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.     

N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道11个预期有血管紧张素转化酶抑制活性的N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸(VII_1～9)、脯氨酸(VII₁₀)和焦谷氨酸(VIl₁₁)的合成和鉴定。所有上述化合物以及与VⅡ_1～9相应的叔丁酯(VI_1～9)均未见文献报道。药理初试结果显示，化合物VII₈，VII₉和VI₁₀均有明显降压活性。     

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.     

HPLC测定安尔眠胶囊中2,3,5,4’-四羟基二苯乙烯-2-O-β-D-葡萄糖苷

目的 建立安尔眠胶囊中2,3,5,4’-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（C₂₀H₂₂0₉）的含量测定方法。方法 采用高效液相色谱（HPLC）法,以Dionex Acclaim 120^® C₁₈色谱柱（150 mm×4.6 mm,5 μm）为分离柱,以乙腈-1%甲酸溶液（23：77）为流动相,体积流量1.0 mL/min,检测波长320 nm,柱温25 ℃。结果 2,3,5,4’-四羟基二苯乙烯-2-O-β-D-葡萄糖苷在0.010～0.200 μg呈现良好的线性关系（r=0.999 6）,平均回收率为97.35%,RSD为2.07%。结论 该方法<准确可靠,适用于安尔眠胶囊中2,3,5,4’-四羟基二苯乙烯-2-O-β-D-葡萄糖苷的含量测定。     

双(2,6-哌嗪二酮)类抗肿瘤药物的研究:2,3-二乙酰氧基-1,4-二(3′,5′-二酮-N4′-取代哌嗪甲基)苯的合成

Seventeen compounds having the structure of 2,3-diacetoxy-1,4-bis(3′,5′- dioxo-N⁴′-substituted piperazinyl methyl)benzene were designed and synthesized based on chelation hypothesis. Their antitumor activities on P388 cells,Hep cells and SGC 7901 cells in vitro were tested. Preliminary results showed that compound 4e has potent antitumor effect against P388 cells and.Hep cells in vitro.     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

新型5-HT2A选择性配体N-取代哌啶-4-苯硫醚和砜类衍生物的合成及其生物活性

目的为寻找新型的5-HT_2A受体选择性配体,设计合成了一系列二芳烷基哌啶类化合物的含硫衍生物。方法以2,3-二甲氧基硫酚为原料,经烃化、氧化和水解等反应合成3个N-取代哌啶-4-苯硫醚和砜类化合物,所有目标化合物结构均经元素分析、¹HNMR谱、质谱和红外光谱确证,并测定其对5-HT_2A,5-HT_2C,5-HT₆和5-HT₇受体及其他一些中枢神经递质受体的体外亲和力。结果3个目标化合物(2a-2c)及5个中间体均为新化合物。体外受体竞争结合试验结果表明2a-2c均有较高的5-HT_2A受体选择性。结论此类化合物对5-HT_2A受体的选择性较高,值得进一步研究。     

7α和7β-甲基-10β,17β-二乙酰氧基-4-雌甾烯-3-酮的合成

由于7α-甲基或10β-乙酰氧基4(5)烯-3-酮雌(雄)甾化合物具有显著的抗着床或抗蜕膜活性,我们合成了既具有7α-甲基或7β-甲基又具有10β-乙酰氧基的两个新甾族化合物(1_a)和(1_b)。经药理试验表明(1_a)和(1_b)对孕鼠均有抗早孕作用。     

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.     

拟人参皂苷F11在大鼠体内的药物代谢研究

目的探讨拟人参皂苷F11在大鼠体内的药物代谢产物及其过程.方法ip拟人参皂苷F₁₁后,应用TLC分析排泄物中的代谢产物,并利用制备薄层分离制备代谢产物,通过波谱解析(MS,¹HNMR,¹³CNMR,¹H-¹HCOSY)确定其结构.结果从粪便中分离鉴定了3种代谢产物,分别为拟人参皂苷R_T5,ocotillol和1个新的代谢产物F-3-1,并确定其结构为6-O-α-L-吡喃鼠李糖基(1-2)-β-D-吡喃葡糖基-(20S,23S,24R)-达玛-20(24)-环氧-3β,6α,12β,23,25-五醇(6-O-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranosyl-(20S,23S,24R)-dammar-20(24)-epoxy-3-β,6α,12β,23,25-pentanol).但在尿液和胆汁中并未发现任何代谢产物.结论拟人参皂苷F₁₁不被肝脏代谢,但胆汁排泄物可在肠道被代谢为水解和氧化产物.     

铀促排药物研究:Ⅳ,N,N′-双-[N-羧甲基-(2,3-二羟基-5-甲氧羰基苄胺乙酰基]-α,ω-二胺的合成

随着核工业的迅速发展,核燃料铀对人类构成了一种潜在威脅。铀在人体脏器内的沉积不但引起损伤,并能诱发肿瘤。关于铀的促排解毒药物,虽有一些报道,但未见在临床应用。作者等曾合成了多个系列新的膦酸类和邻苯二酚类双取代或单取代胺羧酰胺螫合剂,动物试验结果表明其中的大多数排铀效果显著,尤其是邻苯二酚类单取代胺羧酰胺(Ⅰ)中,若干化合物排铀效果远远超过文献报道较多的钛铁试剂和Phosphicine,而且显示了     

血吸虫病化学治疗的研究——ⅩⅩⅩⅦ.β-(5-硝基-4-溴-2-呋喃)-及β-(4,5-二溴-2-呋喃)丙烯酰胺及其酯类的合成

本文报道β-(4,5-二溴-2-呋喃)-及β-(5-硝基-4-溴-2-呋喃)丙烯酰胺及其酯类衍生物26个的合成。动物筛选结果表明;化合物Ⅲ₆,Ⅲ₈和Ⅲ₁₃对感染日本血吸虫小白鼠有明显的治疗作用。化合物Ⅱ₆有较明显的预防作用。     

疟疾防治药物的研究——Ⅹ.2,4-二氨基-6-N1,N2-二取代肼基-喹唑啉类衍生物的合成及其抗疟作用

本文报道了2,4-二氨基-6-N¹,N²-二取代肼基-喹唑啉类衍生物的合成及其抗疟活性的研究。这类化合物的合成是以2,4-二氨基6-取代苄基氨基-喹唑啉为原料经亚硝化、还原成为2,4-二氨基6-(N¹-取代苄基)—肼基喹唑啉,再与相应的醛缩合而成。此类化合物经伯氏鼠疟原虫抑制性治疗初筛表明有少数具有一定的效果。有11个化合物经约氏鼠疟原虫—斯氏按蚊系统病因性初筛有效。其中化合物Ⅱ_1,7,8,11,15和Ⅲ₁口服2.5mg/kg,连续3天,可使受试小鼠全部得到保护。     

Functionally biased modulation of A(3) adenosine receptor agonist efficacy and potency by imidazoquinolinamine allosteric enhancers

Allosteric modulators for the G_i-coupled A₃ adenosine receptor (AR) are of considerable interest as therapeutic agents and as pharmacological tools to probe various signaling pathways. In this study, we initially characterized the effects of several imidazoquinolinamine allosteric modulators (LUF5999, LUF6000 and LUF6001) on the human A₃ AR stably expressed in CHO cells using a cyclic AMP functional assay. These modulators were found to affect efficacy and potency of the agonist Cl-IB-MECA differently. LUF5999 (2-cyclobutyl derivative) enhanced efficacy but decreased potency. LUF6000 (2-cyclohexyl derivative) enhanced efficacy without affecting potency. LUF6001 (2-H derivative) decreased both efficacy and potency. We further compared the agonist enhancing effects of LUF6000 in several other A₃ AR-mediated events. It was shown that although LUF6000 behaved somewhat differently in various signaling pathways, it was more effective in enhancing the effects of low-efficacy than of high-efficacy agonists. In an assay of cyclic AMP accumulation, LUF6000 enhanced the efficacy of all agonists examined, but in the membrane hyperpolarization assay, it only enhanced the efficacy of partial agonists. In calcium mobilization, LUF6000 did not affect the efficacy of the full agonist NECA but was able to switch the nucleoside antagonist MRS542 into a partial agonist. In translocation of β-arrestin2, the agonist-enhancing effect LUF6000 was not pronounced. In an assay of ERK1/2 phosphorylation LUF6000 did not show any effect on the efficacy of Cl-IB-MECA. The differential effects of LUF6000 on the efficacy and potency of the agonist Cl-IB-MECA in various signaling pathway were interpreted quantitatively using a mathematical model.     

罗氟司特中3,5-二氯-4-氨基吡啶引入两个杂质的合成研究

目的 设计并合成罗氟司特中3,5-二氯-4-氨基吡啶引入的两个杂质3-(环丙甲氧基)-N-(3-氯-5-溴-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺和3-(环丙甲氧基)-N-(3-氯-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺。方法 以4-二氟甲氧基-3-羟基苯甲醛为起始原料经过亲核取代、氧化、酰氯化和酰胺化合成了目标化合物。结果 合成了目标化合物,并利用¹H-NMR、¹³C-NMR和MS确证了结构;HPLC归一化法测得样品质量分数分别为98.8%、99.8%。并证明这两个杂质存在于罗氟司特中。结论 这两种杂质的合成为罗氟司特中杂质的研究提供了依据。     

STUDIES ON THE SPASMOLYTIC AND UTERINE RELAXANT ACTIONS OF N -ETHYL AND N -BENZYL-1,2-DIPHENYL ETHANOLAMINES: ELUCIDATION OF THE MECHANISMS OF ACTION

The influence of N -ethyl- and N -benzyl-1,2-diphenyl ethanolamines (compounds E and B, respectively) was examined on the spontaneously contracting rabbit jejunum and the rat uterus together with their influence on the contractions induced by some spasmogens in the guinea-pig ileum and oxytocics and CaCl₂in the pregnant rat uterus. Both E and B inhibited the spontaneous contractions of the rabbit jejunum with ID₅₀values of 0.13 and 0.03 μmol ml⁻¹. Their inhibitory activities were not antagonized by α- or β-adrenoceptor blockers but significantly reversed by CaCl₂(0.015 μmol ml⁻¹). The compounds also antagonized nicotine, ACh-, histamine-, 5-HT- and CaCl₂-induced contractions by 44–100%. Compound E seemed to be several times more potent than B in inhibiting the spontaneous uterine contractions with an ID₅₀of (7 nmol ml⁻¹). Their inhibitory effects were not antagonized by β₂-adrenoceptor or H₂-receptor blocking drugs. Both compounds (40 nmol ml⁻¹) antagonized in a competitive manner CaCl₂-induced contractions in the K⁺-depolarised uterus and PGE₂and oxytocin-induced uterine contractions. The ID₅₀values were in the range of 1.6–10.7 nmol ml⁻¹. The results suggest that E and B compounds may be considered as putative L-Ca²⁺channel blockers with certain selectivities. The E compound seemed to be more selective against uterine L-Ca²⁺channels and the B compound against intestinal smooth muscles. Thus, the compounds may be of potential value in treatment of some colics, the irritant bowel syndrome, dysmenorrhoea and premature deliveries. 1999 Academic Press@p$hr