Compunds and compositions that cause non-apoptotic cell death and uses thereof

Abstract

The present invention relates to erastin analogs, particularly compounds of formulae I and II, including compounds 1-20, 22-24, 34, and 40. The invention also relates to pharmaceutical compositions containing such analogs and to methods of treating conditions in a mammal with such analogs and pharmaceutical compositions.

1 . A compound having formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a hydrophobic or hydrophilic substituent, which is attached to one or more positions of at least one carbon atom of the ring; 
 R 2  is selected from is selected from H, C 1-8 alkyl, C 1-8 alkoxy, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, C 1-4 aralkyl, residues of glycolic acid, ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(R 6 ) 2 COOH, SC(R 6 ) 2 COOH, NHCHR 6 COOH, COR 7 , CO 2 R 7 , sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, propylphthalimide, and thioether; 
 R 3  is a C 2-8  alkoxy; 
 R 6  is selected from H, C 1-8 alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle, wherein each alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle may be optionally substituted with at least one substituent; 
 R 7  is selected from H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic, wherein each alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic may be optionally substituted with at least one substituent; or 
 an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein the hydrophilic substituent is selected from the group consisting of alcohols, amines, nitro, carboxylic acids, carboxylates, hydroxy, amides, sulfamides, sulfonic acids, sulfonates, sulfates, esters, thiol esters, ethers, thiols, thiolates, thiol ethers, morpholino, fluoroaromatics, piperazines, piperadines, phosphonates, and salts thereof, and combinations thereof. 
     
     
         3 . The compound according to  claim 2 , wherein the hydrophilic substituent is selected from the group consisting of NH 2 , NO 2 , NCOCH 3 , and combinations thereof. 
     
     
         4 . The compound according to  claim 1 , wherein R 2  is H or CH 3 . 
     
     
         5 . The compound according to  claim 1 , wherein R 3  is ethoxy or isopropoxy. 
     
     
         6 . A compound having formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a hydrophobic or hydrophilic substituent, which is attached to one or more positions of at least one carbon atom of the ring; 
 R 3  is a C 2-8  alkoxy; or 
 an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
 
     
     
         7 . The compound according to  claim 6 , wherein the hydrophilic substituent is selected from the group consisting of alcohols, amines, nitro, carboxylic acids, carboxylates, hydroxy, amides, sulfamides, sulfonic acids, sulfonates, sulfates, esters, thiol esters, ethers, thiols, thiolates, thiol ethers, morpholino, fluoroaromatics, piperazines, piperadines, phosphonates, and salts thereof, and combinations thereof. 
     
     
         8 . The compound according to  claim 7 , wherein the hydrophilic substituent is selected from the group consisting of NH 2 , NO 2 , NCOCH 3 , and combinations thereof. 
     
     
         9 . The compound according to  claim 6 , wherein R 3  is ethoxy or isopropoxy. 
     
     
         10 . The compound according to  claim 1 , which is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
       
     
     
         11 . A compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 A is selected from the group consisting of C, N, and O; 
 R 1  is a hydrophobic or hydrophilic substituent, which is attached to one or more positions of at least one carbon atom of the ring with the proviso that when A is C, R 1  is not NH 2  or NO 2 ; 
 R 2  is selected from H, C 1-8 alkyl, C 1-8 alkoxy, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, C 1-4 aralkyl, residues of glycolic acid, ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(R 6 ) 2 COOH, SC(R 6 ) 2 COOH, NHCHR 6 COOH, COR 7 , CO 2 R 7 , sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, propylphthalimide, and thioether; 
 R 3  is a C 2-8  alkoxy; 
 R 4  is a hydrophilic substituent, which is attached to at least one position of A, except that when A is O, R 3  is nothing; 
 R 6  is selected from H, C 1-8 alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle, wherein each alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle may be optionally substituted with at least one substituent; 
 R 7  is selected from H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic, wherein each alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic may be optionally substituted with at least one substituent; or 
 an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
 
     
     
         12 . The compound according to  claim 11 , wherein the hydrophilic substituent is selected from the group consisting of alcohols, amines, nitro, carboxylic acids, carboxylates, hydroxy, amides, sulfamides, sulfonic acids, sulfonates, sulfates, esters, thiol esters, ethers, thiols, thiolates, thiol ethers, morpholino, fluoroaromatics, piperazines, piperadines, phosphonates, and salts thereof, and combinations thereof. 
     
     
         13 . The compound according to  claim 12 , wherein the hydrophilic substituent is NCOCH 3 . 
     
     
         14 . The compound according to  claim 11 , wherein R 2  is H or CH 3 . 
     
     
         15 . The compound according to  claim 11 , wherein R 3  is ethoxy or isopropoxy. 
     
     
         16 . The compound according to  claim 11 , wherein A is C. 
     
     
         17 . A compound selected from the group consisting of formula IIa, IIb, and IIc: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a hydrophobic or hydrophilic substituent, which is attached to one or more positions of at least one carbon atom of the ring with the proviso that in formula IIa, R 1  is not NH 2  or NO 2 ; 
 R 2  is selected from H, C 1-8 alkyl; 
 R 3  is a C 2-8  alkoxy; 
 R 4  and R 5 , when present, are independently selected from the group consisting of H and an hydrophilic substituent; or 
 an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
 
     
     
         18 . The compound according to  claim 17 , which is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
       
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10 ,  11 ,  12 ,  13 ,  14 ,  15 ,  16 ,  17 , or  18 . 
     
     
         20 . A method of treating a condition in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10 ,  11 ,  12 ,  13 ,  14 ,  15 ,  16 ,  17 , or  18 . 
     
     
         21 . The method according to  claim 20 , wherein the mammal is a human. 
     
     
         22 . The method according to  claim 20 , wherein the condition is cancer. 
     
     
         23 . The method according to  claim 22 , wherein the cancer is selected from the group consisting of leukemia, non-small cell lung carcinoma, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, and pancreatic cancer. 
     
     
         24 . The method according to  claim 20 , further comprising conjointly administering to the mammal an agent that kills cells through an apoptotic mechanism. 
     
     
         25 . The method, according to  claim 24 , wherein the agent is a chemotherapeutic agent. 
     
     
         26 . The method according to  claim 25 , wherein the chemotherapeutic agent is selected from the group consisting of an EGF-receptor antagonist, arsenic sulfide, adriamycin, cisplatin, carboplatin, cimetidine, caminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, raltitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, enediynes, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxygenated paclitaxel, TL-139, 5′-nor-anhydrovinblastine (hereinafter: 5′-nor-vinblastine), camptothecin, irinotecan (Camptosar, CPT-11), topotecan (Hycamptin), BAY 38-3441, 9-nitrocamptothecin (Orethecin, rubitecan), exatecan (DX-8951), lurtotecan (GI-147211C), gimatecan, homocamptothecins diflomotecan (BN-80915) and 9-aminocamptothecin (IDEC-13′), SN-38, ST1481, karanitecin (BNP1350), indolocarbazoles (e.g., NB-506), protoberberines, intoplicines, idenoisoquinolones, benzo-phenazines, NB-506, and combinations thereof. 
     
     
         27 . A method of treating a condition in a mammal, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition according to  claim 20 . 
     
     
         28 . The method according to  claim 27 , wherein the mammal is a human. 
     
     
         29 . The method according to  claim 28 , wherein the condition is cancer. 
     
     
         30 . The method according to  claim 29 , wherein the cancer is selected from the group consisting of leukemia, non-small cell lung carcinoma, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, and pancreatic cancer. 
     
     
         31 . The method according to  claim 27 , further comprising conjointly administering to the mammal an agent that kills cells through an apoptotic mechanism. 
     
     
         32 . The method according to  claim 31 , wherein the agent is a chemotherapeutic agent. 
     
     
         33 . The method according to  claim 32 , wherein the chemotherapeutic agent is selected from the group consisting of an EGF-receptor antagonist, arsenic sulfide, adriamycin, cisplatin, carboplatin, cimetidine, caminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, raltitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, enediynes, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxygenated paclitaxel, TL-139, 5′-nor-anhydrovinblastine (hereinafter: 5′-nor-vinblastine), camptothecin, irinotecan (Camptosar, CPT-11), topotecan (Hycamptin), BAY 38-3441, 9-nitrocamptothecin (Orethecin, rubitecan), exatecan (DX-8951), lurtotecan (GI-147211C), gimatecan, homocamptothecins diflomotecan (BN-80915) and 9-aminocamptothecin (IDEC-13′), SN-38, ST1481, karanitecin (BNP1350), indolocarbazoles (e.g., NB-506), protoberberines, intoplicines, idenoisoquinolones, benzo-phenazines, NB-506, and combinations thereof. 
     
     
         34 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
       
     
     
         35 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to  claim 34 . 
     
     
         36 . A method of treating a condition in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 34 . 
     
     
         37 . The method according to  claim 36 , wherein the mammal is a human. 
     
     
         38 . The method according to  claim 36 , wherein the condition is cancer. 
     
     
         39 . The method according to  claim 38 , wherein the cancer is selected from the group consisting of leukemia, non-small cell lung carcinoma, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, and pancreatic cancer. 
     
     
         40 . The method according to  claim 36 , further comprising conjointly administering to the mammal an agent that kills cells through an apoptotic mechanism. 
     
     
         41 . The method according to  claim 40 , wherein the agent is a chemotherapeutic agent. 
     
     
         42 . The method according to  claim 41 , wherein the chemotherapeutic agent is selected from the group consisting of an EGF-receptor antagonist, arsenic sulfide, adriamycin, cisplatin, carboplatin, cimetidine, caminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, raltitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, enediynes, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxygenated paclitaxel, TL-139, 5′-nor-anhydrovinblastine (hereinafter: 5′-nor-vinblastine), camptothecin, irinotecan (Camptosar, CPT-11), topotecan (Hycamptin), BAY 38-3441, 9-nitrocamptothecin (Orethecin, rubitecan), exatecan (DX-8951), lurtotecan (GI-147211C), gimatecan, homocamptothecins diflomotecan (BN-80915) and 9-aminocamptothecin (IDEC-13′), SN-38, ST1481, karanitecin (BNP1350), indolocarbazoles (e.g., NB-506), protoberberines, intoplicines, idenoisoquinolones, benzo-phenazines, NB-506, and combinations thereof. 
     
     
         43 . A method of treating a condition in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition according to  claim 35 . 
     
     
         44 . The method according to  claim 43 , wherein the mammal is a human. 
     
     
         45 . The method according to  claim 43 , wherein the condition is cancer. 
     
     
         46 . The method according to  claim 45 , wherein the cancer is selected from the group consisting of leukemia, non-small cell lung carcinoma, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, and pancreatic cancer. 
     
     
         47 . The method according to  claim 43 , further comprising conjointly administering to the mammal an agent that kills cells through an apoptotic mechanism. 
     
     
         48 . The method according to  claim 47 , wherein the agent is a chemotherapeutic agent. 
     
     
         49 . The method according to  claim 48 , wherein the chemotherapeutic agent is selected from the group consisting of an EGF-receptor antagonist, arsenic sulfide, adriamycin, cisplatin, carboplatin, cimetidine, caminomycin, mechlorethamine hydrochloride, pentamethylmelamine, thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide, Treosulfan, podophyllotoxin or podophyllotoxin derivatives, etoposide phosphate, teniposide, etoposide, leurosidine, leurosine, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol, methopterin, mitomycin C, ecteinascidin 743, busulfan, carmustine (BCNU), lomustine (CCNU), lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozocin, phthalocyanine, dacarbazine, aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine (ara C), porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine, raltitrexed, idarubicin, epirubican, pirarubican, zorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, vertoporfin, paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine phosphate sodium, flutamide, bicalutamide, buserelin, leuprolide, pteridines, enediynes, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethosone, gemcitabine hydrochloride, verapamil, VP-16, altretamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxygenated paclitaxel, TL-139, 5′-nor-anhydrovinblastine (hereinafter: 5′-nor-vinblastine), camptothecin, irinotecan (Camptosar, CPT-11), topotecan (Hycamptin), BAY 38-3441, 9-nitrocamptothecin (Orethecin, rubitecan), exatecan (DX-8951), lurtotecan (GI-147211C), gimatecan, homocamptothecins diflomotecan (BN-80915) and 9-aminocamptothecin (IDEC-13′), SN-38, ST1481, karanitecin (BNP1350), indolocarbazoles (e.g., NB-506), protoberberines, intoplicines, idenoisoquinolones, benzo-phenazines, NB-506, and combinations thereof.