New compounds

Abstract

The present invention relates to novel compounds, and therapeutically acceptable salts thereof of the formula (I), which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

1 . A compound of the formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is 
 (a) H,  
 (b) C 1 -C 6  alkyl,  
 (c) C 1 -C 6  alkenyl,  
 (d) CH 2 OH,  
 (e) halogen, or  
 (f) thiocyano  
 
 R 2  is 
 (a) C 1 -C 6  alkyl,  
 (b) hydroxyalkyl,  
 (c) C 1 -C 6  alkoxy C 1 -C 6  alkyl,  
 (d) hydroxy C 1 -C 6  alkoxy C 1 -C 6  alkyl,  
 (e) C 1 -C 6  alkylthio C 1 -C 6  alkyl,  
 (f) cyano C 1 -C 6  alkyl or  
 (g) halogenated C 1 -C 6  alkyl, or  
 (h) aminocarbonyl C 1 -C 6  alkyl,  
 
 R 3  is 
 (a) H,  
 (b) C 1 -C 6  alkoxy,  
 (c) C 1 -C 6  alkyl,  
 (d) halogen,  
 (e) hydroxy C 1 -C 6  alkyl,  
 (f) hydroxy C 1 -C 6  alkoxy,  
 (g) C 1 -C 6  alkoxy C 1 -C 6  alkyl,  
 (h) C 1 -C 6  alkoxy C 1 -C 6  alkoxy,  
 (i) C 1 -C 6  alkoxycarbonyl,  
 (j) C 1 -C 6  alkanoyl,  
 (k) halogenated C 1 -C 6  alkyl,  
 (l) NO 2 ,  
 (m) CN,  
 (n) C 1 -C 6  sulfonyl,  
 (o) C 1 -C 6  sulfinyl,  
 (p) C 1 -C 6  alkylthio,  
 (q) C 1 -C 6  alkylaminosulfonyl,  
 (r) C 1 -C 6  (alkyl) 2 aminosulfonyl,  
 (s) aminosulfonyl,  
 (t) C 1 -C 6  alkylsulfonylamino,  
 (u) C 1 -C 6  (alkylsulfonyl) 2 amino or  
 (v) trifluoromethylsulfonylamino  
 (x) C 1 -C 6  alkylcarbonylamino  
 (y) C 1 -C 6  alkoxycarbonylamino, or  
 (z) C 1 -C 6  aminocarbonylamino, optionally substituted by one or two C 1 -C 6  alkyl groups,  
 
 R 4  is 
 (a) H,  
 (b) C 1 -C 6  alkyl,  
 (c) halogenated C 1 -C 6  alkyl,  
 (d) C 1 -C 6  alkoxy, or  
 (e) halogen,  
 
 Ar is a with R 5 , R 6 , and/or R 7  substituted phenyl, thienyl, furanyl, naphtyl or pyridyl group.  
                     
 R 5  is 
 (a) H,  
 (b) C 1 -C 6  alkyl,  
 (c) C 1 -C 6  alkoxy,  
 (d) hydroxy,  
 (e) hydroxy C 1 -C 6  alkyl,  
 (f) hydroxy C 1 -C 6  alkoxy,  
 (g) halogenated C 1 -C 6  alkyl,  
 (h) halogenated C 1 -C 6  alkoxy,  
 (i) C 1 -C 6  alkoxy C 1 -C 6  alkyl,  
 (j) halogen,  
 (k) hydroxy C 1 -C 6  alkoxy C 1 -C 6  alkyl,  
 (l) CN,  
 (m) C 1 -C 6  alkoxycarbonyl,  
 (n) C 1 -C 6  alkoxycarbonyloxy,  
 (o) C 1 -C 6  alkylsulfonyloxy,  
 (p) trifluoromethylsulfonyloxy,  
 (q) C 1 -C 6  acyloxy C 1 -C 6  alkyl,  
 (r) C 1 -C 6  alkylsulfonyl C 1 -C 6  alkyl,  
 (s) C 1 -C 6  alkylsulfinyl C 1 -C 6  alkyl,  
 (t) C 1 -C 6  alkylthio C 1 -C 6  alkyl,  
 (u) C 1 -C 6  alkoxycarbonylamino C 1 -C 6  alkyl or  
 (v) aryl,  
 (x) amino C 1 -C 6  alkyl  
 (y) NHC═OR 12    
                     
 (ab) C 1 -C 6  alkyl sulfonyl amino  
 
 R 6  is 
 (a) H,  
 (b) C 1 -C 6  alkyl,  
 (c) halogen,  
 (d) hydroxy C 1 -C 6  alkyl,  
 (e) halogenated C 1 -C 6  alkyl,  
 (f) halogenated C 1 -C 6  alkoxy,  
 (e) C 1 -C 6  alkoxy C 1 -C 6  alkyl, or  
 (f) CN  
 
 R 7  is 
 (a) H,  
 (b) C 1 -C 6  alkyl,  
 (c) C 1 -C 6  alkoxy,  
 (d) halogen,  
 (e) NO 2 ,  
 (f) halogenated C 1 -C 6  alkyl,  
 (g) halogenated C 1 -C 6  alkoxy,  
 (h) aryloxy, or  
 (i) CN  
 
 R 8  is 
 (a) H or  
 (b) C 1 -C 6  alkyl  
 
 R 12  is 
 (a) C 1 -C 6  alkoxy,  
 (b) C 1 -C 6  alkoxy C 2 -C 4  alkoxy,  
 (c) NH 2 ,  
 (d) hydroxy C 2 -C 4  alkoxy,  
 (e) C 1 -C 6  alkyl carbonyloxy C 2 -C 4  alkoxy,  
 (f) halogenated C 2 -C 4  alkoxy,  
 (g) halogenated C 1 -C 4  alkyl,  
 (h) hydroxy C 1 -C 4  alkyl,  
 (i) C 1 -C 6  alkyl carbonyloxy C 1 -C 4  alkyl,  
 (j) aryl,  
 (k) aryl C 1 -C 4  alkyl,  
 (l) C 1 -C 4  sulfanyl C 2 -C 4  alkoxy,  
 (m) C 1 -C 4  sulfinyl C 2 -C 4  alkoxy,  
 (n) C 1 -C 4  sulfonyl C 2 -C 4  alkoxy,  
 
 R 5  and R 6  are in the ortho positions relative to X  
 R 7  is in the meta or para position relative to X  
 R 5  and R 8  may together form a hydroxy- or alkoxy-substituted 5- or 6-membered ring,  
 provided that one of R 3  and R 4 ≠H or halogen  
 provided also that at least one of R 5 , R 6  and R 7 ≠H  
 provided also that when R 5 =(y),(z),(aa) or (ab), then one of R 3  and R 4 ≠H  
 provided also that when R 1 ═H, then R 7 ≠CH 3    
 provided also that when R 2 ═CH 2 OH or CH 2 CN, then one of R 5  and R 6 ≠H  
 
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is H, CH 3 , or CH 2 OH,    R 2  is CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 SCH 3 , CH 2 CH 2 OCH 3 , or CH 2 CH 2 CN;    R 3  is H, CH 3 , CH 2 CH 3 , F, Cl, Br, OCH 3 , OCH 2 CH 3 , CH 2 OH, CH 2 CH 2 OH, OCH 2 CH 2 OH, CH 2 CH 2 OCH 3 , OCH 2 CH 2 OCH 3 , C═OOCH 3 , C═OOCH 2 CH 3 , C═OCH 3 , C═OCH 2 CH 3 , C═OCH(CH 3 ) 2  , or C═OCH 2 CH 2 CH 3 ,    R 4 is H, CH 3 , CH 2 CH 3 , F, Cl, Br OCH 3  or OCH 2 CH 3      Ar is phenyl, thienyl, furyl or naphtyl                          R 5 is H, CH 3 , CH 2 CH 3 , OCH 3 , OH, CH 2 OH, CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OC═OOCH 3 , OC═OCH 2 CH 3 , OCHF 2 , OCF 3 , F, Cl, Br, CN, phenyl, CH 2 CH 2 OC═OCH 3 , CH 2 NHC═OOCH 3  or CH 2 NHC═OOCH 2 CH 3      R 6  is H, CH 3 , CH 2 CH 3 , CF 3 , OCF 3 , OCF 2 H, F, Cl, Br or CH 2 OCH 3      R 7  is H, F, Cl, Br, OCF 2 H, or OCF 3      R 8  is H, CH 3 , or CH 2 CH 3      
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is H, CH 3  or CH 2 OH,    R 2  is CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 SCH 3 , CH 2 OCH 3  or CH 2 CN    R 3  is H, CH 3 , CH 2 CH 3 OCH 3 , OCH 3 , CH 2 OH, C═OOCH 3  C═OOCH 2 CH 3 , C═OCH 3 , C═OCH 2 CH 3 , or C═OCH 2 CH 2 CH 3 .    R 4  is H, or CH 3      Ar is phenyl, thienyl or furyl                          R 5  is H, CH 3 , CH 2 CH 3 , OCH 3 , OH, CH 2 OH, CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OC═OOCH 3 , OC═OCH 2 CH 3 , OCHF 2 , OCF 3 , F, Cl, Br, CN, CH 2 CH 2 OC═OCH 3 , CH 2 NHC═OOCH 3  or CH 2 NHC═OOCH 2 CH 3      R 6  is H, CH 3 , CH 2 CH 3 , CF 3 , OCF 3 , OCF 2 H, F, Cl, Br or CH 2 OCH 3      R 7  is H, F, Cl Br, OCF 2 H, or OCF 3      R 8  is H or CH 3      
     
     
         4 . A process for the preparation of a compound according to any of  claims 1  to  3  comprising; 
 reacting a compound of the general formula II                          wherein X 1  is NH 2  or OH, and R 1 , R 2 , R 3 , and R 4  are as defined for Formula I, with a compound of the general Formula III                          wherein “Ar” is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, in an inert solvent, such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N,N-dimethylformamide, and optionally in the presence of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine, to give a compound of the general Formula I.    
     
     
         5 . A process for the preparation of a compound according to any of  claims 1  to  3  wherein X is NH comprising; 
 a) reacting a compound of the general formula IV                          wherein R 1 , R 2 , R 3  and R 4  are as defined for Formula I, with a compound of the general Formula V                          wherein Ar are as defined for Formula I, in an inert solvent in the presence of a Lewis acid, such as zinc chloride, under standard conditions to give a compound of the general formula VI                          wherein R 1 , R 2 , R 3 , R 4  and Ar are as defined for Formula I;    b) treating the compound of the general formula VI, wherein R 1 , R 2 , R 3 , R 4  and Ar are as defined for Formula I, with sodium borohydride or sodium cyanoborohydride under standard condition in an solvent, such as methanol or ethanol, to give a compound of the general formula I, wherein X in NH.    
     
     
         6 . A process for the preparation of a compound according to any of  claims 1  to  3 , wherein R 1  is CH 2 OH or H, comprising; 
 a) reacting a compound of the general formula VII                          wherein X 1  is NH 2  or OH, R 2 , R 3  and R 4  are as defined for Formula I, with a compound of the general formula III                          wherein Ar is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to give a compound of the general Formula VIII                          wherein R 2 , R 3 , R 4 , Ar and X is as defined for Formula I, in an inert solvent, such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N,N-dimethylformamide, and optionally in the presence of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine, under standard conditions,    b) treating a compound of the general formula VIII, wherein R 2 , R 3 , R 4 , Ar and X is as defined for Formula I, with lithium aluminium hydride under standard conditions in an solvent, such as tetrahydrofuran or ether, to give a compound of the general Formula I, wherein R 1  is CH 2 OH, or    b) treating a compound of the general formula VIII, wherein R 2 , R 3 , R 4 , Ar and X is as defined for Formula I, with aqueous base or acid, in an inert solvent, such as diphenylether, under standard conditions, to give a compound of the general formula I, wherein R 1  is H.    
     
     
         7 . A process for the preparation of a compound according to any of  claims 1  to  3 , wherein R 1  is CH 2 OH and X is NH, comprising; 
 a) reacting a compound of the general formula IX                          with a compound of the general formula V                          wherein Ar is as defined for Formula I, in an inert solvent under standard conditions, in the presence of a Lewis acid, such as zinc chloride to give a compound of the general formula the compounds of the Formula X                          wherein R 2 , R 3 , R 4  and Ar are as defined for Formula I;    b) reacting a compound of the general formula X, wherein R 2 , R 3 , R 4  and Ar are as defined for Formula I with sodium borohydride or sodium cyanoborohydride under standard condition in an solvent, such as methanol or ethanol, to give a compound of the general formula XI                          wherein R 2 , R 3 , R 4  and Ar are as defined for Formula I;    c) reacting a compound of the general formula XI, wherein R 2 , R 3 , R 4  and Ar are as defined for Formula I, with lithium aluminium hydride under standard conditions in an solvent, such as tetrahydrofuran or ether, to give a compound of the general Formula I, wherein R 1  is CH 2 OH and X is NH, or;    c) or treating a compound of the general formula XI, wherein R 2 , R 3 , R 4 , and Ar is as defined for Formula I, with aqueous base or acid, in an inert solvent, such as diphenylether, under standard conditions, to give a compound of the general formula I, wherein R 1  is H.    
     
     
         8 . A process for the preparation of a compound according to any of  claims 1  to  3 , wherein X is CH 2 O, comprising; 
 a) reacting a compound of the general formula XII                          with an α-halocarbonyl compound of the general formula R 2 COCH(Z)R 1  wherein R 1  and R 2  are as defined for Formula I and Z is a leaving group, such as Br or Cl, in an inert solvent, such as acetonitrile or ethanol, under standard conditions to give compounds of the general formula XIII                          wherein R 1 , R 2 , R 3 , R 4 , and Ar is as defined for Formula I.    
     
     
         9 . A pharmaceutical formulation containing a compound according to any one of  claims 1  to  3  as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.  
     
     
         10 . Use of a compound according to any one of  claims 1  to  3  for the manufacture of a medicament for the inhibition of gastric acid secretion.  
     
     
         11 . Use of a compound according to any one of  claims 1  to  3  for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.  
     
     
         12 . Use of a compound according to any one of  claims 1  to  3  the manufacture of a medicament for the treatment or prophylaxis of conditions involving infection by  Helicobacter pylori  of human gastric mucosa, wherein the said salt is adapted to be administered in combination with at least one antimicrobial agent.  
     
     
         13 . A method for inhibiting gastric acid secretion which comprises administering to a mammal, including man, in need of such inhibition an effective amount of a compound according to any one of  claims 1  to  3 .  
     
     
         14 . A method for the treatment of gastrointestinal inflammatory diseases which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of  claims 1  to  3 .  
     
     
         15 . A method for the treatment or prophylaxis of conditions involving infection by  Helicobacter pylori  of human gastric mucosa, which comprises administering to a mammal, including humans, in need of such treatment an effective amount of a compound as claimed in any one of  claims 1  to  3 , wherein the said salt is administered in combination with at least one antimicrobial agent.  
     
     
         16 . A pharmaceutical formulation for use in the inhibition of gastric acid secretion wherein the active ingredient is a compound according to any one of  claims 1  to  3 .  
     
     
         17 . A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases wherein the active ingredient is a compound according to any one of  claims 1  to  3 .  
     
     
         18 . A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving infection by  Helicobacter pylori  of human gastric mucosa, wherein the active ingredient is a compound according to any one of  claims 1  to  3  in combination with at least one antimicrobial agent.