Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3h-cycloheptimidazol-4-ones and 2-alkyl-3h-cycloheptimidazol-4-ones

Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (1) and 2-alkyl-3H-cycloheptimidazol-4-one (2) was investigated. 3-[2'-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-1H-cycloheptimidazol-4-one (6) was preferentially obtained under the conditions by using NaH in DMF or THF. On the other hand, 3-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (5), the synthetic intermediate compound of Pratosartan, was obtained selectively in the presence of n-Bu(4)NBr in toluene by using aqueous sodium hydroxide as a base. In this reaction, it was found that the concentration of the alkaline solution influences its regioselectivity. This selectivity was observed even for aldehyde and ester derivatives.     

Synthesis and pharmacological activity of the metabolites of Pratosartan

Three hydroxylated metabolites of 2-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (Pratosartan), which is a selective angiotensin II receptor antagonist, were synthesized in confirmation of their structures and in studies of their pharmacological properties. An MTPA ester of the human main metabolite was identified with the synthesized compound by comparing (1)H-NMR spectra, MS spectra, and HPLC retention time. The structure of the human main metabolite was confirmed to be (S)-(-)-2-(1-hydroxypropyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one ((S)-(-)-1). Also, the rat main metabolites were confirmed to be 8-hydroxylated compound (2) and 5-hydroxylated compound (3). These metabolites showed lower antagonistic activity than that of the parent compound.     

Novel asymmetric dihetarylethenes derived from N-isopropylindole and thiophene: synthesis and photochromic properties

Novel asymmetric dihetarylethenes, viz., 3-(1-isopropyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)furan-2,5-dione and 1-alkyl/aryl-3-(1-isopropyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)-1H-pyrrole-2,5-diones, were obtained. These dihetarylethenes exhibit photochromism in solutions. Replacement of the N-methyl group in the indole fragment by the N-isopropyl group imparts photochromic properties to the resulting furan-2,5-dione derivative. The open forms of (N-isopropylindol-3-yl)pyrrole-2,5-diones are characterized by lower quantum yields of fluorescence, and their cyclic forms are thermally more stable.     

Comments on the ring-opening polymerization of morpholine-2,5-dione derivatives by various metal catalysts and characterization of the products formed in the reactions involving R2SnX2, where X = OPr(i) and NMe2 and R = Bu(n), Ph and p-Me2NC6H4

(3S,6S)-3-Isopropyl-6-methyl-morpholine-2,5-dione (1), and (3S,6S)-3,6-dimethyl-morpholine-2,5-dione (2), do not enter into ring-opening polymerization reactions with metal catalyst precursors commonly employed for lactides, and with Sn(II) octanoate, only low molecular weight oligomers are obtained. Reactions with R2SnX2 compounds, where R = Ph, Bu(n) and p-Me2NC6H4 and X = OPr(i) or NMe2, reveal that ring-opening of the morpholine-2,5-diones does occur, but that polymerization is terminated by the formation of kinetically-inert products such as {Ph2Sn[mu,eta(3)-OCH(Me)CONCH(Pr(i))COOPr(i)]}2 (3), and {[Bu(n))2Sn[mu,eta(3)-OCH(Me)CONCH(Me)CONMe2]}2 (4), with elimination of HX. Ph3SnOPr(i) is seen to react reversibly with morpholine-2,5-diones in toluene-d8 by 1H NMR spectroscopy while (Bu(n))3SnNMe2 reacts by ring opening to give (Bu(n))3SnOCH(Me)C(O)NHCHMeC(O)NMe2. The new organotin compounds have been characterized by 1H, 13C{1H} and 118Sn NMR spectroscopy and compounds 1, 2, 3 and 4 by single crystal X-ray crystallography.     

A new unusual natural pigment from Selaginella sinensis and its noticeable physicochemical properties

A new unusual pigment with a novel carbon framework named selaginellin (1) was isolated from the acetone extract of Selaginella sinensis, and its methoxy derivative (1a) was synthesized. Both selaginellin 1 and 1a are racemic compounds. The structure of selaginellin 1 was established as (R,S)-4-[(4'-hydroxy-4-(hydroxymethyl)-3-((4-hydroxyphenyl)ethynyl)biphenyl-2-yl)(4-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one and 1a as (R,S)-4-[(4'-methoxy-4-(methoxymethyl)-3-((4-methoxyphenyl)ethynyl)biphenyl-2-yl)(4-methoxyphenyl)methylene]-2,5-cyclohexadien-1-one by the analysis of one- and two-dimensional NMR data, HR-ESIMS, EI-MS, IR, UV, CD, and single-crystal X-ray experiments, and the mechanism of their color change according to different pH values and fluorescent properties was studied.     

Rhenium tricarbonyl core complexes of thymidine and uridine derivatives

Thymidine and uridine were modified at the C2' and C5' ribose positions to form amine analogues of the nucleosides (1 and 4). Direct amination with NaBH(OAc)3 in DCE with the appropriate aldehydes yielded 1-{5-[(bis(pyridin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L1), 1-{5-[(bis(quinolin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L2), and 1-[3-(bis(pyridin-2-ylmethyl)amino)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-pyrimidine-2,4-dione (L5), while standard coupling procedures of 1 and 4 with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (2) and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid (3) in the presence of HOBT-EDCI in DMF provided a second novel series of bifunctional chelators: 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L3), 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L4), 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L6), and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L7). The rhenium tricarbonyl complexes of L1-L4, L6, and L7, [Re(CO)3(LX)]Br (X=1-4, 6, 7: compounds 5-10, respectively), have been prepared by reacting the appropriate ligand with [NEt4][Re(CO)3Br3] in methanol. The ligands and their rhenium complexes were obtained in good yields and characterized by common spectroscopic techniques including 1D and 2D NMR, HRMS, IR, cyclic voltammetry, UV, and luminescence spectroscopy and X-ray crystallography. The crystal structure of complex 6.0.5NaPF6 displays a facial geometry of the carbonyl ligands. The nitrogen donors of the tridentate ligand complete the distorted octahedral spheres of the complex. Crystal data: monoclinic, C2, a = 24.618(3) A, b = 11.4787(11) A, c = 15.5902(15) A, beta = 112.422(4) degrees , Z = 4, D(calc) = 1.562 g/cm3.     

4-(5-喹啉-3-基-四氮唑-2-基)丁胺的合成

三苯基膦钯催化3-溴喹啉完成氰化取代制得3-氰喹啉(1);1与叠氮化钠经[2+3]环加成合成了3-(2H-四氮唑-5-基)喹啉(2);2与N-(4-溴丁基)邻苯二甲酰亚胺反应制得2-[4-(5-喹啉-3-基-四氮唑-2-基)丁基]异吲哚-1,3-二酮(3);3经肼解合成了4-(5-喹啉-3-基-四氮唑-2-基)丁胺(4...     

Synthesis and pharmacological evaluation of 5-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine derivatives as platelet aggregation inhibitors

One pot synthesis and characterization of new 5-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridines (3a–k) using amides (2a–k) were reported. The prepared 5-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (3a) is a bioisostere of 4′-(6,7-dihydro-4H-thieno [3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic acid (1), having good in vivo antithrombotic activity compared with Clopidogrel. The new tetrazole derivatives (3a–k) were screened for their in vitro activity as platelet aggregation inhibitors.     

酰氨基硫脲及其相关杂环衍生物的研究——ⅩⅤ.3-[5-(3-吡啶)-四唑-2-亚甲基]-4-芳基-1,2,4-三唑-5-烃硫醚类化合物的合成及其抗菌活性

以3-〔5-(-3吡啶)-四唑-2-亚甲基〕-4-芳基-1,2,4-三唑-5-硫酮为原料合成了19个3-〔5-(3-吡啶)-四唑-2-亚甲基〕4-芳基-1,2,4-三唑-5-烃硫醚类合化物,经元素分析、红外、核磁以及质谱确定了其结构,观察了化合物对枯草芽抱杆菌、大肠杆菌、变形杆菌以及金黄色葡萄菌的抑制,其中以化合物3_(α-k)的抑制活性最强。     

从细脚拟青霉分离的新环二肽与新十元环内酯

利用反相色谱、 凝胶色谱和硅胶色谱从细脚拟青霉发酵液中分离得到4个活性化合物. 通过核磁共振波谱、 质谱、 X射线晶体衍射分析和理化数据鉴定化合物1为新环二肽[(3S)-6-苯乙基-3-异丙基-1-甲基-2,5-二酮哌嗪], 化合物2为新十元环内酯[(4S,10R)-4-羟基-8-氧代-10-甲基癸内酯], 化合物3为Cepharosporolide C, 化合物4为Cepharosporolide E. 细胞毒性实验结果表明, 5 μmol/L的化合物1对前列腺癌细胞22RV1和DU-145的抑制率分别为37.8%和38.6%, 5 μmol/L的化合物2对前列腺癌细胞22RV1和DU-145的抑制率分别为32.5%和40.6%, 具有一定抗肿瘤活性.     

Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions

The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range.     

Stepwise unidirectional synthesis of oligo phenylene vinylenes with a series of monomers. Use in plastic solar cells

Four new monomers for directional stepwise synthesis of oligophenylenevinylenes (OPVs) (4-{2-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2,5-dipropoxyphenyl]vinyl}benzyl)phosphonic acid diethyl ester, (5-{2-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2,5-dipropylphenyl]vinyl}thiophene-2-ylmethyl)phosphonic acid diethyl ester, (5-{2-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2,5-dipropoxyphenyl]vinyl}thiophene-2-ylmethyl)phosphonic acid diethyl ester, and (7-{2-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2,5-dipropylphenyl]vinyl}benzo[1,2,5]thiadiazol-4-ylmethyl)phosphonic acid diethyl ester have been prepared. Trimeric OPVs were then synthesized and tested as active materials in photovoltaic cells. Conversion efficiencies in the range of 0.5-1% were obtained in blends with the soluble C(60) derivative PCBM. A terpyridine end-functionalized trimer and a heterotrimer with a mixed composition of monomers were also prepared.     

钌配合物[Ru(bpy)2(PNT)]2+的合成、表征及与DNA相互作用研究

以cis-Ru(bpy)2Cl2·2H2O与PNT为原料合成钌(Ⅱ)多吡啶配合物[Ru(bpy)2(PNT)]2+(bpy=2,2’-联吡啶, PNT=2-[4’-(5-四唑基)苯基]咪唑-[4,5-f][1,10]邻菲咯啉), 通过元素分析、质谱和核磁共振波谱对该化合物进行了结构表征. 利用紫外-可见吸收光谱、荧光光谱、热变性和黏度实验研究了配合物与CT-DNA的相互作用, 实验结果表明, 该配合物以部分插入模式与DNA结合.     

Synthesis and pharmacological activity of urea and thiourea derivatives of 4-azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione

A series of nineteen new thiourea and urea derivatives of 10-isopropyl-8-methyl-4-azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione, 1-isopropyl-7-methyl-4-azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione and 1,7,8,9,10-pentamethyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared and studied by (1)H-NMR. The compound k1a (1-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-aza-tricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)-3-phenyl-urea) was tested for pharmacological activity on animal central nervous system (CNS). The activities of synthesized compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells. Antimicrobial activity of the newly obtained derivatives was tested against some Gram-positive and Gram-negative bacteria and fungi of the Candida species.     

Cyclization of vicinally substituted heterocyclic analogs of 3,4-bis(indol-1-yl)maleimide under the action of protic acids: a quantum chemical study

B3LYP/6-31G(d) density functional quantum chemical calculations of vicinally substituted bis(indol-1-yl)derivatives of 1,5-dihydropyrrol-2-one, furan-2,5-dione, cyclopent-4-ene-1,3-dione, cyclobut-3-ene-1,2-dione, and pyrrolidine-2,5-dione were carried out to study the effect of modification of the maleimide moiety in 3,4-bis(indol-1-yl)maleimides on the direction of intramolecular cyclization under the action of protic acids. Geometric parameters, charge distributions, energy characteristics, and frontier orbital energies of these compounds and the corresponding indoleninium cations were determined. Alternative protonation routes of 3,4-bis(indol-1-yl)-1,5-dihydropyrrol-2-one have been studied. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1348–1352, July, 2008.     

New photochromic symmetrical and unsymmetrical bis(heteroaryl)maleimides: A spectrokinetic study

The photochromic behavior of two newly synthesized diarylethenes is here presented. The compounds studied are the symmetrical (1-benzyl-3,4-bis(2-methylbenzo[b]thiophen-3-yl)-[1H]-2,5-dihydropyrrol-2,5-dione) and the unsymmetrical (1-benzyl-3-(2-methylbenzo[b]thiophen-3-yl)-4-(2,5-dimethyl-3-thienyl)-[1H]-2,5-dihydropyrrol-2,5-dione). Upon stimulation with UV or violet light, these compounds become red-colored due to photocyclization and cyclorevert to the light yellow open form upon irradiation with visible light. In this work, absorption and fluorescence spectra, molar absorption coefficients of the ethenic and cyclized forms, fluorescence quantum yields and photochemical quantum yields of both the forward and back photoreactions were determined. Temperature, excitation wavelength and solvent effects were explored. The symmetrical compound was found to be a bistable photochrome. In contrast, the unsymmetrical molecule resulted unsuitable as photochrome because of side degradation processes occurring in competition with cyclization.     

Structures and photochromic properties of fulgides based on naphtho[1,2-<Emphasis Type="Italic">b</Emphasis>]furan and benzo[<Emphasis Type="Italic">g</Emphasis>]indole

The novel heterocyclic fulgides, i.e. 3-isopropylidene-4-{1-[5-methoxy-1-(4-methoxy-phenyl)-2-methyl-1H-benzo[g]indol-3-yl]ethylidene}dihydrofuran-2,5-dione and 3-isopropylidene-4-[1-(1-benzyl-5-methoxy-2-methyl-1H-benzo[g]indol-3-yl)ethylidene]dihydrofuran-2,5-dione, were prepared and isolated as E-isomers. Photochromism, E-configuration, and high resistance to photocoloration—photobleaching of solutions of these fulgides as well as 3-isopropylidene-4-[1-(5-methoxy-2-methylnaphtho[1,2-b]furan-3-yl)ethylidene]dihydro-furan-2,5-dione and 3-isopropylidene-4-[1-(5-methoxy-2-methyl-1-phenyl-1H-benzo[g]indol-3-yl)ethylidene]dihydrofuran-2,5-dione synthesized previously were shown by X-ray diffraction analysis, ¹H NMR spectroscopy and electronic absorption spectroscopy. The novel fulgides show fluorescence and high thermal stability of photogenerated cyclic form. Repeated photo-coloration—photobleaching is accompanied by reversible photoinduced E—Z isomerization. Benzo[g]indolyl fulgides are characterized by the longer wavelength absorption of both original (E) and photoisomeric cyclic (C) forms as compared to naphthofuran fulgide.     

Selaginellin A and B, two novel natural pigments isolated from Selaginella tamariscina

Two new unusual natural pigments were first isolated from the whole herbs of Selaginella tamariscina. The structure of selaginellin A (1) was established as (R,S)-4-[(4'-hydroxy-3-((4-hydroxyphenyl)ethynyl)biphenyl-2-yl)(4-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one and selaginellin B (2) as (R,S)-4-[(4'-methoxy-4-(methyl)-3-((4-methoxyphenyl)ethynyl)biphenyl-2-yl)(4-methoxyphenyl)methylene]-2,5-cyclohexadien-1-one, along with four known biflavonoids, amentoflavone (3), hinokiflavone (4), heveaflavone (5), and 7'-O-methylamentoflavone (6). Their chemical structures were elucidated by spectral analysis of electrospray ionization mass spectroscopy (ESI-MS), one-dimensional nuclear magnetic resonance spectroscopy (1D-NMR) and two-dimensional-nuclear magnetic resonance spectroscopy (2D-NMR) including (1)H-NMR, (13)C-NMR, distortionless enhancement by polarization transfer (DEPT) and heteronuclear multiple bond coherence (HMBC), and single-crystal X-ray diffraction techniques.     

Homologues of p-Menthane Derivatives in Roman Camomile

5-Isopropyl-2-propyl-2-cyclohexen-1-one ( 1 ) and 5-isopropyl-2-(2-methylpropyl)-2-cyclohexen-1-one ( 2 ), homologues of the p-methene ketone carvotanacetone, have been identified in the oil of Anthemis nobilis. Their synthesis involved allylation of a cyclohexane-1,3-dione, and the acid-catalyzed cyclization to dihydrofurans of the 2-allylcyclohexane-1,3-diones is described. The stereochemistry of metal hydride reduction of 3-ethoxy-5-isopropyl-2-propyl-2-cyclohexen-1-one ( 18 ) is mentioned in the course of the synthesis of the natural products. Some biogenetic considerations are discussed.     

Three new 2,5-diketopiperazines from the fish intestinal Streptomyces sp. MNU FJ-36

The gut actinobacteria of marine-inhabited fish is one of the most important reservoirs of novel natural products. Currently, the Streptomyces sp. MNU FJ-36 was isolated from the intestinal fabric of Katsuwonus sp. and determined by 16S rRNA analysis. From the cultures of the S. sp. MNU FJ-36, three new 2,5-diketopiperazines (2,5-DKPs) were discovered and identified as 3-(3-hydroxy-4-methoxybenzyl)-6-isobutyl-2,5-diketopiperazine (1), 3-(1,3-benzodioxol-5-ylmethyl)-6-isobutyl-2,5-diketopiperazine (2) and 3-(1,3-benzodioxol-5-ylmethyl)-6-isopropyl-2,5-diketopiperazine (3). Their structures were elucidated on the basis of spectroscopic data analysis. All the compounds were also evaluated for their inhibitory activity against P388, A-549 and HCT-116 cell lines with the MTT assay.