20173-04-0Relevant articles and documents
Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines
Chen, Shuguang,Yang, Langxuan,Shang, Yongjia,Mao, Jianyou,Walsh, Patrick J.
supporting information, p. 1594 - 1599 (2021/03/08)
A novel method to synthesize 2-azaaryl tetrahydroquinolines by the base-promoted tandem reaction of azaaryl methyl amines and styrene derivatives is reported (over 30 examples, yields up to 95%). Mechanistic probe experiments demonstrate that the deprotonation of the benzylic C-H bond and the addition to the styrene vinyl group proceeds via the SNAr mechanism.
CANCER TREATMENTS TARGETING CANCER STEM CELLS
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Paragraph 0331; 0421; 0424-0425, (2019/11/19)
Disclosed are compounds, methods, compositions, and kits that allow for treating cancer by, e.g., targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in the disclosure are of Formula (0), (O'), and (I):
Selective Monomethylation of Amines with Methanol as the C1 Source
Choi, Geunho,Hong, Soon Hyeok
supporting information, p. 6166 - 6170 (2018/04/30)
The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.
EIF4A-INHIBITING COMPOUNDS AND METHODS RELATED THERETO
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Paragraph 1605; 1606, (2017/08/01)
The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X, Y, R1, R2, R3a, R3b, R4a, R4b and R5 are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4A and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
Ren, Yan,Su, Yaning,Sun, Liming,He, Sudan,Meng, Lingjun,Liao, Daohong,Liu, Xiao,Ma, Yongfen,Liu, Chunyan,Li, Sisi,Ruan, Hanying,Lei, Xiaoguang,Wang, Xiaodong,Zhang, Zhiyuan
, p. 972 - 986 (2017/02/19)
On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
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Paragraph 0674; 0675, (2016/03/13)
The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
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Paragraph 0618-0620, (2015/02/25)
The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
Selective N-methylation of aliphatic amines with CO2 and hydrosilanes using nickel-phosphine catalysts
Gonzlez-Sebastin, Lucero,Flores-Alamo, Marcos,Garca, Juventino J.
, p. 763 - 769 (2015/05/12)
A method using CO2 and PhSiH3 for the methylation of primary and secondary aliphatic amines catalyzed by Ni (0) complexes was developed, selectively producing the monomethylated products in moderate to good yields. For that purpose, two catalysts were used: [(dippe)Ni(μ-H)]2 and the commercially available Ni(COD)2/dcype, both of which were rather efficient in this process. With a slight experimental modification, the reaction allowed the production of monomethylated ureas in good yields by using low amounts of PhSiH3. On the basis of the experimental results, we propose a possible reaction mechanism for the formation of the new C-N bond.
Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries
Londregan, Allyn T.,Piotrowski, David W.,Futatsugi, Kentaro,Warmus, Joseph S.,Boehm, Markus,Carpino, Philip A.,Chin, Janice E.,Janssen, Ann M.,Roush, Nicole S.,Buxton, Joanne,Hinchey, Terri
, p. 1407 - 1411 (2013/03/14)
Optimization of a high-throughput screening hit led to the discovery of a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. This novel chemotype was rapidly developed through iterative combinatorial library synthesis. It was determined that in vitro agonist potency correlated with functional activity data from human peripheral blood monocytes.
Synthesis and evaluation of novel carbon-11 labeled oxopurine analogues for positron emission tomography imaging of translocator protein (18 kDa) in peripheral organs
Kumata, Katsushi,Yui, Joji,Hatori, Akiko,Fujinaga, Masayuki,Yanamoto, Kazuhiko,Yamasaki, Tomoteru,Kawamura, Kazunori,Wakizaka, Hidekatsu,Nengaki, Nobuki,Yoshida, Yuichiro,Ogawa, Masanao,Fukumura, Toshimitsu,Zhang, Ming-Rong
experimental part, p. 6040 - 6049 (2011/10/12)
To develop a PET ligand for imaging TSPO in peripheral organs, we designed three novel oxopurine analogues [11C]3a-c (LogD: 1.81-2.17) by introducing a pyridine ring in place of a benzene ring in the lead compound [11C]2 (LogD: 3.48). The desmethyl precursors 10 for radiosynthesis were synthesized by reacting glycine 7 with picolylamines 4, followed by hydrolysis and by Curtius rearrangement with diphenylphosphoryl azide. Methylation of 10a-c with methyl iodide produced unlabeled compounds 3a-c. The radiosynthesis of [11C]3a-c was performed by reacting 10a-c with [11C]methyl iodide. Compounds 3a-c displayed high or moderate in vitro binding affinities (Ki: 5-40 nM) for TSPO. PET with [ 11C]3a-c in rats showed high uptake in the lung, heart, and kidney, which are organs with high TSPO expression. Metabolite analysis with [ 11C]3a showed that radioactivity in these organs mainly corresponded with unchanged [11C]3a. PET with [11C]3a using a rat model of lung inflammation showed a significant signal in the lipopolysaccharide- treated lung.
