- HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS AS INHIBITORS OF BTK ACTIVITY
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Heteroaryl pyridone and aza-pyridone compounds of Formula I are provided, where one or two of X, X, and Xare N, and including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I foranddiagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 1391; 1392
(2015/11/16)
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- Synthesis of substituted 5-bromomethyl-4-nitroimidazoles and use for the preparation of the hypoxia-selective multikinase inhibitor SN29966
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5-Bromomethyl-4-nitroimidazoles have utility as bioreductive trigger precursors for the preparation of hypoxia-selective prodrugs. Here we describe an efficient two-step synthesis of 5-(bromomethyl)-1-methyl-4-nitro-1H- imidazole, a preferred precursor, employing an N-bromosuccinimide mediated radical bromination. Use of this precursor to prepare SN29966, a promising hypoxia-selective irreversible pan-ErbB inhibitor is reported along with the preparation of four other prodrug candidates. 5-Bromomethyl-4-nitroimidazole analogues bearing electron-donating and electron-withdrawing substituents at the N-1 and C-2 positions are also described.
- Lu, Guo-Liang,Ashoorzadeh, Amir,Anderson, Robert F.,Patterson, Adam V.,Smaill, Jeff B.
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p. 9130 - 9138
(2013/09/24)
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- PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
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The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.
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Page/Page column 37; 84
(2010/10/03)
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- Synthesis of 4-Nitro-1-(trialkylsilylalkyl)imidazoles
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1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole (1) reacts with haloalkyltrialkylsilanes to give 4-nitroimidazole derivatives 3 and acetaldehyde.This process involves at least two reaction steps, N-alkyl quaternization and elimination of the hydroxyethyl group. - Key Words: Imidazoles / Alkylsilylation
- Foeldeak, Sandor,Molnar, Maria,Lokoes, Magdalena
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p. 211 - 212
(2007/10/02)
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- ETUDE DE L'ISOMERISATION CATALYSEE DE NITRO-5 EN NITRO-4 IMIDAZOLES
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1-Methyl-2-substituted-5-nitroimidazoles are easily rearranged in very good yields in presence of catalytic amount of CH3I affording the corresponding 4-nitroimidazoles.The synthetic usefulness of this rearrangement and some mechanistic details are discussed.
- Vanelle, Patrice,Jentzer, Olivier,Bahnous, Mebarek,Crozet, Michel P.
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p. 5361 - 5364
(2007/10/02)
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- Reactions with Dimethyl Carbonate, 2. - N-Methylation of Imidazole and Derivatives
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The use of dimethyl carbonate as methylating agent for imidazole derivatives is demonstrated by selected examples.The comparison of the toxicological values of dimethyl carbonate and dimethyl sulfate should inspire to replace the highly toxic dimethyl sulfate by dimethyl carbonate.
- Lissel, Manfred
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