Benzo[A] [phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II

Abstract

A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R 1 to R 4 , which are the same or different, is selected from hydrogen, halogen, hydroxyl, C 1 -C 6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C 1 -C 6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO 2 R 10 , CON(R 12 ) 2 , OCON(R 12 ), SR 10 , SOR 11 , SO 2 (R 11 ), SO 2 N(R 12 ) 2 , N(R 12 ) 2 , NR 10 SO 2 R 11 , N(SO 2 R 11 ) 2 NR 10 (CH 2 ) n CN, NR 10 COR 11 , OCOR 11 or COR 10 ; each of R 5 to R 7 , which are the same or different, is selected from hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, SR 10 and N(R 12 ) 2 ; Q is C 1 -C 6 alkylene which is unsubstituted or substituted by (i) C 1 -C 6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not, to either of the N atoms adjacent to Q in formula (I), (iii) CO 2 R 10 , or (iv) CON(R 12 ); R 1 and R 9 , which are the same or different, are each hydrogen or C 1 -C 6 alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R 8 and R 9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that at least one R 1 to R 4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.

1 . A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I)  
       
         
           
           
               
               
           
         
         wherein each of R 1  to R 4 , which are the same or different, is selected from hydrogen, halogen, hydroxyl, C 1 -C 6  alkoxy which is unsubstituted or substituted, heteroaryloxy, C 1 -C 6  alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO 2 R 10 , CON(R 12 ) 2 , OCON(R 12 ), SR 10 , SOR 11 , SO 2 R 11 , SO 2 N(R 12 ) 2 , N(R 12 ) 2 , NR 10 SO 2 R 11 , N(SO 2 R 11 ) 2  NR 10  (CH 2 ) n CN, NR 10 COR 11 , OCOR 11  or COR 10 ;  
         each of R 5  to R 7 , which are the same or different, is selected from hydrogen, halogen, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, SR 10  and N(R 12 ) 2 ;  
         Q is C 1 -C 6  alkylene which is unsubstituted or substituted by (i) C 1 -C 6  alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not α to either of the N atoms adjacent to Q in formula (I), (iii) CO 2 R 11 , or (iv) CON(R 12 ) 2 ;  
         R 8  and R 9 , which are the same or different, are each hydrogen or C 1 -C 6  alkyl, or R 8  and R 9  together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R 8  and R 9  is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above;  
         R 10  is hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, benzyl or phenyl;  
         R 11  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, benzyl or phenyl;  
         each R 12 , which are the same or different, is hydrogen, C 1 -C 6  alkyl, cycloalkyl, benzyl or phenyl, or the two R 12  groups form, together with the nitrogen atom to which they are attached a 5- or 6-membered saturated N-containing heterocyclic ring which may include 1 or 2 additional heteroatoms selected from O, N and S; and  
         n is 1, 2 or 3;  
         or a pharmaceutically acceptable salt thereof;  
         with the proviso that at least one of R 1  to R 4  is other than hydrogen.  
       
     
     
         2 . A compound according to  claim 1  wherein the benzo[a]phenazine-11-carboxamide derivative is of formula (Ia):  
       
         
           
           
               
               
           
         
         wherein R 1  to R 9  are as defined in  claim 1;   
         p is 1, 2 or 3; and  
         R 13  is (i) hydrogen, (ii) C 1 -C 6  alkyl which is unsubstituted or substituted by hydroxy, aryl or N(R 12 ) 2  in which R 12  is as defined in  claim 1 , (iii) CO 2 R 10 , (iv) CON(R 12 ) 2  or (v) aryl.  
       
     
     
         3 . A compound according to  claim 1  or  2  wherein each of R 1  to R 3  is hydrogen and R 4  is other than hydrogen.  
     
     
         4 . A compound according to any one of the preceding claims wherein R 4  is C 1 -C 6  alkoxy, hydroxy, C 1 -C 6  alkyl, hydroxy-C 1 -C 6  alkyl, nitrile or halogen.  
     
     
         5 . A compound according to any one of the preceding claims wherein R 7  is hydroxy.  
     
     
         6 . A compound as defined in  claim 1  which is selected from: 
 3-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine 11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt  
 2-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 2-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Dimethylaminomethyl-3-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Dimethylaminomethyl-4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 9-Bromo-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4Cyanomethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Benzyloxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Prop-2-ynyloxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 3,4-Dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Ethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Isobutoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 4-(4Chloro-benzyloxy)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 4-(2-Methoxy-ethoxy)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 [11-(2-Dimethylamino-ethylcarbamoyl)-benzo[a]phenazin-4-yloxy]-acetic acid ethyl ester  
 3-Bromo-4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(2-Hydroxy-ethoxy)benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(Pyrimidin-2-yloxy)benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 4-(2-Morpholin-4-yl-ethoxy)benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(3-Cyano-propoxy)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Fluoro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(3-Dimethylamino-propoxy)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl) amide  
 4-Methylsulfanyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Carbamoylmethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (3-amino-2-hydroxy-propyl)amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (3-dimethylamino-propyl)-amide  
 4-Bromo-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 Acetic acid 11-(2-dimethylamino-ethylcarbamoyl)-benzo[a]phenazin-4-yl ester  
 4-(2-Oxo-propoxy)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-methyl-ethyl)-amide  
 4-Cyano-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 Ethyl-carbamic acid 11-(2-dimethylamino-ethylcarbamoyl)benzo[a]phenazin-4-yl ester  
 3-Nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methanesulfonyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Chloro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Azido-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Amino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 [11-(2-Dimethylamino-ethylcarbamoyl)benzo[a]phenazin-4-yloxy]-acetic acid trifluoro-acetate salt  
 4-Acetylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 11-(2-Dimethylamino-ethylcarbamoyl)-benzo[a]phenazine-4-carboxylic acid methyl ester  
 4-Bis-(Methanesulfonylamino)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Amino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(N-Hydroxycarbamimidoyl)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Hydroxymethyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 11-(2-Dimethylamino-ethylcarbamoyl)-benzo[a]phenazine-4-carboxylic acid, trifluoroacetate salt  
 4-Methylsulfamoyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide; trifluoro-acetate  
 3-Methylsulfamoyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide; trifluoro-acetate  
 3-Acetylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Dimethylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methanesulfonylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Methanesulfonylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Dimethylsulfamoyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 3-Dimethylsulfamoyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-(Cyanomethyl-amino)-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4,10-Dirnethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-propyl)-amide  
 Benzo[a]phenazine-4,11-dicarboxylic acid 4-amide 11-[(2-dimethylamine-ethyl)amide]; triflouroacetic acid salt  
 1-Chloro-4,10-dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Sulfamoyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1,1-dimethyl-ethyl)-amide  
 2-Nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-8-methyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4,10-Dihydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 3-Dimethylamino-2-[(4-methoxy-benzo[a]phenazine-11-carbonyl)-amino]-propionic acid methyl ester. Trifluoroacetic acid salt  
 3-Dimethylamino-2-[(4-methoxy-benzo[a]phenazine-11-carbonyl)-amino]-propionic acid; hydrochloride  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (1-dimethylaminomethyl-propyl)-amide  
 4,10-Dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-methyl-ethyl)amide  
 9-Chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (1-dimethylaminomethyl-2-methyl-propyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-hydroxymethyl-ethyl) amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (1-dimethylaminomethyl-2-phenyl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-(S)-methyl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-(R)-methyl-ethyl)-amide  
 4-Nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-methyl-ethyl)-amide  
 3-Nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-methyl-ethyl)amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1-(S)-hydroxymethyl-ethyl)-amide  
 4-Methoxy-10-methylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 10-Hydroxy-4-methoxy-benzo[a]phenazine-1-carboxylic acid (2-dimethylamino-1(R)-methyl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (1-dimethylaminomethyl-2-hydroxy-propyl)-amide  
 10-Hydroxy-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-piperidin-1-yl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid [1-dimethylamino-1-(2-hydroxyethyl)]-ethylamide  
 10-Amino-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-morpholin-4-yl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid {2-[bis-(2-hydroxy-ethyl)-amino]-ethyl}-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-diethylamino-ethyl)-amide  
 4-Methoxy-9-methylsulfanyl-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide  
 4,9-Dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)amide  
 4,10-Dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(S)-hydroxymethyl-ethyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-methylamino-ethyl)-amide  
 10-Hydroxy-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(S)-hydroxymethyl-ethyl)-amide  
 (R 4 -Methoxy-benzo[a]phenazine-11-carboxylic acid (1-dimethylaminomethyl-2-methyl-propyl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (1-methyl-pyrrolidin-3-(R)-yl)-amide  
 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2,3-(bis)-dimethylamino-propyl) amide  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         7 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as defined in any one of  claims 1  to  6 .  
     
     
         8 . A process for producing a compound as defined in  claim 1 , which process comprises: 
 (a) treating an activated derivative of a compound of formula (II):                          wherein R 1  to R 7  are as defined in  claim 1 , with an amine of formula (III):                          wherein Q, R 8  and R 9  are as defined in  claim 1;  or    (a) treating a compound of formula (IV):                          wherein R 1  to R 7  and R 11  are as defined in  claim 1 , with a compound of formula (III) as defined above, either in an organic solvent or neat, and at an elevated temperature; and    (c) if desired, converting the resulting benzo(a)phenazine-11-carboxamide derivative into another such derivative by routine chemical modification, and/or converting a benzo[a]phenazine-11-carboxamide derivative into a pharmaceutically acceptable salt thereof.    
     
     
         9 . A compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein R 1  to R 7  are as defined in  claim 1 , or a salt or ester thereof.  
     
     
         10 . A process for producing a compound of formula (II) as defined in  claim 9 , which process comprises: 
 (a) treating a 1,2-naphthoquinone of formula (V):                          wherein R 1  to R 4  are as defined in  claim 1 , with a benzoic acid of formula (VI):                          or an ester or salt thereof, wherein R 5 , R 6  and R 7  are as defined in  claim 1 , in an organic solvent.    
     
     
         11 . A process according to  claim 10  which is conducted in the presence of from 1 to 5 equivalents of a mineral acid.  
     
     
         12 . A compound as defined in any one of  claims 1  to  6  for use in a method of treatment of the human or animal body by therapy.  
     
     
         13 . A compound as claimed in  claim 12  for use as an inhibitor of topoisomerase I.  
     
     
         14 . A compound as claimed in  claim 12  for use as an inhibitor of topoisomerase II.  
     
     
         15 . A compound as claimed in  claim 12  for use as a joint inhibitor of topoisomerase I and topoisomerase II.  
     
     
         16 . A compound as claimed in any one of  claims 12  to  15  for use in the treatment of a tumour.  
     
     
         17 . A compound as claimed in  claim 16  wherein the tumour expresses MDR.  
     
     
         18 . A compound according to  claim 17  wherein the MDR is P-glycoprotein mediated MDR.  
     
     
         19 . A compound according to  claim 17  wherein the MDR is MRP mediated MDR.  
     
     
         20 . A compound according to  claim 17  wherein the MDR is a typical MDR.  
     
     
         21 . A compound as claimed in  claim 12  for use as an antiviral, antibacterial or antifungal agent.  
     
     
         22 . Use of a compound as defined in any one of  claims 1  to  6  in the manufacture of a medicament for use as an inhibitor of topoisomerase I and/or topoisomerase II.  
     
     
         23 . Use according to  claim 22  wherein the medicament is for oral administration in the treatment of a human or animal bearing a tumour.  
     
     
         24 . Use according to  claim 22  wherein the medicament is for parenteral administration in the treatment of a human or animal bearing a tumour.