- Synthesis and biological activities of some Novel 2-Amino-(5 or 7-Substituted- 2-Oxoindolin-3-Ylidene) Benzoxazole-5-Carbohydrazide derivatives
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A series of 2-amino-(5 or 7-substituted-2-oxoindolin-3-ylidene) benzoxazole-5-carbohydrazide derivatives were synthesized by treating 2-aminobenzoxazole-5-carbohydrazide with different substituted isatins. All the synthesized derivatives (VI a-l) were screened for their in vitro anticancer (against HeLa, IMR-32 & MCF-7 cancer cell lines), antioxidant (against DPPH radicals) and antimicrobial activities. The results of these studies showed the dose dependant anticancer, antioxidant and antimicrobial activities of the test compounds and the IC50 values of some compounds were comparable with their standard agent. The test compounds having substitution with different electron withdrawing groups at C-5 position showed more potent anticancer, antioxidant and antibacterial activities than those at C-7 position.
- Rajyalakshmi,Reddy, A. Rama Narsimha,Sarangapani
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Read Online
- Sulfatase-cleavable linkers for antibody-drug conjugates
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Antibody-drug conjugates (ADCs) are a class of targeted drug delivery agents combining the cell-selectivity of monoclonal antibodies (mAbs) and the cytotoxicity of small molecules. These two components are joined by a covalent linker, whose nature is critical to the efficacy and safety of the ADC. Enzyme-cleavable dipeptidic linkers have emerged as a particularly effective ADC linker type due to their ability to selectively release the payload in the lysosomes of target cells. However, these linkers have a number of drawbacks, including instability in rodent plasma and their inherently high hydrophobicity. Here we show that arylsulfate-containing ADC linkers are cleaved by lysosomal sulfatase enzymes to tracelessly release their payload, while circumventing the instability problems associated with dipeptide-linkers. When incorporated with trastuzumab and the highly potent monomethyl auristatin E (MMAE) payload, the arylsulfate-containing ADC 2 and ADC 3 were more cytotoxic than the non-cleavable ADC 4 against HER2-positive cells, while maintaining selectivity over HER2-negative cells. We propose that the stability, solubility and synthetic tractability of our arylsulfate linkers make them an attractive new motif for cleavable ADC linkers, with clear benefits over the widely used dipeptidic linkers.
- Bargh, Jonathan D.,Carroll, Jason S.,Isidro-Llobet, Albert,Omarjee, Soleilmane,Spring, David R.,Walsh, Stephen J.
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Read Online
- Heterocyclic substituted biphenyl compound as well as preparation method and application thereof
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The invention discloses a heterocyclic substituted biphenyl compound as well as a preparation method and application thereof. According to the present invention, the compound can block the PD-1/PD-L1 signal pathway, and can be used as the immune checkpoint PD-1/PD-L1 small molecule inhibitor; and according to the compound disclosed by the invention, the metabolic stability is improved while the high binding rate with PD-L1 protein is maintained. A hydrophilic group is introduced to a heterocyclic ring, and the PD-1/PD-L1 inhibitory activity is improved.
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Paragraph 0296; 0298; 0301-0302
(2021/08/28)
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- Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors
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Fe(II)/α-ketoglutarate-dependent lysine demethylases (KDMs) are attractive drug targets for several diseases including cancer. In this study, we designed and screened ortho-substituted anilides that are expected to function as Fe(II) chelators, and identified ortho-hydroxy anilide as a novel scaffold for KDM5A inhibitors. Treatment of human lung cancer A549 cells with a prodrug form of 4-carboxy-2-hydroxy-formanilide (9c) increased trimethylated lysine 4 on histone H3 level, suggesting KDM5 inhibition in the cells.
- Jaikhan, Pattaporn,Buranrat, Benjaporn,Itoh, Yukihiro,Chotitumnavee, Jiranan,Kurohara, Takashi,Suzuki, Takayoshi
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supporting information
p. 1173 - 1176
(2019/03/29)
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- Synthesis, Structure Revision, and Cytotoxicity of Nocarbenzoxazole G
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The total synthesis of nocarbenzoxazoles F (1) and G (2), originally obtained from the marine-derived halophilic bacterial strain Nocardiopsis lucentensis DSM 44048, was achieved via a simple and versatile route involving microwave-assisted construction of a benzoxazole skeleton, followed by carbon-carbon bond formation with the corresponding aryl bromides. Unfortunately, the 1H and 13C NMR spectra of natural nocarbenzoxazole G did not agree with those of the synthesized compound. In particular, the spectra of the isolated and synthesized compounds showed considerable differences in the signals from the protons and carbons in the aryl group. The revised structure was validated by the total synthesis of the actual nocarbenzoxazole G (8c) molecule, which is a regioisomer of the compound that was reported earlier as nocarbenzoxazole G. The synthesized derivatives showed specific cytotoxicity to the human cervical carcinoma cell line, HeLa, but did not have any remarkable effect on the other cell lines.
- Kim, Taejung,Lee, Sin-Ae,Noh, Taesub,Choi, Pilju,Choi, Seon-Jun,Song, Bong Geun,Kim, Youngseok,Park, Young-Tae,Huh, Gyuwon,Kim, Young-Joo,Ham, Jungyeob
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p. 1325 - 1330
(2019/05/04)
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- Design, synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors
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We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC50 = 31 μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50 = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3h in vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.
- Shibuya, Kimiyuki,Kawamine, Katsumi,Miura, Toru,Ozaki, Chiyoka,Edano, Toshiyuki,Mizuno, Ken,Yoshinaka, Yasunobu,Tsunenari, Yoshihiko
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p. 4001 - 4013
(2018/06/26)
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- HEPATITIS B CORE PROTEIN MODULATORS
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The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound of formula:
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Page/Page column 103; 104
(2018/04/13)
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- High Performance and Active Sites of a Ceria-Supported Palladium Catalyst for Solvent-Free Chemoselective Hydrogenation of Nitroarenes
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Cerium oxide-supported palladium catalysts (Pd/CeO2) prepared by a simple impregnation method exhibit exciting catalytic activity and high chemoselectivity for the solvent-free hydrogenation of a variety of substituted nitroarenes including the reducible functional groups to the corresponding aromatic amines under mild reaction conditions. Taking nitrobenzene as an example, the Pd/CeO2 catalyst can afford aniline yields of >99 % with turnover frequencies as high as 11 411 h?1 and 69 824 h?1 at 40 °C and 100 °C, respectively. Pd2+ ion species exist as isolated single atoms with ?Pd2+?O2??Ce4+? linkages on the surface of PdxCe1?xO2?σ solid solution and are found to be active sites for the selective hydrogenation of nitroarenes in the absence of solvent. The superior catalytic performance can be attributed to the cooperative effect between Pd2+ ions and unique surface sites of CeO2. A possible mechanism is proposed for the hydrogenation of nitroarenes with H2 over the Pd/CeO2. The Pd/CeO2 catalyst can be recovered easily and reused for at least seven recycling reactions without loss of catalytic properties.
- Shi, Xiuxiu,Wang, Xueguang,Shang, Xingfu,Zou, Xiujing,Ding, Weizhong,Lu, Xionggang
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p. 3743 - 3751
(2017/10/16)
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- Design, Synthesis, and in Vitro and in Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer
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Sphingosine 1-phosphate receptor 1 (S1P1) plays a pivotal signaling role in inflammatory response; because S1P1 modulation has been identified as a therapeutic target for various diseases, a PET tracer for S1P1 would be a useful tool. Fourteen fluorine-containing analogues of S1P ligands were synthesized and their in vitro binding potency measured; four had high potency and selectivity for S1P1 (S1P1 IC50 100-fold selectivity for S1P1 over S1P2 and S1P3). The most potent ligand, 28c (IC50 = 2.63 nM for S1P1) was 18F-labeled and evaluated in a mouse model of LPS-induced acute liver injury to determine its S1P1-binding specificity. The results from biodistribution, autoradiography, and microPET imaging showed higher [18F]28c accumulation in the liver of LPS-treated mice than controls. Increased expression of S1P1 in the LPS model was confirmed by immunohistochemical analysis (IHC). These data suggest that [18F]28c is a S1P1 PET tracer with high potential for imaging S1P1 in vivo.
- Rosenberg, Adam J.,Liu, Hui,Jin, Hongjun,Yue, Xuyi,Riley, Sean,Brown, Steven J.,Tu, Zhude
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p. 6201 - 6220
(2016/07/26)
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- Benzoin oxazole derivatives, preparation method thereof and pharmaceutical compositions that contain them
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Benzoxazole derivatives novel benzo the present invention refers to, effect because of having immunosuppressive effect and manufacturing method thereof including obesity and obesity related metabolic diseases in particular, various diabetes and medicament for the prophylaxis or treatment of diseases associated with diabetes is directed to compositions. Benzoxazole derivatives novel benzo of the present invention a sugar-dependent insulin secretion [...] to increase the weight of an increase in the activity of suppression effect on GPR119 (G protein-coupled receptor 119) by efficiently antifungal is and lipid metabolism per, as well as diabetes, obesity, hyperlipidemia, diabetic vascular disease of a polyimide resin, such data structure for complications diabetes for prophylactic and therapeutic composition can be useful
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Paragraph 0592; 0594-0597
(2021/10/23)
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- NEW CYCLOHEXYL AND QUINUCLIDINYL CARBAMATE DERIVATIVES HAVING BETA2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITY
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The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
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Page/Page column 66
(2014/07/08)
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- Bioactive prenylated phenyl derivatives derived from marine natural products: Novel scaffolds for the design of BACE inhibitors
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Abnormal accumulation of neurotoxic beta-amyloid peptides (Aβ) is a key factor in the development of Alzheimer's disease (AD) and strategies to reduce Aβ production constitute an active field of research for the development of novel therapeutic agents for the treatment of AD. In particular, β-secretase-1 (BACE-1) has been a prime target for modulating Aβ production although obtaining drug-like BACE-1 inhibitors has proven to be highly challenging. Here we report the isolation and biochemical characterization of a marine natural product, the prenylated hydroxybenzoic acid 1, with BACE-1 inhibitory activity and ability to decrease Aβ production in cell-based assays. Synthesis and biological activity of a number of new synthetic analogues are also reported, as well as initial structure-activity relationship (SAR) analysis on this chemical family. Hence, these compounds constitute novel scaffolds from which more potent and selective BACE-1 inhibitors could be designed as potential therapeutic agents for the treatment of Alzheimer's disease.
- López-Ogalla, Javier,García-Palomero, Esther,Sánchez-Quesada, Jorge,Rubio, Laura,Delgado, Elena,García, Pablo,Medina, Miguel,Castro, Ana,Mu?oz, Pilar
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p. 474 - 488
(2014/04/17)
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- Synthesis and biological evaluation of ortho-carborane containing benzoxazole as an inhibitor of hypoxia inducible factor (HIF)-1 transcriptional activity
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ortho-Carborane and adamantane containing benzoxazoles were synthesized by intramolecular dehydration of the corresponding phenoxyacetanilides. Among the compounds synthesized, ortho-carborane containing benzoxazole 2b which has a carboxylic group on the benzoxazole ring, exhibited significant inhibition of hypoxia-induced HIF-1 transcriptional activity with the IC50 value of 14.4 μM toward HeLa cell-based reporter gene assay.
- Nakamura, Hiroyuki,Yasui, Yuka,Ban, Hyun Seung
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p. 189 - 194
(2013/11/19)
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- Tandem Ugi MCR/mitsunobu cyclization as a short, protecting-group-free route to benzoxazinones with four diversity points
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A tandem Ugi/Mitsunobu protocol, starting from o-aminophenols, α-hydroxy acids, amines and aldehydes gives benzo[b][1,4]oxazin-3-ones of general formula 1 in two high-yielding steps, with the introduction of up to four diversity inputs. The mildness of the methodology allows the stereospecific synthesis of enantiomerically pure products as well as the introduction of additional functional groups. The overall procedure can also be carried out in a one-pot manner. A tandem Ugi/Mitsunobu protocol, starting from o-aminophenols and α-hydroxy acids, gives benzo[b][1,4]oxazin-3-ones, with the introduction of up to four diversity inputs, in two high-yielding steps. The procedure may be carried out in a one-pot fashion and has a very broad scope, also allowing the synthesis of enantiomerically pure products.
- Banfi, Luca,Basso, Andrea,Giardini, Lorenzo,Riva, Renata,Rocca, Valeria,Guanti, Giuseppe
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experimental part
p. 100 - 109
(2011/03/21)
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- Synthesis of n-(3-cyano-7-ethoxy-1,4-dihydro-4-oxoquinolin-6-yl)acetamide
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New route for the preparation of N-(3-cyano-7-ethoxy-1,4-dihydro-4- oxoquinolin-6-yl)acetamide (1), a key intermediate for the synthesis of selective EGFR kinase inhibitors, was described.
- Zhang, Qiang,Mao, Yongjun,Liu, Zheng,Xie, Kai,Zhu, Yi,Wei, Yabing,Jiang, Xiangrui,Shen, Jingshan
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experimental part
p. 2851 - 2856
(2012/02/02)
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- Design of benzimidazole- and benzoxazole-2-thione derivatives as inhibitors of bacterial hyaluronan lyase
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Bacterial hyaluronan lyases (Hyal) degrade hyaluronan, an important component of the extracellular matrix, and are involved in microbial spread. Hyal inhibitors may serve as tools to study the role of the enzyme, its substrates and products in the course of bacterial infections. Moreover, such enzyme inhibitors are potential candidates for antibacterial combination therapy. Based on crystal structures of Streptococcus pneumoniae Hyal in complex with a hexasaccharide substrate and with different inhibitors, 1-acylated benzimidazole-2-thiones and benzoxazole-2-thiones were derived as new leads for the inhibition of Streptococcus agalactiae strain 4755 Hyal. Structure-based optimization led to N-(3-phenylpropionyl)benzoxazole-2-thione, one of the most potent compounds known to date (IC50 values: 24 μM at pH 7.4, 15 μM at pH 5). Among the 27 new derivatives, other N-acylated benzimidazoles and benzoxazoles are just as active at pH 7.4, but not at pH 5. The results support a binding mode characterized by interactions with residues in the catalytic site and with a hydrophobic patch.
- Braun, Stephan,Botzki, Alexander,Salmen, Sunnhild,Textor, Christian,Bernhardt, Günther,Dove, Stefan,Buschauer, Armin
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experimental part
p. 4419 - 4429
(2011/11/06)
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- Helix-helix interactions - Homochirality and heterochirality
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The relatively simple molecule 2-amino-4-(thiazolin-2-yl)phenol, 1, as its acetonitrile solvate crystallises such that the lattice can be considered to contain heterochiral sheets of helical, N...HO H-bonded polymers which are linked within their sheets by weaker N...HN H-bonds between adjacent helices of opposite chirality. Weaker interactions of the CH...π type can be discerned as linking helices of the same chirality between these sheets, these interactions being reinforced by weaker interactions still involving the acetonitrile solvent molecules. A similar analysis can be conducted of the helical structures found within the lattice of the related compound 4-(methoxycarbonyl)-2-aminophenol, 2, although here it is more difficult to define the hierarchy of the weak interactions observed.
- Stefankiewicz, Artur R.,De Cian, Andre,Harrowfield, Jack
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experimental part
p. 7207 - 7211
(2012/03/10)
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- COMPOUND HAVING 11 ?-HSD1 INHIBITORY ACTIVITY
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The present invention provides compounds having excellent 11β-HSD1 inhibitory activity. A compound represented by the following formula (I): [wherein X1 represents an oxygen atom, or the formula -(CR11R12)p-, etc., Y1 represents a hydrogen atom, a hydroxyl group, etc., Z1 represents an oxygen atom or the formula -(NR14)-, R1 represents a hydrogen atom, a halogen atom, a cyano group, a C1-4 alkyl group, a C1-4 alkyl group substituted with 1 to 3 halogen atoms, a C1-4 alkoxy group, a C1-4 alkoxycarbonyl group, a carboxyl group, a carbamoyl group, or an amino group, and m represents an integer of 1 or 2, and R2 represents a hydrogen atom or a C1-4 alkyl group, and n represents an integer of 1 or 2].
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Page/Page column 15-16
(2010/04/25)
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- DERIVATIVES OF UREAS OF PIPERIDINE OR PYRROLIDINE, THEIR PREPARATION AND THEIR THERAPEUTICAL USE
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The present invention is related to a compound of formula (I): wherein i, j, n, o, p, q, r, R1a, R1b, R1c, R1d, R2a, R2b, R2c, R2d, R3a, R3b and R4 are as defined herein, or an addition salt with an acid thereof, or a hydrate or solvate thereof, its preparation, pharmaceutical composition, and uses for treating a disease in which the enzyme 11β-HSD1 is involved.
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Page/Page column 29-30
(2009/07/18)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
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A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
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- Synthesis of some novel 2-substituted-N-aryl-benzoxazole-5-carboxamides using cobalt dipyridine dichloride as a catalyst
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(Chemical Equation Presented) An efficient synthesis of some novel 2-substituted-N-aryl-benzoxazole-5-carboxamides from 2-substituted - 5-carbomethoxy benzoxazole on treatment with different substituted anilines promoted by cobalt dipyridine dichloride as a catalyst is described. This new approach has the advantage of excellent yields (90%) and short reaction times 1-2 h.
- Sarangapani,Sridhar,Arjun,Adharvana Chari
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p. 1187 - 1190
(2008/12/20)
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- Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds
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[Problems] The present invention provides pharmaceutical composition which is effective for the prophylaxis or treatment of pathology showing involvement of uric acid (hyperuricemia, gouty tophus, acute gout arthritis, chronic gout arthritis, gouty kidney, urolithiasis, renal function disorder, coronary arterial disease, ischemic heart disease and the like) and the like, and is superior in the time-course stability and dissolution property (disintegration property). [Solving Means] The pharmaceutical composition of the present invention is a pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not in contact with a basic additive: wherein each symbol is as described in the specification.
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- Synthesis, anticonvulsant and neurotoxicity evaluation of 5-carbomethoxybenzoxazole derivatives
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A series of 5-carbomethoxybenzoxazole derivatives (6a-t) were prepared by using methyl-p-hydroxybenzoate. The identity of the compounds was confirmed on the basis of their elemental analysis and spectral data. In anti-MES test compounds 6b, 6d, 6h, 6j, 6m, 6p, 6q and 6s showed potent activity parallel to lipophilicity. Compounds 6b, 6d, 6k, 6n and 6s successfully passed the rotorod test without any sign of neurological deficit.
- Siddiqui, Nadeem,Sarafroz,Alam, M. Mumtaz,Ahsan, Waquar
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experimental part
p. 449 - 455
(2009/04/07)
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- Production Method of Nitrogen-Containing Fused Ring Compounds
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[Problems] The present invention provides a superior production method and a superior purification method of compounds effective for the treatment or prophylaxis of pathology showing involvement of uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease, ischemic heart disease and the like. [Means] A compound represented by the following formula [2] or a pharmaceutically acceptable salt thereof can be produced by reacting a compound represented by the following formula [3] or a salt thereof with a compound represented by the following formula [4], a salt thereof or a reactive derivative thereof. Moreover, crystallization of a compound represented by the formula [2] can be performed with industrially superior workability, and high quality crystals of a compound represented by the formula [2] can be obtained. wherein each symbol is as defined in the description.
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Page/Page column 59
(2010/11/30)
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- Synthesis of platensimycin analogues and their antibiotic potency
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Platensimycin is a natural product isolated from various strains of Streptomyces platensis which exhibits antimicrobial activity against Gram positive bacteria, including vancomycin- and linezolide-resistant species. Analogues of platensimycin were synthesized from 3-aminobenzoic acid or other aniline derivatives and several alkyl- and aryl-carboxylic acids. The resulting compounds were tested in an agar diffusion assay against several bacteria and fungi.
- Krauss, Juergen,Knorr, Veronika,Manhardt, Vera,Scheffels, Stefanie,Bracher, Franz
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body text
p. 386 - 392
(2009/04/16)
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- Novel bicyclic sulfonamide derivatives which are L-CPT1 inhibitors
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The invention is concerned with novel heterobicyclic derivatives of formula (I) wherein R1, R2, R3, R4, R5, R6, V, W, X and Y are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds inhibit L-CPT1 and can be used as medicaments.
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Page/Page column 25
(2010/11/28)
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- Nitrogen-containing fused ring compounds and use thereof
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A URAT1 activity inhibitor containing a nitrogen-containing fused ring compound represented by the following formula [1]: wherein each symbol is as defined in the description. The present invention is useful for the prophylaxis or treatment of pathology showing involvement of uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease, ischemic heart disease and the like.
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Page/Page column 96
(2010/11/25)
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- BICYCLIC COMPOUNDS USEFUL AS CATHEPSIN S INBHIBITORS
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Compounds of formula (I), wherein R1, R2, R3, Ra and E are are defined within, and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof having utility in the treatment of disorders mediated by cathepsin S.
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Page/Page column 43
(2010/11/29)
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- CETP INHIBITORS
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Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
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Page/Page column 92-93
(2008/06/13)
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- Electrochemically induced cascade reaction for the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives
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The scope and mechanism of an electrochemically induced cascade reaction, which leads to highly substituted 1,4-benzoxazine derivatives, have been explored through the variation of the structure of the o-azaquinone mediator. This reaction sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the regiospecific inverse-electron-demand Diels-Alder (IEDDA) reaction of an o-azaquinone heterodiene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities. The cascade reaction was found to be general with electron-poor o-azaquinone entities generated from substituted 2-aminoresorcinol substrates. In the case of o-aminophenol derivatives which lack the 2-hydroxyl group, the generated o-azaquinone species failed to catalyze the oxidation of the amine to the corresponding imine, precursor of the enamine dienophile, because the absence of an intramolecular hydrogen bond at the origin of a highly reactive Schiff base cyclic transition state. To overcome this problem, a tandem oxidation-IEDDA reaction, in which the o-azaquinone is generated in the presence of a preformed enamine, has been developed as an alternative. These one-pot methodologies, which offer the opportunity to introduce variations in both cycloaddition partners, should be particularly useful for the development of libraries of biologically relevant 1,4-benzoxazine derivatives.
- Xu, Daiwang,Chiaroni, Angele,Fleury, Maurice-Bernard,Largeron, Martine
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p. 6374 - 6381
(2007/10/03)
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- CATHEPSIN S INHIBITORS
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Compounds of the formula (I) where R1 is C1-C4 straight or branched alkyl, optionally substituted with up to three substituents selected from halo and hydroxy; R2 is halo, hydroxy, methyloxy, or C1-C2 alkyl, which alkyl is optionally substituted with up to three halogens or an hydroxy or a methyloxy; D is - C3-C7 alkylene-, thereby defining a cycloalkyl ring; E is -C(=O)-, -S(=O)m-, -NRdS(=O)m-, -NRaC(=O)-, -OC(=O)-, R3 is an optionally substituted carbocyclic or heterocyclic ring R10 is H, ORc, SRc or together with the gem H is =O or (ORc)2; Ra is independently selected from H, C1-C4 alkyl; have utility in the inhibition of cathepsin S and are thus useful pharmaceuticals against disorders such as autoimmune disorders and chronic pain.
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Page/Page column 98
(2010/11/08)
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- Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase
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Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here a novel class of allosteric inhibitor of NS5B that shows potent affinity for the NS5B enzyme and effective inhibition of subgenomic HCV RNA replication in HUH-7 cells. Inhibitors from this class have promising characteristics for further development as anti-HCV agents.
- Harper, Steven,Pacini, Barbara,Avolio, Salvatore,Di Filippo, Marcello,Migliaccio, Giovanni,Laufer, Ralph,De Francesco, Raffaele,Rowley, Michael,Narjes, Frank
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p. 1314 - 1317
(2007/10/03)
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- INDOLES AND AZAINDOLES AS ANTIVIRAL AGENTS
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The present invention relates to indoles and azaindoles of formula (I): wherein X1, X2, X3, X4, A1, Ar1, Ar, n, p and q are as defined herein and pharmaceutically acceptable salts thereof, useful in the prevention and treatment of hepatitis C virus infections.
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Page/Page column 19
(2010/02/11)
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- AZOLIDINONE-VINYL FUSED-BENZENE DERIVATIVES
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The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Formula (I), wherein A, X, Y, Z, R1 , R2 and n are as described in the description.
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- INDOLE ACETAMIDES AS INHIBITORS OF THE HEPATITIS C VIRUS NS5B POLYMERASE
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The present invention relates to indole and azaindole compounds of formula (I): wherein X1, X2, X3, X4, A1, Ar1, R1, R2 and n are as defined herein, and pharmaceutically acceptable salts thereof, useful in the prevention and treatment of hepatitis C infections.
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- Synthesis and structure-activity relationships of new antimicrobial active multisubstituted benzazole derivatives
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A series of multisubstituted benzoxazoles, benzimidazoles, and benzothiazoles (5-7) as non-nucleoside fused isosteric heterocyclic compounds was synthesized and tested for their antibacterial activities against various Gram-positive and Gram-negative bacteria and antifungal activity against the fungus Candida albicans. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 100 and 3.12 μg/ml. Structure-activity relationships (SAR) studies revealed that benzothiazole ring system enhanced the antimicrobial activity against Staphylococcus aureus. In these sets of non-nucleoside fused heterocyclic compounds electron withdrawing groups at position 5 of the benzazoles increased the activity against C. albicans.
- Yildiz-Oren, Ilkay,Yalcin, Ismail,Aki-Sener, Esin,Ucarturk, Nejat
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p. 291 - 298
(2007/10/03)
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- INDOLE-DERIVATIVE MODULATORS OF STEROID HORMONE NUCLEAR RECEPTORS
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The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating physiological disorders, particularly congestive heart disease, comprising administering to a patient in thereof an effective amount of a compound of Formula I.
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- Reduction of nitrophenols by zinc and ammonium chloride in aqueous medium
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A simple reduction procedure involving zinc and ammonium chloride in aqueous medium has been employed for the reduction of nitrophenols to aminophenols.
- Sridharan,Karpagavalli,Muthusubramanian,Sivasubramanian
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p. 2243 - 2244
(2007/10/03)
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- Novel synthesis of benzoxazoles from o-nitrophenols and amines
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o-Nitrophenols and o-nitroaniline were reacted with amines at 210-215°C to produce the corresponding benzoxazoles and benzimidazoles, respectively, in moderate yields. The reactions between o-nitrophenols containing a CO2Me or OMe group on their benzene rings and N,N-diethylaniline were examined to investigate the effects of the position and electronic character of these substituents on the formation of the oxazole ring.
- Nishioka, Hiromi,Ohmori, Yukiko,Iba, Yumiko,Tsuda, Eri,Harayama, Takashi
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p. 193 - 198
(2007/10/03)
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- Benzoxazine and benzothiazine derivatives and their use in pharmaceuticals
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Described are benzoxazine and benzothiazine compounds of the formula I defined herein, methods for their preparation and methods for their use in pharmaceuticals based on their activity as NO-synthases (NOS) inhibitors.
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- Heterocyclic amide compounds and medicinal uses thereof
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PCT No. PCT/JP97/03839 Sec. 371 Date Apr. 22, 1999 Sec. 102(e) Date Apr. 22, 1999 PCT Filed Oct. 22, 1997 PCT Pub. No. WO98/18794 PCT Pub. Date May 7, 1998A heterocyclic amide compound of the formula (I) wherein each symbol is as defined in the specification, a pharmacologically acceptable salt thereof, a pharmaceutical composition thereof and a pharmaceutical use thereof. The heterocyclic amide compound and a pharmacologically acceptable salt thereof of the present invention have superior inhibitory action on chymase group in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be used for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.
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- Identification of urinary metabolites of ecabapide in rat
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14C-Ecabapide, 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]amino-N-methyl[14 C]benzamide, was dosed orally to rat (100 mg/kg). Within 48 h after dosing, 36.7 ± 5.4 and 55.7 ± 11.8% of the administered radioactivity was recovered from urine and faeces respectively. The unchanged drug was the major compound excreted in the urine and accounted for 37% of the urinary radioactivity. Seven urinary metabolites were purified by preparative hplc and their structures were elucidated by mass and 1H-nmr spectrometry. The major metabolic pathway of ecabapide was found to be the formation of 3-amino-N-methylbenzamide produced by N-dealkylation of the secondary amine at the 3-position of the benzamide moiety followed by acetylation. Further metabolic pathways of the N-methylbenzamide moiety were N-demethylation via the carbinolamine derivatives, and/or aromatic hydroxylation followed by glucuronidation.
- Fujimaki,Hosokami,Ono
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p. 501 - 510
(2007/10/03)
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