Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Abstract

This present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. The present disclosure provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, heart disease and so on.

1 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a compound of formula (I), an isomer, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is hydrogen, methyl, or ethyl; 
 R 2  and R 3  are independently hydrogen, halogen, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, or acetylenyl; 
 R 4  is trifluoromethyl or fluoro; 
 R 5  is C2-C5 alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2 alkoxy (C1-C3) alkylamino, C2-C5 alkylamino, di(C1-C3 alkyl)amino, C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(C1-C3)alkyloxy; and 
 R 6  is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino, as an active ingredient and a pharmaceutically acceptable carrier. 
 
     
     
         17 . The pharmaceutical composition according to  claim 16 , for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors. 
     
     
         18 . The pharmaceutical composition according to  claim 16 , for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches. 
     
     
         20 . (canceled) 
     
     
         21 . A method of preventing or treating a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor, comprising administering an effective amount of a composition of  claim 16  to a subject in need thereof. 
     
     
         22 . A method of preventing or treating a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity, fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases, hair growth-related disorders, rhinitis and pancreatitis, comprising administering an effective amount of a composition of  claim 16  to a subject in need thereof. 
     
     
         23 . The method of  claim 22 , wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain, visceral pain, migraine, and other types of headaches. 
     
     
         24 . The method of  claim 22 , wherein the urinary bladder hypersensitivity is selected from the group consisting of urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). 
     
     
         25 . The method of  claim 22 , wherein the cardiac disease is myocardial ischemia. 
     
     
         26 . The method of  claim 22 , wherein the hair growth-related disorder is effluvium or alopecia. 
     
     
         27 . The method of  claim 23 , wherein the non-inflammatory musculoskeletal pain is selected from the group consisting of fibromyalgia, myofascial pain syndrome, and back pain.