The dihydrochloride of 2-tertbutyl-1-(3-diethylaminopropyl)imidazo [1, 2-a]-benzimidazole with local anesthetic and antiarrhythmic action


(57) Abstract:

The dihydrochloride of 2-tertbutyl-1-(3-diethylaminopropyl)imidazo-[1,2-a] -benzimidazole of formula I has mestnoanesteziruushim and antiarrhythmic action and can be used as mestnoanesteziruyuschee and antiarrhythmic drugs. table 4.

The invention relates to a new derived in a series of 1H - imidazo[1,2-a]benzimidazole, namely water-soluble dihydrochloride 2-tert-butyl-1-(3-diethylaminopropyl)imidazo[1,2 - a]benzimidazole of formula I:

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with local anesthetic and antiarrhythmic action.

Wide application in medical practice as a local anesthetic found the drug novocaine, which is mainly used for infiltration and block anesthesia and not used for surface anesthesia (L. A. Melekhov, S. E. Mitin. Procaine blockade of the round ligament of the liver in the treatment of some diseases of abdominal cavity organs. Vestn. hir. them. I. I. Grekova, 1988, I. 141, No. 10, S. 134; M. D. Mashkovsky. Drugs, 15th edition, revised and enlarged more., M.: Medicine, 1998, H. 1, S. 371 - 382). In addition, the dose of novocaine used for pain relief, rather you shall e used in infiltration, conductor, spinal and, sometimes, terminal methods of pain relief (A. I. Levchenkov, A. L. Kostyuchenko, E. T. Rostomashvili and other Caudal epidural anesthesia during operations on the lower extremities in traumatology and orthopedics. Anestesiol. and Reanimator. , 1992, N 5-6, S. 15-17; M. D. Mashkovsky, 1998). Lidocaine is usually well tolerated, but may sometimes cause the collapse, anaphylactic reaction, changes in the contents of cytoplasmic proteins, the surface and shape of erythrocytes (, And. Kurizki, A. N. The Kuybida, etc. Withdrawal from anaphylactic shock from clinical death after injection of lidocaine. Vestn., hir. them. I. I. Grekova, 1987, N 4, 131 S.; N. X.Vahidov, I. A. Abdullaev, M. P. Muradov. Successful resuscitation of patients after adverse toxic reactions to lidocaine. Journal of the ear, nose and throat diseases, 1989, No. 6, S. 60-61; E. Nishiguchi et al. Factors of the shape change of human erythrocytes induced with lidocaine. Cell. struct & Funct., 1989, Vol. 14, N 5, p. 569-577; M. D. Mashkovsky, 1998).

In a series of 1H-substituted, imidazo[1,2-a]benzimidazole no known connection with mestnoanesteziruushim action.

The most similar structure among the derivatives of imidazo[1,2-a]benzimidazole are dihydrochloride 1-dialkylaminoalkyl-2-aryl-imidazo[1,2-a]benzoni the ova. 2-Aryl-1-dialkylaminoalkyl[1,2-a]benzimidazole and their antagonism towards calcium ions. Chemical and pharmaceutical journal, 1995, No. 10, S. 17-19.

The technical result of the invention is a new connection in a series of 1H-imidazo[1,2-a] benzimidazole, showing unknown for this class local anesthetic action that is more effective than known mestnoanesteziruyuschie drugs, and expanding the group of compounds with anti-arrhythmic activity.

The technical result is achieved by connection I, which is synthesized from 2-tert-butyl-1-(3-hydroxypropyl)imidazo[1,2-a] benzimidazole obtained by the cyclization of 1-pivaloyloxy-2-(3-hydroxypropylamino)benzimidazole, sequential replacement of the group, HE is on the chlorine atom, and then the last diethylamin. The resulting base was transferred to the dihydrochloride I by conventional methods:

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Below is a synthesis technique proposed connection.

Example. The dihydrochloride of 2-tert-butyl-1-(3-diethylaminopropyl)-imidazo[1,2-a] benzimidazole (I). A mixture of 5 g (25 mmol) of benzimidazole-2-sulfonic acids and 5.7 ml (75 mmol) of 3-aminopropanol-1 heated at 140-150oC (bath temperature) for 2 hours. Then the reaction mass is then cooled to 90oC, in the mouth of the Praz oily sludge, and leave overnight in the refrigerator at 3-5oC. the Precipitate of 2-(3-hydroxypropylamino)benzimidazole is filtered off, washed on the filter with cold water (3 x 10 ml), dried at 100oC. Release 4.1 and 4.5 g (85,4 - 94,5%). White crystals with so pl. 139-140oC (from acetonitrile).

Found,%: C and 62.6; H 6,9; N 22,3


Calculated,%: C to 62.8; H 6,9; N 22,0

IR-spectrum (Wesel. oil), cm-1: 730 (aroma.C-H), 1050, 1250 (C-O, OH), 1500, 1580, 1600 (C=C), 1650 (C=N), 3070-3240 (wide band of OH, NH).

Range PMR (DMSO-d6), , M. D.: 2,70 (2H, q, CH2), to 3.35 (2H, CH2), 3,47 (2H, t, CH2), 4,40-5,20 (1H, Shir. band, OH), of 6.52 (1H, t, NH), 6,83 (2H, K, arene. CH), 7,07-to 7.09 (2H, K, arene. CH), 10,00-11,40 (1H, Shir. strip, NH).

Equimolar amount of 2-(3-hydroxypropylamino)benzimidazole (1,91 g, 10 mmol) and freshly bromopinacolone (1.35 ml, 10 mmol) in isopropyl alcohol (15 ml) was boiled for 4-5 hours. After cooling the reaction mixture the precipitate is filtered off, washed with acetone and obtain 3.13 g (84,5%) of the hydrobromide 1-pivaloyloxy-2- (3-hydroxypropylamino)benzimidazole in the form of white crystals with so pl. 220-221oC (decomp., from 2-propanol).

Found,%: C 51,9; H 6,7; Br 21,6; N 11,2


Calculated,%: C 51,9; H 6,5; Br 21,6; N 11,3

the project (CDCl3), , M. D.: of 1.33 (9H, s, C(CH3)3), of 1.80 (2H, q, CH2), 3,0-of 3.60 (2H, Shir. strip, NH, OH), 3,70 (4H, K, CH2N, CH2O) 4,80 (2H, s, CH2CO) and 6.9 (1H, d), 7,0-7,14 (2H, dt), the 7.43 (1H, d, 4-, 5-, 6-, 7-H).

Boil the obtained salt (10 mmol) in 8 ml of monoethanolamine 6 hours, cool, add 20 ml of water. The extracted oil is washed several times with water, leaking water by decantation, after which clean tricyclic basis chromatography on alumina (eluent - chloroform) and then recrystallized from acetonitrile. Output 1-hydroxypropyl-2-tert-butylimido[1,2-a] benzimidazole 83,7%. White or slightly yellow needles with so pl. 128-129oC.

Found, %: C to 70.7; H 7,6; N 15,3


Calculated, %: C 70,8; H 7,8; N 15,5

IR-spectrum (VAZ.oil), cm-1: 1640 (C=N), 3140 (wide band associer. the OH group).

Range PMR (CDCl3), , M. D.: USD 1.43 (9H, s, C(CH3)3), 2,04 (2H, q, CH2), of 3.57 (2H, t, CH2O), 4,42 (2H, t, NCH2), 6,27 (1H, user.s, OH), of 6.96 (1H, s, 3-H), 7,06-7,28 (2H, m, 6-, 7-H), of 7.48-to 7.64 (2H, DD, 5-, 8-H).

To a suspension of 2.7 g (10 mmol) 1-hydroxypropylamino imidazo[1,2-a] benzimidazole in 25 ml of dry chloroform are added dropwise 0.9 ml (25% excess) chloride tiomila. After 1-hour incubation at comum ether and the precipitate of the hydrochloride of 1-(3-chlorpropyl)-2-tert-butyl-imidazo[1,2-a]benzimidazole is filtered off, washed with petroleum ether. The yield of 3.3 g (98%). Recrystallized from acetonitrile. So pl. 191-192oC.

Found,%: C 56,0; H 6,9; Cl 20,4; N 12,3


Calculated %: C to 55.8; H, 6.7; in Cl 20,6; N 12,2

IR-spectrum (VAZ. oil), cm-11650 (C=N+<), 2400-2700, 3070, 3250, (Shir. band) (=N+H, H2O).

Range PMR base (CDCl3), , M. D.: of 1.33 (9H, s, C(CH3)3), 2,47 (2H, q, CH2), 3,68 (2H, t, CH2), to 4.23 (2H, t, CH2), to 6.75 (1H, s, 3-H), the 6.9 to 7.5 (4H, m, 5-, 6-,7-,8-H).

A mixture of 1.63 g (5 mmol) of the obtained hydrochloride 1 - chloropropyl-substituted and 5 ml of freshly diethylamine heated in an autoclave in a sealed ampoule at 140 - 150oC (bath temperature) for 4-5 hours. The reaction mass after opening the ampoule is treated with 30 ml of water and extracted with separated oil chloroform (3 x 8 ml). The chloroform extract is washed with water (15 -20 ml x 3), evaporated to small volume (~5 - 7 ml) and passed through the layer (4 cm x 3 cm) of alumina (eluent - chloroform). After evaporation of the solvent from the eluate 1-(3-diethylaminopropyl)-2-tert-butylimido[1,2-a]benzimidazole remains in the form of a slightly yellowish oil. It is dissolved in dry acetone, the solution is acidified with a solution of HCl in isopropyl suchaut 1.85 g (to 85.2%) of the dihydrochloride of I in the form of hygroscopic crystals with so pl. 220-221oC (decomposition).

Found, %: C a 55.4; H 8,5; Cl 16,6; N 13,0


Calculated,%: C 55,2; H 8,3; Cl 16,3; N 12,9

IR-spectrum (VAZ. oil), cm-1: 1490, 1610 (C=C), 1650 (C=N+H), 2450 - 2590, 3025, 3400, 3490 (NH, H2).

Range PMR (DMSO-d6+ CCl4), , M. D.: a 1.25 (6H, t, 2CH3), of 1.46 (9H, s, C(CH3)3), is 2.30 (2H, q, CH2), 3,10 (6H, m, CH2N(CH2)2), of 4.45 (2H, t, NCH2), 7,40 to 8.0 (5H, m, fragrance, protons), the 10.40 (2H, user.with that 2N+H).

Below are the methods and results of studies of pharmacological activity and acute toxicity of compounds I.

Infiltration anesthesia was investigated in experiments on Guinea pigs (Bulbring E. , J. Wajda Biological comparison of local anaesthetica. J. Pharmacol. and exp. therap. , 1945, vol. 85, No. 1, p. 78 - 84) and rabbits (N. Pryanishnikov. So , Balls N.A. Trimekain. Pharmacology and clinical use. HP: Medicine, 1967, 239 S.).

When infiltration anesthesia in experiments on Guinea pigs minimum anesthetic concentration for compound I is 0,0156% lidocaine and novocaine - 0,0625%. Full analgesic effect (100% anesthesia for 30 min) Sol I causes of 0.0125% solution, whereas lidocaine and novocaine - 0.5% solution (PL. 1).

From what I 3,39 and 5.39 times more active than lidocaine and novocaine, respectively. When this therapeutic index (LD50/EU50) hydrochloride I also exceeds the reference drugs: lidocaine - 3,05, novocaine - 1.13 times.

In terms of infiltration anesthesia in experiments on rabbits installed (PL. 3) that the 0.25% solution I at the time of onset of anesthesia, the depth and the total duration of 1.95, 1,36 and 2.17-fold, respectively, than lidocaine. It should be noted that the salt I induces full anesthesia during 77,5 min, while under the influence of lidocaine full anesthesia is not observed. 0.5% solution of salt I on the time of onset of analgesia and its depth is not statistically different from lidocaine, and complete and total duration of analgesia in 1,79 and 3.03 times, respectively, significantly more than the comparator drug.

In terms of conduction anesthesia in experiments on the sciatic nerve of rabbits (N.T. Pryanishnikova, N. A. Balls, 1967) is shown (PL. 4), in a 0.5% solution of compound I on the time of onset of anesthesia is not significantly different from lidocaine, whereas depth and the total duration of analgesia is superior to the last 1.42 and 1.20 times, respectively. It should be noted that I induces the floor of the population and the depth of anesthesia is not statistically different from lidocaine and duration of complete and total duration of anesthesia in 1.50 and 1.55 times, respectively, exceeds the reference drug.

Irritant effect was investigated in experiments on the skin of rats (Ignatov Y. D. , Vasiliev, Y. N., Beetles C. N. and other Methodological guidelines for experimental study of local anesthetic funds. M, the USSR Ministry of health, 1990, 49 C. ) Compound I in 0.5, 1.0, and 2.0% of the solutions are irritating and damaging effect on the skin of rats.

Antiarrhythmic effect was studied in experiments on rats in conditions of aconitine (A. I. Bryskin, I. K. Sokolov, E. E. white, N. G.Glazov. About antiarrhythmic properties of thyrocalcitonin. Pharmacol. and toxicol., 1974, T. 37, N 3, S. 303 - 306) and adrenaline (Century A. Shatalov, N. In.Dmitrieva. Multivariate description of the experimental arrhythmias as a measure of specific antiarrhythmic effects of substances. Chem.-Pharm. journal, 1986, T. 20, N 3, S. 322 - 326) models of cardiac arrhythmias.

It is established, that connection I can fix heart rhythm disturbances, induced by aconitine, and to be proactive (preventive) antiarrhythmic action on cardiac arrhythmias induced by epinephrine. On antiarrhythmic is-a]benzimidazole system [A. M. Simonov, G. C. Kovalev, V. A. Anisimov, A. A. Spasov and other Antiarrhythmic agent. RF patent N 2068261, A 61 K 31/415 (1996)], which is recommended by Farmkomiteta MOH for use in medical practice as an antiarrhythmic agent (Protocol No. 7 of the meeting of farmkomiteta MZ the Russian Federation of 25 June 1998).

Acute toxicity (LD50) was investigated in experiments on mice with intraperitoneal injection (PL. 2).

Thus, it is shown that in experiments on Guinea pigs and rabbits connection I on the local anesthetic activity of infiltration and conduction methods of anesthesia and breadth of therapeutic action than procaine and lidocaine. When cardiac arrhythmias in rats induced by aconitine, and in conditions of adrenaline arrhythmia connection I more actively than lidocaine and comparable to the activity of immidatly. Based on this connection possible creation mestoobitaniyakh (for infiltration and block anesthesia) and antiarrhythmic drugs.

The dihydrochloride of 2-tertbutyl-1-(3-diethylaminopropyl)imidazo[1,2-a] -benzimidazole of the formula I


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