Camptothecin analogs having an E-ring ketone

Abstract

Camptothecin analogs having an E-ring ketone are effective anti tumor compounds. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I DNA cleavable complex.

1 . A camptothecin analog having the structure:  
       
         
           
           
               
               
           
         
         where  
         X and Y are each independently NO 2 , NH 2 , H. F. Cl, Br, I, COOH, OH, O-C 1-6  alkyl, SH, S—C 1-6  alkyl, CN, NH—C 1-6  alkyl, N(C 1-6  alkyl) 2 , CHO, C 1-8  alkyl, N 3 ,  
         -Z-(CH 2 ) a -N-((CH 2 ) b OH) 2 , wherein Z is selected from the group consisting of O, NH and S, and a and b are each independently an integer of 2 or 3,  
         -Z-(CH 2 ) a —N—(C 1-6  alkyl) 2  wherein Z is selected from the group consisting of O, NH and S, and a is an integer of 2 or 3, or  
         —CH 2 -L, where L is halogen (F, Cl, Br, I),  + N 2 ,  + (OR 1 ) 2 ,  + S(R 1 ) 2 ,  + N(R 1 ) 3 , OC(O)R 1 , OSO 2 R 1 , OSO 2 CF 3 , OSO 2 C 4 F 9 , C 1-6  alkyl-C(═O)—, C 4-18  aryl-C(═O)—, C 1-6  alkyl-SO 2 —, perfluoro C 1-6  alkyl-SO 2 — or C 4-18  aryl-SO 2 —, (where each R 1  independently is C 1-6  alkyl, C 4-18  aryl or C 4-18  ArC 1-16  alkyl); or  
         —CH 2 NR 2 R 3 , where (a) R 2  and R 3  are, independently, hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-6  alkyl, C 2-6  alkenyl, hydroxy C 1-6  alkyl, C 1-6  alkoxy C 1-6  COR 4  where R 4  is hydrogen, C 1-6  alkyl, perhalo C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-6  alkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6 -alkoxy, or C 1-6  alkoxy-C 1-6  alkyl, or (b) R 2  and R 3  taken together with the nitrogen atom to which they are attached form a saturated 3-7 membered heterocyclic ring which may contain a O, S or NR 5  group, where R 5  is hydrogen, C 1-6  alkyl, perhalo-C 1-6  alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C 1-6  alkyl, halogen, nitro, amino, C 1-6  alkylamino, perhalo-C 1-6  alkyl, hydroxyl-C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6  alkyl and —COR 6  where R 6  is hydrogen, C 1-6  alkyl perhalo-C 1-6  alkyl, C 1-6  alkoxy, aryl, and aryl substituted with one or more C 1-6  alkyl, perhalo-C 1-6  alkyl, hydroxyl-C 1-6  alkyl, or C 1-6  alkoxy-C 1-6  alkyl groups;  
         R 7  is C(O)—(CH 2 ) m —NR 8 R 9 , where m is an integer of 1-6 or —C(O)CHR 10 NR 8 R 9 , where R 10  is the side chain of one of the naturally occurring α-amino acids, R 8  and R 9  are, independently, hydrogen, C 1-8  alkyl or —C(O)CHR 11 NR 12 R 12 ′ where R 11  is the side chain of one of the naturally occurring α-amino acids and R 12  and R 12 ′ are each independently hydrogen or C 1-8  alkyl;  
         W is independently H or F,  
         R 13  and R 14  are each H or combine to form a double bond; and  
         n is an integer of 1 or 2,  
         and salts thereof.  
       
     
     
         2 . The camptothecin analog of  claim 1 , wherein n is 1.  
     
     
         3 . The camptothecin analog of  claim 1 , wherein Y is —CH 2 -L.  
     
     
         4 . The camptothecin analog of  claim 1 , wherein L is selected from the group consisting of Cl, Br and I.  
     
     
         5 . (canceled)  
     
     
         6 . The camptothecin analog of  claim 1 , which is selected from the group consisting of R isomers, S isomers and mixtures thereof.  
     
     
         7 . The camptothecin analog of  claim 6 , wherein the analog is the S isomer.  
     
     
         8 . The camptothecin analog of  claim 6 , wherein tile analog is the R isomer.  
     
     
         9 . The camptothecin analog of  claim 6 , wherein the analog is an S rich mixture of S and R isomers.  
     
     
         10 . The camptothecin analog of  claim 6 , wherein the analog is a R rich mixture of S and R isomers.  
     
     
         11 . The camptothecin analog of  claim 6 , wherein the analog is a racemic mixture of R and S isomers.  
     
     
         12 . A method of treating leukemia or solid tumors comprising administering to a patient in need thereof, the camptothecin analog of  claim 1 .  
     
     
         13 . A pharmaceutical composition comprising the camptothecin analog of  claim 1 .  
     
     
         14 . A method for inhibiting the enzyme topoisomerase I, comprising contacting a DNA-topoisomerase I complex with the camptothecin analog of  claim 1 .  
     
     
         15 . (canceled)