360-97-4Relevant articles and documents
Temozolomide-Hesperetin Drug-Drug Cocrystal with Optimized Performance in Stability, Dissolution, and Tabletability
Wang, Jie,Dai, Xia-Lin,Lu, Tong-Bu,Chen, Jia-Mei
, p. 838 - 846 (2021)
A new 1:1 drug-drug cocrystal of temozolomide and hesperetin was successfully prepared by liquid-assisted grinding, slurry conversion crystallization, and evaporation crystallization. The obtained cocrystal was comprehensively characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, as well as by Fourier transform infrared and nuclear magnetic resonance spectroscopy. The two drug molecules in the cocrystal are connected via O-H···O hydrogen bonds between the carbonyl oxygen of temozolomide and the phenolic hydroxyl group of hesperetin. The drug-drug cocrystal enhances the hydroscopic stability of hesperetin and the physicochemical stability of temozolomide. In addition, the cocrystal optimizes the dissolution behavior of temozolomide and hesperetin at pH 1.2 and pH 6.8 in comparison to the pristine drugs. Further, a compressibility assessment was also conducted, and the cocrystal exhibits a superior tabletability in comparison with temozolomide. Therefore, the drug-drug cocrystal has the potential to be developed as an efficient oral formulation of a drug combination which will overcome the weaknesses of each parent drug.
Synthetic studies of 8-carbamoylimidazo-[5,1-D]-1,2,3,5-tetrazin-4(3H)-one: A key derivative of antitumor drug temozolomide
Wang,Stevens
, p. 185 - 188 (1996)
5-Diazoimidazole-4-carboxamide 4 reacted with trimethylsilyl isocyanate in acetonitrile to afford 8-carbamoylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one 1, which was undergoing a methylation to give antitumour drug temozolomide 2; while 1,5-dicarbamoyl aminoimidazole 6 failed in an azo-cyclization to give 1 but accomplished a carbon-cyclization to produce 8-carbamoylimidazo[1,5-a] s-triazin-4(3H)-one 7.
Development of a One-Step Synthesis of 5-Amino-1 H-imidazole-4-carboxamide
Qi, Ji,Yin, Jingjun,Li, Donghong,Chen, Song,Liu, Zhenguo
, p. 591 - 596 (2021/04/05)
An innovative and efficient synthesis of 5-amino-1H-imidazole-4-carboxamide (AIC) from commercially available hypoxanthine (～$30/kg) is described. The development of the key hydrolysis step and a practical isolation enables a highly efficient one-step manufacturing process for AIC with minimal environmental impact and significant reduction of production cost.
Industrial production method of 4-amino-5-imidazolecarboxamide
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Paragraph 0040; 0045-0048; 0049; 0054, (2020/07/15)
The invention discloses an industrial production method of 4-amino-5-imidazolecarboxamide, belonging to the technical field of organic synthesis. The industrial production method comprises the following steps: S1, reacting diaminomaleonitrile with formamide under the action of phosphorus oxychloride to generate an intermediate 1; and S2, subjecting the intermediate 1 to a ring closing reaction under an alkaline condition so as to generate 4-amino-5-imidazolecarboxamide. The method has the advantages of simple raw materials, low price, short reaction steps, short production period, simple operation and easy realization of industrial production, avoids the generation of cyano-containing wastewater, nitrogen-containing wastewater and the like in traditional synthesis methods, causes very small environmental protection pressure, and realizes preparation of the high-quality 4-amino-5-imidazolecarboxamide only through two reactions.
Optimized synthesis process of anticancer drug dacarbazine
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Paragraph 0032; 0033, (2019/10/17)
The invention provides an optimized synthesis process of an anticancer drug dacarbazine. The optimized synthesis process of the anticancer drug dacarbazine comprises the following steps: synthesis ofglycine methyl ester, synthesis of N-formylglycine methyl ester, synthesis of alpha-methyl isocyanoacetate, synthesis of alpha-isocyanoacetamide, synthesis of 5-amino-4-imidazolecarboxamide and synthesis of dacarbazine. Synthesis of the glycine methyl ester comprises the following steps: weighing 7.5 g of glycine and adding the glycine into a 500 mL round-bottom flask, taking 200 mL of redistilledmethanol as a solvent and cooling with stirring in an ice bath for 15 min; weighing 22 mL of thionyl chloride by a syringe and slowly dropwise adding the thionyl chloride into the reaction flask to react overnight at room temperature; and removing excess thionyl chloride and methanol by rotary evaporation at the room temperature, dissolving the residues by using as little hot methanol as possible, quickly adding a large amount of cold diethyl ether, and cooling in the reaction bottle in an ice bath. By improving the synthesis process of the anticancer drug dacarbazine, the optimized synthesisprocess of the anticancer drug dacarbazine has the advantages of reasonable synthesis circuit, cheap raw materials, mild reaction conditions and high total yield, thereby effectively solving the problems and defects in the prior art.
Strategy for imidazotetrazine prodrugs with anticancer activity independent of MGMT and MMR
Garelnabi, Elrashied A. E.,Pletsas, Dimitrios,Li, Li,Kiakos, Konstantinos,Karodia, Nazira,Hartley, John A.,Phillips, Roger M.,Wheelhouse, Richard T.
supporting information, p. 965 - 968 (2013/02/23)
The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The
Antitumor imidazotetrazines. 41.1 Conjugation of the antitumor agents mitozolomide and temozolomide to peptides and lexitropsins bearing DNA major and minor groove-binding structural motifs
Arrowsmith, Jill,Jennings, Sharon A.,Clark, Alan S.,Stevens, Malcolm F. G.
, p. 5458 - 5470 (2007/10/03)
Carboxylic acids derived from the amido groups of the antitumor agents mitozolomide and temozolomide have been conjugated to simple amino acids and peptides by carbodiimide coupling. Solid-state peptide synthesis has been applied to link the acids to DNA major groove-binding peptidic motifs known to adopt α-helical conformations. Attachment of the acids to pyrrole and imidazole polyamidic lexitropsins gave a series of potential DNA minor groove-binding ligands. In vitro biological evaluation of a limited number of these novel conjugates failed to demonstrate any enhanced growth-inhibitory activity compared to the unconjugated drugs; sites of alkylation at tracts of multiple guanines were also unaffected. Attachment of additional residues at C-8 of the imidazotetrazines did not perturb the chemistry of activation of the bicyclic nucleus, and biological sequelae can be rationalized by invoking the liberation of a common, diffusible, reactive chemical intermediate, the methanediazonium ion.
Synthesis of temozolomide and analogs
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, (2008/06/13)
This invention relates to a novel process for the synthesis of Temozolomide, an antitumor compound, and analogs, and to intermediates useful in this novel process.
Decomposition of the Antitumour Drug Temozolomide in Deuteriated Phosphate Buffer: Methyl Group Transfer is accompanied by Deuterium Exchange
Wheelhouse, Richard T.,Stevens, Malcolm F. G.
, p. 1177 - 1178 (2007/10/02)
The antitumour prodrug temozolomide 1 undergoes ring-opening in deuteriated phosphate buffer; deuterium incorporation into the methyl group transferred from the reactive species 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) 2 has been monitored by observing D-H and P-H couplings in the NMR spectra of the products.
Xanthine oxidase (XO): Relative configuration of complexes formed by the enzyme, 2- or 8-N-alkylhypoxanthines and 2-N-alkyl-8-azahypoxanthines. XII
Biagi,Giorgi,Livi,Scartoni,Tonetti,Lucacchini
, p. 357 - 374 (2007/10/02)
Several 2- or 8-n-alkyl-hypoxanthines and a 2,8-di-n-pentylhypoxanthine were synthesized and tested as substrates or inhibitors of Xanthine Oxidase (XO). 8-Alkyl derivatives showed a substrate behaviour, whereas 2-alkyl substituted compounds were non-substrates and inhibitors. 2,8-di-n-pentylhypoxanthine was ineffective as inhibitor. The comparison between their activity allowed us to conclude that the complexes formed by the enzyme and the cited n-alkylhypoxanthines or 2-n -alkyl-8-azahypoxanthines involve their N(3) and N(9) positions in all the cases. The position of the n-alkyl chain determines the disposition of the molecule inside the complex: 2-n-alkyl-hypoxanthines and 2-n-alkyl-8-azahypoxanthines gave complexes with the same orientation of heterocyclic moieties, opposite that given by 8-n-alkyl-hypoxanthines.
