KR20100053470A - Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanulloid receptor antagonist and pharmaceutical compositions containing the same - Google Patents

Abstract

PURPOSE: A novel compound which functions as a vanilloid receptor 1(VR1) antagonist is provided to prevent or treat disease related to hair growth, rhinitis, and pancreatitis. CONSTITUTION: A vanilloid receptor antagonist compound is denoted by chemical formula I. A pharmaceutical composition contains the compound, isomer, or pharmaceutically acceptable salt thereof. The composition is used for preventing or treating arthritis disease, neuropathy, HIV related neuropathy, nerve injury, neurodegeneration, cerebral apoplexy, urinary incontinence, cough, neuropathy/allergy/inflammation skin disease, atopic dermatitis, psoriasis, pruritus, the prurigo, acouesthesia, aliasing, bregma anaphylaxis, effluvium, or alopecia.

Description

Novel Compounds, Isomer Thereof, or Pharmaceutically Acceptable Salts Thereof as Vanulloid Receptor Antagonist and Pharmaceutical Compositions Containing the Same}

The present invention provides novel compounds, isomers thereof or pharmaceutically acceptable salts thereof that act as TRPV1 antagonists; And it relates to a pharmaceutical composition comprising the same.

Vanyloid receptor-1 (VR1 or transient receptor potential vanilloid-1, TRPV1) is a receptor for capsaicin (8-methyl-N-vanillyl-6-nonenamide), a spicy taste ingredient in hot peppers. Molecular cloning of TRPV1 was reported in 1997 (Caterina et al., 1997, Nature, 389, pp816-824) and belongs to the TRP channel family of non-selective cation channels. TRPV1 is activated or sensitized by stimuli such as capsaicin, resiniferatoxin, heat, acid, anandamide, lipid metabolite, and the like; Thus it plays an important role as a molecular integrator of noxious stimuli in mammals (Tominaga et al., 1998, Neuron, 21 pp531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). . TRPV1 is highly expressed in primary afferent sensory neurons and also in various organs and tissues, such as the bladder, kidneys, lungs, intestines, skin, central nervous system (CNS), and non-neural tissues. (Mezey et al., 2000, PNAS, 97, pp3655-3660; Stander et al., 2004, Exp. Dermatol. 13, pp129-139; Cortright et al., 2001, BBRC, 281, pp1183). -1189) and TRPV1 protein is also reported to be upregulated in pain disease conditions. The activity of TRPV1 by endogenous / exogenous stimuli not only leads to the delivery of noxious stimuli, but also induces the release of neuropeptides, such as substance P and Calcitonin Gene-Related Peptide (CGRP) in the nerves, leading to neurological inflammation . TRPV1 knock-out mice showed normal response in a wide range of behavioral tests, including harmful mechanical and acute thermal stimulation, but showed little thermal hypersensitivity in inflammatory conditions (Caterina et al. al., 2000, Science, 288, pp306-313; Davis et al., 2000, Nature, 405, pp183-187; Karai et al., 2004, J. Clin. Invest., 113, pp1344-1352).

As mentioned earlier, mice lacking TRPV1 exhibited a reduced response to heat or noxious stimuli, which has been supported by the effects of TRPV1 antagonists seen in various pain animal models (Immke et al., 2006, Semin. Cell. Dev. Biol., 17 (5), pp582-91; Ma et al., 2007, Expert Opin.Ther. Targets, 11 (3), pp307-20). Capsazepine, a well-known TRPV1 antagonist, reduces hyperalgesia caused by physical stimulation in several models of inflammation and neuropathic pain (Walker et al., 2003, JPET, 304, pp 56-62; Garcia-Martinez et al., 2002, PNAS, 99, 2374-2379). Further, primary cultured afferent sensory neurons were treated with capsaicin, a TRPV1 antagonist, and the like, resulting in impaired nerve function and further death of nerve cells. TRPV1 antagonists protect against neuronal impairment and neuronal cell death (Holzer P., 1991, Pharmacological Reviews, 43, pp 143-201; Mezey et al., 2000, PNAS, 97, 3655-3660). TRPV1 is expressed in sensory neurons distributed in all gastrointestinal tracts and is highly expressed in inflammatory diseases such as irritable bowel syndrome and inflammatory bowel disease (Chan et al., 2003, Lancet, 361, pp 385-391; Yiangou et al. , 2001, Lancet, 357, pp 1338-1339. In addition, the activity of TRPV1 stimulates sensory neurons, resulting in the release of neuropeptides, which are known to play an important role in the development of gastrointestinal diseases such as gastro-esophageal reflux disease (GERD) and gastrointestinal ulcers. Holzer P., 2004, Eur. J. Pharmacol. 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320.

TRPV1 expressing afferent nerves are abundantly distributed in the airway mucosa, and bronchial hypersensitivity is a mechanism very similar to hyperalgesia. Proton and lipoxygenase products, known as endogenous ligands for TRPV1, are known to be important factors in response to the development of asthma and chronic obstructive pulmonary diseases (Hwang et al., 2002, Curr. Opin). Pharmacol.pp235-242; Spina et al., 2002, Curr. Opin.Pharmacol.pp264-272). Furthermore, it has been reported that asthma-inducing air pollutants, ie particulate matter, in particular act on TRPV1 and this action is inhibited by capsazepine (Veronesi et al., 2001, NeuroToxicology, 22, pp795-810). Urinary bladder hypersensitivity and urinary incontinence are caused by various central / peripheral neurological diseases or injuries, and TRPV1 expressed in afferent nerves and urothelial cells plays an important role in bladder inflammation (Birder et. al., 2001, PNAS, 98, pp 13396-13401). Moreover, mice with TRPV1 impairment are anatomically normal but have higher periods of low-amplitude, non-voiding bladder contractions and reduced reflexes in the bladder compared to wild type mice. Reflex voiding, thus implying that TRPV1 affects the function of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp856-860). TRPV1 is distributed not only in primary afferent sensory cells but also in keratinocytes of human epithelium (Denda et al., 2001, Biochem. Biophys. Res. Commun., 285, pp1250-1252; Inoue et al. , 2002, Biochem.Biophys.Res.Commun., 291, pp124-129), subsequently involved in the transmission of various noxious stimuli and pains such as skin irritation and pruritus, causing neurological and non-neural factors It is closely related to the pathogenesis of the disease. This is supported by the TRPV1 antagonist capsazepine, which inhibits inflammatory mediators in human skin cells (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp217-222).

In recent years, an increase in other roles of TRPV1 has been accumulated. TRPV1 may be involved in the regulation of blood flow / pressure and regulation of plasma glucose levels or the development of type 1 diabetes through sensory-active neuropeptide release (Inoue et al., Cir. Res., 2006, 99, pp119-31). Razavi et al., 2006, Cell, 127, pp1123-35; Gram et al., 2007, Eur. J. Neurosci., 25, pp213-23). Moreover, mice lacking TRPV1 showed less stress-related behavior than wild type herds and had no difference in exercise (Marsch et al., 2007, J. Neurosci., 27 (4), pp832-9). Recently, the relationship between TRPV1 and obesity has also been reported. TRPV1 null mice have lost weight and are reported to have adiposity in higher fat diets (Motter et al., 2008, FEBS lett., 582, pp2257-2262). . Moreover, TRPV1 expressing neurons play a role in type 1 diabetes mellitus (T1DM), and occlusion of TRPV1 by small molecule antagonists has been reported to improve insulin resistance in a rat model of type 2 diabetes mellitus (T2DM) (Suri et al. al., 2008, Trends Pharmacol. l Sci. 29 (1), pp 29-36; Gunthorpe et al., 2008, Curr. Pharm. Des., 14, pp 32-41).

Based on the information mentioned above, various TRPV1 antagonist development is underway, and several patents and patent applications related to the TRPV1 antagonist under development have been published (Szallasi et al., 2007, Nat. Rev. Drug Discov., 6, pp357-). 72; Appendino et al., 2006, Progress in Medicinal Chemistry, 44, pp 145-180; Rami et al., 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp97-104; Correll et al., 2006, Expert Opin. Ther. Patents, 16, pp783-795; Kyle et al., 2006, Expert Opin.Ther. Patents, 16, pp977-996; Gunthorpe et al., 2008, Curr. Pharm.Des., 14, pp32-41) .

The compounds of the present invention are useful for the prevention and treatment of diseases associated with the activity of TRPV1 (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369), acute pain, chronic pain, neurological pain, postoperative pain , Pains such as rheumatoid arthritis pain, arthritis pain, posterior neuralgia, neuralgia, headache, toothache, pelvic pain, migraine, bone cancer pain, breast pain and visceral pain ((Petersen et al., 2000, Pain 88, Walker et al., 2003, J. Pharmacol.Exp. Ther., 304, pp56-62; Morgan et al., 2005, J. Orofac.Pain, 19, pp248-60; Dinis et al., 2005, Eur.Urol., 48, pp 162-7; Akerman et al., 2004, Br. J. Pharmcol., 142, pp 1354-1360; Ghilardi et al., 2005, J. Neurosci., 25, 3126-31 Gopinath et al., 2005, BMC Womens Health, 5, 2-9); neurological disorders such as neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration and stroke (Park et al., 1999, Arch. Pharm.Res. 22, pp 432-434, Kim et al., 2005, J. Neurosci. 25 (3), pp 662-671); Diabetic peripheral neuropathy (Kamei et al., 2001, Eur. J. Pharmacol. 422, pp83-86); fecal urgency; irritable bowel syndrome (Chan et al., 2003, Lancet, 361, pp385-) 391); inflammatory bowel disease (Yiangou et al., 2001, Lancet 357, pp1338-1339); gastrointestinal diseases such as gastroesophageal reflux disease (GERD), gastric duodenal ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm., 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320); Respiratory diseases such as asthma, chronic obstructive pulmonary disease, cough (Hwang et al., 2002, Curr. Opin. Pharmacol. Pp235-242; Spina et al., 2002, Curr. Opin. Pharmacol. Pp264-272; Geppetti et al , 2006, Eur. J. Pharmacol., 533, pp 207-214; McLeod et al., 2006, Cough, 2, 10); Urinary incontinence (Birder et al., 2002, Nat. Neuroscience 5, pp856-860); Urinary bladder hypersensitivity (Birder et al., 2001, PNAS, 98, pp13396-13401); Neurotic / allergic / inflammatory skin diseases such as psoriasis, pruritus, prurigo and dermatitis (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp217-222); Hypersensitivity (Hyperacusis); tinnitus; Vestibular hypersensitiveness (Balaban et al., 2003, Hear Res. 175, pp 165-70); Heart diseases such as myocardial ischemia (Scotland et al., 2004, Circ.Res. 95, pp 1027-1034; Pan et al., 2004, Circulation 110, pp1826-1831); Haemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245 (6), pp964-70); Hair growth-related diseases such as hirsutism, effluvium, and alopecia (Bodo 'et al., 2005, Am. J. Patho. 166, pp985-998; Biro' et al., 2006, J Invest.Drmatol.pp1-4); Rhinitis (Seki et al., 2006, Rhinology, 44, pp 128-34); Pancreatitis (Hutter et al., 2005, Pancreas, 30, pp 260-5); Cystitis (Dinis et al., 2004, J. Neurosci., 24, pp11253-63; Sculptoreanu et al., 2005, Neurosci. Lett. 381, pp42-6); Vulvodynia (Tympanidis et al., 2004, Eur. J. Pain, 8, pp 12-33); Mental disorders such as tension or fear (Marsch et al., 2007, J. Neurosci., 27 (4), pp832-9); Obesity (Motter et al., 2008, FEBS lett., 582, pp2257-2262); T1DM and T2DM (Suri et al., 2008, Trends Pharmacol.l Sci. 29 (1), pp29-36; Gunthorpe et al., 2008, Curr. Pharm. Des., 14, pp32-41) However, it is not limited thereto.

Compounds associated with VR1 activity are described, for example, in WO 02/61317, WO 02/090326, WO 02/16318, WO 02/16319, WO 03/053945, WO 03/099284, WO 03/049702, WO 03/049702, WO 03/029199, WO 03/70247, WO 04/07495, WO 04/72068, WO 04/035549, WO 04/014871, WO 04/024154, WO 04/024710, WO 04/029031, WO 04/089877, WO 04/089881, WO 04/072069, WO 04/111009, WO 05/03084, WO 05/073193, WO 05/051390, WO 05/049613, WO 05/049601, WO 05/047280, WO 05/047279, WO 05/044802, WO 05/044786, WO 06/097817, WO 06/098554, WO 06/100520, WO 06/101321, WO 06/102645, WO 06/103503, WO 06/111346, WO 06/101321, WO 06/101318, WO 06/1113769, WO 06/116563, WO 06/120481, WO 06/122250, WO 06/122799, WO 06/129164, WO 06/51378, WO 06/95263, WO 07/42906, WO 07/45462, WO 07/50732, WO 07/54474, WO 07/54480, WO 07/63925. WO 07/65663, WO 07/65888, WO 07/67619, WO 07/67710, WO 07/67711, WO 07/67756, WO 07/67757, WO07 / 63925, WO07 / 65662, WO07 / 65663, WO07 / 65888 , WO07 / 69773, US20070149517 or US20070149513.

Accordingly, it is an object of the present invention to provide novel compounds, isomers or pharmaceutically acceptable salts thereof that can be used as potent TRPV1 antagonists; And it provides a pharmaceutical composition comprising the same.

One embodiment of the present invention is a compound having the following general formula (I):

(I)

(I)

Or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X, Y and Z are independently CH, CH ₂ , O or C = O,

R ₁ is hydrogen, halogen or C ₁ -C ₅ alkyl,

R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, nitro, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halo (C ₁ -C ₅ ) alkyl, C _2- C ₅ alkenyl or C ₂ -C ₅ alkynyl,

R _6, R ₇ , R ₈ and R ₉ are independently hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, halo (C ₁ -C ₁₀ ) alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, carboxy, C ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkynylcarbonyl, substituted or unsubstituted phenyl or C ₁ -C ₁₀ alkylamino,

은 단일 또는 이중 결합이다.

Is a single or double bond.

In one embodiment, with respect to any of the embodiments mentioned above and below, R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl and R _6, R ₇ , R ₈ and R ₉ are independently hydrogen, halogen, C ₁ -C ₅ alkyl or Halo (C ₁ -C ₃ ) alkyl.

In one embodiment, with respect to any of the above and below embodiments, when X is CH, Y is CH ₂ , Z is O, Z is C = O when X is O and Y is CH, and Z is CH ₂ when X is O and Y is CH ₂ .

In one embodiment, with respect to any of the above and below embodiments, R ₁ is hydrogen or methyl, R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, fluorine, chlorine, bromine, cya O, methyl, trifluoromethyl, vinyl or acetylenyl, R ₆ is Hydrogen, R ₇ and R ₈ are independently hydrogen, chloro, bromo, iodo, C ₁ -C ₄ alkyl or halo (C ₁ -C ₂ ) alkyl, and R ₉ is hydrogen.

In one embodiment, with respect to any of the above and below embodiments, R ₁ is hydrogen or methyl, R ₂ is hydrogen, R ₃ and R ₄ are independently hydrogen, fluoro, cyano, Methyl, trifluoromethyl, vinyl or acetylenyl, R ₅ is hydrogen, R ₆ is hydrogen, R ₇ and R ₈ are independently hydrogen, chlorine, bromine, isopropyl, tert-butyl or trifluoromethyl And R ₉ is hydrogen.

Preferred examples of compounds according to the invention are selected from the group consisting of:

6-chloro-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

6-tert-butyl-4-oxo-4H-chromen-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

6-tert-butyl-chroman-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,

6-tert-butyl-chroman-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

6-trifluoromethyl-chroman-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,

6-trifluoromethyl-chroman-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

6-tert-butyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

6-Bromo-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-isopropyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-tert-butyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-methyl-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid [1- (3-fluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-cyano-5-fluoro-4-methanesulfonylamino-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-vinyl-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide,

7-tert-butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide,

7-trifluoromethyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-trifluoromethyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide,

7-trifluoromethyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-vinyl-benzylamide,

7-trifluoromethyl-2H-chromen-3-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide,

7-trifluoromethyl-2H-chromen-3-carboxylic acid [1- (3-fluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide,

7-isopropyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide,

7-isopropyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide, and

7-tert-Butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-benzylamide.

Another embodiment of the invention relates to the use of a therapeutic agent of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.

The compound of formula (I) of the present invention can be chemically synthesized by the following scheme. However, these are presented to illustrate the invention, but are not limited thereto.

Scheme 1

Scheme 1 shows a proposed process for the synthesis of amide compound (3) having various substituents. Using DMTMM {4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride} variously substituted benzylamines (1) By reaction with substituted phenylacrylic acid (2), benzyl amide (3) is produced (Tetrahedron Lett., 1999 , 40, 5327).

Scheme 2

Scheme 2 shows a proposed procedure for the synthesis of chromaman 2-carboxylic acids (6) having various substituents. Phenolic compound (4) with various substituents was reacted with dimethyl acetylenedicarboxylate and benzyltrimethylammonium hydroxide in a 1,4-dioxane solvent and then cyclized using Eaton's reagent, Conversion to the corresponding 4-oxo-4H-chromen-2-carboxylic acid (5). Substituted 4-oxo-4H-chromen-2-carboxylic acid (5) is then reduced to chromaman 2-carboxylic acid (6) with various substituents using Pd / C in hydrogen, acid solution.

 Scheme 3

Scheme 3 shows the process of synthesizing 2H-chromen-3-carboxylic acid (8) having various substituents. Substituted 2-hydroxy-benzaldehyde (7) with tert-butyl acrylate and t-BuOK in t-BuOH to give tert-butyl 2H-chromen-3-carboxylate, 1N LiOH or trifluoro Hydrolysis with roacetic acid affords the corresponding 2H-chromen-3-carboxylic acid ( 8 ).

 Scheme 4

Scheme 4 shows the process for the synthesis of substituted 2-hydroxy-4-trifluoromethyl benzaldehyde (10). Substituted 2-fluoro-4-trifluoromethyl-benzaldehyde (9) substituted the fluoro group with a methoxy group using NaOMe in MeOH and then deprotected the methoxy group using LiCl in DMF to give a corresponding 2- Converted to hydroxy-4-trifluoromethyl benzaldehyde (10).

Scheme 5

Scheme 5 shows an alternative procedure for the synthesis of substituted 2-hydroxy-benzaldehyde (7). Substituted phenol (11) is converted to the corresponding 2-hydroxy-benzaldehyde (7) by reaction with titanium tetrachloride and methyl dichloromethyl ether in dichloromethane.

Another embodiment of the invention relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Another embodiment of the present invention relates to a pharmaceutical composition for preparing or treating a condition associated with pathogenic stimulation and / or abnormal expression of vanilloid receptors, the composition comprising a compound of formula (I), an isomer thereof, or a pharmaceutical thereof Acceptable salts and pharmaceutically acceptable carriers.

In the pharmaceutical composition, the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier may be used for pain, arthritis disease, neuropathy, HIV-related neuropathy, nerve injury. Urinary bladder hypersensitivity, including neurodegeneration, stroke, urinary incontinence, cystitis, gastroduodenal ulcer, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD), urgency, gastroesophageal reflux disease ( GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathy / allergy / inflammatory skin disease, atopic dermatitis, psoriasis, pruritus, positive, deafness, tinnitus, vestibular hypersensitivity, episodic vertigo, myocardial ischemia It is present in an amount effective for preventing or treating hair growth related diseases such as heart disease, effluvium, alopecia, rhinitis and pancreatitis.

In the stomach, the pain is osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine and The condition is selected or associated with a group of other types of headaches.

Another embodiment of the invention relates to the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic agent.

In a preferred embodiment, the invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable thereof for the preparation of a therapeutic for the prophylaxis or treatment of a condition associated with abnormal expression and / or abnormal activity of vanilloid receptors. It relates to the use of salts.

In a particularly preferred embodiment, the invention relates to pain, arthritis diseases, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary bladder hypersensitivity, including cystitis, gastroduodenal ulcers, irritable bowel syndrome : IBS) and inflammatory bowel disease (IBD), defecation, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurosis / allergy / inflammatory skin disease, atopic dermatitis, psoriasis Selected from the group consisting of pruritus, positivity, deafness, tinnitus, vestibular hypersensitivity, episodic vertigo, heart disease such as myocardial ischemia, hair growth-related diseases such as alopecia, rhinitis and pancreatitis Regarding the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent for the prevention or treatment of a condition Will.

In the stomach, the condition is osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial syndrome and back pain), visceral pain, migraine and Pain associated with a condition or condition selected from the group consisting of other types of headaches.

Another embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, which is applied for oral administration.

Another embodiment of the present invention provides a method in which a vanilloid ligand is vanilloid in a patient comprising contacting a cell expressing a vanilloid receptor with a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof. A method of inhibiting binding to a receptor.

Another embodiment of the present invention is pain, arthritis disease, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary bladder hypersensitivity, including cystitis, gastroduodenal ulcer, irritable bowel syndrome : IBS) and inflammatory bowel disease (IBD), defecation, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurosis / allergy / inflammatory skin disease, atopic dermatitis, psoriasis , Pruritus, positive, deafness, tinnitus, vestibular hypersensitivity, episodic vertigo, heart disease such as myocardial ischemia, hair growth related diseases such as alopecia, alopecia, rhinitis, pancreatitis, vulva, bleeding A method for preventing or treating a condition selected from the group consisting of shock, and mental disorders such as tension or fear, the method comprising: Comprising administering a compound acceptable salts, isomers, or a pharmaceutical thereof, of formula (I) of hyoryang.

In a particularly preferred embodiment, the present invention relates to a method of treating pain by administering the aforementioned compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pain is osteoarthritis. , Rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, other types of headache, bone cancer, breast pain and It is selected or associated with a group of visceral pain.

Here, the formulation method and the type of excipient will be described, but the present invention is not limited thereto.

Compounds of formula (I), isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention may be prepared as pharmaceutical compositions comprising pharmaceutically acceptable carriers, adjuvants, diluents and the like. For example, the compounds of the present invention can be dissolved in oil, propylene glycol or other commonly used solvents to prepare injectables. Suitable examples of carriers include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, and the like. For topical administration, the compounds of the present invention may be formulated in ointment or cream form.

The compounds of the present invention can be used as pharmaceutically acceptable salts thereof, and can be used alone or in combination or in combination with other pharmaceutically active compounds.

The compounds of the present invention may be formulated for injection by dissolving, suspending or emulsifying in water-soluble solvents such as saline and 5% dextrose or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glycerides, higher fatty acid esters and propylene glycol. have. Formulations of the present invention may include any conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

Preferred dosages of the compounds according to the invention may vary depending on a variety of factors, including the condition and weight of the patient, including the severity of the particular disease, the dosage form and route, and the duration of administration, but one of ordinary skill in the art can select as appropriate. The compounds of the present invention are preferably administered in an amount in the range of 0.001 to 100 mg / kg of body weight per day, more preferably in an amount in the range of 0.01 to 30 mg / kg of the body per day. Dosages may be administered once daily, or several times daily with each divided portion. The compounds of the present invention are used in pharmaceutical compositions in amounts of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total amount of the composition.

The pharmaceutical composition of the present invention can be administered to mammalian subjects such as rats, mice, livestock animals, humans, etc. through various routes. Dosage methods include oral, rectal administration; It is readily contemplated to include intravenous, intramuscular, subcutaneous, intrauterine, subcutaneous and cerebrovascular injections.

Compounds according to the invention are pain, arthritis diseases, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, gastric duodenal ulcer, irritable bowel syndrome (IBS) And inflammatory bowel disease (IBD), urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurosis / allergy / inflammatory skin disease, atopic dermatitis, psoriasis, pruritus, It is useful for the prevention or treatment of dysphagia, deafness, tinnitus, vestibular hypersensitivity, episodic vertigo, heart disease such as myocardial ischemia, hair growth-related diseases such as alopecia, alopecia, rhinitis and pancreatitis.

More specifically, the compounds according to the present invention are degenerative arthritis (osteoarthritis), rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain) , Visceral pain, migraine, or other type of headache, selected from the group of or useful for the prevention or treatment of pain associated therewith.

When describing the compound, the pharmaceutical composition comprising the compound, the method of using the compound and the composition, and the use of the compound and the composition, all terms used in the present application are used by those skilled in the relevant art such as a pharmacist, pharmacist or doctor. It may have a meaning that is usually applied. Exemplary definitions for specific groups are as described below:

"Alkyl" means a monovalent saturated aliphatic hydrocarbon group, which hydrocarbon may have a straight or branched structure. "Alkyl" is preferably 1-15 carbon atoms ("C ₁ -C ₁₅ alkyl"), more preferably 1-10 carbon atoms ("C ₁ -C ₁₀ alkyl"), more preferably 1-8 Carbon atoms (“C ₁ -C ₈ alkyl”) or 1-6 carbon atoms (“C ₁ -C ₆ alkyl”), and in some instances more preferably 1-5 carbon atoms (“C ₁ -C ₅ Alkyl "), 1-4 carbon atoms (" C ₁ -C ₄ alkyl ") or 1-3 carbon atoms (" C ₁ -C ₃ alkyl "). This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, t-amyl and the like.

"Alkoxy" includes an -OR group, wherein R is "alkyl" as defined above. Specific alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1,2-dimethylbutoxy and the like. Include.

“Alkoxycarbonyl” means a radical —C (═O) —O—R, wherein R is an alkyl group as previously defined.

"Alkenyl" includes straight or branched monovalent olefin unsaturated hydrocarbyl groups and has one or more double bonds. "Alkenyl" is preferably 2-15 carbon atoms ("C ₂ -C ₁₅ alkenyl"), more preferably 2-10 carbon atoms ("C ₂ -C ₁₀ alkenyl"), more preferably 2-8 Carbon atom (“C ₂ -C ₈ alkenyl”) or 2-6 carbon atoms (“C ₂ -C ₆ alkenyl”), and in some embodiments more preferably 2-5 carbon atoms (“C ₂ -C”). ₅ alkenyl "), 2-4 carbon atoms (" C ₂ -C ₄ alkenyl "), or 2-3 carbon atoms (" C ₂ -C ₃ alkenyl "). Specific alkenyl groups include ethenyl (-CH = CH ₂ ), n-propenyl (-CH ₂ CH = CH ₂ ), isopropenyl ((CH ₃ ) C = CH ₂ ), and the like. Preferred "alkenyl" groups are ethenyl (vinyl).

"Alkynyl" includes straight chain or branched acetylene unsaturated hydrocarbyl groups and has one or more triple bonds. "Alkynyl" is preferably 2-15 carbon atoms ("C ₂ -C ₁₅ alkynyl"), more preferably 2-10 carbon atoms ("C ₂ -C ₁₀ alkynyl"), more preferably 2-8 Carbon atoms (“C ₂ -C ₈ alkynyl”) or 2-6 carbon atoms (“C ₂ -C ₆ alkynyl”), and in some embodiments more preferably 2-5 carbon atoms (“C ₂ -C” ₅ alkynyl "), 2-4 carbon atoms (" C ₂ -C ₄ alkynyl "), or 2-3 carbon atoms (" C ₂ -C3 alkynyl "). Preferred alkynyl groups are ethynyl (acetylenyl).

"Alkylamino" includes the group -NHR ', wherein R' is an alkyl group as previously defined.

"Amino" means radical-NH _{2 .}

"Aryl" means aromatic hydrocarbyl radical. Examples of "aryl" radicals are phenyl, naphthyl, indenyl, azulenyl, florin or anthracene, with phenyl being preferred.

"Carboxy" means the radical -C (= 0) OH.

"Cyano" means the radical -C≡N _.

"Ethenyl" means -CH = CH ₂ and is also referred to herein as "vinyl".

"Ethinyl" means -C≡CH.

"Halo" or "halogen" means fluorine, chlorine, bromine and iodine. Preferred halogen groups are fluorine or chlorine.

"Alloalkyl" includes those in which an alkyl group as previously defined is substituted with one or more halogens, and may be the same or different, for example, trifluoromethyl or pentafluoroethyl.

"Nitro" means radical-NO ₂ .

“Isomers” in particular are not only optical isomers (eg essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof), but also structural isomers (ie, the angle of one or more chemical bonds). Isomers, only positional isomers (particularly tautomers) and geometric isomers.

For example, “essentially pure” associated with the enantiomers and stereoisomers is a specific compound, for example at least about 90%, preferably at least about 95%, more preferably at least about 97%, more preferably at least about 98% , More preferably at least about 99%, more preferably at least about 99.5% (w / w) enantiomer or stereoisomer.

"Pharmaceutically acceptable" means that when used in an amount generally applied in the administration of the drug, a substantial toxic effect can be avoided, and thus approved or otherwise approved by the federal or state government, or It may be on the US Pharmacopoeia list for use in animals and especially humans, or on another commonly recognized list of pharmacopeias.

"Pharmaceutically acceptable salt" means a pharmaceutically acceptable salt of a compound according to the invention and retains the desired weakness of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid , 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3 Acid addition formed by organic acids such as phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like salt; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

"Pharmaceutically acceptable carrier" means that a diluent, adjuvant, excipient or carrier is administered with a compound according to the invention.

"Prevention" or "prevention" means reducing the risk of acquiring a disease or disorder (ie, causing clinical signs of one or more diseases to not develop in an individual, and the disease may be exposed or deposited) They have not yet experienced or are exposed to signs of the disease).

"Object" includes humans. The terms "human", "patient" and "individual" are used interchangeably herein.

A “therapeutically effective amount” means that when administered to a subject to treat a disease, the amount of the compound is sufficient to produce a therapeutic effect on the disease. A "therapeutically effective amount" can vary depending on the compound, the severity of the disease and disorder, and the age and weight of the subject being treated.

"Treating" or "treatment" of a disease or condition means, in one embodiment, that the disease or condition is ameliorated (ie, stops or reduces the development of the disease or one or more clinical signs thereof). In another embodiment, “treating” or “treatment” means alleviating one or more physical parameters that may not be identified in the subject. In another embodiment, “treating” or “treatment” refers to either or both of the disease or condition physically (eg, stabilization of the identified signs) or physiologically (eg, stabilization of physical parameters), or both. It means to include everything. In another embodiment, "treating" or "treatment" means delaying the onset of the disease or condition.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are provided to illustrate the present invention, and the scope of the present invention is not limited thereto.

Various benzyl amine salts used for the preparation of compounds in the examples were prepared according to the following procedure described in WO 02/16318, WO 06/101318 and WO08 / 013414.

In the examples various acids used for the preparation of the compounds were synthesized as described below.

6-tert-butyl-chroman-2-carboxylic acid (7a) was prepared by the procedure described below.

4-tert-butylphenol (4.4 g, 29 mmol), dimethylacetylenecarboxylate (4 ml, 32.5 mmol) in 1,4-dioxane (60 ml), benzyltrimethylammonium hydroxide (40 wt% in MeOH, 120 μL) was stirred at 90 ^° C. for 2 hours. The reaction mixture was cooled to room temperature, to which NaOH solution (20%, 25 ml) was added and stirred for 1.5 h while heating at 90 ^° C. The mixture was cooled to 0 ^° C. and then 2N HCl was added until pH was 3. The solvent was evaporated under reduced pressure and ethyl acetate was added to give a white solid which was filtered off. The filtrate was dried over anhydrous MgSO ₄ , filtered and concentrated to give a yellow solid. The solid was treated with Eaton reagent (38 ml) at 70 ^° C. for 14 hours. The mixture was poured into iced water to give a solid product which was separated by suction filter and washed with EtOAc. A mixture of Pd-C was added to a solution of the compound in EtOH (100 ml) and AcOH (10 ml), stirred at 50 atm H ₂ for 1 day, filtered through a celite pad and concentrated under reduced pressure to give 980 mg of pale Drinking powder 6-tert-butyl-chroman-2-carboxylic acid (7a) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.2 (bs, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.90 (d, 1H, J = 6.6 Hz), 4.72 (m, 1H) , 2.84 (m, 2H), 2.36 (m, 1H), 2.19 (m, 1H), 1.29 (s, 9H).

6-Trifluoromethyl-chroman-2-carboxylic acid (9a) was prepared according to a method similar to the preparation of 7a, including 4-trifluoromethylphenol.

9a

9a

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 7.52 (m, 1H), 7.06 (m, 1H), 4.95 (m, 1H), 2.89 (m, 2H), 2.51 (m, 1H), 2.39 (m, 1H).

Compounds 11a-15a were prepared by the procedure described below.

To the solution of 5-tert-butylsalicylaldehyde (1.00 g, 5.61 mmol) and t-butyl acrylate (2.0 mL, 13.5 mmol) in t-butanol (10 mL) was added t-BuOK (192 mg, 1.70 mmol). The resulting mixture was heated at reflux for 66. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The organic layer was washed successively with water, 1N NaOH and brine, dried over anhydrous MgSO ₄ and then evaporated under reduced pressure. The concentrate was purified by column chromatography (Hex / EtOAc = 8/1) to give 6-tert-butyl-2H-chromen-3-carboxylic acid tert-butyl ester (60 mg, 4%). The butyl ester was dissolved in THF (1.0 mL) and methanol (1.0 mL) and then hydrolyzed with 1N LiOH (2.0 mL) for one day. After acidification with 1N HCl, the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , and evaporated to give 6-tert-butyl-2H-chromen-3-carboxylic acid (40 mg, 83%).

Compound 25a was prepared by the procedure described below.

A mixture of NaOMe (12.5 g, 231 mmol) and 2-fluoro-4-trifluoromethylbenzaldehyde (5.0 g, 26 mmol) in MeOH (80 ml) was heated at reflux for 4 hours and then at 50 ^° C. Heated for 4 hours. The reaction was quenched with water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and evaporated under reduced pressure. The concentrate was purified by column chromatography (5% to 40% EtOAC in hexanes) to give 2-methoxy-4-trifluoromethyl-benzaldehyde (3.54 g, 67%). Aldehyde and LiCl (2.18 g, 51.4 mmol) were dissolved in DMF (35 mL) and then heated at 150 ^° C. for one day. After cooling to room temperature, the reaction mixture was partitioned between ether and 2N HCl. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and then evaporated. The concentrate was purified by column chromatography (2% to 30% EtOAC in hexanes) to afford 2-hydroxy-4-trifluoromethyl-benzaldehyde (2.12 g, 64%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 11.08 (s, 1H), 9.99 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.27 (m, 2H).

7-trifluoromethyl-2H-chromen-3-carboxylic acid (25a) was prepared from 2-hydroxy-4-trifluoromethyl-benzaldehyde, as described in the synthesis of compound 11a.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.37 (s, 1H), 7.22 (d, 1H, J = 7.8 Hz), 7.10 (d, 1H, J = 7.8 Hz), 7.02 (s, 1H), 5.01 (s, 2H).

A general coupling procedure exemplified by the synthesis of 6-fluorochromone-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide is described below. Same as

( R ) -N- [4- (1-amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide, HF salt (100 mg, 0.35 mmol) in a THF (8 mL) suspension of N Methylmorpholine (60 μL, 0.55 mmol) was added. The mixture was stirred for 5 minutes, to which 6-fluorochromone-2-carboxylic acid (73 mg, 0.35 mmol) and DMTMM (96.5 mg, 0.35 mmol) were added. The mixture was stirred at rt for 1 day and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (concentration 50% -67% EtOAc in hexanes) to give 6-fluorochromone-2-carboxylic acid [1- (3,5-difluoro-4-methanesulphate). Ponylamino-phenyl) -ethyl] -amide (12 mg) was obtained.

Example 6: 6-Fluoro-chroman-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide (PAC-14543)

( R ) -N- [4- (1-amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide, HF salt (100 mg, 0.35 mmol) in a THF (8 mL) suspension of N Methylmorpholine (60 μL, 0.55 mmol) was added. The mixture was stirred for 5 minutes, to which 6-fluorochroman-2-carboxylic acid (69 mg, 0.35 mmol) and DMTMM (96.5 mg, 0.35 mmol) were added. The mixture was stirred at rt for 1 day and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (concentration 50% to 67% EtOAc in n-hexane) to give the title compound (29.8 mg, 20%).

¹ H NMR (300MHz, DMSO-d ⁶ ): mixture of diasteromers δ 9.50 to 9.46 (m, 1H), 8.51 to 8.46 (m, 1H), 7.20 to 7.16 (m, 1H), 7.06 to 7.02 (m, 1H ), 6.98 to 6.89 (m, 3H), 5.04 to 4.92 (m, 1H), 4.62 to 4.54 (m, 1H), 3.05 to 3.03 (m, 3H), 2.88 to 2.60 (m, 2H), 2.18 to 1.83 (m, 2H), 1.41-1.36 (m, 3H).

The compounds of Examples 7-32 were prepared by the general coupling procedure mentioned above.

Experimental Example: Biological Potency Test

One. ⁴⁵  Ca inflow test

1) Dorsal root ganglia (DRG) and its primary culture in newborn rats

Newborn (2-3 days old or younger than 2-3 days) SD rats were anesthetized on ice for 5 minutes and disinfected with 70% ethanol. All portions of spinal cord DRG were dissected (Wood et al., 1988, J. Neurosci. 8, pp3208-3220) and collected in DME / F12 medium added with 1.2 g / l sodium bicarbonate and 50 mg / l gentamycin. DRG was incubated in turn with 200 U / ml collagenase and 2.5 mg / ml trypsin, respectively, at 37 ° C. for 30 minutes. Ganglia were washed twice with DME / F12 medium with 10% equine serum, triturated through a fire-polished paster pipette, filtered through a Nitex 80 membrane to obtain a single cell suspension, and the suspension was 1 Washed more times. It was centrifuged and then suspended again in the cell culture medium to a predetermined level of cell density. Like cell culture medium, DME / F12 medium with 10% equine serum was diluted in the same medium under two-day C6 glycoma cell conditions in fusion monolayers (1: 1), and final by adding Nerve Growth Factor (NGF) The concentration was adjusted to 200 ng / ml. After the cells grew in medium for 2 days, differentiated non-neuronal cells were killed by adding cytosine arabinoside (Ara-C, 100 μM), and the medium was changed to one without Ara-C. Resuspended cells were plated at a density of 1500-2000 neurons / well on a Terrasaki plate already coated with 10 μg / ml poly-D-ornithine.

2) ⁴⁵  Ca inflow experiment

DRG neurons primary cultured for 2 days were equilibrated by washing with HBSS (H-HBSS) free of HEPES (10 mM, pH 7.4) -buffered Ca ²⁺ , Mg ²⁺ . The solution in each well was removed from the individual wells. A test compound in H-HBSS and a medium containing capsaicin and ⁴⁵ Ca (final concentration .5 μM) were added to each well and incubated for 10 minutes at room temperature. Terrasaki plates were washed 5 times with H-HBSS and dried at room temperature. 0.3% SDS (10 μl) was added to each well and ⁴⁵ Ca was dissolved. After adding a scintillation cocktail to each well, the amount of ⁴⁵ Ca introduced into the nerve was measured by calculating the radioactivity. Antagonist activity of the test compound against the vanilloid receptor was calculated as the percentage of maximum response inhibition of capsaicin at a concentration of 0.5 μM.

[Table 1] Calcium influx test results

2. Analgesic Activity Test: Phenyl-p-quinone Induced Mouse Writhing Test

Male ICR mice (average 25 g body weight) were preserved in a controlled light environment (12 h on / 12 h off) for the experiment. 0.3 ml of the chemical stimulant phenyl-p-quinone (dissolved in saline containing 5% ethanol to a dose of 4.5 mg / kg) was injected intraperitoneally, and 6 minutes later abdominal constriction recovery was performed for the next 6 minutes. Measured. Animals (10 / group) received 0.2 ml of test compound solution in ethanol / twin 80 / saline (10/10/80) carrier 30 minutes prior to injection of phenyl-p-quinone. For oral administration, a test compound solution was administered 54 minutes prior to 0.2 ml of 0.02% phenyl-p-quinone injection in a carrier of ethanol / twin 80 / saline (5/5/90). The reduction in the number of twist reactions for the test formulation compound against the number of reactions in the saline control group was determined to have an analgesic effect. The analgesic effect was calculated with the percent inhibition formula (% inhibition = (C-T) / C × 100), where C and T represent the number of distortions in the control and compound treatment groups, respectively (Table 2).

TABLE 2 Analgesic activity test results for distortion by phenyl-p-quinone (administration route (oral: p.o.))

Those skilled in the art to which the present invention pertains will be able to perform various applications and modifications within the scope of the present invention based on the above contents.

Claims (15)

A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof;

(I) Where X, Y and Z are independently CH, CH ₂ , O or C = O, R ₁ is hydrogen, halogen or C ₁ -C ₅ alkyl, R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, nitro, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halo (C ₁ -C ₅ ) alkyl, C _2- C ₅ alkenyl or C ₂ -C ₅ alkynyl, R _6, R ₇ , R ₈ and R ₉ are independently hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, halo (C ₁ -C ₁₀ ) alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, carboxy, C ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkynylcarbonyl, substituted or unsubstituted phenyl or C ₁ -C ₁₀ alkylamino,

Is a single or double bond. The method of claim 1, R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl or C _2- A compound of Formula (I), isomer thereof _, wherein C ₅ alkynyl and R _6, R ₇ , R ₈ and R ₉ are independently hydrogen, halogen, C ₁ -C ₅ alkyl or halo (C ₁ -C ₃ ) alkyl Or a pharmaceutically acceptable salt thereof. The method of claim 1, When X is CH, Y is CH ₂ , Z is O, Z is C = O when X is O and Y is CH, When X is O and Y is CH ₂ Z is CH ₂ A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, R ₁ is hydrogen or methyl, R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, vinyl or acetylenyl, R ₆ is Hydrogen, R ₇ and R ₈ are independently hydrogen, chloro, bromo, iodo, C ₁ -C ₄ alkyl or halo (C ₁ -C ₂ ) alkyl, R ₉ is hydrogen, a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen, R ₃ and R ₄ are independently hydrogen, fluoro, cyano, methyl, trifluoromethyl, vinyl or acetylenyl, R ₅ is hydrogen, R ₆ is hydrogen, R ₇ and R ₈ are independently hydrogen, chlorine, bromine, isopropyl, tert-butyl or trifluoromethyl, R ₉ is hydrogen, a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 1, The compound is 6-chloro-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 6-tert-butyl-4-oxo-4H-chromen-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 6-tert-butyl-chroman-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide, 6-tert-butyl-chroman-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 6-trifluoromethyl-chroman-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide, 6-trifluoromethyl-chroman-2-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 6-tert-butyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 6-Bromo-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-isopropyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-tert-butyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-methyl-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid [1- (3-fluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-cyano-5-fluoro-4-methanesulfonylamino-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-vinyl-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylamide, 7-tert-butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide, 7-trifluoromethyl-2H-chromen-3-carboxylic acid [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-trifluoromethyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide, 7-trifluoromethyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-5-vinyl-benzylamide, 7-trifluoromethyl-2H-chromen-3-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide, 7-trifluoromethyl-2H-chromen-3-carboxylic acid [1- (3-fluoro-4-methanesulfonylamino-phenyl) -ethyl] -amide, 7-isopropyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide, 7-isopropyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide, and 7-tert-butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-benzylamide A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. A compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof, used as a therapeutic agent. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The method of claim 8, The composition is a pharmaceutical composition, characterized in that for preventing or treating a condition associated with pathological stimulation and / or abnormal expression of vanilloid receptor. The method of claim 8, The composition includes pain, arthritis diseases, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, gastroduodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel Inflammatory bowel disease (IBD), defecation, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurosis / allergic / inflammatory skin disease, atopic dermatitis, psoriasis Selected from the group consisting of pruritus, positivity, deafness, tinnitus, vestibular hypersensitivity, episodic vertigo, heart disease such as myocardial ischemia, hair growth-related diseases such as alopecia, rhinitis and pancreatitis A pharmaceutical composition, for treating a condition. The method of claim 10, The pain may include osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine and other types Pharmaceutical composition, characterized in that associated with the condition or selected from the group consisting of headache. Use of a compound according to any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent. Use of a compound according to any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent for the prevention or treatment of a condition associated with abnormal expression and / or abnormal activity of the vanilloid receptor. . Pain, arthritis diseases, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, gastric duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease bowel disease (IBD), urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurosis / allergic / inflammatory skin disease, atopic dermatitis, psoriasis, pruritus, A condition selected from the group consisting of positive, deaf, tinnitus, vestibular hypersensitivity, episodic vertigo, heart disease such as myocardial ischemia, hair growth-related diseases such as alopecia, alopecia, rhinitis and pancreatitis A compound according to any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable thereof, for the preparation of a therapeutic agent for the prophylaxis or treatment of The use of. The method of claim 14, These conditions include osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic peripheral neuropathy pain, postoperative pain, toothache, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial syndrome and back pain), visceral pain, migraine and other types A condition selected from the group consisting of headaches or pain associated with a condition.