Substituted naphthalene diimides and their use

Abstract

The present invention relates to naphthalene diimides, NDIs, and methods of synthesising them. The NDIs have DNA-quadruplex binding and stabilising activity, and potential in treatment of pancreatic, prostate, and other human cancers. The NDIs are a compound of Formula I:

1 . A method of treating cancer, inhibiting growth of a solid tumour, or reducing size of a solid tumour, comprising administer a therapeutically effective amount of a composition comprising a compound of Formula I, salts, hydrates or solvates thereof, wherein the compound of Formula I has the following structure: 
       
         
           
           
               
               
           
         
         L is in the meta or para position of the phenyl ring and is selected from the group consisting of (CH 2 ) 1-6  and (CH 2 ) 1-5 NH; 
         R 1  is selected from the group consisting of optionally substituted C 5-7 cycloalkyl, optionally substituted nitrogen-containing 5-7 membered heterocycloalkyl and NR 9 R 10 ; 
         R 2  and R 4  are independently selected from the group consisting of straight and branched chain C 1-6 -alkanediyl; 
         R 3 , R 9  and R 10  are independently selected from the group consisting of H or C 1-6  alkyl; 
         X is selected from the group consisting of halo, OR 5 , NR 6   2 , CONR 7 2, COOR 8 , H and COR 8 ; 
         R 5  is selected from the group consisting of H, C 1-6  alkyl, C 4-7  cycloalkyl, 4-7 membered heterocycloalkyl and aryl; 
         R 6  is selected from the group consisting of H, C 1-6  alkyl, aryl and, C 7-12 -aralkyl, or the groups R 6  together with the N-atom to which they are attached form a N-containing, saturated 4-7 membered heterocyclic group; 
         the groups R 7  are each selected from H and C 1-6  alkyl groups or the groups R 7  together with the N atom to which they are attached form a 4-7 membered heterocyclic group; and 
         R 8  is selected from the group consisting of C 1-6  alkyl, C 7-12  aralkyl, and aryl. 
       
     
     
         2 . The compound method according to  claim 1 , wherein L is (CH 2 ) 1-6 . 
     
     
         3 . The method according to  claim 1 , wherein R 1  is a nitrogen-containing 5-7 membered heterocycloalkyl optionally selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, and diazepanyl. 
     
     
         4 . The method according to  claim 1 , wherein L is (CH 2 ) 1-6 NH and R 1  is a C 6-7 cycloalkyl. 
     
     
         5 . The method according to  claim 1 , wherein L is in the para position. 
     
     
         6 . The method according to  claim 1 , wherein R 2  is a straight chain C 2-4  alkanediyl. 
     
     
         7 . The method according to  claim 1 , wherein R 3  is H. 
     
     
         8 . The method according to  claim 1 , wherein R 4  is a straight or branched chain C 2-4  alkanediyl. 
     
     
         9 . The method according to  claim 8 , wherein R 4  is a straight chain C 2-4  alkanediyl. 
     
     
         10 . The method of any  claim 1 , wherein X is NR 6   2 . 
     
     
         11 . The method of  claim 10 , wherein the R 6  groups together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of 4-methyl piperazine-1-yl, morpholine-4-yl, pyrrolidin-1-yl, pyridin-2-yl and piperidin-1-yl. 
     
     
         12 . The method of  claim 1 , wherein the compound is selected from the group consisting of:
 2,7-bis(3-nnorpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)-9-(4-(pyrrolidin-1-ylmethyl)phenyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   4-(4-(morpholinomethyl)phenyl)-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   2,7-bis(3-morpholinopropyl)-44(2-(pyrrolidin-1-yl)ethyl)amino)-9-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   2,7-bis(3-morpholinopropyl)-4-(4-(piperidin-1-ylmethyl)phenyl)-9-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   4-(4-((diethylamino)methyl)phenyl)-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   4-(4-((cyclopentylamino)methyl)phenyl)-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone;   4-(4-(azepan-1-ylmethyl)phenyl)-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone; and   4-bromo-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone.   
     
     
         13 . The method according to  claim 1 , wherein Formula I has the following structure of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method according to  claim 1 , wherein the composition comprises a pharmaceutically acceptable diluent or carrier. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The method according to  claim 1 , wherein L is (CH 2 ) 1-2 . 
     
     
         19 . The method according to  claim 1 , wherein R 1  is pyrrolidinyl. 
     
     
         20 . The method according to  claim 11 , wherein the heterocyclic group is pyrroliin-1-yl. 
     
     
         21 . The method according to  claim 1 , wherein the method is a method of treating cancer. 
     
     
         22 . The method according to  claim 1 , further comprising administer a therapeutically effective amount of another agent to inhibit undesirable and uncontrolled cell proliferation. 
     
     
         23 . The method according to  claim 21 , wherein treating cancer is treating prostate cancer or pancreatic cancer.