KR20060067738A - Novel arylamide derivatives as vanilloid receptor antagonist showing excellent analgesic activity and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to a novel N-arylamide derivative compound and a pharmaceutical composition containing the same as an antagonist to vanilloid receptor-1 (Vanilloid Receptor-1), a novel N-arylamide derivative compound of the formula to provide.

<Formula 1>

Capsaicin receptor, vanilloid receptor, arylamide derivative, pain, neuropathy, inflammation, pharmaceutical composition

Description

Novel Arylamide Derivatives as Vanilloid Receptor Antagonist Showing Excellent Analgesic Activity and Pharmaceutical Compositions Containing the Same as an Antagonist of Vanilloid Receptor

The present invention relates to a novel N-arylamide derivative and a pharmaceutical composition containing the same, and more particularly, vanilloid receptor (capsaicin receptor; Transient Receptor Potential Channel, Vanilloid subfamily member 1; TRPV-1; Vanilloid receptor-1 It relates to a novel N-arylamide derivative having a strong analgesic effect as an antagonist of VR-1) and a pharmaceutical composition containing the same.

The vanilloid receptor is a receptor of capsaicin (trans-8-methyl-N-vanylyl-6-nonenamide), which is a hot ingredient of red pepper, has been estimated for a long time. The receptor was cloned by Caterina et al. In 1997 and named vanilloid receptor subtype 1 (hereinafter referred to as 'VR-1') (Caterina et al., Nature, 1997, 389, 816). VR-1 is distributed in the anhydrous nerves (C-fibers) and thin flowing nerves (A-fibers) in the human body, and is activated by external or internal stimuli to strongly introduce cations such as calcium and sodium into the nerve fiber ends. It is known as an ion channel that serves to sensitize pain irritation. External stimuli that activate VR-1 include not only vanilloid compounds, but also thermal stimuli and acid toxic stimuli (Tominaga et al., Neuron, 1998, 21, 531). Leukotriene metabolites (Hwang at al., PNAS, 2000, 97, 3655) such as 12-hydroperoxy icosatetranoic acid (12-HPETE) and arachidonic acid derivatives such as anandamide (Premkumar et al. , Nature, 2000, 408, 985).

Based on these physiological actions, VR-1 has attracted attention as an integrated regulator that plays an important role in delivering various external noxious stimuli into neurons in vivo. Indeed, knockout mice with the VR-1 gene removed recently have been produced (Caterina et al., Science, 2000, 288, 306). Significantly attenuated results of pain response confirmed the importance of VR-1 for noxious stimuli.

In vivo, VR-1 is expressed in primary sensory neurons (Caterina et al., Nature, 1997, 389, 816). These sensory nerves are involved in the internal organs of the human body such as skin, bone tissue, bladder, gastrointestinal tract, and lungs. It plays an essential role in function regulation. In addition, VR-1 is also expressed in the central nervous system, kidney, stomach, and T-cells (Nozawa et al., Neuroscience Letter, 2001, 309, 33; Yiangou et al., Lancet (North America Edition), 2001, 357, 1338; Birder et al., PNAS, 2001, 98, 13396) and are distributed in other neurons or whole body, and are believed to play an important role in cell division and cell signal regulation.                         

In this regard, indications based on the current regulation of VR-1 activity include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neurodegenerative disease, Respiratory abnormalities such as neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, asthma and chronic obstructive pulmonary disease, irritation of the skin, eyes, mucous membranes, pruritus, fever, gastric-duodenal ulcer, inflammatory bowel disease or these inflammatory diseases and impending Sex incontinence disease (Korean Patent Publication No. 10-2004-0034804), anti-obesity effect (Pharmacol. Rev., 1986, 38, 179) and the like are mentioned.

Pharmacological Mechanisms VR-1 agonists and antagonists can both be used as treatments for the above mentioned diseases. The analgesic effect by the VR-1 agonist has a pharmacological mechanism based on desensitization of capsaicin-sensitive sensory nerves. In other words, as a way to block the pain caused by other harmful stimuli by desensitizing nerve cells by inducing pain and irritation in the sensory nerve, the situation is currently limited to topical treatments due to the disadvantage of the initial pain. On the other hand, VR-1 antagonists have a mechanism of blocking the pain signal recognition stage of the sensory nerves, so there is no problem of inducing initial pain and irritation, and is mainly studied as a therapeutic agent for treating systemic-related diseases.

The present study on the active modulating compounds of VR-1 is in use or clinical studies of agonists such as capsaicin, DA-5018, and resiniferatoxin (Szallasi, J. Med chem., 2004, 47, 2717). More than 20 antagonists, including capsazepine and iodreciniferatoxin, are actively under preclinical studies (International Publication Nos. WO 0208221, WO 03062209, WO 2004055003, WO 2004055004, WO). 2004002983, WO 0216317, WO 2004035549, WO 2004014871, WO 03099284, WO 03022809, WO 02090326, WO 02072536, WO 03068749, WO 2004033435, WO 02076946, WO 0095420, WO 03055484, WO 03014064, WO 03080578, WO 03097586, WO 03070247, WO 03029199).

The novel N-arylamide derivatives provided by the present invention are compounds having excellent VR-1 antagonistic effects and have different chemical structures from those reported to date.

The compounds belonging to the present invention mainly have VR-1 antagonistic activity on their own, but do not exclude the possibility of exhibiting pharmacological action as an agonist by the specific body environment or the product of metabolism after being absorbed into the body.

The inventors have conducted extensive research on compounds that modulate the activity of VR-1, and as a result have found that the novel N-arylamide derivatives are excellent VR-1 antagonists. In addition, the present invention was completed by confirming the strong pharmacological effects (pain, inflammatory and anti-ulcer effect) and excellent safety of these derivatives in animal models.

Accordingly, an object of the present invention is to provide a novel N-arylamide derivative or a nontoxic salt or solvent compound thereof having excellent activity inhibitory effect on VR-1.

It is also an object of the present invention to provide a process for preparing N-arylamide derivatives or non-toxic salts or solvates thereof.

In addition, an object of the present invention is to provide a pharmaceutical composition having a VR-1 activity inhibitory effect comprising an N- arylamide derivative or a non-toxic salt or a solvent compound thereof as an active ingredient.

In order to achieve the above object, as one embodiment the present invention provides a novel N- arylamide derivative compound of the formula (1).

Where

R ₁ is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen atom, nitro , Hydroxyl, cyano, amino mono- or di-substituted with alkyl of 1 to 3 carbon atoms, amide, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, 1 carbon Haloalkyl of 6 to 6, haloalkoxy of 1 to 6 carbon atoms, monoalkyl, di or trisubstituted or unsubstituted cycloalkyl, pyridine, pyrimidine, pyrazole, phenyl, imidazole, morpholine, benzodioxol, benzo Thiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxodiazole, thiadiazole, indazole, pyrrolidine, cros Monyl, piperidine, morpholine ethyl, dihi A pyrazole, (CH ₂₎ pAr gt;

A is O, NH, NHCO, CO, CO ₂ , SO. SO ₂ , NHSO ₂ ;

n is 0 or 1;

W is N or CR ₆ ;

X is N or CR ₇ ;

Y is N or CR ₈ ;

Z is O, S or NR ₆ (wherein R ₆ is hydrogen, cyano, lower alkyl having 1 to 6 carbon atoms, lower alkoxy group having 1 to 6 carbon atoms, OAr, Ar);

P is lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono, di or tri Substituted or unsubstituted cycloalkyl, piperidine, pyrrolidine, pyrazole, dihydropyrazole, pyrazolone, phenyl, quinoline, quinolinone, thiazole, benzothiazole, tetrahydrobenzothiazole, dihydro Naphthothiazole, thiadiazole, pyridine, naphthalene, isoxazole, indole, benzodioxazole, thiophene;

B is O, NH, NHCO, CO, CO ₂ , SO. SO ₂ , NHSO ₂ ;

m is 0 or 1;

R ₂ is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen atom, nitro , Hydroxyl, cyano, amino mono- or di-substituted with alkyl of 1 to 3 carbon atoms, amide, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, 1 carbon Haloalkyl of 6 to 6, haloalkoxy of 1 to 6 carbon atoms, monoalkyl, di or trisubstituted or unsubstituted cycloalkyl, pyridine, pyrimidine, pyrazole, phenyl, imidazole, morpholine, benzodioxol, benzo Thiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxodiazole, thiadiazole, indazole, chromonyl, piperi Dean, morpholine ethyl, dihydropyrazole , Ar;

이고;Ar is

ego;

R ₃ , R ₄ , R ₅ are the same or different, hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy group of 1 to 6 carbon atoms, of 1 to 6 carbon atoms Haloalkyl group, haloalkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, amino group mono- or di-substituted by alkyl group having 1 to 3 carbon atoms, amide group, nitro, hydroxy, cyano, carbonyl group, ketone, carboxylic acid, Carboxyl ester group;

p is 0, 1, 2, 3 or 4;

R ₆ , R ₇ , R ₈ are the same or different, hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, carbon number 1 to 6 haloalkoxy, halogen atom, nitro, hydroxide, cyano, amino mono- or di-substituted with alkyl of 1 to 3 carbon atoms, hydrogen, lower alkyl of 1 to 6 carbon atoms, lower to 2 to 4 carbon atoms Alkenyl, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, phenyl substituted with a halogen atom, or two of R ₆ , R ₇ , R ₈ together are aromatic or heteroaromatic May form a ring.

As a preferred embodiment, the novel N-arylamide derivative compound according to the present invention comprises the compound of Formula 1 or an isomer thereof, preferably

N- (4-tert-butylphenyl) -3- (3-chloropyridin-2-yl) benzamide,

N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide,

N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-ylamino) benzamide,

N- (4-tert-butylphenyl) -4-phenoxybenzamide,

N- (4-tert-butylphenyl) -3- (4-chloropyrazol-1-ylmethyl) benzamide,

Biphenyl-4-carboxylate (4-tert-butylphenyl) amide,                     

N- (4-tert-butylphenyl) -4- (3-methyl-5-oxo-4,5-dihydropyrazol-1-yl) benzamide,

4-benzoyl-N- (4-tert-butylphenyl) benzamide,

N- (4-tert-butylphenyl) -2- (3-chloropyridin-2-ylamino) nicotinamide,

4- (3-chloropyridin-2yl) -N- (3'-fluorobiphenyl-4-yl) benzamide,

4- (3-chloropyridin-2yl) -N- (4-diethylamino-2-methylphenyl) benzamide,

4- (3-chloropyridin-2yl) -N- (4-phenoxyphenyl) benzamide,

4- (3-chloropyridin-2yl) -N- (4-methylcyclohexyl) benzamide,

4- (3-chloropyridin-2yl) -N- (5-phenylethyl- [1,3,4] -thiadiazol-2-yl) benzamide,

4- (3-chloropyridin-2yl) -N- (quinolin-3-yl) benzamide,

4- (3-chloropyridin-2-yl) -N- [6- (1,1-dimethylpropyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] benzamide,

4-tert-butyl-N- [3- (3-chloropyridin-2-yl) phenyl] benzamide,

4-tert-butyl-N- [4- (3-chloropyridin-2-yl) phenyl] benzamide,

4-tert-butyl-N- (4-diethylamino-2-methylphenyl) benzamide,

4-tert-butyl-N- (4-phenoxyphenyl) benzamide,

4-tert-butyl-N- (2-piperidin-1-ylphenyl) benzamide,

4-phenoxy-N- (4-phenoxyphenyl) benzamide,

N- (1-benzylpiperidin-4-yl) -4-phenoxybenzamide,                     

N- [4- (4-methyl-3-nitrophenyl) thiazol-2-yl] -4-phenoxybenzamide,

2- (4-chlorobenzoyl) -N- [4- (4-nitrobenzenesulfonyl) phenyl] benzamide, and

N- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl) -4-pyrrole-1-ylbenzamide.

In still another aspect, the present invention provides a method for preparing the compound of Formula 1, which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto. The following schemes represent methods for the preparation of representative compounds of the present invention. Other compounds may be prepared by appropriate changes in reagents and starting materials known to those skilled in the art.

In addition, some of the compounds of Formula 1 have asymmetric centers, so they may exist in different enantiomeric forms, and all optical isomers of the compounds of Formula 1, and R or S type stereoisomers, and mixtures thereof are also within the scope of the present invention. It shall be included in. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

It is another object of the present invention to provide a pharmaceutical composition containing an effective amount of the compound of formula 1 together with a pharmaceutically acceptable carrier as an active ingredient.

The process for preparing the compound of Formula 1 is illustrated by the following Schemes 1-12.

As in Scheme 1, compound 4 or 5 may be prepared by reacting 2,3-dichloropyridine with boronic acid and a palladium catalyst under basic conditions. (Tapolcsanyi et. Al., Tetrahedron, 2002, 58, 10137)

As in Scheme 2, Compound 7 or 9 may be prepared simply by reacting the amino acid with 2,3-dichloropyridine under a palladium catalyst. (Hong et. Al., Tetrahedron Lett., 1997, 38, 5607)

As in Scheme 3, amines of compound 11 or 13 may be prepared by reacting 2,3-dichloropyridine with aminoboronic acid of compound 10 or 12. (Zheng et. Al., Tetrahedron: Asymmetry, 2003, 14, 3435)

As in Scheme 4, N- (4-tert-butylphenyl) amide system is condensed with 4-tert-butylaniline and the acid compounds 4, 5 or 7 synthesized in Scheme 1 or 2 and commercially available compounds 14 to 18. Compounds 20-27 can be prepared.

As in Scheme 5, N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide 21 is an intermediate by reacting the acid compound 4 synthesized in Scheme 1 with SOCl ₂ Compound 28 can be prepared by synthesis and reaction with amine compound 19 without purification.

As in Scheme 6, N- (4-tert-butylphenyl) amide compound 29 may be prepared by condensing the acid compound 9 synthesized in Scheme 2 with the amine compound 19.

As in Scheme 7, N-aryl-4- (3-chloropyridin-2-yl) benzamide compound 33 to 35 may be condensed with the acid compound 4 synthesized in Scheme 1 with commercially available amine compounds 30 to 32. It can manufacture.

As in Scheme 8, N-substituted-4- (3-chloropyridin-2-yl) benzamide compound 40 to 43 by condensing the acid compound 4 synthesized in Scheme 1 with commercially available amine compounds 36 to 39 Can be prepared.

As in Scheme 9, 4-tert-butylbenzoic acid is condensed with the amine compound 11 or 13 obtained in Scheme 3, and condensed with a commercially available amine compound 31, 32 or 45 to N-aryl-4-tert-benzamide System compounds 46 to 50 can be prepared.

As in Scheme 10, N-substituted 4-phenoxybenzamide compounds 53 to 55 may be prepared by condensation with 4-phenoxybenzoic acid and commercially available amine compounds 32, 51 or 52.

As in Scheme 11, N-aryl-4- (4-chlorobenzoyl) benzamide compound 58 may be prepared by condensing 4- (4-chlorobenzoyl) benzoic acid with a commercially available amine compound 57.

As in Scheme 12, N-substituted-4- (pyrrole-1-yl) benzamide compound 61 may be prepared by condensation with 4- (pyrrole-1-yl) benzoic acid and a commercially available amine compound 60. .

As indicated above, the compounds of formula 1 may form salts, in particular pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those commonly used in the art, such as acid addition salts, and include those described in J. Pharm. Sci., 1977, 66, 1.

Suitable pharmaceutically acceptable acid addition salts are, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulfuric acid, or for example methamsulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, Salts with added organic acids, such as salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

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 then evaporating and drying the filtrate. As metal salts, in particular, the preparation of sodium, potassium or calcium salts is pharmaceutically suitable, and the corresponding warm salts are obtained by reacting ilkyli or alkaline earth metal salts with a suitable warm salt (for example nitrate).

Salts and / or solvates of pharmaceutically acceptable compounds of Formula 1 may be useful as intermediates in the preparation of salts and / or solvates of pharmaceutically acceptable compounds of Formula 1, or the compounds of Formula 1 themselves. And in such cases forms another aspect of the invention.                     

The compound of formula 1 may be prepared in crystalline or amorphous form, and may be optionally hydrated or solvated if it is in crystalline form. It is within the scope of the present invention to include compounds containing various amounts of water as well as stoichiometric hydrates.

Suitable solvates include pharmaceutically acceptable solvates such as hydrates.

Solvent compounds include stoichiometric solvent compounds and nonstoichiometric solvent compounds.

In another embodiment, the pharmaceutical compositions of the present invention contain a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof as an active ingredient with an acceptable carrier.

In a preferred embodiment, the present invention provides pain, acute pain, chronic pain, containing as an pharmaceutically acceptable carrier and active ingredient an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof according to claim 1, Neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, cough, asthma, chronic obstructive pulmonary disease A pharmaceutical composition for the prevention and treatment of burns, psoriasis, pruritus, vomiting, skin, eye, mucous membrane irritation, gastric-duodenal ulcers, inflammatory bowel disease and inflammatory diseases.

The compounds of formula (1) and their pharmaceutically acceptable salts are believed to have the potential to be used for the treatment or prevention of certain disorders, such as those described as having antagonist activity of vanilloid receptors, or for the treatment of pain associated therewith. .

The disorders include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, cough Respiratory abnormalities such as asthma, chronic obstructive pulmonary disease, burns, psoriasis, pruritus, vomiting, skin, eye, mucous membrane irritation, gastric-duodenal ulcers, inflammatory bowel disease and inflammatory diseases.

Accordingly, the present invention also provides a compound of formula 1 or a pharmaceutically acceptable salt or solvent compound thereof, which is used as an active therapeutic substance, in particular in the treatment and prevention of the disorders of the invention.

In particular, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt or solvent compound thereof for use in the treatment or prevention of pain.

The present invention also relates to a method for the antagonism of vanilloid receptors in mammals, including humans, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof Provided are methods for treating or preventing a beneficial disorder.

The present invention provides the use of a compound of formula (1) or a pharmaceutically acceptable salt or solvent compound thereof in the manufacture of a medicament for treating or preventing a disorder in which the antagonistic action of the vanilloid receptor is beneficial.

In order to use the compounds of the invention in therapy, the compounds are usually formulated into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention also provides a pharmaceutical composition comprising an additive such as a compound of formula 1 or a pharmaceutically acceptable salt or solvent compound thereof and a pharmaceutically acceptable carrier, adjuvant or diluent thereof. For example, the compounds of the present invention can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions. Suitable carriers are not particularly limited but include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils and isopropyl myristate. For topical action, the compounds of the present invention may be formulated in ointments or creams.

Hereinafter, the formulation method and the excipient will be described, but are not limited only to these examples.

Pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salt or solvent compounds, and may also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The compounds of the present invention are formulated as injectables by dissolving, suspending or emulsifying the compound in conventional saline, water-soluble solvents such as 5% dextrose or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol. Can be mad. Formulations of the present invention may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

Preferred dosages of the compounds of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg / kg body weight per day, preferably at 0.001 to 100 mg / kg body weight. The administration may be carried out in one day, or may be divided several times.

Depending on the method of administration, the composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound of the present invention.

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

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely to aid the understanding of the present invention, and the scope of the present invention is not limited to the following examples.

Example 1 Preparation of 3- (3-chloropyridin-2-yl) benzoic acid compound (4)

In 0.7 g (4.70 mmol) of 2,3-dichloropyridine, a compound dissolved in 45 mL of 1,2-dimethoxyethane and 45 mL of distilled water, 2.91 g (27.42 mmol) of Na ₂ CO _{3 and} 0.65 g of 3-carboxyphenylboronic acid ( 3.92 mmol) and 0.1 g of Pd (PPh ₃ ) ₄ were added thereto, and the mixture was stirred for 18 hours under reflux. It was cooled to room temperature, concentrated to about 50% under reduced pressure, and the water layer was washed with ethyl acetate. The water layer was adjusted to pH 1 with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 10/1) to obtain 0.80 g (yield 72%) of 3- (3-chloropyridin-2-yl) benzoic acid compound as white crystals.

¹ H NMR (CD ₃ OD) δ: 8.57 (dd, 1H, J = 4.8, 1.6 Hz), 8.32 (d, 1H, J = 1.6 Hz), 8.00-8.04 (m, 2H), 7.58-7.62 (m , 1H), 7.42-7.49 (m, 2H)

Example 2 Preparation of 4- (3-chloropyridin-2-yl) benzoic acid compound (5)

It carried out in the same manner as in Example 1, was prepared using compounds 1 and 3, to obtain 0.82g (yield 74%) of 4- (3-chloropyridin-2-yl) benzoic acid compound of white crystals.

¹ H NMR (CD ₃ OD) δ: 8.57 (dd, 1H, J = 4.8, 1.4 Hz), 8.13 (dd, 2H, J = 6.9, 1.7 Hz), 8.03 (dd, 1H, J = 8.1, 1.4 Hz ), 7.75 (dd, 2H, J = 6.9, 1.7 Hz), 7.44 (dd, 1H, J = 8.1, 4.8 Hz)

Example 3: Preparation of 3- (3-chloropyridin-2-ylamino) benzoic acid compound (7)

0.40 g (2.70 mmol) of 2,3-dichloropyridine, tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) 30 mg, (S)-(-)-2,2 'in 10 mL of toluene under argon atmosphere Add 64 mg of bis (diphenylphosphino) -1.1'-binafyl (BINAP) and 0.62 g (6.48 mmol) of sodium t-butoxide (tBuONa). 0.41 g (2.97 mmol) of 3-aminobenzoic acid was added thereto, stirred at 85 ° C. for 12 hours, and then concentrated under reduced pressure. The residue was dissolved in distilled water, adjusted to pH 1 with concentrated hydrochloric acid, and extracted several times with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 3/1) to obtain 0.20 g (yield 30%) of 3- (3-chloropyridin-2-ylamino) benzoic acid compound.

¹ H NMR (CD ₃ OD) δ: 8.00-8.03 (m, 2H), 7.63-7.69 (m, 2H), 7.28-7.34 (m, 2H), 6.75 (dd, 1H, J = 7.7, 4.8 Hz)

Example 4 Preparation of 2- (3-chloropyridin-2-ylamino) nicotinic acid compound (9)

It was carried out in the same manner as in Example 3, was prepared using compounds 1 and 8, to obtain 0.24 g (yield 36%) of 4- (3-chloropyridin-2-ylamino) nicotinic acid compound.

¹ H NMR (CD3OD) δ: 8.55 (1H, d, J = 7.6 Hz), 8.24-8.31 (m, 2H), 7.89 (dd, 1H, J = 7.9, 2.4 Hz), 7.10 (dd, 1H, J = 7.6, 2.2 Hz), 7.05 (dd, 1H, J = 7.9, 5.0 Hz)

Example 5 Preparation of 3- (3-chloropyridin-2-yl) phenylamine compound (11)

0.32 g (1.84 mmol) of 3-aminophenylboronic acid hydrochloride, a compound dissolved in 4 mL of THF and 2 mL of 2 M Na ₂ CO ₃ , 0.3 g (2.03 mmol) of 2,3-dichloropyridine, 19 mg (0.07 mmol) of PPh3, and palladium acetate Add 8 mg (0.04 mmol) of (Pd (OAc) ₂ ) and stir for 24 hours under reflux. It is cooled to room temperature and the organic layer is separated. The organic layer is dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 10/1) to obtain 0.35 g (yield 92%) of 3- (3-chloropyridin-2-yl) phenylamine compound.

¹ H NMR (CD ₃ OD) δ: 8.49 (dd, 1H, J = 4.8, 1.6 Hz), 7.95 (dd, 1H, J = 7.9, 1.6 Hz), 7.37 (dd, 1H, J = 7.8, 4.8 Hz ), 7.20 (dd, 1H, J = 7.8, 7.8 Hz), 6.95 (s, 1H), 6.92 (dd, 1H, J = 7.9, 4.8 Hz), 6.70 (dd, 1H, J = 7.8, 4.8 Hz)

Example 6: Preparation of 4- (3-chloropyridin-2-yl) phenylamine compound (13)

It carried out in the same manner as in Example 5, was prepared using compounds 1 and 12, to obtain 0.30g (yield 80%) of 4- (3-chloropyridin-2-yl) phenylamine compound.

¹ H NMR (CD ₃ OD) δ: 8.45 (dd, 1H, J = 4.8, 1.6 Hz), 7.92 (dd, 1H, J = 7.8, 1.6 Hz), 7.45 (dd, 2H, J = 7.8, 4.8 Hz ), 7.28 (dd, 1H, J = 6.6, 2.0 Hz), 6.77 (dd, 2H, J = 6.6, 2.0 Hz)

Example 7 Preparation of N- (4-tert-butylphenyl) -3- (3-chloropyridin-2-yl) benzamide compound (20)

82 mg (0.51) of 0.10 g (0.43 mmol) of 3- (3-chloropyridin-2-yl) benzoic acid, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in 5 mL of anhydrous THF under argon atmosphere mmol), 0.14 mL (1.03 mmol) of triethylamine and 69 mg (0.51 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) are dissolved. 77 mg (0.51 mmol) of 4-tert-butylaniline was added thereto, followed by stirring at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (developing solvent: hexane / ethyl acetate = 4/1) to give N- (4-tert-butylphenyl) -3- (3-chloropyridin-2-yl). 0.12 g (76% yield) of benzamide compounds were obtained.

¹ H NMR (CDCl ₃ ) δ: 8.62 (d, 1H, J = 6.2 Hz), 8.19 (s, 1H), 7.95-8.04 (m, 2H), 7.85 (dd, 1H, J = 8.1, 1.5 Hz) , 7.55-7.62 (m, 2H), 7.36-7.44 (m, 3H), 7.26-7.30 (m, 1H), 7.01 (d, 1H, J = 8.6 Hz), 1.32 (s, 9H)

Example 8 Preparation of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide compound (21)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 5 and 19, and 0.14 g of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide compound (Yield 90%) was obtained.                     

¹ H NMR (CD ₃ OD) δ: 8.58 (dd, 1H, J = 4.8, 1.4 Hz), 8.01-8.06 (m, 3H), 7.81 (dd, 2H, J = 8.7, 1.8 Hz), 7.63 (dd , 2H, J = 8.7, 1.8 Hz), 7.39-7.47 (m, 3H), 1.33 (s, 9H)

Example 9 Preparation of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide compound (21)

0.10 g (0.43 mmol) of 4- (3-chloropyridin-2-yl) benzoic acid was added to 10 mL of SOCl2 under argon atmosphere, followed by stirring for 12 hours under reflux. It is concentrated under reduced pressure and the residue is dissolved in 5 mL of dichloromethane. 0.07 mL (0.51 mmol) of triethylamine and 77 mg (0.51 mmol) of 4-tert-butylaniline were added thereto, followed by stirring at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (developing solvent: hexane / ethyl acetate = 4/1) to give N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl). 0.14 g (90% yield) of benzamide compounds were obtained.

Example 10 Preparation of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-ylamino) benzamide compound (22)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 7 and 19, and N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-ylamino) benzamide compound 0.13 g (yield 80%) was obtained.                     

¹ H NMR (CD ₃ OD) δ: 8.01-8.05 (m, 2H), 7.63-7.75 (m, 4H), 7.28-7.37 (m, 4H), 6.73-6.78 (m, 2H), 1.30 (s, 9H)

Example 11 Preparation of N- (4-tert-butylphenyl) -4-phenoxybenzamide compound (23)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 14 and 19 to obtain 0.12 g (yield 83%) of N- (4-tert-butylphenyl) -4-phenoxybenzamide compound.

¹ H NMR (CD ₃ OD) δ: 7.92 (d, 2H, J = 8.9 Hz), 7.58 (d, 2H, J = 8.7 Hz), 7.37-7.42 (m, 4H), 7.20 (dd, 1H, J = 8.7, 8.7 Hz), 7.01-7.08 (m, 4H), 1.32 (s, 9H)

Example 12 Preparation of N- (4-tert-butylphenyl) -3- (4-chloropyrazol-1-ylmethyl) benzamide compound (24)

It carried out in the same manner as in Example 7 above, was prepared using compounds 15 and 19, N- (4-tert-butylphenyl) -3- (4-chloropyrazol-1-ylmethyl) benzamide compound 0.12 g (yield 78%) was obtained.

¹ H NMR (CD ₃ OD) δ: 7.83-7.88 (m, 3H), 7.58 (dd, 2H, J = 6.7, 1.9 Hz), 7.38-7.47 (m, 5H), 5.38 (s, 2H), 1.33 (s, 9H)

Example 13 Preparation of Biphenyl-4-carboxylate (4-tert-butylphenyl) amide Compound (25)

It carried out in the same manner as in Example 7 above, was prepared using compounds 16 and 19, to obtain 0.11 g (yield 75%) of biphenyl-4-carboxylate (4-tert-butylphenyl) amide compound.

¹ H NMR (CDCl ₃ ) δ: 7.95 (d, 2H, J = 8.3 Hz), 7.80-7.90 (br, 1H), 7.72 (d, 2H, J = 8.3 Hz), 7.57-7.66 (m, 4H) , 7.40-7.50 (m, 4H), 1.34 (s, 9H)

Example 14 Preparation of N- (4-tert-butylphenyl) -4- (3-methyl-5-oxo-4,5-dihydropyrazol-1-yl) benzamide compound (26)

Was carried out in the same manner as in Example 7, above was prepared using compounds 17 and 19, N- (4-tert-butylphenyl) -4- (3-methyl-5-oxo-4,5-dihydro 80 mg (yield 53%) of pyrazol-1-yl) benzamide compounds were obtained.

¹ H NMR (CD ₃ OD) δ: 8.03-8.50 (m, 4H), 7.59-7.62 (m, 2H), 7.39-7.44 (m, 2H), 2.34 (d, 1H, J = 10.8 Hz), 2.18 (d, 1H, J = 10.8 Hz), 1.33 (s, 9H), 1.31 (s, 3H)

[Example 15]: Preparation of 4-benzoyl-N- (4-tert-butylphenyl) benzamide compound (27)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 18 and 19 to obtain 0.14 g (yield 89%) of 4-benzoyl-N- (4-tert-butylphenyl) benzamide compound.

¹ H NMR (CD ₃ OD) δ: 8.06 (d, 2H, J = 8.4 Hz), 7.88 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.0 Hz), 7.55-7.68 ( m, 5H), 7.42 (d, 2H, J = 8.8 Hz), 1.34 (s, 9H)

Example 16 Preparation of N- (4-tert-butylphenyl) -2- (3-chloropyridin-2-ylamino) nicotinamide compound (29)

Was carried out in the same manner as in Example 7, above was prepared using compounds 9 and 19, N- (4-tert-butylphenyl) -2- (3-chloropyridin-2-ylamino) nicotinamide compound 0.11 g (66% yield) was obtained.

¹ H NMR (CD ₃ OD) δ: 7.62 (d, 2H, J = 8.5 Hz), 7.47-7.54 (m, 2H), 7.34-7.40 (m, 4H), 7.20 (d, 2H, J = 8.3 Hz ), 1.35 (s, 9 H)

Example 17 Preparation of 4- (3-chloropyridin-2yl) -N- (3'-fluorobiphenyl-4-yl) benzamide compound (33)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 30, and 4- (3-chloropyridin-2yl) -N- (3'-fluorobiphenyl-4-yl) benzamide 0.15 g (87% yield) of compound was obtained.

¹ H NMR (CD ₃ OD) δ: 8.60 (d, 1H, J = 6.3 Hz), 8.04-8.08 (m, 3H), 7.81-7.84 (m, 3H), 7.68-7.71 (m, 2H), 7.44 -7.53 (m, 5H), 6.90-6.97 (m, 1H)

Example 18 Preparation of 4- (3-chloropyridin-2yl) -N- (4-diethylamino-2-methylphenyl) benzamide compound (34)

Was carried out in the same manner as in Example 7, was prepared using compounds 4 and 31, 4- (3-chloropyridin-2yl) -N- (4-diethylamino-2-methylphenyl) benzamide compound 0.14 g (84% yield) was obtained.

¹ H NMR (CD ₃ OD) δ: 8.59 (dd, 1H, J = 4.8, 1.4 Hz), 8.01-8.09 (m, 3H), 7.78-7.82 (m, 2H), 7.43-7.48 (m, 1H) , 7.15 (d, 1H, J = 8.6 Hz), 6.62-6.68 (m, 2H), 3.39 (q, 4H, J = 7.1 Hz), 2.27 (s, 3H), 1.16 (t, 6H, J = 7.1 Hz)

Example 19 Preparation of 4- (3-chloropyridin-2yl) -N- (4-phenoxyphenyl) benzamide compound (35)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 32, and 0.15 g of 4- (3-chloropyridin-2yl) -N- (4-phenoxyphenyl) benzamide compound (yield) 89%).                     

¹ H NMR (CD ₃ OD) δ: 8.59 (d, 1H, J = 4.7 Hz), 8.01-8.08 (m, 3H), 7.81 (d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 8.9 Hz), 7.44-7.47 (m, 1H), 7.32-7.36 (m, 2H), 7.05-7.08 (m, 1H), 6.98-7.04 (m, 4H)

Example 20 Preparation of 4- (3-chloropyridin-2yl) -N- (4-methylcyclohexyl) benzamide compound (40)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 36, and 0.12 g of 4- (3-chloropyridin-2yl) -N- (4-methylcyclohexyl) benzamide compound (yield) 83%).

¹ H NMR (CD ₃ OD) δ: 8.55-8.58 (m, 1H), 7.98-8.03 (m, 1H), 7.89-7.93 (m, 2H), 7.71-7.75 (m, 2H), 7.42-7.46 ( m, 1H), 3.98-4.03 (m, 0.6H), 3.81-3.90 (m, 0.4H), 1.90-1.96 (m, 1H), 1.65-1.85 (m, 5H), 1.38-1.45 (m, 2H ), 1.05-1.15 (m, 1H), 1.01 (d, 1.8H, J = 6.7 Hz), 0.94 (d, 1.2H, J = 6.5 Hz)

Example 21 Preparation of 4- (3-chloropyridin-2yl) -N- (5-phenylethyl- [1,3,4] -thiadiazol-2-yl) benzamide compound (41)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 37, and 4- (3-chloropyridin-2yl) -N- (5-phenylethyl- [1,3,4]- Tiadiazol-2-yl) benzamide compound 92 mg (yield 50%) was obtained.

¹ H NMR (CD ₃ OD) δ: 8.58 (dd, 1H, J = 4.6, 1.5 Hz), 8.13 (d, 1H, J = 8.4 Hz), 8.01 (dd, 1H, J = 8.2, 6.7 Hz), 7.76 (dd, 1H, J = 8.5, 2.6 Hz), 7.42-7.47 (m, 2H), 7.18-7.30 (m, 6H), 3.18 (t, 2H, J = 6.9 Hz), 3.01 (t, 2H, J = 6.9 Hz)

Example 22: Preparation of 4- (3-chloropyridin-2yl) -N- (quinolin-3-yl) benzamide compound (42)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 38, and 77 mg of 4- (3-chloropyridin-2yl) -N- (quinolin-3-yl) benzamide compound (yield 50) %) Was obtained.

¹ H NMR (CD ₃ OD) δ: 9.10 (d, 1H, J = 2.5 Hz), 8.83 (d, 1H, J = 2.3 Hz), 7.99-8.05 (m, 4H), 7.93 (d, 1H, J = 7.1 Hz), 7.70-7.73 (m, 2H), 7.52-7.64 (m, 4H)

Example 23 4- (3-chloropyridin-2-yl) -N- [6- (1,1-dimethylpropyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl ] Benzamide Compound (43) Preparation

Was carried out in the same manner as in Example 7, and was prepared using Compounds 4 and 39, and 4- (3-chloropyridin-2-yl) -N- [6- (1,1-dimethylpropyl) -4 91 mg (, 50% yield) of the 5,6,7-tetrahydrobenzothiazol-2-yl] benzamide compound were obtained.                     

¹ H NMR (CD ₃ OD) δ: 8.59 (dd, 1H, J = 4.8, 1.4 Hz), 8.11 (dd, 2H, J = 6.7, 1.8 Hz), 8.02 (dd, 1H, J = 8.1, 1.4 Hz ), 7.82 (dd, 2H, J = 6.7, 1.8 Hz), 7.45 (dd, 1H, J = 8.1, 4.8 Hz), 2.72-2.77 (m, 2H), 2.45-2.55 (m, 2H), 2.10- 2.15 (m, 1H), 1.51-1.57 (m, 1H), 1.36-1.46 (m, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.89 (t, 3H, J = 7.5 Hz)

Example 24 Preparation of 4-tert-butyl-N- [3- (3-chloropyridin-2-yl) phenyl] benzamide compound (46)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 11 and 44, and 0.14 g of 4-tert-butyl-N- [3- (3-chloropyridin-2-yl) phenyl] benzamide compound (Yield 89%) was obtained.

¹ H NMR (CDCl ₃ ) δ: 8.59 (d, 1H, J = 3.9 Hz), 7.91-7.93 (m, 2H), 7.79-7.84 (m, 4H), 7.46-7.52 (m, 4H), 7.24- 7.26 (m, 1 H), 1.35 (s, 9 H)

Example 25 Preparation of 4-tert-butyl-N- [4- (3-chloropyridin-2-yl) phenyl] benzamide compound (47)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 13 and 44, and 0.13 g of 4-tert-butyl-N- [4- (3-chloropyridin-2-yl) phenyl] benzamide compound (Yield 83%) was obtained.

¹ H NMR (CDCl ₃ ) δ: 7.79-7.83 (m, 3H), 7.63 (d, 2H, J = 7.6 Hz), 7.51 (dd, 2H, J = 8.8, 2.1 Hz), 7.37 (dd, 2H, J = 8.4, 7.5 Hz), 7.14 (d, 1H, J = 7.5, 7.4 Hz), 5.33-5.38 (br, 1H), 1.26 (s, 9H)

Example 26 Preparation of 4-tert-butyl-N- (4-diethylamino-2-methylphenyl) benzamide compound (48)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 31 and 44, and 0.12 g of 4-tert-butyl-N- (4-diethylamino-2-methylphenyl) benzamide compound (yield 83%) )

¹ H NMR (CD ₃ OD) δ: 7.87 (d, 2H, J = 6.8 Hz), 7.54 (d, 2H, J = 8.5 Hz), 7.08 (d, 1H, J = 8.5 Hz), 6.57-6.63 ( m, 2H), 3.36 (q, 4H, J = 7.0 Hz), 2.23 (s, 3H), 1.37 (s, 9H), 1.15 (t, 6H, J = 7.0 Hz)

Example 27: Preparation of 4-tert-butyl-N- (4-phenoxyphenyl) benzamide compound (49)

It was carried out in the same manner as in Example 7, was prepared using compounds 32 and 44, to obtain 0.13g (yield 89%) of 4-tert-butyl-N- (4-phenoxyphenyl) benzamide compound.                     

¹ H NMR (CDCl ₃ ) δ: 7.80-7.82 (m, 3H), 7.60 (d, 2H, J = 8.9 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.30-7.36 (m, 2H) , 6.98-7.10 (m, 5H), 1.35 (s, 9H)

Example 28: Preparation of 4-tert-butyl-N- (2-piperidin-1-ylphenyl) benzamide compound (50)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 44 and 45, and 0.10 g of 4-tert-butyl-N- (2-piperidin-1-ylphenyl) benzamide compound (yield 72) %) Was obtained.

¹ H NMR (CDCl ₃ ) δ: 9.55-9.65 (br, 1H), 8.60 (dd, 1H, J = 8.3, 1.2 Hz), 7.91 (d, 2H, J = 8.5 Hz), 7.53-7.57 (m, 2H), 7.11-7.22 (m, 2H), 7.05-7.11 (m, 1H), 2.85-2.88 (m, 4H), 1.75-1.83 (m, 5H), 1.38 (s, 9H)

Example 29 Preparation of 4-phenoxy-N- (4-phenoxyphenyl) benzamide compound (53)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 14 and 32 to obtain 0.14 g (yield 86%) of 4-phenoxy-N- (4-phenoxyphenyl) benzamide compound.

¹ H NMR (CD ₃ OD) δ: 7.94 (d, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 9.0 Hz), 7.32-7.43 (m, 4H), 7.09-7.12 (m, 1H ), 6.97-7.08 (m, 9H)

Example 30 Preparation of N- (1-benzylpiperidin-4-yl) -4-phenoxybenzamide compound (54)

It was carried out in the same manner as in Example 7, and was prepared using Compounds 14 and 51, and 0.15 g of N- (1-benzylpiperidin-4-yl) -4-phenoxybenzamide compound (yield 91%) )

¹ H NMR (CD ₃ OD) δ: 7.81 (dd, 2H, J = 8.9, 2.1 Hz), 7.33-7.43 (m, 7H), 7.15-7.21 (m, 1H), 7.04 (dd, 2H, J = 8.8, 1.2 Hz), 6.97 (dd, 2H, J = 8.9, 2.1 Hz), 3.85-3.91 (m, 1H), 3.58 (s, 2H), 2.94-2.99 (m, 2H), 2.16-2.25 (m , 2H), 1.90-1.96 (m, 2H), 1.65-1.70 (m, 2H)

Example 31 Preparation of N- [4- (4-methyl-3-nitrophenyl) thiazol-2-yl] -4-phenoxybenzamide compound (55)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 14 and 52, and N- [4- (4-methyl-3-nitrophenyl) thiazol-2-yl] -4-phenoxybenz 78 mg (42% yield) of an amide compound were obtained.

1 H NMR (CD3OD) δ: 8.57 (s, 1H), 8..4-8.11 (m, 3H), 7.59 (s, 1H), 7.41-7.49 (m, 3H), 7.20-7.26 (m, 1H) , 7.07-7.13 (m, 4H), 2.58 (s, 3H)

Example 32 Preparation of 2- (4-chlorobenzoyl) -N- [4- (4-nitrobenzenesulfonyl) phenyl] benzamide compound (58)

Was carried out in the same manner as in Example 7, and was prepared using Compounds 56 and 57, and 2- (4-chlorobenzoyl) -N- [4- (4-nitrobenzenesulfonyl) phenyl] benzamide compound 0.14 g (yield 62%) was obtained.

1 H NMR (CD3OD) δ: 8.06 (d, 2H, J = 8.9 Hz), 7.65-7.75 (m, 8H), 7.46-7,51 (m, 4H), 7.46 (d, 2H, J = 8.7 Hz)

Example 33 Preparation of N- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl) -4-pyrrole-1-ylbenzamide compound (61)

Was carried out in the same manner as in Example 7, above was prepared using compounds 59 and 60 and N- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl) -4 56 mg (yield 38%) of pyrrole-1-ylbenzamide compound were obtained.

¹ H NMR (CD ₃ OD) δ: 7.73-7.81 (m, 4H), 7.47 (d, 2H, J = 8.6 Hz), 7.23-7.33 (m, 4H), 7.04 (dd, 1H, J = 7.2, 7.3 Hz), 7.28 (d, 2H, J = 2.1 Hz)

Experimental Example 1 Vanilloid Receptor Inhibitory Activity Test

1) Preparation of Test Compound                     

Compounds synthesized as in Example were dissolved in dimethyl sulfoxide (DMSO) and prepared at a concentration of 10 mM. The prepared solution was diluted in a concentration of 1 μM in the saline solution of the same composition as the pipette solution of Table 1 for the evaluation of patch clamp activity inhibitory activity was used in the experiment.

2) Evaluation of VR-1 Patch Clamp Activity Inhibition Activity

In this experiment, electrophysiological methods were used to measure the changes in the activity of VR1 as current.

Rat TRPV1 cDNA was transfected to the passaged HEK293 cell line using lipofectamin and used for experiments.

HEK293 cells transfected with the rat TRPV1 gene were treated with trypsin, detached from the cell culture dish, and sprinkled with cells in a patch clamp chamber.

In this case, the cover glass slip constituting the bottom of the patch clamp chamber was treated with 50% poly-L-lysine solution for at least 15 minutes, so that the HEK cell was attached to the bottom well. Remove the membranes from the HEK cells randomly selected at room temperature (~ 25 ℃) using the inside-out patch clamp method, and then administered 10 μM of capsaicin into the cytoplasmic side to give VR-1. By activating the capsaicin current. When capsaicin current reached plateau, each compound was administered with 10 μM of capsaicin to record the inhibitory effect of the current by the compound and the degree of inhibition was expressed as a percentage. Capsaicin current has a characteristic of quickly run-down by calcium ions inside and outside the cell, so it was tested using an experimental solution having the ionic composition shown in Table 1 in order to prevent this and record the inhibitory ability of the effective compound. .

Experimental solution composition for recording capsaicin currents (in mM) Extracellular solution Bath (cytoplasmic) solution NaCl 140 140 HEPES 10 10 EGTA 0 2 pH 7.3 adjusted with NMG NMG

The test results were amplified by using Axon's Digidata 1200B A / D converter and Axopatch 1D amplifier. The degree of inhibition of the compounds was indicated by the capsaicin current immediately before administration of each compound as 100%. In order to ensure the reproducibility of the experimental results were performed three times for each sample, the average activity inhibition degree is described in Table 2.

VR-14 activity inhibitory test results of test compounds Compound number Activity inhibitory% (1μM) 21 100 23 55 24 50 25 28 26 16 46 14 47 34 48 25 49 60 50 40 53 19 54 49

As an antagonist to vanilloid receptor-1 (Vanilloid Receptor-1) according to the present invention, a novel N-arylamide derivative compound and a pharmaceutical composition containing the same include: pain, acute pain, chronic pain, neuropathic pain, postoperative pain, Migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, cough, asthma, chronic obstructive pulmonary disease, respiratory abnormalities, burns, psoriasis, pruritus, It is useful for the prevention and treatment of vomiting, irritation of skin, eyes, mucous membranes, gastric-duodenal ulcers, inflammatory bowel disease and inflammatory diseases.

Claims (4)

A compound represented by formula (1) or a pharmaceutically acceptable salt or isomer thereof: <Formula 1>

Where R ₁ is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen atom, nitro , Hydroxyl, cyano, amino mono- or di-substituted with alkyl of 1 to 3 carbon atoms, amide, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, 1 carbon Haloalkyl of 6 to 6, haloalkoxy of 1 to 6 carbon atoms, monoalkyl, di or trisubstituted or unsubstituted cycloalkyl, pyridine, pyrimidine, pyrazole, phenyl, imidazole, morpholine, benzodioxol, benzo Thiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxodiazole, thiadiazole, indazole, pyrrolidine, cros Monyl, piperidine, morpholine ethyl, dihi A pyrazole, (CH2) pAr and; A is O, NH, NHCO, CO, CO ₂ , SO. SO ₂ , NHSO ₂ ; n is 0 or 1; W is N or CR ₆ ; X is N or CR ₇ ; Y is N or CR ₈ ; Z is O, S or NR ₆ (wherein R ₆ is hydrogen, cyano, lower alkyl having 1 to 6 carbon atoms, lower alkoxy group having 1 to 6 carbon atoms, OAr, Ar); P is lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, mono, di or tri Substituted or unsubstituted cycloalkyl, piperidine, pyrrolidine, pyrazole, dihydropyrazole, pyrazolone, phenyl, quinoline, quinolinone, thiazole, benzothiazole, tetrahydrobenzothiazole, dihydro Naphthothiazole, thiadiazole, pyridine, naphthalene, isoxazole, indole, benzodioxazole, thiophene; B is O, NH, NHCO, CO, CO ₂ , SO. SO ₂ , NHSO ₂ ; m is 0 or 1; R ₂ is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen atom, nitro , Hydroxyl, cyano, amino mono- or di-substituted with alkyl of 1 to 3 carbon atoms, amide, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, 1 carbon Haloalkyl of 6 to 6, haloalkoxy of 1 to 6 carbon atoms, monoalkyl, di or trisubstituted or unsubstituted cycloalkyl, pyridine, pyrimidine, pyrazole, phenyl, imidazole, morpholine, benzodioxol, benzo Thiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxodiazole, thiadiazole, indazole, chromonyl, piperi Dean, morpholine ethyl, dihydropyrazole , Ar; Ar is

ego; R ₃ , R ₄ , R ₅ are the same or different, hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy group of 1 to 6 carbon atoms, of 1 to 6 carbon atoms Haloalkyl group, haloalkoxy group having 1 to 6 carbon atoms, halogen atom, amino group, amino group mono- or di-substituted by alkyl group having 1 to 3 carbon atoms, amide group, nitro, hydroxy, cyano, carbonyl group, ketone, carboxylic acid, Carboxyl ester group; p is 0, 1, 2, 3 or 4; And R ₆ , R ₇ , R ₈ are the same or different, hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, carbon number Haloalkoxy of 1 to 6, halogen atom, nitro, hydroxide, cyano, amino, amide mono or di-substituted with alkyl of 1 to 3 carbon atoms, hydrogen, lower alkyl of 1 to 6 carbon atoms, of 2 to 4 carbon atoms Lower alkenyl, lower alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, phenyl substituted by a halogen atom, or two of R ₆ , R ₇ , R ₈ together are aromatic or hetero Aromatic rings can be formed. The method of claim 1, wherein the compound of Formula 1 or a pharmaceutically acceptable salt or isomer thereof  N- (4-tert-butylphenyl) -3- (3-chloropyridin-2-yl) benzamide, N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) benzamide, N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-ylamino) benzamide, N- (4-tert-butylphenyl) -4-phenoxybenzamide, N- (4-tert-butylphenyl) -3- (4-chloropyrazol-1-ylmethyl) benzamide, Biphenyl-4-carboxylate (4-tert-butylphenyl) amide, N- (4-tert-butylphenyl) -4- (3-methyl-5-oxo-4,5-dihydropyrazol-1-yl) benzamide, 4-benzoyl-N- (4-tert-butylphenyl) benzamide, N- (4-tert-butylphenyl) -2- (3-chloropyridin-2-ylamino) nicotinamide, 4- (3-chloropyridin-2yl) -N- (3'-fluorobiphenyl-4-yl) benzamide, 4- (3-chloropyridin-2yl) -N- (4-diethylamino-2-methylphenyl) benzamide, 4- (3-chloropyridin-2yl) -N- (4-phenoxyphenyl) benzamide, 4- (3-chloropyridin-2yl) -N- (4-methylcyclohexyl) benzamide, 4- (3-chloropyridin-2yl) -N- (5-phenylethyl- [1,3,4] -thiadiazol-2-yl) benzamide, 4- (3-chloropyridin-2yl) -N- (quinolin-3-yl) benzamide, 4- (3-chloropyridin-2-yl) -N- [6- (1,1-dimethylpropyl) -4,5,6,7-tetrahydrobenzothiazol-2-yl] benzamide, 4-tert-butyl-N- [3- (3-chloropyridin-2-yl) phenyl] benzamide, 4-tert-butyl-N- [4- (3-chloropyridin-2-yl) phenyl] benzamide, 4-tert-butyl-N- (4-diethylamino-2-methylphenyl) benzamide, 4-tert-butyl-N- (4-phenoxyphenyl) benzamide, 4-tert-butyl-N- (2-piperidin-1-ylphenyl) benzamide, 4-phenoxy-N- (4-phenoxyphenyl) benzamide, N- (1-benzylpiperidin-4-yl) -4-phenoxybenzamide, N- [4- (4-methyl-3-nitrophenyl) thiazol-2-yl] -4-phenoxybenzamide, 2- (4-chlorobenzoyl) -N- [4- (4-nitrobenzenesulfonyl) phenyl] benzamide, and N- (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl) -4-pyrrole-1-ylbenzamide Compound selected from the group consisting of. A pharmaceutical composition comprising as an active ingredient a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof as an active ingredient, together with a pharmaceutically acceptable carrier. Pain, acute pain, chronic pain, neuropathic pain, postoperative pain, containing an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or isomer thereof according to claim 1 as a pharmaceutically acceptable carrier and active ingredient; Migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, cough, asthma, chronic obstructive pulmonary disease, respiratory abnormalities, burns, psoriasis, pruritus, Pharmaceutical compositions for the prevention and treatment of vomiting, irritation of skin, eyes, mucous membranes, gastric-duodenal ulcers, inflammatory bowel disease and inflammatory diseases.