(s)-n-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide and pharmaceutically acceptable salts thereof

Abstract

The invention relates to the compound (S)-n-hydroxy-2-(2-(4-methoxyphenyl) butanamido)thiazole-5-carboxamide, which is a novel histone deacetylase inhibitor. The invention further relates to the use of the compound for the inhibition of histone deacetylating activities of HDAC isoforms and treatment of histone deacetylase (HDAC)-associated diseases. The invention also relates to the pharmaceutical compositions and the making of the pharmaceutical compositions comprising the compound.

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition in which the active ingredient consists essentially of:
 (S)—N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         22 . A pharmaceutical composition in which the active ingredient comprises:
 (S)—N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide, or a pharmaceutically acceptable salt or solvate thereof,   wherein the composition demonstrates significantly increased Vz/F or apparent volume of distribution during terminal phase after oral administration compared to N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide or (R)—N-hydroxy-2-(2-(4-methoxy-phenyl)butanamido)thiazole-5-carboxamide indicating preferential and significant tumor uptake and retention.   
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutically acceptable salt is selected from the group consisting of: aluminum, calcium, magnesium, potassium, sodium, zinc, and combinations thereof. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier selected from the group consisting of: a pharmaceutical polymer carrier, a processing agent, a surfactant, and combinations thereof. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical polymer carrier is selected from the group consisting of: a cellulosic pharmaceutical polymer, a cross-linked pharmaceutical polymer, a high melt viscosity pharmaceutical polymer, a non-ionic pharmaceutical polymer, a non-ionic, cellulosic pharmaceutical polymer, a non-ionic, water-soluble pharmaceutical polymer, a thermally labile pharmaceutical polymer, a water-soluble pharmaceutical polymer, a water-soluble, cellulosic pharmaceutical polymer, and combinations thereof. 
     
     
         26 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical polymer carrier is selected from the group consisting of: carbomer, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimelletate, crospovidone, croscarmellose sodium, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, poly(butyl methacylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, polycarbophil, poly(ethylene glycol), poly(ethylene oxide), poly(methacrylate ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:2) copolymer, poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer, poly(vinyl acetate) phthalate, poly(vinyl alcohol), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(vinylpyrrolidone), sodium carboxymethyl-cellulose, and combinations thereof. 
     
     
         27 . The pharmaceutical composition of  claim 24 , wherein the processing agent comprises a plasticizer. 
     
     
         28 . The pharmaceutical composition of  claim 24 , wherein the surfactant is selected from the group consisting of: dioctyl sodium sulphosuccinate, glycerol polyethylene glycol oxystearate-fatty acid glycerol polyglycol esters-polyethylene glycols-glycerol ethoxylate, glycerolpolyethylene glycol ricinoleate-fatty acid esters of polyethylene glycol-polyethylene glycols-ethoxylated glycerol, polyoxyethylene (20) sorbitan monooleate, sodium dodecyl sulfate, sorbitan laurate, vitamin E TPGS, and combinations thereof. 
     
     
         29 . A method of inhibiting the histone deacetylating activity of a histone deacetylase (HDAC) isoform in a cell, the method comprising:
 contacting the cell with the composition of  claim 22 .   
     
     
         30 . The method of  claim 29 , wherein the composition inhibits cell proliferation, induces cell death, or both. 
     
     
         31 . The method of  claim 29 , wherein the composition inhibits the histone deacetylating activity of the HDAC isoform with a half maximal inhibitory concentration (IC 50 ) of 0.0005-2 μM. 
     
     
         32 . The method of  claim 29 , wherein the HDAC isoform is selected from the group consisting of: HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, HDAC8, and HDAC10. 
     
     
         33 . The method of  claim 29 , wherein the cell is selected from the group consisting of: a cancer cell, a neuronal cell, a cell of the immune system, a cell of the circulatory system, and combinations thereof. 
     
     
         34 . The method of  claim 33 , wherein the cancer cell is selected from the group consisting of: an acute lymphocytic leukemia (ALL) cell, an acute myeloid leukemia (AML) cell, an acute promyelocytic leukemia (APL) cell, adenosquamous carcinoma of the pancreas, a blood cancer cell, a brain tumor cell, a breast cancer cell, a cervical squamous cell, a chronic myeloid leukemia (CML) cell, a colon cancer cell, a diffuse large B-cell lymphoma (DLBCL) cell, an endometrial cancer cell, a gastrointestinal stromal tumor (GIST) cell, a glioblastoma (GBM) cell, a hepatocellular carcinoma cell, a Hodgkin lymphoma cell, a leukemia cell, a liver cancer cell, a lung cancer cell, a melanoma cell, a mesothelioma cell, a multiple myeloma cell, a non-Hodgkin's lymphoma cell, a non-small cell lung cancer (NSCLC) cell, a neuroblastoma cell, an ovarian cancer cell, a pancreatic cancer cell, a pancreatic ductal adenocarcinoma cell, a peripheral T-cell lymphoma cell, a pharynx cancer cell, a prostate cancer cell, a renal cancer cell, a rhabdomyocarcoma cell, a skin cancer cell, a thyroid cancer cell, a tongue tumor cell, a uterine cancer cell, a Waldenstrom myeloma cell, and combinations thereof. 
     
     
         35 . A method of treating a cancer in a subject comprising administering to the subject the composition of  claim 22 . 
     
     
         36 . The method of  claim 35 , wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), breast cancer, chronic myeloid leukemia (CML), colon cancer, diffuse large B-cell lymphoma (DLBCL), gastrointestinal stromal tumor (GIST), glioblastoma (GBM), hepatocellular carcinoma, Hodgkin's lymphoma, leukemia, lung cancer, multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, ovarian cancer, pancreatic ductal adenocarcinoma, peripheral T-cell lymphoma, prostate cancer, uterine cancer, Waldenstrom myeloma, and combinations thereof. 
     
     
         37 . The method of  claim 35 , wherein the composition is administered at 10-400 mg per kg of the subject about every 4, 8, 12, 16, or 24 hours. 
     
     
         38 . The method of  claim 35 , wherein the subject is a human. 
     
     
         39 . The method of  claim 35 , wherein the composition further comprises a second active ingredient selected from the group consisting of: a chemotherapy drug, a MEK inhibitor, an agent that enhances antigen presentation, an agent that enhances an effector cell response, an agent that decreases tumor immunosuppression, and combinations thereof. 
     
     
         40 . A pharmaceutical composition in which the active ingredient comprises:
 N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide, or a pharmaceutically acceptable salt or solvate thereof,   wherein the active ingredient comprises at least 80% (S)—N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide.   
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the active ingredient comprises at least 90% (S)—N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the active ingredient comprises at least 99% (S)—N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide. 
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition demonstrates significantly increased inhibition of HDAC enzymes compared to N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide or (R)—N-hydroxy-2-(2-(4-methoxy-phenyl)butanamido)thiazole-5-carboxamide indicating preferential and significant tumor uptake and retention. 
     
     
         44 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition demonstrates significantly increased cell growth reduction against target cells compared to N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide or (R)—N-hydroxy-2-(2-(4-methoxy-phenyl)butanamido)thiazole-5-carboxamide indicating preferential and significant tumor uptake and retention.