KR101152658B1 - Pharmaceutical compositions containing piperazine derivatives for treating as serotonin antagonist - Google Patents

Abstract

The present invention has an inhibitory activity against serotonin 5-HT ₆ , resulting in cognitive and memory impairment due to Alzheimer's disease, including dementia, metabolic and obesity, schizopherenia, Piperazine compounds useful as prophylactic and therapeutic agents for central nervous system (CNS) disorders such as depression, treatment of neuropsychological disorders, affective disorders, and memory damage caused by stress. It relates to a composition containing as an active ingredient.

Serotonin 5-HT6 antagonist, piperazine compound, CNS (central nervous system), central nervous system disease, cognitive improvement, Alzheimer's, schizophrenia, obesity, depression

Description

Pharmaceutical compositions containing piperazine derivatives for treating as serotonin antagonist

The present invention has an inhibitory activity against serotonin 5-HT ₆ , resulting in cognitive and memory impairment due to Alzheimer's disease, including dementia, metabolic and obesity, schizopherenia, Piperazine compounds useful as prophylactic and therapeutic agents for central nervous system (CNS) disorders such as depression, treatment of neuropsychological disorders, affective disorders, and memory damage caused by stress. It relates to a composition containing as an active ingredient.

Serotonin (5-hydroxytryptamine, 5-HT) receptors are distributed throughout the body of humans and animals and play an important role in physiological and behavioral functions. There are currently about 15 clones with genetically different 5-HT receptor subtypes, each of which shows a unique distribution and various preferences and correlations for ligands.

Data reported in 1993 reported that human serotonin 5-HT ₆ receptors and mouse 5-HT ₆ receptors each consist of 440 amino acid glycoproteins, whereas rats consist of 438 amino acids. . Monsma et al, Mol . Pharmacol , 1993 , 43 , 320-327; Pals sat et al, Mol . Pharmacol , 1993 , 44 , 229-236; Ruat et al, Biochem , Biophys . Res . Comm ., 1993 , 193 , 268-276] The 5-HT ₆ receptor is a Gα protein-linked receptor (GPCR) of Gαs-protein that binds positively with c-AMP, the nucleus accumbens, the hippocampus ( It is mainly distributed in the central nervous system such as striatum, hippocampus, and olfactory tubercle of the brain. Hirst, WD et al Mol . Pharmacol , 2003, 64, 1295-1308] As such, 5-HT ₆ receptor is distributed in the central nervous system and has a strong affinity with antipsychotics and antidepressants. It is known that there are few associated side effects, and thus is recognized as a more important target. Woolley, M. L et al, Curr . Drug Targets : CNS Neurol . Disord . 2004 , 3 , 59-79] 5-HT ₆ receptors are mainly distributed in the brain regions that are closely related to cognitive function and memory, and acetylcholine (ACh-) and glutamate menge neurons that promote cognitive processes. It has been reported to interfere with glutamate mediated neurotransmission, and this has been confirmed experimentally through novel-objective discrimination (NOD). In particular, the antagonistic action of 5-HT ₆ receptors has been shown to treat memory and cognitive impairment in Alzheimer's disease (AD) [Johnson CN et al Drug Discov . Today Therapeutic Strategies 2004 , 1 ( 1 ), 13-19], Treatment of metabolic disorders and obesity [Heal D. J et al, Pharmacol . Ther 2008 , 117 ( 2 ), 207-231.

There is no drug available commercially as a selective antagonist for the 5-HT ₆ receptor. However, SGS518, developed by Saegis Pharmaceutical Inc., SB-742457, developed by Glaxo Smith Kline, and SAM531, developed by Wyeth, are the schizophrenic and Alzheimer's drugs, respectively. Phase II clinical trial and PRX-07034, developed by EPIX Pharmaceutical Inc., is in Phase I clinical trial for obesity, schizophrenia and dementia. Christopher N, Johnson et al, Curr. Opinion. Drug. Discovery & developments 2008 , 11 ( 5 ), 642-654]

The present invention provides a new use of the piperazine compound as an active ingredient for the serotonin 5-HT ₆ receptor, thereby using a composition containing the piperazine compound as an active ingredient as a treatment and prevention of central nervous system (CNS) diseases. Let it be the subject which this invention intends to solve.

Cognitive function and memory impairment due to Alzheimer disease, including dementia, composition containing piperazine compound of the present invention as an active ingredient, metabolic disorder and obesity (obesity), schizopherenia, depression Provides new uses for the prevention and treatment of central nervous system (CNS) diseases such as depression, treatment of neuropsychological disorders, affective disorders, and memory damage caused by stress Let it be the subject which this invention intends to solve.

The present invention is used as a pharmaceutical or health food use for the prevention and treatment of central nervous system diseases related to serotonin 5-HT ₆ receptor containing piperazine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient By providing the composition which becomes, the subject of this invention is solved.

In Chemical Formula 1,

는 질소원자가 1 내지 3개 포함된 5각형의 헤테로싸이클기를 나타내고, X는 카르보닐기(C=O); 또는 아미드기(NHC=O)를 나타내고, R₁은 할로 1 내지 3개의 치환체로 치환 또는 비치환된 벤즈히드릴기; 할로, 및 C₁-C₆ 알킬 중에서 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 페닐 C₁-C₆ 알킬기; 또는 할로, C₁-C₆ 알킬, 및 C₁-C₆ 알콕시 중에서 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 페닐기를 나타내고, R₂ 및 R₃은 서로 같거나 다른 것으로 수소원자; C₁-C₆ 알킬기; 할로, C₁-C₆ 알킬, C₁-C₆ 알콕시, 및 피페리딜 중에서 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 페닐기; 또는 퓨라닐기를 나타내고, m 및 n은 각각 0 내지 4의 정수이다.

Represents a pentagonal heterocycle group containing 1 to 3 nitrogen atoms, and X represents a carbonyl group (C═O); Or an amide group (NHC = O), R ₁ is a benzhydryl group unsubstituted or substituted with 1 to 3 substituents; Halo, and C ₁ -C ₆ substituted or unsubstituted with one to three substituents selected from alkyl, phenyl C ₁ -C ₆ alkyl group; Or a phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy, R ₂ and R ₃ are the same as or different from each other a hydrogen atom; C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and piperidyl; Or a furanyl group, and m and n are each an integer of 0 to 4;

Hereinafter, the present invention will be described in detail.

는 피롤기; 피라졸기; 이미다졸기; 또는 트리아졸기를 나타내고, 상기 X는 카르보닐기(C=O); 또는 아미드기(NHC=O)를 나타내고, 상기 R₁은 메틸기; 에틸기; 프로필기; 이소프로필기; 부틸기; 이소부틸기; 할로겐으로 치환 또는 비치환된 벤즈히드릴기; 할로겐으로부터 선택된 1 내지 3개 의 치환체로 치환 또는 비치환된 벤질기; 할로겐으로부터 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 펜에틸기; 또는 할로겐, 메틸, 및 메톡시로부터 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 페닐기를 나타내고, 상기 R₂ 및 R₃은 서로 같거나 다른 것으로 수소원자; 메틸기; 에틸기; 프로필기; 이소프로필기; 부틸기; 이소부틸기; 할로겐, 및 피페리딜 중에서 선택된 1 내지 3개의 치환체로 치환 또는 비치환된 페닐기; 또는 퓨라닐기를 나타내고, 상기 m과 n은 각각 0, 1, 2, 또는 3인 피페라진 화합물의 경우이다.In the piperazine compound represented by the formula (1) contained in the composition according to the present invention, more preferably

The pyrrole group; Pyrazole groups; Imidazole group; Or a triazole group, wherein X is a carbonyl group (C═O); Or an amide group (NHC = O), wherein R ₁ is a methyl group; Ethyl group; Profile group; Isopropyl group; Butyl group; Isobutyl group; Benzhydryl group unsubstituted or substituted with halogen; A benzyl group unsubstituted or substituted with 1 to 3 substituents selected from halogen; A phenethyl group unsubstituted or substituted with 1 to 3 substituents selected from halogen; Or a phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halogen, methyl, and methoxy, wherein R ₂ and R ₃ are the same as or different from each other a hydrogen atom; Methyl group; Ethyl group; Profile group; Isopropyl group; Butyl group; Isobutyl group; A phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halogen and piperidyl; Or a furanyl group, wherein m and n are 0, 1, 2, or 3 in the case of a piperazine compound.

Specific examples of the parasol derivative represented by Formula 1 according to the present invention are as follows.

5- (furan-2-yl) -1-phenyl- N- (2- (4-benzylpiperazin-1-yl) ethyl) pyrazole-3-carboxamide (Compound 1),

N- (2- (4-benzylpiperazin-1-yl) ethyl) -1- tert -butyl-5- (4-chlorophenyl) pyrazole-3-carboxamide (Compound 2),

N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -1-phenyl-5- n -propylpyrazole-3-carboxamide (Compound 3),

4- (4-fluorobenzyl) piperazin-1-yl- (1-phenyl-5-isobutylpyrazole) -3-ketone (compound 4),

4- (4-Pluorophenyl) piperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (Compound 5),

4- (4-Pluorobenzyl) piperazin-1-yl- [1-phenyl-5- (4-piperidylphenyl) pyrazole] -3-ketone (Compound 6),

4-phenylethylpiperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (compound 7),

4-phenylethylpiperazin-1-yl- [1-phenyl-5- (furan-2-yl) pyrazole] -3-ketone (compound 8),

N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 9),

N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (4-phenylimidazol-1-yl) propanamide (Compound 10) ,

1- (4- (2-fluorofluorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 11),

N- (2- (4- (3,4-dichlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 12),

N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 13),

1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 14),

1- (4-phenylpiperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 15),

1- (4- (4-chlorobenzyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 16),

N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (2-phenylimidazol-1-yl) propanamide (Compound 17),

N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (2-phenylimidazol-1-yl) propanamide (Compound 18) , or

N- (2- (4- (4-Pluorophenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 19).

1- (4- (4-methoxyphenyl) piperazin-1-yl) -3- (2-phenylimidazol-1-yl) propanone (Compound 20)

N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -3- (2-methylimidazol-1-yl) propanamide (Compound 21)

N- (2- (4- (3-methylbenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 22)

N- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethyl) -3- (2-phenylimidazol-1-yl) propanamide (Compound 23)

N- (2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 24)

The piperazine compound represented by Chemical Formula 1, which is contained as an active ingredient in the composition according to the present invention, is a known compound known in the art, and various methods for preparing the compound are also known. [Korean Patent Application No. 2008-0061148 and Korean Patent Application No. 2007-0111220]

The present invention confirms that the piperazine compound represented by Formula 1 exhibits an excellent inhibitory effect on the 5-HT ₆ receptor, and the compound is associated with central nervous system diseases associated with pharmacological action due to antagonism of serotonin 5-HT ₆ . It is characterized by its new use as a prophylactic and therapeutic agent.

In other words, the composition according to the present invention acts as an antagonist on the 5-HT ₆ receptor, thereby causing cognitive function and memory damage, metabolic disorders and obesity, schizopherenia, and depression caused by Alzheimer's disease. It is effective as a medicine or health food for the prevention and treatment of diseases of central nervous system (CNS), such as treatment of neuropsychological disorders, affective disorders and memory damage caused by stress.

The piperazine compound represented by Formula 1 included in the composition according to the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. This is useful. The piperazine compound represented by Chemical Formula 1 may form an acid addition salt that is pharmaceutically acceptable according to a conventional method in the art. Organic acids and inorganic acids may be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, or fumaric acid may be used as the organic acid. (fumaric acid), formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, embonic acid, glutamic acid or aspartic acid Etc. can be used.

When using the composition of the present invention as a medicine, the piperazine compound represented by the formula (1) or a pharmaceutically acceptable salt when used clinically in combination with a conventional carrier in the pharmaceutical field is conventional in the pharmaceutical field Phosphorus preparations, for example, oral administration preparations such as tablets, capsules, troches, solutions, and suspensions; Injectable preparations in the form of injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared and used as injectable distilled water at the time of injection; Or in various preparations such as ointments. Pharmaceutical formulations prepared using conventional carriers can be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically. The dosage of the piperazine compound represented by Chemical Formula 1 of the present invention varies depending on the age and condition of the patient, but is generally administered to an adult in an amount of 10 to 500 mg, preferably 50 to 300 mg per day. In accordance with the judgment of the doctor or pharmacist, it may be administered several times a day, preferably once or six times at regular intervals.

In addition, when the composition of the present invention is used as a health food, the piperazine compound represented by Formula 1 may be added to a general food, or may be prepared as a food prepared by encapsulation, powdering, suspension, and the like. 'Health food' is expected to have a specific effect on health by ingestion, unlike the general medicine has the advantage that there is no side effect that can occur when taking long-term use of the drug as a raw material. Examples of the health food include various foods such as confectionery, processed food, combination oils, dairy products, and beverages. The shape and properties of the health food are not particularly limited, and any expected effects such as the solid, semi-solid, gel, liquid, and powder can be sufficiently achieved.

Therefore, the composition containing the piperazine compound represented by Formula 1 as an active ingredient may be administered orally or parenterally during clinical administration, and may be used in the form of general medicines, quasi-drugs, and health foods.

The present invention as described above will be described in more detail based on the following synthesis examples and examples, but the present invention is not limited thereto.

The following synthesis example is only one embodiment of the method for synthesizing the piperazine compound included as an active ingredient in the composition of the present invention, the remaining compounds are known compounds, some of which are the first synthetic by the applicant of the Republic of Korea Patent Patent Application No. 2008-0061148 and Korea Patent Application 2007-0111220 has been filed. Therefore, the method for preparing the piperazine compound represented by Chemical Formula 1 may refer to the specification of the present invention, and can be easily prepared by a generally known organic synthesis method.

[Synthesis Example]

Synthesis Example 1. 5- (furan-2-yl) -1-phenyl- N- (2- (4-benzylphenylpiperazin-1-yl) ethyl) pyrazole-3-carboxamide (Compound 1)

[Method 1]

2- (4-benzylpiperazin-1-yl) ethylamine (0.144 g, 0.6 mmol) was dried under reduced pressure, and 5 mL of methylene chloride was added thereto and stirred. 5- (furan-2-yl) -1-phenylpyrazole-3-carboaldehyde (0.132 g, 0.5 mmol) was added dropwise at room temperature, and dimethylaminoisopropyl chloride (DIC; 0.092 mL, 0.6 mmol) was added dropwise. It was. The reaction was carried out by stirring at room temperature for 3 hours. The progress and completion of the reaction was made by TLC (ethyl acetate: n -hexane = 3: 1 volume ratio). After confirming the completion of the reaction, water was added to the reaction solution and washed with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was dried using concentrated under reduced pressure to afford the title compound.

[Method 2]

50 mg (0.208 mmol) of 2- (4-benzyl) piperazin-1-yl) ethylamine and 25.24 mg (0.104 mmol) of 5- (furan-2-yl) -1-phenylpyrazole-3-carboaldehyde Was dissolved in 5 mL of purified CH ₂ Cl ₂ , and 4 μg molecular sieves (5 beads) were added thereto, followed by stirring at room temperature for 12 hours. 66.28 mg (0.313 mmol) of NaBH (OAc) ₃ was added thereto, followed by stirring at room temperature for 1 hour. Reaction progress and confirmation was confirmed by TLC (CH ₂ Cl ₂ : MeOH = 5: 1 volume ratio). After the reaction was completed, water was added to the reaction mixture, and the aqueous layer was extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1 volume ratio) to give the title compound.

Yield 53%

¹ H NMR δ 7.48-7.39 (m, 6H), 7.28-7.23 (m, 2H), 6.93-6.90 (d, J = 7.92 Hz, 2H), 6.84 (t, 1H), 6.33-6.31 (q, J = 1.81 Hz, 1H), 5.98-5.97 (d, J = 3.39 Hz, 1H), 3.36-3.57 (q, J = 6.13 Hz, 2H), 3.21-3.18 (m, 4H), 2.67-2.62 (m, 6H)

The following compound was synthesized using the piperazilethylamine compound and the pyrazole aldehyde compound in the same manner as in Synthesis Example 1.

Synthesis Example 2. N- (2- (4-benzylpiperazin-1-yl) ethyl) -1- tert -butyl-5- (4-chlorophenyl) pyrazole-3-carboxamide (Compound 2)

Yield 60.4%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.17 (m, 9H), 6.57 (s, 1H), 3.53-3.47 (m, 4H), 2.63-2.51 (m, 10H), 1.39 (s, 9H )

Synthesis Example 3. N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -1-phenyl-5- n -propylpyrazole-3-carboxamide (Compound 3)

Yield 25%

¹ H NMR δ 7.48-7.36 (m, 5H), 7.36 (m, 1H), 6.85-6.84 (m, 2H), 6.77-6.74 (m, 1H), 6.57 (s, 1H), 3.49-3.44 (q1 , J = 5.39 Hz, 2H), 3.10-3.07 (m, 4H), 2.67-2.62 (t, J = 7.50 Hz, 2H), 2.54-2.51 (br, 6H), 1.73-1.66 (m, 2H), 1.01-0.96 (t, J = 7.31 Hz, 3H)

Synthesis Example 4. 4- (4-Pluorobenzyl) piperazin-1-yl- (1-phenyl-5-isobutylpyrazole) -3-ketone (Compound 4)

1- (4-Pluorobenzyl) piperazine (0.115 g, 0.5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 0.115 g, 0.6 mmol) and 1-hydroxy Benzotriazole (HOBt; 0.0811 g, 0.6 mmol) was placed in a reaction vessel and made to dry conditions. CH ₂ Cl ₂ and (1-phenyl-5-isobutylpyrazole) -3-carboxylic acid (0.143 g, 0.6 mmol) purified at 0 ° C were added dropwise. The reaction was carried out by stirring at room temperature for 4 hours. Confirmation of the reaction was confirmed by TLC (ethyl acetate: n -hexane = 3: 1 volume ratio). After the completion of the reaction was confirmed, water was added to the reaction solution and washed with methylene clyde. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was dried using concentrated under reduced pressure to afford the title compound.

Yield 89%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36-7.47 (m, 5H), 7.23-7.31 (m, 5H), 6.62 (s, 1H), 4.07-4.10 (br, 2H), 3.79-3.82 (br , 2H), 3.52 (s, 2H), 2.52-2.54 (d, J = 5.61 Hz, 2H), 2.44-2.50 (m, 4H), 1.79-1.86 (m, J = 6.77 Hz, 1H), 0.85- 0.87 (d, J = 6.61 Hz, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.8, 147.2, 143.6, 139.5, 137.8, 129.1, 128.9, 128.3, 127.1, 126.2, 125.8, 108.6, 62.9, 53.5, 52.9, 47.0, 42.5, 35.0, 28.2, 22.4

Synthesis Example 5. 4- (4-Pluorophenyl) piperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (Compound 5)

Yield 46%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41-7.51 (m, 5H), 6.87-6.98 (m, 4H), 6.70 (s, 1H), 4.27 (br, 2H), 3.95 (br, 2H), 3.11-3.15 (m, 4H), 2.59-2.64 (t, J = 7.51 Hz, 2H), 1.60-1.70 (m, J = 7.78 Hz, 2H), 0.90-0.95 (t, J = 7.37 Hz, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.8, 159.0, 155.8, 147.8, 147.0, 144.7, 139.4, 129.2, 128.4, 125.5, 118.4, 118.3, 115.7, 108.2, 51.0, 50.4, 46.9, 42.5, 28.2, 21.9 , 13.8

Synthesis Example 6. 4- (4-Pluorobenzyl) piperazin-1-yl- [1-phenyl-5- (4-piperidylphenyl) pyrazole] -3-ketone (Compound 6)

Yield 53%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28-7.30 (m, 7H), 7.05-7.08 (d, J = 8.67 Hz, 2H), 6.96-7.01 (t, J = 8.64 Hz, 2H), 6.78- 6.82 (m, 3H), 4.09-4.13 (m, 2H), 3.82 (br, 2H), 3.48 (s, 2H), 3.15-3.18 (m, 4H), 2.47-2.52 (m, 4H), 1.56- 1.65 (m, 6 H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 163.6, 162.7, 160.4, 151.6, 147.4, 144.0, 140.0, 133.5, 130.6, 129.5, 128.9, 127.6, 125.3, 119.4, 115.2, 114.9, 109.2, 62.1, 53.5, 52.8 , 49.5, 47.0, 42.5, 25.6, 24.2

Synthesis Example 7 4-phenylethylpiperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (Compound 7)

Yield 72%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38-7.50 (m, 5H), 7.24-7.29 (m, 2H), 7.15-7.20 (m, 3H), 6.65 (s, 1H), 4.11-4.13 (m , 2H), 3.83-3.85 (m, 2H), 2.78-2.83 (m, 2H), 2.53-2.64 (m, 8H), 1.59-1.67 (m, J = 7.53 Hz, 2H), 0.90-0.95 (t , J = 9.32 Hz, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.8, 147.1, 144.5, 140.0, 139.5, 129.1, 128.6, 128.4, 128.3, 126.1, 125.5, 108.0, 60.3, 53.7, 52.9, 46.9, 42.4, 33.5, 28.2, 21.9 , 13.8

Synthesis Example 8. 4-phenylethylpiperazin-1-yl- [1-phenyl-5- (furan-2-yl) pyrazole] -3-ketone (compound 8)

Yield 98%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.45 (m, 6H), 7.18-7.24 (m, 5H), 7.06 (s, 1H), 6.31-6.33 (m, 1H), 6.00-6.01 (m , 1H), 4.09-4.11 (m, 2H), 3.84-3.85 (m, 2H), 2.78-2.81 (m, 2H), 2.54-2.65 (m, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.2, 147.6, 143.6, 143.0, 140.0, 139.8, 135.1, 129.1, 128.9, 128.7, 128.4, 126.1, 125.8, 111.3, 109.5, 108.6, 60.3, 53.7, 52.9, 47.0 , 42.5, 33.5

Synthesis Example 9. N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 9)

3- (4-phenylimidazol-1-yl) propanoic acid (0.0216 g, 0.1 mmol), EDC (0.0211 g, 0.11 mmol) and HOBt (0.0149 g, 0.11 mmol) were placed in a reaction vessel and made to dry conditions. . 8 mL of purified CH ₂ Cl ₂ and 2- (4- (3-chlorophenyl) piperazin-1-yl) ethylamine (0.0295 g, 0.1 mmol) were added dropwise at 0 ° C. and stirred at room temperature for 3 hours. Reaction progress and completion was confirmed by TLC (CH ₂ Cl ₂ : MeOH = 15: 1 volume ratio). After the reaction was completed, water was added to the reaction mixture, and the water layer was extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (CH ₂ Cl ₂ : MeOH = 15: 1 volume ratio) to obtain the title compound.

Yield 46.23%

¹ H NMR (300 MHz, CDCl ₃ ) δ7.75 (d, J = 7.63 Hz, 2H), 7.45 (s, 1H), 7.36 (t, J = 7.47 Hz, 2H), 7.24 (t, J = 7.23 ㎐, 2H), 7.12 (t, J = 8.15 ㎐, 1H), 6.77 (t, J = 7.86 ㎐, 2H), 6.63 (d, J = 8.27 ㎐, 1H), 6.38 (br, 1H), 4.28 ( t, J = 6.12 ㎐, 2H), 3.32 (q, J = 5.42 ㎐, 2H), 2.95-2.97 (m, 4H), 2.59 (t, J = 5.79 ㎐, 2H), 2.41 (t, J = 4.79 6, 6H)

Synthesis Example 10 N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (4-phenylimidazol-1-yl) propanamide (Compound 10)

Yield 35.29%

¹ H NMR (300 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.24 (m, 13H), 6.53 (br, 1H), 4.30 (t , J = 6.18 ㎐, 2H), 4.11 (s, 1H), 3.33 (q, J = 11.00 ㎐, 2H), 2.64 (t, J = 6.31 ㎐, 2H), 2.44 (m, 6H), 2.28 (br , 4H)

Synthesis Example 11. 1- (4- (2-Pluorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 11)

Yield 42.75%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.76 (d, J = 8.45 Hz, 2H), 7.57 (s, 1H), 7.36 (t, J = 7.32 Hz, 2H), 7.00-7.03 (m, 3H) , 6.82-6.99 (m, 1H), 4.36 (t, J = 6.45 ㎐, 2H), 3.78 (t, J = 4.92 ㎐, 2H), 3.51 (t, J = 4.86 ㎐, 2H), 3.00 (t, J = 5.14 ㎐, 2H), 2.94 (t, J = 5.09 ㎐, 2H), 2.80 (t, J = 6.44 ㎐, 2H)

Synthesis Example 12 N- (2- (4- (3,4-dichlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 12)

Yield 55.03%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.71 (d, J = 8.43 Hz, 2H), 7.45 (s, 1H), 7.30 (m, 4H), 7.20 (m, 2H), 7.06 (d, J = 8.19 ㎐, 1H), 6.37 (br, 1H), 4.28 (t, J = 6.09 ㎐, 2H), 3.31 (m, 4H), 2.59 (t, J = 6.24 ㎐, 2H), 2.39 (m, 10H)

Synthesis Example 13. N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 13)

Yield 46.76%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J = 1.30 Hz, 2H), 7.47 (s, 1H), 7.34 (t, J = 7.35 Hz, 2H), 7.27 (d, J = 1.75 Hz , 1H), 7.21 (m, 4H), 7.13 (m, 1H), 6.33 (br, 1H), 4.29 (t, J = 6.12 ㎐, 2H), 3.36 (s, 1H), 3.28 (q, J = 5.61 ㎐, 2H), 2.60 (t, J = 6.30 ㎐, 2H), 2.41 (m, 10H)

Synthesis Example 14. 1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 14)

Yield 40.50%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.37 Hz, 2H), 7.56 (s, 1H), 7.35 (t, J = 7.40 Hz, 2H), 7.15-7.26 (m, 3H) , 6.81-6.86 (m, 2H), 6.70 (d, J = 7.20 ㎐, 1H), 4.36 (t, J = 6.45 ㎐, 2H), 3.75 (t, J = 4.93 ㎐, 2H), 3.47 (t, J = 4.83 ㎐, 2H), 3.12 (t, J = 5.24 ㎐, 2H), 3.05 (t, J = 5.18 ㎐, 2H), 2.23 (t, J = 6.12 ㎐, 2H)

Synthesis Example 15 1- (4-phenylpiperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 15)

Yield 50.01%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75-7.78 (m, 1H), 7.59 (s, 1H), 7.34-7.39 (m, 2H), 7.21-7.30 (m, 5H), 6.88-6.94 (m , 3H), 4.40 (t, J = 6.55 kPa, 2H), 3.80 (t, J = 5.07 kPa, 2H), 3.54 (t, J = 4.99 kPa, 2H), 3.09-3.17 (m, 4H), 2.85 (t, J = 6.50 Hz, 2H)

Synthesis Example 16 1- (4- (4-chlorobenzyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 16)

3- (4-phenylimidazol-1-yl) propanoic acid (0.0216 g, 0.1 mmol), EDC (0.0211 g, 0.11 mmol) and HOBT (0.0149 g, 0.11 mmol) were placed in a reaction vessel and made to dry conditions. . 8 mL of purified CH ₂ Cl ₂ and 1- (4-chlorobenzyl) piperazine (0.12 mmol) at 0 ° C. were added dropwise, followed by stirring at room temperature for 3 hours. Reaction progress and completion was confirmed by TLC (CH ₂ Cl ₂ : MeOH = 20: 1 volume ratio). After the reaction was completed, water was added to the reaction mixture, and the water layer was extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1 volume ratio) to obtain the title compound.

Yield 67.5%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.12, 2H), 7.53 (s, 1H), 7.39 (t, J = 5.59, 2H), 7.19 (m, 6H), 4.32 (t , J = 6.25, 2H), 3.61 (s, 2H), 3.32 (s, 2H), 2.71 (t, J = 6.28, 2H), 2.30 (s, 2H), 2.18 (s, 2H)

¹³ C NMR (300 MHz, CDCl ₃ ) δ 167.8, 141.4, 140.6, 137.6, 129.1, 128.8, 128.7, 128.6, 127.7, 127.4, 124.7, 115.2, 51.7, 45.6, 43.1, 42.0, 34.5

Synthesis Example 17 N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (2-phenylimidazol-1-yl) propanamide (Compound 17)

Yield 47.23%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (m, 2H), 7.39 (m, 3H), 7.29 (s, 1H), 7.20 (m, 3H), 7.00 (d, J = 7.07 μs, 2H) , 6.56 (br, 1H), 4.30 (t, J = 6.77 kPa, 2H), 3.37 (s, 2H), 3.24 (q, J = 10.97 kPa, 2H), 2.39 (m, 12H)

Synthesis Example 18 N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (2-phenylimidazol-1-yl) propanamide (Compound 18)

Yield 38.44%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57 (m, 2H), 7.42 (m, 3H), 7.33 (m, 9H), 7.07 (s, 1H), 7.04 (s, 1H), 6.22 (br, 1H), 4.36 (t, J = 6.78 μs, 2H), 4.22 (s, 1H), 3.28 (q, J = 11.18 μs, 2H), 2.48 (m, 12H)

Synthesis Example 19. N- (2- (4- (4-pool Luo phenyl) piperazin-1-yl) ethyl) -3- (4-phenyl-imidazole-1-yl) propanamide (Compound 19)

Yield 59.31%

¹ H NMR (300 MHz, CDCl ₃ ) δ7.76 (d, J = 7.11 Hz, 2H), 7.48 (s, 1H), 7.35 (t, J = 7.31 Hz, 2H), 7.22-7.24 (m, 1H ), 6.88-6.95 (m, 3H), 6.69-6.73 (m, 2H), 6.43 (br, 1H), 4.29 (t, J = 6.05 μs, 2H), 3.33 (q, J = 5.75 μs, 2H) , 2.93 (t, J = 4.75 ㎐, 4H), 2.61 (t, J = 5.99 ㎐, 2H), 2.43-2.49 (m, 6H)

Synthesis Example 20 1- (4- (4-methoxyphenyl) piperazin-1-yl) -3- (2-phenylimidazol-1-yl) propanone (Compound 20)

Yield 90.52%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.71-7.74 (m, 2H), 7.49 (s, 2H), 7.38-7.41 (m, 2H), 6.83 (s, 4H), 4.40 (t, J = 6.74 , 2H), 3.76 (s, 3H), 3.70 (t, J = 4.98, 2H), 3.45 (t, J = 4.78, 2H), 2.97 (t, J = 5.20 ㎐, 2H), 2.92 (t, J = 5.12 ㎐, 2H), 2.79 (t, J = 6.73 ㎐, 2H)

Synthesis Example 21

N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -3- (2-methylimidazol-1-yl) propanamide (Compound 21)

Yield 68.85%

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.96 (br, 1H), 6.75-6.85 (m, 6H), 4.11 (t, J = 6.69 μs, 2H), 3.70 (s, 3H), 3.29 (t, J = 5.71 ㎐, 2H), 3.00 (t, J = 4.17 ㎐, 4H), 2.48-2.54 (m, 6H), 2.42 (t, J = 6.03 ㎐, 2H), 2.28 (s, 3H)

Synthesis Example 22 N- (2- (4- (3-methylbenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 22)

Yield 32.00%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75 (d, J = 7.30 Hz, 2H), 7.51 (s, 1H), 7.34 (t, J = 7.42 Hz, 2H), 7.28 (s, 1H), 7.19 (t, J = 2.36 μs, 2H), 7.17 (m, 3H), 6.83 (br, 1H), 4.30 (t, J = 6.15 μs, 2H), 3.38 (s, 2H), 3.33 (t, J = 5.58 ㎐, 2H), 2.66 (t, J = 6.28 ㎐, 2H), 2.47 (m, 6H), 2.40 (br, 4H), 2.34 (s, 3H)

Synthesis Example 23 N- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethyl) -3- (2-phenylimidazol-1-yl) propanamide (Compound 23)

Yield 60.83%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (d, J = 6.31 Hz, 2H), 7.42-7.48 (m, 3H), 7.06-7.11 (m, 3H), 6.91 (d, J = 7.70 Hz, 2H), 6.29 (br, 1H), 4.39 (t, J = 6.79 kPa, 2H), 3.34 (q, J = 5.62 kPa, 2H), 2.88 (t, J = 4.29 kPa, 4H), 2.47-2.58 ( m, 8H), 2.27 (s, 3H), 2.21 (s, 3H)

Synthesis Example 24 N- (2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 24)

Yield 41.09%

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.76 (d, J = 7.13 Hz, 2H), 7.52 (s, 1H), 7.35 (t, J = 7.35 Hz, 2H), 7.26 (m, 2H), 6.96 (t, J = 6.34 ㎐, 2H), 6.79 (d, J = 7.99 ㎐, 2H), 6.46 (br, 1H), 4.33 (t, J = 6.18 ㎐, 2H), 3.36 (q, J = 12.58 ㎐ , 2H), 2.77 (t, J = 4.55 μs, 4H), 2.65 (t, J = 6.35 μs, 2H), 2.48 (m, 6H), 2.27 (s, 3H), 2.21 (s, 3H)

[Example]

Example 1 Assay Method for 5 - HT ₆ Receptor

In this embodiment, in order to confirm the antagonistic activity of the 5-HT ₃ A receptor on the piperazine compound represented by Formula 1, 5-HT ₆ receptor ligand high efficiency screening method using fluorescence imaging (Korea Patent Registration 10-0852284 Arc).

The FDSS6000 HTS instrument from Hamamatsu Photonics was used for fluorescence imaging HST measurements. The device is a new cell-based HTS device with a fluorescence and luminescence dual detector, a digital CCD camera, a filter wheel and a drug application system that can inject three or more drugs in real time. to be

In the present embodiment, only the results of confirming the activity of some compounds of the piperazine compound represented by the formula (1) is illustrated, but the other compounds represented by the formula (1) also showed the antagonistic activity of the same or similar 5-HT ₆ receptor Judging.

1) Cell line (HELA) culture stably expressing 5-HT ₆ receptor

The cell line used in this experiment is a HELA cell line (Korean Patent Application No. 2009-0015404) stably expressing 5-HT ₆ receptor. Cell culture medium was prepared by adding 10% fetal bovine serum, 1% penicillin / streptomycin (v / v) to Dulbecco's modified Eagle's medium (DMEM), and 80 μg / Select cultures were added by adding mL of hygromycine. Cells were incubated at a temperature of 36.5 ° C. in a humidified incubator with 95% air / 5% CO ₂ . The culture solution was replaced every 3 to 4 days and the cells were used every week.

2) Transfection Method

100 mm was inoculated with 5 × 10 ⁶ cells the day before, and the next day, transfected with chimeric G-protein at a ratio of 1: 3 using lipofectamine 2000 (Invitrogen) according to the procedure given. Also Separately, the combination of 5-HT ₆ receptor protein is a 5-HT ₆ experiments how illustration the transfection used to for see their effect on the activity of the receptor is inoculated into the day before 5 × 10 ⁶ cells in 100 mm The next day, using Lipofectamine 2000, the 5-HT ₆ receptor, chimeric G-protein, and binding protein were transfected at a 1: 1: 3 ratio.

3) 96-well plate cell culture conditions and assay method for FDSS6000

① Cell culture conditions fluorescence calcium measurement on 96-well plate

Fluorescence imaging using the FDSS6000 HTS instrument uses a 96-well plate (Nunc cat # 165305), which allows light to penetrate from the bottom of the plate to allow fluorescence measurements, so that cells are tested under both conditions of suspension or attachment. can do. In this experiment, the experiment was carried out in an attached state.

In attachment conditions, transfected cells were dispensed the day before in 96-well plates treated with poly-L-lysine (0.05 mg / mL) 18-24 hours prior to activity detection. Cells per well were dispensed at a density of 5 × 10 ³ cells / well. Serum starvation was performed to increase the reproducibility of the HTS signal by inhibiting receptor internalization. In the present invention, 1% fetal bovine serum, 1% penicillin / 1% streptomycin (v / v) is used in the eagle medium (Dulbecco's modified Eagle's medium, DMEM), and the cells are 95% air / 5%. The incubator was incubated at a temperature of 36.5 ° C. in a humid condition of CO ₂ . On the day of the experiment, cells attached to 96-well plates were prepared using HEPES buffer (150 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 2 mM CaCl ₂ , 10 mM HEPES) using a 96-well plate self-cleaning device (Bio Tek). , 10 mM glucose, pH 7.4), washed three times, and labeled with fluorescent dye at room temperature of HEPES buffer solution containing 4 μM Fluo-4 / AM and 0.001% Pluronic F-127 at room temperature and then 95% After reacting for 1 hour in an incubator in a humid condition of air / 5% CO ₂ / temperature 36.5 ℃, washed twice with HEPES buffer again, the final volume was adjusted to 81 μL and measured by FDSS6000 instrument measurement. This represents the most reproducible and high measurement value, and the following experiments were performed under the above search conditions.

② FDSS6000 Fluorescence Calcium Assay and Drug Plate Preparation

Calcium Imaging Technology Calcium Fluorine-4 / AM in the form of a concentration sensitive acetoxymethyl-ester was used as fluorescent calcium label. Specifically, the excitation wavelength 480 nm was selectively exposed to the cells by a computer-controlled filter wheel in the light of four xenon lamps mounted on the FDSS 6000. Data were obtained every 1.23 seconds, and the emitter fluorescence light entering through a 515 nm long-pass filter was passed through a cooling CCD camera built into the instrument and then 96-well by a digital fluorescence analyzer. An average 480 nm value was obtained for each well in the phase. All image data and analysis was done using the FDSS6000 dedicated program provided by Hamamatsu Photonics.

As a method for blocking experiments, two 96-well drug plates containing 5-HT and a blocker drug to activate 5-HT ₆ receptors were prepared separately from the 96-well plates prepared with cells. Most cell-based HTS instruments have a liquid application system for drug injection but no liquid inhalation system, so the blocking drug and 5-HT to be searched are prepared in 27 μL of HEPES buffer solution at 5-fold higher concentrations. It was measured by diluting 1/5 in 135 μL (81 μL of adherent culture cells + 150 nM 5-HT + 5X drug).

4) Recording of selective regulatory substance activity of 5-HT ₆ receptor using FDSS6000 fluorescence calcium imaging technique

Selective regulation of 5-HT ₆ receptors on 96-well in vitro cell-based HTS screening, measured at 200 seconds, after 5 minutes of block pretreatment outside the FDSS6000 instrument for 5 minutes SB258585, known as a -HT ₆ receptor selective inhibitor, was used to determine the percentage inhibitory effect on the 5-HT ₆ receptor using the fluorescent label dye fluor-4 at each concentration range. That is, the inhibitory ratio (R ₁ / R ₀ ) of the 480 nm ratio value in the control group (SB258585) or the control group not treated with test substance was determined to be 100%, and the HELA cells were obtained after the inhibitory effect of the control agent or the test substance was obtained. Concentration-dependent graphs for and IC ₅₀ values were obtained from them.

Repeatedly performing the same method to calculate the maximum inhibitory concentration and 50% effective inhibitory concentration (IC ₅₀ ) at 30 μM concentration for the serotonin 5-HT ₆ receptor of the piperazine compound is shown in Table 1 below. In particular, IC ₅₀ was calculated for compounds with an inhibitory concentration of at least 50% at 30 μM or at least 30% of inhibitory concentration at 10 μM.

At this time, the concentration for each compound was used 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 100 μM or 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 μM depending on the efficacy of the compound. . Concentration-response curves were prepared for this to obtain IC ₅₀ for each compound.

As described in Table 1 above, be piperazine compounds according to the invention are processed to HELA cells to 5-HT ₆ receptors are stably expressed (expressing), the check gateum the inhibitory activity of the serotonin 5-HT ₆ receptor Could.

That is, it was confirmed that the piperazine compound according to the present invention has excellent activity in central nervous system diseases related to serotonin 5-HT ₆ receptor, as confirmed by inhibition rate and IC ₅₀ . It has almost similar activity compared to SB258585, which is currently being developed by Glaxo Smith Kline, which is well known in the art, and the compounds of the present invention are useful for treating neurological diseases related to 5-HT ₆ receptor.

Example 2 Toxicity Test

In this example, in order to determine the toxicity of the piperazine compound represented by Formula 1, 1 to 20 mg of the active substance was administered to 24 mice intraperitoneally to confirm survival after 24 hours of behavior observation.

As a result, the piperazine compounds of the present invention had no concern for toxicity. It was found that 3 out of 6 mice administered 20 mg survived and the remaining 3 were sacrificed. On the other hand, all mice that received the dose of less than 20 mg survived, and showed no statistically significant difference compared to the mice that did not receive the drug in behavioral observation. Considering the above results, the toxic dose (TD ₅₀ ) at which approximately half of the piperazine compounds will survive in the mouse is judged to be 20 mg (1 mg / g).

Example 3: Preparation of Tablets

In this embodiment, using the piperazine compound represented by the formula (1) as an active ingredient tablets for oral administration with the following composition was prepared using a wet granulation method and a dry granulation method.

[Furtherance]

200 mg of active ingredient, 10 mg of hard silicic anhydride, 2 mg of magnesium stearate, 50 mg of microcrystalline cellulose, 25 mg of sodium starch glycolate, 113 mg of corn starch, proper amount of ethanol anhydride.

Example 4 Preparation of Injection

In this embodiment, an injection was prepared using the piperazine compound represented by Chemical Formula 1 as an active ingredient with the following composition.

[Furtherance]

Active ingredient 100 mg, mannitol 180 mg, sodium dihydrogen phosphate 25 mg, water for injection 2974 mg

Example 5: Beverage Preparation

In this embodiment, a beverage was prepared using the piperazine compound represented by Chemical Formula 1 as an active ingredient with the following composition. That is, after dissolving 500 mg of piperazine compound in an appropriate amount of water, vitamin C as an auxiliary component, citric acid, sodium citrate, and oligosaccharides as an auxiliary component are added, and an appropriate amount of sodium benzoate is added as a preservative, and then the total amount of water is added. 100 ml was prepared to prepare a beverage composition. At this time, taurine, myo-inositol, folic acid, pantothenic acid, etc. may be added alone or together.

Used for the treatment of central nervous system disorders, piperazine compounds of the formula (1), so can act as antagonists to the 5-HT ₆ receptor with excellent inhibitory activity and binding activity of the 5-HT ₆ As described above It is possible.

Therefore, the composition containing the piperazine compound represented by the formula (1) as an active ingredient characterized in that the present invention is characterized by cognitive function and memory damage, metabolism caused by Alzheimer disease due to antagonist action on 5-HT ₆ receptor Central nervous system (CNS) selected from abnormalities and obesity, schizopherenia, depression, treatment of neuropsychological disorders, affective disorders, and memory damage caused by stress nervous system) It is useful as a composition for the manufacture and preparation of medicines and health foods for the treatment and prevention of diseases.

Claims (4)

It contains a piperazine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, cognitive function and memory damage caused by Alzheimer's disease, metabolic abnormality and obesity, schizopherenia Pharmaceutical composition for the prevention and treatment of central nervous system (CNS) disease selected from the group of), affective disorder, and stress-induced memory damage: [Formula 1]

In Chemical Formula 1,

Represents a pentagonal heterocycle group containing two nitrogen atoms, X is a carbonyl group (C═O); Or an amide group (NHC = O), R ₁ is a benzhydryl group unsubstituted or substituted with 1 to 3 substituents selected from halo; A phenyl C ₁ -C ₆ alkyl group unsubstituted or substituted with one to three substituents selected from halo; Or a phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo, R ₂ and R ₃ are the same as or different from each other and are a hydrogen atom; C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo and piperidyl; Or furanyl group, m and n are integers of 0, 1, 2, 3, or 4, respectively. The method according to claim 1, remind

Is a pyrazole group; Or imidazole group, X is a carbonyl group (C═O); Or an amide group (NHC = O), R ₁ is a (3-chlorophenyl) (phenyl) methyl group; (4-chlorophenyl) (phenyl) methyl group; Benzyl groups; 3-chlorobenzyl group; 3-methylbenzyl group; 4-chlorobenzyl group; 4-Pluorobenzyl group; 3,4-dichlorobenzyl group; Phenylethyl group; Phenyl group; 2-Pluorophenyl group; 3-chlorophenyl group; 4-Pluorophenyl group; 2,3-dimethylphenyl group; 2,4-dimethylphenyl group; Or 4-methoxyphenyl group, R ₂ and R ₃ are the same as or different from each other a hydrogen atom; Methyl group; Ethyl group; Profile group; Isopropyl group; Butyl group; Isobutyl group; A phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halogen and piperidyl; Or furanyl group, Wherein m and n each represent an integer of 0, 1, 2, or 3. The method according to claim 1, 5- (furan-2-yl) -1-phenyl- N- (2- (4-benzylpiperazin-1-yl) ethyl) pyrazole-3-carboxamide (Compound 1), N- (2- (4-benzylpiperazin-1-yl) ethyl) -1- tert -butyl-5- (4-chlorophenyl) pyrazole-3-carboxamide (Compound 2), N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -1-phenyl-5- n -propylpyrazole-3-carboxamide (Compound 3), 4- (4-fluorobenzyl) piperazin-1-yl- (1-phenyl-5-isobutylpyrazole) -3-ketone (compound 4), 4- (4-Pluorophenyl) piperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (Compound 5), 4- (4-Pluorobenzyl) piperazin-1-yl- [1-phenyl-5- (4-piperidylphenyl) pyrazole] -3-ketone (Compound 6), 4-phenylethylpiperazin-1-yl- [1-phenyl-5- ( n -propyl) pyrazole] -3-ketone (compound 7), 4-phenylethylpiperazin-1-yl- [1-phenyl-5- (furan-2-yl) pyrazole] -3-ketone (compound 8), N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 9), N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (4-phenylimidazol-1-yl) propanamide (Compound 10) , 1- (4- (2-fluorofluorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 11), N- (2- (4- (3,4-dichlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 12), N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 13), 1- (4- (3-chlorophenyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 14), 1- (4-phenylpiperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 15), 1- (4- (4-chlorobenzyl) piperazin-1-yl) -3- (4-phenylimidazol-1-yl) propanone (Compound 16), N- (2- (4- (3-chlorobenzyl) piperazin-1-yl) ethyl) -3- (2-phenylimidazol-1-yl) propanamide (Compound 17), N- {2- [4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl] ethyl} -3- (2-phenylimidazol-1-yl) propanamide (Compound 18) , And N- (2- (4- (4-fluorofluorophenyl) piperazin-1-yl) ethyl) -3- (4-phenylimidazol-1-yl) propanamide (Compound 19) A pharmaceutical composition comprising a piperazine compound represented by the formula (1) selected from the group consisting of or a pharmaceutically acceptable salt thereof as an active ingredient. It contains a piperazine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, cognitive function and memory damage caused by Alzheimer's disease, metabolic abnormality and obesity, schizopherenia Health food composition for improvement of central nervous system (CNS) disease selected from the group consisting of), affective disorder, and stress-induced memory impairment: [Formula 1]

In Chemical Formula 1,

Represents a pentagonal heterocycle group containing two nitrogen atoms, X is a carbonyl group (C═O); Or an amide group (NHC = O), R ₁ is a benzhydryl group unsubstituted or substituted with 1 to 3 substituents selected from halo; A phenyl C ₁ -C ₆ alkyl group unsubstituted or substituted with one to three substituents selected from halo; Or a phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo, R ₂ and R ₃ are the same as or different from each other and are a hydrogen atom; C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with 1 to 3 substituents selected from halo and piperidyl; Or furanyl group, m and n are integers of 0, 1, 2, 3, or 4, respectively.