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.     

铀促排药物研究Ⅵ:2,3-二羟基-4-甲氧羰基苄基胺羧酰胺螯合剂的合成

铀化合物在国防工业和国民经济建设中有十分重要的地位,但其通过各种途径(主要是吸入)进入人体后对人体造成的危害却十分严重。陈文致、徐美忠等曾对几种新的膦酸类和含邻苯二酚残基的化合物进行研究,发现它们对铀的促排效果比钛铁试剂更好。为进一步探讨含邻苯二酚残基的螯合剂对铀促排的构效关系,我们合成了12种2,3-二羟基-4-甲氧羰基苄基胺羧酰胺类化合物(Ⅳ),并进行了多种金属的解毒试验。以生产香料香兰素的副产物邻香兰素(o-vanillin)为起始原料,经八步反应得到目标化合物(Scheme 1)。     

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

铀化合物在国防和国民经济建设中的重要性及其对人体的危害性日益为人们所知。为此对铀的防护和解毒药物的研究已日益引起各方面的关注,但迄今仍未见找到理想的解毒药物。文献报道钛铁试剂和phosphicine在动物试验对铀化合物的促排效果较好。另外,     

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     

铀促排药物研究Ⅱ:邻苯二酚类胺羧酰胺螯合剂的合成

铀化合物不但有化学毒性,会引起肾炎、蛋白尿等,还有放射性毒害作用,因此,如何有效地防护铀中毒和解毒是一个重要课题。前文报道了几种膦酸类螯合剂的合成及其排铀效果。钛铁试剂(Ⅰ)有较好的排铀能力,主要是由于邻苯二酚基团和UO_2~(2+)的螯合作用。enterobactin和Fe~(3+)的螯合稳定常数达10~(52),其类似物LICAM(Ⅱ)不仅和Fe~(3+),而且和Pu~(4+)的螯合能力极好,估计也会和UO_2~(2+)生成稳定的螯合物。这类化合物除有邻苯二酚结构外,都还含有多个酰胺基团。     

铀促排药物研究Ⅱ:邻苯二酚类胺羧酰胺螯合剂的合成

In searching for drugs against uranium intoxication a series of 2,3-dihydroxy-N, N′-dicarboxymethyl-N, N′-di (substituted phenylcarbamoylmethyl)-1, 4-benzenedimethanamine (Ⅵ) was synthesized starting with 2,3-dihydroxy-1, 4-benzenedimethanamine tetraacetic acid Their ability to enhance the elimination of uranyl nitrate from animal bodies was tested and three of them (Ⅵc, Ⅵe and Ⅵf) were found to be more effective than the reported uranium chelating agents, Tiron and phosphicine.     

羟基吡啶酮促排铀和钚的研究进展

铀和钚是锕系的两种放射性元素,广泛用于军事领域.现代战争中由于大范围使用贫铀弹,使贫铀中毒问题受到世界各国越来越多的关注.治疗铀、钚等重金属中毒的主要方法是使用络合剂将之排除,羟基吡啶酮由于其特殊的结构特点、高度的选择性络合能力以及显著的生理活性,成为促排领域的一大研究热点,本文对近年来羟基吡啶酮对铀、钚的促排研究概况做简要综述,并对其发展前景进行展望.     

双酚酰胺丁酸及其类似物对铀的促排和解毒

本实验研究邻苯二酚单取代胺羧酰胺类螯合剂对铀的促排解毒作用。实验证明１８个该类螯合剂均有一定的促排作用，４８ｈ尿铀排出量与对照组相比，比值在１．２１～２．５１之间，其中双酚酰胺丁酸（Ｎｏ．１６）促排效果最好，大白鼠ｉｍ０．２５ｇ·ｋｇ－１，尿铀比值达２．５１，ｉｇ０．５ｇ·ｋｇ－１或１ｇ·ｋｇ－１也可提高尿铀排出量。解毒试验表明小白鼠ｓｃ双酚酰胺丁酸使铀中毒ＬＤ５０提高到１６．４倍，ｉｇ给药可提高到７．６倍；大白鼠ｉｇ给药可使铀中毒ＬＤ５０提高到３．９倍；延迟４ｈｉｇ仍然有效。此外双酚酰胺丁酸可显著降低小白鼠因ＮｉＣｌ２、ＭｎＣｌ２、ＣｏＣｌ２中毒引起的死亡数。     

邻苯二酚类对称双酰胺螯合剂对铀的促排和解毒

报道9个邻苯二酚类对称双酰胺螯合剂对铀的促排作用,实验证明这些螯合剂均具有一定的促排铀的效果,其中86号化合物促排效果最好,大白鼠肌肉注射500mg·kg~(-I),48h尿铀排出量与对照组相比,比值为2.87;并可显著提高大白鼠铀中毒致死剂量,延迟4h给药,仍然有效;也可使小白鼠铀中毒LD_(50)提高14倍。     

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.     

Synthesis, characterization and pharmacological activities of 5,6,11,12-tetrahydroindolo[2,3-alpha]carbazole derivatives.

A series of new 5,6,11,12-tetrahydroindolo[2,3-alpha]carbazole derivatives (3a-h) was synthesized. Treatment of 8-methyl-1-oxo-1,2,3,4-tetrahydrocarbazole (1a) with phenylhydrazine hydrochloride in ethanol furnished the title compound (3a) in poor yield along with 8-methyl-1-phenylhydrazono-1,2,3,4-tetrahydrocarbazole (2a). Better yields were obtained when 1a-h were treated with phenylhydrazine in glacial acetic acid. All the newly synthesized compounds were characterized on the basis of IR, NMR, mass-spectra and elemental analysis and screened for pharmacological activities.     

Synthesis of the antileukemic compound N,N(11)-[5-[bis(2-chloroethyl)amino]-1, 3-phenylene]bisurea.

Conversion of 5-nitro-1, 3-benzenedicarboxylic acid (1) to the diamide 2 followed by hypochlorite rearrangement to the idamine 3 and subsequent reaction with acetic anhydride gave the bisacetamide 4. Reduction to the amine 5 followed by treatment with ethylene oxide formed the diol 6. The latter was converted to the bistosylate 7, which undrewent facile displacement with lithium chloride in acetone to give the mustard 8. Removal of the acetyl groups with hydrochloric acid gave 9, which reacted with potassium cyanate to provide the bisurea 10. In an alternative, but less satisfactory synthesis of 10, the compound (5-nitro-1, 3-phenylene) biscarbamic acid diphenyl ester (11), or the corresponding diethyl ester 12, was converted by ammonolysis to 13. The nitrodiurea 13 was next reduced to the amine 14, the hydrochloride of which reacted with ethylene oxide to give the diol 15. Treatment of the latter in dimethylformamide with N-chlorosuccinimide in the presence of triphenylphosphine gave 10 in low yield. The nitrogen mustards 8, 9 and 10 showed significant antitumor activities against P388 lymphocytic leukemia in mice.     

Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones

The synthesis of a series of 5-[4-(pyridylalkoxy)benzyl]-2, 4-thiazolidinediones is described. These compounds were evaluated for hypoglycemic and hypolipidemic activities in genetically obese and diabetic mice, yellow KK. 2-(2-Pyridyl)alkoxy derivatives were found to have much better hypoglycemic and hypolipidemic activities than 2-(3-pyridyl)- and 2-(4-pyridyl)alkoxy derivatives or even the previously reported compound, ciglitazone. The introduction of a hydroxyl group at the 2-position of the ethoxy chain potentiated the activities. Among the potent compounds, pioglitazone (AD-4833) was selected as a candidate compound.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.