Amidine derivatives, the preparation and use thereof as medicaments with LTB4 antagonistic effect

Abstract

Compounds of the formula which is explained more fully in the specification, may be prepared by conventional methods and used therapeutically in conventional galenic preparations.

1 . Compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2 , which may be identical or different, denote CF 3 , halogen, R 5 , OR 5 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , C(OH)R 5 R 7  or together may also denote the double-bonded groups —CR 8 ═CR 9 —CH═CH—, —CH═CR 8 —CR 9 ═CH—, —O—CHR 10 —CH 2 —, —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —(CH 2 ) 3-4 —, —NH—CO—O—, —NH—CO—CH 2 —O—, —CO—CH 2 —O— or —CO—CH 2 CH 2 —O—, linked with adjacent carbon atoms of the benzene ring, whilst these groups may in turn be substituted by C 1-4 -alkyl,  
 R 3  denotes halogen, OH, CF 3 , R 5 , OR 6 , COR 6 , CONH 5 R 7 , CH 2 OH, CH 2 —O—(C 1-4 -alkyl), SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , NH—CO—(C 1-4 -alkyl), NH—SO 2 —(C 1-4 -alkyl), NR 5 R 7  or C(OH)R 5 R 7  (whilst if R 3  is the same as R 5 , R 5  can only denote H if at least one of the substituents R 1  and R 2  does not denote H), a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula  
                     
  (wherein D, E and G, which may be identical or different, denote CH, N, C—(C 1-4 -alkyl) or C-phenyl and L denotes O or S),  
 R 4  denotes halogen, NH 2 , NH—(C 1-4 -alkyl), N(C 1-4 -alkyl) 2 , OH, C 1-4 -alkoxy,  
 R 5  denotes H, C 1-12 -alkyl, phenyl, phenyl optionally substituted by halogen, C 1-4 -alkyl, C 1-4 -alkoxy or C 2-5 -acyl, or phenyl-(C 1-4 -alkyl),  
 R 6  denotes C 1-12 -alkyl, phenyl, or phenyl optionally substituted by halogen, C 1-4 -alkyl, C 1-4 -alkoxy or C 2 -C 5 -acyl,  
 R 7  denotes H or C 1-12 -alkyl,  
 R 8 , R 9  (which may be identical or different) denote H, OH, C 1-4 -alkyl, C 1-4 -alkoxy or C 2-5 -acyl,  
 R 10  denotes H or C 1-4 -alkyl,  
 R 11 , R 12 , which may be identical or different, denote H, OH, halogen, CF 3 , C 1-4 -alkyl or C 1-4 -alkoxy,  
 A denotes one of the groups  
 X 1 -A 1 -X 2   (II) X 2 -A 2 -X 3   (III) X 4 -A 2 -X 2   (IV) (CH 2 ) 1-2 —NH—CO—(CH 2 ) 1-3 —X 2   (V) —CH═CH-A 2 -X 2   (VI)  
                     
 B denotes CH═CH, CH═N, S or  
                     
 A 1  denotes C 2-4 -alkylene, cis- or trans-CH 2 —CH═CH—CH 2 , CH 2 —C≡C—CH 2  or  
                     
 A 2  denotes C 1-5 -alkylene,  
 X 1  denotes O, NH, S, SO, SO 2 , CO, CH 2  or  
                     
 X 2  denotes O, NH, S or  
                     
 X 3  denotes NH—CO, CO—NH, SO 2 —NH or  
                     
 X 4  denotes NH—CO, CO—NH, NH—SO 2 , SO 2 —NH or NH—CO—NH,  
 as racemates, in enantiomerically pure or concentrated form, possibly as pairs of diastereomers and in cis- or trans-form and as free bases or as salts, preferably with physiologically acceptable acids.  
 
     
     
         2 . Compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , which may be identical or different, denote R 7 , OR 7 , COR 6 , halogen or together denote the double bonded groups —CR 8 ═R 9 —CH═CH—, —CH═CR 8 —CR 9 ═CH—, —O—CHR 10 —CH 2 — or —CO—CH 2 —CH 2 —O—, linked with adjacent carbon atoms of the benzene ring,  
 R 3  denotes halogen, CF 3 , R 7 , OR 7 , CO—(C 1-4 -alkyl), NH—CO—(C 1-4 -alkyl), NHSO 2 —(C 1-4 -alkyl) or N(R 10 ) 2  (whilst R 7  can only denote H if at least one of the substituents R 1  and R 2  does not denote H) or a heterocyclic five-membered ring such as  
                     
 R 6  and R 7  are at hereinbefore defined, and  
 A denotes the group II.  
 
     
     
         3 . Compounds according to  claim 1  or  2 , wherein 
 R 1 /R 2 /R 3  have the meanings C 2-5 -acyl/H/H;  
 C 6 H 5 CO/H/H; C 1-4 -alkyl/OH/H;  
 C 2-5 -acyl/C 1-4 -alkyl/H;  
 C 2-5 -acyl/OH/C 1-4 -alkyl;  
 OH/C 2-5 -acyl/C 1-4 -alkyl.  
 
     
     
         4 . Compounds according to  claim 1  or  2  characterised in that A denotes 
 O—(CH 2 ) 2 —O, O—(CH 2 ) 4 —O or  
                     
 
     
     
         5 . compounds according to  claim 1  or  2  characterised in that the group II is acetylphenyl.  
     
     
         6 . Compounds according to  claim 1  or  2  characterised in that the group  
       
         
           
           
               
               
           
         
       
     
     
         7 . Compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 a denotes 0 or 1,  
 b denotes 1 or 2,  
 R denotes C 1-4 -alkyl, and if a=0 or 1 and b=1 and 
 if a=1 and b=2 it may also denote hydrogen,  
 
 in the form of free bases or acid addition salts.  
 
     
     
         8 . Compounds according to  claim 7 , wherein a=0 or 1 and b=1 or a=0 and b=2 as free bases or as acid addition salts.  
     
     
         9 . Compounds according to  claim 8 , wherein R denotes H, CH 3 , or C 2 H 5 , a denotes 0 or 1 and b denotes 1, as free bases or as acid addition salts.  
     
     
         10 . Compounds according to  claim 8 , wherein a denotes 0, b denotes 2 and R denotes CH 3 , as free bases or as acid addition salts.  
     
     
         11 . Pharmaceutical compositions, characterised in that they contain a compound according to claims  1 ,  2  or  7 .  
     
     
         12 . Use of compounds according to claims  1 ,  2  or  7  in the preparation of pharmaceutical compositions for the treatment of diseases in which inflammatory and/or allergic processes are involved, especially asthma, ulcerative colitis, psoriasis and for treating gastropathy induced by non-steroidal antiphlogistics.  
     
     
         13 . Use of an effective dose of a compound according to claims  1 ,  2  or  7  for treating diseases in which LTB 4 -antagonistic compounds can be used.  
     
     
         14 . Use of an effective dose of a compound according to claims  1 ,  2  or  7  for the treatment of diseases in which inflammatory and/or allergic processes are involved, particularly asthma, ulcerative colitis, psoriasis, and for treating gastropathy induced by non-steroidal antiphlogistics.  
     
     
         15 . Process for preparing compounds according to claims  1 ,  2  or  7  characterised in that 
 a) an imidoester of the formula  
                     
  wherein R 1  to R 4 , A and B are as hereinbefore defined and R preferably represents a C 1-6 -alkyl group or benzyl, is reacted with ammonia, or  
 b1) a phenol or thiophenol of the formula  
                     
  wherein Z denotes OH or SH and R 1 , R 2  and R 3  are as hereinbefore defined, is reacted with a compound of formula  
                     
  wherein A 1 , A 2 , B, R 4 , X 2  and X 3  are as hereinbefore defined and L denotes a nucleofugic leaving group, or  
 b2) a phenol or thiophenol of formula  
                     
  wherein B, R 4  and Z are as hereinbefore defined, is reacted with a compound of formula  
                     
  wherein A 1 , A 2 , R 1 , R 2 , R 3  and Z are as hereinbefore defined; or  
 c) an amidoxime of the formula  
                     
  wherein A, B and R 1  to R 4  are as hereinbefore defined, is reduced to form the corresponding amidine.