35450-53-4

The invention relates to the field of styrene sulfone compounds and NLRP3 inhibitors, and particularly provides a styrene sulfone NLRP3 inflammasome inhibitor, a preparation method and application thereof, wherein the inhibitor is represented by a formula (1), n is selected from 0 and 1, X is selected from N and O, R1 is selected from different electron withdrawing or electron donating substituents, and R2 is selected from different fat or aromatic substituents. According to the invention, it is verified that the compounds represented by the general formula have NLRP3 inhibitory activity.

The invention discloses a category represented by the following general formula I N - aryl sulfonamide compound, to the compound as the active ingredient of the pharmaceutical composition, and their preparation for treating Lp - PLA2 In the diseases related to the activity of the use. (by machine translation)

The invention belongs to the technical field of medicinal chemistry and particularly relates to a preparation method of a glimepiride impurity. The preparation method comprises the following steps: dropwise adding acetic anhydride into a solution of 2-phenethylamine and an organic solvent with a low boiling point to be subjected to reaction to generate N-acetyl phenethylamine; dropwise adding chlorosulfonic acid into the N-acetyl phenethylamine at the temperature of lower than 20 DEG C to be subjected to chlorosulfonation reaction, and performing hydrolysis after the reaction is completed to remove excess chlorosulfonic acid; performing filtration and washing to obtain an impurity J benzenesulfonyl chloride; performing ammonolysis on the impurity J benzenesulfonyl chloride to obtain an impurity J benzene sulfonamide; in acetone, enabling the impurity J benzene sulfonamide to firstly react with a catalyst and then react with trans-p-methylcyclohexyl isocyanate to obtain an impurity J acetyl substance; enabling the impurity J acetyl substance and ethanol to be subjected to alcoholysis under the condition of the catalyst to generate an impurity J and ethyl acetate; and performing refining to obtain a high-purity impurity J. The purity of the glimepiride impurity J prepared by the method is high, the liquid phase content of the glimepiride impurity J is greater than 98.5%, the rawmaterials used in the method are easily available, the process parameters are controllable, and the reaction is mild.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.

A novel product-derived bimetallic palladium complex catalyzes a sulfonylazide-transfer reaction with the σ-donor/π-acceptor ligand CO, and is advantageous given its broad substrate scope, high efficiency, and mild reaction conditions (atmospheric pressure of CO at room temperature). This methodology provides a new approach to sulfonylureas, which are present in both pharmaceuticals and agrochemicals. The synthesis of Glibenclamide on a gram scale further revealed the practical utility of this procedure. Mechanistically, the generation of a bridged bimetallic palladium species derived from the product sulfonylurea is disclosed as the crucial step for this catalytic cycle.

The invention aims at providing a synthesis process of glibenclamide intermediate 4-Acetamidobenzenesulfonamide. The synthesis process is characterized by comprising the following steps that 1, a crude acetyl phenethylamine acyl compound product is prepared, namely phenethylamine and acetic anhydride perform acylation reaction; 2, acetylamino-benzenesulfonyl chloride is prepared, namely an acetyl phenethylamine acyl compound and chlorosulfonic acid perform chlorosulfonation reaction; 3, the 4-Acetamidobenzenesulfonamide is prepared, namely the acetylamino-benzenesulfonyl chloride and ammonia water perform reaction; The synthesis process has the advantages that by changing the proportion of reactants and reaction conditions, the yield of the glibenclamide intermediate 4-Acetamidobenzenesulfonamide is improved, and further the glyburide yield is improved.

Provided herein are diaminopyrimidyl Compounds having the following structures: wherein X, L, R1, and R2 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidyl Compound, and methods for treating or preventing PKC-theta-mediated disorders, or a condition treatable or preventable by inhibition of a kinase, for example, PKC-theta.

A compound of formula I, (I) or a pharmaceutically-acceptable salt thereof. The compound is useful in the treatment of cancer.

A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of autoimmune diseases and inflammatory conditions.

A novel class of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups were designed and synthesized. The target compounds were assayed for the effects on the insulin release of isolated rat pancreatic islets and the glucose transport in adipocytes of rats. Some of them exhibited high potency. Compound 10 also had potent antiplatelet activity and showed an excellent property to protect collagen-epinephrine-induced mice mortality as well as plasma glucose-lowering activity in vivo. The preliminary pharmacological profile of compound 10 showed that it might be useful in the treatment of diabetics with cardiovascular and nephropathy complications.

The invention relates to sulfonamido derivatives of formula (I) wherein R1-R7 are as defined in the description. Compounds (I) antagonize the 10 vanilloid receptor and can be used for the preparation of medicaments for the treatment of inflammatory states.

Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH2 and H (of the SO2NH function) substituents of SPA with various R1 and R2 groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC50 2NH function and a relatively small R1 substituent (R1 = NH2, CH3). Any increase in the size of R1 led to a moderate decrease of the affinity, and the N-alkylation of the SO2NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R1 and R2 substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R1 substituent. One of the new compounds (R1 = methyl, R2 = propyl) inhibited all human CYP 2Cs with IC50 values between 10 and 20 μM, while another one (R1 = allyl, R2 = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R1 = R2 = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R1 = CH3, R2 = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R1 = NH2, R2 = (CH2)2CH(CH3)2) appears to be particularly interesting for that purpose as its IC50 value for CYP 2C8 is low (3 μM) and 20-fold smaller than those found for CYP 2C9 and 2C19.