- Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026
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Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed.
- Takahama, Yuji,Obitsu, Kazuyoshi,Takeguchi, Kazuhiro,Hirasawa, Shun,Kobayashi, Koji,Akiba, Takahiro,Ueda, Norihiro,Orii, Ryoki,Ohigashi, Atsushi,Takahashi, Takumi,Okada, Minoru,Ieda, Shigeru
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- Small molecule inhibitors of leucine-rich repetitive kinase 2 and their applications
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The present invention provides a small molecule inhibitor of leucine-rich repetitive kinase 2 and applications thereof; compounds as small molecule inhibitors such as compounds shown in formula I of the present invention or isotopic forms thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs. The compound has a high LRRK2 inhibitory activity and has high application value in the preparation of drugs for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases.
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Paragraph 0095-0102
(2022/01/07)
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- Discovery of N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a potent and selective anaplastic lymphoma kinase (ALK) inhibitor
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Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule- associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.
- Iikubo, Kazuhiko,Kondoh, Yutaka,Shimada, Itsuro,Matsuya, Takahiro,Mori, Kenichi,Ueno, Yoko,Okada, Minoru
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p. 251 - 262
(2018/03/13)
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- 2, 4-diaminopyrimidine compound containing phenol fragment, preparation method, pharmaceutical compositions and use thereof
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The invention discloses a 2, 4-diaminopyrimidine compound containing phenol fragment with a general formula I shown in the specification, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, a preparation method thereof, pharmaceutical compositions containing the compounds, and use of the compounds in preparation of drugs for preventing or treating anaplastic lymphoma kinaserelated abnormal cell proliferation, morphological changes, hyperkinesia and other associated diseases in organisms, and angiogenesis or cancerometastasis associated diseases, especially use in drugsfor treating or preventing tumor growth and metastasis.
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Paragraph 0196-0198
(2018/04/02)
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- Triazine derivative anaplastic lymphoma kinase inhibitor
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The invention belongs to the technical field of medicines, and particularly relates to a triazine derivative anaplastic lymphoma kinase inhibitor shown in a general formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer of the inhibitor. R1, R2, R3, R4, R6, R7 and A rings are defined in the description. The invention further relates to a preparation method of compounds, a medicinal preparation containing the compounds, a medicine combination containing the compounds and an application of the compounds, the pharmaceutically acceptable salt, ester, solvate or stereoisomer to preparation of a medicine for treating and/or preventing anaplastic lymphoma kinase-mediated cancer-related diseases.
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Paragraph 0187; 0188; 0189
(2017/01/02)
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- CERTAIN PROTEIN KINASE INHIBITORS
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Provided are certain ALK inhibitors, pharmaceutical compositions thereof, and methods of use therefor.
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Paragraph 0166
(2016/06/13)
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- METHOD FOR PRODUCING DI(ARYLAMINO)ARYL COMPOUND, AND SYNTHETIC INTERMEDIATE THEREFOR
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Provided is a method for producing a di(arylamino)aryl compound that has superior inhibitory activity against the kinase activities of EML4-ALK fusion protein and mutant EGFR protein and is useful as an active ingredient in pharmaceutical compositions for cancer treatment. The production method includes no purification step using silica gel column chromatography or no step possibly producing a mutagenic mesylate ester as a by-product, greatly improves overall yield, and is high yield and low cost and suitable for the industrial production of pharmaceutical products. Also provided is a synthetic intermediate that is useful in the production method.
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Paragraph 0044
(2014/01/07)
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- DI(ARYLAMINO)ARYL COMPOUND
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The present invention provides a compound which is useful as an inhibitor against the kinase activity of EML4-ALK fusion proteins and mutant EGFR proteins. As a result of extensive and intensive studies on compounds having an inhibitory effect against the kinase activity of EML4-ALK fusion proteins and mutant EGFR proteins, the inventors of the present invention have found that the di(arylamino)aryl compound of the present invention has inhibitory activity against the kinase activity of EML4-ALK fusion proteins and mutant EGFR proteins. This finding led to the completion of the present invention. The compound of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide-positive and/or mutant EGFR polynucleotide-positive cancer, EML4-ALK fusion polynucleotide-positive and/or mutant EGFR polynucleotide-positive lung cancer, or EML4-ALK fusion polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small cell lung cancer, etc.
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Page/Page column 43
(2010/04/25)
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