The dihydrochloride of 1-diethylaminopropyl-2-phenylimidazo[1,2-a] benzimidazole with a local anesthetic action


(57) Abstract:

The dihydrochloride of 1-diethylaminopropyl-2-phenylimidazo-[1,2-a] benzimidazole of formula I has mestnoanesteziruushim action in terminal, wiring and spinal anaesthesia. table 2.

The invention relates to a new derivative 1H-imidazo[1,2-a]benzimidazole, namely water-soluble dihydrochloride 1-diethylaminopropyl-2-phenylimidazo[1,2-a]benzimidazole of the formula I

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with mestnoanesteziruushim effect when the terminal wires or spinal anesthesia.

Mestnoanesteziruyuschie funds depending on the indication for use is classified according to the N. N. Karkishchenko (Pharmacological basis of therapeutics (a guide for physicians and students). GMR-M, Medicine, 1996, 559 (C) with some modifications as follows:

1. The tools used for surface anesthesia: cocaine, tetracaine, leakin, benzocaine, piromekain.

2. Drugs used mainly for infiltration and block anesthesia: novocaine, trimekain, lidocaine, rihlokain.

3. Drugs used for spinal and epidural anesthesia: Savkin, marcain.

4. Residuum action and found practical application in terminal anesthesia, was cocaine. However, due to the high toxicity of this drug has limited application (M. D. Mashkovsky. Medicines, 15th ed., Rev. and more. - M.: Medicine, 1998, H. 1, S. 371 - 382).

Subsequently widely used is less toxic anesthetic - 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, 1998).

Widely known anesthetic for terminal anesthesia - tetrakis (dikain), which has analgesic activity in 2 - 3 times that of cocaine and 10 - 12 times novocaine, however, like cocaine has a high toxicity (M. D. Mashkovsky, 1998). In addition, side effects (tachycardia, convulsions, loss of consciousness, paralysis of the respiratory center), called (B. M. beavers. Our experience of applying the solution trimekainom for surface anaesthesia for ENT surgery. The honey.sister, 1990, N 9, p. 14 - 17), hinder its widespread use (O. F. Konovaltsev, N. P. Field. The action of aqueous solutions of dick is theanesthesiology means a new generation was lidocaine, which finds wide application in infiltration, conduction, 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, No. 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. Grekov,, 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, 1986, No. 6, S. 60 - 61; E. Nidhiguchi et al. Factors of the share change of human erythrocytes induced with lidocain Cell. struct. and Funct., 1989, Vol. 14, N, p. 569 - 577; M. D. Mashkovsky, 1998).

Great attention is given local anesthetic marcain (bupivacain), which has practical application as a tool for spinal, epidural, caudal, intra-articular anestes the n of plain and hyperbarric solutions administered to seated pateints Brit. J. Anaesrth., 1988, Vol. 61, N 4, p. 385 - 389; A. R. Wolf, R. D. Valley, D. W. Fear et al. Bupivacaine for caudal analgesia in infants and children: the optimal effective concentration. Anaesthesiology, 1988, Vol. 69, No. 1, p.101 - 105).

It should be noted that marcain, like dikaina not only highly active but also very toxic anesthetic (N. B. Raciborska. Mestnoanesteziruyuschie properties of some new derivatives of piperidine and indole. Abstract. dis. ...candles. the honey. Sciences. Rostov-on-don, 1991; J. Kambarn, B. Mets, R. Hickman et al. Comparative systemic toxicity of intravenously infused bupivacoune (B) cocaine (C) and lidocaine (L) inpigs: [Abstr.] Int. Anesth. Res. Soc. 66thCongr., San Francisco, Calif., March 13 - 17, 1992, anesth. and the play mode display., 1992, Vol. 74, No. 25, p.87), which requires special attention when used in practical medicine. In addition, marcain can cause with generalized rash, angioedema, laryngeal stridor, bronchospasm (H. Gacl, V., Reichert, R. Kaufmann. Localanastheticaintoleranz auf Leitungsanasthesia mit Prilocain und Bupivacain. Allergologie, 1992, Bd. 15, N 3, S. 89 - 91).

A relatively new anesthetic is ralation, which is a derivative of piperidine and with a pronounced analgesic effect and low toxicity. At block anesthesia 1% solution of rihanana causes a more rapid onset anesthesia, depth and duration of analgesic action exceeds 1.3 and 1.5 times, respectively, 2% Rana in surgical practice. Journe. experiment. hir. and anestesiol., 1974, No. 4, S. 56 - 58; K. of Kurakbaev. The use of anesthetic ikanaina during surgery in the maxillofacial region. Abstract. dis. ... candles. the honey. Sciences. Alma-ATA, 1976), and in case of infiltration and spinal anesthesia rihlokain used most often in combination with inulin, causes a pronounced analgesic effect, conceding, however, the effect of tetracaine and marcaine.

In a series of 1-substituted, imidazo[1,2-a]benzimidazole unknown compounds with mestnoanesteziruushim action.

The closest structure substance among the derivatives of imidazo[1,2-a] benzimidazole is the dihydrochloride of 1-diethylamino-ethyl-phenylimidazo[1,2-a] benzimidazole with hypotensive and antiarrhythmic effect (C. A. Anisimov, Y. A. Zhdanov, G. C. Kovalev and other Dihydrochloride 1-diethylaminoethyl-2-phenylimidazo[1,2-a]benzimidazole with hypotensive and antiarrhythmic effect. Auth. mon. N 1483894 (1989)).

The technical result of the invention is a new connection in a series of 1H-2-phenylimidazo[1,2-a] benzimidazole, showing unknown for this class local anesthetic action that is more effective than known mestnoanesteziruyuschie drugs the AI hydrochloride 2-phenyl-1-(3-chlorpropyl)imidazo[1,2-a] benzimidazole with diethylamine (method A) or 1-phenyl-2-chloro-benzimidazole with N, N-diethylaminopropylamine (method B) and the subsequent translation of the obtained 1-diethylaminopropyl-2-phenylimidazo[1,2-a] benzimidazole in water-soluble dihydrochloride I

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The following is the procedure for the synthesis of the proposed connection.

Example. The dihydrochloride of 1-diethylaminopropyl-2-phenylimidazo[1,2-a] benzimidazole.

A. a Mixture of 3.46 g (10 mmol) of the hydrochloride of 2-phenyl-1-(3-chlorpropyl)imidazo[1,2-a]benzimidazole (C. A. Anisimov, A. A. Spasov, M. C. Levchenko, E. A. Alexandrov. Chem.-Pharm. J., 1995, No. 10, S. 18) and 12 ml of diethylamine heat 5 to 6 hours in a sealed ampoule at 145 - 150oC. and Then cooled, the ampoule is opened, its contents poured into 100 ml of water and extracted with chloroform (3 x 15 ml). The extract was washed with water (2 x 30 ml), dried with anhydrous Na2SO4, evaporated to a volume of 10 to 15 ml and passed through a layer of alumina (diameter 4 cm, height 3 cm), elwira 1-(3-diethylaminopropyl)-2-phenylimidazo[1,2-a] benzimidazole chloroform. After evaporation of the eluate is oil, which is dissolved in dry ether or acetone and the solution acidified with ethereal HCl solution or a saturated solution of HCl in isopropyl alcohol. Precipitated white precipitate is filtered off and recrystallized from isopropyl alcohol. Dried/P>C22H26N42HCl.

Calculated,%: C 60,4; H 6,9; Cl 16,2; N 12,8.

Range PMR (DMSO-d6+ CCL4), , M. D.: of 1.23 (6H, m, 2CH3), and 2.27 (2H, q, CH2), of 3.13 (6H, m, (CH2)2NCH2), and 4.40 (2H, m, N-CH2), 7,40 - 8,35 (10H, m, aromatics), of 11.15 (1H, user. s, NH), 13,50 - 17,00 (1H, broad stripe, NH).

IR-spectrum (Wesel. oil), cm-1: 2500 - 27300 (NH, broad band), 3200 - 3470 (NH, broad band).

B. a Mixture of 1.35 g (5 mmol) 1-phenacyl-2-chlorobenzimidazole (P. M. Kochergin, V. S. Sexton. The method of obtaining derivatives of imidazo[1,2-a]benzimidazole. Auth. mon. N 230827 (1968)) and 1.95 g (15 mmol) of 3-diethylaminopropylamine heated to 150oC and kept at this temperature for 1 hour, cooled, poured into 25 ml of water, extracted with chloroform (3 x 10 ml). The chloroform extract is washed with water, dried with anhydrous sodium sulfate, evaporated to a small volume (10 ml) and passed through a column (diameter 2 cm, height 20 cm) with alumina elwira chloroform and collecting the first fraction. The oil remaining after evaporation of the chloroform from the eluate, and represents a 1-diethylaminopropyl-2-phenylimidazo[1,2-a] benzimidazole translate to dihydrochloride I, as described above in the methodology And, receiving 1.5 g (72%) of salt.

The value of acute toxicity (, who and whom observed within 48 hours. LD50to connect with I equal of 41.8 mg/kg

Screening mestnoanesteziruyuschee action of salt I showed that it possesses analgesic effects in terminal (experiments on the cornea of rabbits using the method Rainier-Jack), infiltration (experiments on Guinea pigs) and conductor (experiments on the sciatic nerves of frogs) methods of anesthesia.

The in-depth study of local anesthetic activity under terminal anesthesia in the cornea of rabbits (Iskrev N. A. Stereo-isomers and properties pharmacological activity in a series kokinov: Dis. ... candles. the honey. of Sciences, Minsk, 1959; N. Pryanishnikov.T., Balls N.A. Trimekain. Pharmacology and clinical use. - L. : Medicine, 1967) found that the threshold local anesthetic concentration (MIC) for connection I is equal 0,0156%, and for rihanana, lidocaine and tetracaine Comparators, - of 0.25, 0.25 and 0,0156%, respectively. The index of the Rainier respectively 117,3 13,5, 72,0 14,5, 98,5 24,3 and 11,8 1,8. Based on the mapping PMK and indexes Rainier investigated substances can be arranged in the following descending series: the connection I > tetracaine > lidocaine rihlokain.

In terms of infiltration anesthesia in the skin of Guinea pigs using the method described Bulbring E., J. Wajda (J. Pharmacol. and Exp. Therap., 1945, Vol. 85, No. 1, p. 78 - 84) and Icarium N. A. (1959), compound I and marcain showed mestnorazdrajayuschie action, since the concentration 0,0156%, rihlokain - 0,0312%, novocaine - with 0,0625%, while the index Bullring and Wade for these substances are respectively equal to 7,0 (5,3 - 8,7), 6,4 (4,8 - 8,0), 6,8 (5,2 - 8,4) and 3.6(2,6 - 4,6). Full anesthesia (100%, the index of which is equal to 36) compound I and marcain caused, since the concentration 0.125%, rihlokain - 0,25% novocaine - from 0.5%.

Comparison of local anesthetic activity of the investigated substances in the EU50expressed in mm/l, showed that compound I in 8,42 and 2.39 times higher than novocaine and rihlokain, respectively, and comparable with marcaine.

In the study block anesthesia on the tibial nerves of mice (Ignatov Y. D., Vasiliev, Y. N., Beetles C. N. and other Methodological recommendations for ex the Agen local anesthetic action shows the connection I, its minimum effective concentration (ECmis 0,030 (0,027 - 0,034)% or 0,73 mm/l, whereas EUmnovocaine, rihanana and marcaine Comparators, - 0,182 (0,161 - 0,026), 0,120 (0,113 - 0,129) and 0.036(0,032 - 0,040)% or 6,69, 3.89 and 1.15 mm/l, respectively. Mapping EUm(mm/l) of the investigated substances showed that compound I is superior in 9,16 times novocaine, 5,33 times rihlokain and 1.57 times marcain.

As follows from the table. 2, the ratio of elimination, the corresponding speed elimination of a substance in the introduction, the connection I 1.9 and 1.2 times higher than rihlokain and novocaine, respectively, and was not materially different from such marcaine. While the half-life of compound I, novocaine, rihanana and marcaine respectively was 8.0, 9,8, and 7.6 to 15.4 minutes

Comparison of the concentrations of the investigated substances, causing motor paralysis (MP) limbs in mice for 15 min, showed that the concentration of compound I (0,111%) was in 4,73, 2,13 and 1.26 times less than novocaine, rihanana and marcaine respectively.

In conditions conductive anesthesia in the sciatic nerves of rats that I in a 0.125, 0.25 and 0.5% solutions causes mestnorazdrajayuschie effect later 2,4 0,1 substance at the time of onset of analgesic effect of 1.50 1.57 and 1,80 times respectively inferior to Marciano.

The depth of anesthesia when applying the compound I and marcaine (0,125% solution) were respectively 95,0 2,31 and 82,0 4,24%, i.e., the claimed compound according to this index of 1.16 times higher than the comparison drug.

The duration of analgesia when injecting compound I in the region of the sciatic nerve in 0,125 0,25 and 0,5% solution was equal 136,9 5,09, 175,2 5,55 and 214,6 8,66 min, while similar to the introduction of marcaine she was 93 and 5.30, 134,2 5,19 and 148,0 at 5.27 min, i.e., the claimed connection of 1.46, 1.30 and 1.45 times had a more prolonged effect than the reference drug.

When wiring the pain in the sciatic nerves of rabbits (N. Pryanishnikov.T., Balls N.A., 1967) found that the start time of anesthesia under the influence of compound I (0.25% solution) comes later (16,8 0,6 min) than under the influence of marcaine (14,0 1,0). However, the maximum duration of anesthetic effect by using the first connection was 2.18 times more than the second (246,0 of 1.9 min against level 113.0 1,2 min). The total duration of anesthesia under the influence of compound I was 408,0 2,0 min, and in the case of marcaine - 284,0 3.7 min, i.e., she was 1.44 times more.

In the study of spinal anaesthesia in rats with subarachnoidal the A. Phesiol. Behav., 1976, Vol. 17, p. 1031 - 1036) found that compound I and marcain 0.25% solution can cause the maximum analgesic effect in the first 5 min of the experiment, duration of anesthesia under the influence first made 86.2 6,4 min, second - 28,47 5,0 min, i.e., the connection I 3.03 times a more lasting than marcain. Increasing the concentration to 0.5% did not lead to changes in the time of onset of analgesia, whereas the duration of his under the influence I grew, making 118,6 of 7.5 min, and under the influence of marcaine - 48,4 of 6.7 min, i.e., compound I is 2.45 times higher than marcain.

In terms of spinal anaesthesia in rabbits with epidural introduction (Sachkov Century. And., Shoesince E. A., Kogan E. A. and other Anestesiol. and Reanimator. , 1986, No. 4, S. 7 - 12) found that in a 0.25% solution of salt I shows analgesic effect through 3,6 0,2 min, and marcain taken as ethanol, through 2,4 0,2 min, i.e., the first substance is 1.5 times inferior to the second. The use of compound I has caused a complete local anesthetic action through 4,6 0,2 min, and marcain - later 3,4 0,2, i.e. the investigated compound was superior to the comparator drug 1.35 times. The end of a full anesthesia under the influence I was observed after 77,0 2.5 minutes, and when the application times more than the second. The duration of anesthesia using the connection I was 154,0 of 1.9 min, and in the case of marcaine - 108,0 3 min, i.e., she was the first 1.43 times more than the second.

Thus, compound I may be used as a local anesthetic funds a wide range of actions in terminal, conductor and spinal anesthesia.

In a terminal anesthesia it exhibits a pronounced local anesthetic effect, surpassing activity and the breadth of therapeutic action tetracaine in 2,71 and 1.76% respectively. Unlike last connection I do not intrude on the conjunctival membranes of the eye of the rabbit. Lidocaine and rihlokain in the form of a 0.25% solution of local anesthetic action significantly inferior connection I.

At block anesthesia this connection has a pronounced analgesic effect:

in experiments on the tibial nerve of mice at the minimum effective concentration (ECmin 9,16, 5,33 and 1.57 times that of procaine, rihlokain and marcain respectively. The speed of elimination in the introduction 1.9 and 1.2 times higher than rihlokain and novocaine, but not significantly ncentratio) and duration of analgesic effect in 1.16 and 1.30 and 1.46 times that of lidocaine, but 1,50 - 1,80 times inferior to him in the time of onset of anesthesia;

in experiments on the sciatic nerves of rabbits (0.25 and 0.5% solutions) at the time of onset of analgesia is slightly inferior to marcaine that have the same depth of anesthesia, and duration of the anesthetic effect by 2.18 times greater than his.

In terms of spinal anaesthesia connection I also manifests a pronounced local anesthetic effect:

in experiments on rats with subarachnoid introduction of 0.25 and 0.5% solutions of I at the time of onset of analgesia is not materially different from marcaine, and duration of anesthesia 3.03 and 2.45 times respectively surpasses it;

in experiments on rabbits with epidural introduction of 0.25 and 0.5% solutions on the time of onset of anesthesia 1.5 and 1.86 times inferior to Marciano, and the depth and duration of anesthesia 1.35 and 1.43, 1.38 and 1.40 times respectively surpasses it.

The dihydrochloride of 1-diethylaminopropyl-2-phenylimidazo[1,2-a]benzimidazole of the formula I


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