- Identification and development of non-cytotoxic cell death modulators: Impact of sartans and derivatives on PPARγ activation and on growth of imatinib-resistant chronic myelogenous leukemia cells
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4’-((2-Propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid derived from telmisartan was identified as lead for the design of cell death modulators. In this study, we evaluated the efficacy of telmisartan itself and other sartans in combination with imatinib against K562-resistant cells. The findings were directly used to further optimize the lead structure. Telmisartan and candesartan cilexetil represented the most effective sartans, thus the influence of carboxyl/methyl carboxylate groups at positions 7 (compounds 6, 7) or 4 (compounds 12–14) at the benzimidazole core was studied. Additionally, according to the results of a former structure-activity study, telmisartan was transformed to the related amide (1). Telmisartan amide 1, as well as the esters 6 and 12 markedly sensitized the resistant CML cells to imatinib treatment. Correlation with their potency to activate PPARγ is not given. Candesartan cilexetil, telmisartan and 1 showed the profile of partial agonists at PPARγ with EC50 values of 4.2, 4.3 and 9.1 μM, respectively, while 6 and 12 caused only marginal intrinsic activation at 10 μM (Amax = 22% and 13%). However, the repression of the STAT5 phosphorylation relates with the possibility to sensitize K562-resistant CML cells to imatinib treatment. It is worth mentioning that all compounds were per se non-cytotoxic at relevant concentrations.
- Gust, Ronald,Obexer, Petra,Salcher, Stefan,Schoepf, Anna M.
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supporting information
(2020/04/08)
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- Method for preparing 2-amino-3-methyl nitrobenzoate
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The invention discloses a method for preparing methyl 2-amino-3-nitrobenzoate, which comprises the following steps: pumping a phthalimide solution and a sodium hypochlorite solution into a micro-reaction mixer, reacting, reacting with water in a tubular reactor to obtain methyl anthranilate, and continuously separating to obtain a crude product; pumping the methyl anthranilate crude product, an acetic anhydride solution and fuming nitric acid into a micro-channel reactor, mixing, reacting to obtain N-methyl nitrobenzoate, and continuously separating to obtain a crude product; pumping an N-methyl nitrobenzoate solution, concentrated sulfuric acid and water into a micro-channel reactor, mixing, and reacting to obtain a 2-amino-3-methyl nitrobenzoate crude product; recrystallizing the crude product in methanol to obtain a product, namely methyl 2-amino-3-nitrobenzoate; and the method is high in yield, good in safety and suitable for industrial production.
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- A 2 - ethoxy benzimidazole - 7 - carboxylic acid methyl ester
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The invention discloses a synthesis method of 2-ethoxy benzimidazole-7-carboxylic acid methyl ester. The problem that an existing process is not high in content and is very low in yield is solved. According to the synthesis method, 3-nitryl phthalic acid is used as a raw material, rearrangement is performed in a water solution after methyl esterification, acylation and re-nitridation, then tin powder is adopted to perform reduction and loop closing so as to obtain the 2-ethoxy benzimidazole-7-carboxylic acid methyl ester. By the adoption of the synthesis method, produced impurities are very little, the content is high, and the yield is also high.
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- The discovery of new scaffold of plant activators: From salicylic acid to benzotriazole
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Started from salicylic acid (SA) and related commercialized plant activators, based on molecular three-dimensional shape and pharmacophore similarity comparison (SHAFTS), a new lead compound benzotriazole was predicted and a series of benzotriazole derivatives were designed and synthesized. The bioassay showed that benzotriazole had high activity against a broad spectrum of diseases including fungi and oomycetes in vivo, but no activity in vitro. And the introduction of proper groups at the 1’-position and 5’-position was beneficial to the activity. So, they had the potential to be exploited as novel plant activators.
- Chang, Kang,Chen, Jian-Qin,Shi, Yan-Xia,Sun, Mei-Jian,Li, Peng-Fei,Zhao, Zhen-Jiang,Zhu, Wei-Ping,Li, Hong-Lin,Xu, Yu-Fang,Li, Bao-Ju,Qian, Xu-Hong
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p. 919 - 926
(2017/05/16)
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- ANTI-MALIGNANT TUMOR AGENT COMPOSITION
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To provide a satisfactory anticancer agent composition suppressing the growth of cancer (malignant tumor) reliably and hardly causing side effects, the present invention is directed to an anticancer agent composition including the following agents as active ingredient; a LAT1 inhibitor, and one or more agents selected from the group consisting of an alkylating agent, a platinum-based antineoplastic agent, an anti-metabolite, a topoisomerase inhibitor, an anti-microtubule polymerizing agent, a hormonal agent, an anti-microtubule depolymerizing agent, an anticancer antibiotic, and a molecular targeted agent.
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Paragraph 0103
(2016/01/25)
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- Catalytic formation of ketones from unactivated esters through rhodium chelation-assisted C-O bond activation
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A new method for building aryl aryl ketones containing heterocyclic rings through chelation-assisted C-O bond activation catalyzed by a rhodium complex has been developed. In this reaction, methyl quinoline-8-carboxylate, methyl quinoxaline-5-carboxylate, and their derivatives were reacted with an excess amount of a substituted phenyl boronic acid in the presence of a rhodium(I) complex to give substituted phenyl(quinolin-8-yl)methanone, phenylquinoxalin-5- ylmethanone, and their derivatives in medium to high yields. The current method offers a highly favorable synthetic pathway to efficiently build related drugs with an 8-benzoylquinoline core structure. This method may prove especially valuable for medicinal chemists for the late-stage introduction of versatile ketone moieties into complex scaffolds for diversity-oriented synthetic strategies.
- Wang, Jingjing,Zuo, Sujing,Chen, Weiqiang,Zhang, Xinrui,Tan, Kaixin,Tian, Yun,Wang, Jianhui
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p. 8217 - 8231
(2013/09/24)
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- SUBSTITUTED BENZIMIDAZOLES, BENZOTHIAZOLES AND BENZOXAZOLES
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The present invention relates to substituted benzimidazoles, benzothiazoles and benzoxazoles, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
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Page/Page column 109-110
(2010/12/29)
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- DIHYDROOROTATE DEHYDROGENASE INHIBITORS
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The invention relates to compounds of formula (I) wherein R1, R2, X1, X2, Y, Ra, Rb, Q have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis and also in the treatment of cancer disorders.
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Page/Page column 62
(2010/11/03)
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- New practical synthesis of the key intermediate of candesartan
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The development of a new, practical synthesis of methyl 3-amino-N-(2′-cyanobiphenyl-4-yl)methyl]anthranilate, key intermediate of candesartan, is described, starting from methyl anthranilate. The features of our approach are as follows: (i) introduction of the 3-nitro group by acid catalysed rearrangement of the corresponding methyl N-nitroanthranilate; (ii) introduction of a (2′-cyanobiphenyl-4-yl)methyl side chain by N-alkylation of the appropriate N-nitroanthranilic acid derivative. In the most efficient procedure methyl N,3-dinitroanthranilate was N-alkylated with 4′-bromomethyl-biphenyl-2-nitrile. Catalytic reduction of the aromatic nitro group was accompanied with the removal of the N-nitro function to afford the required key intermediate in good yield.
- Porcs-Makkay, Marta,Mezei, Tibor,Simig, Gyula
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p. 490 - 493
(2012/12/31)
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- NOVEL DUAL ACTION RECEPTORS ANTAGONISTS (DARA) AT THE AT1 AND ETA RECEPTORS
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The present invention relates to new compounds of the formula [Chemical formula should be inserted here. Please see paper copy] wherein R1, R2, R3, and R31 are as specified herein. The invention also relates to a method for preparation thereof, as well as combinations of the new compounds with previously known agents. The invention also relates to the use of the above-mentioned compounds and combinations for the preparation of a medicament for treating hypertension of different kinds, alleviating organ damage of different kinds, treating or preventing diabetic nephropathy, treating endothelin and angiotensin mediated disorders, and treating prostate cancer.
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Page/Page column 253
(2010/11/28)
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- SUBSTITUTED DIHYDROPYRIDINES AND METHODS OF USE
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Compounds are provided that are modulators of the C5a receptor. The compounds are substituted dihydropyridines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of C5a receptors.
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Page/Page column 132
(2010/11/27)
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- Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles
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Four classes of UK-1 analogues were synthesized and their cytotoxicity testing against human A-549, BFTC-905, RD, MES-SA, and HeLa carcinoma cell lines was determined. The results revealed that UK-1 and four of these analogues (15-18) are potent against the cancer cell lines. In particular, compound 16 is more potent than UK-1 against A-549 and HeLa cell lines, and compounds 15, 17, and 18 selectively exhibit potent cytotoxic activity against the BFTV-905 cells (IC50 9.6 μM), A-549 cells (IC50 6.6 μM), and MES-SA cells (IC50 9.2 μM), respectively.
- Huang, Shu-Ting,Hsei, I-Jen,Chen, Chinpiao
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p. 6106 - 6119
(2007/10/03)
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- PROCESS FOR PREPARING CANDESARTAN CILEXETIL
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A process for preparing candesartan cilexetil.
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Page/Page column 14
(2010/10/19)
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- New benzimidazoles as thrombopoietin receptor agonists
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A novel benzimidazole series of small-molecule thrombopoietin receptor agonists has been discovered. Herein, we discuss the preliminary exploration of structure-activity relationships within this chemotype.
- Safonov, Igor G.,Heerding, Dirk A.,Keenan, Richard M.,Price, Alan T.,Erickson-Miller, Connie L.,Hopson, Christopher B.,Levin, Jenna L.,Lord, Kenneth A.,Tapley, Peter M.
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p. 1212 - 1216
(2007/10/03)
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- PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides compounds represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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- Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: Discovery and preliminary SAR of benzimidazole derivatives
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Benzimidazole 5-carboxamide derivatives from a combinatorial screening library were discovered as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive 'drug-like' lead structure for further optimization and the development of potential HCV therapeutics.
- Beaulieu, Pierre L.,Boes, Michael,Bousquet, Yves,Fazal, Gulrez,Gauthier, Jean,Gillard, James,Goulet, Sylvie,LaPlante, Steven,Poupart, Marc-Andre,Lefebvre, Sylvain,McKercher, Ginette,Pellerin, Charles,Austel, Volkhard,Kukolj, George
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p. 119 - 124
(2007/10/03)
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- XANTHINE OXIDASE INHIBITORS
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The invention relates to compounds of the following formula (I) or their salts: in which R1 represents OR4 or others, in which R4 is an alkyl group having 1-8 carbon atoms which may have a substituent or the like; R2 is halogen, nitro, cyano, carboxyl, or the like; R3 is hydrogen, halogen, hydroxyl, amino, carboxyl, or the like; X is NR11, oxygen, or sulfur, in which R11 is hydrogen, or an alkyl group having 1-8 carbon atom which may have a substituent; and each of Y and Z is CR12 or nitrogen, in which R12 has the same meaning as R3 above, and a xanthine oxidase inhibitor containing the compound as an active ingredient.
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- Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase
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The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).
- White,Almassy,Calvert,Curtin,Griffin,Hostomsky,Maegley,Newell,Srinivasan,Golding
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p. 4084 - 4097
(2007/10/03)
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- Benzimidazole compounds
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Benzimidazole-4-carboxamide compounds (I) which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. In formula (I), R and R' may each be selected independently from hydrogen, alkyl, hydroxyalkyl (e.g. CH2CH2OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. R is generally a substituted phenyl group in the most preferred compounds. The compounds may also be used in the form of pharmaceutically acceptable salts or pro-drugs.
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- Imidazopyridine derivatives as angiotensin II receptor antagonists, pharmaceuticals, and treatment of hypertension therewith
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Imidazo-fused iso- and heterocycles, process for their preparation, compositions containing them and their useA compound of the formula STR1 in which the symbols have the following meaning: X is a monocyclic radical having 3,4 or 5 ring atoms,R 1,R 2,R 3,
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- 4H-3,1-BENZOXAZIN-4-ONES AND RELATED COMPOUNDS AND USE AS ENZYME INHIBITORS
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Novel 2-amino-4H-3,1-benzoxazin-4-ones represented by the formula wherein R 1, R 2, R 3 and X are defined herein are useful as enzyme inhibitors in animals.
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