Kv1.3 inhibitors and their medical application

Abstract

Disclosed are compounds within the scope of formula (II) or a salt or solvate thereof, medical uses involving them, and methods for their preparation

1 - 15 . (canceled) 
     
     
         16 . A method for treating a disease or medical condition in which inhibiting the voltage-gated potassium channel Kv1.3 is beneficial, comprising administering to a subject in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 A 1  is C—R 8 ; 
 A 2  is C—R 3 ; 
 A 3  is C—R 9 ; 
 A 4  and A 5  and A 6  are independently N or C—R 1 ; 
 R 1  is hydrogen, (C 1 -C 3 )alkyl, halogen, (C 1 -C 3 )alkoxy, or (C 1 -C 3 )haloalkyl; 
 R 2  is halogen, or (C 1 -C 3 )alkyl; 
 R 3  is hydrogen, (C 1 -C 3 )alkyl, NR 4 R 5 , (C 1 -C 3 )alkyl-NR 4 R 5 , or cyano, 
 R 4  and R 5  are independently hydrogen, (C 3 -C 5 )cycloalkyl, (C 3 -C 5 )heterocycloalkyl or (C 1 -C 3 )alkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring optionally comprising in addition to the aforementioned nitrogen atom a further heteroatom, which is O or NR 6 , 
 R 6  is hydrogen, methyl, acetyl or formyl; 
 Y is O; 
 R 8  is —CH 3 , (C 3 -C 5 )cycloalkyl or (C 3 -C 5 )heterocycloalkyl; and 
 R 9  is hydrogen, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy. 
 
     
     
         17 . The method according to  claim 16 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is —CH 3 .   
     
     
         18 . The method according to  claim 16 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 at least one of the following conditions is fulfilled:   1) R 2  is halogen, or   2) R 3  is NR 4 R 5  or cyano,   3) A 4  or A 5  or A 6  is N.   
     
     
         19 . The method according to  claim 16 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 one of A 4  and A 5  and A 6  is N and the others are N or C—R 1 .   
     
     
         20 . The method according to  claim 16 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is (C 3 -C 5 )cycloalkyl or (C 3 -C 5 )heterocycloalkyl.   
     
     
         21 . The method according to  claim 16 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is methyl; R 9  is methyl; R 1  is hydrogen; R 2  is methyl; and R 3  is hydrogen.   
     
     
         22 . The method according to  claim 16 , wherein the following compound 
       
         
           
           
               
               
           
         
       
       wherein
 A 4  and A 5  and A 6  are independently N or C—R 1 , and 
 R 1  is hydrogen, (C 1 -C 3 )alkyl, halogen, (C 1 -C 3 )alkoxy, or (C 1 -C 3 )haloalkyl 
 
       or the pharmaceutically acceptable salt thereof 
       is administered. 
     
     
         23 . The method according to  claim 16 , wherein the compound of formula (II) or the pharmaceutically acceptable salt or solvate thereof is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         24 . The method according to  claim 16 , wherein the compound of formula (II) or the pharmaceutically acceptable salt thereof is administered. 
     
     
         25 . The method according to  claim 16 , wherein said disease or medical condition is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew), periodontal disease, diabetes type I, multiple sclerosis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, rapidly progressive glomerulonephritis, advanced chronic renal failure, chronic kidney disease, renal fibrosis, uveitis,  Pars planitis , asthma,  Pemphigus foliaceus , inclusion body myositis, dermatomyositis, scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis, irritant contact dermatitis,  Lichen planus , Sjögren's syndrome, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplant rejection, end-stage renal disease, vascularized composite allotransplantation rejection, alopecia areata, inflammatory bone resorption disease, anti-neutrophil cytoplasmic autoantibody-associated vasculitis, osteoarthritis, diseases associated with intimal hyperplasia, breast cancer, leukemia, human lung adenocarcinoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma, neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders, neurodegeneration, HIV-1-associated neurocognitive disorders (HAND), microglia-induced oxidative stress in Alzheimer's disease, obesity, insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis, arteriosclerotic vascular disease, acute coronary syndrome, acute ischemic stroke, and hypertension. 
     
     
         26 . A method for treating a disease or medical condition in which inhibiting the voltage-gated potassium channel Kv1.3 is beneficial, comprising administering to a subject in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 A 1  is C—R 8 ; 
 A 2  is C—R 3 ; 
 A 3  is C—R 9 ; 
 A 4  and A 5  and A 6  are independently N or C-12 1 ; 
 R 1  is hydrogen, methyl, chloro, fluoro, methoxy, ethoxy or trifluoromethyl; 
 R 2  is hydrogen, bromo or methyl; 
 R 3  is hydrogen, methyl, morpholinyl, morpholinomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl or cyano; 
 Y is O; 
 R 8  is methyl or cyclopropyl; and 
 R 9  is hydrogen, methyl or methoxy; 
 
       with the proviso that the following compounds are excluded:
 3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, 
 2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, 
 3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, and 
 2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one. 
 
     
     
         27 . The method according to  claim 26 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 R 2  is hydrogen or methyl; and   R 3  is hydrogen, morpholinyl, morpholinomethyl, N,N-dimethylaminomethyl or cyano.   
     
     
         28 . The method according to  claim 26 , wherein in the compound of formula (II) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is methyl; R 9  is methyl; R 1  is hydrogen or methoxy;   R 2  is hydrogen or methyl; and   R 3  is hydrogen, methyl or N-methylaminomethyl.   
     
     
         29 . The method according to  claim 26 , wherein the compound of formula (II) or the pharmaceutically acceptable salt or solvate thereof is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         30 . The method according to  claim 26 , wherein the compound of formula (II) or the pharmaceutically acceptable salt thereof is administered. 
     
     
         31 . The method according to  claim 26 , wherein said disease or medical condition is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew), periodontal disease, diabetes type I, multiple sclerosis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, rapidly progressive glomerulonephritis, advanced chronic renal failure, chronic kidney disease, renal fibrosis, uveitis,  Pars planitis , asthma,  Pemphigus foliaceus , inclusion body myositis, dermatomyositis, scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis, irritant contact dermatitis,  Lichen planus , Sjögren's syndrome, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplant rejection, end-stage renal disease, vascularized composite allotransplantation rejection, alopecia areata, inflammatory bone resorption disease, anti-neutrophil cytoplasmic autoantibody-associated vasculitis, osteoarthritis, diseases associated with intimal hyperplasia, breast cancer, leukemia, human lung adenocarcinoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma, neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders, neurodegeneration, HIV-1-associated neurocognitive disorders (HAND), microglia-induced oxidative stress in Alzheimer's disease, obesity, insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis, arteriosclerotic vascular disease, acute coronary syndrome, acute ischemic stroke, and hypertension. 
     
     
         32 . A method for treating a disease or medical condition in which inhibiting the voltage-gated potassium channel Kv1.3 is beneficial, comprising administering to a subject in need thereof an effective amount of a compound selected from:
 5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,   2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one, and   5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         33 . The method according to  claim 32 , wherein the following compound 
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof is administered. 
     
     
         34 . The method according to  claim 32 , wherein the following compound 
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof is administered. 
     
     
         35 . The method according to  claim 32 , wherein the compound selected from:
 5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,   2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one, and   5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   or the pharmaceutically acceptable salt or solvate thereof is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent.   
     
     
         36 . The method according to  claim 32 , wherein the compound selected from:
 5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,   2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,   9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,   2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,   3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one, and   5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,   or the pharmaceutically acceptable salt thereof   is administered.   
     
     
         37 . The method according to  claim 32 , wherein said disease or medical condition is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew), periodontal disease, diabetes type I, multiple sclerosis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, rapidly progressive glomerulonephritis, advanced chronic renal failure, chronic kidney disease, renal fibrosis, uveitis,  Pars planitis , asthma,  Pemphigus foliaceus , inclusion body myositis, dermatomyositis, scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis, irritant contact dermatitis,  Lichen planus , Sjögren's syndrome, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplant rejection, end-stage renal disease, vascularized composite allotransplantation rejection, alopecia areata, inflammatory bone resorption disease, anti-neutrophil cytoplasmic autoantibody-associated vasculitis, osteoarthritis, diseases associated with intimal hyperplasia, breast cancer, leukemia, human lung adenocarcinoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma, neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders, neurodegeneration, HIV-1-associated neurocognitive disorders (HAND), microglia-induced oxidative stress in Alzheimer's disease, obesity, insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis, arteriosclerotic vascular disease, acute coronary syndrome, acute ischemic stroke, and hypertension.