- Preparation method of 2, 4-difluoro-3-nitrobenzoic acid
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The invention discloses a preparation method of 2, 4-difluoro-3-nitrobenzoic acid. The preparation method comprises the following technical key points of: carrying out amino protection on 2, 6-difluoroaniline to obtain a compound V; reacting the compound
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Paragraph 0113-0115; 0140; 0144
(2020/07/12)
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- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 96; 97
(2019/08/26)
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- Regioselective, nucleophilic activation of C&F bonds in o-fluoroanilines
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Reactions of ortho-fluorinated anilines with stoichiometric Ti(NMe2)4 in mesitylene (typically for 23 h at 120 °C) afforded moderate to high yields of the corresponding N,N-dimethyl-1,2-phenylenediamine derivatives resulting from def
- Hough, Sarita E.,Hargrove, Willie R.,Deck, Paul A.
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p. 121 - 126
(2019/07/09)
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- REMOTE HETEROARYL ALKENYLATION WITH CATALYTIC BIFUNCTIONAL TEMPLATE
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We report the design of a catalytic, bifunctional template that binds heterocyclic substrate via reversible coordination instead of covalent linkage, allowing remote site- selective C-H olefination of heterocycles. The two metal centers coordinated to this template play different roles; anchoring substrates to the proximity of catalyst and cleaving the remote C-H bonds respectively. Using this strategy, we demonstrate remote site-selective C-H olefination of heterocyclic substrates which do not have functional group handles for covalently attaching templates. For instance the olefination can be an alkenylation of a 3- phenylpyridine with an acrylate alkyl ester selective for the meta position of the phenyl group with respect to the pyridine, or can be an alkenylation of a quinoline with an acrylate alkyl ester selective for the 5-position of the quinoline.
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Page/Page column 23
(2018/09/18)
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- Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling
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One of the challenges for targeting B-RafV600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-RafWT, as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-RafV600E. To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-RafV600E/B-RafWT biochemical (bS), cellular (cS) selectivity, and the phospho-ERK activation (pA). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-RafV600E selectivity.
- Liu, Longbin,Lee, Matthew R.,Kim, Joseph L.,Whittington, Douglas A.,Bregman, Howard,Hua, Zihao,Lewis, Richard T.,Martin, Matthew W.,Nishimura, Nobuko,Potashman, Michele,Yang, Kevin,Yi, Shuyan,Vaida, Karina R.,Epstein, Linda F.,Babij, Carol,Fernando, Manory,Carnahan, Josette,Norman, Mark H.
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p. 2215 - 2234
(2016/04/26)
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- Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
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Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC50 of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED50's of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t1/2, 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (Cmax in sciatic nerve and eye are 2.36 and 1.45 μg equiv/g, respectively, when dosed with [14C] lidorestat at 10 mg/kg po).
- Van Zandt, Michael C.,Jones, Michael L.,Gunn, David E.,Geraci, Leo S.,Jones, J. Howard,Sawicki, Diane R.,Sredy, Janet,Jacot, Jorge L.,DiCioccio, A. Thomas,Petrova, Tatiana,Mitschler, Andre,Podjarny, Alberto D.
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p. 3141 - 3152
(2007/10/03)
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- Fluorination of Aromatic Derivatives with Fluoroxytrifluoromethane and Bis(fluoroxy)difluoromethane
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Fluoroxytrifluoromethane (CF3OF) and bis(fluoroxy)difluoromethane CF2(OF)2 are formed by the reaction of F2 with CO and CO2, respectively, over a CsF catalyst in a continouous-stream process.Both reagents react with aromatic substrates by an electrophilic substitution mechanism to yield fluoro-substituted derivatives.Fluorobenzene is produced in good yield from benzene, and aniline derivatives afford monofluorination products.Acetanilide (1), N-phenylmethanesulfonamide (2), α,α,α-trifluoroacetanilide (3), and 1,1,1-trifluoro(N-phenyl)methanesulfonamide (4) react with either reagent to yield mixtures of o- and p-fluoro-substituted derivatives.Solvent effects and competitive rate experiments demonstrate a preference for ortho substitution, especially in aprotic, nonpolar solvents.With particular substrates, these fluorinating agents are of practical synthetic utility, e.g., 2-fluoro-4-(trifluoromethyl)aniline is produced in high yield by fluorinating the intermediate 4-(trifluoromethyl)acetanilide (6) with CF3OF.Activated substrates such as toluene, xylenes, anisole, and cresols give mixtures of products which reduce the synthetic utility of these reagents.Nitrobenzene is fairly unreactive toward CF3OF and gives low yields of substitution products.
- Fifolt, Michael J.,Olczak, Raymond T.,Mundhenke, Rudolph F.
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p. 4576 - 4582
(2007/10/02)
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