Antimalarial agents preparations

The key intermediate for the preparation of the 8-aminoquin-oline antimalarial agents is obtained by condensation of the substituted aniline, 90, with "dynamite-grade" glycerol in concentrated sulfuric acid. (The reaction may well follow some scheme such as that depicted below.) Ihe nitroquinoline obtained from... 

Coccidiosis is an economically significant respiratory disease of fowl. During the course of studies directed toward antimalarial agents, sulfani-tran (143) was prepared and found to be a coccidiostat. It is prepared conveniently by reaction of p-aceto-amidobenzenesulfonyl chloride with p-nitroaniline in acetic acid.68... 

Diethyl aminomalonate reacts with 1,3-diketones in boiling acetic acid to the corresponding pyrrolecarboxylates 11 (87JOC3986). From N-ac t-amidomalonate and acroleins, pyrrolidines were prepared and they were further transformed into functionalized pyrroles, which are a part of the antibiotic lyncomycin and an antimalarial agent (67JA2459 72JMC1255). 

Dibenzosuberanyl piperazine derivatives, (IV), prepared by Takeuchi (5) were effective in restoring medicament sensitivity of antimalarial agents and used in the treatment of plasmodium infections. 

Vinyl-l,2,4-Trioxyspiro antimalarial agents, (I), prepared by Singh (2) were effective in treating multidrug-resistant malaria strains. 

Chloropyrido[3,2-a]acridines 12 were prepared by the route described in Scheme 1, but with 6-aminoquinolines instead of 7-aminoquinoline (46JCS151 47JCS678). The chloroderivatives 12 were then converted to potent antimalarial agents with dialkylaminoalkylamines or alkylaminoal-kylamines in phenol at 100°C. 

A choice of salts can also expand the formulation options for a material. The antimalarial agent a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene-methanol hydrochloride (Fig. 9) exhibited poor solubility, was delivered as an oral formulation, and required a single dosing of 750 mg (13). Seven salts and the free base were evaluated. The lactate salt was found to be 200 times as soluble as the hydrochloride salt (Table 3). This enhanced solubility would make it possible to reduce the oral dose to achieve the same therapeutic response as well as develop a parenteral formulation for the treatment of malaria. However, the case of lidocaine hydrochloride (Fig. 14) demonstrates that a compound limited to parenteral and topical formulations can be expanded to oral administration by changing to a salt form with acceptable physical properties (16). The hydrochloride salt was hygroscopic, difficult to prepare, and hard to handle. Six salts were evaluated for salt formation, solubility, and hygroscopicity. Other salts, such as phosphate, exhibited properties acceptable for dry pharmaceutical dosage forms. 

This oxidation can be used to prepare the dioxetane 2 that can rearrange to the 1,2,4-trioxane 3, a potent antimalarial agent. 

General methods for the preparation of 1,2,4,5-tetraoxanes Key structures for the development of peroxidic antimalarial agents 12KGS60. Reactions oftetrazines with dienophiles 12KGS1237. 1,2,4,5-Tetrazines and azolo[l,2,4,5]tetrazines Synthesis and reactions with nucleophiles 13KGS75. 

Pyrrolo[2,3-6]azepin-4-ones (223) have been prepared by a Dieckmann cycliz-ation of the appropriately substituted pyrrole, as potential antineoplastic and antimalarial agents. 

Among the aminomethylenemalonates, the A-aryl and A-hetaryl derivatives and their cyclization products are of great importance in organic chemistry, as some of them are key intermediates in the synthesis of different 4-aminoquinoline antimalarials (Scheme 1), in the preparation of anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates (Scheme 2), and in the production of antibacterial agents of the nalidixic acid type (Scheme 3). 

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