RU2160263C1 - 1-(2-TERT-BUTYLAMINOETHYL)-2-TERT-BUTLAMIDAZO (1,2-a)BENZIMIDAZOLE DIHYDROCHLORIDE HAVING LOCALLY ANESTHETIC ACTIVITY - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: described is 1-(2-tert-butylaminoethyl)-2-tert-butylimidazo(1,2- a)benzimidazol dehydrochloride of formula:

Description

обладающему местноанестезирующим действием при терминальной, инфильтрационной и проводниковой анестезии.The invention relates to a new derivative in the series 1H-imidazo [1,2-a] benzimidazole, namely to a water-soluble dihydrochloride of 1- (2-tert-butylaminoethyl) -2-tert-butylimidazole [1,2-a] benzimidazole of the formula I :

possessing local anesthetic effect in terminal, infiltration and conduction anesthesia.

 The drug novocaine, which is mainly used for infiltration and conduction anesthesia and does not find application for surface analgesia, has found widespread use in medical practice as a local anesthetic (L.A. Melekhov, S.E. Mitin. Novocaine blockade of the round ligament of the liver in the treatment of certain diseases organs of the abdominal cavity.Vestn. chir. named after I.I. Grekov, 1988, v. 141, N 10, p. 134; MD Mashkovsky. Medicines, 15th edition, revised and revised, M ., Medicine, 1998, part 1, pp. 371 - 382). In addition, the doses of novocaine used for pain relief are quite high.

 A new generation of local anesthetics is lidocaine, which is widely used in infiltration, conduction, spinal and, sometimes, terminal methods of analgesia (A.I. Levshankov, A.L. Kostyuchenko, E.T. Rostomashvili and others. Caudal epidural anesthesia during operations on the lower extremities in traumatology and orthopedics. Anestesiol. and resuscitation., 1992, N 5-6, p. 15-17; M.D. Mashkovsky, 1998). Lidocaine is usually well tolerated, but sometimes it can cause a 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 Khirim named after I.I. Grekov, 1987, No. 4, p. 131; N.Kh. Vakhidov, I.A. Abdullaeva, and T.R. Muradov. Successful resuscitation of patients after an adverse toxic reaction to the administration of lidocaine. Journal of Ear, Nose, and Throat Diseases, 1989, No. 6, pp. 60-61; E. Nishiguchi et al. Factors of the shape cha nge of human erythrocytes induced with lidocaine. Cell. struct, and Funct, 1989, Vol. 14, No. 5, p. 569-577; M.D. Mashkovsky, 1998).

 In the series of 1H-substituted imidazo [1,2-a] benzimidazole, compounds having a local analgesic effect are not known.

 The closest in structure to imidazo [1,2-a] benzimidazole derivatives are 1-dialkylaminoalkyl-2-aryl-imidazo [1,2-a] benzimidazoles dihydrochlorides exhibiting calcium antagonistic properties (V.A. Anisimova, A. A Spasov, MV Levchenko, EA Aleksandrova 2-Aryl-1-dialkylaminoalkylimidazo [1,2-a] benzimidazoles and their antagonism to calcium ions. Pharmaceutical Chemistry Journal, 1995, 10, p. 17- 19).

 The technical result of the invention is a new compound in the series 1H-imidazo [1,2-a] benzimidazole, which exhibits an unknown local anesthetic effect for this class, more effective than known local anesthetic preparations.

 The technical result is achieved by compound I, the synthesis of which consists in the interaction of 2- (2-hydroxyethylamino) benzimidazole with brompinacoline, cyclization of the resulting 2- (2-hydroxyethylamino) -1-pivaloylmethylbenzimidazole hydrobromide to 1- (2-hydroxyethyl) -2-tert -butylimidazo [1,2-a] benzimidazole, followed by substitution of the hydroxy group with a chlorine atom and the latter with a tert-butyl amino group, after which the resulting base of compound I is converted to a water-soluble dihydrochloride by conventional methods.

Ниже приведена методика синтеза предполагаемого соединения.

The following is the synthesis method of the proposed compound.

 Example. 1- (2-Tert-butylaminoethyl) -2-tert-butylimidazo [1,2-a] benzimidazole dihydrochloride (I).

A mixture of 1.77 g (10 mmol) of 2- (2-hydroxyethylamino) benzimidazole (A.M. Simonov, V. N. Komissarov. Chemistry of heterocycle compounds., 1975, No. 6, pp. 826 - 828) and 1, 35 ml (10 mmol) of freshly distilled brompinacoline in 20 ml of isopropyl alcohol is boiled for 4-5 hours and left at 5 ^° C. The next day, the precipitated precipitate of 2- (2-hydroxyethylamino) -1-pivaloylmethylbenzimidazole hydrobromide is filtered off, washed thoroughly with acetone. The salt yield of 3.23 g (90.7%). White water-soluble flakes with so pl. 212-213 ^o C (decomposition, from ethanol).

Found,%: C 50.5; H 6.5; Br 22.0; N, 11.7. C ₁₅ H ₂₂ BrN ₃ O ₂
Calculated,%: C 50.6; H 6.2; Br 22.4; N, 11.8.

IR (vaseline oil), cm ^-1 : 1730 (C = O), 1670 (C = N ⁺ H), 3145, 3265 (NH, OH).

PMR spectrum of base (CDCl ₃ ), δ, ppm: 0.87 (1H, broad s, OH), 1.16 (9H, s, C (CH ₃ ) ₃ ), 1.2 (1H, s , NH), 3.48 (2H, t, CH ₂ ), 3.74 (2H, t, CH ₂ ), 4.6 (2H, s, CH ₂ CO), 6.66 - 6.75 (1H , m), 6.93 - 7.02 (2H, m) and (7.2 - 7.38 (1H, m, aromatic protons).

A mixture of 2.85 g (8 mmol) of the obtained 1-pivaloylmethyl substituted hydrobromide and 2 ml (≈ 32 mmol) of monoethanolamine is boiled for 4-5 hours. After cooling, the reaction mass was repeatedly treated with cold water to remove excess ethanolamine, and then the remaining oily lump was left under water in the refrigerator. The next day, the precipitate formed after crystallization of the lump is filtered off, washed with water and dried at 100 - 105 ^o C. The yield of 1- (2-hydroxyethyl) -2-tert-butyl-imidazo [1,2-a] benzimidazole 1.93 g (93.7%). Large white crystals with so pl. 157 - 158 ^o C (from ethyl acetate).

Found,%: C 70.2; H 7.6; N, 16.3. C ₁₅ H ₁₉ N ₃ O
Calculated,%: C 70.3; H 7.5; N, 16.1.

IR spectrum (liquid paraffin), cm ^-1 : 1640 (C = N), 3065 - 3205 (acocyan. OH band).

PMR spectrum (CDCl ₃ ), δ, ppm: 1.36 (9H, s, C (CH3) ₃ ), 4.10 (2H, t, (CH ₃ , 4.25 (2H, t, CH ₂ ), 6.23 (1H, br s, OH), 6.82 (1H, C, 3-H), 6.96 - 7.56 (4H, m, 5-, 6-, 7-, 8-H).

To a suspension of 1.8 g (7 mmol) of 1-hydroxyethyl substituted imidazo [1,2-a] benzimidazole in 20 ml of dry chloroform, 1 ml (≈20% excess) of freshly distilled thionyl chloride is added dropwise with vigorous stirring and the mixture is boiled. 2 hours, the solvent is evaporated to dryness, and the residue is triturated with petroleum ether until complete crystallization. The precipitate is filtered off, washed with petroleum ether. The yield of 1- (2-chloroethyl) -2-tert-butylimidazo [1,2-a] benzimidazole hydrochloride was 2.17 g (quantitative). White crystals with so pl. 200 -201 ^o C (decomposition, from acetone with ether).

Found,%: C 57.9; H 6.0; Cl 22.5; N, 13.6. C ₁₅ H ₁₈ ClN ₃ • HCl
Calculated,%: C 57.7; H 6.1; Cl 22.7; N 13.5.

IR spectrum (liquid paraffin), cm ^-1 : 1520, 1620 (C = C), 1650. (C = N), 2300-2800 (= N ⁺ H).

A mixture of 2.17 g (7 mmol) of 1-chloroethyl substituted imidazo [1,2-a] benzimidazole hydrochloride and 3 ml (≈28 mmol) of tert-butylamine in a sealed ampoule in an autoclave is heated at 145-150 ^° C (bath temperature) 5 -6 o'clock. The reaction mass is cooled, poured into 30 ml of water, the resulting oil is extracted with chloroform (3 x 10 ml), washed with 30 ml of water, the solvent is evaporated to a small volume, the remaining solution is passed through a layer of alumina (d-15, h-1.5 cm , eluent is chloroform). After evaporation of chloroform from the eluate, the residue was dried in a vacuum desiccator over KOH and 1.74 g (79.6%) were obtained. 1- (2-H-tert-butylaminoethyl) -2-tert-butylimidazo [1,2-a] benzimidazole as a pale yellow oil, which is dissolved in 20 ml of dry acetone and the solution is acidified with a solution of HCl in isopropyl alcohol to pH 1 The precipitate is filtered off, washed with acetone and dried at 105 ^° C. 1.76 g (82%) of compound I are obtained. Snow-white crystals (from a small amount of acetonitrile) with mp. 265 - 266 ^o C (decomposition), very hygroscopic.

Found,%: C 59.3; H 8.0; Cl 18.2; N, 14.6. C ₁₉ H ₂₈ N ₄ • 2HCl
Calculated,%: C 59.2; H 7.9; Cl 18.4; N, 14.5.

IR spectrum (liquid paraffin), cm ^-1 : 1660 (C = N ⁺ <), 2500 - 2730, 3200 - 3470 (NH, broad bands).

PMR spectrum (DMSO-d ₆ ) ppm: 1.33 (9H, s, C (CH _{3 3} ), 1.46 (9H, s, C (CH ₃ ) ₃ ), 3.6 (2H, t, CH ₂ ), 4.8 (2H, t, CH ₂ ), 7.4 - 8.05 (5H, m, aromatic H), 9.7 (2H, broad s, 2> N ⁺ H )

 Below are the methods and results of a study of the local anesthetic properties of compound I.

Surface (terminal) anesthesia was examined on the cornea of the rabbits' eyes using the Rainier-Valet method (N.T. Pryanishnikova, N.A. Sharov. Trimekain. Pharmacology and clinical use. L .: Medicine, 1967, 239 pp.) in parallel, they studied the possible irritating effect of Sethicar (Sethicar I. Tolerance induces of some β phenoxyaethylammo derivatives with local anesthetic properties. Arzneim. - Forsch. 1966, Vol. 16, No. 5, p. 623.)
It was found that under conditions of surface anesthesia the minimum local anesthetic concentration for compound I is 0.125%, while for lidocaine it is 0.5%. However, it is noteworthy that the Rainier indices of the proposed compound in 0.5, 1 and 2% solutions are 534.0, 689.8 and 849.2, while for lidocaine - 264.7, 429, 2 and 532.0, respectively (Table 1).

 Substance I, like lidocaine, does not irritate the conjunctival membrane in the studied solutions.

In terms of local anesthetic activity - when comparing average effective concentrations (EC ₅₀ ), expressed in mM / L, and therapeutic indices (LD ₅₀ / EC ₅₀ ), compound I is 5.43 times more significant and 2.85 times more broad than therapeutic action (SHD) than lidocaine (Table 2).

 Infiltration anesthesia was investigated in experiments on guinea pigs (Bulbring E., Wajda J. Biological comparison of local anaesthetica. J. Pharmacol. And exp. Therap. 1945, Vol. 85, No. 1, p. 78-84) and rabbits (H .T. Pryanishnikova, N.A. Sharov, 1967).

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

A comparison of the EU ₅₀ , expressed in mmol / l, showed (Table 4) that compound I was 5.70 and 9.73 times more active than lidocaine and novocaine, respectively. At the same time, according to SHD, it also significantly exceeds the reference drugs: lidocaine - 2.96 times, novocaine - 3.27 times.

 Under conditions of infiltration anesthesia in experiments on rabbits, it was established (Table 5) that in a 0.25% solution of compound I, 1.84, 1.32, and 3.93 times the time of anesthesia, its depth and total duration, therefore, superior to lidocaine. It should be noted that it induces complete anesthesia for 196.0 minutes, while under the influence of lidocaine, complete analgesia is not observed. In a 0.5% solution, the proposed compound in terms of the time of anesthesia, its full and total duration is 1.73, 4.0 and 3.52 times, respectively, more significant than the comparison drug, but not statistically by the depth of anesthesia different from lidocaine.

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

 When conducting anesthesia in experiments on the sciatic nerve of rabbits, it was shown (Table 6) that in a 0.5% solution of compound I, in terms of the time of anesthesia, the depth and the total duration of anesthesia, it exceeds lidocaine by 1.60, 1.47 and 2, 57 times, respectively. It should be noted that it induces complete anesthesia within 297.0 minutes, lidocaine does not show such an effect. In a 0.75% solution of I, the onset time, the duration of the total and total duration of anesthesia are 2.10, 6.38 and 2.96 times, respectively, superior to the reference drug. Compound I and lidocaine are comparable in depth of anesthesia.

Acute toxicity was studied [the average lethal (lethal) dose was determined - LD ₅₀ ] in experiments on mice with intraperitoneal administration (Table 2).

 Thus, in terms of local anesthetic activity (with superficial, infiltration and conduction methods of analgesia) and the breadth of therapeutic action, it significantly exceeds lidocaine and novocaine.

 On the basis of compound I, it seems possible to create a local anesthetic drug intended, like lidocaine, for surface, infiltration and conduction anesthesia.

Claims (1)

1- (2-tert-Butylaminoethyl) 2-tert-butylimidazo [1,2-a] benzimidazole dihydrochloride of formula I

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