RU2453311C1 - 8-(TRIFLUOROMETHYL)BENZO[f][1,2,3,4,5]PENTATHIEPIN-6-AMINE AS ANALGESIC - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns application of 8-(trifluoromethyl)benzo[f] [1,2,3,4,5]pentathiepin-6-amine of formula 1

as an analgesic.

EFFECT: agent show high activity and low toxicity.

2 tbl, 3 ex

Description

The invention relates to medicine, namely to medicines having analgesic activity.

Analogs of the proposed means for pharmacological action are non-narcotic analgesics, such as acetylsalicylic acid and analgin [1]. Data on the activity on the model of “vinegar cramps” (ED ₅₀ ), acute toxicity (LD ₅₀ ) and the breadth of therapeutic effect (IS ₅₀ = LD ₅₀ / ED ₅₀ ) of these drugs are presented in [2]. The disadvantages of acetylsalicylic acid are low activity and gastrotoxicity; analginum - possible inhibition of hematopoiesis, up to complete agranulocytosis.

Closest to the claimed means of pharmacological action - the prototype is diclofenac sodium [3]. The disadvantages of diclofenac sodium are gastrointestinal upsets and gastrotoxicity.

The problem to which the invention is directed, is to find a new effective low-toxic drug with analgesic activity.

The problem is solved by using 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine of the formula 1 as an analgesic

including its pharmaceutically acceptable salts.

Compound 1 was first obtained and described in [4, 5]; it exhibits anticonvulsant and anxiolytic activity [4, 5]. Data on its analgesic activity are not available in the literature.

Compound 1 can be synthesized from 1-chloro-4- (trifluoromethyl) benzene 2 using commercially available reagents in accordance with scheme 1 [4, 5].

Compound 1 is moderately toxic (LD ₅₀ > 1000 mg / kg) [4, 5].

The analgesic activity of compound 1 was studied on a model of visceral cramps by means of a single administration in doses of 0.5, 1.0 and 10.0 mg / kg. "Acetic cramps" was 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 The ED _{50 of} compound 1 was shown to be 0.9 mg / kg. The best efficiency (a decrease in the number of cramps in two or more times) was recorded at doses of 0.5 and 1 mg / kg.

The breadth of therapeutic action (IS ₅₀ ) of this substance exceeds 1110, many times surpassing the similar index of comparison drugs. Table 1 presents data on the analgesic effect of known drugs [2] and the proposed compounds.

Table 1 A drug ED ₅₀ mg / kg LD ₅₀ mg / kg IS ₅₀ (LD ₅₀ / ED ₅₀ ) Acetylsalicylic acid 155 1600 10.3 Analgin 55 3300 60.0 Diclofenac Sodium 5 370 74.0 Compound 1 0.9 > 1000 > 1110

The table shows that compound 1 combines high analgesic activity with low toxicity and is promising for the creation of a new effective low-toxic analgesic drug based on it.

Compound 1 can be used for analgesia both as a free base and as salts with pharmaceutically acceptable acids. For example, the use of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine (1 · HCl) hydrochloride at a dose of 10 mg / kg in the vinegar cramps test did not lead to a decrease analgesic activity compared with the use of compound 1 at a dose of 10 mg / kg

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

The invention is illustrated by the following examples.

Example 1. Synthesis of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine 1.

Compound 3 can be obtained from 1-chloro-4- (trifluoromethyl) benzene 2 in accordance with known methods [6, 7]. To a solution of 2.56 g (9.1 mmol) of 4-nitro-6- (trifluoromethyl) benzo [d] dithiol-2-one 3 in 35 ml of DMSO, 3.29 g (70% NaHS, 41 mmol) of NaHS were added with stirring at 25 ° C H ₂ O, stirred at room temperature for 15 hours. 100 ml of H ₂ O were added, hydrochloric acid (conc.) Was added until neutral, extracted with 3 × 30 ml of methylene chloride, washed with 3 × 50 ml of water, dried with Na ₂ SO ₄ . After removal of the solvent in vacuo, 2.77 g of a residue was obtained, which was partitioned by silica gel column chromatography (60-200 µ), eluent hexane / benzene (1: 1). 1.504 g (52%) of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine (1) was obtained. The ¹ H NMR spectrum of compound 1 coincided with the spectrum published in the literature [4].

Example 2. Synthesis of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine hydrochloride (1 · HCl).

To a solution of 0.366 g of 8- (trifluoromethyl) -1,2,3,4,5-benzopentathiepin-6-amine 1 in 6 ml of diethyl ether was added 0.540 g of a 10% solution of HCl in absolute ethanol with stirring, stirred for 1 h at at room temperature, the precipitate was filtered off, washed with diethyl ether, and 0.272 g (67%) of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine hydrochloride was obtained (1 · HCl). Mp 90-92 ° C (with decomposition). Found: m / z 318.8893 [M-HCl] ⁺ C ₇ H ₄ NF ₃ S ₅ . Calculated: M-HCl = 318.8899. Found (%): C, 23.80; H, 1.39; Cl, 9.89; C ₇ H ₄ NF ₃ S ₅ · HCl. Calculated (%) C 23.62; H, 1.42; Cl, 9.96. ¹ H NMR (DMSO-d ₆ ): 7.14 (bd, J = 2.0) and 7.17 (bd, J = 2.0) - HC (9) and HC (11). ¹³ C NMR (DMSO-d ₆ ): 113.74 (d, ³ J (C, F) = 4.0, C (9)); 117.27 (d, ³ J (C, F) = 3.5, C (11)); 122.99 (q, ¹ J (C, F) = 273.3, C (12)); 124.71 (s, C (7)); 131.15 (s, ² J (C, F) = 32.3, C (10)); 146.21 (s, C (1)); 153.37 (s, C (8)).

Example 3. The study of the analgesic activity of compounds 1 and (1 · HCl) 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. Test compound 1 at doses of 0.5, 1.0, and 10.0 mg / kg, and compound (1 · HCl) at a dose of 10 mg / kg was administered once intragastrically one 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.

table 2 Analgesic effect of compounds 1 and (1 · HCl) Group / Agent (Dose) Acetic cramps, quantity (change in the number of cramps compared to the control) The control 13.9 ± 0.6 1 (10 mg / kg) 9.9 ± 0.6 * (-29%) The control 13.8 ± 0.8 1 (1 mg / kg) 6.3 ± 1.8 * (-54%) The control 12.6 ± 1.3 1 (0.5 mg / kg) 6.3 ± 1.7 * (-50%) The control 10.7 ± 0.5 (1 · HCl) (10 mg / kg) 5.9 ± 0.7 * (-45%) * - P <0.001; regarding control

It was found that compounds 1 and (1 · HCl) show a significant analgesic effect on the model of “vinegar cramps”, ED _{50 of} compound 1 is 0.9 mg / kg. Compound 1 and its hydrochloride block the development of the pain effect caused by the introduction of acetic acid, and exhibit high analgesic activity.

Information sources

1. Mashkovsky M.D. Medicines T.1. M .: Medicine. 1993.

2. Syubaev R.D., Mashkovsky M.D., Schwartz G.Ya., Pokryshkin V.I. Chem.-farm. journal 1986, Vol. 20, 33.

3. Reference Vidal. Medicines in Russia: A Handbook. M .: AstraPharmService. 2002. Z-90.

4. Khomenko T. M., Korchagina D. V., Bolkunov A. V., Dolgikh M. P., Volcho K. P., Tolstikova T. G., Salakhutdinov N. F. Patent Ru 2341521. 12.20.2008.

5. Khomenko T.M., Tolstikova T.G., Bolkunov A.V., Dolgikh M.P., Pavlova A.V., Korchagina D.V., Volcho K.P., Salakhutdinov N.F. Letters in Drug Design & Discovery. 2009, Vol.6, 464.

6. Yagupolsky L.M., Mospan B.C. Ukrainian Chemical Journal, 1955, Vol. 21, 81.

7. Rasheed K., Warkentin J.D. J. Org. Chem. 1979, Vol. 44, 267.

Claims (1)

The use of 8- (trifluoromethyl) benzo [f] [1,2,3,4,5] pentathiepin-6-amine of formula 1:

including its pharmaceutically acceptable salts, as an analgesic.