RU2471798C1 - 3-AROYL-2-(2-ARYLHYDRAZONO)PYRROLO [1,2-a] QUINOXALINE,4-(2H,5H)DIONES POSSESSING ANALGESIC ACTIVITY - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-aroyl-2-arylhydrazonopyrrolo[1,2-a]quinozaline-1,4(2H,5H)-diones of formula:

Ar=Ph, R=Me, R¹=H (a); Ar=4-MeC₆H₄ R=Me, R¹=H (b); Ar=Ph, R=H, R¹=COOH (c).

EFFECT: there are produced new compounds possessing analgesic activity that makes them being suggested to be used in medicine as drugs with the analgesic properties.

1 cl, 3 tbl, 4 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class 3-aroyl-2-arylhydrazonopyrroloquinoxaline, namely 3-aroyl-2-arylhydrazonopyrrolo [1,2-a] quinoxaline-1,4 (2H, 5H) -dione of the formula (one):

possessing analgesic activity, which suggests their use in medicine as medicines with analgesic properties (table 1).

The structural analogue of the claimed series of compounds are 3-aroylpyrrolo [1,2-a] quinoxaline-1,2,4-trions (Ia, b) [Mashevskaya IV, Makhmudov PP, Alexandrova GA, Golovnina O. V., Duvalov A.V., Maslivets A.N. Synthesis, antibacterial and analgesic activity of 3-acyl-1,2,4,5-tetrahydropyrrolo [1,2- a ] quinoxaline-1,2,4-trion // Chem-pharm. journal 2001.V. 35. Number 4. S.20-21] formulas:

The reference standard is metamizole sodium of the formula:

which is widely used in medical practice and is an analogue in action [Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. and add. - M .: New Wave LLC, 2005. - p. 170].

Table 1 Connection No. Dose mg / kg LD ₅₀ , mg / kg The time of the defensive reflex at the peak of action (s) Control 2% starch. slime fifty 10.6 ± 1.21 Metamizole sodium 93 16.3 ± 3.0 ρ <0.1 Ia fifty > 1500 24.3 ± 9.3 ρ <0.05 Ib fifty > 1500 24.8 ± 9.4 ρ <0.05

The objective of the invention is to search for a series of derivatives of 3-aroyl-2-arylhydrazono-pyrroloquinoxaline substances with a pronounced analgesic effect and low toxicity.

The problem is achieved by obtaining a number of 3-aroyl-2-arylhydrazonopyrrolo [1,2- a ] quinoxaline-1,4 (2H, 5H) dions, which have analgesic activity.

The claimed compounds IIa-c are synthesized by the interaction of 3-aroylpyrrolo [1,2- a ] quinoxaline-1,2,4 (5H) -trions with arylhydrazines in anhydrous acetonitrile medium at 80-82 ° C, followed by isolation of the fawn product by known methods according to the scheme :

Example 1. Obtaining compound IIa

(E) -3-Benzoyl-2- (o-tolylhydrazono) pyrrolo [1,2- a ] quinoxaline-1,4 (2H, 5H) -dione (IIa)

To a solution of 3.18 g (1.0 mmol) of 3-benzoylpyrrolo [1,2- a ] quinoxaline-1,2,4 (5H) -trione in 30 ml of absolute acetonitrile is added a solution of 1.22 g (1.0 mmol) of o-tolyl hydrazine hydrochloride in 10 ml absolute dimethylformamide (DMF), boil for 3 minutes, cool, the precipitate formed is filtered off and recrystallized from DMF. Yield 2.41 g, 57%, mp. 246-248 ° C. Found,%: C 70.12; H 4.26; N 13.21. C ₂₅ H ₁₈ N ₄ O ₃ . Calculated,%: C 71.08; H 4.30; N 13.26. IR spectrum (FSM-120, liquid paraffin, ν, cm ^-1 ): 3200, 3180 (NH), 1673 (C ¹ = 0), 1660 (C ⁴ = O), 1624 (COPh). ¹ H NMR spectrum (Braker AM-400 [operating frequency 400 MHz] in DMSO-d ₆ , internal standard - TMS. Δ, ppm): 2.07 (s, 3H, Me), 7.07-8.03 g.s. (11H, Ph + C ₆ H ₃ + H ^6-8 ), 8.71 d (1H, H ⁹ , J 7.3 Hz), 11.26 s (1H, N ⁵ H), 13.57 s (1H, = N-NH).

The resulting compound IIa is a dark crimson crystalline substance soluble in DMF, DMSO, acetonitrile, insoluble in water and hexane.

Example 2. Obtaining compound IIb

(E) -3- (4-Methylbenzoyl) -2- (o-tolylhydrazono) pyrrolo [1,2- a ] quinoxaline-1,4 (2H, 5H) -dione (IIa)

To a solution of 3.32 g (1.0 mmol) of 3- (4-methylbenzoyl) pyrrolo [1,2 a ] quinoxaline-1,2,4 (5H) -trione in 30 ml of absolute acetonitrile is added a solution of 1.22 g (1.0 mmol) of o- tolyl hydrazine in 10 ml of absolute dimethylformamide (DMF), boil for 3 minutes, cool, the precipitate formed is filtered off and recrystallized from DMF. Yield 2.14 g 49%, mp. 260-262 ° C. Found,%: C 71.52; H 4.60; N, 12.80. C ₂₆ H ₂₀ N ₄ O ₃ . Calculated,%: C 71.55; H 4.62; N, 12.84. IR spectrum (FSM-120, liquid paraffin, ν, cm ^-1 ): 3180, 3050 (NH), 1671 (C ¹ = O), 1657 (C ⁴ = O), 1617 (COTol). ¹ H NMR spectrum (Bruker AM-400 [operating frequency 400 MHz] in DMSO-d ₆ , internal standard - TMS. Δ, ppm): 2.38 (s, 3H, Me), 2.51 (s, 3H, Me ), 7.09-8.15 gr.s. (11H, 2C ₆ H ₄ + H ^6-8 ), 8.73 d (1H, H ⁹ , J 7.4 Hz), 11.28 s (1H, N ⁵ H), 13.57 s (1H, = N-NH).

The resulting compound IIb is a dark crimson crystalline substance soluble in DMF, DMSO, acetonitrile, insoluble in water and hexane.

Example 3. Obtaining compound IIB

(E) -4- (2- (3-Benzoyl-1,4-dioxopyrrolo) [1,2- a ] quinoxaline-2 (1H) -ilidene) hydrazinyl) benzoic acid (IIc)

To a solution of 3.18 g (1.0 mmol) of 3-benzoylpyrrolo [1,2- a ] quinoxaline-1,2,4 (5H) -trione in 30 ml of absolute acetonitrile, a solution (1.0 mmol) of 4-hydrazinylbenzoic acid hydrochloride (n-carboxyphenylhydrazine) is added ) in 10 ml of absolute dimethylformamide (DMF), boil for 3 minutes, cool, the precipitate formed is filtered off and recrystallized from DMF. Yield 3.12 g, 69%, mp. 310 ° C. Found,%: C 66.35; H 3.54; N, 12.35. C ₂₅ H ₁₆ N ₄ O ₅ . Calculated,%: C 66.37; H 3.57; N, 12.38. IR spectrum (FSM-120, liquid paraffin, ν, cm ^-1 ): 3400 (COOH), 3180, 3050 (NH), 1676 (C ¹ = O), 1660 (C ⁴ = O), 1633 (COPh). ¹ H NMR spectrum (Bruker AM-400 [operating frequency 400 MHz] in DMSO-d ₆ , internal standard - TMS. Δ, ppm): 7.12-7.66 g.s. (12H, Ph + C ₆ H ₄ + H ^6-8 ), 8.68 d (1H, H ⁹ , J 7.4 Hz), 11.27 s (1H, = N ₅ H), 13.28 s (1H, = N-NH).

Example 4. The study of biological activity

Evaluation of the analgesic properties of compounds (IIa, b) was studied on outbred mice weighing 18-22 g by the method of thermal stimulation "hot plate" according to Eddie and Leimbach (Eddy N. B., Leimbarh D. J. Pharmacol and Exper. Gher. 1953., 385-393). The test substance at a dose of 50 mg / kg was administered intraperitoneally in the form of a suspension in a 2% starch solution (table 2)

In the study of the analgesic effect of compounds (IIa-c) by the method of vinegar cramps (Table 3), the compounds were administered at a dose of 50 mg / kg in suspension in 2% starch mucus 30 minutes before the intraperitoneal injection of a 0.75% solution of acetic acid (0.1 ml / 10 g).

The comparison drug is metamizole sodium (93 mg / kg).

table 2 Analgesic activity of compounds IIa, b (“hot plate”) Connection No. Dose mg / kg The time of the defensive reflex at the peak of action (s) Control 2% starch. slime fifty 10.76 ± 1.63 Metamizole sodium 93 16.3 ± 3.0 IIa fifty 26.11 ± 3.38 IIb fifty 26.00 ± 3.26

Table 3 Analgesic activity of compounds IIa-b ("vinegar cramps") Connection No. Dose mg / kg % suppression of writhing Control 2% starch. slime 50, w / b 0 Metamizole sodium 93 58 IIa 50 p / o 65.34 IIb 50 p / o 70.14 IIc 50 p / o 46.6

The studies showed (Tables 2, 3) that compound (IIa-b) significantly increased the threshold of pain sensitivity in animals both under thermal exposure and with “vinegar cramps”, surpassing the reference drug metamizole in activity.

Claims (1)

3-Aroyl-2- (2-arylhydrazono) pyrrolo [1,2-a] quinoxaline-1,4 (2H, 5H) dions of the general formula:

possessing analgesic activity.