RU2556995C2 - 2-[(2-methylphenyl)imino]-9-oxo-7-phenyl-8-(3-phenyl-2-quinoxalinyl)-1,6-dioxaspiro[4,4]-none-3,7-diene-3,4-dicarboxylic acid dimethyl ester showing antinociceptive activity and method for producing it - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to a new compound, namely to 2-[(2-methylphenyl)imino]-9-oxo-7-phenyl-8-(3-phenyl-2-quinoxalinyl)-1,6-dioxaspiro[4,4]none-3,7-diene-3,4-dicarboxylic acid dimethyl ester of formula

possessing antinociceptive activity, and a method for producing it consisting in synthesis of 4-(3-phenylquinoxalin-2-yl)-5-phenylfurane-2,3-dione, acetylene dicarboxylic acid dimethyl ester and o-methylphenylisonitrile.

EFFECT: preparing the new compound.

2 cl, 1 tbl, 4 ex

Description

The invention relates to the field of organic chemistry, to the development of a method for the synthesis of hardly accessible substituted dimethyl esters of 9-oxo-1,6-dioxaspiro [4.4] non-3,7-diene-3,4-dicarboxylic acids, namely to 2- [dimethyl ether (2-methylphenyl) imino] -9-oxo-7-phenyl-8- (3-phenyl-2-quinoxalinyl) -1,6-dioxaspiro [4.4] non-3,7-diene-3,4-dicarboxylic acid formulas (1)

exhibiting antinociceptive activity, which may find application in medicine as a drug. Metamizole sodium was taken as a standard for comparing biological activity [M.D. Mashkovsky. Medicines - M .: New wave, 2010. - P.164].

A known structural analogue of the claimed compounds is dimethyl ether 5 '- (cyclohexylimino) -4,6-dimethyl-3-oxospiro [benzofuran-2 (3H), 2' (5'H) furan] -3 ', 4, -dicarboxylic acid (2) obtained by the ternary synthesis of 4,6-dimethylbenzofuran-2,3-dione, cyclohexylisocyanide and acetylenedicarboxylic acid dimethyl ester [Esmaeili AA, Vesalipoor H. Reaction of Isocyanides, Diakyl Acetylenedicarboxylates, and α-KetoLactones Estonian Unknown Group in the Isocyanide-Based Three-Component Reaction / Synthesis, 2009. No. 10. P.1635-1638]. The biological activity of the structural analogue is unknown.

The synthesis of the structural analogue is carried out according to the following scheme:

The disadvantages of this prototype method include the inability to obtain dimethyl ether 2 - [(2-methylphenyl) imino] -9-oxo-7-phenyl-8- (3-phenyl-2-quinoxalinyl) -1,6-dioxaspiro [4.4] non-3,7-diene-3,4-dicarboxylic acid.

The objective of the invention is to develop a method for the synthesis of previously undescribed dimethyl ether 2 - [(2-methylphenyl) imino] -9-oxo-7-phenyl-8- (3-phenyl-2-quinoxalinyl) -1,6-dioxaspiro [4.4] non-3,7-diene-3,4-dicarboxylic acid (1), exhibiting an antinociceptive effect and having lower toxicity than known drugs.

The task is carried out by three-component synthesis of 4- (3-phenylchnoxalin-2-yl) -5-phenylfuran-2,3dione, dimethyl ether of acetylenedicarboxylic acid and o-methylphenylisonitrile according to the scheme

The technical result is the expansion of the arsenal of means of influence on a living organism.

The invention is illustrated by the following examples.

Example 1. Obtaining compound (1). A solution of 1.1 mmol of o-methylphenyl isocyanide in 10 ml of absolute 1,2-dichloroethane was cooled to -10 ° C, a solution of 1 mmol of 4- (3-phenylquinoxalin-2-yl) -5-phenylfuran-2,3-dione was added dropwise. and 1.1 mmol of acetylenedicarboxylic acid dimethyl ether in 10 ml of absolute 1,2-dichloroethane, cooled to -10 ° C. The mixture was stirred at room temperature for 2 hours. The solvent was removed, the residue was triturated from ethyl alcohol, recrystallized from ethyl alcohol. Yield 0.54 g (84%). _Mp = 145-147 ° C. Found,%: C 71.50; H 4.35; N, 6.66. C ₃₈ H ₂₇ N ₃ O ₇ . Calculated,%: C 71.58; H 4.27; N, 6.59. IR spectrum (FSM 1201, liquid paraffin, ν, cm ^-1 ): 1752 (CO ₂ Me), 1736 (CO ₂ Me), 1723 (C = O), 1687 (C = N). ¹ H NMR spectrum (Varian Mercury 300 (300 MHz), DMSO-d ₆ , HMDS, δ, ppm): 2.13 s (3H, CH ₃ ), 3.85 s (3H, CH ₃ O), 3.99 s ( 3H, CH ₃ O), 7.05-8.22 m (18H, 2C ₆ H ₄ + 2C ₆ H ₅ ). Mass spectrum, m / z (I _rel .,%): 637 (100) [M] ⁺ .

The resulting compound (1) is a yellow crystalline substance insoluble in water, hexane, sparingly soluble in ethanol, readily soluble in DMSO and chloroform.

Example 2. Acute toxicity of the compound (1). Acute toxicity (LD ₅₀ , mg / ml) of compound (1) was studied on white mice (females) weighing 16-18 g with a single intraperitoneal injection. The animals were monitored for 10 days, recording the behavior, intensity and nature of motor activity, the presence and nature of seizures, coordination of movements, skeletal muscle tone, reactions to tactile, sound and light stimuli, the frequency and depth of respiratory movements, heart rate, state hair and skin, the color of visible mucous membranes, water and food intake, weight change.

Acute toxicity was calculated, following the recommendations of the state pharmacological committee for the study of the general toxic effects of biologically active substances [Methodological recommendations for the study of the general toxic effects of pharmacological agents. Approved 12/25/97 / Vestn. Pharmacopoeia. committee. - 1998. - No. 1. - S. 27-32.].

For test compound (1), LD ₅₀ is> 1500 mg / kg. According to the classification of drug toxicity, compound (1) belongs to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. - P.196], while metamizole sodium

Example 3. Antinociceptive activity of the compound (1)

Evaluation of the antinociceptive (analgesic) activity of compound 1 was studied on outbred mice weighing 18-22 grams by the method of "vinegar cramps". The test substances were administered at a dose of 25 mg / kg, ip in the form of a suspension in 2% starch mucus 30 minutes before the ip administration of a 0.75% solution of acetic acid (0.1 ml / 10 grams of body weight). Over the next 15 minutes after the injection, the number of writhing was calculated for each animal. The decrease in the number of cramps in animals compared with the control group was an indicator of the analgesic activity of substances. Antinociceptive activity was expressed as a percentage reduction in the number of vinegar cramps in experimental animals compared with control groups. Each compound was tested in 6 animals.

Statistical processing of the experimental material was carried out using t student criterion [Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. - 2nd ed. - L., 1963. - P.152]. The effect was considered significant at p <0.05.

Example 4. Antinociceptive activity of the compound (1).

The antinociceptive activity of compound (1) was studied on outbred mice weighing 18-22 g using the "hot plate" test [Radell Z.O., Selitto J.J. A method for measurement of analgesic activity on inflamed tissue. // Arch. Intermat. Pharmacodun Et ther. 1957. - Vol. 11. - No. 4 - S.409-419].

The test compound was administered intraperitoneally in the form of 2% starch mucus at a dose of 50 mg / kg 0.5 h before the animals were placed on a metal plate heated to 53.5 ° C. An indicator of pain sensitivity was the duration of the animal’s stay on the hot plate until the hind legs were licked, measured in seconds. Sodium metamizole was taken as ethanol for the comparison of analgesic activity [M.D. Mashkovsky. Medicines. - M.: New Wave, 2010. - P.164]. The test results are presented in the table.

Table 1 The antinociceptive activity of compound (1) by the methods of “hot plate” and “vinegar cramps” No. p / p Connection cipher Dose mg / kg, route of administration in / b "Hot plate" "Acetic cramps" Defensive reflex time after 120 min. The number of cramps % reduction of cramps to control Activity% one Control 2% starch., Mucus fifty 10.10 ± 1.32 25 25.20 ± 2.32 one hundred 2 Metamizole sodium 93 (IU ₅₀ ) 16.33 ± 3.02 p <0.1 55 10.06 ± 1.38 42.6 57.9 3 one fifty 31.00 ± 3.36 p <0.05 25 11.60 ± 1.50 46.03 53.97

As can be seen from the table, the claimed compound (1) exhibits pronounced antinociceptive activity, practically non-toxic. Therefore, the claimed compound (1) may find application in medical practice as an analgesic drug.

Claims (2)

1. Dimethyl ether 2 - [(2-methylphenyl) imino] -9-oxo-7-phenyl-8- (3-phenyl-2-quinoxalinyl) -1,6-dioxaspiro [4.4] non-3,7-diene -3,4-dicarboxylic acid of the formula (1)

possessing antinociceptive activity. 2. The method of obtaining dimethyl ether 2 - [(2-methylphenyl) imino] -9-oxo-7-phenyl-8- (3-phenyl-2-quinoxalinyl) -1,6-dioxaspiro [4.4] non-3.7 -diene-3,4-dicarboxylic acid (1)

characterized in that a three-component synthesis of 4- (3-phenylquinoxalin-2-yl) -5-phenylfuran-2,3-dione, acetylenedicarboxylic acid dimethyl ester and o-methylphenylisonitrile is carried out.