Stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines: highly efficient synthesis of functionalized benzazepine scaffolds

An efficient and highly diastereoselective synthesis of 2-substituted benzo[b]azepin-5-ol via stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines has been developed. The reaction proceeds efficiently starting from versatile skeletons with mild reaction conditions as well as simple operation. Furthermore, 2-substituted benzazepinones could been obtained by simple Dess–Martin oxidation in excellent yields.

An efficient and highly diastereoselective synthesis of 2-substituted benzo[b]azepin-5-ol via stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines has been developed.

Benzofused azepines, a unique family of seven-member aza-heterocycles, are widely found in numerous bioactive molecules, natural products and pharmaceuticals.^1–4 This is due to their chemotherapeutic properties, and exhibiting interesting biological activities,^5–9 for instance, competitive vasopressin receptor antagonist (tolvaptan),^10–12 antidepressants (mianserin),¹³ zilpaterol (beef improvement agent),¹⁴ ACE inhibitor (benazepril)¹⁵ (Fig. 1).Open in a separate windowFig. 1Selected examples containing a benzazepine skeleton.Consequently, tremendous efforts have recently been dedicated to developing new methodologies to construct the benzazepine derivatives. Typically, the benzazepine skeletons could be assembled by expansion of smaller rings, rearrangements,^16,17 Dieckmann cyclization,^18,19 transition-metal-catalyzed coupling, ring closure metathesis,^15,20,21 and others.^22–25 Nevertheless, most of these protocols are limited to highly engineered starting materials, expensive catalysts and hazardous handling, obviously expeditious strategies for the diverse construction of benzazepine backbones from readily available starting materials, remains highly attractive and challenging.Diversity-oriented synthesis (DOS), defined as a powerful synthetic strategy to the libraries of diverse highly valuable molecules from one parent compound,^26,27 is therefore well-suited for the timely design and execution of parallel (library) synthesis.²⁸ In recent years, our group focused on the development of a more facile and efficient diversity-oriented synthesis strategy for the generation of this class of 7-membered heterocyclic compounds.^29–31 This newly introduced ene-type cyclization reaction was used to prepare a series of bridged aromatic fused azepines,²⁹ as a versatile building block, which could be transformed into structurally different ring systems through selective ring opening of the cyclic acetals (Scheme 1A).^30,31Open in a separate windowScheme 1Our previous work (A) and this work (B).As an extension of our ongoing work toward the synthesis of the azepine skeleton, we suggested a new reaction model could be achieved if the suitable nucleophile could be carefully designed. Recently, a couple of efficient approaches to access nitrogen-containing heterocycles has been developed through the nucleophilic addition of cyclic N,O-acetal with Grignard reagents.^32–35 Inspired by their excellent studies and to showcase the utility of cyclic N,O-acetal building blocks for the preparation of functionalized azepines, we present a facile approach to a stereoselective synthesis of 2,5-substituted benzazepine derivatives from oxa-bridged benzazepines by Grignard addition. This strategy is complementary to our recently published cascade reaction to prepare the benzazepinone scaffold. Herein, the details of this study is disclosed.Our investigations commenced by exploring nucleophilic addition of 1a, which was readily prepared in two steps via substitution reaction and subsequent ene-type reaction (see the ESI^†). We started our screening with 1-allyl-2,3,4,5-tetrahydro-1H-2,5-epoxybenzo[b]azepine (1a) as a model substrate for the optimization of the reaction conditions (36,37 We were gratified to find that Grignard reagents could indeed be added with high selectivity (

The migration of acetochlor from feed to milk

Acetochlor has been widely used globally for its effective weed control, but the dietary intake of associated residues by people has become a major concern nowadays. Milk is regarded as the best solvent to dissolve pesticides due to its fat-rich characteristic. In this study, we aimed to evaluate the transfer of acetochlor from feed to raw milk. Twenty lactating Australian Holstein cows were randomly chosen and divided into 1 control group and 3 treatment groups, feeding acetochlor at the dosages of 0, 0.45, 1.35 and 4.05 g per day during the treatment period. The concentration of acetochlor residues in raw milk was detected by QuEChERS together with a gas chromatography-mass spectrometry (GC-MS) method. The results showed that the highest concentrations of acetochlor residues in raw milk for the three treatment groups had a positive correlation with the dosage levels and the transfer efficiency of the low dose group was only 0.080%, higher than those of the other two groups. Besides, the national estimated daily intake (NEDI) of acetochlor from milk is 1.67 × 10⁻⁵ mg kg⁻¹, which is 0.08% of the ADI. Overall, we concluded that the risk of acetochlor residues in milk was low, but high-dose acetochlor had a larger impact on milk quality and low-dose acetochlor had potential risks.

Acetochlor has been widely used globally for its effective weed control, but the dietary intake of associated residues by people has become a major concern nowadays.     

Transcriptional suppression of androgen receptor by 18β-glycyrrhetinic acid in LNCaP human prostate cancer cells

Archives of Pharmacal Research - Androgen receptor (AR) plays a pivotal role as a target for amplification/mutation in pathogenesis and tumor progression in prostate, and thus, controlling AR...     

多模式神经电生理检测对脊髓手术患者神经功能状态的评估分析及其影响因素

 目的 使用肌电图(electromyography,EMG)、体感诱发电位(somatosensory evoked potential,SEP)与运动诱发电位(motor evoked potentials,MEP)多模式方法检测手术前后神经系统的多种电生理信号,探讨患者神经功能状态。方法 收集100例患者作为研究对象,术中监测患者双下肢的SEP与MEP情况;术后6个月复查患者EMG。结果 术中SEP波幅与潜伏期在较稳定情况下,MEP监测中42例患者术中的D波波幅发生降低未超过50%,22例患者出现D波波幅突然下降且超过50%。Pearson相关性分析结果表明,术中出血量与SEP及MEP波幅与潜伏期的改变具有相关性。术后复查,各组患者的腓总神经与胫神经的NCV与DL均有显著改善,异常组患者的改善情况明显低于其他四组。结论 使用EMG、SEP与MEP多模式神经电生理检测可以去除干扰因素,为脊髓手术提供客观、有价值的诊疗依据。     

过表达脑源性神经营养因子的神经干细胞移植对受照海马内神经营养因子的影响

目的 探讨过表达脑源性神经营养因子（BDNF）的神经干细胞（NSCs）移植入放射性脑损伤大鼠模型后,对海马内神经营养因子水平及小胶质细胞活化的影响。方法 从胎鼠脑中分离海马神经干细胞并进行培养。选用绿色荧光蛋白（GFP）-慢病毒、GFP-BDNF-慢病毒感染神经干细胞。将SD大鼠按随机数表法分为4组：健康对照组、单纯照射组（R组）、照射后GFP修饰的神经干细胞移植组（R+NSCs组）、照射后GFP-BDNF修饰的神经干细胞移植组（R+BDNF-NSCs组）。全脑单次20 Gy照射后1个月将神经干细胞移植入大鼠双侧海马内。移植后2和8周检测海马组织中BDNF、胶质源性神经营养因子（GDNF）、神经生长因子（NGF）的表达情况;免疫荧光染色观察小胶质细胞活化情况。结果 移植后2和8周时,与R组相比,R+BDNF-NSCs组海马组织中BDNF、NGF蛋白表达均水平明显增高（P<0.05）;移植后8周R+NSCs组和R+BDNF-NSCs组活化的小胶质细胞与R组相比并未显著减少（P>0.05）。结论 过表达BDNF的神经干细胞移植后促进BDNF、NGF的产生,增加了辐射暴露后的海马内神经营养因子水平。     

舒血宁注射液联合阿托伐他汀治疗老年慢性硬膜下血肿的临床研究

目的探讨舒血宁注射液联合阿托伐他汀治疗慢性硬膜下血肿的临床疗效。方法选取2016年1月—2017年1月在天津医科大学总医院滨海医院治疗的慢性硬膜下血肿患者76例,依据治疗方案的差别分为对照组(38例)和治疗组(38例)。对照组口服阿托伐他汀钙片,20 mg/次,1次/d。治疗组在对照组的基础上静脉滴注舒血宁注射液,20 mL加入5%葡萄糖溶液250 mL,1次/d。两组患者均治疗30 d。评价两组患者临床疗效,同时比较治疗前后两组患者CSS和ADL评分以及血肿量和血清学指标。结果治疗后,对照组和治疗组的总有效率分别为81.58%、97.37%,两组比较差异具有统计学意义(P0.05)。治疗后,两组CSS评分与血肿量均显著降低,ADL评分升高,同组比较差异具有统计学意义(P0.05);且治疗组CSS和ADL评分及血肿量均显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清神经元特异性烯醇化酶(NSE)、基质金属蛋白酶-9(MMP-9)、脑源性神经营养因子(BDNF)水平显著降低,同组比较差异具有统计学意义(P0.05);且治疗组上述血清学指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。结论舒血宁注射液联合阿托伐他汀治疗慢性硬膜下血肿临床疗效显著,可有效改善神经功能和促进血肿吸收,具有一定的临床推广应用价值。     

影响药物毒性神经病理学评价质量的主要因素

神经毒性是许多药物或化合物常见的毒副作用。在新药研发早期要进行神经毒性筛选。对于可能通过血脑屏障影响神经系统的小分子药物或疫苗类的生物制品在临床前安全性评价中要进行非人灵长类动物的神经毒性评价。毒性病理学或神经病理学评价是临床前药物神经毒性评价的金标准。针对影响药物毒性神经病理学评价质量的几个主要因素,包括神经病理学评价的一般策略、最佳的评价时机、特殊的神经组织屏障系统、神经组织病理制片中的取材方法以及人工假象对神经病理学诊断的干扰,进行详细的解析,以期为我国神经毒性评价指导原则的制定和药物非临床神经毒性研究提供参考。     

石辛含片联合碘甘油治疗智齿冠周炎的疗效观察

目的探讨石辛含片联合碘甘油治疗智齿冠周炎的临床疗效。方法选取2016年4月—2017年4月在解放军第101医院进行诊治的智齿冠周炎患者160例,随机分为对照组(80例)和治疗组(80例)。对照组患者将碘甘油涂于牙周袋,3次/d。治疗组在对照组的基础上于牙患处含化石辛含片,1片/次,4次/d。两组患者均治疗5 d。观察两组患者临床疗效,比较治疗前后两组OHIP-14和VAS评分以及菌群变化情况。结果治疗后,对照组和治疗组临床总有效率分别为83.75%、96.25%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者OHIP-14和VAS评分均显著降低,同组比较差异具有统计学意义(P0.05);且治疗组患者OHIP-14和VAS评分显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组细菌密度、格兰阴性菌比例、螺旋体比例均明显降低,而格兰阳性菌比例增加,同组比较差异具有统计学意义(P0.05);且治疗组菌群变化情况明显优于对照组,两组比较差异具有统计学意义(P0.05)。结论石辛含片联合碘甘油治疗智齿冠周炎可有效改善患者口腔健康,具有一定的临床推广应用价值。     

BCG新应用研究进展

近年来人们围绕BCG开展了新应用研究.此文对重组BCG抗结核病、抗寄生虫病和抗肿瘤,BCG多糖核酸与临床药物联合应用以及BCG作为佐剂的研究进展做一综述.