- Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors
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Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, with 5% and 10%body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2 dual inhibitor 25a may achieve better clinical benefits.
- Wei, Manman,Peng, Xia,Xing, Li,Dai, Yang,Huang, Ruimin,Geng, Meiyu,Zhang, Ao,Ai, Jing,Song, Zilan
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- C-N Cross-Coupling via Photoexcitation of Nickel-Amine Complexes
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C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C-N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr2·3H2O), is oxygen tolerant, and proceeds through direct irradiation of the nickel-amine complex. This operationally robust process was employed for the synthesis of diverse C-N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr2·3H2O with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C-N cross-coupling reactivity.
- Lim, Chern-Hooi,Kudisch, Max,Liu, Bin,Miyake, Garret M.
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supporting information
p. 7667 - 7673
(2018/05/31)
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- A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald-Hartwig Amination
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Transition-metal catalysis has revolutionized organic synthesis, but difficulties can often be encountered when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery collections that are enrich
- Richardson, Jeffery,Ruble, J. Craig,Love, Elizabeth A.,Berritt, Simon
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p. 3741 - 3750
(2017/04/11)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The invention relates to the field of medicine, discloses new nitrogen heterocyclic derivatives, preparation method thereof and as medicament in particular as the treatment and prevention of treating tissue fibrosis of the medicament. The invention also discloses a pharmaceutically acceptable compound of the present invention comprise a pharmaceutical composition and methods for using the composition for the treatment of the human or animal tissue fibrosis of diseases, in particular for treating the human or animal renal interstitial fibrosis, glomerular sclerosis, hepatic fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, after the operation of adhering, benign prostate hypertrophy, bone-myocardial, scleroderma, multiple sclerosis, pancreas fibrosis, liver cirrhosis, myosarcoma, neurofibromatosis, interstitial pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis disease in use. (by machine translation)
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Page/Page column 132
(2018/06/01)
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- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 0570
(2015/03/31)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 00306
(2014/02/15)
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- Synthesis and evaluation of some novel dibenzo[b,d]furan carboxylic acids as potential anti-diabetic agents
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A series of novel dibenzo[b,d]furan mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit Protein Tyrosine Phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Structure-activity relationship study led to the identification of potent compound 5E which inhibited PTP1B with IC50 value of 82 ± 0.43 nM. Compound 5E was screened in vivo as drug candidate for anti-diabetic activity using rosiglitazone maleate as the standard. Compound 5E showed significant reduction in body weight, fed-state whole blood glucose (WBG), fasting WBG, plasma glucose and plasma cholesterol levels and non-significant reduction in fasting plasma triglyceride levels in ob/ob mice. A series of dibenzo[b,d]furan carboxylic acids were synthesized and evaluated for anti-diabetic activity. Compound 5E inhibited PTP1B with IC50 of 82 nM and reduced WBG and plasma glucose in ob/ob mice.
- Lakshminarayana,Prasad, Y. Rajendra,Gharat, Laxmikant,Thomas, Abraham,Narayanan, Shridhar,Raghuram,Srinivasan,Gopalan, Balasubramanian
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experimental part
p. 3709 - 3718
(2010/11/04)
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- SUBSTITUTED SULFONAMIDE COMPOUNDS
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Substituted sulfonamide derivatives, a process for their preparation, pharmaceutical compositions containing these compounds, and to the use of substituted sulfonamide derivatives in the treatment or inhibition of pain and/or various disorders or disease states.
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Page/Page column 47
(2008/12/06)
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- Study of the microwave-assisted hydrolysis of nitriles and esters and the implementation of this system in rapid microwave-assisted Pd-catalyzed amination
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Microwave-assisted hydrolysis of benzonitriles and methyl benzoates has been studied using a toluene/concd aq KOH two phase system in the presence and absence of phase transfer catalyst. Conditions to allow and avoid smooth hydrolysis could be identified. Based on the latter, the first microwave protocol which allows the rapid Pd-catalyzed amination of aliphatic amines with chlorobenzenes containing sensitive functional groups has been developed.
- Van Baelen, Gitte,Maes, Bert U.W.
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p. 5604 - 5619
(2008/09/21)
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- Process for the synthesis of morpholinylbenzenes
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A new improved process for synthesizing morpholinylbenzenes of the formula I by reacting morpholine of II with a substituted benzene of formula III, wherein morpholine is used as a reactant and as the only one solvent.
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- Solid phase synthesis of aryl amines
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A method for the solid phase synthesis of aryl amines is reported. The method involves a palladium mediated coupling reaction between aryl bromides and amines. The products are isolated in high purity and good yields. This method should prove to be a useful tool for constructing combinatorial libraries containing the aryl amine moiety.
- Willoughby, Christopher A.,Chapman, Kevin T.
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p. 7181 - 7184
(2007/10/03)
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