- SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME
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The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.
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Paragraph 0097-0101
(2021/08/17)
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- Synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine
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The invention discloses a synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. The synthetic method comprises the following steps: (1) synthesizing 2-(methylthio)-4-(3-pyridyl) pyrimidine; (2) synthesizing 2-(methylsulfonyl)-4-(3-pyridine) pyrimidine; (3) synthesizing N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine and (4) synthesizing the N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. Synthesis raw materials used in the method are low in price and easy to obtain, reaction conditions are mild, the product yield and purity are high, and the methodis suitable for industrial production. Therefore, the synthetic method disclosed by the invention has good advantages in the aspects of production cost control, environmental friendliness and productquality improvement.
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- Synthesis method of imatinib and imatinib mesylate
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The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
- -
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Paragraph 0078-0084
(2020/05/02)
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- N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and preparation method thereof
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The invention discloses an N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and a preparation method thereof, and belongs to the technical field of medicine synthesis. The structural formula of the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity is shown in the description. The invention also discloses a preparation method for the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with anti-cancer activity. The N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative prepared with the preparation method has good inhibition activity for lung carcinoma cells A549, and has a potential for becoming an anti-tumor medicine.
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- Molecular requirements for the expression of antiplatelet effects by synthetic structural optimized analogues of the anticancer drugs imatinib and nilotinib
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Background: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy. Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties. Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed. Results: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds. Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.
- Alivertis, Dimitrios,Brentas, Alexios,Ntemou, Nikoleta,Pantazi, Despoina,Skobridis, Konstantinos,Tselepis, Alexandros D.
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p. 4225 - 4238
(2019/12/25)
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- Synthesis and biological evaluation of phenyl-amino-pyrimidine and indole/oxindole conjugates as potential BCR-ABL inhibitors
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Abstract: Indole/isatin conjugated phenyl-amino-pyrimidine derivatives have been synthesized, characterized and evaluated in vitro for their potential as BCR-ABL inhibitors. Among the series, all derivatives (7a–7o) were found to be more cytotoxic than standard Imatinib against K-562 cell line. Compound 7l was the most active in the series with almost two folds more potency than imitanib (IC50 0.65 μM). In vitro enzymatic studies with recombinant ABL kinase enzyme exhibited promising inhibition in the range of 30–71 μM for most of these novel conjugates. In addition, modelling and other computational studies have been carried out to draw insight into the BCR-ABL protein interactions with the target molecules and drug like properties of the conjugates, respectively. [Figure not available: see fulltext.].
- Rahim, Abdul,Syed, Riyaz,Poornachandra,Malik, M. Shaheer,Reddy, Ch. Venkata Ramana,Alvala, Mallika,Boppana, Kiran,Sridhar,Amanchy, Ramars,Kamal, Ahmed
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p. 633 - 645
(2019/03/23)
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- Imatinib derivative as well as preparation method and application thereof
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The invention discloses an imatinib derivative. The chemical name of the imatinib derivative is (E)-1-(3,5-dibromobenzyl)-4-(4-methyl-3-(4-(pyridine-3-yl)pyrimidine-2-amino)phenyl)semicarbazide, and the structural formula of the derivative is shown in the description, wherein R is 3,5-dibromobenzyl. The invention further discloses a preparation method of the imatinib derivative. The preparation ofthe imatinib derivative with a new structure is disclosed and the derivative has certain antitumor activity; the preparation method of the compound is also disclosed, the reaction cost is low, the yield is high, the reaction process is simple and easy to control, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0043; 0044; 0047-0048
(2019/09/17)
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- Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors
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Novel serious of pyrimidine scaffold benzamide derivatives (9 a-k) were synthesized and characterized by IR, HRMS, and NMR. Docking study of compounds 9 g, 9 h exhibited H-bonding interacts with Met769 into ATP binding site of EGFR-TK which showed similar binding mode to Lapitinib (PDB code: 1M17). Results indicated the ability to potent and selective inhibitors of the Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK). The molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs) and HOMO-LUMO energy gap of the title compounds were investigated by using the B3LYP/6-31G method. The synthesized compounds were screened for in vitro anti-inflammatory activity.
- Thirumurugan,Lakshmanan, Sivalingam,Govindaraj, Dharman,Daniel Prabu, D. Sam,Ramalakshmi,Arul Antony
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p. 541 - 550
(2018/06/20)
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- Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives
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In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
- Manchanda, Priyanka,Parshad, Badri,Kumar, Amit,Tiwari, Rakesh K.,Shirazi, Amir N.,Parang, Keykavous,Sharma, Sunil K.
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-
- Aniline pyrimidine compound and its preparation and use
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The invention belongs to the field of synthesis of medicaments, and relates to an aniline pyrimidine compound of a general formula (I), in particular to an N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-benzamide of which the 4th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the in vitro anti-tumor activity IC50 value of the compound on MKN-45 gastric cancer strains is nM level and the compound can obviously inhibit activity of tumor cells and can be used for preparing new anti-tumor medicaments.
- -
-
Paragraph 0029; 0034; 0039; 0040
(2019/06/09)
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- An optimized approach in the synthesis of imatinib intermediates and analogues
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We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
- Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
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p. 61458 - 61467
(2016/07/12)
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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 0181-0184
(2016/10/09)
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- Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
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The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
- Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
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p. 179 - 183
(2015/02/05)
-
- Application of nanoparticle mediated N-arylation of amines for the synthesis of pharmaceutical entities using vit-E analogues as amphiphiles in water
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The first CuI-nanoparticle catalyzed inter and intramolecular N-arylation of amines using vitamin E analogues (TPGS) as amphipiles has been developed in water. Application of this transition metal-amphiphile C-N bond formation methodology is further extended for the synthesis of substituted indoles, bioactive natural product tryptanthrin and intermediates of pharmaceutical entities such as imatinib, nilotinib, selective D3 agonist/antagonist ligands, and oxacarbazepine. This journal is
- Kumar, Atul,Bishnoi, Ajay Kumar
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p. 20516 - 20520
(2015/03/30)
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- Oligomer-protein tyrosine kinase inhibitor conjugates
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The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
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Page/Page column 32
(2015/09/22)
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- Imatinib intermediate as a two in one dual channel sensor for the recognition of Cu2+ and I- ions in aqueous media and its practical applications
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An imatinib intermediate, 6-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl] benzene-1,3-diaminepyridopyrimidotoluidine (PPT-1), was developed for the colorimetric sensing of Cu2+ ions in aqueous solution. With Cu 2+, the receptor PPT-1 showed a highly selective naked-eye detectable color change from colorless to red over the seventy other tested cations. The colorimetric sensing ability of PPT-1 was successfully utilized in the preparation of test strips and supported silica for the real samples analysis to detect Cu2+ ions from 100% aqueous environment. Moreover, the iodide-sensing ability of receptor PPT-1 was explored among the ten examined anions.
- Patil, Samadhan R.,Nandre, Jitendra P.,Jadhav, Devising,Bothra, Shilpa,Sahoo,Devi, Manisha,Pradeep, Chullikkattil P.,Mahulikar, Pramod P.,Patil, Umesh D.
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supporting information
p. 13299 - 13306
(2014/10/16)
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- Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level
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We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [ 18F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [131I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [ 18F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [18F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.
- Peng, Zhenghong,Maxwell, David S.,Sun, Duoli,Bhanu Prasad, Basvoju A.,Pal, Ashutosh,Wang, Shimei,Balatoni, Julius,Ghosh, Pradip,Lim, Seok T.,Volgin, Andrei,Shavrin, Aleksander,Alauddin, Mian M.,Gelovani, Juri G.,Bornmann, William G.
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p. 623 - 632
(2014/01/17)
-
- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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p. 8551 - 8556
(2013/09/12)
-
- PROCESSES FOR THE PREPARATION OF IMATINIB BASE AND INTERMEDIATES THEREOF
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The invention relates to an improved process for the preparation of highly pure imatinib base (99.99% HPLC purity) of formula (I) and the pharmaceutically acceptable acid addition salts thereof. This invention also relates to processes for the preparation of the intermediates in the synthesis of imatinib base.
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Page/Page column 21; 22
(2013/03/26)
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- Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
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CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
- Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
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p. 6657 - 6661
(2013/01/15)
-
- A "catch-react-release" method for the flow synthesis of 2-aminopyrimidines and preparation of the imatinib base
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The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
- Ingham, Richard J.,Riva, Elena,Nikbin, Nikzad,Baxendale, Ian R.,Ley, Steven V.
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supporting information; experimental part
p. 3920 - 3923
(2012/09/22)
-
- A facile total synthesis for large-scale production of imatinib base
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An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.
- Kompella, Amala,Adibhatla, Bhujanga Rao Kalisatya,Muddasani, Pulla Reddy,Rachakonda, Sreenivas,Gampa, Venugopala Krishna,Dubey, Pramod Kumar
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p. 1794 - 1804
(2013/01/15)
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- N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a Scaffold for the synthesis of inhibitors of Bcr-Abl
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N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated invitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line. Willing and Abl inhibitors! N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized by a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step, with anti-(1,4)-triazole derivatives as the exclusive products. One of these compounds shows general activity similar to that of imatinib, and in particular, it is more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.
- Arioli, Federica,Borrelli, Stella,Colombo, Francesco,Falchi, Federico,Filippi, Irene,Crespan, Emmanuele,Naldini, Antonella,Scalia, Giusy,Silvani, Alessandra,Maga, Giovanni,Carraro, Fabio,Botta, Maurizio,Passarella, Daniele
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p. 2009 - 2018
(2012/06/30)
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- PROCESSES FOR PREPARING IMATINIB AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The processes for preparing imatinib and its pharmaceutically acceptable salts, specifically imatinib mesylate, are disclosed.
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-
- Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents
-
A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC50 values ranging from 5.6 to 12.3 μM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.
- Kamal, Ahmed,Dastagiri,Janaki Ramaiah,Surendranadha Reddy,Vijaya Bharathi,Kashi Reddy,Victor Prem Sagar,Lakshminarayan Reddy,Pushpavalli,Pal-Bhadra, Manika
-
experimental part
p. 5817 - 5824
(2011/12/22)
-
- ALGORITHM FOR DESIGNING IRREVERSIBLE INHIBITORS
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The invention is an algorithm and method for designing an inhibitor that covalently binds a target polypeptide. The algorithm and method can be used to rapidly and efficiently convert reversible inhibitors into irreversible inhibitors.
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-
- A novel synthesis of imatinib and its intermediates
-
A convenient method has been developed for the synthesis of imatinib and two of its intermediates. N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidin amine, obtained from 2-(methylsulfonyl)-4-(3-pyridyl)pyrimidine via nucleophilic substitution, was reduced by N2H4H2O/FeCl 3·6H2O/C in 92% yield. The resulting amine was condensed with 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride, which was prepared from 4-(chloromethyl)benzonitrile via substitution and hydrolysis reactions, to provide the final product imatinib in good yield and high purity. Springer-Verlag 2010.
- Liu, Haiyan,Xia, Wenpin,Luo, Yu,Lu, Wei
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p. 907 - 911
(2011/06/28)
-
- Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors
-
Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
- Skobridis, Konstantinos,Kinigopoulou, Maria,Theodorou, Vassiliki,Giannousi, Emilia,Russell, Alison,Chauhan, Rakhee,Sala, Roberta,Brownlow, Nicola,Kiriakidis, Serafim,Domin, Jan,Tzakos, Andreas G.,Dibb, Nick J.
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scheme or table
p. 130 - 139
(2010/11/02)
-
- PROCESS FOR THE PREPARATION OF IMATINIB AND INTERMEDIATES THEREOF
-
It is the object of the present invention a process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof, intermediates useful for the synthesis of Imatinib, or 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide.
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Page/Page column 10
(2010/04/23)
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- Small molecule probes that target Abl kinase
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Two different strategies, namely a dialdehyde-based cross-linking and photo-affinity labeling, have been developed to generate small molecule activity-based probes (ABPs) for the Abelson (Abl) tyrosine kinase, of which probe 13, derived from the photo-affinity approach, showed specific labeling of Abl kinase present in a crude mammalian proteome.
- Kalesh, Karunakaran A.,Sim, Derek S. B.,Wang, Jigang,Liu, Kai,Lin, Qingsong,Yao, Shao Q.
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supporting information; experimental part
p. 1118 - 1120
(2010/06/18)
-
- Synthesis and biological evaluation of anilino substituted pyrimidine linked pyrrolobenzodiazepines as potential anticancer agents
-
A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4] benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP.
- Kamal, Ahmed,Reddy, J. Surendranadha,Ramaiah, M. Janaki,Bharathi, E. Vijaya,Dastagiri,Reddy, M. Kashi,Pushpavalli,Pal-Bhadra, Manika
-
scheme or table
p. 5232 - 5236
(2010/10/18)
-
- Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha
-
Solvates and crystalline forms of imatinib mesylate are described. Further, methods for preparing such solvates and crystalline forms of imatinib mesylate are described.
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Page/Page column 21
(2009/10/30)
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- Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry
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Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl) tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potent inhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.
- Kalesh, Karunakaran A.,Liu, Kai,Yao, Shao Q.
-
experimental part
p. 5129 - 5136
(2010/04/04)
-
- Design and synthesis of novel 2-phenylaminopyrimidine (PAP) derivatives and their antiproliferative effects in human chronic myeloid leukemia cells
-
A series of novel 2-phenylaminopyrimidine (PAP) derivatives structurally related to STI-571 were designed and synthesized. The abilities of these compounds to inhibit proliferation were tested in human chronic myeloid leukemia K562 cells. (E)-3-(2-bromophenyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)phenyl]acrylamide( 12d) was the most effective cell growth inhibitor and was 3-fold more potent than STI-571.
- Chang, Sheng,Yin, Shi-Liang,Wang, Jian,Jing, Yong-Kui,Dong, Jin-Hua
-
experimental part
p. 4166 - 4179
(2009/12/28)
-
- A facile total synthesis of imatinib base and its analogues
-
Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N2H 4.H2O/FeCl3/C system using water as a solvent in good yield.
- Liu, Yi-Feng,Wang, Cui-Ling,Bai, Ya-Jun,Han, Ning,Jiao, Jun-Ping,Qi, Xiao-Li
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p. 490 - 495
(2013/01/03)
-
- PROCESS FOR THE PREPARATION OF IMATINIB AND INTERMEDIATES THEREOF
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It is the object of the present invention a process for the preparation of 4-methyl-N3- [4- (3-pyridinyl) -2- pyrimidinyl] -1, 3-benzenediamine and analogues thereof, intermediates useful for the synthesis of Imatinib, or 4- [ (4-methyl-l-piperazinyl) methyl] -N- [4-methyl-3- [ [4- (3- pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide.
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Page/Page column 38-39
(2008/12/05)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 50
(2009/01/20)
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- COMPOUNDS AND COMPOSITIONS AS C-KIT AND PDGFR KINASE INHIBITORS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of c-kit, PDGFR and PDGFR kinases.
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Page/Page column 26-27
(2009/01/20)
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- COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to beat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of c-kit, PDGFRα and PDGFRβ kinases. Formula (I).
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Page/Page column 29
(2008/12/05)
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- POLYMORPHIC FORMS OF IMATINIB MESYLATE AND PROCESSES FOR PREPARATION OF NOVEL CRYSTALLINE FORMS AS WELL AS AMORPHOUS AND FORM α
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Solvates and crystalline forms of imatinib mesylate are described. Further, methods for preparing such solvates and crystalline forms of imatinib mesylate are described.
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Page/Page column 58
(2010/11/29)
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- Optimization of the conditions for copper-mediated N-arylation of heteroarylamines
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Simple and inexpensive copper-mediated N-arylation of heteroarylamines was achieved by using N,N′-dimethylethylenediamine as a ligand and K 2CO3 as a base in dioxane heated at 100°C. In this coupling reaction, the influence of the copper species, ligand, base and solvent was investigated in detail. N-Arylated derivatives of several heteroarylamines were synthesized under optimized reaction conditions, and all the products were isolated in good yields. By controlling the amount of CuI/DMEDA added, heteroarylamines with weak nucleophilic activity were coupled with aryl iodides or aryl bromides. The activity of the copper catalyst for this C-N bond-forming reaction follows the order CuI > Cu0 > Cu II. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Liu, Yifeng,Bai, Yajun,Zhang, Juan,Li, Yangyang,Jiao, Junping,Qi, Xiaoli
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p. 6084 - 6088
(2008/09/17)
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- Novel process for preparing Imatinib
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A novel process is disclosed for producing Imatinib, using the precursor 2-chloro-4-(3-pyridyl)-pyrimidine, thus improving Imatinib preparation via an alternative synthetic route, avoiding the use of the toxic reagent cyanamide.
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Page/Page column 8; 9
(2008/06/13)
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- A PROCESS FOR PREPARATION OF IMATINIB BASE
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The invention provides an improved process for preparation of imatinib base and its pharmaceutically acceptable acid addition salts. The process allows for using simple starting materials, while simultaneously avoiding a laborious isolation and purification of intermediates and final product, therefore facilitating its scaling-up.
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Page/Page column 22-23
(2008/06/13)
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- Acid-base profiling of imatinib (Gleevec) and its fragments
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The site-specific basicities of imatinib (Gleevec, a new signal transduction inhibitor drug of chronic myeloid leukemia) and two of its fragment compounds were quantitated in terms of protonation macroconstants, microconstants, and group constants by NMR-pH and pH-potentiometric titrations. Sequential protonation of imatinib follows the N34, N11, N31, N13 order, in which N11 and N31 show commensurable basicity, but negligible intramolecular interaction. Fragment compounds include two "halves" of imatinib, and their moiety-specific basicities confirm the NMR-based protonation sequence of the parent compound. NMR-pH profiles, macro- and/or microscopic protonation schemes, and species-specific distribution diagrams are presented. On the basis of these data, imatinib is shown to be predominantly neutral, monocationic, and tricationic at intestinal, blood, and gastric pH, respectively. The molecular hypotheses on imatinib binding to the Bcr-Abl oncogene fusion protein are interpreted at the site-specific level in view of the moiety basicities of imatinib.
- Szakács, Zoltán,Béni, Szabolcs,Varga, Zoltán,?rfi, László,Kéri, Gy?rgy,Noszál, Béla
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p. 249 - 255
(2007/10/03)
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- N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
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The present invention relates to an N-phenyl-2-pyrimidine-amine derivative showing a superior effect on lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or acute leukemia, hematologic malignancy, encephalophyma, bladder cancer, rectal cancer, or cervical cancer, etc. of warm-blooded animals and its salt. The present invention also relates to a process for preparing the compound, and to a pharmaceutical composition for the treatment of the above various diseases, which comprises an effective amount of the compound as an active ingredient together with pharmaceutically acceptable inert carriers.
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- PROCESS FOR THE PREPARATION OF THE ANTI-CANCER DRUG IMATINIB AND ITS ANALOGUES
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The present invention discloses a process of the manufacture of imatinib of formula (Ia) and its new analogues I (b-d) through the intermediate of formula (II). The mesylate (methane sulfonate ) salt of imatinib base (Ia[(4-(4-methylpiperazin-1-ylmethyl)-N4 [methyl-3-(4-pyridin-3-yl)pyrimidn-2-yl amino)phenyl]benzamide])is a popular life -saving drug to treat chronic myelogenous leukemia (CML).
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- Phenylaminopyrimidine derivatives and methods of use
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The present invention relates to phenylaminopyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states such as cancers associated with tyrosine kinases, especially Bcr-Abl, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of inhibition of tyrosine kinase reducing effects in warm-blooded animals such as humans.
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- N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to an N-phenyl-2-pyrimidine-amine derivative showing a superior effect on tumor, lung cancer, gastric cancer, etc. of warm-blooded animals and its salt. The present invention also relates to a process for preparing the compound and a pharmaceutical composition for the prevention and treatment of such diseases as tumor, lung cancer, gastric cancer, etc., which comprises the compound as an active ingredient.
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- N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to an N-Phenyl-2-pyrimidine-aminine derivative showing a superior effect on lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or accute leukemia, hematologic malignancy, encephalophyma, bladder cancer, rectal cancer or cervical cancer, etc. of warm blooded animals and its salt. The present invention also relates to a process for preparing the compound, and to a pharmaceutical composition for the treatment of the above various disease, which comprises an effective amount of the compound as an active ingredient together with pharmaceutically acceptable inert carriers.
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Page 8-9; 13-14
(2010/02/09)
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