KR100703598B1 - Novel benzoxazole amide compound having lipoxygenase inhibitory activity, the preparation method thereof and a composition containing the same for preventing and treating asthma - Google Patents

Abstract

The present invention provides a novel benzoxazole amide derivative (I) compound having inhibitory activity against lipoxygenase, a preparation method thereof, and a composition for treating and preventing asthma comprising the same. Since the compound according to the present invention shows a strong inhibitory activity against lipoxygenase, the composition containing the same can be used as a medicament for the treatment of asthma.

Lipoxygenase, inhibitory activity, asthma, benzoxazole, derivatives, compounds

Description

 Novel benzoxazole amide compound having lipoxygenase inhibitory activity, the preparation method approximately and a composition containing a novel benzoxazole amide derivative compound having inhibitory activity against lipoxygenase the same for preventing and treating asthma}

The present invention relates to a novel benzoxazole amide derivative compound having inhibitory activity against lipoxygenase, a preparation method thereof, and a composition for treating and preventing asthma comprising the same.

Asthma (ASTHMA) is a respiratory disease characterized by reversible airway obstruction, airway inflammation, and airway hyperresponsiveness. There are currently about 12 million people with asthma in the United States. Statistics from 1982 to 1992 show that asthma prevalence has increased from 34.7 per 1,000 to 49.4 per 1000 and mortality has increased by approximately 40%, from 13.4 per million to 18.8 per million. In 1995, domestic research showed that about 10% of children and adolescents have experienced asthma symptoms within the past year and have similar results in adults. In adults, about 10% of the population experiences asthma symptoms.

Asthma airway obstruction is caused by a combination of factors such as spasm of airway smooth muscle, swelling of the airway mucosa, increased mucus secretion, airway infiltration of inflammatory cells (especially eosinophils and lymphocytes), and damage and loss of airway epithelial cells. Inflammatory mediators are involved in bronchospasm, mucus secretion, and microvascular leakage. Microvascular leakage leads to submucosal edema, increased airway resistance and is also involved in airway hyperresponsiveness. Inflammatory mediators include histamine and arachidonic acid metabolites (leukotriene and thromboxane). Cysteine leukotrienes LTC4 (Leukotriene C4) and LTD4 (Leukotriene D4) are the most potent bronchial contractors. On the other hand, T cell activation in allergic reactions plays the most important role in airway inflammation. The cytokines produced in CD4TH2 cells promote the proliferation, differentiation and activation of inflammatory cells, prolong the movement of inflammatory cells into the airways and prolong cell life. (Higgins, G. Inpharma , 1077 , pp 9-10, 1997).

If you classify asthma according to the cause, it can be classified into exogenous, endogenous, mixed, aspirin-induced, exercise-induced, occupational asthma. Exogenous asthma is symptomatic when exposed to causative antigens. A skin test or bronchial challenge test for causative antigens is positive and the onset age is young. House dust mites are the most common cause antigens, and pollen, animal epithelium, and fungi act as causative antigens. Endogenous asthma is caused or worsened by upper respiratory tract infections, exercise, emotional instability, cold climate and humidity changes, and is common in adult-type asthma. Mixed asthma is caused by a combination of exogenous and endogenous factors, which are common in pediatric asthma. Aspirin-induced asthma is a specific constitutional response to aspirin and refers to the three major symptoms of bronchial asthma, nasal polyps, and aspirin intolerance. Exercise-induced asthma is associated with the development of hyperventilation due to exercise, and thus loss of heat or water in the airways. Occupational asthma is caused by substances that are inhaled in the workplace, initially without symptoms, then asthmatic symptoms appear months or years later, tend to relieve on weekends or vacations, and worsen when returning to work.

Asthma attacks occur suddenly and wheezing, coughing, shortness of breath, etc., most often cough, chest tightness or pressure, and wheezing can be heard. During acute seizures, various symptoms of respiratory distress occur, prompting rapid breathing and rapid pulse. During chest examination, a loud wheezing can be heard during inspiration and most exhalations and an extension of the exhalation can be observed. More severe asthma attacks can lead to rapid and shallow breathing due to fatigue and severe breathing difficulties, and cyanosis as the symptoms become more severe. If the patient shows conscious turbidity and helplessness, it means progression to respiratory failure due to CO ₂ coma, in which case severe mucus plugging hardly hears wheezing and exacerbates gas exchange by exhaustion. The most obvious signs of a severe seizure include difficulty breathing, unable to talk, and the use of cyanosis, acute veins (> 20-30 mmHg), and apnea even at rest. Severity can be assessed most accurately by measuring arterial blood gas.

Asthma medications developed so far include preventive medications that are taken at all times and drugs that quickly relieve sudden symptoms of asthma. The former includes inhaled corticosteroids, metyprednisolone, such as beclomethasone, budnoside, flunisolide, fluticasone, and triamcinolone. Oral corticosteroids such as prednisolone, prednisone, or salmeterol, beta-agonist, nedocromil, sodium chromoglycate, etc. master cell stabilizers such as sodium cromoglycate, methylxanthines such as theophylline, and leukotriene antagonists such as zafirlukast and zileuton Drugs that quickly relieve symptoms include salbutamol, bitolterol, pirbuterol, and terbutaline. Anticholinergic agents such as beta-antagonist, ipratropium bromide and oral corticosteroids such as methylprednisolone, prednisolone, and prednisone Corticosteroids (NAEPP (National Asthma Education and Prevention Program, guideline, 1997)).

Among the above drugs, LT (Leukotrienes) antagonist (antagonist) is a drug that inhibits the synthesis or action of LT, largely cysteinyl-LT antagonist, 5-lipoxygenase inhibitor (5 -lipoxygenase inhibitors, 5-lipoxygenase activating protein inhibitors, and LTB ₄ antagonists. Lipoxygenase is a type of dioxygenase, classified according to the double bond sites (# 5, 11, 15) where oxygen attacks. Leukotriene is a degradation product of 5-lipoxygenase and plays an important role in inflammation. 5-lipoxygenase converts Arachidoic acid to 5-HPETE and back to Leukotriene A ₄ . From this, LTB ₄ , LTC ₄ are produced, and the glutamic acid and glycine residues of LTC ₄ are cut off by dipeptidase and LTD ₄ And LTE ₄ Is generated. HETE and LTB ₄ are involved in the action of neutrophils and eosinophils to relay chemoxis. It stimulates adenylyl cyclase, induces PMN and activates lysosomal hydrolytic enzymes. LTC ₄ and LTD ₄ contract the smooth muscle, contract the lungs and contract the muscles of the bronchus and intestine. It also increases the permeability of capillaries, causing edema. LTB4 is immunosuppressive. This results in suppressing the proliferation of CD4 ⁺ cells and CD8 ⁺ cells. It also promotes adhesion of Neutrophil-endothelial cells to allergy, infection, secretion of insulin, cell movement, cell growth, and flux of Ca2 ⁺ . Get involved. LTC4 and LTD4 are more potent allergens than histamine (Fabien, J. et al, Expert Opinion. Ther. Patents 13 (1), pp1-13. 2003).

Among the LT antagonists described above, the present inventors modeled benzoxazole based on the structure of the representative drugs Zileuton, which is marketed as a 5-lipoxygenase inhibitor, and E-6080 (Eisai), which is being developed in Japan. Synthesis and development of derivatives showing potent activity against 5-lipoxygenase by introducing various substituents based on benzothiazole, pyridinoxazole and pyridinoxazole derivatives The research has been continued.

The present inventors confirmed that the novel benzoxazole amide derivative compounds newly prepared by the present inventors exhibit potent inhibitory activity against 5-lipoxygenase enzyme, and therefore, the compounds of the present invention have high development potential as therapeutic agents for asthma. The invention was completed.

It is an object of the present invention to provide a benzoxazole amide derivative compound exhibiting potent inhibitory activity against the 5-lipoxygenase enzyme, a preparation method thereof, and a composition for preventing and treating asthma comprising the same.

In order to achieve the above object, the present invention provides a benzoxazole amide derivative compound having a structure of the following general formula (I), a pharmacologically acceptable salt thereof, and an isomer thereof, useful for treating and preventing asthma:

(Ⅰ)

(Ⅰ)

Where

R ₁ Are each independently a hydrogen atom, a halogen atom, a nitro group, an amine group, a carboxylic acid, a lower alkyl ester, a haloalkyl group, or C ₁ C ₆ lower alkyl group, or C ₁ At least one substituent selected from the group of C ₆ lower alkoxy groups,

P is a hydrogen atom, a halogen atom, a nitro group, a chain or branched C ₁ C ₆ lower alkyl group, or C ₁ C ₆ lower alkoxy, or a phenyl group unsubstituted or substituted with R ', a phenyl lower alkyl or a phenyl lower alkylene group,

R 'is a halogen atom, haloalkyl group, amine group or C ₁ -A C ₆ lower alkyl group.

In the compound group belonging to the general formula (I), preferably R ₁ is each independently a hydrogen atom, a halogen atom, a nitro group, an amine group, a carboxylic acid, a haloalkyl group, a C ₁ -C ₃ lower alkyl group, or C _A compound group that is a _1- C ₃ lower alkoxy group; P is a phenyl group unsubstituted or substituted with a chain or branched C ₁ -C ₃ lower alkyl group, or C ₁ -C ₃ lower alkoxy group, or a halogen atom, haloalkyl group, or C ₁ -C ₃ lower alkyl group, or phenyl lower group The compound group which is an alkylene group is mentioned.

Particularly preferred groups of compounds in the above general formula (I) include the following compounds and pharmaceutically acceptable salts thereof:

N- (benzo [d] oxazol-2-yl) -benzamide (D1), N- (5-chloro-benzo [d] oxazol-2-yl) -benzamide (D2), N- (5-nitro-benzo [d] oxazol-2-yl) -benzamide (D3), N- (5-methoxy-benzo [d] oxazol-2-yl) -benzamide (D4) , N- (5-methyl-benzo [d] oxazol-2-yl) -benzamide (D5), N- (6-methyl-benzo [d] oxazol-2-yl) -benzamide ( D6), N- (4-methyl-benzo [d] oxazol-2-yl) -benzamide (D7), 2-benzoyl aminobenzoxazole-5-carboxylic acid (D8), N- (5 -Trifuluromethyl-benzo [d] oxazol-2-yl-benzamide (D9), N- (benzo [d] oxazol-2-yl) -isobutyramide (E1), N- (5 -Chloro-benzo [d] oxazol-2-yl) -isobutyramide (E2), N- (5-chloro-benzo [d] oxazol-2-yl) -isobutyramide (E3), N- (5-methoxy-benzo [d] oxazol-2-yl) -isobutyramide (E4), N- (5-methyl-benzo [d] oxazol-2-yl) -isobutyramide (E5) , N- (6-methyl-benzo [d] oxazol-2-yl) -isobutyramide (E6), N- (4-methyl-bene Crude [d] oxazol-2-yl) -isobutyramide (E7), 2- (2-isobutylamino-oxazol-4-ylidene methyl) -acrylic acid (E8), N- (5-triful Luoromethyl-benzo [d] oxazol-2-yl) -isobutyramide (E9), N- (5-chloro-benzo [d] oxazol-2-yl) -3, 5-bis (tripool Fluoromethyl) benzamide (F1), 3,5-bis- (tripulouromethyl) -N- (5-methylbenzo [d] oxazol-2-yl) -benzamide (F2), 3, 5-Bis- (tripulouromethyl) -N- (4-methylbenzo [d] oxazol-2-yl) -benzamide (F3), 3,5-bis- (tripulouromethyl)- N- (6-Methylbenzo [d] oxazol-2-yl) -benzamide (F4), 3,5-bis- (trifuluromethyl) -N- (5-methoxybenzo [d] oxa Zol-2-yl) -benzamide (F5), (E) -N- (5-chlorobenzo [d] oxazol-2-yl) -3- (4-chlorophenyl) acrylamide (G1), ( E) -3- (4-chlorophenyl) -N- (4-methylbenzo [d] oxazol-2-yl) acrylamide (G2), (E) -3- (4-chlorophenyl) -N- (5-methylbenzo [d] oxazol-2-yl) acrylamide (G3), (E) -3- (4-chlorofe ) -N- (6-methylbenzo [d] oxazol-2-yl) acrylamide (G4), (E) -3- (4-chlorophenyl) -N- (5-methoxybenzo [d] oxa Zol-2-yl) acrylamide (G5), N- (5-chlorobenzo [d] oxazol-2-yl) acetamide (H1), N- (5-methylbenzo [d] oxazole-2 -Yl) acetamide (H2), N- (5-chlorobenzo [d] oxazol-2-yl) propionamide (I1), N- (5-chlorobenzo [d] oxazol-2-yl) Propionamide (I2).

The compounds of the present invention represented by the general formula (I) may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

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

Pharmaceutically acceptable salts of the above general formula (I) include salts of acidic or basic groups which may be present in compounds of general formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. It can be prepared through.

In addition, the compounds of the general formula (I) have an asymmetric center and thus have one or more subtitle carbons (*), so that they may exist in various different enantiomeric forms, and all geometric isomers of the compounds of the general formula (I), Stereoisomers, optical isomers and R or S-type stereoisomers, racemates and mixtures thereof are also included within the scope of the present invention. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, wherein the preparation (eg, asymmetric synthesis) and separation of such isomers (eg, Fractionation and Chromatography) It can be easily carried out by adopting a method known in the art, or a method taught herein, that is, a known method in a known manner.

Another object of the present invention is to provide a method for preparing the compound of Formula (I), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

The following schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 2. have. Some compounds of the present invention have been synthesized according to procedures not included in the scope of Schemes 1 and 2, and detailed synthesis procedures for these compounds are described in their respective examples.

As shown in Scheme 1, a mixture of carbon disulfide (CS2), iodine methane (MeI), and solid sodium hydride (NaH) in P-substituted amine (2a) under argon gas at 0 ° C to room temperature A first step of slowly reacting to prepare an N- (bis-methylsulfanylmethylene) amide derivative compound (2b);

As shown in Scheme 2, the N- (bis-methylsulfanylmethylene) amide derivative compound (2b) obtained by the aminophenol compound (1b) obtained in Scheme 1 was refluxed under an inert organic solvent to have various substituents. The benzoxazole amide derivative compounds of the invention of (I) can be prepared.

Accordingly, the present invention provides a method for producing the benzoxazole amide derivative compound of the general formula (I).

      Compounds of general formula (I) obtained by the above production method exhibited potent asthma inhibitory activity through in vitro testing of inhibitory activity against lipoxygenase enzyme and animal experiments of inhibitory activity against asthma using BALB / c mice. It is useful as a therapeutic agent which can confirm that it is indicated and can treat or prevent asthma disease.

Accordingly, the present invention provides a pharmaceutical composition for the treatment and prevention of asthma comprising the benzoxazole amide derivative compound of formula (I) as an active ingredient.

     Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and 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 and suppositories. As the non-aqueous solvent and suspending agent, 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, glycerogelatin and the like can be used.

Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily. The compound of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight relative to the total weight of the total composition.

In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Reference Example  1. Experiment preparation and instrumentation

1-1. Analyzer

The instrument used to confirm the structure of the product obtained in this experiment is as follows. Nuclear magnetic resonance spectra (1H NMR, 13C NMR) were used at 300 MHz or 400 MHz, and the solvents were CDCl ₃ , DMSO-d ₆ . Coupling constants (J) are expressed in Hz. Mass spectra are expressed in m / z.

1-2. TLC and tube chromatography

Thin layer chromatography (TLC) was used as silica gel (Merck F254) manufactured by E. Merck, and silica (Merck EM9385, 230-400 mesh) was used for column chromatography. In addition, using a UV lamp (= 254 nm) or soaked in anisealdehyde (Anisaldehyde), potassium permanganate (KMnO ₄ ) coloring reagent to identify the material separated on the TLC, the plate was confirmed by heating.

1-3. Used reagents

The reagents used in this experiment were purchased from Sigma-Aldrich, Lancaster, and Fluka, and the solvent used in the reaction was Sigma-Aldrich, Merck. A first grade reagent from Merck, Junsei Chemical Co. was used without purification. THF used in the solvent was used when the Na metal and benzophenone were added and heated under reflux in argon to turn blue. In addition, dichloromethane (CH ₂ Cl ₂ ) was used by heating under reflux with CaH ₂ in the argon stream. Ethyl acetate and hexane were purified by heating under reflux in an argon stream.

Example  1.N- ( Benzo [d] oxazole -2 days)- Benzamide (D1) synthesis.

1-1. N- ( Vis - Methylsulfanyl Methylene) Benzamide  Manufacturing (d)

Benzamide (2.00 g, 16.51 mmol) in a round flask substituted with nitrogen gas was dissolved in DMF (66 ml), and carbon disulfide (4 ml, at 0 ° C.). 66.04 mmol), iodomethane (3.3 ml, 52.83 mmol) and sodium hydride 60% (1.32 g, 33.02 mmol) were added sequentially and stirred at room temperature for 5 hours. The reaction was terminated with cold water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure, separated by column chromatography (EtOAc: n-Hexane = 1: 7), and yellow powdery N- (bis-methylsulfanyl-methylene) -benzamide (d) The compound was obtained in 41% yield (1.52 g).

1 H NMR (300 MHz, CDCl ₃ ): 8.13 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 6.6 Hz, 1H), 7.55 (t, J = 6.6 Hz, 2H), 2.47 (s, 6H), 1.19 (s, 3H), 1.17 (s, 3H)

1-2. N- ( Benzo [d] oxazole -2 days)- Benzamide (D1) synthesis

      N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-aminophenol (48 mg, 0.44 mM) obtained in the above step were added to DMF (0.25 M) and stirred vigorously at room temperature. The mixture was then heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to obtain N-((benzo [d] oxazol-2-yl) -benzamide (D1) having the following physical properties. , 80 mg, 76%).

      Pale yellow

      mp: 190.3-192.1 ° C

1 H NMR (Acetone-d ₆ , 400 MHz) δ7.30 to 7.37 (m. 2H), 7.51 to 7.63 (m, 5H), 8.20 (d, 2H J = 7.2 Hz)

FAB-HRMS (m / z): 239.0817 (M ++ 1, C ₁₄ H ₁₁ N ₂ O ₂ requires 239.0821)

Example 2. Synthesis of N- (5-Chloro-benzo [d] oxazol-2-yl) -benzamide (D2)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-chlorophenol (64 mg, 0.44 mmol) were tested in a similar manner to the preparation described in Example 1 above. To obtain N- (5-chloro-benzo [d] oxazol-2-yl) -benzamide (D2) (85 mg, 31%).

        Pale brown,

        mp; 214.6 ~ 218.3 ℃,

1 H NMR (Acetone-d ₆ , 400 MHz) δ7.32 (dd, 1H J = 8.4 and 2.4 Hz), 7.55 (m, 2H), 7.66 (m, 1H), 7.68 (d, 1H, J = 8.4 Hz) , 8.02-8.03 (m, 2H) 8.30 (d, 1H, J = 2.4 Hz),

FABHRMS (m / z): 273.0431 (M ++ 1, C ₁₄ H ₁₀ C _l N ₂ O ₂ requires 273.0431)

Example 3. Synthesis of N- (5-nitro-benzo [d] oxazol-2-yl) -benzamide (D3)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-nitrophenol (54.6 mg, 0.44 mmol) were prepared in a similar manner to the preparation described in Example 1 above. The experiment was carried out to obtain N- (5-nitro-benzo [d] oxazol-2-yl) -benzamide D3 (82 mg, 29%) having the following physical properties.

         Pale yellow,

         mp: 204.9-207.1 ° C,

         1 H NMR (DMSO, 400 MHz) δ 7.55 to 7.59 (m, 2H) 7.65 to 7.69 (m, 1H), 7.92 (d, 1H, J = 9.2 Hz), 8.04 to 8.06 (m, 2H), 8.24 (dd) , 1H, J = 9.2 and 2.0 Hz), 8.46 (d, 1H J = 2.0 Hz),

FABHRMS (m / z): 284.0675 (M ++ 1, C ₁₄ H ₁₀ N ₃ O ₄ requires 284.0671)

Example 4. Synthesis of N- (5-methoxy-benzo [d] oxazol-2-yl) -benzamide (D4)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-methoxyphenol (62 mg, 0.44 mmol) were prepared in a similar manner to the preparation described in Example 1 above. The experiment was carried out to obtain N- (5-methoxy-benzo [d] oxazol-2-yl) -benzamide D4 (53 mg, 45%) having the following physical properties.

         Pale brown,

         mp: 162.4-166.2 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 3.85 (s, 3H), 6.88 (dd, 1H J = 8.8 and 2.4 Hz), 7.14 (d, 1H, J = 2.4 Hz) 7.44 (d, 1H, J = 8.8 Hz), 7.50-7.54 (m, 2H), 7.60 (m, 1H), 8.18-8.20 (m, 2H),

FABHRMS (m / z): 269.0929 (M ++ 1, C ₁₅ H ₁₃ N ₂ O ₃ requires 269.0926)

Example 5. Synthesis of N- (5-methyl-benzo [d] oxazol-2-yl) -benzamide (D5)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-methylphenol (68 mg, 0.44 mmol) were tested in a similar manner to the preparation described in Example 1 above. N- (5-methyl-benzo [d] oxazol-2-yl) -benzamide D5 (66 mg, 59%) having the following physical properties was obtained.

      White powder,

       mp: 158.2-161.8 ° C.,

       1 H NMR (DMSO, 400 MHz) δ 2.45 (s, 1 H), 6.86 (br d, 1 H, J = 8.4 Hz), 7.23 (d, 1H, J = 8.4 Hz), 7.44 to 7.52 (m, 2H), 7.50 (m, 1 H), 8.31 (m, 1 H),

FABHRMS (m / z): 253.0976 (M ++ 1, C ₁₅ H ₁₃ N ₂ O ₂ requires 253.0977)

Example 6. Synthesis of N- (6-Methyl-benzo [d] oxazol-2-yl) -benzamide (D6)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-5-methylphenol (68 mg, 0.44 mmol) were tested in a similar manner to the preparation described in Example 1 above. To obtain N- (6-methyl-benzo [d] oxazol-2-yl) -benzamide D6 (90 mg, 80%) having the following physical properties.

       White powder

       mp: 204.2-206.0 ° C,

       1 H NMR (DMSO, 400 MHz) δ 2.41 (s, 3H), 7.10 (brd, 1H, J = 8.0 Hz), 7.40 to 7.42 (m, 2H), 7.49 to 7.52 (m, 2H), 7.59 (m, 1H), 8.04-8.06 (m, 2H),

FABHRMS (m / z): 253.0976 (M ++ 1, C ₁₅ H ₁₃ N ₂ O ₂ requires 253.0977)

Example 7. Synthesis of N- (4-Methyl-benzo [d] oxazol-2-yl) -benzamide (D7)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-3-methylphenol (68 mg, 0.44 mmol) were tested in a similar manner to the preparation process described in Example 1 above. N- (4-methyl-benzo [d] oxazol-2-yl) -benzamide D7 (31 mg, 28%) having the following physical properties was obtained.

        Yellow powder,

        mp: 141.6-142.2 ° C,

        1 H NMR (CD3OD, 400 MHz) δ 2.47 (s, 3H), 7.04 (brd, 1H, J = 7.6 Hz), 7.10 (t, 1H, J = 7.6 Hz), 7.24 (brd, 1H, J = 7.6 Hz ) 7.43 ~ 7.47 (m, 2H), 7.55 (m, 1H), 7.93 (m, 2H),

FABHRMS (m / z): 253.0983 (M ++ 1, C ₁₅ H ₁₃ N ₂ O ₂ requires 253.0977)

Example 8. Synthesis of 2-benzoylaminobenzoxazole-5-carboxylic acid (D8)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-hydroxybenzoic acid (68 mg, 0.44 mmol) were prepared in a similar manner to the preparation process described in Example 1 above. The experiment yielded 2-benzoyl aminobenzoxazole-5-carboxylic acid D8 (102 mg, 81%) having the following physical properties.

        White powder

         mp:> 280 ° C.,

         1 H NMR (DMSO, 400 MHz) δ 7.54 to 7.57 (m, 2H), 7.65 (m, 1H), 7.74 (d, 1H, J = 8.4 Hz), 7.94 (dd, 1H, J = 8.4 and 1.6 Hz) , 8.05 to 8.07 (m, 2H), 8.11 (d, 1H, 1.6 Hz),

FABHRMS (m / z): 283.0716 (M ++ 1, C ₁₅ H ₁₁ N ₂ O ₄ requires 283.0719)

Example 9. Synthesis of N- (5-Trifluuromethyl-benzo [d] oxazol-2-yl-benzamide (D9)

        N- (bis-methylsulfanyl-methylene) -benzamide compound (100 mg, 0.44 mM) and 2-amino-4-trifluoromethylphenol (79 mg, 0.44 mmol) were prepared in the same manner as in Example 1 The experiment was carried out in a similar manner to obtain N- (5-trifuluromethyl-benzo [d] oxazol-2-yl-benzamide D9 (74 mg, 54%) having the following physical properties.

          Pale brown powder,

          mp; 182.6 ~ 183.9 ℃

1H NMR (CD ₃ OD, 400MHz) δ 7.42 ~ 7.46 (m, 2H), 7.50 ~ 7.57 (m, 2H), 7.59 (d, 1H, J = 8.4Hz) 7.77 (brs, 1H), 7.91 ~ 7.93 (m, 2H),

FABHRMS (m / z): 307.0691 (M ++ 1, C ₁₅ H ₁₀ F ₃ N ₂ O ₂ requires 307.0694)

Example 10. N- ( Benzo [d] oxazol- 2 -yl ) -isobutyramide (E1) Synthesis .

10-1. N- ( Vis - Methylsulfanyl Methylene) Of isobutylamide  Manufacturing (e)

Isobutyramide (1.00 g, 11.47 mmol) in a round flask substituted with nitrogen gas was dissolved in DMF (46 ml) and carbon disulfide (2.8 ml, 45.91 mmol), iodine at 0 ° C. Iodomethane (2.2 ml, 36.73 mmol) and sodium hydride 60% (0.92 g, 22.96 mmol) were added sequentially and stirred at room temperature for 5 hours. The reaction was terminated with DW and extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, separated by column chromatography (EtOAc: n-Hexane = 1: 7), and separated by N- (bis-methylsulfanyl-methylene) -isobutyramide having the following physical properties. (e) The compound was obtained in 64% yield (1.41 g).

Yellow powder,

1 H NMR (300 MHz, CDCl ₃ ) δ 1.17 (s, 3H), 1.19 (s, 3H), 2.47 (s, 6H), 2.71-2.62 (m, 1H)

10-2. N- ( Benzo [d] oxazole -2 days)- Isobutylamide  ( E1 Manufacturing

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (100 mg, 0.52 mM) and 2-aminophenol (57 mg, 0.52 mmol) obtained in the above step were added to DMF (0.25 M) and stirred vigorously at room temperature. The mixture was then heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to obtain N- (benzo [d] oxazol-2-yl) -isobutylamide (E1) ( 54 mg, 51%).

        Yellow powder,

        mp: 137.8-138.9 ° C.,

1 H NMR (CDCl ₃ 400 MHz) δ 1.25 (d, 6H, J = 6.8 Hz), 2.96 (brs, 1H), 7.19 (td, 1H J = 7.6 and 1.2 Hz), 7.25 (td, 1H, J = 7.6 and 1.2 Hz), 7.45 (dd, 1H J = 7.6 and 1.2 Hz), 7.48 (dd, 1H J = 7.6 and 1.2 Hz),

FABHRMS (m / z): 205.0978 (M ++ 1, C ₁₁ H ₁₃ N ₂ O ₂ requires 205.0977)

Example 11. Synthesis of N- (5-Chloro-benzo [d] oxazol-2-yl) -isobutyramide (E2)

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (80 mg, 0.42 mM) and 2-amino-4-chlorophenol (60 mg, 0.42 mmol) were prepared in a similar manner to the preparation process described in Example 10 above. N- (5-chloro-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E2 (34 mg, 34%) was obtained.

        Pale brown powder,

        mp: 177.7-180.8 ° C,

1 H NMR (CD ₃ OD, 400 MHz) δ1.32 (d, 6H, J = 6.4 Hz), 2.75 (q, 1H J = 6.4 Hz), 7.25 (dd, 1H J = 8.8 and 2.0 Hz), 7.45 (d , 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 2.0 Hz),

FABHRMS (m / z): 239.0586 (M ++ 1, C ₁₁ H ₁₂ CN ₂ O ₂ requires 239.0587)

Example 12. N- (5 -Chloro - benzo [d] oxazol- 2 -yl ) -isobutyramide ( E3 ) Synthesis .

       N- (bis-methylsulfanyl-methylene) -isobutyramide compound (80 mg, 0.42 mM) and 2-amino-4-nitrophenol (64 mg, 0.42 mmol) were prepared in a similar manner to the preparation process described in Example 10 above. N- (5-chloro-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E3 (47 mg, 45%) was obtained.

      Yellow powder,

       mp: 212.4-216.1 ° C,

1 H NMR (CD ₃ OD, 400 MHz) δ 1.24 (d, 6H, J = 6.8 Hz), 2.76 (q, 1H, J = 6.8 Hz), 7.66 (d, 1H, J = 9.2 Hz), 8.22 (dd , 1H, J = 9.2 and 2.0 Hz), 8.38 (d, 1H, J = 2.0 Hz),

FABHRMS (m / z): 250.0822 (M ++ 1, C ₁₁ H ₁₂ N ₃ O ₄ requires 250.0828)

Example 13. N- (5-methoxy-benzo [d] oxazol-2-yl) -isobutyramide (E4) synthesis .

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (100 mg, 0.52 mM) and 2-amino-4-methoxyphenol (72.7 mg, 0.52 mM) were similar to the preparation process described in Example 10 above. Experimented by the method, N- (5-methoxy-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E4 (39 mg, 32%) was obtained.

       Pale pink powder,

       mp: 129.4-131.4 ° C.,

1 H NMR (CD ₃ OD, 400 MHz) δ 1.13 (d, 6H, J = 6.8 Hz), 2.67 (q, 1H J = 6.8 Hz), 3.72 (s, 3H), 6.75 (dd, 1H, J = 8.8 and 2.8 Hz), 7.00 (d, 1H, J = 2.8 Hz), 7.26 (d, 1H, J = 8.8 Hz),

FABHRMS (m / z): 235.1082 (M ++ l, C ₁₂ H ₁₅ N ₂ O ₃ requires 235.1083)

Example 14. Synthesis of N- (5-Methyl-benzo [d] oxazol-2-yl) -isobutyramide (E5)

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (100 mg, 0.52 mM) and 2-amino-4-methylphenol (64 mg, 0.52 mmol) were prepared in a similar manner to the preparation described in Example 10 above. N- (5-methyl-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E5 (71 mg, 62%) was obtained.

        White powder,

        mp: 156.5-159.8 ° C.,

H NMR (CD ₃ Cl, 400 MHz) δ 1.30 (d, 6H, J = 6.8 Hz), 2.44 (s, 3H), 2.88 (brs, 1H), 7.07 (dd, 1H, J = 8.4 and 1.6 Hz) , 7.26 (d, 1H, J = 1.6 Hz), 7.35 (d, 1H, J = 8.4 Hz),

FABHRMS (m / z): 219.1137 (M ++ l, C ₁₂ H ₁₅ N ₂ O ₂ requires 219.1134)

Example 15. N- (6-Methyl-benzo [d] oxazol-2-yl) -isobutyramide (E6) Synthesis .

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (100 mg, 0.52 mM) and 2-amino-6-methylphenol (64 mg, 0.52 mmol) were prepared in a similar manner to the preparation process described in Example 10 above. N- (6-methyl-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties by experiment E6 (94 mg, 83%) was obtained.

          Pale yellow powder,

          mp: 156.5-159.8 ° C.,

1 H NMR (CD ₃ OD, 400 MHz) δ1.12 (d, 6H, J = 6.4 Hz), 2.33 (S, 3H), 2.63 (q, 1H, J = 6.4 Hz), 7.01 (d, 1H, J = 7.6 Hz) 7.18 (s, 1 H), 7.30 (d, 1 H, J = 7.6 Hz),

FABHRMS (m / z): 219.1130 (M ++ l, C ₁₂ H ₁₅ N ₂ O ₂ requires 219.1134)

Example 16. N- (4-Methyl-benzo [d] oxazol-2-yl) -isobutyramide (E7) Synthesis .

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (100 mg, 0.52 mM) and 2-amino-3-methylphenol (64 mg, 0.52 mmol) were prepared in a similar manner to the preparation described in Example 10 above. N- (4-methyl-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E7 (30 mg, 36%) was obtained.

         Yellow powder,

         mp: 171.2-173.8 ° C,

         1 H NMR (CD3OD, 400 MHz) δ 1.14 (d, 6H, J = 6.8 Hz), 2.43 (s, 3H), 2.66 (q, 1H J = 6.8 Hz), 7.00 (d, 1H, J = 8.0 Hz) , 7.06 (t, 1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz),

FABHRMS (m / z): 219.1137 (M ++ 1, C ₁₂ H ₁₅ N ₂ O ₂ requires 219.1134)

Example 17. Synthesis of 2- (2-isobutylamino-oxazole-4-ylidene methyl) -acrylic acid (E8) .

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (200 mg, 1.04 mM) and 2-amino-4-hydroxy-benzoic acid (160 mg, 1.04 mmol) were similar to the preparation process described in Example 10 above. 2- (2-isobutylamino-oxazole-4-ylidene methyl) -acrylic acid having the following physical properties E8 (94 mg, 36%) was obtained.

        White powder,

        mp: 253.9-255.0 ° C.,

        1 H NMR (DMSO, 400 MHz) δ 1.13 (d, 6H, J = 6.8), 2.79 (q, 1H, J = 6.8 Hz), 7.7 (d, 1H, J = 8.4 Hz), 7.9 (dd, 1H, J = 8.4 and 1.6 Hz), 8.0 (d, 1H, J = 1.6 Hz), 11.75 (brs, 1H),

FABHRMS (m / z): 249.0877 (M ++ 1, C ₁₂ H ₁₃ N ₂ O ₄ requires 249.0875)

Example 18. N- (5-Trifluuromethyl-benzo [d] oxazol-2-yl) -isobutyramide (E9) Synthesis .

N- (bis-methylsulfanyl-methylene) -isobutyramide compound (200 mg, 1.04 mM) and 2-amino-4-tripulourophenol (185 mg, 1.04 mmol) were prepared in the same manner as in Experimented in a similar manner, N- (5-tripulouromethyl-benzo [d] oxazol-2-yl) -isobutyramide having the following physical properties E9 (156 mg, 76%) was obtained.

          Pale yellow powder,

          mp: 142.8-147.5 ° C,

1 H NMR (CD ₃ OD, 400 MHz) δ 1.14 (d, 6H, J = 6.8 Hz), 2.67 (q, 1H, J = 6.8 Hz), 7.49 (dd, 1H, J = 8.4 and 0.8 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.74 (d, 1H, J = 0.8 Hz),

FABHRMS (m / z): 273.0847 (M ++ 1, C ₁₂ H ₁₂ F ₃ N ₂ O ₂ requires 273.0851)

Example 19 Synthesis of N- (5-Chloro-benzo [d] oxazol-2-yl) -3, 5-bis (trifuluromethyl) benzamide (F1)

19-1. N- ( Vis - Methylsulfanyl Methylene) -3,5- Of bistrifluorofluoromethylbenzamide  Manufacture (f)

Dissolve 3,5-bis (trifuluromethyl) benzamide (500 mg, 1.94 mmol) in a round flask substituted with nitrogen gas in DMF (7.8 ml), and carbon disulfide (0.47 mM), Iodomethane (2.2 ml, 36.73 mmol) and sodium hydride 60% (0.92 g, 22.96 mmol) were added sequentially and stirred at room temperature for 5 hours. Ice water was added followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure, separated by column chromatography (EtOAc: n-Hexane = 1: 7), and then N- (bis-methylsulfanyl-methylene) -3,5-bistrifulo Romethylbenzamide compound f (225 mg, 32%) was obtained.

   White powder,

1 H NMR (400 MHz, CDCl ₃ ) δ 1.26 (6H), 8.03 (s, 1H), 8.64 (s, 2H)

19-2. N- (5- Chloro - Benzo [d] oxazole -2-yl) -3, 5- Vis  ( Tripulomethyl ) Benzamide  Preparation of (F1)

N- (bis-methylsulfanyl-methylene) -3,5-bistrifluorofluoromethylbenzamide compound (100 mg, 0.27 mM) and 2-aminophenol (57 mg, 0.25 mmol) obtained in the above step were added with DMF ( 0.25M) and vigorously stirred at room temperature, then the mixture was heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to obtain N- (5-chloro-benzo [d] oxazol-2-yl) -3, 5 having the following physical properties. -Bis (trifuluromethyl) benzamide (F1) (38 mg, 34%) was obtained.

      Pale yellow powder,

      mp: 179.4-181.2 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 7.402 (dd, 1H, J = 2.4 and 8.8 Hz), 7.614-7.637 (m, 2H), 8.292 (br s, 1H), 8.766 (br s, 2H) ,

FABHRMS (m / z): 409.0188 (M ++ 1, C ₁₆ H ₈ F ₆ N ₂ O ₂ requires 409.0178)

Example 20. 3,5- Bis- ( trifuluromethyl ) -N- (5- methylbenzo [d] oxazol- 2 -yl ) -benzamide (F2) Synthesis .

       N- (bis-methylsulfanyl-methylene) -3,5-bistrifluorofluoromethylbenzamide compound (100 mg, 0.27 mM) and 2-amino-4-methylphenol (34.08 mg, 0.27 mmol) were carried out above. 3,5-bis- (trifuluromethyl) -N- (5-methylbenzo [d] oxazol-2-yl) -benzamide having the following physical properties by experimenting in a similar manner to the preparation process described in Example 19 (F2) (52 mg, 49%) was obtained.

       Pale brown powder,

        mp: 178.6-181.7 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.455 (s, 3H), 7.2115 (d, 1H, J = 8.4 Hz), 7.441 (br s, 1H), 7.467 (d, 1H, J = 8.4 Hz) , 8.257 (br s, 1 H), 8.777 (br s, 1 H),

FABHRMS (m / z): 389.0722 (M ++ 1, C ₁₇ H ₁₁ F ₆ N ₂ O ₂ requires 389.0725)

Example 21. 3,5-Bis- (trifuluromethyl) -N- (4-methylbenzo [d] oxazol-2-yl) -benzamide (F3) Synthesis .

        N- (bis-methylsulfanyl-methylene) -3,5-bistrifluorofluoromethylbenzamide compound (100 mg, 0.27 mM) and 2-amino-3-methylphenol (34.08 mg, 0.27 mmol) were carried out above. 3,5-bis- (trifuluromethyl) -N- (4-methylbenzo [d] oxazol-2-yl) -benzamide having the following physical properties by experimenting in a similar manner to the preparation process described in Example 19 (F3) (39 mg, 36%) was obtained.

         Yellow powder,

         mp: 188.3-189.7 ° C.,

1H NMR (Acetone-d ₆ , 400MHz) δ2.578 (s, 3H), 7.009 (d, 1H, J = 8Hz), 7.277 (t, 1H, J = 8Hz), 7.415 (d, 1H, J = 8Hz ), 8.297 (brs, 1H), 8.768 (brs, 2H),

FABHRMS (m / z): 389.0720 (M ++ 1, C ₁₇ H ₁₁ F ₆ N ₂ O ₂ requires 389.0725)

Example 22. 3,5-Bis- (trifuluromethyl) -N- (6-methylbenzo [d] oxazol-2-yl) -benzamide (F4) Synthesis .

        N- (bis-methylsulfanyl-methylene) -3,5-bistrifluorofluoromethylbenzamide compound (100 mg, 0.27 mM) and 2-amino-5-methylphenol (34.08 mg, 0.27 mmol) were carried out above. 3,5-bis- (trifuluromethyl) -N- (6-methylbenzo [d] oxazol-2-yl) -benzamide having the following physical properties by experimenting in a similar manner to the preparation process described in Example 19 (F4) (50 mg, 47%) was obtained.

        Pale brown powder,

        mp: 170.9-173.5 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.474 (s, 3H), 7.227 (d, 1H, J = 8 Hz), 7.425 (brs, 1H), 7.497 (d, 1H, J = 8 Hz), 8.249 ( brs, 1 H), 8.780 (brs, 2 H)

Example 23. 3,5-Bis- (trifuluromethyl) -N- (5-methoxybenzo [d] oxazol-2-yl) -benzamide (F5) Synthesis .

        N- (bis-methylsulfanyl-methylene) -3,5-bistrifluorofluoromethylbenzamide compound (100 mg, 0.27 mM) and 2-amino-4-methoxyphenol (38.51 mg, 0.27 mmol) 3,5-bis- (trifuluromethyl) -N- (5-methoxybenzo [d] oxazol-2-yl)-having the following physical properties by experimenting in a similar manner to the preparation process described in Example 19 Benzamide (F5) (53 mg, 48%) was obtained.

         Brown powder,

         mp: 110.5-111.2 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ3.869 (s, 3H), 6.947 (dd, 1H, J = 2.8 and 8.8 Hz), 7.199 (d, 1H, J = 2.8 Hz), 7.498 (d, 1H , J = 8.8 Hz), 8.245 (m, 2H), 8.774 (brs, 1H),

FABHRMS (m / z): 405.0670 (M ++ l, C ₁₇ H ₁₁ F ₆ N ₂ O ₃ requires 405.0674)

Example 24 Synthesis of (E) -N- (5-chlorobenzo [d] oxazol-2-yl) -3- (4-chlorophenyl) acrylamide (G1)

24-1. N- ( Vis - Methylsulfanyl Methylene) -4- Of chlorocinnamid  Manufacture (g)

4-chlorocinnamamide (500mg, 2.75mmol) in a round flask substituted with nitrogen gas was dissolved in DMF (11ml), and carbon disulfide (0.67ml, 11mmol) and iodomethane (0.55ml) at 0 ° C. , 8.8 mmol) and sodium hydride (220 mg, 5.5 mmol) were added in this order and stirred at room temperature for 5 hours. Ice water was added followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4, filtered, and concentrated under reduced pressure. The organic layer was separated by column chromatography (EtOAc: n-Hexane = 1: 7), and N- (bis-methylsulfanyl-methylene) -4-chlorocinnaamide compound g ( 207 mg, 26%).

               White powder,

1H NMR (400 MHz, CDCl ₃ ) δ1.50 (s, 6H), 3.38 (s, 1H) 6.63 (d, J = 15.2Hz, 1H), 7.41 ~ 7.45 (m, 1H), 7.49 ~ 7.53 (m , 2H), 7.79 (d, J = 15.2 Hz, 1H)

24-2. (E) -N- (5- Chlorobenzo [d] oxazole -2-yl) -3- (4- Chlorophenyl ) Acrylamide  ( G1 Manufacturing

N- (bis-methylsulfanyl-methylene) -4-chlorocinnaamide compound (100 mg, 0.35 mmol) and 2-amino-4-chlorophenol (50.23 mg, 0.35 mmol) obtained in the above step were added with DMF (0.25 M). ) Was stirred vigorously at room temperature and the mixture was heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to give (E) -N- (5-chlorobenzo [d] oxazol-2-yl)-having the following physical properties. 3- (4-chlorophenyl) acrylamide (G1) (17 mg, 15%) was obtained.

         Pale brown powder,

         mp: 237.7-240.8 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 7.2185 (d, 1H, J = 16 Hz), 7.292-7.318 (m, 1H), 7.495-7.516 (m, 2H), 7.561-7.583 (m, 2H), 7.724 ~ 7.745 (m, 2H), 7.819 (d, 1H, J = 16 Hz),

FABHRMS (m / z): 333.0193 (M ++ l, C ₁₆ H ₁₁ Cl ₂ N ₂ O ₂ requires 333.0198)

Example 25. (E) -3- (4-Chlorophenyl) -N- (4-methylbenzo [d] oxazol-2-yl) acrylamide (G2) Synthesis .

       N- (bis-methylsulfanyl-methylene) -4-chlorocinnamamide (100 mg, 0.35 mmol) and 2-amino-3-methylphenol (34.35 mg, 0.28 mmol) were similar to the preparation process described in Example 24 above. (E) -3- (4-chlorophenyl) -N- (4-methylbenzo [d] oxazol-2-yl) acrylamide (G2) (14 mg, 16%) having the following physical properties Got it.

        Dark yellow powder,

         mp: 199.1-205.9 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.507 (s, 3H), 7.136 (d, 1H, J = 7.6 Hz), 7.178 (t, 1H, J = 7.6 Hz), 7.264 (d, 1H, J = 15.6 Hz), 7.355 (d, 1H, J = 7.6 Hz), 7.499-7.520 (m, 2H), 7.721-7.748 (m, 2H), 7.813 (d, 1H, J = 15.6 Hz),

FABHRMS (m / z): 313.0745 (M ++ 1, C ₁₇ H ₁₄ ClN ₂ O ₂ requires 313.0744)

Example 26. (E) -3- (4-chlorophenyl) -N- (5-methylbenzo [d] oxazol-2-yl) acrylamide (G3) synthesis .

       N- (bis-methylsulfanyl-methylene) -4-chlorocinnamamide (80 mg, 0.28 mmol) and 2-amino-4-methylphenol (30.2 mg, 0.25 mmol) were similar to the preparation process described in Example 24 above. (E) -3- (4-chlorophenyl) -N- (5-methylbenzo [d] oxazol-2-yl) acrylamide (G3) (13 mg, 18%) having the following physical properties Got it.

        Brown powder,

        mp: 129.5-132.8 ° C,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.488 (s, 3H), 6.686 (d, 1H, J = 8.4 Hz), 6.738 (s, 1H), 7.434 (d, 1H, J = 8.8 Hz), 7.604 (d, 1H, J = 8.8 Hz), 7.639-7.661 (m, 2H), 7.718-7.738 (m, 2H), 8.246 (d, 1H, J = 8.4 Hz),

FABHRMS (m / z): 313.0743 (M ++ l, C ₁₇ H ₁₄ ClN ₂ O ₂ requires 313.0744)

Example 27. (E) -3- (4-chlorophenyl) -N- (6-methylbenzo [d] oxazol-2-yl) acrylamide (G4) synthesis .

       N- (bis-methylsulfanyl-methylene) -4-chlorocinnamamide (70 mg, 0.25 mmol) and 2-amino-5-methylphenol (32.3 mg, 0.26 mmol) were similar to the preparation process described in Example 24 above. (E) -3- (4-chlorophenyl) -N- (6-methylbenzo [d] oxazol-2-yl) acrylamide (G4) (41 mg, 49%) having the following physical properties Got it.

           Brown powder,

          mp: 167.8-175.8 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ3.846 (s, 3H), 6.179 (d, 1H, J = 16 Hz), 6.861 (dd, 1H, J = 2.4 and 8.8 Hz), 7.105 (d, 1H, J = 2.Hz), 7.485 ~ 7.524 (m, 2H), 7.600 (d, 1H, J = 8.8Hz), 7.719 ~ 7.740 (m, 2H), 7.802 (d, 1H, J = 16Hz),

FABHRMS (m / z): 313.0742 (M ++ 1, C ₁₇ H ₁₄ ClN ₂ O ₂ requires 313.0744)

Example 28. (E) -3- (4-Chlorophenyl) -N- (5-methoxybenzo [d] oxazol-2-yl) acrylamide (G5) Synthesis .

       N- (bis-methylsulfanyl-methylene) -4-chlorocinnamamide (75 mg, 0.26 mmol) and 2-amino-4-methoxyphenol (26.7 mg, 0.19 mmol) were prepared in the same manner as in Experimented in a similar manner to (E) -3- (4-chlorophenyl) -N- (5-methoxybenzo [d] oxazol-2-yl) acrylamide (G5) having the following physical properties (51 mg, 81% )

         Brown powder,

         mp: 151.8-156.0 ° C.,

1H NMR (Acetone-d ₆ , 400MHz) δ3.846 (s, 3H), 6.718 (d, 1H, J = 15.6Hz), 6.860 (dd, 1H, J = 2.8 and 8.8Hz), 7.104 (d, 1H , J = 2.8 Hz), 7.480 to 7.513 (m, 2H), 7.600 (d, J = 8.8 Hz), 7.717 to 7.739 (m, 2H), 7.800 (d, J = 15.6 Hz),

FABHRMS (m / z): 329.0697 (M ++ l, C ₁₇ H ₁₄ ClN ₂ O ₃ requires 329.0693)

Example 29. N- (5 -Chlorobenzo [d] oxazol- 2 -yl ) acetamide (H1) synthesis .

29-1. N- ( Vis - Methylsulfanyl Methylene) Acetamide  Manufacturing (h)

Acetamide (500 mg, 8.46 mmol) in a round flask substituted with nitrogen gas was dissolved in DMF (33.9 ml), and carbon disulfide (2.0 ml, 33.8 mmol) and iodomethane (1.7) at 0 ° C. ml, 27.1 mmol) and sodium hydride (445 mg, 18.6 mmol) were added sequentially and stirred at room temperature for 5 hours. Ice water was added followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The organic layer was separated by column chromatography (EtOAc: n-Hexane = 1: 7) and was purified by N- (bis-methylsulfanyl-methylene) -acetamide compound h (163 mg). , 25%).

      Yellow oil,

1 H NMR (300 MHz, CDCl ₃ ) δ 2.23 (s, 3H), 2.47 (s, 6H)

29-2. Preparation of N- (5-chlorobenzo [d] oxazol-2-yl) acetamide (H1)

N- (bis-methylsulfanyl-methylene) -acetamide compound (75 mg, 0.46 mmol) and 2-amino-4-chlorophenol (65.9 mg, 0.46 mmol) obtained in the above step were added to DMF (0.25 M). The mixture was stirred vigorously at room temperature and the mixture was heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to obtain N- (5-chlorobenzo [d] oxazol-2-yl) acetamide (H1) having the following physical properties. ) (14 mg, 15%).

        Pale brown powder,

         mp: 209.7-208.3 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.521 (s, 3H), 7.241 (dd, 1H, J = 2.0 and 8.4 Hz, 1H), 7.394 (d, J = 8.4 Hz, 1H), 7.590 (d , J = 2.0Hz, 1H),

FABHRMS (m / z): 211.0272 (M ++ 1, C ₉ H ₈ N ₂ O ₂ requires 211.0274)

Example 30. N- (5-Methylbenzo [d] oxazol-2-yl) acetamide (H2) synthesis .

       N- (bis-methylsulfanyl-methylene) -acetamide compound (75 mg, 0.46 mmol) and 2-amino-4-methylphenol (75.4 mg, 0.61 mmol) were similar to the preparation process described in Example 29 above. The experiment was carried out to obtain N- (5-methylbenzo [d] oxazol-2-yl) acetamide (H2) (30 mg, 26%) having the following physical properties.

        Brown powder,

         mp: 172.3-175.8 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ 2.521 (s, 3H), 7.241 (dd, 1H, J = 2.0 and 8.4 Hz, 1H), 7.394 (d, J = 8.4 Hz, 1H), 7.590 (d , J = 2.0Hz, 1H),

FABHRMS (m / z): 211.0272 (M ++ l, C ₉ H ₈ N ₂ O ₂ requires 211.0274)

Example 31. N- (5-Chlorobenzo [d] oxazol-2-yl) propionamide (I1) Synthesis .

31-1. N- ( Vis - Methylsulfanyl Methylene) Propionamide  Manufacturing (i)

Propionamide (1.0 g, 13.68 mmol) in a round flask substituted with nitrogen gas was dissolved in DMF (54.7 ml), followed by carbon disulfide (3.3 ml, 54.72 mmol) and iodomethane (2.7 ml) at 0 ° C. , 43.78 mmol) and sodium hybrid (1.09 g, 27.36 mmol) were added sequentially and stirred at room temperature for 5 hours. Ice water was added followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure. The organic layer was separated by column chromatography (EtOAc: n-Hexane = 1: 7), and extracted with N- (bis-methylsulfanyl-methylene) -propionamide compound i (850 mg, 35%).

        Yellow oil,

1 H NMR (400 MHz, CDCl ₃ ) δ 1.16 (s, 6H), 2.33 (t, J = 7.2 Hz, 3H), 2.73 (q, J = 7.2 Hz, 2H)

31-2. N- (5- Chlorobenzo [d] oxazole -2 days) Of acetamide (I 1)  Produce

N- (bis-methylsulfanyl-methylene) -propionamide (75mg, 0.46mmol) and 2-amino-4-chlorophenol (65.9mg, 0.46mmol) obtained in the above step were added to DMF (0.25M). After vigorous stirring at, the mixture was heated to reflux and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then DMF was removed under reduced pressure and washed with cold MeOH or diethyl ether to obtain N- (5-chlorobenzo [d] oxazol-2-yl) propionamide (I 1) having the following physical properties. ) (22 mg, 14%).

         Brown powder,

          mp: 184.0-190.1 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ1.173 (t, J = 7.2 Hz, 3H), 2.436 (q, J = 7.2 Hz, 2H), 7.274 (dd, J = 2.4 and 8.4 Hz, 1H), 7.532 (d, J = 8.4 Hz, 1H), 7.537 (d, J = 2.4 Hz, 1H),

FABHRMS (m / z): 211.0272 (M ++ l, C ₉ H ₈ N ₂ O ₂ requires 211.0274)

Example 32. N- (5-Chlorobenzo [d] oxazol-2-yl) propionamide (I2) Synthesis .

       N- (bis-methylsulfanyl-methylene) -propionamide (75 mg, 0.46 mmol) and N- (bis-methylsulfanyl-methylene) -propionamide (75 mg, 0.46 mmol) with 2-amino-4-chlorophenol (65.9 mg, 0.46 mmol) was tested in a similar manner to the preparation process described in Example 31, to obtain N- (5-chlorobenzo [d] oxazol-2-yl) propionamide (I2) (20 mg) having the following physical properties. , 12%).

         Brown powder,

          mp: 169.4-171.5 ° C.,

1 H NMR (Acetone-d ₆ , 400 MHz) δ1.169 (t, J = 7.6 Hz, 3H), 2.411 (s, 3H), 2.699 (q, J = 7.6 Hz, 2H), 7.071 (dd, J = 2.0 and 8.4 Hz, 1H), 7.321 (d, J = 2.0 Hz, 1H), 7.336 (d, J = 8.4 Hz, 1H),

FABHRMS (m / z): 211.0272 (M ++ 1, C ₉ H ₈ N ₂ O ₂ requires 211.0274)

Experimental Example 1. Evaluation of inhibition of lipoxygenase at the cellular level

In order to confirm the inhibitory activity against the lipoxygenase of the compound of the Example was performed as follows.

 1-1. BMMC  Of bone-marrow mast cells

Two female BALB / c mice, 5-6 weeks old, were prepared, sterilized with 71% EtOH, and leg bones were separated. Insert the 25 G needle into the center of the leg bone, push out the bone marrow with 25 ml RPMI and centrifuge (1000 rpm, 5 mins) to discard the supernatant. Incubate with RPMI 1640/10% FBS. Observed about one day later, the passage was cultured and confirmed after 90% or more BMMC experiment.

1-2. Leukotrien  ( LTC ₄ ) Assay

After 3 weeks or more, transfer the BMMC to a 50 ml falcon tube, centrifuge (1000 rpm, 5 min, 4 ° C), discard the supernatant, and add only RPMI 1640. 50 ul supernatant samples, 50 ul LTC ₄ AChE tracer and 50 ul LTC ₄ antiserum were dispensed into each well. EIA buffer was used for dilution. In the NSB well, 100ul EIA buffer and 50ul LTC4 AChE tracer were dispensed, and in B0 well, 50ul EIA buffer and 50ul LTC4 AChE tracer and 50ul LTC4 antiserum were dispensed. After incubation at room temperature for 16-20 hours, wash 5 times with 200ul of wash buffer. Add 200 ul of Elman's reagent to each well. After incubation for 60 minutes, the plate was read at 405 nm.

 As a result of the above experiment, (E) -3- (4-chlorophenyl) -N- (6-methylbenzo [d] oxazol-2-yl) acrylamide (G4) in the example compound of the present invention was obtained at a concentration of 1 uM. It was confirmed that the most potent 5-lipoxygenase inhibitory activity of 97.9% at 97.0%, 10uM concentration (see Table 1 to Table 5).

Compound

R ₁ R ₂ R ₃ (%) Inhibition 1 uM 10 uM D1 H H H -106 57.1 D2 H Cl H -69 74 D3 H NO ₂ H -23 -19 D4 H OCH ₃ H 2 94.7 D5 H CH ₃ H -74 89.6 D6 H H CH ₃ -28 88.6 D7 CH ₃ H H 16.1 82.3 D8 H COOH H -13 -20 D9 H CF ₃ H 3 -301

Compound

R ₁ R ₂ R ₃ (%) Inhibition 1 uM 10 uM E1 H H H -16 24.8 E2 H Cl H 33 89.2 E3 H NO ₂ H 16 40.3 E4 H OCH ₃ H 3 32.6 E5 H CH ₃ H 34 20.8 E6 H H CH ₃ 35 36.6 E7 CH ₃ H H 5 9.6 E8 H COOH H 27 29.1 E9 H CF ₃ H -2 27.7

Compound

R ₁ R ₂ R ₃ (%) Inhibition 1 uM 10 uM F1 H Cl H -19.5 32.4 F2 H CH ₃ H 50.7 -89.3 F3 CH ₃ H H 37.2 88.5 F4 H H CH ₃ 64.1 67.9 F5 H OCH ₃ H 40.5 96.6

Compound

R ₁ R ₂ R ₃ (%) Inhibition 1 uM 10 uM G1 H Cl H 34.7 81.3 G2 CH ₃ H H 31.5 4.6 G3 H CH ₃ H 79.0 96.3 G4 H H CH ₃ 97.0 97.9 G5 H OCH ₃ H -13.7 69.7

Compound

R ₁ R ₂ (%) Inhibition 1 uM 10 uM H1 Cl CH ₃ -20.2 -7.6 I1 Cl CH ₂ CH ₃ 35.7 25.5 I2 H CH ₂ CH ₃ 2.7 1.8

The present invention relates to a benzoxazolamide derivative compound having a novel chemical structure having inhibitory activity against lipoxygenase, wherein the pharmaceutical composition comprising the compound as an active ingredient can be used as a medicament for treating and preventing asthma. Do.

Claims (4)

N- (benzo [d] oxazol-2-yl) -benzamide (D1), N- (5-chloro-benzo [d] oxazol-2-yl) -benzamide (D2), N- (5-nitro-benzo [d] oxazol-2-yl) -benzamide (D3), N- (5-methyl-benzo [d] oxazol-2-yl) -benzamide (D5), N- (6-methyl-benzo [d] oxazol-2-yl) -benzamide (D6), N- (4-methyl-benzo [d] oxazol-2-yl) -benzamide (D7) ), 2-benzoyl aminobenzoxazole-5-carboxylic acid (D8), N- (5-trifuluromethyl-benzo [d] oxazol-2-yl-benzamide (D9), N- ( Benzo [d] oxazol-2-yl) -isobutyramide (E1), N- (5-chloro-benzo [d] oxazol-2-yl) -isobutyramide (E2), N- (5- Chloro-benzo [d] oxazol-2-yl) -isobutyramide (E3), N- (5-methyl-benzo [d] oxazol-2-yl) -isobutyramide (E5), N- ( 6-Methyl-benzo [d] oxazol-2-yl) -isobutyramide (E6), N- (4-methyl-benzo [d] oxazol-2-yl) -isobutyramide (E7), 2 -(2-isobutylamino-oxazole-4-ylidene methyl) -acrylic acid (E8), N- (5- Rifuluromethyl-benzo [d] oxazol-2-yl) -isobutyramide (E9), N- (5-chloro-benzo [d] oxazol-2-yl) -3, 5-bis (tri Pullulomethyl) benzamide (F1), 3,5-bis- (tripulomethyl) -N- (5-methylbenzo [d] oxazol-2-yl) -benzamide (F2), 3 , 5-bis- (trifulomethyl) -N- (4-methylbenzo [d] oxazol-2-yl) -benzamide (F3), 3,5-bis- (trifulomethyl) -N- (6-methylbenzo [d] oxazol-2-yl) -benzamide (F4), 3,5-bis- (trifuluromethyl) -N- (5-methoxybenzo [d] Oxazol-2-yl) -benzamide (F5), (E) -N- (5-chlorobenzo [d] oxazol-2-yl) -3- (4-chlorophenyl) acrylamide (G1), (E) -3- (4-chlorophenyl) -N- (4-methylbenzo [d] oxazol-2-yl) acrylamide (G2), (E) -3- (4-chlorophenyl) -N -(5-methylbenzo [d] oxazol-2-yl) acrylamide (G3), (E) -3- (4-chlorophenyl) -N- (6-methylbenzo [d] oxazole-2- One) acrylamide (G4), (E) -3- (4-chlorophenyl) -N- (5-methoxybenzo [d] oxazol-2-yl) arc Rylamide (G5), N- (5-chlorobenzo [d] oxazol-2-yl) acetamide (H1), N- (5-methylbenzo [d] oxazol-2-yl) acetamide (H2), N- (5-chlorobenzo [d] oxazol-2-yl) propionamide (I1) or N- (5-chlorobenzo [d] oxazol-2-yl) propionamide (I2) compound , Pharmacologically acceptable salts thereof, and geometric isomers of (E) -type. delete delete A pharmaceutical composition for the treatment and prevention of asthma diseases, comprising the compound of claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.