Oxamniquine

1 -p-Chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid Thionyl chloride Hydroxylamine hydrochloride 

The product is relatively stable towards water and aqueous alkalies in which it proves to be insoluble even after dwelling therein several hours at room temperature. It reacts, better if at elevated temperature, with lower alcohols with which it forms the corresponding esters, and with ammonia under suitable conditions for forming the amide (melting point 219°C to 221°C). 

A solution of 1.330 g sodium hydroxide in 20 ml water is slowly admixed with 2.330 g hydroxylamine hydrochloride while cooling, whereupon 1 g chloride of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid is distempered in this neutral or slightly alkaline solution by vigorously stirring during a few minutes. 

The acid chloride reacts with the free hydroxylamine with considerable rapidity apparently without dissolving. The reaction is completed when a sample of the suspension shows to become clear on adding aqueous alkali. The crystalline pale-yellow mass of product Is separated by filtering, lavishly washed with water and dried in vacuum. The crude product yield is actually quantitative. The product is purified with excellent yields by repeatedly crystallizing from hot dioxane and washing with ether melting point 181°C to 182°C (dec.). 

De Martlis, F., Arrigoni-Martelli, E.and Tamietto, T. U.S. Patent 3,624,103 November 30, 1971 assigned to Instituto 8iologico Chemioterapico (A.B.C.) SpA (Italy) 

1 -p-Chlorobenzovl-2-methvl-5-methoxv-3-indoleaeetie acid Thlonyl chloride Hydroxylamlne hydrochloride 

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Oxamniquine. This tetrahydroquinoline (2), C24H2 N202, has been proven effective for the treatment of S. mansoni infections. It is clinically ineffective against S. haematobium and S.japonicum infections. 

Soybean meal, by fermentation Bacitracin Clavulanic acid Cycloserine Erythromycin Gentamicin sulfate Kanamycin sulfate Micronomicin Novobiocin Oleandomycin Oxamniquine Oxytetracycline Paromomycin Ribostamicin Sisomicin... 

Reduction of the heterocyclic ring and incorporation of a nitro function affords a compound with antischistosomal activity, oxamniquine (60). Its synthesis begins with chlorination of 2,6-dimethyl-quinoline, which proceeds regiospecifically on the methyl group adjacent to the ring nitrogen (56). 

Morpholine [110-91-8] Oxamniquine [21738-42-1] 2477C I(3)472A, N(1)335C QD6475000 USP... 

Microbiological oxidation of the methyl group in that last intermediate using Aspergillus sclerx>-torium affords oxamniquine (60). 

Oxamniquine is a second choice agent against Schistosoma mansoni. It is ineffective against other Schistosoma species. It shows activity against both the early developmental as well as the mature stages of Schistosoma mansoni. Its mode of action is not well understood. 

Oxamniquine is given orally and is readily absorbed from the intestinal tract. Peak concentrations in plasma are obtained in about 3 hours. The drug is excreted in urine mostly as a 6-carboxyl derivative. 

Oxamniquine is a very elfeetive anti-sehiztosomidal agent used in the treatment of bilharzia and related conditions. Chemical synthesis was possible, except for the final step which required the hydroxylation of a methyl group attaehed to an aromatie ring. Therefore biologieal approaches were examined (Figure 4.17). 

StractuiE-fimction analysis of other drugs performances indicated the structure of the target molecule (oxamniquine). 

Oxamniquine had good anti-parasite activity, especially versus South American strains, and that was relatively free of side effects. 

Oxamniquine was produced by Pfizer on a conunercial scale through the 1970s in their Brazilian plant close to the markets for this drag. It was successful, but did not make big money and is now only produced occasionally as it has become superseded by more effective drags. 

Product (R)- Glycidyl butanoate Oxamniquine L-PAC Acrylamide 6- Hydroxynicotinic acid ... 

Existing in-house know-how, esp. ease of integration into existing production facilities. oxamniquine, cefuroxime, L-aspartic acid, acrylamide... 

Oxamniquine (9.123), a semisynthetic tetrahydroquinoline, is the treatment of choice for Schistosoma mansoni infections. Its mechanism of action is unknown but appears to entail binding of the drug to the nematode s DNA, somehow causing its death. Alternatively, it may cause worm paralysis and expulsion. 

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