- Design, synthesis, and biological evaluation of novel benzo[b]thiophene-diaryl urea derivatives as potential anticancer agents
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A hybrid pharmacophore approach was applied to design and synthesize a series of benzo[b]thiophene-diaryl urea derivatives 17a–g with potential anticancer effect. In vitro antiproliferative activities of all target compounds were evaluated against HT-29 a
- Zarei, Omid,Azimian, Fereshteh,Hamzeh-Mivehroud, Maryam,Shahbazi Mojarrad, Javid,Hemmati, Salar,Dastmalchi, Siavoush
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- Design, synthesis and biological evaluation of a new thieno[2,3-d]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines
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Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib a
- Sharaky, Marwa,Kamel, Marwa,Aziz, Marwa A.,Omran, Mervat,Rageh, Monira M.,Abouzid, Khaled A. M.,Shouman, Samia A.
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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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- 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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- Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
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In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 μM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.
- Elmeligie, Salwa,Aboul-Magd, Asmaa M.,Lasheen, Deena S.,Ibrahim, Tamer M.,Abdelghany, Tamer M.,Khojah, Sohair M.,Abouzid, Khaled A. M.
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- Novel pyrazolopyrimidine urea derivatives: Synthesis, antiproliferative activity, VEGFR-2 inhibition, and effects on the cell cycle profile
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A series of novel diaryl urea pyrazolopyrimidine derivatives was designed and synthesized. All the synthesized compounds were evaluated for cytotoxic activity by the National Cancer Institute. A significant antiproliferative activity at a 10-μM dose was s
- El-Dash, Yara,Gedawy, Ehab M.,Kassab, Asmaa E.
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- UREA-SUBSTITUTED AROMATIC RING-LINKED DIOXANE-QUINAZOLINE AND -LINKED DIOXANE-QUINOLINE COMPOUNDS, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention relates to a urea-substituted aromatic ring-linked dioxane-quinazoline compound of Formula (I) and a urea-substituted aromatic ring-linked dioxane-quinoline, or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided are the preparation of the compound as shown in Formula (I) and the pharmaceutically acceptable salt thereof and the use thereof as a drug. The drug is used as an inhibitor of tyrosine kinases (e.g., VEGFR-2, C-RAF, B-RAF) for treating tyrosine kinase-related diseases.
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Paragraph 0082-0083
(2020/01/22)
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- Dioxane quinazoline and dioxane quinazoline type compound, and preparation method and application thereof
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The invention relates to a dioxane quinazoline and dioxane quinazoline type compound having a formula (I) as described in the specification or a pharmaceutically acceptable salt thereof. The inventionalso provides preparation of the compound having the formula (I) and the pharmaceutically acceptable salt and application of the compound and the pharmaceutically acceptable salt as a medicine. The medicine is used as a tyrosine kinase (such as VEGFR-2, c-MET and RET) inhibitor for treating diseases relevant to tyrosine kinases.
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Paragraph 0069-0071; 0072-0073
(2020/03/17)
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- Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach
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To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was
- Azimian, Fereshteh,Dastmalchi, Siavoush,Hamzeh-Mivehroud, Maryam,Hemmati, Salar,Shahbazi Mojarrad, Javid
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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 0218-0221
(2019/06/07)
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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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- Carbonic anhydrase inhibitors based on sorafenib scaffold: Design, synthesis, crystallographic investigation and effects on primary breast cancer cells
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Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are r
- Bozdag,Ferraroni,Ward,Carta, Fabrizio,Bua, Silvia,Angeli, Andrea,Langdon, Simon P.,Kunkler,Al-Tamimi, Abdul-Malek S.,Supuran, Claudiu T.
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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; 0033; 0035-0037; 0038
(2018/10/11)
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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; 0031-0033
(2018/10/11)
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- A Unified Approach to Couple Aromatic Heteronucleophiles to Azines and Pharmaceuticals
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Coupling aromatic heteronucleophiles to arenes is a common way to assemble drug-like molecules. Many methods operate via nucleophiles intercepting organometallic intermediates, via Pd-, Cu-, and Ni-catalysis, that facilitate carbon-heteroatom bond formation and a variety of protocols. We present an alternative, unified strategy where phosphonium salts can replicate the behavior of organometallic intermediates. Under a narrow set of reaction conditions, a variety of aromatic heteronucleophile classes can be coupled to pyridines and diazines that are often problematic in metal-catalyzed couplings, such as where (pseudo)halide precursors are unavailable in complex structures with multiple polar functional groups.
- Anderson, Ryan G.,Jett, Brianna M.,McNally, Andrew
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supporting information
p. 12514 - 12518
(2018/09/10)
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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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- 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 0022
(2016/11/21)
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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 0140; 0178
(2015/04/22)
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- METHOD AND PROCESS FOR PREPARATION AND PRODUCTION OF DEUTERATED OMEGA-DIPHENYLUREA
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Methods and processes for preparation and production of deuterated ω-diphenylurea are disclosed. Especially, a kind of deuterated ω-diphenylurea compounds which can inhibit phosphokinase and the preparation method of N-(4-chloro-3-(trifluoromethyl)phenye-N′-(4-(2-(N-d3-methylcarbamoyl)-4-pridinyloxy)phenyl)urea are disclosed. The said deuterated diphenylurea compounds can be used for treating or preventing tumors and relative diseases.
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Paragraph 0147; 0148; 0149
(2013/03/26)
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- Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo
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We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish- based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin -4-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.
- Yang, Ling-Ling,Li, Guo-Bo,Ma, Shuang,Zou, Chan,Zhou, Shu,Sun, Qi-Zheng,Cheng, Chuan,Chen, Xin,Wang, Li-Jiao,Feng, Shan,Li, Lin-Li,Yang, Sheng-Yong
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p. 1641 - 1655
(2013/04/10)
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- Heterocyclic Substituted Acardite Derivate and Application Thereof
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This present invention discloses a heterocyclic substituted acardite derivate and application thereof, namely compounds in the general formula (1) or the general formula (2) or pharmaceutically acceptable salts thereof, wherein A is monosubstituted or polysubstituted quinoline, isoquinoline, quinazoline, pyrrole or pyrimidine, and the substituent is halogen, C1-5alkyl, C1-5haloalkyl, C1-5alkoxy, C1-5haloalkoxy, C1-5alkylamino, C1-5haloalkylamino, amino or nitryl; R1 is C1-5alkyl; R2 is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; and R3 is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy. The compound of the present invention and the pharmaceutically acceptable salt thereof can be used for treating tumor or leukemia.
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- HETEROCYCLIC SUBSTITUTED ACARDITE DERIVATES AND USE THEREOF
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The present invention discloses a heterocyclic substituted acardite derivate and application thereof, namely compounds of the general formula (1) or the general formula (2) or pharmaceutically acceptable salts thereof, wherein A is monosubstituted or polysubstituted quinoline, isoquinoline, quinazoline, pyrrole or pyrimidine, and the substituent is halogen, C1-5alkyl, C1-5haloalkyl, C1-5alkoxy, C1-5haloalkoxy, C1-5alkylamino, C1-5haloalkylamino, amino or nitryl; R1 is C1-5alkyl; R2 is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; and R3 is one or more selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy. The compound of the present invention and the pharmaceutically acceptable salt thereof can be used for treating tumor or leukemia.
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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 20
(2010/12/29)
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- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
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The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
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Page/Page column 66
(2009/06/27)
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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 49
(2009/04/25)
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