Aryl substituted indoles and the use thereof

Abstract

The invention relates to aryl and heteroaryl substituted compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein G, R 1 , and Z 1 -Z 5 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

1 - 14 . (canceled) 
     
     
         15 . A compound of Formula VI: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, wherein
 G is G 1 , wherein 
 G 1  is 
 
       
         
           
           
               
               
           
         
       
       and
 G 2  is 
 
       
         
           
           
               
               
           
         
         m is 1; 
         p is 0, 1, 2, or 3; 
         R 7  is selected from the group consisting of 
         a) —C(═O)NR 10 R 11 , wherein R 10  and R 11  both are hydrogen; or R 10  is hydrogen and R 11  is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; 
         b) —C(═O)OR 12 , wherein R 12  is hydrogen or alkyl; 
         c) —(CH 2 ) n OR 13 , wherein n is 1-3 and R 13  is hydrogen; and 
         d) hydrogen; 
         R 8  and R 9  are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; or 
         —NR 8 R 9  is —NO 2 ; or 
         R 9  is hydrogen, R 7  is —(CH 2 ) n OR 13 , R 8  and R 13  together form a bridge —C(═O)— to form a heterocyclic ring, and m is 1, 2, or 3; 
         R 7a  is selected from the group consisting of 
         a) —(CH 2 ) q OH, wherein q is 1-5; 
         b) —C(═O)OR 12a , wherein R 12a  is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and 
         c) hydrogen; 
         R 8a  is hydrogen or a bond; 
         A is 
       
       
         
           
           
               
               
           
         
       
       wherein
 A 1  is optionally substituted aryl; 
 X is —O—; and 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; 
 R 1  is hydrogen; and 
 R 2 , R 3 , R 5 , and R 6  are each independently selected from the group consisting of hydrogen; optionally substituted alkyl, alkenyl, alkynyl; halogen; hydroxy; cyano; amino; alkylamino; dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy; aminosulfonyl; and alkylsulfonylamino. 
 
     
     
         16 - 22 . (canceled) 
     
     
         23 . The compound of  claim 15 , wherein G is G 1 . 
     
     
         24 . The compound of  claim 23 , wherein R 7  is —C(═O)NR 10 R 11 , wherein R 10  and R 11  both are hydrogen. 
     
     
         25 - 27 . (canceled) 
     
     
         28 . The compound of  claim 23 , wherein R 7  is —C(═O)OR 12 . 
     
     
         29 . (canceled) 
     
     
         30 . The compound of  claim 23 , wherein R 7  is —(CH 2 ) n OR 13 . 
     
     
         31 . (canceled) 
     
     
         32 . The compound of  claim 23 , wherein R 7  is hydrogen. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . The compound of  claim 15 , wherein G is G 1  and is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         38 - 43 . (canceled) 
     
     
         44 . The compound of  claim 15 , wherein G is G 2  and is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and —C(═O)—C(═O)—OH. 
     
     
         45 - 74 . (canceled) 
     
     
         75 . A pharmaceutical composition, comprising the compound of  claim 15 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         76 . A method of treating a disorder responsive to the blockade of Na v 1.7 sodium channels in a mammal suffering from said disorder, comprising administering to a mammal in need of such treatment an effective amount of a compound as claimed in  claim 15  or a pharmaceutically acceptable salt, prodrug or solvate thereof. 
     
     
         77 - 79 . (canceled) 
     
     
         80 . A method for treating stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, pain, migraine, familial primary erythromelalgia, paroxymal extreme pain disorder, cerebellar atrophy, ataxia, distonia, tremor, mental retardation, autism, a neurodegenerative disorder, manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, or providing local anesthesia in a mammal, comprising administering an effective amount of a compound as claimed in  claim 15  or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a mammal in need of such treatment. 
     
     
         81 . The method of  claim 80 , wherein the method is for treating pain. 
     
     
         82 . The method of  claim 80 , wherein the method is for preemptive or palliative treatment of pain. 
     
     
         83 . The method of  claim 80 , wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, postsurgical pain, acute pain, and surgical pain. 
     
     
         84 - 85 . (canceled) 
     
     
         86 . A compound as claimed in  claim 15 , wherein the compound is  3 H,  11 C, or  14 C radiolabeled, or a pharmaceutically acceptable salt, prodrug or solvate thereof. 
     
     
         87 . A method of screening a candidate compound for its ability to bind to a binding site on a protein using a radiolabeled compound of  claim 86 , comprising a) introducing a fixed concentration of the radiolabeled compound to an in vitro preparation comprising a soluble or membrane-associated sodium channel subunit or fragment under conditions that permit the radiolabeled compound to bind to the channel subunit or fragment, respectively, to form a conjugate; b) titrating the mixture with a candidate compound; and c) determining the ability of the candidate compound to displace the radiolabeled compound from said channel, subunit or fragment. 
     
     
         88 - 91 . (canceled)