- Quinoxaline compound, preparation method and application of quinoxaline compound in medicine
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The invention provides a quinoxaline compound, a preparation method and application of the quinoxaline compound in medicine, and particularly relates to a quinoxaline compound with PAR4 antagonistic activity, a preparation method of the quinoxaline compound, a pharmaceutical composition containing the quinoxaline compound and application of the quinoxaline compound. Specifically, the invention provides a compound shown as a general formula I and/or II or a tautomer or pharmaceutically acceptable salt thereof, a preparation method of the compound, and application of the compound or the tautomer or the pharmaceutically acceptable salt in medicines for preventing and/or treating thromboembolic diseases.
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Paragraph 0177-0179; 0181
(2021/07/24)
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- Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold
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Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
- Kong, Yi,Li, Shanshan,Liu, Shangde,Xie, Roujie,Yuan, Duo,Zhu, Xiong
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supporting information
(2021/08/16)
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- Efficient hydrogenation catalyst designing via preferential adsorption sites construction towards active copper
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Based on the experimental and DFT calculation results, here for the first time we built preferential adsorption sites for nitroarenes by modification of the supported Cu catalysts surface with 1,10-phenathroline (1,10-phen), by which the yield of aniline via reduction of nitroarene is enhanced three times. Moreover, a macromolecular layer was in-situ generated on supported Cu catalysts to form a stable macromolecule modified supported Cu catalyst, i.e., CuAlOx-M. By applying the CuAlOx-M, a wide variety of nitroarene substrates react smoothly to afford the desired products in up to > 99% yield with > 99% selectivity. The method tolerates a variety of functional groups, including halides, ketone, amide, and C = C bond moieties. The excellent catalytic performance of the CuAlOx-M can be attributed to that the 1,10-phen modification benefits the preferential adsorption of nitrobenzene and slightly weakens adsorption of aniline on the supported nano-Cu surface.
- Dai, Xingchao,He, Dongcheng,Li, Teng,Shi, Feng,Wang, Hongli,Wang, Tao,Wang, Xinzhi
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p. 397 - 406
(2021/07/21)
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- Nucleophilic aromatic substitution of unactivated fluoroarenes enabled by organic photoredox catalysis
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Nucleophilic aromatic substitution (SNAr) is a classical reaction with well-known reactivity toward electron-poor fluoroarenes. However, electron-neutral and electron-rich fluoro(hetero)arenes are considerably underrepresented. Herein, we present a method for the nucleophilic defluorination of unactivated fluoroarenes enabled by cation radical-accelerated nucleophilic aromatic substitution. The use of organic photoredox catalysis renders this method operationally simple under mild conditions and is amenable to various nucleophile classes, including azoles, amines, and carboxylic acids. Select fluorinated heterocycles can be functionalized using this method. In addition, the late-stage functionalization of pharmaceuticals is also presented. Computational studies demonstrate that the site selectivity of the reaction is dictated by arene electronics.
- Nicewicz, David A.,Pistritto, Vincent A.,Schutzbach-Horton, Megan E.
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supporting information
p. 17187 - 17194
(2020/11/02)
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- Benzotriazine compound with PAR4 antagonistic activity and application thereof
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The invention discloses a benzotriazine compound with PAR4 antagonistic activity and application thereof. The present invention relates to a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, solvate or prodrug t
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Paragraph 0059; 0061; 0063
(2020/08/02)
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- BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
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Page/Page column 455
(2018/03/25)
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- PYRAZOLE DERIVATIVES HAVING ACTIVITY AGAINST PAIN
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The present invention relates to pyrazole derivatives of formula (I) having pharmacological activity towards the α2δ subunit, in particular the α2δ-1 subunit, of the voltage-gated calcium channel, in particular having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ-1 subunit, of the voltage-gated calcium channel and the μ-opioid receptor. The present invention also relates to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 196
(2018/02/03)
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- Regioselectivity of the methanolysis of polychlorinated biphenyls
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Regioselectivity of the methanolysis of lower polychlorinated biphenyls with sodium methoxide in a mixture of methanol and DMSO at 100–130°С was studied. It was found that 2,4,4'-tricholobiphenyl is much more reactive than 2,4-dichlorobiphenyl. This results in different mechanisms of substitution. 2,4-Dichlorobiphenyl reacts with sodium methoxide by the elimination–addition mechanism to form four monosubstitution products in comparable quantities. 2,4,4'-Trichlorobiphenyl reacts with the methodixe ion by the classical SNAr mechanism, with preferential substitution of the 2-chlorine atom.
- Khaibulova, T. Sh.,Boyarskaya,Polukeev,Boyarskii
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p. 2318 - 2324
(2016/11/29)
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- HETEROARYL- SUBSTITUTED PYRROLO` 2, 3- B! PYRIDINE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
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The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).
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Page/Page column 38
(2010/02/07)
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- Imidazopyridines for the treatment of neurological disorders
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Corticotropin releasing factor (CRF) antagonists of formula (I): and their use in treating psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
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- Synthesis of functionalized indole- and benzo-fused heterocyclic derivatives through anionic benzyne cyclization
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The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.
- Barluenga, Jose,Fananas, Francisco J.,Sanz, Roberto,Fernandez, Yolanda
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p. 2034 - 2046
(2007/10/03)
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- Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
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Corticotropin releasing factor (CRF) antagonists of formula (I): and their use in treating psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
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- Azo reactive dyestuffs having an aryl-triazinyl-aryl diazo component
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Optionally metallized azo dyestuffs which in the form of the free acid correspond to the formula STR1 wherein K is the radical of a benzene, naphthalene, pyrazolone, pyridone, pyrimidone, acetoacetic acid arylide or aminopyrazole coupling component; A is a non-ionic substituent; X is STR2 wherein W is a direct bond or a bridge member to a C atom of the benzene or naphthalene nucleus or the coupling component K; R is hydrogen or C1 -C4 -alkyl; B is a direct bond or a bridge member, especially -CO- or -SO2 -, to a C atom of Q; Q is a reactive radical; m is 0, 1 or 2; n is 0, 1 or 2; p is 0 or 1; q is 0, 1 or 2; and r is 0 or 1; and their use for the dyeing and printing of natural and regenerated cellulose fibre materials such as cotton and rayon, as well as natural and synthetic polyamide fibre materials, for example those of wool, silk, poly-ε-caprolactam or polycondensate of hexamethylene-diamine and adipic acid. The dyeings obtained, espeically those on cotton and rayon, are distinguished by good fastness properties, especially fastness to wet processing and to light.
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