WO2010111948A1 - Arylmethylamine compounds, preparation methods and pharmaceutical uses thereof - Google Patents

Abstract

The arylmethylamine compounds (I), wherein the definitions of Ar, X, L and R are the same as those in the description, the preparation methods, the pharmaceutical compositions and the uses thereof. The present arylmethylamine compounds can be used for treating a series of diseases caused by the abnormality of potassium channel function, such as arrhythmia, ischemic damages.

Description

 Aromatic methylamine compound, preparation method thereof and medical use thereof

 Technical field

 The present invention relates to the field of medicinal chemistry, and in particular to a class of arylmethylamine compounds, a process for the preparation thereof, and a pharmaceutical preparation thereof and a medical use thereof. Background technique

 Arrhythmia is a major disease that seriously threatens people's health and quality of life. According to incomplete statistics, about a million people die each year due to failure to effectively control primary or secondary arrhythmia, and the patient population is becoming younger. Therefore, the market size of antiarrhythmic drugs It is expanding year by year.

Antiarrhythmic drugs can be divided into four categories according to their different mechanisms of action. At present, the main clinical applications are class III antiarrhythmic drugs, potassium channel blockers, including dofetilide, sotalol, etc. The mechanism of action of the drug is to specifically block the fast-delayed rectifier potassium channel current (Ικτ), and the other two components of the delayed rectifier potassium channel (Ικ)—slow-delay rectifier potassium channel current (IKS) and ultra-fast delayed rectifier potassium. The channel current (Ι _Κ ) has no blocking effect, and its electrophysiological effect is to prolong the myocardial action potential time course and effective refractory period. However, drugs that block Ικτ alone have severe arrhythmogenic side effects in clinical use: When the heart rate is slow, Ικτ blockers are uncontrolled for prolonged action potential duration, resulting in torsades de pointes ventricular tachycardia; When the heart rate is increased, the expression of IKS is up-regulated, and the therapeutic effect of Ικτ blocker on ventricular arrhythmia is weakened. Therefore, arrhythmia disease should be considered as a combined result of a variety of ion channel properties, and its treatment should not be limited to the regulation of a single ion channel. On the other hand, traditional arrhythmia drugs are mostly directed to ventricular arrhythmias that have begun to deteriorate, blocking the rapid activation of delayed rectifier potassium channels (Ικτ) or sodium and calcium channels present in ventricular myocytes, ignoring arrhythmia Early control of atrial arrhythmia symptoms and prevention of atrial arrhythmia to ventricular arrhythmia, in view of the above problems, ultra-fast delay rectifier potassium channel (I _KUR ) due to its selective presence in the atrial characteristics, It has become a very promising target for the treatment of atrial arrhythmias and adjuvant treatment of ventricular arrhythmias.

Summary of the invention

The present invention closely follows the development trend of antiarrhythmic drugs, designs and synthesizes a class of compounds having an arylmethylamine structure, and pharmacological tests prove that the compounds of the present invention have certain blocking activities for I _KUR , Ικτ and IKS , The compounds and their pharmaceutical preparations can be used to treat a range of diseases caused by abnormal potassium channel function, for example, arrhythmia, ischemic injury and the like.

The compounds of the invention have the general formula:

 (I)

其中 Y表示氮原子或碳原子， 表示氮原子， Α表示苄 基、 苯基或 C Wherein Ar represents a benzene ring, a pyridine ring or a 5- or 6-membered aromatic ring containing 0 to 2 selected from a nitrogen atom, a sulfur atom or an oxygen atom; Ar also indicates

Wherein Y represents a nitrogen atom or a carbon atom, which represents a nitrogen atom, and Α represents a benzyl group, a phenyl group or a C group.

Ar also denotes wherein Y represents a nitrogen atom or a carbon atom, and ₂ represents an oxygen atom or a sulfur atom;

X represents a nitrogen atom or a carbon atom.

L represents -CO-, -SO2-, -NH-, -CONH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n N-, -(CH ₂ ) _n O- or -(CH ₂ ) _n CONH-, where n is an integer from 1 to 4.

R represents a mono- or poly-substitution, and a poly-substitution means a di-, tri- or tetra-substituent; the substituent is selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, ~C ₄ The alkyl group, the oxime group of 〜0», the amino fluorenyl group of ~, the alkylamino group of ~, the acyl group of ^~^, the amide group of ~, the alkoxycarbonyl group of ^~^, and the benzene ring are connected to ~ a 3⁄4 alkyl group or a d-C ₄ alkoxy group bonded to a benzene ring; the substituent may also be selected from a 5- or 6-membered impurity having 1 to ₂ nitrogen atoms, 1 sulfur atom or 1 oxygen atom Ring-bonded ~C ₄ thiol or alkoxy.

 The present invention also includes stereoisomers of the compound of the formula (I), hydrates thereof or pharmaceutically acceptable salts thereof. Ar preferably represents a benzene ring, a benzoxazole ring, a benzimidazole ring, a 1-benzylbenzimidazole ring, a 1-phenylbenzimidazole ring or a benzo[1,3]dioxolane.

L preferably represents -CH ₂ CH ₂ 0-, -CH ₂ N -, -CH ₂ CH ₂ N -, -C CONH -, -CONH -, -NH -, -CO- or -so ₂ -.

 R preferably denotes a para-substituted or o- or para-disubstituted; the substituent is selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, ester or amide .

 The invention also discloses a process for the preparation of the compound of the formula (I).

When X in the formula (I) is a nitrogen atom, the preparation method of the compound is -

 Compound (II) Compound (III) Formula (I) wherein M represents bromine or chlorine, X is a nitrogen atom, and Ar, L and R have the same meanings as defined above.

The compound (Π) is reacted with anhydrous piperazine to obtain the compound (111), and the compound (ΙΠ) is reacted with Ar-CH ₂ -Cl to obtain a compound of the formula (I).

 The reaction temperature of the reaction of the compound (Π) with anhydrous piperazine is preferably 10 to 40 ° C, and the reaction time is preferably 2 to 12 hours. The solvent used for the reaction is preferably anhydrous ethanol or methanol, and 40% hydrobromic acid is preferably added to the reaction liquid.

The reaction temperature of the reaction of the compound (III) with Ar-CH ₂ -Cl is preferably 60 to 90 ° C, and the reaction time is preferably 2 to 2. 4 hours. The solvent used for the reaction is preferably acetonitrile, hydrazine, hydrazine-dimethylformamide (DMF) or chloroform, and a base such as triethylamine or potassium carbonate is preferably added to the reaction liquid.

When x in the formula (i) is a carbon atom and L is a mercaptoamine group of (^~ε ₄ ), the preparation method of the compound includes:

 Compound (IV) Formula (I)

 When other groups of the formula (I) wherein X is a carbon atom and L is an alkylamine group other than 〜, the preparation method of the compound includes -R

 Compound (V) Formula (I)

 Ar-C-Cl is reacted with 4-piperidone or 4-piperidinecarboxylic acid to obtain compound (IV) or compound (V), and Ar, R, and L are as defined above; compound (IV) or compound (V) is respectively Reaction with an R-substituted phenylalkylamine gives a compound of the formula (I).

The reaction temperature at which Ar-CH ₂ -CI is reacted with 4-piperidone or 4-piperidinecarboxylic acid is preferably 60 to 90 ° C, and the reaction time is preferably 4 to 12 hours. The solvent used for the reaction is preferably acetonitrile, chloroform, tetrahydrofuran or DMF, and a base such as triethylamine or potassium carbonate is preferably added to the reaction liquid.

 The reaction temperature of the reaction of the compound (IV) with the R-substituted phenylhydrazine amine is preferably 140 to 160 ° C, and the reaction time is preferably 4 to 8 hours. The solvent used for the reaction is preferably toluene or xylene, and then a reducing agent such as sodium borohydride, lithium aluminum hydride or the like is further added to the reaction liquid.

 The reaction temperature of the reaction of the compound (V) with the R-substituted phenylalkylamine is preferably 10 to 40 ° C, and the reaction time is preferably 2 to 4 hours. The solvent used for the reaction is preferably tetrahydrofuran, chloroform or dichloromethane, and an acylating condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or hydrazine is added to the reaction solution. In the reaction mixture, a base such as triethylamine or 4-dimethylaminopyridine (DMAP) is preferably added to the ruthenium-dicyclohexylcarbodiimide (DCC).

 The compound of the formula (I) can be purified by a usual separation method such as recrystallization, column chromatography or the like. The compound of the present invention may be added into a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.

 The compound of the present invention can be administered clinically by means of oral administration or injection.

 The compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.

The invention has the advantages that the compound has certain blocking activity on the delayed rectifier potassium channels I _KUR , Ικτ and IKS , and the compound and the pharmaceutical preparation thereof can be used for treating the abnormal function of the potassium ion channel. A range of diseases, such as arrhythmia, ischemic injury and other diseases. In addition, the preparation method provided by the invention has the characteristics of mild reaction conditions, abundant raw materials, easy operation and post-treatment. Some pharmacological tests and results of the compounds of the invention are as follows:

 Experiment 1 Detection of the blocking effect of the compound of the present invention on Ικ^ potassium channel current

Experimental method: In view of the fact that the Kvl .5 gene encodes the I _Kur potassium channel in vivo, the present invention uses HEK cells transfected with the Kvl .5 gene, and uses artificial whole cell patch clamp technique to study the effect of the compound on the cell current, and calculate the inhibitory activity IC. ₅₀ values, the experimental results are shown in Table 1. (References: The membrane permeable calcium chelator BAPTA-AM directly blocks human ether a-go-go-related gene potassium channels solved expressed in HEK 293 cells. Biochem Pharmacol 2007, 74, 1596-607)

Blocking activity of compounds on I _Kur potassium channel current IC:

It can be seen from Table 1 that the compound of the present invention has a strong blocking effect of I _K potassium channel current, and the effect is better than that of the positive control drug Azmilide (ΙΟ ₅₀ >10 μΜ).

Experiment 2: Blocking effect of the compounds of the present invention on potassium channel currents of Ικτ and I _KS

Experimental method: The guinea pig cardiomyocytes were isolated by acute enzymatic hydrolysis, and the whole cell patch clamp (model: HEKA, EPC-10) was used to delay the rectifying current in the fast-acting component and the slow-acting component. The data collected from the representative structure of the present invention was dissolved in the perfusion solution of the measured current and collected in at least 10 mi. The data was analyzed in Pulse-fit software, and the IC _5Q values of each compound on kr and IKS were calculated. The results are shown in Table 2.

 Experimental operation:

1. Separation of guinea pig cardiomyocytes: The guinea pig is stunned, the heart is taken quickly, placed in a calcium-free Tyrode solution at 4 °C, trimmed and placed on a Langendorff device, perfused with calcium-free bench solution for 5 min, containing 1 mg/ml Type II collagenase, 0.1 mg/ml Protease, 0.5% BSA, CaCl ₂ 150nmol/L low calcium Tyrode solution perfusion heart, until the heart becomes soft, relax, remove the heart, cut the ventricle into fresh enzyme Incubate at 37 °C in the solution, gently stir for 5-10 min, pour out the supernatant, and dilute with TyC solution containing CaCb lmmol L, this is the first cell storage solution; , the third cell storage solution. The perfusate was saturated with 5% C0 ₂ + 95% 0 ₂ . The cells were used after 2 h.

2. Whole-cell patch clamp technique: Take the cell liquid into the cell pool, wait until the cells are attached, perfuse with extracellular fluid, flow rate 2 ml/min, select cells with calcium tolerance, clear stripes, use 3D manipulator to move the electrode to Cell surface, negative The pressure causes the electrode tip to form a high-resistance sealing on the cell surface, and further absorbs the cell membrane with a negative pressure, so that the electrode liquid and the intracellular fluid are turned on to form a whole cell state, and after performing capacitance and series impedance compensation, voltage clamp recording is performed. . The signal is guided by the Ag/AgCl electrode, amplified by the patch clamp amplifier, and the computer distributes the set excitation pulse to the cell, and the electrical signal generated by the cell is converted by the converter and stored in the computer. All stimulation signal control, current data sampling and analysis were performed by pulse V8.60. After all the test substances in this study were dissolved in absolute ethanol, the same concentration was diluted with water and added to the extracellular fluid. The highest concentration of ethanol was 0.1%. The preliminary results of this study showed that the concentration had no effect on the experimental results. The recording was performed after the recording current was stabilized for 10 minutes, and the current after 10 minutes of administration was recorded, and the experiment was carried out at 25 to 30 °C.

3. Stimulus parameters: ΙΚΓ, I _KS records: Record the wake values of the two currents. Perfused with extracellular fluid containing 0.1 mmol L CdCl ₂ , maintaining a voltage of -50 mV, depolarizing to 60 mV for 500 ms, maintaining the voltage to a 50 mV for 1000 ms, recording I _Ks ; then clamping the voltage at - 50mV 1000ms, record 1 _& .

Table 2 Blocking Effect of Compounds on I _fo and 1 Potassium Channel Currents IC:

 Experiment 3 Effect of the compound of the present invention on the expression of Cx43 protein in myocardium of atrial fibrillation model rats

1. Modeling method: Male Sprague-Dawley rats (250-280g) 30, continuous tail vein injection of calcium chloride acetylcholine (CaCl ₂ -ACh) mixture (10mL / Kg, where CaCl ₂ 10mg / ml, ACh όόμ ^ πιΐ 7 days of modeling; rats were randomly divided into a model group and a drug-administered group on the fourth day of modeling. The rats in the administration group were intraperitoneally injected at a dose of 2.5 mg g 5 minutes before the fourth day of modeling.

2. Preparation of protein sample: On the eighth day of the experiment, the rats were anesthetized, and the heart was quickly removed, and placed in a 0 °C KH solution (NaCl: 118, KC1: 4.7, with a mixture of 95% 0 ₂ and 5% C0 _{2 )} . In MgS0 ₄ : 1.2, KH ₂ P0 ₄ : 1.2, NaHC0 ₃ : 24.8), wash the heart, absorb the water, cut the heart, add the lysate and protease inhibitor, homogenize on ice for about half an hour, centrifuge 5 Minutes (12000 rpm), take the supernatant.

3. Preparation of the standard curve: The protein concentration was measured by Bradford method, and the standard curve was prepared by using BSA as the standard (Fig. 1). The sample concentration was measured, the sample concentration was adjusted to 2 _μβ / μ1, denatured for 5 min, and dispensed. Store at 80 ° C.

 4. Western blotting method to measure myocardial Cx43 protein content: The sample (protein content 50 g) was added to 12% polyacrylamide gel, electrophoresis, transferred to nitrocellulose membrane, 5% skim milk powder closed, rabbit polyclonal antibody

(1:2000 dilution) Incubate overnight at 4 °C, wash TBST three times (lOmin/time), add HRP-labeled goat anti-rabbit (1:5000 dilution), incubate for 90 minutes at room temperature, and wash TBST three times (lOmin/time) . The ECL reactant was applied to the cellulose film, exposed, and autoluminographed onto the X film. Density analysis of protein bands on film was performed using Quantity one image analysis software. The experiment was repeated 4 times, and the average value of the optical density was plotted.

5. Experimental results: As shown in Figure 2, the rat model of atrial fibrillation (AF Model) was established by intravenous injection of 10 mL/Kg CaCl ₂ -ACh mixture. The expression of gap junction protein in rat myocardium was significantly higher than that in the normal group (Control). Decreased, suggesting abnormal myocardial electrical signal transmission in rats. Intraperitoneal injection of the compound of the invention CPUYY18 (corresponding to Example 18) After, the expression of Cx43 protein in the atrial fibrillation model rats was significantly increased, which was close to the normal group. This phenomenon suggests that the compound may improve the electrical signaling between cardiomyocytes by regulating the gap junction function of cardiomyocytes.

 Experiment 4 In vivo anticoagulant effect of the compound of the present invention and its effect on platelet thrombosis

1. Experimental methods: Male Sprague-Dawley rats (body weight 270-300 g) were randomly divided into control group, low-dose and high-dose administration groups, 4 in each group, and low-dose administration group (dose 2.5 mg g/day, Intraperitoneal injection for 3 days), high-dose administration group (dose 5 mg Kg/day, intraperitoneal injection for 3 days), normal control rats were intraperitoneally injected with physiological saline l _m IJKg per day. After the end of the administration, the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate and fixed in the supine position. The right common carotid artery and the left external jugular vein were separated. A curved polyethylene cannula with a length of about 12 cm was inserted, and a 6 cm long cotton thread was inserted in the middle. The heparin physiological saline solution (25 U/mL) was filled with a polyethylene tube. Cavity, one end of the tube was inserted into the left external jugular vein, the heparin was accurately injected by a polyethylene tube, and then the other end of the polyethylene tube was inserted into the right common carotid artery. Open the arterial clip and the blood flows from the right common carotid artery into the polyethylene tube and back to the left external jugular vein. The blood flow was interrupted after 15 minutes of open blood flow, and 1.8 mL of blood was taken from the right common carotid artery. The prothrombin time (PT) value was determined by leaving the sample. Quickly remove the cotton thread and weigh it. The total weight minus the weight of the cotton thread will result in a wet weight of the thrombus.

 2. Experimental results: The compound of the present invention CPUYY18 (corresponding to Example 18) was intraperitoneally injected for three days, prolonging the blood prothrombin time (PT) of rats and inhibiting platelet thrombosis in a certain extent (see Fig. 3). .

• Experiment 5 In vivo antiarrhythmic effects of the compounds of the invention

1. Experimental methods: Male SD rats (body weight 270-300 g) were randomly divided into a model group, a drug-administered group, and a control group. On days 1 to 3 of the experiment, rats were anesthetized with 10% chloral hydrate (0.3 mL/100 g), and an electrocardiogram was recorded after anesthesia. A mixture of CaCl ₂ -ACh (10 mg/mL CaCl ₂ + 6.6 ug/mL Ach mixed at a dose of 0.1 mL/100 g) was injected into the tail vein to record the duration of atrial fibrillation. The atrial fibrillation time began with a typical atrial fibrillation electrocardiogram (P wave disappeared, f wave appeared) after the injection of mixed liquid to restore the 6 consecutive sinus rhythm as a sign of atrial fibrillation disappearance, the whole process of electrocardiogram monitoring. According to the duration of atrial fibrillation in the first three days, the animals were randomly divided into groups on the fourth day. The drug-administered group was intraperitoneally injected with the corresponding dose of the drug 10 minutes before the start of modeling, and the same operation was repeated, and the above operation was repeated until the seventh day. On the eighth day, the rats were sacrificed. The left atrial muscle of the rats was taken and hung in a bath filled with oxygen-saturated constant temperature KH solution. The preload was lg, 1.5 times the threshold potential stimulation at 1 Hz for about 1 hour, and the experiment was started after the specimen was stabilized. The effective refractory period ERP of the myocardium was determined by the continuous double stimuli method using the BL-420F biofunctional system. The number of all experimental cases was not less than 6, and the difference between the two groups was used to perform statistical analysis between groups.

 2. Experimental results: As shown in Fig. 4, the compound of the present invention, CPUYY18 (corresponding to Example 18), was effective against atrial fibrillation in rats, and the effect was stronger than the same dose of sotalol, which atrial fibrillation caused by atrial fibrillation The effective refractory period (ERP) of muscle cells has obvious protective effect, and the ERP value returns to normal level after administration.

The above experimental results show that the arylmethylamine compound of the present invention has a certain blocking activity for the delayed rectifier potassium channel currents I _K , kr and I _Ks , and at an effective dose (2.5 mg/Kg): The expression level of connexin Cx43 in tremor animal can improve the electrical signal transmission between cardiomyocytes; prolong prothrombin time (PT) in rats, and inhibit plate thrombosis in rats to some extent; can effectively shorten arrhythmia persistence Time, prolonging the effective refractory period (ERP) of cardiomyocytes, thus showing a therapeutic effect on arrhythmias. This type of compound The drug and its medicinal preparation can be used for treating a series of diseases caused by abnormal function of potassium ion channels, for example, diseases such as arrhythmia and ischemic injury. DRAWINGS

 Figure 1 is the standard curve of protein quantification

 Figure 2 is the effect of compound CPUYY18 on myocardial Cx43 protein expression in atrial fibrillation rats (A: Western original map; B: grayscale quantitative map)

 Figure 3 shows the in vivo anticoagulant effect of compound CPUYY18 and its effect on platelet thrombosis (A: platelet wet weight; B: prothrombin time PT)

 Figure 4 shows the in vivo antiarrhythmic effect of compound CPUYY18 (A: effect of CPUYY18 on atrial fibrillation time in rats; B: effect of CPUYY18 on rat atrial ERP)

Example 1

1-benzyl-2-[(4-(2-(4-methoxyphenoxy)ethyl)piperazin-1-yl)methyl]-1Η-benzimidazole

(1) Preparation of N ¹ -benzyl o-phenylenediamine

 O-phenylenediamine (0.06 mol) was dissolved in 100 mL of methanol, potassium carbonate (0.03 mol) was added, and stirred at room temperature. Under a nitrogen atmosphere, a solution of benzyl bromide (0.015 mol) in 15 mL of methanol was added dropwise, stirred at room temperature for 10 h, filtered, and concentrated. The next reaction is directly carried out by treatment.

 (2) Preparation of 1-benzyl-2-chloromethyl-1H-benzimidazole

N ¹ -Benzyl phenylenediamine (0.014 mol) was dissolved in 100 mL of 5N hydrochloric acid, chloroacetic acid (0.016 mol) was added, and refluxed for 4 h. The reaction solution was basified with sodium carbonate, extracted with an organic solvent of ethyl acetate: methanol = 10:1, and dried. Column chromatography, the eluent was petroleum ether: ethyl acetate = 5:1, yielded white solid 1.80 g, yield: 50.8%, melting point: 106-108 °C.

Ή-NMR (DMSO) δ 4.76 (s, 2H, ArCH ₂ Cl-), 5.51 (a, 2H, PhCH _r ), 7.09-7.11 (m, 2H, Ar-H), 7.22-7.36 (m, 6H, Ar-H), 7.77-7.81 (m, 1H, Ar-H)

EI-MS m/z 256 ([M] +), m/z 258 ([M+2] +), m/z 221 ([M-Cl] ⁺ ).

 (3) Preparation of the title compound

 1-[2-(4-Methoxyphenoxy)ethyl]pyridazine dihydrochloride (0.016 mol) was dissolved in 20 mL of acetonitrile, and potassium carbonate (0.03 mol) was added thereto, and stirred at 60 ° C for 30 minutes. A solution of 1-benzyl-2-chloromethyl-1H-benzimidazole (0.015 mol) in 10 mL of acetonitrile was added dropwise and refluxed for 3 h. Filtration, concentration of the filtrate, column chromatography (eluent: methanol: chloroform = 1: 20) afforded white solid: 0.18 g, yield: 27%, melting: 97-99.

IR (KBr): 729, 943, 845, 1008, 1047, 1168, 1235, 1459, 1511, 1584, 2833, 2960, 3060, '(-M ^Z (3⁄433⁄4D)N ² HD3⁄430- ⁱ ZRL'S=f 'H2 Ί) '( H^H 'H8 's) 1S 9 ( ^£ 1θαθ) 3⁄4IMN-H,

,.^ εθ '6^62

'038ζ '8291 '0091 'Ζζ Ι '.121 '8SII '6201 Όΐθΐ 'ZPL ' ZL ^f Z69: (JffS) ΉΙ . 9W-SW '%9'8ζ '§εΐΌ ' 邈^二翁

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'(-Μ3(ϋΗ3ΖΗ3)Κ3Η3-ΐν 'HZ 's)

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^^- -i ώ («- 1 茑) - ) ) -3⁄4i_ ί

 +(H--iV 'HI 'ui) 6 L-iLL '(H_JV 'H9 'ui) ζε·乙_6Γ乙'(Η_·>ν 'Ηζ 'ω) ΟΓ/ΓΔΟ·B'(H-JV 's) 289 '(-2H3Md 'H3 's) Z,S'S '(-KZ(3HD3H3)NOT32H30- 'zHfrS=f 'HZ 'ϊ) εθ '(CH30- '-Νί(ζ;Η33Η3)Κ3Η3·ΐν 3⁄4S 's) 9L'i

'(-Κ(3⁄433⁄43)ΝΗ33⁄430- 'H8 'S) ςς·ζ § ( ^ε ι α ) ΉΐΑίΝ-Η ₍

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'(-Μ ^ε (3⁄4 3⁄4 )Ν3⁄453⁄4 0- 3⁄48 's) vz 9 ( ^ε ιοαο) 3⁄4WM-H,

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■• '%9·ει 'Soro ^园 '^邈 ^3⁄43⁄4[3⁄42( 3⁄4*3⁄43⁄4 by inch) - -i

'(+ [Vi z/m spv-ia (H-JV 'HI 'ui) QL'L '(H-JV 'HZ, '" ε ·8Ι '(H-JV 'H5 ' ) £6"9- 08'9 '("2H3Hd 'HZ 's) IS'S '(-N2(2H33H3)N3H3mDO- 'ZHt^=f ΉΖ 'ϊ) 08·ε '(- Νζ(2Η32Η3)ΝΖΗ3·ΐν 'HZ 's) 69 '(-Ν2(3Η32Η3)ΝΖΗ33Η30- 'zjfl^=f

ι; 'ι) οίτ 9 'S) 6ΐτ§ ( ^ε ΐ3αο) ΉΗΚ-Η,

,ωο 6 '£S0£ Ό^6Ζ',08;'0691'S9 l ' W 'mi 0Π '9101 '^6'SZ8 'OW ⁱ⁽ i1L '£69 : e3⁄4) ΉΙ

'%ε ε :南:^ '§eo 缬^二3⁄43⁄4[«7(»3⁄4*3⁄4»由) - -i 袅^ 二二3⁄43⁄4 [养二-93⁄4-di Yi

3⁄4*Ι#*ΉΙ- [ ώ (声一#ι3⁄4ώ(3⁄47(»**3⁄4ώ :-9'z)-2) )]

 (H-JV

Ήε 'ω) ZUL-i^L '(H-JV 'H6 ' ) 8ε·Ζτ8ΓB'(H_JV 'Ht^ '" LO'LO 'L '(-2H3MJ 3⁄4∑; 's) 0S"S (- N∑;(ZH3OT3)N2H33H30- 'ZH,-S=f 3⁄4∑; Ί) W '(- Z(m02H3)K2H3JV 'H2 's) L'£

SSM.0/0T0ZN3/X3d 8ΐ76ΐΐΐ/0ΐ0Ζ OAV 5.50 (s, 2H, PhCH2-), 6.78 (d, 2H, Ar-H), 6.91-7.07 (m, 4H, Ar-H), 7.13 (m, 6H, Ar-H), 7.70 (m, 1H , Ar-H)

EI-MS w/2 510 ([M] ⁺ ).

Example 6

2-[4-((l-Benzyl-1H-benzimidazol-2-yl)methyl)piperazin-1-yl]-N-(4-methoxyphenyl)acetamide

 Prepared according to the method of step (3) in Example 1, replacing N-(4-methoxyphenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with 1-[2-(4- Methoxyphenoxy)ethyl]piperazine dihydrochloride gave 0.15 g of a white solid, yield: 21.3%, m.p.: 167-169.

IR (KBr): 522, 830, 926, 1031, 1178, 1301, 1411, 1455, 1511, 1590, 1618, 2064, 2399, 2821, 2930, 3057, 3324 cm" ¹

Ή-NMR (CDC1 ₃ ) δ 2.68 (s, 6Η,

3.73 (s, 5Η, ArCH ₂ N(CH ₂ CH ₂ ) ₂ N-, -OCH3), 5.50 (s, 2H, PhCH ), 6.78-6.83 (m, 4H, Ar-H): 7.05 (m, 1H , Ar-H), 7.19-7.24 (m, 4H, Ar-H), 7.39-7.72 (m, 4H, Ar-H), 8.84 (s, 1H, -CONH-) EI-MS m/z 469 ( [M] +).

Example 7

2-[4-((l-Benzyl-1H-benzimidazol-2-yl)methyl)piperazin-1-yl]-N-(4-trifluoromethoxyphenyl)acetamide

 Prepared by the method of the step (3) in the first embodiment, replacing N-(4-trifluoromethoxyphenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with 1-[2-( 4-methoxyphenoxy)ethyl]piperazine dihydrochloride, 0.11 g of a white solid, yield: 27.2%, melting: 102-103 ° C o

IR (KBr): 726, 744, 1016, 1245, 1312, 1466, 1510, 1549, 1612, 1703, 2355, 2781, 2826, 2939, 3032, 3193 cm" ¹

2.9 (s, 2H, -NHCOCH2-), 3.65 (s, Ή-NMR (CDCI3) δ 2.42 (s, 8H,

2.9 (s, 2H, -NHCOCH2-), 3.65 (s,

2H, ArCH2N(CH ₂ CH ₂ ) ₂ N-), 5.35 (s, 2H, PhCH _r ), 6.84 (d, 2H, J=6.9Hz, Ar-H), 6.94-7.07 (m, 7H, Ar- H), 7.39 (d, 2H, J=8.7Hz, Ar-H), 7.59 (m, 1H, Ar-H), 9.07 (s, 1H, -CO H-)

 EI-MS m/z 523 (Oka +).

Example 8 2-[4-((l-Benzyl-IH-benzimidazol-2-yl)methyl)piperazine)-N-(3,4-dimethylphenyl)acetamide

 Prepared according to the method of step (3) in Example 1, replacing N-(3,4-dimethylphenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with 1-[2-( 4-methoxyphenoxy)ethyl]piperidine dihydrochloride, 0.41 g of a white solid, yield: 59.3%, melting point: 170-172 °C o

 IR (KBr): 744, 923, 1012, 1156, 1332, 1461, 1504, 1522, 1692, 2384, 2829, 3046, 3291

Ή-NMR (CDC1 ₃ ) δ 1.95 (d, 2H, -C3⁄4x2), 2.47 (d, 8H, ^m « ), 3.00 (s, 2H,

-NHCOCH2-), 3.75 (s, 2H, ArCi^N(CH ₂ CH ₂ ) ₂ N-), 5.50 (s, 2H, PhCH _r ), 7.00 (s, 3H, Ar-H), 7.18-7.24 ( m, 8H, Ar-H), 7.72 (s, IH, Ar-H), 8.89 (s, IH, -CONH-)

 EI-MS m/z 467 peeling +).

Example 9

2-[4-((l-Benzyl-IH-benzimidazol-2-yl)methyl)piperazin-1-yl]-N-(3-nitrophenyl)acetamide

 Prepared according to the method of step (3) in Example 1, replacing N-(3-nitrophenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with 1-[2-(4-A) Oxyphenoxy)ethyl]piperazine dihydrochloride, 0.55 g of a white solid, yield: 37.6%, melting: 161-162 °C.

IR (Br): 742, 1014, 1137, 1301, 1352, 1465, 1529, 1703, 2784, 2818, 2940, 3068, 3174 3466 cm ^-1

- l H -NAN ^a H

 Ή-NMR (CDCI3) 52.46 (s, 4H, h ), 2.54 (s, 4H, ), 3.05 (s, 2H,

-NHCOCH2-), 3.76 (s, 2H, ArCH2N(CH ₂ CH ₂ ) ₂ N-), 5.50 (s, 2H, PhCH _r ), 7.00 (s, 2H, Ar-H), 7.19-7.23 (m, 5H, Ar-H), 7.57 (t, IH, J=8.1Hz, Ar-H), 7.71 (s, IH, Ar-H), 7.90 (d, 2H, J=7.8Hz, Ar-H), 8.34 (s, IH, Ar-H), 9.26 (s, IH, -CONH-)

EI-MS w/z 484 ([M] ⁺ ).

Example 10

2-[4-((l-Benzyl-IH-benzimidazol-2-yl)methyl)piperazine-1-yl]-N-(2-nitrophenyl)acetamide

Prepared according to the method of step (3) in Example 1, replacing N-(2-nitrophenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with 1_[ ₂ _(4-methoxy Phenyloxy)ethyl]piperazine dihydrochloride, 0.45 g of a white solid, yield: 62.6%, m.p.: 156-157.

IR (KBr): 745, 923, 1014, 1158, 1280, 1344, 1455, 147, 1608, 1698, 2828, 3024, 3272, 3480 cm" ¹

3.08 (S, 2H, 'H-NMR (CDC1 ₃ ) 62.49 (s, 4H,

3.08 (S, 2H,

-NHCOCH2-), 3.77 (s, 2H, ArCitN(CH ₂ CH ₂ ) ₂ N-), 5.52 (s, 2H, PhCH _r ), 7.01 (s, 2H, Ar-H), 7.09-7.23 (m, 7H, Ar-H), 7.57 (t, IH, J=8.4Hz, Ar-H), 8.15 (d, IH, J=8.4Hz, Ar-H), 8.76 (d, lH, J=8.4Hz, Ar-H), 11.77 (s, 1H, -CONH-)

 EI-MS w 484 ([M〗+).

Example 11

2-[4-((l-Benzyl-IH-benzimidazol-2-yl)methyl)piperazin-1-yl]-N-(2-chlorophenyl)acetamide

Prepared according to the method (3) in Example 1, replacing N-(2-chlorophenyl)-2-(piperazin-1-yl)acetamide dihydrochloride with p-methoxyphenoxy) Ethyl]piperazine dihydrochloride gave 0.42 _{g of} a white solid. Yield: 60%, m.p.: 122-124.

IR (KBr): 721, 751, 1011, 1130, 1158, 1333, 1441, 1518, 1696, 1947, 2815, 2944, 3202, 3514 cm" ¹

3.05 (s， 2H, -NHCOCH2-), 3.74 (s, Ή-NMR (CDCI3) δ 2.49 (s, 8H,

3.05 (s, 2H, -NHCOCH2-), 3.74 (s,

2H, ArCH2N(CH ₂ CH ₂ ) ₂ N-), 5.51 (s, 2H, PhCH ₂ -), 6.84-7.02 (m, 3H, Ar-H), 7.24-7.47 (m, 8H, Ar-H) , 7.71 (d, lH, J=8.1Hz, Ar-H), 8.36 (d, IH, J=8.1Hz, Ar-H), 9.83 (s, IH, -CO H-)

EI-MS m/z 473 ([M] ⁺ ).

Example 12

,. io ZZH ]0£ '826Z '£08 Ί ίΖ '\Ζ9\ '$8 1 '6SZ\ 'ΠΟΙ 'LU : θ¾)ΉΙ °3。Ζ9Ι-Ι9Ι -^M ^:¾ '⁸S O 1-benzyl-2-((4-toluenesulfonylpiperazin-1-yl)methyl)-IH-benzimidazole

,. io ZZH ]0£ '826Z '£08 Ί ίΖ '\Ζ9\ '$8 1 '6SZ\ 'ΠΟΙ 'LU : θ3⁄4)ΉΙ °3. Ζ9Ι-Ι9Ι -^M ^: 3⁄4 ' ⁸ SO

3⁄43⁄4^*-Ηΐ-(»ώ(3⁄4-ι-3⁄43⁄4ιίι3⁄43⁄4ώ^)Η-3⁄4^-ι w闘•( ₊ ίΐ+νΦ z/i SPV-ISH (H-JV 'H9 '« WL-ZS'L '(H_JV 'Η£ ' ) £'L-ZfL '(H^V 'HC '" ZYL-LVL '(H-JV 'HZ 'ω) ^6'9"16"9 '(-3⁄43Md 'H2 ' s) 6 9 '(-N ^∑ (3⁄4D3⁄43)N ^? H5- ^l V 'HZ 's) W/£

Ζ9Π 'ε9οε '"8∑; Όΐδζ: Oi9i 'ζζςι 'ίςη Ίηι 'Ο Π 'ε^6 'εεζ, '9" :( ^j e3⁄4) 3⁄4ι

°3oS8l-E8l ^: W '%65 -'^ '§6£ M^U '^邈3⁄4 二翁

 ^- -(» i (S- 1 -#)3⁄4S m*))-^3⁄4i- 1

 n闘

•( ₊ [l+Wl) 19 /WS -IS3 (H-JV 3⁄4 l 'ω) 08· "'(H-JV

3⁄43 'ω) 19-Z,-9S"Z, '(H-JV 'HS '^) ^L'ZZL '(H-JV 'Η£ ' ) 9ΓΖτ60·乙'(H^V 'HZ '^) .69'16'9

 'm 's) t8

'S9ii 'sen '6 'οεζ, 's s :(^ja¾) ¾ι

二翻 ¾[¾7(¾¾

'S9ii 'sen '6 'οεζ, 'ss :( ^j a3⁄4) 3⁄4ι

Two turns 3⁄4[3⁄47(3⁄43⁄4

SSM.0/0T0ZN3/X3d 8176ΪΪΪ/0Ϊ0Ζ OAV H-NMR (CDCh) δ 2.45-2.53 (m, 4H

3.80 (s, 2H, ArCH2N(CH ₂ CH ₂ ) ₂ N-), 5.55 (s, 2H, PhCH ₂ -), 7.04-7.07 (m, 2H, Ar-H), 7.24-7.41 (m, HH, Ar-H), 7.71-7.80 (m, 1H, Ar-H)

ESI-MS w/z 411 ([M+l] ⁺ ).

Example 15

1-benzyl-2-((4-chlorobenzoylpiperazin-1-yl)methyl)-1H-benzimidazole

 Prepared by the method of the step (3) in the first embodiment, replacing 4-[2-(4-methoxyphenoxy)ethyl]piperazine dihydrochloride with 4-chlorobenzoylpiperazine hydrochloride. Obtained as a white solid 0.21 g, yield: 48%, m.p.: 161-162.

IR (KBr): 743, 1007, 1091, 1260, 1438, 1456, 1626, 2758, 2922, 3233, 3416 cm ⁴

H-NMR (CDC1 ₃ ) δ 2.49 (m, 4H _;

3.80 (s, 2H, ArCH2N(CH ₂ CH ₂ ) ₂ N-), 5.55 (s, 2H, PhCH ₂ -), 7.04-7.09 (m, 2H, Ar-H), 7.26-7.39 (m, 9H, Ar-H), 7.76-7.80 (m, 1H, Ar-H)

 ESI-MS m/z 445 ([M+l] +).

Example 16

1-(benzoxazole-2-methyl)-N-(4-methoxyphenyl)piperidin-4-amine

(1) Preparation of ² -chloro-N-( ² -hydroxyphenyl)acetamide

 2-Aminophenol (0.01 mol) was dissolved in 20 mL of acetone, potassium carbonate was added, and chloroacetyl chloride (0.011 mol) in 10 mL of acetone solution was added dropwise, and the mixture was stirred at room temperature for 2 h. After filtration, the filtrate was concentrated to dryness, and crystallised from ethyl acetate: petroleum ether = 1 : 1 to give a pale yellow needle crystal 1.66 g, yield: 89%.

EI-MS m/z 185 peel ⁺ ), 187 ([M+2] +).

 (2) Preparation of 2-chloromethylbenzoxazole

 2-Chloro-N-(2-hydroxyphenyl)acetamide (0.027 mol) was dissolved in 50 mL of 1,2-dichloroethane, 20 g of polyphosphoric acid was added, and stirred at 100 ° C for 4 h. After cooling, 100 mL of crushed ice was added, and ethyl acetate was extracted and dried over anhydrous magnesium sulfate. The solution was evaporated to dryness, EtOAcjjjjjjjj

 EI-MS m/z 167 stripped +), 169 ([M+2] +).

(3) Preparation of N-(benzoxazole-2-methyl)-piperidin-4-one 4-piperidone hydrochloride monohydrate (0.04 mol) was dissolved in 80 mL of acetonitrile, potassium carbonate (0.07 mol) was added, and 2-chloromethylbenzoxazole (0.035 mol) in 50 mL of acetonitrile was added dropwise. 4h. Filtration, evaporation of the solvent, column chromatography, eluent ethyl acetate: petroleum ether = 1: 2, hexanes eluent, white needle crystals 6.6 g, yield: 82%, melting point: 86-88 C.

IR (Br): 667, 749, 848, 930, 1094, 1239, 1455, 1570, 1620, 1722, 2840, 2961, 2423 cm" ¹

Ή-NM (CDC1 ₃ ) δ 2.54 (t, 4Η, J=6Hz, -N(CH _? CH _z ) ₂ CO-), 2.98 ((t, 4H, J=6Hz, -N(C3⁄4CH ₂ ) ₂ CO -), 4.02 (s, 2H, -C3⁄4N(CH ₂ CH ₂ ) ₂ CO-), 7.32-7.39 (m, 2H, Ar-H), 7.52-7.57 (m, lH, Ar-H), 7.70- 7.73 (m, 1H, Ar-H)

ESI-MS m/z 230 ([M] ⁺ ).

 (4) Preparation of target compound

 N-(benzoxazole-2-methyl)-piperidin-4-one (0.002 mol) and p-methoxyaniline (0.0025 mol) dissolved in 20 mL of toluene, 0.001 rnol p-toluenesulfonamide, 140 ° C After refluxing for 2 hours, the solvent was evaporated to dryness, and the residue was dissolved in methanol. Saturated ammonium chloride solution was added, extracted with ethyl acetate and dried. The solvent was evaporated to dryness. Obtained white solid 0.14 g, yield: 21%, mp.

IR (KBr): 755, 770, 813, 1047, 1143, 1228, 1285, 1456, 1512, 1616, 2833, 2961, 3053, 3317 cm' ¹

 ψ ψ

 ,,

^- MR (CDCI3) δ 1.50 (m, 2Η, ' ^Ν ) 2.01 (m, 2Η, 2.34 (m, 2H, HH ),

'N,

2.95 (m, 2H, H » ), 3.16 (m, 1H, — ^N 3⁄4" ), 3.67 (s, 3H, -OCH3), 3.85 (s, 2H, -CH2N(CH ₂ CH ₂ ) ₂ -), 6.52 (d, 2H, J= 8.7Hz, a ), 6.69 (d, 2H, J= 8.7Hz, , ),

7.25-7.29 (m, 2H,

EI-MS m/z 337 ([M] ⁺ ).

Example 17

按实施例 16中步骤 (4)方法制备， 以苄胺替代对甲氧基苯胺， 滴加浓盐酸， 蒸千， 得白色固体 0.3g， 产率： 38%,熔点： 275~27?'°C。 IR (KBr): 700, 754, 765, 966, 1022, 1163, 1240, 1455, 1613, 2363, 2513, 2588, 2769,1-(benzoxazole-2-methyl)-N-benzylpiperidin-4-amine dihydrochloride

Prepared by the method of the step (4) in the same manner as in the the the the the the the the the the the the the the the the the the the the the the the the the C. IR (KBr): 700, 754, 765, 966, 1022, 1163, 1240, 1455, 1613, 2363, 2513, 2588, 2769,

2833, 3018, 3206 cm-

Ή-NMR 2.38 (m, 2H, ' ^N H ), 3.19 (m, 2H, HB ),

4.22 (s, 2H, -£¾N(CH₂CH₂)₂-)， 4.70 (s， 2H, 3.28 (m, 1H,

4.22 (s, 2H, -£3⁄4N(CH ₂ CH ₂ ) ₂ -), 4.70 (s, 2H,

PhC3⁄4NH-), 7.48-7.59 (m, 5H, Ar-H), 7.66 (m, 2H, a ° ), 7.85-7.91 (m,

9.73 (s, 2H, 2HC1)

Example 18

N-((l-(benzoxazol-2-methyl)piperidin-4-yl)methyl)-4-methoxybenzylamine dihydrochloride

 Prepared by the method of the step (4) in the same manner as in the above step (4), the p-methoxybenzylamine was replaced by p-methoxybenzylamine, concentrated hydrochloric acid was added dropwise, and evaporated to give a white solid (0.21 g, yield: 24.8%, melting point: 207- 2 ll °C o

IR (KBr): 740, 837, 926, 1179, 1246, 1303, 1373, 1454, 1514, 1611, 2351, 2555, 1776, 2854, 3416, 3741, 3849 cm" ¹

H-NMR (CDC1 ₃ ) δ 1.85-2.17 (m, 6H, HH -~ )) 22..7711 ((mm,, 11HH,, ^MH )),, 2.96 (: m, 2H,

HH ), 3.62 (s, 3H, -OCH3), 3.80 (d, 4H, -CH ₂ N(CH ₇ CH ₇ ) ₇ -, PhCH ₂ N-), 6.79 (d, 2H, J=

7.63 (m， 1H, 8.7Hz, a), 7.23-7.3 (m, 2H,

7.63 (m, 1H,

H^-o ), 9.82 (s, 2H, 2HC1)

 EI-MS w/z 351 class +).

Example 19

N-((l-(benzoxazol-2-methyl)piperidin-4-yl)methyl)-4-fluorobenzylamine dihydrochloride

Prepared by the method of the step (4) in Example 16 to give fluoroaniline instead of p-methoxyaniline, concentrated hydrochloric acid, and evaporated to give a white solid (0.31 g, yield: 37.2%, mp. IR (KBr): 750, 764, 840, 1001, 1165, 1172, 1228, 1452, 1586, 1608, 2399, 2539, 2644, 2937 cm' ¹

2.46 (m， 2H, H ), 3.28 (m, 2H_: H H )， 3.57 Ή-NMR (D ₂ 0) δ 2.01 (m, 2H,

2.46 (m, 2H, H ), 3.28 (m, 2H _: HH ), 3.57

(m, 1H, ^ a )3.81 2H, u H ), 4.26 (s, 2H, - CH2N(CH ₂ CH ₂ ) ₂ -), 4.70 (s, 2H.

7.42-7.53 (m, 4H, tT PhCHbNH-), 7.13-7.21 (m, 2H,

7.42-7.53 (m, 4H, tT

(m, 2H, B-^O )

EI-MS m/z 339 ([M] ⁺ ).

Example 20

1-(benzoxazole-2-methyl)-N-phenethylpiperidine-4-amine dihydrochloride

 Prepared by the method of the step (4) in the same manner as in the step (4), the phenylethylamine was replaced by phenylethylamine, and concentrated hydrochloric acid was added dropwise to dryness to give a white solid (0.22 g, yield: 26.5%, melting point: 270-272 ° C .

 IR (KBr): 697, 748, 841, 942, 1001, 1169, 1240, 1453, 1593, 1613, 1907, 2085, 2405, 2598, 2813, 2939, 3851 cm

'^Ν" ϋ ), 2.96 Ή-NMR (D ₂ 0) δ 1.90 (d, 2H, J = 13.5 Hz,

' ^Ν " ϋ ), 2.96

) (t, 2H, J=7.5Hz, H ^A H ), 3.20-3.33 (m, 4H, HH, PhCH ₂ CH ₇ N-), 3.44-3.52 (m, 1H, a ), 3.66 (d, 2H, J=12Hz, PhC3⁄4CH _z N-), 7.23-7.35 (m, 5H, Ar-H), 7.39-7.50 (m, 2H,

)

 EI-MS m/z 335 peeling +).

Example 21

N-(2-(Benzo[1,3]dioxolyl)ethyl)-1-(benzoxazole-2-methyl)piperidin-4-amine dihydrochloride

Prepared according to the method of step (4) in Example 16, replacing p-methoxyaniline with piperonylamine, adding concentrated hydrochloric acid, steaming Dry, white solid 0.26 g, yield: 28.4%, melting: 267-269.

 IR (KBr): 749, 802, 934, 1037, 1161, 1243, 1456, 1505, 1609, 2498, 2605, 2818, 2982,

3438 cm"

), 3.74 (m, 2Η, PhCH_zC N-), 4.72 (m, 2Η, PhCH₇CH₂N-), 6.05 (s, 2H, Ή-NMR (DMSO) δ 2.09 (m, 2Η, ' ^Ν ^) 2.35 (m, 2Η, ' ^Ν ^Η ^η ), 2.97 (m, 5Η, Η ^Α Η _;

), 3.74 (m, 2Η, PhCH _z C N-), 4.72 (m, 2Η, PhCH ₇ CH ₂ N-), 6.05 (s, 2H,

7.85-7.92 (m, 2H.

-OCH2O-), 6.78-6.95 (m, 3H, Ar-H), 7.49-7.59 (m, 2H,

7.85-7.92 (m, 2H.

 EI-MS m/z 379 ([M] +).

Example 22

1-(benzoxazole-2-methyl)-N-(4-methoxy)piperidine-4-carboxamide

 (1) Preparation of N-tert-butyloxycarbonyl-4-(4-methoxyanilinoyl)piperidine

 Add N-tert-butyloxycarbonyl-4-piperidinecarboxylic acid (O.Olmol) to 15 mL of tetrahydrofuran, stir at room temperature, add O.Olmol hydrochloric acid EDC and O.Olmol DMAP, stir at room temperature for 5 min, add p-methoxyaniline, stir Lh. It was poured into water and suction filtered to give a white solid (···········

Ή-NMR (CDCI3) δ 1.47 (s, 9H, -C(CH ₂ ) ₂ ), 1.59-1.80 (m, 2H, -CH ₂ -), 1.88-1.92 (m, 2H,

-CH ₂ -), 2.32-2.36 (m, 1H, a ^N ^3⁄4"), 2.74-2.83 (m, 2H, -CH ₂ -), 3.79 (s, 3H, -OCH3),

4.16-4.21 (m, 2H, -CH ₂ -), 6.85 (d, 2H, J=9Hz, Ar-H), 7.26 (s,

1H, -NH-), 7.4 (d, 2H, J=9Hz, Ar-H)

 ESI-MS m/z 335 ([M+l] +).

₍₂₎ Preparation of _N- (4-methoxyphenyl)piperidine-4-carboxamide hydrochloride

 N-tert-Butyloxycarbonyl-4-(4-methoxyanilinoyl)piperidine (0.0 mol) was dissolved in methanol, 0.02 mol of acetyl chloride was added, and stirred at room temperature for 12 h. The solvent was evaporated to give a white solid (yield::::::::::::

 (3) Preparation of the title compound

N-(4-Methoxyphenyl)piperidine-4-carboxamide hydrochloride (0.0034 mol) was added 15 mL of acetonitrile, 0.007 mol of potassium carbonate, and refluxed for 1 h. 2-Chloromethylbenzoxazole (0.0034 mol) was added and refluxed for 2 h. The reaction solution was poured into water, extracted with ethyl acetate (30 mL×3×) and dried over anhydrous sodium sulfate. Column chromatography, the eluent was ethyl acetate: petroleum ether = 1 : 4, EtOAc (EtOAc: EtOAc) IR (KBr): 745, 836, 1031, 1243, 1521, 1642, 2390, 2826, 2936, 3299 cm" ¹ Ή-NMR (CDC1 ₃ ) δ 1.72-1.88 (m, 4H, -CH ₂ -x2), 2.23-2.31 (m, 3H, -CH ₂ -,

_ ^N ^H"), 3.11-3.15 (m, 2H, -CH ₂ -), 3.78 (s, 3H, -OCH3), 3.92 (s, 2H, ArCH _z N(CH _? CH ₇ ) ₇ -), 6.83-6.86 (m, 2H, Ar-H), 7.31-7.41 (m, 4H, Ar-H), 7.53-7.57 (m, IH, Ar-H), 7.69-7.74 (m, 1H _; Ar-H )

ESI-MS m/z 366 ([M+l] ⁺ ).

Example 23

1-benzyl-N-(4-methoxyphenyl)piperidine-4-carboxamide

 Prepared by the procedure of Step (3) in Example 22, substituting benzyl bromide to 2-chloromethylbenzoxazole to give a white solid (yield: 0.68 g, yield: 60%, melting point: 157-159. C.

I (KBr): 702, 758, 1024, 1247, 1508, 1644, 2388, 2957, 3381 cm ^-1

H-NMR (CDC1 ₃ ) 51.81-1.91 (m, 4H, -CH ₂ -x2), 2.00-2.24 (m, 3H, -CH ₂ -,

2.98 (m, 2H, -CH ₂ -), 3.53 (s, 2H, PhCH _r ), 3.78 (s, 3H, -OCH3), 6.85 (d, 2H, Ar-H), 7.10 (s, IH, - CONH-), 7.27-7.34 (m, 4H, Ar-H), 7.4 l(d, 2H, J=9Hz, Ar-H)

 EI-MS m/z 324 (Oka +).

Example 24

1-«1-benzyl-IH-benzimidazol-2-yl)methyl)-N-(4-methoxyphenyl)piperidine-4-carboxamide

 Prepared by the method of the step (3) in Example 22, substituting 1-benzyl-2-chloromethyl-1H-benzimidazole for 2-chloromethylbenzoxazole to give a white solid, 0.51 g, yield: 32 %, Melting point: 98-100°Co

IR (KBr): 739, 1037, 1242, 1511, 1673, 1733, 1880, 2305, 2711, 2934, 3125 cm ^-1

Ή-NMR (CDCI3) 6 1.72-1.88 (m, 4H, -CH ₂ -x2), 2.20 (m, 2H, -CH ₂ -), 2.05 (m, IH, a ^N ), 2.91-2.94 (m, 2H, -CH ₂ -), 3.77 (s, 3H, -OCH ₂ ), 3.78 (s, 2H, ArCH ₂ NiC C ), 5.63 (s, 2H, PhCH ), 6.83-6.87 (m, 2H, Ar- H), 7.07-7.11 (m, 2H, Ar-H), 7.23-7.42 (m, 8H, Ar-H), 7.76-7.80 (m, IH, Ar-H)

ESI-MS m/z 455 ([M+l] ⁺ ).

Example 25

 Tablet

 50 g of the compound prepared in the method of Example 24, 150 g of hydroxypropylmethylcellulose E5, 200 g of starch, an appropriate amount of 8% povidone K30, and lg of magnesium stearate were mixed, granulated, and tableted.

Claims

Request A compound of the formula (I), a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof:

 (I)  Wherein Ar represents a benzene ring, a pyridine ring or a 5- or 6-membered aromatic ring containing 0 to 2 selected from a nitrogen atom, a sulfur atom or an oxygen atom; Ar also said

Wherein Y represents a nitrogen atom or a carbon atom, Zi represents a nitrogen atom, and A represents a benzyl group, a phenyl group or a (^-4 alkyl group; Ar also said

Wherein Y represents a nitrogen atom or a carbon atom, and Z ₂ represents an oxygen atom or a sulfur atom; X represents a nitrogen atom or a carbon atom; L represents -CO-, -SO ₂ -, -NH -, -CONH -, -(CH ₂ ) _n O-, -(CH ₂ ) _n N-, -(CH ₂ ) _n O - or -(CH _{2 n} CONH-, where n is an integer from 1 to 4;  R represents a mono- or poly-substitution, and a poly-substitution means a di-, tri- or tetra-substituent; the substituent is selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, CA Alkoxy group of CA, CA, aminoalkyl group of CA, alkyl amine group of CA, acyl group of CA, (^~4 of an amide group, (^~4 of an alkoxycarbonyl group, an alkyl group attached to a benzene ring or an alkyl group bonded to a benzene ring (^~4); the substituent may also be selected from An alkyl or alkoxy group of (^-4) which is bonded to a five- or six-membered heterocyclic ring containing 1 to 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom. The compound according to claim 1, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein Ar represents a benzene ring, a benzoxazole ring, a benzimidazole ring, or a 1-benzylbenzimidazole Ring, 1-phenylbenzimidazole ring or benzo[1,3]dioxolane. A compound according to claim 1, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein L represents -CH ₂ CH ₂ O-, -CH ₂ N -, -CH ₂ CH ₂ N - - CH ₂ CONH -, -CONH -, -NH -, -CO- or -SO ₂ -. A compound according to claim 1, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R represents a para- or o- or para-disubstituted; the substituent is selected from the group consisting of a tetra-, an amino group and a hydroxyl group. , nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, ester or amide. The method for preparing the compound of the formula (I) according to claim 1, wherein when X is a nitrogen atom, the method comprises:

 Wherein M represents bromine or chlorine, X is a nitrogen atom, and Ar L R is as defined in claim 1 6. A process for the preparation of a compound of the formula (I) according to claim 1, When X is a carbon atom and L is an alkylamine group of (^~4), it includes:

When X is a carbon atom and L is another group represented by claim 1 in addition to the alkylamine group of CA, it includes:

 Ar L R is defined in the same claim 1  A pharmaceutical composition comprising the compound of claim 1, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a disorder associated with dysfunction of potassium channels. 9. The use of claim 8, wherein the disease associated with abnormal potassium channel function is arrhythmia or ischemic injury.