Synthesis of 6-chloro(dichloro-, trichloro-)-methyl-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]- quinazolin-2-ones and their modification in reactions with nucleophilic and non-nucleophilic bases

The synthesis of 6-chloro-(dichloro-, trichloro)methyl-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones and their modification under the action of nucleophilic and/or basic reagents are described in this article. It was shown that 6-chloro-(dichloro-, trichloro)methyl-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones can be prepared by cyclocondensation of 3-(aminophenyl)-6-R-1,2;4-triazine-5(2Н)-ones with chloro-(dichloro-)acetaldehyde or chloral hydrate. The reactivity of the synthesized compounds toward nucleophilic base morpholine and non-nucleophilic base diisopropylethylamine (DIPEA) under different conditions was studied. It was shown that the prepared compounds under the action of morpholine and/or DIPEA can be converted into the products of substitution, elimination or elimination followed by isomerization and substitution. Refluxing of 6-(chloromethyl)-3-R-6,7-dihydro-2Н-[1,2,4]triazino[2,3-с]quinazoline-2-ones with equimolar quantity of morpholine and 10% excess of DIPEA in ethylene glycol monoethyl ether (EGEE) yielded the products on N-alkylation. 6-(Morpholinomethyl)-3-R-2H-[1,2,4]triazino[2,3-с]quinazoline-2-ones were obtained by heating of 6-dichloromethyl-3-R-6,7-dihydro-2Н-[1,2,4]triazino[2,3-с]quinazoline-2-ones with five-fold excess of morpholine in EGEE. Reaction of 3-R-6-(trichloromethyl)-6,7-dihydro-2H-[1,2,4]triazino[2,3-с]quinazolin-2-ones with three-fold excess of DIPEA in EGEE yielded 3-R-2Н-[1,2,4]triazino[2,3-с]quinazoline-2-ones. The physicochemical and spectral characteristics of the prepared compounds were determined and discussed.

Improved Biosafety and Transdermal Delivery of Aconitine via Diethylene Glycol Monoethyl Ether-Mediated Microemulsion Assisted with Microneedles

In the current study, diethylene glycol monoethyl ether-mediated microemulsions were combined with microneedles for enhanced transdermal aconitine delivery. The oil-in-water microemulsion increasedaconitine solubility and enhanced transdermal drug delivery and assistance with metal microneedles enhanced permeation of the aconitine-loaded microemulsion. Carried by the microemulsion, the in vitro permeability of aconitine was significantly enhanced, and further improved using microneedles. In vivo microdialysis revealed that the subcutaneous local drug concentration reached a high level within 30 min and remained relatively consistent to the end of the experimental period. AUC0-t of the microemulsion group was significantly higher than that of the aqueous solution group, and the microemulsion combined with microneedles group achieved the highest AUC0-t among the tested groups. The microemulsion and microdialysis probe also showed good biocompatibility with skin tissue. The microemulsion could be internalized by HaCaT and CCC-ESF-1 cells via lysosomes. The in vitro cytotoxicity of aconitine toward skin cells was reduced via encapsulation by microemulsion, and the prepared microemulsion developed no skin irritation. Hence, transdermal aconitine delivery and drug biosafety were effectively improved by loading into the microemulsion and assisting with microneedles, and in vivo microdialysis technique is suitable for realtime monitoring of transdermal drug delivery with microemulsion-based drug vehicles.