- Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations
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The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution 11B NMR were used to show that the rapid decomposition of the excess BisPin from the borylation under the aqueous basic conditions of the Suzuki reaction was responsible for H2 generation. The moles of H2 observed were found equal to the BisPin excess, which is rationalized by mass balance and a stoichiometric reaction. The possible generation of the stoichiometric levels of H2 should be considered in hazard assessments of this class of reaction. Kinetic and process modeling was used to minimize the risk upon scale-up, and results for commercial manufacturing batches are presented, which showed good agreement with the lab scale data. Furthermore, the hydrogen evolution potentials of other common borylating agents including bisboronic acid (BBA) and pinacol borane were demonstrated.
- Merritt, Jeremy M.,Borkar, Indrakant,Buser, Jonas Y.,Brewer, Alison Campbell,Campos, Odilon,Fleming, Jeffrey,Hansen, Caoimhe,Humenik, Ashley,Jeffery, Stephen,Kokitkar, Prashant B.,Kolis, Stanley P.,Forst, Mindy B.,Lambertus, Gordon R.,Martinelli, Joseph R.,McCartan, Ciaran,Moursy, Hossam,Murphy, Donal,Murray, Michael M.,O'Donnell, Kevin,O'Sullivan, Rita,Richardson, Gary A.,Xia, Han
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- A 2-aminopyrimidine heterocyclic compound and its applications
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The present invention discloses a 2-aminopyrimidine heterocyclic compound having a general formula I structure and its applications, which are kinase CDK4, CDK6 and / or CDK9 inhibitors, can be more widely used in the treatment of a variety of cancers, ha
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- A pyrimidine compound and its application
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The present invention discloses a pyrimidine amine compound having a general formula I structure and its applications, the class of compounds belongs to the kinase CDK4, CDK6 and / or CDK9 inhibitors, can be more widely used in the treatment of a variety
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- A piperazine-containing aminopyrimidine derivative and its application
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The present invention discloses a piperazine-containing aminopyrimidine derivative having a general formula I. structure, which belongs to kinase CDK4, CDK6 and / or CDK9 inhibitors, can be more widely used in the treatment of a variety of cancers, has gr
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- CRYSTALLINE POLYMORPHS OF ABEMACICLIB
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The present disclosure provides novel polymorphs of abemaciclib, solid dispersions of abemaciclib with pharmaceutical excipients, and processes for the preparation thereof. The disclosure further provides methods for preparing crystalline abemaciclib form I, amorphous abemaciclib, and methods for synthesizing abemaciclib.
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- AMINO PYRIMIDINE COMPOUND FOR INHIBITING PROTEIN TYROSINE KINASE ACTIVITY
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An amino pyrimidine compound for inhibiting protein tyrosine kinase activity, a pharmaceutical composition thereof, preparation therefor, and an application thereof. Specifically, an amino pyrimidine compound represented by formula (I), R1, R2, L, Y, R6, W, A, m, and n being defined in the specification, and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound, a hydrate, a polymorphism, a prodrug, or an isotope variant thereof. The compound can be used for treating and/or preventing protein tyrosine kinase-related diseases such as cell proliferative diseases, cancers, and immune diseases.
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- CYCLIN DEPENDENT KINASE INHIBITORS
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This invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt thereof, in which R-groups R1 to R23, A, Q, U, V, W, X, Y, Z, n, p and q are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject.
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Paragraph 1161-1162
(2019/11/11)
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- NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUND, AS WELL AS PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND APPLICATION THEREOF
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The present invention discloses a nitrogen-containing fused heterocyclic compound, as well as a preparation method, intermediate, composition and application thereof. The nitrogen-containing fused heterocyclic compound of the present invention as represented by formula (I), as well as the pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, metabolite or drug precursor thereof, exhibit a high selectivity and a high inhibitory activity with respect to CDK4 and CDK6 at a molecular level, an excellent inhibitory activity with respect to breast cancer cells at a cellular level, and significant inhibition of tumor cell proliferation associated with cyclin-dependent kinase activity at an animal level. The invention also exhibits a good stability with respect to human or mouse liver microsomes without significant inhibition of metabolic enzymes, good in vivo absorption in mice and rats, a high bioavailability and good druggability.
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Paragraph 0205; 0206
(2019/01/25)
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- Application of benzimidazole derivative used as inhibitor of cyclin dependent kinase 4/6
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The invention relates to an application of a benzimidazole derivative used as an inhibitor of cyclin dependent kinase 4/6. The benzimidazole derivative provided by the invention has a structure as shown in a formula (I) which is described in the specification. In the formula (I), substituents are described in the description.
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- Substituted benzimidazole derivatives
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The invention belongs to the field of pharmaceutical chemistry, particularly relates to substituted benzimidazole derivatives as well as a preparation method and pharmaceutical composition thereof and further relates to an application of the substituted b
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- Deuterium-modified Abemaciclib derivative
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The invention belongs to the field of medicinal chemistry and specifically relates to a deuterium-modified Abemaciclib derivative, a preparation method of the derivative, a pharmaceutical composition containing the deuterium-modified Abemaciclib derivative, and application of the deuterium-modified Abemaciclib derivative and the pharmaceutical composition in the preparation of a medicine for treating cell proliferative diseases. In comparison with Abemaciclib, some compounds of the invention (especially compounds in the embodiment) have more excellent pharmacokinetic properties. It is expected that clinical dosage will be reduced. Thus, treatment cost is reduced so as to benefit more patients.
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Paragraph 0095; 0096; 0097; 0098; 0099; 0100; 0126-0131
(2017/08/02)
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- CDK kinase inhibitors
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The present invention belongs to the technical field of medicine, and particularly relates to a CDK kinase inhibitor represented by a general formula (I), a pharmaceutically acceptable salt of the CDK kinase inhibitor, an ester of the CDK kinase inhibitor, a solvate of the CDK kinase inhibitor and stereoisomers of the CDK kinase inhibitor, the pharmaceutically acceptable salt, the ester and the solvate, wherein R1, R2, R3, R4, R5 and n are defined in the specification. The present invention further relates to preparation methods of the compounds, pharmaceutical formulations containing the compounds, pharmaceutical compositions containing the compounds, and applications of the compound, the pharmaceutically acceptable salt, the ester, the solvate and the stereoisomers in preparation of treatment and/or preparation of CDK kinase-mediated cancer associated diseases. The formula (I) is defined in the specification.
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Paragraph 0213; 0220-0222
(2017/08/02)
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- KINASE INHIBITOR AND USE THEREOF
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The invention relates to a CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers; a pharmaceutical formulation, pharmaceutical composition and kit comprising said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers, and use of said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers. For example, the compounds of the invention are useful for reducing or inhibiting the activity of CDK4/6 kinase in a cell, and/or treating and/or preventing a cancer-related disease mediated by CDK4/6 kinase.
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- COMBINATION THERAPY FOR CANCER
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The present invention provides preparation of medicaments for use in treating and methods of treating non-small cell lung cancer in a patient comprising: [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H- benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, or a pharmaceutically acceptable salt thereof, in combination, as further described herein, with an anti-VEGFR2 antibody, preferably, ramucirumab.
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- PROTEIN KINASE INHIBITORS
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The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof which is useful in the treatment of cell proliferative diseases.
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Page/Page column 10
(2010/07/04)
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