KR101819472B1 - Novel 1,4-substituted piperazine or piperidine compounds and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a compound of the chemical formula 1 and a pharmaceutically acceptable salt thereof. In the chemical formula 1, R1 and R2 are independently hydrogen, halogen, an alkyl group having one to four carbon atoms, an alkoxy group having one to four carbon atoms, or trifluoromethyl; R3 is a direct bone, an alkyl group having one to four carbon atoms, or an alkenyl group having two to four carbon atoms; R4 is a substituted or unsubstituted aryl group having six to ten carbon atoms or a substituted or unsubstituted heteroaryl group having six to ten carbon atoms. the substituted aryl group and the heteroaryl group of R4 are independently halogen, an alkyl group having one to four carbon atoms, or an alkoxy group having one to four carbon atoms; X is C or N while Y is O, CONH, NHCO, or []. The number n is an integer in the range of 0 to 4.

Description

[0001] The present invention relates to novel 1,4-substituted piperazine or piperidine compounds and pharmaceutical compositions comprising them,

The present invention relates to novel 1,4-substituted piperazine or piperidine compounds.

Depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, phobias and attention-deficit hyperactivity disorder are diseases caused by a variety of cerebral nervous system disorders, and as the social, economic and environmental conditions have changed dramatically recently, have.

Depression is explained by a lack of norepinephrine, serotonin and dopamine in certain areas of the brain, and substances that block reuptake are known to improve depression.

Anxiety disorders are associated with norepinephrine and serotonin neurotransmitters, and occasionally dopamine D2 receptor blockers may be used as therapeutic agents in patients with anxiety disorders.

Panic disorders are associated with norepinephrine and the serotonin nervous system, and obsessive-compulsive disorder is due to serotonin depression or dysregulation, and dopamine is also known to be involved.

Serotonin reuptake inhibitor, selective serotonin reuptake inhibitor, and monoamine oxidase inhibitor, which increases the activity of dopamine, have been reported to be effective for the treatment of phobias.

Attention deficit hyperactivity disorder is closely associated with the dopamine and norepinephrine nervous system, and dopamine and norepinephrine reuptake inhibitors ameliorate the symptoms of attention deficit hyperactivity disorder.

Drugs have been developed to treat these diseases, but as side effects such as dry mouth, constipation, dysuria, visual impairment, erectile dysfunction or cardiovascular side effects are discovered, new drugs that can replace existing drugs are needed .

Korea Patent No. 0149280

The present invention is directed to a novel 1,4-substituted piperazine or piperidine compound and a pharmaceutical composition comprising the same.

1. A compound of the formula 1: < EMI ID =

[Chemical Formula 1]

In Formula 1,

이고; n은 0 내지 4의 정수인 것이다.R ₁ and R ₂ are independently of each other hydrogen, halogen, An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or trifluoromethyl; R ₃ is a direct bond, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms; R ₄ is a substituted or unsubstituted aryl group having 6 to 10 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 10 carbon atoms, and the substituted aryl group and heteroaryl group of R ₄ are independently selected from the group consisting of halogen, An alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; X is C or N; Y is O, CONH, NHCO or

ego; and n is an integer of 0 to 4.

2. The compound of the above-mentioned 1, wherein the halogen of R < ₁ > and R < ₂ > are independently of each other F or Cl, or a pharmaceutically acceptable salt thereof.

3. The compound or a pharmaceutically acceptable salt thereof as in 1 above, wherein said heteroaryl group of R < ₄ > has at least one ring heteroatom N.

4. The compound or a pharmaceutically acceptable salt thereof as described in the above 1, wherein the aryl group and the heteroaryl group of R ₄ are each independently substituted with one or more halogen atoms.

5. The compound of the above-mentioned 3, wherein said heteroaryl group is pyridyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof.

이고; 상기 R₁ 및 R₂은 서로 독립적으로 수소 또는 할로겐이고; 상기 R₃은 직접 결합, 탄소수 1 내지 4인 알킬기, 또는 탄소수 2 내지 4인 알케닐이고; 상기 R₄는 비치환된 탄소수 6 내지 10인 아릴기이고; 상기 X는 C 또는 N이고; 상기 n은 0 내지 4의 정수인, 화합물 또는 이의 약제학적으로 허용 가능한 염.6. The method of claim 1, wherein Y is

ego; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms; R ₄ is an unsubstituted aryl group having 6 to 10 carbon atoms; X is C or N; And n is an integer from 0 to 4. The compound or a pharmaceutically acceptable salt thereof.

7. The compound of 1 above, wherein Y is CONH; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond or an alkyl group having 1 to 4 carbon atoms; R ₄ is an unsubstituted aryl group having 6 to 10 carbon atoms; X is C or N; And n is an integer from 0 to 4. The compound or a pharmaceutically acceptable salt thereof.

8. The compound of 1 above, wherein Y is O; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond or an alkyl group having 1 to 4 carbon atoms; Wherein R ₄ is a substituted or unsubstituted aryl group having 6 to 10 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 10 carbon atoms, and the substituted aryl group and heteroaryl group for R ₄ are each independently 1 Or more halogen; X is C or N; And n is an integer from 0 to 4. The compound or a pharmaceutically acceptable salt thereof.

9. A process for preparing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3)

 (2)

(3)

[Chemical Formula 1]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Y and n are each as defined in claim 1, and L is a halogen, methanesulfonate or toluenesulfonate.

10. A pharmaceutical composition comprising at least one compound selected from the group consisting of depression, anxiety disorder, panic disorder, obsessive compulsive disorder, phobias and attention deficit hyperactivity disorder comprising any one of compounds 1 to 8 above or a pharmaceutically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof.

The piperazine or piperidine compound according to the present invention is a novel substance and acts as an optional blocker of at least one of a serotonin transporter, a norepinephrine transporter and a dopamine transporter, prevent. Thus, the novel piperazine or piperidine compounds of the present invention can be used to prevent or treat depression, anxiety disorder, panic disorder, obsessive compulsive disorder, phobias or attention deficit hyperactivity disorder, which are diseases associated with serotonin, norepinephrine or dopamine have.

FIG. 1 shows an example of a process for producing the compounds 1a to 1c.
Fig. 2 shows an example of a process for producing the compounds 2a to 2i and the compounds 3a to 3c.
FIG. 3 shows an example of a process for preparing the compounds 4a, 4b, 5a and 5b.
Fig. 4 shows an example of a process for preparing Compound 6 and compounds 7a to 7i.

Hereinafter, specific embodiments of the present invention will be described. However, this is merely an example and the present invention is not limited thereto.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

이고; n은 0 내지 4의 정수인 것이다. 상기 화학식 1로 표시되는 화합물은 피페라진 또는 피페리딘 화합물이다. In Formula 1, R_One And R₂Are independently of each other hydrogen, halogen, An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or trifluoromethyl; R₃Is a direct bond, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms; R₄Is a substituted or unsubstituted aryl group having 6 to 10 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 10 carbon atoms,₄Substituted aryl group and heteroaryl group are independently of each other substituted by halogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; X is C or N; Y is O, CONH, NHCO or

ego; and n is an integer of 0 to 4. The compound represented by Formula 1 is a piperazine or piperidine compound.

The compound represented by Formula 1 may form a pharmaceutically acceptable salt. In the present specification, the "pharmaceutically acceptable salt" is not particularly limited as it is commonly used in the art to which the present invention belongs, such as inorganic and organic acid addition salts of the compound. For example, an addition salt of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, nitrous acid, phosphorous acid, perchloric acid or bromic acid, and may be acetic acid, methanesulfonic acid, p- toluenesulfonic acid, fumaric acid, It may be an addition salt of an organic acid such as phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, arabic acid, oxalic acid, benzoic acid, embonic acid or aspartic acid or glutamic acid.

As used herein, "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) unless otherwise stated.

As used herein, the term "alkyl group" means a straight or branched saturated hydrocarbon group. May be an alkyl group having 1 to 10 carbon atoms, and preferably an alkyl group having 1 to 4 carbon atoms, unless otherwise defined. The alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl, Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2- Ethylhexyl, 1-ethylbutyl, 1-ethylbutyl, 1-ethylbutyl, 1-ethylbutyl, Pentyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, n-octyl, n-nonyl, n-decyl, isodecyl, 2-propylheptyl and the like.

As used herein, the term "alkenyl group " means a straight or branched unsaturated hydrocarbon group which may have one or more double bonds depending on the chain length. May be an alkenyl group having 2 to 10 carbon atoms, and may preferably be an alkenyl group having 2 to 4 carbon atoms. The alkenyl group is, for example, an alkenyl group such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, , 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, Di-1-yl, hex-1, 4-diene-3-yl, hexa- 1,4-dien-3-yl, hepta-1,4-dien-3-yl, 1,5-dien-3-yl, hepta-1,5-dien-7-yl, hepta- 1,4-diene-3-yl, hepta-1,6-diene-7-yl, hepta-1,6- Yl, octa-1, 4-dien-1-yl, octa-1, 4-dien-2-yl, 1,4-dien-7-yl, octa-1, 5-dien-1-yl, octa- Dien-3-yl, octa-1, 5-dien-4-yl, Di-3-yl, octa-1, 6-dien-4-yl, Decane, deca-1,5-dienyl, deca-1,6-dienyl, deca-1,7-dienyl, deca-1,8-dienyl, deca- 2,6-dienyl, deca-2,7-dienyl, deca-2,8-dienyl, and the like.

As used herein, "alkoxy group" means an alkyl group bonded through an oxygen atom. May be alkoxy having 1 to 10 carbon atoms, and may preferably be an alkoxy group having 1 to 4 carbon atoms. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1- methylpropoxy, 2- methylpropoxy, , 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, , 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, , 2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1-methyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy, and the like.

As used herein, "aryl group" means a monocyclic or polycyclic aromatic hydrocarbon group. May be an aryl group having 5 to 18 carbon atoms, and is preferably an aryl group having 6 to 10 carbon atoms. The aryl group includes, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, naphthacenyl, chrysenyl or pyrenyl, and the like.

As used herein, the term "heteroaryl group" means that the carbon atom of the above-defined aryl group is substituted with at least one heteroatom. The heteroatom may be O, N, or S. May be a heteroaryl group having 5 to 18 carbon atoms, and may preferably be a heteroaryl group having 6 to 10 carbon atoms. Heteroaryl groups include, for example, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuranyl, benzothiazolyl, benzoimidazolyl, pyridyl, quinolinyl, Pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, purinyl, indazolyl, benzotriazolyl, 1,2,3-triazolyl, ≪ / RTI > and the like.

In one embodiment of the present invention, the halogen of R < ₁ > and R < ₂ > may be independently of each other F or Cl.

In one embodiment of the present invention, the heteroaryl group of R ₄ may be one having at least one ring heteroatom N. For example, a heteroaryl group having one or more ring heteroatoms N is selected from the group consisting of benzoimidazolyl, pyridyl, quinolinyl, acridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, Indolyl, purinyl, indazolyl, benzotriazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl or carbazolyl, and the like. Preferably, the heteroaryl group of R < ₄ > may be pyridyl or pyrimidinyl. More preferably, the heteroaryl group of R < ₄ > may be 2-pyridyl or 2-pyrimidinyl.

The substituted aryl group and the heteroaryl group of R < ₄ > may independently be substituted with at least one halogen atom. The halogen may be F or Cl. When substituted with two or more halogen atoms, each halogen atom may be substituted independently of each other.

이고; 상기 R₁ 및 R₂은 서로 독립적으로 수소 또는 할로겐이고; 상기 R₃은 직접 결합, 탄소수 1 내지 4인 알킬기, 또는 탄소수 2 내지 4인 알케닐이고; 상기 R₄는 비치환된 탄소수 6 내지 10인 아릴기이고; 상기 X는 C 또는 N이고; 상기 n은 0 내지 4의 정수일 수 있다. In one embodiment of the present invention, in Formula 1, Y is

ego; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms; R ₄ is an unsubstituted aryl group having 6 to 10 carbon atoms; X is C or N; And n may be an integer of 0 to 4.

In one embodiment of the present invention, Y in the general formula (1) is CONH; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond or an alkyl group having 1 to 4 carbon atoms; R ₄ is an unsubstituted aryl group having 6 to 10 carbon atoms; X is C or N; And n may be an integer of 0 to 4.

In one embodiment of the present invention, in Formula 1, Y is O; R ₁ and R ₂ are independently of each other hydrogen or halogen; R ₃ is a direct bond or an alkyl group having 1 to 4 carbon atoms; Wherein R ₄ is a substituted or unsubstituted aryl group having 6 to 10 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 10 carbon atoms, and the substituted aryl group and heteroaryl group for R ₄ are each independently 1 Or more halogen; X is C or N; And n may be an integer of 0 to 4.

In one embodiment of the present invention, the compound represented by Formula 1 according to the present invention is more specifically described below.

1- (2- (5-benzhydryl -1 H - tetrazol-1-yl) ethyl) -4-benzyl-piperidine (compound 1a);

1- (3- (5-benzhydryl -1 H - tetrazol-1-yl) propyl) -4-benzyl-piperidine (compound 1b);

1- (4- (5-benzhydryl -1 H - tetrazol-1-yl) butyl) -4-benzyl-piperidine (compound 1c);

1- (2- (5-benzhydryl -1 H - tetrazol-1-yl) ethyl) -4-benzyl-piperazine (compound 2a);

1- (2- (5-benzhydryl -1 H - tetrazol-1-yl) propyl) -4-benzyl-piperazine (compound 2b);

1- (4- (5-benzhydryl -1 H - tetrazol-1-yl) butyl) -4-benzyl-piperazine (compound 2c);

1- (2- (5-benzhydryl -1 H - tetrazol-1-yl) ethyl) -4-phenethyl-piperazine (compound 2d);

1- (2- (5-benzhydryl -1 H - tetrazol-1-yl) propyl) -4-phenethyl-piperazine (compound 2e);

1- (4- (5-benzhydryl -1 H - tetrazol-1-yl) butyl) -4-phenethyl-piperazine (compound 2f);

1- (2- (5-Benzhydryl-1H-tetrazol-1-yl) ethyl) -4- (3-phenylpropyl) piperazine (Compound 2g);

1- (3- (5-benzhydryl -1 H - tetrazol-1-yl) propyl) -4- (3-phenylpropyl) piperazine (compound 2h);

1- (4- (5-benzhydryl -1 H - tetrazol-1-yl) butyl) -4- (3-phenylpropyl) piperazine (Compound 2i);

(E) -1- (2- (5- benzhydryl -1 H - tetrazol-1-yl) ethyl) -4- (3-phenyl-prop-1-en-1-yl) piperazine (compound 3a);

(E) -1- (3- (5- benzhydryl -1 H - tetrazol-1-yl) propyl) -4- (3-phenyl-prop-1-en-1-yl) piperazine (compound 3b);

(E) -1- (4- (5- benzhydryl -1 H - tetrazol-1-yl) butyl) -4- (3-phenyl-prop-1-en-1-yl) piperazine (compound 3c);

N - (2- (4-benzylpiperidin-1-yl) ethyl) -2,2-diphenylacetamide (Compound 4a);

N - (2- (4-benzylpiperidin-1-yl) ethyl) -2,2-bis (4-chlorophenyl) acetamide (compound 4b);

N - (3- (4-benzylpiperidin-1-yl) propyl) -2,2-diphenylacetamide (Compound 5a);

N - (3- (4-benzylpiperidin-1-yl) propyl) -2,2-bis (4-chlorophenyl) acetamide (compound 5b);

4-benzyl-1- (2- (bis (4-fluorophenyl) methoxy) ethyl) piperidine (Compound 6);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4-phenylpiperazine (Compound 7a);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (2-chlorophenyl) piperazine (Compound 7b);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (3-chlorophenyl) piperazine (Compound 7c);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (4-chlorophenyl) piperazine (Compound 7d);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (2,3-dichlorophenyl) piperazine (Compound 7e);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (2,4-dichlorophenyl) piperazine (Compound 7f);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (3,4-dichlorophenyl) piperazine (Compound 7g);

1- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -4- (pyridin-2-yl) piperazine (Compound 7h);

2- (4- (2- (Bis (4-fluorophenyl) methoxy) ethyl) -piperazin-1-ylpyrimidine (Compound 7i).

The present invention provides a process for preparing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3)

(2)

(3)

[Chemical Formula 1]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Y and n are as defined in Formula 1, and L is a halogen, methanesulfonate or toluenesulfonate.

In one embodiment of the present invention, the compound represented by the formula (1) can be prepared by reacting the compound represented by the formula (2) with the compound represented by the formula (3) in the presence of a solvent and a base. The solvent usable in the above reaction is not particularly limited, but a solvent capable of dissolving the above compounds may be used. Specifically, the solvent may be at least one selected from the group consisting of dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylene glycol monomethyl ether, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol , Propanol, butanol or toluene, or a mixture of two or more solvents.

The base usable in the reaction may be an organic base such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine or pyridine, sodium carbonate (Na ₂ CO _{3 )} ), potassium carbonate (K ₂ CO ₃ ) an inorganic base such as sodium hydride (NaH).

The reaction may further comprise a catalyst. The catalysts usable for the reaction include NaI and KI.

In one embodiment of the present invention, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is prepared by reacting a compound represented by the formula (2), a compound represented by the formula (3), a solvent and a base And reacting the mixture. The step of reacting may be to raise the temperature of the mixture to react, and the mixture may be refluxed and reacted. The reaction temperature in the step of reacting may be from 0 to 150 ° C, preferably from room temperature to 100 ° C. Or the catalyst may be added to the mixture in the reacting step. And after the reaction of the mixture is completed, separating the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof from the reaction product.

L in Formula 2 represents a group in which the compound represented by Formula 2 and the compound represented by Formula 3 are separated in the reaction process. The L may be a halogen, a methane sulfonate or a toluene sulfonate.

In one embodiment of the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is prepared by heating the mixture comprising the compound represented by Formula 2, the compound represented by Formula 3, the solvent and the base ≪ / RTI > Or by refluxing a mixture containing the compound represented by the formula (2), the compound represented by the formula (3), the solvent, the base and the catalyst.

In one embodiment of the present invention, some of the compounds of Formula 1 (compounds 1a to 1c) of the present invention may be prepared as shown in Scheme 1 below.

[Reaction Scheme 1]

Compound 8 is reacted with NaN ₃ and TEA-HCl to produce compound 9.

Then, Compound 10a, 10b or 10c can be prepared by reacting Compound 9 with Br (CH ₂ ) _n Cl. The compound Br (CH ₂ ) _n Cl is a halogen- (CH ₂ ) _n -halogen structure, and the halogen is released during the reaction to provide an alkyl group such as - (CH ₂ ) _n - to the compound 9. Accordingly, compounds which can provide an alkyl group such as - (CH ₂ ) _n - to compound 9 instead of the compound Br (CH ₂ ) _n Cl can be used.

Then, the compound 10a, 10b or 10c is reacted with 4-benzylpiperidine to prepare a compound 1a, 1b or 1c.

In each of the reaction steps of Scheme 1, organic bases such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine, pyridine and the like; (Na ₂ CO _{3 )} or potassium carbonate (K ₂ CO ₃ ) sodium hydride (NaH) to the reaction solution. The solvent used in the reaction is dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylene glycol monomethyl ether (DGME), N, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol , Butanol or toluene. The reaction may include heating or refluxing. The reaction temperature may be from 0 to 150 ° C, preferably from room temperature to 100 ° C. The reaction can be carried out with or without the addition of NaI, KI or the like.

Specifically, a mixture containing the compound 10a, 10b or 10c, 4-benzylpiperidine, a solvent and a base may be heated to prepare the compound 1a, 1b or 1c, respectively, or the compound 10a, 10b or 10c, A mixture containing 4-benzylpiperidine, a solvent, a base and a catalyst may be refluxed to prepare compounds 1a, 1b or 1c, respectively. FIG. 1 shows an example of a process for producing the compounds 1a to 1c.

In one embodiment of the invention, some of the compounds of Formula 1 (compounds 2a to 2i and compounds 3a to 3c) of the present invention may be prepared as shown in Scheme 2 below.

와 반응시켜 화합물 12a, 12b 또는 12c를 제조하고,

와 반응시켜 화합물 13을 제조한다. The compound 11

To prepare a compound 12a, 12b or 12c,

To give compound 13.

Compound 12a, 12b or 12c is reacted with trifluoroacetic acid (TFA) to prepare compound 14a, 14b or 14c, respectively, and compound 13 is reacted with TFA to prepare compound 15. TFA removes the Boc group (tert-butyloxycarbonyl) of the compound 12a, 12b, 12c or 13. A compound capable of removing the Boc group in place of the compound TFA can be used.

2b, 2c, 2d, 2e, 2f, 2g, 2h or 2i is prepared by reacting compound 12a, 12b or 12c with compound 10a, 10b or 10c, To prepare a compound 3a, 3b or 3c.

In each of the reaction steps of Reaction Scheme 2, organic bases such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine, and pyridine; (Na ₂ CO _{3 )} or potassium carbonate (K ₂ CO ₃ ) sodium hydride (NaH) to the reaction solution. The solvent used in the reaction may be selected from the group consisting of dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylene glycol monomethyl ether (DGME), N, N-dimethylformamide, tetrahydrofuran (THF), acetonitrile, Ethanol, propanol, butanol or toluene. The reaction may include heating or refluxing. The reaction temperature may be from 0 to 150 ° C, preferably from room temperature to 100 ° C. The reaction can be carried out with or without the addition of NaI, KI or the like.

2b, 2c, 2d, 2e, 2f, 2g, 2h or 2i, respectively, by raising the temperature of the mixture containing the compound 12a, 12b or 12c, the compound 10a, 10b or 10c, Or a mixture containing the compound 15, the compound 10a, 10b or 10c, the solvent, the base and the catalyst may be refluxed to prepare the compound 3a, 3b or 3c, respectively. Fig. 2 shows an example of a process for producing the compounds 2a to 2i and the compounds 3a to 3c.

In one embodiment of the invention, some of the compounds of Formula 1 (compounds 4a-4b and 5a-5b) of the present invention may be prepared as shown in Scheme 3 below.

[Reaction Scheme 3]

Compound 17a 'or 17b' is prepared by reacting Compound 17a or 17b with SOCl ₂ or C ₆ H ₆ . SOCl ₂ serves to convert the carboxylic acid to the carbonyl chloride in the reaction and C ₆ H ₆ serves as the solvent in the reaction. Instead of the compound SOCl ₂ , compounds such as oxalyl chloride and phosphorus oxychloride, which can serve to convert the carboxylic acid to the carbonyl chloride, can be used, and as a substitute for the compound C ₆ H ₆ , Such as toluene, may be used.

The compound 17a 'or 17b' is then reacted with HCl-H ₂ N (CH ₂ ) _n Cl or HBr-H ₂ N (CH ₂ ) _n Br to produce compounds 18a, 18b, 19a or 19b.

Compound 4a, 4b, 5a or 5b is then prepared by reacting compound 18a, 18b, 19a or 19b with 4-benzylpiperidine.

In each reaction step of Scheme 3, organic bases such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine, pyridine and the like; (Na ₂ CO _{3 )} or potassium carbonate (K ₂ CO ₃ ) sodium hydride (NaH) to the reaction solution. The solvent used in the reaction is dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylene glycol monomethyl ether (DGME), N, N-dimethylformaldehyde, tetrahydrofuran (THF), acetonitrile, Ethanol, propanol, butanol or toluene. The reaction may include heating or refluxing. The reaction temperature may be from 0 to 150 ° C, preferably from room temperature to 100 ° C. The reaction can be carried out with or without the addition of NaI, KI or the like.

Specifically, a mixture containing the compound 18a, 18b, 19a or 19b, 4-benzylpiperidine, a solvent and a base may be heated to prepare the compound 4a, 4b, 5a or 5b, 18b, 19a or 19b, 4-benzylpiperidine, a solvent, a base and a catalyst can be refluxed to prepare compounds 4a, 4b, 5a or 5b, respectively. FIG. 3 shows an example of a process for preparing the compounds 4a, 4b, 5a and 5b.

In one embodiment of the present invention, some of the compounds of Formula 1 (Compound 6 and 7a to 7i) of the present invention can be prepared as shown in Reaction Scheme 4 below.

[Reaction Scheme 4]

7b, 7c, 7d, 7e, 7f, 7g, 7h or 7i were prepared by reacting the compound 21 with the compounds 23a, 23b, 23c, 23d, 23e, 23f, 23g, Compound 21 is reacted with 4-benzylpiperidine to give compound 6.

In each reaction step of Scheme 4, organic bases such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine, and pyridine; (Na ₂ CO _{3 )} or potassium carbonate (K ₂ CO ₃ ) sodium hydride (NaH) to the reaction solution. The solvent used in the reaction is dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylene glycol monomethyl ether (DGME), N, N-dimethylformaldehyde, tetrahydrofuran (THF), acetonitrile, Ethanol, propanol, butanol or toluene. The reaction may include heating or refluxing. The reaction temperature may be from 0 to 150 캜, preferably from 25 to 100 캜. The reaction can be carried out with or without the addition of NaI, KI or the like.

Specifically, the mixture containing the compound 21, the compound 23a, 23b, 23c, 23d, 23e, 23f, 23g, 23h or 23i, the solvent and the base was heated to obtain the compounds 7a, 7b, 7c, 7d, 7e, 7f , 7g, 7h or 7i, or the mixture containing the compound 21, the compound 23a, 23b, 23c, 23d, 23e, 23f, 23g, 23h or 23i, the solvent, the base and the catalyst is refluxed Compounds 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h or 7i can be prepared.

Or a mixture containing the compound 21, 4-benzylpiperidine, a solvent and a base can be heated to raise the respective compound 6, or the compound 21, 4-benzylpiperidine, a solvent, a base and a catalyst Is refluxed to give Compound 6. Fig. 4 shows an example of a process for preparing Compound 6 and compounds 7a to 7i.

The present invention also provides at least one prophylactic or therapeutic agent selected from the group consisting of depression, anxiety disorder, panic disorder, obsessive compulsive disorder, phobias and attention deficit hyperactivity disorder comprising a compound of the invention or a pharmaceutically acceptable salt thereof, Gt;

The compounds of the present invention act as selective blockers of at least one of a serotonin transporter, a norepinephrine transporter and a dopamine transporter to prevent the reabsorption of neurotransmitters with high efficiency.

Depression is explained by a lack of norepinephrine, serotonin and dopamine in certain areas of the brain, and substances that block reuptake are known to improve depression. A selective serotonin reuptake inhibitor (SSRI) is a drug that inhibits serotonin reuptake in the brain and has a mechanism to increase insufficient serotonin. Fluoxetine is the most common treatment for depression. Norepinephrine is associated with brain functions such as energy, interest, and motivation, and people with depression have found that norepinephrine is deficient. Dopamine is associated with psychotic symptoms or mood swings. Decreased dopamine activity is associated with depression, and is associated with symptoms such as weakness, decreased motivation, and decreased vitality.

Anxiety disorders are associated with norepinephrine and the serotonin nervous system. Patients with anxiety disorders are known to be unable to function properly with the noradrenalinergic nervous system. Norepinephrine neurons are extensively transcribed from the locus ceruleus to the cerebral cortex, limbic system, spinal cord, etc. In animal experiments, the stimulation of blue nuclei induces a panic reaction, and when the same site is removed, the panic reaction disappears It is known. Anxiety can be caused by various psychological or physical stimuli.

In addition, SSRIs have been used as an anxiety medication since antidepressants that increase serotonin have been reported to be effective in some anxiety disorders. Occasionally, a small amount of an antipsychotic drug, a dopamine D2 receptor blocker, is used in some anxiety disorders. This is particularly the case when anxiety is so extreme that it leads to catastrophic events or when hyperactivity of basal ganglia causes behavioral symptoms of anxiety disorders.

Panic disorder is an anxiety disorder in which severe anxiety attacks and accompanying various physical symptoms occur suddenly without any notice. The cause of panic disorder is known to be abnormal neurotransmitter systems such as norepinephrine, serotonin, and GABA. Panic disorder is characterized by a decrease in serotonin function due to abnormalities in the brain frontal lobe, and is known to be closely related to depression. Therefore, SSRIs that suppress serotonin reuptake are used as therapeutic agents. Serotonin-norepinephrine reuptake inhibitor (SNRI) has also been shown to be effective in the treatment of various anxiety disorders including panic disorder.

Obsessive-compulsive disorder is a persistent and repetitive disorder of obsessive-compulsive thinking or obsessive behavior. It is known that depression of serotonin function or increase of susceptibility to serotonin receptor due to abnormal blood flow in the frontal lobe and basal part of the brain is the cause of OCD. Therefore, taking SSRI, a serotonin-uptake inhibitor, is the primary treatment. In addition to serotonin, dopamine is also known to be associated with OCD.

As a phobia treatment, selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor are used. It is also reported that monoamine oxidase inhibitors that increase the activity of dopamine are effective for treatment.

Attention deficit hyperactivity disorder (ADHD) is closely related to the dopamine and norepinephrine nervous systems, and dopamine and norepinephrine reuptake inhibitors are known to improve ADHD symptoms.

Thus, the compounds of the present invention act as selective blockers of at least one of the serotonin transporter, the norepinephrine transporter and the dopamine transporter to prevent the reabsorption of neurotransmitters with high efficiency, , Obsessive compulsive disorder, phobias, and attention deficit hyperactivity disorder.

The pharmaceutical composition may further comprise a known active ingredient having at least one prophylactic or therapeutic activity selected from the group consisting of depression, anxiety disorder, panic disorder, obsessive compulsive disorder, phobia and attention deficit hyperactivity disorder .

The pharmaceutical composition may further comprise a carrier, an excipient or a diluent. The carrier, excipient and diluent may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.

Each of the above pharmaceutical compositions may be formulated into oral or parenteral administration forms according to conventional methods. The pharmaceutical compositions may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. In the case of formulation, it can be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used.

In the above pharmaceutical composition, the solid preparation for oral administration may be a tablet, a pill, a powder, a granule, or a capsule. The pharmaceutical composition may further comprise a carrier, an excipient, or a diluent. The carrier, excipient or diluent may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, the solid preparation may further comprise a lubricant such as magnesium stearate or talc.

In the above pharmaceutical composition, the liquid preparation for oral administration may be a suspension, a solution, an emulsion, or a syrup. The liquid formulation may comprise water, or liquid paraffin. The liquid preparations may contain excipients such as wetting agents, sweetening agents, perfumes, or preservatives.

In the above pharmaceutical composition, the preparation for parenteral administration may be a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized or a left-over. Non-aqueous solvents or suspensions may include vegetable oils or esters. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The suppository base may be witepsol, macrogol, tween 61, cacao paper, laurin, or glycerogelatin.

The preferred dosage of the pharmaceutical composition varies depending on the condition and the weight of the patient, the severity of the disease, the type of the drug, the route of administration and the period of time, but can be appropriately selected by a method generally applicable to the technical field of the present invention have. However, the compound represented by the above-mentioned formula 1 or a pharmaceutically acceptable salt thereof may be administered in an amount of, for example, about 0.0001 mg / kg body weight to about 100 mg / kg body weight, or about 0.001 mg / kg body weight to about 10 mg / May be administered once or several times per day. In addition, the pharmaceutical composition according to the present invention can be administered in various routes to mammals including mice, mice, livestock, and humans. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous or intra-dermal injection.

The following abbreviations have the following meaning unless otherwise specified and any other abbreviations used and not defined herein have their standard meaning:

ADHD: Attention deficit / hyperactivity disorder

Boc: tert-butyloxycarbonyl (tert-butyloxycarbonyl)

EtOAc: ethyl acetate < RTI ID = 0.0 >

DAT: dopamine transporter

DGME: diethylene glycol monomethyl ether (diethylene glycol monomethyl ether)

DMSO: dimethyl sulfoxide

MeOH: methanol

Mp: melting point

NET: norepinephrine transporter

Rf: retention factor

SERT: Serotonin (5-HT) transporter

SNRI: Serotonin-norepinephrine reuptake inhibitor (Serotonin-norepinephrine reuptake inhibitor)

SSRI: selective serotonin reuptake inhibitor

TEA: triethylamine

TMA: trimethylamine

THF: tetrahydrofuran < RTI ID = 0.0 >

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to be illustrative of the invention and are not intended to limit the scope of the claims. It will be apparent to those skilled in the art that such variations and modifications are within the scope of the appended claims.

Example

Example  1. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) ethyl) -4- Benzylpiperidine  (Compound 1a) Synthesis of

A mixture of compound 10a (140 mg, 0.47 mmol), 4-benzylpiperidine (0.1 mL, 0.56 mmol), TEA (0.19 mL, 1.41 mmol) and DMSO (1.5 mL) . After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate (EtOAc). The organic layer was dried over magnesium sulfate (MgSO ₄₎ and filtered and concentrated. The resulting material was purified by column chromatography on silica gel. The mobile phase was n-hexane: EtOAc: MeOH (10: 1.5: 0.5) to give a pale brown liquid compound la (72 mg, 36%).

_Rf = 0.60 (n-hexane: EtOAc = 1: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.32-7.13 (m, 14H, overlapped with CHCl 3), 7.11-7.08 (m, 2H), 5.80 (s, 1H), 4.66-4.61 (m, 2H), 2.92 - 2.87 (m, 2H), 2.79 (d, J = 11.4 Hz, 2H), 2.47 (d, J < RTI ID = 0.0 & = 6.9 Hz, 2H), 2.0-1.92 (m, 2H), 1.57-1.38 (m, 3H), 1.25-1.12 (m, 2H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 167.7, 140.9, 140.6, 129.2, 128.8, 128.6, 128.3, 127.0, 125.9, 56.8, 53.7, 50.7, 48.6, 43.2, 37.7, 32.1.

Example  2. 1- (3- (5- Benzhydrill -One H - Tetrazole Yl) propyl) -4- Benzylpiperidine  (Compound 1b) Synthesis of

The preparation of example 1 was followed except that a mixture of compound 10b (300 mg, 0.95 mmol), 4-benzylpiperidine (0.20 mL, 1.14 mmol), TEA (0.39 mL, 2.85 mmol) and DMSO To give Compound 1b (340 mg, 79%) as a pale brown liquid.

_Rf = 0.66 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.33-7.10 (m, 17H, overlapped with CHCl 3), 5.79 (s, 1H), 4.63-4.58 (m, 2H), 2.79 (d, J = 11.7 Hz, 2H), 2.49 (d, J = 6.9 Hz, 2H), 2.32-2.27 (m, 2H), 2.17-2.08 (m, 2H), 1.85-1.76 , 1.30-1.16 (m, 2H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 167.8, 140.7, 140.4, 129.1, 128.7, 128.6, 128.2, 127.0, 125.9, 55.1, 53.7, 51.3, 48.6, 42.9, 37.7, 31.6, 26.3.

Example  3. 1- (4- (5- Benzhydrill -One H - Tetrazole Yl) butyl) -4- Benzylpiperidine  (Compound 1c) Synthesis of

The title compound was prepared following the procedure used in the preparation of Example 1 except that a mixture of compound 10c (300 mg, 0.91 mmol), 4-benzylpiperidine (0.20 mL, 1.09 mmol), TEA (0.38 mL, 2.73 mmol) and DMSO (2 mL) The compound 1c (296 mg, 70%) was obtained as a pale brown liquid.

_Rf = 0.62 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.37-7.16 (m, 15H), 5.83 (s, 1H), 4.63-4.60 (m, 2H), 2.83 (d, J = 6.9 Hz, 2H), 2.55 ( d, J = 4.5 Hz, 2H ), 2.34-2.31 (m, 2H), 2.07-2.01 (m, 2H), 1.85-1.80 (m, 2H), 1.63 (d, J = 7.8 Hz, 2H), 1.55 -1.49 (m, 3H), 1.39 - 1.25 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ): δ 167.8, 140.8, 140.5, 129.1, 128.7, 128.6, 128.2, 127.0, 125.9, 57.7, 53.7, 52.9, 48.6, 43.0, 37.7, 31.7, 27.3, 23.4.

Example  4. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) ethyl) -4- Benzylpiperazine  (Compound 2a)

The compound 14a, alkylpiperazine (264, 1.5 mmol), K (30 mg, 1 mmol), compound 10a, and the haloalkyl-5-benzhydryl-1H- tetrazole ₂ CO ₃ (276 mg, 2 mmol), NaI (catalyst) and CH ₃ CN (15 mL) was refluxed. After the reaction was complete, the reaction was cooled, filtered and concentrated. The resulting material was purified by column chromatography on silica gel. The mobile phase was n-hexane: EtOAc: MeOH (10: 1.5: 0.5) to give pale brown liquid compound 2a (131 mg, 30%).

_Rf = 0.56 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.35-7.24 (m, 15H), 5.84 (s, 1H), 4.72-4.69 (m, 2H), 3.49 (s, 2H), 3.04-2.97 (m, 2H ), 2.53-2.42 (m, 8H); ^{13 C} NMR (125 MHz, CDCl ₃ ):? 167.7, 140.9, 138.0, 129.2, 128.8, 128.6, 128.2, 127.1, 127.0, 63.0, 56.4, 52.9, 52.8, 50.5, 48.6.

Example  5. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) propyl) -4- Benzylpiperazine  (Compound 2b) Synthesis of

Except that a mixture of Compound 10b (300 mg, 0.96 mmol), Compound 14a (253 mg, 1.44 mmol), K ₂ CO ₃ (265 mg, 1.92 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to obtain a pale brown liquid compound 2b (261 mg, 60%).

_Rf = 0.59 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.43-7.25 (m, 15H), 5.90 (s, 1H), 4.65 (t, J = 7 Hz, 2H), 3.54 (s, 2H), 2.48-2.39 ( m, 10 H), 2.20 - 2.15 (m, 2 H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 167.7, 140.8, 138.3, 129.2, 128.8, 128.7, 128.3, 127.11, 127.1, 63.1, 54.9, 53.1, 51.4, 48.7, 26.7.

Example  6. 1- (4- (5- Benzhydrill -One H - Tetrazole Yl) butyl) -4- Benzylpiperazine  (Compound 2c) Synthesis of

Except that a mixture of Compound 10c (400 mg, 1.22 mmol), Compound 14a (322 mg, 1.83 mmol), K ₂ CO ₃ (337 mg, 2.44 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to obtain a pale brown liquid compound 2c (296 mg, 52%).

_Rf = 0.56 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.38-7.23 (m, 15H), 5.86 (s, 1H), 4.61 (t, J = 7 Hz, 2H), 3.54 m, 10H), 2.07-2.02 (m, 2H), 1.52-1.49 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 167.8, 140.9, 138.2, 129.2, 128.7, 128.6, 128.2, 127.1, 127.0, 63.1, 57.6, 53.2, 53.1, 53.0, 48.7, 27.4, 23.6.

Example  7. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) ethyl) -4- Phenethylpiperazine  (Compound 2d) Synthesis of

The same procedure as in Example 1 was followed except that a mixture of compound 10a (300 mg, 3 mmol), compound 14b (285 mg, 1.5 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) (95 mg, 21%) was obtained as a white solid.

_Rf = 0.32 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1). Mp = 95-99 [deg.] C.

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.35-7.22 (m, 17H, overlapped with CHCl 3), 5.85 (s, 1H), 4.72 (t, J = 6.5 Hz, 2H), 3.0 (t, J = 6.5 Hz, 2H), 2.83-2.79 (m, 2H), 2.61-2.50 (m, 10H); _{^{13 CNMR (125MHz, CDCl 3)}} : δ167.7, 140.9, 140.2, 129.1, 128.8, 128.6, 128.7, 128.68, 128.6, 128.58, 128.4, 128.0, 127.2, 127.0, 126.1, 60.5, 56.4, 53.0, 52.9, 50.5 , 48.6, 33.7.

Example  8. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) propyl) -4- Phenethylpiperazine  (Compound 2e) Synthesis of

Similar to the preparation method of Example 1 except that a mixture of Compound 10b (300 mg, 0.96 mmol), Compound 14b (274 mg, 1.44 mmol), TEA (0.41 mL, 2.88 mmol) and DMSO (2 mL) To obtain Compound 2e (360 mg, 80%) as a pale brown liquid.

_Rf = 0.63 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (400 MHz, CDCl 3}} ): δ 7.34-7.15 (m, 16H, overlapped with CHCl 3), 5.80 (s, 1H), 4.65-4.62 (m, 2H), 2.80-2.76 (m, 2H), 2.58-2.35 (m, 12H), 2.18-2. 11 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 167.7, 140.8, 140.2, 128.7, 128.71, 128.6, 128.4, 127.0, 126.0, 60.4, 54.9, 53.0, 51.4, 48.7, 33.6, 26.6.

Example  9. 1- (4- (5- Benzhydrill -One H - Tetrazole Yl) butyl) -4- Phenethylpiperazine  (Compound 2f) Synthesis of

Similar to the preparation method of Example 1 except that a mixture of Compound 10c (330 mg, 1 mmol), Compound 14b (285 mg, 1.2 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) To obtain Compound 2f (202 mg, 42%) as a pale brown liquid.

_Rf = 0.36 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.36-7.20 (m, 16H, overlapped with CHCl 3), 5.83 (s, 1H), 4.64-4.61 (m, 2H), 2.84-2.80 (m, 2H), 2.63-2.36 (m, 12H), 2.08-2.02 (m, 2H), 1.56-1.50 (m, 2H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 167.8, 140.8, 140.3, 128.7, 128.6, 128.4, 127.0, 126.1, 60.6, 57.6, 53.2, 53.16, 53.0, 48.6, 33.7, 27.4, 23.6.

Example  10. 1- (2- (5- Benzhydrill -One H - Tetrazole Yl) ethyl) -4- (3- Phenylpropyl ) ≪ / RTI > Synthesis of piperazine (Compound 2g)

Similar to the preparation method of Example 1 except that a mixture of Compound 10a (300 mg, 1 mmol), Compound 14c (306 mg, 1.5 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) 2 g (116 mg, 25%) of a pale brown liquid compound was obtained.

_Rf = 0.32 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.35-7.19 (m, 17H, overlapped with CHCl 3), 5.85 (s, 1H), 4.71 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H), 2.66-2.34 (m, 12H), 1.86-1.79 (m, 2H); _{^{13 CNMR (125MHz, CDCl 3)}} : δ167.7, 142.1, 140.9, 140.2, 137.6, 129.1, 128.8, 128.72, 128.7, 128.6, 128.57, 128.4, 128.3, 128, 127.2, 127.1, 127, 125.8, 57.9, 56.5 , 53.0, 52.9, 50.5, 48.6, 33.7, 28.6.

Example  11. 1- (3- (5- Benzhydrill -One H - Tetrazole -1-yl) propyl) -4- (3- Phenylpropyl ) Piperazine (Compound 2h) Synthesis

Similar to the preparation method of Example 1 except that a mixture of Compound 10b (300 mg, 0.95 mmol), Compound 14c (291 mg, 1.42 mmol), TEA (0.39 mL, 2.85 mmol) and DMSO (2 mL) To give compound 2h (375 mg, 82%) as a pale brown liquid.

_Rf = 0.63 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (400 MHz, CDCl 3}} ): δ 7.33-7.11 (m, 16H, overlapped with CHCl 3), 5.79 (s, 1H), 4.58-4.55 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.38-2.29 (m, 2H), 2.13-2.06 (m, 2H), 1.81-1.74 (m, 2H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 167.7, 142.2, 140.9, 128.8, 128.6, 128.5, 128.4, 127.0, 125.8, 58.0, 54.9, 53.2, 51.4, 48.7, 33.8, 28.7, 26.6.

Example  12. 1- (4- (5- Benzhydrill -One H - Tetrazole -1-yl) butyl) -4- (3- Phenylpropyl ) Piperazine (Compound 2i) Synthesis

Similar to the preparation method of Example 1 except that a mixture of Compound 10c (330 mg, 1 mmol), Compound 14c (306 mg, 1.2 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) To give compound 2i (190 mg, 38%) as a pale brown liquid.

_Rf = 0.36 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.35-7.18 (m, 16H, overlapped with CHCl 3), 5.82 (s, 1H), 4.62 (t, J = 4.2 Hz, 2H), 2.66-2.34 (m, 14H), 2.07-2.01 (m, 2H), 1.86-1.80 (m, 2H), 1.54-1.48 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ): δ 167.8, 142.1, 140.8, 128.7, 128.6, 128.4, 128.3, 127.0, 125.8, 58.0, 57.6, 53.2, 53, 48.6, 33.7, 28.7, 27.4, 23.6.

Example  13. ( E ) -1- (2- (5- Benzhydrill -One H - Tetrazole Yl) ethyl) -4- (3- Phenylprop -1-en-1-yl) piperazine (Compound 3a)

A mixture of compound 10a (500 mg, 1.67 mmol), piperazine (compound 16, 506 mg, 2.50 mmol), K ₂ CO ₃ (461 mg, 3.34 mmol), NaI (catalyst) and CH ₃ CN (30 mL) The procedure of Example 4 was repeated except that the compound 3a (350 mg, 45%) was obtained as a pale brown liquid.

_Rf = 0.44 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.42-7.23 (m, 15H), 6.55 (d, J = 15.5 Hz, 1H), 6.33-6.27 (m, 1H), 5.87 (s, 1H), 4.70 ( t, J = 6.5 Hz, 2H), 3.16 (dd, J = 7,1 Hz, 2H), 3.07-2.98 (m, 2H), 2.56-2.48 (m, 8H); ^{13 C} NMR (125 MHz, CDCl ₃ ):? 167.7, 140.9, 136.9, 133.2, 128.8, 128.6, 128.6, 127.6, 127.0, 126.5, 126.4, 61.0, 56.4, 53.1, 52.9, 50.5, 48.6.

Example  14. ( E ) -1- (3- (5- Benzhydrill -One H - Tetrazole -1-yl) propyl) -4- (3- Phenylprop -1-en-1-yl) piperazine (Compound 3b)

A mixture of compound 10b (550 mg, 1.75 mmol), piperazine (compound 16, 531 mg, 2.60 mmol), K ₂ CO ₃ (624 mg, 4.52 mmol), NaI (catalyst) and CH ₃ CN The procedure of Example 4 was repeated except for using the compound 3b (352 mg, 42%) as a pale brown liquid.

_Rf = 0.38 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.42-7.30 (m, 15H), 6.56 (d, J = 15.5 Hz, 1H), 6.37-6.27 t, J = 7 Hz, 2H), 3.16 (dd, J = 7,1 Hz, 2H), 2.48-2.39 (m, 10H), 2.20-2.15 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 167.7, 140.9, 136.9, 133.1, 128.7, 128.6, 127.5, 127.0, 126.6, 126.3, 61.0, 54.9, 53.1, 51.4, 48.7, 26.6.

Example  15. ( E ) -1- (4- (5- Benzhydrill -One H - Tetrazole -1-yl) butyl) -4- (3- Phenylprop -1-en-1-yl) piperazine (Compound 3c)

A mixture of compound 10c (500 mg, 1.53 mmol), piperazine (compound 16, 464 mg, 2.30 mmol), K ₂ CO ₃ (423 mg, 3.06 mmol), NaI (catalyst) and CH ₃ CN (30 mL) The procedure of Example 4 was repeated except for using the compound 3c (264 mg, 35%) as a pale brown liquid.

_Rf = 0.29 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.39-7.20 (m, 15H), 6.55 (d, J = 16 Hz, 1H), 6.30-6.24 t, J = 7 Hz, 2H), 3.18-3.16 (m, 2H), 2.48-2.36 (m, 10H), 2.06-2.00 (m, 2H), 1.54-1. ¹³ CNMR (125 MHz, CDCl ₃ ): δ 167.8, 140.7, 136.8, 133.4, 128.7, 128.6, 127.6, 127.0, 126.3, 126.0, 60.9, 57.4, 52.9, 52.89, 48.6, 27.3, 23.5.

Example  16. N - (2- (4- Benzylpiperidine Yl) ethyl) -2,2- Diphenylacetamide  (Compound 4a) Synthesis of

The title compound was prepared following the procedure used in the preparation of Example 1 except that a mixture of compound 18a (150 mg, 0.54 mmol), 4-benzylpiperidine (0.19 mL, 1.08 mmol), TEA (0.30 mL, 2.16 mmol) and DMSO (2 mL) To obtain Compound 4a (111 mg, 50%) as a pale brown liquid.

_Rf = 0.31 (n-hexane: EtOAc = 1: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.45-7.42 (m, 1H, Ar-H), 7.29-7.20 (m, 12H, Ar-H overlapped with CHCl 3), 7.10-7.08 (m, 3H), 6.51 (s, 1H), 3.30-3.23 (m, 2H), 2.62 (d, J = 11.1 Hz, 2H), 2.46 (d, J = 6.9 Hz, 2H), 2.29 (t, J = 6.15 Hz, 2H ), 1.78 (t, J = 10.8 Hz, 2H), 1.51-1.38 (m, 3H), 1.10-0.95 (m, 2H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 171.8, 140.5, 139.7, 129.1, 129.0, 128.7, 128.4, 128.2, 127.9, 127.6, 127.1, 125.9, 59.2, 56.2, 53.4, 43.2, 37.7, 36.4, 32.0.

Example  17. N - (2- (4- Benzylpiperidine Yl) ethyl) -2,2- Bis (4-chlorophenyl) acetamide  (Compound 4b) Synthesis of

A mixture of the compound of Example 1 (1), except that a mixture of Compound 18b (180 mg, 0.52 mmol), 4-benzylpiperidine (0.18 mL, 1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO To obtain Compound 4b (82 mg, 33%) as a white solid.

_Rf = 0.35 (n-hexane: EtOAc = 1: 1). Mp = 107 [deg.] C.

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.29-7.24 (m, 6H) 7.18-7.12 (m, 7H), 6.50 (s, 1H), 4.83 (s, 1H), 3.28 (q, J = 5.5 Hz , 2H), 2.46 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 6.9 Hz, 2H), 2.33 (t, J = 5.8 Hz, 2H), 1.81 (t, J = 10.8 Hz, 2H ), 1.55-1.37 (m, 3H), 1.04-0.95 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 171.0, 160.8, 140.6, 137.9, 133.3, 130.3, 129.1, 128.9, 128.2, 125.9, 57.1, 56.1, 53.4, 43.2, 37.8, 36.4, 32.2.

Example  18. N - (3- (4- Benzylpiperidine Yl) propyl) -2,2- Diphenylacetamide  (Compound 5a) Synthesis of

The title compound was prepared from the compound of Example 1, except for using a mixture of Compound 19a (350 mg, 1.05 mmol), 4-benzylpiperidine (0.37 mL, 2.1 mmol), TEA (0.58 mL, 4.2 mmol) and DMSO (237 mg, 53%) was obtained as a white solid.

_Rf = 0.40 (n-hexane: EtOAc = 1: 1). Mp = 115 [deg.] C.

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.54-7.01 (m, 17H, overlapped with CHCl 3), 4.79 (s, 1H), 3.29 (q, J = 5.7 Hz, 2H), 2.75 (d, J = 10.8 Hz, 2H), 2.49 ( d, J = 6.6 Hz, 2H), 2.29 (t, J = 6.3 Hz, 2H), 1.74 (t, J = 11.1 Hz), 1.59-1.43 (m, 5H), 1.14 -1.03 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 171.8, 140.9, 139.6, 128.9, 128.7, 128.4, 128.0, 126.9, 125.7, 59.0, 57.2, 53.7, 42.9, 39.4, 37.6, 31.9, 25.1.

Example  19. N - (3- (4- Benzylpiperidine Yl) propyl) -2,2- Bis (4-chlorophenyl) acetamide  (Compound 5b) Synthesis of

The title compound was prepared from the compound of Example 1, except for using a mixture of Compound 19b (200 mg, 0.49 mmol), 4-benzylpiperidine (0.17 mL, 0.98 mmol), TEA (0.27 mL, 2.96 mmol) and DMSO (2 mL) , To obtain a pale brown liquid compound 5b (84 mg, 35%).

_Rf = 0.30 (n-hexane: EtOAc = 1: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.64 (t, J = 4.0 Hz, 1H -CONH), 7.36-7.25 (m, 7H, Ar-H, overlapped with CHCl 3), 7.20-7.16 (m, 2H ), 3.35 (q, J = 5.7 Hz, 2H), 2.80 (d, J = 11.7 Hz, 2H), 2.51 (d, J = 6.9 Hz, 2H), 2.36 (t, J = 6.1, 2H), 1.83 -1.75 (m, 2H), 1.66-1.45 (m, 5H), 1.11-1.02 (m, 2H); ¹³ CNMR (75 MHz, CDCl ₃ ):? 170.7, 140.2, 137.9, 133.2, 130.0, 129.1, 128.8, 128.2, 125.9, 57.70, 57.66, 53.8, 43.0, 40.0, 37.7, 32.0, 24.6.

Example  20. 4- benzyl -1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) piperidine (Compound 6) of  synthesis

A mixture of compound 21 (100 mg, 0.35 mmol), 4-benzylpiperidine (0.12 mL, 0.70 mmol), K ₂ CO ₃ (96 mg, 0.7 mmol), NaI (catalyst) and CH ₃ CN (103 mg, 70%) was obtained in the same manner as in the production method of Example 4. [

_Rf = 0.83 (n-hexane: EtOAc = 2: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.33-7.29 (m, 3H), 7.24-7.17 (m, 4H), 7.06-7.01 (m, 6H), 5.37 (s, 1H), 3.60 (t, J = 3.6 Hz, 2H), 2.94 (d, J = 7.2 Hz, 2H), 2.69-2.67 (m, 2H), 2.57 (d, J = 4.2 Hz, 2H), 2.05-1.99 (m, 2H), 1.68 -1.52 (m, 3H), 1.38 - 1.30 (m, 2H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163, 161.2, 140.7, 138.0, 137.96, 129.2, 128.7, 128.6, 128.2, 125.8, 115.4, 115.2, 82.4, 67.2, 58.2, 54.4, 43.27, 37.80, 32.3.

Example  21. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- Phenylpiperazine  (Compound 7a) Synthesis of

Similar to the preparation method of Example 1 except for using a mixture of Compound 21 (150 mg, 0.53 mmol), Compound 23a (125 mg, 0.63 mmol), TEA (0.22 mL, 1.6 mmol) and DMSO To obtain a pale brown liquid compound 7a (86 mg, 40%).

_Rf = 0.61 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.30-7.23 (m, 6H), 7.04-6.82 (m, 7H), 5.35 (s, 1H), 3.62-3.58 (t, J = 6 Hz, 2H), 3.19 (t, J = 4.8 Hz, 4H), 2.74-2.65 (m, 6H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.2, 161.2, 151.3, 137.9, 137.91, 129.2, 128.7, 128.6, 119.7, 116.0, 115.4, 115.3, 82.6, 67.0, 57.9, 53.7, 49.2.

Example  22. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (2- Chlorophenyl ) ≪ / RTI > piperazine (Compound 7b)

Except that a mixture of Compound 21 (300 mg, 1.06 mmol), Compound 23b (370 mg, 1.59 mmol), K ₂ CO ₃ (293 mg, 1.6 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to obtain a pale brown liquid compound 7b (273 mg, 58%).

_Rf = 0.77 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.32-7.28 (m, 4H), 7.18-7.15 (m, 1H), 7.05-7.00 (m, 4H), 6.89-6.88 (m, 2H), 2.66 (t, J = 5 Hz, 4H), 2.37-2. ); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.2, 161.2, 152.3, 137.8, 137.79, 134.9, 130.0, 128.6, 128.57, 119.2, 115.7, 115.4, 115.2, 113.8, 82.6, 67.0, 57.8, 53.4, 48.7.

Example  23. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (3- Chlorophenyl ) Piperazine (Compound 7c) Synthesis

Except that a mixture of Compound 21 (320 mg, 1.13 mmol), Compound 23c (395 mg, 1.69 mmol), K ₂ CO ₃ (312 mg, 2.26 mmol), NaI (catalyst) and CH ₃ CN (15 mL) And the procedure of Example 4 was repeated to obtain a pale brown liquid compound 7c (300 mg, 60%).

_Rf = 0.80 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.35-7.31 (m, 4H), 7.19-7.15 (m, 1H), 7.07-7.02 (m, 4H), 6.91-6.90 (m, 2H), 5.39 ( s, 1H), 3.65-3.62 (m, 2H), 3.21 (t, J = 5 Hz, 4H), 2.76-2.74 (m, 2H), 2.69-2.67 (m, 4H ); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.2, 161.2, 152.3, 137.9, 137.8, 134.9, 130.0, 128.7, 128.6, 119.2, 115.4, 115.2, 113.8, 82.6, 67.0, 57.9, 53.4, 48.7.

Example  24. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (4- Chlorophenyl ) ≪ / RTI > piperazine (Compound 7d)

Except that a mixture of Compound 21 (300 mg, 1.06 mmol), Compound 23d (370 mg, 1.59 mmol), K ₂ CO ₃ (293 mg, 2.12 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to give compound 7d (264 mg, 56%) as a white solid.

_Rf = 0.74 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1). Mp = 102-105 [deg.] C.

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.34-7.29 (m, 4H), 7.23-7.20 (m, 2H), 7.06-7.01 (m, 4H), 6.86-6.83 (m, 2H), 5.38 (s 2H), 3.17 (t, J = 5 Hz, 4H), 2.75-2.73 (m, 2H), 2.69-2.67 (m, 4H); 3.62 (t, J = 6 Hz, 2H). ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.2, 161.2, 149.9, 137.8, 137.79, 128.9, 128.6, 128.57, 124.5, 117.2, 115.4, 82.6, 82.59, 67.0, 57.8, 53.5, 49.1.

Example  25. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (2,3- Dichlorophenyl ) ≪ / RTI > piperazine (Compound 7e)

The same procedure as in Example 1 was repeated except for using a mixture of Compound 21 (150 mg, 0.53 mmol), Compound 23e (170 mg, 0.63 mmol), TEA (0.22 mL, 1.59 mmol) and DMSO To obtain Compound 7e (106 mg, 42%) as a pale brown liquid.

_Rf = 0.7 (n-hexane: EtOAc = 2: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 7.32-6.92 (m, 12H, overlapped with CHCl 3), 5.35 (s, 1H), 3.62-3.58 (m, 2H), 3.05-3.03 (m, 4H), 2.76 - 2.69 (m, 6 H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.2, 161.2, 151.1, 137.8, 137.77, 134.0, 128.6, 127.5, 124.6, 115.4, 115.2, 82.6, 66.8, 57.8, 53.8, 51.2.

Example  26. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (2,4- Dichlorophenyl ) ≪ / RTI > piperazine (Compound 7f)

Except that a mixture of Compound 21 (300 mg, 1.06 mmol), Compound 23f (425 mg, 1.59 mmol), K ₂ CO ₃ (293 mg, 2.12 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to obtain a pale brown liquid compound 7f (313 mg, 62%).

_Rf = 0.73 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

¹ H NMR (500 MHz, CDCl ₃ ):? 7.30 (d, J = 2.5 Hz, 1H), 7.32-7.28 (m, 4H), 7.20-7.18 6.96 (d, J = 8.5 Hz , 1H), 5.37 (s, 1H), 3.61 (t, J = 8.5 Hz, 2H), 3.04 (s, 4H), 2.75 (t, J = 6 Hz, 2H), 2.70 (s, 4 H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 163.1, 161.2, 148.0, 137.8, 137.79, 130.3, 128.6, 128.57, 128.52, 128.2, 127.6, 121.1, 115.5, 115.4, 115.3, 115.2, , 51.2.

Example  27. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (3,4- Dichlorophenyl ) ≪ / RTI > Synthesis of piperazine (Compound 7g)

Except that a mixture of Compound 21 (290 mg, 1.02 mmol), 23 g (409 mg, 1.53 mmol), K ₂ CO ₃ (282 mg, 2.04 mmol), NaI (catalyst) and CH ₃ CN And the procedure of Example 4 was repeated to obtain 7 g (340 mg, 70%) of a pale brown liquid compound.

_Rf = 0.77 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (500 MHz, CDCl 3}} ): δ 7.31-7.26 (m, 5H), 7.05-7.00 (m, 4H), 6.95 (d, J = 3 Hz, 1H), 6.75-6.72 (m, 1H), 5.36 (s, 1H), 3.62-3.60 (m, 2H), 3.17 (t, J = 5 Hz, 4H), 2.74-2.71 (m, 2H), 2.67-2.65 (m, 4H); ^{13 C} NMR (125 MHz, CDCl ₃ ): δ 163.2, 161.2, 150.6, 137.8, 137.7, 132.4, 130.4, 128.6, 128.5, 122.1, 117.1, 115.5, 115.4, 115.3, 115.24, 115.21, 82.6, 66.9, , 48.6.

Example  28. 1- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -4- (pyridin-2-yl) piperazine (Compound 7h)

The same procedure as in Example 1 was repeated except for using a mixture of Compound 21 (150 mg, 0.53 mmol), Compound 23h (0.1 mL, 0.63 mmol), TEA (0.22 mL, 1.59 mmol) and DMSO To obtain Compound 7h (60 mg, 28%) as a pale brown liquid.

_Rf = 0.73 (n-hexane: EtOAc: MeOH = 2.5: 1.5: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 8.20-8.17 (m, 1H), 7.30-7.26 (m, 5H), 7.04-6.96 (m, 4H), 6.65-6.6 (m, 2H), 5.35 (s 2H), 3.64-3.59 (m, 2H), 3.54 (t, J = 5.1 Hz, 4H), 2.74-2.74 (m, 2H), 2.64-2.61 (m, 4H); ¹³ CNMR (125 MHz, CDCl ₃ ):? 163.1, 161.2, 159.5, 147.9, 137.8, 137.77, 137.4, 128.6, 128.56, 115.4, 115.2, 113.3, 107.1, 82.6, 66.9, 57.9, 53.4, 45.2.

Example  29. 2- (4- (2- ( Bis (4-fluorophenyl) methoxy ) Ethyl) -piperazin-l- Ylpyrimidine  (Compound 7i) Synthesis of

The same procedure as in Example 1 was repeated except for using a mixture of Compound 21 (100 mg, 0.35 mmol), Compound 23i (0.1 mL, 2 mmol), TEA (0.14 mL, 1.05 mmol) and DMSO To give compound 7i (50 mg, 35%) as a light yellow liquid.

_Rf = 0.83 (n-hexane: EtOAc = 2: 1).

_{^{1 HNMR (300 MHz, CDCl 3}} ): δ 8.28 (d, J = 4.8 Hz, 2H), 7.30-7.26 (m, 4H), 7.02-6.97 (m, 4H), 6.47-6.44 (m, 1H), 5.35 (s, 1H), 3.82 (t, J = 5.1 Hz, 4H), 3.62-3.58 (m, 2H), 2.72-2.68 (m, 2H), 2.58-2.54 (m, 4H).

Experimental Example  1. Synthesis of dopamine, No epinephrine  And restenosis inhibition of serotonin

The compounds synthesized in Examples 1 to 29 were evaluated for inhibiting the reuptake of dopamine, no epinephrine and serotonin. In order to evaluate the resorption inhibiting effect was used as dopamine, norepinephrine or serotonin transporter coding (coding) HEK-293 (Human embryonic kidney-293) cells expressing the complementary DNA (complementary DNA, cDNA) that. Dopamine, ^[3 H] - - an exemplary cell Examples 1 to 29, the 20 minutes 20 nM of ^[3 H] After treatment, each of the compound synthesized by norepinephrine or ^[3 H] - 5 bungan addition of serotonin 37 ^o C Lt; / RTI > After washing the cells three times, dissolved in 1% SDS liquid scintillation counter (liquid scintillation counter) with ^[3 H] - to measure the concentration of the serotonin-dopamine, ^[3 H] - norepinephrine or ^[3 H]. (IC ₅₀ , half maximal inhibitory concentration), which can halve the reuptake of dopamine, norpeinatrin and serotonin. Venlafaxine hydrochloride, bupropion and vanoxerine (GBR 12909), which are used as antidepressant drugs, were used as controls.

[Chemical Formula 1]

Compound name R ₁ R ₂ Y n X R ₃ R ₄ IC ₅₀ ([mu] M) SERT NET DAT 1a H H

2 C methyl Phenyl 7.7 1.71 0.31 1b H H

3 C methyl Phenyl > 10 0.519 0.094 1c H H

4 C methyl Phenyl 0.55 1.53 0.59 2a H H

2 N methyl Phenyl > 10 4.218 2.289 2b H H

3 N methyl Phenyl 5.05 0.521 0.2923 2c H H

4 N methyl Phenyl 1.5 0.323 0.317 2d H H

2 N ethyl Phenyl 4.83 2.83 0.6798 2e H H

3 N ethyl Phenyl 1.121 0.3995 1.115 2f H H

4 N ethyl Phenyl 8 0.329 0.608 2g H H

2 N profile Phenyl 3.86 1.467 0.6921 2h H H

3 N profile Phenyl 8 0.5689 1.636 2i H H

4 N profile Phenyl 0.1587 0.099 0.0975 3a H H

2 N Propenyl Phenyl > 10 1.76 0.94 3b H H

3 N Propenyl Phenyl 7.5 1.327 2.231 3c H H

4 N Propenyl Phenyl 6.29 0.318 3.64 4a H H CONH 2 C methyl Phenyl > 10 1.68 0.19 4b Cl Cl CONH 2 C methyl Phenyl > 10 8.03 0.63 5a H H CONH 3 C methyl Phenyl > 10 2.21 1.07 5b Cl Cl CONH 3 C methyl Phenyl 7.67 2.02 1.35 6 F F O 2 C methyl Phenyl 1.67 5.862 6.816 7a F F O 2 N Direct coupling Phenyl 1.906 5.328 10 7b F F O 2 N Direct coupling o-Chlorophenyl > 10 1.26 5.6 7c F F O 2 N Direct coupling m-Chlorophenyl 4.96 1.313 2.749 7d F F O 2 N Direct coupling p-Chlorophenyl 6.91 1.59 1.39 7e F F O 2 N Direct coupling 2,3-dichlorophenyl 5 3 3 7f F F O 2 N Direct coupling 2,4-dichlorophenyl 3.91 3.75 10 7g F F O 2 N Direct coupling 3,4-dichlorophenyl 5.22 1.323 4.098 7h F F O 2 N Direct coupling 2-pyridyl 0.579 0.6028 0.9895 7i F F O 2 N Direct coupling 2-pyrimidinyl 1.414 1.621 1.704 Venlafaxine HCl - - - - - - - 0.20 2.55 - Bupropion - - - - - - - - 3.24 1.20

The most effective compound as a serotonin reuptake inhibitor is Compound 2i (0.1587 μM), followed by Compound 1c (0.55 μM), Compound 2e (1.121 μM), Compound 2c (1.5 μM), Compound 6 (1.67 μM) 1.906 μM) in order to inhibit serotonin reuptake.

In the case of no epinephrine, the most effective compound as the inhibitor of norepinephrine reuptake was Compound 2i (0.099 μM), followed by Compound 3c (0.318 μM), Compound 2c (0.323 μM), Compound 2f (0.329 μM) mu] M) and compound 1b (0.519 [mu] M) were superior in inhibiting the reuptake of no-epinephrine.

In the case of no epinephrine, the most effective compound as the inhibitor of norepinephrine reuptake was Compound 2i (0.099 μM), followed by Compound 3c (0.318 μM), Compound 2c (0.323 μM), Compound 2f (0.329 μM) mu] M) and compound 1b (0.519 [mu] M) were superior in inhibiting the reuptake of no-epinephrine.

R ₁ and R ₂ of the compounds synthesized in Examples 1 to 29 are hydrogen or halogen, but R ₁ and R ₂ of the compound according to the present invention are an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, Lt; / RTI > may be fluoromethyl. Since an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or trifluoromethyl is regarded as a bioisostere, it is generally considered to have a hydrogen or halogen-like effect in drug development.

R ₄ of the compounds synthesized in Examples 1 to 29 is an aryl group or a heteroaryl group substituted with halogen, but the substituted aryl group and heteroaryl group of compound R ₄ according to the present invention are each independently an alkyl group having 1 to 4 carbon atoms Or an alkoxy group having 1 to 4 carbon atoms. Since an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms is regarded as a bioisostere, it is considered to have an effect similar to an aryl group or a heteroaryl group ordinarily substituted with a halogen in drug development.

이나, 본 발명에 따른 화합물 Y는 NHCO일 수 있다. 치환된 테트라졸은 CONH의 잘 알려진 생물학적동등체(bioisostere)이며, NHCO는 CONH의 역전된 아미드 (reverse amide) 결합이기 때문에, 약물 개발에서 통상적으로 O 또는 CONH와 유사한 효과를 지닌 것으로 여겨진다. Y of the compounds synthesized in Examples 1 to 29 is O, CONH or

However, the compound Y according to the present invention may be NHCO. It is believed that the substituted tetrazoles are well known bioisostere of CONH and that NHCO is usually a reverse amide linkage of CONH and therefore has a similar effect to O or CONH in drug development.

Claims (10)

Claims 1. A compound of the formula 1: < RTI ID = 0.0 >
[Chemical Formula 1]

In Formula 1,
R ₁ and R ₂ are independently of each other hydrogen or halogen;
R ₃ is an alkylene group having 2 to 3 carbon atoms;
R ₄ is a substituted or unsubstituted aryl group having 6 to 10 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 10 carbon atoms,
The substituted aryl group and the heteroaryl group of R < ₄ > are independently of each other substituted with halogen;
X is C or N;
Y is

ego;
and n is an integer of 3 to 4.
_2. The compound according to claim 1, wherein the halogen of R < ₁ > and R < ₂ > are independently of each other F or Cl, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein the heteroaryl group of R < ₄ > has one or more ring heteroatoms N, or a pharmaceutically acceptable salt thereof.
delete 4. The compound according to claim 3, wherein said heteroaryl group is pyridyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
And R ₄ is an unsubstituted aryl group having 6 to 10 carbon atoms.
delete delete Reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) to produce a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
(2)

(3)

[Chemical Formula 1]

(In the above Formulas 1 to 3,
R ₁ , R ₂ , R ₃ , R ₄ , X, Y and n are each as defined in claim 1;
And L is a halogen, methanesulfonate or toluene sulfonate.
At least one selected from the group consisting of depression, anxiety disorder, panic disorder, obsessive compulsive disorder, phobias and attention deficit hyperactivity disorder comprising a compound of any one of claims 1 to 3, 5 and 6 or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating one.

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