- Benzimidazole compound, preparation method thereof and application of the benzimidazole compound in preparation of ferroptosis inhibitor
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The invention discloses a benzimidazole compound, a preparation method thereof and application of the benzimidazole compound in preparation of a ferroptosis inhibitor. The benzimidazole compound has a structure as shown in a formula (I) or a formula (II)
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Paragraph 0096-0100
(2021/06/13)
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- TREATING LONG QT SYNDROME
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This document relates to compounds useful for treating and preventing disorders associated with long QT syndrome such as cardiac arrhythmia, ventricular arrhythmia, hypertrophic cardiomyopathy, and congestive heart failure. Also provided herein are methods and materials for using such compounds to shorten myocardial repolarization time in a patient.
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Page/Page column 45-46
(2020/08/22)
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- A class of GPR40 agonist compounds with amide structure, and uses thereof
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The present invention relates to a class of amide compounds with a novel structure, and a pharmaceutical composition thereof, wherein the structure of the amide compound is represented by a general formula (I). According to the present invention, the amide compound (I) can regulate GPR40 activity, and can be used for GPR40 activity related diseases such as diabetes and metabolic syndrome. The formula I is defined in the specification.
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- Tyrosine Kinase Inhibitor And Uses Thereof
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Disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, which can be used as tyrosine kinase inhibitor. Also disclosed is a method for preparing the compound, a pharmaceutical composition and a kit comprising the compound, and uses of the compound. The compound can be used as tyrosine kinase inhibitor, or can be used to reduce or inhibit activity of EGFR or mutant thereof, such as EGFR mutant comprising T790M mutation, in a cell, or to treat and/or prevent a disease associated with overactivity of EGFR, such as cancer.
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Paragraph 0884-0885
(2017/05/15)
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- Structure-Based Design and Discovery of New M2 Receptor Agonists
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Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
- Fish, Inbar,St??el, Anne,Eitel, Katrin,Valant, Celine,Albold, Sabine,Huebner, Harald,M?ller, Dorothee,Clark, Mary J.,Sunahara, Roger K.,Christopoulos, Arthur,Shoichet, Brian K.,Gmeiner, Peter
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supporting information
p. 9239 - 9250
(2017/11/30)
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- Facile synthesis of 5-To 7-membered benzolactam compounds via strongly facilitated electrophilic aromtic substitution reaction
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We employed our system to activate aromatic ring-Tethered carbamate compounds with trifluoromethanesulfonic acid to obtain benzolactams with 5-To 7-membered rings, and examined the substrate scope and limitations of this activation method. In 5-membered ring formation, a halogen group on the aromatic ring did not greatly affect the reaction yield, but other electron-donating groups inhibited the cyclization reaction, and various side-reactions occurred. In 7-membered ring formation, eletron-donating groups on aromatic ring promoted the cyclization reaction, but cyclization of electron-deficient aromatic rings did not proceed well. The 6-membered ring formation reaction showed the greatest substrate generality.
- Kurouchi, Hiroaki,Otani, Yuko,Ohwada, Tomohiko
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p. 705 - 713
(2017/04/10)
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- Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ2 receptors
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σ2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3, 4-dihydroisoquinolin-1(2H)-one (3), with optimal σ2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ2 profile, was developed and σ2 specific binding for the corresponding [18F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [18F]-26 could not successfully image σ2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [18F]-26 may still be worthy of further investigation for the imaging of σ2 receptors in peripheral tumors devoid of P-gp overexpression.
- Abate, Carmen,Selivanova, Svetlana V.,Müller, Adrienne,Kr?mer, Stefanie D.,Schibli, Roger,Marottoli, Roberta,Perrone, Roberto,Berardi, Francesco,Niso, Mauro,Ametamey, Simon M.
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p. 920 - 930
(2013/11/19)
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- Synthesis and SAR of novel histamine H3 receptor antagonists
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The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H3 receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H3 receptors are reported.
- Jesudason, Cynthia D.,Beavers, Lisa S.,Cramer, Jeffrey W.,Dill, Joelle,Finley, Don R.,Lindsley, Craig W.,Stevens, F. Craig,Gadski, Robert A.,Oldham, Samuel W.,Pickard, R. Todd,Siedem, Christopher S.,Sindelar, Dana K.,Singh, Ajay,Watson, Brian M.,Hipskind, Philip A.
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p. 3415 - 3418
(2007/10/03)
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- ISOTHIAZOLE DIOXIDES AS CXC- AND CC- CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of the formula (IA): and the pharmaceutically acceptable salts and solvates thereof. D and E are different groups wherein one is N and the other is CR50. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of formula IA.
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Page/Page column 330
(2010/02/13)
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- 3,4-DI-SUBSTITUTED CYCLOBUTENE-1, 2-DIONES AS CXC-CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of the formula (I)or a pharmaceutically acceptable salt or solvate thereof. Also disclosed is the treatment of chemokine-mediated diseases using compounds of the formula (II)
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- Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors
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A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT1A affinity.
- Meagher, Kristin L,Mewshaw, Richard E,Evrard, Deborah A,Zhou, Ping,Smith, Deborah L,Scerni, Rosemary,Spangler, Taylor,Abulhawa, Susan,Shi, Xiaojie,Schechter, Lee E,Andree, Terrance H
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p. 1885 - 1888
(2007/10/03)
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- Synthesis of isoquinolines from indanones: Total synthesis of illudinine
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Schmidt reaction of 5-methoxy or 7-methoxyindan-1-ones or their derivatives results exclusively in isocarbostyrils which are converted into 6-methoxy or 8-methoxyisoquinolines in good yields.This strategy has been extended to the total synthesis of illudinine methyl ester (1b) starting from methyl 8-methoxy-2,2-dimethyl-7-oxo-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate (4).
- Shanker, P. Sathya,Rao, G. S. R. Subba
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p. 1209 - 1213
(2007/10/02)
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- Inhibition of phenylethanolamine n-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines: Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site
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In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound β-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound β-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.
- Sall,Grunewald
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p. 2208 - 2216
(2007/10/02)
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- Synthesis of 1,2,3,4-Tetrahydroisoquinolines
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Several aspects of 1,2,3,4-tetrahydroisoquinoline synthesis have been examined.An improved synthesis of 2-(m-methoxyphenyl)ethylamine (4) is reported. m-Anisaldehyde (5) was treated with potassium cyanide and ethyl chloroformate to yield O-(ethoxycarbonyl)-3-methoxymandelonitrile (7).Hydrogenation afforded 2-(m-methoxyphenyl)ethylamine (4) in 87percent yield overall.Some observations have been made regarding the reduction of 3,4-dihydroisoquinolines derived from the Bischler-Napieralski reaction.Amides 3a and 3c were cyclized with phosphorus oxychloride, followed by reduction to the corresponding tetrahydroisoquinolines 1a and 1c.It was shown that 1a and 1c were contaminated with 4percent of 2a and 3percent of 2c, respectively.Both 2a and 2c were independently synthesized by routes with general applicability to 8-alkoxy-1,2,3,4-tetrahydroisoquinolines.
- Kashdan, David S.,Schwartz, John A.,Rapoport, Henry
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p. 2638 - 2643
(2007/10/02)
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