Kv1.3 inhibitors and their medical application

Abstract

Compounds of formula (II) or a pharmaceutically acceptable salt or solvate thereof, the medical uses thereof for diseases or medical conditions where the inhibition of the voltage-gated potassium channel Kv1.3 is beneficial, 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 N; 
 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 hydrogen, 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; and 
 R 8  is (C 1 -C 4 )alkyl, (C 3 -C 5 )cycloalkyl or (C 3 -C 5 )heterocycloalkyl. 
 
     
     
         17 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 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; and   R 8  is methyl, ethyl or cyclopropyl.   
     
     
         18 . The method according to  claim 16 , wherein in the compound of formula (H) 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.   
     
     
         19 . The method according to  claim 16 , wherein in the compound of formula (H) 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, or   3) A 4  or A 5  or A 6  is N.   
     
     
         20 . The method according to  claim 16 , wherein in the compound of formula (H) 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 .   
     
     
         21 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is methyl; R 1  is hydrogen or methoxy;   R 2  is hydrogen or methyl; and   R 3  is hydrogen, methyl or N-methylaminomethyl.   
     
     
         22 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 R 2  is halogen.   
     
     
         23 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 R 3  is NR 4 R 5  or cyano.   
     
     
         24 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 R 8  is methyl and R 3  is methyl.   
     
     
         25 . The method according to  claim 16 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 each of A 4  and A 5  and A 6  are C—R 1 .   
     
     
         26 . The method according to  claim 25 , wherein in the compound of formula (H) or in the pharmaceutically acceptable salt or solvate thereof,
 each R 1  is H.   
     
     
         27 . 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. 
     
     
         28 . The method according to  claim 16 , wherein the compound of formula (II) or the pharmaceutically acceptable salt thereof is administered. 
     
     
         29 . 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. 
     
     
         30 . 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:
 3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one, and   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         31 . The method according to  claim 30 , wherein the following compound 
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof is administered. 
     
     
         32 . The method according to  claim 30 , wherein the compound selected from:
 3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one, and   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,   or the pharmaceutically acceptable salt or solvate thereof   is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent.   
     
     
         33 . The method according to  claim 30 , wherein the compound selected from:
 3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one, and   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,   or the pharmaceutically acceptable salt thereof   is administered.   
     
     
         34 . The method according to  claim 30 , 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.