Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABAA receptors currents with a concentration for EC50 of 0.98 ± 0.02 μM, which was about three times more potent than etomidate (3.07 ± 1.67 μM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED50s of 1.02 (0.93-1.20) mg/kg in rats and 0.5 (0.45-0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED50), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC50 of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function. SIGNIFICANCE STATEMENT: The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.

As a γ-aminobutyric acid A receptor (GABAAR) inhibitor, etomidate fulfills several characteristics of an ideal anesthetic agent, such as rapid onset with rapid clearance and high potency, along with cardiovascular stability. Unfortunately, etomidate has been reported to inhibit CYP11B1 at hypnotic doses, which is associated with a marked increase in patient deaths due to this unexpected off-target effect. In this study, molecular docking was used to simulate the binding mode of etomidate with GABAAR and CYP11B1. Based on the in-depth analysis of the binding mode, strong electron-withdrawing group on the C4 position of the imidazole ring was introduced to reduce the charge density of the nitrogen, which is beneficial in reducing the coordination bond between the imidazole nitrogen and heme iron in CYP11B1, as well as in reducing the adrenocortical suppression. Based on the results of ADMET property prediction, MEP analysis, and molecular docking simulation, 4-fluoroetomidate (EL-0052) was designed and synthesized. In vivo studies in rats and mice confirmed that EL-0052 had the efficacy similar to etomidate, but without adrenocortical suppression. These findings suggested that EL-0052 was superior to etomidate and support the continued development of EL-0052 as a preclinical candidate as an anesthetic.

As the orexin signaling system is crucial for the regulation of the sleep/wake cycle, inhibitors of orexin-1 and orexin-2 receptors are of significant interest in the treatment of insomnia. Herein, a series of novel azacycloheptane sulfonamide derivatives were designed and synthesized, and all the compounds were evaluated as potential orexin receptor inhibitors by FLIPR Tetra calcium assay. A majority of the tested azacycloheptane sulfonamide derivatives showed OX1R and OX2R inhibitory activity. Chloro-substituted derivatives functionalized at the C5 or C6 position of the benzoxazole group exhibited better inhibitory activity for OX1R and OX2R than unsubstituted derivatives functionalized at C5 or C6. In addition, phenyl group modification had positive effects on the inhibitory activities, and an electron-withdrawing fluorine group at theorthoormetaposition of the phenyl ring improved the OX2R inhibitory activity of the derivatives. This suggests that azacycloheptane sulfonamide derivatives are promising scaffolds for the development of OX1R and OX2R antagonists.

Eight tenofovir prodrugs (Ⅲa~Ⅲh) were synthesized from tenofovir (PMPA) through amino protection,acylation,condensation,deprotection and salification,and their yields were between 16.1% and 40.7%.The effects of different alkaline reagents and acetic acid amount on the conversion rate of compound Ⅰ and Ⅲ were investigated,respectively.In addition,the proportion of acetic acid to prodrug parent was discussed.The optimal conditions were obtained as following: triethylamine was selected as alkaline reagent,the molar ratio of acetic acid to prodrug parent was 0.74~0.93∶1.These compounds were confirmed by ESI-MS and 1HNMR.A potential compound Ⅲh (tenofovir dihydroxyacetone ethylene ketal) was screened by preliminary activity study.Compared with that of tenofovir dipivoxil fumarate (TDF),the in vitro stability of compound Ⅲh in rat and human plasma was increased by 2-fold and 2.5-fold,respectively.The area under the curve [AUC (0-t)] of PMMA concentration in the liver and kidney of mice in vivo for compound Ⅲh was (47 314.75±10 128.11) (μg·h)/L and (21 670.64±8 964.98) (μg·h)/L,respectively,while the corresponding value for TDF was (213 269.79±10 750.47) (μg·h)/L and (46 379.24±3 944.65) (μg·h)/L.

2′-O-[4-N,N-dimethylamino-2(R)-fluoro-butyryl]-paclitaxel hydrochloride(Ⅵ) was synthesized via esterification,condensation,selective deprotection using Bakatin Ⅲ (Ⅰ) as raw material.The esterification between 7-O-benzyloxycarbonyl-paclitaxel (Ⅳ) and (R)-4-N,N-dimethylamino-2-fluoro-butyryl chloride hydrochloride (Ⅶ) led to 2′-O-[4-N,N-dimethylamino-2(R)-fluoro-butyryl]-7-O-benzyloxycarbonyl-paclitaxel hydrochloride (Ⅴ).Compound Ⅵ was obtained by the hydrogenolysis of compound Ⅴ.The effects of volume ratio of trifluoroacetic acid and acetic acid on reaction time during the preparation of compound Ⅳ,dosage of (R)-4-N,N-dimethylamino-2-fluoro-butanoic acid hydrochloride (Ⅷ),and dosage of catalyst 4-DMAP on the conversion rate of compound Ⅵ during the preparation of compound Ⅴ were investigated.The optimal conditions were as following:V(trifluoroacetic acid):V(acetic acid)=1:8,n(Ⅳ):n(4-DMAP):n(Ⅷ)=1:3:3.The structure of target product was confirmed by MS,1HNMR and 13CNMR.The synthesis process in this study was simple,and the overall yield was more than 60%.In addition,the purity of compound Ⅵ reached 99%(HPLC).

The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK-193LK-196 was described. The C2-modified compound LK-196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK-196 had the self-evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation.

设计了一条水溶性多西他赛衍生物(Ⅰ)的合成路线.该路线以10-脱乙酰基巴卡丁Ⅲ(Ⅱ)为起始原料,经酯化、缩合和选择性脱保护得到关键中间体7,10-O-二苄氧酰基-多西他赛(Ⅴ),进一步与氨基酸反应,最后经钯碳催化氢解得到多西他赛衍生物(Ⅰ).产物结构经核磁和高分辨质谱进行了表征.该合成路线操作简单,总收率64.1％,终产品纯度(HPLC)可达99％以上.

A new water-soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL-001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL-001 was chosen as the optimal compound for studies of ED50 , LD50 , latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL-001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL-001 has a shorter period of induction despite a slightly longer sedative duration and recovery time.

苯甲酰Corey内酯经Swem氧化得苯甲酰Corey醛,与(2-氧代-4-苯基丁基)磷酸二甲酯经Homer-Wadsworth-Emmons反应生成(1S,5R,6R,7R)-6-[(E)-3-氧代-5-苯基戊烯-1-基]-7-苯甲酰氧基-2-氧杂二环[3.3.0]辛烷-3-酮,再经硼氢化钠还原、脱保护、还原、与4-羧丁基三苯基溴化鏻进行Wittig反应、甲基化和胺解制得贝美前列素,总收率约31.7％,纯度99.3％.

The target compound was synthesized through Grignard reaction,Carroll rearrangement and hydrogenation reaction from acetone with an overall yield of 69. 4%. Carroll rearrangement,the key step to improve the yield,was catalyzed by aluminum iso-propoxide,and the corresponding reaction mechanism was investigated preliminarily. The target compound and key intermediates were confirmed by MS and 1 H-NMR. The improved synthesis was benefited from simple equipment,mild conditions,high yield and could be readily scale-up to mass production.

In order to improve the pharmacy graduate student's innovation ability,"supervisor + team"is introduced,but some indemnificatory measures are needed to ensure the successful accomplishment of "supervisor + team",which mainly include the establishment and operation of the academic team,monitoring mechanism for the cultivation of pharmacy postgraduate students,the innovation ability evaluation index system of pharmacy postgraduate students,as well as the harmonious development of"supervisor + team".From the previous pharmacy postgraduates' research training process and feedback,the"supervisor + team"plays an important role in establishing the postgraduates' innovation consciousness and cultivating their ability of pharmaceutical research.However,the method still needs to be further improved and perfected.

Objective To study the evaluation system for phamacy postgraduate creativity training aiming at the lack of the creativity of pharmacy postgraduates.Methods Questionnaire and interview were combined to study the evaluation system for phamacy postgraduate creativity training.Questionnaire survey was conducted among 33 postgraduate tutors and 104 postgraduates from the majors of medicinal chemismy,phamaceutics,pharmaceutical analysis and phamacology in college of phamacy of Chongqing Medical University.The database was established by using Excel 2003 and SPSS 18.0 software was used to do statistical analysis.Descriptive analysis and t-test were adopted for data analysis of training mode,interests and subject ability,and independent scientific research ability.P＜0.05 indicates the statistical significant differences.Results 67.31％(70/104) postgraduates thought that the tutorial team was better than the single tutor(t=4.409,P=0.011).Both the teachers and the students agree that the postgraduate evaluation system and evaluation indexes were objective,justice and feasible.Attention should be paid to the cultivation of the innovative ability and independent research ability of postgraduates.In addition to the postgraduates' own efforts,the tutor at the same time played a leading role,for example,in the aspects of topic choosing and capacity-building (t=6.220,P=0.002),especially in the aspect of training postgraduates' independent scientific research ability(t=5.115,P=0.004).Conclusions It is necessary to establish the evaluation system for pharmacy postgraduate creativity training.The evaluation system and its indexes are objective,impartial,scientific,feasible,and also has a active influence on promoting the creativity and quality of phamacy postgraduates.

Esomeprazole sodium was synthesized through asymmetric oxidation reaction,and the synthesis process route was optimized. The ufiprazde was prepared firstly,which then oxidazed to esomeprazole. Finally,the esomeprazole sodium was pepared when esompeprazole reacted with sodium hydroxide. The overall yield was 57. 2%. The structures of target compounds were characterized by IR,1H NMR and MS.

The target compound was synthesized through Swern oxidation,Hormer-Wadsworth-Emmons reaction,fluorination,hydrol-ysis,reduction,Wittig reaction and esterification from corey lactone with an overall yield of 47. 2%. The target compound and the key intermediates were confirmed by MS and 1 H NMR. The improved synthesis was benefited from high yield,easy after-treatment procedure,low cost and could be readily scale-up to mass production.

Methylnaltrexone bromide was synthesized from naltrexone hydrochloride via condensation with ethylene glycol,etherification with t-butyldimethylchlorosilane and methylation with methyl iodide to give(R)-3-[(tbutyldimethylsilyl) oxy]-17-cyclopropylmethyl-4,5a-epoxy-14-hydroxy-6-(1,3-dioxolane-2-yl)-N-methylmorphinanium iodide,which was subjected to hydrolysis with hydrobromic acid,ion exchange with bromide anion exchange resin.The overall yield was about 53%and HPLC purity was more than 99%.

The acetate salts of liver targeting prodrug(1a-c),which are regarded adefovir as starting material,have been obtained by amino protection,alogenation,condensation with 1,3-propylene glycol analogues,followed by deprotection with an overall yiled of 50%—60%.Then 1d is obtained by the hydrogenolysis of 1c with the yield of 95%.The structures of target compounds were characterized by IR,1H NMR and MS.

Water-soluble paclitaxel derivatives were synthesized.The structures of target compound were characterized by MS and ~(13)C NMR.Through the release profiles in vitro,2'-N,N-dimethyl -γ-aminobutyryltaxol hydrochloride was screened out.The properties of the selected product on the intravenous acute toxicity and pharmacokinetics and pharmacodynamics was studied.The results showed that it had the possibility to be paclitaxel predrugs.

A novel intermediate of moxif loxacin,(S )-N-benzyl-N-(l-benzyl-2,5- dioxopyrrolidin-3-yl)acrylamide,has been constructed starting from L-aspartate and benzylamine by preparing anhydride,cyclization,deprotection,reprotection,acylation.

OBJECTIVE:To synthesize key intermediate of cabazitaxel,i.e.7β,10β-dimethoxy-10-deacetoxybaccatin Ⅲ with a new method.METHODS:At first,the C(7) and C(10) hydroxy of 10-deacetoxybaccatin Ⅲ was selectively protected;and then,the C(13)hydroxyl was protected by an another reagent.After the deprotection of C(7)and C(10)hydroxyl,the methylation was carried on C(7)and C(10).7β,10β-dimethoxy-10-deacetoxybaccatin Ⅲ was obtained after the deprotection of C(13)hydroxyl,which was characterized by 1H-NMR.RESULTS:7β,10β-dimethoxy-10-deacetoxybaccatin Ⅲ was synthesized successfully with 5 steps of reactions,with purity of 95% and yield of 97%.CONCLUSION:The method will benefit from the good yield,mild conditions and convenient operations,which is suitable for industrial production.

OBJECTIVE: To establish the method for the determination of 4 residual organic solvents in finasteride raw materials, i.e. methanol, acetone, chloroform and methylbenzene. METHODS: Headspace gas chromatography was adopted. The residual organic solvents were separated on Phenomenex ZB-624 capillary column using dimethyl sulfoxide as solvent by temperature programming. FID was used as detector with a temperature of 250 ℃. The inlet temperature was 200 ℃. N2 was used as carrier gas with split ratio of 5 ∶ 1. With headspace sampling, equilibrium temperature was 80 ℃ and equilibrium time was 45 min. RESULTS: The linear ranges of methanol, acetone, chloroform and methylbenzene were 12.0-1 200, 10.0-1 000, 1.20-120 and 1.78-178 μg/ml (r=0.999 6～0.999 8), respectively. Recovery rates were 94.7%-97.5% (RSD2.1%); the detection limits were in the rang of 0.021 6 to 10.93 μg/ml. Residual amount of 4 organic solvents in 5 batches of samples were in line with the requirements of Chinese Pharmacopeia (2010 edition). CONCLUSIONS: The method is sensitive and reproducible. It can be applied for the determination of the residual organic solvents in finasteride raw materials.