Induction of apoptosis in cancer cells

Abstract

The present invention provides compounds that are inducers or inhibitors of apoptosis of apoptosis preceded by cell-cycle arrest. In addition, the present invention provides pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.

1. A compound having formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is adamantyl, bicyclooctyl, bicyclooctenyl, aza-bicyclooctyl, or aza-bicyclooctenyl; 
         wherein the R 1  groups are optionally substituted with one or more C 1-10 alkyl groups; 
         R 2  is hydroxy, —SH, amino, —CN, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, —COOR 14 , —C(═O)R 14 , —C(═O)N(R 14 ) 2 , —N(R 14 )C(═O)R 14 , —P(O)(OR 14 ) 2 (phosphonic acid), —S(O) 2 OR 14 (sulfonic acid), —S(O) 2 N(R 14 ) 2 (sulfonamide), —N—C(NH)—N(R 14 ) 2 (guanidino), (hydroxy)C 1-10 alkylene-, (C 1-10 alkyl)—C(O)—, —C(O)—NHOR 14 (hydroxamic acid), or oxime; 
         R 3  is hydrogen, C 1-10 alkyl, hydroxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, —COOR 14 (carboxylic acid), —P(O)(OR 14 ) 2 (phosphonic acid), —S(O) 2 OR 14 (sulfonic acid), —S(O) 2 N(R 14 ) 2 (sulfonamide), —N—C(NH)—N(R 15 ) 2 (guanidino), (hydroxy)C 1-10 alkylene, (C 1-10 alkyl)—C(O)—, —C(O)—NHOR 14 (hydroxamic acid), carbonyl oxime, fluoro, chloro, bromo, iodo, —CF 3  or nitro; or R 1  and R 3  taken together with the ring to which they are attached can form a polycyclic group which can be fully saturated, partially saturated or aromatic; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         wherein each R 5  is independently hydroxy, C 1-10  alkyl, C 1-10 alkoxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, (amino)C 1-10 alkyleneoxy)—, (acetamido)alkoxy, (C 1-10 )mercapto, (hydroxy)C 1-10 alkylene-, halo, halo(C 1-10 )alkyl, (C 1-10 alkoxy)-C 1-10 alkylene-, nitro, acetamido, phenyl, or substituted phenyl; 
         R 6  is hydrogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, amino, (C 1-10 alkyl)NH—, (C 1-10 alkyl) 2 N—, (amino)C 1-10 alkyleneoxy)-, (acetamido)alkoxy, (C 1-10 alkyl)mercapto, (hydroxy)C 1-10 alkylene-, halo, halo(C 1-10 )alkyl, (C 1-10 alkoxy)C 1-10 alkylene-, nitro, acetamido, phenyl, or substituted phenyl; 
         R 9  is —COOR 14 , —P(O)(OR 14 ) 2 , —S(O) 2 OR 14 , —C(O)—NHOR 14 , thiazolidenedione, tropolone, tetrazole, nitro, —(CH 2 ) j OR 15 , or —N—C(NH)—N(R 15 ) 2 ; 
         R 12  is —C(R 16 )═C(R 16 )(R 9 ), aryl-R 9 , or 2-cyclopropyl-R 9 , where each R 16  is independently hydrogen or fluorine; 
         R 14  is hydrogen, (C 1-25 )alkyl or aryl; 
         R 15  is hydrogen, (C 1-10 alkyl)—C(O)—, or(aryl)—C(O)—; 
         j is from 1 to 10; and n is 0, 1, 2, or 3; 
         wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, polycycloalkyl, polycycloalkenyl, heterocycloalkyl, polyheterocycloalkyl, heterocycloalkenyl, polyheterocycloalkenyl, aryl, or heteroaryl group of R 1 , R 2 , R 3 , R 5 , and R 6  is optionally substituted with one or more, such as 1, 2, 3, or 4, substituents independently selected from oxo(═O), halo, —OH, —CN, —NO 2 , —CF 3 , —OCF 3 , —S(O) 0-2 C 1-6  alkyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl-NR a R b , phenyl, C 1-8 alkanoyl, —NR a R b , —C(═O)NR a R b , or —SO 2 NNR a R b ; 
         wherein each R a  and R b  is independently hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, aryl, (aryl)C 1-8 alkylene-, arylcarbonyl, or aryloxycarbonyl; or R a  and R b  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; or 
         a pharmaceutical acceptable salt thereof. 
       
     
     
       2. The compound of  claim 1  wherein R 1  is adamantyl. 
     
     
       3. The compound of  claim 1  wherein R 2  is hydroxy, —COOR 14 , —C(═O)CH 3 , or —SH. 
     
     
       4. The compound of  claim 3  wherein R 2  is hydroxy. 
     
     
       5. The compound of  claim 1  wherein R 3  is hydrogen, methyl, ethyl, chloro, bromo, fluoro, or —CF 3 . 
     
     
       6. The compound of  claim 5  wherein R 3  is hydrogen, or methyl. 
     
     
       7. The compound of  claim 1  wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
       8. The compound of  claim 7  wherein R 5  and R 6  are independently hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       9. The compound of  claim 8  wherein R 5  and R 6  are independently hydrogen, methyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2  or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       10. The compound of  claim 9  wherein R 5  and R 6  are independently hydrogen, methyl, chloro, bromo, or fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2  or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       11. The compound of  claim 10  wherein one of R 5  and R 6  is hydrogen and the other is methyl, chloro, bromo, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       12. The compound of  claim 1  wherein R 9  is —COOR 14 , —P(O)(OR 14 ) 2 , —S(O) 2 OR 14 , or —C(O)—NHOR 14 . 
     
     
       13. The compound of  claim 12  wherein R 9  is —COOR 14 . 
     
     
       14. The compound of  claim 1  wherein R 12  is —C(H)═C(H)(R 9 ), or aryl-R 9 . 
     
     
       15. The A compound of  claim 1  wherein having the formula (II): 
       
         
           
           
               
               
           
         
         wherein R 1  is adamantyl, bicyclooctyl, bicyclooctenyl, aza-bicyclooctyl, or aza-bicyclooctenyl; 
         wherein R 2  is —OH, R 4  is 
       
       
         
           
           
               
               
           
         
         R 12  is —C(H)═C(H)—C(═O)OR 14  where R 14  is hydrogen or ethyl; and R 5  and R 6  are independently hydrogen, is methyl, methoxy, chloro, or fluoro and R 6  is hydrogen, methyl, methoxy, chloro, or fluoro. 
       
     
     
       16. The compound of  claim 15  wherein R 12  is the E-isomer. 
     
     
       17. The compound of  claim 1  wherein R 3  is —CF 3 . 
     
     
       18. The A compound of  claim 15  having the formula: 
       
         
           
           
               
               
           
         
       
       or a plmrmaceutically acceptable salt thereof. 
     
     
       19. The A compound of  claim 15  having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       20. The compound of  claim 15  having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       21. The A compound of  claim 15  having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       22. A method of treating cancer in a mammal comprising contacting the cancer cells with a compound of  claim 1 , effective to reduce the viability of the cancerous cells, wherein the cancer is lung cancer, breast cancer, prostate cancer, or leukemia. 
     
     
       23. The method of  claim 22  wherein the leukemia is acute lymphocytic leukemia, acute myelogenous leukemia, or chronic myelogenous leukemia. 
     
     
       24. A method for inducing apoptosis, inducing caspase activity, or inducing cell death in a mammal comprising contacting target cells with a compound of  claim 1 , effective to induce apoptosis, induce caspase activity, or induce cell death to the target cells, wherein the target cells are lung cancer, breast cancer, prostate cancer, or leukemia cells. 
     
     
       25. The compound of claim 1 wherein R 6  is methyl, chloro, bromo, trifluoromethyl, —O—(CH 2 ) 3 —NH 2 , —OR or —O—(CH 2 ) 3 —NHC(═O)CH 3  wherein R of —OR is hydrogen or C 1 -C 10  alkyl. 
     
     
       26. The compound of claim 1 wherein n is 0. 
     
     
       27. The compound of claim 26 wherein R 1  is adamantyl. 
     
     
       28. The compound of claim 26 wherein R 2  is hydroxy, —COOR 14 , —C(═O)CH 3 , or —SH. 
     
     
       29. The compound of claim 28 wherein R 2  is hydroxy. 
     
     
       30. The compound of claim 26 wherein R 3  is hydrogen, methyl, ethyl, chloro, bromo, fluoro, or —CF 3 . 
     
     
       31. The compound of claim 26 wherein R 6  is methyl, ethyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2 , or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       32. The compound of claim 31 wherein R 6  is methyl, methoxy, ethoxy, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2  or —O—CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       33. The compound of claim 32 wherein R 6  is methyl, chloro, bromo, fluoro, —CF 3 , —O—(CH 2 ) 3 —NH 2  or —O—(CH 2 ) 3 —NH—C(═O)CH 3 . 
     
     
       34. The compound of claim 33 wherein R 6  is methyl, chloro, bromo, —CF 3 , —O—(CH 2 ) 3 —NH 2  or —O—(CH 2 ) 3 —NH—C(═O)CH 3 .