- Importance of the azole moiety of cimetidine derivatives for the inhibition of human multidrug and toxin extrusion transporter 1 (hmate1)
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Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.
- Shinya, Susumu,Kawai, Kentaro,Tarui, Atsushi,Karuo, Yukiko,Sato, Kazuyuki,Matsuda, Masaya,Kitatani, Kazuyuki,Kobayashi, Naoki,Nabe, Takeshi,Otsuka, Masato,Omote, Masaaki
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p. 905 - 912
(2021/09/06)
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- Process for the manufacture of related intermediates including cistofur
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A process of manufacture of: wherein R is selected from the group consisting of STR1 is provided, the said process comprising reacting R--CH2 OH.HCL with HSCH2 CH2 NH2 .HC1 in a suitable solvent in the presence of an effective amount of Hydrochloric acid.
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- Method for production of 4-methyl-5-(2-aminoethyl)-thiomethyl)-imidazole
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4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole can be effectively produced by causing 4-methylimidazole or a salt thereof to react with at least one member selected from the group consisting of (a) a formaldehyde adduct of cysteamine, (b) 2-aminoethanethiol sulfuric acid and formaldehyde or a formaldehyde oligomer, and (c) thiazolidine or a salt thereof, in the presence of a mineral acid, removing a portion of reaction liquid out of the reaction system while maintaining molar concentration of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole in the reaction system not exceeding 70 mol % based on total mol numbers of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole, then separating a liquid containing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole from the removed portion of reaction liquid, and recycling the remainder into the reaction system.
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- Preparation of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride
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4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride is prepared in a single-step process by thiomethylating 4-methylimidazole. The product is an intermediate for other imidazole derivatives, especially the drug cimetidine.
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- Preparation of 4-methyl-5-chloromethyl-imidazole
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4-Methyl-5-chloromethyl-imidazole is prepared in the form of its hydrochloride by direct chloromethylation of 4-methyl-imidazole, thus becoming readily available industrially as an intermediate.
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- Process for producing 1-hydroxymethylimidazoles
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1-Hydroxymethylimidazoles which are unsubstituted or alkyl-substituted in the 2-position, their manufacture and their use as chemical intermediates, e.g. for other imidazole derivatives or for the drug cimetidine.
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- Process for preparing 4-substituted imidazole compounds
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A process for preparing 4-(oxy, thio or amino)methylimidazole compounds via displacement of the trisubstituted phosphonium group from 4-(trisubstituted phosphonium)methylimidazole compounds is disclosed.
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- Process for preparing 4-(hydroxymethyl)imidazole compounds
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An improved process for the preparation of 4-(hydroxymethyl)imidazoles by reducing 4-imidazolecarboxylic acid esters using an alkali metal or calcium in liquid ammonia with an additional proton source provided during the reaction or upon workup.
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- SULPHOXIDES
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The compounds are sulphoxides of heterocyclicthioalkylthioureas, ureas and guanidines which are useful to produce inhibition of histamine H-2 receptors.
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- PHARMACEUTICAL COMPOSITIONS AND METHOD OF INHIBITING H-1 AND H-2 HISTAMINE RECEPTORS
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Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors by administering an antihistamine and an H-2 histamine receptor inhibitor. Exemplary of the antihistamine in the compositions and methods of this invention is mepyramine and exemplary of the H-2 histamine receptor inhibitor is N-methyl-N'-4-(5)-imidazolyl) butyl!thiourea.
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- PHARMACEUTICAL COMPOSITIONS AND METHODS OF INHIBITING H-1 AND H-2 HISTAMINE RECEPTORS
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Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors by administering an antihistamine and an H-2 histamine receptor inhibitor. Exemplary of the antihistamine in the compositions and methods of this invention is mepyramine and exemplary of the H-2 histamine receptor inhibitor is N-cyano-N'-methyl-N"-2-((4-methyl-5-imidazolyl)-methylthio)ethyl!guanidine. "
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- Process of reduction
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An electrochemical process for preparing 4-(hydroxymethyl)-imidazoles, which are useful as chemical intermediates.
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- PHARMACOLOGICALLY ACTIVE GUANIDINE COMPOUNDS
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The compounds are substituted thioalkyl-, aminoalkyl-and oxyalkyl-guanidines which are inhibitors of histamine activity.
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- PHARMACOLOGICALLY ACTIVE THIOUREA AND UREA COMPOUNDS
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The compounds are substituted thioalkyl-, aminoalkyl-and oxyalkyl-thioureas and ureas which are inhibitors of histamine activity.
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