Treatment of inflammatory disorders with 2,3- benzodiazepines

Abstract

Compounds according to formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined herein, are administered for the treatment of inflammatory disorders, particularly inflammatory disorders mediated by LTB 4 ,

What is claimed is:  
     
         1 . A method of treating an individual afflicted with an inflammatory disorder comprising administering to said individual an effective amount of at least one compound according to Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is —(C 1 -C 7 )hydrocarbyl or —(C 2 -C 6 )heteroalkyl;  
 R 2  is selected from the group consisting of —H, and —(C 1 -C 7 )hydro-carbyl;  
 wherein R 1  and R 2  may combine to form a carbocyclic or heterocyclic 5- or 6-membered ring;  
 R 3  is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, —O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NH-acyl, —NO 2  and halogen;  
 n is 1, 2 or 3;  
 R 4  and R 5  are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , NH-acyl and halogen;  
 wherein, R 4  and R 5  may combine to form a 5-, 6- or 7-membered heterocyclic ring;  
 or a pharmaceutically-acceptable salt of such a compound.  
 
     
     
         2 . The method according to  claim 1 , wherein said inflammatory disorders are mediated by LTB 4 .  
     
     
         3 . The method according to  claim 1  wherein the compound according to formula I comprises a racemic mixture of (R)- and (S)-enantiomers with respect to the absolute conformation at the 5-position of the benzodiazepine ring.  
     
     
         4 . The method according to  claim 3 , wherein: 
 R 1  is —(C 1 -C 6 )alkyl;    R 2  is selected from the group consisting of —H and —(C 1 -C 6 )alkyl;    R 3  is independently selected from the group consisting of —(C 1 -C 6 )alkyl, —O-acyl and —OH;    n is 1, 2 or 3;    R 4  and R 5  are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —O-acyl and —OH, wherein, R 4  and R 5  may combine to form a 5-, 6- or 7-membered heterocyclic ring;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         5 . The method according to  claim 4 , wherein: 
 R 1  is —CH 2 CH 3 ;    R 2  is —CH 3      R 3 , R 4  and R 5  are independently selected from the group consisting of —OH and —O(C 1 -C 6 )alkyl;    n is 1, 2 or 3;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         6 . The method according to  claim 5 , wherein: 
 R 1  is —CH 2 CH 3 ;    R 2  is —CH 3      R 3 , R 4  and R 5  are independently selected from the group consisting of —OH and —OCH 3 ;    n is of 1, 2 or 3;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         7 . The method according to  claim 6 , wherein the compound is selected from the group consisting of: 
 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine;    1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    and pharmaceutically acceptable salts thereof.    
     
     
         8 . The method according to  claim 7 , wherein the compound is 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine; or 
 a pharmaceutically acceptable salt thereof.    
     
     
         9 . The method according to  claim 1 , wherein said wherein said compounds according to formula I are (R)-enantiomers substantially free of the corresponding (S)-enantiomers, with respect to the absolute conformation at the 5-position of the benzodiazepine ring.  
     
     
         10 . The method according to  claim 9 , wherein: 
 R 1  is —(C 1 -C 6 )alkyl;    R 2  is selected from the group consisting of —H and —(C 1 -C 6 )alkyl;    R 3  is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —O-acyl and —OH;    n is 1, 2 or 3;    R 4  and R 5  are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —O-acyl and —OH, wherein, R 4  and R 5  may combine to form a 5-, 6- or 7-membered heterocyclic ring;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         11 . The method according to  claim 10 , wherein: 
 R 1  is —CH 2 CH 3 ;    R 2  is —CH 3      R 3 , R 4  and R 5  are independently selected from the group consisting of —OH and —O(C 1 -C 6 )alkyl;    n is 1, 2 or 3;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         12 . The method according to  claim 11 , wherein: 
 R 1  is —CH 2 CH 3 ;    R 2  is —CH 3      R 3 , R 4  and R 5  are independently selected from the group consisting of —OH and —OCH 3 ;    n is of 1, 2 or 3;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         13 . The method according to  claim 12 , wherein the compound is selected from the group consisting of: 
 (R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    (R)-1-(3,4-dimethoxyphenyl)-4-methyl-S-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    (R)-1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    (R)-1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine;    (R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine;    (R)-1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    (R)-1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine;    substantially free of the corresponding (S)-enantiomers;    and pharmaceutically acceptable salts thereof.    
     
     
         14 . The method according to  claim 13 , wherein the compound is (R)-1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine substantially free of the corresponding (S)-enantiomer; 
 or a pharmaceutically acceptable salt thereof.    
     
     
         15 . A method of treating an individual afflicted with an inflammatory disorder comprising administering to said individual an effective amount of a combination of at least one compound according to Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is —(C 1 -C 7 )hydrocarbyl or —(C 2 -C 6 )heteroalkyl;  
 R 2  is selected from the group consisting of —H, and —(C 1 -C 7 )hydrocarbyl;  
 wherein R 1  and R 2  may combine to form a carbocyclic or heterocyclic 5- or 6-membered ring;  
 R 3  is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, —O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NH-acyl, —NO 2  and halogen;  
 n is 1, 2 or 3;  
 R 4  and R 5  are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , NH-acyl and halogen;  
 wherein, R 4  and R 5  may combine to form a 5-, 6- or 7-membered heterocyclic ring;  
 or a pharmaceutically-acceptable salt of such a compound; and  
 one or more additional therapeutic agents selected from the group consisting of aminosalicylates, corticosteroids, antimetabolites, immunosuppressants, tumor necrosis factor alpha inhibitors, inhibitors of leukotriene synthesis, and leukotriene antagonists;  
 wherein the additional therapeutic agents that are leukotriene antagonists are other than compounds of formula I.  
 
     
     
         16 . The method according to  claim 15 , wherein the amino salicylate is selected from the group consisting of sulfasalazine and mesalamine.  
     
     
         17 . The method according to  claim 15 , wherein the corticosteroid is selected from the group consisting of prednisone and budesonide.  
     
     
         18 . The method according to  claim 15 , wherein the antimetabolite is azathioprine.  
     
     
         19 . The method according to  claim 15 , wherein the immunosuppressant is selected from the group consisting of cyclosporine and tacrolimus.  
     
     
         20 . The method according to  claim 15 , wherein the tumor necrosis factor alpha inhibitor is selected from the group consisting of infliximab, etanercept, and adalimumab.  
     
     
         21 . The method according to  claim 15 , wherein the inhibitor of leukotriene synthesis is a 5-lipoxygenase inhibitor.  
     
     
         22 . The method according to  claim 21 , wherein the 5-lipoxygenase inhibitor is selected from the group consisting of ETH615, linetastine, lonapalene, MK 886, and zileuton.  
     
     
         23 . The method according to  claim 15 , wherein the inhibitor of leukotriene synthesis is selected from the group consisting of 15-HETE and leflunomide.  
     
     
         24 . The method according to  claim 15 , wherein the leukotriene antagonist is selected from the group consisting of SC41930, SC53228, CGS-25019C, ONO-4057, SB-202247, VML295, CP-105696, CP-195543, and U-75302.  
     
     
         25 . The method according to  claim 1  wherein the inflammatory disorder is inflammatory bowel disease.  
     
     
         26 . The method according to  claim 25  wherein the inflammatory bowel disease occurs in an individual suffering from irritable bowel syndrome.  
     
     
         27 . The method according to  claim 2  wherein the inflammatory disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, and radiation-induced gastrointestinal inflammation.  
     
     
         28 . The method according to  claim 27  wherein the inflammatory disorder occurs in an individual suffering from irritable bowel syndrome.  
     
     
         29 . A method of preventing or delaying the onset of an inflammatory disorder in an individual who is at risk of developing an inflammatory disease state, said method comprising: 
 administering to said individual an effective amount of at least one compound according to formula I as described in  claim 1:                           wherein:    R 1  is —(C 1 -C 7 )hydrocarbyl or —(C 2 -C 6 )heteroalkyl;    R 2  is selected from the group consisting of —H, and —(C 1 -C 7 )hydrocarbyl;    wherein R 1  and R 2  may combine to form a carbocyclic or heterocyclic 5- or 6-membered ring;    R 3  is independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, —O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NH-acyl, —NO 2  and halogen;    n is 1, 2 or 3;    R 4  and R 5  are independently selected from the group consisting of —O(C 1 -C 6 )alkyl, —OH, O-acyl, —SH, —S(C 1 -C 3 )alkyl, —NH 2 , NH-acyl and halogen;    wherein, R 4  and R 5  may combine to form a 5, 6 or 7-membered heterocyclic ring;    or a pharmaceutically-acceptable salt of such a compound.    
     
     
         30 . The method according to  claim 29  wherein the inflammatory disorder is mediated by LTB 4 .  
     
     
         31 . The method according to  claim 29 , wherein said wherein said compounds according to formula I are (R)-enantiomers substantially free of the corresponding (S)-enantiomers, with respect to the absolute conformation at the 5-position of the benzodiazepine ring.