- A flexible, convergent approach to polycyclic indole structures: Formal synthesis of (±)-mersicarpine
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The formal synthesis of (±)-mersicarpine was achieved using an lntermolecular radical addition-radical cyclization cascade. This key reaction represents a flexible, convergent route to numerous polycyclic indole derivatives.
- Blechy, Aurellen,Zard, Samir Z.
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Read Online
- Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically related echinosulfonic acids A–D
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A short Friedel-Crafts mediated total synthesis has informed structure revision of the rare marine sponge natural product echinosulfone A (1a) and the biosynthetically related echinosulfonic acids A–D (2a–5a).
- Neupane, Pratik,Salim, Angela A.,Capon, Robert J.
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Read Online
- Synthesis and Pharmacological Profiling of the Metabolites of Synthetic Cannabinoid Drugs APICA, STS-135, ADB-PINACA, and 5F-ADB-PINACA
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Synthetic cannabinoids (SCs) containing a 1-pentyl-1-H substituted indole or indazole are abused around the world and are associated with an array of serious side effects. These compounds undergo extensive phase 1 metabolism after ingestion with little understanding whether these metabolites are contributing to the cannabimimetic activity of the drugs. This work presents the synthesis and pharmacological characterization of the major metabolites of two high concern SCs; APICA and ADB-PINACA. In a fluorometric assay of membrane potential, all metabolites that did not contain a carboxylic acid functionality retained potent activity at both the CB1 (EC50 = 14-787 nM) and CB2 (EC50 = 5.5-291 nM) receptors regardless of heterocyclic core or 3-carboxamide substituent. Of note were the 5-hydroxypentyl and 4-pentanone metabolites which showed significant increases in CB2 functional selectivity. These results suggest that the metabolites of SCs potentially contribute to the overall pharmacological profile of these drugs.
- Longworth, Mitchell,Connor, Mark,Banister, Samuel D.,Kassiou, Michael
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Read Online
- Palladium-Catalyzed Silacyclization of (Hetero)Arenes with a Tetrasilane Reagent through Twofold C?H Activation
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The use of an operationally convenient and stable silicon reagent (octamethyl-1,4-dioxacyclohexasilane, ODCS) for the selective silacyclization of (hetero)arenes via twofold C?H activation is reported. This method is compatible with N-containing heteroarenes such as indoles and carbazoles of varying complexity. The ODCS reagent can also be utilized for silacyclization of other types of substrates, including tertiary phosphines and aryl halides. A series of mechanistic experiments and density functional theory (DFT) calculations were used to investigate the preferred pathway for this twofold C?H activation process.
- Wang, Dingyi,Li, Mingjie,Chen, Xiangyang,Wang, Minyan,Liang, Yong,Zhao, Yue,Houk, Kendall N.,Shi, Zhuangzhi
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supporting information
p. 7066 - 7071
(2021/03/01)
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- PYRIMIDINE COMPOUND, PREPARATION METHOD THEREOF AND MEDICAL USE THEREOF
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The present invention discloses a pyrimidine compound, a preparation method thereof and a medical use thereof. Specifically, the present invention discloses a pyrimidine compound represented by formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof, and a use thereof as a cyclin-dependent kinase 9 (CDK9) inhibitor, particularly for the treatment of cancer. The definition of each group in formula (I) is the same as that in the specification.
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Paragraph 0359; 0362; 0363
(2021/04/10)
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- Indole derivative as well as preparation method and application thereof
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The invention discloses an indole derivative as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to an indole derivative as shown in a general formula I, the invention also relates
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Paragraph 0063-0065
(2021/06/23)
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- Compound capable of inhibiting activity of organic anion transporter 1 as well as preparation method and application of compound
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The invention discloses a compound capable of inhibiting the activity of an organic anion transporter 1 as well as a preparation method and application of the compound, belongs to the technical field of medicines, and provides a compound which has a brand-new structure and is shown in a general formula I and has the activity of inhibiting the organic anion transporter 1. The invention also provides a preparation method of the compound and application of the compound in medicines for treating and/or preventing hyperuricemia and gout diseases. A new product is provided for developing a novel organic anion transporter 1 inhibitor, a new treatment thought is provided for treating hyperuricemia and gout, meanwhile, a preparation method is provided for preparing the compound, and certain guiding significance is achieved.
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Paragraph 0052-0054; 0059-0061; 0174-0176
(2021/06/23)
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- Preparation method of tropisetron hydrochloride
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The invention discloses a preparation method of tropisetron hydrochloride (I). According to the preparation method, an amide solvent is used as a solvent, and chlorination and esterification are performed to obtain tropisetron hydrochloride. The preparation method disclosed by the invention is low in cost and simple and convenient to operate, can be used for large-scale production, and lays a solid foundation for quality research on bulk drugs and related preparations of tropisetron hydrochloride.
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Paragraph 0016
(2020/03/09)
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- Design, synthesis, and evaluation of novel anti-trypanosomal compounds
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Human African trypanosomiasis (HAT) is a deadly neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. During the course of screening a collection of diverse nitrogenous heterocycles, we discovered two novel compounds that contain the tetracyclic core of the Yohimbine and Corynanthe alkaloids, were potent inhibitors of T. brucei proliferation and T. brucei methionyl-tRNA synthetase (TbMetRS) activity. Inspired by these key findings, we prepared several novel series of hydroxyalkyl δ-lactam, δ-lactam, and piperidine analogs and tested their anti-trypanosomal activity. A number of inhibitors were more potent against T. brucei than these initial hits with one hydroxyalkyl δ-lactam derivative being 25-fold more effective in our assay. Surprisingly, most of these active compounds failed to inhibit TbMetRS. This work underscores the importance of verifying, irrespective of close structural similarities, that new compounds designed from a lead with a known biological target engage the putative binding site.
- Lepovitz, Lance T.,Martin, Stephen F.,Meis, Alan R.,Mensa-Wilmot, Kojo,Pham, Alexandra,Thomas, Sarah M.,Wiedeman, Justin
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supporting information
(2020/03/25)
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- METHODS OF TREATING CANCER
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The present disclosure relates to methods of treating cancer in a patient using a combination of an inhibitor of an immune checkpoint protein and an indole compound or its phosphate derivative.
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Paragraph 00215-00216; 00505
(2020/06/10)
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- Heterocyclic compound and preparation and application thereof
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The invention relates to bromodomain inhibitors, and provides a compound represented by a general formula I, a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method thereof, a pharmaceutical composition containing the same, and applicationthereof in pharmacy.
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Paragraph 0291-0293
(2020/07/24)
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- INDOLE COMPOUNDS AND THEIR USE
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The present disclosure relates to indole compounds and pharmaceutical compositions thereof, and their use in stimulating the immune system of patients in need thereof and in treating cancer.
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Paragraph 00191; 00203; 00204
(2019/06/05)
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- Pd(II)-Catalyzed asymmetric oxidative annulation of N-alkoxyheteroaryl amides and 1,3-dienes
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The first Pd(II)-catalyzed asymmetric oxidative annulation of N-alkoxyaryl amides and 1,3-dienes is reported, which features particular applicability for quick assembly of different types of chiral heterocycles with high yields and enantioselectivities. A novel chiral pyridine-oxazoline bearing a methoxyl group at the C-5 position and a gem-dimethyl group on the oxazoline moiety was found to be crucial for conversion.
- Zhang, Tao,Shen, Hong-Cheng,Xu, Jia-Cheng,Fan, Tao,Han, Zhi-Yong,Gong, Liu-Zhu
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supporting information
p. 2048 - 2051
(2019/03/29)
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- Preparation method of tropisetron bisindole impurities
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The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tropisetron bisindole impurities. The preparation method of the tropisetron bisindole impurities comprises the following steps: (1) dissolving 3-indolecarboxylic acid and an acylation reagent in a solvent and reacting, and carrying aftertreatment to obtain 3-indoloformyl chloride; and (2) dissolving tropisetron in tetrahydrofuran, cooling to the temperature of minus 15-20 DEG C, adding alkali, then dropwise adding a tetrahydrofuran solution of the 3-indoloformyl chloride, reacting for 2-10 hours at a room temperature after dropwise adding is finished, and carrying out aftertreatment to obtain tropisetron bisindole impurities. The preparation method is simple to operate, gentle in reaction, high in yield and high in purity of product, is suitable for mass spectrometry on crude drugs, and has quite high commercial value.
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Paragraph 0022; 0023; 0025; 0027
(2018/07/15)
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- Novel inhibitors of Staphylococcus aureus RnpA that synergize with mupirocin
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We recently discovered RnpA as a promising new drug discovery target for methicillin-resistant S. aureus (MRSA). RnpA is an essential protein that is thought to perform two required cellular processes. As part of the RNA degrasome Rnpa mediates RNA degradation. In combination with rnpB it forms RNase P haloenzymes which are required for tRNA maturation. A high throughput screen identified RNPA2000 as an inhibitor of both RnpA-associated activities that displayed antibacterial activity against clinically relevant strains of S. aureus, including MRSA. Structure-activity studies aimed at improving potency and replacing the potentially metabotoxic furan moiety led to the identification of a number of more potent analogs. Many of these new analogs possessed overt cellular toxicity that precluded their use as antibiotics but two derivatives, including compound 5o, displayed an impressive synergy with mupirocin, an antibiotic used for decolonizing MSRA whose effectiveness has recently been jeopardized by bacterial resistance. Based on our results, compounds like 5o may ultimately find use in resensitizing mupirocin-resistant bacteria to mupirocin.
- Lounsbury, Nicole,Eidem, Tess,Colquhoun, Jennifer,Mateo, George,Abou-Gharbia, Magid,Dunman, Paul M.,Childers, Wayne E.
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supporting information
p. 1127 - 1131
(2018/02/21)
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- Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)
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Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 μM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.
- See, Cheng Shang,Kitagawa, Mayumi,Liao, Pei-Ju,Lee, Kyung Hee,Wong, Jasmine,Lee, Sang Hyun,Dymock, Brian W.
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p. 344 - 367
(2018/07/25)
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- Diindolylmethane Derivatives: Potent Agonists of the Immunostimulatory Orphan G Protein-Coupled Receptor GPR84
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The Gi protein-coupled receptor GPR84, which is activated by (hydroxy)fatty acids, is highly expressed on immune cells. Recently, 3,3′-diindolylmethane was identified as a heterocyclic, nonlipid-like GPR84 agonist. We synthesized a broad range of diindolylmethane derivatives by condensation of indoles with formaldehyde in water under microwave irradiation. The products were evaluated at the human GPR84 in cAMP and β-arrestin assays. Structure-activity relationships (SARs) were steep. 3,3′-Diindolylmethanes bearing small lipophilic residues at the 5- and/or 7-position of the indole rings displayed the highest activity in cAMP assays, the most potent agonists being di(5-fluoro-1H-indole-3-yl)methane (38, PSB-15160, EC50 80.0 nM) and di(5,7-difluoro-1H-indole-3-yl)methane (57, PSB-16671, EC50 41.3 nM). In β-arrestin assays, SARs were different, indicating biased agonism. The new compounds were selective versus related fatty acid receptors and the arylhydrocarbon receptor. Selected compounds were further investigated and found to display an ago-allosteric mechanism of action and increased stability in comparison to the lead structure.
- Pillaiyar, Thanigaimalai,K?se, Meryem,Sylvester, Katharina,Weighardt, Heike,Thimm, Dominik,Borges, Gleice,F?rster, Irmgard,Von Kügelgen, Ivar,Müller, Christa E.
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p. 3636 - 3655
(2017/05/17)
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- Improved Synthesis for Modular Ascarosides Uncovers Biological Activity
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A versatile synthesis of modular ascarosides, a family of signaling molecules from Caenorhabditis elegans and other nematodes, via hydrogenolysis of a cyclic sulfate derived from methyl-α-l-rhamnopyranoside is reported. The route enables selective introdu
- Zhang, Ying K.,Sanchez-Ayala, Marco A.,Sternberg, Paul W.,Srinivasan, Jagan,Schroeder, Frank C.
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supporting information
p. 2837 - 2840
(2017/06/07)
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- Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis
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Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
- Shi, Ying,Duan, Yan-Hui,Ji, Yue-Yang,Wang, Zhi-Long,Wu, Yan-Ran,Gunosewoyo, Hendra,Xie, Xiao-Yu,Chen, Jian-Zhong,Yang, Fan,Li, Jing,Tang, Jie,Xie, Xin,Yu, Li-Fang
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p. 7067 - 7083
(2017/09/07)
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- Preparation method of tropisetron hydrochloride
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The invention discloses a preparation method of tropisetron hydrochloride. The Preparation method of the tropisetron hydrochloride is characterized by comprising the following preparation steps: (A) performing substation reaction on 3-indolecarboxylic acid (I) serving as a starting material and thionyl chloride by adding a reaction solvent to prepare 3-indoleformyl chloride (II), and directly performing condensation reaction on the 3-indoleformyl chloride (II) and alpha-tropine (III) under the existence of an acid-binding agent triethylamine to produce tropisetron (IV); and (B) performing acid and alkali salt-forming reaction on the tropisetron (IV) and hydrochloric acid in ethanol to produce the tropisetron hydrochloride (V). Raw materials used in the process reactions are the conventional reagents, are easily available on the market and are low in cost; the conditions are simple and not harsh, the conventional equipment can meet production requirements and are easy to control, and industrialized production can be realized; and dichloromethane and tetrahydrofuran have low boiling point and are easily evaporated to dryness, so energy conservation and safety are achieved.
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Paragraph 0012
(2017/08/29)
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- Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
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A series of novel indole derivatives were synthesized as potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase. Among those, compound 10b demonstrated the highest growth inhibition rate of 66.7% against the VEGFR-2 tyrosine kinase at 10 μM which indicates that indole-benzothiazole might be the favorable structure. The binding mode of compound 10b with VEGFR-2 tyrosine kinase was evaluated by molecular docking.
- Zhang,Xu,Wang,Kang
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p. 3006 - 3016
(2018/02/21)
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- Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents
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New phenothiazine derivatives 6-20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6-8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke's type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.
- Ghinet, Alina,Moise, Iuliana-Monica,Rigo, Beno?t,Homerin, Germain,Farce, Amaury,Dubois, Jo?lle,B?cu, Elena
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p. 2307 - 2317
(2016/04/26)
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- Transition-Metal-Free Synthesis of N-Aryl Hydroxamic Acids via Insertion of Arynes
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An efficient and transition-metal-free N-arylation of amides via the insertion of arynes into the N-H bonds in the N-alkoxy amides is described. A variety of the reactive functional groups including the reactive aldehyde carbonyl group, furan ring, carbon-carbon double bonds, and free N-H bond of indole are found to be compatible with this process. In particular, the protocol is applicable in the synthesis of structurally diverse N-aryl hydroxamates and hydroxamic acids derived from N-protecting amino acids and peptides. In the presence of multiple amide N-H bonds, the N-arylation reaction can proceed selectively in the N-H bonds of terminal N-OBn amides giving rise to the desired N-aryl hydroxamates.
- Zhang, Lanlan,Geng, Yu,Jin, Zhong
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p. 3542 - 3552
(2016/05/24)
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- Selective MS screening reveals a sex pheromone in: Caenorhabditis briggsae and species-specificity in indole ascaroside signalling
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The indole ascarosides (icas) represent a highly potent class of nematode-derived modular signalling components that integrate structural inputs from amino acid, carbohydrate, and fatty acid metabolism. Comparative analysis of the crude exo-metabolome of
- Dong, Chuanfu,Dolke, Franziska,Von Reuss, Stephan H.
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p. 7217 - 7225
(2016/08/05)
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- SELECTIVE ANTI-CANCER COMPOUNDS
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A compound of formula I, wherein the compound of formula I has the structure: wherein R1 to R5, Y, L, Z and X1 to X7 have meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease.
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Page/Page column 107-108
(2017/01/31)
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- Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: Synthesis, biological characterization, and behavioral studies
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Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.
- Brindisi, Margherita,Butini, Stefania,Franceschini, Silvia,Brogi, Simone,Trotta, Francesco,Ros, Sindu,Cagnotto, Alfredo,Salmona, Mario,Casagni, Alice,Andreassi, Marco,Saponara, Simona,Gorelli, Beatrice,Weikop, Pia,Mikkelsen, Jens D.,Scheel-Kruger, Jorgen,Sandager-Nielsen, Karin,Novellino, Ettore,Campiani, Giuseppe,Gemma, Sandra
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p. 9578 - 9597
(2015/01/09)
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- Synthesis and anticancer activity of analogues of phenstatin, with a phenothiazine A-ring, as a new class of microtubule-targeting agents
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A new family of microtubule-targeting agents with a phenothiazine A-ring was synthesized and evaluated for anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferation and tub
- Abuhaie, Cristina-Maria,B?cu, Elena,Rigo, Beno?t,Gautret, Philippe,Belei, Dalila,Farce, Amaury,Dubois, Jo?lle,Ghinet, Alina
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supporting information
p. 147 - 152
(2013/02/23)
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- SMALL MOLECULE COMPOUNDS FOR THE CONTROL OF NEMATODES
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The present invention relates to compounds involved in nematode signaling.
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Paragraph 0246
(2013/03/26)
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- Comparative metabolomics reveals biogenesis of ascarosides, a modular library of small-molecule signals in C. elegans
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In the model organism Caenorhabditis elegans, a family of endogenous small molecules, the ascarosides function as key regulators of developmental timing and behavior that act upstream of conserved signaling pathways. The ascarosides are based on the dideoxysugar ascarylose, which is linked to fatty-acid-like side chains of varying lengths derived from peroxisomal β-oxidation. Despite the importance of ascarosides for many aspects of C. elegans biology, knowledge of their structures, biosynthesis, and homeostasis remains incomplete. We used an MS/MS-based screen to profile ascarosides in C. elegans wild-type and mutant metabolomes, which revealed a much greater structural diversity of ascaroside derivatives than previously reported. Comparison of the metabolomes from wild-type and a series of peroxisomal β-oxidation mutants showed that the enoyl CoA-hydratase MAOC-1 serves an important role in ascaroside biosynthesis and clarified the functions of two other enzymes, ACOX-1 and DHS-28. We show that, following peroxisomal β-oxidation, the ascarosides are selectively derivatized with moieties of varied biogenetic origin and that such modifications can dramatically affect biological activity, producing signaling molecules active at low femtomolar concentrations. Based on these results, the ascarosides appear as a modular library of small-molecule signals, integrating building blocks from three major metabolic pathways: carbohydrate metabolism, peroxisomal β-oxidation of fatty acids, and amino acid catabolism. Our screen further demonstrates that ascaroside biosynthesis is directly affected by nutritional status and that excretion of the final products is highly selective.
- Von Reuss, Stephan H.,Bose, Neelanjan,Srinivasan, Jagan,Yim, Joshua J.,Judkins, Joshua C.,Sternberg, Paul W.,Schroeder, Frank C.
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supporting information; experimental part
p. 1817 - 1824
(2012/03/10)
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- Synthesis of 6-substituted 2-pyrrolyl and indolyl benzoxazoles by intramolecular O-arylation in photostimulated reactions
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The synthesis of a series of 6-substituted 2-pyrrolyl and 2-indolyl benzoxazoles by photostimulated C-O cyclization of anions from 2-pyrrole carboxamides, 2-indole carboxamides, or 3-indole carboxamides has been found to proceed in good to excellent yields (41-100%) in DMSO and liquid ammonia. The pyrrole and indole carboxamides are obtained in good to very good isolated yields by an amidation reaction of different 2-haloanilines with 2-carboxylic acid of pyrrole and 2- or 3-carboxylic acid of indole. To explain the regiochemical outcome of these reactions (C-O arylation vs C-N or C-C arylation), a theoretical analysis was performed using DFT methods and the B3LYP functional.
- Vaillard, Victoria A.,Guastavino, Javier F.,Buden, Maria E.,Bardagi, Javier I.,Barolo, Silvia M.,Rossi, Roberto A.
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experimental part
p. 1507 - 1519
(2012/03/11)
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- Synthesis and pharmacological properties of novel hydrophilic 5-HT 4 receptor antagonists
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Serotonin (5-hydroxytryptamine, 5-HT) is an important signalling molecule in the human body. The 5-HT4 serotonin receptor, coupled to the G protein Gs, plays important physiological and pathophysiological roles in the heart, urinary
- Brudeli, Bjarne,Moltzau, Lise Román,Andressen, Kjetil Wessel,Krobert, Kurt A.,Klaveness, Jo,Levy, Finn Olav
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experimental part
p. 8600 - 8613
(2011/02/25)
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- Novel Aryl Piperazine Derivatives With Medical Utility
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This invention provides novel aryl piperazine derivatives having medical utility, in particular as modulators of dopamine and serotonin receptors, preferably the D3, D2-like and 5-HT2 receptor subtypes, and in particular u
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Page/Page column 37
(2009/10/01)
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- Synthetic studies of cephalandole alkaloids and the revised structure of cephalandole A
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A synthesis of the originally proposed 2-(1H-indol-3-yl)-4H-3,1-benzoxazin- 4-one structure of the alkaloid cephalandole A (1) led to a structural revision, and the isolated natural product has now been identified as the previously known compound 3-(1H-in
- Mason, Jeffrey J.,Bergman, Jan,Janosik, Tomasz
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experimental part
p. 1447 - 1450
(2009/04/05)
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- Catalytic enantioselective Meerwein-Eschenmoser Claisen rearrangement: Asymmetric synthesis of allyl oxindoles
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The first catalytic, enantioselective Meerwein-Eschenmoser Claisen rearrangement has been achieved. Palladium(II) BINAP or phosphinooxazoline catalysts were employed to generate oxindole products with 100% conversion and up to 92% ee. Copyright
- Linton, Elizabeth C.,Kozlowski, Marisa C.
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supporting information; experimental part
p. 16162 - 16163
(2009/05/09)
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- NITROGENATED HETEROCYCLIC COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to novel compounds having a xanthine oxidase inhibitory effect and an uricosuric effect and pharmaceutical compositions comprising the same as an active ingredient. That is, the present invention relates nitrogen-containing heterocyclic compounds represented by the following general formula (I): wherein Y1 represents N or C(R4) ; Y2 represents N or C(R5) ; R4 and R5 independently represent an alkyl group, a hydrogen atom etc. ; one of R1 and R2 represents an optionally substituted aryl group, an alkoxygroup or an optionally substituted heterocyclic group; the other of R1 and R2 represents a haloalkyl group, a cyanogroup, ahalogenatometc.; and R3 represents a 5-tetrazolyl group or a carboxy group, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same as an active ingredient.
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Page/Page column 12; 14
(2008/12/06)
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- Intramolecular sulfoxide electrophilic sulfenylation in 2- and 3-indoleanilides
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When N-[2-(alkylsulfinyl)phenyl]-1H-indole-2-carboxamides with varying degrees of indolic and amidic N-alkylation are heated in an inert solvent or treated with trifluoroacetic anhydride; only compounds in which the amidic nitrogen is methylated cyclize t
- Eggers, Mary E.,Jog, Parag V.,Bates, Dallas K.
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p. 12185 - 12194
(2008/02/11)
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- 5-HTX MODULATORS
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This invention relates to compounds which bind to serotonin receptors inside or outside the central nervous system, in particular compounds which bind to the 5-HT2 or 5-HT7 receptors, their preparation and use, compositions containing them, and methods of treatment using them.
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Page/Page column 25-26
(2008/06/13)
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- Efficient sulfonation of 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile
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The sulfonation of various 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile has been studied, leading to the development of a clean and operationally simple protocol allowing direct synthesis of the corresponding 1-phenylsulfonyl-1H-pyrrole-3- sulfonyl chlorides and 1-phenylsulfonyl-1H-indole-3-sulfonyl chlorides, respectively, both of which may be easily converted to various sulfonamide derivatives by treatment with nitrogen nucleophiles. Efficient and selective removal of the phenylsulfonyl- or tosyl groups in the sulfonamide series may be achieved under mild conditions.
- Janosik, Tomasz,Shirani, Hamid,Wahlstr?m, Niklas,Malky, Ilham,Stensland, Birgitta,Bergman, Jan
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p. 1699 - 1707
(2007/10/03)
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- PROCESS FOR PRODUCING PHENYLACETIC ACID DERIVATIVE
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The present invention provides an advantageous process for producing an intermediate which is useful for producing a compound which exhibits excellent VLA-4 inhibitory effect and safety. Intermediates (III) and (XIII) are produced through conversion throu
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Page/Page column 39
(2010/11/23)
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- A general synthesis of tris-indole derivatives as potential iron chelators
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The development of a novel route for the synthesis of a new class of compounds is described. The first tripodal, tris-indole amines are prepared by straightforward routes.
- Sears, R. Bryan,Carpenter, Russell A.,Whitlock, Christine R.
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p. 488 - 491
(2007/10/03)
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- MODULATORS OF PERIPHERAL 5-HT RECEPTORS
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Novel modulators of 5-HT4 receptors have been developed which have a selectivity for peripheral receptors rather than those of the central nervous systems. Theses include novel derivatives of known modulators as well as entirely novel entities. Surprisingly, the derivatised compounds of the known modulators maintain a high binding affinity to 5-HT4 receptors, despite the presence of an acidic moiety at the end of an optional chain. The entirely novel entities also exhibit good binding affinity to 5-HT4 receptors. All of the compounds of the invention have a common motif which includes a basic nitrogen moiety and an acidic moiety. The compounds of the invention, due at least in part to their high ionisation potential at physiological pH, have the unique properties of selectively for peripheral 5HT4 receptors over those of the CNS, good binding affinity, and selectively of 5HT4 receptors over other serotonin receptors.
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Page/Page column 32
(2010/02/12)
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- Synthesis of 4,6-disubstituted-2-(1H-indol-3-yl)-benzothiazoles
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A new four-step synthesis of substituted 2-(1H-indol-3-yl)benzothiazoles is described, using N3-phenyl-1H-indole-3-carbothioamides as key intermediates. The structure of the obtained products was determined by IR, 1H, 13C NMR and MS spectral methods.
- Zaletova, Janka,Dzurilla, Milan,Kutschy, Peter,Pazdera, Pavel,Kovacik, Vladimir,Aldoelfi, Juraj,Bekesova, Slavka
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p. 453 - 460
(2007/10/03)
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- Convenient synthesis of pyrrole- and indolecarboxylic acid tert-butylesters
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The tert-butylesters of pyrrole- and indolecarboxylic acids are readily accessed by reacting the appropriate carboxylic acids with N,N-dimethylformamide di-tert-butyl acetal.
- Ludwig, Joachim,Lehr, Matthias
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p. 3691 - 3695
(2007/10/03)
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- Anthranilic acid derivatives: A new class of non-peptide CCK1 receptor antagonists
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Having successfully obtained new CCK1 ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK1 receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK1 receptor binding affinity (compound 1: IC50=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.
- Varnavas, Antonio,Lassiani, Lucia,Valenta, Valentina,Berti, Federico,Mennuni, Laura,Makovec, Francesco
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p. 741 - 751
(2007/10/03)
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- Indole, azaindole and related heterocyclic pyrrolidine derivatives
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity
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- Biotransformation of the phytoalexin camalexin by the phytopathogen Rhizoctonia solani
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The unusual metabolism of the cruciferous phytoalexin camalexin by virulent and weakly virulent isolates of the root rot fungus Rhizoctonia solani Kuhn is reported. This biotransformation proceeded via 5- hydroxycamalexin, which was further biotransformed into more polar metabolites. Importantly, the metabolites resulting from transformation of camalexin were significantly less toxic to the pathogen than camalexin. Thus, it was concluded that R. solani can detoxify camalexin through oxidation of the indole ring. The chemistry involved in the structure determination of the intermediates of this pathway, their synthesis as well as antifungal activity is described.
- Pedras, M. Soledade C.,Khan, Abdul Q.
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- Synthesis of some analogs of indole phytoalexins brassinin and methoxybrassenin B and their positional isomers
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Treatment of indole-3-carboxylic acid with phosphorus trichloride and subsequent reaction of the obtained acid chloride with potassium thiocyanate afforded indol-3-ylcarbonyl isothiocyanate (13). Its treatment with sodium hydrogensulfide in the presence of methyl iodide lead to the corresponding methyl dithiocarbamate, an oxo derivative of brassinin (oxobrassinin, 14), which by methylation with methyl iodide afforded brassenin B (8). Corresponding 2-isomers, 21 and 23, were obtained by an analogous sequence, starting from indole-2-carboxylic acid. During the preparation of isooxobrassinin (21), which appeared to be unstable in the basic reaction medium, also an imidazo[3,4-a]indole derivative 22 has been isolated as an unexpected side product. Related oxobrassinin analogs and their 2-isomers were prepared by treatment of indol-3-and indol-2-ylcarbonyl isothiocyanate with methanol and amines. In the case of isothiocyanate 13, besides the expected products of nucleophilic addition to NCS group (monothiocarbamate 25a and thiourea derivatives 25b-25g), also the substitution products were obtained. Their formation could be explained by partial decomposition of the starting isothiocyanate to an unstable ketene, which reacts with methanol and amines to afford the corresponding methyl carboxylate 26a and carboxamides 26b-26g. Antifungal activity of the prepared compounds has been examined, using the fungus Bipolaris leersiae. All of the compounds exhibited lower activity than phytoalexin brassinin.
- Kutschy, Peter,Dzurilla, Milan,Takasugi, Mitsuo,Sabova, Adriana
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p. 348 - 362
(2007/10/03)
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- Azabicyclic indole esters as potent 5-HT4 receptor antagonists
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The synthesis of a series of azabicyclic indole esters is described and their potency reported as 5-HT4 receptor antagonists. Optimization of the most potent compound (19) by preparing the corresponding oxazino[3,2-a]indole ester afforded 34, which had a pIC50 of 9.5 in the guinea pig distal colon longitudinal muscle myenteric plexus preparation.
- Wyman, Paul A.,Gaster, Laramie M.,King, Frank D.,Sutton, Jonathon M.,Ellis, Elizabeth S.,Wardle, Kay A.,Young, Timothy J.
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p. 255 - 261
(2007/10/03)
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- Studies on Neurokinin Antagonists. 3. Design and Structure-Activity Relationships of New Branched Tripeptides Nα-(Substituted L-aspartyl, L-ornithyl, or L-lysyl)-N-methyl-N-(phenylmethyl)-L-phenylalaninamides as Substance P Antagonists
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As an extension of our study on discovering a novel substance P (SP) antagonist, we designed new branched tripeptides containing L-aspartic acid, (2 and 5), L-ornithine (3 and 6), and L-lysine (4 and 7) by reconstructing the structure of the previously re
- Hagiwara, Daijiro,Miyake, Hiroshi,Murano, Kenji,Morimoto, Hiroshi,Murai, Masako,et al.
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p. 2266 - 2278
(2007/10/02)
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