Norastemizole

Zhou, Z., Vorperian, V.R., Gong, Q., Zhang, S. and January, C.T. (1999) Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. Journal of Cardiovascular Electrophysiology, 10, 836-843. 

A similar reaction was applied to an approach to norastemizole (148) and its analogues, which are of significant medicinal interest due to their wide range of biological activity. However, no reaction took place either with bulky amines such as isopropyl amine or with aromatic amines such as anisyl amine (Scheme 41) [94], An alternative method is a palladium-catalyzed amination of 149 based on the Buchwald method [95]. 

Several reports on the application of the intermolecular arylation of primary alkylamines have appeared. For example, the reaction of primary amines with chloro 1,3 azoles has been used to produce the H-l-antihistaminic norastemizole [153]. As shown in Eq. (32), the palladium chemistry is dictated by the steric properties of the amines. This property creates selectivity that complements the thermal chemistry, which is dictated by amine nucleophilicity. These researchers have also shown that this high selectivity for arylation of primary over secondary amines with catalysts containing BINAP as ligand allows for the rapid assembly of other multiamino-based structures [154]. 

During their studies on the synthesis of norastemizol, Senanayake, Tanouxy and co-workers reported that high levels of regioselectivity were observed in the amine arylation such that primary amines reacted in preference to secondary ones [87]. For example, the coupling of 4-aminopiperidine in the presence of the BINAP/Pd-catalyst resulted in reaction at the primary amine functional group, Eq.(72) [34],... 

Other heteroaryl halides may be used in the Pd-catalyzed cross coupling reaction. Senanayake and co-workers reported the reaction of a chlorobenz-imidazole and a primary amine to synthesize the antihistamine norastemizol [34, 87]. The key Pd-catalyzed coupling reaction proceeded in 85% isolated yield using 0.5 mol% Pd, Eq. (160). During these investigations, the Sepracor group also noted that primary amines reacted preferentially over secondary amines. 

Astemizole is metabolized by CYP3A4 to desmethyl-astemizole and norastemizole, although these metabolites may not be free of the potential to prolong the QT interval. 

Norastemizole is a metabolite of the second-generation antihistamine astemizole (1). Its major advantage is that it is not cardiotoxic and does not interact with drngs that increase the risk of serious dysrhjdhmias. 

Bachmann KA. Norastemizole Sepracor. Curr Opin Investig Drugs 2000 l(2) 219-26. 

Astemizole undergoes extensive first-pass hepatic metabolism via cytochrome P450 (CYP 450) enzymes (primarily 3A4) to three primary, active, metabolites, desmethylastemizole, norastemizole, and 6-hydroxydesmethylastemizole. The major metabolites of astemizole, desmethylastemizole and norastemizole, possess antihistaminic activity approaching that of the parent compound. The of astemizole... 

Similarly, the high-pressure amination of A -p-fluorobenzyl-2-chlorobenzimi-dazole (144) provides access to various norastemizole analogues 146 that have a wide range of biological activities (Scheme 7.36). 

Senanayake, C.H. Hong, Y. Xiang, T. Wilkinson, H.S. Bakale, R.P. Jurgens, A. R. Pippert, M.E Butler, H.T. Wald, S.A. Properly tuned first fluoride-catalyzed TGME-mediated amination process for chloroimidazoles inexpensive technology for antihis-taminic norastemizole. Tetrahedron Lett. 1999, 40, 6875-6879. 

Arylation with various heterocyclic compounds can be carried out when their reactive halides are available at proper positions. For example, the antihistamine norastemizole derivative 85 was synthesized by the reaction of the chlorobenzim-idazole 83 with the diamine 84. Selective arylation of the primary amine in the diamine 84 proceeded with high selectivity [58]. BINAP is a good ligand for the amination of 3-bromopyridine (86) [59]. Similarly benzylamine was introduced to the bromopyridine moiety of the 3-carboxy- -carbolines 87 to give 88 [60]. Another example is the C-8 aminated adenosine derivative 90 was obtained in a high yield by the amination of 89 [61]. 

Scheme 14.22 Norastemizole synthesis by exploitation of palladium-catalyzed isocyanide insertion.

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