呼吸性酸（碱）中毒时血浆[HCO3ˉ]的代偿性和原发性变化

血浆[HCO3ˉ]的变化可以分为代偿性(即继发性)和原发性。以[HCO3ˉ]的升高为例，如果[HCO3]的升高是由于发生呼酸后肾脏代偿所致，则为代偿性升高；如果[HCO3ˉ]的升高是由于酸的丢失或碱的摄人过多等原因所致，则为原发性升高。     

呋喃苯胺酸对急性呼吸性酸中毒脑脊液“HCO3-”的影响

通过观察犬急性呼吸性酸中毒动脉血和ＣＳＦ酸碱变量及ＣＳＦ主要离子变化,结果表明,两组ＰａＣＯ２和［ＨＣＯ３－］ａ分别升高约为３．９９９ｋＰａ和３ｍｍｏｌ／Ｌ时,ＰＣＳＦＣＯ２升高同血浆相似。然而,Ｉ组（ｉＣＶ这尿）［ＨＣＯ３－］ＣＳＦ和［Ｃｌ－］ＣＳＦ的互逆变量（８．２ｍｍｏｌ／Ｌ）＞Ⅱ组（ｉＣＶ等量生理盐水,５ｍｍｏｌ／Ｌ,Ｐ＜０．０１）。说明速原有抑制ＣＳＦＨＣＯ３－和血浆Ｃｌ－的交换作用,能增强ＣＳＦ的代偿能力,减少ＣＳＦ的生成,ＨＣＯ３－／Ｃｌ－交换对ＣＳＦ酸碱调节有一定作用。     

失血性休克时兔血浆N-乙酰-β-葡萄糖酐酸酶和丙二醛的变化

休克是临床上死亡率高的危症,一直受到医学界的重视,而休克不同时期病人的变化机制不同。本实验旨在研究失血性休克不同时段,主要集中于早期失血性休克阶段时期细胞损伤变化特点,为临床防治提供理论依据。     

(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐的合成

对甲氧基苯甲醛(3)和2-氨基乙醇进行还原胺化反应得2-(4-甲氧基苄胺基)乙醇(4),4和乙醛酸经成环反应得2-羟基-4-对甲氧基苄基吗啉-3-酮(5),5和三氟乙酐反应得6后与(R)-1-[3,5-二(三氟甲基)苯基]乙醇(7)缩合,再经结晶诱导不对称转化、格氏反应、氢化脱保护及成盐反应制得阿瑞吡坦关键中间体(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐,总收率约18%(以3计)。     

N-[3',3'-双(膦羧基)丙基]-3-{4-[双(2-氯乙基)氨基]苯基}-3-氨基丙酰胺的合成及表征

目的合成N-[3’,3’-双(膦羧基)丙基]-3-{4-[双(2-氯乙基)氨基]苯基}-3-氨基丙酰胺,并进行体外骨靶向性实验。方法以3,3-双(二乙氧膦酰基)-1-硝基丙烷(1)为原料,经氢化还原,再与N-苄氧羰酰异苯丙氨酸氮芥(2)偶联,催化氢化还原得到化合物(4),用溴代三甲基硅烷脱去膦酸酯的烷基得到目标化合物T。用羟磷灰石晶体作为骨模型,测定偶联物T的趋骨性。结果和结论目标物T经1HNMRI、R、MS得到结构确证,体外骨靶向性实验显示,目标物T有良好的骨靶向性。     

(-)-7-羟基-3-羰基-6-[4-苯氧基-3-羟基-1-(E)-丁烯基]-2-氧杂二环[3,3,0]辛烷合成工艺的改进

目的 改进磺前列酮中间体3(S)-烯醇化合物的合成工艺。方法 以双羟化合物为起始原料经硅醚化、选择性氧化、Wittig-Homer反应、水解及立体还原得到3(S)-烯醇化合物。结果 制备得到目标化合物，总收率11％。结论 改进后的合成方法操作简便、易于掌握、反应条件温和、更加适合工业化生产。     

Synthesis of 2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines and 3-(Alkythio)-1,2,4-triazolo[3,4-a]pyrimidines and Their Vasodilator Activity

本文作者合成了新的５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２苄硫醚类（Ｂ系列）５，７二甲基１，２，４三唑并［３，４ａ］嘧啶２苄硫醚类化合物（Ｄ系列），并测定了这两类化合物在体外对８５７ｍｍｏｌ·Ｌ１Ｋ＋和１０４ｍｍｏｌ·Ｌ１ＮＥ（ｎｏｒｅｐｉｎｅｐｈｒｉｎｅ）引起的血管条收缩的抑制作用。测定结果表明，Ｂ系列化合物的活性均高于Ｄ系列化合物，在苯环的对位有体积较大的疏水性基团有助于生物活性的提高。５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２对溴苄硫醚表现出最好的扩张血管活性，在浓度为１０５ｍｏｌ·Ｌ１和１０４ｍｏｌ·Ｌ１时，对１０４ｍｍｏｌ·Ｌ１ＮＥ引起的离体血管条痉挛的抑制率均为１００％；对８５７ｍｍｏｌ·Ｌ１Ｋ＋引起的离体血管条痉挛的抑制率分别为４７％和１００％。     

4-[4-(吡啶-3-基)咪唑-1-基]丁胺的合成

以3-乙酰基吡啶为起始原料,经肟化、磺酰化、氧化、环合、还原得到3-(咪唑-4-基)吡啶,再经与N-(4-溴丁基)邻苯二甲酰亚胺缩合及肼解等反应制得抗菌剂泰利霉素的特定侧链化合物4-[4-(吡啶-3-基)咪唑-1-基]丁胺,总收率24%.     

9-[2-(膦酰甲氧基)乙基]腺苷-钠盐的致突变性研究

目的评价9-[2-(膦酰甲氧基)乙基]腺苷-钠盐(PMEA-Na)的致突变性。方法采用组氨酸缺陷型鼠伤寒沙门氏菌回复突变试验(Am es试验)、中国仓鼠肺细胞(CHL)染色体畸变试验和小鼠骨髓微核试验,观察PMEA-Na的致突变性。结果PMEA-Na在50~5000μg.皿-1剂量范围内,加与不加S9活化系统条件下,对TA97、TA98、TA100、TA102四种菌株的回变菌落数均未超过自发对照的2倍,即Am es试验结果为阴性;染色体畸变试验中,当药物浓度为48、24、12、6 mg.L-1时,活化条件下各浓度细胞的染色体畸变率均低于5%。在非活化条件下,药物浓度为48 mg.L-1培养48 h时,染色体畸变率为10%,因此染色体畸变试验结果为阳性;小鼠静脉注射PMEA-Na剂量为1 000、500、250 mg.kg-1时,骨髓中含微核的嗜多染红细胞数明显增加,即微核试验结果为阳性。结论在本实验条件下,PMEA-Na具有潜在的致突变性。     

新型7-[3-(氟甲基)哌嗪]和-(氟高哌嗪)喹诺酮类的构效关系及其合成

氟哌酸(1)作为一种口服有效的广谱喹诺酮类抗菌剂标志着新一代高效药物的出现。在这些结构相似的化合物中都有C-7哌嗪基和N-1烃基。其中的环丙氟哌酸(2)有极高的活性,它与氟哌酸均已在欧美和日本上市。     

人血浆中Timolol和[~(13)C_3]timolol用选择性离子检测的毛细管柱气液-质谱测定法

Timolol(Ⅰ)是β-肾上腺素能受体阻滞剂,对实验动物和人体在治疗剂量(5～15mg口服)相当低时即有效,在循环血浆中对此低浓度需要有很灵敏的专一检测方法。曾将药物转化成七氟丁基衍生物用电子捕获法可检测出人血浆中timolol的灵敏度接近2mg/ml。本文报道人血浆中未标记的以及用~(13)C_3标记的timolol的测定法,由于叔丁基的羟基化是timolol在人体中的代谢途径,因此选用~(13)C_3-标记的药物(Ⅱ)作为同时服药的化合物,并用9个氘原子标记的timolol(Ⅲ)作为内标,以测定timolol的生物利用度。测定时将已知量的内标加至血浆样品中,于C_(18)反相填充层析柱     

Chronic oral toxicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the dog

Advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate), an N-substituted analog of aspartame, has been developed as a high-intensity sweetener. Groups of 4 dogs of each sex were treated at 0, 2000, 10,000, or 50,000 ppm of advantame in the diet for 52 weeks. Additional groups of 2 dogs/sex at the control, and mid- and high-dose groups were treated for 52 weeks followed by a 6-week recovery period. There was no effect of treatment on mortality, body weight, organ weights, food consumption, or the results of ophthalmological, electrocardiographic, haematological, clinical chemistry or urinalysis examinations. No histopathological changes were associated with advantame treatment. The NOAEL was considered to be 50,000 ppm, the highest concentration tested, which was equivalent to 2057 and 2139 mg/kg body weight/day in males, and females, respectively. The results of the study support the safety of advantame for use as a high-intensity sweetener.     

微波辅助制备3-[2-(7-氯-2-喹啉基)乙烯基]苯甲醛

3-[2-(7-氯-2-喹啉基)乙烯基]苯甲醛(1)是白三烯受体拮抗剂LY0290154和抗过敏、平喘药孟鲁司特钠(montelukast sodium)的重要中间体~([1,2]),文献用7-氯喹哪啶(2)、间苯二甲醛(3)和乙酸酐在甲苯中回流12 h制得1,收率63%~([2]).若改在甲苯和正已烷混合溶液中回流反应13 h,未反应的3可循环套用6次,平均收率82%~([3]).     

用于多巴胺D_4受体体内研究的3-[4-(4-[~(18)F]氟苯甲基)哌嗪-1-基]甲基-1H-吡咯并[2,3-b]吡啶的合成及生物学评价

目的　 7 氮杂吲哚的衍生物L 74 5 ,870是一个新的、高亲和性 (Ki=0 4 3nmol·L-1)的多巴胺D4受体选择性配体 ,我们放化合成了其类似结构的新化合物 3 [4 (4 [18F]氟苯甲基 )哌嗪 1 基 ] 甲基 1H 吡咯并 [2 ,3 b]吡啶 ([18F]C) ,并作了大鼠体内生物学评价。方法　 ([18F]C)的放化合成是通过 3 (哌嗪 1 基 )甲基 1H 吡咯并 [2 ,3 b]吡啶和 4 氟[18F]苯甲醛的胺烷基化反应完成 ,放化产率为 9 0 %～12 0 % ,放化纯度大于 98% ,比活度高于 37GBq·mol-1。结果　额叶皮质、海巴和延髓等脑区有较高的放射性摄取率 ,分别为 0 4 3%ID/ g和 0 35 %ID/g ;而纹状体、小脑处放射性摄取率较低。结论　大鼠体内的组织分布和代谢物研究表明 :[18F]C在大鼠脑组织区域有特异性分布 ,暗示其可能作为适合的显像剂用于多巴胺D4受体的体内研究     

2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺改进

目的改进骨质疏松治疗药米诺膦酸的关键中间体2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺。方法以反式-4-氧基-2-丁烯酸乙酯和2-氨基吡啶为起始原料,经环合、水解得到2-(咪唑并[1,2-a]吡啶-3-基)乙酸。结果与结论该合成方法首次以纯水替代有机溶剂作为反应溶剂,采用"一锅法"合成目标化合物,降低了该中间体的制备成本,而且环境友好,更适合于工业化生产。     

瑞格列奈关键中间体(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺的合成

目的研究合成非磺酰脲类促胰岛素分泌剂瑞格列奈的关键中间体(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺的合成工艺。方法以邻氟苯甲醛(1)为起始原料,首先与盐酸羟胺反应生成邻氟苯甲醛肟(2),再经脱水生成邻氟苯腈(3),然后与哌啶进行胺解反应生成邻哌啶基苯腈(4),再与溴代异丁基镁进行格氏反应生成亚胺衍生物(5),最后经硼氢化钠还原生成消旋伯胺(6),经与N-乙酰-L-谷氨酸成盐、拆分、氢氧化钠水解得到目标产物S-(6)。结果以邻氟苯甲醛为起始原料,经6步反应合成了(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺,总收率达15.4%,目标产物结构经ESI-MS、1H-NMR确证。结论本合成方法原料易得,反应条件温和,适合大规模制备。     

Chronic toxicity and carcinogenicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat

Groups of 55 male and 55 female Han Wistar rats were administered advantame (98.9-99.8% purity) in the diet at concentrations of 0, 2000, 10,000, or 50,000 ppm for 104 weeks, following parental exposure to the same levels from prior to mating and throughout gestation. Additional groups of 20 rats/sex and 10 rats/sex were dosed for a period of 52 weeks and constituted the toxicity and reversibility phases of the study. Achieved doses of advantame over the carcinogenicity study were 0, 97, 488, and 2621 mg/kg body weight/day in males and 0, 125, 630, and 3454 mg/kg body weight/day in females, respectively. A high incidence of a pale and swollen anus and changes in fecal composition were observed in the high-dose groups. There was no effect of treatment on mortality. Body weight gain in the high-dose males (50,000 ppm) was slightly reduced compared to controls after 52 and 104 weeks of treatment; the decrease was not considered to be of toxicological significance, but due to the non-nutritive nature of the high dietary concentration of advantame. During the toxicity phase, food conversion efficiency was slightly decreased in both sexes, at the 50,000 ppm dose level. Given the non-nutritive content of the diet, this finding was not considered biologically significant. There were no relationships between treatment and the results of hematological or urinalysis investigations. Clinical chemistry evaluations showed consistently lower plasma urea concentrations in both sexes treated at 50,000 ppm, which was reversed during the 6-week recovery phase following 52 weeks of treatment, indicating a lack of permanent effects. Terminal investigations at both the 52 and 104-week revealed a number of intergroup differences in absolute and/or relative organ weights; however, the differences did not show dose-response relationships, were minor in nature, and/or occurred only in one sex, and were not associated with any pathological findings, and they were considered not to be treatment-related. Evaluation of the histopathology of the carcinogenicity phase animals revealed an increased incidence of pancreatic islet cell carcinomas in males (incidence rates of 0/55, 1/55, 2/55, and 3/55 in the 0, 2000, 10,000, or 50,000 ppm groups, respectively) and of mammary gland adenomas in the high-dose females (incidence rates of 0 in the control through 10,000 ppm dose groups and 4/41 in the 50,000 ppm dose group). The incidence rates of these tumors did not attain statistical significance and/or remained within background historical control values, and they were considered to be unrelated to advantame treatment. The no-observed-adverse-effect level was considered to be 50,000 ppm in the diet, the highest concentration tested, equivalent to 2621 and 3454 mg/kg body weight/day in males and females, respectively. Advantame was concluded to be without carcinogenic activity.     

1,3-双-[2-(3-氨基苯基)咪唑-1-基甲基]苯的合成

间硝基苯甲腈与乙二胺进行缩合反应生成2-(3-硝基苯基)咪唑啉,继以活性二氧化锰氧化生成2-(3-硝基苯基)咪唑.该咪唑与间-二(溴甲基)苯进行烷基化反应生成1,3-双[2-(3-硝基苯基)咪唑-1-基甲基]苯,再以水合肼还原生成目标化合物.     

Synthesis and anti-HIV-1 screening of novel N′-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides

A novel series of N′-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides was synthesized. The synthesis was carried out by thermal method as well as ultrasonic bath to reduce reaction time and to enhance product yields. The synthesized compounds were characterized by spectroscopic techniques like NMR, infrared and EIMS. The structure of compound 5w was elucidated by X-ray crystallography. The titled compounds were evaluated for anti-human immunodeficiency virus type 1 (anti-HIV-1) and cytotoxic activities. Biological studies indicated that amongst these compounds, 5a, b, j, h and i showed the activity with median effective concentration (EC₅₀) values less than 20 μM. Compound 5i exhibited the most potent anti-HIV-1 activity (EC₅₀ = 3.2 μM) while 5h showed anti-HIV-1 activity (EC₅₀ = 3.8 μM) with no toxicity at all in primary human lymphocytes, CEM and VERO cells.