RU2360914C1 - Analgesic medication - Google Patents

Abstract

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to analgesic medication based on 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2'-(3'-aroyl-4'-hydroxy-1'-o-hydroxyphenyl -5'-oxo-2',5'-dihydropyrrol), of formula:

, where: R=CH₂C₆H₅ (a), C₆H₅ (b), C₆H₄Cl-n (c).

EFFECT: medications possess increased efficiency.

1 tbl, 4 ex

Description

Technical field

The invention relates to the field of organic chemistry, namely to chemical compounds of indole-3-spiro-2'-pyrroles having analgesic activity, which can be used as starting materials for the synthesis of new heterocyclic systems, as well as after in-depth study and in medical practice .

State of the art

Known structural analogues of the proposed compounds are 1-alkyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2- (1-aryl -3-aroyl-4-hydroxy-5-oxo-2,5-dihydropyrroles) obtained by the reaction of 1-aryl-4-aroyl-5-methoxycarbonyl-2,3-dihydro-2,3-pyrroldione with 3-alkylamino 5,5-dimethylcyclohexen-2-oneami-1 (Journal of Organic Chemistry. 2004. V.40. Issue 12. P. 1840-1845).

R = CH ₂ C ₆ H ₅ (I), C ₆ H ₁₁ -c (II); Ar = p-NO ₂ C ₆ H ₄ (I), C ₆ H ₅ (II); Ar '= C ₆ H ₅ (I), p-ClC ₆ H ₄ (II)

The disadvantages of this method include the impossibility of obtaining 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (3'-aroyl- 4'-hydroxy-1'-o-hydroxyphenyl-5'-oxo-2 ', 5'-dihydropyrroles). Structural analogues do not have analgesic activity.

Disclosure of invention

The objective of the invention is to develop a simple method for the synthesis of 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (3'-aroyl- 4'-hydroxy-1'-o-hydroxyphenyl-5'-oxo-2'5'-dihydropyrroles), exhibiting analgesic activity, as well as expanding the arsenal of means of affecting a living organism.

The task is carried out by boiling 3-aroyl-2,4-dihydro-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-trions with N-unsubstituted and N-substituted 3-amino -5,5-dimethyl-2-cyclohexen-1-ones, taken in the ratio 1: 1, in an inert aprotic solvent according to the scheme:

R = CH ₂ C ₆ H ₅ (IIa, IIIa), C ₆ H ₅ (IIb, IIIb), C ₆ H ₄ Cl-n (IIc, IIIc).

The process is carried out at a temperature of 79-80 ° C, and absolute benzene is used as a solvent.

From the patent and technical literature, no methods have been identified for the preparation of 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (3' aroyl-4'-hydroxy-1'-o-hydroxyphenyl-5'-oxo-2 ', 5'-dihydropyrroles) having similar characteristics with the claimed method, namely, the starting products, solvents in which the reaction takes place, were not used, and a temperature range, on the basis of which it can be concluded that the claimed technical solution meets the criteria of "novelty" and "inventive step".

The invention is illustrated by the following examples.

Example 1. 1-Benzyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (4'-hydroxy- 1'-o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2'5'-dihydro-1'H-pyrrole) (IIIa).

To a solution of 1 mmol of 3-n-methoxybenzoyl-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-trion in 2 ml of absolute benzene was added 1 mmol of 3- (benzylamino) -5, 5-dimethyl-2-cyclohexen-1-one, boiled at a temperature of 79 ° C for 3 minutes, cooled, the precipitate was filtered off. Yield 85%, mp. 214-216 ° C (decomposition, from ethyl acetate).

Compound (IIIa) C ₃₄ H ₃₀ N ₂ O ₇

Found,%: C 70.56; H 5.25; N, 4.86.

Calculated,%: C 70.58; H 5.23; N, 4.84.

Example 2. 6,6-Dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1-phenyl-1H-indole-3-spiro-2 '- (4'-hydroxy- 1'-o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2 ', 5'-dihydro-1'H-pyrrole) (IIIb).

To a solution of 1 mmol of 3-n-methoxybenzoyl-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-trion in 2 ml of absolute benzene was added 1 mmol of 3-anilino-5.5- dimethyl-2-cyclohexen-1-one, boiled at a temperature of 79 ° C for 4 minutes, cooled, the precipitate was filtered off. Yield 86%, mp. 232-234 ° C (decomposition, from ethyl acetate).

Compound (IIIb) C ₃₃ H ₂₈ N ₂ O ₇ .

Found,%: C 70.22; H 4.97; N, 4.94.

Calculated,%: C 70.20; H 4.99; N, 4.96.

Example 3. 6,6-Dimethyl-2,4-dioxo-1-n-chlorophenyl-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (4'- hydroxy-1'-o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2'5'-dihydro-1'H-pyrrole) (IIIc).

To a solution of 1 mmol of 3-n-methoxybenzoyl-1H-pyrrolo [2,1-s] [1,4] benzoxazine-1,2,4-trion in 2 ml of absolute benzene was added 1 mmol of 3- (n-chloroanilino-5 , 5-dimethyl-2-cyclohexen-1-one), boiled at a temperature of 79 ° C for 3 minutes, cooled, the precipitate was filtered off. Yield 87%, mp. 189-192 ° C (decomposition, from ethyl acetate).

Compound (IIIc) C ₃₃ H ₂₇ ClN ₂ O ₇ .

Found,%: C 66.19; H 4.57; N, 4.66.

Calculated,%: C 66.17; H 4.54; N, 4.68.

Compounds (IIIa-c) - light yellow crystalline substances with high melting points, readily soluble in DMSO and DMF, insoluble in ordinary organic solvents, insoluble in water and alkanes, giving a positive test (cherry color) for the presence of enol hydroxyl with an alcohol solution of chloride iron (III). Stable under normal storage conditions.

The IR spectra of compounds (IIIa-c) contain stretching vibration bands of the phenolic and enolic OH groups and the NH amide group in the form of a wide band in the region of 3040-3480 cm ^-1 , lactam carbonyl groups of the pyrrolone and indolinone rings in the regions of 1750-1756 and 1710 -1724 cm ^-1 , two enone carbonyl groups in the form of a wide strip in the region of 1610-1660 cm ^-1 .

The NMR spectra of ¹ H solutions of spiro products (IIIa-c) in DMSO-d ₆ contain, in addition to signals from protons of aromatic substituents and related groups, two singlets of methyl groups of a dimedone fragment in the region of 0.56-0.81 ppm, a group of signals of two methylene groups of a dimedone fragment in the region of 1.94–2.42 ppm, doublet of doublets (AB system) of diastereotopic protons of the benzyl radical [in compounds (IIIa)] in the region of 4.70, 4.92 ppm, split due to the proximity to the chiral center, a phenol singlet proton in the region of 9.53-9.76 ppm, broadened singlet en proton ceiling elements in 12.16-12.28 ppm

The proposed method is quite simple to implement, one-stage and allows you to get 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (3 '-aroyl-4'-hydroxy-1'-o-hydroxyphenyl-5'-oxo-2', 5'-dihydropyrroles) exhibiting analgesic activity, with practically quantitative yields. The described method can be used as a new approach to the synthesis of substituted indole-3-spiro-2'-pyrroles.

Example 4

The analgesic activity of compounds (IIIa-b) (Table 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 compounds were 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. Comparison drug - analgin - in a dose of ED50 93 mg / kg [Syubaev R.D., Mashkovsky M.D., Schwartz G.Ya., Pokryshkin V.I. // Chem. - farm. Journal. - 1985. - No. 1. - S.33-39]. 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. The test results are shown in the table.

Table The study of analgesic activity by the "hot plate" method. Connections The time of the onset of the defensive reflex In 2 hours After 2.5 hours 1-Benzyl-6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (4'-hydroxy-1'- o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2 ', 5'-dihydro-1'H-pyrrole) (IIIa) 18.27 ± 5.57 p <0.5 21.6 ± 2.0 p> 0.5 6,6-Dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1-phenyl-1H-indole-3-spiro-2 '- (4'-hydroxy-1'- o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2 ', 5'-dihydro-1'H-pyrrole) (IIIb) 19.52 ± 2.66 p <0.1 22.27 ± 1.95 p <0.01 6,6-Dimethyl-2,4-dioxo-1-n-chlorophenyl-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (4'-hydroxy-1 '-o-hydroxyphenyl-3'-n-methoxybenzoyl-5'-oxo-2', 5'-dihydro-1'H-pyrrole) (IIIc) 19.4 ± 3.2 p <0.05 24.20 ± 2.28 p <0.05 Analgin 12.8 ± 1.9 p <0.05 16.3 ± 3.0 p <0.1 Control 2% starch mucus 8.9 ± 0.8 10.8 ± 1.6

According to the table, the proposed compounds (IIIa-b) can find application in medical practice as analgesic drugs.

Claims (1)

Analgesic, which is 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-indole-3-spiro-2 '- (3'-aroyl-4'-hydroxy-1'-o-hydroxyphenyl-5'-oxo-2',5'-dihydropyrroles) of the general formula

where R = CH ₂ C ₆ H ₅ (a), C ₆ H ₅ (b), C ₆ H ₄ Cl-n (c).