Small-Molecule Choline Kinase Inhibitors as Anti-Cancer Therapeutics
AssigneesAdvanced Cancer Therapeutics, LLC, University of Louisville Research Foundation, Inc.
InventorsPooran Chand, Jason A. Chesney, Brian F. Clem, Gilles H. Tapolsky, Sucheta Telang, John O. Trent
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Abstract
Small molecule choline kinase inhibitors having the following formula: are provided herein. Also provided herein are pharmaceutical compositions containing Formula I compounds, together with methods of treating cancer, methods of inhibiting choline kinase enzymatic activity, and methods of treating tumors by administering an effective amount of a Formula I compound.
Claims16
A compound or its tautomeric, enantiomeric or diastereomeric form or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, said compound having the formula:
- wherein:
- Z is selected from the group consisting of:
- Y is selected from the group consisting of:
- X is O, S, NH, or N-alkyl;
- R is alkyl or substituted alkyl;
- B, C, D, E, F, G, H, and I are independently selected from the group consisting of N or C substituted with one of R2, R3, R4, R5, R6, R7, R8, or R9, wherein if B, C, D, E, F, G, H, or I are N, then R2, R3, R4, R5, R6, R7, R8, or R9 represent the free electron pair at the N atom;
- R2, R3, R4, R5, R6, R7, R8, or R9 are independently, when attached to an N atom, a free electron pair, or, when attached to C, selected from the group consisting of hydrogen, halogen, cyano, nitro, straight-chain or branched (C1-C6)-alkyl, straight-chain or branched (C1-C6)-alkyl substituted with one or more halogen atoms, straight-chain or branched (C1-C6)-alkoxy substituted with one or more halogen atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, straight-chain or branched (C1-C6)-alkoxy, straight-chain or branched (C1-C6)-alkylenedioxy, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyloxy, (C1-C6)-alkylcarbonyl, (C1-C6)-alkylcarbonyloxy, (C1-C6)-alkylthio, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, carboxyl, (C1-C6)-alkyl carboxylate, carboxamide, N—(C1-C4)-alkyl-carboxamide, N,N-di-(C1-C4)-alkyl-carboxamide, (C1-C6)-alkoxy-(C1-C6)-alkyl, amino, mono-(C1-C6)-alkylamino, N,N-di-(C1-C6)-alkylamino, wherein two C1-C6-alkyl radicals together may form a ring, which optionally contains one or more of NH, N—(C1-C6)-alkyl, O or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C4)-alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, hydroxyl, wherein two directly adjacent radicals may be attached to one another;
- and
- R10 is alkyl or substituted'alkyl.
A compound selected from the group set forth in Table 1.
A compound selected from the group consisting of:
- N-(3,5-Dimethyl-phenyl)-2-[5-(4-ethoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- 2-[5-(4-Methoxy-phenyl)-4H-[1,2,4]-triazol-3-ylsulfanyl]-N-(5-methyl-thiazol-2-yl)-acetamide;
- N-(3,5-Dimethyl-phenyl)-2-[5-(1H-indol-2-yl)-4H-[1,2,4]-triazol-3-ylsulfanyl]-acetamide;
- N-(3,5-Dimethyl-phenyl)-2-[5-(4-ethoxy-3-methyl-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- N-(3,5-Dimethyl-phenyl)-2-[5-(6-ethoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- N-(4,6-Dimethyl-pyridin-2-yl)-2-[5-(4-ethoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- N-(4,6-Dimethyl-pyrimidin-2-yl)-2-[5-(4-ethoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- N-(3,5-Dimethyl-phenyl)-2-[5-(4-ethoxy-3-fluoro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide;
- 2-[5-(4-Ethoxy-3-fluoro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-hydroxy-3,5-dimethyl-phenyl)-acetamide;
- and
- N-(3,5-Dimethyl-phenyl)-2-[5-(4-ethylsulfanyl-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide.
Dependencies are inferred from the claim text.