Administration is contraindicated in patients with severe hepatic impairment orarterial hypotension (low blood pressure), as well as in those undergoing treatment with other alpha blockers.[4]
Alfuzosin contains astereocenter, so ischiral, with twoenantiomeric forms, (R)- and (S)-alfuzosin. The drug is used as aracemate, (RS)-alfuzosin, a 1:1 mixture of the (R)- and (S)- forms.[5]
Alfuzosin was patented in 1979 and first developed as anantihypertensive agent in 1982 bySanofi-Synthélabo (nowSanofi).[6] It was approved for medical use in 1988.[7] It was approved in the US for benign prostatic hyperplasia in 2003. In 2020, it was the 336th-most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[8][9]
The nitration ofveratraldehyde (1) gives 6-Nitroveratraldehyde [20357-25-9] (2). Oxidation of the aldehyde to the acid, halogenation withthionyl chloride and amide formation with ammonia gives 4,5-dimethoxy-2-nitrobenzamide [4959-60-8] (3).Béchamp reduction of the nitro group gives 2-amino-4,5-dimethoxybenzamide [5004-88-6] (4). Reaction withurea leads to 6,7-Dimethoxyquinazoline-2,4-dione [28888-44-0] (5). Halogenation withphosphoryl chloride gives 2,4-Dichloro-6,7-dimethoxyquinazoline [27631-29-4] (6). Treatment with one equivalent ofammonia yields 4-Amino-2-chloro-6,7-dimethoxyquinazoline [23680-84-4] (7).
The reaction of 2-tetrahydrofuroic acid [16874-33-2] (8) withethyl chloroformate (9) gives ethoxycarbonyl oxolane-2-carboxylate, PC10997775 (10). Treatment of the mixed anhydride with 3-Methylaminopropionitrile [693-05-0] (11) gives N-(2-Cyanoethyl)tetrahydro-N-methyl-2-furancarboxamide [72104-44-0] (12). Catalytic hydrogenation gives N-(3-Aminopropyl)tetrahydro-N-methyl-2-furancarboxamide [72104-45-1] (13). Migration of the amide methyl group to the terminal position gives N-[3-(methylamino)propyl]oxolane-2-carboxamide [81403-67-0] (14). Convergent synthesis between the two counterparts completed the synthesis of Alfuzosin (15).
^abMichael C. Truß, Christian G. Stief, Stefan Machtens, Till Wagner, Udo Jonas:Pharmakotherapie in der Urologie. 2., vollständig überarbeitete Auflage. Springer, Heidelberg 2005, ISBN 3-540-23449-7, S. 302 ff.
^Rote Liste Service GmbH (Hrsg.):Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, S. 159,ISBN978-3-946057-10-9.
^Cazor, JL; Borg, F.; Dimsdale, M.; Alfuzosin hydrochloride. Drugs Fut 1986, 11, 10, 821.
^Manoury, Philippe M.; Binet, Jean L.; Dumas, Andre P.; Lefevre-Borg, Francoise; Cavero, Icilio (1986). "Synthesis and antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives". Journal of Medicinal Chemistry 29 (1): 19–25. doi:10.1021/jm00151a003.
^Philippe M. Manoury, US4315007 (1982 to Synthelabo SA); CA, 96, 162737e.
^Keshav Deo, et al. WO2009001369 (to Alembic Ltd.).
^Allen, J. (November 1983). "A synthesis of [ 14 C]alfuzosine hydrochloride".Journal of Labelled Compounds and Radiopharmaceuticals.20 (11):1283–1286.doi:10.1002/jlcr.2580201109.
-Alfuzosin_Structural_Formula_V2.svg)
-Alfuzosin_Structural_Formula_V2.svg)
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