KR100917039B1 - Triazole derivatives for T-type calcium channel blocker - Google Patents

Abstract

The present invention is excellent in inhibiting the T-type calcium channel (T-type calcium channel) to prevent various diseases such as brain diseases such as epilepsy, angina pectoris, hypertension, heart diseases such as myocardial infarction, neurological pain, and cancer A triazole derivative useful for the treatment and prophylaxis and a pharmaceutical composition comprising the compound.

Triazole derivatives, T-type calcium channel, angina, hypertension, myocardial infarction, pain, epilepsy and cancer

Description

Triazole derivatives for T-type calcium channel blocker

The present invention is excellent in inhibiting the T-type calcium channel (T-type calcium channel) to prevent various diseases such as brain diseases such as epilepsy, angina pectoris, hypertension, heart diseases such as myocardial infarction, neurological pain, and cancer A triazole derivative useful for the treatment and prophylaxis and a pharmaceutical composition comprising the compound.

Intracellular calcium plays an important role in intercellular signal transduction, and its key role is the calcium channel. Calcium has several distribution pathways, but voltage-dependent Ca ²⁺ channels play an important role in the delivery of terminal stimuli. Muscle contraction and neurons are regulated by regulating the inflow of calcium ions from outside the cell. It regulates various intracellular actions such as development, secretion of neurotransmitters and hormones, gene expression and the like.

Calcium channels play an important role in the excitatory-constriction linking mechanisms in skeletal, vascular, and heart muscle cells and in the regulation of neurotransmitter secretion in the central and peripheral nervous systems. These calcium channels are divided into low voltage activation channels (mainly T type) and high voltage activation channels (L, N, P, Q and R types) according to the time and voltage dependence of channel opening and sensitivity to pharmacological blocking. L-type calcium channel plays a major role in the transport of calcium ions across cell membranes such as vascular, skeletal, and smooth muscle, regulating the contraction of these muscles, and nerves from endocrine glands and nervous tissues. It is also involved in transporter secretion. In addition, T-type calcium channel is present in many cardiac cells such as central muscle cells, adrenal glands, and parietal nodules, so that not only the role of L-type but also the T-type channel present in cardiac cells It plays an important role in producing heart rhythm and is known to be involved in calcium ion influx into muscle cells by small potential difference. Calcium channel antagonists are expected to be able to control the proliferation of blood cells, blood pressure, abnormal neuronal secretion, etc., and many research subjects have many calcium channel antagonists in the development of drugs for the treatment of heart disease and widespread psychomotor disorders. This has been. Most of the early materials developed had inhibitory effects on L-type calcium channels. However, their side effects require antagonists to selectively inhibit T-type calcium channels.

A number of papers have been published on the therapeutic effects of T-type calcium channel antagonists. For example, a paper related to the therapeutic effect of Epilepsy disease is described by Hosravani, Houman et al., "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy", Annals of Neurology (2005), 57 (5 ). ) , 745-749; ② Vitko, Iuliia et al., "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel", Journal of Neuroscience (2005), 25 (19) , 4844-4855. . Papers related to the therapeutic effect of hypertension disease include (1) Moosmang, Sven et al., "Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2.", Circulation Research (2006), 98 (1) , 105-110; Murielle Veniant et al., "Calcium blockade versus ACE inhibition in clipped and unclipped kidneys of 2K-1C rats", Kidney International , Vol 46 , pp. 421-429; Gillian A. Gray et al., "Effects of Calcium blockade on the Aortic Intima in Spontaneously Hypertensive Rats", Hypertension , Vol 22 , No 4 October 1993; ④ Santosh K. Mishra et al., "Selective inhibition of T-Type Ca ²⁺ Channels by Ro 40-5967, Circulation Reasearch , Vol 75 , No 1 July 1994; ⑤ RJ Viskoper et al.," Trial comparing mibefradil and amlodipine ", Journal of Human Hypertention (1997) 11 , 387-393. Papers related to the therapeutic effects of cancer diseases are described in Jae Yeol Lee et al.," Growth inhibition of human cancer cells in vitro by T-type. calcium channel blockers ", Bioorg. & Med. Chem Lett. (2006), 16, 5014-5017. In addition, recent publications related to the effects of pain disease treatment include (1) Daesoo Kim et al., "Thalamic Control of Visceral Nociception Mediated by T-Type Ca ²⁺ Channels", Science Vol 302 , 3 October 2003; ② Helen Ki Shinn et al., "Ethosuximide and Mibefradil, T-type calcium channel blockers in postoperative pain models in rats Antihyperalgesia effect ", Korean J Pain , Vol 20 , No 2, 2007.

Representative drugs for inhibiting T-type calcium channels that have been published to date include several drugs other than 'Mibefradil' developed by Hoffman La Roche. However, these drugs can cause various CNS disturbances such as visual acuity, dizziness, vomiting and sedation, as well as potential life-threatening cardiac arrhythmias and heart failure, all of which have been difficult to use in practice. Thus, the development of new blocking drugs that are selective and have no side effects on T-type calcium channels can lead to breakthroughs in the treatment of cardiovascular diseases, pain disorders and cancer, including brain diseases including epilepsy, hypertension, angina pectoris, hypertension or myocardial infarction. It is expected to be.

From this point of view, the triazole derivative according to the present invention is a novel compound, which has an excellent effect of inhibiting T-type calcium channel, and thus can be usefully applied to various diseases such as angina pectoris, hypertension, myocardial infarction, pain, epilepsy and cancer. have.

It is an object of the present invention to provide triazole derivatives of the novel structure.

It is another object of the present invention to provide a medicinal use of using a triazole derivative or a pharmaceutically acceptable salt thereof as a T-type calcium channel blocker.

The present invention is characterized by a triazole derivative represented by the following formula (1) which is useful as a selective T-type calcium channel blocker.

In Chemical Formula 1,

R ₁ is a group selected from the group consisting of a phenyl group, benzimidazole group, and benzimidazole C ₁ -C ₈ alkyl group; R ₂ is a group selected from the group consisting of a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₂₀ alkanoyl group, a phenyl group, a benzoyl group, and a thiophencarbonyl group; R ₃ is a group selected from the group consisting of a hydrogen atom, and N- phenylacetamide; The benzene rings of the phenyl, benzoyl, benzimidazole and N- phenylacetamide groups for the substituents defined above are halogen, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, and C ₁ -C ₈ halo, respectively. Substituents selected from the group consisting of alkyl may be 1 to 4 substituted or unsubstituted.

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

The 'alkyl group' used in the definition of a compound according to the present invention includes all linear, pulverized or cyclic carbon chains having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, specifically methyl, ethyl , Propyl, isopropyl, n -butyl, t- butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "Alkoxy group" means an alkyl group of carbon linked to oxygen, where alkyl is as defined above, specifically methoxy, ethoxy, protoxy, isoprotoxy, n -butoxy, t- part Oxy and the like. "Alkanoyl group" means an alkylcarbonyl group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, specifically acetyl, ethionyl, n -propionyl, isopropionyl, n -butyryl , Isobutyryl, cyclopropanecarbonyl, cyclohexanecarbonyl, isosanoyl and the like. "Haloalkyl group" means an alkyl group substituted with one or more halogen atoms, wherein alkyl is as defined above, specifically, chloromethyl group, dichloroethyl group, trifluoromethyl group, tetrafluoroethyl group, tetrachloroethyl group, etc. This may be included. "Halogen atom" may include fluoro, chlorine, bromine, iodine and the like.

In the triazole derivative represented by Chemical Formula 1, preferably, R ₁ is a group selected from the group consisting of a phenyl group, a benzimidazole group, a benzimidazole methyl group, a benzimidazole ethyl group, and a benzimidazole propyl group. ego; R ₂ is hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, n -butyl group, t- butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, acetyl Group consisting of group, ethionyl group, n -propionyl group, isopropionyl group, n -butyryl group, isobutyryl group, cyclopropanecarbonyl group, cyclohexanecarbonyl group, isoxanoyl group, phenyl group, benzoyl group, and thiophencarbonyl group A group selected from; R ₃ is a group selected from the group consisting of a hydrogen atom, and N- phenylacetamide; The benzene rings of the phenyl, benzoyl, benzimidazole and N- phenylacetamide groups for the substituents defined above are fluoro, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, isopropyl, n -butyl, t -butyl, pentyl, hexyl, cyclo-propyl, cyclo-butyl, cyclo pentyl, cyclo hexyl, methoxy, ethoxy, pro-ethoxy, isopropoxy ethoxy, n-methyl group with butoxy, t- butoxy, trifluoromethyl, tetrafluoroborate Substituents selected from the group consisting of an ethyl group and tetrachloroethyl may be 1 to 4 substituted or unsubstituted.

In the triazole derivative represented by Chemical Formula 1 according to the present invention, preferred compounds are as follows:

5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol,

2- [5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- nitrophenyl Acetamide,

2- [5-methyl (1 H-benzimidazol-1-yl) methyl -4- -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2-chlorophenyl Acetamide,

2- [5-methyl (1 H-benzimidazol-1-yl) methyl -4- -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- chlorophenyl Acetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- bromo- Phenyl) acetamide,

2- [5- (1 H-benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2- chloro - 4-trifluoromethylphenyl) acetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - -3- triazole ylsulfanyl] - N- (2,5- Diethoxyphenyl) acetamide,

2- [5- (1 H-benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (3- chloro- 4-methylphenyl) acetamide,

5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazole-3-thiol,

5- ( 1H -benzimidazol-1-yl) methyl-4-benzoyl-4 H- [1,2,4] -triazole-3-thiol,

2- [5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (2- chloro-4-trifluoromethyl Methylphenyl) acetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (2- chlorophenyl) acetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (4- chlorophenyl) acetamide,

2- [5- (1 H - benzimidazol-1-yl) methyl-4-ethyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- chlorophenyl Acetamide,

5- (2-chlorophenyl) -4 H- [1,2,4] -triazole-3-thiol,

2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4-acetyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (butoxybenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (4-chloromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (2,4,6-trichlorobenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacet Amide,

2- [5- (2-chlorophenyl) -4- (2-trifluoromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (2-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (3,4,5-trimethoxybenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenyl Acetamide,

2- [5- (2-chlorophenyl) -4- (4-butylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4-benzoyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (3-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide,

5- (2-chlorophenyl) -4-phenyl-4 H- [1,2,4] -triazole-3-thiol,

2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (4- chlorophenyl) acetamide,

2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (2-chloro-4-trifluoromethyl-phenyl) Acetamide,

2- [5- (2-chlorophenyl) -4-yl Ikoma Sano -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide,

2- [5- (2-chlorophenyl) -4-butyryl -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide,

2- [5- (2-chlorophenyl) -4-cyclohexanecarbonayl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4-cyclopropanecaraboyl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (thiophen-2-carbonanyl) -4 H- [1,2,4] -triazol-3 - ylthio] -N- phenylacetamide ,

2- [5- (2-chlorophenyl) -4- (isobutyryl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide,

2- [5- (2-chlorophenyl) -4- (4-chlorobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide,

2- [5- (2-chlorophenyl) -4- (2-chlorobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide,

2- [5- (2-chlorophenyl) -4- (3-bromobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide,

Or pharmaceutically acceptable salts thereof.

The triazole derivative represented by Chemical Formula 1 according to the present invention can be synthesized by a known production method as shown in Schemes 1 and 2 below.

Scheme 1 below is an example of synthesizing a triazole derivative represented by Chemical Formula 1 wherein R ₁ = benzimidazolemethyl group, R ₂ = methyl group, and R ₃ = N- substituted phenylacetamide group.

According to the preparation method according to Scheme 1, the benzimidazole used as a starting material is heated with ethyl chloroacetate (ClCH ₂ COOEt) in the presence of a base such as a dimethyl sulfoxide solvent and sodium hydroxide, and then reacted with 1 H- benzimi. Synthesis of the dazole-acetic acid ethyl ester [E. Cuevas-Yazez et al., Tetrahedron, 2004 , 60 , 9391]. Then, 1 H- benzimidazole-acetic acid ethyl ester synthesizes 1 H- benzimidazole-acetic acid hydrazide in high yield by a transamidation reaction with hydrazine (NH ₂ NH ₂ ) [K. Sung et al., J. Heterocyclic Chem. , 1992 , 29 , 1101]. And 1 H- benzimidazole-acetic acid hydrazide is N- [(2- ( 1H -benzimidazol-1-yl) acetyl in coupling by reflux with methyl isothiocyanate (CH ₃ NCS). ) Synthesis of hydrazinothiocarbonayl] -methylamine, in the presence of a base such as sodium hydroxide, N of the methyl amino group attacks the carbonyl group in the compound to cause an intramolecular cyclization reaction, resulting in 5- ( 1H -benzimi Dazol-1-yl) methyl-4-methyl-4 H- [1,2,4] -triazole-3-thiol is synthesized in high purity and yield [JR Maxwell et al., J. Med. Chem ., 1984 , 27 , 1565 and MY Mhasalkar et al., J. Med. Chem., 1970 , 13 , 672]. And 5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol is substituted bromo N- phenylacetamide General nucleophilic substitution with compounds allows synthesis of compounds in which various N- phenylacetamides are substituted at the R ₃ position [LA Gabriela et al., Bioorg. Med. Chem. Lett. , 2005 , 15 , 2347].

In addition, Scheme 2 below is an example of synthesizing a triazole derivative represented by Formula 1, wherein R ₁ = substituted phenyl group, R ₃ = N- phenylacetamide group.

According to the preparation method according to Scheme 2, the benzohydride used as a starting material is reacted under reflux in a alcoholic solvent with benzoyl isothiocyanate to give N- [(2-chlorobenzoyl) -hydrazinothiocarbonayl]-. Synthesize benzoamide. Then, reflux reaction was carried out in the presence of an alcohol solvent and a base such as sodium hydroxide to synthesize 5- (2-chlorophenyl) -4H- [1,2,4] -triazole-3-thiol. And, as described in Scheme 1, 5- (2-chlorophenyl) -4 H- [1,2,4] -triazole-3-thiol is generally nucleophilic with chloro N- phenylacetamide compounds. Substitution reactions synthesize compounds in which various N- phenylacetamides are substituted at the R ₃ position. If necessary, the desired triazole derivative may be synthesized by substitution with an R ₂ -Cl compound in the presence of a base such as triethylamine to introduce various R ₂ substituents into the N-1 position of the triazole.

On the other hand, the triazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention is very effective as a T-type calcium channel blocker, so the present invention is a novel compound represented by the formula (1) as an active ingredient It includes a pharmaceutical composition contained in the scope of rights. In addition, the present invention is a brain disease such as epilepsy, angina pectoris, hypertension, heart disease such as myocardial infarction, and neurological pain, including the triazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Use as a therapeutic and prophylactic agent of cancer disease includes its use as a right. The pharmaceutical composition may be prepared by adding conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients to the triazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof such as tablets, It may be formulated into a preparation for oral administration such as a capsule, troche, solution, suspension, or parenteral administration. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01-400 mg / day, and can be dividedly administered once a day to several times at regular time intervals according to the judgment of a doctor or a pharmacist.

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

EXAMPLE

Example 1. 1 H- benzimidazole-ethyl acetate

Benzimidazole (21.96 g, 186 mmol) was dissolved in a solution of 600 mL of dimethylsulfoxide (DMSO) in sodium hydroxide (14.9 g, 371.9 mmol) and ethyl chloroacetate (51.5 mL, 483.5 mmol) in a two-necked flask. It was slowly added dropwise at room temperature. The reaction mixture was stirred at room temperature for about 30 minutes and then reacted at 70 ° C. for about 3 hours. After slowly cooling to room temperature, distilled water was added and extracted with 1.5 L of methylene chloride. Methylene chloride was concentrated on a rotary vacuum evaporator and silica gel column separation (solvent composition: 5% MeOH / CHCl ₃ ) afforded the pure target compound (19.73 g).

Yield 52%; Melting point 61-61.5 ° C .; IR (KBr) 2998, 1731, 1496, 1371, 1265 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.1 (s, 1H), 7.6 (m, 1H), 7.3 (s, 3H), 5.0 (s, 2H), 4.2 (q, J = 7.2 Hz, 2H), 2.3 (t, J = 7.2 Hz, 3H).

Example 2 . 1 H- benzimidazole-acetic acid hydrazide

1 H- benzimidazole-ethyl acetate (13.85 g, 67.9 mmol) was added to a two-necked flask, followed by 200 mL of ethanol, followed by hydrazine hydrate (4.35 g, 135.7 mmol), followed by reflux for 6 hours. After cooling slowly to room temperature, the brown solid obtained was recrystallized from ethanol to give the pure target compound (10.4 g).

Yield 81%; Melting point 232 ° C .; IR (KBr) 3436, 3311, 1680, 1662, 1498 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 9.5 (s, 1H), 8.2 (s 1H), 7.6 (dd, J = 8.1, 1.2 Hz, 1H), 7.5 (dd, J = 8.1, 1.2 Hz , 1H), 7.3-7.2 (m, 2H), 4.9 (s, 2H).

Example 3. N- [(2- ( 1H -benzimidazol-1-yl) acetyl) hydrazinothiocaaboyl] -methylamine

1 H- benzimidazole-acetic acid hydrazide (6.36 g, 33.5 mmol) was added to a two-necked flask, and 120 mL of anhydrous ethanol was added, followed by dropwise addition of methyl isothiocyanate (2.5 mL, 36.5 mmol) under a nitrogen atmosphere. Slowly added and refluxed for about 3 hours. After slowly lowering the temperature to room temperature, the resulting brown solid was recrystallized from ethanol and water to obtain the pure target compound (7.1 g).

Yield 86%; Melting point 209 ° C .; IR (KBr) 3327, 3133, 1699, 1558 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ,) δ 10.3 (bs, 1H), 9.4 (bs, 1H), 8.2 (s, 1H), 8.1 (bs, 1H), 7.6 (dd, J = 8.1, 1.2 Hz, 1H), 7.5 (dd, J = 8.1, 1.2 Hz, 1H), 7.3-7.2 (s, 2H), 5.0 (s, 2H), 3.0 (s, 3H).

Example 4. N- [(2- ( 1H -benzimidazol-1-yl) acetyl) hydrazinothiocarbonayl] -ethylamine

1 H- benzimidazole-acetic acid hydrazide (6.36 g, 33.5 mmol) was added to a two-necked flask, and 120 mL of anhydrous ethanol was added. Then, ethyl isothiocyanate (3.2 g, 36.5 mmol) was added dropwise under a nitrogen atmosphere. Slowly added and refluxed for about 3 hours. After slowly lowering the temperature to room temperature, the resulting brown solid was recrystallized from ethanol and water to obtain the pure target compound (7.1 g).

Yield 77%; Melting point 200 ° C .; IR (KBr) 3300, 3139, 1700, 1560 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ,) δ 10.1 (bs, 1H), 9.0 (bs, 1H), 8.1 (s, 1H), 8.0 (bs, 1H), 7.5 (dd, 1H), 7.5 (dd 1H), 7.3-7.0 (s, 2H), 4.9 (s, 2H), 3.5 (q, 2H), 1.29 (t, 3H).

Example 5. 5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol

In a two-necked flask, N- [(2- ( 1H -benzimidazol-1-yl) acetyl) hydrazinothiocacarbonyl] -methylamine (3.0 g, 11.4 mmol) was dissolved in 50 mL of ethanol, followed by 1 N aqueous sodium hydroxide solution (1.74 mL, 17.1 mmol) was slowly added dropwise at room temperature. After refluxing for about 8 hours and slowly cooling to room temperature, ethanol was removed with a rotary vacuum evaporator. After cooling the reaction flask in an ice bath, 2N hydrochloric acid aqueous solution was slowly added dropwise to adjust the hydrogen ion index of the reaction product to be slightly acidic. The resulting brown solid was filtered and washed several times with distilled water. Drying in vacuo and recrystallization with ethanol gave the pure target compound (1.1 g).

Yield 68%; Melting point 242 ° C .; IR (KBr) 3077, 1552, 1492, 1441 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 13.8 (bs, 1H), 9.9 (s, 1H), 8.0 (m, 1H), 8.0-7.9 (m, 1H), 7.6 (m, 2H), 6.1 (s, 2H), 3.6 (s, 3H).

Example 6. 2- [5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenyl Acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (510 mg, 2.1 mmol) N- phenyl bromoacetamide (391.8 mg, 2.3 mmol) was dissolved in anhydrous dimethylformamide (DMF, 8 mL), and anhydrous calcium carbonate (440 mg, 3.2 mmol) was added thereto and reacted under a nitrogen atmosphere at 70 ° C. for 6 hours. . After the reaction, DMF was concentrated on a rotary vacuum evaporator, and then the reaction mixture was dissolved in 2 mL of methanol, and slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (508 mg).

Yield 64%; Melting point 190 ° C .; IR (KBr) 3302, 1689, 1598, 1561, 1494, 1173 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.4 (s, 1H), 7.6-7.0 (m, 9H), 5.7 (s, 2H), 4.0 (s, 2H), 3.6 (s, 3H).

Example 7. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-yl sulfanyl carbonyl] - N- (4-nitrophenyl) acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (510 mg, 2.1 mmol) N- (4-nitrophenyl) bromoacetamide (59.3 mg, 2.3 mmol) was dissolved in anhydrous dimethylformamide (DMF, 8 mL), anhydrous calcium carbonate (440 mg, 3.2 mmol) was added, and the mixture was dried at 70 ° C for 6 hours. The reaction was carried out under a nitrogen atmosphere. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and then the reaction mixture was dissolved in 2 mL of methanol, and slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (508 mg).

Yield 54%; Melting point 190 ° C .; IR (KBr) 3300, 1680, 1590, 1555, 1490, 1171 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.2 (s, 1H), 7.9-7.3 (m, 9H), 5.5 (s, 2H), 4.1 (s, 2H), 3.4 (s, 3H).

Example 8. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 2-chlorophenyl) acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (159 mg, 0.6 mmol) N- (2-chlorophenyl) bromoacetamide (194 mg, 0.8 mmol) was dissolved in anhydrous DMF (5 mL) and anhydrous potassium carbonate (135 mg, 1.0 mmol) was added and reacted at 70 ° C. under a nitrogen atmosphere for 6 hours. . After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (176 mg).

Yield 71%; Melting point 196 ° C .; IR (KBr) 1687, 1592, 1543, 1497, 1443 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 9.9 (bs, 1H), 8.4 (s, 1H), 7.7-7.5 (m, 4H), 7.3-7.2 (m, 4H), 5.8 (s, 2H), 4.2 (s, 2H), 3.6 (s, 3H).

Example 9. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 4-chlorophenyl) acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (159 mg, 0.6 mmol) N- (4-chlorophenyl) bromoacetamide (194 mg, 0.8 mmol) was dissolved in anhydrous DMF (5 mL), and anhydrous potassium carbonate (135 mg, 1.0 mmol) was added and reacted at 70 ° C. under a nitrogen atmosphere for 6 hours. . After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (176 mg).

Yield 68%; Melting point 200 ° C .; IR (KBr) 1680, 1588, 1544, 1490, 1433 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 9.8 (bs, 1H), 8.3 (s, 1H), 7.7-7.3 (m, 4H), 7.3-7.1 (m, 4H), 5.9 (s, 2H), 4.1 (s, 2H), 3.5 (s, 3H).

Example 10. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 4-bromophenyl) acetamide

In a two-necked flask with 5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (150 mg, 0.61 mmol) N- (4-bromophenyl) chloroacetamide (172.8 mg, 0.70 mmol) was dissolved in anhydrous DMF (5 mL), and anhydrous potassium carbonate (127 mg, 0.92 mmol) was added and reacted at 70 ° C. under a nitrogen atmosphere for 6 hours. . After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (161 mg).

Yield 58%; Melting point 190 ° C .; IR (KBr) 1687, 1609, 1548, 1490, 1459 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.4 (bs, 1H), 8.4 (s, 1H), 7.7-7.5 (m, 6H), 7.5-7.2 (m, 2H), 5.7 (s, 2H ), 4.0 (s, 2H), 3.4 (s, 3H).

Example 11. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 2-chloro-4-trifluoromethylphenyl) acetamide

5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (185 mg, 0.8 in a two-necked flask under nitrogen atmosphere mmol) and N- (2-chloro-4-trifluoromethylphenyl) bromoacetamide (263 mg, 0.8 mmol) were dissolved in anhydrous DMF (3 mL), anhydrous potassium carbonate (157 mg, 1.1 mmol) was added thereto, and then 70 ° C. The reaction was carried out for 6 hours. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (237 mg).

Yield 65%; Melting point 211 ° C .; IR (KBr) 1696, 1612, 1593, 1538 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.0 (bs, 1H), 8.3 (s, 1H), 8.1 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.7-7.6 ( m, 2H), 7.5 (m, 1H), 7.2 (m, 2H), 5.6 (s, 2H), 4.1 (s, 2H).

Example 12. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 2,5-diethoxyphenyl) acetamide

5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (185 mg, 0.8 in a two-necked flask under nitrogen atmosphere mmol) and N- (2,5-diethoxyphenyl) bromoacetamide (218 mg, 0.8 mmol) were dissolved in anhydrous DMF (3 mL), and anhydrous potassium carbonate (157 mg, 1.1 mmol) was added thereto. The reaction was time. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (237 mg).

Yield 60%; Melting point 205 ° C .; IR (KBr) 1700, 1600, 1593, 1538 cm ^-1 ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.0 (bs, 1H), 8.1 (s, 1H), 8.1 (d, 1H), 7.90 (s, 1H), 7.7-7.6 (m, 2H), 7.5 (m, 1H), 7.2 (m, 2H), 5.6 (s, 2H), 4.1 (s, 2H), 3.3 (q, 2H), 3.2 (q, 2H), 1.5 (t, 3H), 1.4 (t, 3H).

Example 13. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 3-chloro-4-methylphenyl) acetamide

5- (1 H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol (185 mg, 0.8 in a two-necked flask under nitrogen atmosphere mmol) and N- (3-chloro-4-methylphenyl) bromoacetamide (209 mg, 0.8 mmol) were dissolved in anhydrous DMF (3 mL), and anhydrous potassium carbonate (157 mg, 1.1 mmol) was added thereto. The reaction was time. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (237 mg).

Yield 55%; Melting point 196 ° C .; IR (KBr) 1690, 1599, 1593, 1530 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.0 (bs, 1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.90 (s, 1H), 7.7-7.6 (m, 2H), 7.5 (m, 1H), 7.2 (m, 2H), 5.6 (s, 2H), 4.1 (s, 2H), 3.2 (s, 3H).

Example 14. N- [(2- ( 1H -benzimidazol-1-yl) acetyl) -hydrazinothiocaaboyl] -benzamide

In a two-necked flask, under a nitrogen atmosphere, 1 H- benzimidazole-1-acetic acid hydrazide (3.1 g, 16.2 mmol) and benzoyl isothiocyanate (3.0 mL, 21.1 mmol) were added slowly, 100 mL of anhydrous ethanol was added, and the mixture was stirred under reflux for 2 hours. The flask was slowly cooled to room temperature and the resulting brown solid was filtered and recrystallized with methanol to give the title compound (4.06 g).

Yield 71%, Melting point 173 ° C., IR (KBr) 3233, 1676, 1526, 1264 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 11.8 (bs, 1H), 11.5 (bs, 1H), 11.3 (bs, 1H), 10.2 (s, 1H), 8.0 (m, 2H), 7.8- 7.5 (m, 5H), 7.4-7.2 (m, 2H), 5.2 (s, 2H).

Example 15. 5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazole-3-thiol

To a two-necked flask, add N- [(2- ( 1H -benzimidazol-1-yl-acetyl) -hydrazinothiocaaboyl] -benzamide (3.15 g, 8.14 mmol) in 50 mL of ethanol and sodium hydroxide. (977 mg, 24.4 mmol) was added to the mixture, and the mixture was stirred under reflux for 8 hours, ethanol was concentrated on a rotary vacuum evaporator, 10 mL of distilled water was added, and 2N hydrochloric acid aqueous solution was added slowly. To give the desired compound (1.26 g).

Yield 67%; Melting point 243 ° C. 'IR (KBr) 2839, 1687, 1601, 1326, 1293 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 13.8 (bs, 1H), 13.6 (bs, 1H), 9.9 (s, 1H), 8.0-7.8 (m, 2H), 7.5-7.3 (m, 2H ), 5.9 (s, 2 H).

Example 16. 5- ( 1H -benzimidazol-1-yl) methyl-4-benzoyl-4 H- [1,2,4] -triazole-3-thiol

In a two-necked flask, anhydrous 5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazole-3-thiol (138 mg, 0.6 mmol) After dissolving in tetrahydrofuran, triethyl amine (240 μL, 1.7 mmol) was added thereto, and stirred at room temperature for about 30 minutes. Benzoyl chloride (71 μL, 0.6 mmol) was added thereto and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with methanol to obtain a target compound.

Yield 66%; Melting point 243 ° C .; IR (KBr) 3116, 1700, 1583, 763 cm <^-1>; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.7 (bs, 1H), 8.43-7.22 (m, 9H), 5.5 (s, 2H).

Example 17. 2- [5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

In a two-necked flask under nitrogen atmosphere, 5- (1 H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazole-3-thiol (1.37 g, 5.9 mmol) and N -phenyl-chloro-acetamide (1.2 g, 7.1 mmol) was dissolved in anhydrous DMF (30 mL) into the anhydrous potassium carbonate (1.6 g, 11.9 mmol) was 6 hours at 70 ℃. After the reaction, most of the DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 3 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and recrystallized with ethyl acetate to obtain the target compound (1.4 g).

Yield 65%; Melting point 201 ° C .; IR (KBr) 1601, 1546, 1498, 1445 cm <^-1>; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 14.3 (bs, 1H), 10.3 (s, 1H), 7.9-7.0 (m, 9H), 4.1 (s, 2H).

Example 18. 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2- chloro - 4-trifluoromethylphenyl) acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl- 4H- [1,3,4] -triazole-3-thiol (150 mg, 0.65 mmol) and 2-bromo Dissolve N- (2-chloro-4-trifluoromethylphenyl) acetamide (225 mg, 0.71 mmol) in anhydrous DMF (1.5 mL) and add anhydrous potassium carbonate (180 mg, 1.30 mmol) at 70 ° C. for about 6 hours. The reaction was carried out in a nitrogen atmosphere. After the reaction, the resultant was concentrated by rotary evaporation under reduced pressure, and the resulting brown solid was filtered and recrystallized with ethanol and water to obtain the target compound (180 mg).

Yield 59%; Melting point 211 ° C .; IR (KBr) 1699, 1076, 1612, 1591, 1533, 1502 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.0 (bs, 1H), 8.3 (s, 1H), 8.1 (d, J = 8.7 Hz, 1H), 7.9 (s, 1H), 7.7-7.6 ( m, 2H), 7.5 (m, 1H), 7.2 (m, 2H), 5.6 (s, 2H), 4.1 (s, 2H).

Example 19. 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2- chlorophenyl Acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl- 4H- [1,3,4] -triazole-3-thiol (150 mg, 0.65 mmol) and 2-bromo N- (2-chlorophenyl) acetamide (175 mg, 0.71 mmol) was dissolved in anhydrous DMF (1.5 mL) and anhydrous potassium carbonate (180 mg, 1.30 mmol) was added and reacted at 70 ° C. for about 6 hours in a nitrogen atmosphere. . After the reaction, the resultant was concentrated by rotary evaporation under reduced pressure, and the resulting brown solid was filtered and recrystallized with ethanol and water to obtain the target compound (180 mg).

Yield 49%; Melting point 197 ° C .; IR (KBr) 3334, 1680, 1594, 1529, 1501 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.77 (bs, 1 H), 8.29 (s, 1 H), 7.73-7.15 (m, 8 H), 5.56 (s, 2H), 4.10 (s, 2H).

Example 20 2- [5-methyl -4 H- [1,2,4] (1 H-benzimidazol-1-yl) - triazol-3-ylsulfanyl] - N- (4- chlorophenyl Acetamide

In a two-necked flask, 5- (1 H -benzimidazol-1-yl) methyl- 4H- [1,3,4] -triazole-3-thiol (150 mg, 0.65 mmol) and 2-bromo N- (4-chlorophenyl) acetamide (175 mg, 0.71 mmol) was dissolved in anhydrous DMF (1.5 mL) and anhydrous potassium carbonate (180 mg, 1.30 mmol) was added and reacted at 70 ° C. for about 6 hours in a nitrogen atmosphere. . After the reaction, the resultant was concentrated by rotary evaporation under reduced pressure, and the resulting brown solid was filtered and recrystallized with ethanol and water to obtain the target compound (180 mg).

Yield 61%; Melting point 190 ° C .; IR (KBr) 3343, 1677, 1599, 1523, 1509 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.77 (bs, 1H), 8.29 (s, 1H), 7.73-7.15 (m, 8H), 5.56 (s, 2H), 4.11 (s, 2H).

Example 21. 2- [5- (1 H - benzimidazol-1-yl) methyl-4-ethyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- ( 4-chlorophenyl) acetamide

2 under nitrogen in the flask atmosphere, 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4 -Chlorophenyl) acetamide (230 mg, 0.6 mmol) was dissolved in anhydrous tetrahydrofuran and triethyl amine (240 μL, 1.7 mmol) was added and stirred at room temperature for about 30 minutes. Ethyl iodide (47.9 μL, 0.6 mmol) was added and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound.

Yield 33%; Melting point 205 ° C .; IR (KBr) 1680, 1590, 1544, 1490, 1433 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 9.8 (bs, 1H), 8.3 (s, 1H), 7.7-7.3 (m, 4H), 7.3-7.1 (m, 4H), 5.9 (s, 2H), 4.1 (s, 2H), 3.2 (q, 2H), 1.5 (t, 3H).

Example 22. N- [(2-Chlorobenzoyl) -hydrazinothiocarbonayl] -benzamide

Into a two-necked flask, slowly added 2-chlorophenyl-1-acetic acid hydrazide (12) (1.4 g, 7.5 mmol) and benzoyl isothiocyanate (1.1 mL, 8.2 mmol) under a nitrogen atmosphere and 30 mL of anhydrous ethanol was added thereto. After stirring at reflux for about 3 hours. The flask was slowly cooled to room temperature and the resulting brown solid was filtered and recrystallized with methanol to give the title compound (4.06 g).

Yield 71%; Melting point 180 ° C .; IR (KBr) 3270, 1674, 1620, 1527, 1464 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.4 (bs, 1H), 11.8 (s, 1H), 11.2 (s, 1H), 8.0-7.5 (m, 9H).

Example 23. 5- (2-Chlorophenyl) -4 H- [1,2,4] -triazole-3-thiol

In a two-necked flask, add N- [(2-chlorobenzoyl) -hydrazinothiocarbonayl] -benzamide (2.3 g, 58.2 mmol) to 60 mL of ethanol, and add NaOH (2.3 g, 58.2 mmol) for 8 hours. Stirred at reflux. Ethanol was concentrated on a rotary vacuum evaporator, 10 mL of distilled water was added, and 2N hydrochloric acid aqueous solution was slowly added thereto. The resulting brown solid was filtered and recrystallized with ethanol to give the target compound (3.2 g).

Yield 78%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.8 (bs, 1H), 13.7 (bs, 1H), 7.7-7.5 (m, 4H).

Example 24. 2- [5- (2-Chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

In a two-necked flask under nitrogen atmosphere, 5- (2-chlorophenyl) -4H- [1,2,4] -triazole-3-thiol (4.7 g, 22.2 mmol) and N- phenyl chloroacetamide (4.1 g, 24.5 mmol) was dissolved in anhydrous DMF (50 mL), anhydrous potassium carbonate (4.6 g, 33.3 mmol) was added, and the mixture was reacted at 70 ° C. for 6 hours. After the reaction, most of the DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 3 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and recrystallized with ethyl acetate to obtain the target compound (5.2 g).

Yield 68%; Melting point 156 ° C .; IR (KBr) 3313, 3267, 3062, 1693, 1663, 1602, 1448 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 14.3 (bs, 1H), 10.3 (bs, 1H), 8.0-7.0 (m, 9H), 4.1 (s, 2H).

Example 25. 2- [5- (2-Chlorophenyl) -4-acetyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Anhydrous acetyl chloride (79 μL, 0.3 mmol) was slowly added into a micro syringe and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (75 mg).

Yield 65%; Melting point 206 ° C .; IR (KBr) 3340, 1713, 1685, 1603, 1442 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.0-7.0 (m, 9H), 4.3 (s, 2H), 2.9 (s, 3H).

Example 26. 2- [5- (2-Chlorophenyl) -4- (butoxybenzoyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl) -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 4-butoxybenzoyl chloride (66 mg, 0.3 mmol) was added thereto, and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (80 mg).

Yield 50%; Melting point 180 ° C .; IR (KBr) 1656, 1602, 1542, 1442, 1373 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.4 (bs, 1H), 8.4 (m, 1H), 7.6-6.9 (m, 12H), 4.4 (s, 2H), 4.1 (t, J = 6.6 Hz, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 0.9 (t, J = 7.5 Hz, 3H).

Example 27. 2- [5- (2-chlorophenyl) -4- (4-chloromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacet Amide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl) -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 4-chloromethylbenzoyl chloride (59 mg, 0.3 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (95 mg).

Yield 64%; Melting point 181 ° C .; IR (KBr) 3287, 1660, 1441, 1322 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.3-7.0 (m, 13H), 4.9 (s, 2H), 4.3 (s, 2H).

Example 28. 2- [5- (2-chlorophenyl) -4- (2,4,6-trichlorobenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl]- N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 2,4,6-trichlorobenzoyl chloride (75 mg, 0.3 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (80 mg).

Yield 48%; Melting point 184 ° C .; IR (KBr) 1755, 1655, 1548, 1445, 1240 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.0 (bs, 1H), 7.7-7.1 (m, 11H), 4.0 (s, 2H).

Example 29. 2- [5- (2-chlorophenyl) -4- (2-trifluoromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenyl Acetamide

In a two-necked flask under nitrogen atmosphere, 2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (15) (100 mg , 0.30 mmol) was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 2-trifluoromethyl benzoyl chloride (59 μL, 0.3 mmol) was added thereto, followed by stirring at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary evaporator to recrystallize with ethyl acetate to obtain a target compound (70 mg).

Yield 45%; Melting point 191 ° C .; IR (KBr) 1730, 1655, 1544, 1371 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.0-7.0 (m, 13H), 4.4 (s, 2H).

Example 30. 2- [5- (2-Chlorophenyl) -4- (2-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. o- Toluyl chloride (41 μL, 0.3 mmol) was added thereto and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (90 mg).

Yield 65%; Melting point 166 ° C .; IR (KBr) 1719, 1656, 1442, 1321 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.0-7.0 (m, 13H), 4.3 (s, 2H), 2.4 (s, 3H).

Example 31. 2- [5- (2-chlorophenyl) -4- (3,4,5-trimethoxybenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenyl Acetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 3,4,5-trimethoxybenzoyl chloride (71 mg, 0.3 mmol) was added thereto, and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (75 mg).

Yield 47%; Melting point 204 ° C .; IR (KBr) 1676, 1655, 1305, 1137 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.4 (bs, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.7-7.0 (m, 10H), 4.3 (s, 2H), 3.9 ( s, 6H), 3.8 (s, 3H).

Example 32. 2- [5- (2-chlorophenyl) -4- (4-butylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.30 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (179 mg, 1.72 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 4-butylbenzoyl chloride (61 mg, 0.3 mmol) was added thereto, and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (75 mg).

Yield 54%; Melting point 141 ° C .; IR (KBr) 3296, 1658, 1601, 1398, 1240 cm ^-1 ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.3 (bs, 1H), 7.9-7.0 (m, 13H), 4.1 (s, 2H), 2.7 (t, J = 7.5 Hz, 2H), 1.6 ( m, 2H), 1.3 (m, 2H), 0.9 (t, J = 7.5 Hz, 3H).

Example 33. 2- [5- (2-Chlorophenyl) -4-benzoyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (200 mg, 0.6 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (240 μL, 1.7 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Benzoyl chloride (71 μL, 0.6 mmol) was added thereto and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (130 mg).

Yield 50%; Melting point 148 ° C .; IR (KBr) 1689, 1655, 1538, 1319, 1293 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.3-7.0 (m, 14H), 4.3 (s, 2H).

Example 34. 2- [5- (2-chlorophenyl) -4- (3-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide

2- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol) in a two-necked flask under nitrogen atmosphere ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. m- toluyl chloride (41 μL, 0.3 mmol) was added thereto, and the resultant was stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto, and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (80 mg).

Yield 58%; Melting point 158 ° C .; IR (KBr) 1678, 1666, 1443, 1373 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 7.8-7.1 (m, 13H), 4.3 (s, 2H), 2.4 (s, 3H).

Example 35. N- [(2- chloro-benzoyl) hydrazino Im Oka AVO carbonyl] phenylamine

Add 2-chlorobenzohydrazide (3.5 g, 20.3 mmol) to a two-necked flask, add 80 mL of anhydrous ethanol, and slowly add dropwise phenyl isothiocyanate (2.7 mL, 22.4 mmol) through a dropping funnel under nitrogen atmosphere. It was refluxed for hours. After slowly lowering the temperature to room temperature, the resulting brown solid was recrystallized from ethanol and water to obtain the pure target compound (5.9 g).

Yield 95%; Melting point 139 ° C .; IR (KBr) 1694, 1655, 1624, 1548 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.5 (bs, 1H), 9.8 (bs, 1H), 9.7 (bs, 1H), 7.8-7.2 (m, 9H).

Example 36. 5- (2-Chlorophenyl) -4-phenyl-4 H- [1,2,4] -triazole-3-thiol

2 N- necked flask [(2-chloro-benzoyl) hydrazino Im Oka AVO carbonyl] phenyl amine (4.3 g, 14.12 mmol) was dissolved in ethanol 60 mL, 1 N aqueous sodium hydroxide solution (35.3 mL, 35.3 mmol) Was slowly added dropwise at room temperature. After refluxing for about 8 hours and slowly cooling to room temperature, ethanol was removed with a rotary vacuum evaporator. After cooling the reaction flask under ice bath, a 2 N hydrochloric acid aqueous solution was slowly added dropwise to adjust the hydrogen ion index of the reaction to become slightly acidic. The resulting brown solid was filtered and washed several times with distilled water. Drying in vacuo and recrystallization with ethanol gave the pure target compound (2.6 g).

Yield 65%; Melting point 209 ° C .; IR (KBr) 1603, 1573, 1533, 1309 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 7.7-7.3 (m, 9H).

Example 37. 2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (4- chlorophenyl) acetamide Amide

In a two-necked flask under nitrogen atmosphere, 5- (2-chlorophenyl) -4-phenyl- 4H- [1,2,4] -triazole-3-thiol (229 mg, 0.8 mmol) and N- (4 Chlorophenyl) bromoacetamide (198 mg, 0.8 mmol) was dissolved in anhydrous DMF (3 mL), anhydrous potassium carbonate (157 mg, 1.1 mmol) was added, and the mixture was reacted at 70 ° C. for 6 hours. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and then the reaction mixture was dissolved in 1 mL of methanol and slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol and water to obtain the target compound (237 mg).

Yield 75%; Melting point 200 ° C .; IR (KBr) 1677, 1530, 1420, 1324, 1136 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.21 (bs, 1H), 8.19-7.31 (m, 13H), 4.30 (s, 2H).

Example 38. 2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (2-chloro-4- Trifluoromethylphenyl) acetamide

In a two-necked flask under nitrogen atmosphere, 5- (2-chlorophenyl) -4-phenyl- 4H- [1,2,4] -triazole-3-thiol (229 mg, 0.8 mmol) and N- (2 -Chloro-4-trifluoromethylphenyl) bromoacetamide (252 mg, 0.8 mmol) was dissolved in anhydrous DMF (3 mL), and anhydrous potassium carbonate (157 mg, 1.1 mmol) was added and reacted at 70 ° C for 6 hours. After the reaction, DMF was concentrated on a rotary vacuum evaporator, and the reaction mixture was dissolved in 1 mL of methanol, and then slowly added dropwise to ice water. The resulting brown solid was filtered and then recrystallized with ethanol to obtain the target compound (237 mg).

Yield 45%; Melting point 190 ° C .; IR (KBr) 1686, 1533, 1400, 1324, 1136 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.24 (bs, 1H), 8.19-7.31 (m, 12H), 4.35 (s, 2H).

Example 39. 2- [5- (2-Chlorophenyl) -4-icosanoyl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide

3-necked flask under nitrogen atmosphere was 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Icosanoyl chloride (121 μL, 0.3 mmol) was added and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (65 mg).

Yield 34.3%; mp 130-133 ° C .; IR (KBr) 2919, 1663, 1601, 1329, 744 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.3 (bs, 1H), 7.9-7.0 (m, 9H), 4.3 (s, 2H), 3.1 (t, J = 7.2 Hz, 2H), 1.7 ( m, 2H), 1.2 (m, 30H), 0.9 (t, J = 4.3 Hz, 3H).

Example 40. 2- [5- (2-Chlorophenyl) -4-butyryl- 4H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide

In a three-necked flask under nitrogen atmosphere, 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Butyryl chloride (34 μL, 0.3 mmol) was added thereto and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (55 mg).

Yield 45%; mp 149 ° C; IR (KBr) 2923, 1723, 1600, 1443, 1302 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.4 (bs, 1H), 7.9-7.0 (m, 9H), 4.3 (s, 2H), 3.1 (t, J = 7.3 Hz, 2H), 1.7 ( m, 2H), 0.9 (t, J = 6.6 Hz, 3H).

Example 41. 2- [5- (2-chlorophenyl) -4-cyclohexanecarbonayl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide

3-necked flask under nitrogen atmosphere was 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Cyclohexane carbonyl chloride (46 μL, 0.3 mmol) was added thereto, followed by stirring at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (68 mg).

Yield 50%; mp 173 ° C; IR (KBr) 2937, 2923, 1728, 1600, 1443 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.4 (bs, 1H), 7.9-7.0 (m, 9H), 4.3 (s, 2H), 3.1 (m, 1H), 2.1-1.2 (m, 10H ).

Example 42. 2- [5- (2-Chlorophenyl) -4-cyclopropanecacarbonyl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide

3-necked flask under nitrogen atmosphere was 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Cyclopropanekacarbonyl chloride (28 μL, 0.3 mmol) was added thereto and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (38 mg).

Yield 28%; mp 179 ° C; IR (KBr) 1711, 1656, 1443, 1326 744 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.3 (bs, 1H), 7.9-7.0 (m, 9H), 4.3 (s, 2H), 3.07 (s, 1H), 1.3-1.2 (m, 4H ).

Example 43. 2- [5- (2-chlorophenyl) -4- (thiophen-2-carbonanyl) -4 H- [1,2,4] -triazol-3 - ylthio] -N -phenyl acetamide

2-neck 5- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol) in a three-necked flask ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Thiophen-2-carbonyl chloride (33 μL, 0.3 mmol) was added thereto, followed by stirring at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N diluted hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (40 mg).

Yield 28%; mp 193 ° C; IR (KBr) 1661, 1600, 1423, 1411, 830 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.5-7.0 (m, 13H), 4.3 (s, 2H).

Example 44. 2- [5- (2-Chlorophenyl) -4- (isobutyryl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide

3-necked flask under nitrogen atmosphere was 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. Isobutyryl chloride (33 mg, 0.3 mmol) was added thereto and stirred at room temperature for 8 hours. Saturated aqueous sodium bicarbonate solution was added and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (41 mg).

Yield 33.5%; mp 141 ° C; IR (KBr) 1720, 1600, 1440, 1295, 747 cm ^-1 ; ¹ H NMR (300 MHz, DMSO -d ₆ ) δ 10.3 (bs, 1H), 7.9-7.0 (m, 9H), 4.3 (s, 2H), 3.6 (m, 1H), 1.3 (d, J = 6.9 Hz, 6H).

Example 45. 2- [5- (2-Chlorophenyl) -4- (4-chlorobenzoyl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacet Amide

3-necked flask under nitrogen atmosphere was 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 4-chlorobenzoyl chloride (40 μL, 0.3 mmol) was added thereto, and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (110 mg).

Yield 77%; mp 214 ° C; IR (KBr) 3042, 1687, 1598, 922 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 8.0-7.0 (m, 13H), 4.3 (s, 2H).

Example 46. 2- [5- (2-Chlorophenyl) -4- (2-chlorobenzoyl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacet Amide

In a three-necked flask under nitrogen atmosphere, 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (121 μL, 0.9 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 2-chlorobenzoyl chloride (40 μL, 0.3 mmol) was added thereto, and stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was removed by concentrating on a rotary vacuum evaporator and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (15 mg).

Yield 10.5%; mp 192 ° C; IR (KBr) 1717, 1660, 1600, 1442, 743 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 7.9-7.0 (m, 13H), 4.4 (s, 2H).

Example 47. 2- [5- (2-chlorophenyl) -4- (3-bromobenzoyl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenyl Acetamide

2-neck 5- [5- (2-chlorophenyl) -4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide (100 mg, 0.3 mmol) in a three-necked flask ) Was dissolved in anhydrous tetrahydrofuran and triethyl amine (246 μL, 1.7 mmol) was added thereto, followed by stirring at room temperature for about 30 minutes. 3-bromobenzoyl chloride (140 μL, 1.02 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. Aqueous solution of saturated sodium bicarbonate was added thereto and the reaction was terminated. After stirring at room temperature for about 2 hours, tetrahydrofuran was concentrated by a rotary vacuum evaporator, and extracted with ethyl acetate. The organic layer was washed with 1 N dilute hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated again using a rotary vacuum evaporator to recrystallize with ethyl acetate to obtain a target compound (120 mg).

Yield 77%; mp 182 ° C; IR (KBr) 3069, 1686, 1598, 743 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.4 (bs, 1H), 7.9-7.0 (m, 13H), 4.4 (s, 2H).

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

[Example]

Formulation 1: tablet (direct pressure)

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

Formulation 2: Tablet (Wet Granulation)

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

Formulation 3: Powders and Capsules

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

Formulation 4: Injection

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

On the other hand, the novel compound represented by the formula (1) according to the present invention was tested for antagonism of the T-type calcium channel as follows. The FDSS6000 was used to synthesize the synthesized compounds to search for their activity on T-type calcium channels, and the compounds with good activity were selected to obtain accurate IC ₅₀ by electrophysiological whole cell patch clamp method.

[Experimental Example] T-type calcium channel activity detection method

96-well plates treated with poly-L-lysine (0.05 mg / ml) 12-24 hours prior to activity detection using a 96-well cell distributor (Titertek) to form α _1G T-type calcium channels and Kir2.1. Cells of the stably expressed HEK293 cell line (α _1G cell line: KCTC 10519BP, Korea Biotechnology Research Institute Gene Bank) were dispensed at a density of 4 × 10 ⁴ per well. On the day of the experiment, the cells attached to the 96-well plate were subjected to HEPES buffer solution (unit mM: 150 NaCl, 5 KCl, 1 MgCl ₂ , 2 CaCl ₂ , 10 HEPES, 10) using a 96-well plate self-cleaning device (Bio Tek). After washing three times with glucose, pH 7.4) and reacting for 1 hour at room temperature in HEPES buffer solution containing 5 μM fluor-3 / AM and 0.001% Pluronic F-127, and labeled with fluorescent dye Washed again twice with HEPES buffer. Then, 10 minutes before measuring the FDSS6000 instrument, the cells were washed once with HEPES buffer containing 10 mM CaCl ₂ and the final volume was adjusted to 81 μL. Apart from the 96-well plates in which cells were prepared, two 96-well drug plates were prepared to contain KCl (final concentration 75 mM) and blocker drug to activate T-type calcium channels. Since most cell-based HTS instruments have a liquid application system for drug injection but no liquid inhalation system, 27 μL of blocking drug and KCl in 10 mM CaCl ₂ HEPES buffer at 5 times higher concentration are prepared. Measured by diluting to 1/5 in 135 μL, the final volume of the plate. Specific FDSS6000 measurement conditions were to measure the change in intracellular calcium concentration changed by KCl administration after 75 seconds of drug pretreatment after recording the standard value of 20 seconds, and the area of 340/380 ratio value in the control group not treated with the test substance. A percentage (%) inhibitory effect on the inhibitory effect of the test substance was determined to be 100%, and 10 μM of mibepradil was always used as a control drug.

As a detailed calcium imaging technique, the excitation wavelengths (340 nm and 380 nm) were selectively exposed to cells by a couter-controlled filter wheel in view of four light sources of xenon lamps mounted on the FDSS6000. Data were obtained every 1.23 seconds, and the emitter fluorescence light entering through a 515 nm long-pass filter was passed through a cooling CCD camera built into the instrument and then 96-well by a digital fluorescence analyzer. Average values of 340/380 were obtained for each well in the phase. All image data and analysis was done using the FDSS6000 dedicated program provided by Hamamatsu Photonics.

Table 1 below shows the% inhibition and IC ₅₀ results for calcium mobilization for T- type calcium channels of the novel compound using a FDSS6000.

Test compound constitutional formula % Inhibition (10 μM) IC ₅₀ (μM) Compound 1

21.5 - Compound 2

24.2 1.69 Compound 3

27.8 - Compound 4

55.9 - Compound 5

23.6 - Compound 6

26.6 Compound 7

33.9 Compound 8

27.4 1.01 Compound 9

46.5 - Compound 10

32.3 - Compound 11

39.8 - Compound 12

30.3 -

Compound 13

33.4 - Compound 14

20.0 - Compound 15

28.0 - Compound 16

27.0 Mibefradil 79.29 0.84

As described above, since the triazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention shows excellent activity as an antagonist of T-type calcium channel, the pharmaceutical composition comprising the compound By inhibiting the calcium channel of the cell membrane is effective in the treatment and prevention of a number of diseases, such as brain diseases such as epilepsy, angina pectoris, hypertension, heart diseases such as myocardial infarction, neurological pain, and cancer diseases.

Claims (4)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, R ₁ is a group selected from the group consisting of a phenyl group, benzimidazole group, and benzimidazole C ₁ -C ₈ alkyl group; R ₂ is a group selected from the group consisting of a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₂₀ alkanoyl group, a phenyl group, a benzoyl group, and a thiophencarbonyl group; R ₃ is a group selected from the group consisting of a hydrogen atom, and N- phenylacetamide; The benzene rings of the phenyl, benzoyl, benzimidazole and N- phenylacetamide groups for the substituents defined above are halogen, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, and C ₁ -C ₈ halo, respectively. A substituent selected from the group consisting of alkyl may be substituted or unsubstituted from 1 to 4; Provided that R ₁ is a benzimidazolemethyl group, R ₂ is a methyl group, and R ₃ is N- (4-nitrophenyl) acetamide, N- (4-bromophenyl) acetamide, or N- (3-chloro Excludes compounds that are 4-methylphenyl) acetamide. The method of claim 1, R ₁ is a group selected from the group consisting of a phenyl group, benzimidazole group, benzimidazolemethyl group, benzimidazoleethyl group, and benzimidazolepropyl group; R ₂ is hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, n -butyl group, t- butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, acetyl Group consisting of group, ethionyl group, n -propionyl group, isopropionyl group, n -butyryl group, isobutyryl group, cyclopropanecarbonyl group, cyclohexanecarbonyl group, isoxanoyl group, phenyl group, benzoyl group, and thiophencarbonyl group A group selected from; R ₃ is a group selected from the group consisting of a hydrogen atom, and N- phenylacetamide; The benzene rings of the phenyl, benzoyl, benzimidazole and N- phenylacetamide groups for the substituents defined above are fluoro, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, isopropyl, n -butyl, t -butyl, pentyl, hexyl, cyclo-propyl, cyclo-butyl, cyclo pentyl, cyclo hexyl, methoxy, ethoxy, pro-ethoxy, isopropoxy ethoxy, n-butoxy, t- butoxy, chloromethyl, dichloroethyl, trifluoromethyl 1 to 4 substituents or unsubstituted substituents selected from the group consisting of chloromethyl, tetrafluoroethyl, and tetrachloroethyl; Provided that R ₁ is a benzimidazolemethyl group, R ₂ is a methyl group, and R ₃ is N- (4-nitrophenyl) acetamide, N- (4-bromophenyl) acetamide, or N- (3-chloro A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound which is 4-methylphenyl) acetamide is excluded. The method of claim 1, 5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazole-3-thiol, 2- [5- ( 1H -benzimidazol-1-yl) methyl-4-methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5-methyl (1 H-benzimidazol-1-yl) methyl -4- -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2-chlorophenyl Acetamide, 2- [5-methyl (1 H-benzimidazol-1-yl) methyl -4- -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- chlorophenyl Acetamide, 2- [5- (1 H-benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (2- chloro - 4-trifluoromethylphenyl) acetamide, 2- [5- (1 H - benzimidazol-1-yl) methyl-4-methyl -4 H- [1,2,4] - -3- triazole ylsulfanyl] - N- (2,5- Diethoxyphenyl) acetamide, 5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazole-3-thiol, 5- ( 1H -benzimidazol-1-yl) methyl-4-benzoyl-4 H- [1,2,4] -triazole-3-thiol, 2- [5- ( 1H -benzimidazol-1-yl) methyl- 4H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (2- chloro-4-trifluoromethyl Methylphenyl) acetamide, 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (2- chlorophenyl) acetamide, 2- [5- (1 H - benzimidazol-1-yl) methyl -4 H- [1,2,4] - -3- triazol-ylsulfanyl] - N- (4- chlorophenyl) acetamide, 2- [5- (1 H - benzimidazol-1-yl) methyl-4-ethyl -4 H- [1,2,4] - triazol-3-ylsulfanyl] - N- (4- chlorophenyl Acetamide, 5- (2-chlorophenyl) -4 H- [1,2,4] -triazole-3-thiol, 2- [5- (2-chlorophenyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4-acetyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (butoxybenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (4-chloromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (2,4,6-trichlorobenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacet Amide, 2- [5- (2-chlorophenyl) -4- (2-trifluoromethylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (2-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (3,4,5-trimethoxybenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenyl Acetamide, 2- [5- (2-chlorophenyl) -4- (4-butylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4-benzoyl-4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (3-methylbenzoyl) -4 H- [1,2,4] -triazol-3-ylsulfanyl] -N- phenylacetamide, 5- (2-chlorophenyl) -4-phenyl-4 H- [1,2,4] -triazole-3-thiol, 2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (4- chlorophenyl) acetamide, 2- [5- (2-chlorophenyl) -4-phenyl -4 H- [1,2,4] - triazol-3-yl thio] - N- (2-chloro-4-trifluoromethyl-phenyl) Acetamide, 2- [5- (2-chlorophenyl) -4-yl Ikoma Sano -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide, 2- [5- (2-chlorophenyl) -4-butyryl -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide, 2- [5- (2-chlorophenyl) -4-cyclohexanecarbonayl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4-cyclopropanecaraboyl-4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (thiophen-2-carbonanyl) -4 H- [1,2,4] -triazol-3 - ylthio] -N- phenylacetamide , 2- [5- (2-chlorophenyl) -4- (isobutyryl) -4 H- [1,2,4] -triazol-3-ylthio] -N- phenylacetamide, 2- [5- (2-chlorophenyl) -4- (4-chlorobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide, 2- [5- (2-chlorophenyl) -4- (2-chlorobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide, 2- [5- (2-chlorophenyl) -4- (3-bromobenzoyl) -4 H- [1,2,4] - triazol-3-yl thio] - N- phenyl-acetamide, or Pharmaceutically acceptable salts thereof. A pharmaceutical composition for the treatment of epilepsy, hypertension, cancer, pain diseases, characterized in that the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is contained: [Formula 1]

In Chemical Formula 1, R ₁ is a group selected from the group consisting of a phenyl group, benzimidazole group, and benzimidazole C ₁ -C ₈ alkyl group; R ₂ is a group selected from the group consisting of a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₂₀ alkanoyl group, a phenyl group, a benzoyl group, and a thiophencarbonyl group; R ₃ is a group selected from the group consisting of a hydrogen atom, and N- phenylacetamide; The benzene rings of the phenyl, benzoyl, benzimidazole and N- phenylacetamide groups for the substituents defined above are halogen, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, and C ₁ -C ₈ halo, respectively. Substituents selected from the group consisting of alkyl may be 1 to 4 substituted or unsubstituted.