Pharmaceutically effective compounds

Abstract

The subject invention relates to carboxamidine derivatives, to pharmaceutical compositions containing the carboxamidine derivatives of the invention, and the use thereof for the treatment of vascular diseases and in the preparation of pharmaceutical compositions for the treatment of vascular diseases.

1 . A compound represented in general formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, a straight chained C 1-6  alkyl group optionally substituted with a phenyl group, or a branched C 1-6  alkyl group optionally substituted with a phenyl group, or R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or benzyl groups; 
         A is a phenyl group optionally substituted with one or more C 1-4  alkyl, Cab haloalkyl, nitro group, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is optionally part of a N-oxide structure; 
         n is 0, 1, or 2; 
         z is 0 or 1; 
         X is halogen or —NR 4 R 5 , wherein R 4  and R 5  are independently hydrogen, a straight chained C 1-6  alkyl groups or a branched C 1-6  alkyl group, 
         Y is a hydrogen, hydroxy group, halogen, or C 1-22  acyloxy group, wherein if R 4  and R 5  are both hydrogen, then Y is other than a hydroxy group, 
         with the proviso that 
         a) if Y is hydrogen and/or X is —NR 4 R 5 , then
 R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is substituted with one or more hydroxy, oxy, or benzyl groups, and/or 
 A is a nitrogen containing heteroaromatic ring, wherein said ring has a N-oxide structure on the nitrogen heteroatom, or 
 
         b) if X is halogen, then
 R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups, 
 
         or a pharmaceutically active stereoisomer or salt thereof. 
       
     
     
         2 - 14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         16 . A method for treating or preventing vascular disease or diseases related to vascular disorders comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         17 . A method for treating a condition associated with the dysfunction of endothelial cells comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         18 . A compound represented in general formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, a straight chained C 1-6  alkyl group optionally substituted with a phenyl group, or a branched C 1-6  alkyl group optionally substituted with a phenyl group, or R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or benzyl groups; 
         A is a phenyl group optionally substituted with one or more C 1-4  alkyl, C 1-4  haloalkyl, nitro group, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is optionally part of a N-oxide structure; 
         n is 0, 1, or 2; 
         z is 0 or 1; 
         X is halogen or —NR 4 R 5 , wherein R 4  and R 5  are independently hydrogen, a straight chained C 1-6  alkyl group, or a branched C 1-6  alkyl group, 
         Y is a hydrogen, hydroxy group, or C 1-22  acyloxy group, wherein if R 4  and R 5  are both hydrogen, then Y is other than a hydroxy group, 
         with the proviso that 
         a) if Y is hydrogen and/or X is —NR 4 R 5 , then
 R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is substituted with one or more hydroxy, oxy, or benzyl groups, and/or 
 A is a nitrogen containing heteroaromatic ring, wherein said ring has a N-oxide structure on the nitrogen heteroatom, or 
 
         b) if X is halogen and Y is hydroxy or acyloxy, then
 R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups, 
 
         or a pharmaceutically active stereoisomer or salt thereof. 
       
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 18 . 
     
     
         20 . A method for treating or preventing vascular disease or diseases related to vascular disorders comprising administering to a patient in need thereof an effective amount of a compound of  claim 18 . 
     
     
         21 . A method for treating a condition associated with the dysfunction of endothelial cells comprising administering to a patient in need thereof an effective amount of a compound of  claim 18 . 
     
     
         22 . A compound represented in general formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, a straight chained C 1-6  alkyl group optionally substituted with a phenyl group, or a branched C 1-6  alkyl group optionally substituted with a phenyl group, or R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or benzyl groups; 
         A is a phenyl group substituted with one or more C 1-4  alkyl, C 1-4  haloalkyl, nitro group, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is part of a N-oxide structure; 
         n is 0, 1, or 2; 
         z is 0 or 1; 
         X is halogen, 
         Y is halogen, 
         or a pharmaceutically active stereoisomer or salt thereof. 
       
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 22 . 
     
     
         24 . A method for treating or preventing vascular disease or diseases related to vascular disorders comprising administering to a patient in need thereof an effective amount of a compound of  claim 22 . 
     
     
         25 . A method for treating a condition associated with the dysfunction of endothelial cells comprising administering to a patient in need thereof an effective amount of a compound of  claim 22 . 
     
     
         26 . A compound represented in general formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, a straight chained C 1-6  alkyl group optionally substituted with a phenyl group, or a branched C 1-4  alkyl group optionally substituted with a phenyl group, or R 1  and R 2  together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or benzyl groups; 
         A is a phenyl group optionally substituted with one or more C 1-4  alkyl, C 1-4  haloalkyl, nitro group, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is optionally part of a N-oxide structure; 
         n is 0, 1, or 2; 
         z is 0 or 1; 
         X is halogen, 
         Y is halogen, 
         wherein either A is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is part of a N-oxide structure, or z is 1, 
         or a pharmaceutically active stereoisomer or salt thereof. 
       
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 26 . 
     
     
         28 . A method for treating or preventing vascular disease or diseases related to vascular disorders comprising administering to a patient in need thereof an effective amount of a compound of  claim 26 . 
     
     
         29 . A method for treating a condition associated with the dysfunction of endothelial cells comprising administering to a patient in need thereof an effective amount of a compound of  claim 26 .