- Two Novel Syntheses of the Histamine H3 Antagonist Thioperamide
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The previously described route for the synthesis of the histamine H3 antagonist thioperamide 3 has been improved considerably.Furthermore, two straightforward novel synthetic routes towards 3 are described herein.The last synthetic route (Scheme 3) is preferable as it is very suitable for the production of multigram quantities of thioperamide 3.
- Lange, Jos H. M.,Wals, Henri C.,Hoogenband, Adri van den,Kuilen, Aalt van de,Hartog, Jack A. J. den
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p. 13447 - 13454
(2007/10/02)
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- Design of potent non-thiourea H3-receptor histamine antagonists
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Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. In a short series of open chain thiourea analogues, the optimum chain length for H3- antagonist potency was found to be (CH2)3. Compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side chain amino group in place of thiourea show H3-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO2, CF3, CO2Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5)-imidazolyl]piperidine and its conversion into the (trifluoromethyl)pyridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituting imidazole on the remote N considerably reduced potency. Replacing the side-chain NH by S increased potency still further and the most potent compound is 2-{[2-[4(5)-imidazolyl]ethyl]thio}-5-nitropyridine (UCL 1199) which has K(i) = 4.8 nM.
- Ganellin,Hosseini,Khalaf,Tertiuk,Arrang,Garbarg,Ligneau,Schwartz
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p. 3342 - 3350
(2007/10/02)
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