Hexadepsipeptide analogues as anticancer compounds

Abstract

This invention relates to a method of treatment of cancer comprising administering compound of Formula (1) or derivatives or pharmaceutically acceptable salts thereof.

We claim: 
     
         1 . A method for the treatment of cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula (1); 
       
         
           
           
               
               
           
         
       
       wherein in the compound of Formula (1), when the bond   represents a single bond and R 1  is H; the said compound is referred to as the compound of Formula (1a); and when the bond   is a double bond and R 1  is absent; the said compound is referred to as the compound of Formula (1b);
 or an isomer or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein Formula (1) is the compound of Formula (1a); 
       
         
           
           
               
               
           
         
       
       characterized by:
 a) molecular weight of 826.9, 
 b) molecular formula C 37 H 62 N 8 O 13.    
 c) IR (KBr) spectrum 3325, 2960, 2872, 1755, 1641, 1524, 1445, 1331, 1306, 1288 and 1254 cm −1 , 
 d)  1 H NMR spectrum (500 MHz, CDCl 3 ): δ 9.20, 8.00, 7.10, 6.90, 6.40, 6.10, 5.40, 5.38, 5.29, 5.10, 4.90, 4.80, 4.70, 4.60, 3.90, 3.70, 3.15, 2.70, 2.30, 2.10, 1.98, 1.95, 1.77, 1.71, 1.68, 1.60, 1.52, 1.40, 1.15, 1.10, 1.05, 0.98, 0.95, 0.90, 0.88 and 0.85, and 
 e)  13 C NMR spectrum (75 MHz, CDCl 3 ): δ 176.0, 172.0 (3), 171.0, 170.0, 169.0, 99.9, 78.9, 77.2, 71.7, 53.5, 52.9, 49.3, 49.0, 47.1, 46.7, 46.2, 42.2, 41.0, 39.8, 29.9, 27.4, 24.8, 24.6, 24.2, 24.1, 23.2, 21.7, 21.5 (2), 20.6, 19.9, 19.4, 18.1, 12.9 and 11.7. 
 
     
     
         3 . The method according to  claim 1 , wherein Formula (1) is the compound of Formula (1b); 
       
         
           
           
               
               
           
         
       
       characterized by:
 a) molecular weight of 824.4, 
 b) molecular formula C 37 H 60 N 8 O 13,    
 c) IR (KBr): 3342, 3030, 2953, 1752, 1650, 1524, 1421, 1293, 1255 and 1239 cm −1 , 
 d)  1 H NMR spectrum (500 MHz, CDCl 3 ): δ 9.20, 8.00, 7.19, 7.0, 6.18, 6.14, 5.80, 5.41, 5.39, 5.30, 5.10, 4.80 (2), 4.20, 3.70, 3.19, 2.62, 2.27, 2.10, 2.01, 1.98, 1.77, 1.71, 1.62, 1.58, 1.44, 1.40, 1.39, 1.37, 1.20, 1.10, 1.05, 0.96, 0.91, 0.90, 0.86, and 0.85, and 
 e)  13 C NMR spectrum (75 MHz, CDCl 3 ): δ 176.0, 171.8, 171.7, 170.8, 170.6, 170.3, 168.9, 144.6, 98.8, 79.0, 77.2, 71.7, 53.6, 53.5, 50.6, 49.1, 47.1, 46.4, 42.6, 41.0, 39.8, 29.9, 27.4, 24.7, 24.6, 24.2, 24.0, 22.1, 21.5, 21.4, 19.8, 19.5, 19.4, 18.1, 17.2, 12.9 and 11.8. 
 
     
     
         4 . The method according to  claim 1 , wherein a derivative of the compound of Formula (1) represented by the Formula (1c); 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 4  independently represent H or are absent; 
         R 2  and R 3  are independently selected from the group consisting of H, hydroxy, —O(C 1 -C 6 )alkyl and —OC(O)(C 1 -C 6 )alkyl, 
            represents a single bond or a double bond; 
         wherein, 
         (C 1 -C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, —O(C 1 -C 6 )alkyl, nitro, cyano, —COOH, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —NHC(O)O(C 1 -C 6 )alkyl, —NHC(O)O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, —NH-PEG and (C 6 -C 10 )aryl; 
         (C 6 -C 10 )aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, halo(C 1 -C 6 )alkyl, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —COOH and —NH 2 ; 
         and PEG is polyethylene glycol selected from the group consisting of O,O′-bis[2-(N-succinimidyl-succinylamino)ethyl]polyethylene glycol (α,ω-bis-NHS-PEG), methyl-PEG-NHS ester (MS(PEG)n where n is 24), and a branched trimethyl or succinimide ester derivative of polyethylene glycol (TMS(PEG)n, wherein n is 12); 
         with a proviso that if both R 2  and R 3  are hydroxy, then R 1  and R 4  are absent and   represents a double bond; 
         or an isomer or a tautomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method according to  claim 4 ,
 wherein: R 1  and R 4  are H;   R 2  is —O(C 1 -C 6 )alkyl or —OC(O)(C 1 -C 6 )alkyl;   R 3  is hydroxy or —O(C 1 -C 6 )alkyl;   wherein, (C 1 -C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of —NH 2 , —NHC(O)O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl and —NH-PEG;   or an isomer or a tautomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The method according to  claim 4 ,
 wherein:   R 1  and R 4  independently represent H or are absent;   R 2  and R 3  are independently selected from H and hydroxy;      represents a single bond or a double bond;   with a proviso that if both R 2  and R 3  are hydroxy, then R 1  and R 4  are absent and   represents a double bond;   or an isomer or a tautomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The method according to  claim 4 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or an isomer or a tautomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method according to  claim 1 , wherein the cancer is leukemia, lung cancer, brain tumors, non-Hodgkin's lymphoma, Hodgkin's disease, liver cancer, kidney cancer, bladder cancer, cancer of urinary tract, breast cancer, head and neck cancer, endometrial cancer, lymphoma, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular, cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma or myeloproliferative disorder. 
     
     
         9 . The method according to  claim 1 , wherein the cancer is acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway glioma, pineal tumors, medulloblastoma, primary central nervous system lymphoma, mantle cell lymphoma, Hodgkin's disease, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, cancer of urinary tract, osteosarcoma, breast cancer, endometrial cancer oral cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, pancreatic cancer, neuroblastoma, skin cancer, ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease or myeloproliferative disorder. 
     
     
         10 . The method according to  claim 9 , wherein the cancer is acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, medulloblastoma, renal cell carcinoma, bladder cancer, cancer of urinary tract, breast cancer, oral cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, pancreatic cancer, prostate cancer or colorectal cancer.