疟原虫组织期裂殖体杀灭剂4-甲基-5-(对-氟苯氧基)伯氨喹类似物的合成

A series of. analogues of 4-methyl-5-(p-fluorophenoxy)-primaquine have been prepared for evaluating of tissue schizonticidal actiyity of Plasmodium yoelii in mice. 2-Bromo-4-acetamino-5-nitroanisole was reacted with pfluorophenol in the presence of potassium hydroxide to give 2-(p-fluorophenoxy) 4-acetamino-5-nitroanisole, which was subsequently hydrolyzed to yield corresponding amino compound. Cyclization of the amino compound with methyl vinyl ketone afforded 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-nitroquinoline. This product was reduced by iron and acetic acid to give corresponding 8-aminoquinoline. The latter was condensed with bromoalkylphthalimides to yield 4-methyl-5-(pfluorophenoxy)-6-methony-8- (1-phthalimidoalkyl) aminoquinolines (Ⅳ₁～Ⅳ₇). These compounds were heated with hydrazine hydrate to form 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-(1-aminoalkyl)aminoquinolines(Ⅳ₈～Ⅳ₁₃), and 4-methyl-5-(p-fluorophenoxy) primaquine (Ⅱ).Compound Ⅱ synthesized was radical curative at 10 mg/kg×1, while the analogues Ⅳ₉ and Ⅳ₁₀ were radical curative at 100 mg/kg×1 against P. yoelii in mice.     

1-乙基-6-氟-1,4-二氢-4-氧代-7-(4-芳酰硫代氨甲酰基-1-哌嗪基)-3-喹啉羧酸的合成及抗菌作用

Thirteen new 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-aroyl-thiocarbamoyl- 1 piperazinyl)-3-quinoline carboxylic acids were prepared, Their structures were characterized by elemental analysis, IR, HNMR and MS spectra.Preliminary pharmacological tests indicated that some of compounds Ia～m possess strong inhibiting activity against Escherichia coli, Bacillus subtilis and Proteus at concentration of 100 μg/ml.     

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.     

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.     

若干[(2-羟基-3-胺基)-丙氧基]-黄酮的合成

In the present communication, eleven (2-hydroxy-3-aminopropoxy)-flavones (Ⅰ) were synthesized as potential β-adrenergic blocking agents. These compounds were obtained by reacting the hydroxy-flavones with epichlorohydrin in the presence of a few drops of piperidine, followed by amination of the resulting chlorhydrin derivatives (Ⅲ) with appropriate amines. Preliminary pharmacological test showed thai compounds Ia, Ib, Ic, Ih, and Ii prolonged the survival time under hypoxia condition in mice, but under the same experimental conditions no significant antagonism to isoprenaline was observed.     

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.     

西洋参多糖PPQI-1～4理化性质的研究

AIM: To study the characteristics of the four bioactive pure polysaccharides of Panax quiquefolium L. (PPQI 1～4). METHODS: The polysaccharides were extracted with hot water and grade precipitated with ethanol. They were further purified with Sephadex DEAE A50 and Sephadex G200 chromatography. The molecular weights of the polysaccharides were determined with matrix assisted laser desorption/ionization mass spectrometry (MALDI MS). The sugar compositions were analyzed with GC. The linkage positions of the component sugars were determined by methylation and GC MS. RESULTS: The four polysaccharides are all uronic acid containing heteropolysaccharides with the component sugars of arabinose, galactose and glucose in different molar ratios. The uronic acid contents are within 30%～60%. Their molecular weights are in the range of 2×10⁴～7×10⁴u. CONCLUSION: The four new bioactive polysaccharides are all uronic acid containing heteropolysaccharides.     

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.     

手性毛细管气相色谱法测定人尿中美芬妥英光学异构体含量的方法学研究

A gas chromatographic method equipped with nitrogen-phosphorus detector was developed for the determination of the S-and R-enantiomers of the anticonvulsant, mephenytoin (MP) in human urine. Dichioromethane (4 ml) was added to 1 ml urine, the mixture was shaken and centrifuged. The organic phase was transferred to another tube and blown to dryness under nitrogen on water bath (37℃). The residue was dissolved in 10 μl ethylacetate and 1～2 μl was injected into the GC. Our results showed that direct enantiomeric separation of mephenytoin was obtained by using a chiral capillary column, the retention times for S-and R-mephenytoin were 25. 5 and 26. 2 min respectively, with a detection limit less than 50 ng/ml of mephenytoin. Similar linear and reproducible standard curves were obtained over the concentration range of 53.2 to 2128. 0 ng/ml (for S-MP, r=0. 9914±0. 0070, n=6; and for R-MP, r=0. 9939±0. 0070, n=6), and the mean recoveries of S-and R-MP were 95. 4% and 95. 8% respectively. The within--day relative standard deviations were less than 8. 8% for both S-and R-MP, and that of between--days were less than 14.3%. There was a good reproducibility of the urine S/R mephenytoin determined in China and in Sweden by using similar method in 107 Chinese volunteers after a single oral dose of 100 mg racemic mephenytoin (r=0. 9091, P<0. 001).     

二氢叶酸还原酶抑制剂:5-取代苯硫基(硒基)-2,4-二氨基嘧啶类化合物的合成和抑酶活性

According to the principle of isosterism the-CH₂-group of 5-(substituted benzyl)-2, 4-diaminopyrimidine was modified by—S—and—Se—and some 5-(substituted phenyl)thio-2, 4-diaminopyrimidines and 5-(substituted phenyl)seleno-2,4-diaminopyrimidines were synthesized. Their inhibitory activities on L. casei and chicken liver dihydrofolate reductase were determined. Preliminary data showed that the inhibitory activities of these compounds were less than those of the corresponding 5-(substituted benzyl)-2, 4-diaminopyrimidines. Their selectivities are also decreased.     

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。     

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。     

苯甲酰胺类抗精神病药物的研究:6β-羟基,乙酰氧基和苯甲酰氧基-3α及β-托品烷衍生物的合成

合成了15个3α和β-取代苯申酰氨基-6β-羟基,乙酰氧基和苯甲酰氧基-托品烷类化合物。其中化合物5d,12c和12d对D-1和D-2受体都有一定的亲和作用。     

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。     

去甲乌药碱衍生物及其开环类似物的合成

去甲乌药碱具有强心作用,为了寻找更有效的化合物,设计合成了一系列去甲乌药碱类似物,其中包括B环开环类似物;双-四氢异喹啉类及其开环类似物;氨基侧链取代C环等。在所合成的化合物中,D₂呈明显活性,优于去甲乌药碱。     

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。     

4-酰基-5-吡唑酮的二烃基锡配合物的合成、表征及其抗癌活性研究

目的　设计合成一系列新型有机锡化合物,通过药理筛选寻找具有抗肿瘤活性的药物并探讨其构效关系。方法　以4-酰基-5-吡唑酮为配体合成有机锡化合物,用元素分析、红外光谱、 ¹H,¹³C,¹¹⁹Sn NMR等方法对得到的化合物作结构表征并利用几种药理模型进行体外抗癌活性筛选。结果　合成了一系列R₂SnL₂ 型有机锡新配合物并确定其结构。结论　药理筛选结果表明,多个化合物(3～6,9～11)对HL-60, HCT-8, Bel-7402,BGC-823和KB癌细胞有效,显示了较强的抗癌活性。     

6-或7-（取代苯乙烯基）香豆素类化合物的合成及其抗癌活性的研究

目的：设计合成一系列苯乙烯基香豆素类化合物,并通过药理筛选寻找具有抗肿瘤活性的药物。方法：通过相转移Wittig反应得到目的物,利用几种药理模型进行体外抗肿瘤活性筛选。结果：合成了30个（I₁～II_I6）新的苯乙烯基香豆素类化合物并确定其构型。结论：药理筛选结果表明,7个化合物(I₂,I_4,II_2,II_2c,III_1a,III_2a,III_5a)对L-1210,HL-60,HCT-8,KB和Bel-7402细胞株有效,显示了一定的抗肿瘤活性。     

三氟甲基氨酚喹类似物的合成及其抗疟活性

本文报道了22个7-三氟甲基和2-甲基-7-三氟甲基氨酚喹类似物的合成。用伯氏疟原虫(plasmodium berghei)ANKA正常株感染小鼠作抑制性治疗试验,在剂量为(10 mg/kg)/d×4和(20 mg/kg)/d×4时,有11个化合物(Ⅰ_1～9,Ⅱ₃和Ⅱ₆)对疟原虫完全抑制。其中3个化合物(Ⅰ₂,Ⅰ₆和Ⅰ₇)在剂量为(5 mg/kg)/d×4时,就能对原虫完全抑制。12个化合物(Ⅰ_1～10,Ⅱ₃和Ⅱ₆)用伯氏疟原虫ANKA抗氯喹株感染小鼠作治疗试验,剂量为(20 mg/kg)/d×4,2个化合物(Ⅰ₄和Ⅱ₃)在受试的5只小鼠中,原虫完全被抑制的鼠分别为3和4只,用相同剂量的对照药物盐酸氨酚喹治疗,原虫仍为阳性。     

取代腺嘌呤和腺苷的合成及生物活性

为了探索芳杂环甲基取代腺嘌呤和腺苷的有效合成方法,本文以腺嘌呤和腺苷为原料设计并合成了7个9-取代腺嘌呤(1～7)、6个N⁶,9-双取代腺嘌呤(12～17),3个N⁶-取代腺嘌呤(23～25)、5个N⁶-取代腺苷(18～22),同时合成了3个3-取代腺嘌呤(9～11),共24个化合物,其中23个为未知化合物。对合成的所有腺苷衍生物和部分腺嘌呤衍生物进行了腺苷受体活性筛选。化合物18在大鼠输精管模型上对腺苷受体的激动活性是腺苷的33倍。