Aminotetralin-derived urea modulators of vanilloid VR1 receptor

Abstract

This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to β-aminotetralin-derived ureas that are potent antagonists or agonists of VR1 which are useful for the treatment and prevention of inflammatory and other pain conditions in mammals.

1 - 96 . (canceled)  
     
     
         97 . A method for preventing or treating a chronic-pain causing disease or condition, an acute-pain causing disease or condition, or a pulmonary dysfunction comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a substituent independently selected from the group consisting of hydrogen;  
 hydroxy; fluoro; and chloro; and C 1-8 alkanyloxy;  
 n is an integer from 1 to 3;  
 m is an integer from 0 to 3;  
 R 2  is independently selected from the group consisting of hydrogen; hydroxy;  
 C 1-8 alkanyl; C 2-8 alkenyl; C 1-8 alkylidenyl; C 1-8 alkylidynyl; fluoro; chloro; C 3-8 cycloalkanyl; phenyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkanyl, C 1-8 alkanyloxy, phenyl(C 1-8 )alkanyloxy, fluorinated alkanyl, cyano, nitro, amino, C 1-8 alkanylamino, and C 1-8 dialkanylamino; naphthyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkanyl, C 1-8 alkanyloxy, phenyl(C 1-8 )alkanyloxy, fluorinated alkanyl, cyano, nitro, amino, C 1-8  alkanylamino, and C 1-8 dialkanylamino; phenoxy optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkanyl, C 1-8 alkanyloxy, fluorinated alkanyl, cyano and nitro; and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;  
 L is a direct bond, C 1-8 alkandiyl, C 2-8 alkendiyl, C 1-8 alkyndiyl, or C 3-8 cycloalkandiyl;  
 R 3  is selected from the group consisting of naphthyl substituted with hydroxyl; quinolinyl optionally substituted with one or more substituents selected from the group consisting of methyl and chloro; quinolinyl-N-oxide; isoguinolinyl optionally substituted with one or more substituents selected from the group consisting of methyl and chloro and isoguinolinyl-N-oxide;  
 R 4  is selected from the group consisting of hydrogen and C 1-8 alkanyl;  
 R 5  is selected from the group consisting of hydrogen and C 1-8 alkanyl;  
 X is selected from the group consisting of O and S; and  
 enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.  
 
     
     
         98 . The method according to  claim 97  wherein said disease or condition causes inflammatory pain, burning pain, itch, urinary incontinence, or chronic obstructive pulmonary disease, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of claim  1 .  
     
     
         99 . The method for preventing according to  claim 97  wherein the disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders, inflammatory bowel diseases, pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, post-operative ileus, irritable bowel syndrome, Crohn's Disease, ulcerative colitis, cholecystitis, pancreatitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstrual cramps, cancer, and trauma, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of claim  1 .  
     
     
         100 . The method of  claim 97  wherein said therapeutically effective amount comprises a dose range of from about 0.001 mg to about 1,000 mg.  
     
     
         101 . The method of  claim 97  wherein said therapeutically effective amount comprises a dose range of from about 0.1 mg to about 500 mg.  
     
     
         102 . The method of  claim 97  wherein said therapeutically effective amount comprises a dose range of from about 1 mg to about 250 mg.  
     
     
         103 - 117 . (canceled)