N,n'-bis(phenylacetyl)benzene-1,3-dicarboxamide with anxiolytic activity, and method for its preparation
Through thermal hydrolysis and NMR characterization, N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide is produced and shown to have anxiolytic effects, addressing the lack of knowledge on its structure and activity, and demonstrating efficacy in animal models.
Patent Information
- Authority / Receiving Office
- RU · RU
- Patent Type
- Patents
- Current Assignee / Owner
- FEDERALNOE GOSUDARSTVENNOE BYUDZHETNOE OBRAZOVATELNOE UCHREZHDENIE VYSSHEGO OBRAZOVANIYA SANKT PETERBURGSKIJ GOSUDARSTVENNYJ KHIMIKO FARMATSEVTICHESKIJ UNIV MINISTSTVA ZDRAVOOKHRANENIYA ROSSIJSKOJ FEDERATSII FGBOU VO SPKHFU MINZDRAVA ROSSII
- Filing Date
- 2026-03-11
- Publication Date
- 2026-07-01
AI Technical Summary
The existing literature lacks information on the structure, synthesis method, and biological activity of N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide, limiting its potential as an anxiolytic agent.
The compound is produced through thermal hydrolysis of 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one) for 30 minutes, followed by characterization using NMR spectroscopy to confirm its structure, and tested for anxiolytic activity in elevated plus maze and black-and-white chamber tests.
The synthesized compound demonstrates significant anxiolytic effects in mice, reducing anxiety indices and increasing latency to enter dark environments, indicating its potential as a novel anxiolytic agent.
Smart Images
Figure 00000001 
Figure 00000002 
Figure 00000003
Abstract
Description
[0001] This group of inventions relates to a new compound, N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide I, a method for its preparation, and its biological activity. The new compound with formula I was obtained by thermal hydrolysis of 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one) for 30 minutes. Compound I can find application in medicine as an anxiolytic agent.
[0002]
[0003] Methyl and ethyl esters of N-aroylmalonic acids II are known from the literature, obtained by the interaction of the corresponding 2-aryl-4-hydroxy-6H-1,3-oxazin-6-ones III with alcohols at 18-20 °C for 24 hours [Yakovlev I.P., Prepyalov A.V., Zakhs V.E. Study of azines and azoles. 93. Interaction of ketene with acyl isothiocyanates / / Zhurnal Gen. Khimii. 65(4). - 1995. - P. 687-692].
[0004]
[0005] R 1 = H; Me; Et; R 2 = Me; Et
[0006] A compound such as 3-oxo-2,3-diphenylpropanamideV was described in the scientific literature [Yamagata K., Ohkubo K., Yamazaki M.. Synthesis of 1,3-oxazines and furo[2,3-b]pyrans by reactions of 2-amino-4,5-dihydro-3-furancarbonitriles with dibenzoyldiazomethanes / / Journal für praktische Chemie. 1998 340: 51- 57]. Its synthesis was carried out by the reaction of 2-(2-(di(pyrrolidin-1-yl)amino)-4,5-dihydrofuran-3-yl)-5,6-diphenyl-4H-1,3-oxazin-4-oneVI with aqueous ethanol under reflux for 1.5 hours.
[0007]
[0008] Neither the structure of compound I, nor the method of synthesis, nor its biological activity have been identified from the patent and scientific literature.
[0009] The objective of this group of inventions is to obtain a new compound N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide of formula I, which will expand the range of potential anxiolytic agents.
[0010] The technical result, which the group of inventions is aimed at solving, is the production of a new compound - N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide of formula I, the development of an effective method for producing compound I, which can potentially be used in medicine as an anxiolytic agent.
[0011] The task is accomplished by thermal hydrolysis of 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one) for 30 minutes.
[0012] The method for producing N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide was studied and carried out under laboratory conditions.
[0013] The spectral characteristics of the obtained compound are given in Tables 1 and 2. The results of the in vivo elevated plus maze and black-and-white chamber tests are given in Tables 3 and 4, respectively.
[0014] Example 1. Preparation of N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide I.
[0015] 1 mmol of 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one) was heated under reflux in 5 ml of water for 30 minutes. Then the reaction mixture was cooled and the white precipitate of the target product was filtered off. The yield is 97% of theory for 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one). Melting point 208-210 °C. Molecular formula: C 24 H 20 O4N2.
[0016] The structure of the synthesized N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide was proven by physicochemical methods of identification of organic compounds: 1 H, 13 With NMR spectroscopy.
[0017] The main signals in the NMR spectrum 1 The H-compound I contains signals from the protons of the -NH- and -CH2-groups, which appear in their characteristic regions of 11.38 ppm and 4.32 ppm, respectively. The spectrum also contains signals from the protons of the phenyl substituents (7.43-7.59 ppm) and signals from the protons of the m-phenylene bridge (8.01 and 8.48 ppm).
[0018] In the NMR spectrum 13 The most characteristic signals are those of the carbonyl carbon atoms (167.34-167.73 ppm) and the signal of the CH2 groups (52.83 ppm). The signals at 127.25, 130.74, 134.63, and 134.99 ppm correspond to the carbon atoms of the phenyl substituents; 128.80, 129.18, 131.36, and 132.38 ppm correspond to the carbon atoms of the m-phenylene bridge.
[0019] Example 2. The compound of formula I has anxiolytic activity. The in vivo study was conducted on white outbred male mice weighing 20±2 g. The animals were divided into 3 groups of 10 individuals each. 20 minutes before the start of the experiment, the rodents of the first group were intraperitoneally injected with 5 ml of a suspension of the compound of formula I in a mixture of DMSO:water (1:5) at a dose of 200 mg / kg. Animals of the second group were intraperitoneally injected with 5 ml of a suspension of the reference drug, hydroxyzine (Atarax®, UCB Pharma, Belgium), in water for injection (Grotex, Russia) at a dose of 5 mg / kg. The third control group received an equal volume of 0.9% sodium chloride solution (Grotex, Russia).
[0020] Elevated Plus Maze. Animals were placed in the center of an elevated plus maze consisting of two open light arms and two closed dark arms. The following anxiolytic activity indices were recorded for 3 minutes: time spent in the center (s), number of arm visits, and anxiety index. Based on the data obtained, a decrease in the calculated anxiety index was noted in mice from groups 2 and 3 (Table 3).
[0021] Black-and-white chamber method. Animals were placed in a rectangular chamber divided into two equal parts: a black (BC) section, completely enclosed on all sides, and a white (W) section, open at the top. The chamber was located in a tightly closed tent, without access to natural light, extraneous sounds, and strangers or animals. The tent was equipped with a video system that recorded the number of transitions between the black and white sections, the time spent in each chamber, grooming, and peeking out over a 3-minute period. Twenty minutes after administration of the compound of formula I, a 1.5-fold increase in the latency to enter the black chamber and a 2.5-fold increase in the number of groomings were observed, which can be regarded as evidence of an anxiolytic effect (Table 4).
[0022] Table 1
[0023] NMR spectrum data 1 H (DMSO-d6)
[0024] Connection 1H NMR spectrum data (DMSO-d6), δ, ppm. CH2 CHPh СНAr NH I 4.32 s (2H) 7.43-7.59 m (10H) 7.79 t (1H, 3JHH 7.7) 8.01 dd (2H, 3JHH 7.7; 4JHH 1.7) 8.48 s (1H) 11.38 s (2H)
[0025] Table 2
[0026] NMR spectrum data 13 C (DMSO-d6)
[0027] Compound NMR spectrum data C13 (DMSO-d6), δ, ppm. CH CHPh CHAr C=O I 52.83 127.25-134.99 128.80-132.38 137,97
[0028] Table 3
[0029] Elevated Plus Maze Test Results (M±SM), n=10 in each group
[0030] Group Time in the center, s Number of sleeve visits Anxiety Index 1 47.47±4.80 17.90±2.32 0.65±0.03# 2 48.23±5.24 18.10±1.76# 0.69±0.03# 3 65.68±7.89 13.60±0.81 0.83±0.02
[0031] * differences with group 3 are statistically significant p≤0.01
[0032] # differences with group 3 are statistically significant p≤0.05
[0033] Table 4
[0034] Black and White Camera Test Results, (M±SM), n=10 in each group
[0035] Group Time in the Cheka Grooming frequency in BC, min -1 Frequency of racks in the BC, min -1 Frequency of peeks into the BC, min -1 Transitions Latent. 1st entry into the Cheka Duration of 1 visit to the Cheka 1 130±15.58 0.38±0.11* 4.55±1.37 3.46±0.68# 9.00±1.91 23.53±15.64* 29.50±7.65# 2 128±9.00 0.35±0.10* 4.64±1.30 3.20±0.46# 11.00±2.00 31.41±12.24* 21.89±10.69 3 123±7.63 0.15±0.10 6.43±1.61 2.18±0.36 11.60±1.61 16.34±4.07 19.48±4.48
[0036] * differences with group 3 are statistically significant p≤0.01
[0037] # differences with group 3 are statistically significant p≤0.05
Claims
1. N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide of formula I.
2. A method for obtaining N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide of formula I according to claim 1 by thermal hydrolysis of 1 mmol of 2,2'-(1,3-phenylene)bis(4-hydroxy-5-phenyl-6H-1,3-oxazin-6-one) in 5 ml of water with a reflux condenser for 30 minutes, after which the reaction mass is cooled and the resulting precipitate of the target product is filtered off.
3. An anxiolytic agent characterized in that it includes N,N'-bis(phenylacetyl)benzene-1,3-dicarboxamide of formula I according to claim 1 as an active substance.