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.     

16α-甲基-3β,17α-二羟基-5α-孕甾-20酮-3β-醋酸酯的微生物转化

16 α-Methyl-3 β,17 α-dihydroxy-5 α-pregnane-20-one-3 β-acetate (Ⅰ) was prepared from tigogenin and then incubated with a mixture of Mycobacterium smegmatis (MS₁) and Arthrobacter simplez (A₁) to give 16 α-methyl-17 α-hydroxy-△^{1, 4}-pregnadiene-3,20-dione (Ⅱ) with about 63% yield.Compound (Ⅱ) when incubated with Absidia glauca (AG₁) gave about 55% yield of 16 α-methyl-11 α, 17 α-dihydroxy-pregna-1,4-diene-3,20-dione (Ⅳ).     

对-氯苯丙炔酰胺类化合物的合成及其与肼反应产物的研究

Synthesis of p-chlorophenylpropiolylamides and itsreaction produets with hydrazine hydrate were studied. It was found that the reaction products varied with the different Substituent groups in the amidel When the substituent group was isopropyl or sec-butyl group, p-chloro-β-hydrazino-cinnamamides (Ⅱ) were obtained. Under similar reaction conditions, when the substituent, group was n-propyl, n-butyl or diethyl group, cyclization reaction occurred and the reaction product was 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ). All the compounds were tested in mice for anticonvulsant activity. Prelimary data showed that p-chlorophenyl-propiolyl-sec-butylamide (I₄) and p-chlorophenyl-propiolyl-n-propylamide (I₁) exhibited moderate anticonvulsant activity. The ED₅₀ was 54.5(34.4～86.4), and 56.1(31.6～99.6) mg/kg respectively. The compounds of p-chloro-β-hydrazino-cinnamamide (Ⅱ)and 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ) showed no significant effect on antieonvulsant activity. p-Chloro-cinnamoyl-hydrazide (Ⅳ) provided good anticonvulsant activity.     

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.     

肿瘤的化学治疗ⅩⅩⅩⅣ——DL-N-二氯乙酰基-5-硝基-色氨酸及其有关化合物的合成

In the present work, the compounds DL-N-dichloroacetyl-5-nitrotryptophan (I_c), DL-5-nitro-tryptophan hydrochloride (Ⅱ_c) and their ethyl esters (Ⅰ_d and Ⅱ_d) were prepared and found to be less effective against Hela cells than their corresponding 7-nitro analogs (Ⅰ).5-Nitrogramine (Ⅴ) was condensed with diethyl formamidomalonate and dimethyl sulphate in the presence of sodium alcoholate, affording diethyl α-formamido-α-(5-nitroindolyl methyl)-malonate (Ⅵ). The latter was hydrolyzed in concentrated hydrochloric acid to give 5-nitrotryptophan hydrochloride(Ⅱ_c), from which the desired product, DL-N-dichloroacetyl-5-nitrotryptopban (Ⅰ_c), was obtained by acylation with dichloroacetylchloride in dilute sodium hydroxide. The ethyl ester of DL-5-nitrotryptophan (Ⅱ_d) was obtained by esterification of Ⅱ_c with absolute ethyl alcohol saturated with gaseous hydrogen chloride and was then treated with dichloroacetyl-chloride in the presence of aqueous sodium acetate or in boiling benzene.     

血吸虫病化学治疗的研究——ⅩⅩⅩⅣ.α-氯-β-(5-硝基-2-呋喃)丙烯酰胺类及其乙烯噁二唑类衍生物的合成

Synthesis of 35 new compounds of α-chloro-β-(5-nitro-2-furyl) acrylamides and 5-[α-chloro-β-(5-nitro-2-furyl ) vinyl]-oxadiazoles by known methods are reported. In preliminary test in mice 10 compounds were found to possess pronounced activity against Schistosomiasis japonica. Among these Ⅰ₁₂, Ⅰ₁₃, Ⅰ₁₄, Ⅰ₂₀, Ⅱ₁ and Ⅱ₈ were shown to be the most effective.     

6-取代二氢哒嗪酮类化合物的合成及血小板聚集抑制作用

In order to develop more potent and less toxic, antithrombotic agents, ten 6-(4-substituted piperazinyl acetyl aminophenyi)-4, 5-dihydro-3(2H)-pyridazinones were synthesized. The title compounds were tested in vitro for platelet aggregation inhibitory activity with ADP-induced rat platelets and PAF-induced rabbit platelets. Preliminary tests showed that all of the pyridazinones could inhibit ADP-induced rat platelet aggregation. Ⅰ₇, Ⅰ₈, Ⅰ₉ were more potent than the control compound CI 930. Ⅰ₉ was the most potent compound with IC₅₀ of 0.99 μmol/L. Pertaining to PAF-induced rabbit platelet aggregation. Ⅰ₉ was the most potent inhibitor with IC₅₀ of 3.7 μmol/L.     

4-硝基二苯醚-4′-硫代氨基甲酰胺类化合物的合成及其抗日本血吸虫作用

Ten 4-nitrodiphenylether-4′-thiocarbamides were synthesized from 4-nitro-4′-thiocyanodiphenylether and corresponding amines. Preliminary screening data in table 1 showed that most of them exhibited insignificant or low activity against schistosoma japonicnm in mice, while V₉ with a diethyl substituted nitrogen in thiocarbamide structure was found to possess antischistosomal activity as high as that of nithiocyamine (Amoscanatec₉₃₃₃ GO/COP 4540).     

铀促排药物研究——Ⅲ.2,3-二羟基-5-烷氧羰基苄基胺羧酰胺螯合剂的合成

In searching for new chelation therapy drugs against uranium intoxication, a series of N-carboxymethyl-N-(substituted carbamoylmethyl)-2, 3-dihydroxy-5-carboalkyloxybenzylamine was synthesized starting with 2, 3-dihydroxy-5-carboalkyloxybenzylamine diacetic acid. The effect on the elimination of uranium salts from animal bodies was tested. Four of them (Ⅳ_n, Ⅳ_q, Ⅳ_u and Ⅳ_v) were shown to be more effective than tiron or phosphicine in accelerating uranium excretion in rats.     

一叶萩碱对5种神经递质受体和蛙脊髓膜电位的影响

Using radioligand binding assay method, securinine was shown to be specifically bound to GABA receptors of rat brain with IC₅₀ of 10^(-4)～10^-5mol/L. However, securinine did not exhibit affinity for a₁-, a₂- adrenoceptors and M-cholinergic receptors of rat brain and the β-adrenoceptors of duck erythrocyte membrane. In isolated and perfused bullfrog spinal cord experiment, the depolarization induced by GABA was slightly depressed by securinine (1 mmol/L), but no antagonistic effect on glycine or taurine evoked depolarization was observed with securinine. These results indicate that securinine is a weak GABA antagonist.     

根治间日疟化合物:2,5-双取代苯氧基伯喹衍生物的合成

作者等按Mislow等法先合成6-甲氧基-8-硝基-N-甲基-1 H-喹啉-2-酮后,在喹啉环2位及5位分别引入氯和溴,然后在2、5两位代入相同的取代苯氧基,再经还原、缩合、氯解等反应,最后合成了一类新的2,5-双取代苯氧基伯喹衍生物。化合物1,13和19对子孢子感染的鼠疟P.yoelii有效。     

抗疟新药的研究5-取代苯氧基-6-甲氧基-8-取代氨基喹啉的合成

根据5-(对-氟苯氧基)-6-甲氧基-8-(4-氨基-1-甲基-丁氨基)喹啉(Ⅰ₁)(表1)对猴疟原虫(Plasmodium cynomolgi)的作用略优于伯喹而毒性较低的报道,合成了化合物Ⅰ₁(代号M7844),同时还合成了衍生物5-取代苯氧基-6-甲氧基-8-(4-取代氨基-1-甲基丁氨基)喹啉(Ⅰ_3～17)(表1)以及其同分异构体5-取代苯氧基6-甲氧基-8-(5-取代氨基戊氨基)喹啉(Ⅱ_13～28)(表2)。药理研究证明化合物Ⅰ_1～7、Ⅰ₁₆及Ⅱ₁₈等对鼠疟P.yoelii均有不同程度的作用。化合物Ⅰ₁(M7844)的毒性甚低,对小鼠的毒性比磷酸伯喹低20余倍,对家兔的溶血反应也明显低干伯喹。但在相同剂量下,对猴疟P.cynomolgi的作用不及伯喹。对鼠疟红前期的作用比伯喹低4～5倍。     

4－甲基－5－取代苯氧基－伯氨喹类似物的合成及抗疟活性的初步评价

以2-硝基-4-甲氧基-5-溴乙酰苯胺为原料，经6步反应，合成了7个4-甲基-5-取代苯氧基伯氨喹类似物(Ⅱ_2～8)。抗疟活性的初步评价结果表明，这类化合物对鼠疟 Plasmodium yoelii 的病因性预防作用明显优于伯氨喹．可达伯氨唪的4～8倍；同时，Ⅱ_2～8还有较强的杀血液裂殖体作用．Ⅱ_2,5,6,8在0.781 mg·kg^-1 的剂量对原虫的抑制率为100％。     

抗疟新药咯萘啶及其类似物的合成

作者等根据一些抗疟药的构效关系,合成了一种新化合物2-甲氧基-7-氯-10-[3′,5′-双(四氢吡咯次甲基)一4′-羟基苯胺基]苯骈[b]1,5-萘啶(Ⅰ),代号7351,定名咯萘啶。它对红内期裂殖体的作用显著,毒性低。之后,又合成了它的类似物Ⅱ,这些类似物大多数对鼠疟Plasmodiumberghei的红内期均具有不同程度的作用,其中Ⅱ_1～6,9.10等的作用与Ⅰ相当。对子孢子诱发感染的鼠疟P.yoelii的作用以化合物Ⅰ、Ⅱ_{1,3,5,6,9,10,12,15}等为最强,优于伯喹对照组。值得注意的是,这类化合物既对血液转种的鼠疟P.berghei具有显著的作用,同时对子孢子感染的鼠疟P.yoelii也具有显著的作用。     

山蒟化学成分研究(Ⅱ)

从胡椒科植物山蒟(Piper hancei Maxim)中分得两个新木脂素成分(Ⅰ,Ⅱ)及三个生物碱(Ⅲ,Ⅳ,Ⅴ)。Ⅰ经光谱(IR,UV,MS,¹HNMR,¹³CNMR,APT-¹³SCNMR,2 D-HNMR)分析等证明其结构为rel-(7 S,8 S,1′R,3′S,4′R)-1′烯丙基-7-(3,4-二甲氧基苯基)-4′-羟基-5′-甲氧基-8-甲基-2′-氧双环[3.2.1]辛-5′-烯,为新结构,命名为山蒟醇(hancinol)。经光谱鉴定Ⅱ为burchellin,Ⅲ,Ⅳ,Ⅴ分别为风藤酰胺(futoamide)、荜拨明宁碱(piperlonguminine)和N-异丁基-反-2-反～4-癸二烯酰胺。后四种均首次从该植物中得到。     

抗疟药的研究 Ⅺ.4-甲基-5取代苯氧基伯喹的合成及其抗疟作用

本文报道了6个4-甲基-5取代苯氧基-6-甲氧基-8-(1-甲基-4-氨基丁氨基)喹啉(Ⅲ)的合成。除Ⅲ₃外,所有化合物对鼠疟P.berghei的抑制性治疗作用和对鼠疟P.yoelii的病因性预防作用均优干伯喹,其中以Ⅲ₁最强。Ⅲ₁口服治疗作用的SD₅₀和SD₉₀分别为0.65 mg/kg和1.60 mg/kg,口服预防作用的最小有效剂量(MED)和最小完全有效剂量(MFAD)分别为2.5mg/kg和5.0 mg/kg。对这类化合物的根治作用和毒性试验正在进行中。     

抗疟新药的研究——苯骈[b]1,5-萘啶衍生物的合成

作者等用2-取代基-7,10-二氯苯骈[b]1,5-萘啶分别与取代氨基烃基胺和取代胺在苯酚中作用,合成了2-取代基-7-氯-10-(取代氨基烃基氨基)苯骈[b]1,5-萘啶(Ⅱ_1～10,表1)和相应的10-(取代氨基)-苯骈[b]1,5-萘啶(Ⅱ_11～14,表1);将2-取代基-7,10-二氯苯骈[b]1,5-萘啶与取代苯酚的钾盐作用,又合成了相应的10-(取代苯氧基)苯骈[b]1,5-萘啶(Ⅲ,表2)。在具有取代氨基烃基胺侧链的化合物中,以Ⅱ_2,6,10对血液转种的Plasmodium berghei和子孢子诱发感染的P.yoelii两种鼠疟原虫的作用最显著;具有N-甲基-N′-氨基哌嗪侧链的Ⅱ₁₁,经后一种鼠疟试验,也呈现了优于伯喹的显著的疗效;化合物Ⅲ_1,3,4,7,8仅对后一种模型呈现较弱的作用。     

抗疟药的研究——Ⅸ.5-取代苯氧基-6-甲氧基-8-[(1-乙基-4-氨基丁基)氨基]喹啉类化合物的合成

至今,伯喹仍是唯一能应用的间日疟根治药,但由于毒性较大,化疗指数较低,在使用上受到一定的限制。近年来国内外对伯喹的化学结构进行了多方面的改造,出现了一些有希望的化合物。Chen等郑贤育等和许德余等分别报道在伯喹的5位引入取代苯氧基能提高抗疟作用,降低毒性;Yan等将4-甲基伯喹(Ia)的侧链1-甲基-4-氨基丁氨基改变成     

九里香化学成分的研究

自广东产芸香科(Rutaceae)植物九里香(Murraya paniculata(L.)Jack.)叶中分离得到六个香豆精,其中三个化合物为新的香豆精,根据光谱(UV,IR,NMR和MS)分析和化学方法确定九里香甲素(isomexoticin)九里香乙素(murpanidin)和九里香丙素(murpanicin)分别为(一)5,7-二甲氧基-8-(2′,3′-二羟基-3′-甲基丁基)香豆精(Ⅰ),(+)7-甲氧基-8-(1′,2′-二羟基-3′-甲基-3′-丁烯基香豆精(Ⅲ)和7-甲氧基-8-(1′-乙氧基-2′-羟基-3′-甲基-3′-丁烯基)香豆精(Ⅳ)。同时也得到三个已知香豆精murragatin(Ⅱ),murralongin(Ⅴ)和5,7-二甲氧基-8-(3′-甲基-2′-酮基丁基)香豆精(Ⅵ),最后一个是首次自本植物中得到的。     

抗疟药咯萘啶有关化合物的合成及抗疟活性比较

合成了咯萘啶(Ⅰ)的有关化合物Ⅱ～Ⅴ,以探讨抗疟药咯萘啶化学结构中母环1位上氮杂原子及吡咯烷基Mannich碱侧链的存在,对该化合物抗疟作用的关系。经对有抗药性的疟原虫体内试验,合成的有关化合物Ⅱ～Ⅴ以及抗疟药氯喹和阿的平等的抗疟作用,均不如咯萘啶。提示上述氮杂原子及Mannich碱铡链的存在,对咯萘啶的抗疟作用,起着重要的和不可缺少的作用。