Thienodibenzoazulene compounds as tumor necrosis factor inhibitors

Abstract

The present invention relates to the dibenzoazulene compounds represented by formula I as well as to their pharmaceutical preparations for the inhibition of tumor necrosis factor alpha (TNF-α) and interleukine 1 (IL-1) in mammals at all diseases and conditions where these mediators are excessively secreted. The compounds of the present invention also demonstrate an analgetic action and can be used to relieve pain.

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         16 . A method for the treatment of inflammatory diseases and conditions induced by or associated with excessive production of TNF-α and/or IL-1, which comprises administering to a subject a therapeutically effective amount of a compound of formula I or a pharmacologically acceptable salt or hydrate thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 x represents CH 2 , or a heteroatom selected from the group consisting of O, S, S(═O), S(═O) 2  or NR 13    
 wherein R 13  is hydrogen, C 1-6  alkyl, C 1-6  alkylcarbonyl, arylcarbonyl, C 1-6  alkylsulfonyl, or arylsulfonyl;  
 each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  independently represents hydrogen, fluoro, chloro, bromo; or C 1 -C 7  alkyl, C 2 -C 7  alkenyl; monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and alternating double bonds between carbon atoms and said aryl group can be unsubstituted or substituted with fluoro, chloro, bromo, hydroxy, C 1 -C 7  alkyl, C 1 -C 7  alkoxy, aryloxy, wherein aryl has the meaning as defined above, C 1 -C 7  alkylthio, arylthio wherein aryl has the meaning as defined above, C 1 -C 7  alkylsulfonyl, cyano, or amino; C 1 -C 7  mono or di-C 1 -C 7  substituted amino, heteroaryl which is a monocyclic or bicyclic aromatic hydrocarbon containing at least one heteroatom selected from O, S or N optionally said heteroaryl can be unsubstituted or substituted with fluoro, chloro, bromo, CF 3 , methyl, ethyl or propyl; or halomethyl, hydroxy, C 1 -C 7  alkoxy, aryloxy wherein aryl has the meaning as defined above, C 1 -C 7  alkylthio, arylthio wherein aryl has the meaning as defined above, C 1 -C 7  alkylsulfonyl, cyano, amino, C 1 -C 7  mono- or di-C 1 -C 7  substituted amino, C 1 -C 7  hydroxycarbonyl, C 1 -C 7  alkanoyloxycarbonyl, carbamoyl, mono-N-(C 1 -C 7 )alkylcarbamoyl, di-N,N-(C 1 -C 7 )alkylcarbamoyl, C 1 -C 7  alkyloxycarbonyl, aryloxycarbonyl, C 1 -C 7  alkylcarbonyl, arylcarbonyl;  
 R 10  represents C 2 -C 15  alkyl, C 2 -C 15  alkenyl, C 2 -C 15  alkynyl, aryl or heteroaryl wherein aryl and heteroaryl have the meaning as defined above, C 1 -C 15  haloalkyl, C 1 -C 15  hydroxyalkyl, C 1 -C 15  alkyloxy, C 1 -C 15  alkylthio, C 3 -C 15  alkylcarbonyl, C 2 -C 15  hydroxycarbonyl, C 3 -C 15  alkyloxycarbonyl, C 1 -C 15  alkylsulfonyl, arylsulfonyl or C 1 -C 15  alkylarylsulfonyl wherein aryl has the meaning as defined above, CH═CHCH 2 OH, CH═CHCH 2 O(CH 2 ) n -A, or C 1 -C 15  alkylamino represented by the formula  
   (CH 2 )n-A  
 wherein  
 n is an integer from 1 to 15, optionally one or more methylene groups can be substituted with an oxygen or sulphur atom A represents saturated or unsaturated a five- or six-membered ring having from one to three heteroatoms selected from the group consisting of O, S, N or combinations thereof, or a group of the formula  
                     
 wherein  
 R 11  and R 12  independently represent hydrogen, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, aryl or heteroaryl wherein aryl and heteroaryl have the meaning as defined above, or a saturated or unsaturated five- or six-membered ring having from one to three heteroatoms selected from the group consisting of O, S, N or combinations thereof.  
 
     
     
         17 . The method of  claim 16  wherein R 10  represents CH 2 OH, CH═CHCH 2 OH or CH 2 CH 2 CH 2 OH.  
     
     
         18 . The method of  claim 16  wherein R 10  represents (CH 2 ) n A, CH 2 O(CH 2 ) n -A, CH═CHCH 2 O(CH 2 ) n -A or CH 2 CH 2 CH 2 O(CH 2 ) n -A.  
     
     
         19 . The method of  claim 16  wherein A represents morpholine-4-yl, piperidine-1-yl or pyrrolidine-1-yl.  
     
     
         20 . The method of  claim 16  wherein A represents  
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 12  are as defined in  claim 16 .  
     
     
         21 . The method of  claim 16  wherein R 11  and R 12  represent H, —CH 3  or —CH 2 CH 3 .  
     
     
         22 . The method of  claim 16  wherein R 2  represents H, SCH 3 , F, Cl, Br or CH 3 .  
     
     
         23 . The method of  claim 16  wherein R 3  represents H, OCH 3 , F, Cl, Br, CF 3  or CH 3 .  
     
     
         24 . The method of  claim 16  wherein R 4  represents H, F, Cl or CH 3 .  
     
     
         25 . The method of  claim 16  wherein R 6  represents H, F or Cl.  
     
     
         26 . The method according to  claim 16  wherein R 10  represents C 1 -C 15  hydroxyalkyl, or C 2 -C 15  alkylamino represented by the formula  
         (CH 2 ) n -A.  
     
     
         27 . The method of  claim 26  wherein said heteroaryl group is selected from the group consisting of thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, pyrazole, tetrazole, pyrimidine, pyrazine and triazine.  
     
     
         28 . The method of  claim 16  wherein said heteroaryl group is selected from the group consisting of thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, pyrazole, tetrazole, pyrimidine, pyrazine and triazine.  
     
     
         29 . The method of  claim 16  wherein the compound of formula I is selected from the group consisting of: 
 dimethyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine hydrochloride,    dimethyl-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride,    4-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,    [2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine,    4-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,    1-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,    1-[2-(9-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    [3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,    [2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine,    4-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,    1-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,    1-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    [3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(11-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,    1-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,    1-[2-(11-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    [3-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine, dimethyl-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride,    4-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine,    1-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(10-trifluoromethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,    [2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    1-[2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(10-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    [3-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    1-[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    [2-(10-bromo-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [3-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    1-[2-(9,11-dimethyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,    1-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,    1-[2-(10,11-dichloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,    [3-(9-chloro-11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,    [2-(9-chloro-11-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,    4-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-but-3-ene-2-one,    4-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-but-3-ene-2-one,    3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-acrylic acid,    3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propionic acid,    3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,    3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,    N,N-dimethyl-[3-(11-methylsulfanyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(11-methylsulfanyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    N,N-dimethyl-[3-(10-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(10-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    N,N-dimethyl-[3-(11-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(11-methyl-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    N,N-dimethyl-[3-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    1-(2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-piperidine,    1-(2-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,    3-(10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine,    N,N-dimethyl-[3-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    3-(6-chloro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[3-(10-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(10-fluoro-1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    [2-(3-dimethylamino-propoxymethyl)-1-thia-8-aza-dibenzo[e,h]azulene-8-yl)-phenyl-methanon,    [2-(2-dimethylamino-ethoxymethyl)-1-thia-8-aza-dibenzo[e,h]azulene-8-yl)-phenyl-methanon,    N,N-dimethyl-[3-(8H-1-thia-8-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N,N-dimethyl-[2-(8H-1-thia-8-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    [3-(11-fluoro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine hydrochloride,    [3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine,    N,N-dimethyl-{3-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propyloxy]-propyl}-amine,    N,N-dimethyl-{2-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-propyloxy]-ethyl}-amine,    N,N-dimethyl-{3-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-propyloxy]-propyl}-amine,    N,N-dimethyl-{2-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-propyloxy]-ethyl}-amine,    N,N-dimethyl-{3-(8H-1-thia-dibenzo[e,h]azulene-2-yl)-methoxy]-propyl}-amine,    N,N-dimethyl-{2-(8H-1-thia-dibenzo[e,h]azulene-2-yl)-methoxy]-ethyl}-amine,    N,N-dimethyl-{3-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-allyloxy]-propyl}-amine,    N,N-dimethyl-{2-[3-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-allyloxy]-ethyl}-amine,    N-methyl-[3-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N-methyl-[2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine,    N-methyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    N-methyl-[3-(1,8-dithia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine,    2-bromomethyl-1,8-dithia-dibenzo[e,h]azulene, and    2-(1,8-dithia-dibenzo[e,h]azulene-2-yl)-ethylamine, and salts and hydrates thereof.    
     
     
         30 . The method of  claim 16  wherein the compound of formula I is [2-(11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine.