Substituted Quinolines for the Treatment of Cancer

Abstract

Compounds of formula G1-L-G2, where G1, is a radical structurally close to cryptolepine, -L- is a single covalent bond or a covalent linking biradical selected from —(CH2)rNR′″(CH2)s— and —(CH2)rNR′″(CH2)sNR″″(CH2)t—, —R′″ and —R″″ are radicals, same or different, selected from the group consisting of H and (C1-C3)-alkyl; r, s and t are an integer from 1 to 3 and -G2 is H or a radical structurally close to -G1, are intercalators. They are compounds which intercalate between DNA base pairs, and are useful as therapeutic agents against cancer, as assess by an in vitro test of citotoxicity with human leukemia cells Jurkat E6-1 and human carcinoma cells GLC-4. Preferred compounds are those where -G1 is bonded to -L- through a carbonyl amino and -L- is —(CH2)3NCH3(CH2)3— or —(CH2)2NCH3(CH2)sNCH3(CH2)2— where s=2 or 3. -G1 is a radical selected from (IIa) and (IIb); -G2 is a radical selected from H, a radical of formula (IIa), a radical of formula (IIb), the N-radical of 1,8-naphthalimide, the C4-radical of 2-phenylquinoline and the C9-radical of acridine.

1 . A compound of formula (I)
   G 1 -L-G 2    (I)
   or a pharmaceutically acceptable salt thereof, wherein:   -G 1  is a radical (II)   
       
         
           
           
               
               
           
         
         wherein —R 1  is an electron pair or a (C 1 -C 3 )-alkyl radical; with the condition that (i) when —R′ is an electron pair, a is a N═C double bond and the fused ring 
       
       
         
           
           
               
               
           
         
         is the biradical 
       
       
         
           
           
               
               
           
         
         thus radical (II) is (IIa′), and 
       
       
         
           
           
               
               
           
         
         (ii) when —R′ is a (C 1 -C 3 )-alkyl radical, a is a N—C single bond and the fused ring is the triradical 
       
       
         
           
           
               
               
           
         
         thus radical (II) is (IIa″); 
       
       
         
           
           
               
               
           
         
         wherein —R 1  to —R 12  represent radicals, same or different, selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylamino, phenyl, F, Cl, Br, amino, hydroxy, and nitro; 
         and wherein —B— is a biradical selected from the group consisting of —CONH—, —NR 13 —, —O—, —(CH 2 ) n NH—, —(CH 2 ) n O—, and —CO[NHCHR″CO] m O—; wherein —R 13  is selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylamino; —R″ are side chains radicals, same or different, corresponding to natural aminoacids; n is an integer from 1 to 3 and m is an integer from 1 to 3; 
         -L- is a single covalent bond or a covalent linking biradical selected from the following ones;
   —(CH 2 ) r NR′″(CH 2 ) s —
 
   —(CH 2 ) r NR′″(CH 2 ) s NR″″(CH 2 ) t —
 
 
         wherein —R′″ and —R″″ are radicals, same or different, selected from the group consisting of H and (C 1 -C 3 )-alkyl; r is an integer from 1 to 3; s is an integer from 1 to 3; t is an integer from 1 to 3; and 
         -G 2  is a radical selected from a radical of formula (II), the N-radical of 1,8-naphthalimide, the C4-radical of 2-phenylquinoline, and the C9-radical of acridine. 
       
     
     
         2 . The compound according to  claim 1 , wherein (II) is the radical (IIa′) 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2 , wherein —B— is selected from the group consisting of —CONH— and —NR 13 —. 
     
     
         4 . The compound according to  claim 2 , wherein —B— is —CO[NHCHR″CO] m O—. 
     
     
         5 . The compound according to  claim 4 , wherein m=2, the leftward —R″ is a glicine side chain, and the rightward —R″ is an arginine side chain. 
     
     
         6 . The compound according to  claim 2 , wherein -L- is a single covalent bond. 
     
     
         7 . The compound according to  claim 2 , wherein -L- is a covalent linking biradical selected from the following ones
   —(CH 2 ) r NR′″(CH 2 ) s —
     —(CH 2 ) r NR′″(CH 2 ) s NR″″(CH 2 ) t —
   
     
     
         8 . The compound according to  claim 7 , wherein -L- is the biradical
 —(CH 2 ) r NR′″(CH 2 ) s —, —R′″ is methyl, and both r and s are 3.   
     
     
         9 . The compound according to  claim 7 , wherein -L- is the covalent linking biradical —(CH 2 ) r NR′″(CH 2 ) s NR″″(CH 2 ) t —, both —R′″ and —R″″ are methyl; both r and t are 2, and s is 2 or 3. 
     
     
         10 . The compound according to  claim 1 , wherein (II) is the radical (IIa″) 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 10 , wherein —B— is selected from the group consisiting of —CONH— and —NR 13 —. 
     
     
         12 . The compound according to  claim 10 , wherein —B— is —CO[NHCHR″CO] m O—. 
     
     
         13 . The compound according to  claim 12 , wherein m=2, the leftward —R″ is a glicine side chain, and the rightward —R″ is the arginine side chain. 
     
     
         14 . The compound according to  claim 10 , wherein —R′ is methyl. 
     
     
         15 . The compound according to  claim 14 , wherein -L- is a single covalent bond. 
     
     
         16 . The compound according to  claim 14 , wherein -L- is a biradical selected from the following ones.
   —(CH 2 ) r NR′″(CH 2 ) s —
     —(CH 2 ) r NR′″(CH 2 ) s NR″″(CH 2 ) t —
   
     
     
         17 . The compound according to  claim 16 , wherein -L- is the biradical —(CH 2 ) r NR′″(CH 2 ) s —, R′″ is methyl, and both r and s are 3. 
     
     
         18 . The compound according to  claim 16 , wherein -L- is the biradical —(CH 2 ) r NR′″(CH 2 ) s NR′″(CH 2 ) t —, both —R′″ and —R″″ are methyl; both r and t are 2, and s is an integer from 2 to 3. 
     
     
         19 . The compound according to  claim 1 , which is selected from the group consisting of:
 N-[3-[[3-[(9-acridinecarbonyl)amino]propyl]methylamino]propyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (Ia);   N,N′-(4-methyl-4-azaheptamethylene)-di-(10H-indolo[3,2-b]quinoline-11,11′-carboxamide) (Ib);   N-[3-[3-[[2-(1,3-dioxo-(2,3-dihydro)-1H-benzo[de]isoquinolinyl]propyl]methylamino]propyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (Ic);   N-[3-[[3-[(2-phenyl-4-quinolinecarbonyl)amino]propyl]methylamino]propyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (Id);   N,N′-(3,7-dimethyl-3,7-diazanonamethylene)-di-(10H-indolo[3,2-b]quinoline-11,11′-carboxamide) (Ie);   N-[(9-acridinecarbonyl)-3,7,10-triaza-3,7-dimethyldecyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (If);   N,N′-(3,6-dimethyl-3,6-diazaoctamethylene)-di-(10H-indolo[3,2-b]quinoline-11-11′-carboxamide (Ig);   N-[(9-acridinecarbonyl)-3,6-dimethyl-3,6-diazaoctamethylene]-10H-indolo[3,2-b]quinoline-11-carboxamide (Ih);   N-[[1,3-dioxo-(2,3-dihydro)-1H-benzo[de]isoquinolyl]-3,6-dimethyl-3,6-diazaoctamethylene]-10H-indolo[3,2-b]quinoline-11-carboxamide (Ii);   N-[[1,3-dioxo-(2,3-dihydro)-1H-benzo[de]isoquinolyl]-3,7,10-triaza-3,7-dimethyldecyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (Ij);   N,N′-(4-methyl-4-azaheptamethylene)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-carboxamide) (Im);   N,N′-(4-methyl-4-azaheptamethylen)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-amine (Iq);   N,N′-(3,7-dimethyl-3,7-diazanonamethylene)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-carboxamide) (Iy);   N,N′-(3,6-dimethyl-3,6-diazaoctamethylene)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-carboxamide) (Iz);   (3,7-diazanonamethylene)-di-(10H-indolo[3,2-b]quinoline-11,11′-carboxamide (Iaa);   N,N′-(3,7-dimethyl-3,7-diazanonamethylene)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-amine (Iab); and   N,N′-(3,6-dimethyl-3,6-diazaoctamethylene)-di-(5-methyl-5H-indolo[3,2-b]quinoline-11,11′-amine (Iac).   
     
     
         20 . A method for the preparation of a medicament for the treatment of cancer which comprises administering to a subject a therapeutically effective amount of a compound of formula (I)
   G 1 -L-G 2    (I)
   or a pharmaceutically acceptable salt thereof, wherein:   -G 1  is a radical (II)   
       
         
           
           
               
               
           
         
         wherein —R′ is an electron pair or a (C 1 -C 3 )-alkyl radical; with the condition that (i) when —R′ is an electron pair, a is a N═C double bond and the fused ring 
       
       
         
           
           
               
               
           
         
         is the biradical 
       
       
         
           
           
               
               
           
         
         thus radical (II) is (IIa′), and 
       
       
         
           
           
               
               
           
         
         (ii) when —R′ is a (C 1 -C 3 )-alkyl radical, a is a N—C single bond and the fused ring is the triradical 
       
       
         
           
           
               
               
           
         
         thus radical (II) is (IIa″); 
       
       
         
           
           
               
               
           
         
         wherein —R 1  to —R 12  represent radicals, same or different, selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylamino, phenyl, F, Cl, Br, amino, hydroxy, and nitro; 
         and wherein —B— is a biradical selected from the group consisting of —CONH—, —NR 13 —, —O—,—(CH 2 ) n NH—, —(CH 2 ) n O—, and —CO[NHCHR″CO] m O—; wherein —R 13  is selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylamino; —R″ are side chains radicals, same or different, corresponding to natural aminoacids; n is an integer from 1 to 3 and m is an integer from 1 to 3; 
         -L- is a single covalent bond or a covalent linking biradical selected from the following ones.
   —(CH 2 ) r NR′″(CH 2 ) s —
 
   —(CH 2 ) r NR′″(CH 2 ) s NR′″(CH 2 ) t —
 
 
         wherein —R′″ and —R′″ are radicals, same or different, selected from the group consisting of H and (C 1 -C 3 )-alkyl; r is an integer from 1 to 3; s is an integer from 1 to 3; t is an integer from 1 to 3; and 
         -G 2  is a radical selected from a radical of formula (II), the N-radical of 1,8-naphthalimide, the C4-radical of 2-phenylquinoline, and the C9-radical of acridine. 
       
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in  claim 1 , together with appropriate amounts of pharmaceutical excipients or carriers. 
     
     
         22 . A method of producing a composition of matter of formula (I) comprising one of the following processes: 
       
         
           
           
               
               
           
         
         when biradical —B— in -G 1  is —CONH— and -G 2  is not an N-radical of 1,8-naphtalimide; and 
         wherein GP represents an amino protective group and wherein formula (IV) is a monoprotected bis-amine; or 
       
       
         
           
           
               
               
           
         
         when biradical —B— in -G 1  is —CONH— and -G 2  is 1,8-naphtalimide; and 
         wherein GP represents an amino protective group and wherein formula (IV) is a monoprotected bis-amine; or 
       
       
         
           
           
               
               
           
         
         when biradical —B— is a biradical selected from a group of: —NR 13 —, —O—, —(CH 2 ) n NH, and —(CH 2 ) n O—; and 
         wherein GP represents an amino protective group.