Substituted glutarimides and their use as inhibitors of IL-12 production

Abstract

Substituted glutarimides of formula I and their method of making. Also disclosed are pharmaceutical compositions comprising the glutarimidie, particularly as immunomodulators and as inhibitors of angiopathies, or haematological or oncological diseases, as well as a method for treating various diseases using the glutarimides.

We claim:  
     
         1 . A substituted glutarimide compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 X is CH 2 —NH or S—CH 2 ,  
 R 1  is a carboxyl group; an ester group having the formula COOR 5  in which R 5  is a C 1 -C 6  straight-chain or branched alkyl group or a benzyl group; or an amide group having the formula CONR 6 R 7 , in which 
 R 6  and R 7  are the same or different and represent a hydrogen; a C 1 -C 6  straight-chain or branched alkyl group optionally substituted with a COOR 5  group or a phenyl group or both; or a phenyl group;  
 or R 6  and R 7  taken together with the N atom represent a hydrazide group; a pyrrolidine; a piperidine or a morpholine ring; or an amino group substituted with a CH(═O) or COR 5 ; and  
 
 R 2  is a hydrogen, an amino or a nitro group,  
 or a salt thereof with a physiologically compatible acid.  
 
     
     
         2 . An enantiomer, or a salt thereof with a physiologically compatible acid, of a compound according to  claim 1 .  
     
     
         3 . A mixture of enantiomers, or salts thereof with a physiologically compatible acid, of at least a compound according to  claim 1 .  
     
     
         4 . A racemate, or a salt thereof with a physiologically compatible acid, of a compound according to  claim 1 .  
     
     
         5 . A diastereomer, or mixture of diastereomers thereof, or a salt thereof with a physiologically compatible acid, of a compound according to  claim 1 .  
     
     
         6 . A compound according to  claim 1 , selected from the group consisting of: 
 2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] bezoic acid,    2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,    (3S)-[2-morpholine-4-carbonyl)benzylamino] piperidine-2,6-dione,    {2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoylamino} methyl acetate,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl benzamide,    (3S)-[2-pyrrolidine-1-carbonyl)benzylamino] piperidine-2,6-dione,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzoic acid hydrazide,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,    2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] -N-phenyl benzamide,    2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] -N,N-diethyl benzamide,    2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl] benzamide,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] methyl benzoate,    2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl] benzyl benzoate,    2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate,    N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} acetamide,    N-{2-[2,6-dioxopiperidin-3-ylamino)methyl] phenyl} formamide,    3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitro methylbenzoate,    and    2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate.    
     
     
         7 . A pharmaceutical composition comprising as an active agent at least one compound according to  claim 1 , and a pharmaceutically acceptable excipient.  
     
     
         8 . A method for modulating immune action in a mammal in need thereof, comprising administering to the mammal an effective immunomodulatory amount of a compound of  claim 1 .  
     
     
         9 . A method according to  claim 8 , wherein the mammal is a human.  
     
     
         10 . A method for the treatment of angiopathies, or hematological or oncological diseases, comprising administering to a patient in need thereof an effective amount of a compound according to  claim 1 .  
     
     
         11 . A method for the production of a substituted glutarimide compound according to  claim 1 , the method comprising 
 cyclizing a glutaric acid derivative of formula II,                        wherein X, R 1  and R 2  are as defined in formula I; and A is OH, and B is NH 2  or NHOH; or A is NH 2  or NHOH, and B is OH,    in the presence of an activating reagent.      
     
     
         12 . A method according to  claim 11 , wherein the activating agent is carbonyl diimidazole.  
     
     
         13 . A method according to  claim 11 , wherein X is CH 2 —NH, and wherein cyclization is performed with the —NH group of X protected by a protective group, which protective group is removed after cyclization.  
     
     
         14 . A method according to  claim 13 , wherein the protective group is a benzyloxycarbonyl group.  
     
     
         15 . A method for the production of a substituted glutarimide compound according to  claim 1 , the method comprising 
 heating a glutaric acid derivative of formula II,                        wherein X, R 1  and R 2  are as defined in formula I, and A and B are both OH,      in acetic anhydride to obtain an anhydride by cyclization, and    heating the anhydride with a nitrogen source to obtain a compound of formula I.    
     
     
         16 . A method according to  claim 15 , wherein the nitrogen source is urea.  
     
     
         17 . A method for producing a substituted glutarimide of formula I according to  claim 1 , the method comprising oxidizing a lactam of formula  
       
         
           
           
               
               
           
         
         in which R 1 , R 2  and X are as defined for formula I,  
         thereby converting the lactam to a corresponding imide.  
       
     
     
         18 . A method according to  claim 17 , wherein the lactam is oxidized with at least one oxidizer selected from the group consistin of m-chloroperbenzoic acid, ruthenium(IV) oxide and sodium periodate.  
     
     
         19 . A method for producing a substituted glutarimide of formula I according to  claim 1  wherein X stands for a CH 2 —NH group, the method comprising 
 alkylating an α-aminoglutarimide compound of formula IV,  
                     
 with a compound of formula V,  
                     
 in which R 1  and R 2  are as defined for formula I, and Y is selected from the group consisting of chlorine, bromine, iodine, and a toluene-4-sulfonate group.  
 
     
     
         20 . A method for producing a substituted glutarimide of formula I according to  claim 1  wherein X stands for a CH 2 —NH group, the method comprising 
 reacting by reductive amination a compound of formula VI with a compound of formula IV,  
                     in which R 1  and R 2  are as defined for formula I,    to obtain the substituted glutarimide.    
 
     
     
         21 . A method according to  claim 20 , wherein the compound of formula VI and the compound of formula IV are reduced by a member selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, a borane-pyridine complex, and a catalytically excited hydrogen.  
     
     
         22 . A method for producing a substituted glutarimide of formula I according to  claim 1  wherein X is a CH 2 —NH group, the method comprising: 
 alkylating a compound of formula VII,  
                     in which R 1  and R 2  are as defined for formula I,    with an α-bromoglutarimide of formula VIII                          
 
     
     
         23 . A method for producing a substituted glutarimide of formula I according to  claim 1  wherein X is an S—CH 2  group, the method comprising 
 adding in a solvent a mercaptan of formula X  
                     in which R 1  and R 2  are as defined for formula I,    to a 3-methylene glutarimide of formula IX,                          
 
     
     
         24 . A method according to  claim 23 , wherein the solvent is acetonitrile or toluene.  
     
     
         25 . A method according to  claim 24  wherein the solvent further comprises a tertiary amine.  
     
     
         26 . A method according to  claim 25 , wherein the tertiary amine is triethylamine or diisopropyl ethylamine.  
     
     
         27 . A method according to  claim 24 , wherein the mercaptan is added to the 3-methylene glutarimide at a temperature between about 80° C. and about 110° C.  
     
     
         28 . A method for producing a substituted glutarimide of formula I according to  claim 1  wherein R 2  is an amino group, the method comprising reducing a compound of formula I wherein R 2 ═NO 2  by catalytically excited hydrogen in an acid-containing organic solvent.  
     
     
         29 . A method according to  claim 28 , wherein the organic solvent is ethyl acetate.  
     
     
         30 . A method according to  claim 28 , wherein the reduction is performed using a palladium catalyst or with a metal in an acid solution.  
     
     
         31 . A method according to  claim 30 , wherein the metal is tin or iron.