RU2233280C1 - 10-ω-ARYLOXYALKYL-2,3,4,10-TETRAHYDROPYRIMIDO[1,2-A]BENZIMIDAZOLE SALTS ELICITING TOPICALLY ANESTHETIC EFFECT - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel derivatives of 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole, namely to water-soluble 10-ω-aryloxyalkyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole salts of the general formula:

wherein Ar means C₆H₅, C₆H₄R wherein R means alkoxycarbonyl or carboxy-group at o-, m- and p-position of benzene ring; n = 1-6; X means chlorine (Cl) or bromine (Br) atom. These compounds elicit topically anesthetic effect in infiltration, conduction and intraspinal anesthesia.

EFFECT: valuable medicinal properties of compounds.

2 cl, 4 tbl, 4 ex

Description

The invention relates to new derivatives of 10H-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole, namely to water-soluble salts of 10-co-aryloxyalkyl-2,3,4,10-tetrahydropyrimido [1,2- a] benzimidazole of the formula I

where Ar = C ₆ H ₅ , C ₆ H ₄ R, where R = alkoxycarbonyl or carboxy group in the o-, m- and p-positions of the benzene ring, n = 1-6, X = Cl or Br, having a local anesthetic action in case of infiltration, conduction and spinal anesthesia.

One of the most active and long-acting local anesthetics is the drug markain (bupivacaine). It finds wide practical application for local infiltration anesthesia (0.25%), peripheral nerve blockade (0.25-0.5%) (MD Mashkovsky. Medicines, 15th edition, revised and supplemented. , M .: Medicine, 1998, part 1, p. 378), spinal, epidural, caudal, intraarticular anesthesia, during paracervical and retrobulbar blockade (for example, RP Alston. Spinal anaesthisis with 0.5% bupivacaine 3 ml: Comparison of plain and hyperbarric solutions administered to seated patients. Brit. J. Anatsth., 1988, vol. 61, No. 4, p. 385-389; ARWolf, RDValley, DWFear et al. Bupivacaine for caudal analgesia in infants and childrens the optimal effective concentration. Anaesthesiology, 1988, vo l. 69, No. 1, p. 101-105). It should be noted that marcaine is not only highly active, but also highly toxic anesthetic (NB Ratsiborinskaya. Local anesthetic properties of some derivatives of piperidine and indole. Abstract of thesis. Candidate of Medical Sciences. Rostov-on-Don, 1991; J.Kambam , B. Metz, R. Hickman et al. Comparative systemic toxicity ofintravenously infused bupivacaine (B), cocaine (C) and lidocaine (L) in pigs: [Abstr.] Int. Anaesth. Res. Soc. 66 ^th Congr., San-Francisco, Calif., March 13-17, 1992; Anaesth. And Analg., 1992, vol. 74, No. 25, p. 87), which requires increased attention to its use in practical medicine. With the right selection of doses, the drug provides a strong and lasting anesthesia. With their increase, convulsions, depression of cardiac activity (up to cardiac arrest) are possible (M.D. Mashkovsky, 1998). In addition, marcaine can cause a generalized rash, Quincke's edema, laryngeal stridor, bronchospasm (H. GacI, V. Reichert, R. Kauftnann. Localanaestheticaintoleranz auf Leitungsanaesthesia mit Prilocain und Bupivacain. Allergologie, 1992, Bd. 15, No. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3, S. 3. 89-91).

In the series of 10-substituted 10H-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole, compounds having a local anesthetic effect are not known.

The closest in structure among the derivatives of 10H-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole are salts of 10-dialkylaminoethyl-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole hypoglycemic and antiaggregant properties (VAAnisimova, MVLevchenko, TB Korochma et al. Nouveaux derives du benzimidazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. Fr. Pat. 2691462 (1995); Bull., 95/23. EP 0571253).

The technical result of the invention are new compounds in the series 1 OH-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole, exhibiting an unknown local compound anesthetic effect, more effective than the action of a known local anesthetic drug .

The technical result is achieved by compounds I, the synthesis of which consists in the interaction of N-unsubstituted 1H-1,2,3,4-tetrahydropyrimido [1,2-a] benzimidazole in neutral conditions with 1-ω-aryloxy-2-haloalkanes in a solvent or without it (method A), as well as substitution of a halogen atom in 10-ω-haloalkyl-2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazoles by an aryloxy group under the action of alkali metal phenolates on them (method B).

where Ar, R, n and X are as defined above.

The following are examples of methods for the synthesis of the proposed compounds.

Example 1. 10-β-Phenoxyethyl hydrochloride) -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole (I, Ar = C ₆ H ₅ , n = 2, X = Cl; RU-1151) .

Method A. A mixture of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimidido [1,2-a] benzimidazole and 2.0 ml (15 mmol) of β-phenoxyethyl chloride in 5 ml of dimethylformamide is boiled 3, 5 hours The next day, the precipitate formed is filtered off and washed thoroughly with acetone to obtain 3.2 g (94%) of hygroscopic hydrochloride. The latter is crystallized from isopropyl alcohol and dried at 105 ° C. Mp 206-207 ° C.

Found,%: C 65.5; H 6.2; C1 10.6; N, 12.5.

C ₁₈ H ₁₉ N ₃₀ · HCl.

Calculated,%: C65.6; H6.1; Cl 10.8; N, 12.7.

IR spectrum (petroleum jelly, oil), cm ^-1 : 1660 (C = N).

PMR spectrum (300 MHz, СОСl ₃ ), δ, ppm: 2.25 (2Н, m, 3-CH ₂ , 3.75 (2Н, m, 4-СН ₂ ), 4.06 (2Н, m, 2-CH ₂ ), 4.50 (2H, t, CH ₂ O), 4.93 (2H, t, NCH ₂ ), 6.78 (2H, d, 2'- and 6'-H, J = 7.9 Hz), 6.90 (1H, t, 4'-H, J = 7.3 Hz), 7.19 (1H, d, 6-H, J = 8.5 Hz), 7 20 (2H, t, 3'- and 5'-H), 7.31 (1H, t, 7-H), 7.37 (1H, t, 8-H), 7.57 (1H, d 9-H, .7 = 7.6 Hz), 11.64 (1H, N ⁺ H).

Method B. Into a stirred solution of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimido [1,2-a] benzimidazole in 4 ml of dimethylformamide, obtained by heating, add 1 ml (15 mmol) of ethylene chlorohydrin and the mixture is boiled. The reaction is carried out until the spots of the initial tricycle on TLC disappear. The mixture is left overnight at a low temperature (5-7 ° C). The precipitated precipitate of 10- (β-hydroxyethyl) -2,3,4,10-tetrahydropyrimidido [1,2-a] benzimidazole hydrochloride is filtered off, washed thoroughly with acetone. Yield 2.16 -2.3 g (85.0-91.0%). Mp 238 -240 ° C (decomp., From 2-propanol).

Found,%: C 56.7; H6.5; Cl 14.1; N, 16.6.

C ₁₂ H ₁₅ N ₃ O HCl.

Calculated,%: C 56.8; H 6.4; Cl 14.0; N, 16.6.

IR spectrum (petrolatum, oil), cm ^-1 : 1660 (C = N).

PMR spectrum (300 MHz, DMSO-d ₆ ), δ ppm: 2.13 (2H, q, 3-CH ₂ , J = 5.8 Hz), 3.48-3.56 (2H, m , 2-CH ₂ ), 3.71 (2H, t, CH ₂ O, J = 5.1 Hz), 4.11 (2H, t, 4-CH ₂ , J = 5.9 Hz), 4, 22 (2H, t, NCH ₂ , 7-5.1 Hz), 5.05 (1H, broad s, OH), 7.27-7.34 (2H, m, arom H), 7.47 - 7.59 (2H, m, arom H); 9.53 (1H, s, N ⁺ H).

The base -10- (β-hydroxyethyl) -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole is isolated by treatment with a 22% NH ₄ OH solution of the corresponding hydrochloride, the synthesis of which is described above, and extracted with chloroform . For purification, the extract is passed through a layer of alumina, eluting with chloroform. The residue after evaporation of the solvent from the eluate is recrystallized from ethanol or acetonitrile. Mp 155-156 ° C.

Found,%: C 66.5; H 7.0; N, 19.1. C ₁₂ H ₁₅ N ₃ O.

Calculated,%: C 66.4; H 7.0; N, 19.3.

IR spectrum (petrolatum, oil), cm ^-1 : 1640 (C = N), 3250 (OH).

0.7 ml (15 mmol) of thionyl chloride are added to a solution of 2.17 g (10 mmol) of 10-β-hydroxyethyl substituted in 10-15 ml of dry chloroform, and then it is boiled for 4-5 hours, controlling the chlorination process using TLC ( Al ₂ O ₃ , eluent — CHCl ₃ , R _{f of the} original — 0.1, R _{f of the} final — 0.55). Chloroform is evaporated, the residue is treated with petroleum ether or hexane, distilling off the latter together with an excess of thionyl chloride. The yield of 10- (β-chloroethyl) -2,3,4,10-tetrahydropyrimidido [1,2-] benzimidazole hydrochloride is quantitative.

Mp 221-223 ° C.

Found,%: C 52.8; H 5.6; C1 25.9; N, 15.6.

C ₁₂ H ₁₄ ClN ₃ Hcl.

Calculated,%: C53.0; H5.6; Cl 26.0; N, 15.4.

The salt is introduced into further transformations without further purification or is converted, using an ammonia solution, into a base, which is also used in reactions with variously substituted phenols. Yield 95-98%. Mp 69-70 ° C (from acetonitrile).

Found,%: C 61.3; H6.1; Cl 14.7; N, 18.1.

C ₁₂ H ₁₄ ClN ₃ .

Calculated,%: C 61.2; H 6.0; Cl 14.9; N, 17.9.

To a solution of 0.2 g (~ 2 mmol) of phenol and 0.12 g of KOH in 7-10 ml of methanol is added 2 mmol of 10-chloroethyl substituted and the mixture is boiled until the reaction proceeds (control - TLC: complete disappearance of the spot of the initial chlorine derivative). At the end of the reaction, the alcohol is evaporated, the residue is purified on a chromatographic column with γ-Al ₂ O ₃ , eluting with chloroform and collecting the first fraction with R _f 0.22. The yield of 10- (β-phenoxyethyl) -2,3,4,10-tetrahydropyrimidido [1,2-a] benzimidazole was 74.2%. Mp 98-99 ° C (from isooctane).

Found,%: C 73.6; H 6.5; N14.5.

C ₁₈ H ₁₉ N ₃ O.

Calculated,%: C73.7; H 6.5; N, 14.3.

The resulting base can serve as the basis for any salts with pharmaceutically acceptable acids.

The hydrochloride identical to that described in Method A was obtained by acidifying a solution of the base in alcohol or acetone with a saturated solution of HCl in isopropyl alcohol or ether.

Example 2. Hydrobromide 10- (β-phenoxyethyl) -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole (I, Ar = C ₆ H ₅ , X = Br). A mixture of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimidido [1,2-a] benzimidazole and 2.4 g (20 mmol) of β-phenoxyethyl bromide (M.V. Rubtsov, A.G. .Baychikov. Synthetic chemical-pharmaceutical preparations, M .: Medicine, 1971, p. 86) in 5 ml of dimethylformamide or any other solvent is boiled for 3-5 hours (monitoring of the reaction - TLC). It is cooled, the precipitate formed is filtered off and washed with acetone to obtain 3.2-3.4 g (85.5 - 90.7%) of hydrobromide. Purify the salt by recrystallization from ethyl alcohol. Mp 150-152 ° C.

An identical salt was obtained by acidification of an acetone or alcohol solution of 10- (β-phenoxyethyl) -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole conc. NVg.

Example 3. Hydrobromide 10- [β- (4-methoxycarbonylphenoxy) ethyl] -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole (I, Ar = C ₆ H ₄ COOCH ₃ , X = Br) . A mixture of 0.87 g (5 mmol) of 1H-1,2,3,4-tetrahydropyrimidido [1,2-a] benzimidazole and 1.55 g (6 mmol) of 4- (β-bromoethoxy) benzoic acid methyl ester (P .M. Kochergin, R.M. Paley, L.V. Balandina and others. Chem. Farm.zh., 1995, No. 2, p. 56-57), thoroughly rub and heat at 150 ° C (bath temperature ) within 30 minutes Then the melt is cooled and treated with acetone, the crystalline precipitate is filtered off, washed with acetone. The yield of chromatographically pure hydrobromide 1.88 g (87.3%). Mp 222-223 ° C (from acetonitrile).

Found,%: C 55.5; H 5.2; Bi-18.8; N, 9.9.

C ₂₀ H ₂₁ N ₃ O ₃ HBr.

Calculated,%: C 55.6; H 5.1; Br 18.5; N, 9.7.

IR spectrum (Vaseline oil), cm ^-1 : 1680 (C = N), 1720 (C = O).

PMR spectrum (300 MHz, CDCl ₃ ), δ, ppm: 2.28 (2H, m, 3-CH ₂ ), 3.77 (2H, t, 4-CH ₂ ), 3.84 (3H , s, CH ₂ ), 4.09 (2H, t, 2-CH ₂ , J-6.1 Hz), 4.55 (2H, t, OCH ₂ , J = 4.7 Hz), 4.93 (2H, t, NCH ₂ , J = 4.4 Hz), 6.81 (2H, d, 2 ', 6'-H, J = 8.8 Hz), 7.23 (1H, d, 6- H, J = 7.3 Hz), 7.31 -7.41 (2H, m, 7.8-H), 7.55 (1H, d, 9-H, J = 7.6 Hz), 7 89 (2H, d, 3 ', 5'-H, J = 8.8 Hz), 10.72 (1H, s, N ⁺ H).

Example 4. Hydrobromide 10- [β- (4-carboxyphenoxy) ethyl] -2,3,4,10-tetrahydropyrimido [1,2-a] benzimidazole (I, Ar = C ₆ H ₄ COOH, X = Br)

obtained by the interaction of equimolar amounts of 1H-1,2,3,4-tetrahydropyrimido [1,2-a] benzimidazole and 4- (p-bromoethoxy) benzoic acid (P.M. Kochergin et al., 1995) in dimethylformamide (yield 78 %) or saponification of a methoxycarbonyl group in a 4-methoxycarbonylphenoxyethyl substituted pyrimido [1,2-a] benzimidazole (see Example 3). Saponification is carried out as follows: 0.86 g (2 mmol) of 4-methoxycarbonyl substituted, 10 ml of glacial acetic acid and 2 ml of conc. HBr is boiled for 3 hours. The resulting solution was cooled and left overnight in the refrigerator. The precipitate formed is filtered off, washed with acetone. Yield 0.71 g (84.9%). Mp 260-261 ° C (from ethanol).

Found,%: C 54.6; H 4.9; Br 18.9; N11.1.

C ₁₉ H ₁₉ N ₃ O ₃ · HBr.

Calculated,%: 54.6; H 4.8; Br 19.1; N, 10.0.

IR spectrum (petrolatum, oil), cm ^-1 : 1673 (C = N), 1693 (C = O), 3285-3605 (OH).

PMR spectrum (300 MHz, DMSO-d ₆ ), δ, ppm: 2.15 (2Н, m, 3-СН ₂ ), 3.56 (2Н, t, 4-СН ₂ , J = 5, 3 Hz), 4.10 (2H, t, 2-CH ₂ , J = 5.6 Hz), 4.37 (2H, t, CH ₂ O, J = 4.7 Hz), 4.58 (2H , t, NCH ₂ , J = 4.7 Hz), 6.91 (2H, d, 2.6-H, J = 8.80 Hz), 7.34 (2H, m, 7.8-H) 7.51 (1H, d, 6-H, J = 8.8 Hz), 7.66 (1H, d, 9-H, J = 8.80 Hz), 7.84 (2H, d, 3 ', 5'-H, J = 8.80 Hz), 9.62 (1H, broad m, N ⁺ H), 12.40 (1H, broad. C, OH).

Infiltration anesthesia was investigated in experiments on the skin of guinea pigs (Bulbring E., Wajda J. Biologicak comparison of local anesthetica // J. Pharmacol. And exp. Therap. -1945. -Vol. 85, No. 1. -P. 78-84 )

Conduction anesthesia was studied in experiments on the nerves of the tails of rats (Ignatov Yu.D., Vasiliev Yu.N., Zhukov VN and others. Methodological recommendations for the experimental study of local anesthetics. - M.: MH USSR, 1990. - 49 p.).

Spinal anesthesia was studied in experiments on rats (Yu.D. Ignatov et al., 1990), catheterizing the subarachnoid space (Khvan A.A. Analgesic effect of clonidine when injected into the ventricles of the brain and under the lining of the spinal cord // Farmakol. And toxicol. - 1987. - No. 2. - S. 26 -29; Yaksh TL, Rudy TA Chronic catheterization of the spinal subarachnoid space // Physiol. Behav. -1976. - Vol. 17. - P. 1031 -1036).

The analgesic effect of substances under conduction and spinal anesthesia was evaluated in the standard tail-flick algorithm (Grossman ML, Basbaum AI, Fields HL Afferent and efferent connections of the rat tail flick reflex (a model used to analyze pain control mechanisms) // J. Coll. Neurol. -1982. -Vol. 206. -P. 9-16; Hahn EE Testing and evaluation of opiate analgesics and antagonists // Meth. Find. Exp. Clin. Pharmacol. -1985. -Vol. 7.- P. 373-381).

The local irritating and damaging effect was studied in experiments on the skin of rats (Yu.D. Ignatov et al., 1990).

Acute toxicity was investigated [the average lethal (lethal) dose of LD _{50 was} determined] 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).

Markain (bupivacaine) was taken as the reference substance.

Statistical processing of data recorded in a graduated form was carried out according to M. Belenky (Belenky M. Elements of a quantitative assessment of the pharmacological effect. -L., 1963. -152 p.), In the alternative [determination of LD ₅₀ , average effective concentrations (EC ₅₀ ), the boundaries of their confidence interval, therapeutic index, or breadth of therapeutic effect (LD ₅₀ / EC ₅₀ )] - according to VB Prozorovsky (1962) and Yu.D. Ignatov et al. (1990).

In infiltration anesthesia in experiments on guinea pigs, the minimum analgesic concentration for RU-1151 and marcain is 0.0156%. However, it should be noted that at this concentration, the Bulbring and Wade index for RU-1151 is 13.0, while for markain - 6.4. With an increase in the concentration of solutions to 0.0312 and 0.0625%, the Bulbring and Wade indices for RU-1151 were 26.2 and 36.0, respectively, while for marcain - 10.8 and 32.6 (Table 1).

Comparison of EC ₅₀ showed (Table 2) that RU-1151 is 1.70 times more active than marcain. Moreover, according to the therapeutic index (latitude of therapeutic effect) RU-1151 is 1.34 higher than markain.

As a result of the study of conduction anesthesia in experiments on rats, it was found (Table 3) that in 0.25 and 0.5% solutions both RU-1151 and marcaine 5 minutes after their introduction into the root of the tail cause complete (100% - new) analgesia, while the duration of the anesthetic effect of RU-1151 is 1.89 and 2.60, respectively, more significant than marcain.

In conditions of spinal anesthesia in experiments on rats it was shown (Table 4) that in 0.25 and 0.5% solutions of RU-1151, like marcain, it induces complete (100%) analgesia 5 minutes after subarachnoid administration, then as the duration of the anesthetic effect of RU-1151 in 3.17 and 2.39 times, respectively, exceeds markain.

The compound RU-1151 in 0.5, 1 and 2% solutions does not have an irritating and damaging effect on the skin of rats.

Thus, the substance RU-1151 with infiltration, conduction and spinal anesthesia methods significantly exceeds markain both in local anesthetic activity and in the breadth of therapeutic effect.

Based on the compound RU-1151, it seems possible to create a local anesthetic drug for infiltration, conduction and cerebrospinal anesthesia.

Claims (1)

Salts of 10-ω-aryloxyalkyl-2,3,4,10-tetrahydropyrimidido [1,2-a] benzimidazole of the general formula

where Ar is C ₆ H ₅ , C ₆ H ₄ R, where R is an alkoxycarbonyl or carboxy group at the o-, m- and p-positions of the benzene ring; n is 1-6; X is Cl or Br.

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