SMAC Mimetic for Treating Myelodysplastic Syndromes

Abstract

A SMAC mimetic and pharmaceutical compositions thereof and methods of use.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R5 is —CH2CH3, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A pharmaceutical composition comprising the compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R5 is —CH2CH3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
       
     
     
         3 . The pharmaceutical composition of  claim 2  for the treatment of a proliferative disorder. 
     
     
         4 . The pharmaceutical composition of  claim 2  for the treatment of a cancer. 
     
     
         5 . The pharmaceutical composition of  claim 2  which is a sterile liquid for injection. 
     
     
         6 . The pharmaceutical composition of  claim 2  which is in a unit dose form. 
     
     
         7 . A method of treating a proliferative disorder in a mammal in need thereof that comprises internally administering to the animal an effective amount of Compound 15. 
     
     
         8 . The method of  claim 7  wherein the proliferative disorder is a cancer selected from the group consisting of: lung adenocarcinoma, pancreatic cancer, colon cancer, ovarian cancer, breast cancer, mesothelioma, peripheral neuroma, bladder cancer, glioblastoma, melanoma, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, bladder cancer, meningioma, glioma, astrocytoma, breast cancer, cervical cancer, chronic myeloproliferative disorders (e.g., chronic lymphocytic leukemia, chronic myelogenous leukemia), colon cancer, endocrine cancers, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gestational trophoblastic tumors, hairy cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, lip cancer, oral cavity cancer, liver cancer, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell carcinoma, metastatic squamous neck cancer, multiple myeloma and other plasma cell neoplasms, mycosis fungoides and the Sezary syndrome, myelodysplastic syndromes, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, small cell lung cancer, oropharyngeal cancer, bone cancers, including osteosarcoma and malignant fibrous histiocytoma of bone, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors, pancreatic cancer, paranasal sinus cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumors, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, supratentorial primitive neuroectodermal tumors, pineoblastoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilm's tumor and other childhood kidney tumors. 
     
     
         9 . The method of  claim 7  wherein the proliferative disorder is a cancer selected from the group consisting of: sarcomas, bladder cancer, ovarian cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, blood cancer, skin cancer, lung cancer, and bone cancer. 
     
     
         10 . The method of  claim 7  wherein the cancer is selected from colorectal cancer, renal carinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, breast carcinoma, melanoma, gliobastoma, acute myeloid leukemia, small cell lung cell carcinoma, non-small cell lung carcinoma, rhabdomyosarcoma, and basal cell carcinoma. 
     
     
         11 . A method for inducing apoptosis in a cell comprising contacting the cell with Compound 15 or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 11  wherein the cell is a cancer cell. 
     
     
         13 . The method of  claim 8  that comprises administering Compound 15 in combination with a second cancer therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy, and combinations thereof. 
     
     
         14 . The method of  claim 9  that comprises administering Compound 15 in combination with a second cancer therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy, and combinations thereof. 
     
     
         15 . The method of  claim 10  that comprises administering Compound 15 in combination with a second cancer therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy, and combinations thereof. 
     
     
         16 . A method of treating an autoimmune disease, in a mammal in need thereof, wherein the autoimmune disease is one in which the condition is caused or exacerbated by abnormal regulation of apoptosis and is selected from the group consisting of: systemic lupus erythematosus, psoriasis, and idiopathic thrombocytopenic purpura (Morbus Werlhof) that comprises internally administering to the animal an effective amount of Compound 15 or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A compound selected from the group consisting of Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, and Protected Compound 15. 
     
     
         18 . The compound of  claim 15  that is Compound 14. 
     
     
         19 . A process for preparing Compound 15 that comprises deprotecting a Protected Compound 15. 
     
     
         20 . The process of  claim 19  wherein the Protected Compound 15 is Compound 14. 
     
     
         21 . A compound selected from the group consisting of Compound 19, Compound 20, Compound 28, Compound 29, Compound 31, and Compound 32.