6575-28-6

Upstream product

• 83-38-5 2,6-dichlorobenzaldehyde 

Downstream Products

• 1194-65-6 2,6-dichloro-benzonitrile 
• 55151-92-3 3-(2,6-dichlorophenyl)-5-methyl-1,2,4-oxadiazole 
• 50-30-6 2,6-dichlorobenzoic acid 
• 774605-58-2 3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carboxylic acid 
• 278597-28-7 methyl 3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carboxylate 
• 946426-88-6 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylic acid methyl ester 

Relevant academic research and scientific papers

Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio

The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non-steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.

ISOXAZOLE DERIVATIVE AS MUTATED ISOCITRATE DEHYDROGENASE 1 INHIBITOR

It has been found that a compound of the general formula (I) having an isoxazole skeleton has excellent inhibitory activity against mutant IDH1 protein and inhibits the production of 2-HG by this protein, while the compound is also capable of effectively inhibiting the growth of various tumors expressing the protein. In the formula, R1, R2, R3, Y, and Z are as defined in claim 1.

Heterocyclic farnesoid X receptor modifier

The invention relates to a preparation method of a heterocyclic compound and a composition with components the same as those of the heterocyclic compound and application of the heterocyclic compound as a farnesoid X receptor active modifier. The modifier is the heterocyclic compound shown as the formula I or salt acceptable pharmaceutically or a predrug or a solvent compound or a polycrystal or an isomer or a stable isotope derivative. The compound can be used for treating or preventing related diseases mediated by FXR, and the related diseases are caused by saccharide or lipid or bile metabolic disturbance. The formula I is shown in the specification.

Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism

Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.

Novel FXR (NR1H4) binding and activity modulating compounds

The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of the NR1H4 receptor (FXR). The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds, and to a process for the synthesis of said compounds.

Highly efficient and catalytic conversion of aldoximes to nitriles

(Matrix Presented) Catalytic dehydration of aldoximes can be performed highly efficiently with a catalyst system of [RuCl2(p-cymene)]2/molecular sieves under essentially neutral and mild conditions, and various types of cyano compounds are produced in good to excellent yields.

Ceric ammonium nitrate oxidation of aldoximes in aliphatic nitriles as solvents: A new way for synthesis of 1,2,4-oxadiazoles

Oxidation of aromatic aldoximes with one-electron oxidant ceric ammonium nitrate CAN in acetonitrile and propionitrile, has been investigated. Aromatic nitrile oxides, formed in situ, underwent 1,3-cycloaddition with aliphatic nitriles and 5-alkyl-3-aryl-1,2,4-oxadiazoles are produced in moderate to high yields. The mechanism of the reaction based on the transformations of intermediate aldazine di-N-oxides is discussed.

Imines and Derivatives. Part 20. N-Phosphinoyloxaziridines: Synthesis and Structural Characterisation by Nuclear Magnetic Resonance Spectroscopy and a Crystal Structure of 3-(4-Chlorophenyl)-2-(diphenylphosphinoyl)oxaziridine

The preparation of a new class of oxaziridines containing an N-phosphinoyl group is described.The compounds were obtained by peroxyacid oxidation of N-phosphinoyl imines under basic or neutral conditions, and characterised by n.m.r. spectroscopy.Revelant 2JPC, 3JPH, and 1JCH coupling constants are reported.An X-ray structure analysis of the title compound establishes that the 2-diphenylphosphinoyl group is trans to the 3-aryl ring.The P-N bond length (1.76 Angstroem) is abnormally high for an aminophosphorus(v) compound and the nitrogen atom is pyramidal (ΣN=280 deg).This geometry is interpreted in terms of an unusually low degree of ?-bonding between nitrogen and phosphorus due to the high s-character of the nitrogen lone pair.