3-(2-羟基-2-环戊基-2-苯基-乙氧基)奎宁环烷及其光学异构体与外周毒蕈碱性受体的结合特性

采用放射性配体-受体结合实验, 研究了3-(2-羟基-20环戊基-2-苯基-乙氧基)奎宁环烷 (PCHEQ)及其4个光学异构体对豚鼠心脏, 小肠纵肌, 颌下腺和猪虹膜中的M受体的作用. 结果表明, 4种组织中的M受体对PCHEQ及其异构体表现出相似的立体选择性. PCHEQ及其异构体对4种组织中M受体的亲和力顺序相同,即RR′>PCHEQ>SR′>RS′>SS′. 这些化合物对颌下腺中的M受体的选择性较高, 尤以SR′异构体为显著.     

3S-(2R-2-苯基-2-环戊基-2-羟基乙氧基)奎宁环烷的晶体结构

选择性抗胆碱药3-(2-苯基-2-环戊基-2-羟基乙氧基)奎宁环烷盐酸盐的分子结构中有两个手性碳原子,其中奎宁环3位的手性碳绝对构型已知。本文报道用X衍射技术,测定了其中一个光学异构体(S-1)的碘甲烷季铵盐的分子结构,确定了另外一个手性碳的绝对构型。该化合物命名为:S-(2R-2-苯基-2-环戈基-2-羟基-乙氧基)-奎宁环烷。     

S048用芳基1、2-重排合成光学活性2-芳基烷酸

2-芳基烷酸类抗炎药物中,如萘普生(Naproxen),为(S)-异构体,较(R)-体的活性强28倍。可用以下通法分别合成二个光学异构体。例如萘普生,可将(1)与甲醇钠甲醇溶液作用,定量地得到(2),再与l-10-樟脑磺酰氯反应,得到1:1的二个非对映体(3),拆分后(理论收率为66％),将(S)-异构体在H_2O-DMF中与碳酸钙作用,经芳基1,2-重排,β-     

3-苯亚甲基-2-吲哚酮衍生物几何异构体的合成分离与NMR分析

本文合成了一系列3-（4＇-取代苯亚甲基）-2-吲哚酮的E和Z几何异构体,并采用反相硅胶色谱的方法首次对所有异构体进行了成功分离。通过对E和Z异构体1H NMR特征的分析发现了E和Z异构体中处于取代苯环屏蔽区的质子实际受到较明显去屏蔽效应的反常现象并对这种现象进行了分析。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯的合成

前报报道在“催醒安”的对位异构体的苯环上引入烷基,可以增强对胆碱酯酶的抑制作用。为了探索在邻位异构体(Ⅰ)的苯环上引入烷基对生理活性的影响,合成了二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯(Ⅱ)。     

衍生化法分离（2R，4R）-4-甲基-2-哌啶甲酸乙酯酒石酸盐手性异构体

目的 建立衍生化法分离（2R,4R）-4-甲基-2-哌啶甲酸乙酯酒石酸盐（MPFET）3种手性异构体。方法 以2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖异硫氰酸酯（GITC）为柱前衍生化试剂,对MPFET手性异构体进行分离,并对衍生化条件进行优化。采用Venusil AQ C₁₈（250 mm×4.6 mm,5 μm）色谱柱作为固定相进行分离、监测和定量。以0.01 mol/L磷酸二氢钾溶液（用磷酸调pH至3.6）-乙腈（60∶40）为流动相,体积流量1.5 mL/min进行等度洗脱,采用紫外检测器,检测波长266 nm;柱温30℃;进样量20 μL。结果 MPFET与2S,4S-异构体分离度为1.76。2S,4R-异构体的线性范围为1.500～8.999 μg/mL,2R,4S-异构体的线性范围为0.255 2～1.531 0 μg/mL,2S,4S-异构体的线性范围为0.250 1～75.000 0 μg/mL,MPFET的线性范围为0.250 1～600.100 0 μg/mL,回收率均在90%～108%内,RSD均不大于3.0%。结论 柱前衍生化法分离MPFET中3种手性异构体,专属性强、准确度高、灵敏度高、重复性好,可用于MPFET手性异构体的分离和质量控制。     

毛细管电泳法测定(S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯中R异构体

目的建立毛细管电泳法测定(S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯中R异构体的方法。方法采用毛细管电泳法。以磺酸-β-环糊精(S-β-CD)为选择剂;25 mmol/L硼酸盐缓冲液(pH 8.9,含S-β-CD 1.8%)为运行缓冲液;运行电压为25 kV;柱温为15℃;检测波长:214 nm;3.4 kPa压力进样10 s。结果 (S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯与R异构体的分离度为2.9。R异构体在2~30μg/m L与峰面积线性关系良好(r=0.999 5),平均回收率为96.6%,RSD值为4.9%(n=6)。结论建立的毛细管电泳法操作简便,结果准确可靠,可用于(S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯中R异构体的控制。     

从环氧氯丙烷制备1,3-二氯-2-丙醇

1,3-二氯-2-丙醇(1)是生产 H_2受体拮抗药法莫替丁(famotidine)的中间体1,3-二氯丙酮(2)的原料。文献报道的合成路线主要有二,一是以甘油和盐酸反应,产率55～57%,此法较老,有异构体2,3-二氯-1-丙醇(3)产生。二是3-氯丙烯(4)与次氯酸     

2-(2-氨基噻唑-4-基)-(z)-2-甲氧亚胺基乙酸乙酯合成方法的改进

2-(2-氨基噻唑-4-基)-(z)-2-甲氧亚胺基乙酸乙酯是制备头孢噻肟等三代头孢菌素的重要中间原料。它是以乙酰乙酸乙酯为起始原料，经肟化、甲基化、溴化、环合四步反应合成。产物顺式异构体的总收率达60％，熔点162．5～164℃，质量经检查符合标准。     

2-(异丁基苯基)丙醇异构体的高效液相色谱分离法

2-(异丁基苯基)丙醇邻、间、对位异构体混合物是合成非甾体消炎镇痛药布洛芬新路线的中间产物,其中,对位异构体是所需的原料。本实验选用β-环糊精柱,以水和甲醇为流动相,经高效液相色谱法使对位异构体得以完全分离,为建立中间体的含量测定方法提供了证据。     

新型抗胆碱能药物盐酸戊乙奎醚及其光学异构体的细胞毒性评价

目的:评价新型抗胆碱能药物盐酸戊乙奎醚(PHC)及其4个光学异构体R-1、R-2、S-1和S-2的细胞毒性。方法:不同浓度的PHC及其光学异构体作用HepG2细胞24 h后,采用MTT法和中性红吸收法测定细胞毒性:结果:PHC及其光学异构体均能浓度依赖性地降低细胞存活率。根据半数抑制浓度(IC_(50))比较这5个抗胆碱能化合物的细胞毒性:MTT法所测定的细胞毒性强弱次序为PHC>R-2>R-1>S-2>S-1,中性红吸收法所测定的细胞毒性强弱次序为R-2>PHC≈R-1>S-2>S-1。结论:就HepG2细胞而言,R构型异构体的细胞毒性强于S构型。并且,在PHC的4个光学异构体中,R-2的细胞毒性相对最强,而S-1相对最弱。     

Asymmetrische reduktive Aminierung von Cycloalkanonen, 7. Mitt. Die asymmetrische Synthese von cis-1R,2R- und cis-1S,2S-2-Arylcyclohexanaminen

Asymmetric Reductive Amination of Cycloalkanones, VII: Asymmetric Synthesis of cis-1R,2R- and cis-1S,2S-2-Arylcyclohexanamines The asymmetric synthesis of cis-2-arylcyclohexanamines 4 by a three-step procedure is reported: condensation of racemic 2-arylcyclohexanones 1 with the chiral auxiliary R-(+)- or S-(?)-1-phenylethylamin, respectively, leads to a mixture of the imin isomers 2 . Upon hydrogenation with Raney-Nickel just one secondary amin of type 3 is obtained, which is hydrogenolized to the optically active primary cis-2-arylcyclohexanamines 4 . The relative configuration as well as the conformation were derived from ¹H-NMR data. The absolute configuration of the highly enantiomerically pure compounds 4 was determined by CD spectra.     

N-methyl derivatives of the 5-HT2 agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane

1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) is a serotonin (5-HT) agonist that displays a high affinity and selectivity for a certain population of central 5-HT binding sites (i.e., 5-HT2 sites). In the present study, (a) an enantiomeric potency comparison was made for the optical isomers of DOB and (b) the activity of N-monomethyl-,N,N-dimethyl-, and N,N,N-trimethyl-DOB was examined. (R)-(-)-DOB (Ki = 0.39 nM) was found to have 6 times greater affinity than its S-(+) enantiomer at [3H]DOB-labeled (rat cortical homogenates) 5-HT2 sites; N-methylation of racemic DOB resulted in a decrease in affinity that was at least 1 order of magnitude per methyl group. Similar results were obtained in an in vivo drug discrimination paradigm with rats as subjects and (R)-(-)-DOB (0.2 mg/kg) as the training drug. Thus, the R-(-) isomer of DOB is more active than its S-(+) enantiomer and than any of the possible N-methyl derivatives of DOB, both with respect to affinity at central 5-HT2 binding sites and with respect to potency in the behavioral (i.e., stimulus generalization) studies.     

Studies on metabolism and toxicity of styrene--VI. Regioselectivity in glutathione S-conjugation and hydrolysis of racemic, R- and S-phenyloxiranes in rat liver

Rat liver cytosol converted phenyloxirane enantiomers regioselectively to glutathione S-conjugates. R-(+)-Phenyloxirane was converted to S-(1-phenyl-2-hydroxyethyl)glutathione (conjugate 1) and S-(2-phenyl-2-hydroxyethyl)glutathione (conjugate 2) (ratio 6.1:1), and S-(-)-phenyloxirane to conjugates 1 and 2 (ratio 1:32). Racemic phenyloxirane was converted to conjugates 1 and 2 (ratio 1.8:1). The conjugates were separated by HPLC on an octadecylsilicone column and identified with synthetic specimens whose structures were assigned by 13C NMR spectrometry. R-(+)-, S-(-)- and racemic phenyloxiranes were hydrolyzed to R-(-)-, S-(+)- and racemic phenylethanediols by microsomal epoxide hydrolase without inversion of absolute configurations of their benzylic carbons. R-(+)-Phenyloxirane had much smaller Km and Vmax than the S-(-)-oxirane did. The R-(+)-oxirane potentially inhibited the microsomal hydrolysis of the S-(-)-oxirane and was preferentially hydrolyzed when the racemic oxirane was used as the substrate. Microsomal monooxygenase oxidized styrene to R-(+)- and S-(-)-phenyloxiranes (ratio 1.3:1), and the ratio was little changed by the pretreatment of the animal with phenobarbital, 3-methylcholanthrene and polychlorinated biphenyls.     

Resolution and electrophysiological effects of mexiletine enantiomers.

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(-)- and S-(+)-mexiletine were resolved with an optical purity greater than 98% (yield approximately 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7-30 days after coronary ligation. R-(-)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0.5 mg kg-1, 1 after 8 mg kg-1); two animals died after 1 and 8 mg kg-1, respectively; one remained unchanged even at the highest dosage (16 mg kg-1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg-1); two died after 4 and 8 mg kg-1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg-1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0.5-16.0 mg kg-1). These results suggest that R-(-)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.     

Mutagenesis of the supF gene by stereoisomers of 1,2,3,4-diepoxybutane

1,2,3,4-diepoxybutane (DEB) is a key metabolite of the important industrial chemical and environmental contaminant, 1,3-butadiene (BD). Although all three optical isomers of DEB, S,S-, R,R-, and meso-DEB, are produced by metabolic processing of BD, S,S-DEB exhibits the most potent genotoxicity and cytotoxicity, followed by R,R- and then meso-DEB. Our previous studies suggested that the observed differences between the biological effects of DEB optical isomers may be structural in their origin. Although S,S- and R,R-DEB produced mainly 1,3-interstrand 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links, meso-diepoxide induced equal numbers of intrastrand and interstrand bis-N7G-BD lesions. In the present study, the mutagenicity of the three DEB stereoisomers in the supF gene was investigated. We found that S,S-DEB was the most potent mutagen. Interestingly, mutation specificity and mutant spectra were strongly dependent on DEB stereochemistry. Although A:T to T:A transversions were the major form of mutation observed following treatment with each of the three stereoisomers (35-40%), S,S-DEB induced higher numbers of G:C to A:T transitions, whereas R,R-DEB treatment resulted in a greater frequency of G:C to T:A transversions. Our results are consistent with the stereospecific induction of promutagenic nucleobase adducts other than G-G cross-links by DEB stereoisomers.     

Stereoisomeric probes for the D1 dopamine receptor: synthesis and characterization of R-(+) and S-(-) enantiomers of 3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its 6-bromo analogue.

Substituted 1-phenyl-3-benzazepines (e.g., SKF 38393 and fenoldopam) exhibit stereoselectivity in moderately high-affinity binding to and partial agonist activation of D1 dopamine receptors. The 3-allyl (APB) and the 3-allyl-6-chloro (6-Cl-APB) analogues of SKF 38393 are reported to have higher affinity and selectivity for the D1 DA receptor and higher in vivo central neuropharmacologic activity than SKF 38393. We recently reported the corresponding 3-allyl-6-bromo analogue (6-Br-APB) also to be a high-affinity D1 agonist. We now describe the synthesis and characterization of the R-(+) and S-(-) enantiomers of both APB and 6-Br-APB and their comparison with corresponding enantiomers of SKF 38393 with respect to D1 receptor binding affinity and D1 and D2 selectivity. The R-(+) enantiomers of both novel substituted 1-phenyl-3-benzazepines bound to the D1 receptor sites in rat forebrain tissue with much higher affinity and selectivity than their S-(-) antipodes. R-(+)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine [(R)-(+)-6-Br-APB, 18] exhibits the highest affinity of the reported 1-phenyl-3-benzazepine D1 agonists.     

蝙蝠葛苏林碱光学异构体的合成及其钙拮抗活性的研究

以香兰醛和苯乙腈为起始原料,经合成及拆分得到四个光学活性的单苄基异喹啉化合物5～8。进而通过 Ullmann 反应,使5-7,6-8,5-8,6-7结合,然后分别脱苄基得 R,R-、S,S-、R,S-和 S,R-蝙蝠葛苏林碱。药理试验表明,其钙拮抗活性的顺序是 S,R-构型>R,S-构型>R,R-构型>S,S-构型。     

Dopamine D-2 receptor imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N- [(1-ethyl-2-pyrrolidinyl)methyl]benzamide

In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-[125I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamide, [125I]IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-[125I]IBZM showed high specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone greater than (S)-(-)-IBZM greater than (+)-butaclamol much greater than (R)-(+)-IBZM greater than (S)-(-)-BZM greater than dopamine greater than ketanserin greater than SCH23390 much greater than propanolol. The results indicate that [125I]IBZM binds specifically to the dopamine D-2-receptor with stereospecificity. The [123I]IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.