- Reactions of 5-Aminoisoxazoles with α-Diazocarbonyl Compounds: Wolff Rearrangement vs N-H Insertion
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A highly chemoselective reaction between 5-aminoisoxazoles and α-diazocarbonyl compounds has been described. Both Wolff rearrangement and N-H insertion products can be obtained selectively by the judicious choice of reaction conditions. In the case of the
- Ge, Yun,Sun, Wangbin,Chen, Yang,Huang, Yulin,Liu, Zhuang,Jiang, Yaojia,Loh, Teck-Peng
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p. 2676 - 2688
(2019/02/26)
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- (4-(([1,2,4]TRIAZOLO[4,3-A]PYRIDINE-6-YL)OXY)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL) UREIDO DERIVATIVES AS ANTI-INFLAMMATORY P38 MAPK INHIBITORS FOR TREATING DISEASES OF THE RESPIRATORY TRACT
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This invention relates to (4-(([l,2,4]triazolo[4,3-a]pyridine-6-yl) oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)ureido derivatives that are p38 MAPK (mitogen activated protein kinase) inhibitors as antiinflammatory agents for treating diseases of the respirato
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Page/Page column 64
(2019/01/06)
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- Hoveyda-Grubbs II Catalyst: A Useful Catalyst for One-Pot Visible-Light-Promoted Ring Contraction and Olefin Metathesis Reactions
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A one-pot reaction to synthesize functionalized 2H-azirines through visible-light-mediated ring contraction and olefin metathesis of isoxazoles is described. Hoveyda-Grubbs II catalyst was found to function as a photocatalyst for these transformations, al
- Ge, Yun,Sun, Wangbin,Pei, Bingbing,Ding, Jia,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
p. 2774 - 2777
(2018/05/22)
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- Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model
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Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.
- Li, Guo-Bo,Ma, Shuang,Yang, Ling-Ling,Ji, Sen,Fang, Zhen,Zhang, Guo,Wang, Li-Jiao,Zhong, Jie-Min,Xiong, Yu,Wang, Jiang-Hong,Huang, Shen-Zhen,Li, Lin-Li,Xiang, Rong,Niu, Dawen,Chen, Ying-Chun,Yang, Sheng-Yong
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p. 8293 - 8305
(2016/10/03)
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- Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors
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Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.
- Liu, Gang,Abraham, Sunny,Liu, Xing,Xu, Shimin,Rooks, Allison M.,Nepomuceno, Ron,Dao, Alan,Brigham, Daniel,Gitnick, Dana,Insko, Darren E.,Gardner, Michael F.,Zarrinkar, Patrick P.,Christopher, Ron,Belli, Barbara,Armstrong, Robert C.,Holladay, Mark W.
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p. 3436 - 3441
(2015/08/11)
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- Synthesis and Biological Evaluation of Chromenylurea and Chromanylurea Derivatives as Anti-TNF-a agents that Target the p38 MAPK Pathway
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A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-a production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-a release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).
- Li, Xingzhou,Zhou, Xinming,Zhang, Jing,Wang, Lili,Long, Long,Zheng, Zhibing,Li, Song,Zhong, Wu
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p. 2004 - 2028
(2014/03/21)
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- Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E
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The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAFV600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAFV600E inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
- Rowbottom, Martin W.,Faraoni, Raffaella,Chao, Qi,Campbell, Brian T.,Lai, Andiliy G.,Setti, Eduardo,Ezawa, Maiko,Sprankle, Kelly G.,Abraham, Sunny,Tran, Lan,Struss, Brian,Gibney, Michael,Armstrong, Robert C.,Gunawardane, Ruwanthi N.,Nepomuceno, Ronald R.,Valenta, Ianina,Hua, Helen,Gardner, Michael F.,Cramer, Merryl D.,Gitnick, Dana,Insko, Darren E.,Apuy, Julius L.,Jones-Bolin, Susan,Ghose, Arup K.,Herbertz, Torsten,Ator, Mark A.,Dorsey, Bruce D.,Ruggeri, Bruce,Williams, Michael,Bhagwat, Shripad,James, Joyce,Holladay, Mark W.
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experimental part
p. 1082 - 1105
(2012/04/04)
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- PYRROLIDINE COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds which modulate the CB2 receptor are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 131
(2010/08/04)
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- The synthesis and properties of highly organosoluble metal(II) complexes with hydrazone ligands derived from pivaloylacetonitrile
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Using pivaloylacetonitrile as starting material and coupling component, a novel hydrazone ligand and four, highly organosoluble metal(II) complexes were synthesized via the procedure of oximation, cyclization, diazotization, coupling and metal chelation. In addition to elemental analysis, the structures of the novel compounds were postulated based on a series of spectroscopic methods. Smooth thin films of these metal(II) complexes on K9 glass substrates were prepared by spin-coating from 2,2,3,3-tetrafluoro-1-propanol solutions. The behaviour and relationships of the absorption bands both in solution and in spin-coated films are discussed; the thermal properties, photostability and the solubility of the metal(II) complexes were investigated. The synthesized Ni(II) complex exhibited a remarkable combination of excellent solubility and photostability, suitable absorption band and desirable thermal properties and, therefore, offers the potential of becoming a recording material for the recordable blu-ray disc system.
- Chen, Zhimin,Wu, Yiqun,Gu, Donghong,Gan, Fuxi
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experimental part
p. 42 - 49
(2010/11/04)
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- KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFIC DISEASES AND OTHER PROLIFERATIVE DISEASES
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Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast c
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Page/Page column 16
(2008/12/04)
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- Discovery of a new class of p38 kinase inhibitors
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The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and e
- Dumas, Jacques,Sibley, Robert,Riedl, Bernd,Monahan, Mary Katherine,Lee, Wendy,Lowinger, Timothy B.,Redman, Aniko M.,Johnson, Jeffrey S.,Kingery-Wood, Jill,Scott, William J.,Smith, Roger A.,Bobko, Mark,Schoenleber, Robert,Ranges, Gerald E.,Housley, Timothy J.,Bhargava, Ajay,Wilhelm, Scott M.,Shrikhande, Alka
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p. 2047 - 2050
(2007/10/03)
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- PRACTICAL SYNTHESIS OF 3-AMINO-5-tert-BUTYLISOXAZOLE FROM 4,4-DIMETHYL-3-OXOPENTANENITRILE WITH HYDROXYLAMINE
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A good yield of 3-amino-5-tert-butylisoxazole (3) was obtained regioselectively from a reaction of 4,4-dimethyl-3-oxopentanenitrile (1) with hydroxylamine in the aqueous solution of which was adjusted to weak basic, followed by treatment of the resulting
- Takase, Akira,Murabayashi, Akira,Sumimoto, Shinzaburo,Ueda, Shiro,Makisumi, Yasuo
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p. 1153 - 1158
(2007/10/02)
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- Analytical Studies on Isoxazoles. V. Colorimetric Determination of Isouron and Its Isomer with p-Dimethylaminocinnamaldehyde
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Isouron (1) and its isomer, 1-(3-tert-butylisoxazol-5-yl)-3,3-dimethylurea (2), were determined by a colorimetric method with p-dimethylaminocinnamaldehyde (DACA) as the reagent.Compounds 1 and 2 were hydrolyzed to give 3-amino-5-tert-butylisoxazole (3) a
- Kitagawa, Takayasu,Iwakura, Kumiko,Ohsugi, Masako,Hirai, Eizo
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p. 2736 - 2744
(2007/10/02)
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