RU2068847C1 - DERIVATIVES OF 3,4-DIHYDRO- OR 1,2,3,4-TETRAHYDRO-β--CARBOLINES OR THEIR SALTS WITH ORGANIC OR INORGANIC ACIDS SHOWING ANTIMICROBIAL ACTIVITY - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of 3,4-dihydro- or 1,2,3,4-tetrahydro-β--carbolines substituted with alkyl, acyl, carboxyl, alkoxy, hydroxy or bromine. Reagent 1: 3-(2-aminoethyl)-indole. Reagent 2: corresponding carboxylic acid chloroanhydrides. Reaction conditions: in chloroform solution in the presence of triethylamine, at 0-5 C followed by cyclization with phosphorus oxychloride in dry dioxane. Synthesized compounds were used for synthesis of medicinal preparations showing antibacterial action. EFFECT: improved method of synthesis. 4 tbl

Description

 The invention relates to the field of new biologically active compounds - derivatives of 3,4, -dihydro- or 1,2,3,4-tetrahydro-b-carbolines and their salts with antibacterial action, as a result of which they can find application as pharmaceuticals in medical practice.

 The use in medicine of antibacterial drugs related in structure to the claimed object is unknown.

 The search for new effective antimicrobial agents is an urgent modern chemotherapy for bacterial infections, which is due to several reasons: the incidence of the population caused by bacterial microflora stably remains at a high level; there has been a steady increase in the populations of resistant microorganisms to the currently used antibacterial agents (antibiotics, sulfa drugs, etc. side effects of certain groups of antibacterial drugs).

 The aim of the invention are new chemical compounds exhibiting antimicrobial activity, as well as active against multiresistant strains of Staphylococcus aureus, resistant to the effects of many antibacterial drugs used in staphylococcal infections.

где R¹ алкил, галогеналкил, аралкил, фенил, арил;
R²-H; R² + R³ связь;
R³-H;

;
R⁴-H;
R⁵-H, Br, окси, алкокси
и их солями с органическими и неорганическими кислотами.This goal is achieved by previously undescribed 3,4-dihydro- or 1,2,3,4-tetrahydro-b-carbolines of the general formula I

where R ^{1 is} alkyl, haloalkyl, aralkyl, phenyl, aryl;
R ² -H; R ² + R ³ bond;
R ^{3 is} H;

;
R ^{4 is} H;
R ⁵ -H, Br, hydroxy, alkoxy
and their salts with organic and inorganic acids.

 The compounds of formula I are prepared in a known manner according to schemes 1, 2 or 3.

 According to Scheme I, by acylation of derivatives of 3- (2-aminoethyl) indole (II) anhydrides or carboxylic acid chlorides and subsequent cyclization of N-acyl derivatives (III) under the action of phosphorus oxychloride in dry dioxane (Spath E. Lederer E. Ber. Bd. 63, S 2102, 1930; Petrova M.F. Kaverina N.S. ZhOKh, vol. 33, No. 4, p. 1333, 1973) give compounds I.

 The interaction of 3,4-dihydro - β-carbolines with mineral or organic acids gives stable salts. Scheme 1.

где А органическая или неорганическая кислота.

where A is an organic or inorganic acid.

 Dimethylation of derivatives of 6-methoxy-3,4-dihydro-β-carbolines under severe conditions makes it possible to obtain 6-hydroxy substituted corresponding 3,4-dihydro - β-carbolines 1.

 The bromination of 3,4-dihydro - β-carbolines of bromine hydrochlorides in chloroform gives a mixture of 6- and 7-bromo substituted compounds I.

Acylation of DL-tryptophan (IV) with acids in the presence of acetic anhydride (Dalgleish CEJChem. Soc. 137, 1952) or Schotten-Baumann carboxylic acid chlorides (Milne HB Peng CHJAm.Chem. Soc. V.78, p.639, 1957) gives the corresponding amides (V), which in excess of an acylating agent at 50-55 ^o C cyclize to 1-alkyl-3,4-dihydro-b-carboline-3-carboxylic acids 1 according to scheme 2 (Maclaren JA Aust. J. Chem .v.40, p.1716, 1987; ibid., v. 42. p.813, 1989).

Взаимодействие 3-(2-аминоэтил)индола (II) с алифатическими или ароматическими альдегидами приводит к получению 1-замещенных 1,2,3,4-тетрагидро-β-карболинов и их солей 1 по схеме 3 (Supnieuki J. Misztal St. "Dissert. Pharmac. PAN", т.16, N 1, с.9, 1964; Буров Ю.В, Загоревский В.А. Жуков В.Н. Новикова Н.Н. Силенко И.Д. ХФЖ, т.17, N 8, с,936, 1983).

The interaction of 3- (2-aminoethyl) indole (II) with aliphatic or aromatic aldehydes gives 1-substituted 1,2,3,4-tetrahydro-β-carbolines and their salts 1 according to Scheme 3 (Supnieuki J. Misztal St. "Dissert. Pharmac. PAN", v.16, N 1, p.9, 1964; Burov Yu.V., Zagorevsky V.A. Zhukov V.N. Novikova N.N. Silenko I.D. 17, No. 8, s, 936, 1983).

Ацилирование 1,2,3,4-тетрагидро-β-карболинов позволяет получить соответствующие N-ацильные производные 1.

Acylation of 1,2,3,4-tetrahydro-β-carbolines allows to obtain the corresponding N-acyl derivatives 1.

 The method for producing compounds of the invention is illustrated by the following examples.

 Example 1. Obtaining 3- (2-acylaminoethyl) indoles (typical experiment).

To a suspension of 0.04 mol of the corresponding hydrochloride of 3- (2-aminoethyl) indole (II) in chloroform and 0.13 mol of tyrethylamine with vigorous stirring at a temperature of 0-5 ^o C add a solution of 0.04 mol of anhydride or carboxylic acid chloride in chloroform . The reaction mass is stirred at room temperature for 3-5 hours. At the end of the reaction, the chloroform solution is washed with water, dried, evaporated. The residue was triturated in hexane, the precipitate was filtered off and recrystallized.

 The yield and characteristics of compounds III (1-14) are given in table 1.

Example 2. Obtaining 1-substituted 3,4-dihydro - β - carbolines 1 (typical experiment)
To a solution of 10 mmol, the corresponding amide (III) in dioxane was added 30 mmol of phosphorus oxychloride, heated to a boil in a stream of nitrogen and boiled for 1-2 hours. The reaction mixture was cooled, evaporated in vacuo, a mixture of concentrated hydrochloric acid and crushed ice was added to the residue, stirred within 1 h. The reaction mass is made alkaline with a 40% sodium hydroxide solution to a pH of 10 ^{° C.} and extracted with methylene chloride. The combined organic solution was washed with water, dried and evaporated to dryness. The residue is dissolved in isopropyl alcohol with heating, activated carbon is added, boiled for 15-20 minutes, filtered from charcoal. The filtrate was evaporated, the residue was triturated in hexane, and the precipitate was filtered off.

 The yield and characteristics of the obtained compounds 1 (10, 16, 18, 21, 23, 27, 28, 30) are shown in table 2.

 Example. 3 Preparation of derivatives of 6-hydroxy-3,4-dihydro - β - carbolines (typical experiment).

 A mixture of 6 mmol of the corresponding 6-methoxy-3,4-dihydro-β-carboline, 10 ml of concentrated hydrochloric acid and 5 ml of acetic acid is boiled in a stream of gaseous hydrogen chloride for 6-7 hours. At the end of the reaction, the reaction mixture is evaporated in vacuo and the compound is isolated. 1 (31-33) (tab. 2).

 Example 4. Obtaining a mixture of 6- and 7-bromo-substituted 3,4-dihydro-b-carbolines (typical experiment).

To a suspension of 5 mmol of 3,4-dihydro-b-carboline hydrochloride in chloroform, a solution of 5.1 mmol of bromine in chloroform is added at 30 ± 2 ^° C. The reaction mixture is stirred at 25-30 ^{° C.} for 3-4 hours, washed with saturated sodium bicarbonate solution, then water. The chloroform solution was dried, evaporated, the residue was triturated in hexane, the precipitate was filtered off, and compounds 1 (34, 35) were obtained (Table 2).

 Example 5. Obtaining (2-acylamino-3-indolyl-3) -propionic acids (typical experiment).

To a mixture of 0.03 mol of D, L-tryptophan (IV) and 40 ml of a 2N sodium hydroxide solution, with stirring at a temperature of 5-10 ^° C., 0.03 ^{° C.} 0.04 mol of a carboxylic acid chloride are added. The reaction mass is stirred at room temperature for 8-10 hours, washed with ether. The aqueous alkaline solution is separated, acidified with hydrochloric acid to pH 1 ^o C2, the precipitate formed is filtered off, recrystallized and compound V (1, 2) is obtained (Table 1).

 Example 6. Obtaining D, L-1-alkyl-3,4-dihydro-β-carboline-3-carboxylic acid methanesulfonate (typical experiment).

A mixture of 10 mmol of amide V, 25 ml of propionic anhydride and 12 mmol of methanesulfonic acid is stirred at 50-55 ^o C for 3-4 hours. At the end of the exposure, the reaction mass is cooled to 0-5 ^o C, the precipitate is filtered off and recrystallized from alcohol, get compounds 1 (36, 37) (table. 2).

 Example 7. Obtaining 1- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,2,3,4-tetrahydro - β - carbolines (typical experiment).

A mixture of 10 mmol of the base of the corresponding 3- (2-aminoethyl) indole (II) and 10 mmol of 3,5-ditretbutyl-4-hydroxybenzaldehyde is heated to 190-200 ^o C, maintained at this temperature for 15-20 minutes, cooled to 75-80 ^o С, the melt is dissolved in ethanol, 0.5 g of activated carbon is added, after 15-20 minutes it is filtered off. The filtrate was evaporated, compound I was isolated from the residue (38, 40), and then compound I was obtained (table 2).

 Example 8. Obtaining 2-acyl-substituted 1,2,3,4-tetrahydro - β - carbolines (typical experiment).

 A mixture of 5 mmol of the corresponding 1-substituted 1,2,3,4-tetrahydra - β - carboline, 14 mmol of triethylamine, 6 mmol of propionic anhydride or palmitic acid chloride in chloroform is stirred at room temperature for 4-5 hours. The reaction is washed. weight with water, the chloroform solution is evaporated and the target compound I (41-43) is isolated from the residue (Table 2).

 Salts of substituted 3,4-dihydro-β or 1,2,3,4-tetrahydro-b-carbolines are prepared in a known manner by reaction of equimolar amounts of the bases of 3,4-dihydro-or 1,2,3,4-tetrahydro-b-carbolines with appropriate organic or inorganic acids in an aqueous or alcoholic medium, or in excess of acid.

 The toxicity of the substances was evaluated on white nonlinear mice by determining the maximum tolerated dose (MTD) in mg / kg with a single intragastric administration and subsequent observation of the animals for 14 days.

 The inventive substances are moderately toxic compounds.

The maximum tolerated dose for intragastric administration to mice is 500 ^° C. 1000 mg / kg.

By the method of double dilutions in a liquid nutrient medium (Hottinger broth), the antibacterial effect of β-carbolines was studied. The microbial load for bacteria was 2.5 x 10 ⁵ cells / ml. The maximum concentration of the claimed substances is 200 μg / ml. Samples of substances were previously dissolved in dimethyl sulfoxide. The results were taken into account after 18 h of incubation at 37 ^° C. The antimicrobial activity of the substances was evaluated by the absolute values of the minimum bacteriostatic concentrations (MBSK), which completely suppressed the growth of bacterial test strains and expressed in μg / ml.

 In our experiments, it was found that b-carbolines are active against gram-positive and inactive against gram-negative bacteria (table 3). It should be noted that the substances are active against multiresistant clinical strains of Staphylococcus aureus, resistant to the effects of many antibacterial drugs used in staphylococcal infections (Table 4).

 Thus, the claimed substances 3,4-dihydro- or 1,2,3,4-tetrahydro-β-carbolines have an antibacterial effect against gram-positive bacteria. Compared to other antibacterial drugs, β-carbolines are active against multiresistant strains of Staphylococcus aureus. The introduction into clinical practice of antibacterial agents of a new chemical class will allow their use in infections caused by bacteria that are resistant to currently used antibacterial drugs. TTT1 TTT2 TTT3 TTT4 TTT5 TTT6 TTT7 TTT8 TTT9 TTT10 TTT11

Claims (1)

Derivatives of 3,4-dihydro- or 1,2,3,4-tetrahydro-beta-carbolines of the general formula

where R _{1 is} alkyl, halogen (lower) alkyl substituted with hydroxyl and branched lower alkyl phenyl (lower) alkyl or phenylthio (lower) alkyl, phenyl substituted with hydroxyl and branched lower alkyl;
R _{2 is} hydrogen, R ₂ + R _{3 is a} bond;
R _{3 is} hydrogen, acyl;
R ₄ hydrogen, carboxy;
R ₅ hydrogen, bromine, hydroxy, lower alkoxygroup,
or their salts with organic or inorganic acids exhibiting antimicrobial activity.

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