JP2001048882A - Pharmaceuticals comprising 2-aryl-8-oxodihydropurine derivatives - Google Patents

Abstract

(57) Abstract: selectively acts on A BZomega ₃ receptor, anxiety-related disorders, depression, providing a medicament useful as a therapeutic and prophylactic agent for central diseases such as epilepsy. SOLUTION: 2-Aryl-8 represented by the following formula (I)
-A medicament comprising an oxodihydropurine derivative or a pharmaceutically acceptable acid addition salt thereof. Embedded image Wherein W is H, lower alkyl, halogen, lower alkoxy, etc .; X is H, lower alkyl, formula [Q]: -CH (R ³ )
A group represented by CON (R ¹ ) (R ² ); Y is H, lower alkyl, a group represented by the above formula [Q], etc .; A is unsubstituted or substituted phenyl or unsubstituted or substituted heteroaryl means. However, in the formula (I), one of X and Y is a group represented by the formula [Q], and the other is the same group as the above X and Y except the formula [Q].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 2-aryl-type which selectively acts on peripheral benzodiazepine receptors.
The present invention relates to an 8-oxodihydropurine derivative, and more particularly, to a medicament comprising a 2-aryl-8-oxodihydropurine derivative having an acetate amide moiety at the 7- or 9-position of the purine ring.

[0002]

2. Description of the Related Art Tissues of mammals including humans include three benzodiazepines (hereinafter sometimes abbreviated as "BZ").
There is recognition sites, respectively "central-type (ω _1, ω _2)" and "peripheral-type (omega _3)" is referred to as benzodiazepine receptor (hereinafter, respectively "BZomega ₁ receptor", "BZomega ₂ receptor "and it may be referred to as" BZomega ₃ receptor "). Among them, central BZ receptor is γ-aminobutyric acid of central nervous system.
(Hereinafter, it may be referred to as “GABA”.) _A -BZ receptor is a binding site of a BZ-based compound existing on a Cl-ion channel complex, whereas peripheral BZ receptor is central or peripheral. Is widely distributed in tissues and organs (brain,
Kidney, liver, heart, etc.). In particular, peripheral BZ receptors are present at high density in endocrine organs such as the adrenal gland and testis, and cells closely related to biological inflammatory immune mechanisms such as mast cells, lymphocytes, macrophages, and platelets. There is a growing interest in social roles. On the other hand, the peripheral BZ receptor in the brain is abundant in the mitochondrial membrane of glial cells, is involved in the incorporation of cholesterol into the mitochondrial membrane, and via pregnenolone to progesterone and allopregnanolone called neurosteroids. It is thought to affect the biosynthetic pathway. Therefore, peripheral type B
Stimulation of Z receptors promotes the production of neurosteroids in the brain, and these steroids are GABA _A- B
It is thought to bind to the neurosteroid recognition site (different from the benzodiazepine receptor) present on the Z receptor-Cl-ion channel complex and affect the Cl ion channel opening process [Romeo, E., et al. Et al., J. P
harmacol. 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 No. 1756 (= EP-A-94271), a considerable number of reports have been made in patent applications and the like, but no compound has been put to practical use as a drug.

[0004] The following compounds are known as compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors.

[0005] Japanese Patent Application Laid-Open No. 62-5946 [USP-4]
788199, EP-A-205375 (patent family)] include amides represented by the following formula in peripheral BZ
It binds to receptors and is described as being useful as an anxiolytic, antispasmodic and antianginal, and as a therapeutic for immunodeficiency conditions.

[0006]

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JP-A-2-32058 (= EP-A)
No. 3,346,208 and US Pat. No. 5,026,711) disclose that 4-amino-3-carboxyquinolines represented by the following formula have an affinity for peripheral BZ receptor in vitro and in vivo and prevent human cardiovascular disease. And can be used as a therapeutic or antiallergic agent, and for the prevention or treatment of infectious symptoms, or the treatment of anxiety symptoms.

[0008]

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[0009] The WO96-32383 discloses, have anxiolytic and anti-rheumatic action with acetic acid amide derivative represented by the following formula selectively acts on the BZomega ₃ receptor,
It is described that it can be used for treating anxiety-related diseases and immune diseases.

[0010]

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 is lower alkyl group, cycloalkyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyl (lower)
R ³ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group, R ⁴ represents a hydrogen atom, a lower alkyl group, or the like; R ⁵ represents a hydrogen atom, a lower alkyl group; , Lower alkenyl group, hydroxy
(Lower) alkyl group, unsubstituted or substituted benzyloxy
(Lower) alkyl group, acyloxy (lower) alkyl group, lower alkoxy (lower) alkyl group, amino group, mono- or di-lower alkylamino group, acylamino group, amino
(Lower) alkyl, nitro, carbamoyl, mono- or di-lower alkylcarbamoyl, carboxyl, protected carboxyl, carboxy (lower) alkyl or protected carboxy (lower) alkyl; 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 represent-(CH ₂ )
n- (where n means 3, 4, 5 or 6), and R ⁷ is 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, and R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group]

[0012]

SUMMARY OF THE INVENTION The present inventors have found that BZω
As a result of intensive studies to obtain a drug comprising a compound which selectively and strongly acts on ₃ receptors, a drug comprising a 2-aryl-8-oxodihydropurine derivative represented by the following formula (I) has been developed for this purpose. And completed the present invention.

[0013]

According to the present invention, the following formula is provided.
There is provided a drug comprising the 2-aryl-8-oxodihydropurine derivative represented by (I) and a pharmaceutically acceptable acid addition salt thereof (hereinafter, also referred to as “the compound according to the present invention”). Is done.

[0014]

Embedded image

Wherein W is a hydrogen atom, a lower alkyl group,
A halogen atom, a lower alkoxy group, an amino group, a mono- or di- (lower) alkylamino group or an unsubstituted or substituted phenyl group,

X is a hydrogen atom, a lower alkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl
(Lower) alkyl group, lower alkenyl group, carbamoyl group, di (lower) alkylcarbamoyl group or the following formula [Q]
Means a group represented by

[0017]

Embedded image —CH (R ³ ) CON (R ¹ ) (R ² ) [Q]

(Wherein R ¹ represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group or a hydroxy (lower) alkyl group;
² is lower alkyl group, cycloalkyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyl (lower)
A piperidine ring, which means an alkyl group or an unsubstituted or substituted heteroaryl group, or R ¹ and R ² may be substituted with one or two lower alkyl groups together with an adjacent nitrogen atom, A pyrrolidine ring, a morpholine ring or a piperazine ring may be formed,
R ³ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group)

Y represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a lower alkenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or a group represented by the following formula [Q]. Means

[0020]

Embedded image —CH (R ³ ) CON (R ¹ ) (R ² ) [Q]

(Wherein R ¹ , R ² and R ³ have the same meanings as described above)

A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group. However, in the formula (I), one of X and Y is a group represented by the above formula [Q], and the other is the same group as the above X and Y except the formula [Q], respectively]

A pharmaceutically acceptable acid addition salt of a compound represented by the formula (I) is defined as a pharmaceutically acceptable acid addition salt of the compound of the formula (I) when it has a sufficient basicity to form an acid addition salt. Means a chemically acceptable acid addition salt, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and other inorganic acid salts such as maleate, fumarate, Organic acid salts such as oxalate, citrate, tartrate, lactate, benzoate, methanesulfonate and the like can be mentioned.

The compound represented by the formula (I) and the acid addition salt thereof may be present in the form of a hydrate and / or a solvate. Are included in the compounds according to

The compounds of the 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, mixtures and racemates thereof are encompassed by the compounds of formula (I).

The 2-aryl-8-oxodihydropurine derivative, which is a compound according to the present invention, is assigned a purine ring position number as shown in the following formula, and is named according to this position number in the present specification.

[0027]

Embedded image

(Wherein, A, W, X and Y mean the same as above)

The terms used in this specification are described below.

The lower alkyl group and the lower alkyl moiety mean those having 1 to 6 carbon atoms unless otherwise specified, and may be linear or branched. Specific examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl, and the lower alkyl group has 1 to 4 carbon atoms.
Are preferred. “Lower alkoxy group” means having 1 carbon atom
To 6 alkoxy groups, for example, methoxy, ethoxy, propoxy, isopropoxy 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 includes, for example, allyl and 2-butenyl. The “cycloalkyl group” means one having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl and cyclooctyl are mentioned. "Cycloalkyl (lower) alkyl group"
1 to 4 carbon atoms substituted by the above “cycloalkyl group”
And includes, for example, cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl. “Hydroxy (lower) alkyl group” means a lower alkyl group substituted with a hydroxy group, and includes, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl. “Halogen atom” means fluorine, chlorine, bromine, and iodine. “Mono or di (lower) alkylamino group” refers to a group having 1 to 4 carbon atoms.
Means an amino group substituted by one or two alkyl groups, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, and ethylmethylamino.

"Unsubstituted or substituted phenyl group"
Halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, amino, mono or di
(Lower) means a phenyl group optionally substituted by one or two selected from alkylamino, cyano and nitro, for example, phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl; 2
-, 3- or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl;
2-, 3- or 4-methoxyphenyl; 2-, 3- or 4-trifluoromethylphenyl; 2-, 3- or 4-hydroxyphenyl; 2-, 3- or 4-aminophenyl; -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" refers to a halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, amino,
A mono- or di- (lower) alkylamino, cyano or nitro, alkyl group having 1 to 4 carbon atoms which is substituted by a phenyl group which may be substituted by 1 or 2; for example, benzyl; 2-, 3- or 4-
Chlorobenzyl; 2-, 3- or 4-bromobenzyl; 2-, 3- or 4-fluorobenzyl; 2,4-
Dichlorobenzyl; 2,4-dibromobenzyl; 2,4-
2-, 3- or 4-methylbenzyl; 2-, 3- or 4-methoxybenzyl; 2-,
3- or 4-trifluoromethylbenzyl; 2-3
-Or 4-hydroxybenzyl; 2-, 3- or 4
2-, 3- or 4-methylaminobenzyl; 2-, 3- or 4-dimethylaminobenzyl; 2-, 3- or 4-cyanobenzyl; 2-, 3-
Or 4-nitrobenzyl; phenethyl; 2- (4-chlorophenyl) ethyl.

The following formula [B]:

[0034]

Embedded image

Specific examples of the group represented by the above include the above-mentioned “unsubstituted or substituted phenyl group” and the above-mentioned “unsubstituted or substituted phenyl group” substituted alkyl group having 1 or 2 carbon atoms. Preferred examples include, but are not limited to, phenyl; 4- or 3-chlorophenyl; 4- or 3-bromophenyl; 4- or 3-fluorophenyl; 4-methoxyphenyl; 4-trifluoromethylphenyl; -Hydroxyphenyl;
Benzyl; 2-, 3- or 4-chlorobenzyl; 4-
Bromobenzyl; 3- or 4-fluorobenzyl; 4
4-methylbenzyl; 4-trifluoromethylbenzyl; 4-hydroxybenzyl; phenethyl; 2- (4-chlorophenyl) ethyl.

"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 by C ₁ -C ₃ alkyl or trifluoromethyl, or 5 A 6-membered to 6-membered bicyclic heteroaryl group, for example 2-, 3- or 4-pyridyl; 5-methyl-2-pyridyl; 2- or 3-thienyl; 2- or 3-furyl; 2-, 4- or 5-
2- or 3-pyrazinyl; 1-pyrazolyl; 2-imidazolyl; 2-thiazolyl; 3-isoxazolyl; 5-methyl-3-isoxazolyl; quinolyl; isoquinolyl. Among the compounds of formula (I), preferred are those of the formula (I) wherein A is of the following formula [A ']

[0037]

Embedded image

Wherein R ⁴ is 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. Means R
⁵ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group), a pyridyl group, a thienyl group or a furyl group,
Compounds wherein W, X and Y are the same as described above, and pharmaceutically acceptable acid addition salts thereof, are mentioned.

Among the compounds of the formula (I), more preferred are those wherein (a) X is a group represented by the following formula [Qx]

[0040]

Embedded image —CH (R ³¹ ) CON (R ¹¹ ) (R ²¹ ) [Qx]

[Wherein R ¹¹ represents a lower alkyl group;
R ²¹ is a lower alkyl group or the following formula [B]

[0042]

Embedded image

(Wherein R ⁶ is 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. Means R
⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group, and m represents 0, 1 or 2.)

Or a group represented by R¹¹You
And R^{twenty one}Is taken together with the adjacent nitrogen atom to form one or
Pipette each of which may be substituted with two lower alkyl groups
Lysine ring, pyrrolidine ring, morpholine ring or piperazi
May form a ring; ³¹Is a hydrogen atom, lower alkyl
A alkyl group or a hydroxy (lower) alkyl group]
And

Y is a hydrogen atom or a lower alkyl group, or (b) X is a hydrogen atom, a lower alkyl group or a carbamoyl group, and Y is a group represented by the following formula [Qy].

[0046]

Embedded image —CH (R ³¹ ) CON (R ¹¹ ) (R ²¹ ) [Qy]

Wherein R ¹¹ , R ²¹ and R ³¹ have the same meanings as described above, and A is a group represented by the above formula [A ′], a pyridyl group, a thienyl group or a furyl group. , W
Include the same compounds as described above and pharmaceutically acceptable acid addition salts thereof.

More preferred compounds are of the formula (I)
(a) X is a group represented by the above formula [Qx] (wherein R ¹¹ is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ²¹ is an ethyl group, a propyl group, an isopropyl group, Butyl group, phenyl group, halogen, methoxy,
A phenyl group substituted with trifluoromethyl or hydroxy, a benzyl group or a benzyl group substituted with halogen, methoxy, trifluoromethyl or hydroxy, and R ³¹ is the same as described above), and Y is a hydrogen atom, A methyl group or an ethyl group, or

(B) X is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and Y is a group represented by the above formula [Qy] (wherein R ¹¹ is a methyl group, ethyl Group, propyl group, isopropyl group or butyl group, and R ²¹ is ethyl group, propyl group, isopropyl group, butyl group, phenyl group, halogen, methoxy,
A phenyl group or a benzyl group substituted with trifluoromethyl or hydroxy, or a benzyl group substituted with halogen, methoxy, trifluoromethyl or hydroxy, and R ³¹ is the same as described above); A ′], a pyridyl group, a thienyl group or a furyl group, and W is the same compound as described above and a pharmaceutically acceptable acid addition salt thereof.

Particularly preferred compounds include compounds of the following formula (Ia)
Or a 2-aryl-8-oxodihydropurine derivative represented by (Ib) and a pharmaceutically acceptable acid addition salt thereof.

[0051]

Embedded image

(Where R¹²And R^{twenty two}Are the same or different
Means ethyl, propyl or butyl
Or R¹²Is a methyl, ethyl or propyl group
And R ^{twenty two}Is phenyl, halogenophenyl, methoxy
Phenyl, benzyl, halogenobenzyl or methyl
Means a toxicoxy group,³²Is hydrogen atom, methyl group
Or an ethyl group, Y¹Is hydrogen atom, methyl group
Or ethyl group;⁴¹Is a hydrogen atom, a halogen atom
, Methyl, methoxy, nitro or trifluoro
A methyl group),

[0053]

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(Wherein X ¹ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group, R ¹² and R ²² are the same or different and represent an ethyl group, a propyl group or a butyl group, or R ¹² represents a methyl group, an ethyl group or a propyl group, R ²² represents a phenyl group, a halogenophenyl group,
A methoxyphenyl group, a benzyl group, a halogenobenzyl group or a methoxybenzyl group, wherein R ³² is a hydrogen atom,
R ⁴¹ represents a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group or a trifluoromethyl group.

In the above formulas (Ia) and (Ib), R ³²
Are each more preferably a hydrogen atom.

Specific examples of particularly preferred compounds include, for example, the following compounds and pharmaceutically acceptable acid addition salts thereof.

N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-
Purine-7-acetamide,

8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-N-phenyl-7H-
Purine-7-acetamide,

8,9-dihydro-2- (4-fluorophenyl) -9-methyl-N-methyl-8-oxo-N-phenyl-7H-purine-7-acetamide,

N-ethyl-8,9-dihydro-2- (4-
(Fluorophenyl) -9-methyl-8-oxo-N-phenyl-7H-purine-7-acetamide,

7,8-dihydro-7-methyl-8-oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide,

7-ethyl-7,8-dihydro-8-oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide,

N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-
Purine-9-acetamide,

N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-phenyl-9H-
Purine-9-acetamide,

N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-purine-9-acetamide;

N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-purine-9-acetamide, and

N- (4-chlorobenzyl) -N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide.

As specific examples of the compounds contained in the compound of the formula (I), in addition to the compounds of the following Preparation Examples, the compounds of Tables 1 and 2 represented by the following formula 24 and Table 3 represented by the following formula 25 And the compounds of Table 4 and pharmaceutically acceptable acid addition salts thereof.

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

Me: methyl group Et: ethyl group Pr: n-propyl group Bu: n-butyl group Pent: n-pentyl group Bzl: benzyl group Ph: phenyl group Py: pyridyl group Fur: furyl group Thi: thienyl group

Accordingly, for example, Ph-4-Cl is a 4-chlorophenyl group, Ph-4-F is a 4-fluorophenyl group, and 2-Thi is a 2-chlorophenyl group.
-Represents a thienyl group.

[0072]

Embedded image

[0073]

[Table 1]

Table 2 below is a continuation of Table 1.

[0075]

[Table 2]

[0076]

Embedded image

[0077]

[Table 3]

Table 4 below is a continuation of Table 3.

[0079]

[Table 4]

The compound of the formula (I) can be produced, for example, by the following method.

Production method (a) --- In formula (I), Y represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a lower alkenyl group or an unsubstituted or substituted phenyl (lower)
The compound which is an alkyl group has the following formula (II)

[0082]

Embedded image

(Wherein Y ² is a hydrogen atom, a lower alkyl group,
Cycloalkyl group, cycloalkyl (lower) alkyl group,
Lower alkenyl group or unsubstituted or substituted phenyl
A lower alkyl group, A and W have the same meanings as described above) and a compound represented by the following formula (III):

[0084]

Embedded image Z-CH (R ³ ) -CON (R ¹ ) (R ² ) (III)

(Wherein, Z represents a leaving atom or leaving group, and R ¹ , R ² and R ³ have the same meanings as described above). be able to.

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

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

In the above formula (III), R ¹ and / or R
^{When 3} is a hydroxy (lower) alkyl group, the hydroxy (lower) alkyl group is preferably protected with a protecting group that can be eliminated by hydrogenolysis, such as benzyloxy. , 4-chlorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy, 4-methylbenzyloxy, 4-methoxybenzyloxy. These protecting groups can be easily converted to hydroxy groups by conventional hydrogenolysis. Also, in the production methods (b) to (e) described below, when R ¹ and / or R ³ is a hydroxy (lower) alkyl group, the same protection is carried out, followed by deprotection.
It is desirable to lead to the desired compound.

The compound of the formula (III) can be produced by a method known per se, for example, the method described in JP-A-62-64 or a method analogous thereto.

The starting compound (II) can be produced, for example, by the method represented by the route A or route B shown in the following formulas 28 and 29.

[0091]

Embedded image

(Wherein R represents a lower alkyl group, Z ¹
Represents a halogen atom or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group or an alkanesulfonyloxy group, and A, W and Y ² have the same meanings as described above. )

[0093]

Embedded image

Wherein A, W, Y ² and Z ¹ have the same meanings as described above.

Step 1 : Halogenation or Sulfonylation Halogenation is carried out, for example, by reacting a compound of the formula (A) or (F) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide). Will be Sulfonylation is performed, for example, by using a compound of the formula (A) or (F) and a sulfonylating agent (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride).
And by reacting

Step 2 : Amination The reaction of the compound of the formula (B) or (G) with the compound of the formula (C) 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 carried out in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, sodium hydrogencarbonate, alkali hydrogencarbonates such as potassium hydrogencarbonate, and alkali salts such as triethylamine. Triamines can be mentioned, but they can also serve as an excess of the compound of the formula (C). The reaction temperature varies depending on the type of the starting compound, reaction conditions, and the like, but is usually about 0 ° C.
At 200C, preferably from about 20C to about 100C.

Step 3 of Route A : Hydrolysis This hydrolysis can be carried out according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
Specific examples of acids include hydrochloric acid, mineral acids such as sulfuric acid, formic acid,
Organic acids such as acetic acid, propionic acid and oxalic acid. Specific examples of the base include sodium hydroxide, alkali hydroxides such as potassium hydroxide, sodium carbonate,
Alkali carbonates such as potassium carbonate are mentioned. The reaction temperature is usually about 20 ° C to 100 ° C.

Step 3 of Route B : Reduction This reduction can be performed according to a conventional method, for example, by reacting with hydrogen in a suitable solvent in the presence of a catalyst such as palladium carbon, Raney nickel, or platinum oxide. . In addition, the present reduction reaction is a metal (for example, tin, zinc, iron)
Alternatively, the reaction can be performed using a combination of a metal salt (for example, stannous chloride) and an acid (for example, hydrochloric acid or acetic acid), or iron or stannous chloride alone. As the solvent, for example, ethanol, alcohols such as methanol, water, acetic acid,
Dioxane and tetrahydrofuran are used. The reaction temperature is usually about 0 ° C. to about 80 ° C., and the reaction is carried out under normal pressure or under pressure.

Step 4 : Cyclization This reaction can be carried out by the same method as described in the following production method (b) or (c).

The compounds of the starting materials (A) and (F) are commercially available or can be obtained in a manner known per se, for example J. Am.
Chem. Soc., 74 , 842 (1952); Chem. Ber., 95 , 937 (196
2); J. Org. Chem., 29 , 2887 (1964); J. Med. Chem.,
35 , 4751 (1992); J. Org.Chem., 58 , 4490 (1993); S
synthesis, 86 (1985), and the methods described in Reference Examples 1, 11, and 15 below, or a method analogous thereto.

Production method (b) : In the formula (I), a compound wherein X is a hydrogen atom and Y is a group represented by the formula [Q] is represented by the following formula (IV)

[0103]

Embedded image

(Wherein Y ³ represents a group represented by the above formula [Q], and A and W represent the same as those described above) by reacting an azide compound with the compound represented by the above formula. can do.

The azide compound used in this reaction includes, for example, diphenylphosphoric acid azide and sodium azide.

This reaction 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 to be used, for example, toluene, xylene,
Examples include dimethoxyethane, 1,2-dichloroethane, acetone, methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamide, and dimethyl sulfoxide. Examples of the base include triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about 10 ° C to about 150 ° C, preferably about 30 ° C to about 1 ° C.
20 ° C.

The starting compound (IV) has the formula
The compounds of (C) is used a compound of Y ³ -NH ₂ in which those of the formula (B), it is possible to be produced by the method of Step 2 and Step 3 as shown in the route A. Further, the starting compound (I
V) uses the compound of formula (B) of Route A and an amino acid to introduce a substituted amino group at the 4-position of the pyrimidine ring by the method of Step 2 of Route A, and then describes the process (e) described below. The compound can also be produced by amidation and, if necessary, alkylation according to the method described in Reference Example 63 below.
Shown in

Production method (c) -In the formula (I), the compound wherein X is a hydrogen atom and Y is a group represented by the formula [Q] is represented by the following formula (V)

[0109]

Embedded image

Wherein A, W and Y ³ have the same meanings as described above, by reacting the compound with urea, carbonyldiimidazole or diethyl carbonate.

This reaction can be carried out without a solvent or in a suitable solvent. Examples of the solvent used include tetrahydrofuran, toluene, dimethyl sulfoxide, and ethylene glycol. The reaction temperature is usually about 20 ° C to about 250 ° C, preferably about 60 ° C to about 220 ° C.

The starting compound (V) is obtained by converting (C)
Can be prepared by using the compound of the formula (G) in which the compound of formula (I) is Y ³ —NH ₂ and the method of step 2 and step 3 shown in the route B.

Production method (d) : In the formula (I), a compound wherein X is a group other than a hydrogen atom and a group represented by the formula [Q], and Y is a group represented by the formula [Q] is The following formula (VI) obtained by the production method (b)

[0114]

Embedded image

Wherein A, W and Y ³ have the same meanings as described above, to a compound of the following formula (VII)

[0116]

Embedded image ZX ² (VII)

Wherein X ² is the same group as X except for a hydrogen atom and the group represented by the formula [Q], and Z is the same as defined above. It can be manufactured by doing.

In this reaction, the method described in the production method (a) can be used as it is.

The starting compound (VII) is commercially available or can be produced by a method known per se.

Production method (e) -In the formula (I), the compound wherein X is a group represented by the formula [Q] is represented by the following formula (VIII)

[0121]

Embedded image

(Wherein A, R ³ , W and Y ² have the same meanings as described above) or a reactive derivative thereof, and the following formula (IX)

[0123]

Embedded image HN (R ¹³ ) (R ²³ ) (IX)

[0124] (wherein, R ¹³ and R ²³ are the same meaning as those defined in the hydrogen atom or each R ¹ and R ²⁾ by reacting a compound represented by, R ¹³ and R
^{When one of 23} is a hydrogen atom, the following formula (X)
Or (XI)

[0125]

Embedded image R ²⁴ —Z (X) R ¹⁴ —Z (XI)

(Wherein, R ²⁴ represents a lower alkyl group, a cycloalkyl group or an unsubstituted or substituted phenyl (lower) alkyl group, and R ¹⁴ represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl ( A lower) alkyl group or a hydroxy (lower) alkyl group, and Z has the same meaning as described above, provided that when R ¹³ is a hydrogen atom, the compound of the above formula (X) is reacted, and R ²³ is In the case of a hydrogen atom, the compound of the formula (XI) is reacted) to produce a compound represented by the formula (XI).

Examples of the reactive derivative of the compound of the formula (VIII) include lower alkyl esters (especially methyl esters), active esters, acid anhydrides and acid halides (especially acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, and N-hydroxysuccinimide ester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include ethyl chlorocarbonate, a mixed acid anhydride with an alkyl chlorocarbonate such as isobutyl chlorocarbonate,
Mixed anhydride with aralkyl chlorocarbonate such as benzyl chlorocarbonate, mixed anhydride with aryl chlorocarbonate such as phenyl chlorocarbonate, mixed anhydride with alkanoic acid such as isovaleric acid and pivalic acid Things.

When the compound of formula (VIII) itself is used,
N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N, N'-carbonyldisuccinimide, 1-ethoxycarbonyl-
Reacting in the presence of a condensing agent such as 2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate Can be.

The reaction of the compound of the formula (VIII) or a reactive derivative thereof with the compound of the formula (IX) is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but, for example, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, ethers such as dioxane, methylene chloride , Halogenated hydrocarbons such as chloroform, ethanol, alcohols such as isopropanol, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, water and the like, each of which alone, Alternatively, two or more kinds are used in combination. This reaction is carried out in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and sodium hydrogen carbonate. , Alkali hydrogen carbonate such as potassium hydrogen carbonate, or triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine can be mentioned, but can also serve as excess of the compound of formula (IX). The reaction temperature varies depending on the type of the starting compound used and the like, but is usually from about -30C to about 200C, preferably from about -10C to about 150C.

The reaction between the product obtained by the reaction of the compound of the formula (VIII) with the compound of the formula (IX) and the compound of the formula (X) or the formula (XI) was described in the above-mentioned production method (a). Can be done in a way.

The compound of the formula (VIII) has the following formula (II)

[0132]

Embedded image

Wherein A, W and Y ² have the same meanings as described above, and a compound represented by the following formula (XII):

[0134]

Embedded image Z ¹ —CH (R ³ ) —COOR (XII)

(Wherein, R, R ³ and Z ¹ have the same meanings as described above), and then the product is hydrolyzed according to a conventional method. .

For this reaction, the method described in the above production method (a) can be used as it is.

The compounds of the formulas (X) and (XI) are commercially available or can be prepared by a method known per se.

The compound of the formula (I) can also be produced by the following method.

The compound of the formula (I) wherein W is a lower alkoxy group can be produced by reacting a compound of the formula (I) wherein W is a halogen atom with a metal lower alkylate. Production Example 46 is shown in FIG.

Compounds of formula (I) wherein W is a mono- or di- (lower) alkylamino group are represented by W in the compounds of formula (I)
Can be produced by reacting a compound in which is a halogen atom with a mono- or di- (lower) alkylamine, which is specifically shown in Production Example 47.

The compound of the formula (I) wherein the phenyl group is substituted by a hydroxy group may be obtained by treating the compound of the formula (I) wherein the phenyl group is substituted by a methoxy group with boron tribromide or hydrogen bromide. This is specifically shown in Production Example 174.

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 formula (I) having a basicity sufficient 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.

[0143]

The test results of representative compounds according to the present invention are shown below, and the pharmacological characteristics of the compounds according to the present invention will be described. However, the present invention is not limited to these test examples.

Test Example 1 : Central type (ω ₁ , ω ₂ ) and peripheral type
(ω ₃ ) benzodiazepine receptor binding test-BZ ω ₁ and ω ₂ receptor binding test and preparation of receptor membrane preparation were performed according to the method of Stephens, DN et al. [J. Pharmacol. Exp.
Ther., 253, conforms to the 334-343 (1990)], BZω ₃
Receptor binding studies and preparation of receptor membrane preparations were performed by Schoemak
er, H. [J. Pharmacol. Exp. Ther., 225 , 61-69
(1983)]. ω _1, ω ₂ and ω ₃ receptor membrane preparation is of male Wistar rats of 7-8 weeks old cerebellum
(ω ₁ ), spinal cord (ω ₂ ) or kidney (ω ₃ ) were prepared by the following procedures. The cerebellum or spinal cord was homogenized by adding a 20-fold volume of ice-cold buffer (50 mM Tris-citrate buffer, pH 7.1), and centrifuged at 40,000 g for 15 minutes. After washing the obtained sediment four times by the same operation,
It was 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 combined with a buffer I for binding test (120 mM sodium chloride, 5 mM potassium chloride, 2 mM
Suspension (1 g tissue wet weight / 1 g tissue wet weight / 50 mM Tris-HCl buffer containing 7.4 mM calcium chloride, 1 mM magnesium chloride / pH 7.4)
A material obtained by 40ml) was used in the binding test as BZomega ₁ or omega ₂ receptor membrane preparation. On the other hand, a 20-fold volume of ice-cold binding buffer II (5 mM containing 100 mM sodium chloride) was added to the kidney.
0 mM sodium phosphate-potassium phosphate buffer, pH 7.
After the addition of 4) and homogenization, the filtrate filtered with quadruplicated gauze was centrifuged at 40,000 g for 20 minutes. The obtained precipitate is suspended in buffer II (1 g tissue wet weight / 100 ml).
Were those used in the binding assay as BZomega ₃ receptor membrane preparation.

[0145] 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: 0.3nM) (ω} 2: 1n
M)] and flunitrazepam (final concentration 10 μM) were added to BZω ₃
[ ³ H] 4′-chlorodiazepam: 7-
Chloro-1,3-dihydro-1-methyl-5- (4-chlorophenyl) -2H-1,4-diazepin-2-one (Ro5
-4864) (final concentration 0.5 nM) and diazepam (final concentration 100
μM). Incubation conditions were B
Zw ₁ and omega ₂ receptors 30 min at 37 ° C. in binding studies,
In BZomega ₃ receptor binding assay was carried out for 150 minutes at 0 ° C..
Incidentally, BZω ₁ and omega ₂ receptor binding studies Bikyukurin
(bicuculline: final concentration 100 μM).

The receptor binding test was performed according to the following procedure. A test compound having a known concentration, a tritium-labeled ligand, a receptor membrane standard, and a buffer I or II for binding test were added to each test tube to make a total volume of 1 ml, and the reaction was started by adding the receptor membrane standard. . After the incubation, the reaction was stopped by suction-filtering the labeled ligand bound to the receptor onto a Whatman GF / B glass fiber filter using a cell harvester (Brandel, USA). Immediately, ice-cold buffer [in ω ₁ and ω ₂ 50mM
Tris-HCl buffer (pH 7.7); at ω ₃ , buffer II] 5 m
Washed 3 times with l. For radioactivity, the filter was transferred to a vial, and 10 ml of a liquid scintillation cocktail (ACS-II, manufactured by Amersham, USA) was added.
It was 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 test compound increases the specific binding amount of the labeled ligand by 50%.
The inhibitory concentration (IC ₅₀ value) was determined by the probit method. Table 5 shows the results. Note that the test compounds shown in Table 5, IC for benzodiazepine omega ₁ and omega ₂ receptor
All ₅₀ values were 1000 nM or more.

[0147]

[Table 5]

* It means the compound of Production Example 1 (hereinafter, it means the compound corresponding to Production Example No.).

[0149] Compounds of formula (I) shown in Table 5 BZomega ₃
Strongly binds to receptors. In contrast, BZω ₁ and BZω _{2 IC 50} values of the receptors for these compounds 1000
Since it nM or more, it is clear that the compounds of formula (I) are selective and potent binding to BZomega ₃ receptor.

Test Example 2 : Light / dark box test (anti-anxiety action)-Crawley, J and Goodwin, FK et al.
acol. Biochem. Behav., 13 , 167-170 (1980)], the presence or absence of an anxiolytic effect of the test compound was examined.

The light / dark box test utilizes the habit of rodents such as mice and rats to prefer dark places, and uses the increase in relative residence time in bright places, which are uncomfortable environments, as an index to evaluate the anxiolytic effect of drugs. Is an effective and simple behavioral pharmacological test method for assessing In this method, cholecystokinin-
Many of the B-type antagonists and benzodiazepines show positive effects.

In the light / dark box test, the illuminance was 1700 using an incandescent lamp.
Light box made of transparent acrylic plate illuminated by looks (20 × 17
× 15cm) and a dark box made of black acrylic plate (15 × 17 × 15cm) are connected, and a barrier (4.4 × 5.
0 cm) using an apparatus (35 × 17 × 15 cm).

In the test, 10 male Std-ddY mice weighing 25 to 30 g were used per group. Oral administration of test compound 30
Minutes later, the mouse was placed in the center of the light box, the time spent in the light box during the 5-minute test time was measured, and the ratio of the time spent in the light box to the total test time (light box stay rate,%) was calculated. .

The anxiolytic potency of the test compound was expressed as the minimum effective dose (MED) that statistically significantly (Dunnett's method, 5% risk) increased the stay rate in the bright box. Table 6 shows the results.

[0155]

[Table 6]

* It means the compound of Production Example 1 (hereinafter, it means the compound corresponding to Production Example No.).

The compound of the formula (I) shown in Table 6 was 1 mg / k
The anti-anxiety effect is shown at a dose of not more than g.
Compounds 2, 5, 106, 107, 136, 137, 146 and 147 showed anxiolytic effects at doses as low as 0.001 to 0.003 mg / kg.

Test Example 3 : Test for action on isoniazid-induced clonic seizures (anticonvulsant action)-Since isoniazid inhibits glutamate decarboxylase, a GABA biosynthetic enzyme, the administration of isoniazid decreases the amount of GABA in the brain. Convulsive seizures are induced. Auta, J. et al. [J. Pharmacol. Exp. Ther., 26
5 , 649-656 (1993)], the antagonism of the test compound against isoniazid-induced clonic seizures was tested. In this test, many drugs having an indirect or direct enhancer of GABA _A receptor function, such as BZ receptor agonists represented by diazepam, allopregnanolone and allotetrahydrodeoxycorticosterone (TH
BZomega ₃ receptor agonists having promoting action neurosteroids or neurosteroids generation of DOC), etc. are known to exhibit positive effect.

In the test, six male Std-ddY mice weighing 22 to 24 g were used per group. Thirty minutes after oral administration of the test compound, isoniazid (200 mg / kg) was subcutaneously administered. Immediately thereafter, the mice were placed in a plastic cage, and the onset latency of clonic seizures was observed for 90 minutes. The onset latency of the solvent control group was about 40 minutes.

The antagonism potency of the test compound was determined by measuring the dose that would increase net latency by 25% compared to the vehicle control group.
(ED ₂₅ value). The ED ₂₅ value was calculated by the probit method. Table 7 shows the results.

[0161]

[Table 7]

* It means the compound of Production Example 106 (hereinafter, each means the compound corresponding to the Production Example No.).

Test Example 4: Action test on immobility time in forced swimming model (anti-depressant action)-As a model for evaluating antidepressants, a despair state model in forced swimming of animals is an indicator of the despair state of many antidepressants. Is widely used because it has the effect of reducing the immobility time. Porsolt RD et al. [Eur. J. Pharmacol., 47 ,
379-391 (1978)], the effect of the test compound on the despair state of the forced swimming model was tested.

[0164] The body weight selected in the trial for the test was 95.
A group of 6 male Std-Wistar rats weighing 120 g was used. The selection criteria for animals are in a water tank at 23 to 25 ° C. Transparent acrylic cylinder (inner diameter: 24.5cm, height: 33cm, water depth:
(15 cm)} once a day for 10 minutes, 4 times of break-in trials, and the fourth trial of the day before the test, the immobilization time of 6 minutes after water entry exceeded 180 seconds. Grouping was performed by random sampling.

Sixty minutes after the oral administration of the test compound (the compound of Production Example 146), the rats were placed in an aquarium and the immobility time observed during the 6-minute test was measured. The immobilization time shortening effect of the test compound group was compared with the vehicle control group by parametric Dunnet.
A multiple comparison test by the t method was performed to judge.

[0166] Furthermore, the test compound (the compound of preparation 146) 10mg / kg BZω ₃ receptor antagonist for oral administration 30 minutes after the
PK-11195 [1- (2-chlorophenyl) -N-methyl-
N- (1-methylpropyl) -3-isoquinolinecarboxamide] 3 mg / kg was intraperitoneally administered, 30 minutes later, the rat was placed in an aquarium, and the immobility time observed during the 6-minute test was measured. To reduce the immobility time of
An antagonistic test of PK-11195 was performed. Antagonism by PK-11195 was determined by performing a parametric Student's t2 group comparison test between the test compound alone group and the test compound and PK-11195 combination group.

The compound of Preparation Example 146 showed a significant (p <0.01) reduction in immobility time of 22.1% at a dose of 3 mg / kg and 28.4% at a dose of 10 mg / kg. Was done. Further, the immobility time shortening effect of the compound of Example 146 was completely antagonize the omega ₃ receptor antagonist PK-11195.

Test Example 5 : Acute toxicity--An experiment was conducted on the compound of Production Example 1 using 10 Std-ddY male mice (body weight 25 to 30 g) in each group. 0.
5% test compound suspended in lagant solution 2000 mg / k
g was administered orally, and the presence or absence of death was observed for 7 days after administration. As a result, there was no death of the compound of Production Example 1.

As is clear from the above pharmacological test results,
Compounds of formula (I), as well as showing a selective and remarkable affinity for BZomega ₃ receptor in vitro studies, exhibits excellent pharmacological activities such as anxiolytic and antiepileptic effects in animal studies , Anxiety-related diseases (neurosis, psychosomatic disorders, anxiety disorders, and others), central illnesses such as depression and epilepsy, immune nervous diseases such as multiple sclerosis, circulatory system such as angina pectoris and hypertension It is useful as a drug for treating and preventing diseases.

[0170] with showing a selective and remarkable affinity for BZomega ₃ receptor, strong as the anxiolytic shows the active compound, for example, the following compounds and their pharmaceutically acceptable acid addition salt thereof No.

(1) N-ethyl-8,9-dihydro-9-
Methyl-8-oxo-2-phenyl-N-phenyl-7
H-purine-7-acetamide (compound of Production Example 1)

(2) 8,9-dihydro-9-methyl-N-
Methyl-8-oxo-2-phenyl-N-phenyl-7
H-purine-7-acetamide (compound of Production Example 2)

(3) 8,9-dihydro-2- (4-fluorophenyl) -9-methyl-N-methyl-8-oxo-
N-phenyl-7H-purine-7-acetamide (compound of Production Example 5)

(4) N-ethyl-8,9-dihydro-2-
(4-Fluorophenyl) -9-methyl-8-oxo-N
-Phenyl-7H-purine-7-acetamide (compound of Production Example 12) (5) 7,8-dihydro-7-methyl-8-oxo-2
-Phenyl-N, N-dipropyl-9H-purine-9-
Acetamide (Compound of Production Example 106)

(6) 7-ethyl-7,8-dihydro-8-
Oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide (compound of Preparation 107)

(7) N-benzyl-N-ethyl-7,8-
Dihydro-7-methyl-8-oxo-2-phenyl-9
H-purine-9-acetamide (Compound of Production Example 146)

(8) N-benzyl-7,8-dihydro-
N-methyl-7-methyl-8-oxo-2-phenyl-
9H-purine-9-acetamide (Compound of Production Example 136)

(9) N-benzyl-N-ethyl-7,8-
Dihydro-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-purine-9-acetamide (Production Example 1
(47 compounds)

(10) N-benzyl-7,8-dihydro-
N-methyl-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-purine-9-acetamide (compound of Production Example 137)

N- (4-chlorobenzyl) -N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide (Preparation Example 20)
Compound 3)

The administration route of the compound of the formula (I) may be any of oral administration, parenteral administration and rectal administration. The dosage depends on the type of compound, administration method,
Usually varies from 0.01 to 50 mg / kg /
Days, preferably 0.03 to 5 mg / kg / day.

The compound of the formula (I) is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and does not react with the compound of the formula (I) is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partially pregelatinized starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose,
Hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose,
Gelatin, gum arabic, hydroxypropylcellulose, low-substituted 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, 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. Also tablets,
Granules may be coated by known methods. In the case of injections, the compounds are prepared by dissolving the compound of the formula (I) in water, but may be dissolved using an isotonic agent or a solubilizing agent as necessary. Buffers and preservatives may be added.

These preparations were prepared by adding the compound of formula (I) to 0.1%.
It can be contained at a rate of 01% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically effective ingredients.

[0185]

[Production Examples] The compounds according to the present invention will be more specifically described below with reference to Production Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, and the like.

In the tables showing the production examples of Reference Examples 1 to 112 and Production Examples 1 to 232, the following abbreviations may be used for simplification of the description.

[Recrystallization solvent] A: ethanol AN: acetonitrile CF: chloroform E: diethyl ether M: methanol IP: isopropanol IPE: diisopropyl ether DMF: dimethylformamide

Reference Example 1 Preparation of ethyl 3,4-dihydro-4-oxo-2-phenylpyrimidine-5-carboxylate

To a mixture of 16.5 g of sodium methoxide and 200 ml of absolute ethanol was added, at 0-5 ° C., 16 g of benzamidine hydrochloride. After stirring at 0 ° C. for 30 minutes, a solution of 20 g of diethyl ethoxymethylenemalonate in 50 ml of absolute ethanol was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then heated and refluxed for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in water, and concentrated hydrochloric acid was added dropwise while stirring at 0 to 5 ° C. until the pH became 4. The precipitate was collected by filtration, washed with water, washed with diethyl ether, and then with ethanol to obtain 17.5 g of the desired product.

Reference Examples 2 to 10 The corresponding starting compounds were used and reacted and treated in the same manner as in Reference Example 1 to obtain compounds shown in Table 8 of Chemical Formula 39.

[0191]

Embedded image

[0192]

[Table 8]

Reference Example 11 --Production of ethyl 3,4-dihydro-4-oxo-2,6-diphenylpyrimidine-5-carboxylate

(1) To a mixture of 44.9 g of a 20% sodium ethoxide-ethanol solution and 200 ml of ethanol, 10.3 g of benzamidine hydrochloride was added at room temperature. After stirring at the same temperature for 2 hours, 14.9 g of ethyl benzalmalonate was added, and the mixture was heated under reflux for 3 hours. After the reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and concentrated hydrochloric acid was added dropwise until pH 4 was reached. The precipitate was collected by filtration and washed with water to give crude 3,4,5,6-tetrahydro-4-oxo-2,6-diphenylpyrimidine-
15.8 g of ethyl 5-carboxylate were obtained.

(2) A mixture of 15.5 g of the above product, 13.6 g of 2,3-dichloro-2,3-dicyano-p-benzoquinone and 300 ml of ethanol was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added, 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, diisopropyl ether was added to the residue, and the precipitate was collected by filtration to obtain 10.7 g of the desired product.

Reference Examples 12 to 14 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 11.
After treatment, the compound shown in Table 9 of Chemical Formula 40 was obtained.

[0197]

Embedded image

[0198]

[Table 9]

Reference Example 15 Production of 5-nitro-2-phenyl-4 (3H) -pyrimidinone

To a mixture of 8 g of sodium methoxide and 100 ml of absolute ethanol at 0 ° C. was added 11.7 g of benzamidine hydrochloride. After stirring at 0 ° C. for 30 minutes, a mixture of 10 g of ethyl nitroacetate and 10.7 g of N, N-dimethylformamide dimethyl acetal was heated under reflux for 3 hours and concentrated under reduced pressure to obtain crude 2- (N, N
A solution of 14 g of ethyl (dimethylaminomethylene) nitroacetate in 50 ml of absolute ethanol was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes and then heated and refluxed for 12 hours. After the reaction mixture was concentrated under reduced pressure, 150 ml of water was added to the residue, and concentrated hydrochloric acid was added dropwise with stirring at 0 ° C. until the pH became 4. The precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 7 g of the desired product. 264-266 ° C

Reference Examples 16 to 18 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 15.
After treatment, a compound represented by Table 10 in Chemical Formula 41 was obtained.

[0202]

Embedded image

[0203]

[Table 10]

Reference Example 19 Production of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate

A mixture of 12 g of ethyl 3,4-dihydro-4-oxo-2-phenylpyrimidine-5-carboxylate and 22.6 g of phosphorus oxychloride was stirred at 90 ° C. for 4 hours. The reaction mixture was added to ice water, neutralized with a 1N aqueous sodium hydroxide solution, and the precipitate was collected by filtration and washed with water to obtain 11 g of the desired product.

Reference Examples 20 to 28 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 19.
After treatment, the compound shown in Table 11 of Chemical Formula 42 was obtained.

[0207]

Embedded image

[0208]

[Table 11]

Reference Example 29 Production of 4-chloro-5-nitro-2-phenylpyrimidine

A mixture of 6 g of 5-nitro-2-phenyl-4 (3H) -pyrimidinone and 8.5 g of phosphorus oxychloride was stirred at 90 ° C. for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. After neutralization with a 1N aqueous sodium hydroxide solution, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 5.6 g of the desired product. 160-161 ° C

Reference Examples 30 to 32 --Reactions were carried out in the same manner as in Reference Example 29 using the corresponding starting compounds.
After treatment, a compound represented by Table 12 in Chemical Formula 43 was obtained.

[0212]

Embedded image

[0213]

[Table 12]

Reference Example 33 Production of 4,6-dichloro-5-nitro-2-phenylpyrimidine

(1) Using 150 g of a 20% sodium ethoxide-ethanol solution, 34.5 g of benzamidine hydrochloride, 32 g of diethyl malonate and 500 ml of ethanol, the reaction and treatment were carried out in the same manner as in Reference Example 11 (1). 6-
31.5 g of dihydroxy-2-phenylpyrimidine were obtained.

(2) The above product 30 was added to 150 ml of 90% nitric acid.
g was added little by little at 0-5 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to ice water, and the precipitate was collected by filtration and washed with water to obtain 32 g of crude 4,6-dihydroxy-5-nitro-2-phenylpyrimidine.

(3) To a mixture of 8 g of the above product and 4 g of dimethylaniline, phosphorus oxychloride was added dropwise at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 3 hours. The reaction mixture was added to ice water, and the precipitate was collected by filtration and washed with water to obtain 8.7 g of the desired product.

Reference Example 34 Production of 4-methylamino-2-phenylpyrimidine-5-carboxylic acid

(1) 10 g of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate, methylamine hydrochloride 2.
A mixture of 8 g, 8.5 g of triethylamine and 100 ml of isopropanol was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added to the residue,
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 ethanol to obtain 8 g of ethyl 4-methylamino-2-phenylpyrimidine-5-carboxylate.

(2) A mixture of 8 g of the above product, 150 ml of 1N aqueous sodium hydroxide solution and 50 ml of ethanol was added to 2
Heated to reflux for an hour. The reaction mixture was concentrated under reduced pressure, dissolved in ice water, and concentrated hydrochloric acid was added until the pH reached 1. The precipitated crystals were collected by filtration, washed with water, and then washed with ethanol to obtain 7.3 g of the desired product.

Reference Examples 35 to 50 --- Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 34.
After treatment, a compound represented by Table 13 in Chemical Formula 44 was obtained.

[0222]

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[0223]

[Table 13]

Reference Example 51 Production of 2-phenyl-4-propylaminopyrimidine-5-carboxylic acid

(1) 3,4-dihydro-4-oxo-2-
9.8 g of ethyl phenylpyrimidine-5-carboxylate, 10.1 g of triethylamine and dimethylformamide 2
A solution of 8.4 g of p-toluenesulfonyl chloride in 20 ml of dimethylformamide was added dropwise to the 0 ml of the mixture at room temperature, and the mixture was stirred at the same temperature for 10 minutes. A solution of 2.8 g of propylamine in 20 ml of dimethylformamide was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Chloroform and water were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11 g of crude ethyl 2-phenyl-4-propylaminopyrimidine-5-carboxylate.

(2) A mixture of 11 g of the above product, 100 ml of 1N aqueous sodium hydroxide solution and 100 ml of ethanol was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ice water, concentrated hydrochloric acid was added until the pH reached 1, the precipitated crystals were collected by filtration, washed with water, and then washed with ethanol to obtain 9.6 g of the desired product.

Reference Examples 52 to 62 -- Reactions were carried out in the same manner as in Reference Example 51 using the corresponding starting compounds.
After treatment, a compound represented by Table 14 in Chemical Formula 45 was obtained.

[0228]

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[0229]

[Table 14]

Reference Example 63 Production of 4- (N-benzyl-N-methylcarbamoylmethylamino) -2-phenylpyrimidine-5-carboxylic acid

(1) A mixture of 21 g of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate, 6.6 g of glycine, 17.8 g of triethylamine and 200 ml of ethanol was heated under reflux for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and concentrated hydrochloric acid was added dropwise while stirring at 0 to 5 ° C. until the pH reached 4. The precipitate was collected by filtration, washed with water, and crude N- (5-ethoxycarbonyl-2-phenyl-
24 g of 4-pyrimidinyl) glycine were obtained.

(2) 6 g of the above product, 3.6 g of N-methylbenzylamine, benzotriazol-1-yloxy-
Tris (dimethylamino) phosphonium hexafluorophosphate (hereinafter referred to as "BOP reagent") 13.3
g, 3.0 g of triethylamine and 100 ml of dimethylformamide were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted and purified with chloroform to obtain 7.8 g of crude ethyl 4- (N-benzyl-N-methylcarbamoylmethylamino) -2-phenylpyrimidine-5-carboxylate. .

(3) A mixture of 7.8 g of the above product, 100 ml of 1N aqueous sodium hydroxide solution and 100 ml of ethanol was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ice water, concentrated hydrochloric acid was added until the pH reached 1, the precipitated crystals were collected by filtration, washed with water, and then washed with ethanol to obtain 7.0 g of the desired product.

Reference Examples 64 to 80 -- Reactions were carried out in the same manner as in Reference Example 63 using the corresponding starting compounds.
After treatment, a compound represented by Table 15 in Chemical Formula 46 was obtained.

[0235]

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[0236]

[Table 15]

Reference Example 81 Production of 4-ethylamino-5-nitro-2-phenylpyrimidine

A mixture of 3 g of 4-chloro-5-nitro-2-phenylpyrimidine, 1.6 g of ethylamine hydrochloride, 3.9 g of triethylamine and 60 ml of isopropanol was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added to the residue, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography,
After elution and purification with chloroform, recrystallization from isopropanol gave 2.9 g of the desired product. 136-137 ° C

Reference Example 82 Production of 4-methylamino-5-nitro-2- (4-trifluoromethylphenyl) pyrimidine

The corresponding starting compounds were used and reacted and treated in the same manner as in Reference Example 81, and recrystallized from isopropanol to obtain the desired product. 170-172 ° C

Reference Examples 83 to 92 -- Reactions were carried out in the same manner as in Reference Example 81 using the corresponding starting compounds.
After treatment, a compound represented by Table 16 in Chemical Formula 47 was obtained.

[0242]

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[0243]

[Table 16]

Reference Example 93 Production of 6-chloro-6-methylamino-5-nitro-2-phenylpyrimidine The corresponding starting compound was reacted and treated in the same manner as in Reference Example 81 to obtain the desired product. .

Production Example 1 N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-
Production of acetamide

7,9-Dihydro-9-methyl-2-phenyl-8H-purine-8 was added to a mixture of 1.4 g of about 60% sodium hydride (oily) and 70 ml of dimethylformamide.
7.0 g of -one was added little by little at 0 to 5 ° C., and the mixture was stirred at 0 ° C. for 1 hour, and 8.3 g of 2-bromo-N-ethyl-N-phenylacetamide was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. 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 ethanol to obtain 10.3 g of the desired product.
240-242 ° C

Production Examples 2 to 44 --Reactions and treatments were carried out in the same manner as in Production Example 1 using the corresponding starting compounds, and the compounds of Tables 17 and 18 represented by Chemical Formula 48 and Table 19 represented by Chemical Formula 49 were obtained. Was obtained.

[0248]

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[0249]

[Table 17]

Table 18 below is a continuation of Table 17

[0251]

[Table 18]

[0252]

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[0253]

[Table 19]

Production Example 45 6-Chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-
Production of Purine-7-acetamide

To a mixture of 1.6 g of 6-chloro-7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one, 1.0 g of potassium carbonate and 15 ml of dimethylformamide was added 2-chloro-N- Ethyl-N-phenylacetamide (1.4 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ethanol to obtain 1.
8 g were obtained. Melting point 212-213 ° C

Production Example 46 N-ethyl-8,9-dihydro-6-methoxy-9-methyl-8-oxo-2-phenyl-N-phenyl-7H
Preparation of Purine-7-acetamide

6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2 obtained in Production Example 45
A mixture of 0.6 g of -phenyl-N-phenyl-7H-purine-7-acetamide, 0.3 g of a 28% sodium methoxide-methanol solution, 20 ml of methanol and 5 ml of 1,3-dimethyl-2-imidazolidinone for 4 hours. Heated to reflux. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ethanol to obtain 0.3 g of the desired product. 173-175 ° C

Production Example 47 Production of N-ethyl-8,9-dihydro-9-methyl-6-dimethylamino-8-oxo-2-phenyl-N-phenyl-7H-purine-7-acetamide

6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2 obtained in Production Example 45
A mixture of 0.6 g of -phenyl-N-phenyl-7H-purine-7-acetamide, 0.2 g of dimethylamine hydrochloride, 0.4 g of triethylamine and 20 ml of dimethylformamide was stirred at 100 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from diisopropyl ether to obtain 0.34 g of the desired product.
179-181 ° C

Production Example 48 N-benzyl-8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-7H-purine-7-
Production of acetamide

(1) 7,9-dihydro-9-methyl-2-
A mixture of 22.6 g of phenyl-8H-purin-8-one, 13.5 g of ethyl chloroacetate, 15.2 g of potassium carbonate and 250 ml of dimethylformamide was stirred at room temperature for 1 hour. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 8,9-dihydro-9-methyl-.
8-oxo-2-phenyl-7H-purine-7-acetic acid 2
6 g were obtained.

(2) A mixture of 26 g of the above product, 500 ml of a 1N aqueous sodium hydroxide solution and 500 ml of ethanol was heated under reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and concentrated hydrochloric acid was added dropwise until the pH reached 1. The precipitate was collected by filtration, washed with water, and then washed with ethanol to give crude 8,9-dihydro-9-methyl-8-oxo-2-.
22 g of phenyl-7H-purine-7-acetic acid were obtained.

(3) 1.1 g of the above product, 0.7 g of methylbenzylamine, 2.6 g of BOP reagent, 0.7 g of triethylamine.
A mixture of 6 g and 30 ml of dimethylformamide was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography,
After elution and purification with chloroform, recrystallization from ethanol and diisopropyl ether gave 1.1 g of the desired product.
160-161 ° C

Production Examples 49 to 65 -- Reactions were carried out in the same manner as in Production Example 48 using the corresponding starting compounds.
After treatment, the compound of Table 20 represented by Chemical Formula 50 was obtained.

[0265]

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[0266]

[Table 20]

Production Example 66 Production of 8,9-dihydro-9-methyl-7- (2,6-dimethylmorpholin-4-ylcarbonylmethyl) -8-oxo-2-phenyl-7H-purine

Using 2,6-dimethylmorpholine, the reaction and treatment were carried out in the same manner as in Production Example 48 (3), and the target product was obtained by recrystallization from acetonitrile and diisopropyl ether. 160-161 ° C

Production Example 67 --N-ethyl-N-phenyl-2- (8,9-dihydro-9
-Methyl-8-oxo-2-phenyl-7H-purine-
Preparation of 7-yl) propanamide

Ethyl 2-chloropropionate was used in place of ethyl chloroacetate in Preparation Example 48 (1), and N-ethylaniline was used in place of methylbenzylamine in Preparation Example 48 (3). The reaction and treatment were conducted in the same manner as in Example 48, and the product was recrystallized from ethanol to obtain the desired product. Melting point 150-151 ° C

Production Example 68--8,9-Dihydro-N- (2-hydroxyethyl) -9-
Methyl-8-oxo-2-phenyl-N-phenyl-7
Production of H-purine-7-acetamide

(1) The 8,9- compound obtained in (2) of Production Example 48
Dihydro-9-methyl-8-oxo-2-phenyl-7
A mixture of 3 g of H-purine-7-acetic acid, 1.3 g of aniline, 5.1 g of BOP reagent, 1.2 g of triethylamine and 20 ml of dimethylformamide was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration and washed with water to give crude 8,9-
Dihydro-9-methyl-8-oxo-2-phenyl-N
3.5 g of -phenyl-7H-purine-7-acetamide were obtained.

(2) About 60% sodium hydride (oil-based)
2.5 g of the above product was added little by little to a mixture of 3 g and 30 ml of dimethylformamide at 0 to 5 ° C., stirred at 0 ° C. for 1 hour, and then 2.2 g of 2-bromoethyl acetate at the same temperature.
Was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. 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, recrystallized from isopropanol to give N- (2-acetoxyethyl) -8,9-dihydro-9-methyl-8-oxo-2-phenyl -N-
0.9 g of phenyl-7H-purine-7-acetamide was obtained. 158-160 ° C

(3) 0.9 g of the above product, 0.9 g of potassium carbonate.
A mixture of 3 g and 15 ml of methanol was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from methanol and acetonitrile to obtain 0.05 g of the desired product. Melting point 231-233 ° C

Production Example 69 N- (4-fluorobenzyl) -8,9-dihydro-9-
Methyl-N-methyl-8-oxo-2-phenyl-7H
Preparation of Purine-7-acetamide

(1) The 8,9- compound obtained in (2) of Production Example 48
Dihydro-9-methyl-8-oxo-2-phenyl-7
9.1 g of H-purine-7-acetic acid, methylamine hydrochloride 3.
A mixture of 2 g of BOP reagent, 21.2 g of BOP reagent, 9.7 g of triethylamine and 100 ml of dimethylformamide was added at room temperature to 2
Stirred for hours. Water is added to the reaction mixture, and the precipitate is collected by filtration.
After washing with water, 8.1 g of crude 8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-7H-purine-7-acetamide was obtained.

(2) About 60% sodium hydride (oil-based)
1.2 g of the above product was added little by little to a mixture of 2 g and 30 ml of dimethylformamide at 0 to 5 ° C., and the mixture was stirred at 0 ° C. for 1 hour.
0 g was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours.
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 ethanol to obtain 0.6 g of the desired product. Melting point 197-19
9 ℃

Production Examples 70 to 78 -- Reactions were carried out in the same manner as in Production Example 69 using the corresponding starting compounds.
After treatment, a compound of Table 21 represented by Chemical Formula 51 was obtained.

[0279]

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[0280]

[Table 21] * In the above table, Bzl-3-F means a 3-fluorobenzyl group.

Production Example 79--7,8-Dihydro-8-oxo-2-phenyl-N, N-
Production of dipropyl-9H-purine-9-acetamide

2.8 g of triethylamine was added to a mixture of 10 g of 2-phenyl-4- (N, N-dipropylcarbamoylmethylamino) pyrimidine-5-carboxylic acid and 70 ml of dimethylformamide at room temperature, and the mixture was stirred for 10 minutes. At warm 7.7 g of diphenylphosphoric azide were added. After the reaction mixture was stirred at 100 ° C. for 2 hours, it was concentrated under reduced pressure. The residue was poured into ice water, the precipitate was collected by filtration, washed with water,
Recrystallization from ethanol gave 7 g of the desired product. Melting point
190-191 ° C

Production Examples 80-96 -- Reactions were carried out in the same manner as in Production Example 79 using the corresponding starting compounds.
After treatment, a compound of Table 22 represented by Chemical Formula 52 was obtained.

[0284]

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[0285]

[Table 22]

Production Example 97 Production of 2- (4-chlorophenyl) -7,8-dihydro-8-oxo-N, N-dipropyl-9H-purine-9-acetamide

9 g of 2- [2- (4-chlorophenyl) -5-nitro-4-pyrimidinylamino] -N, N-dipropylacetamide, 1 g of platinum (IV) oxide and ethanol 15
After stirring 0 ml of the mixture under a hydrogen atmosphere for 4 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and 2.1 g of urea was added to the obtained residue, followed by stirring at 200 ° C. for 2 hours. After cooling, water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 7 g of the desired product. Melting point 1
77-178 ° C

Production Examples 98 to 105 --Reactions were carried out in the same manner as in Production Example 97 using the corresponding starting compounds.
After treatment, the compound of Table 23 represented by Chemical Formula 53 was obtained.

[0289]

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[0290]

[Table 23]

Production Example 106 Production of 7,8-dihydro-7-methyl-8-oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide

To a mixture of 0.8 g of about 60% sodium hydride (oily) and 50 ml of dimethylformamide, Preparation Example 79 was prepared.
6 g of 7,8-dihydro-8-oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide obtained in above was added little by little at 0 to 5 ° C., and the mixture was stirred at 0 ° C. for 1 hour. At the same temperature, 2.9 g of methyl iodide was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. 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 ethanol to obtain 6 g of the desired product. Melting point 156-157 ° C

Production Examples 107 to 172 The corresponding starting materials were used and reacted and treated in the same manner as in Production Example 106 to obtain compounds shown in Tables 24 to 26 represented by Chemical Formula 54.

[0294]

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[0295]

[Table 24] *: Obtained as 1/4 hydrate.

Table 25 below is a continuation of Table 24.

[0297]

[Table 25]

The following Table 26 is a continuation of Table 25

[0299]

[Table 26] *: Obtained as 1/4 hydrate.

Production Example 173--8,9-Dihydro-N- (4-methoxyphenyl) -9-
Methyl-N-ethyl-8-oxo-2-phenyl-7H
Preparation of Purine-7-acetamide

The corresponding starting compounds were used and reacted and treated in the same manner as in Production Example 48, and recrystallized from ethanol to obtain the desired product. 208-209 ° C

Production Example 174--8,9-Dihydro-N- (4-hydroxyphenyl) -9
-Methyl-N-ethyl-8-oxo-2-phenyl-7
Production of H-purine-7-acetamide 8,9-dihydro-N- (4-methoxyphenyl) -9-methyl-N-ethyl-8-oxo-2-phenyl-7H-purine obtained in Production Example 173 To a mixture of 0.83 g of -7-acetamide and 10 ml of dichloromethane was added 4 ml of a 1M boron tribromide-dichloromethane solution at 0 ° C, and the mixture was stirred at room temperature for 5 days. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol and diisopropyl ether to obtain 0.38 g of the desired product. Melting point
254 to 256 ° C

Production Example 175 --N-benzyl-N-ethyl-7,8-dihydro-9-methyl-8-oxo-2-phenyl-9H-purine-9-
Production of acetamide hydrochloride

The N-benzyl-N obtained in Production Example 146
-Ethyl-7,8-dihydro-9-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide 0.1.
30% at 80 ° C. in a mixture of 8 g and 15 ml of ethanol
15 ml of hydrochloric acid ethanol was added and stirred for 30 minutes. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration and washed with ethanol to obtain 0.85 g of the desired product. Melting point 169-1
72 ° C

Production Example 176 N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-
Production of acetamide hydrochloride

The N-ethyl-8,9- obtained in Production Example 1
Dihydro-9-methyl-8-oxo-2-phenyl-N
Using -phenyl-7H-purine-7-acetamide, the reaction and treatment were conducted in the same manner as in Production Example 175 to obtain the desired product. 248-249 ° C

Production Examples 177 to 186 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Production Example 79.
After treatment, the compound of Table 27 represented by Chemical Formula 55 was obtained.

[0308]

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[0309]

[Table 27]

Production Examples 187 to 206 The corresponding starting materials were used and reacted and treated in the same manner as in Production Example 106 to obtain the compounds of Table 28 represented by Chemical Formula 56.

[0311]

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[0312]

[Table 28]

Production Example 207 N-ethyl-8,9-dihydro-2- (4-hydroxyphenyl) -9-methyl-8-oxo-N-phenyl-
Production of 7H-purine-7-acetamide N-ethyl-8,9-dihydro- obtained in Production Example 13
Using 2- (4-methoxyphenyl) -9-methyl-8-oxo-N-phenyl-7H-purine-7-acetamide, the reaction and treatment were carried out in the same manner as in Production Example 173, and the target product was recrystallized from ethanol. I got Melting point 280-282
° C

Production Example 208 --N-Isopropyl-8,9-dihydro-9-methyl-8
Production of -oxo-2-phenyl-N-phenyl-7H-purine-7-acetamide Using the corresponding starting compound, reacting and treating in the same manner as in Production Example 68 (1) and (2), and recrystallizing from acetonitrile To obtain the desired product. 262-263 ° C

Production Examples 209 to 210 --Reactions and treatments were carried out in the same manner as in Production Example 1 using the corresponding starting compounds to obtain the following compounds.

( Production Example 209 )-N-cyclopropyl-8,9-dihydro-9-methyl-
8-oxo-2-phenyl-N-phenyl-7H-purine-7-acetamide Melting point 260-262 ° C (recrystallized from acetonitrile)

( Production Example 210 )-N- (2,2,2-trifluoroethyl) -8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-
Phenyl-7H-purine-7-acetamide melting point 24
5-247 ° C (recrystallized from acetonitrile)

Production Examples 211 to 216 --Reactions were carried out in the same manner as in Production Example 79 using the corresponding starting compounds.
After treatment, a compound of Table 29 represented by Chemical Formula 57 was obtained.

[0319]

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[0320]

[Table 29]

Production Examples 217 to 232 The corresponding starting materials were used and reacted and treated in the same manner as in Production Example 106 to obtain the compounds shown in Table 30 represented by Chemical Formula 58.

[0322]

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[0323]

[Table 30]

The following are reference examples of the intermediate represented by the formula (II).

Reference Example 94--7,9-Dihydro-9-methyl-2-phenyl-8H-
Production of pudding-8-one

7 g of 4-methylamino-2-phenylpyrimidine-5-carboxylic acid and dimethylformamide 5
To 0.1 ml of the mixture at room temperature was added 3.1 g of triethylamine.
After stirring for 10 minutes, 8.4 g of diphenylphosphoric azide was added at the same temperature. After the reaction mixture was stirred at 120 ° C. for 4 hours, it was concentrated under reduced pressure. The residue was poured into ice water, and the precipitate was collected by filtration, washed with water and ethanol, and then recrystallized from chloroform to obtain 5 g of the desired product. Melting point 286-28
9 ℃

Reference Examples 95 to 107 -- Reactions were carried out in the same manner as in Reference Example 94 using the corresponding starting compounds.
After treatment, the compound of Table 31 represented by Chemical Formula 59 was obtained.

[0328]

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[0329]

[Table 31]

Reference Example 108--7,9-Dihydro-9-benzyl-2-phenyl-8H
-Production of pudding-8-one

The corresponding starting compound was reacted and treated in the same manner as in Reference Example 94 to obtain the desired product. Melting point 286-
287 ° C (recrystallized from chloroform)

Reference Example 109--7,9-Dihydro-2-phenyl-9-propyl-8H
-Production of pudding-8-one

The corresponding starting compound was reacted and treated in the same manner as in Production Example 94 to obtain the desired product. Melting point 263-
264 ° C (recrystallized from ethanol)

Reference Example 110 --- 9-ethyl-7,9-dihydro-2-phenyl-8H-
Production of pudding-8-one

After stirring a mixture of 2.7 g of 4-ethylamino-5-nitro-2-phenylpyrimidine, 0.3 g of palladium on carbon and 50 ml of ethanol at room temperature under a hydrogen atmosphere for 5 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, 1.4 g of urea was added to the obtained residue, and the mixture was stirred at 200 ° C. for 2 hours. After cooling, water was added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with water, and then washed with ethanol to obtain 2.4 g of the desired product. 268-270 ° C (recrystallized from chloroform)

Reference Example 111 Preparation of 7,9-dihydro-9-methyl-2- (4-trifluoromethylphenyl) -8H-purin-8-one As in Reference Example 110, using the corresponding starting compounds. And recrystallized from isopropanol to obtain the desired product. 248-250 ° C

Reference Example 112 Preparation of 6-chloro-7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one

Using the corresponding starting compounds, Reference Example 110
Reaction and treatment were carried out in the same manner as in the above to give the desired product as a solid.

Formulation Example 1 : Production of tablets-N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide · · · 1 g · Lactose · · · 84 g · corn starch · · · · 30 g of crystalline cellulose 25 g of hydroxypropyl cellulose 3 g

After the above components were mixed and granulated by a conventional method, light anhydrous silicic acid (0.7 g) and magnesium stearate (1.
3g), and tablet at 145mg per tablet,
Make 0 tablets.

Formulation Example 2 : Production of capsule ---- N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-acetamide・ ・ 2 g ・ Lactose ・ ・ ・ ・ ・ ・ ・ ・ 165 g ・ Maize starch ・ ・ ・ ・ ・ ・ ・・ ・ ・ 25 g ・ Hydroxypropylcellulose ・ ・ ・ 3.5 g ・ Light silicic anhydride ・ ・ ・ ・ ・ ・ ・ ・ ・ ・・ 1.8 g ・ Magnesium stearate ・ ・ ・ ・ ・ ・ ・ ・ ・ 2.7 g

According to a conventional method, the above ingredients are mixed and granulated, and 200 mg of the granules are filled in a capsule to produce 1,000 capsules.

Formulation Example 3 : Production of powder --- N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide・ ・ ・ ・ 10 g ・ Lactose ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 960 g ・ Hydroxypropylcellulose ・ ・ ・ ・ ・ ・ ・ ・ ・ ・・ ・ ・ ・ 25 g ・ Light silicic anhydride ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 5 g

According to a conventional method, after mixing the above components, the mixture is made into a powder.

[0345]

As described above, the compound represented by the formula (I) and a pharmaceutically acceptable acid addition salt thereof are
Together show a selective and remarkable affinity for the peripheral-type BZomega ₃ receptors, since having excellent pharmacological actions such as anti-anxiety activity in animal tests, anxiety-related disorders (neurosis, psychosomatic disorders,
Anxiety disorders and others), central illness such as depression, epilepsy, and circulatory system diseases such as angina pectoris and hypertension.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/22 A61P 25/22 25/24 25/24 (72) Inventor Kiyoshi Furukawa Shiga-cho, Shiga-gun, Shiga Prefecture Mizuaki Ono 2-12-12 4 (72) Inventor Makoto Oka 17-26 Takadacho, Ibaraki-shi, Osaka F-term (reference) 4C086 AA01 AA02 AA03 CB07 NA14 ZA02 ZA05 ZA06 ZA12 ZA36 ZA42 ZC42

Claims (12)

[Claims] 1. 2-aryl-8 represented by the following formula (I):
-A medicament comprising an oxodihydropurine derivative or a pharmaceutically acceptable acid addition salt thereof. Embedded image [Wherein, W represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, an amino group, a mono- or di- (lower) alkylamino group or an unsubstituted or substituted phenyl group, and X represents a hydrogen atom, a lower alkyl group. Group, cycloalkyl (lower) alkyl group, unsubstituted or substituted phenyl (lower) alkyl group, lower alkenyl group, carbamoyl group, di (lower) alkylcarbamoyl group or the following formula [Q]
And represents a group represented by the formula: ## STR2 ## wherein R ¹ is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a group represented by the formula: —CH (R ³ ) CON (R ¹ ) (R ² ) [Q] A cycloalkyl (lower) alkyl group or a hydroxy (lower) alkyl group, wherein R ² is a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group or an unsubstituted or Represents a substituted heteroaryl group, or R ¹ and R ² together with an adjacent nitrogen atom are each optionally substituted with one or two lower alkyl groups, a piperidine ring, a pyrrolidine ring, a morpholine ring or may form a piperazine ring, R ³ denotes a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl) Y is a hydrogen atom, a lower alkyl group, a cycloalkyl , Cycloalkyl (lower) alkyl, lower alkenyl group means an unsubstituted or substituted phenyl (lower) alkyl group or a group represented by the following formula [Q], embedded image -CH (R ³⁾ CON ( R ¹ ) (R ² ) [Q] (wherein R ¹ , R ² and R ³ have the same meanings as described above) A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group . However, the above formula (I)
In formula (I), one of X and Y is a group represented by the above formula [Q], and the other is each the same group as the above X and Y other than the formula [Q]] 2. A is represented by the following formula [A ']. (In the formula, R ⁴ 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. And R ⁵ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group), a pyridyl group, a thienyl group or a furyl group. (A) X is a group represented by the following formula [Qx]: -CH (R ³¹ ) CON (R ¹¹ ) (R ²¹ ) [Qx] wherein R ¹¹ is lower R ²¹ represents a lower alkyl group or the following formula [B]: (In the formula, R ⁶ 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. , R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group, and m represents 0, 1 or 2, or R ¹¹ and R ^{11 21} one or two lower alkyl optionally piperidine ring substituted respectively with group together with the adjacent nitrogen atom, a pyrrolidine ring, may form a morpholine ring or piperazine ring, R ³¹ is hydrogen Atom, lower alkyl group or hydroxy (lower) alkyl group], and Y is a hydrogen atom or a lower alkyl group, or (b) X is a hydrogen atom, An alkyl group or a carbamoyl group, Y group embedded image represented by the following formula [Qy] is ^{-CH (R 31) CON (R} 11) (R 21) [Qy] ( wherein, R ^11, R ²¹ and R ³¹ have the same meanings as described above). (A) X is a group represented by the formula [Qx] (in the formula,
R ¹¹ is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ²¹ is substituted with an ethyl group, a propyl group, an isopropyl group, a butyl group, a phenyl group, a halogen, methoxy, trifluoromethyl or hydroxy. Phenyl, benzyl or halogen,
A benzyl group substituted by methoxy, trifluoromethyl or hydroxy, R ³¹ is the same as defined in claim 3), Y is a hydrogen atom, a methyl group or an ethyl group, or (b) X is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and Y is a group represented by the formula [Qy] (wherein R ¹¹ is a methyl group, an ethyl group, a propyl group, an isopropyl group). a group or a butyl group, R ²¹ is an ethyl group, a propyl group, an isopropyl group, a butyl group, a phenyl group, a halogen, a methoxy, a phenyl group substituted by trifluoromethyl or hydroxy, a benzyl group or a halogen, methoxy,
A medicament comprising the compound according to claim 3, which is a benzyl group substituted with trifluoromethyl or hydroxy, and R ³¹ is the same as defined in claim 3. 5. An aryl group represented by the following formula (Ia):
8-oxodihydropurine derivatives or their pharmaceutically
A medicament comprising an acceptable acid addition salt. Embedded image(Where R¹²And R^{twenty two}Are the same or different ethyl
Group, propyl or butyl, or R
¹²Represents a methyl group, an ethyl group or a propyl group;^{twenty two}Is
Phenyl, halogenophenyl, methoxyphenyl,
Benzyl, halogenobenzyl or methoxybenzyl
R³²Is hydrogen atom, methyl group or ethyl
A group, Y¹Is hydrogen atom, methyl group or ethyl group
Means R^{Four 1}Represents a hydrogen atom, a halogen atom, a methyl group,
Methoxy, nitro or trifluoromethyl
Taste) 6. A 2-aryl-represented by the following formula (Ib):
A medicament comprising an 8-oxodihydropurine derivative or a pharmaceutically acceptable acid addition salt thereof. Embedded image (Wherein X ¹ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group, R ¹² and R ²² are the same or different and represent an ethyl group, a propyl group or a butyl group, or R ¹² is a methyl group Group, an ethyl group or a propyl group,
²² represents a phenyl group, a halogenophenyl group, a methoxyphenyl group, a benzyl group, a halogenobenzyl group or a methoxybenzyl group, R ³² represents a hydrogen atom, a methyl group or an ethyl group, R ⁴¹ represents a hydrogen atom, a halogen atom , Methyl, methoxy, nitro or trifluoromethyl) 7. 9,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-N-phenyl-7H
-Purine-7-acetamide, 8,9-dihydro-2- (4-fluorophenyl) -9-
Methyl-N-methyl-8-oxo-N-phenyl-7H
-Purine-7-acetamide, N-ethyl-8,9-dihydro-2- (4-fluorophenyl) -9-methyl-8-oxo-N-phenyl-7H
-Purine-7-acetamide, 7,8-dihydro-7-methyl-8-oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide, 7-ethyl-7,8-dihydro-8 -Oxo-2-phenyl-N, N-dipropyl-9H-purine-9-acetamide, N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-phenyl-9H-purine -9-
Acetamide, N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-
Purine-9-acetamide, N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2- (4-chlorophenyl) -9H-
Any one selected from purine-9-acetamide and N- (4-chlorobenzyl) -N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purine-9-acetamide Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable acid addition salt thereof. 8. N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H
-A medicament comprising purine-7-acetamide or a pharmaceutically acceptable acid addition salt thereof. 9. N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H
-A medicament comprising purine-9-acetamide or a pharmaceutically acceptable acid addition salt thereof. 10. The medicament according to any one of claims 1 to 9, which is a therapeutic or prophylactic agent for an anxiety-related disease. 11. The medicament according to claim 1, which is an anxiolytic. 12. The medicament according to claim 1, which is an antidepressant.