KR101073703B1 - Piperazine derivatives, pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of central nervous system diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a piperazine derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating central nervous system diseases containing the same as an active ingredient, according to the present invention. Piperazine derivatives not only have high affinity for the 5-HT2C receptor, but also the 5-HT2C receptor and 5-HT6. Since it acts as an antagonist to the receptor, it can be usefully used as a preventive or therapeutic agent for central nervous system diseases such as dementia, schizophrenia caused by dementia, depression and anxiety.

[Formula 1]

Piperazine derivatives, serotonin antagonists, central nervous system diseases

Description

Piperazine derivatives, pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions for the prevention or treatment of central nervous system diseases containing the same as active ingredients or treatment of central nervous system diseases containing the same as an active ingredient}

The present invention relates to a piperazine derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating central nervous system diseases containing the same as an active ingredient.

Central nervous system disease may be caused by a kind of neurological disease drug; May be due to genetic predisposition, infection or trauma; Or it may be due to unknown etiology. Central nervous system diseases include neuropsychiatric diseases, neurological diseases and psychosis; Neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive emotional disorders. Relatively common central nervous system disorders include: elderly dementia (Alzheimer's disease in young), senile dementia (Alzheimer's dementia), Parkinson's disease, including Parkinson's disease, Huntington's chorea, late dyskinesia, hyperactivity , Mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette syndrome.

Schizophrenia is a particularly destructive neuropsychiatric disorder that affects approximately 1% of humanity, characterized by loss of contact with reality, hallucinations, delusions, abnormal thinking, monotonous feelings, reduced motivation and work and social dysfunction. Mental disorder. The overall financial costs of diagnosing and treating schizophrenia and the loss of social productivity of individuals with the disease are estimated to exceed 2% of the gross national product (GNP). Treatment for schizophrenia includes pharmacotherapy, which uses a group of drugs known as antipsychotics. Antipsychotic agents are effective in improving positive symptom (eg hallucinations and paranoia) but lack negative symptom (eg social and emotional collapse, indifference and speech). It is not very effective in improving).

Currently, nine major groups of antipsychotic agents are prescribed to treat psychotic symptoms. However, the use of such compounds is limited due to their side effect profile. Almost all conventional or previous generations of compounds have a significant negative effect on human motor function. Negative effects on the human regulatory motor system have led to these effects being called progressive extraramidal side effects, which are acute (e.g., muscle tone, rarely, but potentially life-threatening). Neuroleptic malignant syndrome) and chronic (eg, akathisia, tremor and tardive dyskinesia). Thus, efforts to develop drugs have been focused on newer atypical formulations that do not have this negative effect.

Atypical antipsychotics offer several clinical advantages over conventional antipsychotics, which have been the center of treatment for the last decade. The underlying mechanism underlying many of the clinical benefits of atypical drugs is their ability to separate antipsychotic effects and extrapyramidal side effects (EPS). Obvious advantages over conventional antipsychotic agents include greater improvement in negative and cognitive symptoms, better antidepressant and mood stabilizing effects, lower risk of Parkinson side effects and delayed dyskinesia and more in refractory or treatment-resistant patients. A great effect is included.

Antipsychotic drugs include many dopaminergic receptors, serotonergic receptors, adrenergic receptors, muscarinic receptors, and histaminergic receptors. It has been shown to interact with central monoamine neurotransmitter receptors. Most antipsychotic drugs work by blocking dopamine receptors, particularly the D2 and D1 receptors. A representative antipsychotic drug to date is Chlorpromazine, first developed in 1952. It was originally developed for use as an antihistamine, but a number of dopamine antagonists were developed during animal experiments, when clopromazine was found to have an inhibitory effect on drugs such as amphetamine. Most antipsychotics are known to affect cAMP production by central synapse and adrenal cyclase. However, the dopamine blocking ability of these drugs causes side effects such as decreased libido, orthostatic hypotension, endocrine system disorders, and weight gain, including extraramidal side effects such as Parkinson's disease. Has been constrained. Moreover, these drugs could improve positive symptoms such as delusions and hallucinations of schizophrenia, but they did not recover any negative symptoms such as apathy or atrophy and impaired cognition. In addition, since the currently used clinical treatment for depression and sleep disorders is incomplete in terms of efficacy and side effects, it is urgent to develop a new class of drugs that can supplement the problems of conventional treatments.

Depression is one of the most important health care problems, especially in developed countries. Often in life, about 5-10% of the population suffers from major depression and more than 25% of the population suffers from depression. The World Health Organization estimates that depression will cause more global disasters than any other disease. The main symptom of depression is the depression of mood and emotion, but it is caused by a decrease in thinking ability, pessimistic and autonomous thinking disorder, mental activity such as a decrease in daily activity, a decrease in motivation, anxiety and nervousness, and even an abnormal autonomic nervous system. Physical symptoms are also shown and are associated with other diseases, especially cardiovascular disease.

Depression has typically been treated recently with a combination of antidepressants selected from one of three major compound groups. These are tricyclic and tetracyclic antidepressants and related compounds (tricyclics), monoamine oxidase inhibitors (MAOIs) and selective or partially selective serotonin uptake inhibitors (SRIs). Tricyclics have many complex mechanisms and are associated with many side effects, including cardiovascular side effects and toxicity that can be used for suicide attempts. Monoamine oxidase inhibitors (MAOIs) inhibit one of the main enzymes involved in the degradation of catecholamines and can also have many side effects. Both tricyclic and monoamine oxidase inhibitors should be used very carefully in patients with cardiovascular disease. Selective or partially selective serotonin uptake inhibitors act relatively more selectively to inhibit reingestion of serotonin by nerve endings and usually have fewer side effects than other populations. However, almost the same number of patients with the old tricyclic drug as to the new SRI antidepressant are dropped from clinical studies due to side effects (KR Abrams, British Medical Journal, 1998; 316: 1183-1184).

Anxiety is a widespread very unpleasant and vaguely disturbing feeling, accompanied by associated physical symptoms (throbbing, sweating, etc.) and behavioral symptoms (such as irritability, pacing, etc.) (Robert F. Scmidt., Human Physiology, 366). Min Sung-gil, Modern Psychiatry, 238-240; Argyropoulos SV, et al., Pharmacol. Ther. 2000; 88: 213-227. Increasingly, patients are receiving specialized psychiatric counseling at hospitals for depression or anxiety, and anti-anxiety sales increased by 200% in 2002.

Anxiety is a defense system to protect the human body. Exciting the autonomic nervous system, fatigue when too much anxiety, and excessive activating sympathetic nerve due to stress and overwork, always anxious to life and develops anxiety disorder. If anxiety persists or worsens, it develops into anxiety disorders. Anxiety disorders include panic disorder, obsessive compulsive disorder, stress disorder, social phobia, and panic anxiety disorder.

Representative anti-anxiety agents currently available are benzodiazepine, diazepam, oxazepam, prazepam, lorazepam, alprazolam, helazepam, clonazepam (clonazepam), these drugs are also used primarily for the purpose of sedation and sleep (Yoon Do Joon, side effects of psychiatric drugs, Journal of the Korean Medical Association, 1995: 38 (10): 1196-1202). Benzodiazepines are the most commonly used anti-anxiety agents, and their mechanism of action has been shown to increase the affinity of GABA receptors, which are representative inhibitory neurotransmitters in the central nervous system, thus opening adjacent Cl ⁻ channels more often to increase Cl ⁻ ion permeability. . This benzodiazepine is effective immediately, but it is a habit and addictive disadvantage. If the medicine is not used according to the medical treatment, symptoms recur or withdrawal symptoms. Other side effects include drowsiness, ataxia, orthostatic hypotension, respiratory depression, headache, chronic Sleep disorders, liver disease, and others have been reported (Mary J. Mycek, et al., Pharmacology 2nd edition, Lipincott Williams & Wilkins, 2000; 89-93). The development of drugs is required.

Serotonin or 5-hydroxytryptamine (5-HT) plays an important role in the functioning of the mammalian body. Within the central nervous system, 5-HT is an important neurotransmitter and neuromodulator involved in a variety of behaviors and reactions such as sleep, eating, exercise, pain perception, learning and memory, sexual behavior, temperature and blood pressure control, etc. (neuromodulator). In the spinal column, serotonin plays an important role in the regulatory system of afferent peripheral nociceptors (Moulignier, Rev. Neurol. 1994; 150: 3-15), cardiovascular system, blood system Peripheral functions in the hematological system and gastrointestinal system (GI) are also due to 5-HT. 5-HT is known to mediate various contractile, secretory and electrophysiologic effects, including smooth muscle contractility and platelet aggregation of blood vessels and non-vascular vessels (Fuller, Biology of Serotonergic Transmission, 1982; Boullin, Serotonin In Mental Abnormalities 1978; 1: 316; Barchas, et al., Serotonin and Behavior, 1973).

From the widespread distribution of serotonin in the body, interest in drugs affecting the serotonin system has grown (Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 1989; 246; Saxena, et. al., J. Cardiovascular Pharmacol. 1990; 15: Supp. 7). Serotonin receptors are members of a huge family of human genes of membrane-spanning proteins that function as transducers of intercellular interactions. Serotonin is present on the surface of various cell types, including neurons and platelets, which, when activated by their endogenous ligand serotonin or drugs administered from the outside, alter the conformational structure And then interact with a downstream mediator of cellular signaling.

At least 15 genetically different 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7). Each subtype exhibits a unique distribution, preference for various ligands, and functional correlation (s).

Recent studies report that 5-HT2 receptor subtypes are associated with hypertension, thrombosis, migraine, vaspaspasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders, and It has been strongly suggested to be associated with the etiology of medical conditions such as appetite disorders.

5-HT2C, one of the serotonin receptor subtypes, is transcribed and expressed in hypothalamic structures associated with appetite regulation. 5-HT2C with affinity for 5-HT2C receptor Agonist m-chlorophenylpiperazine (mCPP) is normal 5-HT2C 5-HT2C while reducing food intake in mice expressing receptors Mice expressing mutated inactivated forms of the receptor have been demonstrated to be inactive (Nature, 1995; 374: 542-546). In a recent clinical study, sustained weight loss occurred after two weeks of mCPP treatment in obese subjects (Pyschopharmacology, 1997; 133: 309-312). In addition, 5-HT2C receptors have been suggested to be involved in central nervous system (CNS) diseases such as depression and anxiety (IDrugs, 1999; 2; 109-120) and have been suggested to be involved in urinary diseases such as urinary incontinence (IDrugs, 1999; 2; 109-120). IDrugs 1998; 1: 456-470).

Looking at the prior art for the 5-HT2C receptor antagonist is as follows. U.S. Patent No. 3,253,989 discloses the use of mCPP as an appetite suppressant. EP 863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2C receptor antagonists with antidepressant activity and can be used for the treatment or prevention of serotonin-related diseases, including eating disorders and anxiety. International Publication No. 87/04928 discloses 2- (1-piperazinyl) pyrimidine as a therapeutic agent for neuropathy. EP 226842 discloses 1,4-naphthalenedione heterocyclic derivatives as anti-allergic and anti-asthmatic agents comprising 2- (3-bromophenyl) -4- (1-piperazinyl) pyrimidine It was. EP 657 426 discloses tricyclic pyrrole derivatives which have activity on the 5-HT2C receptor and can be used in particular for the treatment of eating disorders. EP-A-655 440 discloses 1-aminoentindole which has activity on the 5-HT2C receptor and can be used in particular for the treatment of eating disorders. EP-A-572 863 discloses paragininoindoles which have activity against the 5-HT2C receptor and can be used in particular for the treatment of eating disorders. International Publication No. 00/012475 discloses indole derivatives, particularly for the treatment of obesity, as 5-HT2B or 5-HT2C receptor ligands. WO 00/012510 discloses pyrroloindole, pyridoindole and azepineindole, particularly for the treatment of obesity, as 5-HT2C receptor antagonists. International Publication No. 00/012482 discloses selective direct active 5-HT2C. Indazole derivatives have been disclosed, particularly for use as anti-obesity agents, as receptor antagonists. International Publication No. 00/012502 discloses pyrroloquinoline, particularly for anti-obesity use as a 5-HT2C receptor antagonist. International Publication No. 00/035922 discloses 2,3,4,4, α-tetrahydro-1H-pyrazino [1,2-α] quinoxaline-5, which can be used to treat obesity as a 5-HT2C receptor antagonist. 6H) one was initiated. WO 00/044737 discloses aminoalkylbenzofurans that can be used to treat obesity as a 5-HT2C receptor antagonist. However, 5-HT2C, which is more selective for the 5-HT2C receptor There is still a need for the development of receptor antagonists.

One of the serotonin receptor subtypes, 5-HT6, consists of 440 amino acid polypeptides and increases the activity of the secondary signal receptor adenylase (Kohen, R. et al., J. Neurochem. 1996; 66: 47 -56). 5-HT6 m-RNA is present in the striatum, amygdala, nucleus accumbens, hippocampus, cortex and olfactory tubercle, but found in peripheral organs There is no bar.

Tricyclic structured antipsychotics and some antidepressants have a significantly higher affinity for 5-HT6 Binds to receptors. Representative examples include phenothiazine, chloropromazine, thioxanthene, chloroprothixene, diphenylbutylpiperidine pimozide, and heterocyclic antipsychotics. Loxapine and clozapine, etc. (Roth, BL et al., J. Pharmacol. Exp. Ther. 1994; 268: 1403-1410). These results show that the 5-HT6 receptor is associated with certain types of psychosis, and could in particular be a target for atypical antipsychotics. In addition, 5-HT6 Evidence that relates to receptor recognition and learning, and many evidences that show association with seizure disorders and control of food consumption, are being reported continuously. Thus, the new 5-HT6 with superior selectivity over conventional drugs Much effort is being made in the development of antagonists and 5-HT6 The potential of receptor ligands for the treatment of central nervous system diseases is enormous.

Accordingly, the present inventors are studying to develop a therapeutic agent for central nervous system diseases having excellent selectivity to 5-HT2C receptor, and novel piperazine derivative compounds are used to develop 5-HT2C. 5-HT2C as well as high affinity for the receptor Receptor and 5-HT6 Simultaneously acting as an antagonist to the receptor, the present invention was found to be useful in the treatment of diseases of the central nervous system such as dementia, schizophrenia, depression and anxiety.

It is an object of the present invention to provide a novel piperazine derivative compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the novel derivative compound.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing the novel derivative compound as an active ingredient.

In order to achieve the above object, the present invention provides a piperazine derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Chemical Formula 1, the R ¹ , R ² And R ³ is as defined herein).

The present invention also provides a method for preparing a piperazine derivative compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing the piperazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Piperazine derivatives of Formula 1 according to the present invention not only have a high affinity for the 5-HT2C receptor, but also act as an antagonist for the 5-HT2C receptor and the 5-HT6 receptor, and thus the derivatives are induced by dementia and dementia. It can be usefully used as a preventive or therapeutic agent for central nervous system diseases such as schizophrenia, depression and anxiety.

The present invention provides a piperazine derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

R ¹ is C ₁ -C ₅ straight or branched chain alkyl or benzyl substituted with any substituent selected from the group consisting of unsubstituted or C ₃ -C ₅ cycloalkyl and C ₅ -C ₆ heteroaryl,

이고,R ² is

ego,

R ³ is phenyl unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₄ straight or branched alkyl, halogen and nitro; Amino group substituted with C ₅ -C ₆ aryl or unsubstituted naphthyl.

Preferably, in the derivative compound of formula 1 according to the present invention,

R ¹ is methyl, ethyl, propyl, isopropyl, butyl, 1-ethyl-propyl, sec-butyl, pentyl, cyclopropylmethyl, cyclopentylmethyl, pyridin-3-ylmethyl or benzyl;

이고,R ² is

ego,

R ³ is phenyl, 4-methylphenyl, 4-nitrophenyl, 4-chlorophenyl, phenylamino and naphthylene-1-yl, naphthylene-2-yl.

More preferably, the piperazine derivative represented by Formula 1 according to the present invention,

(1) naphthalene-2-sulfonic acid isopropyl- [2- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(2) naphthalene-2-sulfonic acid isopropyl- [3- (4-methyl-piperazin-1-yl) phenyl] -amide;

(3) naphthalene-2-sulfonic acid isopropyl- [4- (4-methyl-piperazin-1-yl) phenyl] -amide;

(4) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide;

(5) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzamide;

(6) benzyl-isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine;

(7) naphthalene-1-carboxylic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(8) 1-isopropyl-1- [3- (4-methyl-piperazin-1-yl) -phenyl] -3-phenyl-urea;

(9) naphthalene-1-sulfonic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(10) N-isopropyl-4-methyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide;

(11) 4-chloro-N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide;

(12) naphthalene-2-carboxylic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(13) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -4-nitro-benzenesulfonamide;

(14) 4-chloro-N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzamide;

(15) naphthalene-2-sulfonic acid (1-ethyl-propyl)-[3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(16) methyl naphthalene-2-sulfonic acid- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(17) naphthalene-2-sulfonic acid- [3- (4-methyl-piperazin-1-yl) -phenyl] -propyl-amide;

(18) naphthalene-2-sulfonic acid ethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(19) naphthalene-2-sulfonic acid cyclopropylmethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(20) naphthalene-2-sulfonic acid cyclopentylmethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(21) naphthalene-2-sulfonic acid sec-butyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide;

(22) naphthalene-2-sulfonic acid benzyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide; And

(23) naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -pyridin-3-yl-methyl-amide.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution, which salt is water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using.

Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The present invention includes not only piperazine derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, and the like that can be prepared therefrom.

Furthermore, the present invention provides a method for preparing a piperazine derivative represented by Chemical Formula 1.

Preparation 1:

As shown in Scheme 1, the derivative of formula 1 according to the present invention,

Reacting a compound of Formula 2 with N-methyl piperazine of Formula 3 to produce a compound of Formula 4 (step 1);

Preparing a compound of formula 5 by reducing the compound of formula 4 obtained in step 1 (step 2);

Introducing a substituent R ¹ into an amine group of the compound of Formula 5 obtained in step 2 (step 3); And

로 표시되는 치환기를 추가적으로 도입하는 단계(단계 4)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다:Amine group of the compound of formula 6 obtained in step 3

It may be prepared by a manufacturing method comprising the step (step 4) of additionally introducing a substituent represented by:

(In Scheme 1, R ¹ , R ² and R ³ are as defined in Formula 1, Formula 1a is a derivative of Formula 1).

Hereinafter, the preparation method 1 according to the present invention will be described in more detail step by step.

First, Step 1 according to the present invention is a step of preparing a compound of Formula 4 having a piperazinyl group introduced by nucleophilic substitution reaction of the compound of Formula 2 with an excess of N-methyl piperazine.

The substitution reaction is performed using a basic solvent such as pyridine, acetonitrile, aprotic solvent such as N, N-dimethylformamide, or sodium carbonate, potassium carbonate, triethylamine as a base under neat conditions at reflux temperature. It may be carried out at 75-85 ℃.

In addition, the introduction of the pyrerazinyl group can be carried out by a Buchwald type palladium-catalyst cross-coupling reaction. As the catalyst, Pd ₂ dba ₃ , 1,1′-bis (diphenylpropino) ferrosine may be used, Na-Ot-Bu may be used as a base, and 1,4-dioxane is used as a solvent. Can be. The reaction is preferably carried out at 55-75 ° C for 1-3 hours.

Next, step 2 is a step of preparing a compound of formula 5 by reducing the compound of formula 4 obtained in step 1.

Step 2 may be performed by reacting the compound of Formula 4 having introduced the piperazinyl group obtained in step 1 with reacting tin chloride (SnCl ₂ · H ₂ O) in ethanol.

Next, step 3 is a step of preparing a compound of formula 6 by introducing a substituent R ¹ to the amine group of the compound of formula 5 obtained in step 2.

The reaction is performed using 1,2-dichloroethane as a solvent and reacting a compound containing a carbonyl group to which a substituent R ¹ may be introduced in the presence of acetic acid and sodium triacetoxyborohydride (NaBH (OAc) ₃ ). And reducing their carbonyl groups. The reaction is preferably carried out at room temperature for 7-8 hours.

로 표시되는 치환기를 추가적으로 도입하여 본 발명에 따른 화학식 1a의 화합물을 제조하는 단계이다.Next, the step 4 is an amine group of the compound of Formula 6

It is a step of preparing a compound of Formula 1a according to the present invention by additionally introducing a substituent represented by.

는 상기 화학식 6의 화합물을 산 염화물(acid chloride), 설포닐 클로라이드(sulphonyl chloride), 이소시아네티트(isocyanate), 알킬 할라이드(alkyl halide) 등과 상온에서 반응시킴으로써 도입될 수 있다. Substituents introduced

May be introduced by reacting the compound of Formula 6 with acid chloride, sulfonyl chloride, isocyanate, alkyl halide, and the like at room temperature.

인 치환기를 도입할 수 있고, 설포닐 클로라이드를 트리에틸아민 및 디클로로메탄과 함께 사용하여 반응시킴으로써 상기 화학식 1a의 R²가

인 치환기를 도입할 수 있다. 이소시아네이트를 피리딘, 디클로로메탄과 함께 사용하여 반응시킴으로써 상기 화학식 1a의 R²가

인 치환기의 도입이 가능하며, 알킬 할라이드를 수소화나트륨, t-부틸암모늄 아이오다이드 및 DMF와 함께 사용하여 반응시킴으로써 상기 화학식 1a의 R²가

인 치환기를 도입할 수 있다.For example, by reacting an acid chloride with triethylamine and dichloromethane, R ² of Formula 1a

Phosphorus substituents can be introduced, and R ² of formula 1a is obtained by reacting sulfonyl chloride with triethylamine and dichloromethane.

Phosphorus substituents can be introduced. R ² of Formula 1a is obtained by reacting an isocyanate with pyridine and dichloromethane.

It is possible to introduce a phosphorus substituent, and by reacting an alkyl halide with sodium hydride, t-butylammonium iodide and DMF, R ² of Formula 1a

Phosphorus substituents can be introduced.

Recipe 2:

The present invention also provides another method of preparing a derivative of formula (I). As shown in Scheme 2, the derivative of Formula 1 according to the present invention,

Reacting a compound of Formula 2 with N-methyl piperazine of Formula 3 to produce a compound of Formula 4 (step A);

Reducing the compound of Formula 4 obtained in step A to prepare a compound of Formula 5 (step B);

Reacting the compound of formula 5 obtained in step B with naphthalenesulfonylchloride to obtain a compound of formula 7 (step C); And

It may be prepared by a preparation method comprising the step (step D) of introducing a substituent R ¹ to the amine group of the compound of formula 7 obtained in step C:

(In Formula 1, R ¹ is as defined in Formula 1, and Formula 1b is a derivative of Formula 1).

Hereinafter, the preparation method 2 according to the present invention will be described in more detail step by step.

First, the step A and step B according to the present invention is a step of obtaining a compound of the formula (5) from the compound of the formula (2), it can be carried out in the same manner as in step 1 and step 2 of Preparation Method 1.

Next, step C is a step of obtaining a compound of formula 7 into which a naphthalenesulfonyl group is introduced by reacting the compound of formula 5 obtained in step B with naphthalenesulfonyl chloride.

As the naphthalene sulfonyl chloride, a sulfonyl chloride group may be used in which carbon 1 or carbon 2 of naphthalene is substituted. The reaction can be carried out at room temperature using pyridine, triethylamine, diisopropylethylamine and the like as a solvent.

Next, step D is introducing a substituent R ¹ to the amine group of the compound of formula 7 obtained in step C.

The reaction can be carried out at room temperature using potassium carbonate as a base in DMF or acetone solvent. A compound capable of introducing the substituent R ¹ may be used for various kinds of alkyl halide compound containing a substituent R ^1.

Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases of the central nervous system containing the derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The central nervous system diseases may include dementia, schizophrenia caused by dementia, depression and anxiety.

It can be seen that the derivative of Formula 1 according to the present invention exhibits a very good IC ₅₀ value compared to the conventional 5-HT2C receptor from the binding experiment with the 5-HT2C receptor (see Experimental Example 1 and Table 2).

In addition, the derivative of Formula 1 according to the present invention is high in similar receptors (5-HT1A, 5-HT2A, 5-HT7, D2, D3 and D4) other than the 5-HT2C receptor and the 5-HT6 receptor in the receptor selectivity experiment. Almost no binding by having an IC ₅₀ value, 5-HT2C receptor and 5-HT6 It can be seen that the selective binding only to the receptor (see Experimental Example 2 and Table 4).

Furthermore, it can be seen that the derivative of Formula 1 according to the present invention inhibits the increase of intracellular serotonin (5-HT) -induced GTP levels in vitro and can be usefully used as a 5-HT2C receptor antagonist (FIG. 1), inhibit the increase in the concentration of cAMP by intracellular serotonin (5-HT), 5-HT6 It can be seen that it can be usefully used as a receptor antagonist (see Fig. 2).

Therefore, the derivative of formula 1 according to the present invention prevents these diseases by simultaneously binding with 5-HT2C receptor and 5-HT6 receptor that causes central nervous system diseases such as dementia, schizophrenia, depression and anxiety caused by dementia. It can be useful for treatment.

When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

The pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

Herein, the piperazine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

As an active ingredient, the derivative of formula (1) may be used orally once a day or in divided portions in an amount of 0.1 to 500 mg / kg body weight, preferably 0.5 to 100 mg / kg body weight, per day for mammals including humans. Or by parenteral routes.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< Example  1> naphthalene-2- Sulfonic acid  Isopropyl- [2- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Step 1: 1- methyl -4- (2-nitro- Phenyl ) -Synthesis of Piperazine

1-iodine-2-nitrobenzene (2.00 g, 8.03 mmol) was added to room temperature N -methylpiperazine (4 mL), and the mixture was stirred at 120 ° C for 3 hours. After the reaction was completed, the product was washed, filtered and chromatographed (methanol: dichloromethane = 1:30) to give 1-methyl-4- (2-nitro-phenyl) -piperazine (1.75 g) as a yellow oil. , 7.91 mmol) was obtained.

Step 2: 2- (4- methyl Piperazin-1-yl) Phenylamine  synthesis

1-methyl-4- (2-nitro-phenyl) -piperazine (5.0 g, 23.00 mmol) and tin chloride (12.85 g) obtained in step 1 were added to ethanol (80 mL) and concentrated hydrochloric acid (20 mL) at room temperature. , 67.80 mmol) and stirred at 80 ° C for 1 hour. After neutralization with 6N aqueous sodium hydroxide solution, the organic layer was extracted with dichloromethane and dehydrated under anhydrous sodium sulfide to give a yellow solid of 2- (4-methyl-piperazin-1-yl) -phenylamine (4.50 g, 23.00 mmol).

Step 3: isopropyl- [2- (4- methyl Piperazin-1-yl) Phenyl ]- Amine  synthesis

2- (4-methyl-piperazin-1-yl) -phenylamine (1.00 g, 5.22 mmol) and acetone (0.38 mL, 5.22) obtained in the above step 2 in room temperature 1,2-dichloroethane (15 mL) mmol), sodium triacetoxyborohydride (1.40 g, 6.80 mmol) and acetic acid (0.30 mL, 5.22 mmol) were added thereto, followed by stirring at room temperature for 8 hours. The reaction was terminated with 1N sodium hydroxide, the organic layer was extracted with dichloromethane, dehydrated in anhydrous magnesium sulfide and chromatographed (methanol: dichloromethane = 1: 20) to give isopropyl- [2- (4) as a yellow liquid. -Methyl-piperazin-1-yl) -phenyl] -amine (0.60 g, 2.61 mmol) was obtained.

Step 4: Naphthalene-2- Sulfonic acid  Isopropyl- [2- (4- methyl Piperazin-1-yl) Phenyl ] -Amide synthesis

Isopropyl- [2- (4-methyl-piperazin-1-yl) -phenyl] -amine (0.10 g, 0.42 mmol) and 2-naphthalenesulfonyl chloride (0.10 g, 0.51 mmol) obtained in step 3 were prepared. To dichloromethane (10.0 mL), triethylamine (0.07 mL, 0.51 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the product was washed and filtered, and then chromatographed (methanol: dichloromethane = 1:20) to give naphthalene-2-sulfonic acid isopropyl- [2- (4-methyl-piperazine) of white oil. -1-yl) -phenyl] -amide (0.10 g, 34%) was obtained.

< Example  2> naphthalene-2- Sulfonic acid  Isopropyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Step 1: 1- methyl -4- (3-nitro- Phenyl ) -Synthesis of Piperazine

3-iodine-1-nitrobenzene (1.00 g, 4.02 mmol), Pd ₂ dba ₃ (0.37 g, 0.40 mmol), and 1,1'-bis (diphenylphosphate) in 1,4-dioxane (10 mL) at room temperature Pino) ferrocene (0.67 g, 1.21 mmol), Na-Ot-Bu (0.54 g, 5.62 mmol) and N -methylpiperazine (2.20 mL, 20.10 mmol) were added and stirred at 60 ° C. for 2 hours. After the reaction was completed, the product was washed and filtered, and then chromatographed (methanol: dichloromethane = 1:20) to give 1-methyl-4- (3-nitro-phenyl) -piperazine (0.92) as a red oil. g, 3.22 mmol) was obtained.

Step 2: 3- (4- methyl Piperazin-1-yl) Phenylamine  synthesis

In ethanol (20 mL) and concentrated hydrochloric acid (7 mL) at room temperature, 1-methyl-4- (3-nitro-phenyl) -piperazine (0.92 g, 4.16 mmol) and tin tin chloride (3.30 g) obtained in step 1 were used. , 14.60 mmol) was added and stirred at 60 ° C. for 1 hour. After neutralization with 6N aqueous sodium hydroxide solution, the organic layer was extracted with dichloromethane and dehydrated under anhydrous sodium sulfide to give brown liquid 3- (4-methyl-piperazin-1-yl) -phenylamine (0.78 g, 4.08 mmol) was obtained.

Step 3: isopropyl- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Amine  synthesis

3- (4-methyl-piperazin-1-yl) -phenylamine (0.38 g, 2.01 mmol) and acetone (0.15 mL, 2.01 mmol) obtained in the above step 2 in room temperature 1,2-dichloroethane (10 mL) ) And sodium triacetoxyborohydride (0.63 g, 2.81 mmol) were added and stirred at room temperature for 24 hours. The reaction was terminated with 1N sodium hydroxide, the organic layer was extracted with dichloromethane, dehydrated in anhydrous magnesium sulfide and chromatographed (methanol: dichloromethane = 1: 20) to give isopropyl- [3- (4) as brown oil. -Methyl-piperazin-1-yl) -phenyl] -amine (0.30 g, 1.29 mmol) was obtained.

Step 4: Naphthalene-2- Sulfonic acid  Isopropyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Amide synthesis

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (82 mg, 0.35 mmol) and 2-naphthalenesulfonyl chloride (96 mg, 0.42 mmol) obtained in step 3 were prepared. To dichloromethane (3.0 mL), triethylamine (0.07 mL, 0.44 mmol) was added, followed by stirring at room temperature for 12 hours. After the reaction was completed, the product was washed, filtered and chromatographed (methanol: dichloromethane = 1:20) to give white solid naphthalene-2-sulfonic acid isopropyl- [3- (4-methyl-piperazine). -1-yl) phenyl] -amide (43 mg, 29%) was obtained.

< Example  3> naphthalene-2- Sulfonic acid  Isopropyl- [4- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Naphthalene-2-sulfonic acid isopropyl- [4 in the same manner as in Example 1 except that 1-chloro-4-nitrobenzene was used instead of 1-iodine-2-nitrobenzene in Step 1 of Example 1 -(4-methyl-piperazin-1-yl) phenyl] -amide (0.13 g, 21%) was obtained.

< Example  4> N-isopropyl-N- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Of benzenesulfonamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (30 mg, 0.13 mmol) and benzenesulfur synthesized in the same manner as in steps 1, 2 and 3 of Example 2 Phenyl chloride (27 mg, 0.15 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.02 mL, 0.15 mmol) was added, followed by stirring at room temperature for 12 hours. After the reaction was completed, the product was washed, filtered and chromatographed (methanol: dichloromethane = 1:30) to give N-isopropyl-N- [3- (4-methyl-piperazine-1) as a yellow oil. -Yl) -phenyl] -benzenesulfonamide (42 mg, 86%) was obtained.

< Example  5> N-isopropyl-N- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Benzamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (30 mg, 0.13 mmol) and benzoyl chloride synthesized in the same manner as in steps 1, 2 and 3 of Example 2 (22 mg, 0.15 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.02 mL, 0.15 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:30) to give N-isopropyl-N- [3- (4-methyl-piperazine-) in yellow oil. 1-yl) -phenyl] -benzamide (18 mg, 41%) was obtained.

< Example  6> benzyl-isopropyl- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Amine  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (0.10 g, 0.43 mmol) synthesized in the same manner as in steps 1, 2 and 3 of Example 2 was prepared using DMF ( 2.0 mL), NaH (0.01 g, 0.51 mmol), benzyl bromide (80 mg, 0.47 mmol), and a catalytic amount of t-butylammonium iodide were added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1: 20) to give benzyl-isopropyl- [3- (4-methyl-piperazin-1-yl) as a yellow oil. ) -Phenyl] -amine (0.10 g, 72%) was obtained.

< Example  7> naphthalene-1-carboxylic acid isopropyl- [3- (4- methyl Preparation of -piperazin-1-yl) -phenyl] -amide

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (40 mg, 0.17 mmol) and 1- synthesized in the same manner as in Example 1, 2 and 3 of Example 2 Naphthoyl chloride (30 mg, 0.17 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.03 mL, 0.21 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the product was washed and filtered, followed by chromatography (methanol: dichloromethane = 1:20) to give naphthalene-1-carboxylic acid isopropyl- [3- (4-methyl-piperazine-) as a yellow oil. 1-yl) -phenyl] -amide (25 mg, 40%) was obtained.

< Example  8> 1-isopropyl-1- [3- (4- methyl Piperazin-1-yl) Phenyl ] -3- Phenyl -Manufacturing of elements

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (70 mg, 0.30 mmol) and pyridine synthesized in the same manner as in Steps 1, 2 and 3 of Example 2 0.12 mL, 1.50 mmol) was added to dichloromethane (3.0 mL), and phenyl isocyanate (0.04 mL, 0.33 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give 1-isopropyl-1- [3- (4-methyl-piperazine-1) in yellow oil. -Yl) -phenyl] -3-phenyl-urea (37 mg, 35%) was obtained.

< Example  9> naphthalene-1- Sulfonic acid  Isopropyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (36 mg, 0.15 mmol) and 1- synthesized in the same manner as in Example 1, 2 and 3 of Example 2 Naphthalenesulfonyl chloride (42 mg, 0.19 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.03 mL, 0.19 mmol) was added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed, filtered and subjected to chromatography (methanol: dichloromethane = 1: 20) to give naphthalene-1-sulfonic acid isopropyl- [3- (4-methyl-piperazine) as a brown solid. -1-yl) -phenyl] -amide (40 mg, 63%) was obtained.

< Example  10> N-isopropyl-4- methyl -N- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Of benzenesulfonamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (50 mg, 0.26 mmol) and p − synthesized in the same manner as in Steps 1, 2 and 3 of Example 2; Toluenesulfonyl chloride (42 mg, 0.19 mmol) was added to dichloromethane (2.0 mL), triethylamine (0.04 mL, 0.26 mmol) was added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give N-isopropyl-4-methyl-N- [3- (4-methyl-) as a yellow oil. Piperazin-1-yl) -phenyl] -benzenesulfonamide (60 mg, 60%) was obtained.

< Example  11> 4- Chloro -N-isopropyl-N- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Of benzenesulfonamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (50 mg, 0.26 mmol) and 4- synthesized in the same manner as in Steps 1, 2 and 3 of Example 2; Chlorobenzenesulfonyl chloride (40 mg, 0.21 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.03 mL, 0.21 mmol) was added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1: 20) to give 4-chloro-N-isopropyl-N- [3- (4-methyl-) as a yellow oil. Piperazin-1-yl) -phenyl] -benzenesulfonamide (60 mg, 70%) was obtained.

< Example  12> naphthalene-2-carboxylic acid isopropyl- [3- (4- methyl Preparation of -piperazin-1-yl) -phenyl] -amide

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (50 mg, 0.28 mmol) synthesized in the same manner as in steps 1, 2 and 3 of Example 2 was prepared using DMF ( 2.0 mL), NaH (7 mg, 0.28 mmol) and 2-naphthoyl chloride (50 mg, 0.26 mmol) were added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give naphthalene-2-carboxylic acid isopropyl- [3- (4-methyl-piperazine-) as a yellow oil. 1-yl) -phenyl] -amide (5 mg, 5%) was obtained.

< Example  13> N-isopropyl-N- [3- (4- methyl Piperazin-1-yl) Phenyl ] -4-nitro- Of benzenesulfonamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (50 mg, 0.26 mmol) and 4- synthesized in the same manner as in Steps 1, 2 and 3 of Example 2; Nitrobenzenesulfonyl chloride (60 mg, 0.26 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.03 mL, 0.26 mmol) was added, followed by stirring at room temperature for 8 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give N-isopropyl-N- [3- (4-methyl-piperazine-1) as a yellow solid. -Yl) -phenyl] -4-nitro-benzenesulfonamide (60 mg, 70%) was obtained.

< Example  14> 4- Chloro -N-isopropyl-N- [3- (4- methyl Piperazin-1-yl) Phenyl ]- Benzamide  Produce

Isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (50 mg, 0.26 mmol) and 4- synthesized in the same manner as in Steps 1, 2 and 3 of Example 2; Chlorobenzoyl chloride (45 mg, 0.26 mmol) was added to dichloromethane (1.0 mL), triethylamine (0.04 mL, 0.29 mmol) was added, followed by stirring at room temperature for 5 hours. After the reaction was completed, the product was washed and filtered, followed by chromatography (methanol: dichloromethane = 1:20) to give 4-chloro-N-isopropyl-N- [3- (4-methyl-) as a white oil. Piperazin-1-yl) -phenyl] -benzamide (20 mg, 21%) was obtained.

< Example  15> naphthalene-2- Sulfonic acid (1-ethyl-propyl)-[3- (4- methyl Preparation of -piperazin-1-yl) -phenyl] -amide

Step 3: (1-ethyl-propyl)-[3- (4- methyl Piperazin-1-yl) Phenyl ]- Amine  synthesis

3- (4-methyl-piperazin-1-yl) -phenylamine (0.40 g, 2.09 mmol) synthesized in the same manner as in Step 1 and 2 of Example 2 to 1,2-dichloroethane (10 mL) at room temperature ), 3-pentanone (0.22 mL, 2.09 mmol), acetic acid (0.12 mL, 2.09 mmol) and sodium triacetoxyborohydride (0.65 g, 2.93 mmol) were added thereto, and the mixture was stirred at room temperature for 8 hours. The reaction was terminated, the organic layer was extracted with dichloromethane, dehydrated in anhydrous magnesium sulfide and chromatographed (methanol: dichloromethane = 1: 20) to give (1-ethyl-propyl)-[3- ( 4-Methyl-piperazin-1-yl) -phenyl] -amine (0.36 g, 1.36 mmol) was obtained.

Step 4: Naphthalene-2- Sulfonic acid (1-ethyl-propyl)-[3- (4- methyl Piperazin-1-yl) Pe Synthesis of Neyl] -amide

(1-ethyl-propyl)-[3- (4-methyl-piperazin-1-yl) -phenyl] -amine (114 mg, 0.44 mmol) and 2-naphthalenesulfonyl chloride (119 mg) obtained in step 3 above. , 0.52 mmol) was added to dichloromethane (4.0 mL), triethylamine (0.07 mL, 0.44 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the product was washed and filtered, followed by chromatography (methanol: dichloromethane = 1:20) to give naphthalene-2-sulfonic acid (1-ethyl-propyl)-[3- (4 as a brown solid. -Methyl-piperazin-1-yl) -phenyl] -amide (85 mg, 43%) was obtained.

< Example  16> Naphthalene-2- Sulfonic acid methyl -[3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Step A: 1- methyl -4- (2-nitro- Phenyl ) -Synthesis of Piperazine

1-iodine-2-nitrobenzene (2.00 g, 8.03 mmol) was added to room temperature N -methylpiperazine (4 mL), and the mixture was stirred at 120 ° C for 3 hours. After the reaction was completed, the product was washed, filtered and chromatographed (methanol: dichloromethane = 1:30) to give 1-methyl-4- (2-nitro-phenyl) -piperazine (1.75 g) as a yellow oil. , 7.91 mmol) was obtained.

Step B: 2- (4- methyl Piperazin-1-yl) Phenylamine  synthesis

In ethanol (80 mL) and concentrated hydrochloric acid (20 mL) at room temperature, 1-methyl-4- (2-nitro-phenyl) -piperazine (5.0 g, 23.00 mmol) and tin chloride (12.85 g) obtained in step A were obtained. , 67.80 mmol) and stirred at 80 ° C for 1 hour. After neutralization with 6N aqueous sodium hydroxide solution, the organic layer was extracted with dichloromethane and dehydrated under anhydrous sodium sulfide to give a yellow solid of 2- (4-methyl-piperazin-1-yl) -phenylamine (4.50 g, 23.00 mmol).

Step C: Naphthalene-2- Sulfonic acid [3- (4- methyl Piperazin-1-yl) Phenyl ] -Amide synthesis

3- (4-methyl-piperazin-1-yl) -phenylamine (0.30 g, 1.57 mmol) and 2-naphthalenesulfonyl chloride (0.35 g, 1.57 mmol) obtained in step B in room temperature pyridine (3 mL) ) Was added and stirred at room temperature for 1 hour. The organic layer was extracted with dichloromethane, dehydrated in anhydrous sodium sulfide and chromatographed (methanol: dichloromethane = 1:15) to give white solid naphthalene-2-sulfonic acid [3- (4-methyl-piperazine- 1-yl) -phenyl] -amide (0.48 g, 1.24 mmol) was obtained.

Step D: Naphthalene-2- Sulfonic acid methyl -[3- (4- methyl Piperazin-1-yl) Phenyl ] -Amide synthesis

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (20 mg, 0.05 mmol) obtained in step C was added to DMF (2.0 mL), and iodine methane ( 8.9 μl, 0.06 mmol) and potassium carbonate (36 mg, 0.26 mmol) were added, followed by stirring at 80 ° C. for 1 hour. After the reaction was completed, the product was washed and filtered, and then chromatographed (methanol: dichloromethane = 1:15) to carry out yellow oil naphthalene-2-sulfonic acid methyl- [3- (4-methyl-piperazine-). 1-yl) -phenyl] -amide (5 mg, 25%) was obtained.

< Example  17> naphthalene-2- Sulfonic acid -[3- (4- methyl Piperazin-1-yl) Phenyl ] -Propyl-amide

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (0.10 g, 0.26 mmol) synthesized in the same manner as in Steps A, B, and C of Example 16; Was added to DMF (2.0 mL), iodine propane (0.05 g, 0.31 mmol) and potassium carbonate (110 mg, 0.79 mmol) were added, followed by stirring at room temperature for 12 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1: 20) to give naphthalene-2-sulfonic acid- [3- (4-methyl-piperazine-1) as a yellow oil. -Yl) -phenyl] -propyl-amide (0.06 g, 54%) was obtained.

< Example  18> naphthalene-2- Sulfonic acid  Ethyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (0.10 g, 0.26 mmol) synthesized in the same manner as in Steps A, B, and C of Example 16; Was added to DMF (2.0 mL), iodine ethane (0.06 g, 0.31 mmol) and potassium carbonate (0.10 g, 0.78 mmol) were added, followed by stirring at room temperature for 1 hour. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give ethyl naphthalene-2-sulfonic acid ethyl- [3- (4-methyl-piperazine-) as a yellow oil. 1-yl) -phenyl] -amide (0.06 g, 56%) was obtained.

< Example  19> Naphthalene-2- Sulfonic acid Cyclopropylmethyl -[3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (0.10 g, 0.26 mmol) synthesized in the same manner as in Steps A, B, and C of Example 16; Was added to acetone (2.0 mL), bromo methylcyclopropane (0.04 g, 0.26 mmol) and potassium carbonate (0.10 g, 0.78 mmol) were added, followed by stirring at 50 ° C. for 6 hours. After the reaction was completed, the product was washed and filtered, and then chromatographed (methanol: dichloromethane = 1:20) to carry out yellow oil naphthalene-2-sulfonic acid cyclopropylmethyl- [3- (4-methyl-pipee). Razin-1-yl) -phenyl] -amide (0.10 g, 88%) was obtained.

< Example  20> naphthalene-2- Sulfonic acid Cychloropentylmethyl -[3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Step 3: Cyclopentylmethyl -[3- (4- methyl Piperazin-1-yl) Phenyl ]- Amine  synthesis

3- (4-methyl-piperazin-1-yl) -phenylamine (0.10 g, 0.52 mmol) synthesized in the same manner as in Examples 1, 2, and 3 above at room temperature of 1,2-dichloroethane (2.0 ml) ), Cyclopentane carbaaldehyde (0.05 g, 0.52 mmol), acetic acid (0.03 mL, 0.52 mmol) and sodium triacetoxyborohydride (0.10 g, 0.63 mmol) were added thereto, and the mixture was stirred at room temperature for 8 hours. The reaction was terminated, the organic layer was extracted with dichloromethane, dehydrated in anhydrous magnesium sulfide and chromatographed (methanol: dichloromethane = 1: 20) to give pale yellow oil cyclopentylmethyl- [3- (4-methyl -Piperazin-1-yl) -phenyl] -amine (0.05 g, 0.18 mmol) was obtained.

Step 4: Naphthalene-2- Sulfonic acid Cychloropentylmethyl -[3- (4- methyl Synthesis of -piperazin-1-yl) -phenyl] -amide

Cyclopentylmethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (0.05 g, 0.18 mmol) and 2-naphthalenesulfonyl chloride (0.04 g, 0.18 mmol) are pyridine ( 1.0 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1:20) to give naphthalene-2-sulfonic acid cichloropentylmethyl- [3- (4-methyl-) as a yellow oil. Piperazin-1-yl) -phenyl] -amide (0.05 g, 60%) was obtained.

< Example  21> naphthalene-2- Sulfonic acid sec -Butyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Naphthalene-2-sulfonic acid sec-butyl- [3- (4-methyl-piperazine) in the same manner as in Example 20, except that methylethylketone was used instead of cyclopentane carbaaldehyde in Step 3 of Example 20 -1-yl) -phenyl] -amide (10 mg, 4%) was obtained.

< Example  22> naphthalene-2- Sulfonic acid  Benzyl- [3- (4- methyl Piperazin-1-yl) Phenyl ] -Made of Amide

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (0.10 g, 0.26 mmol) synthesized in the same manner as in Steps A, B, and C of Example 16; Was added to acetone (2.0 mL), benzyl bromide (0.05 g, 0.31 mmol) and potassium carbonate (0.18 g, 1.31 mmol) were added, followed by stirring at room temperature for 2 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1: 20) to give naphthalene-2-sulfonic acid benzyl- [3- (4-methyl-piperazine-) as a yellow solid. 1-yl) -phenyl] -amide (0.05 g, 41%) was obtained.

< Example  23> naphthalene-2- Sulfonic acid  [3- (4- methyl Piperazin-1-yl) Phenyl ] -Pyridin-3-yl- methyl Preparation of -amides

Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (0.10 g, 0.26 mmol) synthesized in the same manner as in Steps A, B, and C of Example 16; Was added to acetone (2.0 ml), 3- (bromomethyl) pyridine borate (0.06 g, 0.26 mmol) and potassium carbonate (0.18 g, 1.31 mmol) were added, followed by stirring at room temperature for 2 hours. After the reaction was completed, the product was washed and filtered and then chromatographed (methanol: dichloromethane = 1: 20) to give naphthalene-2-sulfonic acid [3- (4-methyl-piperazine-1-) as a yellow solid. Yl) -phenyl] -pyridin-3-yl-methyl-amide (24%).

< Comparative example > Naphthalene-2-sulfonic acid [3- (4- Methylpiperazine -1 day) Phenyl ] Production of Amide

Naphthalene-2-sulfonic acid [3- (4-methylpiperazin-1-yl) phenyl] amide, a 5-HT2C receptor antagonist described in WO 98/27081, was prepared.

Appearance: White Solid

mp: 173-175 ℃

MS (EI): m / e 472.2 [M] ⁺

¹ H NMR (200 MHz, CDCl ₃ ): δ 2.32 (s. 3H, NCH ₃ ), 2.50 (t, J = 3.4 Hz, NCH ₂ × 2), 3.10 (t, J = 3.4 Hz, NCH ₂ × 2 ), 6.46 (d, J = 4.4 Hz, ArH), 6.62-6.69 (m, 2H, ArH), 7.05 (m, 1H, ArH), 7.55-7.65 (m, 2H, ArH), 7.74 (d, J = 4.6 Hz, 1H, ArH), 7.88 (m, 3H, ArH), 8.36 (s, 1H, ArH)

The properties, melting point and ¹ H NMR data of the pyrerazine derivative represented by Chemical Formula 1 obtained according to the preparation method of the embodiment of the present invention are shown in Table 1 below.

division Appearance mp (℃) MS (EI) ¹ H NMR data


Example 1


White oil


-


m / e 424.12 [M + 1] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 1.25 (d, J = 6.6 Hz, 3H, CH ₃ ), 1.29 (d, J = 6.6 Hz, 3H, CH ₃ ), 2.37 (s, 3H, NCH ₃ ), 2.62 (t, J = 3.0 Hz, 4H, NCH ₂ × 2), 2.76 (t, J = 3.0 Hz, 4H, NCH ₂ × 2), 4.37 (Se, J = 7.0 Hz, 1H, CH), 6.94-7.08 (m, 2H, ArH), 7.26 (m, 2H, ArH), 7.58-7.70 (m, 2H, ArH), 7.92-8.03 (m, 4H, ArH), 8.49 (s, 1H, ArH)


Example 2


White solid


69-70

m / e 423 [M] ⁺ , 408, 379 ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.07 (d, J = 6.7 Hz, 6H, CH ₃ × 2), 2.31 (s, 3H, CH ₃ ), 2.46 (m, 4H, CH ₂ × 2) , 3.04 (m, 4H, CH ₂ × 2), 4.68 (m, 1H, CH), 6.51 (m, 2H, ArH), 6.89 (m, 1H, ArH), 7.18 (m, 1H, ArH), 7.62 (m, 2H, ArH), 7.89 (dd, J = 1.9, 8.7 Hz, 1H, ArH), 7.91 (m, 2H, ArH), 8.29 (d, J = 1.7 Hz, 1H, ArH)


Example 3


Yellow oil


-


m / e 424.09 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.05 (d, J = 4.0 Hz, 6H, CH ₃ × 2), 2.35 (s, 3H, NCH ₃ ), 2.56 (t, J = 1.0 Hz, 4H, NCH ₂ × 2), 3.23 (t, J = 1.0 Hz, 4H, NCH ₂ × 2), 4.66 (Se, J = 5.3 Hz, 1H, CH), 6.79-6.93 (m, 4H, ArH), 7.27 ( d, J = 2.4 Hz, 1H, ArH), 7.59-7.92 (m, 5H, ArH), 8.28 (s, 1H, ArH)



Example 4



Yellow oil



-



m / e 373.1 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.05 (s, 3H, CH ₃ ), 1.07 (s, 3H, CH ₃ ), 2.35 (s, 3H, NCH ₃ ), 2.54 (t, J = 5.0 Hz , 4H, NCH ₂ × 2), 3.13 (t, J = 5.0 Hz, 4H, NCH ₂ × 2), 4.61 (Se, J = 6.8 Hz, 1H, CH) 6.50 (d, J = 6.0 Hz, 1H, ArH), 6.53 (s, 1H, ArH), 6.90 (d, J = 5.7 Hz, 1H, ArH), 7.21 (t, J = 8.1 Hz, 1H, ArH), 7.46 (t, J = 5.4 Hz, 2H , ArH), 7.52 (t, J = 2.4 Hz, 1H, ArH), 7.78 (d, J = 6.3 Hz, 2H, ArH)


Example 5


Yellow oil


-


m / e 337.2 [M] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 1.24 (d, J = 7.0 Hz, 6H, CH ₃ × 2), 2.36 (s, 3H, NCH ₃ ), 2.55 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 3.06 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 5.07 (Se, J = 6.4 Hz, 1H, CH), 6.48 (s, 1H, ArH) 6.57 (d, J = 7.6 Hz, 1H, ArH), 6.73 (d, J = 8.2 Hz, 1H, ArH), 7.06-7.15 (m, 4H, ArH), 7.24 (s, 1H, ArH), 7.28 (s, 1H , ArH)



Example 6



Yellow oil



-



m / e 323.2 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.20 (d, J = 6.6 Hz, 6H, CH ₃ × 2), 3.19 (t, J = 11.0 Hz, 2H, CH ₂ ), 3.40 (d, J = 12.6 Hz, 2H, CH ₂ ), 3.67 (t, J = 10.0 Hz, 2H, CH ₂ ), 3.88 (d, J = 12.6 Hz, 2H, CH ₂ ), 4.23 (Se, J = 6.6 Hz, 1H, CH), 6.18 (t, J = 8.0 Hz, 2H, ArH), 6.36 (d, J = 7.0 Hz, 1H, ArH), 7.05 (t, J = 8.1 Hz, 1H, ArH), 7.30 (m, 1H , ArH), 7.43 (d, J = 4.5 Hz, 2H, ArH), 7.73 (d, J = 6.3 Hz, 2H, ArH)


Example 7


Yellow oil


-


m / e 388.13 [M + 1] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 1.31 (d, J = 6.6 Hz, 6H, CH ₃ × 2), 2.25 (s, 3H, NCH ₃ ), 2.31 (s, 4H, NCH ₂ × 2) , 2.63 (s, 4H, NCH ₂ × 2), 6.35 (s, 1H, ArH), 6.54 (s, 2H, ArH), 6.91 (t, J = 8.0 Hz, 1H, ArH), 7.16 (t, J = 7.4 Hz, 2H, ArH), 7.40-7.72 (d, J = 8.2 Hz, 1H, ArH), 8.05 (d, J = 8.2 Hz, 1H, ArH)

Example 8

Yellow oil

-
m / e 353 [M + 1] ⁺ , 260 ¹ H NMR (200 MHz, CDCl ₃ ): δ 1.13 (d, J = 6.9 Hz, 6H, CH ₃ × 2), 2.36 (s, 3H, CH ₃ ), 2.59 (m, 4H, CH ₂ × 2) , 3.24 (m, 4H, CH ₂ × 2), 4.93 (m, 1H, CH), 6.00 (s, 1H, NH), 6.74 (m, 2H, ArH), 6.97 (m, 2H, ArH), 7.24 (m, 5H, ArH)




Example 9




Brown
solid




79-83




m / e 424.09 [M + 1] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 1.10 (d, J = 6.4 Hz, 6H, CH ₃ × 2), 2.34 (s, 3H, NCH ₃ ), 2.49 (t, J = 7.0 Hz, NCH ₂ × 2), 2.95 (t, J = 6.1 Hz, NCH ₂ × 2), 4.72 (Se, J = 7.0 Hz, 1H, CH), 6.40 (s, 1H, ArH), 6.55 (d, J = 8.6 Hz , 1H, ArH), 6.83 (d, J = 8.2 Hz, 1H, ArH), 7.13 (t, J = 8.0 Hz, 1H, ArH), 7.43 (t, J = 8.0 Hz, 1H, ArH), 7.63 ( m, 2H, ArH), 7.90 (d, J = 7.0 Hz, 1H, ArH), 8.02 (d, J = 8.0 Hz, 1H, ArH), 8.13 (d, J = 7.4 Hz, 1H, ArH)



Example 10



Yellow oil



-



m / e 388.12 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.08 (d, J = 7.6 Hz, 6H, CH ₃ × 2), 2.35 (s, 3H, ArCH ₃ ), 2.41 (s, 3H, NCH ₃ ), 2.54 (t, J = 5.1 Hz, 4H, NCH ₂ × 2), 3.13 (t, J = 5.0 Hz, 4H, NCH ₂ × 2), 4.58 (Se, J = 6.6 Hz, 1H, CH), 6.50 (d , J = 7.8 Hz, 1H, ArH), 6.55 (s, 1H, ArH), 6.90 (d, J = 6.6 Hz, 1H, ArH), 7.18 (t, J = 8.1 Hz, 1H, ArH), 7.25 ( d, J = 8.1 Hz, 2H, ArH), 7.65 (d, J = 8.4 Hz, 2H, ArH)



Example 11



Yellow oil



-



m / e 408.06 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.10 (d, J = 6.6 Hz, 6H, CH ₃ × 2), 2.35 (s, 3H, NCH ₃ ), 2.55 (t, J = 5.4 Hz, 4H, NCH ₂ × 2), 3.14 (t, J = 5.1 Hz, 4H, NCH ₂ × 2), 4.59 (Se, J = 6.9 Hz, 1H, CH), 6.44 (d, J = 6.6 Hz, 1H, ArH) , 6.54 (t, J = 2.1 Hz, 1H, ArH), 6.90 (d, J = 6.3 Hz, 1H, ArH), 7.18 (t, J = 8.1 Hz, 1H, ArH), 7.42 (d, J = 8.7 Hz, 2H, ArH), 7.70 (d, J = 8.7 Hz, 2H, ArH)




Example 12




Yellow oil




-




m / e 388.13 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.07 (d, J = 4.4 Hz, 6H, CH ₃ × 2), 2.32 (s, 3H, CH ₃ ), 2.44 (broad s, 4H, NCH ₂ × 2 ), 2.87 (broad s, 4H, NCH ₂ × 2), 4.65 (Se, J = 6.0 Hz, 1H, CH), 6.37 (s, 1H, ArH), 6.54 (d, J = 4.0 Hz, 1H, ArH) ), 6.82 (d, J = 6.0 Hz, 1H, ArH), 7.10 (t, J = 8.0 Hz, 2H, ArH), 7.42 (t, J = 12.0 Hz, 2H, ArH), 7.90 (d, J = 9.0 Hz, 1H, ArH), 8.0 (d, J = 12.0 Hz, 1H, ArH), 8.12 (d, J = 6.0 Hz, 1H, ArH), 8.65 (d, J = 6.0 Hz, 1H, ArH)



Example 13



Yellow solid



131-142



m / e 420.14 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.09 (d, J = 4.6 Hz, 6H, CH ₃ × 2), 2.35 (s, 3H, NCH ₃ ), 2.55 (t, J = 3.4 Hz, 4H, NCH ₂ × 2), 3.16 (t, J = 3.4 Hz, 4H, NCH ₂ × 2), 4.65 (Se, J = 4.4 Hz, 1H, CH), 6.36 (d, J = 4.4 Hz, 1H, ArH) , 6.59 (t, J = 1.6 Hz, 1H, ArH), 6.93 (d, J = 4.2 Hz, 1H, ArH), 7.18 (t, J = 5.4 Hz, 1H, ArH), 7.93 (d, J = 6.0 Hz, 2H, ArH), 8.31 (d, J = 8.7 Hz, 2H, ArH)


Example 14


White oil


-


m / e 372.17 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 1.22 (d, J = 4.6 Hz, 6H, CH ₃ × 2), 2.34 (s, 3H, NCH ₃ ), 2.52 (t, J = 3.3 Hz, NCH ₂ × 2), 3.07 (t, J = 3.4 Hz, NCH ₂ × 2), 5.04 (s, 1H, CH), 6.45 (s, 1H, CH), 6.45 (s, 1H, ArH), 6.52 (d, J = 5.0 Hz, 1H, ArH), 6.75 (d, J = 4.2 Hz, 1H, ArH), 7.10 (d, J = 5.6 Hz, 3H, ArH), 7.20 (d, J = 5.8 Hz, 2H, ArH )


Example 15


Brown
solid


55-56


m / e 452 [M + 1] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 0.92 (t, J = 7.3 Hz, 6H, CH ₃ × 2), 1.35 (m, 4H, CH ₂ × 2), 2.31 (s, 3H, CH ₃ ), 2.44 (m, 4H, CH ₂ × 2), 3.00 (m, 4H, CH ₂ × 2), 4.12 (m, 1H, NCH), 6.51 (m , 2H, ArH), 6.89 (m, 1H, ArH), 7.16 (m, 1H, ArH), 7.60 (m, 2H, ArH), 7.74 (m, 1H, ArH), 7.90 (m, 3H, ArH) , 8.23 (s, 1H, ArH)


Example 16


Yellow oil


-


m / e 395 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 2.34 (s, 3H, NCH ₃ ), 2.51 (t, J = 3.4 Hz, 4H, NCH ₂ × 2), 3.11 (t, J = 3.3 Hz, 4H, NCH ₂ × 2), 3.20 (s, 3H, CH ₃ ), 6.45 (d, J = 4.2 Hz, 1H, ArH), 6.71 (t, J = 1.5 Hz, 1H, ArH), 6.82 (d, J = 3.8 Hz, 1H, ArH), 7.12 (t, J = 6.0 Hz, 1H, ArH), 7.53-7.67 (t, J = 4.5 Hz, 3H, ArH), 8.2 (s, 1H, ArH)



Example 17



Yellow oil



-



m / e 423.2 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 0.91 (t, J = 7.2 Hz, 3H, CH ₃ ), 1.47 (Se, J = 7.2 Hz, 2H, CH ₂ ), 2.31 (s, 1H, NCH ₃ ), 2.46 (t, J = 5.1 Hz, 4H, NCH ₂ × 2), 3.04 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 3.52 (t, J = 7.2 Hz, 2H, CH ₂ ) , 6.47 (d, J = 5.1 Hz, 1H, ArH), 6.57 (d, J = 2.1 Hz, 1H, ArH), 6.82 (d, J = 6.0 aHz, 1H, ArH), 7.13 (t, J = 8.1 Hz, 1H, ArH), 7.58-7.65 (m, 3H, ArH), 7.90 (d, J = 8.4 Hz, 3H, ArH), 8.19 (s, 1H, ArH)



Example 18



Yellow oil



-



m / e 409.1 [M] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 1.10 (t, J = 7.0 Hz, 3H, CH ₃ ), 2.31 (s, 3H, NCH ₃ ), 2.46 (t, J = 5.0 Hz, 4H, NCH ₂ × 2), 3.05 (t, J = 5.0 Hz, 4H, NCH ₂ × 2), 3.63 (q, J = 7.4 Hz, 2H, CH ₂ ), 6.46 (d, J = 8.0 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 6.80 (d, J = 9.0 Hz, 1H, ArH), 7.14 (t, J = 9.4 Hz, 1H, ArH), 7.61-7.67 (m, 3H, ArH), 7.90 ( d, J = 9.0 Hz, 3H, ArH), 8.21 (s, 1H, ArH)



Example 19



Yellow oil



-



m / e 435.2 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 0.15 (d, J = 5.4 Hz, 2H, CH ₂ ), 0.42 (d, J = 7.5 Hz, 2H, CH ₃ ), 0.90 (m, 1H, CH) , 2.30 (s, 3H, NCH ₃ ), 2.45 (t, J = 4.8 Hz, 4H, NCH 2 × 2), 3.03 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 3.46 (d, J = 6.2 Hz, 2H, CH ₂ ), 6.52 (d, J = 6.6 Hz, 1H, ArH), 6.61 (s, 1H, ArH), 6.82 (d, J = 6.3 Hz , 1H, ArH), 7.13 (t, J = 8.1 Hz, 1H, ArH), 7.55-7.67 (m, 3H, ArH), 7.88 (t, J = 8.4 Hz, 3H, ArH), 8.20 (s, 1H , ArH)



Example 20



Yellow oil



-



m / e 463.2 [M] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 0.85-1.65 (m, 9H, cycloppentane H), 2.31 (s, 3H, NCH ₃ ), 2.47 (t, J = 5.0 Hz, 4H, NCH ₂ × 2) , 3.10 (t, J = 5.0 Hz, 4H, NCH ₂ × 2), 3.46 (d, J = 7.8 Hz, 2H, CH ₂ ), 6.47 (d, J = 10.0 Hz, 1H, ArH), 6.56 (s , 1H, ArH), 6.82 (d, J = 10.0 Hz, 1H, ArH), 6.82 (d, J = 10.0 Hz, 1H, ArH), 7.13 (t, J = 8.2 Hz, 1H, ArH), 7.61 ( m, 3H, ArH), 7.88 (d, J = 8.2 Hz, 3H, ArH), 8.19 (s, 1H, ArH)


Example 21


Yellow oil


-


m / e 437.2 [M] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 0.95-2.04 (m, 8H, CHCH ₃ ), 2.40 (s, 3H, NCH ₃ ), 2.55 (s, 4H, NCH ₂ × 2), 3.1 (s, 4H, NCH ₂ x 2), 4.40 (q, J = 8.0 Hz, 1H, CH), 6.50 (d, J = 12.0 Hz, 2H, ArH), 6.90 (d, J = 8.0 Hz, 1H, ArH), 7.21 (t, J = 8.0 Hz, 1H, ArH), 7.60-8.00 (m, 7H, ArH)


Example 22


Yellow solid


82-83


m / e 471.2 [M] ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ 2.32 (s, 3H, NCH ₃ ), 2.43 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 2.95 (t, J = 5.1 Hz, 4H, NCH ₂ × 2), 6.40 (d, J = 6.0 Hz, 1H, ArH), 6.47 (s, 1H, ArH), 6.74 (s, 1H, ArH), 7.05 (d, J = 6.0 Hz, 1H, ArH ), 7.17-7.26 (m, 5H, ArH), 7.58-7.71 (m, 3H, ArH), 7.90-7.95 (m, 3H, ArH), 8.26 (s, 1H, ArH)



Example 23



Yellow oil



-



m / e 472.2 [M] ^{+ 1} H NMR (200 MHz, CDCl ₃ ): δ 2.30 (s, 3H, NCH ₃ ), 2.43 (t, J = 4.8 Hz, 4H, NCH ₂ × 2), 2.97 (t, J = 4.4 Hz, 4H, NCH ₂ × 2), 4.77 (s, 2H, CH ₂ ), 6.35 (d, J = 12.0 Hz, 1H, ArH), 6.46 (s, 1H, ArH), 6.75 (d, J = 14.0 Hz, 1H, ArH), 7.05 (t, J = 10.0 Hz, 1H, ArH), 7.20 (d, J = 6.0 Hz, 1H, ArH), 7.64-7.70 (m, 4H, ArH), 7.93 (m, 4H, ArH) , 8.28 (s, 1H, ArH), 8.38 (s, 1H, ArH), 8.45 (d, J = 10.0 Hz, 1H, ArH)

< Experimental Example  1> Serotonin 5- HT2C  Receptor binding experiment

In order to determine the degree of binding of the derivative according to the present invention with serotonin 5-HT2C receptor, the following experiment was performed.

As a receptor, a human recombinant 5-HT2C receptor expressed in CHO-K1 cells was purchased from Euroscreen, Belgium and used as a radioisotope [ ³ H] Mesulergine (Amersham Bioscience, UK).

The compound of Example 1-23 or the compound of Comparative Example, [ ³ H] mesorized 1 nM, 5-HT2C receptor membrane (4 μg / well), 0.1% ascorbic acid and 10 μM pargyline Including 50 mM Tris-HCl buffer (pH 7.7) and the like was added to make a reaction volume of the final volume of 0.25 ml and incubated for 30 minutes at 37 ℃. After incubation, the reaction was terminated by filtration through a Whatman GF / C glass fiber filter pre-soaked in 1% BSA using an Inotech harvester (Inotech) and washed with cold 50 mM Tris-HCl buffer. The filter was covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). Nonspecific binding was measured in the presence of 0.5 μM Mianserin. The IC ₅₀ value of the compound of Example 1-23 or the compound of Comparative Example is a non-linear regression analysis of the isotherm obtained by repeated experiments of 7-8 steps of the drug three times in two test tubes (GraphPad Prism Program, San Diego, USA). Calculated by). Lower IC ₅₀ values indicate higher affinity with the 5-HT2C receptor.

The results are shown in Table 2 below.

division IC ₅₀ (nM) Example 1 4638 Example 2 3.5 Example 3 1715 Example 4 20.6 Example 5 4164 Example 6 〉 10000 Example 7 96.8 Example 8 〉 10000 Example 9 100 Example 10 106 Example 11 243 Example 12 420 Example 13 462 Example 14 7702 Example 15 159 Example 16 36 Example 17 7.2 Example 18 16 Example 19 6.3 Example 20 10.9 Example 21 168 Example 22 32 Example 23 34 Comparative example 5147

Referring to Table 2, it was confirmed that the compound according to the present invention has a very low excellent IC ₅₀ value when compared with the conventional 5-HT2C receptor antagonist (Comparative Example). Particularly, in Examples 2, 4, 7, 16-19, 20, 22, and 23, IC ₅₀ values of several to several tens of nM can be seen to have significantly lower IC ₅₀ values than the comparative example. Thus, the compound according to the present invention has a high affinity for the 5-HT2C receptor and relatively inhibits the binding of serotonin to the 5-HT2C receptor, thereby preventing or treating a disease caused by the excessive binding of the serotonin to the 5-HT2C receptor. This can be useful.

< Experimental Example  2> Serotonin Receptor Selectivity Experiment

2-1: 5- HT6  Receptor binding experiment

In order to determine whether the derivative according to the present invention selectively binds to serotonin 5-HT2C and 5-HT6 receptors, the following experiment was performed.

As a receptor, human recombinant 5-HT6 receptor expressed in CHO-K1 cells was purchased from Euroscreen, Belgium, and [ ³ H] LSD (lysergic acid diethylamide) was used as a radioisotope. .

For drug screening, compounds of the invention, replicated receptor membranes (9 μg / well), 50 mM Tris-HCl buffer (pH 7.4) containing [ ³ H] LSD 1.87 nM, 10 mM MgCl ₂ and 0.5 mM EDTA, and the like. To this was added a final volume of 0.25 ml of reaction mixture, which was incubated at 37 ° C. for 60 minutes. For drug screening, the compounds of the present invention were incubated as above in a reaction mixture comprising 1.87 nM [ ³ H] LSD. After incubation, the reaction was terminated by rapid filtration through a Wallac GF / C glass fiber filter (Wallac, Finland) pre-soaked with 0.5% PEI using an Inotech harvester (Inotech) and cold 50 mM Tris-HCl buffer. Washed with solution. The filter was covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). Compounds of the present invention were prepared at 7 to 8 concentrations and subjected to competitive binding studies in two test tubes, and the isotherms of three replicates were calculated by nonlinear regression analysis by computer (GraphPad Prism Program, San Diego). , USA), IC ₅₀ The value was calculated. Nonspecific binding was measured in the presence of 10 μM Methiothepin. All compounds used in the test for binding analysis were dissolved in DMSO and diluted to various concentrations, the results are shown in Table 4 below.

2-2: 5- HT  Receptor To family  For combined experiments

Binding assays for the 5-HT receptor family 5-HT1A, 5-HT2A and 5-HT7 were conducted with radioligand binding probes according to the test method provided by the supplier of the receptor membrane (Euroscreen / BioSignal Packard Inc.).

Detailed analysis conditions are shown in the table below. Shown in Table 3, the results are shown in the following table. 4 is shown.

5-HT1A 5-HT2A 5-HT7 origin Stable CHO-K1 Cell Line Expressing Human Recombinant Receptor (Euroscreen / BioSignal) Binding buffer 50 mM Tris-HCl, pH 7.4
10 mM MgSO4
0.5 mM EDTA
0.1% ascorbic acid 50 mM Tris-HCl, pH 7.4 50 mM Tris-HCl (pH 7.4)
10 mM MgSO4
0.5 mM EDTA Final volume 250 μl 250 μl 250 μl Membrane content 40 µg 15 µg 10 µg Radioactive ligand [ ³ H] 8-OH-DPAT
0.5 nM [ ³ H] ketanserine
1 nM [ ³ H] LSD
3 nM Nonspecific binding Methiotepine
0.5 μM Mianserin
1 μM Methiotepine
10 μM culture 27 ℃, 60 min 37 ℃, 15 min 27 ℃, 120 min percolation GF / C, 0.3% PEI GF / C, 0.05% Brij GF / C, 0.3% PEI

2-3: dopamine receptor To family  For combined experiments

Binding assays for the dopamine receptor family were conducted for radioligand binding assays according to the test methods provided by the supplier of receptor proteins (BioSignal Packard Inc., Montreal, Canada). [ ³ H] spiferon (hD2L and hD3 receptor, 1 nM) and [ ³ H] YM-09151-2 (hD4 receptor, 0.06 nM) were used as radioligands. In brief, the buffers used for D2 and D3 receptor binding assays were 50 mM Tris-HCl (pH 7.4), 10 mM MgCl ₂ , 1 mM EDTA, or 50 mM Tris-HCl (pH 7.4), 5, respectively. mM MgCl ₂ , 5 mM EDTA, 5 mM KCl, 1.5 mM CaCl ₂ , 120 mM NaCl. In the [ ³ H] YM-09151-2 receptor binding assay, 50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ , 5 mM EDTA, 5 mM KCl and 1.5 mM CaCl ₂ were used as buffers. Haloperidol (10 μM) was used for D2 and D3, and clozapine (clozapine, 10 μM) was used for D4 and D4 receptors, respectively.

The compound of the present invention was prepared at a concentration of 7-8 steps to perform a competitive binding investigation in a double test tube, and the isotherms obtained from three replicates were calculated by nonlinear regression analysis by computer (GraphPad Prism Program, San Diego). , Canada), IC ₅₀ The value was obtained.

Selectivity results for dopamine and serotonin receptor subtypes of the compounds of the present invention 4 is shown.

division 5-HT2C 5-HT1A 5-HT2A 5-HT6 5-HT7 D2 D3 D4 Example 2 4 〉 1000 118 3 NR 〉 10000 248 〉 10000 Example 4 20.6 3399 172 644 1006 〉 10000 2893 〉 10000 Example 9 100 298 122 15.6 2874 〉 10000 1195 〉 10000 Example 16 36.2 95 1423 7.0 4425 〉 10000 2416 〉 10000 Example 17 7 3756 389 4.3 3865 〉 10000 2508 〉 10000 Example 18 16 485 218 3.4 2059 〉 10000 1171 〉 10000 Example 19 6 672 88 5.7 3038 〉 10000 1426 〉 10000 Example 20 10.9 101 268 7.3 4310 〉 10000 2094 〉 10000 Example 21 168 116 545 7.2 3158 〉 10000 1334 〉 10000 Example 22 32 280 50 2.7 2044 〉 10000 943 〉 10000 Example 23 34 182 568 12.5 2710 〉 10000 3865 〉 10000 Comparative example 5147 57 1616 13.3 1582 〉 10000 2102 〉 10000

Referring to Table 4, the derivative according to the present invention shows a high affinity in 5-HT2C and 5-HT6, other receptors (5-HT1A, 5-HT2A, 5-HT7, D2, D3 and D4) Equation of high IC ₅₀ value shows little coupling. Therefore, the derivative according to the present invention can be usefully used for preventing or treating diseases caused by over-binding of serotonin to 5-HT2C receptor or 5-HT6 receptor by simultaneously binding to 5-HT2C and 5-HT6 receptors.

< Experimental Example  3> In in vitro  Experiment

In order to determine whether the derivative according to the present invention exhibits antagonist activity on G protein bound to 5-HT2C receptor, the following experiment was performed.

Experiments were carried out using MDSPS (MDS Pharma Service PT # 1110036) (Adlersberg M et al ., J Neurosci Res. 2000, 61 (6): 674-685, Cussac D et al ., Mol. Pharmacol. 2002, 62 (3): 578-589), and [ ³⁵ S] GTPγS activity in CHO cells transformed with human 5-HT2C receptor was measured.

Specifically, human CHO cells were suspended in 0.4% DMSO and then 0.001, 0.01, 0.1, 1 and 10 in culture buffer consisting of 20 mM HEPES (pH 7.4), 100 mM NaCl, 10 mM MgCl ₂ , 1 mM EDTA. The compound and the suspension of Example 2 at various concentrations of μM were added and incubated at 30 ° C. for 45 minutes. After incubation, the concentration of bound [ ³⁵ S] GTPγS was measured to calculate the inhibition rate of serotonin (5-HT) -induced [ ³⁵ S] GTPγS-increasing activity, and serotonin (5-HT) -induced [ ³⁵ Compounds that inhibit S] GTPγS augmentation by 50% or more were classified as antagonists. At this time, the antagonist SB242084 of 5-HT2C was used as a comparison group.

The results are shown in FIG. 1 and Table 5.

Concentration (μM) % Inhibition 0.001 -2 0.01 0 0.1 54 One 91 10 105

As shown in Fig. 1 and Table 4, human 5-HT2C receptors, 5-HT concentration-dependent ^[35 S] GTPγS showed the concentration levels increase, the ^[35 S] increase in the GTPγS in Example 2 or 5-HT2C Inhibited by the antagonist SB242084. In particular, the compound of Example 2 according to the present invention inhibited the increase in serotonin (5-HT) -induced GTP levels at concentrations of 0.001, 0.01, 0.1, 1 and 10 μM to -2, 0, 54, 91 and 105%, respectively. The IC ₅₀ value of the compound of Example 2 was 0.0936 μM, indicating significant antagonist activity.

Thus, the derivatives according to the invention are human 5-HT2C By exhibiting significant antagonist activity on the receptor, it can be usefully used for preventing or treating diseases caused by over binding of serotonin to the 5-HT2C receptor.

In addition, the following experiment was carried out to determine whether the derivative of the present invention exhibits antagonist activity on the 5-HT6 receptor.

Routing C et using MDSPS (MDS Pharma Service PT # 1110036) al ., 2000, Br J Pharmacol. 130: 1605-1612), adenylyl cyclase activity was measured in HeLa cells selectively expressing the human 5-HT6 receptor.

Specifically, the cell culture medium was composed of HBSS (Hanks' balanced salt solution, pH 7.4), 1 mM MgCl ₂ , 1 mM CaCl ₂ , 100 μM 1-methyl-3-isobutylxanthine (IBMX), the enzyme and the present invention The compound of Example 2 was added to various concentrations to start the culture. After incubation at 37 ° C. for 20 minutes, intracellular cAMP levels were measured by EIA (enzyme-immunoassay), and compounds that inhibited cAMP-increasing activity induced by serotonin (5-HT), which is an agonist, were classified as antagonists. At this time, methiothepin, known as an antagonist of 5-HT6, was used as a comparison group.

The results are shown in Figure 2 and Table 6.

Concentration (μM) % Inhibition 0.001 103 0.01 101 0.1 87 One 30 10 -18

As shown in FIG. 2 and Table 6, agonist serotonin (5-HT) increased cAMP secretion in HeLa cells selectively expressing 5-HT6 receptor, while Example 2 and methiotepine were serotonin-induced cAMP Increasing action was inhibited concentration-dependently. In particular, the compound of Example 2 according to the present invention inhibits serotonin (5-HT) induced cAMP increasing action at concentrations of 0.001, 0.01, 0.1, 1 and 10 μM to 100, 101, 87, 30 and -18%, respectively. The IC ₅₀ value of the compound of Example 2 was 0.0207 μM, indicating significant antagonist activity.

Therefore, the derivatives according to the present invention exhibit significant antagonist activity on the human 5-HT6 receptor, and thus can be usefully used for the prophylaxis or treatment caused by the excessive binding of serotonin to the 5-HT6 receptor.

Therefore, the derivatives according to the present invention are 5-HT2C and 5-HT6. Simultaneous binding to the receptor can be useful for preventing or treating central nervous system diseases such as dementia caused by over binding of the serotonin to the 5-HT2C receptor or 5-HT6 receptor, schizophrenia caused by dementia, depression and anxiety. .

Meanwhile, the piperazine derivative represented by Chemical Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of 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 example  1> tablet (direct pressure)

After sifting 5.0 mg of the piperazine derivative of Formula 1, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

< Formulation example  2> tablets (wet assembly)

5.0 mg of the piperazine derivative of Formula 1 was sieved, followed by mixing 16.0 mg of lactose and 4.0 mg of starch. 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 to make tablets.

< Formulation example  3> with powder Capsule

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

< Formulation example  4> Injection

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

1 is a graph showing the activity inhibition rate of G protein bound to the 5-HT2C receptor according to the concentration of the derivative according to an embodiment of the present invention (●: Example 2, ■: SB242084);

Figure 2 is a graph showing the effect of inhibiting 5-HT6 receptor mediated cAMP accumulation in human Hela cells of the compound and methiotepine according to an embodiment of the present invention (●: Example 2, ■: methiotepine).

Claims (14)

Piperazine derivatives represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

(In the formula 1, R ¹ is C ₁ -C ₅ straight or branched chain alkyl or benzyl substituted with any substituent selected from the group consisting of unsubstituted or C ₃ -C ₅ cycloalkyl and C ₅ -C ₆ heteroaryl, R ² is

ego, R ³ is phenyl unsubstituted or substituted with any substituent selected from the group consisting of C ₁ -C ₄ straight or branched alkyl, halogen and nitro; Amino group substituted with C ₅ -C ₆ aryl or unsubstituted naphthyl). The method of claim 1, R ¹ is methyl, ethyl, propyl, isopropyl, butyl, 1-ethyl-propyl, sec-butyl, pentyl, cyclopropylmethyl, cyclopentylmethyl, pyridin-3-ylmethyl or benzyl; R ² is

ego, R ³ is a piperazine derivative or a pharmaceutically acceptable salt thereof characterized in that phenyl, 4-methylphenyl, 4-nitrophenyl, 4-chlorophenyl, phenylamino and naphthylene-1-yl, naphthylene-2-yl . The method of claim 1, wherein the derivative of Formula 1 (1) naphthalene-2-sulfonic acid isopropyl- [2- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 1); (2) naphthalene-2-sulfonic acid isopropyl- [3- (4-methyl-piperazin-1-yl) phenyl] -amide (Example 2); (3) naphthalene-2-sulfonic acid isopropyl- [4- (4-methyl-piperazin-1-yl) phenyl] -amide (Example 3); (4) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide (Example 4); (5) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzamide (Example 5) (6) benzyl-isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amine (Example 6); (7) naphthalene-1-carboxylic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 7); (8) 1-isopropyl-1- [3- (4-methyl-piperazin-1-yl) -phenyl] -3-phenyl-urea (Example 8); (9) naphthalene-1-sulfonic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 9); (10) N-isopropyl-4-methyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide (Example 10); (11) 4-chloro-N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide (Example 11); (12) naphthalene-2-carboxylic acid isopropyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 12); (13) N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -4-nitro-benzenesulfonamide (Example 13); (14) 4-chloro-N-isopropyl-N- [3- (4-methyl-piperazin-1-yl) -phenyl] -benzamide (Example 14); (15) naphthalene-2-sulfonic acid (1-ethyl-propyl)-[3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 15); (16) methyl naphthalene-2-sulfonic acid- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 16); (17) naphthalene-2-sulfonic acid- [3- (4-methyl-piperazin-1-yl) -phenyl] -propyl-amide (Example 17); (18) naphthalene-2-sulfonic acid ethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 18); (19) naphthalene-2-sulfonic acid cyclopropylmethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 19); (20) naphthalene-2-sulfonic acid cyclopentylmethyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 20); (21) naphthalene-2-sulfonic acid sec-butyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 21); (22) naphthalene-2-sulfonic acid benzyl- [3- (4-methyl-piperazin-1-yl) -phenyl] -amide (Example 22); And (23) any one selected from the group consisting of naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -pyridin-3-yl-methyl-amide (Example 23) Piperazine derivatives or pharmaceutically acceptable salts thereof, characterized in that. As shown in Scheme 1 below, Reacting a compound of Formula 2 with N-methyl piperazine of Formula 3 to prepare a compound of Formula 4 (step 1); Preparing a compound of formula 5 by reducing the compound of formula 4 obtained in step 1 (step 2); Introducing a substituent R ¹ into an amine group of the compound of Formula 5 obtained in step 2 (step 3); And Amine group of the compound of formula 6 obtained in step 3

Method for preparing a piperazine derivative of claim 1 comprising the step of additionally introducing a substituent represented by (step 4): Scheme 1

(In Reaction Scheme 1, R ¹ , R ² and R ³ are as defined in Formula 1, R ¹ made by this method is isopropyl, 1-ethyl-propyl, cyclopentylmethyl and sec-butyl, Formula 1a is Derivatives of formula 1). 5. The method of claim 4, wherein the step 1 introduces a piperazinyl group by nucleophilic substitution of the compound of Formula 2. 6. 5. The method of claim 4, wherein step 1 introduces a piperazinyl group by reacting a compound of Formula 2 with a palladium-catalyst cross-pairing reaction of the Buchwald type. 6. According to claim 4, Step 4 is a compound of formula 1a by introducing a substituent R ¹ using any one selected from the group consisting of acid chloride, sulfonyl chloride, isocyanate and alkyl halide in the amine group of the compound of formula (6) A method for producing a piperazine derivative according to claim 1, which is prepared. As shown in Scheme 2 below, Reacting a compound of Formula 2 with N-methyl piperazine of Formula 3 to produce a compound of Formula 4 (step A); Reducing the compound of Formula 4 obtained in step A to prepare a compound of Formula 5 (step B); Reacting the compound of Formula 5 obtained in step B with naphthalenesulfonylchloride to obtain a compound of Formula 7 (step C); And A process for preparing the piperazine derivative of claim 1 comprising introducing a substituent R ¹ into an amine group of the compound of formula 7 obtained in step C (step D): Scheme 2

(In Formula 1, R ¹ is as defined in Formula 1, and Formula 1b is a derivative of Formula 1). The method according to claim 8, wherein the step A introduces a piperazinyl group by nucleophilic substitution reaction of the compound of Formula 2. The method according to claim 8, wherein the step A introduces a piperazinyl group by reacting a compound of Formula 2 with a palladium-catalyst cross-coupling reaction of the Buchwald type. The method of claim 8, wherein the solvent in the reaction of step C is any one selected from the group consisting of pyridine, triethylamine and diisopropylethylamine. Prevention of central nervous system diseases selected from the group consisting of dementia, schizophrenia caused by dementia, depression and anxiety, containing piperazine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic pharmaceutical composition. delete delete

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