- Synthesis method of glatianide intermediate
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The invention provides a synthesis method of a strain facitinib intermediate, which takes acetone oxalate as a starting raw material in a simple and easy manner and is cyclized in sequence. The bromo, propionamide, bromination, amidation, deprotection and dehydration 7 steps give (4 - bromo -5 - cyano -1 - methyl - 1H - pyraz -3 -yl) methyl tert-butyl carbamate. The synthesis method of the Litinib intermediate disclosed by the invention has the characteristics of easily available raw materials, simple operation, low cost, short steps and high yield.
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- Synthesis of 1, 3, 4, 5-tetrasubstituted 1H-pyrazole derivative
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The invention relates to synthesis of an important intermediate N-Boc-4-bromine-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole of an antitumor drug, namely loratinib (PF-06463922). The preparation method comprises the following steps: by taking bromoacetone and diethyl oxalate as initial raw materials, carrying out seven steps of reactions such as condensation, ring closure, bromination, ammonolysis, methylation, dehydration and N-H protection, and finally synthesizing N-Boc-4-bromine-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole. Compared with the prior art, the method has the advantages that the reaction selectivity is better, and the designed route is more environment-friendly and economical.
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- Benzoxadiazepine tetradecene derivative and application thereof
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The invention discloses a benzoxadiazepine tetradecene derivative and application thereof, belonging to the field of medicines. The benzoxadiazepine tetradecene derivative with a structure as shown ina general formula (I) has excellent anaplastic lymphoma enzyme (ALK) inhibition activity and excellent pharmacodynamic performance, and can obviously prolong the large metabolic half-life period of adrug; the derivative can be safely and effectively used for treating anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC) and the like, thereby providing a new means for treating cancers, metabolic and immune diseases, cardiovascular diseases, neurological diseases and the like.
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- MACROCYCLE AND COMPOSITION COMPRISING THEREOF
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A macrocycle represented by formula (I) and a pharmaceutical composition comprising the macrocycle, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvent compound, stereoisomer, prodrug, or isotopic variant of the macrocycle. The macrocycle and the composition thereof inhibit a protein kinase.
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- Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Congeners
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Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable
- Elleraas, Jeff,Ewanicki, Jason,Johnson, Ted W.,Sach, Neal W.,Collins, Michael R.,Richardson, Paul F.
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p. 3590 - 3595
(2016/03/25)
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- SOLID FORMS OF A MACROCYCLIC KINASE INHIBITOR
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This invention relates to crystalline solvates of (10R)-7-amino-12-fluoro-2,10,16- trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benz- oxadiazacyclotetradecine-3-carbonitrile, useful in the treatment of abnormal cell growt
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- Discovery of (10 R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17- tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations
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Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
- Johnson, Ted W.,Richardson, Paul F.,Bailey, Simon,Brooun, Alexei,Burke, Benjamin J.,Collins, Michael R.,Cui, J. Jean,Deal, Judith G.,Deng, Ya-Li,Dinh, Dac,Engstrom, Lars D.,He, Mingying,Hoffman, Jacqui,Hoffman, Robert L.,Huang, Qinhua,Kania, Robert S.,Kath, John C.,Lam, Hieu,Lam, Justine L.,Le, Phuong T.,Lingardo, Laura,Liu, Wei,McTigue, Michele,Palmer, Cynthia L.,Sach, Neal W.,Smeal, Tod,Smith, Graham L.,Stewart, Albert E.,Timofeevski, Sergei,Zhu, Huichun,Zhu, Jinjiang,Zou, Helen Y.,Edwards, Martin P.
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p. 4720 - 4744
(2014/07/07)
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- MACROCYCLIC DERIVATIVES FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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The invention relates to compounds of formula (Φ) as further defined herein and to the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds and salts of the present invention inhibit anaplastic lymphoma kinase (ALK) and/or EML4-ALK and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
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Page/Page column 163
(2013/09/26)
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