Phenanthroline derivatives

Abstract

The present invention provides a phenanthroline derivative of formula (I) wherein, for example, R 1 is hydrogen, carboxy, cyano, nitro, (1-4C)alkyl, (1-6C)alkoxycarbonyl, (1-4C)alkylamino, (2-4C)alkanoyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl or N-[amino-(2-8C)alkyl]carbamoyl; R 2 is, for example, hydrogen, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl, 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl or N,N-[di-(l -4C)alkyl]thiocarbamoyl; R 3 and R 4 , which may be the same or different, are, for example, hydrogen or halo; and R 5 is, for example, hydrogen, di-(1-4C)alkylamino or halo; or a pharmaceutically-acceptable salt thereof. The invention further provides pharmaceutical compositions comprising phenanthroline derivatives, processes for making the same and their use in producing an anti-fibroproliferative effect.

We claim:  
     
         1 . A compound of formula (I):  
                   
       wherein R 1  is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-[amino-(2-8C)alkyl]carbamoyl; 
 R 2  is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-[amino-(2-8C)alkyl)carbamoyl, N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl, N-[di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-[phenyl-(1-4C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl, or N,N-di-[phenyl-(1-4C)alkyl]carbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl, N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl, N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or N,N-[di-fluoro-(2-6C)alkyl]carbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or N-[(1-4)alkoxycarbonyl]amino;  
 R 3  and R 4 , which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;  
 or R 4  is methoxy; or R 3  is methoxy; and  
 R 5  is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; or  
 a pharmaceutically-acceptable salt thereof; provided that:  
 R 1 , R 2 , R 3  , R 4  and R 5  are not together H;  
 where R 1  is carboxy and R 3  and R 4  are hydroxy; R 2  and R 5  are not together H;  
 where R 1  is carboxy, R 2  is H or OH, R 3  is H and R 5  is H; R 4 is not H, OH alkoxy, alkyl or halo;  
 where R 1  is carboxy, R 2  is H or OH, R 4  is H and R 5  is H; R 3  is not H, OH alkoxy, alkyl or halo;  
 where R 1  is ethoxycarbonyl; R 2 , R 3 , R 4  and R 5  are not together H;  
 where R 1  is ethoxycarbonyl and R 4  is F; R 2 , R 3  and R 5  are not together H  
 where R 1  is carboxy and R 3  is H or alkyl; R 2 , R 4  and R 5  are not together H;  
 where R 3  is OH; R 1  , R 2 , R 4  and R 5  are not together H;  
 where R 5  is OH, R 3  is H or alkyl, and R 4  is H; R 1  and R 2  are not together ethoxycarbonyl, carboxy, methoxycarbonyl or H; and  
 where R 5  is —N(CH 3 ) 2 ; R 1 , R 2 , R 3  and R 4  are not together H.  
 
     
     
         2 . A compound of    claim 1   : 
 3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-nitro-8-(4-benzylpiperazin-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-trifluoromethylsulphonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline; or    3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or    a pharmaceutically-acceptable salt thereof, or a metabolically labile ester derivative of those compounds bearing a carboxy group.    
     
     
         3 . A pharmaceutical composition comprising one or more compounds of formula (I):  
                   
       wherein R 1  is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-[amino-(2-8C)alkyl]carbamoyl; 
 R 2  is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-[amino-(2-8C)alkyl)carbamoyl, N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl, N-[di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-[phenyl-(1-4C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl or N,N-di-[phenyl-(1-4C)alkyl]carbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C) alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl, N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl, N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or N,N-[di-fluoro-(2-6C)alkyl]carbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or N-[(1-4)alkoxycarbonyl]amino;  
 R 3  and R 4 , which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;  
 or R 4  is methoxy; or R 3  is methoxy; and  
 R 5  is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; or  
 a pharmaceutically-acceptable salt thereof; and  
 a pharmaceutically-acceptable diluent or carrier.  
 
     
     
         4 . The composition of    claim 3   , comprising a compound selected from: 
 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro 1,10-phenanthroline;    3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro 1,10-phenanthroline;    3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or    3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.    
     
     
         5 . A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a composition of    claim 3   .  
     
     
         6 . The method of    claim 5    wherein said composition comprises: 
 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or  
 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.  
 
     
     
         7 . A method of treating the symptoms of a fibroproliferative disease or disorder in a host in need of such treatment comprising administering an effective amount of a composition of    claim 3   .  
     
     
         8 . The method of    claim 7    wherein said composition comprises: 
 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or  
 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.  
 
     
     
         9 . The method of    claim 7    wherein the disease is rheumatoid arthritis, chronic arthritis or osteoarthritis.  
     
     
         10 . The method of    claim 7    wherein the disease is hepatic cirrhosis.  
     
     
         11 . The method of    claim 7    wherein the disease is pulmonary fibrosis, renal fibrosis, cardiac fibrosis, arteriosclerosis or tumor associated fibrosis.  
     
     
         12 . A method of treating scar tissue formation following injury or surgery in a host in need of such treatment comprising administering an effective amount of a composition of    claim 3   .  
     
     
         13 . The method of    claim 12    wherein said composition comprises: 
 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-(2-{morpholino }ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or  
 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;  
 or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.  
 
     
     
         14 . The use of one or more phenanthroline derivatives of formula (I):  
                   
       wherein R 1  is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-[amino-(2-8C)alkyl]carbamoyl; 
 R 2  is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-[amino-(2-8C)alkyl)carbamoyl, N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl, N-[di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-[phenyl-(1-4C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl or N,N-di-[phenyl-(1-4C)alkyl]carbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl, N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl, N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or N,N-[di-fluoro-(2-6C)alkyl]carbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or N-[(1-4)alkoxycarbonyl]amino;  
 R 3  and R 4 , which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;  
 or R 4  is methoxy; or R 3  is methoxy; and  
 R 5  is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl in the manufacture of a medicament for use in the production of an anti-fibroproliferative effect.  
 
     
     
         15 . The use of 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline; 
 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;    3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or    3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;    or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof, according to    claim 14   .    
     
     
         16 . The use of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline according to    claim 14   .  
     
     
         17 . A pharmaceutical composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; and a pharmaceutically-acceptable diluent or carrier.  
     
     
         18 . A pharmaceutical composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.  
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically-acceptable salt of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.  
     
     
         20 . A pharmaceutical composition comprising a metabolically labile ester derivative of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.  
     
     
         21 . A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; or an effective amount of a composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; and a pharmaceutically-acceptable diluent or carrier.  
     
     
         22 . A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.  
     
     
         23 . A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a pharmaceutically-acceptable salt of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.  
     
     
         24 . A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a metabolically labile ester derivative of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.