Mild Reductive Cleavage of α-Aminoethers

1,2,3,4-Tetrahydro-6,7-dimethoxy-2-methylisoquinoline (1) is converted by ethyl chloroformate (ECF)/NaBH₃CN to 2-[β-(N-ethoxycarbonyl-N-methyl)aminoethyl]-4,5-dimethoxytoluene (4) via the quaternary urethane 2 . The same procedure leads from laudanosine (5) to the dibenzyl derivative 9 . The reaction with ECF/NaBH₃CN followed by LiAlH₄ reduction is a versatile approach to Emde degradation products avoiding strongly basic conditions and elevated temperature. Cleavage reactions of other α-amino ethers, e.g. thebaine ( 18 ), and N-demethylation reactions of the tetrahydroisoquinolines 1 and 10 with ECF are reported.     

含双环哌啶结构 HIV-1 抑制剂的设计合成及生物活性研究

目的 设计合成一系列具有新型结构特征的双环哌啶类 C-C 族趋化因子受体5(CCR5) 抑制剂并测定其抗 HIV-1 活性。方法 以HIV-1 辅助受体 CCR5 抑制剂 Vicriviroc 的结构为模板,通过改变左侧哌嗪结构、取代基位置等方法设计并合成一系列新化合物。并利用 MS 及 ¹H-NMR 谱对这些化合物进行了结构表征。结果与结论 合成了 15 个新结构化合物,活性测试结果表明,该系列化合物具有较强的抗 HIV-1 R5 病毒株的活性 (IC₅₀ = 1.20 ～ 66.24 µmol·L^-1 )。 当 R¹ 为芳基结构且两个氮原子满足标准的丙二胺结构时,化合物的活性更好。     

Imidlactone,I: N-(2-Phenylethyl)-1,3-dihydro-isobenzofuran-1-imine

Imidolactones, I N-(2-Phenylethyl)-1,3-dihydroisobenzofuran- 1-imines N-(2-Phenylethyl)-2-(hydroxymethyl)-benzamides 1 cyclize on treatment with SOCl₂ to yield the N-(2-phenylethyl)-1,3-dihydroisobenzofuranimines 5 which are characterized by their spectra and by chemical reactions. The imidolactones 5 may be reduced by NaBH₄ to yield the N-(2-phenylethyl)-2-(hydroxymethyl)benzylamines 3 .     

Enantioselective Synthesis of Some Nicotiana Alkaloids

A modified approach to myosmine ( 6 ) via a silyl enol ether of 3-acetylpyridine ( 1 ) is described. Chiral reduction of 6 with N-(benzyloxycarbonyl)-L-proline/NaBH₄ and formylation leads to (R)-N-formylnornicotine ( 8 ) (35 % ee) which in turn is converted to (R)-nornicotine ( 11 ) and (R)-nicotine ( 10 ).     

Racemate und Enantiomere von 5,5-disubstituierten Hexahydropyrimidinen

Racemates and Enantiomers of 5,5-Disubstituted Hexahydropyrimidines The racemic and the enantiomeric hexahydropyrimidin-2-ones 1a-1e can be reduced by LiAlH₄ in high yields to the racemic and the enantiomeric hexahydropyrimidines 2a-2e . The enantiomers of 2a-2e show the same direction of rotations as the starting compounds. The enantiomers dextro-rotating in ethanol (+)- 2a-2d possess S-configuration.     

Evaluation of New Indole and Bromoindole Derivatives as pp60c‐Src Tyrosine Kinase Inhibitors

A series of N‐benzyl‐indole‐3‐imine‐, amine derivatives and their 5‐bromo congeners were synthesized and their biological activity were evaluated against the pp60^c‐Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH₄ reduction of these imines. Except insoluble N‐benzyl‐indole‐3‐imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N‐benzyl‐indole derivatives, those bearing 5‐bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.     

A Novel Antifungal Agent with Broad Spectrum: 1‐(4‐Biphenylyl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanone

A series of (1‐substituted aryl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanones was synthesized through the N‐alkylation of imidazole with 3‐dimethylamino‐1‐(substituted aryl)‐1‐propanone hydrochlorides (ketonic Mannich bases). A second series of N¹‐substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole–ketones in the previous series by means of NaBH₄. All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3‐(1H‐imidazol‐1‐yl)‐1‐(4‐biphenylyl)‐1‐propanone emerged as a broad‐spectrum antifungal agent. Several 3‐(1H‐imidazol‐1‐yl)‐1‐(2′‐(substituted benzyl)oxyphenyl)‐1‐propanones were also active towards Candida kefyr.     

吡咯并嘧啶类化合物的合成及其抑制JAK3激酶活性的研究

目的设计合成吡咯并嘧啶类化合物并研究其抑制JAK3激酶的活性。方法以4-氯-7H-吡咯并[2,3-d]嘧啶为原料,经过取代、氨基脱保护和N-酰化反应合成两类(Ⅰa和Ⅰb)吡咯并嘧啶类化合物,经体外细胞试验测定其对JAK3激酶的抑制活性。结果设计并合成了8个新化合物,结构经1H-NMR和HR-MS确证。初步活性测试结果显示Ⅰa-1和Ⅰb-3对JAK3的抑制强度与阳性对照药tofacitinib相近。结论目标化合物对JAK3依赖的DAUDI细胞抑制活性较好,对非JAK3依赖的BT-20细胞抑制作用弱。     

Zyklische Harnstoffe, 1. Mitt.: Racemate und Enantiomere von Hexahydropyrimidin-2-onen: Synthese,Konfiguration und sedativ-hypnotische Wirkung

Cyclic Ureas, I: Racemates and Enantiomers of Hexahydropyrimidin-2-ones: Syntheses, Configurations and Sedative-hypnotic Activity The racemates and the enantiomers of the hexahydropyrimidin-2-ones 2a-2e which can be regarded as cyclic ureas are obtained from the racemates and the enantiomers of the barbiturates 1a-1e by reduction with LiAlH₄/AlCl₃. The enantiomers of 2a-2d , dextrorotatory in ethanol, possess S-configuration. - In a study with rats all cyclic ureas synthesized showed sedative-hypnotic activity. Some of the enantiomers exhibited marked enantioselective differences in their potency.     

Synthesis of [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins with 9‐β‐d, 7‐β‐d‐glucopyranosyl,or 9‐β‐d‐ribofuranosyl group

Synthesis of [¹⁵N₄] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9‐β‐d , 7‐β‐d ‐glucopyranosyl, or 9‐β‐d ‐ribofuranosyl group is described. These N⁶‐substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6‐chloro[¹⁵N₄]purine ( 1 ). The equilibrium reaction of 1 with acetobromo‐α‐d ‐glucose gave isomeric 7‐β‐d ( 3 ) and 9‐β‐d ( 4 ) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7‐β‐d ( 6 ) and 9‐β‐d ( 5 ) glucopyranosides. Cytokinins containing 9‐β‐d ‐ribofuranosyl group ( 8 ) were obtained by direct enzymatic transglycosylation reaction of cytokinins ( 7 ) prepared from 6‐chloro[¹⁵N₄] purine ( 1 ).     

Untersuchungen an 1,3-Dicarbonylverbindungen, 15. Mitt. 4,5-Dihydro-5-alkyl-4-oxo-pyrano[3,2-b]indole

1,3-Dicarbonyl Compounds, XV: 4,5-Dihydro-5-alkyl-4-oxopyrano[3,2-b]indoles N-Alkylanthranilic acids react with chloroacetone/K₂CO₃ to form the 1-alkyl-2-acetyl-3-hydroxy-indoles 3 . The 1,3-dicarbonyl compounds 3 condense with dialkyl oxalates to yield the 1,3,5,6-tetra-carbonyl compounds 5 , which cyclize on heating with alcohols, saturated with HCl, to form the alkyl 4-pyrone-2-carboxylates 6 . The acids 8 , obtained from 6 , possess antiallergic activity. Decarboxylation of 8 affords the pyrono[3,2-b]indoles 9 . Condensation of 5 with triethyl orthoformate/acetic anhydride yield the alkyl 4-pyrone-3-ketocarboxylates 7 . Compounds 6 and 9 are converted to the thiocarbonyl compounds 11 and 12 . The amide 10 is obtained from 6c by reaction with ammonia.     

Selektive katalytische Hydrierungen und Hydrogenolysen, 6. Mitt. Eine verbesserte Synthese von 1-Benzyl-2-methyloctahydroisochinolinen

Selective Catalytic Hydrogenations and Hydrogenolyses, VI: An Improved Synthesis of 1-Benzyl-2-methyloctahydroisoquinolines The title compounds 3 are conveniently prepared from the methoiodides 2 of the benzyl-tetrahydroisoquinolines 1 by reduction with NaBH₄.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 14. Mitt. 4-Oxo-4H-[1]benzofuro[3,2-b]pyrane und 4-Oxo-4H[1]benzothieno-[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XIV: 4-Oxo-4H-[1]benzofuro[3,2-b]pyranes and 4-Oxo-4H-[1]benzothieno[3,2-b]pyranes The 1,3-dicarbonyl compounds 1 condense with dialkyl oxalates to form the 1,3,5,6-tetracarbonyl compounds 2 , which hydrolize under mildly alkaline conditions to give the ketocarboxylic acids 3 . Compounds 2 and 3 cyclize on heating with alcohols, saturated with HCl, to yield the alkyl 4-pyrone-2-carboxylates 4 . The acids 5 , obtained from 4 , decarboxylate on heating with quinoline/copper to give the heterocycles 6 . Compound 6b is also obtained from 1b by reaction with N,N-dimethylformamide dimethyl acetal (DMFDMA) and treatment with acid of the product 8b , whereas 1a and DMFDMA give the derivative 7a . Compounds 4 were characterized in the form of their amides 10 . The pyrylium salts 11 were obtained from 6 by reaction with dimethyl sulfate/HClO₄. Compounds 4 and 6 are converted to the thiocarbonyl compounds 12 and 13 by reaction with P₄S₁₀. Condensation of 2 with triethyl orthoformate/acetic anhydride yields the alkyl 4-pyrone-3-ketocarboxylates 14 . Compound 15b , formed by hydrolysis from 14b, afforded the 4-pyrone-3-carboxylic acid 16b by oxidative decarbonylation.     

Synthesis and kinetics studies of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazide derivatives as potent antidiabetic agents

A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC₅₀ values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC₅₀ = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode.     

抗肿瘤及抗病毒药物的研究——Vβ-乙氧基-α-正丁酮醛双缩氨硫脲类似物的合成

本文报告了β-甲氧-,β-乙氧-β-正丙氧-,β-正丁氧-α-正丁酮醛与N⁴-取代氨硫脲,S-甲基氨硫脲,氨脲,氨胍,苯肼,异烟肼以及对氨基苯甲酸缩合物共29个化合物的合成,以寻找抗肿瘤及抗病毒药物。     

Structure–activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a–9d ) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a–3f ) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC₅₀ = 1.11 ± 0.08 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.     

Protoberberine aus Reissert-Verbindungen, 2. Mitt.: Eine neue Synthese von 8-Methyldibenzo[a,g]chinolizidinen

Protoberberines from Reissert Compounds, II: A New Synthesis of 8-Methyldibenzo[a,g]quinolizidines The Reissert compounds 16 are benzylated by 2-bromomethylacetophenone dioxolane 14 to give the dihydroisoquinolines 5 . Treatment of 5 with KOH yields the 1-benzylisoquinolines 6 which spontaneously form the deoxygenated coralynes 4 in acidic solution. 4a and 18 are reduced by NaBH₄ to give the 8-methyl-trans-dibenzoquinolizidines 19 . The sequence 5 → 6 → 4 → 19 is a new efficient access to coralyne analogues and 8-substituted tetrahydroprotoberberines.- Bromination of 2-methylacetophenone does not lead to 2-bromomethylacetophenone but to the benzalbromide 9 or to the phenacylbromide 11 .     

Intramolekulare Aromatenalkylierungen, 14. Mitt. Synthese partiell hydrierter cis-Naphtho[1,8-f,g]chinoline

Intramolekular Alkylations of Aromatic Compounds, XIV: Synthesis of Partially Hydrogenated cis-Naphtho[1,8-f,g]quinolines Reduction of the lutidinium salts 2 with NaBH₄ yields mixtures of the diastereomers 3A and 3B , which are separated by column chromatography. Only one of them can be converted into the title compound 5 , which is formed stereospecifically. The dihydroxy compounds 5 (R¹, R² or R², R³ = OH) are readily oxidized by air and can be isolated only as the diacetates 5e,f . The structures of 3 and 5 are elucidated by spectroscopy (IR, ¹H- and ¹³C-nmr).     

含有替加氟的卵磷脂类似物设计、合成及抗癌活性

目的合成含有替加氟的以卵磷脂类似物作载体的缀合物,并测定其生物活性。方法将替加氟转化为羟烷基衍生物,六乙基亚磷酰三胺作磷酰化试剂,与羟烷基替加氟、1-十六烷基甘油及硫作用,经一锅法合成得到环甘油硫代磷脂羟烷基替加氟缀合物,通过三乙胺对环甘油硫代磷脂替加氟缀合物开环得到标题产物。结果得到新化合物9个(2a～c,3a～c,4a～c),其结构经IR,NMR和元素分析确证。结论体外活性测定表明,化合物4a对人体膀胱癌细胞的抑制效果比替加氟好。