肿瘤化学治疗的研究 ⅩⅦ.5-烷氧基和5-取代苯氧基嘧啶化合物的合成

本文报导了一系列5-烷氧基和5-取代苯氧基硫氧嘧啶(Ⅳ,Ⅴ)、5-烷氧基和5-取代苯氧基尿嘧啶(Ⅵ,Ⅶ)、5-烷氧基-和5-取代苯氧基-4-徑基-2-羧甲硫基嘧啶(Ⅷ,Ⅸ)及5-取代苯氧基-2-氨基-4-羟基嘧啶(Ⅹ)等化合物的合成,以进行抗肿瘤試驗. 初步药理試驗結果显示:化合物(Ⅳ₁),(Ⅳ₄),(Ⅴ₄),(Ⅴ₆),(Ⅴ₇),(Ⅵ₃),(Ⅶ₈),(Ⅶ₁₅),(Ⅶ₁₆),(Ⅸ₇)和(Ⅹ₁)对肉瘤180有明显的抑制作用.

STUDIES ON CANCER CHEMOTHERAPY ⅩⅦ. SYNTHESIS OF 5-ALKOXYL AND 5-SUBSTITUTED PHENOXY PYRIMIDINES

5-Alkoxy and 5-substituted phenoxy-2-thiouracils (Ⅳ, Ⅴ), uracils (Ⅵ, Ⅶ), 2-carboxymethyl mercapto-4-hydroxypyrimidines (Ⅷ, Ⅸ) and 2-amino-4-hydroxypyrimidines (Ⅹ) have been synthesized for the investigation of cancer chemotherapy. 5-Substituted thiouracils (Ⅳ, Ⅴ) or 2-amino-4-hydroxy 5-substituted pyrimidines (Ⅷ, Ⅸ) were prepared by the condensation of an appropriate ethyl α-substituted (β-hydroxy acrylate (ⅩⅡ) with thiourea or guanidine. (Ⅳ) or (Ⅴ) reacted with chloroacetic acid in sodium hydroxide solution to form 2-carboxymethyl mercaptopyrimidines (Ⅷ) or (Ⅸ). After acidifying and refluxing for 3-4 hrs., the corresponding uracils (Ⅵ) or (Ⅶ) were obtained. They could also be prepared directly by treating the appropriate thiouracils (Ⅳ) or (Ⅴ) with Chloroacetic acid. The ethyl a-substituted β-hydroxyacrylate (ⅩⅡ) were prepared by formylating the ethyl alkoxy (or aryloxy) acetate with ethyl formate in the presence of sodium or sodium methoxide. 5-p(or m)-Amino-phenoxy-thiouracil (V₁₂) or (V₁₃) was readily formed when 5-p (or m)-acetamido compound (V₁₀) or (V₁₁) was hydrolyzed with hydrochloric acid. On treating with chloroacetic acid, 5-p(or m)-amino-phenoxy-uracil (Ⅶ₁₁) or (Ⅶ₁₂) was obtained. (Ⅶ₁₁) could also be prepared by hydrogenation of 5-p-nitro-phenoxy-uracil (Ⅶ₁₀), which was prepared by nitration of 5-phenoxy-uracil (Ⅶ₁) or thiouracil (Ⅴ₁). When 5-p-amino-phenoxy thiouracil (V₁₁) was treated first with fluoro-boric acid and sodium nitrite (Schiemann reaction) and then with chloroacetic acid, 5-p-fluorophenoxy uracil (Ⅶ₉) was obtained. An alternative route was carried out through the condensation of an appropriate ethyl α-p (or o, m)-fluoro phenoxy β-hydroxy acrylate with thiourea and then treatment with chloroacetic acid. Hydroxyethylation of the corresponding 5-amino phenoxy uracil (Ⅶ₁₁) or (Ⅶ₁₂) with ethylene oxide, or condensation of the ethyl α-bis (β-hydroxyethyl) amino phenoxy β-hydroxyacrylate with thiourea following with chloroacetic acid treatement, afforded the 5-p (or m)-bis (β-hydroxyethyl) amino phenoxy uracil (Ⅶ₁₃) or (Ⅶ₁₃), from which 5-p-(or m)-bis (β-chloroethyl) aminophenoxy 2,4-dichloro pyrimidine (ⅩⅢ) was prepared by chlorination with phosphorus oxychloride. On hydrolysis of the tetrachloro compounds (ⅩⅢ) with hydrochloric acid, the two new nitrogen mustards-5-p (and m)-bis (β-chloro-ethyl) amino phenoxy uracils were obtained. Preliminary biological test showed that compounds (Ⅳ-1, (Ⅳ-4), (Ⅴ₅), (Ⅴ₆), (Ⅴ₇), (Ⅵ₃), (Ⅶ₈), (Ⅶ₁₅), (Ⅶ₁₆), (Ⅸ₇) and (Ⅹ₁) inhibited the growth of sarcoma 180 in mice.