Substituted nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Abstract

The present invention is directed to substituted nicotinamides and analogs thereof, represented by Formula V: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ar′ and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; and R 11 is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted. The present invention also relates to the discovery that compounds having Formula V are activators of caspases and inducers of apoptosis. Therefore, the compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

1 . A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Ar′ and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; and  
 R 11 , is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.  
 
     
     
         2 . The method of  claim 1 , wherein said compound is of Formula I:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or prodrugs thereof, wherein: 
 A is N or C—R 8 , B is N or C—R 9 , D is N or C—R 10 , E is N or C—R 6  and F is N or C—R 7 , provided that not more than two of A, B, D, E and F are N in the same time;  
 Ar is optionally substituted and is an aryl or heteroaryl;  
 R 6 -R 10  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; and  
 R 11  is hydrogen or optionally substituted alkyl, cycloalkyl, aryl, or heteroaryl.  
 
     
     
         3 . The method of  claim 2 , wherein A is N, B is C—R 9  and F is C—R 7 .  
     
     
         4 . The method of  claim 1 , wherein Ar′ is optionally substituted and is furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or phenyl.  
     
     
         5 . The method of  claim 4 , wherein Ar′ is optionally substituted furyl.  
     
     
         6 . The method of  claim 5 , wherein Ar is optionally substituted phenyl.  
     
     
         7 . The method of  claim 6 , wherein Ar′ is optionally substituted 3-furyl.  
     
     
         8 . The method of  claim 7 , wherein Ar′ is unsubstituted 3-furyl.  
     
     
         9 . The method of  claim 8 , wherein said compound is N-(4-ethoxy-2-nitrophenyl)-3-furancarboxamide.  
     
     
         10 . The method of  claim 4 , wherein Ar′ is optionally substituted pyrrolyl.  
     
     
         11 . The method of  claim 10 , wherein Ar is optionally substituted phenyl.  
     
     
         12 . The method of  claim 11 , wherein Ar′ is optionally substituted 3-pyrrolyl.  
     
     
         13 . The method of  claim 12 , wherein Ar′ is unsubstituted 3-pyrrolyl.  
     
     
         14 . The method of  claim 13 , wherein said compound is N-(4-ethoxy-2-nitrophenyl)-3-pyrrolecarboxamide.  
     
     
         15 . The method of  claim 4 , wherein Ar′ is optionally substituted phenyl.  
     
     
         16 . The method of  claim 15 , wherein Ar is optionally substituted phenyl.  
     
     
         17 . The method of  claim 16 , wherein said compound is selected from the group consisting of: 
 4-Chloro-N-(4-ethoxy-2-nitrophenyl)-benzoylamide; and    4-Chloromethyl-N-(4-ethoxy-2-nitrophenyl)-benzoylamide.    
     
     
         18 . The method of  claim 15 , wherein Ar is optionally substituted pyridyl.  
     
     
         19 . The method of  claim 18 , wherein said compound is selected from the group consisting of: 
 4-Chloro-2-nitro-N-(6-chloro-3-pyridyl)-benzoylamide;    4-Chloro-2-nitro-N-(6-methyl-3-pyridyl)-benzoylamide; and    4-Bromomethyl-3-nitro-N-(6-chloro-3-pyridyl)-benzoylamide.    
     
     
         20 . The method of  claim 4 , wherein Ar′ is optionally substituted pyrazinyl.  
     
     
         21 . The method of  claim 20 , wherein Ar is optionally substituted phenyl.  
     
     
         22 . The method of  claim 21 , wherein Ar′ is 3-pyrazinyl.  
     
     
         23 . The method of  claim 22 , wherein said compound is selected from the group consisting of: 
 6-Methyl-N-(4-ethoxy-2-nitrophenyl)-3-pyrazinecarboxamide; and    N-(4-Ethoxy-2-nitrophenyl)-3-pyrazinecarboxamide.    
     
     
         24 . The method of  claim 4 , wherein Ar′ is optionally substituted pyrimidinyl.  
     
     
         25 . The method of  claim 24 , wherein Ar is optionally substituted phenyl.  
     
     
         26 . The method of  claim 25 , wherein Ar′ is optionally substituted 5-pyrimidinyl.  
     
     
         27 . The method of  claim 26 , wherein said compound is N-(4-ethoxy-2-nitrophenyl)-5-pyrimidinecarboxamide.  
     
     
         28 . The method of  claim 4 , wherein Ar′ is optionally substituted pyridyl.  
     
     
         29 . The method of  claim 28 , wherein Ar is optionally substituted phenyl.  
     
     
         30 . The method of  claim 29 , wherein Ar′ is optionally substituted 2-pyridyl.  
     
     
         31 . The method of  claim 30 , wherein said compound is selected from the group consisting of: 
 N-(4-Ethoxy-2-nitrophenyl)-2-pyridinecarboxamide; and    N-(4-Ethoxy-2-nitrophenyl)-1-N-oxide-2-pyridinecarboxamide.    
     
     
         32 - 41  (canceled)  
     
     
         42 . A method for treating or preventing cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of Formula V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Ar′ and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; and  
 R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.  
 
     
     
         43 . The method of  claim 42 , wherein said compound is of Formula I:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or prodrugs thereof, wherein: 
 A is N or C—R 8 , B is N or C—R 9 , D is N or C—R 10 , E is N or C—R 6  and F is N or C—R 7 , provided that not more than two of A, B, D, E and F are N in the same time;  
 Ar is optionally substituted and is an aryl or heteroaryl;  
 R 6 -R 10  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; and  
 R 11  is hydrogen or optionally substituted alkyl, cycloalkyl, aryl, or heteroaryl.  
 
     
     
         44 . The method of  claim 42 , wherein Ar′ is optionally substituted and is furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or phenyl.  
     
     
         45 . The method of  claim 42 , wherein said cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer and prostatic carcinoma.  
     
     
         46 . A method for the treatment of drug resistant cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of the Formula V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Ar′ and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; and  
 R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.  
 
     
     
         47 . The method of  claim 46 , wherein said compound is of Formula I:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or prodrugs thereof, wherein: 
 A is N or C—R 8 , B is N or C—R 9 , D is N or C—R 10 , E is N or C—R 6  and F is N or C—R 7 , provided that not more than two of A, B, D, E and F are N in the same time;  
 Ar is optionally substituted and is an aryl or heteroaryl;  
 R 6 -R 10  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; and  
 R 11  is hydrogen or optionally substituted alkyl, cycloalkyl, aryl, or heteroaryl.  
 
     
     
         48 . The method of  claim 46 , wherein Ar′ is optionally substituted and is furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or phenyl.  
     
     
         49 . The method of  claim 42  or  46 , additionally comprising administering at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.  
     
     
         50 . The method of  claim 49 , wherein said known cancer therapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.  
     
     
         51 . The method of  claim 42  or  46 , additionally comprising treating said animal with radiation-therapy.  
     
     
         52 . The method of  claim 42  or  46 , wherein said compound is administered after the surgical treatment of said animal for cancer.  
     
     
         53 . The method of  claim 1 , wherein said disorder is an autoimmune disease.  
     
     
         54 . The method of  claim 1 , wherein said disorder is rheumatoid arthritis.  
     
     
         55 . The method of  claim 1 , wherein said disorder is inflamatory bowel disease.  
     
     
         56 . The method of  claim 1 , wherein said disorder is a skin disease.  
     
     
         57 . The method of  claim 56 , wherein said disorder is psoriasis.  
     
     
         58 - 61  (canceled)  
     
     
         62 . A compound of Formula (VI):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1 -R 5 , R 7  and R 9 -R 10  are independently hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido or alkylthiol; and  
 R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.  
 
     
     
         63 . The compound of  claim 62 , or a pharmaceutically acceptable salt thereof, with the prioviso that at least one of R 1  and R 5  is selected from the group consisting of NO 2 , cyano, alkyl and haloalkyl.  
     
     
         64 . The compound of  claim 62  or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  and R 5  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, haloalkoxy, amino and aminoalkyl;  
 R 2  and R 4  are independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, haloalkoxy, amino and aminoalkyl;  
 R 3  is alkyl, Cl, F, haloalkyl, alkoxy, arylalkoxy, cyano, haloalkoxy, amino or aminoalkyl;  
 R 7 , R 9  and R 10  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, alkoxy, haloalkoxy, amino and aminoalkyl; and  
 R 11  is hydrogen, alkyl or haloalkyl.  
 
     
     
         65 . The compound of  claim 64 , wherein said compound is selected from the group consisting of: 
 6-Methyl-N-(4-ethoxy-2-nitrophenyl)-3-pyrazinecarboxamide; and    N-(4-Ethoxy-2-nitrophenyl)-3-pyrazinecarboxamide.    
     
     
         66 . A compound of Formula (VII):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1 -R 3 , R 5 -R 10  are independently hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido or alkylthiol; and  
 R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.  
 
     
     
         67 . The compound of  claim 66 , or a pharmaceutically acceptable salt thereof, with the prioviso that at least one of R 6  and R 7  is selected from the group consisting of NO 2 , cyano, alkyl and haloalkyl.  
     
     
         68 . The compound of  claim 67  or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1 , R 2 , R 3  and R 5  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, alkoxy, haloalkoxy, amino and aminoalkyl;  
 R 6  and R 7  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, haloalkoxy, amino and aminoalkyl;  
 R 8  and R 10  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, haloalkoxy, amino and aminoalkyl;  
 R 9  is hydroxy, alkyl, halogen, NO 2 , cyano, haloalkyl, alkoxy, haloalkoxy, amino or aminoalkyl; and  
 R 11  is hydroxy, alkyl or haloalky.  
 
     
     
         69 . The compound of  claim 68 , wherein said compound is selected from the group consisting of: 
 4-Chloro-2-nitro-N-(6-chloro-3-pyridyl)-benzoylamide;    4-Chloro-2-nitro-N-(6-methyl-3-pyridyl)-benzoylamide; and    4-Bromomethyl-3-nitro-N-(6-chloro-3-pyridyl)-benzoylamide.    
     
     
         70 . A compound selected from the group consisting of: 
 N-(4-Ethoxy-2-nitrophenyl)-3-pyrrolylcarboxamide;    4-Chloro-N-(4-ethoxy-2-nitrophenyl)-benzoylamide;    4-Chloromethyl-N-(4-ethoxy-2-nitrophenyl)-benzoylamide;    N-(4-Ethoxy-2-nitrophenyl)-5-pyrimidinecarboxamide;    N-(4-Ethoxy-2-nitrophenyl-2-pyridinecarboxamide; and    N-(4-Ethoxy-2-nitrophenyl)-1-N-oxide-2-pyridinecarboxamide.    
     
     
         71 . A pharmaceutical composition, comprising the compound of any one of claims  62 - 70 , and a pharmaceutically acceptable carrier.  
     
     
         72 . The pharmaceutical composition of  claim 71 , further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.  
     
     
         73 . The pharmaceutical composition of  claim 72 , wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® and alanosine.