Fluorocyclopentenylcytosine methods of use
AssigneeRexahn Pharmaceuticals, Inc.
InventorsYoung Bok Lee, Deog Joong Kim, Godefridus J. Peters, Reza Mazhari, Dzjemma Sarkisjan
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Abstract
The disclosed subject matter provides methods using and kits comprising a compound of formula (I) or a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The disclosed subject matter further provides a method of treating one or more symptoms of cancer comprising administering to a subject in need thereof a compound of formula (I) and a process for preparing such.
Claims15
A process for preparing of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)pyrimidin-2(1H)-one 1H2O (RX-3117-MH), comprising converting tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (ASM11) to 4-amino-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (INT14) in a continuous process with more than one step without isolation of any intermediate.
A continuous process for preparing 4-amino-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (INT14) from tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (ASM11), comprising the steps of:
- dissolving the ASM11 in 2-methyl tetrahydrofuran;
- adding tetra-n-butylammonium fluoride to form ((3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol) (INT12);
- adding trimethylamine and methanesulphonyl chloride in 2-methyl tetrahydrofuran to the INT12 to form ((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate) (INT13);
- and
- adding cesium carbonate and cytosine to the INT13 to form 4-amino-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (INT14);
- wherein the steps are performed in one or more fixed reactors without isolation of INT12 or INT13.
A continuous process for preparing 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)pyrimidin-2(1H)-one 1H2O (RX-3117-MH) from 4-amino-1-((3 aS,4 S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (INT14), comprising the steps of:
- reacting the INT14 with an acid to form 4-amino-1-((1 S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)pyrimidin-2(1H)-one (RX-3117);
- washing the RX-3117 with methyl tert-butyl ether and water to form an organic phase and an aqueous phase having RX-3117;
- separating the aqueous phase having RX-3117 from the organic phase;
- washing the aqueous phase having RX-3117 with methyl tert-butyl ether until less than about 0.5% w/w trityl alcohol is detected in the aqueous phase;
- adding a strongly basic anion resin to the aqueous phase having RX-3117 to form a slurry;
- filtering the slurry to retain a mother liquor;
- concentrating the mother liquor to form a concentrate;
- adding acetonitrile to the concentrate to form purified RX-3117-MH;
- and
- isolating the purified RX-3117-MH;
- wherein the steps are performed in one or more fixed reactors.
A method of sensitizing a cell to an apoptotic signal comprising contacting the cell with an effective amount of a compound of formula (I)
- or a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
A method of treating one or more symptoms of cancer in a subject, comprising administering a compound of formula (I)
- or a hydrate, a solvate, or a pharmaceutically acceptable salt thereof in an amount effective to inhibit methyltransferase and to upregulate at least one hypomethylated target in the subject.
Dependencies are inferred from the claim text.