- 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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- Catalytic Decarboxylative C?N Formation to Generate Alkyl, Alkenyl, and Aryl Amines
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Transition-metal-catalyzed sp2 C?N bond formation is a reliable method for the synthesis of aryl amines. Catalytic sp3 C?N formation reactions have been reported occasionally, and methods that can realize both sp2 and sp3 C?N formation are relatively unexplored. Herein, we address this challenge with a method of catalytic decarboxylative C?N formation that proceeds through a cascade carboxylic acid activation, acyl azide formation, Curtius rearrangement and nucleophilic addition reaction. The reaction uses naturally abundant organic carboxylic acids as carbon sources, readily prepared azidoformates as the nitrogen sources, and 4-dimethylaminopyridine (DMAP) and Cu(OAc)2 as catalysts with as low as 0.1 mol % loading, providing protected alkyl, alkenyl and aryl amines in high yields with gaseous N2 and CO2 as the only byproducts. Examples are demonstrated of the late-stage functionalization of natural products and drug molecules, stereospecific synthesis of useful α-chiral alkyl amines, and rapid construction of different ureas and primary amines.
- Zhang, Yipin,Ge, Xia,Lu, Hongjian,Li, Guigen
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supporting information
p. 1845 - 1852
(2020/12/01)
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- Synthesis, anticancer activity, and β-lactoglobulin binding interactions of multitargeted kinase inhibitor sorafenib tosylate (SORt) using spectroscopic and molecular modelling approaches
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Sorafenib tosylate (SORt) is an oral multikinase inhibitor used for treatment of advanced renal cell, liver, and thyroid cancers. In this study, this drug was synthesized and its antiproliferative activities against HCT116 and CT26 cells were assessed. The interaction of SORt with β-lactoglobulin (BLG) was studied using different fluorescence techniques, circular dichroism (CD), zeta potential measurements, and docking simulation. The results of infrared (IR), mass, HNMR, and CNMR spectra demonstrated that the drug was produced with high quality, purity, and efficiency. SORt showed potent cytotoxicity against HCT116 and CT26 cells with IC50 of 8.12 and 5.42 μM, respectively. For BLG binding of SORt, the results showed that static quenching was the cause of the high affinity drug–protein interaction. Three-dimensional fluorescence and synchronous spectra indicated that SORt conformation was changed at different levels. CD suggested that the α-helix content remained almost constant in the BLG–SORt complex, whereas random coil content decreased. Zeta potential values of BLG were more positive after binding with SORt, due to electrostatic interactions between BLG and SORt. Thermodynamic parameters confirmed van der Waals and hydrogen bond interactions in the complex formation. Molecular modelling predicted the presence of hydrogen bonds and electrostatic forces in the BLG–SORt system, which was consistent with the experimental results.
- Tanzadehpanah, Hamid,Bahmani, Asrin,Hosseinpour Moghadam, Neda,Gholami, Hamid,Mahaki, Hanie,Farmany, Abbas,Saidijam, Massoud
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p. 117 - 128
(2020/08/19)
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- Method for preparing amine compounds based on novel catalytic Curtius rearrangement reaction
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The invention relates to a method for preparing amine compounds based on a novel catalytic Curtius rearrangement reaction. Transition metal catalyzed formation of sp C-N bond is an effective methodfor synthesizing arylamine, a coupling reaction for catalyzing sp C-N bond is also reported, but a method for simultaneously realizing generation of sp C-N bond and sp C-N bond is relativelynot fully developed. According to the method, organic carboxylic acid with rich resources is used as a carbon source, alkyl/aryloxy acyl azide easy to prepare is used as a nitrogen source, under thecatalysis of DMAP and Cu(OAc)2 as low as 0.1mol%, gas N2 and CO2 are used as unique byproducts, and protected alkyl, alkenyl and aryl amine compounds are generated through a one-pot method. The reaction can be applied to later functionalization of natural products and drug molecules, synthesis of chiral alkylamine and rapid construction of different ureas and primary amines. Mechanism research shows that the reaction is carried out through cascade carboxylic acid activation, azidation, Curtius rearrangement and nucleophilic addition reaction.
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Paragraph 0076-0081
(2020/12/15)
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- Sorafenib hemicamsylate and processes for preparation thereof
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The present invention relates to: novel sorafenib hemi camsylate salt for treating cancer (chemical formula III); a novel crystalline form thereof; and a method for manufacturing the same. More specifically, the present invention relates to: hemi camsylate salt having high stability, solubility, and purity; a crystalline form thereof; and a method for manufacturing the same. The problem to be solved by the present invention is to provide novel sorafenib salt which is easy to make various preparations, and the method for manufacturing novel salt.COPYRIGHT KIPO 2020
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Paragraph 0082-0086
(2020/05/26)
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- Preparation method of high-purity tosylate salt crystal III (by machine translation)
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The invention belongs to the field of pharmaceutical chemical engineering, and particularly relates to a preparation method of a high-purity tosylate salt crystal III. The method can effectively reduce the content of genotoxic impurities by controlling specific reaction conditions, and has a good technical effect. (by machine translation)
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Paragraph 0050-0053
(2020/10/05)
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- Method for preparing sorafenib tosylate salt targeted anti-tumor drug
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The invention discloses a method for preparing a sorafenib tosylate salt targeted anti-tumor drug. The method is characterized in that a synthesis route is as followings (please see the specificationsfor the synthesis route), wherein carbonate (M2CO3) in the synthesis route is sodium carbonate, potassium carbonate or cesium carbonate, and a solvent in the synthesis route is MDF or DMA. The carbonate is adopted to replace potassium tert-butoxide, reaction operation is greatly simplified, and the cost is lowered; and through repeated testing and condition screening, the problem of excessively long reaction time is solved finally through heating reflux.
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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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- A urea compound of preparation method
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The invention relates to a preparation method of a urea compound, belongs to the technical field of pharmacy and in particular relates to a preparation method of sorafenib. The preparation method comprises the following steps: forming a mixed solution by using 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide solids, a solvent and water; stirring, and then removing a water layer; and reacting with 4-chloro-3-trifluoromethyl-phenyl isocyanate to prepare a target product namely sorafenib. According to the preparation method, a reactant is mixed with water to remove alkali and avoid the generation of impurities, thereby obtaining a high-purity product; and the preparation method is simple to operate and easy to control, and is suitable for industrial production.
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- Two novel platinum(II) complexes with sorafenib and regorafenib: Synthesis, structural characterization, and evaluation of in vitro antitumor activity
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Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV–Vis spectroscopy, elemental analyses, and 1H and 13C NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18 ± 0.15 μM and 0.13 ± 0.03 μM) than SRFN (45.03 ± 0.79 μM), RGFN (40.11 ± 2.15 μM), and cisplatin (97.63 ± 1.06 μM), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.
- Qin, Qi-Pin,Wang, Zhen-Feng,Tan, Ming-Xiong,Wang, Shu-Long,Zou, Bi-Qun,Luo, Dong-Mei,Qin, Jiao-Lan,Zhang, Shu-Hua
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- Applications of continuous micro-channel reactor in pharmaceutical synthesis
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The present invention provides applications of a continuous micro-channel reactor in pharmaceutical synthesis, and particularly relates to the multi-reaction continuation of a continuous micro-channelreactor, wherein the multi-reaction continuation can significantly perform the continuous feeding, the continuous reaction and the continuous product output of the multi-step reaction so as to achieve the advantages of safety, environmental protection and industrialization.
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Paragraph 0054-0060
(2019/10/01)
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- Direct conversion of carboxylic acids to various nitrogen-containing compounds in the one-pot exploiting curtius rearrangement
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Herein we report, a single-pot multistep conversion of inactivated carboxylic acids to various N-containing compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as a direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides, and N-formyls, exploiting the Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds, starting from a single carboxylic acid, based on the selection of the nucleophile.
- Kumar, Arun,Kumar, Naveen,Sharma, Ritika,Bhargava, Gaurav,Mahajan, Dinesh
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p. 11323 - 11334
(2019/09/10)
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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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- Synthetic method and application of urea compound
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The invention relates to a synthetic method of a urea compound, comprising the following steps: adding substituted oxazolone and sodium acetate into a methanol solution, and adding substituted amine under the stirring condition, reacting and carrying out column chromatography to obtain the urea compound. The defect that dangerous compounds need to be used during existing synthetic process is overcome, and a one-pot method is adopted to replace an existing reaction with low yield. The method of the invention has mild reaction condition, the operation is simple, raw materials are easily available, and the substrate can be converted into various other useful molecules. The compound has strong practicality, and can be applied to synthesis of the pesticide daimuron, dieresis long and the anti-cancer drug Sorafenib. The invention relates to a green and environmentally-friendly unsymmetrical urea compound synthesis method with simple process and low cost.
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Paragraph 0215-0217
(2019/06/07)
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- Preparation method for medicine for treating tumors and application of medicine
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The invention discloses a preparation method for a medicine for treating tumors and an application of the medicine. A structural formula of the medicine for treating the tumors is shown in the description. The preparation method disclosed by the invention greatly simplifies the operation steps, has a short reaction route, a stable reaction system, very good controllability, mild reaction conditions, low costs, and a higher total yield; the obtained product has higher purity; the medicine disclosed by the invention can inhibit growth of tumor cells, facilitate prolonging life span of patients,and improve quality of life of the patients; and the medicine has a very good therapeutic effect on human lung cancers, human melanoma and human fibrosarcoma.
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Paragraph 0030; 0034; 0040-0042; 0043
(2018/10/11)
-
- 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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- 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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- Preparation method of sorafenib
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The invention relates to a preparation method of sorafenib. The method comprises the following steps of allowing p-nitrophenol and 4-chlorine-N-picoline-2-formamide to react under the action of anhydrous potassium carbonate and PEG (polyethylene glycol)-400, generating a compound I via hydrazine hydrate reduction, allowing the compound I, 3-trifluoromethyl-4-chloroaniline and diphenyl carbonate orN,N-disuccinimidyl carbonate to give a 'one-pot' reaction by the action of a catalyst, performing post-treatment to form a sorafenib crude product, and performing further purification to form pure sorafenib. The method is high in conversion rate, safe, free from harm and pollution, mild in reaction condition, high in yield and applicable to industrial production, and can ensure high product purity.
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- A preparation method of zola non-nepal (by machine translation)
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The invention relates to a preparation method of zola non-nepal, the method comprises the following steps: the aminophenol heating molten, in KOH under the action of the 4 - chloro - N - methyl pyridine - 2 - carboxamide [...] condensation reaction to produce intermediate I; I after the intermediate, 3 - trifluoromethyl - 4 - chlorobenzene with methanol in the catalyst under the action of the "one-pot" reaction, after treatment [...], further purify zola non-nepal pure product. The method of the invention high conversion rate, without endangering the safe, pollution-free, mild reaction conditions, high yield, high purity of the product and is suitable for industrial production. (by machine translation)
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Paragraph 0044; 0045
(2019/01/08)
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- RAF-DEGRADING CONJUGATE COMPOUNDS
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The present disclosure provides, inter alia, RAF-Degrading Conjugate Compounds that are useful in the treatment of cancer and other RAF related diseases. Also provided are, pharmaceutical compositions, methods of treatment, and kits comprising a RAF- Degrading Conjugate Compound.
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- Method for synthesizing sorafenib
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The invention discloses a method for synthesizing sorafenib. According to the method provided by the invention, 2-chloro-5-aminotrifluorotoluene reacts with p-aminophenol and urea, and then a compoundIV is prepared; and the obtained compound IV reacts with a compound V, and then the final product sorafenib (I) is prepared. The synthetic technical route is simple, the reaction condition is mild, the total yield is high, the by-products are few, and the method is suitable for industrial production.
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Paragraph 0015; 0041; 0042
(2018/10/11)
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- A preparation method of zola non-nepal (by machine translation)
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The invention relates to a preparation method of zola non-nepal, the method comprises the following steps: the P-nitrophenol heating molten, in KOH under the action of the 4 - chloro - N - methyl pyridine - 2 - carboxamide [...] condensation reaction, by hydrazine hydrate also primary into intermediate I; I after the intermediate, 3 - trifluoromethyl - 4 - chloroaniline in under the action of a catalyst carried out with methyl ethyl carbonate one-pot reaction, after treatment [...], further purify zola non-nepal pure product. The method of the invention high conversion rate, without endangering the safe, pollution-free, mild reaction conditions, high yield, high purity of the product and is suitable for industrial production. (by machine translation)
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Paragraph 0028; 0048-0081
(2018/07/30)
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- A paratoluene sulfonic acid zola non-nepal preparation method (by machine translation)
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The invention relates to a preparation method of toluene sulfonic acid zola non-nepal, in particular relates to a 3 - trifluoromethyl - 4 - chloroaniline, triphosgene, diisopropyl serotonin reuptake, 4 - (4 - aminophenoxy) - N - methyl - 2 - pyridine carboxamide, paratoluene sulfonic acid as the raw material, after [...] reaction, coupling reaction, salt forming reaction three-step reaction. Wherein the two-step reaction without the need of separation, the use of "one-pot" reaction, to obtain a simple and highly efficient zola non-nepal, the invention provides a paratoluene sulfonic acid zola non-nepal preparation method is a high-yield, low-cost, three-wastes, and easy to operate, safe, suitable for industrial preparation method. (by machine translation)
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- Preparation method of sorafenib compound
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The invention discloses a preparation method of a sorafenib compound. The preparation method comprises the following steps of: adopting reaction of 2-chloro-5-aminotrifluorotoluene and sodium cyanateto prepare a compound III, reaction of 4-bromophenol (compound IV) and a compound V to prepare a compound VI, and reaction of the compound VI and the compound III to obtain a final product, i.e., sorafenib (I). The preparation method disclosed by the invention has the beneficial effects that raw materials for reaction are low in cost and easy in obtaining, the process route is simple, the total yield is high, the side products are fewer, so that the preparation method is suitable for industrial production.
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- Method for synthesizing sorafenib through solid ball milling
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The invention relates to a method for synthesizing sorafenib through solid ball milling. The method comprises the following steps: taking a compound 4-(4-aminophenoxy)-N-methylpyridine-2-formamide anda compound 4-chlorine-3-trifluoromethyl isocyanate as raw materials, or taking a compound 4-chlorine-3-trifluoromethyl phenylamine, a compound N,N'-carbonyl diimidazole and a compound 4-(4-aminophenoxy)-N-methylpyridine-2-formamide as raw materials, and performing solid ball milling on the raw materials in a ball mill under the catalysis of a small amount of liquid (and alkali), so as to synthesize the sorafenib. The method has the main innovation points that the sorafenib is firstly synthesized in the ball mill through solid ball milling, and compared with the conventional method of synthesizing sorafenib in a liquid solvent, the method has the advantages of high reaction speed, not overflowed dust, good reaction controllability, high simpleness in operation, high reaction yield, small pollution and high feasibility.
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Paragraph 0031; 0032; 0033
(2018/12/05)
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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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- 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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- A process for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid (by machine translation)
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The invention discloses a method for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid. The method is as follows: P-amino-phenol and 4?Polybromide?2?Cyano pyridine the reaction is performed in the presence of sodium hydroxide, then is acidified to obtain 4?(4?Aminophenoxy)?2?(Formic acid) pyridine; the substitution after the reaction, thionyl chloride, in the presence of potassium carbonate, the reaction is carried out with methyl amine, to obtain the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine; then with compound 4?Chlorotrifluoromethylbenzene?3?Phenylisocyanate (trifluoromethyl) after direct condensation, with toluene-P-sulfonic acid salifying-toluene-sulfonic acid SUO draw non-Buddhist nun. The preparation method adopts a 4?Polybromide?2?Cyano pyridine as the starting raw materials for preparing the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine, the follow-up at the same time simplifying the step of reacting, simple steps of the reaction, the yield of the product is high. (by machine translation)
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- Preparation method of sorafenib tosylate
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The invention relates to a preparation method of sorafenib tosylate. The preparation method comprises the steps of reacting propylene chloroformate (5) with low cost and 4-chloro-3-trifluoromethyl phenylamine (2) with low cost to generate activated ester (6); reacting activated ester and 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide (3) under the catalysis of N-methylpyrrolidine to obtain sorafenib with high yield; carrying out simple aftertreatment on the reaction to obtain sorafenib with relatively high purity; and then, reacting sorafenib and p-toluene sulphonic acid to generate the target product. The method is low in cost, simple in operation, few in reaction step, short in period, low in energy consumption, safe in process, free of high-toxicity reagents and suitable for industrial production, and the obtained product is high in yield and purity and free of potential safety problems.
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Paragraph 0042-0043
(2017/02/28)
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- Method for preparing sorafenib through one-pot process
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The invention relates to a method for preparing sorafenib through a one-pot process, and belongs to the field of medical chemistry. The method allows sorafenib to be obtained in a high efficiency manner by changing the feeding mode. The method comprises the following steps: adding 4-chloro-N-methylpyridine-2-carboxamide, p-aminophenol and 4-chloro-3-trifluoromethylphenyl isocyanate or 4-chloro-3-trifluoromethylanilinophenyl carbamate or N-(4-chloro-3-trifluoromethylphenyl)-1H-imidazole-1-amide or N-chloroformyl-4-chloro-3-trifluoromethyl phenylamine in an organic solvent containing an alkali, and reacting at 20-80DEG C to obtain the target product. The method has the advantages of simple operation, short production period, high yield, realization of the purity of the obtained product reaching 97% or above, no need of intermediate separation, and suitableness for industrial production.
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Paragraph 0029
(2017/02/09)
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- Method for preparing a SUO draw non-Buddhist nun (by machine translation)
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This invention involves a kind of SUO draw non-Buddhist nun (structural formula as follows) and its toluene sulfonate preparation method, this method, in order to P-nitro-phenol as raw materials, by the benzyl protection, reduction, condensation, debenzylation, coupling and salt forming the several step to synthesize SUO draw non-Buddhist nun. The preparation method of fewer steps, high yield, low cost, environmental pollution is small, is suitable for industrial production. (by machine translation)
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- SUO draw non-Buddhist nun A of the crystal and its preparation method
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The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a crystal form A of 4-[4-[3-(4-chloro-3-trifluoromethyl phenyl) ureide) phenoxy]-pyridine-2-formamide (sorafenib) with antitumor activity and a preparation method thereof. The purity of a crystal form A of Sorafenib prepared according to the invention is high, and is over 99.0%, an X-ray powder diffraction of the crystal form expressed by a 2theta angle has characteristic peaks at angles of 11.2-11.6 degrees, 11.4-11.8 degrees, 18.4-18.8 degrees, 22.3-22.7 degrees, 24.6-25.0 degrees and 29.5-29.9 degrees, and the crystal form is uneasy to decompose at a temperature of 25-50 DEG C, so that the crystal form shows good stability.
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Paragraph 0040; 0041; 0042
(2017/02/24)
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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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- PROCESS FOR SORAFENIB TOSYLATE POLYMORPH III
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The present invention provides a novel process for the preparation of sorafenib tosylate polymorph III.
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Paragraph 0025
(2015/05/26)
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- PROCESS FOR PREPARING CRYSTALLINE SORAFENIB TOSYLATE
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The present invention provides an industrially suitable process for the preparation of substantially pure 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide or Sorafenib and its tosylate salt, with a suitable impurity profile and without requirement of any additional purification steps. The present invention also provides Sorafenib base (II) as stable crystalline Form-SSB. The present invention further relates to a process for the preparation of crystalline Sorafenib tosylate Form-I which is free from contamination of any other polymorphic form of Sorafenib tosylate, for e.g. Form II or Form III, and does not involve any seeding requirement for crystallization step.
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Paragraph 0075-0076
(2015/04/28)
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- DEUTERIUM-SUBSTITUTED OMEGA-DIPHENYLUREA AND DERIVATIVES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE COMPOUNDS
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This invention relates to deuterated ω-diphenylurea and derivatives and pharmaceutical acceptable salts thereof. And the pharmaceutical compositions comprising the pharmaceutically acceptable carrier and the deuterium-substituted ω-diphenylurea and derivatives and pharmaceutical acceptable salts thereof are also provided. The deuterium-substituted diphenylurea can be used in treatment or prevention of cancer and other related diseases.
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Paragraph 0138-0139
(2013/03/26)
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- PROCESS FOR PREPARING CRYSTALLINE SORAFENIB TOSYLATE
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The present invention provides an industrially suitable process for the preparation of substantially pure 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide or Sorafenib and its tosylate salt, with a suitable impurity profile and without requirement of any additional purification steps. The present invention also provides Sorafenib base (II) as stable crystalline Form-SSB. The present invention further relates to a process for the preparation of crystalline Sorafenib tosylate Form-I which is free from contamination of any other polymorphic form of Sorafenib tosylate, for e.g. Form II or Form III, and does not involve any seeding requirement for crystallization step.
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Page/Page column 17
(2014/01/07)
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- SORAFENIB DIMETHYL SULPHOXIDE SOLVATE
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The present invention provides dimethyl sulphoxide solvate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide, process for its preparation, pharmaceutical composition comprising it and its use for the treatment of cancer. The present invention also provides a novel HPLC method for the identification, quantification and isolation of related substances of sorafenib.
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Paragraph 0115; 0116
(2013/08/28)
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- Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: Kinetics and application
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N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.
- Rawling, Tristan,McDonagh, Andrew M.,Tattam, Bruce,Murray, Michael
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p. 6065 - 6070
(2012/09/22)
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- SOLID STATE FORMS OF SORAFENIB BESYLATE, AND PROCESSES FOR PREPARATIONS THEREOF
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The application discloses novel solid state forms, referred to herein as Forms IV, V and VI, of Sorafenib Besylate; processes for preparing them; and pharmaceutical compositions and formulations comprising these forms. The invention further encompasses the above described solid state forms of Sorafenib Besylate for use in the preparation of other salts of Sorafenib, solid state forms thereof and pharmaceutical formulations containing them, and for use in the treatment of cancers, particularly, renal and hepatocellular cancer.
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Page/Page column 9-10
(2012/06/15)
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- Synthesis of aryl urea derivatives from aryl amines and aryl isocyanates
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The present study describes the synthesis of novel diaryl urea derivatives derived from aryl amine and aryl isocyanates. The synthesized compounds are analogs of sorafenib [4-[4-[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]phenoxy]-N-methylpyridine-2- carboxamide] having potential antiproliferative activity.
- Usharani,Bhujanga Rao,Reddy,Dubey
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p. 1802 - 1806
(2011/12/22)
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- Convenient synthesis of sorafenib and its derivatives
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This article describes a convenient synthesis of sorafinib and its derivatives from phenyl carbamates in good yields. This procedure, avoiding toxic phosgene, is especially suitable for large-scale preparation. Copyright
- Zhang, Lijuan,Xia, Wenpin,Wang, Bo,Luo, Yu,Lu, Wei
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p. 3140 - 3146
(2011/09/20)
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- Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions
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A facile synthesis of unsymmetrical N,N′-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation-deprotection protocol, followed by a second arylation.
- Breitler, Simon,Oldenhuis, Nathan J.,Fors, Brett P.,Buchwald, Stephen L.
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p. 3262 - 3265
(2011/08/07)
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- 4-(4-{3-[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]UREIDO}PHENOXY)-N2-METHYLPYRIDINE-2-CARBOXAMIDE DIMETHYL SULPHOXIDE SOLVATE
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The present invention provides dimethyl sulphoxide solvate of 4-(4-{3-[4-chloro- 3-(trifluoromethyl)phenyl]ureido }phenoxy)-N2 -methylpyridine-2-carboxamide, process for its preparation, pharmaceutical composition comprising it and its use for the treatment of cancer. The present invention also provides a novel HPLC method for the identification, quantification and isolation of related substances of sorafenib.
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Page/Page column 17
(2011/08/21)
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- Process for the Preparation of a RAF Kinase Inhibitor and Intermediates for Use in the Process
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There is provided a process for preparing sorafenib or a salt thereof comprising the use of a compound of formula (A) wherein R′ is selected from the group consisting of hydrogen, —C(O)OA, —C(O)CX3, —C(O)NH2, —C(O)—NHOH or There is also provided intermediate compounds of general formula (A), N-methyl-4-(4-ureidophenoxy)picolinamide, 4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate derivative and N-methyl-4-(4-(2,2,2-trihaloacetamido)phenoxy)picolinamide, processes for their preparation and their use in the preparation of sorafenib.
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Page/Page column 22-23
(2010/12/29)
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- Process for the preparation of sorafenib and salts thereof
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Methods for the synthesis of the N-carbamoyl imidazole (I) and its 1:1 adduct with imidazole are provided. Methods for the preparation of these crystalline intermediates in a high state of purity are also provided. These intermediates react cleanly under mild conditions to produce sorafenib in high yield and purity, without generating difficult-to-remove impurities.
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Page/Page column 6-7
(2009/10/18)
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- PROCESS FOR THE PREPARATION OF A RAF KINASE INHIBITOR AND INTERMEDIATES FOR USE IN THE PROCESS
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There is provided a process for preparing sorafenib or a salt thereof comprising the use of a compound of formula (A), wherein R' is selected from the group consisting of hydrogen, -C(O)OA, -C(O)CX3, - OH C(O)NH2, -C(O)-NHOH or (a). There is also provided intermediate compounds of general formula (A), N-methyl-4-(4-ureidophenoxy)picolinamide, 4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate derivative and N-methyl-4-(4-(2,2,2- trihaloacetamido)phenoxy)picolinamide, processes for their preparation and their use in the preparation of sorafenib.
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Page/Page column 53
(2009/04/25)
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- POLYMORPHS OF SORAFENIB TOSYLATE AND SORAFENIB HEMI-TOSYLATE, AND PROCESSES FOR PREPARATION THEREOF
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Provided are sorafenib hemi-tosylate, polymorphs thereof, polymorphs of sorafenib tosylate, preparation thereof and pharmaceutical compositions thereof.
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Page/Page column 6
(2009/08/14)
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- TREATMENT OF CANCERS HAVING RESISTANCE TO CHEMOTHERAPEUTIC AGENTS
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The present invention provides compositions and methods for treating cancer with sorafenib, wherein the cancer that has acquired resistance to another therapeutic agent, such as kinase inhibitors. Sorafinb can also be used to treat cancers which have become refractory to other chemotherapeutic agents .
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Page/Page column 16-17
(2010/11/27)
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- DIARYL UREAS AND COMBINATIONS
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The present invention provides methods for treating cancer in humans and other mammals comprising administering a chemotherapeutic agent, such as an interferon, and an aryl urea compound of Formula (I) : B-NH-C(O)-NH-L-M-L1-(Q)1-3 (I). In Formula (I), B and L and are each, independently, optionally substituted phenyl, naphthyl, a 5 or 6 membered monocyclic heteroaryl group, or an 8 to 10 membered bicyclic heteroaryl group; M is a bridging group. Each Q is independently C(O)R4, C(O)OR4 and C(O)NR4R5; and L' is optionally substituted phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl, or a saturated or partially saturated, monocyclic or bicyclic carbocyclic moiety or heterocyclic moiety.
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Page/Page column 47
(2008/06/13)
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