JPS5929665A - Piperazine derivative and its acid addition salt - Google Patents

Abstract

NEW MATERIAL:The piperazine derivative of formula I [R1 is R4Z; R2 is H or R4'Z' (R4 and R4' are alkyl, aryl, alkoxy, phenoxy, benzyloxy, H or amino; Z and Z' are sulfonyl or carbonyl); n is 2-4; R3 is 2-pyridyl or 2-pyridinyl] and its acid addition salt. EXAMPLE:1-[4-(N-Methoxycarbonylamino)butyl]-4-(2-pyrimidinyl)piperazine. USE:Antianxiety agent. PROCESS:The compound of formula I -A can be prepared, e.g. by reacting the amine derivative of formula II with the ester derivative of formula III (R5 is H or alkyl; R6 is alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to piperazine derivatives. For more details,
The present invention has an anxiolytic effect and is useful as an anxiolytic drug according to the general formula (1) [wherein R represents a group represented by the general formula R or Z;
, represents a hydrogen atom or a group represented by the general formula R4°2'. R4 and R4° are the same or different and each represents a lower alkyl group, an aryl group, an alkoxy group, a phenoxy group,
Indicates a benzyloxy group, a hydrogen atom, or an amino group. Z
and 2' are the same or different and each represents a sulfonyl group or a carbonyl group. n represents an integer of 2, 8 or 4.

R represents a 2-pyridyl group or a 2-pyrimidinyl group. ] or a pharmaceutically acceptable acid addition salt thereof.

The lower A alkyl group herein means a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl groups. The aryl group means an unsubstituted or substituted furunyl group, and examples of the substituted phenyl group include lower alkyl-substituted phenyl groups such as a P-)lyl group. Alkoxy group means a lower alkyloxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Examples include isobutoxy group.

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, and propionic acid. , tartaric acid, citric acid, maleic acid, fumaric acid, and other acids.

The compound of the present invention can be synthesized by various methods by applying known methods, but for example, it can be synthesized by any one of the following methods a to d.

(a) A piperazine derivative represented by general formula (IA) can be obtained by reacting an amine derivative represented by general formula (1) with an ester derivative represented by general formula (1).

(1-A) [In the formula, Rs is a hydrogen atom or a lower alkyl group, Ra
represents a lower alkyl group, and Rs and 11 have the same meanings as above. ] R is preferably a methyl group or an ethyl group. This reaction can be carried out in an inert solvent, but preferably the ester derivative is used in excess as a solvent. The reaction is carried out in the range from room temperature to the boiling point of the reaction system, but may be carried out under pressure in an autoclave if necessary.

(b) The amine derivative of the formula (1) and the general formula (IV
A piperazine derivative represented by the general formula CI-B) can be obtained by reacting with a halogen compound represented by :).

R, -Z　-X　10(1) (ff) R.

[In the formula, R1 represents a lower alkyl group or an aryl group. X
represents a halogen atom, and R,, Z and n have the same meanings as above. ] X is preferably a chlorine atom or a bromine atom. Although this reaction is preferably carried out in an inert solvent, it is not necessary to use a solvent. As the solvent, for example, ether solvents such as diethyl ether and tetrahydrofuran, and halogenated hydrocarbon solvents such as methylene chloride can be used (5). This reaction is preferably carried out in the presence of an acid binder, such as triethylamine, pyridine, etc. The reaction temperature is usually in the range of 0°C to the boiling point of the reaction system, and the reaction time is several seconds. It is 24 hours from the time.

(C) By reacting the amine derivative of the above formula [薯] with the acid anhydride represented by the general formula (D), the general formula (1
A piperazine derivative represented by -C) can be obtained.

(R@CO)嘗+(1) (V) R9 1 [In the formula, R9 is the same as the group represented by R or CO, or represents a hydrogen atom, and Rs, Rs and n have the same meanings as above. . ] Although an inert solvent may be used in this reaction, an excess of the acid anhydride (V) is preferably used as the solvent (6). The reaction is carried out in a range from room temperature to the boiling point of the reaction system, and may be carried out under pressure in an autoclave if necessary.

(d) The amine derivative of the above formula [summer] and the general formula (VD
A piperazine derivative represented by general formula (1-D) can be obtained by reacting with a cyanate represented by formula (1-D).

M-0-CN + (1) (VI) [In the formula, M represents an alkali metal atom, and R1 and n have the same meanings as above. ]M is preferably a sodium atom or a potassium atom.

This reaction is preferably carried out in water to which the same amount of acid, such as hydrochloric acid or acetic acid, has been added, usually at room temperature for several hours.

The amine derivative represented by the formula (1), which is a raw material for the compound of the present invention, can be used, for example, by Yao-HuaWu et al.
d, Chem, 15.4'lTC1972):
) can be easily synthesized based on the method of

Specific examples of the present invention include the following.

1(4-(N-methoxycarbonylamino)butyl)-
4-(2-pyrimidinyl)piperazine 1-(4-(N-ethoxycarbonylafoot))butyl)
-4-(2-pyrimidinyl)piperazine 1-(4-(N-(n-butoxycarbonyl)butyl)-4-(2-pyrimidinyl)piperazine 1-(4-(N-(8-methylpropoxy) carbonylamino))methyl]-4-(2-pyrimidinyl)piperazine 1-(4-(N-phenoxycarbonylamino)butyl)-4-(2-pyrimidinyl)piperazine 1-(4-(N-benzyloxycarbonylamino) )butyl)-4-(2-pyrimidinyl)piperazine 1-(8-(N-methoxycarbonylamino)propyl)-4-(2-pyrimidinyl)piperazine 1-(8-(N-ethoxycarbonylamino)propyl)- 4-(2-pyrimidinyl)piperazine 1-(8-(N-(n-butoxycarbonylamino))
propyl]-4-(2-pyrimidinyl)piperazine 1-(8-(N-(8-methylpropoxycarbonylamino))propyl]-4-(2-pyrimidinyl)piperazine 1-(8-(N-phenoxycarbonylamino) ) propyl)-4-(2-pyrimidinyl)piperazine 1-(8-(N-benzyloxycarbonylamino)propyl)-4-(2-pyrimidinyl)piperazine 1-(2-(N-methoxycarbonylamino)ethyl)
-4-(2-pyrimidinyl)piperazine 1-(2-(N-ethoxycarbonylamino)ethyl)
-4-(2-pyrimidinyl)piperazine 1-(2-(N-(n-butoxycarbonylaminoethyl))-4-(2-pyrimidinyl)piperazine 1-(2-(N-(8-methylpropoxycarbonylamino) )) Ethyl]-4-(2-pyrimidinyl)piperazine 1-(2-(N-phenoxycarbonylamino)ethyl)-4-(2-pyrimidinyl)piperazine 1-(2-(N-benzyloxycarbonylamino)ethyl )-4-(2-pyrimidinyl)piperazine (9) 1(4-(N-ethoxycarbonylamino)butyl)-
4-(2-pyridyl)piperazine 1-(8-(N-ethoxycarbonylamino)propyl)-4-(2-pyridyl)piperazine 1-(4-(N-aminocarbonylamino[])butyl)-
4-(2-pyrimidinyl)piperazine 1-(4-(N-formylamino)butyl)-4-(2
-pyrimidinyl)piperazine 1(4-(N-acetylamino)butyl)-4-(2-
Pi1-dinyl) piperazine 1(4-(N,N-diacetyl[])butyl)-4-
(2-pyrimidinyl)piperazine 1-(4-(N-methanesulfonylbutyl)-4
-(2-pyrimidinyl)piperazine 1-[4-N,N-dimethanesulfonylamino)butyl)-4-, (2-pyrimidinyl)piperazine 1-(4-(N-paratoluenesulfonylamino)butyl)-4 -(2-pyrimidinyl)piperazine (10) The anxiolytic effects of the compounds of the present invention can be demonstrated by an anti-conflict test using rats. Conflict experiment is G
e1ler and Seifter (Pgychopharm
Acologia, 1, 482 (1960)).

When a hungry male Wistar rat (Kitayama) who has learned that pressing a lever receives food is given an electric shock at the same time as pressing the lever, the rat is in a state of conflict where it wants food but is afraid of the electric shock. They fall into a situation where they no longer press the lever to receive food. When given an anti-anxiety drug, the conflict state is alleviated, and the animals begin to push the lever and take food despite receiving electric shocks.

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, 1(8-(N-ethoxycarbonylamino)propyl)-4-,(2-pyrimidinyl)piperazine hydrochloride (compound A) 8~/kri<i
, p, > and 1-(4-(N-ethoxycarbonylamino)butyl)-4-(2-pyrimidinyl)piperazine hydrochloride (Compound B) 3 capes/kg (i, p,) is diazepam 1 cap/phantom (i, p-) showed a four-speed anti-conflict effect, ie, an anxiolytic effect, and both compounds had almost no effect on general behavior.

On the other hand, central depressant side effects, such as hex, which is an indicator of sleepiness,
o barbital When looking at the anesthetic enhancing effect, diazepam shows a significant enhancing effect on I W/ky (p, o,
Jllf/Toge (p, 0.) did not have any significant effect1.From these facts, it can be said that the compounds A and B of the present invention are selective anxiolytics with weak central depressant side effects. .

Further, a compound having a structure similar to the compound of the present invention was disclosed by Hans Heinck Heck et al. [Japanese Patent Application Laid-Open No. 141478/1983] and is described as having anti-aggressive activity. A typical compound thereof is 1-(2-(N-acetylamino)ethyl]-4-(8-trifluoromethylphenyl)piperazine (compound C).

A comparative experiment was conducted between Compound C and the compound of the present invention using a foot current-induced fight mouse test, which is an indicator of anti-aggressive action. This experiment was carried out by Y. Asami et al.
, 'For sch, , 25s 584-589
(1975)). That is, when dd-Y male mice (Shizuoka) are given an electric shock through the soles of their feet, the fighting instinct is induced. The degree to which the induction of this fighting instinct was suppressed by the test drug was used as an index of anti-aggressive effect.

The test drug was administered orally (1), 0. ) L/ta.

As a result of a comparative experiment, the ED value of compound C was 2.8 W/k.
1, but the compounds A and B of the present invention were 50IIv/
The compound of the present invention, unlike compound C, does not have any anti-aggressive effect. Compound C also did not exhibit any significant activity in the anti-conflict effect comparison experiment.

Furthermore, according to Keiji Nakamura et al. [Pharmacology of Psychotropic Drugs, p. 184, Asakura Shoten, published in 1972], habituation effect (anti-aggressive effect) is not necessarily a good indicator of clinical anxiolytic effect. has not been considered.

Taking these things into consideration, it is presumed that the compound of Hans Heinz Q. Heck et al. and the compound of the present invention have completely different biological activities.

The compound of the present invention represented by the general formula (1) 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. Furthermore, when used in the form of an injection, acceptable buffers, solubilizing agents, isotonic agents, etc. may be added.

(14) 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 to preferably 5 to 100 IIIF can be administered once or in several divided doses.

Next, the method of the present invention will be explained by examples, but the present invention is not limited thereto.

Example 1゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
Piperazine Iy (4,25 t mol), triethylamine 860W (8,5 mmol), anhydrous ethyl ether 1
69 ethyl chlorocarbonate was added to a solution of 104 g and anhydrous tetrahydrofurane under ice water cooling.
2~(6,88i: rimole) in anhydrous ethyl ether 10
Drop the solution dissolved in
The temperature was kept at °C. After the reaction was completed, the reaction solution was extracted with caustic soda water and chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was treated with 15% hydrogen chloride/isopropyl alcohol to give a yield of 61,611 Iy (yield of 88.5
%) of the title compound was obtained. Melting point 184-185℃ (decomposition) (recrystallization solvent acetone/isopropyl alcohol =
1/1) Example 2゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
Methyl chlorocarbonate 1.51 (15.9 mmol) was added to a solution of 2.6 F (10.6 mmol) of piperazine, 2.1 F (21.2 mmol) of triethylamine and 25 mmol of anhydrous tetrahydrofuran under stirring at room temperature. Drop a solution dissolved in 25 ml of anhydrous tetrahydrofuran,
The mixture was stirred at the same temperature for 2 hours and 50 minutes.

After the reaction was completed, the same post-treatment as in Example 1 was carried out to give 1.96
The title compound F (yield 50.8%) was obtained.

Melting point 194°C (decomposition) Example 8゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
Piperazine 2.5 fi (10,6 mmol), triethylamine 2.11 (21,2 mmol) and anhydrous tetrahydrofuran 25 are added under ice-water cooling to n-buty)L chloroO carbonate 2.2 f ( A solution of 15.9 mmol) dissolved in 25 s+l of anhydrous tetrahydrofuran was added dropwise, followed by reaction at room temperature for 5 hours, and the same post-treatment as in Example 1 was carried out, yielding 2.0 IC 46.5%.
) was obtained.

Melting point: 156°C (decomposition) Example 4゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
In a solution of 2.5 f (10.6 mmol) of piperazine, 2.1 f (21.2 mmol) of triethylamine and 25 m +/- of anhydrous tetrahydrofuran under cooling with ice water, 2.21 g of inbutyl chlorocarbonate is added. (15.9 mmol) dissolved in 25 g/anhydrous tetrahydrofuran was added dropwise,
Thereafter, the reaction was carried out at room temperature for 25 hours. The same post-treatment as in Example 1 was carried out to obtain 2,14F (yield 49.4
%) of the title compound was obtained.

Melting point: 172°C (decomposition) Example 5゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
Phenyl chlorocarbonate 2.5 F (21.2 mmol) was added to a solution of 2.5110.6 mmol of piperazine), 2.1 jl of triethylamine (21.2 (limol)) and 25 ml of anhydrous tetrahydrofuran under cooling with ice water. Drop the solution dissolved in 25s+l,
Thereafter, the reaction was carried out for 2 hours and 50 minutes at room temperature. The same post-treatment as in Example I was carried out to obtain the title compound (18) 2, Of (yield 44.496).

Melting point: 209°C (decomposed) Example 6゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
8.71 (21.6 mmol) of carbobebenzo r dichloride was added to a solution of 8.41 (14.4 mmol) of piperazine, 2.9 F (28.9 mmol) of triethylamine, and 84 ml of anhydrous dichloromethane under constant water cooling. A solution dissolved in 84 g/methylene chloride was added dropwise, and the reaction was then carried out at room temperature for 9 hours and 85 minutes. The same post-treatment as in Example 1 was performed to obtain the title compound (1.581 (yield: 28.9%)). Melting point 185"c <decomposition) Example 7 1.5 f (6,78 mmol) of -(8-aminopropyl)-4-(2-pyrimidinyl)piperazine, 1.4 p (1B, 56 mmol) of triethylamine, and A solution of methyl chlorocarbonate 9609 (10,17 f mol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise to a solution of 15 g/anhydrous tetrahydrofuran with stirring at room temperature, and the reaction was then carried out at the same temperature for 4 hours. Example 1 The same post-treatment as above was carried out to obtain the title compound of 1.8F (yield 54.296). Melting point 185°C (decomposition) Example 8 l-(8-aminopropyl)-4-(2-pyrimidinyl) into a solution of 2.4 F (10.8 mmol) of piperazine, 2.21 (21.7 mmol) of triethylamine and 24 ml of anhydrous tetrahydrofuran under stirring at room temperature.
A solution of 1.2 f (16.8 mmol) of ethyl chlorocarbonate dissolved in 24 liters of anhydrous tetrahydrofuran was added dropwise, and the reaction was then carried out at the same temperature for 2 hours. The same post-treatment as in Example 1 was carried out to obtain 2.17f (yield: 54.796
) was obtained. Melting point 157-8°C Example 9 1-(8-aminopropyl)-4-(2-pyrimidinyl)piperazine 1.5f (6,78 mmol), triethylamine 1.4F (1B, 56f mmol) and anhydrous tetrahydrofuran A solution of 1.4 F (10.17 mmol) of n-butyl chlorocarbonate dissolved in 16 ml of anhydrous tetrahydrofuran was added dropwise to the 15 g solution at room temperature while stirring, and the reaction was then carried out at the same temperature for 6 hours and 25 minutes. After the same post-treatment as in Example 1, the yield was 1.61 and 61.59.
The title compound of 6) was obtained. Melting point: 160°C (decomposed) (21) Example 10°■-(8-aminopropyl)-4-(2-pyrimidinyl)piperazine 1.5! (6,78 mmol), triethylamine 1.4F (18,56 mmol) and anhydrous tetrahydrofuran 15g/in a solution of isobutyl chlorocarbonate 1.4f (10,17 mmol) in anhydrous tetrahydrofuran 15g/in anhydrous tetrahydrofuran under stirring at room temperature. The solution was added dropwise, and the reaction was then carried out at the same temperature for 7 hours and 20 minutes.

1+□Perform the same post-processing as in Example 1. The title compound of 1.2F (yield 46.2%) was obtained.

Melting point 190°C (decomposition) Example 11゜1-(8-aminopropyl)-4-(2-pyrimi(22
) dinyl) piperazine 1.51 (6.78 mmol),
A solution of 1.61 fl' (10.17 mmol) of phenyl chlorocarbonate dissolved in 15 g of anhydrous tetrahydrofuran was added dropwise to a solution of 1.41 (1B, 56i, rimole) of triethylamine and 15 sJ of anhydrous tetrahydrofuran with stirring at room temperature, and then the same solution was added. The reaction was carried out for 4 hours and 20 minutes at the same temperature. The same post-treatment as in Example 1 was carried out to obtain the title compound of 1.25 IC (yield: 48.1%). Melting point: 198°C (
Decomposition) Example 12 A solution of 1.51 (6.78 mmol) of 1-(3-aminopropyl)-4-(2-pyrimidinyl)piperazine, 1.41 (18.56 mmol) of triethylamine and 15 g of anhydrous tetrahydrofuran. A solution of 1.7 F of carbobenzoxy chloride (10.17° C. mol) dissolved in 15 g of anhydrous tetrahydrofuran was added dropwise to the mixture under stirring at room temperature, and the reaction was carried out at the same temperature for 4 hours and 15 minutes. Example 1
After the same post-treatment as above, 1.61f (yield 47.4%) was obtained.
The title compound was obtained.

Melting point 188°C (decomposition) Example 13゜1-(2-aminoethyl)-4-(2-pyrimidinyl)
Into a solution of 2j' piperazine (9.65 mmol), 2 g (19.8 mmol) of triethylamine, and 20 ml of anhydrous tetrahydrofuran was added 1.1 N (10.6 f mol) of ethyl chlorocarbonate to a solution of 1 g/1 g of anhydrous tetrahydrofuran under cooling with ice water. A solution dissolved in was added dropwise, and the reaction was then carried out overnight at room temperature. The same post-treatment as in Example 1 was performed to obtain the title compound with a yield of 1.91 (yield: 55.9%). Melting point: 229°C (decomposition) Example 14゜■-(3-aminopropyl)-4-(2-pyridyl)piperazine 2.6 f (11.8 mmol), triethylamine 2.4j' (28.6 mmol) A solution of 1.9 F (17.7 mmol) of ethyl chlorocarbonate dissolved in 26 ml of anhydrous tetrahydrofuran was added dropwise to a solution of 26 ml of anhydrous tetrahydrofuran with stirring at room temperature, and the reaction was then carried out at the same temperature for 10 hours and 40 minutes. . The same post-treatment as in Example 1 was carried out to obtain the title compound 2f (yield 46.9%). Melting point 207-208°C (decomposition) Example 15゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
Piperazine Ig (8.5 mmol), IN-hydrochloric acid 17
Potassium cyanate 1.7 F (20.4 mmol) was added to a mixture of g/g/g and 8.5 l/l water at room temperature with stirring.
A solution prepared by dissolving this in 12.8 ml of water was added dropwise, and the reaction was then carried out at the same temperature for 9 hours. After completion of the reaction (25) 80% caustic soda water was added dropwise to neutralize the reaction solution. The reaction solution was then extracted with chloroform, and the organic layer was washed with saturated brine. After drying the organic layer with magnesium sulfate,
The solvent was removed under reduced pressure to give the title compound. Melting point 1511
1-160°C Example 16゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
piperazine 2f (8,5i: rimole) to ethyl formate 20
The mixture was dissolved in at and refluxed for 11 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel using chloroform/methyl alcohol/aqueous ammonia (500:25:2) as the eluent.
The title compound was obtained in a yield of 1.18f and a yield of 50.596.

Melting point: 81-88°C (26) Example 17゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
In a solution of piperazine 1f (4.25 mmol), triethylamine 86011F (8.5 mmol) and 20 ml of anhydrous tetrahydrofuran, under ice-water cooling, acetyl chloride 500 Iv (6,88 iE mol) was dissolved in 10 ml of anhydrous ethyl ether. The solution was added dropwise and then refluxed for 7 hours. After the reaction was completed, extraction was performed using a 10% caustic soda water-chloroform system. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure.

The remaining liquid was washed with isopropyl ether and washed at 950 mL.
9 (yield: 89.6%) of the title compound was obtained. Melting point 145
-146°C Example 18゜1-(4-aminobutyl)-4-(2-pyri(dinyl)
Piperazine 2N (8.5f mol) in acetic anhydride 20g/
The mixture was dissolved in water and refluxed for 5 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was purified by eluate column chromatography to obtain the title compound 2.6f (yield 96.8%). Melting point 91-92'C Example 19゜1-(4-aminobutyl)-4-(2-pyrimidinyl)
In a solution of 2 g (8.5 mmol) of piperazine, 1.7 f (17 mmol) of triethylamine and 20 g of anhydrous tetrahydrofuran, 1.17 fl (10.2 mmol) of methanesulfonyl chloride was added to 1 (10.2 mmol) of anhydrous tetrahydrofuran under stirring at room temperature. A solution containing 1+llζ was added dropwise and stirred at the same temperature overnight.After the reaction was completed, it was poured into water.
After adding caustic soda water, the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was diluted with chloroform/methyl alcohol/aqueous ammonia (500:25:2
) was purified by silica gel column chromatography and treated with 8% hydrogen chloride/isopropyl alcohol to obtain the title compound of 760W (yield 18.5%).

Melting point 208°C (decomposition) Example 20° The same operation as in Example 19 was carried out to obtain 700IIv (yield 2
1.05%) of the title compound was obtained. Melting point 11B-118
°C Example 21° (29) 1-(4-aminobutyl)-4-(2-pyrimidinyl)
In a solution of piperazine 2F (8.5 mmol), triethylamine 1.7F (17 mmol) and anhydrous tetrahydrofuran 50 ml, para-toluenesulfonyl chloride 1.9 fl (10.2 mmol) was dissolved in anhydrous tetrahydrofuran 20 ml under stirring at room temperature. The solution was added dropwise to the mixture, and the mixture was stirred at the same temperature overnight. After the reaction was completed, the same post-treatment as in Example 19 was carried out to give a yield of 1.071 2
The title compound of 7.891)) was obtained. Melting point 166-16
8°C (decomposition) (80 complete)

Claims (1)

[Claims] General formula [wherein, R represents a group represented by the general formula R, Z,
1 represents a hydrogen atom or a group represented by the general formula R, 'Z'. R4 and R4° are the same or different and each represents a lower alkyl group, an aryl group, an alkoxy group, a phenoxy group,
Indicates a benzyloxy group, a hydrogen atom, or an amino group. Z
and 2° are the same or different and each represents a sulfonyl group or a carbonyl group. n represents an integer of 2, 8 or 4. R represents a 2-pyridyl group or a 2-pyrimidinyl group. ] Pharmaceutically acceptable acid addition salts of piperazine derivatives.