RU2806189C1 - Application of 3-aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5h-spiro[furan-2, 3'-indole]-2',4',5(1'h,5'h)-triones as agent with antioxidant activity - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to 3-aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5H-spiro[furan- 2,3'-indole]-2',4',5(1'H,5'H)-triones of the general formula:

,

where Ar = 4-BrC6H4 (a); Ar = 4-ClC6H4 (b).

EFFECT: new -aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5H-spiro[furan -2,3'-indole]-2',4',5(1'H,5'H)-triones have been obtained with antioxidant activity, which can be used in pharmacology and medicine as an antioxidant agent.

1 cl, 3 ex, 1 tbl

Description

The invention relates to the field of pharmacology and medicine, namely to the use of individual compounds of the class spiro[furan-2,3'-indole]ov-3-aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'- dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5H-spiro[furan-2,3'-indole]-2',4',5(1'H,5'H)- trions with antioxidant activity, which can be used in pharmacology and medicine as an antioxidant agent.

Structural analogues of the claimed compound are known - 3-benzoyl-1'-(4-bromophenyl)-4-[2-(hydroxymethyl)phenylamino]-6',6'-dimethyl-6',7'-dihydro-5H-spiro[ furan-2,3'-indole]-2',4',5(1'H,5'H)-trione and 1'-benzyl-4-[2-(hydroxymethyl)phenylamino]-6',6' -dimethyl-3-(4-chlorobenzoyl)-6',7'-dihydro-5H-spiro[furan-2,3'-indole]-2',4',5(1'H,5'H)- trione obtained from 3-aroylpyrrolo[1,2-a][4,1]benzoxazepine-1,2,4-triones (Maslivets A.A., Maslivets A.N. //Russian Journal of Organic Chemistry. - 2015. - V 51. - No. 8. - PP. 1194-1195.). The synthesis of structural analogues is carried out according to the following scheme:

Antioxidant properties of 9-aroyl-8-hydroxy-6-[2-(hydroxymethyl)phenyl]-2-thioxo-1,3,6-triazaspiro[4.4]non-8-ene-4,7-diones (1a,b ) have not been previously studied.

The objective of the invention is to search among the derivatives of spiro[furan-2,3'-indoles] for substances with a pronounced antioxidant effect, to expand the arsenal of means of influencing a living organism.

The goal is achieved by the synthesis of 4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(2-fluorophenyl)-3-(4-chlorobenzoyl)-6',7'-dihydro-5H -spiro[furan-2,3'-indole]-2',4',5(1'H,5'H)-triones 1a,b and the study of compounds 1a,b for the presence of antioxidant activity.

The claimed compounds are synthesized by the reaction of 3-(4-chlorobenzoyl)-pyrrolo[1,2-c][4,1]benzoxazepine-1,2,4-trione with 3-((3-fluorophenyl)amino)-5,5- dimethylcyclohex-2-en-1-one in boiling anhydrous chloroform for 30 minutes according to the following scheme:

The invention is illustrated by the following examples.

Example 1. 3-(4-Brombenzoyl)-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5H- spiro[furan-2,3'-indole]-2',4',5(1'H,5'H)-trione.

A solution of 1.0 mmol of compound 2a and 1.0 mmol of 3-((3-fluorophenyl)amino)-5,5-dimethylcyclohex-2-en-1-one in 10 ml of anhydrous chloroform was boiled for 30 min (until the bright red color of the starting compound 2a disappeared ), cooled, and the resulting precipitate was filtered off. Yield 56%, mp. 137-138°C Compound 1a C ₃₃ H ₂₆ BrFN ₂ O ₆ .

Found, %: -

Calculated, %; C, 61.41; N, 4.06; Br, 12.38; F, 2.94; N, 4.34.

Compound 1a is a yellow, high-melting crystalline substance, readily soluble in DMSO and DMF, soluble in acetone, toluene, chloroform, ethanol, ethyl acetate, moderately soluble in acetonitrile, insoluble in alkanes and water. Stable when stored under normal conditions.

In the IR spectrum of compound 1a, removed as a paste in liquid paraffin, there are bands of stretching vibrations of the NH groups at 3465 cm ^-1 and OH at 3376 cm ^-1 , the lactone carbonyl group at 1776 cm ^-1 , and the lactam carbonyl group at 1758 cm ^-1 , carbonyl groups (C ^4' =O, C(Ar)=O) at 1655 cm ^-1 and 1630 cm ^-1 .

1H NMR spectrum, δ ppm, DMSO- _d6 : 0.72 s (3H, _CH3 ), 1.03 s (3H, _CH3 ), 2.01 d, 2.36 d (2H, ^C7H2 _, J 16.1 Hz) , 2.27 d, 2.76 d (2H, C ⁵ H ₂ , J 18.4 Hz), 4.22 d, 4.49 d (2H, CH ₂ OH, J 13.4 Hz), 5.25 br.s (1H, OH), 6.77-7.69 g .s (12H, 3C ₆ H ₄ ) 8.76 s (1H, NH).

Example 2. 4-[2-(Hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-3-(4-chlorobenzoyl)-6',7'-dihydro-5H- spiro[furan-2,3'-indole]-2',4',5(1'H,5'H)-trione.

A solution of 1.0 mmol of compound 2b and 1.0 mmol of 3-((3-fluorophenyl)amino)-5,5-dimethylcyclohex-2-en-1-one in 10 ml of anhydrous chloroform was boiled for 30 min (until the bright red color of the starting compound 26 disappeared ), cooled, and the resulting precipitate was filtered off. Yield 55%, mp. 135-136°C. Compound 1b C ₃₃ H ₂₆ ClFN ₂ O ₆ .

Found, %: -

Calculated, %; From 65.95; H 4.36; Cl 5.90; F 3.16; N 4.66.

Compound 1b is a yellow, high-melting crystalline substance, readily soluble in DMSO and DMF, soluble in acetone, toluene, chloroform, ethanol, ethyl acetate, moderately soluble in acetonitrile, insoluble in alkanes and water. Stable when stored under normal conditions.

The IR spectrum of compound 1b, taken as a paste in petroleum jelly, contains bands of stretching vibrations of the NH groups at 3468 cm ^-1 and OH at 3377 cm ^-1 , the lactone carbonyl group at 1776 cm ^-1 , and the lactam carbonyl group at 1758 cm ^-1 , carbonyl groups (C ^4' =O, C(Ar)=O) at 1655 cm ^-1 and 1631 cm ^-1 .

1H NMR spectrum, δ, ppm, DMSO-d ₆ : 0.71 s (3H, CH ₃ ), 103 s (3H, CH ₃ ), 2.01 d, 2.37 d (J=16.1 Hz, 2H, C ^7' H ₂ ), 2.27 d, 2.76 d (J=18.3 Hz, 2H, C ^5'H ₂ ), 4.22 d, 4.49 d (J=13.4 Hz, 2H, CH ₂ OH), 5.26 s (1H, OH), 6.76-7.74 deg.s. (12H, CH _Ar ), 8.75 s (1H, NH).

Example 3. Study of 3-aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3'-fluorophenyl)-6',7'-dihydro-5H-spiro[ furan-2,3-indole]-2',4',5(1'H,5'H)-triones 1a,b for the presence of antioxidant activity.

Antioxidant activity was studied by the spectrophotometric method by the ability of solutions of the studied substances to capture brightly colored 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals [Moore J.C., Liangli L.Yu. P. 118-172. DOI: 10.1002/9780470228333.CH9; Wheat Antioxidants (ed. Liangli Yu). Wiley. 2008. DOI: 10.1002/9780470228333].

The photometric DPPH reagent contained a 0.2 mM solution of DPPH in methanol. Solutions (concentration 15 µmol/ml) of the studied compounds and standards (agidol-1, ascorbic acid) in DMSO in an amount of 100 µl were added to the DPPH reagent (100 µl) into the wells of a 96-well plate. The reaction mixture was kept at 20°C for 20 minutes. In the dark. The optical density of the reaction mixtures was measured at 517 nm. Calibration was carried out using a freshly prepared DPPH solution in a DMSO-methanol mixture, 1 to 1. The loss of the radical was calculated using the formula:

Loss of radical (%)=[(A ₀ -A ₁ )/A ₀ ]⋅100, where A ₀ is the absorption of the DPPH solution without the test sample, A ₁ is the absorption of the DPPH solution in the presence of the test sample.

The research results are shown in the Table.

As a result of the study, it was revealed that compounds 1a, b exhibit antioxidant activity against the free radical DPPH, comparable to that of the reference drug - ascorbic acid.

Claims (4)

3-Aroyl-4-[2-(hydroxymethyl)-phenylamino]-6',6'-dimethyl-1'-(3-fluorophenyl)-6',7'-dihydro-5H-spiro[furan-2,3 '-indole]-2',4',5(1'H,5'H)-triones of the general formula: , where Ar = 4-BrC6H4 ( a ); Ar = 4-ClC6H4 ( b ), having antioxidant activity.