Substituted aniline derivatives

Abstract

The present invention relates to aniline derivatives of formula I: wherein R 1 , R 2 , R 3 , R 4 , Z and q are as defined herein; or salts thereof and their use.

1 . A compound having the general formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 Z is O or S; 
 q is 1; 
 R 1  and R 2  are each independently selected from the group consisting of halogen, cyano, amino, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Aryl, Heteroaryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, and C 3-8 -heterocycloalk(en)yloxy; 
 R 3  is selected from the group consisting of C 1-8 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl, Aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 3-8 -cycloalk(en)yl, Heteroaryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, amino-C 1-6 -alk(en/yn)yl, amino-C 3-8 -cycloalk(en)yl, amino-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl and halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; and 
 R 4  is selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Aryl, Heteroaryl, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl, Aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -heterocycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, NR 5 R 6  and R 7 NH—C 1-6 -alk(en/yn)yl; wherein;
 R 5  and R 6  are each independently selected from the group consisting of hydrogen, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl, Aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 3-8 -cycloalk(en)yl and Heteroaryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, with the proviso that R 5  and R 6  can not both be hydrogen; and 
 R 7  is selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl and Heteroaryl; 
 
 
     or
 Z is O or S; 
 q is 0; 
 R 1  and R 2  are each independently selected from the group consisting of C 3-8 -heterocycloalk(en)yl, Heteroaryl, and C 3-8 -heterocycloalk(en)yloxy; 
 R 3  is selected from the group consisting of C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 3-8 -cycloalk(en)yl, and Heteroaryl-C 3-8 -cycloalk(en)yl-C 1-16 -alk(en/yn)yl; and 
 R 4  is selected from the group consisting of C 3-8 -heterocycloalk(en)yl, Heteroaryl, Aryl-C 3-8 -heterocycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -heterocycloalk(en)yl-C 1-6 -alk(en/yn)yl, NR 5 R 6  and R 7 NH—C 1-6 -alk(en/yn)yl; wherein:
 R 5  and R 6  are each independently selected from the group consisting of Heteroaryl-C 1-6 -alk(en/yn)yl, Heteroaryl-C 3-8 -cycloalk(en)yl and Heteroaryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and 
 R 7  is Heteroaryl; or 
 
 
     a pharmaceutically acceptable salt thereof. 
   
   
       2 . The compound according to  claim 1 , wherein R 1  and R 2  are each independently selected from the group consisting of halogen, amino, C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Aryl, Heteroaryl and halo-C 1-6 -alk(en/yn)yl. 
   
   
       3 . The compound according to  claim 1 , wherein q is 0. 
   
   
       4 . The compound according to  claim 1 , wherein q is 1. 
   
   
       5 . The compound according to  claim 4 , wherein Z is an oxygen atom. 
   
   
       6 . The compound according to  claim 1 , wherein R 3  is selected from the group consisting of C 1-8 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 -alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl, Heteroaryl-C 1-6 -alk(en/yn)yl and amino-C 1-6 -alk(en/yn)yl. 
   
   
       7 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of halogen, C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Heteroaryl, Aryl-C 3-8 -heterocycloalk(en)yl, NR 5 R 6  and R 7 NH—C 1-6 -alk(en/yn)yl, wherein R 5 , R 6  and R 7  are as previously defined. 
   
   
       8 . The compound according to  claim 7 , wherein R 4  is NR 5 R 6  and R 5  and R 6  are each independently selected from the group consisting of hydrogen, Aryl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl and Heteroaryl-C 1-6 -alk(en/yn)yl with the proviso that R 5  and R 6  cannot both be hydrogen. 
   
   
       9 . The compound according to  claim 7 , wherein R 4  is R 7 NH—C 1-6 -alk(en/yn)yl and R 7  is Aryl. 
   
   
       10 . The compound according to  claim 1 , wherein any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, hydroxy, C 1-6 -alk(en/yn)yloxy, halo-C 1-6 -alk(en/yn)yloxy, di-(C 1-6 -alk(en/yn)yl)amino, C 1-6 -alk(en/yn)yl-CO—NH— and C 1-6 -alk(en/yn)yl-sulfonamide; or two adjacent substituents may together with the Aryl group to which they are attached form a 4-8 membered ring, which optionally contains one or two heteroatoms and is optionally substituted with one or more C 1-6 -alk(en/yn)yl groups. 
   
   
       11 . The compound according to  claim 1 , wherein any Heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl, Aryl, C 1-6 -alk(en/yn)yloxy and C 1-6 -alk(en/yn)yl-phenoxy. 
   
   
       12 . The compound according to  claim 1 , wherein the compound is being selected from the group consisting of:
 N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide,   2-Bicyclo[2.2.1]hept-2-yl-N-(2,4-difluoro-6-morpholin-4-yl-phenyl)-acetamide,   2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-phenyl}-acetamide,   N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide,   2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-yl-phenyl)-acetamide,   N-(2,4-Dimethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro-phenyl)-acetamide,   N-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4-fluoro-phenyl)-acetamide,   N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phenyl]-2-(4-fluoro-phenyl)-acetamide,   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   [4-(4-Fluoro-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester,   [2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester,   [4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester,   {2,6-Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester,   {2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester,   {4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   {4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   2-Cyclopentyl-N-{2,6-dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl}-acetamide,   N-{2,6-Dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl}-3,3-dimethyl-butyramide,   N-{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-phenyl}-3-cyclohexyl-propionamide,   {4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid ethyl ester,   {2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic acid ethyl ester,   {4-[(4-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   {4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   {2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic acid propyl ester,   {4-[(3,5-Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   {4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,   N-(4-Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide,   {4-[(4-Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic acid propyl ester,   {2,6-Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phenyl}-carbamic acid 2-methoxyethyl ester,   N-{4-[(5-Chloro-pyridin-2-ylamino)-methyl]-2,6-dimethylphenyl}-2-cyclopentylacetamide,   2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-methyl]-2,6-dimethylphenyl}-acetamide,   N-{2-Chloro-6-methyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl}-2-(3-fluoro-phenyl)-acetamide,   3,3-Dimethyl-N-[2-methyl-6-morpholin-4-yl-4-(4-trifluoromethylbenzylamino)-phenyl]-butyramide, and   2-Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-methyl]-phenyl}-acetamide; or   
     a pharmaceutically acceptable salt thereof. 
   
   
       13 . A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents; and a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       14 . A method of increasing ion flow in a potassium channel of a mammal, the method comprising administering the composition of  claim 13  to the mammal. 
   
   
       15 . The method according to  claim 14 , wherein the method is for the treatment of a disorder or disease being responsive to an increased ion flow in a potassium channel, and a therapeutically effective amount of the composition is administered. 
   
   
       16 . The method according to  claim 15 , wherein the disorder or disease to be treated is selected from the group consisting of a seizure disorder, an anxiety disorder, a neuropathic pain disorder, a migraine pain disorder, a neurodegenerative disorder, stroke, cocaine abuse, nicotine withdrawal, ethanol withdrawal and tinnitus. 
   
   
       17 . The method according to  claim 16 , wherein the seizure disorder is selected from the group consisting of acute seizure, convulsion, status epilepticus, epilepsy, an epileptic syndrome and an epileptic seizure. 
   
   
       18 . The method according to  claim 16 , wherein the anxiety disorder is selected from the group consisting of anxiety, a disease or disorder related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, a phobia, obsessive-compulsive disorder, post-traumatic stress disorder, an acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, an adjustment disorder, performance anxiety, a hypochondriacal disorder disorders, an anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. 
   
   
       19 . The method according to  claim 16 , wherein the neuropathic pain disorder and migraine pain disorder is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to trigeminal neuralgia and neupathic pain related to migraine. 
   
   
       20 . The method according to  claim 16 , wherein the neurodegenerative disorder is e selected from the group consisting of Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease, an encephalopathy induced by AIDS, an encephalopathy induced by rubella viruses, a herpes virus, borrelia, a trauma-induced neurodegeneration, a neuronal hyperexcitation state and a neurodegenerative disease of the peripheral nervous system.