641571-11-1Relevant articles and documents
High Turnover Pd/C Catalyst for Nitro Group Reductions in Water. One-Pot Sequences and Syntheses of Pharmaceutical Intermediates
Gallou, Fabrice,Li, Xiaohan,Lipshutz, Bruce H.,Takale, Balaram S.,Thakore, Ruchita R.
supporting information, p. 8114 - 8118 (2021/10/25)
Commercially available Pd/C can be used as a catalyst for nitro group reductions with only 0.4 mol % Pd loading. The reaction can be performed using either silane as a transfer hydrogenating agent or simply a hydrogen balloon (μ1 atm pressure). With this technology, a series of nitro compounds was reduced to the desired amines in high chemical yields. Both the catalyst and surfactant were recycled several times without loss of reactivity.
SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
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Page/Page column 40, (2021/04/23)
Processes and useful intermediates for the synthesis of the tyrosine kinase inhibitors Formula (II) nilotinib and Formula (IV) imatinib. Key intermediates, method for their synthesis and their use in a divergent synthesis, making use of a Curtius rearrangement, to nilotinib and imatinib are described.
SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME
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Paragraph 0141-0145, (2021/08/17)
The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.
Method for synthesizing 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline
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, (2020/10/14)
The invention relates to a method for synthesizing 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline, which comprises the following steps: 1, by using 3,5-diaminobenzotrifluoride as a raw material, carrying out protection to obtain a mono-substituted product and an intermediate byproduct; and 2, carrying out a cyclization reaction on the mono-substituted product, and carrying out deprotection to obtain the 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline. The synthesis process is safe and reliable, and has the advantages of low cost, easy control of reaction, simple post-treatment, economy, environmental protection and the like.
METHOD FOR PRODUCING ANILINE COMPOUND
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Paragraph 0037; 0038; 0039-0047, (2020/03/28)
PROBLEM TO BE SOLVED: To provide a method for highly selectively producing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline from 3-bromo-5-trifluoromethylaniline. SOLUTION: There is provided a method for producing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline, which comprises (1) a step of obtaining 3-iodo-5-trifluoromethylaniline by reacting 3-bromo-5-trifluoromethylaniline and an iodizing agent in a solvent in the presence of a transition metal catalyst and a compound represented by the formula [6] (wherein, R1 and R2 are the same or different and represents an alkyl group, W represents a divalent hydrocarbon group) and (2) a step of obtaining 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline by reacting the 3-iodo-5-trifluoromethylaniline obtained in the step (1) and 4-methyl-1H-imidazole in the presence of a base. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove
Bonnar, James,Dixon, Ian,Evison, Benny J.,Kelly, Graham E.,Kumar, Sanjay,Lambert, Gilles,Nativel, Brice,Palmer, James T.,Parmar, Jasneet,Rathi, Anuj Kumar,Suchowerska, Alexandra K.,Tang, Wei,Teng, Yanfen,Treutlein, Herbert,Wang, Jie,Xu, Yanfeng,Zeng, Jun,Zhu, Qing,Chemello, Kévin
supporting information, (2020/02/13)
Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 μM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 μM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.
Investigations into the potential role of metabolites on the anti-leukemic activity of imatinib, nilotinib and midostaurin
Manley, Paul W.
, p. 561 - 570 (2019/09/03)
The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The N-desmethylmetabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients producing high levels of this metabolite show a relatively low response rate in chronic myeloid leukaemia (CML) treatment. The hydroxymethylphenyl and N-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy of either drug in CML. The 3-(R)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the PDPK1 and VEGFR2 kinases (IC50 values 100 nM), suggesting that it might contribute to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.
AN IMPROVED PROCESS FOR 3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL) ANILINE
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Page/Page column 22, (2019/07/17)
The present invention relates to an improved process for the preparation of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) aniline of Formula (I).
3 - (4 - Methyl - 1 H - imidazole - 1 - yl) - 5 - (trifluoromethyl) aniline preparation method
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, (2018/02/23)
The invention provides a preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline. The method includes: S1. subjecting a compound A and 4-methyl-1H-imidazole to coupling reaction to generate a coupling product; S2. carrying out hydrazinolysis reaction on the coupling product to generate a hydrazinolysis product; and S3. subjecting the hydrazinolysis product to diazotization and Curtius rearrangement reaction in order to generate 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline. Specifically, the compound A is 3-halogen-5-trifluoromethylbenzoic acid, a salt derivative of 3-halogen-5-trifluoromethylbenzoic acid or an ester derivative of 3-halogen-5-trifluoromethylbenzoic acid. The method for preparation of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline provided by the invention has the characteristics of short synthesis route, low cost of raw materials, mild reaction conditions and high yield, thus being applicable to large-scale industrial production.
HETEROCYCLIC INHIBITORS OF PCSK9
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Page/Page column 66, (2018/10/24)
This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, PCSK9, or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof, and to compositions and formulations comprising such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I): (I) wherein A, D and Q are described herein.
