RU2314310C1 - 3-methoxycarbonyl-4-(2-piperidinoethyl)-2-ethylpyrazolo[1,5-a]benzimidazole hydrochloride possessing topical anesthetic effect - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel derivative in order of pyrazolo[1,5-a]benzimidazole possessing topical anesthetic effect in surface (terminal), infiltration and conduction anesthesia. Invention describes 3-methoxycarbonyl-4-(2-piperidinoethyl)-2-ethylpyrazolo[1,5-a]benzimidazole hydrochloride of the formula (I):

Invention provides synthesis of a novel compound possessing valuable biological properties.

EFFECT: valuable medicinal property of compound.

6 tbl, 1 ex

Description

The invention relates to a new derivative in the series of pyrazolo- [1,5-a] benzimidazole, namely to 3-methoxycarbonyl-4- (2-piperidinoethyl) -2-ethylpyrazolo [1,5-a] benzimidazole hydrochloride of the formula I:

possessing local anesthetic effect with superficial (terminal), infiltration and conduction anesthesia.

An effective drug widely used as a local anesthetic for infiltration, conduction and terminal methods of pain relief is lidocaine (A.I. Levshankov, A.L. Kostyuchenko, E.T. Rostomashvili and others. Caudal epidural anesthesia for operations on the lower extremities in traumatology and orthopedics. Anesthesiol. and resuscitation., 1992, No. 5-6, p. 15-17; MD Mashkovsky, Medicines, 15th ed., revised and supplemented, M .: Medicine, 1998, part 1, p. 371-382).

Lidocaine is usually well tolerated, but it can sometimes cause collapse, anaphylactic reaction, changes in the content of cytoplasmic proteins, the surface and the shape of red blood cells (G.I. Karitsky, A.N. Kuybida, etc. Elimination from anaphylactic shock with clinical death after administration of lidocaine. Vestnik Khirin named after II Grekov, 1987, No. 4, p. 131; N.Kh. Vakhidov, I.A. Abdullaeva, and TR Muradov, Successful resuscitation of patients after an adverse toxic reaction to lidocaine. Journal of Ear, Nose, and Throat Diseases, 1989, No. 6, pp. 60-61; E. Nidhiguchi et al. Factors of the share c hange of human erythrocytes induced with lidocaine. Cell. struct. and Funct., 1989, Vol.14, No. p.569-577; M.D. Mashkovsky, 1998).

In the pyrazolo [1,5-a] benzimidazole series, compounds having a local anesthetic effect are not known.

The closest in structure among the derivatives of pyrazolo [1,5-a] benzimidazole are 3-alkoxycarbonyl-2,4-dimethylpyrazolo [1,5-a] benzimidazoles (Kuzmenko T.A., Kuzmenko V.V., Simonov AM 3-α-Halogenocarbonyl derivatives of pyrazolo [1,5-a] benzimidazole and their transformations. CGS, 1988, No. 1, pp. 43-48). However, no compounds exhibiting biological activity were found among them.

The technical result of the invention is a new compound in the series of pyrazolo [1,5-a] benzimidazole, exhibiting a local anesthetic effect unknown for this class of substances, more effective than the action of a known local anesthetic.

The technical result is achieved by compound I, the synthesis of which consists in the saponification of the acyl group in 3-propionyl-2-ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole under the action of conc. HCl, further acylation of the obtained 2-ethyl-4-piperidinoethylpyrazolo [1,5-a] benzimidazole with trichloroacetic acid chloride while heating in xylene to 3-trichloroacetyl substituted and subsequent haloform cleavage of the latter under the influence of sodium methylate. The synthesized 3-methoxycarbonyl-2-ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole was converted to the desired water-soluble hydrochloride I by conventional methods.

The following are the synthesis methods of the proposed compounds.

Example. 3-Methoxycarbonyl-2-ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole hydrochloride.

Stage 1. 2-Ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole (III). A solution of 7.8 g (0.02 mol) of 3-propionyl-2-ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole (II) hydrochloride in 100 ml conc. HCl is boiled for 6 hours. It is cooled, made basic with a 22% ammonia solution, and the separated oil is extracted with CHCl ₃ (3 × 30 ml). The extract was evaporated to dryness and, after drying in a vacuum desiccator over P ₂ O _5, base III as a thick oil was used in the next step without further purification. Yield 5.2 g (88%).

Stage 2. Hydrochloride of 2-ethyl-3-trichloroacetyl-4- (2-piperidinoethyl) -pyrazolo [1,5-a] benzimidazole (IV). In a solution of 2.96 g (0.01 mol) of compound III in 50 ml of dry xylene, heated to 70-80 ° C, 1.1 ml (0.01 mol) of freshly distilled trichloroacetic acid chloride are added with stirring for 10 minutes. Then the reaction mixture is heated to boiling and boiled for 2 hours. After cooling, the precipitate of compound IV is filtered off, washed with acetone. Yield 4.2 g (87%). Pale yellow needles with so pl. 253-255 ° C (decomp., From butanol), insoluble in water.

Found,%: C 50.0; H 5.3; Cl 30.0; N, 12.0.

C ₂₀ H ₂₃ Cl ₃ N ₄ O · HCl.

Calculated,%: C 50.2; H 5.0; Cl 29.7; N, 11.7.

IR spectrum (petroleum jelly), cm ^-1 : 1640 (С = O), 2380-2600 (N ⁺ Н).

Step 3. 3-Methoxycarbonyl-2-ethyl-4- (2-piperidinoethyl) pyrazolo [1,5-a] benzimidazole hydrochloride. 4.78 g (0.01 mol) of IV hydrochloride are added in small portions to a solution of sodium methylate obtained from 0.6 g of sodium and 20 ml of methyl alcohol. After the violent reaction ceases, the mixture is boiled for 3-5 minutes. The alcohol is evaporated to dryness, the residue is chromatographed on an Al ₂ O ₃ column, eluting with chloroform. The eluate is evaporated to dryness, the remaining thick oil after drying in a vacuum desiccator over P ₂ O _{5 is} dissolved in dry acetone and acidified with a solution of HCl in ether. The precipitate of hydrochloride is separated, washed with dry ether. Yield 3.7 g (94%). Colorless crystals with so pl. 222-223 ° C (from alcohol).

Found,%: C 61.3; H 6.7; Cl 8.8; N, 14.0.

C ₂₀ H ₂₆ N ₄ O ₂ · HCl.

Calculated,%: C 61.5; H 6.9; Cl 9.1; N, 14.3.

IR (petroleum jelly), cm ^-1 : 1675 (C = O), 2380-2700 (N ⁺ H).

The screening studies are based on guidelines for studying the local anesthetic activity of pharmacological substances (Ignatov Yu.D., Chervyakova I.V., Vasiliev Yu.N., Galenko-Yaroshevsky A.P., Zhukov V.N. Guidelines for the study of local anesthetic activity of pharmacological substances // In the book: Manual on the experimental (preclinical) study of new pharmacological substances / Under the General editorship of Corresponding Member of RAMS, Prof. R.U. Khabriev. - 2nd ed., revised and add. - M .: OJSC "Publishing house" Medicine ", 2005. - S.364-392).

The experiments were carried out in accordance with Article 11 of the Helsinki Declaration of the World Medical Association (1964), "International Recommendations for Biomedical Research Using Animals" (1985) and the Laboratory Practice Rules in the Russian Federation (Order of the Ministry of Health of the Russian Federation No. 267 of 19.06. 2003).

Surface (terminal) anesthesia was investigated in experiments on the cornea of the rabbits eyes using the Rainier-Valet method (Pryanishnikova N.T., Sharov N.A. Trimekain. Pharmacology and clinical use. - L .: Medicine, 1967. - 239 p .; Yu.D. Ignatov et al., 2005), while simultaneously studying the possible irritating effect of Setnicar (Setnicar I. Tolerance indices of some phenoxyethylamino derivatives with local anesthetic properties // Arzneim. - Forsch. - 1966. - Bd. 16, No. 5. - S.623).

Infiltration anesthesia was investigated in experiments on guinea pigs (Bülbring E., Wajda J. Biological comparison of local anaesthetica // J. pharmacol. And exp.therap. - 1945. - Vol.85, No. 1. - P.78-84) and rabbits (Pryanishnikova N.T., Sharov N.A. Trimekain. Pharmacology and clinical use. - L .: Medicine, 1967. - 239 p.).

Conduction anesthesia was studied in experiments on the sciatic nerve of rabbits (N.T. Pryanishnikova, N.A. Sharov, 1967).

Acute toxicity was investigated [the average lethal (lethal) dose was determined - LD ₅₀ ] in experiments on mice with subcutaneous administration (Prozorovsky VB Use of the least squares method for probit analysis of mortality curves // Farmakol. And Toxicol. - 1962. - T .25, No. 1. - S.115-119).

Statistical processing of data recorded in graduated form was carried out according to M.L. Belenky (Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. - L., 1963. - 152 p.) And using N.N. tables Samoilova (Samoilov NN Tables of mean error and confidence interval of the arithmetic mean of the variational series. - Tomsk. 1970. - 63 p.).

Accounting for the results of studies expressed in an alternative form, the determination of LD ₅₀ , EC ₅₀ , the boundaries of the confidence interval and therapeutic index, or the breadth of the therapeutic effect (LD ₅₀ / EC ₅₀ ) was carried out according to the methods described by B. B. Prozorovsky (1962) and M.L. Belenky (1963).

It was established that under conditions of surface anesthesia in experiments on the cornea of rabbits' eyes, the minimum and maximum anesthetic concentrations for compound I are 0.125 and 2.0%, and for lidocaine, 1.0 and 5.0%, respectively. The Rainier indices expressing the strength of the anesthetic effect in the tested concentrations for I in 0.125, 0.25, 0.5, 1 and 2% solutions are 122.5, 369.4, 535.0, 690.0 and 848.6, for lidocaine in 1, 2 and 5% solutions - 297.9, 354.8 and 676.9, respectively. Valet indices for salt I relative to lidocaine, taken for comparison in 1 and 2% solutions, are 2.5 and 2.8; equivalent anesthetic concentrations were 0.4 and 0.72%, respectively (Table 1).

Substance I, like lidocaine, in the studied solutions does not irritate the conjunctiva of the eye.

In terms of local anesthetic activity - when comparing EC ₅₀ expressed in mm and therapeutic indices - compound I is 8.38 times more significant, respectively, and 6.08 times has a wider therapeutic effect than lidocaine (Table 2).

In infiltration anesthesia in experiments on guinea pigs, the minimum analgesic concentration for salt I is 0.0156%, for lidocaine - 0.0625%. Compound analgesic effect (100% anesthesia for 30 minutes) causes compound I in 0.125% solution, while lidocaine in 0.5% solution (Table 3).

A comparison of EC ₅₀ , expressed in mm, showed (Table 4) that I is 3.94 times more active than lidocaine. Moreover, in terms of the breadth of its therapeutic effect, it is 2.84 times greater than lidocaine.

It was established in experiments on rabbits (Table 5) that under the influence of 0.5% solution I, the analgesic effect occurs 1.52 times faster than when using lidocaine. According to the duration of complete anesthesia and the total duration of anesthesia, salt I is 3.38 and 3.04 times higher than lidocaine, respectively. The depth of the anesthetic effect of I and lidocaine are comparable.

In conditions of conduction anesthesia in experiments on the sciatic nerve of rabbits, it was revealed (Table 6) that when using a 0.5% solution of hydrochloride I, the analgesic effect occurs 1.33 times faster than when using lidocaine in a similar concentration. The total duration of anesthesia I is 2.45 times greater than lidocaine. It is important to note that I induces a complete analgesic effect within 262.0 minutes, while lidocaine does not show complete anesthesia: the depth of analgesia in the first case is 100.0%, and in the second 64.0%.

Thus, compound I is significantly superior to lidocaine in activity and breadth of therapeutic action. Based on it, it is possible to create a local anesthetic drug intended, like lidocaine, for surface, infiltration and conduction anesthesia.

Claims (1)

3-Methoxycarbonyl-4- (2-piperidinoethyl) -2-ethylpyrazolo [1,5-a] benzimidazole hydrochloride of formula I