RU2024516C1 - Method of synthesis of tetrahydrobenzimidazole derivative or its pharmaceutically acceptable salt - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product of the formula (I), where Het - a residue of indole, 2,3-dihydroindole, benzoxazine, dihydrobenzoxazine, phenothiazine, tetrahydroquinoline, benzothiophene, pyrrole, tetrahydroisoquinoline, thiadiazole, pyridine, 2,3-dihydrobenzimidazole, benzofuran, pyrrolidine, pyrimidine, benzimidazole, benzothiazole, quinoline, indazole, cyclopentathiazole, dihydrocyclopentathiazole, carbazole, 2,3-dihydrobenzimidazole-2-one, tetrahydrobenzothiophene, indene, thiophene, indolysidine or furan which can be substituted with 1-3 substituents taken from the group consisting of the lower alkyl group, lower alkenyl group, lower alkinyl group, cycloalkyl-lower alkyl group, aralkyl group, lower alkoxy-group, nitro-group, hydroxyl-group, lower alkoxycarbonyl-group or halide atom. X² - bond linked with carbon atom of heterocyclic ring Het. Reagent 1: heterocyclic compound of the formula (II) where Het and X² - as indicated above. Reagent 2: compound of the formula (III), or its reactive derivative. Synthesized compounds are used as preparations usable as 3-HI₃-receptor antagonists. EFFECT: improved method of synthesis.

Description

(1) где Неt является гетероциклической группой, возможно замещенной 1-3 заместителями, выбранными из низшего алкила, низшего алкенила, низшего алкинила, группы циклоалкил-низший алкил, арилалкил, низший алкоксикарбонил, атома галогена;
Х представляет собой одинарную связь, присоединенную к атому углерода гетероциклической группы.The invention relates to tetrahydrobenzimidazole derivatives of the formula (1) or to their pharmaceutically acceptable salts, suitable as 3-HT _3- chain antagonists:

(1) where He is a heterocyclic group optionally substituted with 1-3 substituents selected from lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, arylalkyl, lower alkoxycarbonyl, halogen atom;
X represents a single bond attached to the carbon atom of a heterocyclic group.

Known 5-HT ₃ receptor antagonists include the tetrahydrocarbazole compounds and the azabicyclo compounds described.

The invention is based on intensive studies of compounds exhibiting antagonism with respect to 5-HT ₃ receptors. As a result, it was found that the compounds of formula 1, which are new, exhibit high 5-HT ₃ receptor antagonistic activity, which is the essence of this invention. The compounds of this invention are completely different in structure from any of the above 5-HT ₃ receptor antagonists.

 In Formula 1, the heterocyclic group He includes residues of monocyclic or fused heterocyclic rings. Specific examples of heterocycles are pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridazine, pyridazine, indyrene pyridine, pyridazine, pyridazino isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazolin-2-one , isoquinolyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoline, 1,4-benz oxazine, phenothiazine, carbazole, β-carboline, etc.

 The heterocycle may have substituent (s) at various positions, such as lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, arylalkyl, lower alkoxyl, nitro, lower alkoxycarbonyl, halogen, etc.

 Unless otherwise indicated, the term "lower alkyl" means a linear or branched alkyl group having 1-6 carbon atoms. Specific examples of lower alkyl are: methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl isopentyl, tert-pentyl, isohexyl, etc.

 Examples of lower alkenyl are vinyl, allyl, 1-propenyl, 2-butenyl, isopropenyl, etc. Examples of lower alkynyl are ethynyl, 2-propynyl, etc. Examples of a cycloalkyl lower alkyl group are cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl-ethyl, cycloheptylmethyl, etc. Examples of arylalkyl are benzyl, phenethyl, etc. Examples of lower methoxy, ethoxy-ethoxy, are -, butoxy, pentyloxy, hexyloxy, isopropoxy, isobutoxy, tert-butoxy, isopentyloxy, tert-pentyloxy, isohexyloxy, 2-ethylbutoxy groups, etc. Examples of lower alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.

где R¹ представляет собой водород, низший алкил, низший алкенил, низший алкинил, группу циклоалкил-низший алкил или арилалкил; R² является водородом, низшим алкилом или арилалкилом; R³ представляет собой водород, низший алкоксил, нитрогруппу, гидроксил, низший алкоксикарбонил или галоген.A halogen atom includes atoms of chlorine, bromine, iodine, and fluorine. Preferred are those compounds of formula I wherein He is the following formula
R

where R ¹ represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, a cycloalkyl lower alkyl or arylalkyl group; R ² is hydrogen, lower alkyl or arylalkyl; R ³ represents hydrogen, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl or halogen.

 The invention also includes salts of certain compounds of formula I. Examples of such salts are salts with inorganic bases, for example, sodium and potassium salts, salts with organic bases, for example, with ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-ethylpiperidine, diethinolamine and cyclohexylamine, salts with basic amino acids, for example with lysine and ornithine, ammonium salts, salts with inorganic acids, for example, with hydrochloric, sulfuric, phosphoric and hydrobromic acid acids, salts with organic acids, for example, acetic acid, oxalic, succinic, citric, maleic, malic, fumaric acids, with dibenzoyl tartaric acid, tartaric acid, methanesulfonic acid, salts with acidic amino acids, for example, glutamic and aspartic acids.

Кроме того, соединения по данному изобретению имеют в своей молекуле асимметричный атом углерода, и все изомеры, обусловленные этими асимметричными атомами углерода, такие как оптически активные соединения, рацематы, диастереомеры и пр. входят в соединения по данному изобретению.Since the compounds of this invention correspond to formula I, the invention also includes tautomers of these compounds, for example, compounds of the following formula:

In addition, the compounds of this invention have an asymmetric carbon atom in their molecule, and all isomers due to these asymmetric carbon atoms, such as optically active compounds, racemates, diastereomers, etc., are included in the compounds of this invention.

 A method for producing the compounds of this invention is described below.

 Method 1

где Неt такой, как указано выше; Х² является одинарной связью соединений с атомом углерода гетероцикла Неt.H

where Not is as described above; X ² is a single bond of compounds with the carbon atom of the heterocycle He.

 Compound I can be prepared by reacting a heterocyclic compound IIIa with a carboxylic acid II or a reactive derivative thereof.

 The reaction can be carried out by any known method for the synthesis of carbonyl compounds, using a carboxylic acid or its reactive derivative.

 When using a carboxylic acid of formula II, the reaction with compound IIIa is a dehydration condensation reaction using, for example, polyphosphoric acid as the condensing agent. The reaction is carried out with or without a solvent. If the solvents are inert with respect to the reaction, but usually those are selected that have the desired boiling point corresponding to the temperature of the condensation reaction. Examples of suitable solvents are decalin, tetralin, diglyme, etc. The reaction is carried out at room temperature or, preferably, by heating.

 If carboxylic acid halide II is used, this is the Friedel-Crafts reaction, which is carried out by any known method using Lewis acids such as aluminum chloride, iron chloride, tin chloride, bromine trifluoride ethyl ester and titanium tetrachloride. Preferred solvents are those which are inert to the reaction, depending on the type of Lewis acid used. Examples of suitable solvents are acetonitrile and carbon disulfide. The reaction is carried out at room temperature, or, usually, by heating.

 If carboxylic acid amide II is used, this is the Vilsmeier reaction, which is a known reaction often used to synthesize heterocyclic carbonyl compounds. Reagents for converting the acid amide to the Vilsmeier complex include conventional halogenating agents, for example phosphorus pentachloride and phosphorus chloride oxide. This reaction can be carried out with or without a solvent. When using a solvent, various types of solvents that are inert to the reaction can be used. A suitable example of a solvent is 1,2-dichloroethane. The reaction is carried out at room temperature or by heating, preferably by heating.

_Ie где Х такой, как определено выше: Het¹ является гетероциклом, имеющим в кольце - NH: Неt² представляет собой гетероцил, где остаток -NH-, в Het¹превращен в -N-, где R⁴ является низшим алкилом, низшим алкенилом, низшим алкинилом, группой циклоалкил-низший алкил или арилалкилом.Method 2, N-alkylation:

_Ie where X is as defined above: Het ¹ is a heterocycle having in the ring —NH: Het ² is heterocyl, where the —NH— moiety is converted to -N— in Het ¹ , where R ⁴ is lower alkyl, lower alkenyl lower alkynyl; a cycloalkyl lower alkyl or arylalkyl group.

 This is an N-alkylation reaction. Alkylation means the introduction of lower alkyl, lower alkenyl, lower alkynyl, a cycloalkyl lower alkyl group or arylalakyl. Any known methidoalkylation is applicable. For example, if direct N-alkylation is carried out using an alkidizing agent, the reaction is carried out under cooling, at room temperature or heating, preferably under cooling at room temperature. Any solvent inert to the reaction may be used, for example dioxane and dimethylformamide. The reaction is carried out in the presence of a base or using an alkali metal salt of compound (Id) on its amino group. Examples of suitable alkylating agents are haloalkyls and alkyl sulfates. Examples of suitable bases are inorganic bases, for example sodium hydride, sodium or potassium bicarbonate, sodium or potassium carbonate, and organic bases, for example triethylamine, cyisopropylamine, dimethylaniline and pyridine.

 The compound of this invention thus obtained is isolated and purified in free or salt form by conventional chemical methods such as extraction, crystallization, recrystallization and various chromatographic methods.

 Compounds obtained in racemic form can be obtained in the form of stereochemically pure isomers using the corresponding starting compounds or by general resolution methods (for example, by a method involving the preparation of a diastereomer salt with a conventional optically active acid, for example, dibenzoyl tartaric acid, followed by optical resolution).

The compounds of this invention and their salts specifically inhibit serotonin-induced intermittent bradycardia in anesthetized rats, as described in Test Example 1 below, and therefore are believed to be antagonized to 5-HT ₃ receptors. Therefore, it is believed that the compounds of this invention and their salts suppress vomiting caused by antitumor agents, for example cisplatin, or radiation and are suitable for the prevention and treatment of migraine, headache, trigeminal neuralgia, anxiety, gastrointestinal disturbances, peptic ulcers, intestinal irritations and so forth

 A pharmaceutical composition containing at least one compound of this invention or a salt thereof as an active ingredient is prepared in various dosage forms such as tablets, powders, granules, capsules, pills, liquids, injections, suppositories, ointments, pastes, etc. P. using carriers, diluents and other additives commonly used in pharmacy. The formulation can be administered orally, including sublingual administration or parenterally.

 Carriers or diluents for pharmaceutical compositions include solid or liquid non-toxic caused by serotonin or 2-methylserotonin inhibited by dose.

 The inhibitory activity of the compounds of this invention with respect to the serotonin-induced Bezold-Jarish (BJ) reflex in rats is shown below.

An example of test compound N 36. The activity inhibiting the BJ reflex (ED ₅₀ , mg / kg intravenously) 0,063.

 Test Example 2. Inhibition of vomiting caused by an anti-cancer agent.

 When administered to males of an African ferret weighing 1-1.5 kg subcutaneously or orally, 0.01-0.3 mg / kg of the compound of this invention, vomiting is induced by intraperitoneal administration of 10 mg / kg of cisplatin.

 Test Example 3

 Inhibition of stressful bowel movements.

 Male Wistar rats, 9 weeks old, were placed in a cage for restrictive stress and the number of feces was measured. Intravenous administration of a compound of this invention or a salt thereof (1-100 μg / kg), depending on the dose, inhibits the acceleration of defecation caused by restrictive stress.

 Test Example 4

 Toxicity.

 The acute toxicity of the compounds of this invention, determined by increasing and decreasing doses when administered intravenously to male mice, is 100-150 mg / kg, indicating a low toxicity of these compounds.

 Below the invention is illustrated in more detail by Reference examples, examples and prescription examples, which, however, do not limit the invention.

 Reference example 1.

HCl _____→

HCl
К 0,30 г гидрохлорида 4,5,6,7-тетрагидробензимидазол-5-карбоновой кислоты, содержащего хлорид натрия, прибавляют 5 мл тионилхлорида и перемешивают 2 час при 90^оС. Избыток тионилхлорида отгоняют под вакуумом. К остатку прибавляют 10 мл дихлорметана и 2 мл диэтиламина при 5^оС, затем перемешивают 16 час при комнатной температуре.

HCl _____ →

Hcl
To 0.30 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid containing sodium chloride, 5 ml of thionyl chloride and stirred for 2 h at 90 ° ^C. Excess thionyl chloride was distilled off in vacuo. To the residue was added 10 ml of dichloromethane and 2 ml of diethylamine at ⁵ ° C, then stirred 16 h at room temperature.

 40 ml of dichloromethane was added to the mixture, the mixture was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to give 0.22 g of N, N-dimethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide.

Physicochemical properties:
NMR (TMS, CDCl ₃ ): 1.15 (t, 6H), 2.0-3.5 (m, 7H), 3.10 (q, 4H), 8.15 (s, 1H), 9, 50 (s, 1H),
Mass spectrum (FAB, Pos (m / z, 222 (M ⁺ +1).

 To the above compound, 1 ml of a 4N HCl solution in ethyl acetate was added, the solvent was removed in vacuo to give 0.27 g of hydrochloride, N, N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide.

 Example 1

Смесь 0,27 г (1,05 ммоля) гидрохлорида N,N-диэтил 4,5,6,7-тетрагидробензимидазол-5-карбоксамида 0,16 мл (1,25 ммоля) 1-метиландола и 0,15 мл (1,65 ммоля) оксихлорида фосфора нагревают 2 час при 80^оС и перемешивают. Прибавляют 30 мл воды и смесь подщелачивают 1Н водным раствором гидроксида натрия, затем экстрагируют этилацетатом. Этилацетатный слой сушат над безводным сульфатом магния и фильтруют. Фильтрат отгоняют под вакуумом, остаток очищают на колонке с силикагелем (элюент: дихлорметан: метанол: водный аммиак 10:1:0,1, по объему) и препаративной тонкослойной хроматографией (растворитель: дихлорметан: метанол: водный аммиак 10:1:0,1, по объему) и получают 20 мг пенообразного соединения. К продукту прибавляют 10 мг фумаровой кислоты, превращая его в фумарат. Перекристаллизацией из смеси этилацетат (метанол) (10: 1 по объему) получают 10 мг фумарата-5-(1-метилиндол-3-ил)-карбонил)-4,5,6,7-тетра- гидробензимидазола.

A mixture of 0.27 g (1.05 mmol) of N, N-diethyl hydrochloride 4,5,6,7-tetrahydrobenzimidazole-5-carboxamide 0.16 ml (1.25 mmol) of 1-methylandole and 0.15 ml (1 , 65 mmol) of phosphorus oxychloride is heated for 2 hours at 80 ^about C and stirred. 30 ml of water are added and the mixture is made basic with a 1N aqueous sodium hydroxide solution, then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate is distilled off under vacuum, the residue is purified on a column of silica gel (eluent: dichloromethane: methanol: aqueous ammonia 10: 1: 0.1, by volume) and preparative thin-layer chromatography (solvent: dichloromethane: methanol: aqueous ammonia 10: 1: 0, 1, by volume) and 20 mg of a foamy compound are obtained. 10 mg of fumaric acid is added to the product, turning it into fumarate. Recrystallization from ethyl acetate (methanol) (10: 1 by volume) gave 10 mg of fumarate-5- (1-methylindol-3-yl) -carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

Physicochemical properties:
Mass spectrum (E1): m / z, 279 (M ⁺ , as free compound)
NMR (CDCl ₃ (δ) as a free compound):
1.90-3.00 (7H, m, CH ₂ , CH) 3.80 (3H, s, N-Me) 7.20 (2H, m, ArH)
7.50-8.00 (4H, m, ArH); 8.30 (1H, m, NH).

 Example 2

HCl ___→

4 г Гидрохлорида N-[/4,5,6,7-тетрагидробензимидазол-5-ил/карбонил]пирролиди-на, добавляют и 40 мл дихлорэтана и прибавляют 2,74 г индола и 4,4 мл оксихлорида фосфора. Смесь перемешивают 7 час при 80-85^оС и затем ночь при комнатной температуре. К смеси добавляют 40 мл холодного водного раствора карбоната калия и затем экстрагируют хлороформом. Экстракт сушат над безводным сульфатом магния и растворитель отгоняют под вакуумом. Остаток подвергают колоночной хроматографии с использованием смеси хлороформ/метаном в качестве элюента и получают 1,82 г-5-(индол-3-ил)карбонил(-4,5,6,7-тетраги- дробензимидазола в виде пенообразного продукта 0,16 г. Результирующего продукта растворяют в 1 мл метанола и к раствору прибавляют 0,06 г фумаровой кислоты и 5 мл ацетонитрила. Полученные кристаллы собирают фильтрованием и получают 0,13 г фумарата 5-(индол-3-ил) карбонил- 4,5,6,7-тетрагидробензимидазола.

HCl ___ →

4 g of N - [/ 4,5,6,7-tetrahydrobenzimidazol-5-yl / carbonyl] pyrrolidine hydrochloride, 40 ml of dichloroethane are added and 2.74 g of indole and 4.4 ml of phosphorus oxychloride are added. The mixture was stirred for 7 hours at 80-85 ^{° C} and then overnight at room temperature. 40 ml of a cold aqueous solution of potassium carbonate are added to the mixture and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off in vacuo. The residue was subjected to column chromatography using a mixture of chloroform / methane as an eluent to obtain 1.82 g of 5- (indol-3-yl) carbonyl (-4,5,6,7-tetrahydrobenzenimidazole as a foamy product 0.16 The resulting product was dissolved in 1 ml of methanol and 0.06 g of fumaric acid and 5 ml of acetonitrile were added to the solution.The resulting crystals were collected by filtration to obtain 0.13 g of 5- (indol-3-yl) carbonyl-4,5 fumarate, 6,7-tetrahydrobenzimidazole.

Physicochemical properties:
Mp 153-154 ^about S.

Elemental analysis for C ₁₆ H ₁₅ N ₃ OC ₄ H ₄ O ₄ 0.15 CH ₃ CN0.65 H ₂ O:
Calculated (%): C 61.07, H 5.24, N 11.05.

 Found,%: C 61.11, H 5.01, N 11.04.

Mass spectrum (FAB): m / z 266 (M ⁺ +1, as a free compound).

 Analogously to example 2, the following compounds are synthesized.

 Example 3

 3/4 5- (1,2-Diethylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate.

· 3/4

Физико-химические свойства:
Т.пл. 220-223^оС
Элементный анализ для С₁₈Н₁₉N 3/4 С₄Н₄О_4:
Рассчитано (%): С 66,30; Н 5. 83. N 11.05.

3/4

Physicochemical properties:
Mp 220-223 ^about With
Elemental analysis for C ₁₈ H ₁₉ N 3/4 C ₄ H ₄ O _4:
Calculated (%): C 66.30; H 5. 83. N 11.05.

Found, (%) C 66.50; H 5.83; N 11.13
Mass spectrum (EI): m / z 293 (M ⁺ , as a free compound)
Example 4

· 1/2

Физико-химические свойства:
Т.пл. 221-223^оС.1/2 fumarate 5 - // 2-methylindol-3-yl) carbonyl-4,5,6,7, -tetrahydrobenzimide-azole

1/2

Physicochemical properties:
Mp 221-223 ^about S.

Elemental analysis for C ₁₇ H ₁₇ N ₃ O.1 / (2O ₄ H ₄ O ₄ 0.25 N ₂ O:
Calculated (%): C 66.75, H 5.75, N 12.29.

 Found,%: C 66.73, H 5.75, N 12.29.

Mass spectrum (EI): m / z 279 (M ⁺ , as a free compound)
Example 5

·

Физико-химическое свойства:
Т.пл. 183-186^оС.Fumarate 5 - ((2-benzylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole

·

Physico-chemical properties:
Mp 183-186 ^about S.

Elemental analysis for C ₂₃ H ₂₁ N ₃ O C ₄ H ₄ O ₄ 0.1 H ₂ O
Calculated,%: C 68.52, H 5.37, N 8.88.

Found,%: C 68.38, H 5.50 N 8.87
Mass spectrum (EI): m / z 355 (M ⁺ , as a free compound).

 Example 6

· 3/4

Физическое-химические свойства:
Т.пл. 162-164^оС.3/4 5- (5-Methoxyindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate

3/4

Physical and chemical properties:
Mp 162-164 ^about S.

Elemental analysis for С ₁₇ Н ₁₇ N ₃ O ₂ 3 / 4С ₄ Н ₄ О ₄ 0.2СН ₃ С 0,85 Н ₂ О:
Calculated (%): C 60.36: H 5.54 11.04
Found, (%): C 60.33, H 5.25, 10.93.

Mass spectrum (EI): m / z 295 (M +, as a free compound)
Example 7

·

Физико-химическое свойства:
Т.пл. 212-213^оС.5- (5-Chloro-2-methylindol-3-yl (carbonyl) -4,5,6,7-tetrahydro-benzimidazole fumarate

·

Physico-chemical properties:
Mp 212-213 ^about S.

Elemental analysis for C ₁₇ H ₁₆ N ₃ OSl C ₄ H ₄ O ₄ :
Calculated: (%): C 58.68, H 4.67, N 9.78, Cl 8.25.

 Found,%: C 58.43; H 4.91; N, 9.67; Cl, 8.24.

Mass Spectrum (FAB), Pos (: m / z, 314 (M ⁺ +1, as a free compound).

 Example 8

 5- (5-Nitroindol-3-yl) carbonyl-4,5,6,7-tetrahydrobenzimidazole.

Физико-химическое свойства:
Т.пл. 227-229^оС. ЯМР(DMCO-d₅) 100M, δ: 2,00 (2Н, м), 2,70 (4Н, м), 3,63 (1Н, м) 7,44 (1Н, с), 7,64 (1Н, д), J_6,7=12 Гц).

Physico-chemical properties:
Mp 227-229 ^C. NMR (DMCO-d ₅₎ 100M, δ: 2,00 (2H, m), 2.70 (4H, m), 3.63 (1H, m) 7.44 (1H, s ), 7.64 (1H, d), J _6.7 = 12 Hz).

8.10 (1H, d) J _6.7 = 12 Hz, J _4.6 = 4 Hz, 8.72 (1H, s), 9.07 (1H, d J _4.6 = 4 Hz), 12 56 (1H, br).

Mass spectrum (EI): m / z 310 (M ⁺ ).

 Example 9

 5- (5-Methoxycarbonylindol-3-yl (carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

Физико-химические свойства:
Т.пл.: 205-209^оС.

Physicochemical properties:
Mp .: 205-209 ^° C

NMR (DMCO-d ₆ ), 100M δ: 1.90-2.15 (2H, m), 2.83 (4H) 3.75 (1H, m) 7.56 (1H, g, J _6.7 = 12 Hz) 7.84 (1 H, _6.7 = 12 Hz, J _4.6 = 37 q) 8.62 (1 H, d, ₂ = 4 Hz), 8.90 (2 H, s), 12 , 60 (1H, d, ₂ = 4 Hz).

Mass spectrum (EI): m / z, 323 (M ⁺ )
Example 10

 1/2 Sumarate-5- (5-hydroxyindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

· 1/2

Физико-химические свойства:
Т.пл. 282-286^оС.

1/2

Physicochemical properties:
Mp 282-286 ^about S.

NMR (DMCO-d ₆ ): 100 m, δ: 1.90 (2H, w), 2.85 (4H, w), 3.74 (1H, w), 6.76 (1H, s), 6 84 (1H, gg, J _6.7 = 12 Hz, J _4.6 = 4 Hz), 7.41 (1H, d) J _6.7 = 12 Hz).

7.74 (1H, d, J _4.6 = 4 Hz (8.50 (1H, d 2NH = 5 G-), 9.07 (1H, s), 11.95 (1H, d, J ₂ , NH).

Mass spectrum (EI): m / z, 281 (M ⁺ , as free compound)
Example 11

___→

К 5 мл сухого диметилформамида прибавляют 0,04 г 60% гидрида натрия в масле и медленно, при комнатной температуре прибавляют 0,51 г 5-(индол-3-ил(карбонил)-4,5,6,7, -тетрагидро-1Н-бензимидазола, полученого в примере 2. Через 30 мин медленно, при 0^оС прибавляют 0,07 г бензилбромида и затем перемешивают ночь при комнатной температуре. К реакционной смеси прибавляют 20 мл воды и 20 мл хлороформа для разделения на фазы. Органический слой промывают водой и сушат над безводным сульфатом магния. Растворитель отгоняют и остаток хромато- графируют с использованием смеси хлороформ (метанол в качестве элюента. Результирующий пенообразный продукт (0,12 г) перекристаллизовывают вместе с 0,04 г фумаровой кислоты из смеси этанол (этилацетата и получают 0,10 г фумарата 5-(1-бензил- индол-3-ил(карбонил)-4,5,6,7-тетрагидробензимидазола.

___ →

To 5 ml of dry dimethylformamide, 0.04 g of 60% sodium hydride in oil is added and slowly, at room temperature, 0.51 g of 5- (indol-3-yl (carbonyl) -4,5,6,7, -tetrahydro- 1H-benzimidazole obtained in example 2. After 30 minutes, slowly, at ⁰ ° C was added 0.07 g of benzyl bromide and then stirred at room temperature overnight. to the reaction mixture was added 20 ml of water and 20 ml of chloroform for phase separation. The organic layer was washed with water and dried over anhydrous magnesium sulfate.The solvent is distilled off and the residue is chromatographed using cm if chloroform (methanol as eluent. The resulting foamy product (0.12 g) was recrystallized with 0.04 g of fumaric acid from ethanol (ethyl acetate) to give 0.10 g of 5- (1-benzyl-indol-3-yl fumarate) (carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

Physicochemical properties:
Mp 117-118 ^about S.

Elemental analysis for C ₂₃ H ₂₁ N ₃ O C ₄ H ₄ O ₄ 0.75 H ₂ O:
Found,%: C 66.83; H, 5.48. N, 8.88.

 Calculated,%: C 66.86; H 5.51; N, 8.66.

Mass spectrum (EI): m / z, 321 (M ⁺ , as free compound).

 Analogously to example 11, the following compounds are synthesized.

 Example 12

 5- (1-Cyclohexylmethylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimiimidazole fumarate.

Физико-химические свойства:
Т.пл. 95-100^оС (Этанол(этилацетат).

Physicochemical properties:
Mp 95-100 ^about C (Ethanol (ethyl acetate).

Elemental analysis for C ₂₃ H ₂₇ N ₃ O C ₄ H ₄ O ₄ 0.54 sOE,
Calculated (%): C 62.46, H 7.05. N, 7.54.

 Found, (%): C 62.59; H, 6.69; N, 7.19.

 Max Spectrum (EI): m / z: 361 (M +, as free compound).

 Example 13

 5- (1-Allylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate.

Физико-химические свойства:
Т.пл. 144-145^оС (метанол(этилацетат)
Элементный анализ для С₁₉Н₁₉N₃O C₄H₄O₄ 0,35 AcOEt 0,3Н₂О,
Рассчитано, (%): С 64,03; Н 5,81; N 9,18.

Physicochemical properties:
Mp 144-145 ^about C (methanol (ethyl acetate)
Elemental analysis for C ₁₉ H ₁₉ N ₃ OC ₄ H ₄ O ₄ 0.35 AcOEt 0.3 H ₂ O,
Calculated, (%): C 64.03; H 5.81; N, 9.18.

 Found, (%): C 64.00; H 5.74; N, 9.17.

Mass Spectrum (EI) m / z 305 (M ⁺ , as a free compound)
Example 14

 5- (1-n-Butylindole (-3-yl) carbonyl (-4,5,6,7-tetrahydrobenzimidazole fumarate) fumarate.

Физико-химические свойства:
Т.пл. 104-106^оС (этанол/ацетонитрил)
Элементный анализ для С₂₀Н₂₃N₃О С₄Н₄О₄ 0,8Н₂О:
Рассчитано: (%) C 63,78, H 6,38, N 9,30.

Physicochemical properties:
Mp 104-106 ^C (ethanol / acetonitrile)
Elemental analysis for C ₂₀ H ₂₃ N ₃ O C ₄ H ₄ O ₄ 0.8 H ₂ O:
Calculated: (%) C 63.78, H 6.38, N 9.30.

 Found, (%): C 63.82, H 6.14, N 9.33.

Mass spectrum (EI): m / z 321 (M ⁺ as free compound).

 Example 15

 5- (1- (2-Propynyl (indol-3-yl) carbonyl) -4,5,6,6-tetrahydrobenziimidazole fumarate.

Физико-химические свойства:
Т.пл. 130-131^оС (этанол/ацетонитрил)
Элементный анализ для С₁₉Н₁₇N₃O x x C₄H₄O₄ 1,3H₂O:
Рассчитано, (%): С 62,38; Н 5,37, N 9,49.

Physicochemical properties:
Mp 130-131 ^about With (ethanol / acetonitrile)
Elemental analysis for C ₁₉ H ₁₇ N ₃ O xx C ₄ H ₄ O ₄ 1,3H ₂ O:
Calculated (%): C 62.38; H, 5.37; N, 9.49.

 Found,%: C 62.38; H 5.19; N, 9.21.

 Mass spectrum (EI) m / z, 303 (M +, as free compound).

 Example 16

SO

В 5 мл ацетонитрила суспендируют 0,53 г сульфата 4,5,6,7-тетрагидробензимидазол-5-карбоновой кислоты и суспензии прибавляют 0,29 мл тионилхлорида. Суспензию перемешивают 1 час при -55-60^оС и растворитель отгоняют при пониженном давлении. К остатку прибавляют 4,6 мл бензотиофена и затем 0,4 г хлорида алюминия. После перемешивания 3 час при 60^о смесь выливают в холодный водный раствор карбоната калия. Раствор доводят до рН 8-9 и экстрагируют хлороформом.

SO

0.53 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate are suspended in 5 ml of acetonitrile, and 0.29 ml of thionyl chloride are added to the suspension. The suspension was stirred for 1 hour at -55-60 ^{° C} and the solvent was distilled off under reduced pressure. 4.6 ml of benzothiophene and then 0.4 g of aluminum chloride are added to the residue. After stirring for 3 hours at 60 °, ^the mixture was poured into a cold aqueous solution of potassium carbonate. The solution was adjusted to pH 8-9 and extracted with chloroform.

 The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under vacuum. The residue was purified by silica gel column chromatography using chloroform / methanol as an eluent to give 5- (benzothiophen-3-yl (carbonyl) -4,5,6,7-tetrahydro-benzimidazole. The product was treated with an equimolar amount of fumaric acid in the usual manner and ethanol (acetonitrile) was recrystallized from the mixture to give 0.04 g of 5- (benzothiophen-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate.

Physicochemical properties:
Mp 135-137 ^about S.

Elemental analysis for C ₁₆ H ₁₄ N ₂ OS x x C ₄ H ₄ O ₄ 0.3 EtOH 0.2 H ₂ O:
Calculated (%): C 59.50, H, 4.90, N 6.74, S 7.71.

 Found, (%): C 59.41; H 5.07; N, 6.53; S 7.91.

Mass spectrum (EI) m / z, 282 (M ⁺ , as free compound).

 Example 17

HCl
Смесь 2 г фосфрной кислоты, 5 мл тиофена и 2,91 г сульфата 4,5,6,7-тетрагидробензимидазол-5-карбоновой кислоты перемешивают 8 час при 100^оС. После охлаждения прибавляют 20 мл холодной воды и реакционную смесь промывают толуолом (20 мл х 2). Водный слой доводят до рН 8-9 карбонатом калия и экстрагируют хлороформом. Органический слой сушат над безводным сульфатом магния и растворитель отгоняют. Остаток обрабатывают 4Н раствором HCl в этилацетате, перекристаллизовывают из смеси метанол (ацетонитрил и получают 0,12 г гидрохлорида 5-(тиофен-2-ил)карбонил)-4,5,6,7-тетрагидробензимида- зола.

Hcl
A mixture of 2 g fosfrnoy acid, 5 ml of thiophene, and 2.91 g of sulfate of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid was stirred for 8 h at 100 ^C. After cooling, 20 ml of cold water and the reaction mixture was washed with toluene ( 20 ml x 2). The aqueous layer was adjusted to pH 8-9 with potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is treated with a 4N solution of HCl in ethyl acetate, recrystallized from a mixture of methanol (acetonitrile, and 0.12 g of 5- (thiophen-2-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole hydrochloride is obtained.

Physicochemical properties:
Mp 218-220 ^about C.

Elemental analysis for C ₁₂ H ₁₂ N ₂ OS x x HCl:
Calculated (%): C 53.63. H 4.88; N 10.42; S 11.93.

 Found,%: C 53.25, H 4.98, N 10.62, S 11.70.

Mass spectrum (EI): m / z; 232 (M ⁺ , as a free connection)
Example 18

_{HCl ___→}

К раствору 0,50 г гидрохлорида N-[(4,5,6,7-тетрагидробензимидазол-5-ил)карбонил] пиролидина и 0,39 г 2-метилиндолизина в 5 мл 1,2-дихлорэтана по каплям прибавляют 0,90 г оксихлорида фосфора. Реакционную смесь нагревают ночь с обратным холодильником при 85^оС. После охлаждения до комнатной температуры прибавляют 5 мл воды. Органический слой удаляют и к водному слою прибавляют 10 мл хлороформа. Раствор доводят до рН 9 20% водным раствором гидроксида натрия и экстрагируют хлороформом. Органический слой сушат над безводным сульфатом магния и растворитель отгоняют. Остаток очищают колоночной хроматографией на силикагеле с использованием смеси хлороформ (метанол в качестве элюента и получают 0,21 г 5-(2-метилиндолизин-3-ил) карбонил)-4,5,6,7-тетрагидробензимидазола.

_{HCl ___ →}

To a solution of 0.50 g of N - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] pyrrolidine hydrochloride and 0.39 g of 2-methylindolizine in 5 ml of 1,2-dichloroethane was added dropwise 0.90 g of phosphorus oxychloride. The reaction mixture was heated overnight under reflux at 85 ^C. After cooling to room temperature, add 5 ml of water. The organic layer was removed and 10 ml of chloroform was added to the aqueous layer. The solution was adjusted to pH 9 with a 20% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography using a mixture of chloroform (methanol as an eluent, and 0.21 g of 5- (2-methylindolizin-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole was obtained.

Physicochemical properties:
Mp 260-264 ^about S.

Elemental analysis for C ₁₇ H ₁₇ N ₃ O x 0.15 C ₂ H ₅ OH 0.2H ₂ O:
Calculated (%): C 71.68; H 6.36; N, 14.50.

 Found (%): C 71.71; H 6.16. N, 14.46.

Mass spectrum (EI) m / z; 279 (M ⁺ ).

 Example 19

 Analogously to example 18, but replacing 2-methylindolisine with pyrrole, 5- (2-pyrrolyl) carbonyl) -4,5,6,7-tetrahydro-benzimidazole of the following formula is synthesized.

Физико-химические свойства:
Т.пл. 255-256^оС
Элементный анализ для С₁₂Н₁₃N₃O:
Рассчитано: (%) С 66,96; Н 6,09; N 19,52.

Physicochemical properties:
Mp 255-256 ^about With
Elemental analysis for C ₁₂ H ₁₃ N ₃ O:
Calculated: (%) C 66.96; H 6.09; N, 19.52.

 Found (%): C 66.74; H, 6.23; N, 19.41.

Mass spectrum (EI): m / z, 215 (M ⁺ ).

 Example 20

К суспензии 7,0 г гидрохлорида N-[(4,5,6,7-тетрагидробензимидазол-5-ил)кар- бонил] пирролидина и 5,4 г-метилиндола в 70 мл этиленхлорида прибавляют 12,6 г оксихлорида фосфора и смесь перемешивают 7 час при 80-85^оС. Смесь охлаждают до 0-5^оС и медленно прибавляют 70 мл воды, поддерживая температуру смеси ниже комнатной, для разложения избытка оксихлорида фосфора. Органический слой удаляют, водный слой доводят до рН 9 20% водным раствором гидроксида натрия при охлаждении и экстрагируют хлороформом. К хлороформному слою прибавляют 70 мл воды и 6Н HCl при охлаждении льдом и перемешивании для доведения рН до 2,4-2,8. Хлороформный слой отбрасывают. Водный слой промывают хлороформом и прибавляют 40 мл метанола. Раствор подщелачивают 20% водным раствором гидроксида натрия при охлаждении. Образовавшиеся кристаллы собирают фильтрованием, промывают холодной смесью 1:1 (по объему) метанола и воды и получают 6,87 (89,9%) 5-(1-метилиндол-3-ил)-карбонил)-4,5,6,7-тетрагидробен- зимидазола.

To a suspension of 7.0 g of N - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] pyrrolidine hydrochloride and 5.4 g of methylindole in 70 ml of ethylene chloride were added 12.6 g of phosphorus oxychloride and the mixture stirred for 7 hours at 80-85 ^C. The mixture was cooled to ^0-5 ° C and slowly add 70 ml of water, keeping the mixture below room temperature, to decompose excess phosphorus oxychloride. The organic layer was removed, the aqueous layer was adjusted to pH 9 with a 20% aqueous sodium hydroxide solution under cooling and extracted with chloroform. 70 ml of water and 6N HCl are added to the chloroform layer, while cooling with ice and stirring to adjust the pH to 2.4-2.8. The chloroform layer is discarded. The aqueous layer was washed with chloroform and 40 ml of methanol was added. The solution was alkalinized with a 20% aqueous sodium hydroxide solution while cooling. The resulting crystals were collected by filtration, washed with a cold 1: 1 mixture (by volume) of methanol and water to obtain 6.87 (89.9%) 5- (1-methylindol-3-yl) -carbonyl) -4,5,6, 7-tetrahydrobenzimidazole.

Physicochemical properties:
Mp 139-141 ^about S.

Mass spectrum (EI): m / z, 279 (M ⁺ ).

¹ H-NMR (CDCl ₃ -DMCO-d ₆ ): 1.80-2.32 (m, 2H), 2.56-3.04 (m, 4H), 3.32-3.60 (m, 1H), 3.90 (s, 3H), 7.12-7.20 (m, 3H), 7.40 (s, 1H), 7.92 (s, 1H), 8.20-8.40 (m, 1H).

Elemental analysis for C ₁₇ H ₁₇ N ₃ O 0.2 EtOH 0.35 H ₂ O:
Calculated (%): 70.88; H, 6.46; N, 14.25.

 Found, (%): 70.83, H 6.50. N, 14.23.

 Example 21

· 1/2

5-(1-Метилиндол-3-ил)карбонил)-4,5,6,7-тетра- гидробензимидазол обрабатывают половиной эквимольного количества фумаровой кислоты в этаноле известным способом с получением 1/2 фумарата 5-(1-метилиндол-3-ил)карбонил)-4,5,6,7-тетрагидробензимидазола.

1/2

5- (1-Methylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole is treated with half an equimolar amount of fumaric acid in ethanol in a known manner to give 1/2 5- (1-methylindol-3- fumarate silt) carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

Physicochemical properties:
Mp 224-225 ^about S.

Elemental analysis for C ₁₉ H ₁₉ N ₃ O ₃ :
Calculated (%): C 67.64, H 5.68. N, 12.45.

 Found, (%): C 67.56; H 5.66; N, 12.35.

Mass spectrum (FAB): m / z, 280 (M ⁺ +1, as a free compound).

 Example 22

 Optical separation of (1) 5- (1-methylindol-3-ycarbonyl) -4,5,6,7-tetrahydrobenzimidazole.

 (a) in 60 ml of methanol add 5.87 g of 5- (1-methylindol-3-yl) -carbonyl-4,5,6,7-te-trahydrobenzimidazole obtained in example 20 and a solution of 7.52 g ( +) - dibenzoyl tartaric acid in 240 ml of methanol to obtain a clear solution. After the solution was allowed to stand overnight at room temperature, crystals precipitated, which were collected by filtration, recrystallized three times from dimethylformamide (water) and 2.30 g of (+) -dibenzoyltartrate (R) - (- 5- (1-methylindol-3-yl) carbonyl ) -4,5,6,7-tetrahydrobenzimidazole.

Physicochemical properties:
[α] _D ²⁰ = + 30.6 ^about (Cl, 10, dimethylformamide)
Mp: 169.0-170.0 ^about C
Elemental analysis for C ₁₇ H ₁₇ N ₃ O x x C ₁₈ H ₁₄ O ₈ H ₂ O:
Calculated (%): C 64.12; H 5.07; N, 6.41.

 Found, (%): C 64.13; H 5.03; N, 6.55.

Mass spectrum (FAB): m / z 280 (M ⁺ +1, as a free compound) (c) 2.2 g of the compound obtained above in (a) are added to a 2N aqueous HCl solution, the solution is washed with ethyl acetate and adjusted to pH approximately 9 sodium carbonate. The aqueous layer was extracted with a mixture of chloroform / methanol (4: 1 by volume). The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.94 g of (R) - (-) - (5-1-methylin-dol-3-yl / carbonyl) -4,5,6,6-tetrahydrobenzimidazole in the form of a foamy compound [α] _D ²⁰ = -16.5 ^about (c = 1.13, methanol).

 (c) The above obtained in (b) (R) - (-) - 5 - // 1-methylindol-3-yl / carbonyl) -4,5,6,7-tetra-hydrobenzimidazole (0.56 g) is treated 0.21 g of fumaric acid in a methanol / acetonitrile mixture to give 0.64 g of fumarate (R) - (-) - 5- (1-methylindol-3-yl / carbonyl) -4,5,6,7- tetrahydrobenzimidazole.

[α] _D ²⁰ = -28.1 ^o (c = 1.22, methanol).

M.p .: 150.5-151.5 ^about C.

Elemental analysis for C ₁₇ H ₁₇ N ₃ O x x C ₄ H ₄ O ₄ 0.35 CH ₃ CN 0.25 H ₂ O:
Calculated (%): C 62.91; N, 5.49; N, 11.33.

 Found,%: C 62.94; H 5.41; N, 11.35.

Mass spectrum (EI): m / z; 279 / m ⁺ , as a loose connection)
Example 23

 In an ethanol / ethyl acetate mixture, 100 mg of (R) - (-) - 5- (1-methyl-3-indolyl-carbonyl) -4,5,6,7-tetrahydrobenzimidazole obtained in Example 43 (b) is dissolved and the solution is added HCl in ethyl acetate. The resulting crystals were collected, recrystallized from ethanol to give 70 mg of (R) - (-) - 5- (1-methylindol-3-yl) -4,5,6,7-tetrahydrobenzimidazole hydrochloride.

[α] _D ²⁰ = -42.9 ^o (c = 1.02, methanol).

Mp : 215-230 ^{° C}
Elemental analysis for C ₁₇ H ₁₇ N ₃ O HCl:
Calculated (%): C 64.66; H 5.75; N 13.31; Cl 11.23.

 Found (%): C 64.37; H 5.80; N 13.12; Cl 11.17.

Mass spectrum (EI): m / z, 279 (M ⁺ , as free compound)
Example 24

 Optical separation of (2) 5- (1-methylindol-3-yl / carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

 (a) Analogously to example 22 (a), but using (-) - dibenzoyl tartaric acid, (-) - dibenzoyl tartrate (R) - (+) - 5- (1-methylindol-3-yl / carbonyl) 4,5 6,7-tetrahydrobenzimidazole.

[α] _D ²⁰ = 230.3 ^about (c = 1,07, dimethylformamide).

M.p .: 168-169.5 ^about S.

Elemental analysis for C ₁₇ H ₁₇ N ₃ O x x C ₁₈ H ₁₄ O ₈ H ₂ O
Calculated (%): C 64.12; H 5.07; N, 6.41.

 Found (%): C 6 4.13; H 5.13; N, 6.171.

Mass spectrum (FAB): m / z, 280 (M ⁺ +1, as a free compound)
(c) Analogously to example 22 (c), but using the salt obtained in (a) above, (S) - (+) - 5- (1-methylindol-3-yl / carbonyl) -4.5.6 is obtained, 7-tetrahydrobenzimidazole as a foamy compound.

[α] _D ²⁰ = + 16.7 ^about (s = 0.35, methanol).

 (c) Similarly to example 22 (c), using the above in (c) (S) - (+) - 5- (1-methylindol-3-yl / carbonyl) -4,5,6,7-tetra- hydrobenzimidazole crystals give fumarate crystals of (S) - (+) - ((1-methylindol-3-yl / carbonyl) -4,5,6,7-tetrahydrobenzimidazole.

[α] _D ²⁰ = + 28.3 ^o (c = 1.14, methanol).

Mp 151.0-152.0 ^about C.

Elemental analysis for C ₁₇ H ₁₇ N ₃ OC ₄ H ₄ O ₄ 0.35 CH ₃ C 0.25 H ₂ O:
Calculated (%): C 62.91; H 5.49; N, 11.33.

 Found, (%): C 62.96; H 5, 39; N, 11.37.

Mass spectrum (EI): m / z: 279 (M ⁺ , as free compound).

 Example 25

В 40 мл ацетонитрила суспендируют 5,00 г сульфата 4,5,6,7-тетрагидробензимидазол-5-карбоновой кислоты и к суспензии прибавляют 2,75 ил тионилхлорида. Суспензию перемешивают 1 час при 55^оС и растворитель отгоняют под вакуумом. К остатку прибавляют 20 мл нитробензола и 1,80 мл 2-метилбензофурана, а также 2,10 мл тетрахлорида олова. После перемешивания в течение ночи при 85^оС прибавляют 40 мл 1М водного раствора HCl и 40 мл этилового эфира. Органический слой отбрасывают, прибавляют 40 мл хлороформа и раствор доводят до рН=9 10% водным раствором гидроксида натрия. Реакционный раствор фильтруют через цеолит и экстрагируют хлороформом, содержащим 10% метанола. Органический слой собирают и растворитель отгоняют. К целевому продукту в форме свободного основания, обработанному хроматографией на силикагеле с использованием смеси хлороформ/метанол, добавляют рассчитанное количество фумаровой кислоты для превращения в фумарат, перекристаллизовывают из этанола и получают 0,14 г фумарата-5-(2-метилбензофуран-3-ил/кар-бонил)-4,5,6,7-тетрагидробензимидазол а.

5.00 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate are suspended in 40 ml of acetonitrile, and 2.75 yl of thionyl chloride are added to the suspension. The suspension was stirred for 1 hour at 55 ^{° C} and the solvent was distilled off in vacuo. To the residue were added 20 ml of nitrobenzene and 1.80 ml of 2-methylbenzofuran, as well as 2.10 ml of tin tetrachloride. After stirring overnight at 85 ^{° C} was added 40 mL of 1M aqueous HCl solution and 40 ml of ethyl ether. The organic layer was discarded, 40 ml of chloroform was added, and the solution was adjusted to pH = 9 with a 10% aqueous solution of sodium hydroxide. The reaction solution was filtered through zeolite and extracted with chloroform containing 10% methanol. The organic layer was collected and the solvent was distilled off. To the target product in the form of a free base, chromatographed on silica gel using a mixture of chloroform / methanol, add the calculated amount of fumaric acid to convert to fumarate, recrystallize from ethanol and obtain 0.14 g of fumarate-5- (2-methylbenzofuran-3-yl / carbonyl) -4,5,6,7-tetrahydrobenzimidazole a.

Physicochemical properties:
Mp 188-189 ^about S.

Elemental analysis for C ₁₇ H ₁₆ N ₂ O ₂ C ₄ H ₄ O ₄ :
Calculated (%): C 63.63; H 5.09; N, 7.07.

 Found (%): C 63.47; H 5.06; N, 7.01.

Mass spectrum (EI): m / z, 280 (M ⁺ , as free base).

 Example 26

Аналогично примеру 18 но заменяя 2-метилиндолизин индолизином получают целевое соединение.5- (Indolysin-3-yl) carbonyl-4,5,6,7-tetrahydrobenzimidazole

Analogously to example 18, but replacing 2-methylindolisin with indolysin, the desired compound is obtained.

Physicochemical properties:
Mp 210-212 ^about C.

Elemental analysis for C ₁₆ H ₁₅ N ₃ O 0.1 H ₂ O
Calculated (%): C 71.94; H 5.74; N, 11.73.

 Found, (%): C 72.08; H 5.79; N, 15.67.

Mass spectrum (EI): m / z, 265 (M ⁺ ).

 Example 27

Аналогично примеру 18 но заменяя 2-метилиндолизин на 1-метилиндолизин, получают целевое соединение.5- (1-Methylindolisin-3-yl / carbonyl) -4,5,6,7-tetrahydrobenzimidazole

Analogously to example 18, but replacing 2-methylindolisin with 1-methylindolysin, the desired compound is obtained.

Physicochemical properties:
Mp 122-123 ^about S.

Elemental analysis for C ₁₇ H ₁₇ N ₃ O 0.25 C ₄ H ₁₀ O 0.4H ₂ O:
Calculated, (%): C 70.87; H 6.71; N, 13.77.

 Found, (%): C 70.88; H, 6.68; N, 13.66.

Mass spectrum (EI): m / z, 279 (M ⁺ ).

Prescription example 1 (tablets)
The compound of example 44 (hereinafter compound A) 0.2 mg Lactose 106.4 mg Corn starch 48.0 mg
Hydroxypropylcellulose 4.8 mg Magnesium stearate 0.6 mg
________________
Total: 160/0 mg
per pill.

 Compound A (200 mg), lactose (106.4 mg) and corn starch (48 g) are thoroughly mixed and 48 mg of a 10% aqueous hydroxypropyl cellulose solution are added. The mixture is granulated in a granulator. 0.6 magnesium stearate is added to the granules and the mixture is pressed to produce 1000 tablets, each weighing 160 mg.

Prescription example 2 (powder) Compound A 0.4 mg Mannitol 770.0 mg Corn starch 199.6 mg Polyvinylpyrrolidone 30.0 mg
________________ Total: 1000/0 mg
Compound A (0.4 g) mannitol (770 g) and corn starch (199.6 g) are thoroughly mixed and 300 ml of a 10% aqueous solution of polyvinylpyrrolidone are added, then granulated in a granulator to obtain 1 kg of powder.

Prescription example 3 (capsules). Compound A 0.2 mg Corn starch 198.8 mg Calcium stearate 1.0 mg
________________ Total: 200 mg
Compound A (0.2 g), corn starch (198.8 g) in calcium stearate (1 g) was thoroughly mixed and the mixture was placed in 200 mg capsules No. 3 to obtain 1000 capsules.

Prescription example 4 (syrup) Compound A 0.2 mg Sucrose 8.0 mg Pure water 5 ml
Compound A (0.2 g) and sucrose (8 g) were dissolved in distilled water to give 5 L of syrup.

Prescription example 5 (injection) Compound A 0.3 ml Sodium chloride 9 ml Distilled water for injection 1.0 ml
Compound A (300 mg) and sodium chloride (9 g) were dissolved in distilled water for injection and 1000 ml of solution was obtained. The solution is filtered and placed in 1000 vials of 1 ml, displacing atmospheric gases from the vial with nitrogen gas. Ampoules are autoclaved.

 Since the invention is described in detail, with specific options, it will be clear to a person skilled in the art that many changes and modifications can be made without departing from the scope and without deviating from the essence of the present invention.

Claims (1)

A method of producing a tetrahydrobenzimidazole derivative of the general formula

where Het is a heterocyclic group, such as the residue of indole, 2,3-dihydroindole, benzoxazine, dihydrobenzoxazine, phenothiazine, tetrahydroquinoline, benzothiophene, pyrrole, tetrahydroisoquinoline, thiadiazole, pyridine, 2,3-dihydrobenzuinazimidazole pyridine , quinoline, indazole, cyclopentathiazole, dihydrocyclopentathiazole, carbazole, 2,3-dihydrobenzimidazol-2-one, tetrahydrobenzothiophene, indene, thiophene, indolysin or furan, which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl lower alkyl group, an aralkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a lower alkoxycarbonyl group or a halogen atom;
X ₂ is a single bond connected to the carbon atom of the heterocyclic ring Het,
or its pharmaceutically acceptable salt, characterized in that the heterocyclic compound of the formula
Het - X ₂ - H,
where Het and X ₂ have the indicated meanings,
are reacted with a carboxylic acid of the formula

or its reactive derivative. Priority by signs:
02.02.89 when X ₂ is a single bond connected to the carbon atom of the heterocyclic ring Het, Het is an indole group which may be substituted by a lower alkyl group;
12/28/89 at Het - a heterocyclic group, such as the residue of 2,3-dihydroindole, benzoxazine, dihydrobenzoxazine, phenothiazine, tetrahydroquinoline, benzothiophene, pyrrole, tetrahydroisoquinoline, thiadiazole, pyridine, 2,3-dihydrobenzimidinidazole, pyridine benzothiazole, quinoline, indazole, cyclopentathiazole, dihydrocyclopentathiazole, carbazole, 2,3-dihydrobenzimidazol-2-one, tetrahydrobenzothiophene, indene, thiophene, indolizin or furan, which may be substituted by 1-3 substituents selected from the group c standing of a lower alkyl group, lower alkenyl group, lower alkynyl group, a cycloalkyl-alkyl group, an aralkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a lower alkoxycarbonyl group or a halogen atom.