1: 1-phenyl-2- (2-pyridyl) ethanone Melting point 59-60 ° C. Reference example compound 3-2: 1- (4-methoxyphenyl) -2- (2-pyridyl) ethanone melting point 77-78 ° C. Reference Example Compound 3-3: 1-phenyl-2- (4-pyridyl) ethanone Melting point 109-110 ° C. Reference Example Compound 3-4: 1- (4-methoxyphenyl) -2- (4-pyridyl) ethanone Melting point 103-104 ° C. Reference Example Compound 3-5: 2- (5-methyl-3-pyridyl) -1-phenylethanone Melting point 53-54 ° C.

Reference Example 4 Ethyl 2-cyano-2-phenyl-1- (3-pyridyl) ethanone nicotinate (10 g) and phenylacetonitrile (5.1
g) and tert-butyl alcohol (30 mL) solution in potassium
Tert-butoxide (6.4 g) was added, and the reaction mixture was stirred at 100 ° C. for 3 hours. After cooling, the reaction solution was diluted with water and washed with isopropyl ether. The aqueous layer is pH 7.0 with 2N hydrochloric acid
And the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound.
6.0 g (62% yield) were obtained. 148-149 ° C. Reference Example 5 2-phenyl-1- (3-pyridyl) ethanone 2-cyano-2-phenyl-1- (3-pyridyl) ethanone (5.0 g)
Was dissolved in 48% hydrobromic acid (50 mL) and heated to 140 ° C. for 5 hours. After cooling, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The remaining crude crystals were recrystallized from isopropyl ether to give 3.9 g of the title compound (yield
88%). 61-62 ° C.

Reference Example 6 2-bromo-1- (4-methoxyphenyl) -2- (3-pyridyl) ethanone hydrobromide 1- (4-methoxyphenyl) -2- (3-pyridyl) ethanone ( 6.85
g) was dissolved in acetic acid (36 mL), and bromine (1.7 mL) was added.
Stir at 3 ° C. for 3 hours. The reaction solution was cooled with ice water, and the precipitated crude crystals were collected by filtration. The crude crystals were recrystallized from ethanol-ethyl ether to obtain 10.4 g (yield 89%) of the title compound. 188-195 ° C. Reference Example 7 According to the above Reference Example 6, 1-phenyl-2- (3-pyridyl) ethanone was replaced by 1- (4-methoxyphenyl) -2- (3-pyridyl) ethanone, and 1- (3,4 -Dimethoxyphenyl) -2- (3-pyridyl) ethanone, 2- (3-pyridyl) -1- (3,4,5-trimethoxyphenyl) ethanone, 1- (4-methoxymethoxyphenyl) -2- ( 3-pyridyl) ethanone, 1- (4-fluorophenyl)
-2- (3-pyridyl) ethanone, 1-phenyl-2- (2-pyridyl)
Ethanone, 1- (4-methoxyphenyl) -2- (2-pyridyl) ethanone, 1-phenyl-2- (4-pyridyl) ethanone, 1- (4-methoxyphenyl) -2- (4-pyridyl) ethanone , 2- (5-methyl-3-pyridyl) -1-phenylethanone, 1- (4-ethylphenyl) -2- (3-pyridyl) ethanone, 1- (3,4-methylenedioxyphenyl)- 2- (3-pyridyl) ethanone, 1- (5-indanyl) -2- (3-pyridyl) ethanone, 2- (3-pyridyl) -1- (5,
6,7,8-tetrahydro-2-naphthyl) ethanone, 1- (1,4-benzodioxan-6-yl) -2- (3-pyridyl) ethanone, 1-
(2-Naphthyl) -2- (3-pyridyl) ethanone, 1- (4-methoxyphenyl) -2- (2-pyridyl) ethanone, 2-phenyl-1- (3-
The following Reference Example Compounds 7-1 to 7-18 were synthesized using (pyridyl) ethanone, respectively. Reference Example Compound 7-1: 2-bromo-1-phenyl-2- (3-pyridyl) ethanone hydrobromide Melting point: 208-215 ° C. Reference Example Compound 7-2: 2-bromo-1- (3,4-dimethoxyphenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point 19
1-193 ° C. Reference Example Compound 7-3: 2-bromo-2- (3-pyridyl) -1- (3,
4,5-Trimethoxyphenyl) ethanone hydrobromide mp 184-186 ° C. Reference Example Compound 7-4: 2-bromo-1- (4-hydroxyphenyl) -2- (3-pyridyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 7-5: 2-bromo-1- (4-fluorophenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point 189-
191 ° C. Reference Example Compound 7-6: 2-bromo-1-phenyl-2- (2-pyridyl) ethanone hydrobromide Melting point: 180-181 ° C. Reference Example Compound 7-7: 2-bromo-1- (4-methoxyphenyl) -2- (2-pyridyl) ethanone hydrobromide Melting point 170-
171 ° C. Reference Example Compound 7-8: 2-bromo-1-phenyl-2- (4-pyridyl) ethanone hydrobromide Melting point 230-232 ° C. Reference Example Compound 7-9: 2-bromo-1- (4-methoxyphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 207-
209 ° C. Reference Example Compound 7-10: 2-bromo-2- (5-methyl-3-pyridyl) -1-phenylethanone hydrobromide Melting point 189-19
3 ° C. Reference Example Compound 7-11: 2-bromo-1- (4-ethylphenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point 145-1
146 ° C. Reference Example Compound 7-12: 2-bromo-1- (3,4-methylenedioxyphenyl) -2- (3-pyridyl) ethanone hydrobromide
Mp 174-175 ° C. Reference Example Compound 7-13: 2-bromo-1- (5-indanyl) -2-
(3-pyridyl) ethanone hydrobromide Melting point 177-178
° C. Reference Example Compound 7-14: 2-bromo-2- (3-pyridyl) -1-
(5,6,7,8-Tetrahydro-2-naphthyl) ethanone hydrobromide Melting point 160-162 ° C. Reference Example Compound 7-15: 1- (1,4-benzodioxan-6-yl) -2-bromo-2- (3-pyridyl) ethanone hydrobromide
Oil. Reference Example Compound 7-16: 2-bromo-1- (2-naphthyl) -2- (3
-Pyridyl) ethanone hydrobromide mp 197-199 ° C. Reference Example Compound 7-17: 2-bromo-1- (4-methoxyphenyl) -2- (2-pyridyl) ethanone hydrobromide Melting point 170-
171 ° C. Reference Example Compound 7-18: 2-bromo-2-phenyl-1- (3-pyridyl) ethanone hydrobromide Melting point 213-218 ° C.

Reference Example 8 [4- (4-Methoxyphenyl) -5- (3-pyridyl) -1,3-thiazol-2-yl] amine A suspension of thiourea (516 mg) in acetonitrile (40 mL) was added. , 2-bromo-1- (4-methoxyphenyl) -2- (3-pyridyl)
Ethanone hydrobromide (2.5 g) was added, and triethylamine (0.95 mL) was slowly added dropwise with stirring. After completion of the dropwise addition, the mixture was stirred at the reflux temperature for 3 hours, allowed to cool, and the precipitated crystals were collected by filtration. The crystals were washed with saturated aqueous sodium hydrogen carbonate, water, ethanol and ethyl ether in that order, and dried. The obtained crude crystals were recrystallized from tetrahydrofuran to give 1.5 g (yield 90%) of the title compound. 265-266 ° C. Reference Example 9 N-methyl [4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3
-Thiazol-2-yl] amine N-methylthiourea (242 mg) in acetonitrile (18 mL)
2-Bromo-1- (4-methoxyphenyl) -2- (3-pyridyl) ethanone hydrobromide (1.0 g) was added to the suspension, and triethylamine (0.4 mL) was slowly added dropwise with stirring.
After completion of the dropwise addition, the mixture was stirred at the reflux temperature for 3 hours, and the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off.
The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (650 mg, yield 85%). 158-159 ° C.

Reference Example 10 N- [4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3-thiazol-2-yl] acetamide The starting compound was [(4-methoxyphenyl) -5- (3-pyridyl)-
Example 3 described below using 1,3-thiazol-2-yl] amine
The title compound was obtained in the same manner as described above. 82% yield. 208-210 ° C. Reference Example 11 2- (4-acetylpiperazin-1-yl) -4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3-thiazole 1-piperazinecarbothioamide (387 mg) in acetonitrile ( 15 mL) solution, 2-bromo-1- (4-methoxyphenyl) -2
-(3-pyridyl) ethanone hydrobromide (1.0 g) was suspended,
While stirring, triethylamine (0.4 mL) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at the reflux temperature for 3 hours, and the solvent was distilled off. Add saturated aqueous sodium bicarbonate to the residue,
After extraction with ethyl acetate, the extract was washed with water and dried, and the solvent was distilled off. The residue was dissolved in pyridine (2 mL), cooled with ice, added with acetyl chloride (0.3 mL), and left at room temperature for 1 hour. The reaction solution was poured into ice water, and the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate-methanol = 9: 1) to give the title compound (300 mg, yield 28%). Oil.

Reference Example 12 [4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3-thiazol-2-yl] amine hydrochloride [4- (4-methoxyphenyl) -5- ( 3-pyridyl) -1,3-thiazol-2-yl] amine (200 mg) in 1% methanolic hydrochloric acid (3.2
mL), and the solvent was distilled off. The obtained crude crystals were recrystallized from methanol-ethyl acetate to give the title compound (180 mg)
(80% yield). Melting point 145-150 ° C.

The chemical structures of the compounds obtained in Reference Examples 8 to 12 are shown in Table 1 below.

[Table 1]

Reference Example 13 Reference Example Compounds 13-1 to 13-13 shown in Tables 2 to 7 below.
-102 as Reference Examples 8 to 12, JP-A-61-10580.
No. 4,612,321.

[Table 2]

[Table 3]

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[Table 4]

[Table 5]

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[Table 6]

[Table 7]

Reference Example 14 N- (4-Chlorobenzoyl) propyleneimine Propyleneimine (12.3 mL) in tetrahydrofuran (160
mL) solution was added to a 1N aqueous solution of sodium hydroxide. 4-Chlorobenzoyl chloride (25 g) was added dropwise to the mixture at 0 ° C. After the addition was completed, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off to obtain 24.9 g (89% yield) of the title compound. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 5.5 Hz), 2.15
(1H, d, J = 2.9 Hz), 2.51-2.66 (2H, m), 7.39-7.47
(2H, m), 7.93-8.01 (2H, m). Reference Example 15 According to Reference Example 14, instead of 4-chlorobenzoyl chloride, 3-chlorobenzoyl chloride, 2-chlorobenzoyl chloride, and 2-methylbenzoyl chloride. , 3-methylbenzoyl chloride, 4-methylbenzoyl chloride, 2-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 4-ethylbenzoyl chloride, 4- (1-methylethyl) benzoyl chloride, 4- (1,1-dimethyl Ethyl) benzoyl chloride, 4-propylbenzoyl chloride, 4-butylbenzoyl chloride, 4-hexylbenzoyl chloride, 4-trifluoromethoxybenzoyl chloride, 4-trifluoromethylbenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,4 -Dimethylbenzoyl chloride, 3,5-dimethylbenzoyl chloride, 3,4-methylenedioxyben Irukurorido, respectively using 2-naphthoyl chloride, the following Reference Example compound 15-1～15-2
0 was synthesized. Reference Example Compound 15-1: N- (3-chlorobenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 5.1 Hz), 2.17
(1H, d, J = 3.3 Hz), 2.53-2.68 (2H, m), 7.40 (1H, d
d, J = 8.1, 7.7 Hz), 7.53 (1H, ddd, J = 8.1, 2.2, 1.
5 Hz), 7.90 (1H, dt, J = 7.7, 1.5 Hz), 8.00 (1H, d
d, J = 2.2, 1.5 Hz). Reference Example Compound 15-2: N- (2-chlorobenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 5.1 Hz), 2.12
(1H, d, J = 3.3 Hz), 2.53 (1H, d, J = 5.5 Hz), 2.56-
2.68 (1H, m), 7.28-7.48 (3H, m), 7.75-7.81 (1H,
m). Reference Example Compound 15-3: N- (2-methylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 5.5 Hz), 2.08
(1H, d, J = 3.3 Hz), 2.43-2.57 (5H, m), 7.20-7.31
(2H, m), 7.33-7.43 (1H, m), 7.89 (1H, d, J = 7.7 H
z). Reference Example Compound 15-4: N- (3-methylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 5.5 Hz), 2.14
(1H, d, J = 3.3 Hz), 2.41 (3H, s), 2.51-2.66 (2H,
m), 7.32-7.39 (2H, m), 7.79-7.87 (2H, m). Reference Example Compound 15-5: N- (4-methylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 5.5 Hz), 2.12
(1H, d, J = 2.9 Hz), 2.42 (3H, s), 2.50-2.62 (2H,
m), 7.25 (2H, d, J = 8.1 Hz), 7.92 (2H, d, J = 8.1 H)
z). Reference Example Compound 15-6: N- (2-methoxybenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 5.5 Hz), 2.10
(1H, d, J = 3.3 Hz), 2.50 (1H, d, J = 5.9Hz), 2.53-
2.65 (1H, m), 3.90 (3H, s), 6.95-7.05 (2H, m), 7.4
1-7.52 (1H, m), 7.81-7.88 (1H, m). Reference Example Compound 15-7: N- (3-methoxybenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 5.9 Hz), 2.14
(1H, d, J = 2.9 Hz), 2.52-2.65 (2H, m), 3.86 (3H,
s), 7.10 (1H, ddd, J = 8.4, 2.6, 1.1 Hz), 7.37 (1H,
dd, J = 8.4, 7.3 Hz), 7.55 (1H, dd, J = 2.6, 1.5 H
z), 7.63 (1H, ddd, J = 7.3, 1.5, 1.1 Hz). Reference Example Compound 15-8: N- (4-ethylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 1.39
(3H, d, J = 5.5 Hz), 2.13 (1H, d, J = 3.3 Hz), 2.50-
2.61 (2H, m), 2.71 (2H, q, J = 7.6 Hz), 7.28 (2H, d,
J = 7.7 Hz), 7.95 (2H, d, J = 7.7 Hz). Reference Example Compound 15-9: N- [4- (1-methylethyl) benzoyl] propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 7.0 Hz), 1.40
(3H, d, J = 5.5 Hz), 2.13 (1H, d, J = 3.3 Hz), 2.50-
2.64 (2H, m), 2.90-3.05 (1H, m), 7.31 (2H, d, J =
8.2 Hz), 7.96 (2H, d, J = 8.2 Hz). Reference Example Compound 15-10: N- [4- (1,1-dimethylethyl)
Benzoyl] propyleneimine A solution of propyleneimine (11 mL, 0.14 mol) in tetrahydrofuran (160 mL) is added to a 2N aqueous sodium hydroxide solution (70 mL)
Added. 4- (1,1-dimethylethyl) at 0 ° C
Benzoyl chloride (25 g, 0.13 mol) was added dropwise. After the addition was completed, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off to obtain 27 g (0.13 mol, yield 99%) of the title compound. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.41 (3H, d, J = 5.
5 Hz), 2.12 (1H, d, J = 2.9 Hz), 2.51-2.64 (2H, m),
7.47 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz). Reference Example Compound 15-11: N- (4-propylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.3 Hz), 1.39
(3H, d, J = 5.5 Hz), 1.57-1.75 (2H, m), 2.12 (1H,
d, J = 3.3 Hz), 2.50-2.59 (2H, m), 2.65 (2H, t, J =
7.7 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.94 (2H, d, J =
8.1 Hz). Reference Example Compound 15-12: N- (4-butylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.1 Hz), 1.26-
1.47 (5H, m), 1.54-1.73 (2H, m), 2.12 (1H, d, J =
2.9 Hz), 2.51-2.62 (2H, m), 2.67 (2H, t, J = 7.7 H
z), 7.26 (2H, d, J = 8.1 Hz), 7.94 (2H, d, J = 8.1 H
z). Reference Example Compound 15-13: N- (4-hexylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 6.6 Hz), 1.24-
1.38 (6H, m), 1.39 (3H, d, J = 5.5 Hz), 1.56-1.68
(2H, m), 2.12 (1H, d, J = 3.3 Hz), 2.51-2.61 (2H, m
m), 2.66 (2H, t, J = 7.7 Hz), 7.26 (2H, d, J = 8.1 H
z), 7.94 (2H, d, J = 8.1 Hz). Reference Example Compound 15-14: N- (4-trifluoromethoxybenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 5.5 Hz), 2.16
(1H, d, J = 3.3 Hz), 2.53-2.68 (2H, m), 7.29 (2H,
d, J = 9.0 Hz), 8.08 (2H, d, J = 9.0 Hz). Reference Example Compound 15-15: N- (4-trifluoromethylbenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 5.5 Hz), 2.19
(1H, d, J = 3.7 Hz), 2.54-2.70 (2H, m), 7.73 (2H,
d, J = 8.0 Hz), 8.13 (2H, d, J = 8.0 Hz). Reference Example Compound 15-16: N- (3,4-dimethoxybenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 5.5 Hz), 2.12
(1H, d, J = 3.3 Hz), 2.51-2.63 (2H, m), 3.94 (3H,
s), 3.95 (3H, s), 6.92 (1H, d, J = 8.5 Hz), 7.56 (1
H, d, J = 2.2 Hz), 7.69 (1H, dd, J = 8.5, 2.2 Hz). Reference Example Compound 15-17: N- (3,4-dimethylbenzoyl)
Propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 5.5 Hz), 2.12
(1H, d, J = 3.3 Hz), 2.32 (6H, s), 2.49-2.61 (2H,
m), 7.21 (1H, d, J = 7.7 Hz), 7.77 (1H, dd, J = 7.7,
1.8 Hz), 7.80 (1H, d, J = 1.8 Hz). Reference Example Compound 15-18: N- (3,5-dimethylbenzoyl)
Propyleneimine 3,5-dimethylbenzoic acid (25 g, 0.17 mol) and dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0 ° C. The mixture was heated at reflux for 2 hours. Excess thionyl chloride was distilled off under reduced pressure, and toluene (50 mL) was added to the residue. The toluene was distilled off under reduced pressure to obtain oily 3,5-dimethylbenzoyl chloride. Propylene imine (14 mL, 0.
A solution of 18 mol) in tetrahydrofuran (160 mL) was added to a 1N aqueous solution of sodium hydroxide (180 mL). 0 ° C to this mixture
3,5-dimethylbenzoyl chloride was added dropwise. After the addition was completed, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract is dried and the solvent is distilled off to give the title compound.
31 g (0.16 mol, 99% yield) were obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 5.5 Hz), 2.13 (1
H, d, J = 3.7 Hz), 2.37 (6H, s), 2.47-2.62 (2H, m),
7.19 (1H, s), 7.64 (2H, s). Reference Example Compound 15-19: N- (3,4-methylenedioxybenzoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, d, J = 4.9 Hz), 2.11
(1H, d, J = 3.1 Hz), 2.48-2.64 (2H, m), 6.05 (2H,
s), 6.86 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 1.7 H
z), 7.65 (1H, dd, J = 8.2, 1.7 Hz). Reference Example Compound 15-20: N- (2-naphthoyl) propyleneimine oil. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 5.5 Hz), 2.22
(1H, d, J = 3.3 Hz), 2.57-2.84 (2H, m), 7.50-7.65
(2H, m), 7.85-8.00 (3H, m), 8.06 (1H, dd, J = 8.6,
1.5 Hz), 8.59 (1H, s).

Reference Example 16 1- (2-Chlorophenyl) -2- (4-pyridyl) ethanone A solution of diisopropylamine (15.4 mL) in anhydrous tetrahydrofuran (100 mL) was cooled to -50 ° C., and stirred for 1.6 hours.
M n-butyllithium hexane solution (69 mL) was added dropwise.
Stir for 10 minutes after the completion of dropping, and then γ-picoline (20 g)
Anhydrous tetrahydrofuran (10 mL) solution was added dropwise at -30.degree. After stirring for 1 hour, N- (2-chlorobenzoyl) propyleneimine (20 g) in anhydrous tetrahydrofuran (10 mL)
The solution was added dropwise at -10 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give the title compound (16.4 g, yield 71%)
I got Oil. ¹ H-NMR (CDCl ₃ ) δ: 4.28 (2H, s), 7.20 (2H, d, J =
6.2 Hz), 7.28-7.39 (1H, m), 7.41-7.48 (3H, m), 8.5
6 (2H, d, J = 6.2 Hz).

Reference Example 17 According to Reference Example 16, instead of N- (2-chlorobenzoyl) propyleneimine, N- (3-chlorobenzoyl) propyleneimine, N- (4-chlorobenzoyl) propyleneimine, N- ( Two
-Methylbenzoyl) propyleneimine, N- (3-methylbenzoyl) propyleneimine, N- (4-methylbenzoyl)
Propyleneimine, N- (2-methoxybenzoyl) propyleneimine, N- (3-methoxybenzoyl) propyleneimine, N- (4-ethylbenzoyl) propyleneimine, N- [4-
(1-methylethyl) benzoyl] propyleneimine, N- [4-
(1,1-dimethylethyl) benzoyl] propyleneimine, N
-(4-propylbenzoyl) propyleneimine, N- (4-butylbenzoyl) propyleneimine, N- (4-hexylbenzoyl) propyleneimine, N- (4-trifluoromethoxybenzoyl) propyleneimine, N- (4- (Trifluoromethylbenzoyl) propyleneimine, N- (3,4-dimethoxybenzoyl) propyleneimine, N- (3,4-dimethylbenzoyl) propyleneimine, N- (3,5-dimethylbenzoyl) propyleneimine, N- ( 3,4-methylenedioxybenzoyl)
Using propylene imine and N- (2-naphthoyl) propylene imine respectively, the following Reference Examples Compounds 17-1 to 17-17
-20 was synthesized. Reference example compound 17-1: 1- (3-chlorophenyl) -2- (4-pyridyl) ethanone melting point 79-80 ° C. Reference example compound 17-2: 1- (4-chlorophenyl) -2- (4-pyridyl) ethanone Melting point 93-94 ° C. Reference Example Compound 17-3: 1- (2-methylphenyl) -2- (4-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 4.23 (2H, s), 7.
19 (2H, d, J = 6.2 Hz), 7.24-7.47 (3H, m), 7.73 (1H,
d, J = 7.7 Hz), 8.56 (2H, d, J = 6.2 Hz). Reference Example Compound 17-4: 1- (3-methylphenyl) -2- (4-pyridyl) ethanone Melting point 115-116 ° C. Reference example compound 17-5: 1- (4-methylphenyl) -2- (4-pyridyl) ethanone Melting point 110-111 ° C. Reference Example Compound 17-6: 1- (2-methoxyphenyl) -2- (4-
Pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 3.92 (3H, s), 4.30 (2H, s), 6.
95-7.07 (2H, m), 7.17 (2H, d, J = 5.9 Hz), 7.50 (1H,
ddd, J = 8.4, 7.3, 1.8 Hz), 7.73 (1H, dd, J = 7.7,
1.8 Hz), 8.53 (2H, d, J = 5.9 Hz). Reference Example Compound 17-7: 1- (3-methoxyphenyl) -2- (4-
Pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 3.86 (3H, s), 4.28 (2H, s), 7.
14 (1H, ddd, J = 8.1, 2.6, 1.1 Hz), 7.20 (2H, d, J =
6.2 Hz), 7.36 (1H, dd, J = 8.1, 7.7 Hz), 7.51 (1
H, dd, J = 2.6, 1.5 Hz), 7.58 (1H, ddd, J = 7.7, 1.
5,1.1 Hz), 8.57 (2H, d, J = 6.2 Hz). Reference Example Compound 17-8: 1- (4-ethylphenyl) -2- (4-pyridyl) ethanone Melting point 87-89 ° C. Reference example compound 17-9: 1- [4- (1-methylethyl) phenyl] -2- (4-pyridyl) ethanone Melting point 86-88 ° C. Reference Example Compound 17-10: 1- [4- (1,1-dimethylethyl)
[Phenyl] -2- (4-pyridyl) ethanone A solution of diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (100 mL) was cooled to -50 ° C, and stirred, and a 1.6 M n-butyllithium hexane solution (69 mL,
0.11 mol) was added dropwise. After the dropwise addition, the mixture was stirred for 10 minutes, and then a solution of γ-picoline (9.3 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30 ° C. After stirring for 1 hour, N- [4- (1,1-dimethylethyl) benzoyl] propyleneimine (22 g, 0.10 mol) in anhydrous tetrahydrofuran
(10 mL) solution was added dropwise at -30 ° C. After completion of the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. Add water (100 m
L) was added and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1) and recrystallized from diisopropyl ether-hexane to obtain 11 g (yield 43%) of the title compound. 75-76 ° C. Reference Example Compound 17-11: 1- (4-propylphenyl) -2-
(4-pyridyl) ethanone melting point 71-72 ° C. Reference Example Compound 17-12: 1- (4-butylphenyl) -2- (4-
Pyridyl) ethanone melting point 41-43 ° C. Reference Example Compound 17-13: 1- (4-hexylphenyl) -2-
(4-pyridyl) ethanone melting point 57-58 ° C. Reference Example Compound 17-14: 2- (4-pyridyl) -1- (4-trifluoromethoxyphenyl) ethanone Melting point 65-66 ° C. Reference Example Compound 17-15: 2- (4-pyridyl) -1- (4-trifluoromethylphenyl) ethanone Melting point 94-95 ° C. Reference Example Compound 17-16: 1- (3,4-dimethoxyphenyl)
2- (4-pyridyl) ethanone melting point 110-111 ° C. Reference Example Compound 17-17: 1- (3,4-dimethylphenyl) -2
-(4-Pyridyl) ethanone melting point 81-83 ° C. Reference Example Compound 17-18 A solution of 1- (3,5-dimethylphenyl) -2- (4-pyridyl) ethanone diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (100 mL) was cooled to -50 ° C, While stirring, 1.6 M n-butyllithium hexane solution (69 mL,
0.11 mol) was added dropwise. After the dropwise addition, the mixture was stirred for 10 minutes, and then a solution of γ-picoline (9.3 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30 ° C. After stirring for 1 hour, N- (3,5-dimethylbenzoyl) propyleneimine
(19 g, 0.10 mol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30 ° C. After completion of the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was crystallized from diisopropyl ether-hexane to give the title compound (13 g, yield 58%). 90-91 ° C. Reference Example Compound 17-19: 1- (3,4-methylenedioxyphenyl) -2- (4-pyridyl) ethanone Melting point 126-127 ° C. Reference example compound 17-20: 1- (2-naphthyl) -2- (4-pyridyl) ethanone Melting point 114-115 ° C. Reference Example 18 According to Reference Example 17, the following Reference Example Compounds 18-1 to 18-9 were synthesized using β-picoline instead of γ-picoline. Reference Example Compound 18-1: 1- (2-chlorophenyl) -2- (3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 4.28 (2H, s), 7.18-7.49 (5H,
m), 7.59-7.67 (1H, m), 8.47-8.56 (2H, m). Reference Example Compound 18-2: 1- (3-chlorophenyl) -2- (3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 4.29 (2H, s), 7.25-7.34 (1H,
m), 7.44 (1H, t, J = 7.7Hz), 7.54-7.63 (2H, m), 7.9
0 (1H, dt, J = 7.7, 1.5 Hz), 8.00 (1H, dd, J = 1.8,
1.5 Hz), 8.49-8.57 (2H, m). Reference Example Compound 18-3: 1- (4-chlorophenyl) -2- (3-pyridyl) ethanone ¹ H-NMR (CDCl ₃ ) δ: 4.27 (2H, m) s), 7.24-7.31 (1H,
m), 7.47 (2H, d, J = 8.8Hz), 7.55-7.63 (1H, m), 7.9
6 (2H, d, J = 8.8 Hz), 8.46-8.53 (2H, m). Reference Example Compound 18-4: 1- (2-methylphenyl) -2- (3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 4.23 (2H, s), 7.
18-7.47 (5H, m), 7.73 (1H, d, J = 7.7 Hz), 8.47-8.56
(2H, m). Reference Example Compound 18-5: 1- (3-methylphenyl) -2- (3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 4.29 (2H, s), 7.
17-7.36 (1H, m), 7.36-7.46 (2H, m), 7.58-7.65 (1H, m
m), 7.78-7.86 (2H, m), 8.50-8.56 (2H, m). Reference Example Compound 18-6: 1- (4-methylphenyl) -2- (3-pyridyl) ethanone Melting point 72-74 ° C . Reference Example Compound 18-7: 1- (3-methoxyphenyl) -2- (3-
Pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 3.86 (3H, s), 4.29 (2H, s), 7.
14 (1H, ddd, J = 8.1, 2.6, 1.8 Hz), 7.28 (1H, dd, J
= 7.3, 4.8 Hz), 7.40 (1H, dd, J = 8.1, 7.7 Hz), 7.5
3 (1H, dd, J = 2.6, 1.8 Hz), 7.58-7.65 (2H, m), 8.5
0-8.55 (2H, m). Reference Example Compound 18-8: 1- [4- (1,1-dimethylethyl) phenyl] -2- (3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 4.28 (2H, s), 7.
22-7.31 (1H, m), 7.50 (2H, d, J = 8.4 Hz), 7.56-7.65
(1H, m), 7.96 (2H, d, J = 8.4 Hz), 8.48-8.55 (2H,
m). Reference Example Compound 18-9: 1- (3,5-dimethylphenyl) -2-
(3-pyridyl) ethanone oil. ¹ H-NMR (CDCl ₃ ) δ: 2.38 (6H, s), 4.27 (2H, s), 7.
24-7.30 (2H, m), 7.58-7.63 (3H, m), 8.50-8.52 (2H, m
m).

Reference Example 19 In accordance with Reference Example 1, the following Reference Example Compound 19 was synthesized using ethyl 4-dimethylaminobenzoate instead of ethyl p-anisate. Reference Example Compound 19: 1- (4-dimethylaminophenyl) -2-
(4-pyridyl) ethanone melting point 189-192 ° C. Reference Example 20 2- [4- (1,1-dimethylethyl) phenyl] -1- (4-pyridyl)
Ethanone ethyl isonicotinate (12 g) and 4- (1,1-dimethylethyl)
To a solution of phenylacetonitrile (9.1 g) in tert-butyl alcohol (36 mL) was added potassium tert-butoxide (7.3 g).
Was added and the reaction mixture was stirred at 100 ° C. for 3 hours. After cooling, the reaction solution was diluted with water and washed with isopropyl ether. The aqueous layer was adjusted to pH 7.0 with 2N-hydrochloric acid, and the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give 5.09 g of 2-cyano-2- [4- (1,1-dimethylethyl) phenyl] -1- (4-pyridyl) ethanone (yield 35
%). The obtained 2-cyano-2- [4- (1,1-dimethylethyl) phenyl] -1- (4-pyridyl) ethanone (5.0 g) was added to 48
Dissolved in 50% hydrobromic acid (50 mL) and heated at 140 ° C. for 5 hours. After cooling, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give the title compound (3.1 g, yield 68%). Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 4.25 (2H, s), 7.
18 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.7
8 (2H, d, J = 6.2 Hz), 8.81 (2H, d, J = 6.2 Hz).

Reference Example 21 2- (3,5-dimethylphenyl) -1- (4-pyridyl) ethanone According to Reference Example 20, 3,5- (1,1-dimethylethyl) phenylacetonitrile was used instead of 4- (1,1-dimethylethyl) phenylacetonitrile. The title compound was synthesized using dimethylphenylacetonitrile. 96-97 ° C. Reference Example 22 According to Reference Example 6, 1- (2-methoxyphenyl) -2- (3-pyridyl) ethanone was used instead of 1- (2-chlorophenyl) -2- (3-
Pyridyl) ethanone, 1- (3-chlorophenyl) -2- (3-pyridyl) ethanone, 1- (4-chlorophenyl) -2- (3-pyridyl)
Ethanone, 1- (2-methylphenyl) -2- (3-pyridyl) ethanone, 1- (3-methylphenyl) -2- (3-pyridyl) ethanone, 1- (4-methylphenyl) -2- ( 3-Pyridyl) ethanone, 1
-(3-methoxyphenyl) -2- (3-pyridyl) ethanone, 1- [4
-(1,1-dimethylethyl) phenyl] -2- (3-pyridyl) ethanone, 1- (3,5-dimethylphenyl) -2- (3-pyridyl) ethanone, 1- (2-chlorophenyl) -2 -(4-pyridyl) ethanone, 1- (3-chlorophenyl) -2- (4-pyridyl) ethanone, 1
-(4-chlorophenyl) -2- (4-pyridyl) ethanone, 1- (2-
Methylphenyl) -2- (4-pyridyl) ethanone, 1- (3-methylphenyl) -2- (4-pyridyl) ethanone, 1- (4-methylphenyl) -2- (4-pyridyl) ethanone, 1 -(2-methoxyphenyl) -2- (4-pyridyl) ethanone, 1- (3-methoxyphenyl) -2- (4-pyridyl) ethanone, 1- (4-ethylphenyl) -2
-(4-pyridyl) ethanone, 1- [4- (1-methylethyl) phenyl] -2- (4-pyridyl) ethanone, 1- [4- (1,1-dimethylethyl) phenyl] -2- ( 4-pyridyl) ethanone, 1- (4-propylphenyl) -2- (4-pyridyl) ethanone, 1- (4-butylphenyl) -2- (4-pyridyl) ethanone, 1- (4-hexylphenyl) -2- (4-pyridyl) ethanone, 2- (4-pyridyl) -1- (4-trifluoromethoxyphenyl) ethanone, 2- (4-pyridyl) -1- (4-trifluoromethylphenyl) ethanone, 1- (4
-Dimethylaminophenyl) -2- (4-pyridyl) ethanone hydrobromide, 1- (3,4-dimethoxyphenyl) -2- (4-pyridyl) ethanone, 1- (3,4-dimethylphenyl) 2- (4-pyridyl) ethanone, 1- (3,5-dimethylphenyl) -2- (4-pyridyl) ethanone, 1- (3,4-methylenedioxyphenyl) -2- (4
-Pyridyl) ethanone, 1- (2-naphthyl) -2- (4-pyridyl)
Ethanone, 2- [4- (1,1-dimethylethyl) phenyl] -1- (4-
Pyridyl) ethanone, 2- (3,5-dimethylphenyl) -1- (4-
The following Reference Examples Compounds 22-1 to 22-33 were synthesized using (pyridyl) ethanone, respectively. Reference Example Compound 22-1: 2-bromo-1- (2-chlorophenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point: 88-90 ° C. Reference Example Compound 22-2: 2-bromo-1- (3-chlorophenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point 164-166 ° C. Reference Example Compound 22-3: 2-bromo-1- (4-Chlorophenyl) -2- (3-pyridyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 22-4: 2-bromo-1- (2-methylphenyl) -2- (3-pyridyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 22-5: 2-bromo-1- (3-methylphenyl) -2- (3-pyridyl) ethanone hydrobromide Unpurified and used for the next reaction. Reference Example Compound 22-6: 2-bromo-1- (4-methylphenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point 96-98 ° C.

Reference Example Compound 22-7: 2-bromo-1- (3-methoxyphenyl) -2- (3-pyridyl) ethanone hydrobromide The crude product was used in the next reaction without purification. Reference Example Compound 22-8: 2-bromo-1- [4- (1,1-dimethylethyl) phenyl] -2- (3-pyridyl) ethanone hydrobromide Melting point 190-194 ° C. Reference Example Compound 22-9: 2-bromo-1- (3,5-dimethylphenyl) -2- (3-pyridyl) ethanone hydrobromide Melting point: 195-197 ° C. Reference Example Compound 22-10: 2-bromo-1- (2-chlorophenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 157-159 ° C. Reference Example Compound 22-11: 2-bromo-1- (3-chlorophenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 178-181 ° C. Reference Example Compound 22-12: 2-bromo-1- (4-chlorophenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 189-193 ° C. Reference Example Compound 22-13: 2-bromo-1- (2-methylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point: 183-186 ° C. Reference Example Compound 22-14: 2-bromo-1- (3-methylphenyl) -2- (4-pyridyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 22-15: 2-bromo-1- (4-methylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 111-113 ° C. Reference Example Compound 22-16: 2-bromo-1- (2-methoxyphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 168-171 ° C. Reference Example Compound 22-17: 2-Bromo-1- (3-methoxyphenyl) -2- (4-pyridyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 22-18: 2-bromo-1- (4-ethylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 170-173 ° C.

Reference Example Compound 22-19: 2-bromo-1- [4-
(1-Methylethyl) phenyl] -2- (4-pyridyl) ethanone hydrobromide Melting point 185-188 ° C. Reference Example Compound 22-20: 2-bromo-1- [4- (1,1-dimethylethyl) phenyl] -2- (4-pyridyl) ethanone hydrobromide 1- [4- (1,1- Dimethylethyl) phenyl] -2- (4-pyridyl)
Dissolve ethanone (10 g, 39 mmol) in acetic acid (40 mL) and add bromine
(2.0 mL, 39 mmol) and stirred at 80 ° C. for 3 hours. The reaction solution was cooled with ice water, and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate, and the title compound (9.6 g, yield 81%)
I got 209-212 ° C. Reference Example Compound 22-21: 2-bromo-1- (4-propylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 167-170 ° C. Reference Example Compound 22-22: 2-bromo-1
-(4-Butylphenyl) -2- (4-pyridyl) ethanone hydrobromide mp 158-161 ° C. Reference Example Compound 22-23: 2-bromo-1- (4-hexylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 153-155 ° C. Reference Example Compound 22-24: 2-bromo-2- (4-pyridyl) -1-
(4-Trifluoromethoxyphenyl) ethanone hydrobromide Used in the next reaction without purification. Reference Example Compound 22-25: 2-bromo-2- (4-pyridyl) -1-
(4-trifluoromethylphenyl) ethanone hydrobromide mp 190-194 ° C. Reference Example Compound 22-26: 2-bromo-1- (4-dimethylaminophenyl) -2- (4-pyridyl) ethanone dihydrobromide Melting point 163-167 ° C. Reference Example Compound 22-27: 2-bromo-1- (3,4-dimethoxyphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 174-175 ° C. Reference Example Compound 22-28: 2-bromo-1- (3,4-dimethylphenyl) -2- (4-pyridyl) ethanone hydrobromide Melting point 196-199 ° C. Reference Example Compound 22-29: 2-bromo-1- (3,5-dimethylphenyl) -2- (4-pyridyl) ethanone hydrobromide 1- (3,5-dimethylphenyl) -2- (4 -Pyridyl) ethanone (7.
0 g, 31 mmol) in acetic acid (35 mL) and bromine (1.6 mL, 31 mmol).
mmol) and stirred at 80 ° C. for 3 hours. Ethyl acetate was added to the residue, and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate to give the title compound (16 g, yield 96%). 216-219 ° C. Reference Example Compound 22-30: 2-bromo-1- (3,4-methylenedioxyphenyl) -2- (4-hydridyl) ethanone hydrobromide Melting point 211-214 ° C. Reference Example Compound 22-31: 2-bromo-1- (2-naphthyl) -2-
(4-pyridyl) ethanone hydrobromide mp 149-152 ° C. Reference Example Compound 22-32: 2-bromo-2- [4- (1,1-dimethylethyl) phenyl] -1- (4-pyridyl) ethanone hydrobromide Used in the next reaction without purification. . Reference Example Compound 22-33: 2-bromo-2- (3,5-dimethylphenyl) -1- (4-pyridyl) ethanone hydrobromide Melting point: 186-188 ° C.

Reference Example 23 Reference Examples Compounds 23-1 and 23-2 shown in Tables 8 to 21 below.
3-222 in Reference Examples 8 to 12, JP-A-61-1058.
No. 0 and USP 4,612,321.

[Table 8]

[Table 9]

[0063]

[Table 10]

[Table 11]

[0064]

[Table 12]

[Table 13]

[0065]

[Table 14]

[Table 15]

[0066]

[Table 16]

[Table 17]

[0067]

[Table 18]

[Table 19]

[0068]

[Table 20]

[Table 21]

[0069]

[Table 22]

[Table 23]

[0070]

[Table 24]

[Table 25]

[0071]

[Table 26]

[Table 27]

[Table 28]

Reference Example 23-128 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] acetamide N- [4- (3,5 -Dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.78 mmol) and 4-dimethylaminopyridine (0.06 g, 0.51 mmol) in N, N-dimethyl In an acetamide (5 mL) solution, add acetyl chloride (0.21
g, 2.67 mmol) and stirred at 80 ° C. for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.17 g, yield 29%). 284-286 ° C. Reference Example 23-133 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine 2-bromo-1- (3,5-dimethyl Phenyl) -2- (4-pyridyl) ethanone hydrobromide (5.0 g, 13 mmol) and thiourea (1.
0 g, 14 mmol) in acetonitrile (60 mL) was added dropwise with triethylamine (1.9 ml, 14 mmol).
Stir for hours. The solvent 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 organic layer was washed with water, dried, and the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate to give 2.0 g of the title compound (7.
2 mmol, 55% yield). 242-244 ° C. Reference Example 23-137 N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] acetamide N- [4- [4 -(1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.40 g, 1.29 mmo
l) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol)
Acetyl chloride (0.15 g, 1.94 mmol) was added to a solution of N, N-dimethylacetamide (4 mL), and the mixture was stirred at 80 ° C. for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.23 g (yield 50%) was obtained. 280-281 ° C. Reference Example 23-143 N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] amine 2-bromo-1- [ 4- (1,1-dimethylethyl) phenyl] -2- (4-
Pyridyl) ethanone hydrobromide (5.0 g, 12 mmol) and thiourea (0.95 g, 13 mmol) in acetonitrile (60 mL)
Triethylamine (1.8 ml, 13 mmol) was added dropwise to the solution, and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized from ethanol to give the title compound (2.6 g, 8.4 mmol, yield 69%). Mp 254-257 ° C.

Reference Example 23-164 N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] benzamide N- [4 -[4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.62 mmo
l) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol)
Benzoyl chloride (0.15 g, 1.94 mmol) was added to a N, N-dimethylacetamide (5 mL) solution, and the mixture was stirred at 80 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.44 g (66% yield) was obtained. 292-294 ° C. Reference Example 23-165 N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] nicotinamide N- [4- [ 4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.62 mmo
l) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol)
Nicotinoyl chloride hydrochloride (0.43 g, 2.42 mmol) was added to the N, N-dimethylacetamide (5 mL) solution, and the mixture was added at 70 ° C.
Stirred for hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.49 g, yield 73%). 326-328 ° C. Reference Example 23-168 N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] cyclopentanecarboxamide N- [4- [4- (1,1-dimethylethyl) phenyl] -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.62 mmo
l) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol)
To a solution of N, N-dimethylacetamide (5 mL) was added cyclopentanecarbonyl chloride (0.32 g, 2.42 mmol), and 70
Stirred at C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.43 g, yield 66%). 309-311 ° C.

Reference Example 23-194 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] propionamide N- [4- (3, N, N- of 5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) Propionyl chloride in dimethylacetamide (20 mL) solution
(0.18 g, 1.96 mmol) and the mixture was stirred at 80 ° C. for 14 hours.
An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound 0.4
1 g (67% yield) was obtained. Mp 291-293 ° C. Reference Example 23-195 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -2-methylpropionamide N- [4- (3 , 5-Dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) To a solution of -dimethylacetamide (20 mL) was added 2-methylpropionyl chloride (0.20 g, 1.91 mmol), and the mixture was stirred at 80 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. After washing the obtained solid with water,
Dried. The crude crystals were recrystallized from ethanol to give the title compound (0.52 g, yield 83%). 270-272 ° C. Reference Example 23-196 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -2-phenylacetamide N- [4- (3, N, N- of 5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) 2-Phenylacetyl chloride (0.32 g, 2.0 mmol) was added to a dimethylacetamide (15 mL) solution, and the mixture was stirred at 80 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.33 g (46% yield) was obtained. 226-229 ° C. Reference Example 23-197 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] benzamide N- [4- (3,5-dimethylphenyl) ) -5- (4-Pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N, N-dimethylacetamide (20 mL) solution to the benzoyl chloride
(0.30 g, 2.15 mmol) was added, and the mixture was stirred at 80 ° C for 14 hours.
An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound 0.1
8 g (26% yield) was obtained. Mp 285-286 ° C. Reference Example 23-198 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] cyclopentanecarboxamide N- [4- (3,5- N, N-dimethylacetamide of (dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) (10 mL) To the solution was added cyclopentanecarbonyl chloride (0.33 g, 2.47 mmol).
Stirred for hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 59%). 275-278 ° C.

Reference Example 23-199 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] nicotinamide N- [4- (3, N, N- of 5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.52 g, 1.9 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) Nicotinoyl chloride hydrochloride (0.51 g, 2.86 mmol) was added to a dimethylacetamide (10 mL) solution, and the mixture was stirred at 80 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.44 g (yield 61%) was obtained. 267-270 ° C. Reference Example 23-200 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] isonicotinamide N- [4- (3,5- N, N-dimethylacetamide of (dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) (10 mL) To the solution was added isonicotinoyl chloride hydrochloride (0.48 g, 2.72 mmol), and the mixture was stirred at 80 ° C for 14 hours. Pour aqueous sodium bicarbonate solution into the reaction mixture,
The precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.22 g, yield 32%). Melting point 302-304 ° C. Reference Example 23-201 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -N'-ethylurea N- [4- (3, To a solution of 5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) in N, N-dimethylacetamide (10 mL) was added ethyl isocyanate ( (0.20 g, 2.8 mmol) and stirred at 80 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.27 g (yield 42%) was obtained. 202-203 ° C. Reference Example 23-202 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] -N'-propylurea N- [4- (3 , 5-Dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.51 g, 1.8 mmol) in N, N-dimethylacetamide (15 mL) (0.23 g, 2.67 mmol) was added and the mixture was stirred at 80 ° C. for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.23 g (33% yield) was obtained. 128-130 ° C. Reference Example 23-246 N- [4- (3,5-dimethylphenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] pyrazinecarboxamide N- [4- (3,5-dimethyl Phenyl) -5- (4-pyridyl) -1,3-thiazol-2-yl] amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) in N, N-dimethylacetamide ( To the solution was added pyrazinecarbonyl chloride (0.44 g, 2.67 mmol), and the mixture was stirred at 70 ° C for 14 hours. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude compound was recrystallized from ethanol to give the title compound.
0.41 g (yield 59%) was obtained. 269-270 ° C.

Experimental Example 1 Measurement of Brain Tissue Water Content Jcl: Wistar male rats (10-11 weeks old) were exposed to the right (or left) bifurcation of the carotid artery under halothane anesthesia. A thread plug (diameter 0.28-0.30 mm) was inserted to occlude the middle cerebral artery (MCAO). In addition, those that did not show turning or sloping walking during ischemia, and those that showed hemorrhage in the basilar part at the end of the experiment were excluded from the experiment. The compound of Reference Example 13-99 was dissolved in 5% 0.1N HCl / saline, and 1 ml / kg was intravenously injected. The control group received the solvent. Administration was performed twice immediately after and 4 hours after reperfusion of ischemia, and in the morning (8: 00-10: 00) and in the evening (16: 00-18: 00) on the next day and two days after the next day. Rats were sacrificed by decapitation 3 days after MCAO, and tissue wet weight (WW) was measured immediately after fractionation of the left and right cerebral cortices.
After drying at 5-C) for 72 hours or more, the dry weight (DW) was measured. The tissue moisture content was calculated from the calculation formula [(WW-DW) / WW%]. For the statistical analysis, a Student t test was performed between the control group. Table 7 shows the results. The Sham group represents a sham operation group, and the Vehicle group represents a control group (solvent administration group).

[Table 29] From these results, it can be seen that compound (I) reduces the water content of brain tissue after cerebrovascular disorder and has an excellent therapeutic effect on cerebral edema.

Experimental Example 2 Effect on cerebral vascular permeability after cerebral freezing injury Jcl: Wistar male rats (11 weeks old) were fixed to a stereotaxic apparatus under halothane inhalation under light anesthesia, and along the midline. After incising the scalp and exposing the skull, a copper rod (tip diameter 4 mm) cooled (-50 ° C) in dry ice acetone was
The right cerebral cortex was injured by pressing against the middle skull of a and Lamda sutures for 15 seconds. After freeze injury, the scalp was sutured and returned to the home cage. The compound of Reference Example 13-99 was dissolved in 5% 0.1N HCl / saline, and 1 ml / kg was intravenously injected. The control group received the solvent. Administration was performed immediately after resumption of ischemia and 7 hours later, and the next day in the morning (8: 00-10: 00) and evening (16: 00-18: 0)
0) was performed twice. Rats were evaluated for cerebral vascular permeability 2 days after brain freeze injury. Evans Blue (EB: Rat, 5%, 5 ml / kg)
Was injected intravenously, and one hour later, a physiological saline was injected from the left ventricle under halothane anesthesia to perfuse the brain with blood. After the brain is removed,
The hemisphere, including the cerebral cortex, hippocampus, and striatum, was divided into left and right. The tissue was measured for wet weight, homogenized by adding 1 ml 50% TCA, and centrifuged (15,000 rpm, 15 minutes) to obtain a supernatant. The supernatant was measured for absorbance at 610 nm using a microplate reader, and the amount of EB leakage was measured. Cerebral vascular permeability is
After calculating the amount of EB leakage per tissue wet weight (μg / g tissue), the difference between the Sham group (sham operation group) and the Vehicle group (control group (solvent administration group)) was expressed as 100%. From this result,
Compound (I) has an excellent inhibitory action on cerebral vascular hyperpermeability, and has an excellent therapeutic effect on head trauma.

[Table 30]

[0078]

EFFECT OF THE INVENTION Compound (I) has an excellent cerebral protective action and low toxicity, so that it can be used as a prophylactic / therapeutic agent for cerebral edema, cerebrovascular disorder and head injury. it can.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/497 A61K 31/495 603 // C07D 417/04 C07D 417/04 417/14 417/14 F-term (Reference) 4C063 AA01 AA03 BB01 CC62 CC75 CC92 DD04 DD11 DD12 DD23 DD62 EE01 4C086 AA01 AA02 BC17 BC36 BC82 GA02 GA04 GA07 GA08 GA10 MA01 MA04 NA14 ZA36 ZC21

Claims (12)

[Claims] 1. A brain edema or cerebrovascular disorder characterized in that at least one of the 4-position and 5-position contains a 1,3-azole compound substituted with a pyridyl group which may have a substituent. Or a prophylactic or therapeutic agent for head injury. 2. A compound of the formula 1, wherein the 1,3-azole compound may be N-oxidized. [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an amino group or an acyl group which may have a substituent. One of R ² and R ³ represents a hydrogen atom, a pyridyl group which may have a substituent or an aromatic hydrocarbon group which may have a substituent, and the other has a substituent X may be an oxidized sulfur atom, an oxygen atom or a formula NR ⁴ (wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, )). The prophylactic / therapeutic agent according to claim 1, which is a compound represented by the formula: 3. R ¹ is (i) a hydrogen atom, (ii) C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _optionally having 1 to 5 substituents,
A C _3-6 cycloalkyl, a C _6-14 aryl or a C _7-16 aralkyl group; (iii) _optionally having 1 to 5 substituents, from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom 5 to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected; (iv) (a) C _1-6 alkyl _optionally having 1 to 5 substituents, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C
_7-16 aralkyl, (b) C _1-6 alkylidene optionally having 1 to 5 substituents, (c) 1 to 5 substituents
A 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, which may have a carbon atom, and (d) a formula:-(C =
^{O) -R 5, - (C} = O) -OR 5, - (C = O) -NR
⁵ R ⁶ , — (C ＝ S) —NHR ⁵ or —SO ₂ —R ⁷ (where R ⁵ is a hydrogen atom, a hydrocarbon group which may have a substituent or a A heterocyclic group, R ⁶ represents a hydrogen atom or C _1-6 alkyl, and R ⁷ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.) (V) C _1-6 alkyl, C _6-14 aryl, C _1-6 alkyl-carbonyl, 5 to 10 amino groups which may have one or two substituents selected from acyl represented by 1 to 4 substituents selected from nitrogen, sulfur and oxygen other than carbon and at least one nitrogen which may have 1 to 3 substituents selected from membered aromatic heterocyclic groups and oxo. A 5- to 7-membered non-aromatic cyclic amino group optionally containing two heteroatoms, or (vi) a compound of the formula:-(C = O) -R ^{5, - (C = O)} -OR 5, -
^{(C = O) -NR 5 R} 6, - (C = S) -NHR 5 or -S
An acyl group represented by O ₂ —R ⁷ (wherein each symbol is as defined above); one of R ² and R ³ is (i) a hydrogen atom,
(Ii) a pyridyl group optionally having 1 to 5 substituents or (iii) a C _6-14 aryl group _optionally having 1 to 5 substituents (when two adjacent substituents are Combined 4
Or a 7-membered non-aromatic carbocyclic ring); the other is a pyridyl group optionally having 1 to 5 substituents; and a sulfur atom, oxygen atom or A group represented by the formula NR ⁴ , wherein R ⁴ is (i) a hydrogen atom,
(Ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl optionally having 1 to 5 substituents,
C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, or (iii) formula: — (C ＝ O) —R ⁵ , — (CＣO)
^{-OR 5, - (C = O} ) -NR 5 R 6, - (C = S) -NHR
⁵ or —SO ₂ —R ⁷ (wherein each symbol has the same meaning as described above) (R ¹ , R ² , R ³ , R ⁴ ,
When the groups represented by R ⁵ , R ⁶ and R ⁷ have a substituent, the substituent may be (1) a halogen atom, (2) C _1-3 alkylenedioxy, (3) nitro, ( 4) cyano, (5) optionally halogenated C _1-6 alkyl, (6) optionally halogenated C _2-6 alkenyl, (7) carboxy C _2-6 alkenyl, (8) halogen _Optionally substituted C _2-6 alkynyl, (9) optionally halogenated C
_3-6 cycloalkyl, (10) C _6-14 aryl, (11) optionally halogenated C _1-8 alkoxy, (12) C
_1-6 alkoxy-carbonyl-C _1-6 alkoxy, (13)
Hydroxy, (14) C _6-14 aryloxy, (15) C
_7-16 aralkyloxy, (16) mercapto, (17) optionally halogenated C _1-6 alkylthio, (18) C
_6-14 arylthio, (19) _C7-16 aralkylthio, (2
0) amino, (21) mono-C _1-6 alkylamino, (22)
Mono-C _6-14 arylamino, (23) di-C _1-6 alkylamino, (24) di-C _6-14 arylamino, (25) formyl, (26) carboxy, (27) C _1-6 Alkyl-carbonyl, (28) C _3-6 cycloalkyl-carbonyl,
(29) C _1-6 alkoxy-carbonyl, (30) C _6-14 aryl-carbonyl, (31) C _7-16 aralkyl-carbonyl, (32) C _6-14 aryloxy-carbonyl, (3
3) C _7-16 aralkyloxy-carbonyl, (34) 5- or 6-membered heterocyclic carbonyl, (35) carbamoyl or thiocarbamoyl, (36) mono-C _1-6 alkyl-carbamoyl, (37) di-C _{1 -6} alkyl-carbamoyl, (3
8) mono- or di-C _6-14 aryl-carbamoyl, (3
9) mono- or di-5 or 6 membered heterocyclic carbamoyl, (4
0) C _1-6 alkylsulfonyl, (41) C _6-14 arylsulfonyl, (42) formylamino, (43) C _1-6 alkyl-carbonylamino, (44) C _6-14 aryl-carbonylamino, ( 45) C _1-6 alkoxy-carbonylamino, (46) C _1-6 alkylsulfonylamino, (47) C
_6-14 arylsulfonylamino, (48) C _1-6 alkyl - carbonyloxy, (49) C _6-14 aryl - carbonyloxy, (50) C _1-6 alkoxy - carbonyloxy, (51) mono -C _{1 -6} alkyl - carbamoyloxy, (52) di -C _1-6 alkyl - carbamoyloxy,
(53) mono- or di-C _6-14 aryl-carbamoyloxy, (54) nicotinoyloxy, (55) C _1-6 alkyl, C _6-14 aryl, C _1-6 alkyl-carbonyl, 5
A 5- to 7-membered saturated cyclic amino optionally having 1 to 3 substituents selected from a to 10-membered aromatic heterocyclic group and oxo, (56) a 5- to 10-membered aromatic heterocyclic group and (57) 3. The prophylactic / therapeutic agent according to claim 2, which is selected from sulfo). 4. R ⁵ is (i) a hydrogen atom, (ii) a C _1-6 alkyl _optionally having 1 to 5 substituents,
_2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl or (iii)
A 5- to 14-membered heterocyclic group optionally having 1 to 5 substituents and containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; R
⁶ is a hydrogen atom or C _1-6 alkyl; and R ⁷ is (i) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl optionally having 1 to 5 substituents, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl or (ii) _optionally having 1 to 5 substituents, selected from nitrogen, sulfur and oxygen other than carbon atoms The prophylactic / therapeutic agent according to claim 3, which is a 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms. 5. The preventive / therapeutic agent according to claim 2, wherein R ¹ is an amino group which may have a substituent. 6. A method according to claim 1, wherein R ¹ is of the formula:-(C = O) -R ⁵ ,-(C = O)-
^{OR 5, - (C = O} ) -NR 5 R 6, - (C = S) -NHR 5
Or -SO ₂ -R ⁷ (the symbols in the formula according to claim 3 as defined shows a) prophylactic treatment agent according to claim 3, wherein the acyl represented by a 1 or 2 having an amino group which may be . 7. The method according to claim 1, wherein R ¹ is of the formula: — (C−O) —R ⁵ or — (C =
O) -NR ⁵ R ⁶ (the symbols in the formula according to claim 3 and optionally having one or two acyl represented by as defined shows a) is also an amino group according to claim 3, wherein the agent for prevention and treatment . 8. The prophylactic / therapeutic agent according to claim 2, wherein X is a sulfur atom. 9. The method according to claim ² , wherein R ² is a pyridyl group which may have a substituent. 10. A C _6-14 wherein R ³ may have a substituent.
The prophylactic / therapeutic agent according to claim 2, which is an aryl group. 11. The method according to claim 11, wherein R ¹ has the formula: — (C ＝ O) —R ⁵ or — (C
ＯO) —NR ⁵ R ⁶ (wherein the symbols have the same meanings as in claim 3), an amino group optionally having one or two acyl groups; R ² is a C _1-6 alkyl A pyridyl group optionally having 1 to 5 substituents selected from, hydroxy and C _1-6 alkyl-carbonyloxy; R ³ is a halogen atom, an optionally halogenated C _1-6 alkyl, halogen _4. The prophylactic treatment according to claim 3, wherein X is a sulfur atom, and a C _6-14 aryl group optionally having 1 to 5 substituents selected from optionally substituted C _1-6 alkoxy and carboxy. Agent. (12) R ¹ is (i) a halogen atom, an optionally halogenated C _1-6 alkyl, carboxy C _2-6 alkenyl, an optionally halogenated C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl-C _1-6 alkoxy, hydroxy, amino, mono- or di-C _1-6 alkylamino, carboxy, C _1-6 alkoxy-carbonyl, mono- or di-C _1-6 alkyl C _1-8 alkyl group _optionally having 1 to 5 substituents selected from carbamoyl and C _6-14 aryl-carbonylamino,
_3-6 cycloalkyl group or C _6-10 aryl group, (ii) 5
Membered heterocyclic group, (iii) (1) C _1-6 alkyl, (2) C _6-14
Selected from carbonyl - aryl, (3) C _7-16 aralkyl, (4) 6-membered heterocyclic group and (5) a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, carboxy and C _1-6 alkoxy a substituent 1 to 3 each have optionally a C _1-6 alkyl - carbonyl, C _3-6 cycloalkyl - carbonyl, C _6-14 aryl - carbonyl, C _7-16 aralkyl - carbonyl, C _1- 1 or 2 substituents selected from _6- alkyl-carbamoyl or 5- or 6-membered heterocyclic carbonyl, or (6) di-C _1-6 alkylamino-C
_1-6 amino group optionally having alkylidene, (iv)
C _1-6 alkyl - carbonyl or oxo 5 or 6 membered optionally substituted non-aromatic cyclic amino group or (v) carboxy group; R ² is C _1-6 alkyl, hydroxy and C
Pyridyl group optionally having 1 to 3 substituents selected from _1-6 alkyl-carbonyloxy; R ³ is a halogen atom, C _1-3 alkylenedioxy, optionally halogenated C _{1 -6} alkyl, carboxy C _2-6 alkenyl, optionally halogenated be C _1-8 alkoxy, hydroxy, C _7-16 aralkyloxy and C _1-6 alkyl -, 1 to substituents selected from carbonyloxy 3 An _optionally substituted C _6-10 aryl group ( _optionally, two adjacent alkyl groups may combine to form a 5-membered non-aromatic carbocyclic ring); and X is a sulfur atom 3. The prophylactic / therapeutic agent according to claim 2.