JPS6087284A - Succinimide derivative and its acid addition salt - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> and R<2> are H, lower alkyl, R<1> and R<2> form single bond; R<3>-R<6> are H, or lower alkyl; R<1>-R<6> are not H at the same time; X is N, or methylene; n is 3 or 4; dotted line part is single bond or double bond). EXAMPLE:N-[ 4-[4-(2-Pyrimidyl)-1-piperazinyl]butyl ]-1-cyclohexene-1,2-dicarboxyimide. USE:An antianxiety agent. A selective antianxiety agent having low side effect of central inhibition. PREPARATION:An acid anhydride shown by the formula II is reacted with an amine derivative shown by the formula III in an inert organic solvent such as pyridine, n-butyl alcohol, etc. under heating, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cyclic imide derivatives substituted with piperazinyl alkyls at the N-position. More specifically, the present invention provides a compound of the general formula (1) which has an anxiolytic effect and is useful as an anxiolytic drug [wherein R1 and R2 independently or differently represent a hydrogen atom or a lower alkyl group, or R1 and R2 represent a single bond, and Ra, R4, R5 and R6 are the same or different and do not contain a hydrogen atom. Further, X represents a nitrogen atom or a methine group, n represents an integer of 8 or 4, and = represents a single bond or a double bond. ] The present invention relates to a cyclic imide derivative represented by the above or a pharmaceutically acceptable acid addition salt thereof.

Here, in the compound represented by the general formula El'), the lower alkyl group has, for example, 1 to 4 carbon atoms.
Examples include linear or branched alkyl groups, and more specific examples include methyl, ethyl, n-propyl, 1so-propyl, n-butyl, and the like.

Pharmaceutically acceptable acid addition salts of the compound represented by formula (1) include inorganic or organic acids commonly used for this purpose, such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, butyric acid, propionic acid, It is formed together with tartaric acid, citric acid, maleic acid, fumaric acid, etc.

Although the compound of the present invention can be synthesized by various methods, for example, it is produced by the following method.

[In the formula, R, R, R, R, R, R', X, n, and = have the same meaning as supplier. ]

By reacting the acid anhydride represented by the general formula (1) with the amine derivative represented by the general formula (1), the general formula [I
) is obtained. This reaction is generally carried out by heating in an inert organic solvent.

Preferred solvents include pyridine and n-butyl alcohol.

Among the raw material compounds represented by the general formula [1], compounds in which R1 and R2 are a bond are known or can be synthesized according to known methods. In addition, starting compounds in which R1 and R2 are a hydrogen atom or a lower alkyl group are known, or according to the following reaction formula (4) [wherein R1' and R2' are the same or different and are a hydrogen atom or a lower alkyl group] represents a group, R9R', R'
, R', X and n have the same meaning as before. ] Specific examples of the present invention include the following compounds.

(2) N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-t-cyclohexene-1,2-dicarboximide.

■ N-(8-(4-(2-pyrimidinyl)-1-piperazinyl)propyl)-t-cyclohexene-1,2-
Dicarboximide.

(2) N-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4-methyl-4-cyclohexene-1,2-dicarboximide.

■ N-(8-(4-(2-pyrimidinyl)-1-piperazinyl)propyl]-4-methyl-4(6) monocyclohexene-1,2-dicarboximide.

■ N-(4-(4-(2-pyridyl)-1-piperazinyl)butyl]-4-methyl-4-cyclohexene-1
,2-dicarboximide.

■ N -(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl-4-methylcyclohexane-1
,2-dicarboximide.

■ N -(8-(4-(2-pyrimidinyl)-1-piperazinyl)propyl]-4-methylcyclohexane-
1,2-Cica, lupoximide.

■ N-(4-(4-(2-pyridyl)-1-piperazinyl)butyl-4-methylcyclohexane-1,2-
Dicarboximide.

ON-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-8,6-dimethyl-4-cyclohexene-1,2-dicarboximide.

@N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-8,6-dimethy6) q> Clohexane-1,2-dicarboximide.

(2) N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4,5-dimethyl-4-cyclohexene-1,2-dicarboximide.

o N-(4-(4-(2-pyrimidinyl>-1-piperazinyl)butyl)-4,5-dimethylcyclohexane-1,2-dicarboximide.

ON-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl-1,2-dimethylcyclohexane-1
,2-dicarboximide.

[Phase] N-(8-(4-(2-pyrimidinyl)-1-
piperazinyl)propyl-1,2-'; methylcyclohexane-1,2-dicarboximide.

The anxiolytic effect of the compounds of the present invention can be tested in an anti-conflict test using rats. Anti-conflict experiment is G
e1ler and 5eiffer (Psychbopher
Macologia, 1, 482 (1960)
).

When hungry male Wistar rats (Kitayama) have learned that pressing a lever will give them food, we give them an electric shock at the same time they press the lever. You will be able to take food by pressing the lever.

The number of times the animal presses the lever and takes the food while receiving electric shock is used as an index of the conflict-reducing effect, that is, the anxiolytic effect. The test drug was administered intraperitoneally (i,p,), and the test was conducted during the time period when its effect was at its maximum.Diazepam, a known anxiolytic drug, was used as a control drug.

For example, among the compounds of the present invention, N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4-methylcyclohexane-1,2-dicarboximide hydrochloride (Compound A; Example 1 compound) 8 q/#t(i,
p, ) is diazepam lq/&g(i, p, )
It exhibits a four-speed anti-conflict effect, that is, an anti-anxiety effect,
Shujo compound had almost no effect on general behavior.

On the other hand, central depressant side effects such as drowsiness and nalhexoharbital tv (hexobarbital)
Looking at the anesthetic enhancing effect, diazepam has a 1111/kti
(p.

o, ), but the compound of the present invention (c) had no significant effect on l 00 III/kicp, O,). From these facts, it can be said that the compound (c) of the present invention is a selective anxiolytic drug with weak central depressant side effects.

The compound of the present invention represented by the general formula [I] and its salt can be administered orally or parenterally when used as an anxiolytic agent. That is, it can be administered orally in commonly used dosage forms, such as tablets, capsules, syrups, suspensions, etc., or in the form of solutions, emulsions, suspensions, etc. It can be administered parenterally in the form of an injection.

It can also be administered rectally in the form of suppositories.

The appropriate dosage forms also include acceptable conventional carriers,
It can be manufactured by blending the active compound with excipients, binders, stabilizers, and the like. In addition, when used in the form of an injection, acceptable buffers, solubilizing agents, isotonic agents, etc. (9) may also be added.

Dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but are usually about 1 to 80 doses per day for adults.
0 Mg, preferably 5 to 100 Mg, may be administered once or divided into several doses, but the present invention is not limited thereby.

Reference example 1 2,8-dimethyl-1,8-butadiene 10 f (0
, 122 mol), maleic anhydride 11.9 II (0
, 122 mo#) and Hensen's 80 l mixture was stirred at room temperature for 10 hours. The suspended solids were removed and the filtrate was concentrated under reduced pressure to obtain the title compound in a yield of 18.66F (yield 86.6%). Melting point 78-74°C (10) Reference example 24 Anhydrous 4,5-dimethyl-4-cyclohexene-1,2-
A mixed solution of 10 g (0,0555 mol) of dicarboxylic acid, 1501 sg of platinum dioxide, and 100 ml of tetrahydrofuran was hydrogenated at room temperature for 8 hours. The suspended solids were removed, and the filtrate solution was concentrated under reduced pressure to quantitatively obtain the title compound.

IRv　F”m(am　’): 186L 1760ax The following compound was obtained in the same manner as in Reference Example 1 or 2.

0 Anhydrous 8,6-dimethyl-4-cyclohexene-1,2
-dicarboxylic acid melting point 48-45°C O anhydrous 8,6-dimethylcyclohexane-1,2-dicarboxylic acid ■R, Fi1m max (CM'): 1855, 17900 anhydrous t,
2-dimethylcyclohexane-1,2-dicarboxylic acid Melting point 98-99"C OAnhydrous 1,2-dimethylcyclohexane-1,2-dicarboxylic acid Film -1 1Rν (cll) 1845, 1825, 1780a
x Reference Example 8 4-chlorobutyronitrit 8.811 (0,082
mol), 1-(2-pyrimidinyl)piperazine 8.8 g
(0,082 mol), sodium carbonate 6.4f (0,0
608, mol) and n-butyl a! Recole 50ml
The mixture was refluxed for 19 hours.

After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography using silica gel, yielding 4.6 IC.
The title compound was obtained with a yield of 62.2%.

mp, 56-57°C Reference Example 4 A mixture of I-(4-aminobutyl)-4-(2-pyryl) and 240 ml of dry ether was cooled to 1-(8-cyanobutyl) at -54"C. A solution of 8 g (8.46 mmol) of (propyl)-4-(2-pyrimidinyl)piperazine dissolved in 80 g of dry ether was added dropwise, kept at the same temperature for 1 hour and 30 minutes, and then 2 ml of water was added dropwise. Next, 2 ml of 15% KOH water was added dropwise, and then 6 ml of water was added dropwise again.After stirring at room temperature for 80 minutes, the reaction solution was passed through Celite and washed with chloroform.

The furnace liquid was concentrated under reduced pressure, and the residue was purified by chromatography using silica gel to obtain the title compound.

IRv ””m (as '): 8100~8600゜m
ax 1580,. 1540 Example 1 N-[4-(4-(2-pyrimidinyl)-(13) 1-piperazinyl)butyl]-4-methylcyanhydride 4-methyI diclohexane 1,2-dicarboxylic acid l, 70
f (10,0 mmol), 1-(4-aminobutyl)
-4-(2-pyrimidinyl)piperazine 2.00 g (8
, 50 mmol) and 20 ml of dry pyridine was refluxed for 12 hours.

Next, the reaction solvent was distilled off under reduced pressure, and the residue was mixed with chloroform:methyl alcohol:ammonia water (500:25) as an eluent.
:2) was purified by column chromatography on silica gel. The resulting oil was treated with 8% hydrogen chloride/isopropyl alcohol to give the hydrochloride.

Recrystallization was performed with isopropyl alcohol to obtain the title compound.

Melting point: 156-158°C Example 2 (14) as in Example 1 using appropriate starting materials. The following compound was synthesized by performing the operation.

N-[:4-(4-(2-virimijini Jshi)-
1=piperazinyl)butyl]-1-cyclohexene-1
,2-'3carboximide hydrochloride Melting point 194-196°C N-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4-methyl-4-cyclohexene-1
,2-dicarboximide hydrochloride Melting point 164-165.5"C N-(4-(4-(2-pyridyl)-1-piperazinyl)butyl]-4-methyl-4=cyclohexene-1,2
-dicarboximide hydrochloride Melting point 122°C (decomposition) N-114-(4-(2-pyridyl)-1-piperazinyl)buty]-4-methylcyclohexane-1,2-
Dicarboximide hydrochloride (15) Melting point 125°C (decomposition) N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-8,6-dimethylcyclohexane-1
,2-dicarboximide hydrochloride Melting point 187°C (decomposition) 2-dicarboximide hydrochloride Melting point 209 below 2Ll”0 N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)4.5-dimethylcyclohexane-1,
2-Dicarboximide hydrochloride Melting point 225-227°C N-(4-(4-(2-bi-midinyl)-1-piperazinyl)butyl:)-1,2-dimethylcyclohexane-
1,2-dicarboximide hydrochloride Melting point 208-210°C (decomposed) (16 completed) Continued from page 1

Claims (1)

[Claims] General formula [wherein R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, or R1 and R2
represents a single bond, and R, R, R and R are the same but different and represent a hydrogen atom or a lower alkyl group,
R, R, R. R4, R6 and R6 do not represent a hydrogen atom at the same time. Further, X represents a nitrogen atom or a methine group, n represents an integer of 8 or 4, and = represents a single bond or a double bond. ] A cyclic imide derivative represented by or a pharmaceutically acceptable acid addition salt thereof.