JP2001199982A - 6-heteroarylpyrimidine derivative and drug composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound selectively acting on a BZω3 receptor and useful as a treating agent and a preventing agent for central diseases such as anxiety-associated diseases, depression and epilepsy. SOLUTION: A 6-heteroarylpyrimidine derivative of the formula (wherein, X is O or NR4; R1 is hydrogen, a lower alkyl or the like; R2 is a lower alkyl, a (substitued) phenyl or the like; R3 and R4 are same to or different from each other, and each hydrogen or a lower alkyl; R5 is hydrogen, a halogen or the like; R6 is a (substituted) heteroaryl; A is a (substituted) phenyl or a (substituted) heteroaryl) or its physiologically permissible acid-addition salt, and a compound of the formula, and a drug composition containing a compound of the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 6-heteroarylpyrimidine derivative which selectively acts on a peripheral benzodiazepine receptor, and more specifically, a 2-aminoacetic acid amide moiety or 2-aminoacetamide moiety at the 4-position of the pyrimidine ring. The present invention relates to a 6-heteroarylpyrimidine derivative having an oxyacetic acid amide moiety having a phenyl or heteroaryl group at the 2-position of a pyrimidine ring, and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art Tissues of mammals including humans have three benzodiazepine (hereinafter sometimes abbreviated as "BZ") recognition sites, each of which has a "central type (ω ₁ ,
omega ₂₎ "and" peripheral-type (omega ₃₎ "is referred to as benzodiazepine receptor (hereinafter, respectively" BZomega ₁ receptor ", also referred to as" BZomega ₂ receptor "and" BZomega ₃ receptor " ). Among them, peripheral BZ receptors are widely distributed in central and peripheral tissues and organs (brain, kidney, liver, heart, etc.), and especially endocrine organs such as adrenal glands and testes, mast cells, lymphocytes, and macrophages. In recent years, interest in its physiological role has been increasing because of its high density in cells deeply involved in the inflammation immune system, such as platelets. On the other hand, in the brain, it is abundant in the mitochondrial membrane of glial cells, is involved in the uptake of cholesterol into the mitochondrial membrane, and affects the biosynthetic pathway to progesterone and allopregnanolone called neurosteroids via pregnenolone. It is thought to give. Therefore, stimulation of peripheral BZ receptors promotes the production of neurosteroids in the brain, and these steroids are converted to γ-aminobutyric acid (hereinafter sometimes abbreviated as “GABA”) a
It is thought that it binds to a neurosteroid recognition site (a site different from the BZ receptor) existing on the -BZ receptor-Cl- ion channel complex and affects the Cl ion channel opening process [Romeo, E Et al., J. Pharmaco
l. Exp. Ther., 262 , 971-978 (1992)].

A compound having a non-BZ skeleton and selectively exhibiting affinity for a peripheral BZ receptor is disclosed in JP-A-58-20.
Since it was reported in Japanese Patent Publication No. 1756, a considerable number of reports have been made in patent applications and the like (JP-A-62-5946 and JP-A-2-32058). However, no compound has been put to practical use as a pharmaceutical.

[0004] WO96 / 32383 and JP-A-10-130150 disclose that an acetate amide derivative represented by the following formula ₃ has an anxiolytic action and an antirheumatic action as well as selectively acting on the BZω3 receptor. It can be used for treating anxiety-related diseases and immune diseases.

[0005]

Embedded image

Wherein X represents —O— or —NR ₄ —, and R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
R ₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group and the like, and R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group. Means, R ₄
Represents a hydrogen atom, a lower alkyl group, etc., R ₅ represents a hydrogen atom, a lower alkyl group, a halogen atom, etc., and R ₆ represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group or an unsubstituted or substituted phenyl group. Or R ₅ and R ₆ together form — (CH ₂ ) _n — where n means 3, 4, 5 or 6;
₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, etc., and R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

[0007] WO 98/09960 discloses BZω
An acetic acid amide derivative represented by the following formula 4 which selectively acts on ₃ receptors is described.

[0008]

Embedded image

Wherein X represents —O— or —NR ₄ —, and R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
R ² represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group and the like, and R ³ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group. Means, R ⁴
Represents a hydrogen atom, a lower alkyl group, R ⁵ represents a hydrogen atom, a lower alkyl group, a halogen atom, etc., and R ⁶ represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group, a halogen atom, a lower alkoxy group, A hydroxy (lower) alkyl group or the like, or R ⁵ and R ⁶ together form — (CH ₂ ) _n — (where n means 3, 4, 5 or 6) A may represent an unsubstituted or substituted heteroaryl group, etc.

The compounds of the above formulas (3) and (4) have no heteroaryl group at the 6-position of the pyrimidine ring.
Different from the compound of (I).

[0011]

SUMMARY OF THE INVENTION The present inventors have found that BZω
As a result of intensive studies to obtain a compound that selectively and strongly acts on the ₃ receptor, it was found that a 6-heteroarylpyrimidine derivative represented by the following formula (I) meets this purpose, and the present invention completed.

[0012]

According to the present invention, there is provided a 6-heteroarylpyrimidine derivative represented by the following formula (I), a physiologically acceptable acid addition salt thereof, and a pharmaceutical composition containing the same. Provided.

[0013]

Embedded image

[Wherein, X represents —O— or —NR ₄ —; R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group, wherein R ₃ and R ₄ are the same or different, R ₅ represents a hydrogen atom, a lower alkyl group or a halogen atom, R ₆ represents an unsubstituted or substituted heteroaryl group, and A represents an unsubstituted or substituted heteroaryl group. Or means a group represented by the following formula 6,

[0015]

Embedded image

(Wherein R ₇ is a hydrogen atom, a halogen atom,
Lower alkyl group, a lower alkoxy group, a trifluoromethyl group, hydroxy group, amino group, mono- or di-lower alkylamino group means a cyano group or a nitro group, R ₈
Represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. )]

The physiologically acceptable acid addition salts of the compounds of the formula (I) are defined as the physiologically acceptable acid addition salts of the compounds of the formula (I) when they have a basicity sufficient to form acid addition salts. And the like; for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and maleate, fumarate and oxalic acid Organic salts such as salt, citrate, tartrate, lactate, benzoate, methanesulfonate and the like can be mentioned. Since the compound represented by the formula (I) and the acid addition salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates and / or solvates are also compounds of the present invention. Is included.

The compounds of formula (I) optionally have one or more asymmetric carbon atoms and can give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist in more than one stereoisomeric form. These stereoisomers,
The mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are described below.

The lower alkyl group and the lower alkyl moiety are
Unless otherwise specified, it means one having 1 to 6 carbon atoms, which may be linear or branched. Specific examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈
The lower alkyl group preferably has 1 to 4 carbon atoms. Specific examples of the “lower alkoxy group” include methoxy, ethoxy, propoxy and butoxy.
The "lower alkenyl group" means a group having 3 to 6 carbon atoms having one double bond other than between the 1-2 position, and examples include allyl and 2-butenyl. "Cycloalkyl group" means a group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl and cyclooctyl are mentioned. The “cycloalkyl (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted by the above “cycloalkyl group”, and examples thereof include cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl. "Halogen atom" means fluorine, chlorine,
It means bromine and iodine.

"Unsubstituted or substituted phenyl group"
Substituted by one or two selected from a halogen atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, amino, mono- or di (C ₁ -C ₃ ) alkylamino, cyano and nitro Phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl;
2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2
-, 3- or 4-methoxyphenyl; 2-, 3- or 4
2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2
-, 3- or 4-cyanophenyl; 2-, 3- or 4-
Nitrophenyl.

The term "unsubstituted or substituted phenyl (lower) alkyl group" means an alkyl group having 1 to 4 carbon atoms which is substituted by "unsubstituted or substituted phenyl group".
For example, benzyl, phenethyl, 3-phenylpropyl,
4-fluorophenylmethyl and 4-chlorophenylmethyl.

[0023]

Embedded image

Specific examples of the group represented by the above formula 7 include:
Although those listed in the above “unsubstituted or substituted phenyl group” can be used as they are, preferred specific examples are phenyl, 4- or 3-chlorophenyl,
-Or 3-bromophenyl, 4- or 3-fluorophenyl, 4-methoxyphenyl.

"Unsubstituted or substituted heteroaryl group"
Is a 5- to 6-membered monocyclic heteroaryl group containing at least one nitrogen atom, oxygen atom or sulfur atom which may be substituted with C ₁ -C ₃ alkyl or trifluoromethyl, or 5 2-membered to 6-membered bicyclic heteroaryl group, for example, 2-, 3- or 4-pyridyl; 2- or 3-thienyl; 2- or 3-furyl;
2- or 3-pyrazinyl; 1-pyrazolyl; 2-imidazolyl; 2-thiazolyl; 2-isoxazolyl; 5-methyl-3-isoxazolyl; 5-methyl-2-pyridyl; quinolyl; Isoquinolyl.

Preferred among the compounds of the present invention are those wherein in formula (I), R ₁ is a lower alkyl group and R ₂ is a lower alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl. A, X, R
₃ , a compound wherein R ₅ and R ₆ are the same as described above, and a physiologically acceptable acid addition salt thereof.

Further preferred compounds of the present invention are those wherein R ₁ is a methyl group, ethyl group, propyl group, isopropyl group or butyl group in the formula (I), and R ₂ is propyl group, isopropyl group, butyl group, a phenyl group, a phenyl group substituted by halogen or methoxy, pyridyl or thiazolyl group, R ₃ is a hydrogen atom, R ₆ is a pyridyl group, a thienyl group or a furyl group, R _5, a And X are the same as described above, and physiologically acceptable acid addition salts thereof.

More preferred compounds include the compounds represented by formula (I ') and physiologically acceptable acid addition salts thereof.

[0029]

Embedded image

(Wherein X ′ is —O— or —NR₄'-
Means R₁'Is a methyl, ethyl, propyl, a
A propyl group or a butyl group;₂'Is propyl
Group, isopropyl group, butyl group, phenyl group or halogen
Or a phenyl group substituted with methoxy,
R₄'Represents a hydrogen atom, a methyl group or an ethyl group,
₅'Represents a hydrogen atom or a halogen atom;₆'Is piri
A jyl group, a thienyl group or a furyl group;₇'Is water
Elemental atom, halogen atom, methoxy group, trifluoromethyl
, An amino group, a cyano group or a nitro group. )
As specific examples of the compounds included in the present invention,
In addition to the compounds, compounds of Tables 1 and 2
And physiologically acceptable acid addition salts thereof.

The following abbreviations may be used in Tables 1 and 2 of the present specification and in the following Reference Examples and Examples for simplification.

Me: methyl group, Et: ethyl group, Pr: propyl group, i-Pr: isopropyl group, Bu: butyl group, Ph: phenyl group.

Thus, for example, Ph-4-Cl represents a 4-chlorophenyl group.

[0034]

Embedded image

[0035]

[Table 1] ―――――――――――――――――――――――――――― R ₁ R ₂ R ₅ R ₆ R ₇ X ――――― ――――――――――――――――――――――――― Et Et H 4-pyridyl 4-Cl NH Pr Pr H 2-pyridyl 4-OMe NH Pr Pr H 3- Pyridyl 2-F NMe i-Pr i-Pr H 2-Pyridyl 4-Cl NH Bu Bu H 3-Pyridyl 3-Cl NH Bu Bu H 2-Pyridyl 4-F NHMe Ph H 3-Pyridyl 4-F NH Me Ph H 2-furyl 3-Cl NH ―――――――――――――――――――――――――――― Me Ph-4-F H 3-pyridyl 4 -Cl NHMe Ph-2-F H 2-pyridyl 4-F NH Et Ph H 2-thienyl 4-Cl NH Et Ph-4-Cl H 3-pyridyl 3-Br NH Me Ph-4-Cl H 3- Pyridyl 4-OMe NH Me Ph-2-Cl H 2-Pyridyl 4-F NH ―――――――――――――――――――――――――――― Et Et H 3-pyridyl 4-CF ₃ NH Pr Pr H 4-pyridyl 4-CF ₃ NH Pr Pr H 2-furyl 4-CF ₃ NMe Pr Pr H 2-thienyl 4-CF ₃ NEt ―――――――――――――――――――― ―――――――――― Pr Pr Cl 4-pyridyl H NH Me Ph-4-Cl Cl 3-pyridyl H NH Pr Pr Cl 2-furyl H NH ―――――――――――― ――――――――――――――――――

[0036]

[Table 2] Continued from Table 1 ―――――――――――――――――――――――――――― R ₁ R ₂ R ₅ R ₆ R ₇ X ― ――――――――――――――――――――――――――――― Et Et H 2-pyridyl 3-Cl O Pr Pr H 3-pyridyl 4-Cl O i -Pr i-Pr H 2-pyridyl 4-F O Bu Bu H 3-pyridyl 4-OMe O Me Ph H 2-pyridyl 4-Cl O Me Ph-4-Cl H 3-pyridyl 4-FO Et Ph H 2-furyl 2-Cl O Et Ph-4-Cl H 2-thienyl 2-Br O ――――――――――――――――――――――――――――― ― Pr Pr Cl 3-pyridyl H O Pr Pr Cl 3-furyl H O ――――――――――――――――――――――――――――――

The compound of the present invention can be produced, for example, by the following method.

Production method (a) : In the formula (I), X is-
The compound represented by the following formula (II), wherein NR ₄ — and R ₅ is a hydrogen atom or a lower alkyl group:

[0039]

Embedded image

Wherein Z represents a leaving atom or a leaving group, R ₅ represents a hydrogen atom or a lower alkyl group,
₆ and A mean the same as above. And a compound represented by the following formula (III):

[0041]

Embedded image HN (R ₄ ) —CH (R ₃ ) —CON (R ₁ ) (R ₂ ) (III)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above. And a compound represented by the following formula:

The leaving atom or leaving group represented by Z in the formula (II) is an atom or group capable of leaving in the form of HZ together with a hydrogen atom in the NH moiety of the compound of the formula (III) under the reaction conditions. A halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyl And arylsulfonyloxy groups such as oxy.

The reaction between the compound represented by the formula (II) and the compound represented by the formula (III) is carried out at normal pressure or under pressure in the absence of a solvent or in a suitable solvent.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as methyl ethyl ketone and methyl isobutyl ketone; dioxane;
Examples include ethers such as diglyme, alcohols such as ethanol, isopropanol and butanol, acetonitrile, dimethylformamide, and dimethylsulfoxide. This reaction is preferably performed in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and tribasic amines such as triethylamine. Triamines can be mentioned, but they can also serve as excess of the compound of the formula (III). The reaction temperature varies depending on the type of the starting compound, the reaction conditions, etc., but is usually about 40 to
At about 200 ° C, preferably from about 100 ° C to about 170 ° C.

The starting compound (II) is, for example, represented by the following formula (IV)

[0047]

Embedded image

(Wherein Y represents an oxygen atom or a sulfur atom, R ₅ represents a hydrogen atom or a lower alkyl group, and R _{6 represents}
And A mean the same as above. ) Can be produced by halogenating or sulfonylating the compound represented by the general formula (1).

The halogenation is carried out, for example, by reacting a compound of the formula (IV) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide)
And by reacting Sulfonylation is
For example, in the formula (IV), a compound wherein Y is an oxygen atom and a sulfonylating agent (for example, methanesulfonyl chloride, p
-Toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride).

Compounds in which R ₆ is 1-imidazolyl or 1-pyrazolyl in the starting compound (II) are 4,6
A dihydroxypyrimidine derivative is halogenated according to a conventional method to produce a 4,6-dihalogenopyrimidine derivative, and the 4,6-dihalogenopyrimidine derivative is reacted with imidazole or pyrazole in the presence of a suitable base. be able to. Specific examples are shown in Reference Examples 20 to 22.

The starting materials (IV) are commercially available or are known per se, for example in J. Am. Chem. Soc., 74 , 842.
(1952), Chem. Ber., 95 , 937 (1962) and J. Org.
m., 29 , 2887 (1964), WO 96/32383, and the method described in Reference Example 1 below, or a method analogous thereto.

The compound of formula (III), which is the other starting compound in the present production method, can be prepared by a method known per se, for example, the method described in JP-A-2-32058 and WO 96/32383 or a method analogous thereto. Can be manufactured.

Production method (b) : In the formula (I), X is-
O— and the compound in which R ₅ is a hydrogen atom or a lower alkyl group is represented by the following formula (IVa):

[0054]

Embedded image

(Wherein, R ₅ represents a hydrogen atom or a lower alkyl group, and R ₆ and A have the same meanings as described above) and a compound represented by the following formula (V):

[0056]

Embedded image Z ₁ —CH (R ₃ ) —CON (R ₁ ) (R ₂ ) (V)

(Wherein Z ₁ represents a halogen atom;
₁ , R ₂ and R ₃ have the same meanings as described above. The compound represented by the formula: can be produced by reacting the compound.

The reaction of the compound of the formula (IVa) with the compound of the formula (V) can be carried out in the presence of a base, without solvent or in a suitable solvent under normal pressure or pressure. As the solvent used, for example, toluene, xylene, dimethoxyethane,
1,2-dichloroethane, acetone, methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide. Examples of the base include sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about -10 ° C to about 150 ° C, preferably about 10 ° C to about 70 ° C.

The compound of the formula (V) can be prepared by a method known per se, for example, in JP-A-62-64 and WO96 / 3238.
It can be produced by the method described in Japanese Patent Publication No. 3 or a method analogous thereto.

Production method (c) : In the formula (I), the compound wherein R ₅ is a halogen atom is represented by the following formula (Ia)

[0061]

Embedded image

(Wherein, R ₁ , R ₂ , R ₃ , R ₆ , A and X have the same meanings as described above), and can be produced by halogenating the compound.

As the halogenating agent in this reaction, N
Chlorinating agents such as chlorosuccinimide, bromine, N
A brominating agent such as bromosuccinimide, iodine,
An iodinating agent such as N-iodosuccinimide is used.

Specific examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, and acidic solvents such as acetic acid, hydrochloric acid and sulfuric acid. The reaction temperature is
Although it depends on the type of the starting compound, the reaction conditions and the like, it is usually about 0 ° C to about 150 ° C, preferably about 20 ° C to about 100 ° C.
It is.

The compound of the formula (Ia) is a compound of the present invention and can be produced by the production method (a) or (b).

The product obtained by each of the above-mentioned production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
It can be purified. The compound of the formula (I) having a sufficient basicity to form an acid addition salt can be converted into an acid addition salt by treating with a variety of acids according to a conventional method.

Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography.

The test results of typical compounds of the present invention are shown below, and the pharmacological properties of the compounds of the present invention will be described.

Test Example 1 -Central (ω ₁ , ω ₂ ) and peripheral (ω ₃ ) benzodiazepine receptor binding test

[0070] Preparation of BZomega ₁ and omega ₂ receptor binding assay and receptor membrane preparation is, Stephens, a method of DN et al [J. Pha
rmacol. Exp. Ther., 253 , 334-343 (1990) conforms to], the preparation of BZomega ₃ receptor binding assay and receptor membrane preparation is, Schoemaker, method H [J. Pharmacol. Exp. The
r., 225 , 61-69 (1983)].

Receptor membrane preparations were prepared from the cerebellum, spinal cord or kidney of 7-8 week old male Wistar rats by the following procedures.

A 20-fold volume of ice-cold buffer (50 mM Tris-citrate buffer, pH 7.1) was added to the cerebellum or spinal cord, homogenized, and centrifuged at 40,000 g for 15 minutes. The obtained sediment was washed four times by the same operation, and then stored frozen at -60 ° C for 24 hours. After the frozen sediment is thawed, it is washed and centrifuged with a buffer, and the sediment obtained is subjected to a binding test buffer I (50 mM Tris-HCl buffer containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, pH 7.
4) (1g tissue wet weight / 40 ml) suspended in BZω
Used in binding assay as ₁ or omega ₂ receptor membrane preparation. On the other hand, 20 times the volume of ice-cold binding buffer II (100
50 mM sodium phosphate-potassium phosphate buffer containing 10 mM sodium chloride, pH 7.4) and homogenized.
The filtrate filtered through the quadruplicated gauze was centrifuged at 40,000 g for 20 minutes. The resulting sediment which was suspended in buffer II (1 g tissue wet weight / 100 ml) was used for the binding assay as BZomega ₃ receptor membrane preparation.

[0073] As the labeled ligand and unlabeled ligands, the BZomega ₁ and omega ₂ receptor binding assay ^[3 H] flumazenil (Ro 15-1788) [final concentration _{(ω 1: 0.3 nM) (} ω
₂ : 1 nM)] and flunitrazepam (final concentration 10 μM)
BZomega ₃ The receptor binding assay ^[3 H] 4'-chloro Diazepam: 7-chloro-1,3-dihydro-1-methyl-5
-(4-Chlorophenyl) -2H-1,4-diazepin-2-one (Ro 5-4864) (final concentration 0.5 nM) and diazepam (final concentration 100 μM) were used, respectively. Incubation conditions, in BZomega ₁ and omega ₂ receptor binding test
37 ° C. for 30 minutes, at 0 ℃ in BZomega ₃ receptor binding test 150
Minutes. Incidentally, BZω ₁ and omega ₂ receptor binding studies Bikyukurin (bicuculline: final concentration 100 [mu] M) were performed in the presence.

The receptor binding test was performed according to the following procedure. Test compounds of known concentrations in each test tube, tritium-labeled ligand, receptor membrane preparation, and buffer I or II for binding test
Was added to obtain a reaction solution having a total volume of 1 ml, and the reaction was started by adding a receptor membrane preparation. After the incubation, the reaction was stopped by filtering the labeled ligand bound to the receptor on a Whatman GF / B glass fiber filter using a cell harvester (Brandel, USA). Immediately, ice-cold buffer [omega ₁ and omega ₂ in 50 mM Tris - HCl buffer (pH 7.7); ω ₃ in buffer II] 3 in 5ml
Washed twice. Radioactivity transfers the filter to a vial,
After adding 10 ml of liquid scintillation cocktail (ACS-II, manufactured by Amersham, USA), the mixture was left for a certain period of time, and then measured with a scintillation counter. The specific binding amount was determined by subtracting the simultaneously measured non-specific binding amount in the presence of the unlabeled ligand from the total binding amount. The concentration at which the test compound inhibited the specific binding amount of the labeled ligand by 50% (IC ₅₀ value) was determined by the probit method. The results for omega ₃ receptors are shown in Table 3. The tested compounds had ω ₁ and ω ₂ IC ₅₀ values of 1000 nM or more.

[0075]

[Table 3] * Refers to the compound of Example 2 (the same applies hereinafter).

[0076] Compounds and their physiologically acceptable acid addition salts of formula (I), exhibits a selective and remarkable affinity for BZomega ₃ receptor in vitro studies, anxiety-related diseases (nerve Central illness such as depression, epilepsy, immune nervous diseases such as multiple sclerosis, circulatory diseases such as angina pectoris, hypertension, or immunity such as rheumatism It is useful as a therapeutic or prophylactic agent for inflammatory inflammatory diseases.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration. The dosage depends on the type of compound, administration method,
Depending on the age etc., it is usually 0.01-50 mg / kg /
Days, preferably 0.03 to 5 mg / kg / day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch,
Partially pregelatinized starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low substitution Degree hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate,
Light silicic anhydride, magnesium stearate, talc,
Carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin,
Fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, ethanol, polyoxyethylene hydrogenated castor oil (HCO), sodium chloride,
Examples include sodium hydroxide, hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, glutamic acid, benzyl alcohol, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, the compound of the present invention is prepared by dissolving the compound in water. If necessary, the compound may be dissolved using an isotonic agent or a solubilizing agent. And a preservative may be added.

These preparations contain the compound of the present invention in an amount of 0.0
It can be contained at a rate of 1% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically effective ingredients.

[0081]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description.

[Recrystallization solvent] A: ethanol, AN: acetonitrile, E: diethyl ether, HX: n-hexane, IP: isopropanol.

REFERENCE EXAMPLE 1 --2-phenyl-6- (2-
Production of (pyridyl) -4 (3H) -pyrimidinone

To a mixture of 26 g of sodium methoxide and 300 ml of absolute ethanol at 25 ° C. was added 25 g of benzamidine hydrochloride. After stirring this at room temperature for 15 minutes, 28 g of ethyl picolinoyl acetate was slowly added dropwise again at 0 to 5 ° C. After the completion of the dropwise addition, the temperature was gradually raised and the mixture was heated and refluxed for 12 hours. The reaction mixture was ice-cooled, concentrated hydrochloric acid was added dropwise until pH 4, and the precipitate was collected by filtration, washed with water, then with diethyl ether, and then with methanol-water to obtain 30 g of the desired product. 279-280 ° C

Reference Examples 2 to 9 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the compounds of Table 4 represented by Chemical Formula 16.

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[Table 4] ―――――――――――――――――――――― Reference example R ₆ A Melting point (℃) ――――――――――――― ――――――――――― 2 2-Pyridyl Ph-4-CF ₃ > 300 3 3-Pyridyl Ph-4-CF ₃ 282-284 4 4-Pyridyl Ph-4-CF ₃ > 300 5 2 - furyl Ph 266-267 6 2- furyl _{Ph-4-CF 3 292-295 7} 2- furyl 4-pyridyl 267-268 8 2-thienyl Ph> 300 9 2-thienyl 2-thienyl> 300 ----- ―――――――――――――――――――

Reference Example 10 --2-phenyl-6- (3
-Pyridyl) -4 (3H) -pyrimidinone

17.3 g of anhydrous potassium carbonate was dissolved in 170 ml of water, and 18 g of benzamidine hydrochloride was added at room temperature. After stirring this at room temperature for 15 minutes, 22 g of ethyl nicotinoyl acetate was slowly added dropwise at the same temperature. After dropping, leave at room temperature for 1 hour.
After stirring for 2 hours, the precipitate was collected by filtration, washed with water, then with diethyl ether, and then washed with methanol-water to obtain 12 g of the desired product. Melting point 254-256 ° C

Reference Example 11 Production of 4-chloro-2-phenyl-6- (3-pyridyl) pyrimidine

2-phenyl-6- (3-pyridyl) -4
(3H) -pyrimidinone 6 g and phosphorus oxychloride 6.7 m
The mixture was stirred at 75 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added and the mixture was stirred. After neutralization with an aqueous solution of sodium hydroxide (1 mol / L), the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 4.3 g of the desired product. Melting point 129-131
° C

[0093] Reference Example 12 to 19 - using the corresponding starting compounds, Reference Example 11 and, reactions and treatments were performed in the same manner to give the compounds in Table 5, represented by Formula 17.

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[Table 5] ――――――――――――――――――――――――――――― Reference example R ₆ A Melting point (℃) Recrystallization solvent ――― ―――――――――――――――――――――――――――― 12 2-Pyridyl Ph 129-131 A 13 2-Pyridyl Ph-4-CF ₃ 111-113 IP 14 3-pyridyl Ph-4-CF ₃ 109-110 IP 15 4-pyridyl Ph-4-CF ₃ 124-125 IP 16 2-furyl Ph 97-99 IP 17 2-furyl Ph-4-CF ₃ 88- 89 A 18 2-furyl 4-pyridyl 116-118 A 19 2-thienyl 2-thienyl 121-122 A ―――――――――――――――――――――――――― ―――――

Reference Example 20 --4,6-dihydroxy-5
Production of -methyl-2- (4-trifluoromethylphenyl) pyrimidine

To a mixture of 121 g of a 28% sodium methoxide-methanol solution and 400 ml of methanol, 55 g of diethyl methylmalonate was added dropwise at 0 to 5 ° C.
45 g of (trifluoromethyl) benzamidine hydrochloride was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, concentrated hydrochloric acid was added dropwise until pH 4, and the precipitate was collected by filtration, washed with water, washed with diethyl ether, and dried by heating and drying. g was obtained.

Reference Example 21 Production of 4,6-dichloro-5-methyl-2- (4-trifluoromethylphenyl) pyrimidine

4,6-dihydroxy-5-methyl-2-
(4-trifluoromethylphenyl) pyrimidine 27.5
g and 38 ml of phosphorus oxychloride were heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added and the mixture was stirred. Sodium hydroxide
After neutralization with an aqueous solution (1 mol / L), the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and washed with isopropanol to obtain 18 g of the desired product.

Reference Example 22 Production of 4-chloro-6- (1-imidazolyl) -5-methyl-2- (4-trifluoromethylphenyl) pyrimidine

4,6-dichloro-5-methyl-2- (4
To a mixture of 3 g of -trifluoromethylphenyl) pyrimidine, 1 g of imidazole and 10 ml of isopropanol was added 1.5 g of triethylamine at room temperature, and the mixture was heated under reflux for 4 hours. After the reaction mixture was concentrated under reduced pressure, 5% hydrochloric acid and chloroform were added, the aqueous layer was separated, and made alkaline with an aqueous sodium hydroxide solution. The precipitate was collected by filtration, washed with water and then with diethyl ether, and recrystallized from acetonitrile to obtain 1.4 g of the desired product.

Example 1 Production of N-methyl-N-phenyl-2- [2-phenyl-6- (3-pyridyl) -4-pyrimidinylamino] acetamide

1.0 g of 4-chloro-2-phenyl-6- (3-pyridyl) pyrimidine, 2-amino-N-methyl-
A mixture of 0.92 g of N-phenylacetamide and 0.57 g of triethylamine was heated under reflux at 150 ° C. for 3 hours with stirring. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 1.4 g of the desired product. Melting point 1
99-201 ° C

Examples 2 to 14 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds of Table 6 represented by Chemical Formula 18.

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[Table 6] ―――――――――――――――――――――――――――――― Example R ₁ R ₂ R ₆ R ₇ Melting point (° C.) Recrystallization solvent ―――――――――――――――――――――――――――――― 2 Me Ph-4-Cl 3-pyridyl H 202-204 AN 3 Pr Pr 3-pyridyl H 118-120 IP 4 Me Me 3-pyridyl CF ₃ 210-212 A 5 Me Ph 2-pyridyl H 166-168 IP 6 Pr Pr 2-pyridyl H 136-137 IP 7 Me Me 2- Pyridyl CF ₃ 210-212 A 8 Pr Pr 4-pyridyl CF ₃ 157-158 IP 9 H Pr 4-pyridyl CF ₃ 215-217 IP 10 Me Me 4-pyridyl CF ₃ 251-253 A 11 Me Ph 2-furyl H 147-149 IP 12 Et Ph 2-furyl H 157-159 IP 13 Pr Pr 2-furyl H 99-101 IP 14 Pr Pr 2-furyl CF ₃ 117-119 HX-E ―――――――――― ――――――――――――――――――――――

Examples 15 to 18 The corresponding compounds were reacted and treated in the same manner as in Example 1 to obtain the following compounds.

Example 15 N-ethyl-N-
(5-methyl-3-isoxazolyl) -2- [2-phenyl-6- (2-pyridyl) -4-pyrimidinylamino] acetamide; mp 139-142 ° C (recrystallized from acetonitrile)

( Example 16 )-2- [6- (2-
Furyl) -2- (4-pyridyl) -4-pyrimidinylamino] -N, N-dipropylacetamide 1/5 hydrate; melting point 163-165 ° C (recrystallized from isopropanol)

Example 17 N-methyl-N-
Phenyl-2- [2,6-di- (2-thienyl) -4-
Pyrimidinylamino] acetamide; melting point 151-1
53 ° C (recrystallized from acetonitrile)

( Example 18 )-2- [6- (1-
Imidazolyl) -5-methyl-2- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N
-Dipropylacetamide; melting point 174-175 ° C
(Recrystallized from isopropanol)

Example 19 --N-methyl-N-phenyl-2- [2-phenyl-6- (3-pyridyl) -4-
Preparation of [pyrimidinyloxy] acetamide

2-phenyl-6- (3-pyridyl) -4
To a mixture of 1.0 g of (3H) -pyrimidinone and 20 ml of dimethylformamide was added 0.16 g of about 60% sodium hydride (oily) at 0 to 5 ° C, and the mixture was stirred at room temperature for 1 hour, and then stirred at 0 to 5 ° C.
With 2-bromo-N-methyl-N-phenylacetamide
0.92 g was added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate, and recrystallized from isopropanol to obtain 1.0 g of the desired product.
136-137 ° C

Examples 20 to 27 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 19 to obtain the compounds of Table 7 represented by Chemical Formula 19.

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[Table 7] ――――――――――――――――――――――――――――― Example R ₁ R ₂ R ₆ Melting point (℃) Recrystallization solvent ――――――――――――――――――――――――――――――― 20 Et Ph 3-Pyridyl 143-145 IP 21 Pr Pr 3-Pyridyl 98-100 IP 22 Me Ph 2-pyridyl 195-197 AN 23 Me Ph 2-furyl 151-153 IP 24 Et Ph 2-furyl 161-163 IP 25 Pr Pr 2-furyl 113-115 IP 26 Me Ph 2-thienyl 122-124 IP 27 Et Ph 2-thienyl 132-134 IP ―――――――――――――――――――――――――――――――

Examples 28 to 29 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 19 to obtain the following compounds.

( Example 28 )-2- [6- (2-
Furyl) -2- (4-pyridyl) -4-pyrimidinyloxy] -N-methyl-N-phenylacetamide; melting point 155-157 ° C (recrystallized from isopropanol)

Example 29 N-methyl-N-
Phenyl-2- [2,6-di- (2-thienyl) -4-
Pyrimidinyloxy] acetamide; melting point 135-1
37 ° C (recrystallized from isopropanol)

Formulation Example 1- Production of tablets-N-methyl-N-phenyl-2- [2-phenyl-6- (3-pyridyl) -4-pyrimidinylamino] acetamide (1
g), lactose (84 g), corn starch (30 g),
Microcrystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g), and magnesium stearate (1.3 g).

The above components are mixed and granulated by a conventional method, and the mixture is tableted at 145 mg per tablet to produce 1000 tablets.

Formulation Example 2 Production of Capsules 2-
[6- (2-furyl) -2-phenyl-4-pyrimidinylamino] -N, N-dipropylacetamide (2 g),
Lactose (165 g), corn starch (25 g), hydroxypropylcellulose (3.5 g), light anhydrous silicic acid (1.
8 g) and magnesium stearate (2.7 g).

According to a conventional method, the above components are mixed and granulated.
Fill 200 mg into capsules to make 1000 capsules.

[0124]

The compound of the present invention represented by the formula (I)
It indicates selective and remarkable affinity for the peripheral-type BZomega ₃ receptors, anxiety-related disorders (neurosis, psychosomatic disorders, and other anxiety disorders), depression, central diseases such as epilepsy, angina It is useful as a therapeutic or prophylactic for cardiovascular diseases such as hypertension. Further, the compound of the present invention represented by the formula (I) is expected as a therapeutic or preventive agent for immune neurological diseases such as multiple sclerosis or immune inflammatory diseases such as rheumatism.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/24 A61P 25/24 43/00 111 43/00 111 C07D 403/04 C07D 403/04 405/04 405/04 405/14 405/14 409/04 409/04 409/14 409/14 413/14 413/14 (72) Inventor Makoto Oka 17-26 Takadacho, Ibaraki-shi, Osaka F-term (reference) 4C063 AA01 AA03 BB01 BB02 CC29 CC51 CC75 CC92 DD12 DD25 DD29 EE01 4C086 AA01 AA02 AA03 GA01 GA02 GA04 GA07 GA08 GA09 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA12 ZA18 ZA36 ZA40 ZA42 ZB15

Claims (2)

[Claims] 1. A 6-heteroarylpyrimidine derivative represented by the following formula 1, or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein, X represents —O— or —NR ₄ —, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group, R ₂ represents a lower alkyl group, R _{3 represents a} cycloalkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, a substituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group;
And R ₄ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ₅ represents a hydrogen atom, a lower alkyl group or a halogen atom; R ₆ represents an unsubstituted or substituted heteroaryl group; A represents an unsubstituted or substituted heteroaryl group or a group represented by the following formula: (Wherein R ₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group or a nitro group, ₈ is a hydrogen atom,
It means a halogen atom, a lower alkyl group or a lower alkoxy group. )] 2. A pharmaceutical composition comprising the 6-heteroarylpyrimidine derivative according to claim 1 or a physiologically acceptable acid addition salt thereof.