RU2800863C1 - 1,3-dioxo-n,n'-diphenylisoindoline-2-carboximidamide, method of its preparation and analgesic agent - Google Patents

Abstract

FIELD: organic and medicinal chemistry.

SUBSTANCE: invention relates to 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of formula I. The invention also relates to a method of producing a compound of formula I and an analgesic agent based on it. The method of obtaining 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of formula I is performed by boiling a mixture of diphenylguanidine and phthalic anhydride at a molar ratio of 1:1.2, respectively, in toluene for 2 hours, with solvent distilled off, and the residue of the target product recrystallized from acetone.

EFFECT: 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide compound with analgesic activity.

3 cl, 2 dwg, 3 tbl, 3 ex

Description

The invention relates to the field of organic and medicinal chemistry, namely to 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of the formula I. The invention also relates to a method for producing a compound of the formula I and an agent based on it.

The scientific and technical literature describes a method for obtaining 2-(phenyl(phenylimino)methyl)isoindoline-1,3-dione (IV), which is carried out by the interaction of N-phenylbenzenecarboximidamide (II) with phthalic anhydride (III) by boiling in o-xylene within 4 hours [RF Patent 2 768 824 C1, Trukhanova Yu.A., Kolesnik D.A., Yakovlev I.P. et al./2-(phenyl(phenylimino)methyl)isoindoline-1,3-dione and method for its production]:

A method for the preparation of N-phthaloylguanidines (VIII) by the reaction of substituted isonitriles (VI) with N-chlorophthalimide (VII) and p-anisidine (VII) in an acetonitrile medium with the addition of triethylamine as a catalyst is described. The reaction proceeds for 2 hours at ambient temperature [Demjén A, Angyal A, Wölfling J, Puskás LG, Kanizsai I / One-pot synthesis of diverse N,N'-disubstituted guanidines from N-chlorophthalimide, isocyanides and amines via N-phthaloyl-guanidines // Org Biomol Chem. 2018, Vol.16, No. 12, P.2143-2149. DOI: 10.1039/C7OB03109B]:

Neither the structure of the new compound claimed by the authors, nor the method of synthesis, nor its biological activity have been identified from the patent and scientific literature.

The task of the proposed group of inventions is to create a new compound, not described in the literature - 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of the formula I, which will expand the range of potential analgesics.

The technical result, to which the group of inventions is directed, is the development of a simple method for obtaining a new compound I, which can potentially be used in medicine as an analgesic.

According to the developed method for obtaining a compound of formula I, the interaction of diphenylguanidine (IX) with phthalic anhydride (III) is carried out according to the scheme:

A mixture of diphenylguanidine (IX) and phthalic anhydride (III) is boiled in toluene for 2 hours, then the solvent is distilled off on a rotary film evaporator, the residue, which is the target product, is recrystallized from acetone.

The method of obtaining 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide (I) was studied and carried out in laboratory conditions on standard commercial raw materials.

Example 1 Preparation of 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide (I).

0.5 g (2.4 mmol) of diphenylguanidine (IX), 50 ml of toluene are placed in a flat-bottomed flask with a volume of 250 ml, and 0.42 g (2.8 mmol) of phthalic anhydride (III) are added. The reaction mixture is boiled for 2 hours, then the solvent is evaporated to dryness on a rotary film evaporator. The resulting precipitate is recrystallized from acetone.

The product is almost white, the yield is 0.56 g, 69.0% of theory based on diphenylguanidine (IX).

Melting point 164-166°C. The chromatographic homogeneity of the target product was confirmed by chromatography of its solution in ethanol using a mixture of ethyl acetate-hexane (3:4) as an eluent. R _f =0.56. The composition of the synthesized compound was confirmed by elemental analysis. Gross formula: C ₂₁ H ₁₅ N ₃ O ₂ . % calculated: C - 73.89; H - 4.43; N-12.31. Found %: С-73.81; H-4.47; N- 12.29.

The structure of the synthesized substance was proved by physicochemical methods for the identification of organic compounds: ^1H , ^13C NMR spectroscopy and mass spectrometry.

In the ^1H NMR spectrum of compound I in DMSO-d ₆ (400.13) MHz, there are signals of protons of diphenylguanidine benzene rings δ 7.75 (d, J=8.0 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 7.16 (t, J=7.7 Hz, 2H), 7.08 (t, J=7.4 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.76 (d, J=7.4 Hz, 2H), group proton - NH- 9.79 (s, 1Н), as well as proton signals of phthalic anhydride 7.90 (m, 4Н) (Table 1, Fig. 1).

The ^13C NMR spectrum of compound I is characterized by the signals of the carbon nuclei of the benzene rings (140.01, 135.86, 135.64, 131.07, 129.40, 129.16, 124.49, 123.51, 123.33, 121.24, 118.88, 118.81 ppm). ), amide carbons of the phthalimide ring (165.77 m .d.) and the carbon atom of the imino group (148.01 ppm) (Table 2, Fig. 2).

MS-ESI mass spectrometry: m/z [M+H] ⁺ calculated for C ₂₁ H ₁₅ N ₃ O ₂ : 342.36; found: 342.24.

In the study of acute toxicity and biological activity of compound I, all animal experiments were carried out in accordance with the Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 No. 81 "On Approval of the Rules of Good Laboratory Practice of the Eurasian Economic Union in the field of circulation of medicines" and the National standard of the Russian Federation GOST R-53434-2009 "Principles of Good Laboratory Practice".

All experimental and control animals were taken from one shipment and were quarantined for 14 days. Laboratory animals were kept under standard conditions of the Center for Experimental Pharmacology. All ongoing manipulations with laboratory animals were reviewed and approved at a meeting of the bioethical commission of the FSBEI HE SFCFU of the Ministry of Health of Russia.

Example 2 Acute toxicity of 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide (I).

The determination of acute toxicity of compound I was carried out on white outbred male mice weighing 20 ± 2 g. Compound I was administered once, intraperitoneally in the dose range from 700 to 1500 mg/kg in the form of suspensions in a mixture of dimethyl sulfoxide (DMSO): water for injection (1:5 ) using as a stabilizer the resulting suspension of hydroxyethylated sorbitan - tween-80. The survival of animals was determined by observing them after 24 and 48 hours from the moment of injection. The animals were observed for 72 hours. The development of the main symptoms and the time of death of the animals were recorded. The experimental mean lethal dose (LD ₅₀ ) was calculated using the installed STATISTICA 7.0 software, which uses the least squares method to calculate LD ₅₀ . The toxicity of compound I was 1400±10 mg/kg. According to the classification of Sidorov K.K., compound I belongs to class 5 "practically non-toxic".

Example 3. Study of the analgesic activity of 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide (I).

For the modeling of acetic “writhing”, white outbred male mice weighing 20 ± 2 g were used, from which 3 groups of 5 individuals each were formed. Convulsions in animals were induced by intraperitoneal injection of 0.5% acetic acid solution. Compound I was administered intraperitoneally to the first group at a dose of 100 mg/kg 40 minutes before the start of the experiment as a suspension in a mixture of dimethyl sulfoxide (DMSO): water for injection (1:5) using hydroxyethylated sorbitan-tween-80 as a stabilizer. The second group, 40 minutes before the start of the experiment, was injected intraperitoneally with the comparison drug, metamizole sodium, in the form of an injection at a dose of 168.57 mg/kg. In the control group, only a solution of 0.5% acetic acid was injected intraperitoneally. The time of onset of convulsions and their number were recorded within 20 minutes. The analgesic activity of the test compound was evaluated by a significant decrease in the number of writhing in the treated group relative to the control group. The effectiveness indicator was the coefficient of pain reaction suppression (PBR), which was calculated by the formula:

The study showed that compound I has a pronounced analgesic activity, acting on pain caused by chemical irritants-algogens (peritovisceral pain model). The test compound is at the same level as the reference drug. The results of analgesic activity are presented in table.3. estimates

Claims (4)

1. 1,3-Dioxo-N,N'-diphenylisoindoline-2-carboximidamide of formula I 2. The method of obtaining 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of formula I according to claim 1, which consists in the fact that a mixture of diphenylguanidine and phthalic anhydride at a molar ratio of 1:1.2, respectively, is boiled in toluene within 2 hours, the solvent is distilled off, the residue of the target product is recrystallized from acetone. 3. An analgesic agent, characterized in that it includes 1,3-dioxo-N,N'-diphenylisoindoline-2-carboximidamide of the formula I according to claim 1 as an active substance.

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