- Development of a Leuckart-Wallach Reaction in Flow for the Synthesis of Abemaciclib
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The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart-Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. Key to the Leuckart-Wallach reductive amination was the addition of trimethyl orthoformate for water removal, running the reaction continuously in a pipes-in-series reactor for rapid heat-up, and building a kinetic model to understand time and temperature parameters for the feed tank storage. The product of the Leuckart-Wallach reductive amination is forward processed in batch and telescoped with the Ullmann amination and subsequent workup. The development resulted in a robust process that has successfully been run on the production scale.
- Frederick, Michael O.,Pietz, Mark A.,Kjell, Douglas P.,Richey, Rachel N.,Tharp, Gregg A.,Touge, Taichiro,Yokoyama, Naota,Kida, Michio,Matsuo, Toshiyasu
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Read Online
- Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma
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Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.
- Yuan, Kai,Kuang, Wenbin,Chen, Weijiao,Ji, Minghui,Min, Wenjian,Zhu, Yasheng,Hou, Yi,Wang, Xiao,Li, Jiaxing,Wang, Liping,Yang, Peng
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supporting information
(2021/12/09)
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- Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia
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Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51, which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.
- Yuan, Kai,Ji, Minghui,Xie, Shengnan,Qiu, Zhixia,Chen, Weijiao,Min, Wenjian,Xia, Fei,Zheng, Mingming,Wang, Xiao,Li, Jiaxing,Hou, Yi,Kuang, Wenbin,Wang, Liping,Gu, Wanjian,Li, Zhiyu,Yang, Peng
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p. 857 - 875
(2022/01/12)
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- Sustainable synthesis of potential antitumor new derivatives of Abemaciclib and Fedratinib via C-N cross coupling reactions using Pd/Cu-free Co-catalyst
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Herein, chitosan as an inexpensive, abundant, and biodegradable bio-material, produced from a key constituent of the exoskeletons of crustaceans, was used to generate the cobalt-based magnetic silica nanocomposite for the performance of the C-N cross-coupling reaction as the main step of the synthesis of Abemaciclib and Fedratinibs. Several derivatives of these recently FDA-approved anti-cancer drugs were synthesized for the first time by using Pd/Cu-free co-catalyzed under both, the conventional heating and microwave (MW) irradiation conditions. The potential anticancer activity of synthesized compounds was investigated by molecular docking study.
- Khorsandi, Zahra,Keshavarzipour, Fariba,Varma, Rajender S.,Hajipour, Abdol R.,Sadeghi-Aliabadi, Hojjat
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- Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors
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FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure–activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.
- Chen, Lijuan,Chen, Yong,Deng, Dexin,Fu, Suhong,Guo, Yong,Hu, Mengshi,Li, Xiandeng,Liu, Kongjun,Peng, Bin,Si, Wenting,Tan, Yan,Tang, Minghai,Wang, Huan,Yang, Tao,Yang, Yingxue,Yang, Zhuang,Zhang, Chufeng
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- CDK6/DYRK2 Double-target inhibitor as well as preparation method and application thereof
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The present invention discloses a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound and application of the compound in prevention and/or treatment of cancers or tumor-related diseases, especially breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma and other diseases. The compound provided by the invention is expected to be developed into a new generation of anti-cancer drugs.
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Paragraph 0052
(2021/02/24)
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- Novel CDK4/6 inhibitor as well as preparation method and application thereof
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The invention discloses a novel CDK4/6 inhibitor and a preparation method and application thereof.The novel CDK4/6 inhibitor is shown in the formula (I), has CDK4/6 inhibitory activity and has a treatment effect on CDK4/6 regulation related diseases including multiple myeloma, lung cancer, liver cancer, prostatic cancer, breast cancer and the like.
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Paragraph 0054-0057
(2021/07/14)
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- Intermediate compound as well as preparation method and application thereof
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The invention discloses an intermediate compound as well as a preparation method and application thereof. The synthesized intermediate compound is used for preparing targeted anti-cancer drugs, such as CDK4, CDK6, DYRK2 and other inhibitors, and is used for preventing and/or treating cancers or tumor related diseases including breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma. The intermediate compound is simple in preparation condition, high in reaction yield and stable in performance.
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Paragraph 0062-0065
(2021/07/24)
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- Azaindole pyrimidinamine heterocyclic compound as well as preparation method and application thereof
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The invention discloses an azaindole pyrimidinamine heterocyclic compound as well as a preparation method and application thereof. The compound is shown as a formula (S). The compound provided by the invention can inhibit malignant proliferation of cancers, has good treatment effect, low toxicity and good drug metabolism characteristics, is not easy to generate drug resistance, and can be used for preparing drugs for treating cancers or tumor-related diseases. The cancers or tumor-related diseases include multiple myeloma, leukemia, breast cancer, prostate cancer, lung cancer, liver cancer, gastric cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer and endometrial cancer.
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Paragraph 0032; 0047
(2021/08/14)
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- CDK6 inhibitor of pyrimidine benzo six-membered ring mother nucleus as well as preparation method and application of CDK6 inhibitor
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The invention discloses a CDK6 inhibitor of a pyrimidine benzo six-membered ring mother nucleus and a preparation method and application of the CDK6 inhibitor, the compound structure of the CDK6 inhibitor is shown as a formula (C), and A is selected from O, C (O) or-NR1; R1 is selected from hydrogen or C1-C8 alkyl; B is selected from O or C; X is selected from C, C (O) or-NR2; R2 is selected from hydrogen or C1-C8 alkyl; Y is selected from C (O) or (CH2) n; n is 0 or 1; and Z is selected from hydrogen, C1-C8 alkyl or-C (O) OC1-C3. The invention also discloses a preparation method and application of the compound.
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Paragraph 0048; 0059-0064
(2021/08/19)
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- Anti-cancer quinoxaline pyrimidinamine heterocyclic compound as well as preparation method and application thereof
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The invention discloses an anti-cancer quinoxaline pyrimidinamine heterocyclic compound and a preparation method and application thereof, the structure of the compound is shown as a formula (S), and X is selected from C (O) or (CH2) n; n is 0 or 1; R1 is selected from hydrogen and C1-C8 alkyl; R2 is selected from hydrogen, C1-C8 alkyl, morpholine ring or-NR5R6, and R5 and R6 are selected from hydrogen and C1-C8 alkyl; R3 is selected from hydrogen, methoxyl and halogen; and R4 is selected from hydrogen, C1-C8 alkyl,-S (O) 2Me and-C (O) OC1-C3. The invention also discloses a preparation method and application of the compound.
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Paragraph 0110-0112; 0122-0124
(2021/07/21)
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- CRYSTAL FORM, SALT TYPE OF SUBSTITUTED 2-HYDRO-PYRAZOLE DERIVATIVE AND PREPARATION METHOD THEREFOR
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A crystal form and a salt type of a substituted 2-hydro-pyrazole derivative, preparation method therefor, and use of the crystal form and the salt type in preparation of a medicament for treating cancers such as breast cancer, lung cancer and the like.
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- CDK4/6 INHIBITORS AND USE THEREOF
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The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or tautomer thereof, a pharmaceutical composition comprising a compound of formula (A) or formula (B), and any subgenera thereof, and use of said compounds and compositions thereof, wherein R1, R2, R3a, R3b, R5, R6, X1, X2, Y and n are described herein.
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- Novel synthesis method of Abemaciclib mesylate
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The invention discloses a synthesis method of Abemaciclib mesylate. The method comprises steps as follows: (1), a compound 9 in the description is subjected to a reaction with a compound 5 in the description under the action of strong base, and a compound
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- Inhibiting effect of trisubstituted pyrimidine derivative on protein kinase
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The invention discloses a trisubstituted pyrimidine derivative with a structure shown as general formula (I), and pharmaceutically acceptable salt, ester or solvent compound thereof. The derivative isa protein kinase inhibitor, can be used individually or in combination with other drugs for cancer treatment, and has tremendous clinical application value. General formula (I) is shown as the specification.
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- Development of an Improved Route for the Synthesis of an Abemaciclib Intermediate
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A new synthesis for an intermediate of abemaciclib is described. Keys to this route are the use of inexpensive starting materials, biphasic amine alkylation for mild C-N bond formation, anhydrous coupling of a 2-chloropyridine derivative with LiHMDS to avoid a hydroxy impurity, and neutral, fluoride-free conditions to affect desilylation. Scale-up of the optimized conditions are described on a kilogram scale.
- Carroll, Michael P.,Moloney, Harold,Gowran, Olivia,O'Connor, Aoibheann,Wilson, Eoin M.,Murray, Michael M.,Pietz, Mark A.,Kjell, Douglas P.,Held, C. Brad,Frederick, Michael O.
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p. 2549 - 2555
(2019/11/11)
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- A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy
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Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.
- Yin, Lei,Li, Heng,Liu, Wenjian,Yao, Zhenglin,Cheng, Zhenzhen,Zhang, Huabei,Zou, Hui
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- Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships
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Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs.
- Wang, Yan,Liu, Wen-Jian,Yin, Lei,Li, Heng,Chen, Zhen-Hua,Zhu, Dian-Xi,Song, Xiu-Qing,Cheng, Zhen-Zhen,Song, Peng,Wang, Zhan,Li, Zhi-Gang
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p. 974 - 978
(2018/02/13)
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- PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF
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The present invention provides compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. The present invention also provides a preparation method and a medical use of the compounds, The compounds of the present invention have an activity superior or equivalent to the candidate drug LY283521 9 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of the present invention thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.
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- Preparation method of 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine
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The invention discloses a preparation method of an Abemaciclib intermediate, namely, 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine. The method comprises the steps as follows: 2-chloro-5-chloromethylpyridine and N-ethylpiperazine are mixed and react at 60-90 DEG C for 1-24 h, aftertreatment is performed after cooling, and a compound shown in formula II is obtained; step 2, the compound shown in the formula II, a catalyst and a reaction reagent are mixed, react in a pressure tank in an airtight manner and react at 130-140 DEG C for 1-24 h, aftertreatment is performed after cooling, and a compound shown in formula I is obtained. Cheap pesticide imidacloprid and acetamiprid intermediate 2-chloro-5-chloromethylpyridine are used as raw materials in the method, and the method has the advantages that the raw materials are cheaper, the process is greener and more environmentally friendly and industrial production is better facilitated.
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Paragraph 0014; 0032-0040; 0047; 0048
(2018/09/12)
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- Preparation method of Abemaciclib intermediate
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The invention discloses a preparation method of an Abemaciclib intermediate, and belongs to the field of pharmaceutical chemicals. The preparation method comprises the steps that by reducing carbonyland nitryl of 5-(4-ethylpyrazine-1-carbonyl)-2-nitro pyridine in sequence, the Abemaciclib intermediate 5-(4-ethyl-piperazine-1-base methyl)-pyridine-2-base amine is obtained. According to the method,the applied raw materials and reagents are easy to obtain, the reaction conditions are mild, toxic, stimulating and corrosive reagents are avoided, environmental friendliness is achieved, preparationis simple and easy to operate, the obtained product is high in yield and purity, and the method is specially suitable for industrial production.
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Paragraph 0067-0068; 0071-0072
(2018/07/15)
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- Benzimidazole derivatives, preparation methods and uses theirof
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The present invention relates to benzimidazole compounds useful in treating for protein kinase-associated disorders. There is also a need for compounds useful in the treatment or prevention of one or more symptoms of cancer, transplant rejections. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK4 and/or CDK6, using the compounds provided herein.
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Page/Page column 30
(2018/12/01)
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- Protein kinase inhibitor and its preparation method and medical application
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The invention provides a compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture, or a pharmaceutically acceptable salt or solvate of the compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture. The ring A, R1, R2, R3 and R4 are defined in the specification. The invention also provides a preparation method of the compound shown in the structural formula I and a use of the compound in preparation of a drug for treating cell proliferative disorder.
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- Preparation method of Abemaciclib intermediate
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The invention belongs to the field of medicine and chemical industry, and concretely relates to a preparation method of an Abemaciclib intermediate. Nitro and carbonyl of 5-(4-ethyl piperazine-1-carbonyl)-2-nitropyridine are reduced successively, and the Abemaciclib intermediate 5-(4-ethyl-piperazin-1-yl)methyl)pyridin-2-amine is obtained; the raw materials and reagents are easy to obtain, reaction conditions are mild, usage of reagents with toxicity or irritation or strong corrosivity is avoided, the method is green and environmentally friendly, and the preparation is simple and easy to operate; the product has high yield and high purity, and is especially suitable for industrial production.
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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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- Method for preparing abemaciclib intermediate compound
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The invention relates to a method for preparing an abemaciclib intermediate compound. The method comprises the following steps: fumaronitrile and nitromethane are subjected to condensation, hydrogenation cyclization is performed to obtain 2-amino-5-amino methylpyridine, and ring formation is performed on 2-amino-5-amino methylpyridine and N,N-bis(2-chloroethyl)ethylamine to prepare 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine which can be used for preparing abemaciclib. Reagents with high price are not used, the atom economy is high, side reaction is less, the method is safe and high in product yield and purity, the raw materials are cheap and easily accessible, the operation is simple and convenient, and the cost is low.
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Paragraph 0040; 0053; 0054; 0057; 0058; 0061; 0062
(2017/12/06)
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- CERTAIN PROTEIN KINASE INHIBITORS
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Provided are certain CDK4/6 inhibitors, pharmaceutical compositions thereof, and methods of use therefor.
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Paragraph 207; 208; 219; 220
(2017/12/27)
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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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- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
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The invention discloses a kind of type I of the pyrimidine or pyridine pyridine ketone compound and its preparation and application, which belongs to the technical field of pharmaceutical preparation. The compounds have high-efficient and selectively inhibit the cell cycle dependent kinases (Cdks) CDK4 and CDK6 active, and then by inhibiting CDK4/CDK6 prevent tumor cell division. Therefore, the compounds of this invention can be used for CDK4 and CDK6 the involved in cell cycle control disorders result in various diseases, especially suitable for the treatment of malignant tumors. (by machine translation)
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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 9
(2010/07/04)
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