RU2477283C1 - 4,7-DIMETHYL-2-(2,4,5-TRIMETHOXYPHENYL)-3,4,4a,5,8,8a-HEXAHYDRO-2H-4,8-EPOXYCHROMEN POSSESSING ANALGESIC ACTIVITY - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, more specifically to new 4,7-dimethyl-2-(2,4_,5-trimethoxyphenyl)-3,4,4a,5,8,8a-hexahydro-2H-4,8-epoxychromen of formula

possessing high analgesic activity, and may be used in medicine.

EFFECT: compound possess low toxicity and is synthetised from the available natural compound α-pinene.

1 cl, 4 ex, 2 tbl

Description

The invention relates to the field of pharmaceuticals, specifically to a new 4,7-dimethyl-2- (2,4,5-trimethoxyphenyl) -3,4,4a, 5,8,8a-hexahydro-2H-4,8-epoxychromene of the general formula 1 (including its spatial isomers, including optically active forms):

possessing analgesic activity.

Known analgesics, which are pharmacologically non-narcotic analgesics, such as acetylsalicylic acid, analgin and others [Mashkovsky MD Medicines T.1. M .: Medicine. 2007]. Data on the activity on the model of “vinegar cramps” (ED ₅₀ ), acute toxicity (LD ₅₀ ) and selectivity index (SI = LD ₅₀ / ED ₅₀ ) of a number of known drugs are given in [Syubaev RD, Mashkovsky MD , Schwartz G.Ya., Pokryshkin V.I. Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs. Chem.-farm. journal 1986.V.20. No. 1. S.33-39] and are shown in table 1.

Table 1 Toxicity and analgesic effects of known drugs A drug ED ₅₀ , mg / kg LD ₅₀ , mg / kg SI Acetylsalicylic acid 155 1600 10.3 Analgin 55 3300 60.0 Diclofenac Sodium 5 370 74.0

The disadvantages of acetylsalicylic acid are low selective analgesic effect and gastrotoxicity; analginum - possible inhibition of hematopoiesis, up to complete agranulocytosis.

The closest analogue in pharmacological action to the claimed drug is diclofenac sodium [Vidal Handbook. Medicines in Russia: A Handbook. M: AstraPharmService. 2002.3-90.].

The disadvantages of diclofenac sodium are gastrointestinal upsets and gastrotoxicity.

The problem to which the invention is directed, is to create a new compound with analgesic activity.

The problem is solved by 4,7-dimethyl-2- (2,4,5-trimethoxyphenyl) -3,4,4a, 5,8,8a-hexahydro-2H-4,8-epoxychromene of the general formula 1, including its spatial isomers , including optically active forms:

Compound 1 has not been previously described in the literature; it can be synthesized according to Scheme 1 by reaction of 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 3 with 2 , 4,5-trimethoxybenzaldehyde 2 in the presence of an acid catalyst, for example montmorillonite clay, using a solvent, preferably methylene chloride, or in the absence of a solvent. Compound 4 is formed as another intermolecular product in this reaction.

To obtain compound 1 in the form of various stereoisomers, including in optically active form, various spatial isomers of compound 3 can be used as starting materials, including those with optical activity.

Compound 4 can also be converted to compound 1 by keeping compound 4 in the presence of an acid catalyst, for example montmorillonite clay, preferably in the presence of aldehyde 2.

Compound 3, including in optically active form, can be synthesized in accordance with Scheme 2 starting from monoterpen α-pinene 5, widely used in domestic plant materials, using available reagents according to the previously described methods [Ardashov OV, Pavlova AV, Il'ina IV, Morozova EA, Korchagina DV, Karpova EV, Volcho KP, Tolstikova TG, Salakhutdinov NF Highly potent activity of (1R, 2R, 6S) -3-methyl-6- (prop-1-en-2-yl) cyclohex-3-ene-1,2-diol in animal models of Parkinson's disease. J. Med. Chem. 2011, 54, 3866-3874].

The acute toxicity of compound 1 was determined on outbred white mice weighing 20-22 g with a single intragastric administration according to the Kerber method. It was shown that compound 1 is a low toxic substance; its LD ₅₀ exceeds 1500 mg / kg.

The analgesic activity of compound 1 was studied on models of visceral pain “vinegar cramps” and thermal stimulation “hot plate” by a single injection at doses of 10, 20 and 30 mg / kg.

Acetic cramps were reproduced by intraperitoneal injection of 0.75% acetic acid in 0.1 ml per animal. Assessment of activity was carried out by the number of writhing for 3 minutes

“Hot plate” is a test characterizing thermal irritation. Animals were placed on a copper plate, T = 54 ° C. The effect was evaluated by the duration of the animal on the hot plate until the first "vocalization" in seconds.

From the data of table 2 it is seen that compound 1 shows a high analgesic activity in both models. Compound 1 blocks the development of the pain effect caused by the introduction of acetic acid, and increases the time until the first “vocalization” in the “hot plate” test compared to the control.

table 2 Analgesic effect of compound 1. "Hot plate" latent time (sec) the control 10 mg / kg 20 mg / kg 30 mg / kg ED ₅₀ SI 9.8 ± 0.7 16.3 ± 1.3 ** 13.1 ± 0.5 * 16.8 ± 1.8 * 25 mg / kg > 60 "Vinegar cramps" number the control 10 mg / kg 20 mg / kg 30 mg / kg ED ₅₀ SI 14.5 ± 1.1 9.4 ± 2.3 7.5 ± 1.6 * 5.8 ± 1.5 ** 22 mg / kg > 68 * P <0.01; ** P <0.001 compared with the control group

It was found that the ED _{50 of} compound 1 in the test “hot plate” is 25 mg / kg, and in the test “vinegar cramps” - 22 mg / kg. Given that the LD _{50 of} compound 1 exceeds 1500 mg / kg, the selectivity index SI of compound 1 exceeds 60 in the hot plate test and 68 in the vinegar cramp test.

Based on the foregoing, it can be concluded that compound 1 combines high analgesic activity with low toxicity and can, after appropriate tests, be used both in pure form or as a component of low toxic, highly effective analgesic dosage forms.

The invention is illustrated by the following examples.

Example 1. Synthesis of (2S, 4R, 4aR, 8S, 8aR) -4,7-dimethyl-2- (2,4,5-trimethoxyphenyl) -3,4,4a, 5,8,8a-hexahydro-2H- 4,8-epoxychromene 1 according to scheme 1.

To a suspension of 3 g of clay in 10 ml of CH ₂ Cl _{2 was} added 0.8 g of 2,4,5-trimethoxybenzaldehyde 2, then a solution of 0.7 g (1R, 2R, 6S) -3-methyl-6- (prop-1-en-2 -yl) cyclohex-3-en-1,2-diol 3 in 20 ml of CH ₂ Cl ₂ . The reaction mixture was allowed to stand for 10 minutes, the solvent was distilled off, and kept for 7 days at room temperature. Added 20 ml of ethyl acetate, the catalyst was filtered off, the solvent was distilled off. The residue was divided on a column with 12 g of silica gel; the eluent was a gradient of ethyl acetate in hexane containing from 0 to 100% ethyl acetate. 0.217 g (15%) of compound 1 was obtained and 0.616 g (40%) of (2S, 4S, 4aR, 8aR) -2- (2,4,5-trimethoxyphenyl) -4,7-dimethyl-3,4,4a, 5,8,8a-hexahydro-2H-chromene-4,8-diol 4.

Compound 1. ¹ H NMR Spectrum (CDCl ₃ ): 1.36 (s, Me (17)); 1.52 (dd, J (4a, 4e) = 13.1 Hz, J (4a, 3a) = 10.6 Hz, H _a -C (4)); 1.75 (m, all J≤2.5 Hz, Me (18)); 1.91 (dd, J (4e, 4a) = 13.1 Hz; J (4e, 3a) = 4.2 Hz, H _e -C (4)); 2.08 (bd, J (6.7) = 5.6 Hz; HC (6)); 2.37 (ddc, J (7.7 ′) = 18.6 Hz, J (7.6) = 5.6 Hz, J (7.8) = 3.0 Hz, J (7.18) = 2.2 Hz HC (7)); 2.53 (dm, J (7.7 ′) = 18.6 Hz, H′-C (7)); 3.77 (s, OMe (19)); 3.84 (s, OMe (21)); 3.85 (s, OMe (20)); 4.25 (bs, HC (10)); 4.44 (d, J (1.6) = 1.2 Hz, HC (1)); 5.13-5.17 (m, HC (8)); 5.42 (dd, J (3a, 4a) = 10.6 Hz; J (3a, 4e) = 4.2 Hz, H _a -C (3)); 6.47 (s, HC (13)); 7.01 (s, HC (16)). ¹³ C NMR Spectrum (CDCl ₃ ): 81.07 (d, C (1)); 68.21 (d, C (3)); 45.69 (t, C (4)); 83.33 (s, C (5)); 45.66 (d, C (6)); 28.20 (t, C (7)); 120.66 (d, C (8)); 139.86 (s, C (9)); 80.21 (d, C (10)); 122.15 (s, C (11)); 150.31 (s, C (12)); 97.44 (d, C (13)); 148.54 (s, C (14)); 143.20 (s, C (15)); 110.67 (d, C (16)); 21.48 (q, C (17)); 20.91 (q, C (18)); 56.27 (q, C (19)); 56.07 (q, C (20)); 56.51 (q, C (21)). HR-MS: 346.1774 (M ⁺ , C ₂₀ H ₂₆ O ₅ , calculated value 346.1774).

Compound 4. ¹ H NMR Spectrum (CDCl ₃ ): 1.52 (s, Me (17)); 1.68 (ddd, J (4e, 4a) = 13.2 Hz, J (4e, 3a) = 2.7 Hz, J (4e, 6) = 1.1 Hz, H _e -C (4)); 1.77-1.85 (m, HC (6), H _a- C (4)); 1.81 (m, all J≤2.5 Hz, Me (18)); 2.15-2.20 (m, 2H-C (7)); 3.78 s, 3.79 s, 3.84 s, (3 OCH ₃ ); 3.81 (dd, J (1e, 6) = 2.4 Hz, J (1e, 10e) = 2.0 Hz, H _e -C (1)); 3.90 (br s, H _e -C (10)); 4.76 (dd, J (3a, 4a) = 11.4 Hz, J (3a, 4e) = 2.7 Hz, H _a -C (3)); 5.63-5.67 (m, HC (8)); 6.46 (s, HC (13)); 6.88 (s, HC (16)). ¹³ C NMR Spectrum (CDCl ₃ ): 77.72 (d, C (1)); 71.58 (d, C (3)); 41.87 (t, C (4)); 71.16 (s, C (5)); 38.50 (d, C (6)); 22.71 (t, C (7)); 124.58 (d, C (8)); 131.43 (s, C (9)); 70.61 (d, C (10)); 122.09 (s, C (11)); 150.24 (s, C (12)); 97.67 (d, C (13)); 149.03 (s, C (14)); 143.31 (s, C (15)); 111.10 (d, C (16)); 27.00 (q, C (17)); 20.67 (q, C (18)); 56.49 (q, C (19)); 56.07 (q, C (20)); 56.77 (q, C (21)).

Example 2. Obtaining compound 1 by cyclization of compound 4.

0.2 g of aldehyde _{2 was} added to a suspension of 0.8 g of clay in 15 ml of CH ₂ Cl ₂ , then a solution of 0.2 g of compound 4 in 15 ml of CH ₂ Cl ₂ , the solvent was distilled off, the reaction mixture was kept for 3 days at room temperature. 20 ml of ethyl acetate was added, the catalyst was filtered off, a mixture was obtained, the ratio of compounds 4 and 1 was 4: 1 (GLC-MS data).

Example 3. The study of the analgesic activity of compound 1 in the test "vinegar cramps".

The experiment was carried out on outbred male mice weighing 22-25 g. The experimental groups were formed of 8 animals each. Acetic cramps were reproduced by intraperitoneal injection of 0.75% acetic acid in 0.1 ml per animal. The studied agents were administered once intragastrically at doses of 10, 20, and 30 mg / kg an hour before model reproduction. The control was animals with the introduction of only acetic acid. Assessment of activity was carried out by the number of writhing for 3 minutes The results are shown in table 2.

It was found that compound 1 exhibits high analgesic activity on the model of “acetic cramps”, blocking the development of the pain effect caused by the introduction of acetic acid. The ED _{50 of} compound 1 in the vinegar cramps test is 22 mg / kg.

Example 4. The study of the analgesic activity of the compounds of General formula 1 in the test "hot plate".

The experiments were performed on outbred male mice weighing 22-25 g. The experimental groups were formed of 8 animals each. Animals were placed on a copper plate T = 54 ° C. The effect was evaluated by the duration of the animal on the hot plate until the first "vocalization", in seconds.

The studied agents were administered once intragastrically at doses of 10, 20, and 30 mg / kg an hour before model reproduction. The control animals were injected with the appropriate solvent. The results are shown in table 2.

In the “hot plate” test, compound 1 exhibited a high analgesic effect; its ED ₅₀ was 25 mg / kg.

Claims (1)

4,7-Dimethyl-2- (2,4,5-trimethoxyphenyl) -3,4,4a, 5,8,8a-hexahydro-2H-4,8-epoxychromene of the general formula 1, including its spatial isomers, including including optically active forms:

possessing analgesic activity.