Pyrimethamine

Chemical Name 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine Common Name — 

The solution was heated on a steam bath for 6 hours. After cooling, the whole was poured into water and the oil extracted well with ether, the ether solution was discarded and the aqueous solution neutralized with 1 N sulfuric acid. A heavy oil separated which was taken into ether, washed with water, bicarbonate solution and again with water. After drying, the ether was removed to give a thick oil which solidified on standing (34.6 grams). After recrystallization from an ether-petroleum ether mixture it formed needles, MP 108°-112°C. 

The above keto-nitrile (15 grams) was methylated with a solution of diazomethane in ether. (The diazomethane solution was prepared using 20 grams of N-nitrosomethylurea.) The ether and excess diazomethane were evaporated on the steam bath and the oil dissolved in ethanol (50 ml). To this was added a solution of guanidine in ethanol (100 ml) (prepared from 8.1 grams of the hydrochloride). The solution was refluxed for 5 hours, the alcohol removed and the residue treated with 5N sodium hydroxide. The insoluble material was then filtered. After purification by precipitation from dilute acetic acid with sodium hydroxide and by recrystallization from ethanol the product formed clear colorless needles (8.0 grams), MP 218°-220°C as described in U.S. Patent 2,602,794. 

Merck Index 7BB4 Kleeman Engel p. 791 PDR pp. 741,1484 OCDS Vol. 1 p.262 (1977) 

Patent 2,680,740 June 8, 1954 assigned to Societe des Usines Chimiques Rhone-Poulenc (France) 

Daraprim Daraprim Erbaprelina Fansidar Wlalocide Pirimecldan Pyrimethamin-Heyl Tindurin 

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The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Metrizoic acid Diazomethane Diazepam Epirizole Methoxsalen Pyrimethamine Dibenzo[a,el cycloheptadiene Butriptyline... 

Tindurin - Pyrimethamine Tinidil Isosorbide dinitrate Tinigyn - Tinidazole Tinol - Dipyridamole Tinset - Oxatomide Tintorane Warfarin sodium Tinver - Salicylic acid... 

ACTs are currently recommended artemether-lume-fantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine [1, 5]. In areas with amodiaquine and sulfadoxine-pyrimethamine resistance exceeding 20%, i.e., SE Asia, artesunate + mefloquine or artemether-lumefantrine should be used [1,5]. 

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

GM2-gangl iosidosis Lysosomal, heterodimeric ss-hexosaminidase A (Hex A) Pyrimethamine... 

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