- Five-membered azole heterocyclic compound and its preparation method, pharmaceutical composition and use thereof
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The present invention relates to a five-membered azole heterocycle compound represented by the following general formula (I), a preparation method of the five-membered azole heterocycle compound, a drug composition of the five-membered azole heterocycle compound, and a use of the five-membered azole heterocycle compound in preparation of drugs for prevention or treatment of TGR5-mediated diseases. The formula (I) is represented by the instruction.
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Paragraph 0644; 0645; 0646; 0657; 0658
(2017/02/28)
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- Design, synthesis, and structure-activity relationships of 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazoles as TGR5 agonists
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Given its role in the mediation of energy and glucose homeostasis, the G-protein-coupled bile acid receptor1 (TGR5) is considered a potential target for the treatment of type2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand-based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5-dihydro-1,2,4-oxadiazoles and extensive structure-activity relationship studies are reported herein. Compound (R)-54n, the structure of which was determined by single-crystal X-ray diffraction and quantum chemical solid-state TDDFT-ECD calculations, showed the best potency, with an EC50 value of 1.4nM toward hTGR5. Its favorable properties invitro warrant further investigation.
- Zhu, Junjie,Ye, Yangliang,Ning, Mengmeng,Mandi, Attila,Feng, Ying,Zou, Qingan,Kurtan, Tibor,Leng, Ying,Shen, Jianhua
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supporting information
p. 1210 - 1223
(2013/07/26)
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- Regioselective synthesis of polysubstituted pyridines via hetero-Diels-Alder reaction of isotellurazoles with acetylenic dienophiles
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Treatment of substituted isotellurazoles or their Te-oxides with acetylenic dienophiles efficiently afforded polysubstituted pyridine derivatives through a pathway involving hetero-Diels-Alder reaction of isotellurazoles and the subsequent tellurium extru
- Shimada, Kazuaki,Takata, Yukichi,Osaki, Yu,Moro-oka, Akiko,Kogawa, Hisashi,Sakuraba, Maiko,Aoyagi, Shigenobu,Takikawa, Yuji,Ogawa, Satoshi
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scheme or table
p. 6651 - 6653
(2010/03/01)
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- SYNTHESES OF 2-AZAFLUORENONES FROM 3-SUBSTITUTED 4-ARYLPYRIDINES
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3-substituted 4-arylpyridines (5a-i) were synthesized in good yields by reaction of mixed copper, zinc aryl organometallics (2a-e) with 1-ethoxycarbonylpyridinium chlorides (1a-d) followed by o-chloranil oxidation under reflux in toluene.The arylpyridines (5a-i) are obtained predominantly.Having compounds (5a-i) in hand, a convenient method was developed for the synthesis of 2-azafluorenones (7a-f) by using cyclization of 4-arylpyridines (5a-i) with phosphoric acid.
- Shiao, Min-Jen,Liu, Kang-Hsiuan,Lin, Pen-Yuan
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p. 507 - 518
(2007/10/02)
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- Regioselective Addition ofd Copper-Zinc Aryl Organometallic Reagents to 3-substituted Pyridinium Salts
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A number of 3-substituted pyridinium salts are subjected to nucleophilic addition by copper-zinc aryl organometallic reagents.The adducts are oxidized subsequently to form the corresponding 4-arylpyridines.In all the cases 1,4-addition products are obtained predominantly.The regioselectivity can be rationalized according to the hard-soft acid-base principle.Calculations on both charge distributions and FMO coefficients indicate that these reactions may be classified on the basis of the type of soft acid-soft base reactions.The observed γ-attack complies very well with the orientation of the FMO coefficients as estimated by a semiempirical method.
- Shiao, Min-Jen,Chia, Win-Long,Shing, Tai-Li,Chow, Tahsin J.
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p. 2101 - 2121
(2007/10/02)
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