Therapeutic compounds and methods of use thereof

Abstract

The invention provides a compounds and salts that are sodium channel modulators, as well as compositions containing such a compound or salt and therapeutic methods for using such a compound, salt, or composition.

We claim: 
     
         1 . A method of treating a disease or condition in a mammal selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
 (S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide; and   (S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide; or a pharmaceutically acceptable thereof.   
     
     
         2 . The method of  claim 1 , wherein said disease or condition is selected from the group consisting of acute pain, chronic pain, neuropathic pain, inflammatory pain, acute pain, chronic pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein said disease or condition is selected from the group consisting of pain associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation and ventricular fibrillation. 
     
     
         4 . A method of treating pain in a mammal by the inhibition of ion flux through a voltage-dependent sodium channel in the mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of:
 (S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide; and   (S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide; or a pharmaceutically acceptable thereof.   
     
     
         5 . A method of decreasing ion flux through a voltage-dependent sodium channel in a cell in a mammal, wherein the method comprises contacting the cell with a compound selected from the group consisting of:
 (S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;   (S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide; and   (S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide; or a pharmaceutically acceptable thereof.