- Fabrication of deferasirox-decorated aptamer-targeted superparamagnetic iron oxide nanoparticles (SPION) as a therapeutic and magnetic resonance imaging agent in cancer therapy
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In the current study, the synthesis of a theranostic platform composed of superparamagnetic iron oxide nanoparticles (SPION)-deferasirox conjugates targeted with AS1411 DNA aptamer was reported. In this regard, SPION was amine-functionalized by (3-aminopropyl)trimethoxysilane (ATPMS), and then deferasirox was covalently conjugated onto its surface. Finally, to provide guided drug delivery to cancerous tissue, AS1411 aptamer was conjugated to the complex of SPION-deferasirox. The cellular toxicity assay on CHO, C-26 and AGS cell lines verified higher cellular toxicity of targeted complex in comparison with non-targeted one. The evaluation of in vivo tumor growth inhibitory effect in C26 tumor-bearing mice illustrated that the aptamer-targeted complex significantly enhanced the therapeutic outcome in comparison with both non-targeted complex and free drug. The diagnostic capability of the prepared platform was also evaluated implementing C26-tumor-bearing mice. Obtained data confirmed higher tumor accumulation and higher tumor residence time for targeted complex through MRI imaging due to the existence of SPION as a contrast agent in the core of the prepared complex. The prepared multimodal theranostic system provides a safe and effective platform for fighting against cancer.
- Moghadam, Seyed Mojtaba Mashmoul,Alibolandi, Mona,Babaei, Maryam,Mosafer, Jafar,Saljooghi, Amir Sh.,Ramezani, Mohammad
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- Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator
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Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.
- Salehi, Samie,Saljooghi, Amir Sh.,Shiri, Ali
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- Deferasirox loaded on fumed silica nanoparticles used in cancer treatment
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The present study has demonstrated a paradigm of successful in vitro drug delivery systems using Fumed Silica Nanoparticles (FSNPs) as a scaffold. The surface of FSNPs was first coated with (3-aminopropyl)trimethoxysilane (APTMS) by a silanization reaction and then was linked with deferasirox via the reaction between -NH2 and -COOH to form well-dispersed surface functionalized biocompatible FSNPs. The obtained nanoparticles were thoroughly characterized by various spectroscopic and microscopic methods such as Fourier Transform Infrared Spectroscopy (FT-IR), Thermo Gravimetric Analysis (TGA) and Brunauer, Emmett and Teller (BET) surface area analysis. The morphology of these structures was investigated by Scanning Electron Microscopy (SEM). The cytotoxicity of these compounds were screened for antitumor activity against MCF-7, MDA-MB-231, HeLa, HT-29, Neuro-2a, L929 cell lines and cisplatin was used as a comparative standard by a MTT assay. Our results presented herein provide experimental evidence that fumed silica nanoparticles loaded with deferasirox induce apoptosis in cancer cell lines. Our flow cytometry results confirm that the investigated compound showed a high population of apoptotic cells (55.20%) and 1.2-fold higher than cisplatin (45.15%) at the same concentration and could induce apoptosis of human breast cancer cell lines (MDA-MB-231).
- Taghavi, Faezeh,Gholizadeh, Mostafa,Saljooghi, Amir Sh.
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Read Online
- Deferasirox-coated iron oxide nanoparticles as a potential cytotoxic agent
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Two broad strategies for the use of iron chelators in cancer treatment have been explored. The first was using iron chelators to reduce the iron level in cancer cells. Cancer cells typically require more iron than normal cells to mediate their generally rapid DNA synthesis and growth. The second more recent strategy is using chelators that help the redox cycling of iron to generate cytotoxic ROS (reactive oxygen species) within tumors. Both methods are currently being pursued. Deferasirox is an FDA-approved medication used to reduce chronic iron overload. Because of the low toxicity and oral administration of deferasirox, the use of this drug in cancer therapy is a new approach. Therefore, a number of recent studies have examined the potential of deferasirox as an anticancer agent. According to these strategies, the present study has reported the new role of deferasirox (DFX) loaded on iron oxide nanoparticles (Fe3O4@DFX) as an anticancer agent. The cytotoxicity of Fe3O4@DFX was screened against MCF-7, HeLa, HT-29, K-562, Neuro-2a, and L-929 cell lines by MTT assay. The surface of magnetic nanoparticles (MNPs) was first coated with (3-aminopropyl) trimethoxysilane (APTMS) and was then linked with deferasirox via an amidation reaction between-NH2 and-COOH to form well-dispersed surface-functionalized biocompatible MNPs. The obtained nanoparticles were thoroughly characterized by various spectroscopic and microscopic methods such as SEM, FT-IR, TGA and VSM. Because of the ability of magnetic nanoparticles in biomedical applications to be targeted toward the site of action using magnetic field gradients, we suggest that MNPs loaded with deferasirox could be considered as a potential formulation, which can simultaneously be used as a theranostic agent for both cancer treatment and imaging. The obtained results provide experimental evidence that magnetite nanoparticles loaded with deferasirox induce apoptosis in cancer cell lines. Moreover, flow cytometry results confirm that the investigated compound produces a high population of apoptotic cells (69.3%), 1.2 fold higher than cisplatin (58.1%) at the same concentration, and could induce apoptosis in human leukemia cell lines (K-562).
- Taghavi, Faezeh,Saljooghi, Amir Sh.,Gholizadeh, Mostafa,Ramezani, Mohammad
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- 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid: A novel efficient and selective iron(III) complexing agent
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An exceptionally stable 1:2 complex [FeL2]3- is formed from the ligand H3L and Fe(III). In contrast, the affinity of this ligand for other biometals is relatively small. These properties make H3L a highly promising candidate for medical applications (e.g. for the treatment of iron overload).
- Heinz, Uwe,Hegetschweiler, Kaspar,Acklin, Pierre,Faller, Bernard,Lattmann, Rene,Schnebli, Hans Peter
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Read Online
- In vitrostudies of deferasirox derivatives as potential organelle-targeting traceable anti-cancer therapeutics
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We report here strategic functionalization of the FDA approved chelator deferasirox (1) in an effort to produce organelle-targeting iron chelators with enhanced activity against A549 lung cancer cells. Derivative 8 was found to have improved antiproliferative activity relative to 1. Fluorescent cell imaging revealed that compound 8 preferentially localises within the lysosome.
- Han, Hai-Hao,He, Xiao-Peng,Huang, Dan-Ying,Li, Jia,Sedgwick, Adam C.,Sen, Sajal,Sessler, Jonathan L.,Steinbrueck, Axel,Zang, Yi,Zhao, Michael Y.
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p. 5678 - 5681
(2021/06/16)
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- Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties
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Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.
- Sedgwick, Adam C.,Yan, Kai-Cheng,Mangel, Daniel N.,Shang, Ying,Steinbrueck, Axel,Han, Hai-Hao,Brewster, James T.,Hu, Xi-Le,Snelson, Dylan W.,Lynch, Vincent M.,Tian, He,He, Xiao-Peng,Sessler, Jonathan L.
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supporting information
p. 1278 - 1283
(2021/02/01)
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- Synthesis of 2-(2-Hydroxyaryl)-4H-benzo[e][1,3]oxazin-4-ones by Palladium-Catalyzed C(sp2)?H Hydroxylation via Electro-chemical Oxidation
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An electrochemical direct ortho-hydroxylation of 2-aryl-4H-benzo[e][1,3]oxazin-4-ones was developed with Pd(OAc)2 as catalyst, oxazine ring as a directing group and Oxone as the hydroxylation reagent. A series of hydroxylation products were obtained under mild conditions, and the yields were from medium to good. This method is characterized by good functional group tolerance and a wide range of substrates. More importantly, use anodic oxidation to avoid the use of potentially toxic and polluting oxidants. A gram-scale direct electrochemical hydroxylation of 2-phenyl-4H-benzo[e][1,3]oxazin-4-one was performed, and the hydroxylation product was applied to synthesize the drug deferasirox. In addition, the single crystal of 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one was obtained and determined by X-ray diffraction. Finally, the reaction mechanism was proposed and verified by cyclic voltammetry (CV). This protocol also provides an alternative electrochemical hydroxylation methodology for the functionalization of molecules. (Figure presented.).
- Wu, Hongfeng,An, Qi,He, Chaoyin,Fan, Xiaodong,Guo, Weihao,Zuo, Minghui,Xu, Chunzhao,Guo, Rui,Chu, Wenyi,Sun, Zhizhong
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p. 2459 - 2465
(2020/04/29)
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- Industrialized production method of deferasirox
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The invention discloses an industrialized production method of deferasirox. The industrialized production method includes the following steps that (1) 2-Cyanophenol reacts with acyl chloride or acid anhydride, and after the reaction is completed, an alcohol solution of hydrogen chloride is added to a reaction solution to obtain a compound IV; (2) the compound IV reacts with salicylic acid chlorideto obtain a compound VI; and (3) the compound VI reacts with p-hydrazinobenzoic acid or hydrochloride thereof to obtain deferasirox. According to the synthesis method, the problems of complicated operation, large pollution and potential safety hazards in existing methods are solved, the synthesis method adjusts starting materials for synthesis, so that the reaction conditions of an entire processroute are mild, hydrogen chloride gas is not need to be introduced in the reaction process, using of diethyl ether to wash intermediate products is not needed, using of palladium-carbon catalytic hydrogenation to remove corresponding substituents is not needed, the process is greatly simplified, the production cost and potential safety hazards are reduced, and large scale industrial production can be carried out.
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Paragraph 0051-0054
(2020/12/08)
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- Design, synthesis and evaluation of a novel metal chelator as multifunctional agents for the treatment of Alzheimer's disease
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A series of compounds following the lead compounds including deferasirox and tacrine were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most synthesized compounds exhibited good multifunctional activities in inhibiting acetylcholinesterase (bAChE), and chelating metal ions. Especially, compound TDe demonstrated significant metal chelating property, a moderate acetylcholinesterase (AChE) inhibitory activity and an antioxidant activity. Results from the molecular modeling indicated that TD compounds were mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of TcAChE. Moreover, TDe showed a low cytotoxicity but a good protective activity against the injury caused by H2O2. These results suggest that TD compounds might be considered as attractive multi-target cholinesterase inhibitor and will play important roles in the treatment of AD.
- Wang, Yingying,Yang, Yue,Hong, Kwon Ho,Ning, Yao,Yu, Ping,Ren, Jinghui,Ji, Min,Cai, Jin
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p. 720 - 727
(2019/04/08)
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- Excitation Wavelength Dependent Fluorescence of an ESIPT Triazole Derivative for Amine Sensing and Anti-Counterfeiting Applications
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Excitation wavelength dependent (Ex-De) emission materials have potential applications in anti-counterfeiting labels and bioimaging. Nevertheless, few purely organic chromophores are used in these areas. In this study, multiple excited states were incorporated into a molecule that was excited state intramolecular proton transfer (ESIPT) active, with the goal of manipulating the relaxation pathways of the excited states. The triazole derivative exhibits Ex-De photoluminescence (PL), and the maximum PL wavelength is located at 526 nm and 593 nm under a series of excitation wavelengths. Spectral identification indicates that the excimer and ESIPT processes are responsible for the green (526 nm) and orange (593 nm) fluorescence, respectively. Importantly, the quick response code and test strip prepared with this triazole derivative can be used for anti-counterfeiting and food spoilage detection applications, respectively. This research opens the door for developing novel Ex-De materials for anti-counterfeiting purposes.
- Zhang, Yujian,Yang, Heyi,Ma, Huili,Bian, Gaofeng,Zang, Qiguang,Sun, Jingwei,Zhang, Cheng,An, Zhongfu,Wong, Wai-Yeung
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p. 8773 - 8778
(2019/04/14)
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- A PROCESS FOR THE PREPARATION OF DEFERASIROX
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The present invention provides an improved process for the preparation of Deferasirox of Formula - I substantially free from 'hydrazino impurity' by the condensation of 2-(2-hydrophenyl)-4H-1,3-benzoxazin-4-one of Formula - IV with 4-hydrazino benzoic acid of Formula - V in a polar solvent.
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Page/Page column 8-9
(2019/02/06)
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- 1,2,4-triazole compound, salt thereof and applications of compound and salt
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The invention discloses a 1,2,4-triazole compound, salt thereof and applications of the compound and salt. The compound has a structural formula shown in the description, wherein R represents hydrogen, phenyl or substituted phenyl, and a substituted group of substituted phenyl is selected from carboxyl, an ester group, C1-4 alkyl, C1-4 alkoxy groups, C1-4 halogenated alkyl, C1-4 halogenated alkoxygroups, C2-4 alkynyl, halogen, cyano groups, acyl, nitryl or hydroxyl. The compound has high insecticidal activity for aphids, part of compound has the insecticidal activity for aphids equivalent tothat of a commercial insecticide dinotefuran, and the compound can be used for controlling lepidoptera pests, coleoptera pests, heteropteran pests, diptera pests, orthoptera pests and homoptera pests.
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- Cu(II) immobilized on Fe3O4@APTMS-DFX nanoparticles: An efficient catalyst for the synthesis of 5-substituted 1: H -tetrazoles with cytotoxic activity
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Cu(ii) immobilized on deferasirox loaded amine functionalized magnetic nanoparticles (Cu(ii)/Fe3O4@APTMS-DFX) as a novel magnetically recyclable heterogeneous catalyst is able to catalyze the [3 + 2] cycloaddition reactions of various organic nitriles with sodium azide. Using this method, a series of 5-substituted-1H-tetrazoles under mild conditions in DMSO were prepared. The reaction involves mild reaction conditions with efficient transformation capability. The developed catalyst could be easily separated by applying an external magnetic field. Furthermore, it could be recycled for 5 runs with negligible leaching of copper from the surface of the catalyst. The catalyst was characterized by various techniques such as FT-IR, TGA, VSM, SEM-EDX, and ICP-OES. Several derivatives of 1H-tetrazoles were prepared using this catalyst, and their structures were confirmed using different techniques. Then, the synthesized anthraquinones were evaluated for their cytotoxicity against several cell lines including MCF-7, MAD-MD-231, HT-29, HeLa, neuro-2a and L-929. The results obtained from the MTT assay revealed that the 6 derivatives exhibited a high level of cytotoxicity. In order to determine the cytotoxicity mechanism, 2 derivatives with the highest cytotoxic activity were selected, and an apoptosis assay was carried out by flow cytometry, which supported that apoptosis is the major mechanism.
- Taghavi, Faezeh,Gholizadeh, Mostafa,Saljooghi, Amir Sh.,Ramezani, Mohammad
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p. 1953 - 1964
(2017/10/27)
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- PROCESS FOR THE PREPARATION OF DEFERASIROX
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Present disclosure discloses the commercially viable process for the preparation of Deferasirox and its polymorph with. Disclosed process involves the preparation of Deferasirox via metal salt of the corresponding intermediate and deferasirox metal salt.
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- IRON COMPLEXING AGENT AND USES THEREOF IN THE TREATMENT AND PREVENTION OF COLORECTAL CANCER
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A complex comprising a non-absorbable portion attached to an iron chelator moiety, a composition comprising the complex and the use of the complex in the treatment of colorectal cancer. In one embodiment the non-absorbable portion is a polymer such as a polysaccharide, including chitosan, chitin, cellulose or pectin. In one embodiment the iron chelator moiety comprises at least one functional group selected from catechol, hydroxamate or carboxylate, or any combination thereof.
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- Microemulsion technique for the novel synthesis of deferasirox using metal mediated coupling
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A novel and efficient synthesis of Deferasirox has been accomplished using transition metal catalyzed sequential cross coupling reactions. First stage of the synthesis employs the use of Chan-Lam coupling between 3,5-dibromo-1H[1,2,4] triazole and (4-(methoxycarbonyl)-phenyl)boronic acid to give methyl 4-(3,5-dibromo-1H-1,2,4-triazol-1-yl)benzoate which is further elaboarated to Deferasirox by Suzuki-Miyaura coupling with 2-hydroxyphenyl-boronic acid pinacol ester in microemlusion.
- Roy, Bhairab Nath,Singh, Girij Pal,George, Shaji K.,Lathi, Piyush S.,Agrawal, Manoj K.,Trivedi, Anurag,Mishra, Madhan,Singh, Gajendra
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p. 610 - 618
(2014/06/23)
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- PROCESS FOR THE PREPARATION OF DEFERASIROX
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The present invention provides improved process for the preparation of Deferasirox of formula (I).
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Paragraph 0044
(2014/02/16)
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- Process for the preparation, of 2-(2-hydroxyphenyl)-benz [1, 3] oxazin-4-one and its use for preparation of 4-[3, 5-bis (2-hydroxyphenyl)-lH-l , 2, 4-triazolTl-yl] benzoic acid
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The invention provides a novel process for the synthesis of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one, the process comprising of reacting the salicylic acid with salicylamide in the presence of p-toluenesulfonyl chloride, base and solvent. The use of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one in the preparation of Deferasirox is also disclosed in the invention.
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Paragraph 0021
(2014/02/15)
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- A PROCESS FOR THE PREPARATION OF 2-(2-HYDROXYPHENYL)-BENZ[1,3]OXAZIN-4-ONE AND ITS USE FOR PREPARATION OF 4-[3, 5-BIS (2-HYDROXYPHENYL)-1H-1, 2, 4-TRIAZOL-1-YL] BENZOIC ACID
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The invention provides a novel process for the synthesis of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one, the process comprising of reacting the salicylic acid with salicylamide in the presence of p-toluenesulfonyl chloride, base and solvent. The use of 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one in the preparation of Deferasirox is also disclosed in the invention
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- PROCESS FOR THE PRODUCTION OF DEFERASIROX
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A new process is described for the preparation of deferasirox, 4-[(3Z,5E)-3,5-bis(6- oxo-1 -cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1 -yl]benzoic acid, having the following structural formula (I).
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- Synthesis and characterization of related substances of deferasirox, an iron (Fe3+) chelating agent
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Deferasirox is an orally active iron chelating agent, and during process development for deferasirox, we observed six related substances (impurities), namely deferasirox methyl ester, deferasirox salicylyl derivative, deferasirox ethyl ester, deferasirox methoxy carbonyl derivative, bis(salicyl)imide, and deferasirox-2-isomer. The present work describes the detection, origin, synthesis, and characterization of these related substances.
- Rao, Vascuri Janardhana,Mukkanti, Kagga,Vekariya,Gupta, P. Badrinadh,Islam, Aminul
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p. 3200 - 3210
(2012/11/13)
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- A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding
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Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic
- Kielar, Filip,Wang, Qin,Boyle, Paul D.,Franz, Katherine J.
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p. 294 - 303
(2013/01/15)
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- PROCESS FOR THE PREPARATION OF DEFERASIROX
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The present invention provides improved process for the preparation of Deferasirox of formula (I).
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Page/Page column 4-5
(2012/06/15)
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- PROCESS FOR THE PREPARATION OF 4-[3,5-BIS(2-HYDROXYPHENYL)-1H-1,2,4-TRIAZOL-1-YL]-BENZOIC ACID AND ITS AMINE SALTS
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The present invention relates to an improved process for the preparation of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid compound of formula (1) and process for its purification.
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Page/Page column 24
(2011/04/13)
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- SOLID STATE FORMS OF DEFERASIROX SALTS AND PROCESS FOR THE PREPARATION THEREOF
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Provided herein are novel solid state forms of deferasirox salts, process for the preparation, pharmaceutical compositions, and method of treating thereof. The solid state forms of deferasirox salts are useful for preparing deferasirox (I) in high purity.
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- PROCESSES FOR THE PREPARATION OF DEFERASIROX, AND DEFERASIROX POLYMORPHS
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The present invention relates to processes for the preparation of deferasirox, an oral iron chelator developed to treat iron overload due to e.g. multiple blood transfusions. The present invention further provides novel deferasirox pseudopolymorphs and a novel amorphous form of deferasirox, processes for their preparation, as well as pharmaceutical compositions comprising same, and use thereof in treating iron overload.
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- SUBSTANTIALLY PURE DEFERASIROX AND PROCESSES FOR THE PREPARATION THEREOF
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Provided herein is a highly pure deferasirox or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity, 4-hydrazinobenzoic acid, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure deferasirox or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity.
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Page/Page column 6
(2011/08/02)
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- Four-component synthesis of fully substituted 1,2,4-triazoles
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Chemical Equation Presented All 4 one: Palladium-catalyzed carbonylation initiates a highly regioselective triazole synthesis. In this four-partner protocol, the aryl halide, amidine, and hydrazine partners are easily varied, allowing the synthesis of fully substituted 1,2,4-triazoles in a modular fashion. This methodology is demonstrated with the synthesis of druglike and/or pharmaceutically relevant molecules such as deferasirox.
- Staben, Steven T.,Blaquiere, Nicole
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supporting information; experimental part
p. 325 - 328
(2010/04/02)
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- CRYSTALLINE FORM OF 2-(2-HYDROXY PHENYL)BENZ[E][1,3]OXAZIN-4-ONE, PROCESS FOR THE SAME AND USE FOR PRODUCING 4-(3,5-BIS(2-HYDROXYPHENYL)-1H-1,2,4-TRIAZOL-1-YL)BENZOIC ACID
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The present invention relates to a crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one, a process for production thereof and its use in the preparation of 4- (3, 5-bis (2-hydroxyphenyl)-1H-1, 2, 4-triazol-1-yl) benzoic acid. The improved process for the preparation 4-(3,5-bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl) benzoic acid (Deferasirox), wherein salicylic chloride is reacted with salicylamide in presence of a solvent to give acyl compound, which is heated to higher temperature in-situ to undergo cyclization to obtain crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-on and further reaction with hydrazino benzoic acid to give 4-(3,5- bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid.
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(2010/04/06)
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- A METHOD FOR PREPARING 4-[3,5-BIS(2-HYDROXYPHENYL)-[1,2,4]TRIAZOL-1-YL]-BENZOIC ACID
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A method for preparing 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid of formula (I) by reaction of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one of formula (II) with 4-hydrazinobenzoic acid of formula (III) in an organic acid or in a mixture of an organic acid and an organic solvent.
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Page/Page column 11-12
(2009/09/05)
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- SUBSTANTIALLY PURE DEFERASIROX AND PROCESSES FOR THE PREPARATION THEREOF
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Provided herein is a highly pure deferasirox or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity, 4-hydrazinobenzoic acid, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure deferasirox or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity.
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Page/Page column 15
(2009/12/28)
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- CRYSTALLINE FORMS OF DEFERASIROX
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The present invention provides novel crystalline forms of deferasirox, methods for their production, and methods for conversion of the novel forms to the known crystalline form I.
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Page/Page column 12
(2008/12/07)
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- Complex formation of ICL670 and related ligands with FeIII and FeII
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Complex formation of 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (ICL670, H3Lx), 4-[3,5-bis(2-hydroxyphenyl)-1,2,4- triazol-1-yl]benzosulfonic acid (H3Ly), and 3,5-bis(2-hydroxyphenyl)-1-phenyl-1,2,4-triazole (H2Lz) with Fe3+ and Fe2+ was investigated in H2O and in H2O/DMSO mixtures by potentiometry, spectrophotometry and cyclic voltammetry. ICL670 has previously been considered as a promising drug for an oral treatment of iron overload. In this paper, the stability and redox properties of the various FeII and FeIII complexes were elucidated with a particular focus on their potential involvement in the generation of oxidative stress. The overall stability constants of [Fe III(Lx)] and [FeIII(Lx) 2]3- (25 °C, 0.1 M KCl in H2O) are log β1 = 22.0 and log β2 = 36.9, respectively. The affinity of these ligands for Fe2+ is remarkably poor. In particular, the 1:2 complexes [FeIII(Lx)2]4- and [FeII(Ly)2]4- were found to be less stable. As a consequence, the redox chemistry of the [Fe III(Lx)]/[FeII(Lx)]- and the [FeIII(Lx)2]3-/[Fe II(Lx)2]4- couples differs significantly. [FeIII(Lx)2]3- is a very weak oxidizing agent (E1/2 is approximately -0.6 V versus NHE) and reduction of [FeIII(Lx)2]3- is not anticipated under physiological conditions. The reduction potential of the [FeIII(Lx)]/[FeII(Lx)]- couple is considerably less negative and was estimated to be +0.1 V (versus NHE). The possible roles of the various Fe complexes as catalysts for the Fenton reaction in biological media are discussed. The crystal structures of H 3LX, Na[Fe(Lz)2]·4EtOH, Na[Al(Lz)2]· 4EtOH, and [Cu(Lz) (pyridine)]2 were investigated by single-crystal X-ray diffraction, and the possible influence of the particular steric requirements of these ligands on the stability of the metal complexes has been analyzed. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004).
- Steinhauser, Stefan,Heinz, Uwe,Bartholomae, Mark,Weyliermueller, Thomas,Nick, Hanspeter,Hegetschweiler, Kaspar
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p. 4177 - 4192
(2007/10/03)
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- Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
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The use is described of 3,5-diphenyl-1,2,4-triazoles of the formula I in which R1-R5are as defined in the description. The compounds have useful pharmaceutical properties and are particularly active as iron chelators. They can be used for the treatment of iron overload in warm-blooded animals.
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