疟疾防治药物的研究——Ⅺ.2,4-二氨基-6-(N-取代-对氯苄氨基)喹唑啉衍生物的合成及其抗疟作用

合成2,4-二氨基-6-(N-取代-对氯苄氨基)喹唑啉衍生物33个,经伯氏鼠疟原虫(Plasmodium berghei)抑制性治疗筛选,剂量20mg/kg×3d,有10个化合物(1,2,5～8,14,20,21,26)抑制率在90%以上。经约氏鼠疟原虫(P.yoelii)斯氏按蚊系统的病因性预防筛选,剂量5mg/kg×3d,有26个化合物(1～12,14,20～22,24～33)使小白鼠全部得到保护;剂量下降到0.625mg/kg×3d,有14个化合物(5～12,14,20,21,26,31,33)使小白鼠全部得到保护(表1)。4个化合物(1,8,20,25,表2,3)进行了猴疟(P.cynomolgi)试验,效果不及伯喹和乙胺嘧啶。

STUDIES ON ANTIMALARIALS XI. SYNTHESIS AND ANTIMALARIAL ACTIVITIES OF SOME 2, 4-DIAMINO-6-(N-SUBSTITU-TED-P-CHLOROBENZYLAMINO) QUINAZOLINE DERIVATIVES

Thirty three 2, 4-diamino-6-(N-substituted-p-chlorobenzylamino)-quinazolines were synthesized. These compounds were prepared by treatment of 2, 4-diamino-6-p-chlorobenzylamino quinazoline(Ⅰ) with acyl chloride, sulfonyl chloride, isosulfocyanate or acrylonitrile, the corresponding compounds(20～30) were obtained respectively. Some substituted amino methyl compounds(31～33) were prepared by Mannich reaction of(Ⅰ). Moreover, the nitroso derivative(5) of(Ⅰ) through reduction afforded amino-compound(14) which was condensed with the appropriate benzaldehyde to give the requisite Schiff bases(15～19).Suppressive therapeutic tests in mice infected with Plasmodium berghei showed that ten(1, 2, 5～8, 14, 20, 21, 26) out of these compounds produced 90% suppression of the parasites when administered orally at dose of 20 mg/kg/d × 3. Twenty six compounds(1～12, 14, 20～22, 24～33) given orally at dose of 5 mg/kg/d × 3 were shown to possess causal prophylactic activity against P. yoelii in mice. When the regimen was reduced to 0.625 mg/kg/d × 3 thirteen compounds(5～12, 20, 21, 26, 31, 33) were shown to prevent the test mice from being infected. In tests against P. cynomolgi in rhesus monkeys, four compounds(1, 8, 20, 25) were found to be less effective than primaquine and pyrimethamine in the same dosage level.