- Development of novel benzimidazole-derived neddylation inhibitors for suppressing tumor growth in vitro and in vivo
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Ubiquitin-like protein neddylation is overactivated in various human cancers and correlates with disease progression, and targeting this pathway represents a valuable therapeutic strategy. Our previous work disclosed an antihypertensive agent, candesartan cilexetic (CDC), serves as a novel neddylation inhibitor for suppressing tumor growth by targeting Nedd8-activating enzyme (NAE). In this study, 42 benzimidazole derivatives were designed and synthesized based on lead compound CDC to improve the neddylation inhibition and anticancer efficacy. Optimal benzimidazole-derived 35 displayed superior neddylation inhibition in enzyme assay compared to CDC (IC50 = 5.51 μM vs 16.43 μM), along with promising target inhibitory activity and killing selectivity in cancer cell. The results of cellular mechanism research combined with tumor growth suppression in human lung cancer cell A549 in vivo, accompanied with docking model, revealed that 35 has the potential to be developed as a promising neddylation inhibitor for anticancer therapy.
- Chen, Xin,Yang, Xi,Mao, Fei,Wei, Jinlian,Xu, Yixiang,Li, Baoli,Zhu, Jin,Ni, Shuaishuai,Jia, Lijun,Li, Jian
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- Benzimidazole compound and medical application thereof
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The invention relates to the field of medicinal chemistry and pharmacotherapeutics, and particularly discloses a benzimidazole compound which has a structure as shown in a formula I. In the formula I, R1 is H, hydroxyl and C1-C3 alkoxy; R2 is H or a C4-C6-membered heterocyclic ring; R3 is H, C1-C6 straight-chain or branched-chain alkyl, C1-C6 straight-chain or branched-chain hetero-alkyl, C3-C6 alicyclic ring, C3-C6 heterocyclic ring, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocyclic ring, substituent groups are fluorine, chlorine, bromine, methyl, ester group or methoxy group, and the number of the substituent groups is an integer from 0 to 2. The invention also discloses an application of the benzimidazole compound in preparation of a medicine for treating diseases participated in or mediated by a Neddylation pathway, and the compound can be used for treating tumor diseases by inhibiting the Neddylation pathway.
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Paragraph 0038-0041
(2021/05/05)
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- METHOD FOR PREPARING TRITYL CANDESARTAN
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The present invention uses a candesartan cyclic compound as a starting material and performs thereon a three-step reaction of forming tetrazole, hydrolysis and adding a protecting group to directly obtain trityl candesartan without separating an intermediate product via crystallization. The operating process is simple and thus is more applicable to industrial production.
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- A method for preparing ester
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The invention provides a preparation method of candesartan cilexetil. The preparation method comprises steps I-IV. The step I concretely comprises the following substeps of adding candesartan and dichloromethane in a reaction container; slowly and dropwise adding triethylamine at the temperature of 10-15 DEG C; raising the temperature of a reaction system to 21-25 DEG C after dropwise adding of the triethylamine is fnished; adding triphenylchloromethane in batches; reacting for 3-4 hours; adding 0.1 mol/L HCl at one step after reaction is complete and adjusting pH (potential of hydrogen) to be 5-6; then slowly and dropwise adding 9 mol/L HCl and adjusting pH to be 2-3; leaving standstill; separating a water layer and an organic layer; adding saturated salt water in the organic layer to wash the organic layer; leaving standstill to achieve a layering effect; separating out the organic layer; performing decompress concentration on the organic layer to remove the dichloromethane; adding absolute ethyl alcohol in residual viscous substances; raising temperature to 45-50 DEG C; stirring for 3 hours; stopping heating after a large amount of white solids are separated out; reducing to room temperature; performing suction filtration; washing filter cakes with ethyl alcohol; and drying to obtain trityl candesartan.
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Paragraph 0005; 0054; 0055; 0076; 0090
(2018/05/24)
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- PROCESS FOR PREPARATION OF CANDESART AN CILEXETIL SUBSTANTIALLY FREE OF DES-CANDESARTAN CILEXETIL IMPURITY
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The present invention provides a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]ethylester-lH-benzimidazole-7- carboxylate (des-candesartan cilexetil) impurity.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL, POLYMORPHIC FORMS OF N-TRITYL CANDESARTAN AND THEIR USES THEREOF
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The present invention provides an improved process for the preparation of candesartan cilexetil comprising the use of polymorphic Form A and Form B of N-trityl candesartan. Also, provided herein, new polymorphic Form A and Form B of N-trityl candesartan and the processes for their preparation.
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Page/Page column 12
(2011/08/21)
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- PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL
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The present invention relates to an improved process for the preparation of tritylated candesartan acid of formula (I) comprising a step of, reacting candesartan acid of formula (II) with trityl chloride in the presence of a base in a ketonic solvent.
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Page/Page column 5
(2010/08/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL
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The present invention relates to an improved process for the preparation of tritylated candesartan acid of formula (I) comprising a step of, reacting candesartan acid of formula (II) with trityl chloride in the presence of a base in a ketonic solvent.
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Page/Page column 13
(2009/03/07)
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- Novel O-[11C]methylated derivatives of candesartan as angiotensin II AT1 receptor imaging ligands: Radiosynthesis and ex vivo evaluation in rats
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[11C]Methyl-candesartan and its desethyl derivative ([11C]TH4) were developed as potential radiotracers for imaging angiotensin II (Ang II) type 1 (AT1) receptors. These compounds were synthesized via methylation of tetrazole-protected candesartan using [11C]methyl iodide followed by deprotection through HCl hydrolysis at 65 °C to produce [11C]methyl-candesartan, and 90 °C for [11C]TH4. Ex vivo biodistribution and competition studies were carried out for both [11C]methyl-candesartan and [11C]TH4 to assess tissue retention time course and binding selectivity. Besides the liver, [11C]methyl-candesartan and [11C]TH4 displayed highest tissue retention in the AT1 receptor-rich renal cortex and outer medulla. At tracer doses 15 min post-injection, [11C]methyl-candesartan demonstrated higher specific binding proportion for AT1 receptors, and selectivity for AT1 over Ang II AT2, Mas, β-adrenergic, and α2-adrenergic receptors in rat kidneys compared to [11C]TH4. This study indicates that [11C]methyl-candesartan has potential for in vivo imaging renal AT1 receptors selectively using positron emission tomography.
- Hadizad, Tayebeh,Kirkpatrick, Sheryn A.,Mason, Samantha,Burns, Kevin,Beanlands, Rob. S.,DaSilva, Jean N.
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experimental part
p. 7971 - 7977
(2010/04/02)
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- PROCESS FOR PREPARATION OF CANDESARTAN CILEXETIL
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There was provided a process for preparing candesartan cilexetil, the said process comprises hydrogenating a solution of trityl candesartan cilexetil in an alcohol with hydrogen in the presence of a palladium catalyst. Mixture of toluene and methanol was added to 1-(Cyclohexyloxy carbonyloxy)ethyl-2-ethoxy-1-[[2'-(N-triphenylmethyltetrazole-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate and hydrogenated at room temperature with hydrogen at atmospheric pressure in the presence of palladium on carbon until the hydrogen uptake was ceased. Filtered over celite bed, washed the bed with a mixture of toluene and methanol, filtrate was collected and concentrated. Co- distilled with acetonitrile, acetonitrile was added, stirred at room temperature, cooled to 0°C. stirred, filtered, washed with chilled acetonitrile and dried to get candesartan cilexetil.
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Page/Page column 4
(2010/01/30)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL
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The invention relates to process for the preparation of Candesartan cilexetil. More particularly, it relates to the preparation of pure candesartan cilexetil by the deprotection of Trityl candesartan cilexetil with inorganic acids.
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Page/Page column 5-6
(2008/06/13)
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- PROCESS FOR THE SYNTHESIS OF TETRAZOLES
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A process for the synthesis of tetrazol derivative has been developed which starts from a tetrazole derivative where acidic hydrogen atom has been replaced by a protecting group and the deprotection is performed with a catalytic amount of organic acid and can proceed in an aqueous solvent.
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Page/Page column 12
(2008/06/13)
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- Production method of aminobenzene compound
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The present invention is to provide an industrially useful production method of an aminobenzene compound represented by the formula: which is characterized by reacting a mixture of a mono-halogeno compound represented by the formula: and di-halogeno compound represented by the formula: with a compound of the formula:
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- 1-(CYCLOHEXYLOXYCARBONYLOXY)ETHYL 2-ETHOXY-1-[[2'-(1H-TETRAZOL-5-YL)BIPHENYL-4-YL]METHYL]BENZIMIDAZOLE-7-CARBOXYLATE AND COMPOSITIONS AND METHODS OF PHARMACEUTICAL USE THEREOF
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1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-y l)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof has potent angiotensin II antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
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