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     

培西达替尼合成路线图解

培西达替尼(pexidartinib,PLX-3397)化学名称为5-((5-氯-1H-吡咯并[2,3-b]吡啶-3-基)甲基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺,分子式:C20H15C1F3N5,分子量:417.82,CAS登记号:1029044-16-3.培西达替尼于2019年8月2日获FD...     

维奈托克关键中间体的合成工艺优化与位置异构体合成

目的 为了控制维奈托克(venetoclax)中的位置异构体，溯源并分析该有关物质产生的源头。方法 以5-溴-7-氮杂吲哚(2)为起始原料，经过甲氧基化、脱甲基以及醚化得到维奈托克关键中间体2-[(1H-吡咯[2,3-b]吡啶-5-基)氧基]-4-氟苯甲酸甲酯(6);采用N,N-二甲基甲酰胺/碳酸钾体系定向合成关键中间体6的位置异构体4-[(1H-吡咯[2,3-b]吡啶-5-基)氧基]-2-氟苯甲酸甲酯(IMP-1)。结果与结论采用二乙二醇二甲醚/磷酸三钾体系合成关键中间体(6),收率提升至80%,HPLC测定纯度大于99%。合成的有关物质IMP-1的结构经2D-NMR得到结构确证，可用于维奈托克原料药的质量研究和质量控制。     

Venetoclax合成路线图解

<正>Venetoclax(Venclexta)的化学名称为4-(4-{[2-(4-氯苯基)-4,4-双甲基-1-环己烯基]}-1-哌嗪基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺,是一种可以口服的选择性B细胞淋巴瘤因子-2(Bcl-2)小分子抑制剂。Bcl-2在细胞凋亡中发挥重要作用,可阻止一些细胞(包括淋巴细胞)的凋亡。Venclexta的作用机制是选择性抑制Bcl-2的功能,通过与Bcl-2蛋白直接结合,恢复细胞的通讯系统,让癌细胞自我毁灭,达     

应激性肠综合征治疗药阿洛司琼(Alosetron)

1商品名 Lotronex 2化学名 2,3,4,5-四氢-5-甲基-2-[(5-甲基-1H-咪唑-4-基)甲基]-1H-吡啶并[4,3-b]吲哚-1-酮盐酸盐     

奥氮平原料药中相关杂质的合成及结构鉴定

目的合成奥氮平原料药中的相关杂质并进行结构鉴定。方法分别以奥氮平的合成中间体4-氨基-2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓盐酸盐和奥氮平为起始原料合成奥氮平的3个相关杂质:2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓-4-(5H)-酮(1)、1-氯甲基-1-甲基-4-(2-甲基-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓-4-哌嗪基)-1-氯化物(2)和2-甲基-4-(4-甲基-1-哌嗪基)-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓4’-N-氧化物(3)。结果与结论合成并鉴定了奥氮平质量标准中提及的3种杂质,其结构经1H-NMR、13C-NMR谱及高分辨质谱确证;并且探讨了3种杂质可能的产生途径,以期为奥氮平的质量研究和相关杂质的控制提供帮助。     

ND-011氟嗪酸(Ofloxacin)

9-氟-3-甲基-10-(4-甲基-1-哌嗪基)-7-氧-2,3-二氢-7H-吡啶并[1,2,3-de][1,4]苯并噁嗪-6-羧酸     

一种富马酸沃诺拉赞杂质的制备及表征

目的 制备富马酸沃诺拉赞合成工艺中产生的一个杂质,加强其质量控制.方法 以5-(2-氟苯基)-1H-吡咯-3-甲醛为起始原料,按照原研路线合成富马酸沃诺拉赞,富马酸沃诺拉赞经高温降解得到目标杂质:N-[5-(2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯-3-基]甲基-N-甲基天冬氨酸,通过制备液相得到该杂质纯品...     

莫西沙星的合成

1-环丙基-6,7,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯(5)经水解、缩合和甲氧基化制得抗菌剂莫西沙星,总收率为71.5%(以5计).缩合剂(S,S)-八氢-6H-吡咯并[3,4-b]吡啶可由8-苄基-八氢-6H-吡咯并[3,4-b]吡啶经D-(-)-酒石酸拆分和氢解脱苄制得.     

克拉维酸钾有关物质F的合成

为了保证克拉维酸钾(1)的质量,本研究合成了欧洲药典收载的有关物质F,即4-[[[4-(2-羟乙基)-1H-吡咯-3-羰基]-氧]甲基]-1H-吡咯-3-羧酸。4-氯乙酰乙酸甲酯(2)与原甲酸三乙酯反应得4-氯-2-(二乙氧基甲基)-3-氧代丁酸甲酯(3),3与甘氨酸反应得烯胺。烯胺在乙酸酐中回流,经环合、脱羧得4-(氯甲基)-1H-吡咯-3-羧酸甲酯(5)。5和1的降解产物4-(2-羟乙基)-1H-吡咯-3-羧酸(8)反应得[4-(甲氧基羰基)-1H-吡咯-3-基]甲基4-(2-羟乙基)-1H-吡咯-3-羧酸甲酯(6),6经水解得有关物质F。产物结构经MS、1H NMR和13C NMR确证。     

Synthesis and evaluation of 5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[18F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid as a potential NMDA ligand to study glutamatergic neurotransmission in vivo

The neurotransmitter glutamate is thought to be crucially involved in a huge number of neurological and psychiatric disorders, such as Morbus Parkinson, Alzheimer's disease and schizophrenia. Aiming at an improved diagnostic tool for PET a new [¹⁸F]fluorine labelled NMDA receptor ligand was developed that may potentially allow the in vivo visualization of glutama‐tergic neurotransmission. The ¹⁹F‐analogue trans‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydro quinoline‐2‐carboxylic acid was synthesised to determine the binding affinity, lipophilicity and biodistribution of the ligand. This substance exhibits a K_i of 12 nM for the glycine binding site using [³H]MDL‐105,519 assays on pig cortical membranes. A logD of 1.3 was determined for this compound according to the OECD guidelines employing the HPLC method. Radiosynthesis of this ligand was achieved by labelling the precursor trans‐5,7‐dichloro‐4‐[3‐(4‐piperazin‐1‐yl‐phenyl)‐ureido]‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid methyl ester with 2‐[¹⁸F]fluoroethyltosylate and subsequent cleaving of the methyl ester moiety, resulting in an overall decay corrected yield of 35% of the final product trans‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[¹⁸F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid. The biodistribution kinetics of this compound were determined with Sprague Dawley rats ex vivo for brain, liver, kidney, and bone. The ligand showed a maximum brain uptake 30 min.p.i. of about 0.1% ID/g. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3‐Aryl‐pyrrolidine‐2,5‐diones. Part 1

A series of new Mannich bases of N‐[(4‐arylpiperazin‐1‐yl)‐methyl]‐3‐(chlorophenyl)‐pyrrolidine‐2,5‐diones 10–23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES‐test. In this model of seizures, the most active were N‐[{4‐(4‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 16 and N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 17 with ED₅₀ values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10 , 14 , and 16 were tested in the psychomotor seizure 6‐Hz test from which N‐[{4‐(2‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(2‐chlorophenyl)‐pyrrolidine‐2,5‐dione 10 revealed the highest protection with an ED₅₀ of 78 mg/kg. Compounds 10 , 12 , and 17 were also tested in the pilocarpine‐induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.     

Synthesis and preliminary in vivo evaluation of 4‐[18F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide,a potential PET radioligand for the 5‐HT1A receptor

4‐Fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide is a full 5‐HT_1A agonist with high affinity (pK_i=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4‐[¹⁸F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[¹⁸F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd.     

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides

Affinity chromatography was used to identify potential cellular targets that are responsible for neuroprotective activity of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides. Active and inactive representatives of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides bearing an extended linker were synthesized and immobilized on an agarose‐based matrix. This was followed by the identification of specifically bound proteins isolated out of the whole rat brain extract. Inducible flavoprotein NAD(P)H:quinone oxidoreductase (NQO1) was identified as candidates for cellular targets.     

18F‐labelling of a potent nonpeptide CCR1 antagonist: synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[18F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea in an automated module

The synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[¹⁸F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea ( [¹⁸F]4 ), a potent nonpeptide CCR1 antagonist, is described as a module‐assisted two‐step one‐pot procedure. The final product was obtained utilizing the reductive amination of the formed 4‐[¹⁸F]fluorobenzaldehyde ( 2 ) with a piperazine derivative 3 and sodium cyanoborohydride. After HPLC purification of the final product [¹⁸F]4 , its solid phase extraction, formulation and sterile filtration, the isolated (not decay‐corrected) radiochemical yields of [¹⁸F]4 were between 7 and 13% (n=28). The time of the entire manufacturing process did not exceed 95 min. The radiochemical purity of [¹⁸F]4 was higher than 95%, the chemical purity ?60% and the enantiomeric purity >99.5%. The specific radioactivity was in the range of 59–226 GBq/µmol at starting radioactivities of 23.6–65.0 GBq [¹⁸F]fluoride. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and Anticonvulsant Properties of New N‐Mannich Bases Derived from 3,3‐Diphenyl‐ and 3‐Ethyl‐3‐methyl‐pyrrolidine‐2,5‐diones. Part III

Twenty‐four new N‐[(4‐phenylpiperazin‐1‐yl)‐methyl] derivatives of 3,3‐diphenyl‐ ( 7 – 18 ) and 3‐ethyl‐3‐methyl‐pyrrolidine‐2,5‐dione ( 19 – 30 ) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3,3‐diphenyl‐pyrrolidine‐2,5‐dione ( 14 ) with an ED₅₀ value of 30.3 mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7 , 8 , 9 , 11 , 14 , 23 , and 26 , their influence on Na_V1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules ( 8 , 10 , and 11 ) were solved.     

Synthesis of 3‐[[4‐(4‐[18F] fluorophenyl)piperazin‐1‐yl]methyl]‐1H‐pyrrolo[2,3‐b]pyridine

3‐[[4hyphen;(4‐[¹⁸F]fluorophenyl)piperazin‐1‐yl] methyl] ‐1H‐pyrrolo[2,3‐b]pyridine, acandidate to image dopamine D₄ receptors, was synthesised via electrophilic fluorination of a trimethylstannyl precursor with high specific radioactivity [¹⁸F]F₂. The precursor was obtained by a facile four‐step synthetic approach; the trimethylstannyl leaving group was introduced by displacement of iodine utilising palladium catalysis and hexamethyldistannane in an inert solvent. The total radiosynthesis time was 50 min, including purification and formulation for injection. Decay corrected radiochemical yield was <1% as calculated from the amount of [¹⁸F]F^? produced. Specific radioactivity at the end of synthesis was 12.8–16.4 GBq/μmol. Radiochemical purity was 88–92%. Ex vivo studies in rats showed homogeneous distribution of radioactivity within rat brain. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and Antimicrobial Activity of Some Novel 2‐[4‐(Substituted Piperazin‐/Piperidin‐1‐ylcarbonyl)phenyl]‐1H‐benzimidazole Derivatives

In this study, we report the synthesis and antimicrobial evaluation of several new 4‐(1H‐benzimidazol‐2‐yl)benzamides ( 11 – 30 ) and 5‐chloro‐1‐(p‐fluorobenzyl)‐2‐{4‐[(4‐methylpiperazin‐1‐yl)carbonyl]phenyl}‐1H‐benzimidazole ( 33 ). Compound 20 exhibited the best antibacterial activity with MIC value of 6.25 μg/mL against Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus (MRSA). Significant antifungal activities were obtained with the compounds 13 , 14, 18 , 19, and 33 with MIC values of 3.12 μg/mL which are close to fluconazole.