Novel Anti-Inflammatory and Analgesic Heterocyclic Amidines that Inhibit Nitrogen Oxide (NO) Production

Abstract

Heterocyclic amidines with anti-inflammatory and analgesic activity that inhibit nitrogen oxide production, of formula (I): in which: G 1 and G 2 are hydrogen, halogen, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, and an amidino substituent of formula Q, provided that, for each compound of formula (I), only one of the two substituents G 1 or G 2 is an amidino substituent of formula Q: and in which the substituents W, Y and X are combined to form 9- or 10-membered bicyclic heteroaromatic derivatives containing up to 2 hetero atoms in the same ring; and Z is an aryl or heteroaryl group, a linear or branched C 1 -C 6 alkyl or alkenyl chain, a C 1 -C 4 alkyl-aryl group or a C 1 -C 4 alkyl-heteroaryl group.

1 . A compound represented by the general formula (I) indicated below and in which: 
     
       
         
         
             
             
         
       
       G 1  and G 2  are independently selected from hydrogen and the amidine substituent of formula Q, provided that, for each compound of formula (I), only one of the two substituents G 1  or G 2  is the amidine substituent of formula Q; the amidine substituent of formula Q is represented by the structure given below, in which R is methyl: 
       Amidine substituent of formula Q: 
     
     
       
         
         
             
             
         
       
       W is independently: a bond, an unsubstituted carbon atom, or a carbon atom substituted with a methyl, an unsubstituted nitrogen atom (═N—); 
       Y is an unsubstituted carbon atom, a carbon atom substituted with a methyl, or an unsubstituted nitrogen atom (═N—); 
       X is a substituted or unsubstituted carbon atom (═CR 1 — or ═CH—), a unsubstituted nitrogen atom substituted with a hydrogen or a methyl, a sulfur atom (—S—) or an oxygen atom (—O—), provided that the substituents W, Y and X give rise, suitably in combination, to 9- or 10-membered bicyclic heteroaromatic derivatives containing up to 2 hetero atoms in the same ring; 
       R 3  and R 4  are both hydrogen; 
       Z is an aryl or heteroaryl group, a linear or branched C 3 -C 6  alkyl or alkenyl chain, a C 1 -C 4  alkyl-aryl group or alkenylaryl group, or a C 1 -C 4  alkyl-heteroaryl group in which the aryl group is a phenyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, trifluoromethyl, hydroxyl, nitro, cyano, carboxyl, carboxamido, carbonyl, thio, methylthio, methanesulfonyl, methanesulfinyl, sulfonamido, trifluoromethoxy, C 1 -C 6  alkoxy and C 1 -C 6  alkyl, and the heteroaryl group is a 5- or 6-atom heterocyclic aromatic ring containing one or more hetero atoms, which is unsubstituted or substituted with one or more substituents independently selected from halogen, trifluoromethyl, hydroxyl, nitro, cyano, carboxyl, carbonyl, thio, methylthio, methanesulfonyl, methanesulfinyl, trifluoromethoxy, C 1 -C 6  alkoxy and C 1 -C 6  alkyl; 
       the C 1 -C 4  alkyl-aryl group is a linear or branched, saturated or unsaturated C 1 -C 4  hydrocarbon chain substituted with an aryl group. When the C 1 -C 4  chain is unsaturated, it is intended to contain only one substituted or unsubstituted double bond; substituents for the aryl group are independently selected from the groups defined above as substituents for the aryl group; 
       the C 1 -C 4  alkyl-heteroaryl group is a linear or branched, saturated or unsaturated C 1 -C 4  hydrocarbon chain substituted with a substituted or unsubstituted heteroaryl group; when the C 1 -C 4  chain is unsaturated, it is intended to contain only one substituted or unsubstituted double bond; 
       the term “heteroaryl” means any of the heterocyclic nuclei defined above; 
       the compounds of formula (I) being either in free base form or as pharmaceutically acceptable salts. 
     
   
   
       2 - 3 . (canceled) 
   
   
       4 . The compound according to  claim 1 , wherein X is a nitrogen atom substituted with hydrogen or with methyl. 
   
   
       5 . The compound according to  claim 1 , wherein X, is an oxygen atom. 
   
   
       6 . The compound according to  claim 1 , wherein Y is an unsubstituted carbon atom (═CH—) or a carbon atom substituted with methyl instead of a nitrogen atom (—N═) X, is a nitrogen atom substituted with hydrogen or with methyl. 
   
   
       7 . The compound according to  claim 6  wherein X, is an oxygen atom. 
   
   
       8 . The compound according to  claim 6 , wherein X, is a sulfur atom. 
   
   
       9 . The compound according to  claim 1 , wherein W is an unsubstituted carbon atom (═CH—) or a carbon atom substituted with methyl, and X, is an unsubstituted nitrogen atom (═N—). 
   
   
       10 . The compound according to  claim 9 , wherein Y is an unsubstituted carbon atom (═C—) or a carbon atom substituted with a methyl. 
   
   
       11 . The compound according to  claim 9 , wherein X is an unsubstituted carbon atom (═CH—) or a carbon atom substituted with methyl. 
   
   
       12 . The compound according to  claim 9 , wherein W is an unsubstituted nitrogen atom (═N—), and is an unsubstituted carbon atom (═CH—) or a carbon atom substituted with methyl. 
   
   
       13 . The compound according to  claim 9 , wherein W, is an unsubstituted nitrogen atom (═N—), and is an unsubstituted carbon atom (═CH—). 
   
   
       14 . The compound according to  claim 1 , in the form of pharmaceutically acceptable salts, chosen from hydrochloride, hydrobromide, sulfate, hydrogen sulfate, methanesulfonate, maleate, citrate, fumarate and succinate. 
   
   
       15 . A method of treating pathological conditions associated with inflammatory or autoimmune phenomena, comprising administering the compound according to  claim 1 , or of a pharmaceutically acceptable salt thereof. 
   
   
       16 . A method of treating conditions comprising administering the compound according to  claim 1 , or of a pharmaceutically acceptable salt thereof, to inhibit the production of nitric oxide (NO) and of interleukin-6 (IL-6). 
   
   
       17 . A pharmaceutical preparation comprising, as active substance, at least compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable vehicle. 
   
   
       18 . A method for the therapeutic treatment of pathological conditions associated with inflammatory and autoimmune phenomena comprising administering the pharmaceutical preparation according to  claim 17 . 
   
   
       19 . A method for controlling and preventing degenerative articular diseases such as rheumatoid arthritis and osteoarthritis comprising administering the pharmaceutical preparation according to  claim 17 . 
   
   
       20 . A method for the analgesic treatment of pain of articular or neuropathic origin comprising administering the pharmaceutical preparation according to  claim 17 . 
   
   
       21 . A method for the therapeutic treatment of inflammatory diseases of the gastrointestinal tract, for instance ulcerative colitis and Crohn's disease comprising administering the pharmaceutical preparation according to  claim 17 . 
   
   
       22 . Pharmaceutical The pharmaceutical preparation according to  claim 17 , comprising pharmaceutically acceptable inactive ingredients chosen from the group consisting of vehicles, binders, flavourings, sweeteners, disintegrants, preserving agents, humectants and mixtures thereof, or ingredients to facilitate rectal, transdermal or transmucosal absorption or that allow controlled release of the active substance over time, and also ingredients suitable for parenteral use, for instance intravenous, intramuscular, subcutaneous, intradermal and intra-articular administration, in which cases the salified compounds as described in  claims 1  and  14  are preferably used. 
   
   
       23 . A process for preparing a compound of general formula (I) in which W, Y, X, G 1 , G 2 , R 3  and R 4  have the meaning given in  claim 1 , which comprises the operations of reacting a compound of formula (II) 
     
       
         
         
             
             
         
       
       in which W, Y, X, Z, R 3  and R 4  are defined as for the compounds of formula (I), while G′ 1  and G′ 2  are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 4  alkoxy, C 1 -C 4  alkyl, and the amine group (—NH 2 ), provided that, for each compound of formula (II), only one of the two substituents G′ 1  or G′ 2  is an amine group (—NH 2 ), with a compound of formula (III) 
     
     
       
         
         
             
             
         
       
       in which R is as defined above in  claim 1  for the amidino substituent of formula Q and L is a leaving group, such as an alkoxy group (ethoxy or methoxy), an alkylthio group (RS—; thiomethyl or thiomethylnaphthyl) or an arylthio group (Ar—S; thiophenyl), in a suitable solvent such as alcohol, acetonitrile, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), at temperatures of between 0° C. and 50° C.; 
       optionally, the conversion of a compound of formula (II) into a compound of formula (I) possibly being completed by the removal of any protecting groups present; 
       the compounds of formula (I) are finally recovered from the reaction mass, purified via conventional methods and isolated in unmodified form or in the form of pharmaceutically acceptable salts.