- Oxadiazole and thiadiazole compounds and preparation methods and applications thereof
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The invention discloses oxadiazole and thiadiazole compoundsand preparation methods and applications thereof.The compounds is shown as a formula I or a formula II.The oxadiazole or thiadiazole compound or a pharmaceutically acceptable salt, racemate, opti
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Paragraph 0051-0053
(2019/07/04)
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- Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox
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Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids to explore the structure-plasma stability relationships in these series and to identify which enzyme(s) and which pharmacophores are critical for plasma stability. Arylesterases and carboxylesterases were identified as the main metabolic enzymes for hydroxamic acids. Finally, we suggest structural features to be introduced or removed to improve stability. This work thus provides the first medicinal chemistry toolbox (experimental procedures and structural guidance) to assess and control the plasma stability of hydroxamic acids and realize their full potential as in vivo pharmacological probes and therapeutic agents. This study is particularly relevant to preclinical development as it allows obtaining compounds equally stable in human and rodent models.
- Hermant, Paul,Bosc, Damien,Piveteau, Catherine,Gealageas, Ronan,Lam, Baovy,Ronco, Cyril,Roignant, Matthieu,Tolojanahary, Hasina,Jean, Ludovic,Renard, Pierre-Yves,Lemdani, Mohamed,Bourotte, Marilyne,Herledan, Adrien,Bedart, Corentin,Biela, Alexandre,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 9067 - 9089
(2017/11/14)
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- Discovery of potent c-MET inhibitors with new scaffold having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine headgroups
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Cellular mesenchymal-epithelial transition factor (c-MET) is closely linked to human malignancies, which makes it an important target for treatment of cancer. In this study, a series of 3-methoxy-N-phenylbenzamide derivatives, N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl) benzamide derivatives and N1-(3-fluoro-4-methoxyphenyl)-N3-(4-fluorophenyl) malonamide derivatives were designed and synthesized, some of them were identified as c-MET inhibitors. Among these compounds with new scaffolds having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine head groups, compound 11c, 11i, 13b, 13h exhibited both potent inhibitory activities against c-MET and high anticancer activity against tested cancer cell lines in vitro. In addition, kinase selectivity assay further demonstrated that both 13b and 13h are potent and selective c-MET inhibitors. Molecular docking supported that they bound well to c-MET and VEGFR2, which demonstrates that they are potential c-MET RTK inhibitors for cancer therapy.
- Jiang, Yingnan,Zhang, Ke,Gao, Suyu,Wang, Guihua,Huang, Jian,Wang, Jinhui,Chen, Lixia
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- METHOD OF PRODUCING CARBOXYLATE
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PROBLEM TO BE SOLVED: To provide a method of producing useful chemicals of carboxylates through hydrocarboxylation reaction of olefins by effectively utilizing carbon dioxide without using any expensive reducing agent. SOLUTION: A method of producing a carboxylate represented by the general formula (3) includes reacting an olefin with a formate represented by the general formula (2). (An+ is an n-valent cation; n is an integer from 1 to 4; and R1 to R4 are each independently H or a C1-24 organic group, where two or more of the R1 to R4 may be connected with each other.) SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0064-0068
(2018/10/16)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 101; 102
(2015/07/07)
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- Generation of carbanions through stibine-metal and bismuthine-metal exchange reactions and its applications to precision synthesis of ω-end-functionalized polymers
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Generation of carbanions from organostibines and organobismuthines through heteroatom-metal exchange reactions was examined from synthetic and mechanistic viewpoints. The exchange reaction proceeded spontaneously upon treatment with various organometallic reagents, such as alkyl lithiums, tetraalkyl zincates, and alkyl magnesium halides to afford the corresponding carbanions quantitatively. Due to the high reactivity of these heteroatom compounds, the exchange reactions took place exclusively even in the presence of various polar functional groups, which potentially react with organometallic species. The advantage of this method was exemplified by the end-group transformation of living polymers that bear these heteroatom species at the ω-polymer end, prepared by using organostibine and bismuthine-mediated living radical polymerizations. Various polymers that bear polar functional groups and acidic hydrogen-for example, poly(methyl methacrylate), poly(butyl acrylate), poly(N-isopropyl acrylamide), and poly(2-hydroxyethyl methacrylate)-could be used in the exchange reactions, and subsequent trapping with electrophiles afforded the corresponding polymers with controlled molecular weights, molecular weight distributions, and end-group functionalities. Competition experiments showed that organostibines and organobismuthines were among the most reactive heteroatom compounds towards organometallic reagents and that their high reactivity was responsible for the high chemoselectivity in the exchange reaction. All's well that ends well: The generation of carbanions from organostibine and -bismuthine compounds was achieved thorough a heteroatom-metal exchange reaction (see scheme). The highly chemoselective exchange reaction could be applied to precision synthesis of varieties of ω-end- functionalized polymers that possess a polar functional group.
- Kayahara, Eiichi,Yamada, Hiroto,Yamago, Shigeru
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supporting information; experimental part
p. 5272 - 5280
(2011/06/20)
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- Compounds Which Selectively Modulate The CB2 Receptor
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 31
(2011/04/18)
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- Hydroxamates: Relationships between structure and plasma stability
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Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of selectivity, toxicity, or poor stability. To help medicinal chemists with respect to plasma stability, we have performed the first and preliminary study on structure-plasma stability for hydroxamates. We define some structural rules to predict or improve the plasma stability in the preclinical stage.
- Flipo, Marion,Charton, Julie,Hocine, Akila,Dassonneville, Sandrine,Deprez, Benoit,Deprez-Poulain, Rebecca
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experimental part
p. 6790 - 6802
(2010/04/04)
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- NOVEL 6-5 BICYCIC HETEROCYCLIC DERIVATIVE AND MEDICAL USE THEREOF
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An object of the present invention is to provide a medicament as a thyroid hormone receptor ligand which is sufficient in drug efficacy and safety, and has the excellent action as a drug. The present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: [wherein [Chemical Formula 2] is a single bond or a double bond; A is -CH2- or -CO-; X, Y, and Z are each independently a nitrogen atom or a carbon atom; R1 is a hydrogen atom or an aralkyl group; R2 is an alkyl group or an aralkyl group, etc.; R3 is a hydrogen atom or an alkyl group, etc.; R4 is a hydrogen atom or an alkyl group; R5 is a hydrogen atom, an alkyl group or a halo lower alkyl group, etc.; R6 is a hydrogen atom or an alkyl group; R7 is a hydrogen atom, etc.; R8 is a hydrogen atom, or an alkyl group, etc.; and E is -NHCO-G-COR12, etc. (wherein G is a single bond or an alkylene group, and R12 is a hydroxy group or an alkoxy group)].
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Page/Page column 60
(2009/04/23)
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- BICYCLO HETEROCYCLIC COMPOUND HAVING ANTIFUNGAL ACTION
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It is intended to provide a 1,6-β-glucan synthase inhibitor which strongly inhibits proliferation and has a high safety. It is intended to provide a compound which can specifically or selectively expressing an antifungal action on a broad spectrum based on the action mechanism of inhibiting the synthesis of 1,6-β-glucan. Further, it is intended to provide a drug, in particular, an antifungal agent containing the above compound, its salt or a hydrate thereof. More specifically speaking, a compound represented by the following general formula (I), its salt or a hydrate thereof; and a drug or an antifungal agent containing the above compound, its salt or a hydrate thereof.
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Page/Page column 114-115
(2008/06/13)
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- PYRAZOLE DERIVATIVES, MEDICINAL COMPOSITION CONTAINING THE SAME, MEDICINAL USE THEREOF, AND INTERMEDIATE FOR PRODUCTION THEREOF
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The present invention provides pyrazole derivatives represented by the general formula: wherein R1 represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group represented by the general formula: or a group represented by the general formula: while the other represents an optionally substituted C1-6 alkyl group etc.; R2 represents H, a halogen atom, OH, an optionally substituted C1-6 alkyl group etc.; X represents a single bond, O or S; Y represents an optionally substituted C1-6 alkylene group etc.; Z represents -RB, -CORC etc. in which RB represents an optionally substituted C1-6 alkyl group etc.; and RC represents an optionally substituted C1-6 alkyl group etc.,; R4 represents H, an optionally substituted C1-6 alkyl group etc.; and R3, R5 and R6 represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase of blood galactose level such as galactosemia, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.
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Page/Page column 72
(2010/02/12)
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- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
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Page 386 - 387
(2010/02/07)
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- Conformations of Saturated Six-Membered Ring Phosphorus Heterocycles. Axial, Nonplanar Dimethylamino Group of 5,5-Dimethyl-2-(dimethylamino)-2-oxo-1,3,2-oxazaphosphorinane As Determined by X-Ray Crystallography. (1)H NMR and IR Spectroscopic Analysis of Conformation in Solution
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The title compound (7) crystallized in space group Pbca with a=7.409(2) Angstroem, b=12.180(2) Angstroem, c=12.912(4) Angstroem, Z=8, R=0.061, Rw=0.075.The molecule adopts a chair conformation with the 2-dimethylamino substituent axial.The sum of the bond angles about the exocyclic Me2N(2) (349.3(13) deg) shows a considerable deviation from planarity.The exocyclic P-N(2) bond length is unusually long (1.644(5) Angstroem).The molecules are intermolecularly hydrogen bonded in chains by way of the N(3)H and phosphoryl oxygen.From (1)H NMR measurements at 300 MHzalong with IR results, it is concluded that the same chair conformation is the predominant one populated in solution, by contrast to the known corresponding 1,3,2-dioxaphosphorinane for which Me2N is equatorial.It is concluded that the dimethylamino group is an effectively smaller substituent (lower axial conformational energy) in the 1,3,2-oxazaphosphorinane ring and in that system is also smaller than the mustard moeity N(CH2CH2Cl)2.Intermolecular hydrogen bonding can play a secondary role in determining conformation.The P-N(2) bond lengthening and pyramidal N(2) are attributed to the nonoptimal conformation about the P-N bond required for the axial Me2N to avoid potential 1,3-syn-axial repulsive steric interactions with the axial hydrogens at C4 and C6.
- Holmes, Robert R.,Day, Roberta O.,Setzer, William N.,Sopchik, Alan E.,Bentrude, Wesley G.
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p. 2353 - 2358
(2007/10/02)
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- Production of malonic anhydrides and derivatives thereof
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Malonic anhydride and substituted malonic anhydrides are prepared by ozonolysis of the enol-lactone dimers of ketenes. The resulting malonic anhydrides can be hydrolyzed with water to form the corresponding acid, reacted with an alcohol to yield the monoester, or reacted with an amine to yield the monoamide.
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