RU2642468C2 - Method of producing nitronylnitroxyl radical 2-(5-methyl-1n-imidazole-4-yl)-4,5-bis(spiropentane)-4,5-dihydro-1n-imidazol-3-oxid-1-oxyl - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing nitronylnitroxyl radical 2-(5-methyl-1N-imidazole-4-yl)-4.5-bis(spiropentane)-4.5-dihydro-1N-imidazole-3-oxide-1-oxyl, which consists in interacting 1.1'-dihydroxylation-bicyclopentyl produced by the neutralisation of the alkaline agent to the corresponding sulfate salt of 1,1'-dihydroxylation-bicyclopentyl, 4-methylimidazole-5-carbaldehydes in an aqueous solution when heated, and by the oxidation of the resulting product with sodium periodate, with the subsequent release of the specified nitronylnitroxide radical.

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EFFECT: application as an effective and low-toxic contrast agent for MR-tomography of living organisms.

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Description

The invention relates to a method for producing a water-soluble and stable in aqueous solution, including when heated, nitronyl nitroxyl radical of 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4.5 -dihydro-1H-imidazole-3-oxide-1-oxyl, characterized in that in the first stage receive 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4, 5-dihydro-1H-imidazole by condensation of 1,1'-dihydroxylamino-biscyclopentyl, obtained by neutralization with an alkaline agent of the corresponding sulfate salt of 1,1'-dihydroxylamino-biscyclopentyl, from 4-methylimide ol-5-carbaldehyde in aqueous solution under heating, and the subsequent oxidation of the resulting product with sodium periodate.

The method allows to obtain this compound with a high degree of purity.

EFFECT: possibility of obtaining a kinetically stable nitronyl nitroxyl radical soluble in water and stable in an aqueous solution, including when heated, which can be used as a contrast agent for magnetic resonance imaging.

The invention relates to the field of organic magnetic compounds and magnetic resonance imaging, namely: nitronyl nitroxyl radical of the 2-imidazoline series, 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4, 5-dihydro-1H-imidazole-3-oxide-1-oxyl, which has a unique combination of useful properties - solubility in water and kinetic stability in an aqueous solution, including when heated to 80 ° C. The structural formula of the compound is given below.

This compound can be used as an effective and low-toxic contrast reagent for MP-tomography of living organisms, since it does not contain transition metals. It can be used in in vivo studies, since it is stable when heated in an aqueous solution to 80 ° C, that is, it can be sterilized before being introduced into a living organism.

Researchers are actively exploring the diverse uses of nitroxyl radicals in biology biochemistry and medicine (modern monographs and reviews: Likhtenshtein, GI; Jun Yamauchi, J .; Nakatsuji, S .; Smirnov, AI; Tamura, R. Nitroxides: Applications in Chemistry, Biomedicine, and Materials Science, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2008; Kokorin, AI, Ed. Nitroxides: Theory, Experiment and Applications; InTech: Croatia, 2012; Likhtenshtein, GI IRJPAC, 2015, 8 (1), 1; Article no.IRJPAC.2015.069). One of the most important tasks in the field of creating contrast agents for MP tomography is to exclude from the medical practice the currently widely used contrast agents containing metals of the first transition series or rare-earth metals, by creating a kinetically stable water-soluble pure organic paramagnet capable of changing the proton relaxivity water molecules and thereby regulate the contrast of MR images.

The recently described water-soluble organic paramagnets based on nitronyl nitroxyl radicals, promising for use as contrast agents, were synthesized based on vicinal tetramethyl-substituted bishydroxylamine. Low toxicity and the ability to accumulate in pathological foci were demonstrated for them (DAN, 2005, v. 404 (2), pp. 198-200; DAN, 2007, v. 416 (4), p. 493-495). However, the nitronyl nitroxyl radicals shown did not possess sufficient stability in an aqueous solution upon heating and, therefore, cannot be subjected to the necessary thermal sterilization procedure, and therefore cannot be used as contrast agents for MP tomography of living organisms.

The water soluble and stable aqueous solution described in this patent, including when heated to 80 ° C., is an organic paramagnet 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) - 4,5-dihydro-1H-imidazole-3-oxide-1-oxyl solves the problem of creating a water-soluble organic paramagnet with high kinetic stability in aqueous solutions, including when heated.

The indicated useful combination of properties inherent to the 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4,5-dihydro-1H-imidazole-3-oxide-1-oxyl nitronyl nitroxyl radical , due to the presence in its molecule of spirocyclic substituents at positions 4 and 5 of the imidazoline cycle, which are in close proximity to functional fragments carrying an unpaired electron. This modification of the substituents in the 2-imidazoline cycle provides high kinetic stability of the radical, which consists in the fact that it can be maintained in an aqueous solution at a temperature of 40-80 ° C for 1 hour without decomposition, and also boil without decomposition in an aqueous solution at 100 ° C for 10 minutes. These characteristics of the kinetic stability of the compound potentially provide the possibility of thermal sterilization of the compound before its introduction into a living organism.

The essence of the invention is illustrated by the following examples of experimental data.

Example 1

Method for the synthesis of compounds. At room temperature, 4-methylimidazole-5-carbaldehyde (0.125 g, 1.1 mmol) was added to a solution of 1,1'-dihydroxylamino-biscyclopentyl sulfate monohydrate (0.150 g, 0.5 mmol) in water, the reaction mixture was stirred for 3 h at temperature of 50 ° C, then neutralized with dry acidic sodium carbonate (NaHCO ₃ ) until gas evolution ceases. 3 ml of methylene chloride (CH ₂ Cl ₂ ) were added to the resulting mixture and 30 mg of sodium periodate (NaIO ₄ ) were added and the organic phase was separated, the aqueous phase was treated with 10 ml of CH ₂ Cl ₂ three times. The combined organic extracts were evaporated, dissolved in ethyl acetate, filtered through a 1.5 (diameter) × 10 (height) cm SiO ₂ layer and evaporated. The dry residue is purified by recrystallization from methanol, maintaining the mother liquor at 4 ° C for 1-2 days. Yield 0.025 g (17%), prismatic crystals of dark blue color. Calculated for C ₁₅ H ₂₁ N ₄ O ₂ ,%: C, 62.3; H, 7.2; N, 19.4. Found (%): C, 62.0; H, 6.8; N, 19.1. The molecular structure of the nitronyl nitroxyl radical of 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4,5-dihydro-1H-imidazole-3-oxide-1-oxyl is confirmed by X-ray diffraction analysis made for his single crystal. The effective magnetic moment of the compound is 1.73 ± 0.01 Bohr magneton at 298 K.

Example 2

Data on the solubility of the radical in water at 25 ° C: solubility of 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4,5-dihydro-1H-imidazole-3-oxide -1-oxyl is 3.3 ± 0.1 g / liter.

Example 3

Investigation of the stability of 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4,5-dihydro-1H-imidazole-3-oxide-1-oxyl in an aqueous solution under ordinary conditions and when heated.

a) The nitronyl nitroxyl radical does not undergo changes in the aqueous solution during storage under ordinary conditions for 3 weeks.

b) For the nitronyl nitroxyl radical, no traces of decomposition are detected upon thermal exposure in an aqueous solution at a temperature of 40-80 ° C for 1 hour.

c) An aqueous solution of the radical is stable when boiled at 100 ° C for 10 minutes.

Claims (1)

The method of obtaining the nitronyl nitroxyl radical of 2- (5-methyl-1H-imidazol-4-yl) -4,5-bis (spiropentane) -4,5-dihydro-1H-imidazole-3-oxide-1-oxyl, which consists in the interaction 1,1'-dihydroxylamino-biscyclopentyl obtained by neutralizing with an alkaline agent the corresponding sulfate salt of 1,1'-dihydroxylamino-biscyclopentyl with 4-methylimidazole-5-carbaldehyde in an aqueous solution by heating and oxidizing the resulting product with sodium periodate, followed by the selection of the specified nitronyl nitroxyl radical.