New toll-like receptor 9 antagonists

Abstract

The present invention relates to a compound or a pharmaceutically acceptable salt thereof or a solvate thereof or a pharmaceutical composition comprising said compound, a process for obtaining or screening for a toll-like receptor 9 (TLR9) antagonist and a toll-like receptor 9 (TLR9) antagonist or a pharmaceutically acceptable salt thereof or a solvate thereof, preferably being obtainable thereby.

1 . A compound or a pharmaceutically acceptable salt thereof or a solvate thereof or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof or a solvate thereof for use in a method for treatment of a human or animal body, wherein the compound is selected from a group of compounds consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to  claim 1  for use in a method for treatment of the human or animal body, wherein the compound comprises a structure of 
       
         
           
           
               
               
           
         
         and is selected from a group of compounds consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to  claim 1  for use in a method for treatment of the human or animal body, wherein the compound comprises a structure of 
       
         
           
           
               
               
           
         
         wherein y is 0 or 1 and X is CH or N and is selected from a group of compounds consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to  claim 1  for use in a method for treatment of the human or animal body, wherein the compound comprises a structure of 
       
         
           
           
               
               
           
         
         and is selected from a group of compounds consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to  claim 1  for use in a method for treatment or prevention of at least one disease with an excessive immune response. 
     
     
         6 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to any one of the preceding claims for use in a method according to  claim 5 , wherein the disease with an excessive immune response is selected from toll-like receptor 9 (TLR9)-mediated autoimmune diseases, atopic diseases, transplant rejections, and sepsis. 
     
     
         7 . The compound or a pharmaceutically acceptable salt thereof or a solvate thereof or the pharmaceutical composition according to any one of the preceding claims for use in a method according to  claim 5 , wherein the disease with an excessive immune response is selected from lupus erythematosus, multiple sclerosis, rheumatoid arthritis, atopic dermatitis, psoriasis, hyperlipidaemia, atherosclerosis and human sepsis. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , which comprises further a pharmaceutically acceptable carrier. 
     
     
         9 . A process for obtaining a toll-like receptor 9 (TLR9) antagonist, comprising the following steps:
 a) providing a group of search molecules,   b) filtering the group of search molecules based on at least one physico-chemical molecular descriptor as to obtain a first group of target molecules,   c) determining TLR9 antagonist activity of at least one molecule of the first group of target molecules and   d) selecting at least one molecule with a TLR9 antagonist activity determined in step (c) as to obtain a toll-like receptor 9 (TLR9) antagonist.   
     
     
         10 . The process of  claim 9 , wherein steps a) and b) screen for a toll like receptor 9 (TLR9) antagonist. 
     
     
         11 . The process according to  claim 9 , wherein the first group of target molecules of step (b) is further filtered based on at least one molecule property selected from a group consisting of molecular weight, logP (logarithm of partition coefficient), number of hydrogen bond donors and number of hydrogen bond acceptors, as to obtain a second group of target molecules and TLR9 antagonist activity of at least one molecule of the second group of target molecules is determined in step (c). 
     
     
         12 . The process according to  claim 10 , wherein a second group of target molecules is further filtered based on their solubility as to obtain a third group of target molecules and TLR9 antagonist activity of at least one molecule of the third group of target molecules is determined in step (c). 
     
     
         13 . The process according to  claim 12 , wherein the third group of target molecules has a log S (logarithm of solubility) of −8.0 or higher. 
     
     
         14 . The process according to  claim 9 , wherein the filtering in step b) is performed by using a model system. 
     
     
         15 . The process according to  claim 14 , wherein the model system is prepared by:
 (aa) providing (i) a group of known active molecules known to be TLR9 antagonists and (ii) a group of inactive and/or less active molecules,   (bb) calculating physico-chemical molecular descriptors of the molecules of the group of known active molecules and of the group of inactive and/or less active molecules and   (cc) selecting at least one physico-chemical molecular descriptor of the calculated physico-chemical molecular descriptors for filtering the group of search molecules.   
     
     
         16 . The process according to  claim 15 , wherein prior to step (bb) molecules with a molecular weight of 150 g/mol or less and/or of 1500 g/mol or more are removed from at least one of the groups of known active molecules, of inactive and/or less active molecules and of search molecules. 
     
     
         17 . The process according to  claim 9 , wherein the process is free of a Tanimoto filtering. 
     
     
         18 . The process according to  claim 15 , wherein prior to step (bb) molecules from the group of inactive and/or less active molecules are removed, which molecular weight, calculated logP (logarithm of partition coefficient), number of hydrogen bond donors or number of hydrogen bond acceptors deviates more than plus or minus two standard deviations from an average value of all molecules of the group of active molecules. 
     
     
         19 . A toll-like receptor 9 (TLR9) antagonist or a pharmaceutically acceptable salt thereof or a solvate thereof, selected from a group of molecules consisting of: