- A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer
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Urea 3 (BAY 43-9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases > 50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.
- Bankston, Donald,Dumas, Jacques,Natero, Reina,Riedl, Bernd,Monahan, Mary-Katherine,Sibley, Robert
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Read Online
- Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-RafV600E and C-Raf kinase inhibitory activities
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A new series of benzothiazole amide and urea derivatives tethered with the privileged pyridylamide moiety by ether linkage at the 6-position of benzothiazole (22 final compounds) has been designed and synthesized as potent anticancer sorafenib analogs. A selected group of twelve derivatives was appraised for its antiproliferative activity over a panel of 60 human cancer cell lines at a single dose concentration of 10 1/4M at National Cancer Institute (NCI, USA). Compounds 4b, 5a, 5b and 5d exhibited promising growth inhibitions and thus were further tested in advanced 5-dose testing assay to determine their GI50 values. The cellular based assay results revealed that 3,5-bis-trifluoromethylphenyl (5b) urea member is the best derivative with superior potency and efficacy compared to sorafenib as well as notable extended spectrum activity covering 57 human cancer cell lines. Kinase screening of compound 5b showed its kinase inhibitory effect against both B-RafV600E and C-Raf. Moreover, the most potent derivatives in cells were investigated for their RAF inhibitory activities, and the results were rationalized with the molecular docking study. Profiling of CYP450 and hERG channel inhibitory effects for the active compounds revealed their low possibilities to exhibit undesirable drug-drug interactions and cardiac side effects.
- El-Damasy, Ashraf Kareem,Lee, Ju-Hyeon,Seo, Seon Hee,Cho, Nam-Chul,Pae, Ae Nim,Keum, Gyochang
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Read Online
- An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy
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An improved, high-yielding, and efficient protocol for the production of Regorafenib (1), a novel diaryl urea inhibitor of multiple protein kinases, is described. The highlight of the process chemistry design and development is an optimization of the route for preparing key intermediate 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (7) by O-alkylation, nitration and reduction reactions. The developed process avoids using column chromatography to isolate 7, reduces the reaction requirements and is cost-saving, resulting in an increased overall yield from 35.0 to 57.0 % and purity from 97.0 to 99.8 %.
- Wang, Li-Mei,Du, Bao-Quan,Zuo, Da-Zhuang,Cheng, Ming-Ke,Zhao, Meng,Zhao, Si-Jia,Zhai, Xin,Gong, Ping
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Read Online
- Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit
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Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a–o, 7a–e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50values of 0.56?±?0.83?μM, 3.88?±?1.03?μM and 3.15?±?0.81?μM, which were 1.03–6.14-fold more active than sorafenib (3.44?±?1.50?μM, 3.18?±?1.43?μM, 3.24?±?0.45?μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50value was 0.72?μM. Structure–activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity.
- Wang, Min,Xu, Shan,Wu, Chunjiang,Liu, Xiaobo,Tao, Hong,Huang, Yanli,Liu, Yongchan,Zheng, Pengwu,Zhu, Wufu
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Read Online
- Synthesis and biological evaluation of novel 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives as potential antitumor agents
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A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.
- Hu, Min,Meng, Nana,Xia, Yong,Xu, Youzhi,Yu, Luoting,Zeng, Xiuxiu,Zhou, Shuyan
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- METHODS OF USING REBASTINIB IN THE TREATMENT OF DISORDERS
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Described herein are methods of treating various disorders in patients in need thereof, comprising administering to the patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof. Exemplary disorders that can be treated by the methods described herein include gynecologic carcinosarcomas, endometrial adenocarcinomas, mesotheliomas, ovarian cancers, pancreatic ductal adenocarcinomas, and lung cancers.
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- Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
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A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
- Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
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p. 15651 - 15670
(2021/11/16)
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- 4 -phenoxypyridine compound containing quinoxalinone and application thereof (by machine translation)
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The invention belongs to the field of medicines, and particularly relates to 4 -phenoxypyridine compounds containing quinoxalinone and application thereof. The 4 -phenoxypyridine compound containing quinoxalinone has the structure of the general formula (I). The invention also relates to the application of the compound of the general formula (I) to inhibit c-Met kinase and provide 4 -phenoxypyridine compounds containing quinoxalinone and pharmaceutically acceptable salts thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression c-Met kinase. (by machine translation)
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- Regorafenib analogues and their ferrocenic counterparts: Synthesis and biological evaluation
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Approved by the FDA in 2012, regorafenib is one of the last chance treatments for colorectal cancer. While various analogues have already been prepared, ferrocenic derivatives have never been evaluated. In this study, we prepared various ferrocene-containing derivatives of regorafenib and recorded their biological activity in kinase and cellular assays. This led to the identification of a squaramide derivative which shows a good cellular activity and three ferrocene analogues with promising activity in both kinase and cellular assays. This journal is
- Wilde, Myron,Arzur, Danielle,Baratte, Blandine,Lefebvre, Dorian,Robert, Thomas,Roisnel, Thierry,Le Jossic-Corcos, Catherine,Bach, Stéphane,Corcos, Laurent,Erb, William
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p. 19723 - 19733
(2020/12/04)
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- HIGHLY ACTIVE CSF1R INHIBITOR COMPOUND
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ABSTRACT The present invention relates to a CSF1R inhibitor, and in particular to a highly active CSF1R inhibitor compound having the structure of formula (I). Said compound of the present invention has high inhibitory activity on CSF1R.
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Paragraph 0164-0165
(2020/12/10)
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- A new pathway via intermediate 4-amino-3-fluorophenol for the synthesis of regorafenib
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A practical synthetic route to regorafenib, in which the target compound was obtained via a 10-step synthesis starting from 2-picolinic acid, 4-chloro-3-(trifluoromethyl)aniline, and 3-fluorophenol, is reported. Crucial to the strategy is the preparation of 4-amino-3-fluorophenol via Fries and Beckman rearrangements using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and an acceptable overall yield. A scale-up experiment was carried out to provide regorafenib with 99.96% purity in 46.5% total yield.
- Du, Fangyu,Zhou, Qifan,Shi, Yajie,Yu, Miao,Sun, Wenjiao,Chen, Guoliang
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p. 576 - 586
(2019/02/01)
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- Styryl pyridine compound containing pyridine structure, preparation method and application of styryl pyridine compound in preparation of antitumor drugs (by machine translation)
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The invention belongs to the field, and particularly relates to a styryl pyridine compound containing a pyridine structure, a preparation method and an application of the styryl pyridine compound in preparation of anti-tumor drugs, wherein the compound is a compound as shown in the formula I. The compound of the general formula I has good inhibitory activity on non-small cell lung cancer A549 and liver cancer cell HepepepG2, can be used for preparing antitumor drugs, and is especially suitable for cancers, kidney cancer, lung cancer, thyroid cancer, colon cancer and other tumors. (by machine translation)
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- Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines via a C-H Activation Strategy Using Ethenesulfonyl Fluoride as Ethylene Provider
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A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for modification of Sorafenib was also accomplished.
- Li, Chen,Qin, Hua-Li
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supporting information
p. 4495 - 4499
(2019/06/27)
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- Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities
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Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.
- Zhong, Lili,Hou, Chenhui,Zhang, Liang,Zhao, Jianchun,Li, Feng,Li, Wenbao
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p. 341 - 350
(2018/10/02)
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- Method of preparing key intermediate of sorafenib
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The present application relates to a method of preparing a key intermediate of sorafenib. The invention discloses the method for preparing a compound I by a condensation reaction of methylamine with 4-chloro-2-picolinic acid, and also discloses a method for purifying an oxalate prepared from the compound I. The preparation and purification methods provided by the invention are suitable for large-scale production, the obtained intermediate I is easy to purify and separate, and the product has high purity.
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Paragraph 0036-0047
(2019/10/01)
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- A process for preparing auspicious standard phinney intermediates
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The invention discloses a method for preparing a regorafenib intermediate; a compound represented by the formula II and a compound represented by the formula III are subjected to three stages of a step A, a step B and a step C, intermediates of all the stages are not separated, and thus the regorafenib intermediate I is prepared. According to the method, the intermediates of all the steps are not separated, post-treatment procedures are reduced, the process operational flow is saved, the solvent recovery and utilization efficiency is improved, pollution emissions and energy consumption are reduced, the requirements on green chemical process are met, and the method is suitable for industrialized production.
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Paragraph 0007; 0014-0017; 0023; 0028; 0033
(2019/05/06)
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- Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents
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A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α PDGFR-β c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.
- Duan, Yongli,Xu, Shan,Xiong, Hehua,Wang, Linxiao,Zhao, Bingbing,Wang, Ping,Wang, Caolin,Peng, Yiqing,Cai, Shifan,Luo, Rong,Zheng, Pengwu,Tang, Qidong
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p. 254 - 259
(2018/01/10)
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- Preparation and application of 2-carbamoyl-4-heteroaromatic pyridine compounds
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The invention provides 2-carbamoyl-4-heteroaromatic pyridine derivatives and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof. The substituent groups R1, R2 and Y have definitions in the specification. The invention further relates to compounds with a general formula I having strong effects of inhibiting c-Met kinase, and also relates to an application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of medicines for treating diseases caused by abnormal high expression of the c-Met kinase, particularly an application in preparation of medicines for treating and/or preventing cancers.
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- Discovery of novel picolinamide-based derivatives as novel VEGFR-2 kinase inhibitors: Synthesis,: in vitro biological evaluation and molecular docking
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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines. Molecular docking was performed to investigate the binding capacity and binding mode with VEGFR-2 (PDB code: 4ASD).
- Sun, Wuji,Fang, Shubiao,Yan, Hong
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p. 1054 - 1058
(2018/06/27)
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- Pyridazinone-containing 4-phenoxy-pyridine compound and application thereof
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The invention discloses a pyridazinone-containing 4-phenoxy-pyridine compound with structure as shown in formula (I) and application thereof. The in vitro cell activity experiment verifies that the pyridazinone-containing 4-phenoxy-pyridine compound has good effect on inhibiting human lung carcinoma A549, human gastric carcinoma cell BGC-823, human gastric carcinoma cell MKN-45, human lung carcinoma H460 and human colon cancer cell HT-29. The invention also relates to application of the compound as shown in formula I in high inhibition of VEGFR2 kinase, and also relates to the application of the compound and pharmacologically acceptable salt, an aquo-complex a solvent compound or a prodrug in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression ofVEGFR2 kinase, and particularly application in preparation of drugs for treating and/or preventing cancers. The formula refers to the description.
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- Design, synthesis and biological evaluation of phenylpicolinamide sorafenib derivatives as antitumor agents
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Two series of phenylpicolinamide sorafenib derivatives (14a–k, 15a–k) were designed and synthesized. They were evaluated for IC50 values against three cancer cell lines (A549, Hela, and MCF-7) and VEGFR2/KDR, BRAF, and CRAF kinases. Fourteen target compounds showed moderate to excellent cytotoxicity activity against the different cancer cells with potency from the single-digit μM to nanomole range. What’s more, six of them were equal to more potent than sorafenib against one or more cell lines. Most of the compounds showed bad activity against VEGFR2/KDR, BRAF, or CRAF kinases. The most promising compound 15f showed strong antitumor activities against A549 and MCF-7 cell lines with IC50 values of 5.43 ± 0.74 and 0.62 ± 0.21 μM, which were 1.29–6.79-fold more active than sorafenib (6.53 ± 0.82, 4.21 ± 0.62 μM), respectively and it exhibited moderate IC50 (7.1 μM) than 14f (IC50 = 3.1 μM). Structure–activity relationships (SARs) and docking studies indicated that replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefits to the activity. The position of aryl group and the substitutions of aryl group have a great influence on antitumor activity and selectivity. Small volume groups of aryl group such as (substituted) alkyl groups (–CH3, –CF3), halogen atoms (–F) were favorable to the cytotoxicity. Exact action mechanism of target compounds is not quite clear and further study will be carried out to identify the target in near future.
- Wu, Chunjiang,Xu, Shan,Guo, Yuping,Wu, Jielian,Luo, Rong,Wang, Wenhui,Tu, Yuanbiao,Le Chen,Zhu, Wufu,Zheng, Pengwu
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p. 374 - 387
(2017/10/07)
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- 3-Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus
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The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC50 values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h-1·kg-1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.
- Kim, Jinwoo,Shin, Jin Soo,Ahn, Sunjoo,Han, Soo Bong,Jung, Young-Sik
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supporting information
p. 667 - 672
(2018/05/14)
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- KINASE INHIBITOR COMPOUNDS, COMPOSITIONS, AND METHODS OF TREATING CANCER
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The present invention relates to a compound having the structure of formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, where X, Y, Z, R, R1, R2, R3, R4, R5, and R6 are as described herein. The present invention also relates to compositions containing the compound having the structure of formula (I), and a method of treating cancer in a subject.
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- The preparation method of the zola non-nepal (by machine translation)
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The invention discloses a method for preparing zola non-nepal, the states the zola non-nepal the chemical name is 4 - {4 - [( {4 - chloro - 3 - (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} - N - methylpyridine - 2 - carboxamide; the process of the invention has simple process, raw materials are easy, economic and environmental protection, help to realize industrialization, can promote the zola non-nepal drug of economic and technological development, and reduces the production cost, high yield, low environmental pollution, is suitable for mass production. (by machine translation)
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Paragraph 0012-0014
(2018/04/28)
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- Design, synthesis and antitumor activity of Novel Sorafenib derivatives bearing pyrazole scaffold
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Four series of Sorafenib derivatives bearing pyrazole scaffold (8a–m, 9a–c, 10a–e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0.56 μM. And compound 8b exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, c-Met, EGFR, Flt-3 kinases. Eleven of the target compounds exhibited moderate to good antitumor activities. The most promising compound 8b showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC50 values of 2.84 ± 0.78 μM, 1.85 ± 0.03 μM and 1.96 ± 0.28 μM, which were equivalent to Sorafenib (2.92 ± 0.68 μM, 3.44 ± 0.50 μM and 3.18 ± 0.18 μM). Structure–activity relationships (SARs) and docking studies indicated that the pyrazole scaffolds exerted key effect on antitumor activities of target compounds. Substitutions of aryl group at C-3 positions had a significant impact on the antitumor activities, and 3-Br substitution produced the best potency.
- Wang, Min,Xu, Shan,Lei, Huajun,Wang, Caolin,Xiao, Zhen,Jia, Shuang,Zhi, Jia,Zheng, Pengwu,Zhu, Wufu
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p. 5754 - 5763
(2017/10/09)
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- Synthesis, biological evaluation and docking studies of sorafenib derivatives N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4(5)-phenylpicolinamides
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Background: Sorafenib is an important VEGFR2/KDR inhibitor which is widely used for the treatment of cancer. Objective: In this paper, two series of sorafenib analogues N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4- phenylpicolinamides(13a-k) and N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-5-phenylpicolinamides (14a-k) were designed and synthesized. Methods: Their structures were confirmed by various analytical methods, such as 1 H and 13 C NMR, m.p., MS, HRMS. All of them were evaluated for IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Results: Eleven of the synthesized compounds showed moderate to excellent cytotoxicity activity against different cancer cells, whose potency from single-digit μM to nanomolar range. And five of them were equal to more potent than sorafenib against one or more cell lines. The most promising compound 14c showed excellent antitumor activities against PC-3 and MCF-7 cell lines with IC50 values of 2.62±1.07 μM and 1.14±0.92 μM, which were 1.15 to 2.75-fold more active than sorafenib (3.03±1.01 μM, 3.14±1.65 μM), respectively. Conclusion: Structure-activity relationships (SARs) and docking studies indicated that the replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefited to the activity. The position of aryl group and the substituents of aryl group had a great influence on antitumor activity and selectivity. The aryl groups with the substitute of alkyl groups (-CH3), halogen atoms (-F,Cl) were favorable to the cytotoxicity. However, this series of compounds showed moderate activity against VEGFR2/KDR kinase. Mechanism of target compounds was not quite clear and further study will be carried out to identify the possible target.
- Wang, Min,Wu, Chunjiang,Xu, Shan,Zhu, Yan,Li, Wei,Zheng, Pengwu,Zhu, Wufu
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p. 176 - 185
(2017/03/08)
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- N,N'-bis-substituted aryl thiourea derivatives and synthetic method and application thereof
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The invention discloses N,N'-bis-substituted aryl thiourea derivatives which are a series of compounds simultaneously containing various substituted aromatic ring structures and asymmetric substituted thiourea structures and are all novel structural compounds which are not reported in the literature. The biological activity test analysis of all the target compounds includes determination of DPPH antioxidant activity and antiviral activity. Results indicate that, in general, the designed and synthesized compounds are novel in structures and have the antioxidant activity and the antiviral activity revealed for the first time. In addition, the unknown biological activity is not fully elucidated, and thus the compounds are expected to provide a certain material basis for further research and development of new drugs.
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- The structure of the amine-containing thiourea compound and its preparation method and application
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A disclosed thiourea compounds containing an arylamine structure comprises compounds of a general formula I and pharmaceutically acceptable salts. In the general formula I shown in the specification, R1 is selected from H, C1-C8 alkyl, halogens, -CF3, -OCF3, -NO2, -CN, R2O-, -SO2NH2, -NHSO2R3, -NR4R5, -CONR6R7, -COOR8, R9CO- and disubstituted and trisubstituted combinations thereof, R2, R3, R4, R5, R6, R7, R8 and R9 are respectively H or C1-C8 alkyl, L is selected from -NHR10, -NHOR11, -NR12R13, pyrrolidin-1-yl, 4-piperidyl and (4-methyl-1-piperazinyl)methylene, and R10, R11, R12 and R13 are respectively H, C1-C8 alkyl, cycloalkyl or aryl. The compounds have inhibiting effect on multiple tumor cell strains.
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- The sulfonylurea-containing structure of the preparation and application of zola non-nepal derivatives (by machine translation)
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The invention discloses a sulfonylurea structure containing sorafenib derivative, its geometric isomer and pharmaceutically acceptable salt, hydrate, solvate or prodrug, and application thereof in preparation of drugs treating and/or preventing hyperplastic diseases, application in preparation of drugs treating and/or preventing cancers, and application in preparation of drugs treating and/or preventing lung cancer, liver cancer, gastric cancer, colon cancer and breast cancer.
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- LIVER-TARGETED PRODRUG COMPOSITIONS AND METHODS OF USING THE SAME
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Disclosed are compositions and methods of delivering a drug to a liver cell or liver tissue in a subject. In some forms, the composition is a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together. The hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
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- IMIDAZO[1,2-A]PYRIDINE DERIVATIVES AS HISTONE DEMETHYLASE INHIBITORS
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This disclosure relates, inter alia, to compounds that inhibit histone demethylase activity. In particular, the disclosure relates to compounds that inhibit histone lysine demethylase KDM5B, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions disclosed herein.
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Paragraph 0274
(2018/01/15)
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- A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication
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Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
- Kim, Jinwoo,Jung, Yu Kyoung,Kim, Chonsaeng,Shin, Jin Soo,Scheers, Els,Lee, Joo-Youn,Han, Soo Bong,Lee, Chong-Kyo,Neyts, Johan,Ha, Jae-Du,Jung, Young-Sik
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p. 5472 - 5492
(2017/07/22)
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- 4-substituted pyridine-2-formamide compound, preparation method thereof and application
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The invention discloses a 4-substituted pyridine-2-formamide compound, a preparation method thereof and an application. The 4-substituted pyridine-2-formamide compound has a structure as shown in a formula I, and the chemical name of the compound is 4-{4-[3-(4-chlorine-3-trifluoromethyl-phenyl)-ureide]-3-carboxyl phenoxy}-N-picoline-2-carboxylic methylamine. According to the preparation method of the 4-substituted pyridine-2-formamide compound, 4-chlorine-2-picolinic acid serves as an initial raw material, and the compound in the formula I is prepared by acylating chlorination, amination, substitution reaction and condensation reaction. The 4-substituted pyridine-2-formamide compound retains a Sorafenib efficacy structure, 5-aminosalicylic acid or aminosalicylic acid ester achieving a positive pharmacological function in the metabolic process replaces p-aminophenol with large toxic and side effects, efficacy can be improved, and the toxic and side effects are reduced.
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- N-indazole substituted thiourea derivatives and preparation method and application thereof
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The invention discloses N-indazole substituted thiourea derivatives and a preparation method and application thereof and belongs to the technical field of chemical medicine.The thiourea derivatives are a series of compounds simultaneously containing the 1H-indazole ring structure and the asymmetrical thiourea structure, and the compounds are not reported in the literature.The bioactivity test result analysis of the thiourea derivatives show that the compounds are good in antioxidant activity, the average scavenging rate is above 80%, the scavenging rate of the compound 12b, the compound 12c, and the compound 12d and the compound 12h is higher than 90%, the scavenging activity IC50 of the compound 12h on DPPH is 0.14mg/mL; part of the target compounds has certain inhibition activity on herpes viruses, vaccinia viruses, reoviruses, Coxsackie viruses, Feline coronary herpes viruses, HIV viruses and the like, and the compound 12c and the compound 12n are high in antivirus activity; the synthesized compounds hopefully have new bioactivity which is not expounded, and a certain material basis is provided for the development of new medicine.
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- Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives
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Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.
- Wang, Wenhui,Wu, Chunjiang,Wang, Jianqiang,Luo, Rong,Wang, Caolin,Liu, Xiaobo,Li, Jiqing,Zhu, Wufu,Zheng, Pengwu
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p. 6166 - 6173
(2016/12/06)
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- Sorafenib derivatives containing chalcone-like structures as well as preparation method and application of Sorafenib derivatives
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The invention discloses Sorafenib derivatives containing chalcone and chalcone-like structures, geometric isomers of the Sorafenib derivatives as well as pharmaceutically acceptable salts, hydrates, solvate or prodrugs of the Sorafenib derivatives, and also discloses a preparation method of the Sorafenib derivatives. The Sorafenib derivatives containing chalcone and the chalcone-like structures, as well as the pharmaceutically acceptable salts, hydrates or solvate of the Sorafenib derivatives, are taken as active ingredients and mixed with pharmaceutically acceptable carriers or excipients, then composition is formed, and clinically acceptable dosage forms are prepared. The compounds are applied to preparation of drugs for treating and/or preventing hyperplastic diseases, preparation of drugs for treating and/or preventing cancers and preparation of drugs for treating and/or preventing prostatic cancer, lung cancer and breast cancer.
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- Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug
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The invention provides a deuterated bisarylurea compound and a preparation method thereof, and application of the compound in preparation of an antitumor drug. The compound has a structure as shown in a general formula (I). The preparation method comprises the following steps: with methyl 4-chloropyridine-2-formate as a raw material, sucjecting methyl 4-chloropyridine-2-formate and methylamine or deuterated methylamine to a substitution reaction; then subjecting a product obtained in the previous step to condensation with p-aminophenol or deuterated p-aminophenol; and reacting a product obtained in the previous step with 4-chloro-3-(trifluoromethyl)phenyl isocyanate or deuterated 4-chloro-3-(trifluoromethyl)phenyl isocyanate so as to prepare the deuterated bisarylurea compound. Experiment results show that the deuterated bisarylurea compound provided by the invention has tumor treatment effect. The invention also provides application of the compound to research and development of the antitumor drug.
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Paragraph 0049; 0050
(2016/10/08)
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- Sorafenib preparation method
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The invention relates to the technical field of sorafenib, and especially relates to a method for preparing sorafenib. According to the method, 4-chlorine-3-trifluoromethyl phenylamine, p-aminophenol and triphosgene are subjected to a nucleophilic substitution reaction to obtain a compound IV; 4-chlorine-2-pyridylaldehyde and a methylamine alcohol solution are subjected to a Schiff base reaction to obtain a compound VI; and the compound VI and the compound Iv are subjected to the reaction under effect of alkali and a phase-transfer catalyst to obtain sorafenib. The route of the method for preparing sorafenib is shortened with only three steps, operation technology is simplified, the reaction condition is mild, post-treatment is simple, and the method is more suitable for industrial production requirement, production time and labor cost are saved, production cost is reduced, reaction yield is greatly increased, the overall yield of the route can reach more than 60%.
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Paragraph 0023
(2016/11/21)
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- 2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
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The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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Paragraph 0165-0168
(2016/10/09)
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- Discovery of potent c-MET inhibitors with new scaffold having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine headgroups
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Cellular mesenchymal-epithelial transition factor (c-MET) is closely linked to human malignancies, which makes it an important target for treatment of cancer. In this study, a series of 3-methoxy-N-phenylbenzamide derivatives, N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl) benzamide derivatives and N1-(3-fluoro-4-methoxyphenyl)-N3-(4-fluorophenyl) malonamide derivatives were designed and synthesized, some of them were identified as c-MET inhibitors. Among these compounds with new scaffolds having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine head groups, compound 11c, 11i, 13b, 13h exhibited both potent inhibitory activities against c-MET and high anticancer activity against tested cancer cell lines in vitro. In addition, kinase selectivity assay further demonstrated that both 13b and 13h are potent and selective c-MET inhibitors. Molecular docking supported that they bound well to c-MET and VEGFR2, which demonstrates that they are potential c-MET RTK inhibitors for cancer therapy.
- Jiang, Yingnan,Zhang, Ke,Gao, Suyu,Wang, Guihua,Huang, Jian,Wang, Jinhui,Chen, Lixia
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- ARYL UREAS WITH ANGIOGENISIS INHIBITING ACTIVITY
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This invention relates to methods of using aryl ureas to treat diseases mediated by the VEGF induced signal transduction pathway characterized by abnormal angiogenesis or hyperpermeability processes.
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Paragraph 0201; 0206
(2016/02/12)
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- Preparation method of Stivarga
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The invention discloses a preparation method of Stivarga. New compound 4-(3-fluorophenoxy)-N-methylpyridine-2-methanamide(5) and 4-(3-fluorine-4-aminophenoxy)-N-methylpyridine-2-methanamide(6) are introduced as intermediates. Through the introduction of the intermediates, the invention provides the preparation method of the Stivarga, which is mild in reaction condition, simple in after-treatment, high in reaction yield and purity, low in cost and more reasonable.
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Paragraph 0043; 0044; 0045
(2016/10/10)
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- SORAFENIB ANALOGS AND USES THEREOF
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The present invention provides, inter alia, compounds according to formula I. Also provided are pharmaceutical compositions and kits containing such compounds. Methods for using such compounds, compositions, and kits for treating a subject having system xc-, dysregulation for activating ferroptosis, for inhibiting system xc- in a cell, and for monitoring treatment of a subject having system xc- dysregulation are provided as well.
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Paragraph 0133; 0135
(2015/04/22)
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- 1,2,4-TRIAZOL-5-ONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-lR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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- 2-AMINOPYRIMIDIN-6-ONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-IR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c- FMS, c-KIT, or PDGFR kinases.
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula 1 which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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- IMIDAZOLIDINONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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- FUSED TRICYCLIC UREA COMPOUNDS AS RAF KINASE AND/OR RAF KINASE DIMER INHIBITORS
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Provided are certain fused tricyclic urea compounds and salts thereof, compositions thereof, and methods of use therefor.
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- FUSED TRICYCLIC AMIDE COMPOUNDS AS MULTIPLE KINASE INHIBITORS
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Provided are fused tricyclic amide compounds, pharmaceutical compositions comprising at least one such fused tricyclic compound, processes for the preparation thereof, and the use thereof in therapy. Disclosed herein are certain tricyclic amide compounds that can be useful for inhibiting multiple (specifically BRAF and/or EGFR-T790M) kinases and for treating disorders mediated thereby.
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- INHIBITORS OF THE KYNURENINE PATHWAY
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The present application provides novel inhibitors of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase, metabolites thereof, and phannaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. A therapeutically effective amount of one or more of the compounds of formula (I) is useful in treating diseases resulting from dysregulation of the kynurenine pathway. Compounds of formula (I) act by inhibiting the enzymatic activity or expression of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase.
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Page/Page column 210
(2014/12/12)
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- Thiourea and thioether derivatives of sorafenib: Synthesis, crystal structure, and antiproliferative activity
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A series of novel sorafenib derivatives containing diaryl thiourea and thioether, 9a-u, was designed and synthesized, and their antiproliferative activities against HCT116 and MDA-MB-231 cell lines were also evaluated and described. Most compounds exhibited potent antiproliferative activity against HCT116 cells with IC50 = 1.8-80.4 μM. Compounds 9p, 9r, and 9s demonstrated competitive antiproliferative activities to sorafenib, against all two cancer cell lines. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR, and HRMS, and compound 9n was characterized by single-crystal X-ray diffraction. Primary structure-activity relationships (SAR) have also been established.
- Yao, Jianwen,Chen, Jing,He, Zuopeng,Sun, Wei,Fang, Hao,Xu, Wenfang
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p. 3959 - 3968
(2013/07/26)
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