Radioprotector compounds and methods

Abstract

The invention relates to novel compounds, processes for their preparation and their use in protecting biological materials from radiation damage (radioprotection). Preferred compounds of the invention are those of Formula II, as follows: wherein W represents —N(R 1 R 2 ) where R 1 and R 2 are not both hydrogen and where they may together form a 5, 6 or 7 membered ring structure, —NHN(R 1 R 2 ), —NHR 3 N(R 1 R 2 ), —NHR 3 OR 2 , —N(R 3 )R 3 OR 2 , —N(R 1 )R 3 OR 3 OR 3 , —OR 3 NR 1 R 2 , —OR 3 or W represents piperidyl, piperazinyl, morpholinyl, thiomorpholinyl or diazepanyl each of which may be optionally substituted by C 1 to C 4 alkyl, C 2 to C 4 alkenyl, —N(CO)N(R 1 R 2 ), —N(CO)OR 1 , —N(CO)OR 3 OH, —(CO)NR 1 R 2 , —R 3 (CO)NR 1 R 2 , —R 3 OR 1 , —OR 1 , —N(R 1 R 2 ) or —NH—; R 1 and R 2 are the same or different and are selected from hydrogen, C 1 to C 4 alkyl or C 2 to C 4 alkenyl; R 3 is a C 1 to C 4 alkyl or C 2 to C 4 alkenyl group or chain; Z is the same or different and represents N or CH; Z′ is the same or different and represents N or C; X represents CH, N or NH, where is a double bond when X is CH or N and a single bond when X is NH; X′ represents N or NH, wherein when X is CH or NX′ is NH and wherein X and X′ are different and further where is a double bond when X′ is N and a single bond when X′ is NH; Q represents H, alkoxyl, —NR 1 R 2 , F or Cl; Q 1 is absent when Z′ is N and when Z′ is C it represents H, alkoxyl, —NR 1 R 2 , F Cl; A represents a five to ten membered single or multiple ring structure with heterocyclic N or O located at the ortho position, said ring including optional double bonds, substitutions and/or other heteroatoms and pharmaceutically acceptable derivatives thereof.

The invention claimed is: 
     
       1. A radioprotector compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein
 X represents N or NH, where   is a double bond when X is N and a single bond when X is NH; 
 X′ represents N or NH, where X and X′ are different and where   is a double bond when X′ is N and a single bond when X′ is NH; 
 Q represents methoxyl or H; 
 Y represents O, methylene, hydroxymethyl or methylamino; and 
 A represents optionally substituted 2-pyridyl, optionally substituted 2-pyrimidyl, optionally substituted 2-pyrazinyl, optionally substituted 3-pyrazolyl, optionally substituted 5-pyrazolyl, optionally substituted 2-furanyl, optionally substituted 2-quinolinyl, optionally substituted 1-isoquinolinyl or optionally substituted 3-isoquinolinyl 
 
         and pharmaceutically acceptable salts, hydrates, solvates or tautomers thereof. 
       
     
     
       2. The compound of  claim 1  wherein Y represents methylamino or hydroxymethyl. 
     
     
       3. The compound of  claim 1  wherein A represents optionally substituted 2-pyridyl. 
     
     
       4. A radioprotector compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein
 W represents —N(R 1 R 2 ) where R 1  and R 2  are not both hydrogen and where they may together form a 5, 6 or 7 membered ring structure, —NHN(R 1 R 2 ), —NHR 3 N(R 1 R 2 ), —NHR 3 OR 2 , —N(R 3 )R 3 OR 2 , —N(R 1 )R 3 OR 3 OR 3 , —OR 3 NR 1 R 2 , —OR 3  or W represents piperidyl, piperazinyl, morpholinyl, thiomorpholinyl or diazepanyl each of which may be optionally substituted by C 1  to C 4  alkyl, C 2  to C 4  alkenyl, —N(CO)N(R 1  R 2 ), —N(CO)OR 1 , —N(CO)OR 3 OH, —(CO)NR 1 R 2 , —R 3 (CO)NR 1 R 2 , —N(R 1 R 2 ) or —NH—; 
 R 1  and R 2  are the same or different and are selected from hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; 
 R 3  is a C 1  to C 4  alkyl or C 2  to C 4  alkenyl group or chain; 
 Z is the same or different and represents N or CH; 
 Z′ is the same or different and represents N or C; 
 X represents CH, N or NH, where   is a double bond when X is CH or N and a single bond when X is NH; 
 X′ represents N or NH, wherein when X is CH or NX′ is NH and wherein X and X′ are different and further where   is a double bond when X′ is N and a single bond when X′ is NH; 
 Q represents H, alkoxyl, —NR 1 R 2 F or Cl; 
 Q 1  is absent when Z′ is N and when Z′ is C it represents H, alkoxyl, —NR 1 R 2 ,F or Cl; 
 A represents a five to ten membered single or multiple ring structure with heterocyclic N or O located at the ortho position, said ring including optional double bonds, substitutions and/or other heteroatoms 
 
         and pharmaceutically acceptable salts, hydrates, solvates or tautomers thereof. 
       
     
     
       5. The compound of  claim 4  wherein A represents optionally substituted 2-pyridyl, optionally substituted 2-pyrimidyl, optionally substituted 2-pyrazinyl, optionally substituted 3-pyrazolyl, optionally substituted 5-pyrazolyl, optionally substituted 2-furanyl, optionally substituted 2-quinolinyl, optionally substituted 1-isoquinolinyl or optionally substituted 3-isoquinolinyl. 
     
     
       6. The compound of claim  5  1 wherein the optional substitution of A is by chloro, fluoro, C 1  to C 4  fluoroalkyl, C 1  to C 4  alkyl, C 2  to C 4  alkenyl, C 1  to C 4  alkoxy, C 1  to C 4  alkoxyalkyl, C 1  to C 4  alkylamino, C 2  to C 4  di-alkylamino or C 1  to C 4  aminoalkyl. 
     
     
       7. The compound of claim  5  1 wherein the optional substitution of A is by methyl or methoxyl. 
     
     
       8. The compound of  claim 4  wherein at least one Q represents methoxyl. 
     
     
       9. The compound of claim  4  1 selected from:
 2-(5′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-Methyl-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-Chloro-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-Methoxy-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 1-(5′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″yl)benzimidazol-2′-yl)isoquinoline 
 3-(5′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)isoquinoline 
 3-(5′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)indazole 
 2-(5′-(5″-Morpholinobenzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-Morpholinobenzimidazol-2″-yl)benzimidazol-2′-yl)-4-methylpyridine 
 3-(5′-(5″-Morpholinobenzimidazol-2″-yl)benzimidazol-2′-yl)isoquinoline 
 2-(5′-(5″-(4′″-Methyl-1′″,4′″-diazepan-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-Methoxypiperidin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(4′-Methoxy-6′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(6′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″-yl)indol-2′-yl)pyridine 
 2-(5′-(5″-(morpholinoamino)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-Isopropylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-Butylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″((2′″-Methoxyethyl)(methyl)amino)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 5-Methyl-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-methoxy-6′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 3-(5′-(5″-(4′″-hydroxypiperidin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)isoquinoline 
 2-(5′-(5″-(4′″-(2″″methoxyethyl)piperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(2′″-(2″″-methoxyethoxy)ethylamino)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 5-fluoro-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-hydroxypiperidin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)-5-methylpyridine. 
 
     
     
       10. The compound of claim  4  1 selected from:
 2-(5′-(5″-(4′″-Methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-Chloro-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-Methyl-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-Morpholinobenzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(4′-Methoxy-6′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-Butylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-methoxy-6′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 4-methoxy-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 3-(5′-(5″-(4′″-hydroxypiperidin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)isoquinoline 
 2-(5′-(5″-(2′″-(2″″-methoxyethoxy)ethylamino)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 2-(5′-(5″-(4′″-Isopropylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine 
 5-fluoro-2-(5′-(5″-(4′″-methylpiperazin-1′″-yl)benzimidazol-2″-yl)benzimidazol-2′-yl)pyridine. 
 
     
     
       11. A method of protecting biological material from ionising radiation damage comprising administering to said material an effective amount of a compound of  claim 1  prior to and/or in conjunction with exposure of the material to ionising radiation. 
     
     
       12. The method of  claim 11  wherein said biological material comprises a human or animal patient undergoing radiation therapy. 
     
     
       13. The method of  claim 11  wherein said biological material comprises a human or animal patient undergoing a diagnostic procedure involving exposure to ionising radiation. 
     
     
       14. A method of preventing ionising radiation damage in a human at risk of exposure to ionising radiation comprising administration to the human of an effective amount of a compound of  claim 1  prior to possible exposure of the human to ionising radiation. 
     
     
       15. A composition comprising a compound of  claim 1  in combination with one or more of a pharmaceutically or veterinarily acceptable carrier. 
     
     
       16. A radioprotector compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 W represents —N(R 1 R 2 ) where R 1  and R 2  are not both hydrogen and where they may together form a 5, 6 or 7 membered ring structure, —NHN(R 1 R 2 ), —NHR 3 N(R 1 R 2 ), —NHR 3 OR 2 , —N(R 3 )R 3 OR 2 , —N(R 1 )R 3 OR 3 OR 3 , —OR 3 NR 1 R 2 , —OR 3  or W represents piperidyl, morpholinyl, thiomorpholinyl or diazepanyl each of which may be optionally substituted by C 1  to C 4  alkyl, C 2  to C 4  alkenyl, —N(CO)N(R 1 R 2 ), —N(CO)OR 1 , —N(CO)OR 3 OH, —(CO)NR 1 R 2 , —R 3 (CO)NR 1 R 2 , —R 3 OR 1 , —OR 1 , —N(R 1 R 2 ) or —NH—; 
 R 1  and R 2  are the same or different and are selected from hydrogen, C 1  to C 4  alkyl or C 2  to C 4  alkenyl; 
 R 3  is a C 1  to C 4  alkyl or C 2  to C 4  alkenyl group or chain; 
 Z is the same or different and represents N or CH; 
 Z′ is the same or different and represents N or C; 
 X represents CH, N or NH, where   is a double bond when X is CH or N and a single bond when X is NH; 
 X′ represents N or NH, wherein when X is CH or N X′ is NH and wherein X and X′ are different and further where   is a double bond when X′ is N and a single bond when X′ is NH; 
 Q represents H, alkoxyl, —NR 1 R 2 , F or Cl; 
 Q 1  is absent when Z′ is N and when Z′ is C it represents H, alkoxyl, —NR 1 R 2 , F or Cl; 
 A represents a five to ten membered single or multiple ring structure with heterocyclic N or O located at the ortho position, said ring including optional double bonds, substitutions and/or other heteroatoms 
 and pharmaceutically acceptable salts, hydrates, solvates or tautomers thereof.  
 
     
     
       17. The compound of claim 16 wherein A represents optionally substituted 2-pyridyl, optionally substituted 2-pyrimidyl, optionally substituted 2-pyrazinyl, optionally substituted 3-pyrazolyl, optionally substituted 5-pyrazolyl, optionally substituted 2-furanyl, optionally substituted 2-quinolinyl, optionally substituted 1-isoquinolinyl or optionally substituted 3-isoquinolinyl.  
     
     
       18. The compound of claim 17 wherein the optional substitution of A is by chloro, fluoro, C 1  to C 4  fluoroalkyl, C 1  to C 4  alkyl, C 2  to C 4  alkenyl, C 1  to C 4  alkoxy, C 1  to C 4  alkoxyalkyl, C 1  to C 4  alkylamino, C 2  to C 4  di-alkylamino or C 1  to C 4  aminoalkyl.  
     
     
       19. The compound of claim 17 wherein the optional substitution of A is by methyl or methoxyl.  
     
     
       20. The compound of claim 16 wherein at least one Q represents methoxyl.