RU2404185C1 - UNIFORMLY TRITIUM-LABELLED (R)-(+)-[5-METHYL-3-(4-MORPHOLINYLMETHYL) -2,3-DIHYDRO-[1,4]OXAZINE[2,3,4-hi]-6-INDOLYL]-1-NAPHTHALINYLMETHANONE ACETATE - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to uniformly tritium-labelled (R)-(+)-[5-methyl-3-(4-morpholinylmethyl)-2,3-dihydro-[1,4]oxazine[2,3,4-hi]-6-indolyl]-1-naphthalinylmethanone acetate of formula I: . ^ EFFECT: wide range of labelled analogues of physiologically active compounds. ^ 1 ex

Description

The invention relates to the field of organic chemistry and may find application in analytical chemistry and biological research.

When studying the biological properties of physiologically active compounds, their labeled analogues are necessary.

It is known that replacing the atoms of compounds with their labeled analogues does not lead to a change in any characteristics of the initial compound that change its behavior in biological systems (Evans EA Tritium and its compounds. / London: Butterworths, 1974. - P.48) [1] and also that, in the isotopic exchange of hydrogen for tritium, all the hydrogens of the compound can react (Myasoedov NF Introduction of Tritium into Organic Compounds by Isotope Exchange Reactions // J. Label. Comp. Radiopharm. 1993. Vol. 33. N5. P .391-401 [2] and Shevchenko V.P., Nagaev I.Yu., Myasoedov NF Tritium-labeled lipophilic compounds. - M .: Nauka. 2003. 246 p. [3]), resulting in equal tritium-labeled compounds.

Known (R) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4-hi] -6-indolyl] -1 naphthalenylmethanone acetate of the formula I:

This compound is one of the most intensively studied selective cannabinoid receptor agonists, the effect of which is already manifested in nanomolecular concentrations (Martellotta et al. Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug naive mice. // Neuroscience. - 1998. - 85. - P.327 [4]).

However, its counterpart uniformly labeled with tritium is not described.

The technical result achieved by the present invention is to expand the range of labeled analogues of physiologically active compounds.

The technical result is achieved by obtaining uniformly labeled with tritium (R) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4-hi] - 6-indolyl] -1-naphthalenylmethanone acetate of formula I:

The following is an example implementation of the invention.

Example 1

Solution 2 mg (R) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4-hi] -6-indolyl] -1-naphthalenylmethanone acetate in 0.15 ml of methanol was added to 180 mg of CaCO ₃ , evaporated on a rotor and lyophilized. The dry mixture was transferred to a mortar and triturated with 20 mg of 5% Pd / CaCO ₃ . Then, the ampoule was evacuated to a pressure of 0.1 Pa, filled with gaseous tritium to a pressure of 400 GPa and kept at a temperature of 145 ° С for 15 min. Excess tritium gas was removed by vacuum. The substance from the catalyst was separated by filtration, extraction was carried out with methanol (5 × 0.5 ml). Labile tritium was removed by dissolving the substance several times in methanol (5 × 0.5 ml) and evaporating the latter. The yield of uniformly labeled with tritium (R) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4-hi] -6-indolyl] -1-naphthalenylmethanone acetate reached 70-75%.

Preparative chromatography was performed on a Kromasil 100C ₁₈ , 8 × 150 mm, 7 μm column, system: 70% methanol with 0.1% acetic acid, flow rate 2 ml / min, retention time 11.13 min. After purification, the radiochemical purity of the labeled preparation was 98%, the yield was 70%, and the molar radioactivity was 50-55 Ci / mmol.

Analysis of uniformly labeled with tritium (K) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4, -hi] -6-indolyl ] -1-naphthalenylmethanone acetate was carried out on Milichrome A-02, ProntoSIL-120-5-C ₁₈ AQ DB-2003 column, 2.0 × 75 mm, 5 μm, 0.2 ml / min, 35 ° C, detection - 210 nm, A 0.2 M LiClO ₄ + 0.005 M HClO ₄ buffer, B methanol, gradient B → (55-100) for 12.5 min, retention time 4.98 min, gradient B → (65-100) 12.5 min, retention time 3.47 min, gradient B → (75-100) for 12.5 min, retention time - 2.14 min.

Thus, a new tritium-labeled compound was obtained.

Claims (1)

Evenly labeled with tritium (R) - (+) - [5-methyl-3- (4-morpholinylmethyl) -2,3-dihydro [1,4] oxazino [2,3,4-hi] -6-indolyl] -1-naphthalenylmethanone acetate of formula I