- Indole-2-carboxamidines as novel NR2B selective NMDA receptor antagonists
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A novel series of indole-2-carboxamidine derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substituents on the indole skeleton as well as the substitution of the benzyl moiety on the biological activ
- Borza, Istvan,Kolok, Sandor,Ignacz-Szendrei, Gyoergyi,Greiner, Istvan,Tarkanyi, Gabor,Galgoczy, Kornel,Horvath, Csilla,Farkas, Sandor,Domany, Gyoergy
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- Screening of NOS activity and selectivity of newly synthesized acetamidines using RP-HPLC
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Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection.All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10 μM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53 nM) and selective iNOS inhibitor.
- Fantacuzzi, Marialuigia,Maccallini, Cristina,Di Matteo, Mauro,Ammazzalorso, Alessandra,Bruno, Isabella,De Filippis, Barbara,Giampietro, Letizia,Mollica, Adriano,Amoroso, Rosa
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- Synthesis of new highly functionalized 1h-indole-2-carbonitriles via cross-coupling reactions
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An approach for the preparation of polysubstituted indole-2-carbonitriles through a cross-coupling reaction of compounds 1-(but-2-ynyl)-1H-indole-2-carbonitriles and 1-benzyl-3-iodo-1H-indole-2-carbonitriles is described. The reactivity of indole derivatives with iodine at position 3 was studied using cross-coupling reactions. The Sonogashira, Suzuki–Miyaura, Stille and Heck cross-couplings afforded a variety of di-, tri-and tetra-substituted indole-2-carbonitriles.
- Hrizi, Asma,Cailler, Manon,Romdhani-Younes, Moufida,Carcenac, Yvan,Thibonnet, Jér?me
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- A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction
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The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na2S2O4 in dioxane/water at reflux.
- Mamedov, Vakhid A.,Mamedova, Vera L.,Syakaev, Victor V.,Khikmatova, Gul'naz Z.,Korshin, Dmitry E.,Kushatov, Temur A.,Latypov, Shamil K.
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p. 3923 - 3925
(2018/10/02)
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- TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to substituted indole compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, adisease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 48; 49
(2016/05/02)
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- Ruthenium(II) complexes bearing pyridine-functionalized N-heterocyclic carbene ligands: Synthesis, structure and catalytic application over amide synthesis
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A series of four imidazolium salts was synthesized by the reaction of 2-bromopyridine with 1-substituted imidazoles. These imidazolium salts (1a–d) were successfully employed as ligand precursors for the syntheses of new ruthenium(II) complexes bearing neutral bidentate ligands of N-heterocyclic carbene and pyridine donor moiety. The NHC-ruthenium(II) complexes (3a–d) were synthesized by reacting the appropriately substituted pyridine-functionalized N-heterocyclic carbenes with Ag2O forming the NHC–silver bromide in situ followed by transmetalation with [RuHCl(CO)(PPh3)3]. The new complexes were characterized by elemental analyses and spectroscopy (IR, UV-Vis,1H,13C,31P-NMR) as well as ESI mass spectrometry. Based on the spectral results, an octahedral geometry was assigned for all the complexes. The complexes were shown to be efficient catalysts for the one-pot conversion of various aldehydes to their corresponding primary amides with good to excellent isolated yields using NH2OH.HCl and NaHCO3. The effects of solvent, base, temperature, time and catalyst loading were also investigated. A broad range of amides were successfully synthesized with excellent isolated yields using the above optimized protocol. Notably, the complex 3a was found to be a very efficient and versatile catalyst towards amidation of a wide range of aldehydes. [Figure not available: see fulltext.]
- Nirmala, Muthukumaran,Viswanathamurthi, Periasamy
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p. 1725 - 1735
(2017/03/08)
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- Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
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The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.
- Zhou, Han-Jie,Wang, Jinhai,Yao, Bing,Wong, Steve,Djakovic, Stevan,Kumar, Brajesh,Rice, Julie,Valle, Eduardo,Soriano, Ferdie,Menon, Mary-Kamala,Madriaga, Antonett,Kiss Von Soly, Szerenke,Kumar, Abhinav,Parlati, Francesco,Yakes, F. Michael,Shawver, Laura,Le Moigne, Ronan,Anderson, Daniel J.,Rolfe, Mark,Wustrow, David
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p. 9480 - 9497
(2016/01/12)
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- Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
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Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
- Mistry, Shailesh N.,Shonberg, Jeremy,Draper-Joyce, Christopher J.,Klein Herenbrink, Carmen,Michino, Mayako,Shi, Lei,Christopoulos, Arthur,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert
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p. 6819 - 6843
(2015/09/22)
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- CuI-catalyzed intramolecular cyclization of 3-(2-aminophenyl)-2- bromoacrylate: Synthesis of 2-carboxyindoles
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A new approach was described for the synthesis of substituted 2-carboxyindole using 3-(2-aminophenyl)-2-bromo-acrylates through a CuI-catalyzed intramolecular coupling. The reactions were mild, rapid and with good to excellent yields.
- Xiao, Xiong,Chen, Tian-Qi,Ren, Jiangmeng,Chen, Wei-Dong,Zeng, Bu-Bing
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p. 2056 - 2060
(2014/04/03)
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- Super acid catalysed sequential hydrolysis/cycloisomerization of o-(acetylenic)benzamides under microwave condition: Synthesis, antinociceptive and antiinflammatory activity of substituted isocoumarins
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Synthesis of isocoumarins and related compounds via triflic acid promoted hydrolysis/cyclization sequence of 2-(alkynyl)benzamides under microwave condition was achieved. The substrate scope of the reaction was broad to include not only aromatic but also
- Praveen, Chandrasekaran,Dheenkumar,Perumal
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- Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents
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In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).
- Lu, Yan,Li, Chien-Ming,Wang, Zhao,Chen, Jianjun,Mohler, Michael L.,Li, Wei,Dalton, James T.,Miller, Duane D.
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p. 4678 - 4693
(2011/09/14)
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- Synthesis and in-vitro anticancer activity of 3,5-bis(indolyl)-1,2,4- thiadiazoles
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A series of 3,5-bis(indolyl)-1,2,4-thiadiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of indole-3-thiocarboxamide 3 with iodobenzene diacetate underwent oxidative dimerization to give 3,5-bis(indolyl)-1,2,4-thiadiazoles 4a-n. Among the synthesized bis(indoly)-1,2,4-thiadiazoles, the compound 4h with 4-chlorobenzyl and methoxy substituents showed the most potent activity.
- Kumar, Dalip,Kumar, N. Maruthi,Chang, Kuei-Hua,Gupta, Ritika,Shah, Kavita
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p. 5897 - 5900
(2011/10/18)
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- COMPOUNDS FOR TREATMENT OF CANCER
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The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.
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- An efficient route for the synthesis of 2-arylthiazino[5,6-b]indole derivatives
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Substituted 2-thiobenzamidomethylindole derivatives (14a-e) were prepared by the reaction of 2-aminomethylindole (9) with substituted benzoyl chlorides, followed by sulfurization using Lawesson's reagent. Alternatively, these thioamides were obtained from the amine in one step in an efficient manner by using substituted benzaldehydes in the presence of sulfur, or at room temperature with the aid of substituted methyl dithiobenzoates. The Hugerschoff reactions of thiobenzamides (14a-e) with phenyltrimethylammonium tribromide provided the rare title 2-arylthiazino[5,6-b]indoles (15a-e) in good yields. A convenient one-pot approach for the synthesis of 2-phenyl-1,3-thiazino[5,6-b]indole (15a) from 2-aminomethylindole (9) is also described.
- Csomós, Péter,Fodor, Lajos,Mándity, István,Bernáth, Gábor
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p. 4983 - 4989
(2008/02/01)
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- INDOLE-2 -CARBOXAMIDINE DERIVATIVES AS NMDA RECEPTOR ANTAGONISTS
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The present invention relates therefore first to new indole-2-carboxamidine derivatives of formula (I) - wherein the meaning of X is hydrogen or halogen atom, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl group, Y,
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(2008/06/13)
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- COMPOUNDS TO TREAT AMYLOIDOSIS AND PREVENT DEATH OF BETA-CELLS IN TYPE 2 DIABETES MELLITUS
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The invention discloses aromatic amides and sulfonates to treat or prevent type 2 diabetes mellitus (T2DM), the pathological consequences of T2DM, to inhibit amyloidosis or to prevent death of β-cells of the pancreas.
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Page/Page column 44; 45
(2010/11/24)
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- Beta-strand mimetics and method relating thereto
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Conformationally constrained compounds which mimic the secondary structure of β-strand regions of biologically active peptides and proteins are disclosed. Such β-strand mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the β-strand mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members.
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- BETA-STRAND MIMETICS AND METHOD RELATING THERETO
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Conformationally constrained compounds which mimic the secondary structure of ?-strand regions of biologically active peptides and proteins are disclosed. Such ?-strand mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the ?-strand mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members.
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- Carbopalladation of nitriles: Synthesis of 2,3-diarylindenones and polycyclic aromatic ketones by the Pd-catalyzed annulation of alkynes and bicyclic alkenes by 2-iodoarenenitriles
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2-Iodobenzonitrile, its derivatives, and various heterocyclic analogues undergo palladium(O)-catalyzed annulation onto diarylacetylenes or bicyclic alkenes to afford 2,3-diarylindenones and polycyclic aromatic ketones in very good to excellent yields. This reaction represents one of the first examples of the addition of an organopalladium moiety to the carbon-nitrogen triple bond of a nitrile. The reaction is compatible with a number of functional groups. A reaction mechanism, as well as a model accounting for the electronic effects of substituents on the aromatic ring of the nitrile, is proposed.
- Pletnev, Alexandre A.,Tian, Qingping,Larock, Richard C.
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p. 9276 - 9287
(2007/10/03)
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- Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases
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Use of a compound for treating a respiratory disease in a mammal wherein the compound is a cannabinoid receptor modulator is disclosed. Compounds useful as cannabinoid receptor modulators for treating respiratory and non-respiratory leukocyte-activation associated diseases comprise compounds of formula (I), in which A and B are nitrogen or carbon, provided only one of A and B is nitrogen; and R1-R6 are as defined in the specification, wherein R2 with R5 may form a ring, and/or two R4 groups may form a six-membered aryl or heteroaryl ring, optionally having a substituent R6 forming a ring with R3.
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- 4-indole derivatives as serotonin agonists and antagonists
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The present invention relates to compounds of the formula
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- Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity
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Vitronectin receptor antagonists having the formula: STR1 which are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporsis.
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- Oxoazepine derivatives
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This invention relates to novel oxoazepine derivatives of Formula (I), to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit agonist ac
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- N-SUBSTITUTED IMIDAZOLE AND BENZIMIDAZOLE DERIVATIVES USEFUL AS ANGIOTENSON II ANTAGONISTS
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Compounds are disclosed having the formula STR1 These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- ANTIMIGRAINE DERIVATIVES OF INDOLYLCYCLOALKANYLAMINES
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A series of novel serotonergic indolyl derivatives of cycloalkanyl-and cycloalkenyl-amines of Formula I are intended for use in the alleviation of vascular headaches. STR1
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- Substitute indole and benzimidazole derivatives
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Novel compounds are disclosed having the formula STR1 or its isomer STR2 wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders
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A compound having the formula: STR1 wherein R1 and R2 independently is selected from the group consisting of H, C3 -C12 straight or branched alkyl, aryl or lower alkyl-substituted aryl; or R1 and R2 may be joined to form a 4-to 6-membered saturated or unsaturated ring or a 4-to 6-membered saturated or unsaturated lower alkyl-substituted ring; R3 is H, C1 -C12 straight or branched alkyl, NO2, NH2, N3, CN, halogen, CO2 R, OR, or SR wherein R is H or lower alkyl; R4 is H, C1 -C12 straight or branched alkyl, NO2, NH2, N3, CN, halogen, CO2 R, OR, or SR wherein R is H or lower alkyl; A is nothing or a C1 -C5 alkylene to form a ring; Z is 0, NH, S or --CH=CH--; and n is an integer of 1-3; or a pharmaceutically acceptable salt thereof. The compounds are useful in compositions and methods for treating psychiatric and neurological disorders.
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- Enolamides, pharmaceutical compositions and methods for treating inflammation
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The present invention relates to novel enolamide type compounds, pharmaceutical compositions, and methods of use thereof, useful in the treatment of diseases in which products of lipoxygenase enzyme activity or the action of leukotrienes contribute to the
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