KR20100022619A - 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 - Google Patents

Abstract

PURPOSE: A 2-benzylsulfanyl-benzimidazole-4-carboximide derivative is provided to ensure activity of suppressing poly(ADP-ribose)polymerase-1-(PARP-1) and to prevent or treat diseases caused by over-activation of the PARP-1. CONSTITUTION: A 2-benzylsulfanyl-benzimidazole-4-carboximide derivative is denoted by chemical formula 1. The 2-benzylsulfanyl-benzimidazole-4-carboximide derivative is prepared by performing alkylation of a compound of chemical formula 2 with a compound of chemical formula 3 at room temperature to boiling point under the presence of basic catalyst. The catalyst is carbonate, hydroxise, hydride, alkoxide, triethylamine, or pyridine. A pharmaceutical composition for preventing or treating diseases caused by over-activation of poly(ADP-ribose)polymerase-1(PARP-1) contains the 2-benzylsulfanyl-benzimidazole-4-carboximide derivative of chemical formula 1 or its pharmaceutically acceptable salt as an active ingredient.

Description

2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof, and poly (ADP-ribose) polymerase-1 (PARP-1) containing the same as an active ingredient Pharmaceutical compositions for the prevention or treatment of diseases caused by overactivation of 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts according to the preparation of the composition and the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of Poly (ADP-ribose) polymerase-1}

The present invention provides a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a poly (ADP-ribose) polymerase-1 containing the same as an active ingredient. It relates to a pharmaceutical composition for the prevention or treatment of diseases caused by the overactivity of PARP-1).

Poly (ADP-ribose) polymerase-1 (PARP-1) is an enzyme that exists in the nucleus of many organs, including the heart. It recognizes damaged DNA and activates several proteins. Poly ADP-ribosylation is an enzyme that repairs damaged DNA. The most important of the known polyADP-ribosylation substrates (acceptor or target proteins) is PARP-1 itself, and other histones, DNA topoisomerases, DNA ligase, caspase, p53 and NF- κ B and the like are known in many nuclear proteins, such as the transcription-related factor. PARP catalyzes the transfer of ADP-ribose from the NAD, where nicotinamide is released from the NAD. Nicotinamide is converted back to NAD by another enzyme, consuming ATP, the energy carrier. Thus, overactivation of PARP consumes large amounts of ATP resulting in cell damage and cell death (P. Jagtap et al., Nature Rev. Drug Discov. 2005, 4, 421).

When a cell is exposed to a substance that damages DNA, the following pathways depend on the intensity of the stimulus: First, when mild DNA damage is stimulated, PARP activated by damage stimulation interacts with DNA repair enzymes to repair damaged DNA. As a result, DNA damage is repaired and cells survive without the risk of genetic mutation. PARP inhibitors can be used as anticancer drugs because chemotherapy or radiation therapy is used in the treatment of cancer, and PARP inhibition increases the cytotoxicity of anticancer drugs because PARP is involved in repairing DNA damage. Curr. Opin. Pharmacol. 2006, 6, 364). Therefore, it has been reported to be effective as a sensitizer in tumor chemotherapy (L. Tentori et al., Pharmacol. Res. 2005, 52, 25).

Other pathways occur when DNA is severely damaged by various oxidative stresses (eg hydroxyl radicals, peroxynitrite, nitroxylanion, etc.). In this case, PARP is overactivated and consumes a lot of NAD ⁺ , resulting in a rapid consumption of ATP. In addition, depletion of NAD ⁺ , a major coenzyme of biochemical reactions in cells, inhibits glycolysis and oxidative phosphorylation of mitochondria, leading to energy depletion in cells and stopping many cell functions that require energy, resulting in cell death. Will lead to. Inhibition of PARP in cells subjected to oxidative stress preserves intracellular ATP and NAD ⁺ , resulting in normal functioning (G. Graziani et al., Pharmacol. Res. 2005, 52, 109).

Thus, inhibitors of PARP have shown remarkable protective effects in cell and animal tissues in many disease models and are known to be used for the treatment and prevention of diseases associated with increased activity of PARP by oxidative stress. Such diseases include, for example, myocardial infarction due to ischemia and reperfusion injury, renal failure, cerebral ischemia (stroke), neurodegenerative diseases (eg Parkinson's disease), diabetes, inflammatory diseases (eg arthritis), glaucoma, septic shock, immunological Diseases and the like. The therapeutic efficacy of various diseases by PARP-1 inhibition is summarized in the literature (eg L. Virag et al., Pharmacol. Rev. 2002, 54, 375 .; P. Jagtap et al., Nature Rev). Drug Discov. 2005, 4, 421).

It is described in the literature that many different classes of compounds, such as isoquinolinone, quinazolinone, phthalazine, phenantrione and pyridinone derivatives, can be used as PARP-1 inhibitors (eg, ECY Woon et. al., Curr. Med. Chem. 2005, 12, 2373). Further, the use of benzimidazole derivatives as PARP inhibitors, for example, discloses benzimidazole derivatives substituted with a quaternary carbon at 2-position in WO 2006/110816, WO WO 2007/041357 and WO 2007/131016 disclose derivatives substituted with phenyl or heteroaryl groups in the 2-position of benzimidazole, and WO 03/106430 discloses alkyl or the 2-position of benzimidazole in WO 03/106430. Benzimidazole derivatives substituted with sulfanyl groups are described.

Therefore, the present inventors synthesized novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives while studying a drug selective for PARP-1, and these compounds selectively inhibited PARP-1. It is shown that, to improve the recovery of cardiac function damage by ischemia / reperfusion, and significantly reduced the size of myocardial infarction confirmed that the excellent cardioprotective effect and completed the present invention.

An object of the present invention is to provide a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a poly (ADP-ribose) polymerase-1 (PARP) containing a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention and treatment of diseases caused by overactivity of -1).

In order to achieve the above object, the present invention provides a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a poly (ADP-) containing the same as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of diseases caused by the overactivity of ribose) polymerase-1 (PARP-1).

The novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative represented by Formula 1 of the present invention recognizes damaged DNA and activates the damaged DNA through poly ADP-ribosylation of various proteins. When it is repaired and overactivated, it consumes a large amount of ATP, and shows a strong inhibitory effect on PARP-1, an enzyme that causes cell damage and cell death, thereby preventing or preventing diseases caused by overactivity of PARP-1. It can be used to treat. Specifically, the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the present invention are ischemic and Parkinson's disease, including myocardial infarction, angina pectoris, arrhythmia, heart failure, stroke, brain trauma or kidney failure, Useful for the prophylaxis or treatment of neurodegenerative diseases including Alzheimer's disease or multiple sclerosis, and also for cardioprotection during pharmacotherapy such as revascularization using thrombolytics and surgery including coronary artery bypass surgery or coronary percutaneous plastic surgery. Can be used.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

R ¹ is any one selected from the group consisting of hydrogen, halogen, NO ₂ , CN, OR ² , CHO, COOR ² , CONHR ² and CH ₂ X,

,

,

및

로 이루어지는 군으로부터 선택되는 어느 하나이다.Here, R ² is hydrogen or C _{1 ~} is a straight or branched chain alkyl of C _4, X is hydrogen, _{halogen, OH, CN, NHCH 3,} N (CH 3) 2,

,

,

And

It is any one selected from the group consisting of.

More preferably, R ¹ is selected from the group consisting of hydrogen, fluoro, bromo, chloro, NO ₂ , CN, methoxy, ethoxy, CHO, COOH, COOCH ₃ , CONH ₂ and CH ₂ X One,

,

,

및

로 이루어지는 군으로부터 선택되는 어느 하나이다. Wherein X is hydrogen, bromo, chloro, CN, NHCH ₃ , N (CH ₃ ) ₂ ,

,

,

And

It is any one selected from the group consisting of.

The most preferable example of the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative represented by Chemical Formula 1 according to the present invention is as follows.

(1) 2-benzylsulfanyl-1H-benzimidazole-4-carboxamide

(2) 2- (3-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(3) 2- (4-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(4) 2- (3-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(5) 2- (4-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(6) 2- (2-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(7) 2- (3-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(8) 2- (4-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(9) 2- (2-bromobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(10) 2- (4-bromobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(11) 2- (3-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(12) 2- (4-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(13) 2- (4-cyanobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(14) 2- (4-nitrobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(15) 2- (4-methoxycarbonyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(16) 2- (4-carboxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(17) 2- (4-carbamoyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(18) 2- (4-formylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide

(19) 2- (4-hydroxymethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(20) 2- (3-chloromethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(21) 2- (4-chloromethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(22) 2- (4-bromomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(23) 2- (4-cyanomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(24) 2- [4- (methylaminomethyl) benzylsulfanyl] -1 H-benzimidazole-4-carboxamide

(25) 2- [4- (dimethylaminomethyl) benzylsulfanyl) -1H-benzimidazole-4-carboxamide

(26) 2- [3- (pyrrolidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

(27) 2- [4- (pyrrolidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

(28) 2- [4- (piperidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

(29) 2- [4- (4-methylpiperazin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

(30) 2- [4- (morpholin-4-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

The present invention is not only 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, racemics that can be prepared therefrom. Include all sieves or stereoisomers.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide , Fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate, Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfo Yate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

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

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

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

The present invention also provides a method for preparing a novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

Specifically, the method for preparing 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of the present invention is shown in Scheme 1 below,

2 Murray captopril of formula 2 starting materials -1H- benzimidazole-4-leaving group on the carboxamide formula 3 (leaving group, L) by having a benzyl derivative and alkylation substituted with R ¹ R ¹ This may comprise the step of obtaining the introduced 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of formula (1).

In Scheme 1,

R ¹ is as defined in Formula 1, and L is any one leaving group selected from the group consisting of halogen, mesylate and tosylate.

In the manufacturing method according to the present invention,

Since the benzyl derivative (3) used in the alkylation reaction has a leaving group (L) which can be easily removed, it can be easily substituted when reacting with compound 2.

The compound of Formula 3 is preferably used in 1 to 3 equivalents based on the compound of Formula 2.

In the preparation method according to the invention, Scheme 1 is reacted under conventional alkylation conditions in the presence of a base catalyst. The base that can be used includes carbonates (e.g. sodium carbonate, potassium carbonate, cesium carbonate), hydroxides (e.g. potassium hydroxide, sodium hydroxide), hydrides (e.g. sodium hydride), alkoxides (e.g. sodium methoxide, sodium t -Butoxide) or an organic base such as triethylamine or pyridine may be used, preferably 1 to 3 equivalents. Reaction solvents include dimethylformamide, dimethyl sulfoxide, ether solvents (e.g. tetrahydrofuran, dioxane), acetone, acetonitrile, aromatic hydrocarbon compound solvents (e.g. benzene, toluene), halogenated hydrocarbon compound solvents (e.g. Dichloromethane, chloroform), water (H ₂ O), acetic acid, or the like, or a mixed solvent thereof may be used. In addition, the reaction temperature may be carried out in the temperature range of the boiling point of the solvent from room temperature.

As described above, the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives prepared according to the present invention are separated, purified by high performance liquid chromatography, and then subjected to molecular structure by nuclear magnetic resonance spectra and mass spectroscopy. You can check.

Furthermore, the present invention provides a poly (ADP-ribose) polymerase-1 (PARP-1) containing 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of diseases caused by the overactivity of).

2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of formula (I) of the present invention are poly (ADP-ribose) polymerase-1 (PARP-1), which is an enzyme present in the nucleus of various organs including the heart Was inhibited (see Table 2).

When DNA is severely damaged by oxidative stress, PARP is overactive and consumes a lot of NAD +, resulting in a rapid consumption of ATP. In addition, the depletion of NAD ⁺ , a major coenzyme of biochemical reactions in cells, inhibits glycolysis and oxidative phosphorylation of mitochondria, leading to energy depletion in cells, and stopping many cell functions that require energy, resulting in cell death. This leads to. Therefore, inhibition of PARP in cells subjected to oxidative stress preserves intracellular ATP and NAD ⁺ , thereby treating or preventing diseases caused by the overactivity of PARP-1.

In addition, the 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives represented by the general formula (1) of the present invention are anti-ischemic effects in the in-vivo ischemic heart model (rat). Effect) In the measurement experiment, the results showed that the myocardial infarction rate was significantly reduced compared to the negative control group (see Table 3).

Thus, the compounds of formula 1 of the present invention can be used to prevent or treat ischemic diseases. The specific ischemic diseases include damage to the heart after cardiac ischemia (myocardial infarction, angina pectoris, arrhythmia, heart failure, etc.), brain injury after cerebral ischemia (stroke, brain trauma, etc.), kidney damage after kidney ischemia (renal failure, etc.) have.

In addition, the compounds of formula 1 of the present invention can be used to prevent or treat neurodegenerative diseases. Specific neurodegenerative diseases include Parkinson's disease, Alzheimer's disease, multiple sclerosis, and the like.

Furthermore, the compound of formula 1 of the present invention can be used for cardioprotection during surgery or pharmacotherapy. The specific surgical therapy may include coronary artery bypass surgery, coronary percutaneous plastic surgery, and the drug therapy may include reperfusion therapy using thrombolytic release.

In addition, the compound of formula 1 of the present invention can be used for chemotherapy for inflammation such as rheumatoid arthritis, diabetes, glaucoma, septic shock, immunological diseases, tumors and tumor metastasis.

The pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention may be administered in various oral and parenteral dosage forms at the time of clinical administration, and is usually used when formulated. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like. Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, It may be prepared by mixing sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

Furthermore, the dosage of a compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. These examples are for illustrating the present invention in detail, and the scope of the present invention is not limited by these examples.

Example 1 Preparation of 2-benzylsulfanyl-1H-benzimidazole-4-carboxamide

2-mercapto-1H-benzimidazole-4-carboxamide (100 mg, 0.52 mmol) and benzylbromide (89 mg, 0.52 mmol) were dissolved in dimethylformamide (3 mL), followed by K ₂ CO ₃ (108). mg, 0.78 mmol) was added and reacted at room temperature for 1 hour. H ₂ O (20 mL) was added, extracted with ethyl acetate (20 mL) and washed with aqueous NaCl solution. The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (5% methanol / dichloromethane) to obtain 70 mg (0.25 mmol, 47%) of the title compound as a yellow solid.

Rf = 0.38 (5% MeOH / MC)

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ = 4.57 (s, 2H), 7.28 (m, 4H), 7.42 (m, 2H), 7.50 (d, 1H, J = 8.1 Hz), 7.98 (d, 1H, J = 7.8 Hz)

mass (M + 1) ⁺ = 284 (99.21%)

Example 2: Preparation of 2- (3-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide

85 mg (0.29 mmol, 55) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 3-methylbenzylbromide (96 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. %) Was obtained.

Rf = 0.30 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.27 (s, 3H), 4.57 (s, 2H), 7.08 (d, 1H, J = 7.5 Hz), 7.23 (m, 4H), 7.57 (d, 1H, J = 7.8 Hz), 7.73 (bs , 1H), 7.78 (d, 1H, J = 7.5 Hz), 9.08 (br-s, 1H)

mass (M + 1) ⁺ = 298 (100%)

Example 3: Preparation of 2- (4-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide

91 mg (0.30 mmol, 59) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 4-methylbenzylbromide (96 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. %) Was obtained.

Rf = 0.18 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.26 (s, 3H), 4.57 (s, 2H), 7.12 (d, 2H, J = 7.5 Hz), 7.24 (t, 1H), 7.36 (d, 2H, J = 7.8 Hz),, 7.55 ( d, 1H, J = 7.8 Hz), 7.71 (br-s, 1H), 7.77 (d, 1H, J = 7.5 Hz), 9.08 (br-s, 1H)

mass (M + 1) ⁺ = 298 (95.61%)

Example 4: Preparation of 2- (3-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

135 mg (0.30 mmol, 82) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 3-chlorobenzylbromide (109 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. %) Was obtained.

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 4.63 (s, 2H), 7.25 (t, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.45 (d, 1H), 7.56 (m, 2H), 7.70 (br-s, 1H), 7.80 (d, 1H), 9.02 (br-s, 1H)

mass (M + 1) ⁺ = 319 (100%)

Example 5: Preparation of 2- (4-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

Except for using 4-chlorobenzyl bromide (107 mg, 0.52 mmol) in place of benzyl bromide in Example 1 was reacted in the same manner as in Example 1 83 mg (0.26 mmol, 50) of the target compound as a pale yellow solid %) Was obtained.

Rf = 0.2 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.50 (s, 2H), 7.13 (t, 1H), 7.28 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.45 (d, 1H, J = 7.8 Hz ), 7.57 (br-s, 1 H), 7.67 (d, 1 H, J = 7.5 Hz), 8.91 (br-s, 1 H)

mass (M + 1) ⁺ = 319 (96.68%)

Example  6: 2- (2- Fluorobenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

96 mg (0.32 mmol) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 2-fluorobenzylbromide (98 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. , 61%).

Rf = 0.19 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 4.63 (s, 2H), 7.10-7.30 (m, 4H), 7.54 (m, 2H), 7.72 (br-s, 1H), 7.79 (d, 1H), 9.03 (br-s, 1H)

mass (M + 1) ⁺ = 303 (100%)

Example  7: 2- (3- Fluorobenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

Except for using 3-fluorobenzyl bromide (98 mg, 0.52 mmol) in place of benzyl bromide in Example 1 was reacted in the same manner as in Example 1 110 mg (0.37 mmol, 70%).

Rf = 0.27 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.46 (s, 2H), 6.92 (t, 1H), 7.07 (t, 1H), 7.18 (m, 3H), 7.35 (d, 1H, J = 7.92 Hz), 7.53 (br-s, 1H) , 7.63 (d, 1H, J = 7.65 Hz), 8.85 (br-s, 1H)

mass (M + 1) ⁺ = 303 (100%)

Example  8: 2- (4- Fluorobenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

Except for using 3-fluorobenzyl chloride (75 mg, 0.52 mmol) in place of benzyl bromide in Example 1 was reacted in the same manner as in Example 1 101 mg (0.34 mmol, 65%).

Rf = 0.16 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.61 (s, 2H), 7.15 (m, 2H), 7.24 (t, 1H), 7.52 (m, 3H), 7.70 (br-s, 1H), 7.78 ( d, 1H), 9.04 (br-s, 1H)

mass (M + 1) ⁺ = 303 (100%)

Example  9: 2- (2- Bromobenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

In the same manner as in Example 1, except that 2-bromobenzylchloride (107 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1, 105 mg (0.29 mmol, 56%).

Rf = 0.32 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.63 (s, 2H), 7.17 (m, 2H), 7.26 (t, 1H), 7.49 (d, 1H, J = 7.8 Hz), 7.53 (d, 2H), 7.58 (d, 1H), 7.65 (br-s, 1H), 7.72 (d, 1H, J = 7.8 Hz), 8.97 (br-s, 1H)

mass (M + 1) ⁺ = 364 (100%)

Example  10: 2- (4- Bromobenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

Except for using 4-bromobenzylbromide (129 mg, 0.52 mmol) in place of benzyl bromide in Example 1 was reacted in the same manner as in Example 1 86 mg (0.24 mmol of the target compound as a pale yellow solid , 46%).

Rf = 0.32 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.58 (s, 2H), 7.25 (t, 1H), 7.44 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.1 Hz), 7.57 (d, 1H), 7.71 (br -s, 1H), 7.78 (d, 1H), 9.02 (br-s, 1H)

mass (M + 1) ⁺ = 363 (88.61%)

Example 11: Preparation of 2- (3-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide

In Example 1 50 mg (0.26 mmol) was used instead of 100 mg of 2-mercapto-1H-benzimidazole-4-carboxamide and 3-methoxybenzylchloride (41) instead of benzylbromide. mg, 0.26 mmol) was reacted in the same manner as in Example 1, except that 70 mg (0.22 mmol, 86%) of the title compound was obtained as a pale yellow solid.

Rf = 0.28 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.71 (s, 3H), 4.59 (s, 2H), 6.87 (d, 1H, J = 8.1 Hz), 7.02 (d, 1H, J = 8.4 Hz), 7.05 (s, 1H), 7.23 (m , 2H), 7.56 (d, 1H, J = 8.1 Hz), 7.73 (br-s, 1H), 7.80 (d, 1H, J = 7.5 Hz), 9.99 (br-s, 1H)

mass (M + 1) ⁺ = 314 (95.07%)

Example 12 Preparation of 2- (4-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide

In the same manner as in Example 1, except that 4-methoxybenzylchloride (81 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1, 77 mg (0.24 mmol, 47%).

Rf = 0.17 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.67 (s, 3H), 4.52 (s, 2H), 6.83 (d, 2H, J = 8.7 Hz), 7.19 (t, 1H), 7.35 (d, 2H, J = 8.7 Hz), 7.50 (d , 1H, J = 7.8Hz), 7.67 (br-s, 1H), 7.73 (d, 1H, J = 7.5Hz), 9.04 (br-s, 1H)

mass (M + 1) ⁺ = 314, 121 (95.01%)

Example 13: Preparation of 2- (4-cyanobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

Example 1 uses 200 mg (1.04 mmol) instead of 100 mg of 2-mercapto-1H-benzimidazole-4-carboxamide and 4-cyanobenzylbromide (203) instead of benzylbromide. 185 mg (0.60 mmol, 58%) of the target compound as a pale yellow solid was obtained in the same manner as in Example 1, except that mg, 1.04 mmol) was used.

 Rf = 0.35 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.68 (s, 2H), 7.24 (t, 1H), 7.55 (d, 1H, J = 8.1 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.67 (d, 2H, J = 8.4 Hz ), 7767 (br-s, 1H), 7.80 (d, 2H, J = 8.1 Hz), 8.94 (br-s, 1H)

mass (M + 1) ⁺ = 310 (100%)

Example 14 Preparation of 2- (4-nitrobenzylsulfanyl) -1H-benzimidazole-4-carboxamide

260 mg (0.79 mmol, 76) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 4-nitrobenzylbromide (224 mg, 1.04 mmol) was used instead of benzyl bromide in Example 1. %) Was obtained.

Rf = 0.12 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO)

delta = 4.73 (s, 2H), 7.23 (t, 1H), 7.57 (d, 1H), 7.70 (br-s, 1H), 7.77 (m, 3H), 8.20 (d, 2H), 8.95 (br- s, 1 H)

mass: 328, 283

Example 15 Preparation of 2- (4-methoxycarbonyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

143 mg of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that methyl 4- (bromomethyl) benzoate (119 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. (0.42 mmol, 80%) was obtained.

Rf = 0.27 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.83 (s, 3H), 4.67 (s, 2H), 7.23 (t, 1H), 7.55 (d, 1H, J = 7.8 Hz), 7.62 (d, 2H, J = 8.1 Hz), 7.71 (br-s, 1H), 7.76 (d, 1H, J = 7.8 Hz), 7.90 (d, 2H, J = 8.1 Hz), 8.99 (br-s, 1H), 13.08 ( br-s, 1 H)

mass: 341, 296

Example  16: 2- (4- Carboxybenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

150 mg of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that methyl α-bromo-p-toluic acid (112 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. (0.46 mmol, 88%) was obtained.

Rf = 0.27 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.44 (s, 2H), 7.00 (t, 1H), 7.28 (d, 2H, J = 8.1 Hz), 7.39 (d, 1H, J = 7.8 Hz), 7.46 (br-s, 1H), 7.54 (d, 1H, J = 7.8 Hz), 7.67 (d, 2H, J = 8.1 Hz), 8.88 (br-s, 1H)

mass: 327, 193, 176

Example  17: 2- (4- Carbamoyl - Benzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

83 mg of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 2- (bromomethyl) benzamide (111 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. 0.20 mmol, 49%).

Rf = 0.23 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 4.65 (s, 2H), 7.22 (t, 1H), 7.32 (br-s, 1H), 7.55 (m, 3H), 7.71 (br-s, 1H), 7.79 (m, 3H), 7.90 ( br-s, 1 H), 9.03 (br-s, 1 H)

mass = 326, 281

Example  18: 2- (4- Formylbenzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

130 mg (0.42) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 4- (bromomethyl) benzaldehyde (104 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. mmol, 80%).

Rf = 0.32 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.76 (s, 2H), 7.29 (t, 1H), 7.62 (d, 1H, J = 7.5 Hz), 7.77 (m, 3H), 7.83 (d, 1H, J = 7.5 Hz), 7.92 (d, 2H, J = 8.1 Hz), 9.05 (br-s, 1H), 10.02 (s, 1H)

mass: 311, 266

Example  19: 2- (4- Hydroxymethyl - Benzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

The compound obtained in Example 18 (85 mg, 0.27 mmol) was dissolved in EtOH (2 mL) and H ₂ O (1 mL), followed by addition of sodium borohydride (21 mg, 0.54 mmol) at room temperature for 30 minutes. Was stirred. H ₂ O (20 mL) was added, extracted with ethyl acetate (30 mL) and washed with aqueous NaCl solution. The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 51 mg (0.16 mmol, 60%) of the title compound as a pale yellow solid.

Rf = 0.46 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.44 (d, 2H), 4.58 (d, 2H), 5.14 (t, 1H), 7.24 (m, 3H), 7.42 (d, 2H), 7.56 (d, 1H), 7.70 (br-s, 1H), 7.75 (d, 1H), 9.08 (br-s, 1H)

mass: 313, 268, 121

Example  20: 2- (3- Chloromethyl - Benzylsulfanyl ) -1H- Benzimidazole -4- Carboxamide  Produce

Except for using α, α'-dichloro-m-xylene (91 mg, 0.52 mmol) in place of benzyl bromide in Example 1 was reacted in the same manner as in Example 1 above to give a pale yellow solid of the target compound 116 mg (0.35 mmol, 67%).

Rf = 0.15 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 4.61 (s, 2H), 4.73 (s, 2H), 7.23 (t, 1H), 7.33 (m, 2H), 7.43 (d, 1H), 7.54 (s, 1H), 7.70 (br-s, 1H), 7.76 (d, 1H), 9.06 (br-s, 1H)

mass = 331, 286

Example 21 Preparation of 2- (4-Chloromethyl-benzylsulfanyl) -1 H-benzimidazole-4-carboxamide

In Example 1 130 mg (0.67 mmol) was used instead of 100 mg of 2-mercapto-1H-benzimidazole-4-carboxamide and α, α'-dichloro-p instead of benzylbromide. In the same manner as in Example 1, except that xylene (118 mg, 0.67 mmol) was used, 92 mg (0.28 mmol, 42%) of the title compound was obtained as a pale yellow solid.

Rf = 0.32 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.61 (s, 2H), 4.72 (s, 2H), 7.22 (t, 1H), 7.38 (d, 2H, J = 7.8 Hz), 7.48 (d, 2H, J = 8.1 Hz), 7.55 (d , 1H), 7.69 (br-s, 1H), 7.75 (d, 1H), 9.04 (br-s, 1H)

mass (M + 1) ⁺ = 332 (100%)

Example 22 Preparation of 2- (4-bromomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

Example 1 uses 200 mg (1.04 mmol) instead of 100 mg of 2-mercapto-1H-benzimidazole-4-carboxamide and α, α'-dibromo instead of benzylbromide. 127 mg (0.34 mmol, 32%) of the title compound was obtained as a light yellow solid, except that -p-xylene (275 mg, 1.04 mmol) was used.

Rf = 0.41 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 4.60 (s, 2H), 4.67 (s, 2H), 7.23 (t, 1H), 7.38 (d, 2H, J = 8.1 Hz), 7.46 (d, 2H, J = 8.1 Hz), 7.57 (d , 1H), 7.63 (br-s, 1H), 7.76 (d, 1H), 9.03 (br-s, 1H)

mass = 183, 104

Example 23 Preparation of 2- (4-cyanomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide

102 mg of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that 4- (bromomethyl) benzylcyanide (109 mg, 0.52 mmol) was used instead of benzyl bromide in Example 1. (0.31 mmol, 61%).

Rf = 0.3 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.99 (s, 2H), 4.60 (s, 2H), 7.21 (t, 1H), 7.30 (d, 2H), 7.49 (d, 2H), 7.56 (d, 1H), 7.71 (br-s, 1H), 7.77 (d, 1H), 9.05 (br-s, 1H), 13.06 (br-s, 1H)

mass: 322, 277

Example 24 Preparation of 2- [4- (methylaminomethyl) benzylsulfanyl] -1 H-benzimidazole-4-carboxamide

The compound obtained in Example 18 (262 mg, 0.84 mmol) was dissolved in methanol (10 mL), and methylamine monohydrate (114 mg, 1.68 mmol) and triethylamine (0.12 mL, 1.68 mmol) were added for 2 hours. It was heated to reflux. Sodium borohydride (32 mg, 1.68 mmol) was added and stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). Washed with aqueous NaCl solution, dried over MgSO ₄ , and concentrated. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 172 mg (0.53 mmol, 63%) of the title compound as a pale yellow solid.

Rf = 0.04 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.25 (s, 3H), 3.62 (s, 2H), 4.58 (s, 2H), 7.21 (t, 1H), 7.26 (d, 2H, J = 8.00Hz), 7.41 (d, 2H, J = 8.00 Hz), 7.57 (d, 1H, J = 8.60 Hz), 7.64 (br-s, 1H), 7.57 (d, 1H, J = 8.60 Hz), 8.95 (br-s, 1H)

mass = 326, 133

Example 25 Preparation of 2- [4- (dimethylaminomethyl) benzylsulfanyl] -1 H-benzimidazole-4-carboxamide

The compound (50 mg, 0.15 mmol) obtained in Example 21 was dissolved in dichloromethane (3 mL), 40% dimethylamine aqueous solution (0.3 mL) was added thereto, and the mixture was stirred at 50 ^° C. for 1 hour. Water (20 mL) was added and extracted with ethyl acetate (30 mL). Washed with saturated aqueous NaCl solution, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to obtain 29 mg (0.09 mmol, 57%) of the title compound as a white solid.

Rf = 0.1 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.13 (s, 6H), 3.32 (s, 2H), 4.60 (s, 2H), 7.25 (m, 3H), 7.43 (d, 2H), 7.56 (d, 1H), 7.71 (br-s, 1H), 7.78 (d, 1H), 9.06 (br-s, 1H), 13.05 (br-s, 1H)

mass (M + 1) ⁺ = 341 (77.99%)

Example 26 Preparation of 2- [3- (pyrrolidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide

After dissolving the compound (70 mg, 0.21 mmol) obtained in Example 20 in dimethylformamide (3 mL), pyrrolidine (18 μl, 0.21 mmol) and K ₂ CO ₃ (44 mg, 0.32 mmol) were added thereto, and room temperature. Stirred for 1 h. Water (20 mL) was added and extracted with ethyl acetate (30 mL). Washed with saturated aqueous NaCl solution, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 35 mg (0.10 mmol, 45%) of the title compound as a white solid.

Rf = 0.15 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.49 (m, 4H), 2.33 (m, 4H), 3.51 (s, 2H), 4.42 (s, 2H), 7.06 (m, 3H), 7.25 (m, 2H), 7.39 (d, 1H) , 7.56 (br-s, 1 H), 7.58 (d, 1 H), 8.89 (br-s, 1 H)

mass = 365, 173

Example  27: 2- [4- ( Pyrrolidine -One- Yl methyl ) Benzylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound obtained in Example 21 (80 mg, 0.24 mmol) was dissolved in dimethylformamide (3 mL), and pyrrolidine (20 μL, 0.24 mmol) and K ₂ CO ₃ (50 mg, 0.36 mmol) were added thereto. Stir at room temperature for 1 hour. Water (20 mL) was added and extracted with ethyl acetate (30 mL). Washed with saturated aqueous NaCl solution, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 58 mg (0.16 mmol, 66%) of the title compound as a pale yellow solid.

Rf = 0.05 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.69 (m, 4H), 2.44 (m, 4H), 3.57 (s, 2H), 4.59 (s, 2H), 7.23 (m, 3H), 7.42 (d, 2H), 7.58 (d, 1H) , 7.68 (br-s, 1 H), 7.77 (d, 1 H), 9.06 (br-s, 1 H)

mass (M + 1) ⁺ = 367 (100%)

Example  28: 2- [4- (piperidine-1- Yl methyl ) Benzylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound obtained in Example 21 (80 mg, 0.24 mmol) was dissolved in acetonitrile (3 mL), and then piperidine (24 μL, 0.24 mmol) and triethylamine (67 μl, 0.48 mmol) were added thereto at 60 ^° C. Stir for 1 hour. Water (20 mL) was added and extracted with ethyl acetate (30 mL). Washed with saturated aqueous NaCl solution, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 90 mg (0.23 mmol, 99%) of the title compound as a white solid.

Rf = 0.1 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.39 (m, 2H), 1.49 (m, 4H), 2.29 (m, 4H), 3.32 (s, 2H), 4.60 (s, 2H), 7.24 (m, 3H), 7.44 (d, 2H) , 7.57 (d, 1H), 7.71 (br-s, 1H), 7.79 (d, 1H), 9.06 (br-s, 1H)

mass: 379, 187

Example  29: 2- [4- (4- Methylpiperazine -One- Yl methyl ) Benzylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Using the compound (80 mg, 0.24 mmol) obtained in Example 21 and 1-methylpiperazine (30 μl, 0.24 mmol) in the same manner as in Example 28, 88 mg (0.22 mmol, 93%).

 Rf = 0.2 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.23 (s, 3H), 2.38 (m, 4H), 3.17 (m, 4H), 3.42 (s, 2H), 4.59 (s, 2H), 7.25 (m, 3H), 7.43 (d, 2H) , 7.55 (d, 1H), 7.71 (br-s, 1H), 7.78 (d, 1H), 9.06 (br-s, 1H)

mass (M + 1) ⁺ = 396 (100%)

Example  30: 2- [4- ( Morpholine -4- Yl methyl ) Benzylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Using the compound obtained in Example 21 (80 mg, 0.24 mmol) and morpholine (22 μL, 0.24 mmol) in the same manner as in Example 28, 88 mg (0.23 mmol, 96%) of the target compound as a white solid was obtained. )

Rf = 0.1 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.33 (m, 4H), 3.42 (s, 2H), 3.54 (m, 4H), 4.58 (s, 2H), 7.25 (m, 3H), 7.4 (d, 2H), 7.57 (d, 1H) , 7.72 (br-s, 1 H), 7.83 (d, 1 H), 9.06 (br-s, 1 H)

mass: 382, 189

The structure of the example compound according to the present invention is shown in Table 1.

Example Structure of a Compound Example rescue Example rescue One

2

3

4

5

5

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

The 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the general formula (1) according to the present invention were subjected to the following experiments to investigate various pharmacological actions.

Experimental Example 1 Measurement of PARP-1 Inhibitory Effect

In order to measure the PARP-1 inhibitory effect of the 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of the present invention, the following experiment was performed.

This experiment was performed using the Universal Colorimetric PARP Assay-Histones kit (TREVIGEN, 4671-096-K). Dilute histones and coating buffers, concentrated 10-fold and 5-fold, with water to coat histone plates (Greiner, 781061, standard clear plate) with water, and dispense 25 μL of the mixture for each assay for 12 to 18 hours at 4 ° C. It was left for hours. Then, the solution remaining on the plate was removed at one time and washed four times with 1 × PBS (pH 7.4). In each experimental step, the solution was repeatedly removed and washed off, so that the solution of the previous step was not left on the plate. Paper towels were used to remove residual solution. 10 × Strep-Diluent was diluted with 1 × PBS (pH 7.4), 50 μL was dispensed for each assay, and left at room temperature for 2 hours. During the time of standing, the concentrated reagents required for the enzymatic reaction were diluted in the required amounts. Prepare 1X PARP buffer (20-fold concentrate diluted with water), 1X PARP cocktail (10-fold concentrated PARP cocktail and DNA diluted with 1X PARP buffer) on ice, and after time, remove the solution from the plate After washing four times with 1X PBS, enzyme reactions were mixed. The total volume of the reaction per each assay was 25 μL and 12.5 μL of 1 × PARP cocktail, 5 μL of test sample, and 7.5 μL (0.5 U) of PARP enzyme (diluted with 1 × PARP buffer) were mixed in this order. After reacting for 1 hour at room temperature, the solution was removed and washed 4 times with 1X PBS. 25 μL of Strep-HRP (Horseradish Peroxidase) diluted 500 × with 1 × Strep-Diluent was dispensed for each assay. After standing at room temperature for 20 minutes, it was removed and washed 4 times with 1X PBS. The remaining solution was completely removed and 25 μL of TACS-Sapphire (Peroxidase substrate) was dispensed for each assay. After reacting for 20 minutes in the dark, 25 µL of 0.2N HCl was added to stop the reaction. Absorbance was measured at 450 nm with a multilabel counter (Victor ² , PerkinElmer, Turku, Finland) within 30 minutes after the addition of 0.2N HCl.

Initially, the inhibition rate at 10 μM was determined, and the IC 50 value was obtained only for the drug inhibited by 50% or more.

Inhibition rate = [(high absorbance mean-drug absorbance) / (high absorbance mean-low absorbance mean)] * 100

Drugs inhibited by 50% or more were absorbed at concentrations of 0.01 to 10 μM, respectively, and IC ₅₀ was calculated through Excel-data analysis-regression analysis.

The measurement results are shown in Table 2 below.

Inhibitory Effect of Example Compound on PARP-1 Example IC ₅₀ (μM) Example IC ₅₀ (μM) One 0.075 2 0.089 3 0.760 4 0.520 5 1.110 6 0.860 7 0.310 8 0.570 9 0.550 10 0.043 11 0.067 12 0.270 13 0.090 14 0.095 15 0.369 16 2.167 17 0.142 18 0.297 19 1.045 20 0.144 21 0.066 22 > 10 23 0.134 24 0.143 25 0.160 26 1.535 27 0.017 28 0.614 29 > 10 30 0.694

As shown in Table 2, the compounds of the examples of the present invention showed a generally excellent PARP-1 inhibitory effect. In particular, the compounds of Examples 1, 2, 7, 10, 11, 12, 13, 14, 15, 17, 18, 20, 21, 23, 24, 25 and 27 exhibited IC ₅₀ values of 0.5 μM or less, Among them, especially the compounds of Examples 1, 2, 10, 11, 13, 14, 21 and 27 showed IC ₅₀ value of 0.1 μM or less, showing a strong inhibitory effect on PARP-1.

Thus, the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the present invention exhibit a potent inhibitory effect on PARP-1, leading to diseases caused by PARP-1 overactivity, i.e., ischemic disease, It can be usefully used in neurodegenerative diseases and can be usefully used for cardioprotection in surgical or pharmacotherapy procedures.

Experimental Example  2: of rat in vivo Cardioprotection against ischemic heart model

Novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the invention in In order to determine whether it protects the ischemic heart in vivo , the anti-ischemic effects (Antiischemic effects) on the rats were investigated through the following experiment.

Male rats (350-450 g, Korea Research Institute of Chemical Technology) were anesthetized by intraperitoneal injection of pentobarbital at 75 mg / kg. After tracheotomy, artificial respiration was performed at a stroke volume of 10 mL / kg and a heart rate of 60 beats per minute. Cannula was inserted into the femoral vein and the femoral artery and used for drug administration and blood pressure measurement, respectively. On the other hand, in the ischemic myocardial injury model, the body temperature has a significant effect on the results, so that the temperature of the rat is constant at 37 ° C. using a probe inserted in the rectum and a homeothermic blanket control unit. Maintained. Since then, the mean arterial blood pressure and heart rate (HR) of the rat were continuously measured. At this time, the Statham P23XL pressure transducer (Statham P23XL pressure transducer, Grass Ins., MA, USA) was used, and the ECG / RATE Coupler, Hugo Sachs Electronic (Germany) was used to measure the heart rate. . In addition, all changes were recorded continuously using a Graphtec Linearcorder WR 3310, Hugo Sachs Electronic.

The left coronary artery was ligated by the method of Selye H. as follows. In other words, a part of the chest of the rat is opened by left thoracotomy, the pressure is applied to the right chest of the anesthetized rat with the left limb, and the heart is pushed outwards to lightly touch the heart with the thumb and index finger of the left hand. Fixed. The surgeon (5-0 silk ligature) attached to the suture (suture) and carefully carefully cut the part containing the left anterior desending coronary artery (LAD) and then quickly thoracic heart repositioned in the cavity and both ends of the surgeon were positioned externally. Both ends of the surgeon were allowed to pass through a PE tube (PE100, 2.5 cm) and left for 20 minutes to stabilize. Thereafter, a vehicle or a drug was administered through the cannula inserted into the femoral vein, and left for 30 minutes to fully exhibit the effect of the drug. At this time, the carrier was used as a drug carrier.

After that, the PE tube inserted into the thread was pushed into the heart, and the end thread of the tube was pulled with hemostatic tweezers, and the PE tube was pressed vertically to the coronary artery, and the pressure was left to remain for 45 minutes. After occlusion, hemostatic tweezers were removed and reperfused for 90 minutes.

The coronary artery was religated by the method and 2 mL of 1% Evans blue solution was administered intravenously. Pentobarbital was then intravenously administered to slaughter rats and the heart was removed to remove the right ventricle and both atria. The left ventricle was horizontally cut into 5-6 slices from the apex and the weight of each section was measured. The surface of each cardiac segment is input to a computer using a Hi-scope, a compact micro vision system, and an image pro plus, from which the blue Areas of normal blood flow tissue colored and uncolored areas were measured. The area ratio of the uncolored area was calculated for the total area of each section, and the weight of each section was multiplied to calculate the area at risk (AAR). The AAR for each section thus obtained was summed and divided by the total left ventricular weight to obtain AAR (%) by Equation 1 below.

In addition, heart sections were incubated for 15 minutes in 1% 2,3,5-triphenyltetrazolium chloride phosphate buffer solution (2,3,5-triphenyltetrazolium chloride (TTC) phosphate buffer, 37 ° C, pH 7.4) and 10% It was fixed in formalin solution for 20-24 hours. In this way, 2,3,5-triphenyltetrazolium chloride is reduced by the dehydrogenase and cofactor NADH of the myocardium, thereby forming a formazan dye. (brick-red color). On the other hand, since there are no dehydrogenases and cofactors in the infarcts of tissues, 2,3,5-triphenyltetrazolium chloride is not reduced and thus does not have a red brick color.

As described above, the normal area and the infarct zone of each section were determined by the same method as that of the AAR by whether the tissue site was colored by 2,3,5-triphenyltetrazolium chloride . The infarct regions for each of the sections thus obtained were summed and divided by the total AAR weight or the total left ventricular weight to obtain IS (%) by the following equation (2). In this experimental model, the lower the IS (%), the smaller the infarct area, and therefore, the anti-ischemic effect of the test substance was determined to be strong. The measurement results are shown in Table 3.

Example Antiischemic Effects of Compounds Example Myocardial infarction rate (IS / AAR ¹ ,%) One 1 mg / kg 40.1 2 1 mg / kg 35.5 10 1 mg / kg 44.0 11 1 mg / kg 41.9 13 1 mg / kg 37.1 14 1 mg / kg 43.9 17 1 mg / kg 40.7 20 1 mg / kg 40.3 21 1 mg / kg 35.1 24 1 mg / kg 44.2 27 1 mg / kg 42.6 29 1 mg / kg 41.5 Negative Control 58.6 1: IS / AAR (infacrt size / area at risk)

As shown in Table 3, even in the in vivo ischemic myocardial injury model using rats, the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the present invention has a significant myocardial infarction rate to the danger zone The figure decreased. Specifically, in the solvent-administered group, myocardial infarction (IS / AAR,%) was 58.6% for the risk area (AAR), indicating that myocardial damage due to ischemia is very severe. The compounds of the Examples showed a myocardial infarction rate of 45% or less at 1 mg / kg administration, which was significantly lower than 58.6% of the negative control group. In particular, the compounds of Examples 2, 13 and 21 were administered at 1 mg / kg, respectively. Myocardial infarction was found to be 35.5% and 37.1% and 35.1%, indicating an excellent cardioprotective effect.

Therefore, the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the present invention have an excellent protection against ischemic heart by reducing myocardial infarction in the ischemic heart model in vivo . It can be used as a prophylactic and therapeutic agent for ischemic heart disease such as angina pectoris. It can be used as a cardioprotective agent during cardiac procedures such as coronary artery bypass surgery and coronary percutaneous plastic surgery.

Experimental Example 3: Acute Toxicity of Oral Administration in Rats

In order to determine the acute toxicity of the novel 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives of the present invention, the following experiment was performed.

Acute toxicity test was performed using SPF SD rats at 6 weeks of age. Two animals per group were suspended orally at a dose of 10 mg / kg / 15 mL each of the compounds of Example 19 in 0.5% methylcellulose solution.

After administration of the test substance, the mortality, clinical symptoms and changes in body weight were observed, and hematological and blood biochemical tests were performed. The necropsy was performed to visually observe the abdominal and thoracic organ abnormalities.

As a result, all animals treated with test substance showed no clinical symptoms and no dead animals, and no toxicity change was observed in weight change, blood test, blood biochemical test, autopsy findings. As a result, all of the tested compounds did not show toxic changes up to 10 mg / kg in rats, and the minimum lethal dose (LD ₅₀ ) was determined to be a safe substance of at least 100 mg / kg or more.

On the other hand, the compound according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation Example 1 Preparation of Tablet (Direct Pressing)

5.0 mg of derivative compounds of the invention

Lactose 14.1 mg

Crospovidone USNF 0.8 mg

Magnesium Stearate 0.1 mg

After sifting the derivative compound of the present invention, lactose, crospovidone USNF and magnesium stearate were mixed and pressed to prepare a tablet.

Formulation Example 2: Preparation of Tablet (Wet Granulation)

5.0 mg of the derivative compound of the present invention,

Lactose 16.0 mg

Starch 4.0 mg

Polysorbate 80 0.3 mg

Colloidal Silicon Dioxide 2.7 mg

Magnesium Stearate 2.0 mg

Distilled water

After sifting the derivative compound of the present invention, lactose and starch were mixed. After dissolving Polysorbate 80 in distilled water, an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with colloidal silicon dioxide and magnesium stearate. The granules were pressed to produce tablets.

Formulation Example 3 Preparation of Powder

5.0 mg of the derivative compound of the present invention,

Lactose 14.8 mg

10.0 mg polyvinyl pyrrolidone

Magnesium Stearate 0.2 mg

After sifting the derivative compound of the present invention, a powder was prepared by mixing with lactose, polyvinyl pyrrolidone and magnesium stearate and filling into an airtight cloth.

Formulation example  4: Preparation of Capsule

5.0 mg of the derivative compound of the present invention,

Lactose 14.8 mg

10.0 mg polyvinyl pyrrolidone

Magnesium Stearate 0.2 mg

After sifting the derivative compound of the present invention, it was mixed with lactose, polyvinyl pyrrolidone and magnesium stearate. The mixture was compressed into tablets according to a conventional capsule preparation method and filled into gelatin capsules to prepare gelatin capsules.

Formulation example  5: Preparation of Injection

100 mg of the derivative compound of the present invention,

Mannitol 180 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

Distilled water 2974 mg

The derivative compound of the present invention was dissolved in distilled water together with mannitol and Na ₂ HPO ₄ 12H ₂ O, sterilized by adjusting the pH to about 7.5, and then injections were prepared according to a conventional method.

Claims (15)

2-Benzylsulfanyl-benzimidazole-4-carboxamide derivatives of Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] In Chemical Formula 1, R ¹ is any one selected from the group consisting of hydrogen, halogen, NO ₂ , CN, OR ² , CHO, COOR ² , CONHR ² and CH ₂ X, Wherein R ² is hydrogen or C _{1 to} C ₄ straight or branched alkyl, X is hydrogen, halogen, OH, CN, NHCH ₃ , N (CH ₃ ) ₂ ,

,

,

And

It is any one selected from the group consisting of. The compound of claim 1, wherein R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, NO ₂ , CN, methoxy, ethoxy, CHO, COOH, COOCH ₃ , CONH ₂ and CH ₂ X. Either wherein X is hydrogen, fluoro, chloro, bromo, CN, NHCH ₃ , N (CH ₃ ) ₂ ,

,

,

And

2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, characterized in that any one selected from the group consisting of: The method of claim 1, wherein the 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative is (1) 2-benzylsulfanyl-1H-benzimidazole-4-carboxamide; (2) 2- (3-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (3) 2- (4-methylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (4) 2- (3-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (5) 2- (4-chlorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (6) 2- (2-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (7) 2- (3-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (8) 2- (4-fluorobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (9) 2- (2-bromobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (10) 2- (4-bromobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (11) 2- (3-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (12) 2- (4-methoxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (13) 2- (4-cyanobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (14) 2- (4-nitrobenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (15) 2- (4-methoxycarbonyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (16) 2- (4-carboxybenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (17) 2- (4-carbamoyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (18) 2- (4-formylbenzylsulfanyl) -1H-benzimidazole-4-carboxamide; (19) 2- (4-hydroxymethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (20) 2- (3-chloromethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (21) 2- (4-chloromethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (22) 2- (4-bromomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (23) 2- (4-cyanomethyl-benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (24) 2- [4- (methylaminomethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide; (25) 2- [4- (dimethylaminomethyl) benzylsulfanyl) -1H-benzimidazole-4-carboxamide; (26) 2- [3- (pyrrolidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide; (27) 2- [4- (pyrrolidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide; (28) 2- [4- (piperidin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide; (29) 2- [4- (4-methylpiperazin-1-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide; And (30) 2- [4- (morpholin-4-ylmethyl) benzylsulfanyl] -1H-benzimidazole-4-carboxamide 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, characterized in that any one selected from the group consisting of: As shown in Scheme 1 below, 2-benzylsulfanyl-benzimidazole-4-carboxes comprising alkylating a starting compound of formula 2 with a compound of formula 3 to obtain a compound of formula 1 wherein R ¹ is introduced Process for the preparation of amide derivatives. Scheme 1

(In the above scheme, R ¹ is as defined in formula 1, L is any one leaving group selected from the group consisting of halogen element, mesylate and tosylate.) [Claim 5] The 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of claim 4, wherein the compound of Formula 3 is used in an amount of 1 to 3 equivalents based on the compound of Formula 2 in the presence of a base catalyst. Manufacturing method. The method of claim 5, wherein the base catalyst is carbonate comprising sodium carbonate, potassium carbonate or cesium carbonate; Hydroxides including potassium hydroxide or sodium hydroxide; Hydrides including sodium hydride; Alkoxides including sodium methoxide, sodium t-butoxide; Triethylamine; And pyridine, any one or more inorganic or organic bases selected from the group consisting of: pyridine, 2-benzylsulfanylbenzimidazole-4-carboxamide derivative. The method of claim 5, wherein the reaction solvent is dimethylformamide; Dimethyl sulfoxide; Ether solvents including tetrahydrofuran or dioxane; Acetone; Acetonitrile; Aromatic hydrocarbon compound solvents including benzene or toluene; Halogenated hydrocarbon compound solvents including dichloromethane or chloroform; water; And any one or a mixed solvent thereof selected from the group consisting of acetic acid. 2. A process for producing 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives. The method of claim 5, wherein the reaction is performed at room temperature from the boiling point of the solvent. A poly (ADP-ribose) polymerase-1 (PARP-1) containing the 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical compositions for the prevention or treatment of diseases caused by activity. The pharmaceutical composition for preventing or treating a disease caused by the overactivity of poly (ADP-ribose) polymerase-1 (PARP-1), wherein the disease is an ischemic disease. The poly (ADP-ribose) polymerase-1 (PARP) according to claim 10, wherein the ischemic disease is any one selected from the group consisting of myocardial infarction, angina pectoris, arrhythmia, heart failure, stroke, brain trauma and renal failure. A pharmaceutical composition for preventing or treating a disease caused by overactivity of -1). The pharmaceutical composition for preventing or treating a disease caused by the overactivity of poly (ADP-ribose) polymerase-1 (PARP-1), wherein the disease is a neurodegenerative disease. 13. The family of poly (ADP-ribose) polymerase-1 (PARP-1) according to claim 12, wherein the neurodegenerative disease is at least one selected from the group consisting of Parkinson's disease, Alzheimer's disease and multiple sclerosis. Pharmaceutical compositions for the prevention or treatment of diseases caused by activity. A pharmaceutical composition for use in cardioprotection during a surgical or pharmacotherapy procedure comprising the 2-benzylsulfanyl-benzimidazole-4-carboxamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. . The pharmaceutical composition according to claim 15, wherein the surgery is coronary artery bypass surgery or coronary percutaneous plastic surgery, and the drug therapy is reperfusion therapy using thrombolytics.