- 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 0205; 0206
(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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- Switching pathways: Room-temperature neutral solvolysis and substitution of amides
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Stick or twist: By introducing steric hindrance at the nitrogen atom, stable linear amides bearing an electron-withdrawing α-substituent (Z=Ar, PhSO2, P(O)(OR)2, CN, or CO2R) can be induced to undergo solvolysis and substitution reactions through an elimination-addition mechanism (see picture). Key to this process is a low barrier to rotation around the amide bond and the α-substituentZ. Copyright
- Hutchby, Marc,Houlden, Chris E.,Haddow, Mairi F.,Tyler, Simon N. G.,Lloyd-Jones, Guy C.,Booker-Milburn, Kevin I.
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supporting information; experimental part
p. 548 - 551
(2012/02/04)
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- Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and VAP-1 mediated adhesion useful for treatment and prevention of diseases
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Compositions and methods of using compositions for treatment of inflammatory diseases and immune disorders are provided. Allylamino compounds are disclosed which are inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein 1 (VAP-1). The compounds have therapeutic utility in suppressing inflammation and inflammatory responses, and in treatment of several disorders, including multiple sclerosis and stroke.
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Page/Page column 67
(2008/06/13)
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- PIPERIDINE COMPOUND AND PROCESS FOR PREPARING THE SAME
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The present invention is to provide a piperidine compound represented by the formula [I]: wherein Ring A is an optionally substituted benzene ring, Ring B is an optionally substituted benzene ring, R1 is hydrogen atom or a substituent for amino group, R2 is hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z is oxygen atom or -N(R3)-, R3 is hydrogen atom or an optionally substituted alkyl group, R4a and R4b may be the same or different, and each is hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, which has an excellent tachykinin receptor antagonistic action.
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Page/Page column 54-56
(2010/10/20)
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- 1-AMIDO-4-PHENYL-4-BENZYLOXYMETHYL-PIPERIDINE DERIVATIVES AND RELATED COMPOUNDS AS NEUROKININ-1(NK-1) ANTAGONISTS FOR THE TREATMENT OF EMESIS, DEPRESSION, ANXIETY AND COUGH
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Disclosed are NK1 antagonists having the formula: Also disclosed are uses of compounds of formula (I) for the manufacture of a medicament for treating a number of physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.
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Page/Page column 63
(2010/02/06)
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- Novel dihydropyridinone compounds
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Disclosed are novel dihydropridinone compounds that are selective inhibitors of both KDR and FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon lung and prostate tumors. Also, disclosed are pharmaceutical compositions containing these compounds and methods of treating cancer.
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Page/Page column 18
(2010/02/07)
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- Cyclohexyl derivatives and their use as therapeutic agents
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The present invention relates compounds of the formula (I): wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of: (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R?17, R18, R19, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- Cyclohexane derivatives and their use as therapeutic agents
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The present invention relates compounds of formula (I), wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of formulae: (a), (b), (c), (d), and (e); and R1, R2, R3, R4, R5, R6, R7, R13, R14, R15, R16, R17, R21a and R21b are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.
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- Process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof and dialkyl [bis-(trifluoromethyl)-phenyl]-malonates
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[Bis-(trifluoromethyl)-phenyl]-acetic acids are obtained in an advantageous manner by reacting an appropriate bromo- or iodo-bis-(trifluoromethyl)-benzene with a di-C1-C4-alkyl malonate in the presence of a deprotonating agent and a copper salt and hydrolysing and decarboxylating the reaction product in basic medium. It is possible to obtain a mixture of alkyl [bis-(trifluoromethyl)-phenyl]-acetate and alkyl [bis-(tri-fluoromethyl)-phenyl]-malonate by admixing the reaction mixture which is present before hydrolysis and complete decarboxylation with water and acid and heating. From the mixture, it is possible to obtain alkyl [bis-(trifluoromethyl)-phenyl]-acetate by distillation under reduced pressure and dialkyl [bis-(trifluoromethyl)-phenyl]-malonate by work-up by column chromatography, fractional distillation or film distillation. [Bis-(trifluoromethyl)-phenyl]-malonic esters are novel compounds.
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Page column 6-7
(2010/11/30)
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- Gem-disubstituted azacyclic tachykinin antagonists
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The present invention is directed to certain compounds represented by structural formula I: STR1 or a pharmaceutically acceptable salt thereof wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, A 1, A 2, X, m and n are defined herein. The compounds of this invention are tachykinin receptor antagonists and are of particular use in the treatment of pain, inflammation, migraine and emesis.
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- Aralkoxy and aralkylthio substituted azacyclic compounds as tachykinin antagonists
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The present invention relates to compounds of formula (I) wherein n is 3 and where any carbon atom of (CH2)n may be substituted by R4 and/or R5 ; X represents O or S; R1 represents (CH2)su
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- Non-Peptide Angiotensin II Receptor Antagonists. 2. Design, Synthesis, and Biological Activity of N-Substituted (Phenylamino)phenylacetic Acids and Acyl Sulfonamides
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The design, synthesis, and biological activity of a new class of highly potent non-peptide AII receptor antagonists derived from N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides which exhibit a high selectivity for the AT1 receptor are described.A series of N-substituted (phenylamino)phenylacetic acids (9) and acyl sulfonamides (16) and a tetrazole derivative (19) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay.The (phenylamino)phenylacetic acids 9c (AT1 IC50=4 nM, AT2 IC50=0.74 μM), 9d (AT1 IC50=5.3 nM, AT2 IC50=0.49 μM), and 9e (AT1 IC50=5.3 nM, AT2 IC50=0.56 μM) were found to be the most potent AT1-selective AII antagonists in the acid series.Incorporation of various substituents in the central and bottom phenyl rings led to a decrease in the AT1 and AT2 binding affinity of the resulting compounds.Replacement of the carboxylic acid (CO2H) in 9c, 9d, and 9e with the bioisostere acyl sulfonamide (CONHSO2Ph) resulted in a (5-7)-fold increase in the AT1 potency of 16a (AT1 IC50=0.9 nM, AT2 IC50=0.2 μM), 16b (AT1 IC50=1 nM, AT2 IC50=2.9 μM), and 16c (AT1 IC50=0.8 nM, AT2 IC50=0.42 μM) and yielded acyl sulfonamides with subnanomolar AT1 activity.Incorporation of the acyl sulfonamide (CONHSO2Ph) for the CO2H of 9c not only enhanced the AT1 potency but also effected a marked increase in the AT2 potency of 16a (AT2 IC50=0.74 μM of 9c vs 0.2 μM of 16a) and made it the most potent AT2 antagonist in this study.Replacement of the CO2H of 9b with the bioisostere tetrazole resulted in 19 (AT1 IC50=15 nM) with a 2-fold loss in the AT1 and a complete loss in the AT2 binding affinity. (Phenylamino)phenylacetic acid 9c demonstrated good oral activity in AII-infused conscious normotensive rats at an oral dose of 1.0 mg/kg by inhibiting the pressor response for >6 h.Acyl sulfonamides 16a-c displayed excellent in vivo activity by blocking the AII-induced pressor response for >6 h after oral administration in conscious rats at a 3.0 mg/kg dose level.Both acyl sulfonamides 16a and 16c exhibited superior in vivo activity in rats compared to that of (phenylamino)phenylacetic acid 9c.
- Dhanoa, Daljit S.,Bagley, Scott W.,Chang, Raymond S. L.,Lotti, Victor J.,Chen, Tsing-Bau,et al.
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p. 4239 - 4249
(2007/10/02)
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