JPH0827149A - Pyrimidinenone derivative and its salt - Google Patents

Abstract

PURPOSE:To obtain a derivative having antimethamphetamine action, useful as an antipsychotic agent, a tranquilizer and an antidepressive agent and hardly having adverse effects because of weak extrapyramidal action. CONSTITUTION:A derivative (salt) of formula I [(n) is 1-5; R<1> is H or methyl; alternate long and short dash line is a single bond or a double bond; when A has the single bond, A IS CH2 or NR<3> (R<3> is H, acyl, etc.) and when A has the double bond, A is CH or N; W is formula II or formula III (B is O or S; D is C or N; E is CH or N; X is H or a halogen), etc.], e.g. 3-{4-[4-(1,2- benzoisothiazol-3-yl)-1-piperazinyl]butyl}-5,6,7,8-tetrahydro-2-methyl -3H- quinazolin-4-one. This derivative is obtained by reacting a compound of formula IV (Y is a halogen, p-toluenesulfonyloxy, etc.) with a compound of the formula H-W in an inert solvent in the presence of an acid scavenger, etc., at 20-110 deg.C (preferably 40-80 deg.C) for 2-24hr (normally 2-6hr).

Description

Detailed Description of the Invention

[Background of the Invention]

TECHNICAL FIELD The present invention relates to a psychotropic drug containing a compound having a psychotropic action and at least one of the compound and a pharmacologically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, as derivatives having a similar pyrimidinone skeleton, those relating to a quinazolinone structure are disclosed in Japanese Patent Laid-Open No. 62-135464, Indian J. Pharm., 34 , 72.
(1972), J. Med. Chem., 12 , 936 (1969), but all of them are limited.

[Outline of the Invention]

The present inventors have now found that certain pyrimidinone compounds have a strong psychotropic effect, and have completed the present invention. The present invention therefore aims to provide compounds having psychotropic effects. Another object of the present invention is to provide a psychotropic drug containing the above derivative.

[0004]

The compounds according to the invention are
A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0005]

Embedded image [In the above formula, n represents an integer of 1 to 5, R ¹ represents a hydrogen atom or a methyl group, a solid line with a dotted line represents a single bond or a double bond, and A represents a single bond. Is CH ₂ ,
Or NR ³ (R ³ represents a hydrogen atom, an acyl group, an alkoxycarbonyl group or a lower alkyl group), a double bond represents ═CH— or a nitrogen atom, and the group W is represented by the following formula (i ) To (iii).

[0006]

[Chemical 4] (In the above groups, X represents a hydrogen atom or a halogen atom, B represents an oxygen atom or a sulfur atom, D represents a carbon atom or a nitrogen atom, E represents CH or a nitrogen atom, and R ² Represents a hydrogen atom or an optionally substituted phenyl group.)

The compound represented by the general formula (I) or a salt thereof has a strong psychotropic action. Therefore, according to the present invention, it is possible to provide a psychotropic drug (an antipsychotic drug, an anxiolytic drug, an antidepressant drug, etc.) that effectively acts on mental functions.

DETAILED DESCRIPTION OF THE INVENTION Compound of Formula (I) In the present specification, the lower alkyl group means alkyl having 1 to 6 carbon atoms such as methyl group, ethyl group and isopropyl group. The alkoxycarbonyl group means an alkoxycarbonyl group having 2 to 7 carbon atoms such as ethoxycarbonyl group and t-butoxycarbonyl group, and the acyl group means 1 carbon number such as acetyl group and propionyl group.
~ 7 means an acyl group, and the halogen atom as a group means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the general formula (I), W is the above formula (i) to
The group represented by (iii) is shown. As a preferred example of R ¹ ,
A methyl group is a preferable example of R ² , and a hydrogen atom is
A preferable example of R ³ is a hydrogen atom.

As a preferred example of the compound according to the present invention, X in the formula (i) is a fluorine atom or a hydrogen atom,
A compound in which B is an oxygen atom or a sulfur atom, D is a carbon atom or a nitrogen atom, and E is a nitrogen atom or CH;
In the compound (i), X is a fluorine atom or a hydrogen atom, R ² is a hydrogen atom, and E is a nitrogen atom or CH.
A compound in which X is a fluorine atom in ii) can be mentioned.

Further, as a specific example of the preferred compound group of the present invention, 3- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl]-
5,6,7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (6-fluoro-1-benzothiophen-3-yl) -1-piperidinyl] butyl ] -5,6,7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4-
(6-fluoro-1,2-benzisoxazole-3
-Yl) -1-piperidinyl] butyl] -5,6,7,
8-Tetrahydro-2-methyl-3H-quinazoline-4
-One, 3- [4- [4- (1H-indazole-3-
Il) -1-piperazinyl] butyl] -5,6,7,8
-Tetrahydro-2-methyl-3H-quinazoline-4-
On, 3- [4- [4- (6-fluoro-1H-indazol-3-yl) -1-piperidinyl] butyl]-
5,6,7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (5-fluoro-1H-benzotriazol-1-yl) -1-piperidinyl] butyl ] -5,6,7,8-tetrahydro-2
-Methyl-3H-quinazolin-4-one, 3- [3-
[4- (1,2-benzisothiazol-3-yl)-
1-piperazinyl] propyl] -5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one,
3- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -2-methyl-
3H-quinazolin-4-one, 3- [4- [4- (1H
-5-Fluoro-benzotriazol-1-yl) -1
-Piperidinyl] butyl] -2-methyl-3H-quinazolin-4-one, 7- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2 , 3,4-Tetrahydro-2-butoxycarbonyl-6-methyl-7H-pyrido [3,4-e] pyrimidin-8-one, 7- [4- [4- (1,2-benzisothiazole-3 -Yl) -1-piperazinyl] butyl] -1,2,3,4-tetrahydro-6-methyl-
7H-pyrido [3,4-e] pyrimidin-8-one and the like.

The compound of the present invention can be a salt thereof. Such salts include medically acceptable non-toxic salts. Examples thereof include hydrohalides such as hydrochlorides, inorganic acid salts such as sulfates, organic acid salts such as succinic acid, citric acid, fumaric acid and maleic acid, and amino acid salts such as glycine and phenylalanine. To be

Preparation of Compounds of General Formula (I) The compounds according to the present invention can be prepared by the following methods. The compound of the general formula (I) according to the present invention has the following general formula (II): H-W (II) (wherein W represents the same meaning as defined in the general formula (I)). And a compound represented by the following general formula (III):

[0014]

Embedded image (In the above formula, the solid line with R ¹ , A and the dotted line has the same meaning as defined in the general formula (I), and Y is
Chlorine atom, halogen atom such as bromine atom, or p-
It represents a leaving group such as a toluenesulfonyloxy group and a methanesulfonyloxy group, and when A is an amino group, a suitable protecting group such as t-butoxycarbonyl group, an acyl group,
It is protected with a p-methoxybenzyl group or the like, and after the reaction, it is eliminated by a general method. ) In a solvent that does not participate in the reaction (for example, anhydrous acetonitrile, dimethylformamide, dimethylacetamide or tetrahydrofuran) in the presence of an acid scavenger and optionally a small amount of potassium iodide at 20 to 110 ° C., preferably Can be obtained by reacting at a reaction temperature of 40 to 80 ° C. for 2 to 24 hours, usually 2 to 6 hours.

Examples of the acid scavenger used in the above reaction include alkali carbonates such as potassium carbonate and sodium bicarbonate, and organic amines such as triethylamine.

Use of Compound / Pharmaceutical Composition The compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof according to the present invention have an anti-methamphetamine action. Therefore, the compound and the pharmacologically acceptable salt according to the present invention can be used as an antipsychotic drug (antipsychotic drug, anxiolytic drug, antidepressant drug, etc.).

A pharmaceutical composition containing the present invention as an active ingredient can be administered to humans or non-humans by any of oral and parenteral (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) routes of administration. Can be administered to any animal. Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is made into a suitable dosage form depending on the administration route.

Specifically, oral preparations include tablets, capsules, powders, granules, syrups, etc., and parenteral preparations include injections such as intravenous injection and intramuscular injection, rectal administration preparations, Examples include oily suppositories and aqueous suppositories. These various preparations can be manufactured by a conventional method using commonly used excipients, disintegrants, binders, lubricants, coloring agents, and the like.

Examples of the excipient include lactose, glucose,
Corn starch, sorbit, crystalline cellulose, etc.
Examples of the disintegrant include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, and the like, and examples of the binder include dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose. , Polyvinylpyrrolidone and the like, and examples of the lubricant include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like. In addition, the above injection can be produced by adding a buffer, a pH adjuster, a stabilizer, etc., if necessary.

The content of the compound according to the present invention in the pharmaceutical composition varies depending on its dosage form, but it is usually 0.
It is about 5 to 50% by weight, preferably about 0.5 to 20% by weight. The dose depends on the age, weight, sex, and disease of the patient,
It is appropriately determined depending on the individual case in consideration of the degree of symptoms, etc., but is usually 1 to 1000 mg, preferably 5 to 500 mg per day for an adult, and this is administered once or several times a day. To do.

[0021]

EXAMPLES The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples. The chemical structural formulas of the compounds synthesized in the examples are shown below as a table.

[0022]

[Table 1]

[0023]

[Table 2]

Example 1 3- [4- [4- (1,2-beta)
Nzoisothiazol-3-yl) -1-piperazinyl]
Butyl] -5,6,7,8-tetrahydro-2-methyl
-3H-Quinazolin-4-one 1- (1,2-benzisothiazol-3-yl) piperazine (124 mg, 0.57 mmol), 3- (4-
Bromobutyl) -5,6,7,8-tetrahydro-2-
Methyl-3H-quinazolin-4-one (170 mg,
0.57 mmol) and potassium carbonate (97 mg,
0.70 mmol) was suspended in 3 ml of dimethylformamide and stirred at room temperature for 24 hours. The insoluble matter was filtered, and the solvent was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water. The residue was purified by silica gel column chromatography to give 220 m of the title compound.
g (88% yield) was obtained.

¹ H-NMR (CDCl ₃ ) δ1.62-
1.8 (8H, m), 2.45-2.58 (6H,
m), 2.54 (3H, s, CH ₃ ), 2.68 (4
H, bt, J = 4.9 Hz, piperazine CH ₂ ), 3.
56 (4H, bt, J = 4.9Hz, piperazine C
H ₂ ), 4.03 (2H, t, J = 7.7 Hz, NC
H ₂ ), 7.36 (1H, ddd, J = 8.0, 6.
9, 1.0Hz, Ar), 7.47 (1H, ddd, J
= 8.2, 6.9, 1.0 Hz, Ar), 7.81 (1
H, d, J = 8.0 Hz, Ar), 7.90 (1H,
d, J = 8.2 Hz, Ar); MW437.6 (C ₂₄ H
₃₁ N ₅ OS); mass spectrum EIMS, m / z 43
7 (M) ⁺ . Mp. 173-175 ° C

The crystals were dissolved in dioxane, a dioxane solution containing 4N hydrochloric acid was added, and the resulting precipitate was collected by filtration to obtain the desired hydrochloride as a white powder. Hydrochloride: Mass spectrum EIMS, m / z 437 (M
-HCl) ⁺ . Mp. 195 ° C. dec.

Example 2 3- [4- [4- (6-full
Oro-1-benzothiophen-3-yl) -1-piperi
Dinyl] butyl] -5,6,7,8-tetrahydro-2
-Methyl-3H-quinazolin-4-one 1- (1,2-benzisothiazol-3-yl) piperazine was replaced with 4- (6-fluoro-1-benzothiophen-3-yl) piperidine. Example 1
Was synthesized in the same manner as.

¹ H-NMR (CDCl ₃ ) δ1.6-1.
_{88 (10H, m, CH 2} ), 2.0-2.06 (2
_{H, m, CH 2),} 2.09-2.18 (2H, m, C
_{H 2), 2.42-2.52 (4H,} m, CH 2), 2.
_{53 (3H, s, CH 3} ), 2.53-2.59 (2
_{H, m, CH 2),} 2.83-2.93 (1H, m, piperidine CH), 3.04-3.1 (2H, m , C
_{H 2), 4.0-4.04 (2H,} m, NCH 2), 7.
05 (1H, d, J = 0.8 Hz, Ar), 7.12
(1H, ddd, J = 8.9, 8.9, 2.5Hz, A
r), 7.53 (1H, dd, J = 8.9, 2.5H
z, Ar), 7.70 (1H, dd, J = 8.9, 5.
0 Hz, Ar); MW 453.6 (C ₂₆ H ₃₂ N ₃ OS
F); mass spectrum EIMS, m / z 453 (M)
⁺ .

Hydrochloride: Mass spectrum EIMS, m / z
453 (M-HCl) ⁺ . Mp. 248 ° C de
c.

Example 3 3- [4- [4- (6-full
Oro-1,2-benzisoxazol-3-yl)-
1-piperidinyl] butyl] -5,6,7,8-tetra
Hydro-2-methyl-3H-quinazolin-4-one 4- (6-fluoro-1,2-benzisoxazol-3-yl) instead of 1- (1,2-benzisothiazol-3-yl) piperazine ) It synthesize | combined by the method similar to Example 1 except having used piperidine.

¹ H-NMR (CDCl ₃ ) δ1.6-1.
7 (2H, m, CH ₂ ), 1.7-1.8 (6H, m,
_{CH 2), 2.02-2.2 (6H,} m, CH 2), 2.
_{42-2.51 (4H, m, CH 2} ), 2.54 (3
_{H, s, CH 3),} 2.54-2.58 (2H, m, C
H ₂ ), 3.02-3.1 (3H, m), 4.02 (2
H, t, J = 7.7Hz, NCH 2), 7.02-7.
08 (1H, m, Ar), 7.22-7.27 (1H,
m, Ar), 7.68-7.72 (1H, m, A
r). MW 438.5 (C ₂₅ H ₃₁ N ₄ O ₂ F); mass spectrum EIMS, m / z 438 (M) ⁺ . ; Mp
117-119 ° C

Hydrochloride: Mass spectrum EIMS, m / z
438 (M-HCl) ⁺ . Mp. 215 ° C de
c.

Example 4 3- [4- [4- (1H-yne
Dazol-3-yl) -1-piperazinyl] butyl]-
5,6,7,8-tetrahydro-2-methyl-3H-ki
Nazolin-4-one 1- (1H-indazol-3-yl) instead of 1- (1,2-benzisothiazol-3-yl) piperazine
Synthesis was carried out in the same manner as in Example 1 except that piperazine was used.

¹ H-NMR (CDCl ₃ ) δ1.55-
_{1.8 (8H, m, CH 2} ), 2.44-2.5 (4
H, m, CH ₂ ), 2.53 (3H, s, CH ₃ ), 2.
_{53-2.58 (2H, m, CH 2} ), 2.65-2.
71 (4H, m, piperazine CH ₂ ), 3.48 (4
H, bt, J = 4.9 Hz, piperazine CH ₂ ), 4.
03 (2H, t, J = 7.6 Hz, NCH ₂ ), 7.0
4-7.08 (1H, m, Ar), 7.33 (2H,
d, J = 3.3 Hz, Ar), 7.71-7.73 (1
H, m, Ar), 9.11 (1H, br, NH); MW
420.5 (C ₂₄ H ₃₂ N ₆ O); mass spectrum EI
MS, m / z 420 (M) ⁺ . Mp. 185-18
7 ° C

Hydrochloride: Mass spectrum EIMS, m / z
421 (M + 1-HCl) ⁺ . Mp. 214 ° C d
ec.

Example 5 3- [4- [4- (6-fluor
Ro-1H-indazol-3-yl) -1-piperidini
Lu] butyl] -5,6,7,8-tetrahydro-2-me
Tyl-3H-quinazolin-4-one 1- (1,2-benzisothiazol-3-yl) piperazine was replaced with 4- (6-fluoro-1H-indazol-3-yl) piperidine, except that It was synthesized in the same manner as in Example 1.

[0037]¹H-NMR (CDCl₃) Δ 1.6-1.
7 (2H, m), 1.7-1.8 (8H, m), 2.0
4-2.08 (2H, m), 2.12-2.14 (2
H, m), 2.42-2.5 (4H, m) 2.54 (3
H, s, CH₃), 2.52-2.6 (2H, m),
3.04-3.1 (3H, m), 4.03 (2H, t,
J = 7.8Hz, NCH₂), 6.89 (1H, dd
d, J = 9.2, 8.9, 2.2 Hz, Ar), 7.0
8 (1H, dd, J = 9.2, 2.2Hz, Ar),
7.71 (1H, dd, J = 8.9, 5.0Hz, A
r); MW 437.5 (C _{twenty five}H₃₂N_FiveOF); Mass
Vector EIMS, m / z 437 (M)⁺． Mp.
174-176 ° C

Example 6 3- [4- [4- (5-fluor
Ro-1H-benzotriazol-1-yl) -1-pipet
Lydinyl] butyl] -5,6,7,8-tetrahydro-
2-Methyl-3H-quinazolin-4-one 1- (1,2-benzisothiazol-3-yl) piperazine was replaced with 4- (5-fluoro-1H-benzotriazol-1-yl) piperidine. Other than that, it synthesize | combined by the method similar to Example 1.

¹ H-NMR (CDCl ₃ ) δ1.59-
1.69 (2H, m), 1.69-1.8 (6H,
m), 2.16 (2H, bd, J = 13.9Hz, CH
₂ ), 2.22 (2H, t, J = 11.8Hz, C
_{H 2), 2.38-2.52 (6H,} m), 2.55
_{(3H, s, CH 3)} , 2.55-2.57 (2H,
m), 3.13 (2H, bd, J = 11.8Hz, CH
₂ ), 4.03 (2H, t, J = 7.7Hz, NCH ₂ )
4.66-4.72 (1H, m, piperidine NH),
7.23-7.29 (1H, m, Ar), 7.55-
7.59 (1H, m, Ar), 7.67-7.70 (1
H, m, Ar); MW 438.5 (C ₂₄ H ₃₁ N ₆ O
F); mass spectrum EIMS, m / z 438 (M)
⁺ . Mp. 140-141 ° C

Hydrochloride: Mass spectrum EIMS, m / z
438 (M-HCl) ⁺ . Mp. 234 ° C de
c.

Example 7 3- [3- [4- (1,2-beta)
Nzoisothiazol-3-yl) -1-piperazinyl]
Propyl] -5,6,7,8-tetrahydro-2-methyl
Lu-3H-quinazolin-4-one 3- (4-bromobutyl) -5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one instead of 3- (3-bromopropyl) -5,6,7,8-
Synthesis was performed in the same manner as in Example 1 except that tetrahydro-2-methyl-3H-quinazolin-4-one was used.

¹ H-NMR (CDCl ₃ ) δ1.7-1.
_{8 (4H, m, CH 2} ), 1.91-2.0 (2H,
m, CH ₂ ), 2.46-1.51 (2H, m, C
_{H 2), 2.51-2.56 (4H,} m, CH 2), 2.
_{56 (3H, s, CH 3} ), 2.68-2.72 (4
H, m, piperazine CH _2), 3.53-3.58 (4
H, m, piperazine CH ₂ ), 4.09 (2H, t, J
= 7.7 Hz, NCH ₂ ), 7.36 (1H, t, J =
7.6 Hz, Ar), 7.47 (1H, t, J = 7.6)
Hz, Ar), 7.81 (1H, d, J = 8.2 Hz,
Ar), 7.89 (1H, d, J = 8.2Hz, A
r); MW 423.6 (C ₂₃ H ₂₉ N ₅ OS); mass spectrum EIMS, m / z 423 (M) ⁺ . Mp.
124-126 ° C.

Hydrochloride: Mass spectrum EIMS, m / z
423 (M-HCl) ⁺ . Mp. 165 ° C de
c.

Example 8 3- [4- [4- (1,2-beta)
Nzoisothiazol-3-yl) -1-piperazinyl]
Butyl] -2-methyl-3H-quinazolin-4-one 3- (4-bromobutyl) -5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one instead of 3- ( 4-Bromobutyl) -2-methyl-3H-
Synthesis was carried out in the same manner as in Example 1 except that quinazolin-4-one was used.

[0045]¹H-NMR (CDCl₃) Δ 1.68-
1.73 (2H, m, CH₂), 1.78-1.86
(2H, m, CH₂), 2.52 (2H, t, J = 7.
2Hz, NCH₂), 2.68 (3H, s, CH₃),
2.68-2.70 (4H, m, piperazine CH₂),
3.57 (4H, bt, J = 4.6Hz, piperazine C
H₂), 4.15 (2H, t, J = 7.7Hz, NC
H₂), 7.33-7.38 (1H, m, Ar), 7.
42-7.48 (2H, m, Ar), 7.61 (1H,
d, J = 7.7 Hz, Ar), 7.69-7.74 (1
H, m, Ar), 7.81 (1H, d, J = 8.0H
z, Ar), 7.91 (1H, d, J = 8.2Hz, A
r), 8.24-8.26 (1H, m, Ar); MW
433.6 (C_{twenty four}H₂₇N _FiveOS); mass spectrum EI
MS, m / z 433 (M)⁺．

Hydrochloride: Mass spectrum EIMS, m / z
433 (M-HCl) ⁺ . Mp. 224-226 ° C

Example 9 3- [4- [4- (1H-5-
Fluoro-benzotriazol-1-yl) -1-pipet
Lysinyl] butyl] -2-methyl-3H-quinazoline-
4- (5-fluoro-1-benzotriazol-1-yl) piperidine was replaced with 3- (4-bromobutyl) -5 instead of 4-one 1- (1,2-benzisothiazol-3-yl) piperazine. , 6,7,8-Tetrahydro-2-methyl-
Synthesis was performed in the same manner as in Example 1 except that 3- (4-bromobutyl) -2-methyl-3H-quinazolin-4-one was used instead of 3H-quinazolin-4-one.

¹ H-NMR (CDCl ₃ ) δ1.64-
_{1.73 (2H, m, CH 2} ), 1.78-1.87
(2H, m, CH ₂ ), 2.16-2.19 (2H,
m, CH ₂ ), 2.20-2.26 (2H, m, C
_{H 2), 2.40-2.47 (2H,} m, CH 2), 2.
51 (2H, t, J = 7.2 Hz, NCH ₂ ), 2.6
9 (3H, s, CH ₃ ), 3.14 (2H, bd, J =
12.1 Hz, CH ₂ ), 4.16 (2H, t, J =
_{7.7Hz, NCH 2), 4.70 (} 1H, m, piperidine CH), 7.23-7.29 (1H, m , Ar),
7.44 (1H, ddd, J = 8.2, 7.0, 1.3
Hz, Ar), 7.55-7.59 (1H, m, A
r), 7.61 (1H, d, J = 7.4Hz, Ar),
7.67-7.75 (2H, m, Ar), 8.25 (1
H, dd, J = 8.2, 1.3 Hz, Ar); MW 4
34.5 (C ₂₄ H ₂₇ N ₆ OF); mass spectrum EIM
S, m / z 434 (M) ⁺ . Mp. 122-124
℃

Hydrochloride: Mass spectrum EIMS, m / z
423 (M-HCl) ⁺ . Mp. 247 ° C de
c.

Example 10 7- [4- [4- (1,2-
Benzisothiazol-3-yl) -1-piperazini
Lu] butyl] -1,2,3,4-tetrahydro-2-bu
Toxycarbonyl-6-methyl-7H-pyrido [3,4
-E] Pyrimidin-8-one 3- (4-bromobutyl) -5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one instead of 7- (4-bromobutyl) -1 , 2,3,4-Tetrahydro-2-butoxycarbonyl-6-methyl-7
It was synthesized in the same manner as in Example 1 except that H-pyrido [3,4-e] pyrimidin-8-one was used.

¹ H-NMR (CDCl ₃ ) δ 1.48 (9
_{H, s, C (CH 3} ) 3), 1.61-1.71 (2H,
m, CH ₂ ), 1.71-1.8 (2H, m, CH ₂ ),
2.50 (2H, t, J = 7.2Hz, NCH ₂ ),
_{2.56 (3H, s, CH 3} ), 2.6-2.65 (2
H, m, CH ₂ ), 2.68 (4H, bt, J = 4.9)
Hz, piperazine CH ₂ ), 3.56 (4H, bt, J
= 4.9 Hz, piperazine CH ₂ ), 3.65 (2H,
t, J = 5.6 Hz, NCH ₂ ), 4.05 (2H,
t, J = 8.0 Hz, NCH ₂ ), 4.33 (2H, b
r, CH ₂ ), 7.36 (1H, ddd, J = 8.2,
1.0, 0.8 Hz, Ar), 7.47 (1H, dd
d, J = 8.0, 1.3, 1.0 Hz, Ar), 7.8
1 (1H, d, J = 8.0 Hz, Ar), 7.91 (1
H, d, J = 8.2 Hz, Ar); MW 538.7
_{(C 28 H 38 N 6 O} 3 S); Mass spectrum EIMS, m /
z 538 (M) ⁺ .

Example 11 7- [4- [4- (1,2-
Benzisothiazol-3-yl) -1-piperazini
Lu] butyl] -1,2,3,4-tetrahydro-6-me
Cyl-7H-pyrido [3,4-e] pyrimidin-8-o
Emissions 7- [4- [4- (1,2-benzisothiazol -3
-Yl) -1-piperazinyl] butyl] -1,2,3,
4-Tetrahydro-2-butoxycarbonyl-6-methyl-7-pyrido [3,4-e] pyrimidin-8-one (280 mg, 0.52 mmol) was added to ethyl acetate (5 ml).
, 0.12 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, adjusted to pH 10 with 0.1N sodium hydroxide, and the organic layer was separated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 150 mg of the title compound (yield 66%).
I got

¹ H-NMR (CDCl ₃ ) δ1.61-
_{1.71 (2H, m, CH 2} ), 1.71-1.8 (2
H, m, CH ₂ ), 2.04 (1H, br, NH),
2.50 (2H, t, J = 7.2Hz, NCH ₂ ),
2.56 (3H, s, CH ₃ ), 2.60 (2H, t,
J = 5.9Hz, CH ₂ ), 2.68 (4H, bt, J
= 4.9 Hz, piperazine CH ₂ ), 3.12 (2H,
t, J = 5.9 Hz, CH ₂ ), 3.56 (4H, b
t, J = 4.9 Hz, piperazine CH ₂ ), 3.79
(2H, br, NCH ₂ ), 4.04 (2H, t, J =
_{7.8Hz, NCH 2), 7.33-7.38 (} 1H,
m, Ar), 7.44-7.49 (1H, m, Ar),
7.81 (1H, d, J = 8.0 Hz, Ar), 7.9
0 (1H, d, J = 8.2 Hz, Ar); MW 43
_{8.6 (C 23 H 30 N 6} OS); mass spectrum EIM
S, m / z 438 (M) ⁺ . Mp. 159-160
° C.

Pharmacological test [Evaluation method] (1) Antipsychotic effect The antipsychotic effect of the compound according to the present invention was used as an index for the inhibitory effect on methamphetamine-induced hyperlocomotion in mice. Male ddY mice with a body weight of 25 to 35 g were used, and each group consisted of 3 to 6 mice. Methamphetamine 2 in mice
mg / kg was subcutaneously administered, and 15 minutes later, the compound of the present invention was intraperitoneally administered. After 15 minutes, the mouse was placed in a transparent acrylic box (both vertical and horizontal height 30 cm) installed on a momentum measuring device (Muromachi Kikai ANIMEX AUTO MK-110), and the momentum was measured for 30 minutes. The effects of haloperidol and chlorpromazine as comparative drugs were also evaluated. The results are shown in Table 3.

[0055]

Table 3 Anti-methamphetamine action compound name ED ₅₀ value (mg / kg, ip) Example 1 0.38 haloperidol 0.16 chlorpromazine 1.05

(2) Extrapyramidal system action The extrapyramidal system action of the compound according to the present invention was determined using the catalepsy inducing action, which is a typical pharmacological evaluation method, as an index. body weight
25 to 35 g of male ddY mice were used, and each group consisted of 3 to 6 mice. The compound of the present invention was intraperitoneally administered, and after 20, 30 and 40 minutes, the presence or absence of catalepsy was determined. The presence or absence of catalepsy was judged to be positive for catalepsy when a mouse whose forelimbs were forcibly hung on a horizontal iron rod having a diameter of 1 mm and horizontally placed at a height of 3 cm for 30 seconds or longer. The effects of haloperidol and chlorpromazine as comparative drugs were also evaluated. The results are shown in Table 4.

[0057]

Table 4 Catalepsy-inducing compound name ED ₅₀ value (mg / kg, ip) Example 1 38.4 haloperidol 1.3 chlorpromazine 6.2

(3) Binding Affinity with Various Receptors (a) Dopamine-D ₂ Receptor The affinity of the compound of the present invention for D ₂ receptor was examined using rat brain striatal P2 fraction. Rat brain striatum was homogenized in 10 volumes of 0.32M sucrose and 900 x
The supernatant obtained by centrifugation for 10 minutes at g
Centrifuge at 00 xg for 20 minutes. Incubate buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 1 mM
MgCl ₂ , 1 mM CaCl ₂ , pH 7.4) and then 39,900 × g
The precipitate obtained by centrifugal separation for 20 minutes was used as P2 fraction.
This was incubated for 30 minutes at 37 ° C. in a buffer containing [ ³ H] spiperone 0.1 nM and each concentration of the compound of the present invention,
After the reaction, they were collected by Whatman GF / B glass filter, and the amount of bound [ ³ H] spiperone was measured by a liquid scintillation counter. The amount of non-specific binding was measured in the presence of 10 ^-5 M sulpiride, and the specific binding of [ ³ H] spiperone to the D ₂ receptor was calculated from the following formula, and the IC ₅₀ value was calculated from the inhibition curve to obtain the Ki value. It was Specific binding amount = total binding amount-non-specific binding amount * The results are shown in Table 5.

[0059]

[Table 5] Binding affinity (Ki value) with dopamine-D ₂ receptor Compound name Example 8 31.4 Haloperidol 1.8 chloropromazine 6.0

[0060] (b) to evaluate the affinity of the compound of the present invention 5-HT ₂ receptors of serotonin -5-HT ₂ receptor Rat cerebral cortex as follows. P2 fraction was prepared in the same manner as in (a). This is [ ³ H] Ketanserin 1 nM
And incubated at 37 ° C. for 15 minutes in a 50 mM Tris / HCl buffer (pH 7.4) containing each concentration of the compound of the present invention, and the amount of bound [ ³ H] ketanserin was measured after the reaction. The amount of non-specific binding was measured in the presence of 10 μM ketanserin, and the Ki value was determined by the same method as above. The results are shown in Table 6.

[0061]

Table 6 Binding affinity (Ki value) for serotonin-5-HT ₂ receptor Compound name Example 8 4.7 Ketanserin 1.3

As is clear from these results, it is understood that haloperidol and chlorpromazine evaluated as comparative drugs have antipsychotic effects, but at the same time have strong extrapyramidal actions such as catalepsy inducing action. .

On the other hand, among the compounds of the present invention, for example, Example 1
Has an antipsychotic effect similar to the comparative drug,
It is clear that the extrapyramidal action is very weak. Therefore, the compound of the present invention is considered to be a drug having a wide safety range as an antipsychotic drug.

In addition to the compounds of the present invention having a high binding affinity with the D ₂ receptor, which is considered to be an important mechanism of antipsychotic action (eg, Example 8), depression
A compound having a high affinity for the 5HT receptor (eg, Example 1), which is said to be associated with psychiatric / neurological disorders of the central nervous system including schizophrenia such as anxiety, has been found.
The present invention compounds from this is believed also adapt to the central nervous system disease involving D _2, 5-HT ₂ receptors.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 413/12 239 471/04 117 Z (72) Inventor Mio Miyashiro Miooka Town, Kohoku Ward, Yokohama City, Kanagawa Prefecture 760 Meiji Confectionery Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Nobuyuki Yamashita Meiji Confectionary Co., Ltd. Chemical Research Laboratory, 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa

Claims (7)

[Claims] 1. A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof: [In the above formula, n represents an integer of 1 to 5, R ¹ represents a hydrogen atom or a methyl group, a solid line with a dotted line represents a single bond or a double bond, and A represents a single bond. is, -CH ₂
Or -NR ^3- (R ³ represents a hydrogen atom, an acyl group, an alkoxycarbonyl group or a lower alkyl group), and in the case of a double bond, represents = CH- or a nitrogen atom,
The group W represents any of the groups represented by the following formulas (i) to (iii). Embedded image (In the above groups, X represents a hydrogen atom or a halogen atom, B represents an oxygen atom or a sulfur atom, D represents a carbon atom or a nitrogen atom, E represents a CH or a nitrogen atom, R ² Represents a hydrogen atom or an optionally substituted phenyl group.) 2. The compound according to claim 1, wherein the solid line with the dotted line in the general formula (I) is a single bond, and A is NR ³ , and a pharmacologically acceptable salt thereof. 3. In the general formula (I), W represents a group (i) (wherein X represents a hydrogen atom or a halogen atom, B represents an oxygen atom or a sulfur atom, and D represents a carbon atom or a nitrogen atom). Represents a atom, and E represents CH or a nitrogen atom.) The compound according to claim 1, and a pharmacologically acceptable salt thereof. 4. In the general formula (I), W represents a group (ii) (wherein X represents a hydrogen atom or a halogen atom, E represents CH or a nitrogen atom, and R ² represents a hydrogen atom or a substituted atom). And a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, wherein W in the general formula (I) is a group (iii) (wherein X represents a hydrogen atom or a halogen atom) and a pharmacologically acceptable compound. Its salt. 6. 3- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl]-
5,6,7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (6-fluoro-1-benzothiophen-3-yl) -1-piperidinyl] butyl ] -5,
6,7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] Butyl] -5,6,7,8-tetrahydro-2-methyl-3
H-quinazolin-4-one, 3- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butyl] -5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (6-fluoro-1H-indazol-3-yl) -1-Piperidinyl] butyl] -5,6,6
7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (5-Fluoro-1H-benzotriazol-1-yl) -1-piperidinyl] butyl]-
5,6,7,8-tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [3- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] propyl] -5,6,6
7,8-Tetrahydro-2-methyl-3H-quinazolin-4-one, 3- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -2-methyl-
3H-quinazolin-4-one, 3- [4- [4- (1H-5-fluoro-benzotriazol-1-yl) -1-piperidinyl] butyl] -2
-Methyl-3H-quinazolin-4-one, 7- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -1,2,3,
4-Tetrahydro-2-butoxycarbonyl-6-methyl-7H-pyrido [3,4-e] pyrimidin-8-one, 7- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -1,2,3,
4-Tetrahydro-6-methyl-7H-pyrido [3,4
-E] selected from pyrimidin-8-ones.
The described compounds and pharmacologically acceptable salts thereof. 7. A psychotropic drug comprising, as an active ingredient, at least one compound of the general formula (I) according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof.