- Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives
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The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs.
- Pereira, Glaécia A. N.,Souza, Gisele C.,Santos, Lourivaldo S.,Barata, Lauro E. S.,Meneses, Carla C. F.,Krettli, Antoniana U.,Daniel-Ribeiro, Cláudio Tadeu,Alves, Cláudio Nahum
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Read Online
- Chemical diversification of essential oils, evaluation of complex mixtures and identification of a xanthine oxidase inhibitor
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A set of chemically engineered essential oils has been generated through chemical diversification by reaction with bromine. The impact of the reaction over the chemical composition of the mixtures was qualitatively demonstrated through GC-MS and utilizing multivariate analysis of 1H NMR and GC-MS. Most of the components of the essential oils are transformed by the reaction expanding the chemical diversity of the mixtures. Biological changes between essential oils and brominated essential oils were demonstrated through image analysis of xanthine oxidase autography profiles. The highest biological activity increase was obtained for the Foeniculum vulgare Mill essential oil. Coupling of xanthine oxidase autography with the BIOMSID strategy allowed the identification of the molecular formula of the active compound. Bioguided fractionation of the mixture led to the isolation of (RS)-2-bromo-1-(4-methoxyphenyl) propan-1-one for being responsible for the observed bioactivity. This xanthine oxidase inhibitor could have been formed from the inactive natural component anethole. The inhibitory potency of this semisynthetic compound was in the same order of magnitude as allopurinol, the most used inhibitor.
- García,Ramallo,Salazar,Furlan
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Read Online
- Aldol-Tishchenko Reaction of α-Oxy Ketones: Diastereoselective Synthesis of 1,2,3-Triol Derivatives
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α-Oxy ketones, easily accessible by conventional routes, can be selectively deprotonated generating an enolate intermediate, which upon treatment with paraformaldehyde undergoes an aldol-Tishchenko reaction, leading to relevant 1,2,3-triol fragments in a totally diastereoselective manner. The excellent stereocontrol in the generation of a quaternary stereocenter is attributed to stereoelectronic effects in the Evans intermediate. This methodology allows overcoming some limitations of our previously reported strategy, based on the reaction of α-lithiobenzyl ethers with esters and paraformaldehyde, broadening the scope of the obtained polyols. Synthetic applications of this process include the preparation of a new dilignol model and some functionalized oxetanes.
- Sedano, Carlos,Virumbrales, Cintia,Suárez-Pantiga, Samuel,Sanz, Roberto
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supporting information
p. 3725 - 3734
(2021/07/02)
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- Reactivity of substrates with multiple competitive reactive sites toward NBS under neat reaction conditions promoted by visible light
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Regioselectivity of visible-light-induced transformations of a range of (hetero)aryl alkyl-substituted ketones bearing several competitive reactive sites (α-carbonyl, benzyl and aromatic ring) with N-bromosuccinimide (NBS) was studied under solvent-free reaction conditions (SFRC) and in the absence of inert-gas atmosphere, radical initiators and catalysts. An 8-W energy-saving household lamp was used for irradiation. Heterogeneous reaction conditions were dealt with throughout the study. All substrates were mono- or dibrominated at the α-carbonyl position, and additionally, some benzylic or aromatic bromination was observed in substrates with benzylic carbon atoms or electron-donating methoxy groups, respectively. Surprisingly, ipso-substitution of the acyl group with a bromine atom took place with (4-methoxynaphthyl) alkyl ketones. While the addition of the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxy) decreased the extent of α- and ring bromination, it completely suppressed the benzylic bromination and α,α-dibromination with NBS under SFRC.
- Grjol, Bla?,Jereb, Marjan
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p. 5235 - 5248
(2021/06/07)
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- Catalytic Lewis and Br?nsted acid syn-diastereoselective benzylic substitutions of α-hydroxy-β-nitro- and α-hydroxy-β-azido-alkyl arenes
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A series of alkyl and alkenyl p-methoxy arenes containing α,β-disubstituted diamino and amino alcohol groups were synthesized from β-nitro and β-azido benzylic alcohols in the presence of AuCl3 as catalyst. The formation of predominantly syn-disubstituted products were rationalized on the basis of mechanistic considerations and transition state models relying on A1,3-allylic strain. The products could have utility in the design of medicinally relevant compounds and as chiral ligands for asymmetric catalysis. A new synthesis of (+)-sertraline (Zoloft) was achieved.
- Chénard, étienne,Cusson, Jean-Philippe,Hanessian, Stephen,Hensienne, Rapha?l
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p. 292 - 306
(2020/06/17)
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- ESTROGEN RECEPTOR-MODULATING COMPOUNDS
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Described herein are compounds that are estrogen receptor modulators of formula I' Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
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Paragraph 000242; 000268
(2019/08/08)
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- Novel benzene-based carbamates for ache/bche inhibition: Synthesis and ligand/structure-oriented sar study
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A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl-and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl-compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure–activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host–target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.
- Bak, Andrzej,Kozik, Violetta,Kozakiewicz, Dariusz,Gajcy, Kamila,Strub, Daniel Jan,Swietlicka, Aleksandra,Stepankova, Sarka,Imramovsky, Ales,Polanski, Jaroslaw,Smolinski, Adam,Jampilek, Josef
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- Synthesis of α,β-dibromo ketones by photolysis of α-bromo ketones with N-bromosuccinimide: Photoinduced β-bromination of α-bromo ketones
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Irradiation of α-bromopropiophenones in the presence of NBS results in the formation of α,β-dibromopropiophenones, which can be viewed as β-bromination of α-bromopropiophenones. The reaction is believed to go through a series of reactions; photoinduced C–Br bond cleavage, elimination of HBr to give α,β-unsaturated ketone intermediates, and addition of Br2, which are formed by the reaction between HBr and NBS. From mechanistic studies of the reaction, we have also found a very convenient method for α-debromination of the α,β-dibromopropiophenones which is by simple irradiation of the dibromo ketones in acetone or 2-propanol without the use of any additives. Our results demonstrate that bromine can be added into or eliminated from the alpha, beta, or both positions to the carbonyl group by photochemical methods, which make synthetic options of bromine containing carbonyl compounds versatile.
- Moon, Da Yoon,An, Sejin,Park, Bong Ser
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- Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation
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The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.
- Chen, Wei,Guo, Renyu,Yang, Zhen,Gong, Jianxian
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p. 15524 - 15532
(2019/01/03)
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- Structure-activity relationships of talaumidin derivatives: Their neurite-outgrowth promotion in vitro and optic nerve regeneration in vivo
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(–)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan, shows potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection. Previously, we found that (–)-(1S,2R,3S,4R)-stereoisomer 2 exhibited more significant activity than did the natural product talaumidin (1). However, the preparation of optically active (–)-2 requires a complicated synthetic route. To explore new neurotrophic compounds that can be obtained on a large scale, we established a short step synthetic route for talaumidin derivatives and synthesized fourteen analogues based on the structure of (–)-2. First, we synthesized a racemic compound of (–)-2 (2a) and assessed its neurotrophic activity. We found that the neurotrophic property of racemic 2a is similar in activity to that of (–)-2. Using the same synthetic methodology, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. As a result, bis(methylenedioxybenzene) derivative 2b possessed the highest neurotrophic activity. Furthermore, examination of the structure-activity relationships of 2b revealed that the 2,5-diphenyl-tetrahydrofuran structure was an essential structure and that two methyl groups on THF ring could enhance neurotrophic activity. In addition, compounds 2a and 2b were found to induce mouse optic nerve regeneration in vivo.
- Harada, Kenichi,Zaha, Katsuyoshi,Bando, Rina,Irimaziri, Ryo,Kubo, Miwa,Koriyama, Yoshiki,Fukuyama, Yoshiyasu
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- Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C-Br/C-H Functionalization
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Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10-phenanthroline (1,10-Phen) ligand enables the formation of three new C-C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency.
- Ouyang, Xuan-Hui,Hu, Chao,Song, Ren-Jie,Li, Jin-Heng
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supporting information
p. 4659 - 4662
(2018/08/09)
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- Solvent free, light induced 1,2-bromine shift reaction of α-bromo ketones
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Photolysis of α-bromopropiophenones in acetonitrile results in formation of β-bromopropiophenones with good product selectivity, which can be coined as 1,2-Br shift reaction. The product selectivity increases when the reaction is done in neat or solid state, where only the 1,2-Br shift product is formed in some cases. The reaction is suggested to proceed by C–Br bond homolysis to give a radical pair, followed by disproportionation and conjugate addition of HBr to the α,β-unsaturated ketone intermediate. When the unsaturated intermediate is stabilized by an extra conjugation, the reaction stops at the stage, in which the unsaturated ketone becomes a major product. The synthetic method described in this research fits in a category of eco-friendly organic synthesis nicely since the reaction does not use volatile organic solvents and any other additives such as acid, base or metal catalysts, etc. Besides, the method fits into perfect atom economy, which does not give any side products. The synthetic method should find much advantage over other alternative methods to obtain β-bromo carbonyl compounds.
- An, Sejin,Moon, Da Yoon,Park, Bong Ser
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p. 6922 - 6928
(2018/10/24)
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- Enantioselective and Diastereoselective Construction of Chiral Amino Alcohols by Iridium-f-Amphox-Catalyzed Asymmetric Hydrogenation via Dynamic Kinetic Resolution
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The iridium-f-amphox-catalyzed asymmetric hydrogenation of racemic α-amino β-unfunctionalized ketones proceeds via a DKR (dynamic kinetic resolution) process for the construction of various chiral N,N-disubstituted α-amino β-unfunctionalized alcohols in quantitative yields with excellent enantioselectivities and diastereoselectivities (all products >99% ee and >99:1 dr, TON up to 100 000). Importantly, this catalytic asymmetric hydrogenation with a DKR process provided a highly efficient and powerful synthetic strategy for the preparation of key chiral intermediates of the preclinical antitumor agent (S,S)-R116010.
- Wu, Weilong,You, Cai,Yin, Congcong,Liu, Yuanhua,Dong, Xiu-Qin,Zhang, Xumu
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supporting information
p. 2548 - 2551
(2017/05/24)
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- Synthesis, characterization and in vitro anticancer activity of novel 8,4’-oxyneolignan analogues
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Neolignans are a class of natural products with a wide range of biological effects. These substances are of great synthetic and biological interest, especially in searching for novel anticancer agents. In this paper, we report the synthesis of a new subclass of 8,4’-oxyneolignan analogues (Β-ketoethers and Β-ketoesters) and their cell viability assay on twenty four different cancer cells, among leukemias and carcinomas. Three compounds inhibited the growth of most human cancer cells. 2-Oxo-2-phenylethyl(2E)-3-[4-(2-oxo-2-phenylethoxy) phenyl]prop-2-enoate showed an antiproliferative activity superior to doxorubicin for U-87, U-138 MG and H1299 cell types and (E)-2-oxo-2-phenylethyl 3-(3-methoxy-4-(2-oxo-2-phenylethoxy)phenyl)acrylate was found to be very selective, demonstrating a growth inhibition of 92.0% against KG-1 cells. Furthermore, 1-oxo-1-phenylpropan-2-yl cinnamate exhibited significant inhibition activity in a range of 52.2 to 91.2% against twelve kinds of leukemia cell lines, revealing excellent results and very comparable to the reference drug.
- Souza, Gisele C.,Franchi, Gilberto C.,Nowill, Alexandre E.,Santos, Lourivaldo S.,Alves, Cláudio N.,Barata, Lauro E.S.,Andrade, Carlos K. Z.
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p. 2229 - 2243
(2017/09/23)
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- Mechanistic study on iodine-catalyzed aromatic bromination of aryl ethers by N-Bromosuccinimide
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Although iodine-catalyzed reaction has rapid advances in recent years, examples on iodine-catalyzed bromination are rare and the mechanism of these reactions remains unclear. Herein, we reported an I2-catalyzed aromatic bromination of aryl ethers by NBS and presented the details of the mechanistic study including kinetic study and the study of kinetic isotope effects. The study revealed that the reaction was actually catalyzed by IBr formed in the induction period, and the rate-determining step was the HBr-elimination of the Wheland intermediate assisted by IBr.
- Pramanick, Pranab Kumar,Hou, Zhen-Lin,Yao, Bo
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p. 7105 - 7114
(2017/11/27)
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- Preparation method for high purity ritodrine hydrochloride
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The invention provides a preparation method for erythro form ritodrine hydrochloride shown as formula I. The method includes: subjecting a compound II and a bromination reagent to alpha bromination reaction to obtain a compound III, then conducting nucleophilic substitution with a compound IV to synthesize a compound V, performing deprotection to generate (1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propyl-1-one (VI), and then conducting reduction synthesis of ritodrine, performing splitting, and finally adding hydrochloric acid to form ritodrine hydrochloride. The method provided by the invention can significantly reduce the isomer impurity D, and can achieve efficient preparation of the medicinal purity product.
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Paragraph 0072-0075
(2018/03/28)
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- Phosphonic acid derivatives and application thereof
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The invention belongs to the field of medical chemistry, relates to phosphonic acid derivatives for treating virus infectious diseases and an application thereof, and in particular, relates to the compounds represented by the formula (I) or isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof, pharmaceutical compositions containing the compounds and an application of the compounds or the compositions in preparation of drugs for treating the virus infection diseases.
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Paragraph 0113; 0115; 0116
(2017/07/21)
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- Stereodivergent Synthesis of Chromanones and Flavanones via Intramolecular Benzoin Reaction
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The strategy of stereodivergent reactions on racemic mixtures (stereodivergent RRM) was employed for the first time in intramolecular benzoin reactions and led to the rapid access of chromanones/flavanones with two consecutive stereocenters. The easily separable stereoisomers of the products were obtained with moderate to excellent enantioselectivities in a single step. Catechol type additives proved crucial in achieving the desired diastereo- and enantioselectivities.
- Wen, Genfa,Su, Yingpeng,Zhang, Guoxiang,Lin, Qiqiao,Zhu, Yujin,Zhang, Qianqian,Fang, Xinqiang
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supporting information
p. 3980 - 3983
(2016/09/09)
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- Copper-catalyzed 1,2-addition of α-carbonyl iodides to alkynes
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β,γ-Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β-γ-unsaturated ketones through 1,2-addition of α-carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)-trichostatin A, a histone deacetylase inhibitor.
- Xu, Tao,Hu, Xile
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supporting information
p. 1307 - 1311
(2015/01/30)
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- Kinetic diastereomer differentiation in Au(III)- and Bi(III)-catalyzed benzylic arylation: Concise and stereocontrolled synthesis of 2-amino-1,1-diarylalkanes
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Benzylic alcohols carrying an adjacent α-nitro or α-azido group on the alkane chain are converted into syn-1,1-diaryl-2-nitro- and 2-azidoalkanes with electron-rich arenes in stereoselective reactions catalyzed by Bronsted and Lewis acids. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric α-substituted benzyl alcohols. Applications to therapeutically relevant syn- and anti- 2-amino-1,1-diarylalkanes are projected.
- Chenard, Etienne,Hanessian, Stephen
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supporting information
p. 2668 - 2671
(2014/06/09)
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- PYRAZOL-3-ONES THAT ACTIVATE PRO-APOPTOTIC BAX
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This application features pyrazol-3-one compounds that activate pro-apoptotic BAX. Also featured are methods of using such compounds, e.g., for the treatment or prevention of diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., insufficient apoptosis of diseased or damaged cells or essentially the absence of apoptosis of diseased or damaged cells).
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Page/Page column 36
(2013/04/25)
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- IMPROVED MODULATORS OF HEC1 ACTIVITY AND METHODS THEREFOR
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Compounds, compositions, and methods for modulation of Hec1/Nek2 interaction are provided. Such compounds disrupt Nek2/Hec1 binding and may be useful as chemotherapeutic agents for neoplastic diseases
- -
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Paragraph 00345
(2013/06/27)
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- Synthesis of phenacyl bromides via K2S2O 8-mediated tandem hydroxybromination and oxidation of styrenes in water
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Non-transition metal-catalyzed synthesis of phenacyl bromides was achieved through K2S2O8-mediated tandem hydroxybromination and oxidation of styrenes. The advantages of this reaction are its excellent functional group compatibility, mild reaction conditions (60 °C) and use of pure water as reaction medium. Based upon experimental observations, a plausible reaction mechanism is proposed.
- Jiang, Qing,Sheng, Wenbing,Guo, Cancheng
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p. 2175 - 2179
(2013/09/24)
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- Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors
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A series of arylalkanol-piperidine derivatives was synthesized, and their triple reuptake inhibition and in vivo activities have been evaluated. Among them, compounds 2a, 2j, 2k, 2m and 2n exhibited high potency for 5-HT, NA and DA transporters. Optimized compounds 2j and 2m showed significant reduction of immobility time compared to that of vehicle in the mouse tail suspension test (TST) test at doses ranging from 10 to 50 mg/kg po, and were not generally motor stimulants at 50 mg/kg dose. In addition, compounds 2j and 2m displayed desirable pharmacokinetic properties in SD rats.
- Zheng, Yong-Yong,Guo, Lin,Zhen, Xue-Chu,Li, Jian-Qi
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experimental part
p. 123 - 136
(2012/09/08)
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- Visible-light photoredox catalysis: Dehalogenation of vicinal dibromo-, α-halo-, and α,α-dibromocarbonyl compounds
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vic-Dibromo-, α-halo-, or α,α-dibromocarbonyl compounds can be efficiently dehalogenated using catalytic tris(2,2′-bipyridyl) ruthenium dichloride (Ru(bpy)3Cl2) in combination with 1,5-dimethoxynaphthalene (DMN) and ascorbate as sacrificial electron donor. For this process, a visible light promoted photocatalytic cycle is proposed that involves the reduction of carbon halogen bonds via free radical intermediates.
- Maji, Tapan,Karmakar, Ananta,Reiser, Oliver
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supporting information; experimental part
p. 736 - 739
(2011/03/20)
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- Modulators Of HEC1 Activity And Methods Therefor
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Compounds, compositions, and methods for modulation of Hec1/Nek2 interaction are provided. Especially preferred compounds disrupt Nek2/Hec1 binding and are therefore useful as chemotherapeutic agent for neoplastic diseases.
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Page/Page column 29
(2011/10/10)
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- Synthesis and investigations on the oxidative degradation of C3/C5-Alkyl-1,2,4-triarylpyrroles as ligands for the estrogen receptor
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In this study, we synthesized 1,2,4-triarylpyrroles as ligands for the estrogen receptor (ER). Two pyrrole series were prepared with either C3-alkyl or C3/C5-dialkyl residues. Compounds from both series were susceptible to oxidative degradation-dialkylated compounds (t1/2=33-66h) to a higher extent than their monoalkylated congeners (t1/2=140-211h). Nevertheless, stability was sufficient for determination of in vitro ER binding affinity. The most active agonist in hormone-dependent, ERα-positive MCF-7/2a and U2-OS/α cells was 1,2,4-tris(4-hydroxyphenyl)-3-propyl-1H-pyrrole (6d) (MCF-7/2a: EC50=70nM; U2-OS/α: EC50=1.6nM). A corresponding inactivity in U2-OS/β cells demonstrated the high ERα selectivity. This trend was confirmed in a competition experiment using estradiol (E2) and purified hERα and hERβ proteins (relative binding affinity (RBA) calculated for 6d: RBA(ERα)=1.85%; RBA(ERβ) 0.01%). Generally, C3/C5-dialkyl substitution led to reduction of activity, possibly due to lower stability. Triarylpyrroles with C3-alkyl or C3/C5-dialkyl residues were synthesized as ligands for the estrogen receptor (ER). The compounds exhibited transcription activation selectively for ERα but only marginally displaced estradiol from its binding site. The compounds were susceptible to oxidative degradation-dialkylated compounds to a higher extent than their monoalkylated congeners. The reasons for instability were elucidated; thus, by changing the substitution pattern, it will be possible to generate stable triarylpyrroles.
- Schaefer, Anja,Wellner, Anja,Gust, Ronald
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scheme or table
p. 794 - 803
(2012/01/06)
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- Substituted Phenylpiperazinyl Aralkylalcohol Derivatives, Pharmaceutical Compositions Containing Such Derivatives and Uses Thereof
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The invention relates to a substituted phenylpiperazine aryl alkanol derivative represented by the following general formula and its salt and hydrate, wherein C1 and C2 represent chiral carbon atoms, and the compound is one of the six isomers: (1RS, 2SR), (1RS, 2RS), (1R, 2S), (1S, 2S), (1R, 2R) or (1S, 2R); and R, R1, R2, R3 and Ar are as defined in the specification. The derivative is non-opioid analgesic, has good analgesic effect and relatively small side effects. The invention also relates to a composition comprising the derivative and its use.
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Page/Page column 14-15
(2011/12/13)
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- FUNGICIDAL PYRIDAZINES
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Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N-oxides, and salts thereof, wherein R1, R2, R3, R4, X, Y and m are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling plant disease caused by a fungal pathogen comprising applying an effective amount of a compound or a composition of the invention.
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Page/Page column 43
(2010/04/27)
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- Catalytic asymmetric cross-couplings of racemic α-bromoketones with arylzinc reagents
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(Chemical Equation Presented) Nickel box: The first catalytic asymmetric method for cross-coupling arylzinc reagents with α-bromoketones has been developed (see scheme). This stereoconvergent carbon-carbon bond-forming process occurs under unusually mild conditions and without activators, thereby allowing the generation of potentially labile tertiary stereocenters.
- Lundin, Pamela M.,Esquivias, Jorge,Fu, Gregory C.
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supporting information; experimental part
p. 154 - 156
(2009/04/07)
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- Chiral benzylic carbocations: Low-temperature NMR studies and theoretical calculations
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(Chemical Equation Presented) The α-chiral secondary and tertiary benzylic carbocations 19-30 were generated from the corresponding benzylic alcohols 1, 2, and 5-14 by treatment with FSO3H or FSO 3H/SbF5 in SO2ClF as the solvent at -70°C and characterized by one- and two-dimensional NMR spectroscopy. Coupling constants and NOESY measurements suggest a preferred conformation in which the α-hydrogen atom occupies the 1,3-allylic-strain position and the diastereotopic faces of the cations are differentiated by the alkyl substituent and a functional group (FG). The existence of this preferred conformation is further supported by calculations using a DFT method at the B3LYP/6- 311+G** level. Quenching experiments with an arene nucleophile showed a preferential attack from the less shielded diastereotopic face delivering high diastereomeric ratios, supporting the hypothesis that these carbocations are involved as intermediates in previously studied SN1 reactions. A strong shielding effect at the benzylic carbocationic center is observed for most of the secondary benzylic carbocations (derived from precursors 5-13) investigated, indicating a strong mesomeric distribution of the positive charge to the carbon atom in the para-position of the anisyl substituent. For α-halogen-substituted carbocations (5-7, 12), no neighboring halogen participation leading to halonium ion formation was observed.
- Stadler, Daniel,Goeppert, Alain,Rasul, Golam,Olah, George A.,Prakash, G. K. Surya,Bach, Thorsten
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supporting information; experimental part
p. 312 - 318
(2009/04/10)
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- 2,4,5-TRISUBSTITUTED THIAZOLE COMPOUNDS,PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS AND MEDICAL USES THEREOF
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The present invention relates to 2,4,5-trisubstituted thiazole compounds of formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof for the inhibition of plasma PLTP activity and/or plasma CETP activity, wherein the substituents are as defined in the specification; a process for the preparation of the compounds of formula (I); a pharmaceutical composition comprising the compound of formula (I) and its use for the preparation of a medicament for treatment and/or prevention of diseases associated with the increased plasma PLTP activity and/or the increased plasma CETP activity in a mammal, such as atherosclerosis, cardiovascular diseases and peripheral vascular diseases, etc.
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Page/Page column 46
(2009/04/23)
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- TRISUBSTITUTED THIAZOLE COMPOUNDS, PREPARATIONS METHODS, PHARMACEUTICAL COMPOSITIONS AND MEDICALS USES THEREOF
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The present invention relates to 2,4,5-trisubstituted thiazole compounds of formula (I) or all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof for the inhibition of plasma PLTP activity and/or plasma CETP activity, wherein the substituents are as defined in the specification; a process for the preparation of the compounds of formula (I); a pharmaceutical composition comprising the compound of formula (I) and its use for the preparation of a medicament for treatment and/or prevention of diseases associated with the increased plasma PLTP activity and/or the increased plasma CETP activity in a mammal, such as atherosclerosis, cardiovascular diseases and peripheral vascular diseases, etc.
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Page/Page column 32
(2009/12/23)
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- An expedient protocol for conversion of olefins to α-bromo/iodoketones using IBX and NBS/NIS
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A variety of olefins have been shown to undergo conversion to the corresponding α-bromo/iodoketones when reacted with NBS/NIS and IBX in DMSO at room temperature. While the reaction is found to occur rapidly with e-rich arylolefins leading to the corresponding haloketones in 65-95% yields in 0.3-3.0 h, those containing e-withdrawing groups are found to yield diketones concomitantly, such that the latter are the exclusive products over extended duration of the reactions.
- Moorthy, Jarugu Narasimha,Senapati, Kalyan,Singhal, Nidhi
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experimental part
p. 2493 - 2496
(2009/08/17)
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- 5-Aryl-imidazolin-2-ones as a scaffold for potent antioxidant and memory-improving activity
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A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.
- Watanabe, Kazutoshi,Morinaka, Yasuhiro,Hayashi, Yoshio,Shinoda, Masaki,Nishi, Hiroyoshi,Fukushima, Nobuko,Watanabe, Toshiaki,Ishibashi, Akira,Yuki, Satoshi,Tanaka, Masahiko
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p. 1478 - 1483
(2008/09/18)
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- NOVEL THIENOPYRIMIDINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel thienopyrimidine derivative having an excellent anti? inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. The compound according to the present invention strongly inhibits IKB kinase-β (IKK-β) involved in the activation of a transcriptional factor, NF-κB, which is associated with inducing various immune and inflammatory diseases, whereby a composition comprising the compound is a useful therapeutic agent against inflammatory diseases, in particular, arthritis and cancer.
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Page/Page column 71-72
(2010/11/28)
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- Structure-activity relationship study to understand the estrogen receptor-dependent gene activation of aryl- and alkyl-substituted 1H-imidazoles
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A series of C5-substituted 1,2,4-triaryl-1H-imidazoles was synthesized. Their gene-activating properties were determined on estrogen receptor alpha positive MCF-7 breast cancer cells, stably transfected with the plasmid ERE wtcluc (MCF-7-2a cells). The influence of 4-OH and 2-Cl substituents on the phenyl rings as well as the significance of a methyl, ethyl, or phenyl group at C5 on the estrogen receptor binding and the resulting gene activation in MCF-7-2a cells was studied. The alkyl and aryl groups at C5 of 1,2,4-tris(4-hydroxyphenyl)-1H-imidazole 1 increased the transactivation, while chlorine atoms on the phenyl rings diminished this effect. 5-Ethyl-1,2,4-tris(4- hydroxyphenyl)-1H-imidazole 9 was identified as the most active compound. Its excellent transcriptional activity did not only depend on the C5 ethyl group, but also on the three hydroxyl groups of the phenyl rings. Compounds (11-14) with a reduced number of hydroxyl groups displayed distinctly lower gene activation.
- Wiglenda, Thomas,Gust, Ronald
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p. 1475 - 1484
(2007/10/03)
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- CINNOLINE DERIVATIVES AS PHOSPHODIESTERASE 10 INHIBITORS
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The present invention is directed to certain cinnoline compounds of formula (I) that are PDE10 inhibitors, pharmaceutical compositions containing such compounds and process for preparing such compounds. The invention is also directed to methods of treating diseases treatable by modulation of PDE10 enzyme, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
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Page/Page column 49
(2010/11/28)
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- CINNOLINE AND QUINAZOLINE DERIVATES AS PHOSPHODIESTERASE 10 INHIBITORS
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The present invention is directed to cinnoline and quinazoline compounds of formula (I) that are PDE10 inhibitors, pharmaceutical compounds containing the same and processes for preparing the same. The invention is also directed to methods of treating diseases mediated by PDE10 enzyme such as obesity, non-insulin dependent diabetes, schizophrenia or bipolar disorder, obsessive-compulsive disorder, and the like.
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Page/Page column 51-52
(2010/11/28)
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- COMPOUND FOR INHIBITING TYROSINE KINASE ACTIVITY OF DDR2 PROTEIN
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A new furopyrimidine compound, their pharmaceutically acceptable salt, and a tyrosine kinase activity inhibitor. The furopyrimidine compound is a compound defined by chemical formula 1, 2, 3 or 4, on their precursor, and can exist as a form of free base or in an acid-addition salt. Since the furopyrimidine compound has an effect of inhibiting activity of DDR2 tyrosine kinase, it can be used in treating illnesses caused by the DDR2 tyrosine kinase activity such as hepatocirrhosis, rheumatoid arthritis or cancer.
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Page/Page column 28; 31
(2010/02/14)
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- Generation and reactivity of ketyl radicals with lignin related structures. On the importance of the ketyl pathway in the photoyellowing of lignin containing pulps and papers
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(Chemical Equation Presented) Ketyl radicals with lignin related structures have been generated by means of radiation chemical and photochemical techniques. In the former studies ketyl radicals are produced by reaction of α-carbonyl-β-aryl ether lignin models with the solvated electron produced by pulse radiolysis of an aqueous solution at pH 6.0. The UV-vis spectra of ketyl radicals are characterized by three main absorption bands. The shape and position of these bands slightly change when the spectra are recorded in alkaline solution (pH 11.0) being now assigned to the ketyl radical anions and a pKa = 9.5 is determined for the 1-(3,4,5-trimethoxyphenyl)-2- phenoxyethanol-1-yl radical. Decay rates of ketyl radicals are found to be dose dependent and, at low doses, lie in the range (1.7-2.7) × 103 s-1. In the presence of oxygen a fast decay of the ketyl radicals is observed (k2 = 1.8-2.7 × 109 M-1 s -1) that is accompanied by the formation of stable products, i.e., the starting ketones. In the photochemical studies ketyl radicals have been produced by charge-transfer (CT) photoactivation of the electron donor-acceptor salts of methyl viologen (MV2+) with α-hydroxy-α- phenoxymethylaryl acetates. This process leads to the instantaneous formation of the reduced acceptor (methyl viologen radical cation, MV+?), as is clearly shown in a laser flash photolysis experiment by the two absorption bands centered at 390 and 605 nm, and an acyloxyl radical [ArC(CO 2?)(OH)CH2(OC6H5)], which undergoes a very fast decarboxylation with formation of the ketyl radicals. Steady-state photoirradiation of the CT ion pairs indicates that 1-aryl-2-phenoxyethanones are formed as primary photoproducts by oxidation of ketyl radicals by MV2+ (under argon) or by molecular oxygen. Small amounts of acetophenones are formed by further photolysis of 1-aryl-2-phenoxyethanones and not by β-fragmentation of the ketyl radicals. The high reactivity of ketyl radicals with oxygen coupled with the low rates of β-fragmentation of the same species have an important bearing in the context of the photoyellowing of lignin containing pulps and papers.
- Fabbri, Claudia,Bietti, Massimo,Lanzalunga, Osvaldo
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p. 2720 - 2728
(2007/10/03)
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- Efficient microwave induced direct α-halogenation of carbonyl compounds
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A novel and direct method for the synthesis of α-halocarbonyl compounds using sequential treatment of carbonyl compounds with [hydroxy(tosyloxy)iodo]benzene followed by magnesium halides under solvent-free microwave irradiation conditions is described.
- Lee, Jong Chan,Park, Jin Young,Yoon, So Young,Bae, Yong Hun,Lee, Seung Jun
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p. 191 - 193
(2007/10/03)
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- N-aminoimidazole derivatives inhibiting retroviral replication via a yet unidentified mode of action
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The synthesis of a series of N-aminoimidazoles (NAIMs) with an uncommon spectrum of antiretroviral activity is described. From a group of 60 closely related molecules, we were able to subdivide the molecules in different groups based on their anti-HIV and anti-SIV activity in vitro: (i) molecules acting on a new, immediate postintegration step, (ii) molecules acting on both postintegration and HIV-1 reverse transcriptase (RT) as NNRTI, and (iii) molecules that mainly act at the HIV-1 RT according to an NNRTI-type mode of action.
- Lagoja, Irene M.,Pannecouque, Christophe,Van Aerschot, Arthur,Witvrouw, Myriam,Debyser, Zeger,Balzarini, Jan,Herdewijn, Piet,De Clercq, Erik
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p. 1546 - 1553
(2007/10/03)
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- Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: A novel series of potent dual PDE3/PDE4 inhibitory agents
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In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,-8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC50 = 7.0-8.7), whereas the pIC50 values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30μmol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.
- Van der Mey, Margaretha,Bommelé, Kirsten M.,Boss, Hildegard,Hatzelmann, Armin,Van Slingerland, Mike,Sterk, Geert J.,Timmerman, Hendrik
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p. 2008 - 2016
(2007/10/03)
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- Estrogenic diazenes: Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes
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Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.
- Ghosh, Usha,Ganessunker, Deshanie,Sattigeri, Viswajanani J.,Carlson, Kathryn E.,Mortensen, Deborah J.,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.
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p. 629 - 657
(2007/10/03)
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- Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein Ar, B, R1, R2, R3a, R3b, R4, R5, R6and m are as defined herein.
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Page column 29-30
(2010/01/30)
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- Initial structure-activity relationship studies of a novel series of pyrrolo[1,2-a]pyrimid-7-ones as GnRH receptor antagonists
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Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2-a]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM (Ki) binding affinity to human GnRH receptor.
- Zhu, Yun-Fei,Struthers,Connors, Jr., Patrick J.,Gao, Yinghong,Gross, Timothy D.,Saunders, John,Wilcoxen, Keith,Reinhart, Greg J.,Ling, Nicholas,Chen, Chen
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p. 399 - 402
(2007/10/03)
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- Synthesis and biological evaluation of a novel series of furans: Ligands selective for estrogen receptor α
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A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subtypes, ERα or ERβ. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavior as ER ligands. An aldehyde enone conjugate addition approach and an enolate alkylation approach were developed to prepare the 1,4-dione systems that were precursors to the trisubstituted and tetrasubstituted systems, respectively. All of the diones were easily converted into the corresponding furans, but formation of the thiophenes and pyrroles from the more highly substituted 1,4-diones was problematical. Of the systems investigated, the tetrasubstituted furans proved to be most interesting. They were ERα bindingand potency-selective agents, with the triphenolic 3-alkyl-2,4,5-tris(4-hydroxyphenyl)furans (15a-d) displaying generally higher subtype binding selectivity than the bisphenolic analogues (15f-i). Binding selectivity for ERα was as high as 50-70-fold, and transcriptional activation studies showed that several members of this series were ERα selective agonists, with the best compound [3-ethyl-2,4,5-tris(4-hydroxyphenyl)furan, 15b] having full transcriptional activity on ERα while being inactive on ERβ. Comparative binding affinity analysis and molecular modeling were used to investigate the preferred binding mode adopted by the furan ligands, which appears to have the C(2) phenol mimicking the important role of the A-ring of estradiol. These ligands should be useful in studying the biological roles of both ERα and ERβ, and they might form the basis for the development of novel estrogen pharmaceuticals.
- Mortensen,Rodriguez,Carlson,Sun,Katzenellenbogen,Katzenellenbogen
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p. 3838 - 3848
(2007/10/03)
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- 2-phenylindoles as antiestrogenic pharmaceutical agents
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PCT No. PCT/EP95/03000 Sec. 371 Date May 14, 1997 Sec. 102(e) Date May 14, 1997 PCT Filed Jul. 27, 1995 PCT Pub. No. WO96/03375 PCT Pub. Date Feb. 8, 1996Novel 2-phenyl indoles are disclosed of general formula (I), wherein: R1 represents one of the rests -(CH2)n-S(O)m-R4, -(CH2)n-NR6-SO2-R4, (a), and n' being integers between 4 and 12 and m and m' are 0, 1 or 2; X represents a methylene group, an imino group =NR6, or an oxygen or sulphur atom; R2 and R3 independently of one another represent a hydrogen atom, a C1-C10 alkyl group, a benzyl, alkanoyl or alkanoyloxy, or carbarnoyl rest of formula -C(O)R5 or -C(O)NR6R7 or a tetrahydropyranyl group; R4 represents a hydrogen atom, a C1-C10 alkyl, a completely or partially fluorinated alkyl group -(CH2)o-(CF2)pCF3, o and p being independently of one another integers between 0 and 6, an (alkyl)amino or (alkyl)carbamoyl group of formula (CH2)q-Y-NR8R9, q being an integer between 0 and 6 and Y representing a direct bond, a methylene or carbamoyl group (a condition being that q cannot be 0 when Y is a carbonyl group and m is 2), an aryl, aralkyl or heteroaryl group; R5 represents a C1-C10 alkyl group or a C1-C10 alkoxy group, a phenyl or benzyl group; R6, R7, R8 and R9 independently of one another represent a hydrogen atom, a C1-C10 alkyl group, or a benzyl group; and R10 represents a methyl group and R11 represents a hydrogen atom, or R10 and R11 both represent a di-, tri- or tetramethylene bridge which can also have a C-C double bond at any location in the bridge. These novel compounds have strong and selective anti-oestrogen properties and are suitable for use in particular in the treatment of oestrogen-related diseases.
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- Enantioselective synthesis of α-bromo acid derivatives and bromohydrins from tartrate derived bromoacetals
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Bromination of the acetals 4 derived from aryl alkyl ketones, ArCOR, and (2R,3R)-tartaric acid results in bromoacetals 5 with 78-90% de. Hydrolysis of those compounds with Ar = 4-methoxyphenyl or 3-bromo-4-methoxyphenyl results, after recrystallisation, in α-bromoketones 8 with 66-98% ee which are shown to undergo the Baeyer-Villiger oxidation to α-bromoesters 9 with minimal racemisation, α-Bromoketone 8d is shown to undergo carbonyl reduction to threo-bromohydrin 15 with retention of stereochemistry.
- Boyes, Scott A.,Hewson, Alan T.
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p. 2759 - 2765
(2007/10/03)
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