RU2577523C2 - 1'-ARYL-4'-HYDROXY-3'-CYNNAMOYL-2H,4H-SPIRO[FURO[3,2-c]CHROMEN-3,2'-PYRROL]-2,4,5'(1'H)-TRIONES EXHIBITING ANALGESIC ACTIVITY, AND METHOD FOR PRODUCING THEM - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new individual compounds of 1'-aryl-4'-hydroxy-3'-cynnamoyl-2H,4H-spiro[furo[3,2-c]chromen-3,2'-pyrrol]-2,4,5'(1'H)-triones of formula (IIIa-c)

wherein Ar = Ph (a), C₆H₄Me-4 (b), C₆H₄OMe-4 (b), which are applicable as primary products for synthesis of new heterocyclic systems and in pharmacology as those exhibiting analgesic activity, and to a method for producing them.

EFFECT: producing new compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry, in particular to new individual compounds of the spiro [furo [3,2-c] chromene-3,2′-pyrroles] class and to a method for their preparation, which can be used as starting materials for the synthesis of new heterocyclic systems and in pharmacology.

Known structural analogues of the claimed compounds obtained by the interaction of 3-aroyl-1H-pyrrolo [2,1-c] [1,4] benzoxazine-1,2,4-triones (Ia-e) with dimedone (II) in the ratio 1: 1 in boiling absolute benzene for 10-50 min are formed to 3′-aroyl-4′-hydroxy-1 ′ - (2-hydroxyphenyl) -6,6-dimethyl-6,7-dihydrospiro [1-benzofuran-3, 2′-pyrrole] -2,4,5 ′ (1′H, 5H) -trions (IIIa-e) (Tutynina N.M., Racheva N.L., Maslivets V.A., Aliev Z.G. , Maslivets A.N. // ZhORKh. 2013.V. 49, issue 1. S. 101-104.):

I, III, Ar = Ph (a), C ₆ H ₄ OMe-4 (b), C ₆ H ₄ Br-4 (c), C ₆ H ₄ NO ₂ -4 (d), C ₆ H ₄ OEt -4 (d), C ₆ H ₄ F-4 (e).

The disadvantages of this method include the inability to obtain 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-s] chromene-3,2′-pyrrole] -2,4, 5 ′ (1′H) -trions.

The objective of the invention is to develop a simple method for the synthesis of 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-c] chromene-3,2′-pyrrole] -2 , 4,5 ′ (1′Н) -trions.

The task is carried out by boiling in absolute toluene methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates (Silaichev P.S., Filimonov V.O., Slepukhin P.A., Maslivets A.N. // ZhORKh. 2012, T. 48, S. 563-567) (Ia-c) with 4-hydroxy-2H-chromen-2-one (II) according to the scheme:

I, III Ar = Ph (a), C ₆ H ₄ Me-4 (b), C ₆ H ₄ OMe-4 (c).

The process is carried out by keeping the reagent solution in absolute toluene at a temperature of 108-110 ° C for 2-3 hours.

From the patent and technical literature, no methods have been identified for the preparation of 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-c] chromene-3,2′-pyrrole] -2 , 4,5 ′ (1′H) -trions having similar characteristics with the claimed method, namely, the starting products, solvents in which the reaction takes place, and the temperature range were not used, on the basis of which we can conclude that the claimed technical solution meets the criterion “Novelty” and “inventive step”.

The invention is illustrated by the following examples.

Example 1. 4′-Hydroxy-1′-phenyl-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-c] chromene-3,2′-pyrrole] -2,4,5 ′ (1 ′ H) -trion (IIIa).

To a solution of 1.0 mmol of compound (Ia) in 15 ml of absolute toluene, 1 mmol of compound (II) was added, boiled for 3 hours, cooled, the precipitate formed was filtered off and recrystallized from toluene-ethyl acetate (5: 1). Yield 78%, mp. 253-254 ° C (toluene-ethyl acetate). Compound (IIIa) C ₂₉ H ₁₇ NO ₇ .

Found,%: C 70.84; H 3.46; N, 2.82.

Calculated,%: C 70.88; H 3.49; N, 2.85.

Compound (IIIa) is a light yellow crystalline substance, readily soluble in DMF and DMSO, insoluble in ordinary organic solvents, insoluble in alkanes and water, giving a positive test for the presence of enol hydroxyl with an alcoholic solution of iron (III) chloride.

The IR spectrum of compound (IIIa), recorded as a paste in liquid paraffin, contains stretching vibrations of the enol hydroxyl group at 3208 cm ^-1 , the lactone carbonyl groups of the furan and chromene structural fragments at 1852 and 1725 cm ^-1 , and the lactam carbonyl group of the pyrrole structural a fragment at 1715 cm ^-1 , a ketone carbonyl group and a double bond of a cinnamoyl substituent at 1675 and 1650 cm ^-1 .

In the 1H NMR spectrum of compound (IIIa), recorded in a solution in DMSO-d ₆ , in addition to signals of protons of aromatic rings and related groups, there are doublets of protons of the double bond of the cinnamoyl substituent at 7.57 and 7.75 ppm. with spin-spin coupling constants characteristic of trans-substituted alkenes ( ³ J _trans 15.8 Hz).

Example 2. 4′-Hydroxy-1 ′ - (4-methylphenyl) -3′-cinnamoyl-2H, 4H-spiro [furo [3,2-s] chromene-3,2′-pyrrole] -2,4 , 5 ′ (1′H) -trion (IIIb).

To a solution of 1.0 mmol of compound (IB) in 15 ml of absolute toluene, 1 mmol of compound (II) was added, boiled for 2 hours, cooled, the precipitate formed was filtered off and recrystallized from toluene-ethyl acetate (5: 1). Yield 80%, mp. 236-237 ° C (toluene-ethyl acetate). Compound (IIIb) C ₃₀ H ₁₉ NO ₇ .

Found,%: C 71.23; H 3.75; N, 2.74.

Calculated,%: C 71.28; H 3.79; N, 2.77.

Compound (IIIb) is a light yellow crystalline substance, readily soluble in DMF and DMSO, insoluble in ordinary organic solvents, insoluble in alkanes and water, giving a positive test for the presence of enol hydroxyl with an alcoholic solution of iron (III) chloride.

The IR spectrum of compound (IIIb), recorded as a paste in liquid paraffin, contains stretching vibrations of the enol hydroxyl group at 3183 cm ^-1 , lactone carbonyl groups of the furan and chromene structural fragments at 1840 and 1738 cm ^-1 , and the lactam carbonyl group of the pyrrole structural a fragment at 1717 cm ^-1 , a ketone carbonyl group and a double bond of a cinnamoyl substituent at 1664 and 1651 cm ^-1 .

In the 1H NMR spectrum of compound (IIIb) recorded in a solution in DMSO-d ₆ , in addition to proton signals of aromatic rings and related groups, there are doublets of protons of the double bond of the cinnamoyl substituent at 7.60 and 7.74 ppm. with spin-spin coupling constants characteristic of trans-substituted alkenes ( ³ J _trans 15.8 Hz).

при 182.46 м.д., лактамной карбонильной группы С5′=O при 165.82 м.д., лактонных карбонильных групп С2=O при 157.63 м.д. и С4=O при 155.18 м.д., сигнал спиро-углеродного атома при 67.85 м.д., а также сигналы атомов углерода гетероциклической системы спиро[фуро[3,2-с]хромен-3,2′-пиррола]: С4′ при 170.89 м.д., C9b при 163.53 м.д., C5a при 154.83 м.д., C3a при 101.80 м.д.In the ¹³ C NMR spectrum of compound (IIIb), recorded in a solution in DMSO-d ₆ , in addition to the signals of the carbon atoms of aromatic substituents and related groups, as well as the double bond of the cinnamoyl substituent, there are signals of carbon atoms of the ketone carbonyl group $$C3\text{'}\text{'}-\underset{\_}{C}=O$$

at 182.46 ppm, the lactam carbonyl group C5 ′ = O at 165.82 ppm, the lactone carbonyl groups C2 = O at 157.63 ppm and C4 = O at 155.18 ppm, the signal of the spiro-carbon atom at 67.85 ppm, as well as the signals of the carbon atoms of the spiro [furo [3,2-s] chromene-3,2′-pyrrole] heterocyclic system: C4 ′ at 170.89 ppm, C9 b at 163.53 ppm, C5 a at 154.83 ppm, C3 a at 101.80 ppm

Compound (IIIc) was synthesized in a similar manner.

The proposed method is simple to implement, one-step and allows to obtain 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-c] chromene-3,2′-pyrrole not described in the literature ] -2,4,5 ′ (1′Н) -trions (IIIa-b) with good yields that will find application as starting materials for the synthesis of new heterocyclic systems and in pharmacology as potential drugs.

Example 3. Pharmacological study of 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-s] chromene-3,2′-pyrrole] -2,4,5 ′ (1′H) -trions (IIIa, c), for the presence of analgesic activity.

Assessment of the analgesic properties of compounds (IIIa, c) was studied on outbred mice weighing 18-22 grams using the hot plate thermal irritation method according to Eddie and Leimbach (Eddy N. B., Leimbarh D. J. Pharmacol and Exper. Gher. 1953., 385-393). Metamizole sodium was used as a reference drug.

Studies have shown (see table.) That the compounds (IIIa, c) have a pronounced analgesic activity at or above that of the comparison drug. Data on the pharmacological activity of analogues of the claimed compounds in the available literature are not available.

Claims (5)

1. 1′-Aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-s] chromene-3,2′-pyrrole] -2,4,5 ′ (1 ′ H) -trions of the formula

where III, Ar = Ph (a), C ₆ H ₄ Me-4 (b), C ₆ H ₄ OMe-4 (c). 2. 1′-Aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-s] chromene-3,2′-pyrrole] -2,4,5 ′ (1 ′ H) -trions of the formula

where III, Ar = Ph (a), C ₆ H ₄ OMe-4 (c),
possessing analgesic activity. 3. The method of obtaining 1′-aryl-4′-hydroxy-3′-cinnamoyl-2H, 4H-spiro [furo [3,2-c] chromene-3,2′-pyrrole] -2,4,5 ′ ( 1H) -trions,
characterized in that methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates (Ia-b) are reacted with 4-hydroxy-2H-chromene-2- one (II) in an inert aprotic solvent - toluene, at a temperature of 108-110 ° C for 2-3 hours.

where III, Ar = Ph (a), C ₆ H ₄ Me-4 (b), C ₆ H ₄ OMe-4 (c). 4. The method according to p. 3, characterized in that the process is carried out at a temperature of 108-110 ° C - the boiling point of toluene. 5. The method according to p. 3 or 4, characterized in that the solvent used is absolute toluene.