JPS63146872A - Pyrimidinylpiperazine compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (A is CR<1>R<2>CR<3>R<4>, OCR<5>R<6> or SOnCR<7>R<8>; R<1>-R<8> are H or lower alkyl or one of R<1> and R<2> bonds with one of R<3> and R<4> to and form single bond; n is 0, 1 or 2; R<9> and R<10> are H, halogen, OH, lower alkyl or lower alkoxy) and its acid addition salt. EXAMPLE:6-Bromo-4,4'-dimethyl-1-{4-[ 4-(2-pyrimidinyl)piperazin-1-yl ]butyl}-1,2,3, 4-tetrahydorquinolin-2-one dihydrochloride. USE:An antianxiety agent having extremely weak muscle relaxation action and sedative actin and strong anticonflict action. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II (X<1> is reactive atom or group such as halogen, sulfonyloxy, etc.) with 4-(2-pyrimidinyl)piperazine or reacting a compound of formula III with a compound of formula IV (X<2> is group defined in X<1>).

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel pyrimidinylpiperazine compound and an acid addition salt thereof useful as a medicine, particularly an anxiolytic.

[Conventional technology]

JP-A No. 56-49359 describes a carbostyril compound that has an antihistamine and central nervous system depressing effect, and German Published Patent Application No. 2009685 describes a carbostyril compound that has analgesic effect, histamine and serotonin antagonistic effect, and anti-adrenergic effect. has been done.

[Problem that the invention seeks to solve]

The present inventors have conducted extensive research with the aim of developing compounds useful as medicines, particularly as anti-anxiety drugs.

[Means for solving problems]

As a result, the present inventors discovered that a novel pyrimidinylpiperazine compound has an anxiolytic effect, and completed the present invention.

That is, the present invention relates to a pyrimidinylpiperazine compound represented by the general formula and an acid addition salt thereof.

In the formula, A C(R')(R'') -C(R3)(R'
) -(,:,:, R-, R'', R'', R' are the same or different and represent hydrogen or lower alkyl, or R1
and Hz and one of R3 and R4 combine to form a single bond. ), -0C(R')(R")-(
Here, R% and R& are the same or different and represent hydrogen or lower alkyl. ) or -5(0), ko(R')
(R") - (wherein R1 and Rs are the same or different and represent hydrogen or lower alkyl, and n represents 0, 1 or 2.

), and R'lR'' are the same or different and represent hydrogen, halogen, hydroxyl group, lower alkyl or lower alkoxy.

In the above definition, halogen refers to chlorine, bromine, iodine, and fluorine, and lower alkyl refers to alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl, and lower alkoxy means alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertiary butoxy.

The acid addition salt of the compound of general formula (1) is preferably a pharmaceutically acceptable acid addition salt, such as inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, fumarate,
maleate, succinate, malate, citrate,
Examples include organic acid salts such as methanesulfonate. “The compound of the general formula (1) is, for example, a compound of the general formula [wherein XI
represents a reactive atom or a reactive atom (halogen such as chlorine, bromine, or sulfonyloxy such as methanesulfonyloxy, benzenesulfonyloxy, p-)luenesulfonyloxy, etc.), and other symbols are as defined above. ] It is manufactured by reacting the compound represented by these with 4-(2-pyrimidinyl)piperazine.

The reaction was carried out in an inert solvent (benzene, toluene, ethanol,
deoxidizing agent (sodium hydroxide, sodium carbonate,
The reaction proceeds by heating under reflux for 5 to 24 hours in the presence of potassium carbonate, sodium hydrogen carbonate, triethylamine, pyridine, etc.).

In addition, the compound of general formula (1) is a compound represented by the general formula (in which each symbol has the same meaning as above) and the general formula (wherein, X8 is a reactive atom or group (chlorine, bromine, etc.). halogen or sulfonyloxy such as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.). ] It can also be produced by reacting with a compound represented by:

The reaction was carried out using an inert solvent (acetone, methyl ethyl ketone, benzene, toluene, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide,
Tetrahydrofuran, dioxane, etc.) in the presence of a deoxidizing agent (sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, etc.) under cooling or from room temperature to the reflux temperature of the solvent used from 1 to Proceeds in lO hours.

The compound of general formula (1) thus obtained can be made into the above-mentioned acid addition salt by treating with a non-acid or an organic acid in a conventional manner.

[Action and effect of the invention]

The compound of general formula (r) of the present invention and its acid addition salts are useful as anxiolytic drugs because they specifically exhibited conflict relieving action in conflict experiments showing a high correlation with anxiolytic action.

In the development of anxiolytic drugs, experimental conflict (
Conflict experiments have been widely conducted to investigate ways to specifically alleviate the situation [for example, Ueki et al., "Neuropsychopharmacology", Vol. 6, No. 11, pp. 751-773 (1984
)], and the water-lick method (Vogel,
Psychopharmacolo, by J. R. et al.
gta% Vol. 21, pages 1-7 (1971)] is known.

The present inventors have conducted studies with the aim of developing a new type of clinically useful anxiolytic drug that has very weak muscle relaxant and sedative effects and strong anti-conflict effects, and found that the compound of the present invention has the above-mentioned -ater -The compound of the present invention, which was found to have a significant effect in the 1ick method, showed almost no effect on locomotor activity, maximal WaS effect, anti-bicuculline effect, anti-pentylentitrazole effect, ethanol-enhancing effect, and anesthesia-enhancing effect. It also showed almost no effect in pharmacological tests such as the rotating rod test.

The anti-conflict effects of the compounds of the present invention are shown below along with experimental methods.

Experiment: Anti-conflict effect (water-1ick method)
The method of Vogel et al.
logia, 214th! -pages 1-7 (1971)
].

A group of 10 mice that had been deprived of water for 4 days were used. Twenty minutes after administering the test drug intraperitoneally, it was placed in an experimental box with a water inlet on one side, and the time required to drink a drop of water was measured. A shock (footshock, 25 volts, 2 seconds) was applied. Thereafter, the time required to drink water and receive a foot-shock was measured three times, and a dose that significantly shortened the time required to drink water was determined.

The results are summarized in Table 1.

Table 1 When the compounds of the present invention are used as pharmaceuticals, they can be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., and can be used as tablets, capsules, powders, granules, syrups, etc. It can be administered orally or parenterally in the form of a full opening, ointment scraping, injection side, etc. Dosage depends on patient's age,
Although it varies depending on body weight, symptoms, etc., 5 to 500 μl per day for adults is usually appropriate, and this can be administered once a day or in divided doses.

Next, the present invention will be specifically described with reference to Examples.

Example 1 6-bromo-1-(4-bromobutyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-2-
9.3 g, 4-(2-pyrimidinyl)piperazine 4
．． 0g and anhydrous potassium carbonate 3.3g toluene 20g
The mixture was added to a mixed solvent of 0+*l and N,N-dimethylformamide room, and heated to reflux overnight. Add cold water and separate the organic layer and wash with water. Extracted with dilute hydrochloric acid, 10%
The mixture is made alkaline using aqueous sodium hydroxide solution and the resulting oil is extracted with ethyl acetate. The extract is washed with water, dehydrated and dried using anhydrous potassium carbonate, and then the solvent is distilled off under reduced pressure. The obtained oil was made into a hydrochloride using 25% hydrogen chloride-isopropanol, collected by filtration, and recrystallized from alcohol to obtain colorless needle-like crystals of 6-bromo-4,4-dimethyl-1-(4- 7.5 g of (4-(2-pyrimidinyl)piperazin-1-yl)butyl)-1,2,3,4-tetrahydroquinolin-2-one dihydrochloride are obtained.

Melting point 218-222°C (decomposed) Example 2 4-(4-bromobutyl)-2H-1,4-benzothiazin-3-one 7.2 g, 4-(2-pyrimidinyl)
4.0 g of perazine and 3.3 g of anhydrous potassium carbonate were mixed with 200 ml of toluene and 1 ml of N,N-dimethylformamide.
Heat and reflux for 24 hours in a mixed solvent with 00+al. After cooling, water is added and the organic layer is separated, washed with water, and extracted with dilute hydrochloric acid. The extract is made alkaline with a 10% aqueous sodium hydroxide solution, and the resulting oil is extracted with chloroform. After dehydrating and drying with anhydrous potassium carbonate, the solvent was distilled off under reduced pressure.
The obtained oil was converted into a hydrochloride with 25% hydrogen chloride-isopropanol. This was collected by filtration and recrystallized from alcohol, resulting in colorless needle crystals of 4-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-28-1,
8.0 g of 4-benzothiazine-3one hydrochloride are obtained. Melting point 219-221"c (decomposition) Example 3 8-chloro-1,2,3,4-tetrahydroquinoline-
7.2 g of 2-one and 2.8 g of potassium hydroxide are added to 200 ml of a7ton and stirred. Then 4- (4-
Add 13 g of (2-pyrimidinyl)piperazin-1-ylcobutyl chloride and keep at room temperature for 5 hours. After filtering off the resulting precipitate, the solvent was distilled off under reduced pressure and extracted with ethyl acetate.

The extract is washed with water, dehydrated and dried over anhydrous potassium carbonate, and then the solvent is distilled off under reduced pressure. 8-chloro-1-(4-(4-(2-pyrimidinyl) )piperazin-1-yl)butyl)-1,2,3
,4-tetrahydroquinolin-2-one dihydrochloride 4.2
g is obtained. Melting point 160-163°C (decomposition) Example 4 4-(4-bromobutyl)-2H-1 in Example 2
, 4-Benzothiazin-3-one was replaced with 4-(4-bromobutyl)-2-methyl-2H-1,4-benzothiazine, and when the reaction was carried out in the same manner, 2-methyl-4-(
4-(4-(2-pyrimidinyl)-piperazin-1-yl)butyl]-2)T-1,4-benzothiazine-3-
On hydrochloride is obtained. Melting point 217-219℃ (decomposition)
Example 5 6=chloro-7-methyl-1,2,3,4-tetrahydroquinolin-2-one instead of 8-chloro-1,2,3,4-tetrahydroquinolin-2-one in Example 3 When the reaction is carried out in the same manner using Quinolin-2-one dihydrochloride monohydrate is obtained.

Melting point: 200-203°C (decomposition) Example 6 1°2.3.4-tetrahydroquinolin-2-one instead of 8-chloro-1,2,3,4-tetrahydroquinolin-2-one in Example 3 When a similar reaction is carried out using can get. Melting point 19
4-197°C (decomposition) Example 7 In place of 6-bromo-1-(4-bromobutyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one in Example 1, 1- (4-bromobutyl)
-8-Methoxy-4-methyl-1.2,3.4-tetrahydroquinolin-2-one was used in the same reaction, and 8-methoxy-4-methyl-1-(4-(4-(2 −
Pyrimidinyl)piperazin-1-yl)butyl]-1°2.3.4-tetrahydroquinolin-2-one dihydrochloride is obtained. Melting point 152-154°C (decomposition) Example 8 4-(4-bromobutyl)-2H-1,4- of Example 2
When the same reaction is carried out using 4-(4-bromobutyl)-2H-1,4-benzoxazin-3-one instead of benzothiazin-3-one, 4-(4-(4-(2-
pyrimidinyl)piperazin-1-yl)butyl)-2H
-1,4-benzoxazin-3-one dihydrochloride is obtained. Melting point 220-221°C (decomposition) Example 9 4-(4-bromobutyl)-2H-1,4- of Example 2
4-(4-bromobutyl)-2H-1,4-benzothiazin-3-one·l instead of benzothiazin-3-one
When the reaction is carried out in the same manner using -oxide, 4- (4-
(4-(2-pyrimidinyl)piperazin-1-yl)butyl) -2H-1,4-benzothiazin-3-one.
1-oxide is obtained.

Example 10 Similar to Example 9, 4-(4-bromobutyl)-2H-
When the reaction is carried out using 1,4-benzothiazin-3-one 1,1-dioxide, 4-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-2H-1
, 4-benzothiazin-3-one 1,1-dioxide is obtained.

Melting point 185-187°C Example 11 Same as Example 2, 4-(4-bromobutyl)-6-chloro-2H-1,4-benzothiazin-3-one and 4-
When reacted with (2-pyrimidinyl)piperazine, 6
-chloro-4-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-2H-1,4-benzothiazin-3-one is obtained.

Example 12 Similarly to Example 2, 4-(4-bromobutyl)-6-methyl-2H-1,4-benzoxazin-3-one and 4-
When reacted with (2-pyrimidinyl)piperazine, 6
-Methyl-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-2H-1,4-benzoxazin-3-one is obtained.

Example 13 In place of 8-chloro-1,2,3,4-tetrahydroquinolin-2-one in Example 3, 7-medoxy 1.
2. 3.4-(4-(2-pyrimidinyl)piperazin-1-ylcobutyl) using 4-tetrahydroquinolin-2-one or 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one When reacted with chloride, 7-medoxy-1-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-1,2,
3゜4-tetrahydroquinolin-2-one and 7-hydroxy-1-(4-(4-(2-pyrimidinyl)piperazin-1-yl)butyl)-1,2゜3.4-tetrahydroquinoline-2- On is obtained respectively.

Example 14 Same as Example 1, 1-(4-bromobutyl)-1,2-
When dihydroquinolin-2-one and 4-(2-pyrimidinyl)piperazine are reacted, 1-(4-(4-(
2-pyrimidinyl)piperazin-1-yl)butyl]-
1,2-dihydroquinolin-2-one is obtained.

Claims (1)

[Claims] A pyrimidinylpiperazine compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ and its acid addition salt. In the formula, A is -C(R^1)(R^2)-C(R^3)(
R^4) - (Here, R^1, R^2, R^3, R^4
are the same or different and represent hydrogen or lower alkyl, or a group in which one of R^1 and R^2 and one of R^3 and R^4 combine to form a single bond. ), -OC(R^5
)(R^6)-(Here, R^5 and R^6 are the same or different and represent hydrogen or lower alkyl.) or -S
(O)_nC(R^7)(R^8)-(Here, R^7
, R^8 are the same or different and represent hydrogen or lower alkyl, and n represents 0, 1 or 2. ), and R^9 and R^1^0 are the same or different and represent hydrogen, halogen, hydroxyl group, lower alkyl or lower alkoxy.