KR20050017158A - Novel piperazinyl alkyl triazole compounds having selective biological activity at dopamine receptors - Google Patents

Abstract

PURPOSE: Piperazinyl alkyl triazole compounds having selectively inhibiting activity at dopamine receptors are provided, which compounds are dopamine antagonists, so that they can be useful for treatment of psychomancy disease. CONSTITUTION: The piperazinyl alkyl triazole compounds represented by formula (1) or pharmaceutically acceptable salts thereof are provided, wherein n is an integer of 3 or 4; R1 is optionally substituted phenyl or optionally substituted benzhydryl, in which the substituent is C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C6 hydroxyalkyl, aryl, heteroaryl, amino, C1-C6 alkylamino, C2-C6 alkenyl, carbonyl, C3-C9 cycloalkyl and C3-C9 hetero ring; and R2 and R3 are independently hydrogen, C1-C6 alkyl or C1-C6 alkylester. A method for preparing the piperazinyl alkyl triazole compounds of formula (1) comprises reacting azide compound of formula (2) with alkylester compound of formula (3) in solution through combinatorial synthesis, wherein the solvent is dimethylformamide or acetonitrile.

Description

Novel piperazinyl alkyl triazole compounds having selective biological activity at dopamine receptors

The present invention relates to a piperazinylalkyl triazole compound, which has a selective antagonism of the dopamine receptor and is effective as an antipsychotic agent. It relates to a method for producing by using the pharmaceutical composition and a pharmaceutical composition containing the compound as an active ingredient.

[Formula 1]

In Formula 1, n represents an integer of 3 or 4; R ¹ represents a substituted or unsubstituted phenyl group or a substituted or an unsubstituted benzhydryl, wherein the substituents are halogen atom, C ₁ ~C ₆ alkyl group, an alkoxy group, a hydroxy group of the C ₁ ~C _6, C ₁ ~C a _6-hydroxy group, an aryl group, a heteroaryl group, an amino group, C ₁ ~C ₆ alkyl group, C ₂ ~C ₆ alkenyl group, a carbonyl group, C ₃ ~C ₉ cycloalkyl and C ₃ ~C ₉ of the Heterocyclic group; R ² And R ³ represent each a hydrogen atom, an alkyl ester of a C ₁ ~C ₆ alkyl group or a C ₁ ~C ₆ in.

Combinatorial Synthesis is a new field of research technology in the development of new materials and materials. Whereas conventional synthesis methods synthesize one compound in one reaction, combinatorial synthesis is a new concept of chemical synthesis that synthesizes a greater number of compounds in a single reaction. This combination synthesis has been used in various fields such as catalysts and biosynthesis as well as drug discovery as it becomes easier to search for a lead compound having a new structure and to optimize its structure and function.

Combination synthesis can be largely divided into solid phase combination synthesis and solution phase combination synthesis. Combination of solid phase has the advantage of easy separation and manipulation of products and easy automation, while the reaction scale is limited and solvents and samples are used in excess. In addition, the solution phase combination is difficult to automate the reaction process and to separate the desired product, while the reaction scale is not limited and the progress of the reaction can be easily confirmed. It has the advantage of providing diversity.

Dopamine is known as a neurotransmitter that is essential for the transmission of nerve signals found in the brains of animals, including humans, and is one of the most catecholamines present in the central nervous system. . Dopamine antagonists are antipsychotics that inhibit the binding of dopamine to dopamine receptors and are used in the treatment of mental disorders such as schizophrenia.

Dopamine's function consists of binding and acting on the membrane receptor, the dopamine receptor, so dopamine receptors are a major target for drugs used to deal with such psychomotor disorders. Dopamine receptors include a class of receptors that have biological effects through G-proteins. Dopamine receptors are divided into two subtypes, D ₁ and D ₂ , based on their pharmacological and biochemical properties. The D ₁ -like receptor group belongs to the D ₁ and D ₅ receptors, and the D ₂ -like receptor group includes the D ₂ and D ₃ , D ₄ receptors.

A compound such as haloperidol, known as a conventional schizophrenic drug, is a drug that acts on the dopamine receptor D ₂ , but is known to have extrapyramidal side effects (EPs) after long-term treatment. These side effects are due to hypersensitivity reactions due to long-term blockade of central dopamine receptors, such as involuntary exercise (hypermotor disorders) and hyperprolactinaemia due to pituitary dopamine receptor blockade. On the other hand, antagonists that selectively act on dopamine D ₃ and D ₄ receptors are known to be free from side effects such as extrapyramidal side effects and tardive dyskinesias.

Therefore, in the treatment of mental disorders such as schizophrenia, the development of new drugs with little side effects, namely new compounds selectively acting on dopamine D ₃ and D ₄ receptors, is very important.

On the other hand, the applicant has received a patent registration for a novel compound of piperazinylethyl triazole and its preparation method of the same compound represented by the formula (1) characterized by the present invention and its parent nucleus [Korean Patent No. 343,948] ].

The Applicant has synthesized a novel structure of an extension of the alkyl chain of the piperazinylethyl triazole compound disclosed in Korean Patent Registration No. 343,948, and found that the compound exhibits selective antagonism of the dopamine receptor. To complete.

Accordingly, an object of the present invention is to provide a novel compound having a dopaminergic antagonism and effective for treating mental disorders and a method for preparing the same.

In addition, an object of the present invention is to provide a pharmaceutical composition for the central nervous system containing the novel compound as an active ingredient.

The present invention is characterized by a piperazinylalkyl triazole compound represented by the following Chemical Formula 1 having selective physiological activity with respect to the dopamine receptor and pharmaceutically acceptable salts thereof.

[Formula 1]

In Formula 1, n, R ¹ , R ² and R ³ are each as defined above.

In addition, the piperazinylalkyl triazole compound represented by Chemical Formula 1 according to the present invention may have a chiral center, and in the case of such compounds, racemic compounds or all possible isomers thereof may exist. Accordingly, the present invention includes racemates, individual isomers or mixtures of these isomers.

In addition, the present invention includes a radioactive derivative of the piperazinylalkyl triazole compound represented by Chemical Formula 1, and these radioactive compounds are useful in the field of biological research.

In addition, the piperazinylalkyl triazole compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid, or propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid Together with non-toxic organic acids, they may form salts of pharmaceutically acceptable acids, or may form quaternary ammonium salts.

When explaining the substituent in the piperazinylalkyl triazole compound represented by the formula (1) according to the present invention in more detail. The "alkyl group" includes all linear or pulverized carbon chains, and specifically includes methyl, ethyl, propyl, isopropyl, butyl and t-butyl groups. Specifically as a "cycloalkyl group", a cyclopentyl group, a cyclohexyl group, etc. are mentioned. 'Alkoxy group' represents an alkyl group of carbon linked to oxygen. 'Alkylamino group' represents an alkyl group to which carbon atoms are linked through a nitrogen atom. 'Aryl group' includes one ring having at least six atoms, two rings having 10 atoms, or both aromatic rings resonancely stabilized by double bonds to adjacent carbon atoms, and specifically, a phenyl group or a naphthyl group And the like, and such an aryl group may have a substituent such as a halogen atom, an alkyl group, an alkoxy group, or a phenoxy group. 'Heterocyclic group' refers to a heterocyclic ring having 5 to 7 atoms that is stable regardless of saturation or unsaturation, and is composed of 1 to 3 heteroatoms and carbon atoms composed of N, O, and S. Specifically, a pyridine group and a pyrazine Group, pyrimidine group, pyridazine group, triazine group, imidazole group, triazole group, quinoline group, isoquinoline group, quinazoline group, quinoxaline group, phthalazine group, oxazole group, isoxazole group, thiazole group, iso Thiazole group, thiadiazole group, oxadiazole group, pyrrole group, furan group, thiophene group, and the hydrogenated derivatives such as piperidine group, pyrrolidine group, azetidine group, tetrahydrofuran group and N- of basic nitrogen It includes an oxide derivative and may have a substituent such as a halogen atom, an alkyl group, an amine group, and an alkylamino group.

In the compound represented by Formula 1, preferably n is an integer of 3 or 4, R ¹ is a phenyl group, an alkyl substituted phenyl group, an alkoxy substituted phenyl group or a benzhydryl group, R ² and R ³ are each In the case of a hydrogen atom or an alkyl ester group.

In the compound represented by Formula 1, more preferably n is an integer of 3 or 4, R ¹ is a phenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-ethoxyphenyl group or benzhydryl group , R ² and R ³ are each a hydrogen atom, a methyl ester group (-COOMe) or an ethyl ester group (-COOEt).

In addition, in the compound represented by Formula 1, two regioisomers may be generated when one of R ² and R ³ is a hydrogen atom and the other is an alkylester group.

Specific examples of the piperazinylalkyl triazole compounds represented by Chemical Formula 1 according to the present invention are as follows:

1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 1),

3- [3- (4-phenylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 2),

1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 3),

3- [3- (4-phenylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 4),

1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 5),

1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 6),

1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 7),

3- [3- (4-o-tolylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 8),

1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 9),

3- [3- (4-o-tolylpiperazinyl) -propyl] -1 H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 10),

1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 11),

1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 12),

1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 13),

3- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 14),

1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 15),

3- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 16),

1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 17),

1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 18) ,

1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 19),

3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 20),

1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 21),

3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 22),

1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 23),

1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 24) ,

1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 25),

3- [3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 26),

1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 27),

3- [3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 28),

1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 29),

1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 30),

1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 31),

3- [4- (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 32),

1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 33),

3- [4- (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 34),

1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 35),

1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 36),

1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 37),

3- [4- (4-o-tolylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 38),

1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 39),

3- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 40),

1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 41),

1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 42),

1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 43),

3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 44),

1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 45),

3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 46),

1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 47),

1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 48) ,

1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 49),

3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 50),

1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 51),

3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 52),

1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 53),

1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 54) ,

1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 55),

3- [4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 56),

1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 57),

3- [4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 58),

1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 59),

1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 60).

On the other hand, the present invention includes a method for producing a piperazinylalkyl triazole compound represented by the formula (1), characterized in that the production method according to the invention is carried out using a solution phase combination synthesis (combinatorial synthesis) method do.

The preparation method according to the present invention is represented by Chemical Formula 1 by the 1,3-dipole ring addition reaction of the azide compound represented by the following Chemical Formula 2 and the alkyl ester compound represented by Chemical Formula 3, as shown in the following Scheme 1 It includes the process of preparing the compound.

In Scheme 1, n, R ¹ , R ² and R ³ are each as defined above.

The reaction between the azide compound represented by Formula 2 and the dipole itself represented by Formula 3 is performed at room temperature, and many reactions are simultaneously performed using a multifunctional reactor. The alkyl ester compound represented by Chemical Formula 3 is preferably used in an amount of 3 equivalents to the compound represented by Chemical Formula 2, and dimethylformamide or acetonitrile was used as the solvent. The reaction time is on the order of 1 to 5 hours, and the reactivity of the mono-molded ester is shown to be greater. The progress of the reaction was tracked using thin-layer chromatography. After the reaction was completed, the solvent was distilled off under reduced pressure and dried to obtain a reaction mixture.

In addition, a method for preparing a pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 may be easily prepared by a conventional synthetic method according to known literature, and may be purely separated without any further purification. Next, a method for preparing a pharmaceutically acceptable salt of a compound represented by Chemical Formula 1 will be described based on the preparation of hydrochloride. That is, the extractant is dried and evaporated, and then the residue is dissolved in a small amount of ether, and about 1-10 equivalents of an ether solution of hydrogen chloride is added to form a hydrochloride of the desired target compound in the form of a white solid. The organic solvent that can be used to prepare the hydrogen chloride solution may be used chloroform, dichloromethane, ether, methanol, ethyl acetate or a mixed solvent thereof, preferably ether. At this time, the resulting product in the form of a white solid can be separated by centrifugation or simple filtration. The solids are washed 2-3 times with ether and dried well to obtain high purity hydrochloride. In addition, the regioisomers produced when reacted with mono-substituted alkylesters were easily separated using tube chromatography. The structure of the isolated positional isomer was confirmed using the results of the Nuclear Overhauser Effect (NOE) experiment as shown below.

In addition, the azide compound represented by Chemical Formula 2 and the alkyl ester compound represented by Chemical Formula 3 to be used as starting materials in the production method according to the present invention can be easily prepared and used by known literature. For example, the azide compound represented by Chemical Formula 2 may be easily prepared and used through a synthetic route as in Scheme 2 below.

In Scheme 2, n and R ¹ are each as defined above.

Meanwhile, the piperazinylalkyl triazole compound represented by Chemical Formula 1 according to the present invention is very effective in treating mental disorders, and thus the present invention is used for the central nervous system in which the novel compound represented by Chemical Formula 1 is contained as an active ingredient. Pharmaceutical compositions and dopaminergic antagonists. Pharmaceutical compositions and dopaminergic antagonists include conventional, non-toxic pharmaceutically acceptable carriers, adjuvant and excipients to the compound represented by the formula (1), such as tablets, capsules, troches, solutions It may be formulated into a preparation for oral administration such as a suspending agent or a preparation for parenteral administration. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01-400 mg / day, and may be divided once a day or several times at regular time intervals according to the judgment of a doctor or a pharmacist.

When the present invention is described in more detail as follows, the present invention is not limited thereto.

The following reference is an example of a method for producing the azide compound represented by Formula 2 or the alkyl ester compound represented by Formula 3 used in the present invention as a starting material.

[Reference Example]

Reference Example 1 Synthesis of 4-azido-1-butanol

4-bromo-1-butanol (1.77 g, 11.5 mmol) was dissolved in 20 mL of well-dried dimethylformamide, and sodium azide (3 g, 46.1 mmol) was added thereto, followed by reaction at 70 ° C. for 5 hours. After completion of the reaction, water was added and extracted several times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (hexane / ethyl acetate = 1/2) to obtain 1.02 g (76.7%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.55-1.72 (m, 4H), 2.44 (bs, 1H), 3.30 (t, 2H, J = 6.3 Hz), 3.63 (t, 2H, J = 6.3 Hz )

Reference Example 2 Synthesis of Methanesulfonic Acid-4-azido-Butyl Ester

4-azido-1-butanol (430 mg, 3.73 mmol) was dissolved in 10 mL of well-dried dichloromethane, triethylamine (3.12 mL, 22.4 mmol) was added thereto, and the mixture was stirred at 0 ° C. After 20 minutes, methanesulfonyl chloride (1.28 mL, 11.2 mmol) was added thereto and reacted at room temperature for 2 hours. After completion of the reaction, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain 589.5 mg (89.2%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.73 (m, 2H), 1.86 (m, 2H), 3.03 (s, 3H), 3.36 (t, 2H, J = 6.3 Hz), 4.27 (t, 2H , J = 6.3 Hz)

Reference Example 3) Synthesis of 1- (4-azido-butyl) -4-phenyl-piperazine

1-phenylpiperazine (359.2 μL, 2.35 mmol) was dissolved in 10 mL of well-dried dimethylformamide, potassium carbonate (487.2 mg, 3.53 mmol) was added thereto, followed by stirring. After 10 minutes, methanesulfonic acid-4-azido-butyl ester (500 mg 2.82 mmol) was added thereto and reacted at 90 ° C. for 3 hours. After completion of the reaction, water was added and extracted several times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain 376.8 mg (61.8%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64 (m, 4H), 2.43 (t, 2H, J = 7.02 Hz), 2.61 (m, 4H), 3.21 (m, 4H), 3.32 (t, 2H , J = 6.84 Hz), 6.92 (m, 2H), 7.21 (m, 3H)

EXAMPLE

The following example is an embodiment for the 1,3-dipole ring addition reaction of the azide compound represented by the formula (2) and the alkyl ester represented by the formula (3), the present invention is limited by the following examples It doesn't happen.

Example 1) 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 1) and 1- [3- Synthesis of (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 2)

1- (3-azido-propyl) -4-phenyl-piperazine (100.0 mg, 0.41 mmol) and methylpropiorate (103.1 μL, 1.23 mmol) were added to 3 mL of dried acetonitrile. The reaction was carried out for 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 1 (86.5 mg, 64.4%) and compound No. 2 (21.6 mg, 16.1%) were obtained, respectively.

Compound No. 1: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.16 (m, 2H), 2.39 (t, 2H, J = 6.9 Hz), 2.58 (br, 4H), 3.20 (br, 4H), 4.54 (t, 3H, J = 7.2 Hz), 6.95 (m, 3H), 7.27 (m, 2H), 8.13 (s, 1H)

Compound No. 2: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.14 (m, 2H), 2.48 (t, 2H, J = 6.9 Hz), 2.57 (br, 4H), 3.16 (br, 4H), 4.84 (t, 3H, J = 7.2 Hz), 6.94 (m, 3H), 7.27 (m, 2H), 8.12 (s, 1H)

Example 2) 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 3) and 3- [3- Synthesis of (4-phenylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 4)

1- (3-azido-propyl) -4-phenyl-piperazine (100.0 mg, 0.41 mmol) and ethyl propiorate (125.0 μL, 1.23 mmol) were added to 3 mL of well-dried acetonitrile. The reaction was carried out for 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 3 (86.1 mg, 61.0%) and compound No. 4 (21.5 mg, 15.3%) were obtained, respectively.

Compound No. 3: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.39 (t, 3H, J = 7.14 Hz), 2.13 (m, 2H), 2.38 (t, 2H, J = 6.9 Hz), 2.56 (br , 4H), 3.18 (br, 4H), 4.42 (t, 3H, J = 7.2 Hz), 4.52 (t, 2H, J = 7.2 Hz), 6.90 (m, 3H), 7.26 (m, 2H), 8.12 (s, 1H)

Compound No. 4: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H, J = 7.14 Hz), 2.13 (m, 2H), 2.48 (t, 2H, J = 6.9 Hz), 2.58 (br) , 4H), 3.17 (br, 4H), 4.39 (t, 3H, J = 7.2 Hz), 4.83 (t, 2H, J = 7.2 Hz), 6.90 (m, 3H), 7.26 (m, 2H), 8.12 (s, 1H)

Example 3) Synthesis of 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 5)

1- (3-azido-propyl) -4-phenyl-piperazine (100.0 mg, 0.41 mol) and dimethylacetylenecarbocylate (151.2 μL, 1.23 mmol) were added to 3 mL of dried acetonitrile at 85 ° C. The reaction was carried out for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 119.9 mg (75.4%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.14 (m, 2H), 2.43 (t, 2H, J = 6.9 Hz), 2.54 (br, 4H), 3.14 (br, 4H), 3.96 (s, 3H ), 4.00 (s, 3H), 4.70 (t, 2H, J = 7.2 Hz), 6.90 (m, 3H), 7.26 (m, 2H)

Example 4) Synthesis of 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 6)

1- (3-azido-propyl) -4-phenyl-piperazine (100.0 mg, 0.41 mol) and diethylacetylenecarbocylate (196.9 μL, 1.23 mmol) were added to 3 mL of well-dried acetonitrile at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 133.9 mg (78.8%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.39 (m, 6H), 2.14 (m, 2H), 2.45 (t, 2H, J = 6.9 Hz), 2.55 (br, 4H), 3.16 (br, 4H ), 4.44 (m, 4H), 4.70 (t, 3H, J = 7.2 Hz), 6.91 (m, 3H), 7.26 (m, 2H)

Example 5) 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 7) and 3- [ Synthesis of 3- (4-o-tolylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 8)

1- (3-azido-propyl) -4-o-tolyl-piperazine (200.0 mg, 0.77 mmol) and methylpropiorate (193.3 μL, 2.31 mmol) were added to 3 mL of dried acetonitrile at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the desired compound No. 7 (147.5 mg, 61.2%), and compound No. 8 (29.5). mg, 15.3%) were obtained, respectively.

Compound No. 7: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.16 (m, 2H), 2.29 (s, 3H), 2.40 (t, 2H, J = 6.9 Hz), 2.57 (br, 4H), 2.93 (br, 4H), 3.97 (s, 3H), 4.54 (t, 3H, J = 7.2 Hz), 7.01 (m, 2H), 7.20 (m, 2H), 8.15 (s, 1H)

Compound No. 8: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.13 (m, 2H), 2.28 (s, 3H), 2.48 (t, 2H), 2.56 (br, 4H), 2.89 (br, 4H) , 3.92 (s, 3H), 4.81 (t, 3H), 7.00 (m, 2H), 7.14 (m, 2H), 8.12 (s, 1H)

Example 6) 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 9) and 3- [ Synthesis of 3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 10)

1- (3-azido-propyl) -4-o-tolyl-piperazine (100.0 mg, 0.39 mmol) and ethyl propiorate (117.0 μL, 1.16 mmol) were added to 3 mL of dried acetonitrile at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 9 (95.9 mg, 74.6%) and compound No. 10 (16.5) mg, 12.8%) were obtained, respectively.

Compound No. 9: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.42 (t, 3H), 2.15 (m, 2H), 2.29 (s, 3H), 2.40 (t, 2H), 2.57 (br, 4H) , 2.93 (br, 4H), 4.43 (m, 2H), 4.55 (t, 2H), 7.01 (m, 2H), 7.17 (m, 2H), 8.14 (s, 1H)

Compound No. 10: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (t, 3H), 2.14 (m, 2H), 2.29 (s, 3H), 2.49 (t, 2H), 2.58 (br, 4H) , 2.91 (br, 4H), 4.40 (m, 2H), 4.84 (t, 2H), 7.01 (m, 2H), 7.16 (m, 2H), 8.13 (s, 1H)

Example 7) of 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 11) synthesis

To 3 mL of dried acetonitrile, add 1- (3-azido-propyl) -4-o-tolyl-piperazine (200.0 mg, 0.77 mol) and dimethylacetylenecarbocylate (142.1 μL, 2.31 mmol). The reaction was carried out for 4 hours and 30 minutes at ℃. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 258.4 mg (85.5%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.26 (t, 3H), 2.14 (m, 2H), 2.28 (s, 3H), 2.45 (t, 2H), 2.54 (br, 4H), 2.88 (br , 4H), 4.00 (s, 3H), 4.01 (s, 3H), 4.71 (m, 2H), 7.01 (m, 2H), 7.16 (m, 2H)

Example 8) 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 12) Synthesis of

To 3 mL of dried acetonitrile, add 1- (3-azido-propyl) -4-o-tolyl-piperazine (100.0 mg, 0.39 mol) and diethylacetylenecarbocylate (184.9 μL, 1.16 mmol). The reaction was carried out at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 131.5 mg (78.5%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35 (m, 3H), 1.41 (m, 3H), 2.13 (m, 2H), 2.28 (s, 3H), 2.43 (t, 2H), 2.56 (br , 4H), 2.88 (br, 4H), 4.30 (m, 2H), 4.44 (m, 2H), 4.71 (t, 2H), 7.01 (m, 2H), 7.16 (m, 2H)

Example 9) 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 13) And synthesis of 3- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 14)

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4- (2-methoxyphenyl) piperazine (200.0 mg, 0.73 mmol) and methylpropiorate (182.1 μL, 2.18 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 13 (156.9 mg, 84.4%) and compound No. 14 (28.7) mg, 15.6%) respectively.

Compound No. 13: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.15 (m, 2H), 2.41 (t, 2H), 2.62 (br, 4H), 3.10 (br, 4H), 3.87 (s, 3H) , 3.96 (s, 3H), 4.54 (t, 2H), 6.95 (m, 2H), 7.26 (m, 2H), 8.14 (s, 1H)

Compound No. 14: ¹ H NMR (300 MHz, CDCl ₃ ) δ2.05 (m, 2H), 2.41 (t, 2H), 2.54 (br, 4H), 3.00 (br, 4H), 3.77 (s, 3H) , 3.85 (s, 3H), 4.75 (t, 2H), 6.80 (m, 2H), 6.85 (m, 2H), 8.05 (s, 1H)

Example 10) 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 15) And synthesis of 3- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 16)

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4- (2-methoxyphenyl) piperazine (200.0 mg, 0.73 mmol) and ethylpropiorate (220.7 μL, 2.18 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 15 (195.3 mg, 88.5%) and compound No. 16 (24.4 mg, 11.5%) were obtained, respectively.

Compound No. 15: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (t, 3H), 2.14 (m, 2H), 2.41 (t, 2H), 2.62 (br, 4H), 3.09 (br, 4H) , 3.87 (s, 3H), 4.43 (m, 2H), 4.53 (t, 2H), 6.94 (m, 4H), 8.13 (s, 1H)

Compound No. 16: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H), 2.13 (m, 2H), 2.49 (t, 2H), 2.62 (br, 4H), 3.06 (br, 4H) , 3.86 (s, 3H), 4.40 (m, 2H), 4.83 (t, 2H), 6.93 (m, 4H), 8.12 (s, 1H)

Example 11) 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (compound Synthesis of number 17)

1- (3-azido-propyl) -4- (2-methoxyphenyl) piperazine (31.0 mg, 0.11 mmol) and dimethylacetylenedicarbosilicate (39.5 μL, 0.32 mmol) in 3 mL of well-dried acetonitrile ) Was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure gave 28.6 mg (85.5%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.42 (t, 3H), 2.15 (m, 2H), 2.29 (s, 3H), 2.40 (t, 2H), 2.57 (br, 4H), 2.93 (br , 4H), 4.43 (m, 2H), 4.55 (t, 2H), 7.01 (m, 2H), 7.17 (m, 2H), 8.14 (s, 1H)

Example 12) 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester ( Synthesis of Compound No. 18)

1- (3-azido-propyl) -4- (2-methoxyphenyl) piperazine (31.4 mg, 0.11 mmol) and diethylacetylenedicarbosilicate (52.2 μL, 0.33) in 3 mL of well-dried acetonitrile. mmol) was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 29.7 mg (88.4%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (m, 6H), 1.95 (m, 2H), 2.43 (t, 2H, J = 7.14 Hz), 2.62 (br, 4H), 3.08 (br, 4H ), 3.86 (s, 3H), 4.43 (m, 4H), 4.64 (t, 2H, J = 6.09 Hz), 6.91 (m, 4H)

Example 13) 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 19) And synthesis of 3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 20)

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4- (2-ethoxyphenyl) piperazine (123.0 mg, 0.43 mmol) and methylpropiorate (95.3 μL, 2.65 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 19 (102.7 mg, 88.5%) and compound No. 20 (20.1 mg, 11.5%) were obtained, respectively.

Compound No. 19: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (t, 3H, J = 3.99), 2.08 (m, 2H), 2.33 (m, 2H), 2.55 (br, 4H), 3.02 ( br, 4H), 3.88 (s, 3H), 4.02 (m, 2H), 4.46 (t, 2H, J = 6.84), 6.85 (m, 4H), 8.79 (s, 1H)

Compound No. 20: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (t, 3H, J = 6.99), 2.08 (m, 2H), 2.33 (m, 2H), 2.55 (br, 4H), 3.02 ( br, 4H), 3.85 (s, 3H), 4.02 (m, 2H), 4.46 (t, 2H, J = 6.84), 6.85 (m, 4H), 8.39 (s, 1H)

Example 14) 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 21) And synthesis of 3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 22)

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4- (2-ethoxyphenyl) piperazine (38.8 mg, 0.13 mmol) and ethylpropiorate (36.4 μL, 0.36 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the desired compound No. 21 (32.3 mg, 72.2%) and compound No. 22 (10.5). mg, 27.8%) were obtained respectively.

Compound No. 21: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.43 (m, 3H), 2.15 (m, 2H), 2.48 (m, 2H), 2.64 (br, 4H), 3.10 (br, 4H) , 4.08 (m, 2H), 4.42 (m, 2H), 4.56 (m, 2H), 6.92 (m, 4H), 8.14 (s, 1H)

Compound No. 22: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.43 (m, 3H), 2.15 (m, 2H), 2.48 (m, 2H), 2.64 (br, 4H), 3.10 (br, 4H) , 4.08 (m, 2H), 4.42 (m, 2H), 4.56 (m, 2H), 6.92 (m, 4H), 8.10 (s, 1H)

Example 15) 1- [3- {4- (2-Ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (compound Synthesis of Number 23)

1- (3-azido-propyl) -4- (2-ethoxyphenyl) piperazine (59.4 mg, 0.20 mmol) and dimethylacetylenedicarbosilicate (67.7 μL, 0.55 mmol) in 3 mL of well-dried acetonitrile. ) Was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 55.8 mg (87.5%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.43 (t, 3H, J = 6.18 Hz), 2.18 (m, 2H), 2.50 (m, 2H), 2.64 (br, 4H), 3.09 (br, 4H ), 3.94 (s, 3H), 3.98 (s, 3H), 4.02 (m, 2H), 4.69 (m, 2H), 6.88 (m, 4H)

Example 16) 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester ( Synthesis of Compound No. 24)

1- (3-azido-propyl) -4- (2-ethoxyphenyl) piperazine (32.4 mg, 0.11 mmol) and diethylacetylenedicarbosilicate (48.1 μL, 0.30) in 3 mL of well-dried acetonitrile. mmol) was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 36.7 mg (88.9%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (m, 9H), 2.14 (m, 2H), 2.45 (m, 2H), 2.59 (br, 4H), 3.07 (br, 4H), 4.05 (m , 2H), 4.44 (m, 4H), 4.70 (m, 2H), 6.91 (m, 4H)

Example 17) 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 25) and 3- [ Synthesis of 3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 26)

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4-benzhydryl-piperazine (43.4 mg, 0.13 mmol) and methyl propiorate (21.7 μL, 0.26 mmol) at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 25 (40.6 mg, 81.8%) and compound No. 26 (10.3) mg, 18.2%) of each compound were obtained.

Compound No. 25: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.12 (m, 2H), 2.37 (m, 2H), 2.48 (br, 8H), 3.96 (s, 3H), 4.24 (s, 1H) , 4.49 (m, 2H), 7.21 (m, 10H), 8.12 (s, 1H)

Compound No. 26: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.12 (m, 2H), 2.37 (m, 2H), 2.48 (br, 8H), 3.96 (s, 3H), 4.24 (s, 1H) , 4.49 (m, 2H), 7.21 (m, 10H), 8.11 (s, 1H)

Example 18) 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 27) and 3- [ Synthesis of 3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 28)

To 3 mL of dried acetonitrile, add 1- (3-azido-propyl) -4-benzhydryl-piperazine (32.1 mg, 0.10 mmol) and methyl propiorate (29.2 μL, 0.29 mmol) at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 27 (30.6 mg, 88.2%) and compound number 28 (8.5). mg, 11.8%).

Compound No. 27: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H, J = 7.14 Hz), 2.11 (m, 2H), 2.36 (m, 2H), 2.40 (br, 8H), 4.23 (s, 1H), 4.45 (m, 2H), 4.48 (m, 2H), 7.27 (m, 10H), 8.10 (s, 1H)

Compound No. 28: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H, J = 7.14 Hz), 2.11 (m, 2H), 2.36 (m, 2H), 2.40 (br, 8H), 4.23 (s, 1H), 4.45 (m, 2H), 4.48 (m, 2H), 7.27 (m, 10H), 8.08 (s, 1H)

Example 19) of 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 29) synthesis

To 3 mL of dried acetonitrile, add 1- (3-azido-propyl) -4-benzhydryl-piperazine (20.9 mg, 0.06 mmol) and dimethylacetylenedicarbocylate (23.0 μL, 0.19 mmol). The reaction was carried out at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 19.8 mg (84.5%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ2.07 (m, 2H), 2.37 (m, 10H), 3.95 (s, 3H), 3.96 (s, 3H), 4.02 (s, 1H), 4.65 (t , 2H, J = 7.26 Hz), 7.29 (m, 10H)

Example 20) 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 30) Synthesis of

To 3 mL of well-dried acetonitrile, add 1- (3-azido-propyl) -4-benzhydryl-piperazine (55.6 mg, 0.17 mmol) and diethylacetylenedicarbosyrate (84.6 μL, 0.50 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 52.9 mg (80.3%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (m, 6H), 2.15 (m, 2H), 2.37 (m, 10H), 4.19 (s, 1H), 4.42 (m, 2H), 4.63 (m , 2H), 7.28 (m, 10H)

Example 21) 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 31) and 3- [4- Synthesis of (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 32)

1- (4-azido-butyl) -4-phenyl-piperazine (50.0 mg, 0.19 mmol) and methylpropiorate (49.1 μL, 0.58 mmol) were added to 3 mL of dried acetonitrile. The reaction was carried out for 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 31 (48.2 mg, 85.9%) and compound No. 32 (6.0 mg, 14.1%) of each compound were obtained.

Compound No. 31: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58 (m, 2H), 2.00 (m, 2H), 2.43 (m, 2H), 2.55 (m, 4H), 3.21 (m, 4H) , 3.96 (s, 3H), 4.50 (m, 2H), 6.89 (m, 3H), 7.25 (m, 2H), 8.11 (s, 1H)

Compound No. 32: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58 (m, 2H), 2.00 (m, 2H), 2.43 (m, 2H), 2.55 (m, 4H), 3.21 (m, 4H) , 3.96 (s, 3H), 4.50 (m, 2H), 6.89 (m, 3H), 7.25 (m, 2H), 8.13 (s, 1H)

Example 22) 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 33) and 3- [4- Synthesis of (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 34)

1- (4-azido-butyl) -4-phenyl-piperazine (104.1 mg, 0.40 mmol) and ethyl propiorate (122.0 μL, 1.21 mmol) were added to 3 mL of dried acetonitrile. The reaction was carried out for 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the desired compound No. 33 (96.8 mg, 82.1%), and compound No. 34 (24.5). mg, 17.9%) were obtained, respectively.

Compound No. 33: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.43 (m, 2H), 2.01 (m, 2H), 2.43 (t, 2H, J = 6.9 Hz), 2.55 (m, 4H), 3.19 (m, 4H), 4.42 (m, 4H), 6.91 (m, 3H), 7.26 (m, 2H), 8.10 (s, 1H)

Compound No. 34: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.43 (m, 2H), 2.01 (m, 2H), 2.43 (t, 2H, J = 6.9 Hz), 2.55 (m, 4H), 3.19 (m, 4H), 4.42 (m, 4H), 6.91 (m, 3H), 7.26 (m, 2H), 8.12 (s, 1H)

Example 23 Synthesis of 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 35)

1- (4-azido-butyl) -4-phenyl-piperazine (31.0 mg, 0.12 mol) and dimethylacetylenecarbocylate (44.1 μL, 0.36 mmol) were added to 3 mL of well-dried acetonitrile at 85 ° C. The reaction was carried out for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 28.6 mg (78.0%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58 (m, 2H), 2.01 (m, 2H), 2.43 (t, 2H, J = 6.9 Hz), 2.60 (m, 4H), 3.25 (m, 4H ), 3.98 (s, 3H), 3.99 (s, 3H), 6.98 (m, 3H), 7.25 (m, 2H)

Example 24) Synthesis of 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 36)

1- (4-azido-butyl) -4-phenyl-piperazine (37.5 mg, 0.15 mol) and diethylacetylenecarbosirate (69.5 μL, 0.43 mmol) were added to 3 mL of well-dried acetonitrile. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 30.1 mg (71.5%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.43 (m, 6H), 1.53 (m, 2H), 1.97 (m, 2H), 2.41 (t, 2H, J = 6.96 Hz), 2.56 (br, 4H ), 3.18 (br, 4H), 4.43 (m, 4H), 4.64 (t, 2H, J = 7.2 Hz), 7.25 (m, 2H)

Example 25) 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 37) and 3- [ Synthesis of 4- (4-o-tolylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 38)

1- (4-azido-butyl) -4-o-tolyl-piperazine (32.0 mg, 0.12 mmol) and methylpropiorate (29.3 μL, 0.35 mmol) were added to 3 mL of dried acetonitrile at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 37 (30.2 mg, 88.4%) and compound number 38 (8.6). mg, 11.6%) were obtained, respectively.

Compound 37: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.55 (m, 2H), 2.01 (m, 2H), 2.28 (s, 3H), 2.44 (t, 2H, J = 7.14 Hz), 2.57 (br, 4H), 2.92 (br, 4H), 3.94 (s, 3H), 4.46 (t, 2H, J = 7.14 Hz), 6.99 (m, 2H), 7.15 (m, 2H), 8.11 (s, 1H)

Compound No. 38: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.55 (m, 2H), 2.01 (m, 2H), 2.28 (s, 3H), 2.44 (t, 2H, J = 7.14 Hz), 2.57 (br, 4H), 2.92 (br, 4H), 3.94 (s, 3H), 4.46 (t, 2H, J = 7.14 Hz), 6.99 (m, 2H), 7.15 (m, 2H), 8.12 (s, 1H)

Example 26) 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 39) and 3- [ Synthesis of 4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 40)

1- (4-azido-butyl) -4-o-tolyl-piperazine (28.2 mg, 0.10 mmol) and ethyl propiorate (29.6 μL, 0.29 mmol) were added to 3 mL of dried acetonitrile. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 39 (28.5 mg, 84.6%) and compound number 40 (7.9). mg, 15.4%) of the compound were obtained, respectively.

Compound No. 39: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.34 (t, 3H, J = 7.14 Hz), 1.49 (m, 2H), 1.94 (m, 2H), 2.22 (s, 3H), 2.38 (t, 2H, J = 7.14 Hz), 2.51 (br, 4H), 2.86 (br, 4H), 4.37 (m, 2H), 6.93 (m, 2H), 7.09 (m, 2H), 8.04 (s, 1H)

Compound No. 40: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.34 (t, 3H, J = 7.14 Hz), 1.49 (m, 2H), 1.94 (m, 2H), 2.22 (s, 3H), 2.38 (t, 2H, J = 7.14 Hz), 2.59 (br, 4H), 2.93 (br, 4H), 4.39 (m, 2H), 4.78 (t, 2H, J = 7.23 Hz), 6.93 (m, 2H) , 7.09 (m, 2H), 8.12 (s, 1H)

Example 27) of 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 41) synthesis

To 3 mL of dried acetonitrile, add 1- (4-azido-butyl) -4-o-tolyl-piperazine (39.3 mg, 0.14 mol) and dimethylacetylenecarbocylate (53.0 μL, 0.43 mmol). The reaction was carried out for 4 hours and 30 minutes at ℃. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 30.5 mg (82.1%) of the title compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.99 (m, 2H), 2.30 (s, 3H), 2.44 (m, 2H), 2.58 (br, 4H), 2.93 (br, 4H), 3.98 (m , 2H), 4.55 (s, 3H), 4.01 (s, 3H), 4.66 (t, 2H, J = 7.2 Hz), 7.00 (m, 2H), 7.17 (m, 2H)

Example 28) 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 42) Synthesis of

To 3 mL of dried acetonitrile, add 1- (4-azido-butyl) -4-o-tolyl-piperazine (31.4 mg, 0.11 mol) and diethylacetylenecarbocylate (52.2 μL, 0.33 mmol). The reaction was carried out at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure gave 32.6 mg (91.0%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (m, 6H), 1.56 (m, 2H), 1.97 (m, 2H), 2.41 (s, 3H), 2.43 (m, 2H), 2.56 (br , 4H), 2.92 (br, 4H), 4.44 (m, 4H), 4.64 (t, 2H, J = 7.26 Hz), 6.99 (m, 2H), 7.16 (m, 2H)

Example 29) 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 43) And 3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 44)

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4- (2-methoxyphenyl) piperazine (27.1 mg, 0.10 mmol) and methylpropiorate (23.5 μL, 0.28 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (hexane / ethyl acetate = 1/1) to the desired compound No. 43 (25.0 mg, 87.0%) and compound No. 44 (6.6 mg, 13.0%) were obtained, respectively.

Compound No. 43: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.23 (t, 2H, J = 7.14 Hz), 1.53 (m, 2H), 2.41 (t, 2H), 2.59 (br, 4H), 3.05 (br, 4H), 3.80 (s, 3H), 3.83 (s, 3H), 4.45 (t, 2H, J = 7.02), 6.90 (m, 4H), 8.10 (s, 1H)

Compound No. 44: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.23 (t, 2H, J = 7.14 Hz), 1.53 (m, 2H), 2.41 (t, 2H), 2.59 (br, 4H), 3.05 (br, 4H), 3.80 (s, 3H), 3.83 (s, 3H), 4.45 (t, 2H, J = 7.02), 6.90 (m, 4H), 8.11 (s, 1H)

Example 30) 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 45) And 3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 46)

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4- (2-methoxyphenyl) piperazine (28.2 mg, 0.10 mmol) and ethylpropiorate (29.6 μL, 0.29 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 45 (21.1 mg, 72.9%) and compound number 46 (9.6). mg, 27.1%) of compounds were obtained, respectively.

Compound number 45: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (m, 3H), 2.14 m, 2H, 2.25 (m, 2H), 2.41 (t, 2H), 2.62 (br, 4H), 3.09 (br, 4H), 3.87 (s, 3H), 4.43 (m, 2H), 4.53 (t, 2H), 6.94 (m, 4H), 8.13 (s, 1H)

Compound No. 46: ¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (m, 3H), 2.14 (m, 2H), 2.25 (m, 2H), 2.41 (t, 2H), 2.62 (br, 4H) , 3.09 (br, 4H), 3.87 (s, 3H), 4.43 (m, 2H), 4.53 (t, 2H), 6.94 (m, 4H), 8.14 (s, 1H)

Example 31) 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (compound Synthesis of number 47)

1- (4-azido-butyl) -4- (2-methoxyphenyl) piperazine (39.3 mg, 0.14 mmol) and dimethylacetylenedicarbosilicate (53.0 μL, 0.43 mmol) in 3 mL of well-dried acetonitrile. ) Was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 38.6 mg (89.3%) of the target compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.56 (m, 2H), 1.98 (m, 2H), 2.43 (m, 2H), 2.62 (br, 4H), 3.08 (br, 4H), 3.86 (s , 3H), 3.98 (s, 3H), 4.00 (s, 3H), 4.65 (t, 2H, J = 7.14 Hz), 6.91 (m, 4H)

Example 32) 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester ( Synthesis of Compound No. 48)

1- (4-azido-butyl) -4- (2-methoxyphenyl) piperazine (31.4 mg, 0.11 mmol) and diethylacetylenedicarbosilicate (52.2 μL, 0.33) in 3 mL of well-dried acetonitrile. mmol) was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 30.2 mg (90.2%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.41 (m, 6H), 1.53 (m, 2H), 1.95 (m, 2H), 2.43 (t, 2H, J = 7.14), 2.62 (br, 4H) , 3.08 (br, 4H), 3.86 (s, 3H), 4.43 (m, 4H), 4.64 (t, 2H, J = 6.09 Hz), 6.91 (m, 4H)

Example 33) 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 49) And synthesis of 3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 50)

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4- (2-ethoxyphenyl) piperazine (103.1 mg, 0.34 mmol) and methylpropiorate (85.2 μL, 1.09 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 49 (99.4 mg, 86.5%) and compound number 50 (20.8). mg, 13.5%) were obtained, respectively.

Compound No. 49: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44 (t, 3H, J = 6.9 Hz), 1.55 (m, 2H), 1.99 (m, 2H), 2.42 (t, 2H, J = 7.2 Hz), 2.59 (br, 4H), 3.09 (br, 4H), 3.94 (s, 3H), 4.06 (m, 2H), 4.46 (t, 2H, J = 7.15 Hz), 6.89 (m, 4H) , 8.10 (s, 1H)

Compound No. 50: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44 (t, 3H, J = 6.9 Hz), 1.55 (m, 2H), 1.99 (m, 2H), 2.42 (t, 2H, J = 7.2 Hz), 2.59 (br, 4H), 3.09 (br, 4H), 3.94 (s, 3H), 4.06 (m, 2H), 4.46 (t, 2H, J = 7.15 Hz), 6.89 (m, 4H) , 8.11 (s, 1H)

Example 34) 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 51) And 3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 52)

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4- (2-ethoxyphenyl) piperazine (84.5 mg, 0.28 mmol) and ethyl propiorate (84.7 μL, 0.84 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 51 (79.9 mg, 84.8%) and compound number 52 (18.7). mg, 15.2%) were obtained, respectively.

Compound 51: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (m, 6H), 1.58 (m, 2H), 2.06 (m, 2H), 2.43 (m, 2H), 2.81 (br, 4H) , 3.16 (br, 4H), 4.05 (m, 2H), 4.45 (m, 4H), 6.98 (m, 4H), 8.09 (s, 1H)

Compound 52: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (m, 6H), 1.58 (m, 2H), 2.06 (m, 2H), 2.43 (m, 2H), 2.81 (br, 4H) , 3.16 (br, 4H), 4.05 (m, 2H), 4.45 (m, 4H), 6.98 (m, 4H), 8.10 (s, 1H)

Example 35) 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (compound Synthesis of number 53)

1- (4-azido-butyl) -4- (2-ethoxyphenyl) piperazine (60.4 mg, 0.20 mmol) and dimethylacetylenedicarbosilicate (73.4 μL, 0.60 mmol) in 3 mL of well-dried acetonitrile. ) Was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 53.1 mg (74.2%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45 (t, 2H, J = 7.02 Hz), 1.57 (m, 2H), 1.97 (m, 2H), 2.43 (t, 2H, J = 7.2 Hz), 2.61 (br, 4H), 3.10 (br, 4H), 4.00 (s, 3H), 4.02 (s, 3H), 4.07 (m, 2H), 4.64 (t, 2H, J = 7.26 Hz), 6.89 (m , 4H)

Example 36) 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester ( Synthesis of Compound No. 54)

1- (4-azido-butyl) -4- (2-ethoxyphenyl) piperazine (52.5 mg, 0.17 mmol) and diethylacetylenedicarbosilicate (83.2 μL, 0.52) in 3 mL of well-dried acetonitrile mmol) was added and reacted at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. It dried well under reduced pressure and obtained 46.2 mg (76.5%) of the title compounds.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.42 (m, 2H), 1,56 (m, 2H), 1.96 (m, 2H), 2.42 (t, 2H, J = 6.72 Hz), 2.61 (br , 4H), 3.10 (br, 4H), 4.05 (m, 2H), 4.43 (m, 2H), 4.63 (t, 2H, J = 6.84 Hz), 6.89 (m, 4H)

Example 37) 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 55) and 3- [ Synthesis of 4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 56)

To 1 mL of dried acetonitrile, add 1- (4-azido-butyl) -4-benzhydryl-piperazine (22.3 mg, 0.06 mmol) and methylpropiorate (16.0 μL, 0.19 mmol) at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 55 (24.5 mg, 85.3%) and compound number 56 (7.0). mg, 14.7%) were obtained, respectively.

Compound 55: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45 (m, 2H), 1.96 (m, 2H), 2.48 (m, 10H), 3.99 (s, 3H), 4.12 (s, 1H) , 4.43 (m, 2H), 7.25 (m, 10H), 8.09 (s, 1H)

Compound No. 56: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45 (m, 2H), 1.96 (m, 2H), 2.48 (m, 10H), 3.99 (s, 3H), 4.12 (s, 1H) , 4.43 (m, 2H), 7.25 (m, 10H), 8.12 (s, 1H)

Example 38) 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 57) and 3- [ Synthesis of 4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 58)

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4-benzhydryl-piperazine (22.5 mg, 0.06 mmol) and methyl propiorate (19.6 μL, 0.19 mmol) at 85 ° C. Reaction was carried out for 4 hours and 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, purified by column chromatography (hexane / ethyl acetate = 1/1), and the desired compound number 57 (18.9 mg, 78.3%) and compound number 58 (6.6 mg, 21.7%).

Compound 57: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H, J = 7.14 Hz), 2.11 (m, 2H), 2.36 (m, 2H), 2.40 (br, 10H), 4.23 (s, 1H), 4.45 (m, 2H), 4.48 (m, 2H), 7.27 (m, 10H), 8.10 (s, 1H)

Compound No. 58: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H, J = 7.14 Hz), 2.11 (m, 2H), 2.36 (m, 2H), 2.40 (br, 10H), 4.23 (s, 1H), 4.45 (m, 2H), 4.48 (m, 2H), 7.27 (m, 10H), 8.11 (s, 1H)

Example 39) of 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 59) synthesis

To 3 mL of dried acetonitrile, add 1- (4-azido-butyl) -4-benzhydryl-piperazine (44.8 mg, 0.13 mmol) and dimethylacetylenedicarbocylate (47.3 μL, 0.39 mmol). The reaction was carried out at 85 ° C. for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure yielded 40.6 mg (82.8%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.49 (m, 3H), 1.92 (m, 2H), 2.86 (m, 10H), 3.96 (s, 3H), 3.97 (s, 3H), 4.20 (s , 1H), 4.59 (t, 2H, J = 7.14 Hz), 7.26 (m, 10H)

Example 40) 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 60) Synthesis of

To 3 mL of well-dried acetonitrile, add 1- (4-azido-butyl) -4-benzhydryl-piperazine (48.6 mg, 0.14 mmol) and diethylacetylenedicarbocylate (66.8 μL, 0.42 mmol). The reaction was carried out at 85 ℃ for 4 hours 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, the reaction mixture was dissolved in 1 mL of ethyl ether, and then ethereal HCl was slowly dropped. White hydrochloride was obtained by filtering in the reaction vessel, and washed several times with ethyl ether. Drying well under reduced pressure gave 45.7 mg (88.6%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (m, 6H), 1.45 (m, 2H), 1.89 (m, 2H), 2.35 (m, 10H), 4.20 (s, 1H), 4.43 (m , 4H), 4.59 (t, 2H, J = 7.26 Hz), 7.26 (m, 10H)

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1 : tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2 : Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3 : Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

Formulation 4 : Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

Experimental Example: Affinity test using radioisotopes

To study the effect of each drug on the dopamine receptor and the receptor-ligand interactions, the ligand is reacted with a radioisotope attached ligand and then filtered through a glass wool filter to remove excess ligand that is not bound. After removal, the amount of isotope remaining in the washed filter plate was measured to quantify the binding reaction of the ligand to the receptor, and used to determine the effect of the drug.

The experimental method suspended the receptor fractions frozen at −70 ° C. with buffer for each experiment, confirmed the protein content with the Bio-Rad DC Protein Assay Kit, and adjusted to the optimal concentration for each receptor. At this time, the setting of the protein concentration represented by the content of the receptor was determined through the basic experiment, and then dispensed by appropriate volume, and stored frozen at -70 ℃. Samples of all experiments were run in duplicate, and the buffers required for the experiments were used for the respective buffers to which each receptor could bind in optimal conditions. The final volume of the reaction was 0.25 mL, which included 50 μL of hot-ligand and 10 μL of test drug. 100 μL of receptor suspension was added and reacted at 27 ° C. for 30 to 60 minutes. In the first stage drug screening, the binding affinity of the drug for the two concentrations (1 μM, 10 μM) was searched for, and the drug showed a significant effect in two stages. After measurement, IC ₅₀ values were calculated with a 10-step concentration gradient for the finally selected compound. On the other hand, the standard drug used in the drug screening was haloperidol (haloperidol).

After incubation for 1 hour, using a Wallac glass fiber filtermat GF / C, the reaction was terminated by filtration with cold Tris buffer using an inotech cell harvester system, and the isotope bound to the receptor was separated. After washing, the amount of isotope remaining on the filter mat was measured with a liquid scintillation counter.

Table 1 below shows the binding affinity for some of the selected ligands to the dopamine receptor. In the case of the compound of the compound No. 52 according to the present invention, the dopamine D4 receptor showed about two times better activity than the control compound haloperidol, and showed excellent effects on selectivity for D2.

As described above, the compound represented by the formula (1) according to the present invention is excellent in the selective inhibitory activity on the dopamine receptor is effective in the treatment of mental disorders.

Claims (8)

Piperazinylalkyl triazole compounds represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1] In Formula 1, n represents an integer of 3 or 4; R ¹ represents a substituted or unsubstituted phenyl group or a substituted or an unsubstituted benzhydryl, wherein the substituents are halogen atom, C ₁ ~C ₆ alkyl group, an alkoxy group, a hydroxy group of the C ₁ ~C _6, C ₁ ~C a _6-hydroxy group, an aryl group, a heteroaryl group, an amino group, C ₁ ~C ₆ alkyl group, C ₂ ~C ₆ alkenyl group, a carbonyl group, C ₃ ~C ₉ cycloalkyl and C ₃ ~C ₉ of the Heterocyclic group; R ² And R ³ represent each a hydrogen atom, an alkyl ester of a C ₁ ~C ₆ alkyl group or a C ₁ ~C ₆ in. The compound according to claim 1, wherein the compound has a chiral center and is a racemic compound or an isomer thereof. The compound of claim 1, wherein n is an integer of 3 or 4, R ¹ is a phenyl group, an alkyl substituted phenyl group, an alkoxy substituted phenyl group or a benzhydryl group, and R ² and R ³ are each a hydrogen atom or an alkyl ester group. Characterized in that the compound. The compound of claim 1, wherein n is an integer of 3 or 4, R ¹ is a phenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-ethoxyphenyl group or benzhydryl group, and R ² and R ³ are Compounds, characterized in that each of the hydrogen atom, methyl ester group (-COOMe) or ethyl ester group (-COOEt). According to claim 1, wherein the compound represented by the formula (1) 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 1), 3- [3- (4-phenylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 2), 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 3), 3- [3- (4-phenylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 4), 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 5), 1- [3- (4-phenylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 6), 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 7), 3- [3- (4-o-tolylpiperazinyl) -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 8), 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 9), 3- [3- (4-o-tolylpiperazinyl) -propyl] -1 H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 10), 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 11), 1- [3- (4-o-tolylpiperazinyl) -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 12), 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 13), 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 14), 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 15), 3- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 16), 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 17), 1- [3- {4- (2-methoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 18) , 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 19), 3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 20), 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 21), 3- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 22), 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 23), 1- [3- {4- (2-ethoxyphenyl) piperazinyl} -propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 24) , 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 25), 3- [3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 26), 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 27), 3- [3- (4-benzhydryl) piperazinyl-propyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 28), 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 29), 1- [3- (4-benzhydryl) piperazinyl-propyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 30), 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 31), 3- [4- (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 32), 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 33), 3- [4- (4-phenylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 34), 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 35), 1- [4- (4-phenylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 36), 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 37), 3- [4- (4-o-tolylpiperazinyl) -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 38), 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 39), 3- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 40), 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 41), 1- [4- (4-o-tolylpiperazinyl) -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 42), 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 43), 3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 44), 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 45), 3- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 46), 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 47), 1- [4- {4- (2-methoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 48) , 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 49), 3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 50), 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 51), 3- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 52), 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 53), 1- [4- {4- (2-ethoxyphenyl) piperazinyl} -butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 54) , 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 55), 3- [4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid methyl ester (Compound No. 56), 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 57), 3- [4- (4-benzhydryl) piperazinyl-butyl] -3H- [1,2,3] triazole-4-carboic acid ethyl ester (Compound No. 58), 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid dimethyl ester (Compound No. 59), 1- [4- (4-benzhydryl) piperazinyl-butyl] -1H- [1,2,3] triazole-4,5-dicarboic acid diethyl ester (Compound No. 60), And a pharmaceutically acceptable salt thereof. The azide compound represented by the following formula (2) and the alkyl ester compound represented by the following formula (3) are prepared by a 1,3-dipole cyclization addition reaction by a combinatorial synthesis. Process for preparing the indicated piperazinylalkyl triazole compound: [Formula 1] In the formula: n represents an integer of 3 or 4; R ¹ represents a substituted or unsubstituted phenyl group or a substituted or an unsubstituted benzhydryl, wherein the substituents are halogen atom, C ₁ ~C ₆ alkyl group, an alkoxy group, a hydroxy group of the C ₁ ~C _6, C ₁ ~C a _6-hydroxy group, an aryl group, a heteroaryl group, an amino group, C ₁ ~C ₆ alkyl group, C ₂ ~C ₆ alkenyl group, a carbonyl group, C ₃ ~C ₉ cycloalkyl and C ₃ ~C ₉ of the Heterocyclic group; R ² And R ³ represent each a hydrogen atom, an alkyl ester of a C ₁ ~C ₆ alkyl group or a C ₁ ~C ₆ in. 7. The process according to claim 6, wherein the reaction solvent is dimethylformamide or acetonitrile. Central nervous system pharmaceutical composition characterized in that it contains a piperazinylalkyl triazole compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1] In Formula 1, n represents an integer of 3 or 4; R ¹ represents a substituted or unsubstituted phenyl group or a substituted or an unsubstituted benzhydryl, wherein the substituents are halogen atom, C ₁ ~C ₆ alkyl group, an alkoxy group, a hydroxy group of the C ₁ ~C _6, C ₁ ~C a _6-hydroxy group, an aryl group, a heteroaryl group, an amino group, C ₁ ~C ₆ alkyl group, C ₂ ~C ₆ alkenyl group, a carbonyl group, C ₃ ~C ₉ cycloalkyl and C ₃ ~C ₉ of the Heterocyclic group; R ² And R ³ represent each a hydrogen atom, an alkyl ester of a C ₁ ~C ₆ alkyl group or a C ₁ ~C ₆ in.