51145-57-4Relevant articles and documents
Synthesis method of 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid
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Paragraph 0025; 0032; 0037, (2021/03/13)
The invention relates to a synthesis method of 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid, and the method comprises the following steps: 1, carrying out condensation reaction on N, N-dimethylamino ethyl acrylate, triethylamine and acetyl chloride to generate ethyl 2-dimethylamino-3-oxobutyrate and triethylamine hydrochloride; 2, carrying out a cyclization reaction on 2-dimethylamino ethyl-3-oxobutyrate and methylhydrazine to generate 1, 3-dimethyl-1H-pyrazole ethyl-4-formate and a dimethylamine aqueous solution; 3, carrying out a reaction on formic acid, ethyl acetoacetate and dimethylamine generated in the step 2 cyclization reaction to generate 2-dimethylamino ethyl-3-oxobutyrate and water, wherein the ethyl 2-dimethylamino-3-oxobutyrate generated in the step 3 is recycled as a reactantin the step 2; 4, hydrolyzing the ethyl 1, 3-dimethyl-1H-pyrazole-4-formate to obtain the 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid. The 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid has the advantages of few synthesis steps, safe reaction process and no three-waste pollution, and is suitable for industrial batch large-scale preparation.
INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
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Page/Page column 347, (2021/01/29)
The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Design, Synthesis, In Silico Docking Studies, and Antibacterial Activity of Some Thiadiazines and 1,2,4-Triazole-3-Thiones Bearing Pyrazole Moiety
Nayak, Soukhyarani Gopal,Poojary, Boja
, p. 97 - 106 (2020/04/15)
Abstract: In view of developing new bioactive compounds, a series of 6-(substituted-phenyl)-3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and 4-[(substituted-benzylidene)amino]-5-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones were synthesized in good yields. The compounds were confirmed by elemental analyses, mass spectrometry, FT-IR, 1H, and 13CNMR spectroscopy. To study the binding interactions of the derivatives with the receptor, they were docked with the prostaglandin D2 synthase (PGDS). The docking pose and non-covalent interactions gave insights into their plausible inhibitory action. They showed good antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. Particularly, chloro, fluoro, dimethoxy, and dihydroxy substituted derivatives displayed good activity over other derivatives.
Fused tetracyclic compounds and application thereof in medicines
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Paragraph 0512; 0530-0532, (2020/04/17)
The invention relates to fused tetracyclic compounds and an application thereof in medicines, and in particular, relates to the application of the fused tetracyclic compounds as medicines for treatingand/or preventing hepatitis B. Specifically, the invention relates to the compounds represented by a general formula (I) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, wherein the variables are defined in the specification. The invention further relates to the application of the compounds represented by the general formula (I) or the stereoisomers, the tautomers, the nitric oxides, the solvates, the metabolites, the pharmaceutically acceptable salts or the prodrugs thereof as medicines, and in particular, relates tothe application of the compounds as the medicines for treating and/or preventing hepatitis B.
Preparation method of (by machine translation)
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Paragraph 0025; 0027; 0029; 0031; 0033; 0035; 0037, (2020/06/24)
The invention relates to a novel process for preparing flutamipide by using a pharmaceutical active pharmaceutical ingredient, wherein ethyl acetoacetate is taken as a raw material and mixed with hydroxylamine hydrochloride to obtain fluticide. The process not only can better control the content of 3 - methyl isomers and 4 - trifluoromethylaniline in the baflunomide product, and is higher in yield and more concise. The industrial wastewater generated by the process is less in waste gas, environmentally friendly, capable of effectively reducing production cost and corrosion to equipment. (by machine translation)
1-(4-(ISOXAZOL-5-YL)-1H-PYRAZOL-1-YL)-2-METHYLPROPAN-2-OL DERIVATIVES AND RELATED COMPOUNDS AS IL-17 AND IFN-GAMMA INHIBITORS FOR TREATING AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATION
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, (2019/04/10)
The present invention relates to compounds of the general formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein Ar, Z and Y are as described herein and R1 is a group of the structure (formula (II)), wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, trilluoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group, or R3 forms a methylene bridge to the carbon atom marked *, which are suitable for the treatment of autoimmune diseases and chronic inflammation.
Novel N-thioamide analogues of pyrazolylpyrimidine based piperazine: Design, synthesis, characterization, in-silico molecular docking study and biological evaluation
Vekariya, Mayur K.,Patel, Dhaval B.,Pandya, Pranav A.,Vekariya, Rajesh H.,Shah, Prapti U.,Rajani, Dhanji P.,Shah, Nisha K.
, p. 551 - 565 (2018/09/18)
Utilizing molecular hybridization approach, a progression of novel pyrazolylpyrimidine based N-thioamide derivatives of piperazine were identified in an effort to develop newer antibacterial and antitubercular agents against the cumulative bacterial resistance. Spectral analysis using Mass, 1H NMR and 13C NMR spectral techniques have been studied in order to affirm the structure of synthesized end molecules. Biological evaluation of all synthesized molecules were studied in-vitro for their antibacterial, antituberculosis and antimalarial efficacy against various bacterial and fungal strains, H37Rv and Plasmodium falciparum respectively. Molecular docking and ADME properties prediction study were also carried out for better insights of responsible proteins with the synthesized molecules. Interestingly, some of the pyrazolylpyrimidine based piperazine N-thioamide derivatives exhibited potential antibacterial, antifungal and antimalarial potency.
Polysubstituted thieno[2,3-b]pyridine derivatives, and preparation method and application thereof
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Paragraph 0117-0119, (2020/01/12)
The invention discloses polysubstituted thieno[2,3-b]pyridine derivatives, and a preparation method and an application thereof. The structural formula of the derivatives are represented by formula I shown in the description. A compound for inhibiting a urea transporter is screened by using an erythrocyte model. Experimental results show that the compounds (represented by formula I-1) can inhibit the permeation of a urea transporter UT-B mediated erythrocyte membrane to urea, and the effect of the compounds has a dose-dependent relationship; the compounds represented by the formula I-1 have nocytotoxic effect on MDCK cells within an effective dose range, so the effect of the compounds represented by the formula I-1 on inhibiting cell permeation urea is irrelevant to the cytotoxicity of thecompounds; the inhibition effect of the compounds represented by the formula I-1 on the urea transporter UT-B is gradually enhanced; the inhibiting effect of the compounds represented by the formulaI-1 on the UT-B is reversible; and in-vivo test results show that the compounds represented by the formula I-1 can significantly increase the urination volume of rats, reduce the concentration of ureain rat urine and reduce the osmotic pressure, so that the compounds represented by the formula I-1 generate a urea selective diuresis effect in vivo.
Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation
Yang, Wei,Li, Yingjun,Ai, Yong,Obianom, Obinna N.,Guo, Dong,Yang, Hong,Sakamuru, Srilatha,Xia, Menghang,Shu, Yan,Xue, Fengtian
, p. 11151 - 11164 (2019/12/27)
Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (1c) which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.
