疟疾防治药物的研究——ⅩⅤ.双-(2,4-二氨基喹唑啉-6-取代氨甲基)芳香类化合物的合成及其抗疟作用

A series of bis(2,4-diamino-quinazol-6-yl-substituted aminomethyl) aromatic derivatives were synthesized. Compounds Ⅱ_1～5 were synthesized by two ways. In the first, 2,4,6-triaminoquinazoline was condensed with the corresponding aryl dialdehydes to form Schiff bases which were reduced with sodium borohydride; the second used a new method in which 2,4,6-triaminoquinazoline was directly condensed with the corresponding aralkyl dihalides to afford the same products. The derivatives Ⅱ_6～16 were prepared by formylation, nitrosation or methylation respectively.The inhibition activities of the title compounds on dihydrofolate reductase in rat liver were assayed. The activities of formylated or nitrosated products were 6-9 times, and of methylated products were twofold as active as that of the parent compounds. Ⅱ₆, Ⅱ₉, Ⅱ₁₀ and Ⅱ₁₄ were nearly as potent as pyrimethamine. Primary antimalarial screening in mice showed that no one possessed significant activity.     

α,ω-双(对烃氧基苯氨基)-烷及 N,N′-双(对取代基苯基)-烃二醯胺类化合物的合成

1. α,ω-Bis- (p-alkoxyphenylamino) -alkanes, N,N'-bis-(p-substituted phenyl)- alkane dicarboxamides and N, N'-bis-(p-substituted phenyl)-alkane dicarboxylates were prepared for studying the relationship between chemical structure and thera- peutic activity, against Schistosomiasis japonica in experimental animals. 2. α,ω-Bis-(p-alkoxyphenylamino)-heptanes were prepared from p-alkoxyaniline and 1,7-dibromoheptane in the presence of sodium bicarbonate. α,ω-Bis-(p-alkoxy- phenylamino)-pentanes were prepared by hydrolysis of N,N'-bis-(p-alkoxyphenyl)- N, N'-bis-(p-toluene sulfonyl)-pentanediamines with 25% hydrochloric acid, while the latter were obtained by condensation of N-(p-alkoxyphenyl)-p-toluene sulfonamides with 1,5-dibromopentane in alcoholic alkaline solution. 3. N, N'-Bis-(p-substituted phenyl)-alkane dicarboxamides were prepared from p-substituted aniline and alkane dicarboxylic acid chlorides. According to Grimmel's method, we also prepared these compounds of this series by the reaction of p,p'-bis- (dimethylamino)-phosphazo benzene with corresponding alkane dicarboxylic acid. In the case of succinic acid, we obtained, however, mainly N-(p-dimethylaminophenyl)- succinimide instead of succinic diamide. 4. The intermediate, p-diethylamino-ethoxyaniline, was prepared by hydrolysis of the condensation product of p-acetaminophenol and diethylaminoethyl chloride. 5. Sodium salt of dimethylaminophenol was treated with alkane dicarboxylic acid chloride to give the corresponding N, N'-bis-(p-dimethylaminophenyl) -alkane dicar- boxylates.     

青蒿素类似物的研究 Ⅶ.双(二氢青蒿素)醚和双(二氢脱氧青蒿素)醚类化合物的合成

二氢青蒿素甲醚(Ⅰ)是青蒿素衍生物中最简单的一种醚类化合物。临床验证表明,它的抗疟效果优于青蒿素。鉴于二氢青蒿素用二元酸酯化后活性有较大提高,推测二个青蒿素基的存在可能有利于抗疟作用。作者试图在醚类中寻找更好的抗疟药并研究其构效关系,因此用二元醇与2克分子的二氢青蒿素在三氟化硼乙醚溶液的催化下合成了一系列双(二氢青     

抗心肌缺血药3-{4-[(2-羟基-3-烷氨基)丙氧基]苯基(苄基)}-取代4(3H)-喹唑酮的合成

In order to search for effective antimyocardial ischemic agents, fourteen new 3 4-[(3-alkylamino-2-hydroxy)propoxy] phenyl(benzyl)]-substituted 4(3H)-quin zolinones (Ⅱ) were synthesized. Substituted o-aminobenzoic acids used as the starting materials were allowed to react with acetic anhydride and then p-aminophenol (method A), or with N- (4- hydroxyphenyl)formamide (method B), or with thionyl chloride and then N - (4 - hydroxybenzyl) formamide (methode C) to form 3-[(4-hydroxyphenyl(benzyl)]-substituted 4(3H)-quinazolinones (Ⅲ). The intermediate Ⅲ reacted with epichiorohydrin to form the epoxides (Ⅳ). The reaction of Ⅳ with an excess of isopropylamine or tert-butylamine in boiling chloroform gave the desired products. Of all the compounds synthesized, Compounds Ⅱ_3～5 and Ⅱ₁₃ were found to increase the tolerance of mice to hypoxia. Further evaluation is in progress.     

抗疟药的研究Ⅳ——2,4-二氨基-6-取代氨基磺酰喹唑啉的合成

2,4-Diamino-6-substituted amino sulfonyl quinazolines generally were prepared by refluxing 2,4-diamino-6-chloro-sulfonylquinazoline sulfate with suitable amines in dilute ethanol. For 2,4-diamino-6-(2-pyridy) amino sulfonyl quinazoline, it was prepared in dry pyridine. Compounds Ⅰ₂, Ⅰ₉ and Ⅰ₁₀ were shown to be more active against chloroquine resistant strain of P. berghei than sensitive strain. Compounds Ⅰ₂, Ⅰ₁₂ and Ⅰ₁₃ showed prophylactic action against P. yoelii.     

15-14C标记青蒿素的合成

15-¹⁴C]Artemisinin(8) was prepared by the biosynthesis of[15-¹⁴C]dihydroartemisic acid(14) which was synthesized from diketone in 6 steps. A supernatant liquidprepared from the tender leaves of ripe Shanghai Qinghao(Artemisia annua L.)was incubated with themixture of compounds l3 and l4(100 mg, total activity 3. 26 MBq, 13:14=1:1) at 30℃ or 37℃ for 4 hr. After the addition of natural artemisinin(100 mg) ,the mixture was heated at l00℃for5min , and extracted with chloroform(method A)or petroleum ether(bp. 60～90℃, method B).Theextract was evaporated and the residue was recrystallized(method B)or purified py preparative thinlayer chromatography(methed The crude product was recrystallized from methylene chloride—Petroleum ether to yield 8 with constant specific radioactivity. The mean rate of incorporation in runs1～8was l.17%。The possible influence factors of the biotransformation were studied. The incuhation temperaturewas considered as a key factor.     

豹皮菌中2-Amino-3-(1,2-dicarboxyethylthio)propanoic acid非对映异构体的绝对构型

Four stereoisomers of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid were prepared by reaction of L- and D-cysteine with fumaric acid. The absolute configuration of the diastereoisomer of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid from Amanita pantherina were assigned as (2R, 1'R) and (2R, 1'S) by analysis of the optical properties. Pharmacological tests showed that all of the four stereoisomers inhibited the depolarization of NMDA on spinal motorneurones in newborn rats, The inhibition intensity of L-A,D-A and D-B were higher than that of L-B.     

16-(m-氯苯氧基)-17,18,19,20失四碳前列腺素F2α的全合成

A simplified synthetic method for compound (1) was described. Both α,β-unsaturated ketone and y-lactone of (4)b were reduced with Dibal simultaneously to corresponding allylic hydroxy group and γ-lactol in good yield. Without protecting the hydroxy group, the mixture (6) was transformed to the target compound (1) by the known method.     

肿瘤的化学治疗ⅩⅩⅩⅣ.与对-双(2-氯乙基)氨基-ω-溴代苯乙酮-六甲撑四胺复合物(AT-584)有关的研究——Ⅲ.对-[双(2-氯乙基)氨甲基]-ω-溴代苯乙酮-六甲撑四胺复合物的合成

In a previous paper of this series we reported that the hexamethylenetetramine salt of p-bis-(2-chloroethyl)-amino-ω-bromoacetophenone (Ⅰ, AT-584) had pronounced inhibitory action with long-acting efficacy on the growth of several experimental tumoturs, and that the antiturnout property was due to the mustard group-and the long-acting efficacy was probably related to the quarternary structure. Since nitrogen mustards of aliphatic type usually possess more effective action than those of aromatic ones, the hexamethylenetetramine salt of p-[bis-(2-chloroethyl)-aminomethyl]-ω-bromoacetophenone (Ⅱ) was synthesized.The starting material for the synthesis of compound Ⅱ was p-[bis-(2-chloroethyl) aminomethyl]-benzoic acid hydrochloride (Ⅷ), which was prepared from ethyl p-toluate or p-tolunitrile via bromination with NBS, condensation with diethanolamine, Chlorination with thionyl chloride and hydrolysis with hydrochloric acid successively. Gompound Ⅷ was chlorinated by thionyl chloride in dry benzene to give its acid chloride (Ⅸ), which without being isolated, was treated with diazomethane to yield the corresponding diazoketone(Ⅹ). The latter, without being isolated in pure state was decomposed in dioxane by hydrobromic acid to give p-[bis (2-chloroethyl) aminomethyl]-ω-bromoacetophenone (Ⅺ). Finally, the desired product (Ⅱ) was obtained by treating Ⅺ with hexamethylenetetramine in chloroform.Preliminary pharmacological tests showed that compound Ⅱ did not possess significant inhibitory action against sarcoma 180 in mice.     

1-氨基-6-氟-1,4-二氢-4-氧代-7-(取代)哌嗪基-3-喹啉羧酸及其衍生物的合成与抗菌活性

The title compounds 6～24 were obtained by the reaction of 5 with corresponding benzaldehydes. 5 wes prepared with ethyl 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate by hydrolysis, amination and condensation with piperazine. Anti—bacterical activities of 5～24 were tested in vitro.     

青蒿素类似物的研究 Ⅳ.含卤素、氮、硫等杂原子的青蒿素衍生物的合成

为增强双氢青蒿素酯和醚类衍生物的抗疟作用,我们合成了42个侧链上带有卤素、氮或硫取代的双氢青蒿素酯和醚类化合物。抗疟筛选表明,多数化合物的活性高于青蒿素,但并未超过相应的无杂原子取代的衍生物,唯双氢青蒿素的问-三氟甲基苯甲酸酯(17)的抗疟活性为间-甲基苯甲酸酯的4倍,化合物(17)和(6)为青蒿素的10倍。     

6-(2-氰乙基)-17α-乙酰氧基黄体酮类化合物的合成

在合成甾体口服避孕药的研究中,我们曾经合成了一系列4位及6位具有甲基,氯和氰乙基黄体酮类化合物。本文报道新化合物6-(2-氰乙基)-17α-乙酰氧基黄体酮类化合物(Ⅲ_a,Ⅲb,Ⅳ和Ⅶ)的合成。     

双联苄类化合物结构多样性的研究进展

目的对双联苄类化合物结构多样性进行综述。方法查阅国内外相关文献29篇,从生源合成、旋阻异构和化学合成三方面介绍双联苄类化合物的结构多样性。结果与结论双联苄化合物是光学活性奇特的天然产物,其结构类型多样,深入研究其结构特征,对理解这类天然产物的构效关系的研究和生物合成都具有指导性作用。     

青蒿素类似物的研究 Ⅲ.二氢青蒿素二元酸双酯和单酯类衍生物的合成

青蒿素是新型化学结构的抗疟药。为了克服复燃率高及不溶解于水的缺点,我们以二氢青蒿素为原料与二元酸或酸酐和二环已基碳二亚胺(DCC)在4-二甲氨基吡啶(DMAP)催化下合成一系列的二氢青蒿素二元酸双酯及单酯类衍生物。经鼠疟(Plasmodium berghei)抗氯喹虫株筛选结果表明,化合物3的抗疟效果比青蒿素强9倍。     

阿魏酸衍生物的合成

本文报道3种类型18个阿魏酸衍生物的化学合成:Ⅰ.氨基醇酯类化合物,Ⅱ.5-(烷胺基)一次甲基阿魏酸,Ⅲ.双分子阿魏酸的醚类化合物。药理筛选的初步结果表明:Ⅰ类化合物的体外抗凝作用比阿魏酸本身为强,Ⅱ类化合物作用很弱。     

血吸虫病化学治疗的研究——Ⅳ.β-(5-硝基-2-呋喃)丙酰胺类及其α,β-二溴取代衍生物的合成

本文报道38个β-(5-硝基-2-呋喃)丙酰胺及其α,β-二溴取代衍生物的合成。这类化合物的制备是以相应的β-(5-硝基-2-呋喃)丙烯酰胺类化合物(Ⅰ)进行催化氢化或与溴加成而得。经动物筛选发现β-(5-硝基-2-呋喃)丙烯酰胺类的丙烯双键以氢饱和以后生成丙酰胺类化合物(Ⅱ),对感染日本血吸虫病的小白鼠完全失去治疗或预防作用。而以溴饱和双键的α,β-二溴化合物(Ⅲ)则仍然有较显著的杀虫作用。其中尤以β-(5-硝基-2-呋喃)-α,β-二溴丙酰异丙胺(Ⅲ₁₁)和β-(5-硝基-2-呋喃)-α,β-二溴丙酰甘氨酸乙酯(Ⅲ₂₄)最为显著,后者曾试用于临床,证明有一定疗效。     

神香草化学成分研究

目的研究神香草Hyssopus cuspidatus Boriss．的化学成分。方法采用硅胶、Sephadex LH-20柱分离纯化,通过理化常数和光谱数据鉴定化合物的结构。结果从神香草乙醇提取物的乙酸乙酯和正丁醇部分分离得到7个化合物,经理化常数和波谱数据分析,分别鉴定为白杨素（Ⅰ）、二十四亚甲基环阿尔廷醇（Ⅱ）、齐墩果酸（Ⅲ）、正十六烷醇（Ⅳ）、蜡醇（Ⅴ）、β-谷甾醇（Ⅵ）、胡萝卜苷（Ⅶ）。结论化合物Ⅰ,Ⅱ,Ⅳ为首次从该植物中分离得到。     

抗高血压药物2-亚氨基-3-(β-羟基苯乙基)-噻唑烷衍生物的合成

2-Imino-3-(β-hydroxyphenethyl)thiazolidine showed hypotensive activity. In order to find more active derivatives, a series of compounds has been synthesized.In preliminary screening tests, Compounds (Ⅱ-2) and (Ⅳ-1) showed considerable hypotensive effect.     

金荞麦的化学成分研究

目的研究中药金荞麦中的化学成分。方法运用多种色谱方法分离化学成分 ,依据理化性质、波谱 (NMR、EI- MS)数据分析鉴定化合物结构。结果从金荞麦中初步分离得到 5个化合物 ,分别鉴定为赤杨酮 (glutinone ,Ⅰ )、赤杨醇 (glutinol,Ⅱ )、棕榈酸单甘油酯 (glycerolmonopalmitate ,Ⅲ )、木犀草素 (luteolin ,Ⅳ )、正丁醇 - β- D- 吡喃型果糖苷 (n butyl -β- D fructopyronoside ,Ⅴ )。 结论 5个化合物均为首次从荞麦属植物中分离得到。     

珊瑚兰酚类化学成分的研究

从珊瑚兰(Galeola faberi Rolfe)根茎的乙醇提取物中首次分离鉴定出五个脂溶性酚类衍生物(Ⅰ～Ⅴ)和三个水溶性酚类衍生物(Ⅵ～Ⅷ),即:对羟基苯甲醛(Ⅰ)、4,4′-二羟基二苯基甲烷(Ⅱ)、2,4-二对羟苄基苯酚(Ⅲ)、5-甲氧基-3-(2-苯基-反-乙烯基)-2,4-二对羟苄基苯酚(Ⅳ)、对羟基苯甲醇(Ⅴ)、对羟甲基苯-β-D-吡喃葡萄糖甙(天麻素,Ⅵ)、二[4-(β-D-吡喃葡萄糖氧)苄基](S)-(-)-2-异丙基苹果酸酯(Ⅶ)和二[4-(β-D-吡喃葡萄糖氧)苄基](S)-(-)-2-仲丁基苹果酸酯(Ⅷ)。其中Ⅳ和Ⅷ为新化合物,Ⅲ为新天然产物。