DD291761A5 - PROCESS FOR THE PREPARATION OF TETRAHYDROBENZIMIDAZOLE DERIVATIVES - Google Patents

Abstract

The invention relates to tetrahydrobenzimidazole derivatives of the formula (I) in which Het is a heterocyclic radical containing from 1 to 3 substituents selected from the group consisting of lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl -, aralkyl, lower alkoxy, nitro, hydroxyl and lower alkoxycarbonyl radicals and halogen atoms are selected, may be substituted; and X represents a single bond or NH attached to the carbon or nitrogen atom of the heterocyclic ring, and pharmaceutically acceptable salts thereof. The compounds of the formula (I) and their salts have an antagonistic activity against 5-HT3 receptors. The compounds of the invention may be used in medicaments for the treatment of gastrointestinal disorders, for the control of nausea and / or vomiting caused by chemotherapy or radiation, for the treatment of migraine, cluster headache and trigeminal neuralgia, and for the treatment of anxiety and psychotic disorders. Formula (I) {Tetrahydrobenzimidazole derivatives; 5-HT3 receptor; Antagonism; gastrointestinal disorders; Nausea; Vomit; Migraine; Cluster headache; trigeminal neuralgia; Angstzustaende; psychotic disorders}

Description

Field of application of the invention

The application of the present invention is in the field of drugs with 5-HT ₃ receptor antagonist activity.

Characteristic of the known technical solutions

Among the better known. Antagonists to 5-HT ₃ recursors include azabicyclo compounds according to GB-A-2,125,398, 2,166,726, 2,166,727 and 2,126,728 (corresponding to JP-A-59-36675 and JP-A-59-67284) tetrahydrocarbazole compounds according to GB-A- No. 2,153,821 (corresponding to JP-A-60-214784) and azabicyclo compounds according to EP-A-200,444 (corresponding to JP-A-61-275276).

Object of the invention

The invention has for its object to provide new drugs with antagonistic activity against 5-HT ₃ receptors.

Explanation of the essence of the invention

In the context of the present invention, extensive investigations were carried out on compounds having antagonistic activity against 5-HT ₃ receptors. New compounds with strong antagonist activity against 5-HT ₃ receptors were found, the structure of which differs markedly from the conventional 5-HT ₃ receptor antagonists mentioned above

The invention relates to a process for the preparation of tetrahydrobenzimidazole derivatives of the formula (I) ₍

in

in which heterocyclic radical is defined by 1 to 3 substituents selected from the group consisting of lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower-alkoxy, nitro, Hydroxyl and lower alkoxycarbonyl and halogen atoms may be substituted; and X is a single bond or -NH- bonded to a carbon or nitrogen atom of the heterocyclic radical and pharmaceutically acceptable salts thereof, characterized in that (a) for the preparation of compounds of formula (la)

TX>

in which Het is a heterocyclic radical represented by 1 to 3 substituents selected from the group lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl lower alkyl, aralkyl, lower alkoxy, nitro, hydroxyl and lower alkoxycarbonyl radicals and halogen atoms may be substituted; and X 'represents a single bond linked to a nitrogen atom of the heterocyclic ring or an -NH group linked to a carbon atom of the heterocyclic ring, an amine, amide or urea of the formula (III).

Het-X'-H (III)

in which Het and X 'have the meaning defined above, with a carboxylic acid of the formula (II)

(II)

or a reactive derivative thereof, (b) for the preparation of compounds of the formula (I b) ₍

in which Het is a heterocyclic radical represented by 1 to 3 substituents selected from the group consisting of lower-alkyl, lower-alkenyl, lower-alkynyl, cyloalkyl-lower-alkyl, aralkyl, lower-alkoxy, nitro -, hydroxy 'and lower alkoxycarbonyl and halogen atoms may be substituted; and X ^{2 represents} a single bond connected to a carbon atom of the heterocyclic ring represented by Het, a heterocyclic compound of the formula (IIIa) ₁

Het-X ² -H (purple)

in which Het and X ^{2 have} the meaning defined above, with a carboxylic acid of the formula (II)

HOOC *

H or a reactive derivative thereof,

(c) for the preparation of compounds of the formula (I c)

Il

Yeast ² -X-Cl · _

(Ic)

wherein Het ^{2 represents} a heterocyclic radical derived from Het ¹ which is a heterocyclic radical having the group -NH- in the ring represented by 1 to 3 substituents selected from lower alkyl, lower alkenyl, lower Alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower alkoxy, nitro, hydroxyl and lower alkoxycarbonyl radicals and halogen atoms, the group -NH- being substituted for Het 'in Het ² in the group

-NR ⁴

R ^{4 is} a lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl or aralkyl radical; and X represents a single bond or -NH group connected to a carbon atom or nitrogen atom of the heterocyclic ring, a compound of the formula (Id)

) O

Il Het ¹ -XC

in which Het 'and X' have the meaning defined above which subjects N-alkylation.

In the formula (I), the heterocyclic group represented by Het includes groups of monocyclic or fused heterocyclic rings. Specific examples of heterocyclic rings are pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophane, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, Indole, isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazol-2-one , Quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole, β-carboline and the like.

The heterocyclic radical may have one or more substituents at one or more arbitrary positions, such as lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower-alkoxy, nitro, Hydroxyl and lower alkoxycarbonyl radicals, halogen atoms and the like.

Unless otherwise indicated, as used herein, the term "lower" in the context of alkyl, alkenyl, alkynyl, and alkoxy means a straight or branched chain radical of from 1 to about 6. Specific examples of lower alkoxy radicals include methyl, ethyl, propyl, Butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, isopentyl, tert-pentyl and isohexyl and the like. Examples of the "lower alkenyl" are vinyl, allyl, 1 Examples of the "lower alkynyl" are ethynyl and 2-propynyl groups and the like. Examples of the din "cycloalkyl-lower-alkyl" are cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl Examples of the "aralkyl" are benzyl and phenethyl groups and the like. Examples of the "lower alkoxy" are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexaloxy, Isopropoxy, isobutoxy, tert. Butoxy, isopentyloxy, tert-pentyloxy, isohexyloxy and 2-ethylbutoxy groups and the like. Examples of the "lower alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl , Pentyloxycarbonyl and hexyloxycarbonyl groups and the like. The halogen atom includes chlorine, bromine, iodine and fluorine atoms. Preferred among the compounds of the formula (I) are those in which Het is the radical of the following formula

wherein R 'represents a hydrogen atom, a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower alkyl, or aralkyl radical; R ^{2 represents} a hydrogen atom, a lower alkyl, or aralkyl radical; and R ^{3 represents} a hydrogen atom, a lower alkoxy, nitro, hydroxyl, lower alkdxycarbonyl group or a halogen atom; and X represents a single bond; and compounds in which Het is a nitrogen-containing heterocyclic radical; and X represents a single bond linked to a nitrogen atom of the nitrogen-containing heterocyclic ring.

The compounds of the invention also include salts of some of the compounds of formula (I). Examples of such salts are salts with inorganic bases, e.g. Sodium and potassium salts; Salts with organic bases, e.g. Ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-ethylpiperidine, diethanolamine and cyclohexylamine; Salts with basic amino acids, eg. Lysine and ornithine; Ammonium salts; Salts with mineral acids, e.g. Hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, salts with organic acids, e.g. Acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, malic acid, fumaric acid, dibenzoyltartaric acid, tartaric acid and methanesulfonic acid; and salts with acidic amino acids, e.g. As glutamic acid and aspartic acid.

While the compounds of the invention are represented by the formula (I), the present invention further includes the tautomers of these compounds, i. H. Compounds of the formula

Further, the compounds of the present invention carry asymmetric carbon atoms in the molecule. All isomers associated with these asymmetric carbon atoms, such as optically active compounds, racemates, diastereomers and the like, are included among the compounds of the invention.

Exemplary embodiments

Hereinafter, the methods for producing the compounds of the invention will be explained in more detail.

Method ¹ (amidation):

Het-X ¹ -H +

H (II) (Ia) _f

wherein Het has the meaning as defined above; and X 'represents a single bond attached to a nitrogen atom of the heterocyclic group, or X ^{1 represents} an -NH group attached to a carbon atom of the heterocyclic group.

The compound (Ia) of the invention can be obtained by reacting an amine, amide or urea of the formula (III) with 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid of the formula (II) or a reactive derivative thereof. The reaction is carried out by any known method for forming an amide linkage. There are no particular restrictions on the solvents to be used. Examples of these are dioxane, diethyl ether, tetrahydrofuran, chloroform, ethyl acetate and dimethylformamide.

The compound (II) is reacted with the compound (III) either in the form of a free acid or in the form of a reactive derivative thereof, e.g. an acid halide, an acid anhydride, an acid azide and various active esters generally used in peptide synthesis. In the former case, the formation of the amide linkage can be achieved by using any conventionally employed condensing agent, e.g. N, N-dicyclohexylcarbodiimide.

In some cases, depending on the nature of the reactive derivative of compound (II), the reaction is preferably carried out in the presence of a base, e.g. From inorganic bases such as sodium hydrogencarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate; and organic bases such as triethylamine, diisopropylethylamine, dimethylaniline and pyridine.

The compound (III) is usually used directly or optionally after conversion to an alkali metal salt.

The compound (III) is preferably used in equimolar amounts or in excess of the compound (II) or the reactive derivative thereof.

The reaction can be carried out at room temperature, with cooling or with heating, the choice being chosen depending on the reaction mode of the amide linkage, which is usually carried out at room temperature or under cooling.

Method 2:

UO

(Ilia). ^H

wherein Het has the meaning defined above; and X ^{2 represents} a single bond bonded to a carbon atom of the heterocyclic ring represented by Het.

The compound (Ib) can be obtained by reacting a heterocyclic compound of the formula (IIIa) with a carboxylic acid of the formula (III) or a reactive derivative thereof.

The reaction may be carried out by any known method for the synthesis of carbonyl compounds using carboxylic acid or a derivative thereof.

When a carboxylic acid of the formula (II) is used, the reaction with the compound of the formula (III a) is a dehydrating condensation reaction, polyphosphoric acid being used as the condensation agent, for example. The reaction is carried out with or without solvent. There are no limitations on the solvents that can be used, provided that they are inert in the reaction, but solvents are usually selected with corresponding boiling points, taking into account the reaction temperature. Examples of suitable solvents are decalin, tetralin, diglyme and the like. The reaction is carried out at room temperature or preferably with heating.

When an acid halide of the carboxylic acid of formula (II) is used, the reaction is a Friedel-Crafts reaction which is carried out by known methods or various modifications thereof using a Lewis acid, e.g. As aluminum chloride, iron (III) chloride, tin (IV) chloride, boron trifluoride ethy letherat and titanium tetrachloride, can be performed. Solvents that are inert in the reaction can be used, which are preferably selected 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 with heating.

When using an acid amide of the carboxylic acid of the formula (II), the reaction is a Vilsmeyer reaction in which rs is a known type of reaction which is frequently used for the synthesis of heterocyclic carbonyl compounds. Reagents for converting the acid amide into a Vilsmeyer complex include general halogenating agents, e.g. As phosphorus pentachloride and phosphorus oxychloride. This reaction can be carried out with or without a solvent. When using a solvent, various solvents can be used as long as they are inert to the reaction. A suitable example of a solvent is 1,2-dichloroethane. The reaction is carried out at room temperature or with heating and preferably with heating.

Process 3 (N-alkylation):

O O

II ₂ Il

Het ² -XC

H H

(Id) (Ic) ι

wherein X has the meaning as defined above, Het 'means a heterocyclic radical having an -NH group in the ring; and Het ^{2 represents} a heterocyclic radical in which the -NH group in Het ¹ belongs to the group

where R ^{4 is} a lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl or aralkyl radical.

This reaction is an N-alkylation reaction. The term "alkylation" as used herein refers to the introduction of a lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl, lower-alkyl or aralkyl radical Any of the known alkylation techniques are applicable, for example, when alkylation is carried out by direct N The reaction is carried out under cooling, at room temperature or with heating and preferably under cooling or at room temperature, any reaction-inert solvents may be used, for example dioxane and dimethylformamide Examples of suitable alkylating agents are alkyl halides and alkyl sulfates Examples of suitable bases are inorganic bases,

e.g. Sodium hydride, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate and potassium carbonate; and organic bases, e.g. For example, triethylamine, Qilsopropylamln, dimethylaniline and pyridine.

The compound of the invention prepared in this way is in the free form or in the form of a salt by conventional

chemical measures, such as extraction, crystallization, recrystallization and various chromatographic techniques, isolated and purified.

The compound obtained in the form of a racemate can be converted into stereochemically pure isomers by using an appropriate starting compound or by employing general resolution techniques (for example, a process comprising first preparing a diastereomeric salt with a conventional optically active acid, e.g. dibenzoyltartaric.

receives, and then performs an optical separation).

The compounds of the invention and the salts thereof inhibit serotonin-induced transient bradycardia in anesthetized rats as demonstrated in Test Example 1 below. It is therefore believed that the compounds of the invention have antagonistic activity against 5-HT ₃ receptors. Therefore, for the compounds of the present invention and the salts thereof, a suppressive effect on ktebe-controlling agents such as cisplatin or irradiation-induced vomiting is presumed. It is also believed to be useful in the prophylaxis and treatment of migraine, cluster headache, trigeminal neuralgia, anxiety, gastrointestinal disorders, peptic ulcers, irritable bowel syndromes and the like.

A pharmaceutical composition containing at least one of the compounds of the invention or salts thereof as an active ingredient is used in various dosage forms such as tablets, powders, granules, capsules, pills, liquids, injection liquids, suppositories, ointments, pastes and the like of carriers, diluents and other additives commonly used in pharmaceuticals. The preparation may be administered orally, including sublingually, or parenterally.

Carriers or vehicles for pharmaceutical compositions include solid or liquid, non-toxic, pharmaceutically acceptable materials such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and the like.

A clinical dose of the compound of the invention is suitably determined taking into consideration the condition, the body weight, the age, the sex of the patient and the like. Usually, the dose is in the range of 0.1 to 10 mg / day for intravenous administration and in the range of 0.5 to 50 mg / day for oral administration to adult individuals in a single dose or in multiple divided doses.

The pharmacological effects of the compounds of the invention are confirmed by the test examples.

Test Example 1

Antagonism against 5-HT ₃ receptors

Male Wistar rats 9 weeks of age were anesthetized by intraperitoneal administration of 1 g / kg urethane. Blood pressure and heart rate were measured during artificial respiration. The transient reduction in heart rate and blood pressure induced by intravenous administration of serotonin or 2-methylserotonin, selective agonists of 5-HT ₃ , was taken as an index of response via the 5-HT ₃ receptor (Bezold-Jarish Reflex, AS Paintal, Pysiol Rev., Vol.53 (1973), page 159).

When the compound of the invention or a salt thereof was administered intravenously (0.03 to 3 μg / kg) or orally (1 to 3 ° C / kg) 10 minutes or 60 minutes before the administration of serotonin (or 2-methylserotonin), thus, serotonin or 2-methyl serotonin-induced reduction in heart rate and blood pressure was inhibited in a dose-dependent manner.

The inhibitory effect of the compound of the invention on the serotonin-induced Bezold-Jarish (BJ) reflex in rats is shown in Table I below.

Table I

Example No. of bJ Reflex inhibitory effect test compound (ED ₆₀ , Mg / kg, intravenously) 2 0.29 4 0,044 9 0.80 36 0.063

Test Example 2

Inhibition of vomiting caused by anticancer mortality

When male to ferret of 1 to 1.5 kg were administered subcutaneously or orally 0.01 to 0.3 mg / kg of the compound of the invention, emesis induced by intraperitoneal administration of 10 mg / kg of cisplatin was inhibited.

Test Example 3

Inhibition of stress defecation

Nine-week-old male Wistar rats were kept in a cage to produce restriction stress. The number of feces was measured. Intravenous administration of the compound of the invention or a salt thereof (1 to 100 pg / kg) dose-dependently inhibited the restriction stress-induced defecation acceleration.

Test Example 4

toxicity

The acute toxicity of the compounds of the invention in male mice was 100 to 150 mg / kg i.v. as determined by the up-and-down method, indicating that the compounds have low toxicity.

In the following, the invention will be explained in more detail with reference to comparative examples, examples and formulation examples, but this is not intended to be limiting.

Reference Example 1 (a)

CCXDCH ₃ ^N N - "\ ^ ^ CCKDCH ₃

-H ₂ SO ₄ -H ₂ SO ₄

In 600 ml of acetic acid, 40.0 g of methyl S-benzimidazolecarboxylate sulfate were dissolved in an autoclave of 1 liter volume. The solution was treated with 11 g of 10% palladium-on-carbon catalyst, followed by hydrogenation for 5 hours at 20 ° C. and 60at pressure. The catalyst was filtered off and the mother liquor was concentrated under reduced pressure. There was obtained 41, Og methyl ^ .S ^ tetrahydrobenzimidazole B-carboxylate sulfate in the form of an oil.

HCl ^N

COOCH ₃ U ^ ^ ^ ^ COOH.

-H ₂ SO ₄ 'H ₂ SO ₄

In a mixture of 350 ml of water and 340 ml concentrated hydrochloric acid were dissolved 41,0g of Estersulfats in the above step (a) obtained oily, and the mixture was stirred for 3 hours at 100 ⁰ C. After concentration, the obtained

Washed crystals with acetone. This gave 29.6 g (76.8%, based on the benzimidazole ester) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate.

Physicochemical properties:

F .: 145-148 ⁰ C

NMR (d ₆ -DMSO): δ 1.60-3.00 (7H, m), 8.84 (1H, s)

Mass spectrum (El): m / z; 16u (M *, as a free connection)

(Cl): m / z; 167 (M ⁺ +1, as a free compound)

Reference Example 2

0.30 g _4,5,6> 7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride containing sodium chloride was then treated with 5 ml of thionyl chloride ir.d 2 hours at 9O ⁰ C stirred. The excess thionyl chloride was removed by distillation under reduced pressure. The residue was treated with 10 ml of dichloromethane. Subsequently, 2 ml of diethylamine were added at 5 ° C. Then, it was stirred at room temperature for 16 hours. The mixture was then added with 40 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation., Reduced pressure. This gave 0.22 g of NN-DiethyMjBie ^ -tetrahydrobenzimidazol-B-carboxamide

 Physicochemical properties:

NMR (TMS, CDCl ₃ ): δ 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)

The compound obtained above was added with 1 ml of a 4 η solution of hydrogen chloride in ethyl acetate. The solvent was removed by distillation under reduced pressure. 0.27 g of N, N-diethyl-4,5,6,7-tetrahydrobenzimioozole-S-carboxamide hydrochloride was obtained.

example 1

HCl

^ ''! (fX ^ V -HCCOOH

H HOOCCH

In 0.7 ml of thionyl chloride was added 0.13 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride (containing Sodium chloride) for 30 minutes under reflux. The volatiles were then removed by distillation

Removed reduced pressure. The residue was added to a solution of 0.15 g of 3,3-dimethylindoline and 0.15 ml of triethylamine in 2 ml of dichloromethane while cooling with ice. After stirring the mixture overnight at room temperature, 5 ml of an aqueous sodium carbonate solubilizer was added. The mixture was extracted with chloroform. The organic phase was dried and the solvent removed by distillation under reduced pressure. The residue became the

Column chromatography on silica gel using chloroform / methanol as eluent. One received

0.11 g of 5 - [(2,3-dihydro-3,3-dimethylindol-1-yl) -carbonyl-4,5,6,7-tetrahydrobenzimidazole in the form of an oily substance. The oily

Substance was treated with a solution of fumaric acid in methanol / acetonitrile. This gave 0.09 g of 5 - [(2,3-dihydro-3,3-

dimethylindol-1-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate.

Physicochemical properties:

F .: 119-123 ° C

Elemontaranalysis for C ₁₈ H ₂ IN ₃ O.C ₄ H ₄ O ₄ .H ₂ O .3CH ₃ CN:

calc. (%): C, 61.44; H 6,36; N 10.46f. (%): C 61.60; H 6.03; N 10.46

Mass spectrum (El): m / z; 295 (M ⁺ , as a free connection) In the same manner as in Example 1, the following compounds were prepared.

Example 2 5 [(2,3-Dihydrolndol-1-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole fumarate

• HCCOOH

Il HOOCCH

Physicochemical properties: F .: ".06-208 ⁰ C (methanol / acetonitrile) Elemental analyzes for C, Hi ₇ N ₃ O.C ₄ H ₄ O ₄ .0.3H ₂ O:

calc. (%): C 61.78; H 5.60; N 10.81f. (%): C, 61.92; H 5.53; N 10.68

Mass spectrum (El): m / z; 267 (M ⁺ , as a free connection)

Example 3 5 - [(2-Methyl-2,3-dlhydro-ndol-1-yl) -carbonyl] -4,5,6,7-tetrahydro-benzimidazole

Physicochemical properties: F .: 230-234 ° C (dec.) (Recrystallized from Essigsäureethyiestor / hexane) Elemental analysis for C ₁₇ Ht ₉ N ₃ O:

calc. (%): C 72.57; H, 6.81; N 14,93 (%): C 72,76; H 6.78; N 14.62

Mass spectrum: m / z; 281 (M ⁺ )

A mixture of 0.27 g (1.05 mmol) of N, N-diethyM, e.ej-tetrahydrobenzimidazole S-carboxamide hydrochloride, 0.16 mL (1.25 mmol) of 1-methylindole and 0.15 mL (1.65 mmol) of phosphorus oxychloride was heated with stirring to 80 ⁰ C for 2 hours. Then, 30 ml of water was added, and the mixture was made alkaline with 1N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol / aqueous ammonia = 10: 1: 0/1 parts by volume) and preparative thin-layer chromatography (eluent: dichloromethane / methanol / aqueous ammonia = 10: 1: 0.1 parts by volume). 20 mg of a foaming substance were obtained. The product was mixed with 10 mg fumaric acid to convert it to fumarate. Recrystallization from ethyl acetate / ethyl acetate (10: 1 by volume) gave 10 mg of 5 - [(1-methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydro-bonimidazole fumarate

Physicochemical properties: Q .: 97-102 ⁰ C

Mass spectrum (El): m / z; 279 (M ", as free compound) NMR (CDCl ₃ ) δ (as free compound):

1.90 to 3.00 (7H, m, CH _2, CH), 3.80 (3H, s, N-Me), 7.20 (2H, m, ArH), 7.50 to 8.00 ( 4H, m, ArH), 8.30 (1H, m, NH)

Example 5

H-HCl

53 ml of acetonitrile were spiked with 5.3 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid e-sulfate and 2.9 ml of thionyl chloride. The mixture was stirred at 53 to 55 ° C for 1.5 hours. Then, the mixture was distilled under reduced pressure to remove 10 to 15 ml of the solvent. After adding 15 ml of acetonitrile, the mixture was further distilled under reduced pressure to again remove 10 to 15 ml of the solvent. The remaining solution was added dropwise at 2 ° C or below to a solution of 14.2 g of pyrrolidine in 50 ml of acetonitrile. After the addition, the temperature was returned to room temperature. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was mixed with 30 ml of saturated aqueous sodium chloride solution. The mixture was extracted with chloroform (3 × 50 ml). The chloroform phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, treated with hydrochloric acid in ethanol and recrystallized from ethanol / ethyl acetate. 4.25 g (82.9%) of N - [(4,5,6,7-tetrahydrobenzimidazole-6-yl-carbonyl-pyrrolidine hydrochloride,

Physicochemical properties:

F .: 234-236X

Elemental analysis for: Ci ₂ Hi ₈ N ₃ OCI 0.2H ₂ O

calc. (%): C 55.57; H 7,15; N 16.20; Cl 13:67

gef. (%): CI 5.64; H 6.99; N 16,18; Cl 13,79

Mass spectrum (El): m / z; 291 (M ⁺ , as free connection)

In the same manner as in Example 5, the following compound was prepared.

Example 6 4- (4,5,6,7-Tetrahydrobenzimidazol-5-ylcarbonyl) -2,3-dlhydro-1,4-benzoxazoline fumarate

COOH

Physicochemical properties:

M.p .: 176-178 ⁰ C (methanol / acetonitrile)

Mass spectrum (El): m / z; 283 (M ⁺ , as a free connection)

elemental analysis for Ci ₆ H _n N ₃ O ₂ .C ₄ H ₄ O ₄ :

bsr (%): C60.14; H5.30; N10.52

gjf. (%): C 59.95; H 5,28; N 10.55

Example 7

HOOC

HCl

• COOH

HOOC-

To 5 ml of thionyl chloride was added 0.58 g (0.98 mmol) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride having a purity of 34.5% (containing sodium chloride). The mixture was stirred for 4 hours at 90 ° C. After cooling, the solution was distilled under reduced pressure to remove thionyl chloride. The residue was mixed with 10 ml of dichloromethane. Then, 0.20 ml (1.59 mmol) of 1,2,3,4-tetrahydroquinoline and 0.35 ml (2.53 mmol) of triethylamine were added. It was then stirred for 48 hours at room temperature. The reaction mixture was then added with 40 ml of dichloromethane, and the mixture was washed with 1N aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography on silica gel using dichloromethane / methanol / aqueous ammonia (10: 1: 0.1 by volume) as eluent. 100mg of a foamy substance was obtained, which was then treated with 40mg of fumaric acid in ethanol to convert to fumarate. Recrystallization from ethyl acetate / methanol (10: 1 by volume) gave 90mg (33.3%) of 1 - ((4,5,6,7-tetrahydrobenzimidazol-5-yd-carbonyl-1-yl) -s-tetrahydroquinoline fumarate ,

Physicochemical properties:

F.:98-100°C

Elemental analysis for C ₁₇ Hi ₉ N ₃ O - C ₄ H ₄ O ₄ · 2H ₂ O:

calc. (%): C, 58.19; H 6,27; N 9.69

% (%): C 58.43; H 5.73; N 9.53

NMR (DMSO-d _e ) 5ppm:

1.90 (4H, q, 7Hz, quinoline CH ₂ x 2), 2.00-3.00 (7H, m, benzimidazoles ^ x 3, CH), 3.70 (2H, t, J = 7Hz, CH ₂ N), 6.60 (2H,

s, fumaric acid CH x 2), 7.16 (5H, m, ArH, NH), 7.55 (1H, s, imidazole CH) Mass Spectrum (El): m / i; 281 (M ⁺ , as a free connection)

Example 8

HOOC

N H

• HC1

To 5 ml of thionyl chloride were added 0.58 g (0.98 mmol) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride having a purity of 34.5% (containing sodium chloride). The mixture was then stirred at 9O ⁰ C for 4 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove thionyl chloride. To the residue were added 10 ml of dichloromethane, 0.20 ml (1.57 mmol) of 1,2,3,4-tetrahydroisoquinoline and 0.35 ml (2.53 mmol) of triethylamine.

The mixture was stirred at room temperature for 48 hours. Then, the reaction mixture was added with 40 ml of dichloromethane, and the mixture was washed with 1N aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was removed from the residue by distillation under reduced pressure. The residue was subjected to column chromatography on silica gel using dichloromethane / methanol / aqueous ammonia (10: 1: 0.1 v / v) as eluent. There was obtained 0.15 g of a white foamy substance, which was then recrystallized from diethyl ether / ethyl acetate. 40mg (14.8%) of 2 - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline was obtained

Physicochemical properties: M .: 128-13O ⁰ C NMR (DMSO-d _e ) ppm:

2.00-3.00 (7H, m, CH ₂ x 3, CH, benzimidazole), 3.00 (2H, t, J = 5Hz, CH ₂ ), 3.40 (2H, t, J = 5Hz ₁ -CH ₂ -), 4.24 (2 H, s, CH ₂ N),

7.22 (6H, m, ArH, NH) mass spectrum (El): m / z; 281 (M ⁺ )

Example 9

H ₂ SO ₄ * -

H HH

A mixture of 0.78 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 3 ml of thionyl chloride was heated to 50 ° C for 20 minutes. The excess thionyl chloride was removed by concentration under reduced pressure. A carboxylic acid chloride was obtained. A solution of the carboxylic acid chloride in 3 ml of dimethylformamide was added to a dimethylformamide solution (30 ml) of 1.61 g of 2-hydroxybenzimidazole and 0.50 g of 60% oily sodium hydride under ice cooling. The reaction mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure. The residue was acidified with 0.5 N hydrochloric acid. Insolubles were removed by filtration. The filtrate was made alkaline with potassium carbonate. The crystals formed were filtered off, washed with water and stirred in acetone overnight. The obtained crystals were recovered by filtration. 0.20 g (24%) of 1 - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) -carbonyl-2,3-dihydrobenzimidazol-2-one was obtained.

Physicochemical properties:

F.:271-274°C(Zers.)

Elemental analysis for Ci ₆ H ₁₄ N ₄ O ₂ .0.4 H ₂ O:

calc. (%): C 62.23; H 5.15; N 19.35

% (%): C62.41; H 5.02; N 19.06

Mass spectrum (El): m / z; 282 (M ⁺ )

In the same manner as in Example 9, the following compounds were prepared.

Example 10 5-Methoxy-1 - [(4,5,6,7-tetrahydrobenzlnildazol-5-yl) carbonyl] -2,3-dihydrobenzimidazol-2-one fumarate

COOH CH ₃ O '

J

Physicochemical Properties: m.p .: 215-218 ⁰ C (dec.) (Recrystallized from methanol) Mass spectrum (El): m / z; 312 (M ⁺ , as free compound) NMR (DMSO-d ₆ ) ppm:

1.57-2.34 (2H, m), 2.34-3.10 (4H, m), 3.76 (3H, s), 3.90-4.28 (1H, m), 6.58 (2H, s), 6.32-6.84 (2H, m), 7.62 (1H, s), 7.89 (1H, d, J = 8Hz)

Example 11 1-Methyl-3 - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] -2,3-dihydro-phenzimidazol-2-one-funiarate

Physicochemical properties:

M.p .: 145-147 ⁰ C (recrystallized from methanol / acetonitrile)

Mass spectrum (El): m / z; 296 (M ⁺ , as a free connection)

Elemental analysis for C ₆ Hien ₄ O ₂ C ₄ H ₄ O ₄ · 0.5H ₂ O):

calc. (%): C 57.00 ;; I ^c 02; N 13,30

gef. (%): C, 56.91; H 5.06; N 13.31

COOH

-H ₂ SO ₄

In 10 ml of 1,2-dichloroethane, 1.32 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 1.78 g of thionyl chloride were refluxed for 30 minutes. The excess thionyl chloride and the solvent were removed by distillation under reduced pressure. The residue was dissolved in 4.0 ml of dry dimethylformamide. The solution was added under ice-cooling to a solution of 2.7 g of 2-aminobenzothiazole in 10 ml of dry dimethylformamide. The mixture was then stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel using a solvent mixture of methylene chloride / methanol as eluent. It was then recrystallized from ethanol. 0.8 g (53.7% N- (2-benzothiazolyl) -4,5,6,7-tetrahydrobenzimidazol-5-ylcarboxamide was obtained.

Physicochemical properties:

F .: 165-167 ⁰ C

Elemental analysis for CiSHi ₄ N ₄ OS 0.25H ₂ O:

calc. (%): C 59.49: H 4.82; N 18.50; S 10,59 gef. (%): C 59.30; H 4.73; N 18.49; S 10.68 Mass spectrum (El): m / z; 298 (M ⁺ ) In the same manner as in Example 12, the following compounds were prepared.

Example 13 N- (2-Benzimidazolyl) -4,5,6,7-tetrahydrobenzimidazol-5-ylcarboxamld

Physicochemical properties:

F .: 182-185 ⁰ C

Elemental analysis for Ci ₆ HiSN ₅ O · 0.6H ₂ O:

calc. (%): C, 61.67; H, 5.58; N 23.97 gef. (%): C, 61.63; H 5.44; N, 23.97 Mass Spectrum (El): m / z; 281 (M ⁺ )

Example 14 N-chloro-nolin-S-ylM ^ ej-tetrahydrobenzimidazole-S-ylcarboxamide

Physicochemical properties:

F .: 296-297 ° C

Elemental Analysis for C | ₇ H | ₈ N ₄ O · 0.25H ₂ O:

calc. (%): C 68.79; H 5.60; N 18.87 gef. (%): C 68.69; H 5.66; N 18.75 mass spectrum (El): m / z; 292 (M *)

Example 15 N-IS-Moth yM.S ^ -thiadiazol-1-yl-yl-S'-yl-tetrahydrobenzimidazole-S-carboxamide

^NHC

N H

Physicochemical property: Elemental analysis for C ₁ , Hi ₃ N ₅ OS · 0.2H ₂ O:

calc. (%): C 49.50; H 5.06; N 26,24; S12,01gef. (%): C, 49.86; H 4,97; N 26.40; P 11:68

Mass spectrum (El): m / z; 263 (M ⁺ )

Example 16 N- (9-Ethylcarbazol-3-yl) -4,5,6,7-tetrahydrobenzimidazole-5-carboxamide

NHC

Physicochemical properties:

Q .: 168-17O ⁰ C

Elemental analysis for C ₂₂ H ₂₂ N ₄ O 0.5H ₂ O:

calc. (%): C, 71.91; H, 6.31; N 15.25 (%): C, 71.77; H 6,13; N 15,13

Mass spectrum (El): m / z; 358 (M ⁺ )

Example 17 N - [(4,5,6,7-Tetrahydrobenzimidazol-5-yl) carbonyl] phenothiazine hydrochloride

HCl

Physicochemical properties:

F .: 268-27O ⁰ C

Elemental analysis for C ₂₀ Hi ₇ N ₃ OS · HCI · 0.5H ₂ O:

calc. (%): C 61.14; H, 4.87; N, 10.69; Cl 9.02 gef. (%): C 61.15; H 4.64; N 10.60; Cl 8.59 mass spectrum (El): m / z; 347 (M ⁺ , as a free connection)

Example 18 N-1Se-Dihydro-1H-cyclopentathlazole-1-yl-methyl-B. Ej-tetrahydrobenzimidazole-S-carboxamide

Physicochemical properties:

F .: 164-165 ⁰ C

NMR (DMSO,) ppm: 1.70-3.00 (13H), 7.426 (IH) Mass spectrum (El): m / z; 288 (M ⁺ ),

Example 19 N-IPyrlmldln ^ -ylH.S.ej ^ etrahydro-benzimidazole-S-carboxamide-dlhydrochloride

2HCl

Physicochemical properties:

F.:287-289°C

Elemental analysis for C ₁₂ H ₁₃ N ₆ O.2HCl · 1.4H ₂ O:

calc. (%): C 42.22; H 5.25; N 20.51; Cl 20.77. (%): C 42.35; H 5.00; N 20.69; Cl 20,45

Mass spectrum (El): m / z; 243 (M ⁺ , as a free connection)

Example 20 N- (pyridin-3-yl) 4,5,6,7-tetrahydrobenzimidazole-5-carboxanilide dihydrochloride

NHC

2HCl

Physicochemical properties:

F .: 285-287 ⁰ C

Elemental analysis for C ₁₃ H ₁₄ N ₄ O.2HCl:

calc. (%): C49.54; H 5,12; N 17,77f. (%): C, 49.74; H 5.26; N 17.53

Mass spectrum (El): m / z; 242 (M ⁺ , as a free connection)

Example 21 N- (3-Ethoxycarbonyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -4,5,6,7-tetrahydrobenzimidazole-5-carboxamide

Physicochemical properties:

F .: 159-161 ⁰ C

Elemental analysis for C ₁₉ H ₂₃ N ₃ O ₃ S:

calc. (%): C 61.10; H 6.21; N 11,25; S8.59gef. (%): C, 60.87; H 6,16; N 11.05; S 8,62

Mass spectrum (El): m / z; 373 (M ⁺ )

Example 22 N-Ilndazol-e-ylM ^ ej-tetrahydrobenzimidazole-S-carboxamide

Il

NHC

Physicochemical properties: F.:300 ^o C

Elemental analysis for C ₁₅ H ₁₆ N ₅ O: calc. (%): C, 64.04; H 5.37; N 24.89 gef. (%): C 63.79; H 5.42; N 24.75 Moss spectrum (El): m / z; 281 (M ⁺ )

Example 23

CV

TX>

HCX

CO ₂ H

4 g of N - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] -pyrrolidine hydrochloride obtained according to Example 5 were added to 40 ml of dichloroethane. 274g of indole and 4.4ml of phosphorus oxychloride were added. The mixture was stirred for hours at 80 to 85 ⁰ C and then overnight at room temperature. Then, the mixture was added with 40 ml of cold aqueous potassium carbonate solution and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography using chloroform / methanol as the eluent. 1.82 g of 5 - [(indole-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole were obtained as a foamy substance. In 1 ml of methanol was dissolved 0.16 g of the obtained product and 0.06 g of fumaric acid. The solution was treated with 5 ml of acetonitrile. The crystals formed were recovered by filtration. 0.13 g of 5 - ((indole-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole fumarate was obtained.

Physicochemical properties:

F .: 153-154 ⁰ C

Elemental analysis for C ₁₆ H ₁₅ N ₃ O · C ₄ H ₄ C ₄ · 0,15CH ₃ CN · 0.65 H _s O Calculated (%). C 61.07; H 5.24; N 11.05% (%): C 61.11; H, 5.01; N 11.04 Mass Spectrum (FAB): m / z; 266 (M ⁺ + 1, as a free compound) In the same manner as in Example 23, the following compounds were prepared.

Example 24 5 - [(1,2-Dlmethylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole-3/4-fumarate

COOH

Physicochromic properties:

F .: 220-223 ⁰ C

Elemental analysis for C ₁₈ H ₁₉ N ₃ O 3 / 4C ₄ H ₄ O _4:

calc. (%): C 66.30; H 5.83; N 11.05 gef. (%): C 66.50; H 5.83; N 11.13 mass spectrum (El): m / z; 293 (M ⁺ , as a free connection)

Example 25 F - [(2-Methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole-1/2-fumarate

Physicochemical properties:

F .: 221-223 ⁰ C

Elemental analysis for C ₁₇ H ₁₇ N ₃ O · 1 / 2C ₄ H ₄ O ₄ · 0.25H ₂ O:

COOH

calc. (%): C 66.75; H 5.75; N 12.29f. (%): C 66.73; H 5.75; N 12,29>

Mass spectrum (El): m / z; 279 (M \ as free connection)

Example 26 5-f (2-Benzyllindol-3-yl) carbonyl] - '<5,6,7-tetrahydrobenzimidazole fumarate

N COOH

HOOC

Physicochemical properties:

F .: 183-186 ⁰ C

Elemental analysis for C ₂₃ H ₂₁ N ₃ O.C ₄ H ₄ O ₄ .0.1 H ₂ O:

calc. (%): C 68.52; H 5.37; N 8,88 gef. (%): C 68.38; H 5.50; N 8,87

Mass spectrum (El): m / z; 355 (M ⁺ , as free connection)

Example 27 5 - [(5-Methoxyindol-3-yl) carbonyl] -4,5,6,7-tetrahydro-β-imidazole-3/4-fumarate

^v4

BOOC

COOH

PhysiKochemical properties:

F .: 162-164 ⁰ C

Elemental analysis for C ₁₇ H ₁₇ N ₃ O ₂ 3 / 4C ₄ H ₄ O ₄ · 0,2CH ₃ CN · 0.85H ₂ O:

calc. (%): C 60.36; H, 5.54; N 11.04% (F): C 60.33; H 5.25; N, 10.93 mass spectrum (El): m / z; 295 (M ⁺ , as a free connection)

Example 28 S-KB-chloro-methylindol-S-yl-carbonyl-^. S.e.-tetrahydrobenzimidazole fumarate

me

COOH

HOOC

Physikochenvsche characteristics:

F .: 212-213 ⁰ C

Elemental analysis for C ₁₇ Hi ₈ N ₃ OCI.C ₄ H ₄ O ₄ :

calc. (%): C, 58.68; H 4.67; N 9.78; Cl 8,25 gef. (%): C 58.43; H 4.91; N, 9.67; Cl 8,24

Mass spectrum (FAB, Pos): m / z; 314 (M ⁺ + 1, as free association)

Example 29 5 - [(5-Nitroindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

Physicochemical Properties: m.p .: 227-229 ⁰ C NMR (DMSO-d _e) 100M, ö:

2.00 (2H, m), 2.70 (4H, m), 3.63 (1H, m), 7.44 (1H, s), 7.64 (1H, d _{e 7} = 12 Hz), 8.10 (1 H, dd, J _e , ₇ = 12 Hz, J _{4 e} = 4 Hz), 8.72

(1H, s), 9.07 (1H, d, J, _e = 4Hz), 12.56 (1H, br) Mass Spectrum (El): m / z; 310 (M ⁺ )

Example 30 5 - [(5-Methoxycarbonylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

MeOC

rJ

Physicochemical properties: M .: 205-209 ⁰ C NMR (DMSO-d ₆ ) 100Mo:

1.90-2.15 (2H, m), 2.83 (4H, br), 3.75 (1H, br), 7.56 (1H, d, J _{e, 7} = 12Hz) , 7.84 (1 H, dd, J ₆ ... = 12 Hz, J _{4 e} = 3 Hz), 8.62 (1 H,

d, J ₂ . mi = 4 Hz), 8.90 (2H, s), 12.60 (1H, d, J ₂ , _ml = 4Hz) Mass Spectrum (El): m / z; 323 (M *)

Example 31 5 [(5-hydroxylindole-3-yl) -carbonyl] 4, S, 6,7-t-tetrahydroboroziridazole 1/2-fumarate

.COOH

Physicochemical properties: F .: 282-286X NMR (DMSO-d ₆ ) 100M5:

1.90 (2H, br), 2.85 (4H, br), 3.74 (1H, br), 6.76 (1H, s), 6.84 (1H, dd, J ₆₇ = 12Hz, J ₄₆ = 4Hz), 7.41 (1H, d, J ₆₇ = 12Hz), 7.74

(1 h, d, J = ₄ .e 4 Hz), 8.50 (1 H, d, J _{2, m,} = 5Hz), 9.07 (1 H, s), 11.95 (1 H, d , J ₂ , _N ,) mass spectrum (El): m / z; 281 (M *, as a free connection)

Example 32

HO ₂ C-

^s C0 ₂ H

0.04 g of 60% oily sodium hydride were added to 5 ml of dry dimethylformamide. At room temperature, 0.51 g of 5 - ((indole-3-yl) carbonyl] -4,5,6,7-tetrahydro-1 were then slowly added 30 minutes later, 0.07 g of benzyl bromide was added slowly at ⁰ ° C. and then stirred at room temperature overnight The reaction mixture was then treated with 20 ml of water and 20 ml of chloroform to carry out a .multidot The organic phase was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the residue was subjected to chromatography using chloroform / methanol as the eluent to obtain the resulting foamy substance (0.12 g). was recrystallized from ethanol / ethyl acetate along with 0.04 g of fumaric acid to give 0.10 g of 5- | (1-benzylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole-fumar t.

Physicochemical properties:

F .: 117-118 "C

Elemental analysis for C ₂₃ H ₂₎ N ₃ O.C ₄ H ₄ O ₄ .0.75H ₂ O:

calc. (%): C 66.86; H, 5.51; N 8,66 gef. (%): C 66.83; H 5.48; N 8.88 Mass Spectrum (El): m / z; 321 (M ⁺ , as free compound) In the same manner as in Example 32, the following compounds were prepared.

Example 33 S-ld-cyclohexylmethylindole-S-ylcarbonylAS.ej-tetrahydrobonzine diazole-funiarate

HOOC

^ COOH

Physicochemical properties:

F .: 95-100T (ethanol / ethyl acetate) Glementaranalyse for C ₂₃ H ₂₇ N ₃ O · C ₄ H ₄ O ₄ · 0,5AcOEt:

calc. (%): C, 62.46; H 7.05; N, 7.54% (F): C, 62.59; H 6.69; N, 7.19 Mass spectrum (El): m / z; 361 (M ⁺ , as free connection)

Example 34 5 - [(1-Allylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole fumarate

I HOOC v.

I _n ^ _n ^/ cooh

CH ₂ -CH = CH ₂

Physicochemical properties:

F .: 144-145 "C (methanol / ethyl acetate) elemental analysis for C, ₉ H _{) 9} N ₃ O.C ₄ H ₄ O _4. 0.35 AcOEt. 0.3H ₂ O:

calc. (%): C 64.03; H 5.81; N 9,18 gef. (%): C 64.00; H 5.74; N, 9.17 mass spectrum (El): m / z; 305 (M ⁺ , as a free connection)

Example 35 S-ni-n-Butyllndol-S-y-carbonyl ^ S.beta.-tetrahydrobenzititazol fumarate

Π HOOC>

", / ^ COOH

υ ::

nBu

Physicochemical properties: _t F .: 104-106 ° C (ethanol / acetonitrile) Elemental analysis for C ₂₀ H ₂₃ N ₃ O.C ₄ H ₄ O ₄ .0.8H ₂ O:

calc. (%): C 63.78; H 6,38; N 9.30

gef. (%): C, 63.82; H 6 14; N 9.33

Mass spectrum (El): m / z; 321 (M ⁺ , as a free connection) Example 36

OOH

CH ₂ CaCH

Physicochemical properties: M.p .: 130-131 ⁰ C (ethanol / acetonitrile) Elemental analysis for C ₁₉ Hi ₇ N ₃ OC ₄ H ₄ O ₄ 1.3H ₂ O:

calc. (%): C 62.38; H 5.37; N 9.49

gef. (%): C, 62.38; H 5:19; N 9,21

Mass spectrum (El): m / z; 303 (M *, as free connection) Example 37

" ^c xx>

H ₂ SO ₄

%. H ₂ SO ₄

HO ₂ C

CO ₂ H

In 5 ml of acetonitrile, 0.53 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate were suspended. The suspension was treated with 0.29 ml of thionyl chloride. Then, the suspension was stirred 1 Stunclu at 55 to 60 ⁰ C and the solvent removed by distillation under reduced pressure. The residue was treated with 4.6 ml of benzothiophene. Then, 0.4 g of aluminum chloride was added. After 3 hours of stirring at 60 ⁰ C, the reaction mixture was poured into a cold aqueous potassium carbonate solution. The solution was adjusted to a pH of 8 to 9 and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The residue was purified by column chromatography on silica gel using ve η chloroform / methanol as eluent. There was obtained S-KBenzothiophen-S-yD-carbonyl ^ .B.ej-tetrahydrobenzimidaiiol. The product was treated with an equimolar amount of fumaric acid in the usual manner and recrystallized from ethanol / acetonitrile. There was obtained 0.04 g of o-cyanothiazothiophene-S-yl-J-carbonyl-β-S.ej-tetrahydrobenzimidazole fumarate

 Physicochemical properties: F.: 135-137 ° C

-22- 291 781

Elementalanulyso for CeH ₁₄ N ₂ OS · C ₄ H ₄ O ₄ · 0.3EtOH · 0.2HjO calc. ("/ 'C 59.50; H 4.90; N 6.74; %): C, 69.41, H, 5.07, N, 6.53, S, 7.91, mass spectrum (EI): m / z, 282 (M *, as free-stranding)

H ₂ SO ₄

A mixture of 2 g of polyphosphoric acid, 5 ml of thiophone and 2.91 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate was stirred at 10O ⁰ C for 8 hours. After cooling, 20 ml of cold water were added and the reaction mixture was washed with toluene (20 ml χ 2). The aqueous phase was adjusted to pH 8-9 with potassium carbonate and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The residue was treated with a 4N solution of hydrogen chloride in ethyl acetate and then recrystallized from methanol / acetonitrile. This gave 0.12 g of 5 - [(thiophon-2-yl) -carbonyl-4,5,6,7-

tetrahydrobenzimidazole hydrochloride.

Physicochemical property:

F.:218-220°C

Elemental analysis for C ₁₂ H ₁₂ N ₂ OS · HCl:

calc. (%): C, 53.63; H 4,88; N, 10.42; S11.93 gef. (%): C 53.25; H4,98; N, 10.62; S 11.70 Mass spectrum (El): m / z; 232 (M *, as a free connection)

Example 3S

HCl

A solution of 0.50 g of N - [(4,5,6,7-tetrahydrobenzimidazol-5-ylkrbonylpyrrolidine hydrochloride and 0.39 g of 2-methylindolizine in 5 ml of 1,2-dichloroethane was added dropwise with 0.90 g of phosphorus oxychloride . the reaction mixture was heated overnight at 85 ⁰ C under reflux. After cooling to room temperature 5ml water were added. the organic phase was removed and added to the aqueous phase with 10 ml of chloroform. the solution was treated with a 20% aqueous solution of sodium hydroxide The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation, and the residue was purified by column chromatography on silica gel using chloroform / methanol as an eluent, followed by recrystallization from ethanol 0.21 g of 5 - [(2-methylindolizin-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole was obtained. Physicochemical properties: Q .: 260-264 ⁰ C

. Elemental analysis for C ₁₇ H ₁₇ N ₃ O · 0.15C ₂ H ₆ OH · 0.2H ₂ O Calculated (%): C 71.68; H 6,36; N 14.50% (%): C 71.71; H 6,16; N 14.46 mass spectrum (El): m / z; 270 (M *)

Example 40

According to Example 39, using pyrrole instead of 2-methylindolizine, 5 - ((2-pyrrolyl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole of the formula given below was prepared.

Physicochemical properties: F .: 225-226 ° C

Elementary.dlyse for Ci ₂ Hi ₃ N ₃ O: calc. (%): C, 66.96; H 6.09; N 19.52 gef. (%): C 66.74; H 6,23; N, 19.41 mass spectrum (El): m / z; 215 (M ⁺ )

Example 41

H • HCl

A suspension of 7.0 g of N - ((4,5,6,7-tetrahydrobenzimidazol-6-yl) carbonyl) -pyrrolidine hydrochloride and 5.4 g of N-methylindole in 70 ml of ethylene chloride was treated with 12.6 g of phosphorus oxychloride. The mixture was stirred at 80 to 85 ^° C. for 7 hours. The mixture was allowed to cool, then further cooled to 0-5 ° C and added slowly with 70 ml of cold water, keeping the temperature of the mixture below room temperature. Thereafter, excess phosphorus oxychloride was decomposed. The organic phase was removed. The aqueous phase was adjusted to pH 9 with aqueous 20% sodium hydroxide solution with cooling and then extracted with chloroform. Did chloroform phase was mixed with 70 ml of water. 6N hydrochloric acid was added under ice-cooling and with stirring to adjust the pH to 2.4 to 2.8. The chloroform phase was removed. The aqueous phase was washed with chloroform and treated with 40 ml of methanol. The solution was made alkaline with aqueous 20% sodium hydroxide solution with cooling. The crystals formed were recovered by filtration and washed with a cold 1: 1 (by volume) mixture of methanol and water. This gave 6.87 g (89.9%) of δ-KI-methylindole-S-yD-carbonyl ^^. E ^ -tetrahydrobenzimidazole. Physicochemical properties: Q .: 139-141 ⁰ C

Mass spectrum (El): m / z; 279 (M ⁺ ) ¹ H-NMR (CDCl 3 DMSO-de):

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), 8.20-0.40 (m, 1H)

Elemental analysis for Ci ₇ H ₁₇ N ₃ O. 0.2EtOH. 0.35H ₂ O: calc. (%): C, 70.88; H 6,46; N 14.25% (%): C 70.83; H 6,50; N 14,23

Example 42 \\ 0 ii H ex Il

HOOC-

1.2

* C00h

CH ₁

5 - [(1-Methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole was treated with half the molecular weight of fumaric acid in ethanol in a manner known per se. 5 - ((1-Dimethylthyl-3-yl) carbonyl] -. 4,5,6,7-tetrahydro-phenimidazole 1/2-fumarate was obtained.

Physicochemical properties:

F .: 224-225 ⁰ C

Elemental analysis for Ci ₉ Hi ₃ N ₃ Oa:

calc. (%): C, 67.64; H 5.68; N 12,45

(%): C 67.56) H 5.66; N 12.35

Mass Spectrum (FAB): m / z; 280 (M * + 1, as free connection) Example 43 Optical resolution (1) of 5 - [(1-methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

(a) 60ml of methanol were added with 5.87g of 5 - [(1-methylindol-3-yl) -carbonyl-4,5,6,7-tetrahydrobenzimidazole obtained according to Example 41. A solution of 7.52 g of (+) - dibenzoyltartaric acid in 240 ml of methanol was added, resulting in a clear solution immediately. On standing the solution at room temperature overnight, crystals precipitated through

Filtration were recovered and recrystallized three times from dimethylformamide / water. This gave 2.30 g of (R) - (-) - 5

[(I-methyl indole-S-y D-carbonylM.S.e ^ -tetrahydrobenzimidazoM + J dibenzoyltartrate.

Physicochemical properties:

[a] D ^M = + 30.6 ° (c = 1.10; dimethylformamide)

F .: 169.0-170.0 ⁰ C

Elemental analysis for Ci ₇ Hi ₇ N ₃ O. C ₁₈ Hi ₄ O ₈ .H ₂ O:

calc. (%): C 64.12; H 5.07; N 6,41

% (%): C 64.13; H 5.03; N 6,55

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

(b) To a 2N aqueous hydrochloric acid solution was added 2.2 g of the compound obtained in the above (a). The solution was washed with ethyl acetate and then adjusted to about pH with sodium carbonate. The aqueous phase was extralated with chloroform / methanol (4: 1 by volume). The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. There was obtained 0.94 g of (R) - (-) - 5- (1-methylindol-3-yl) carbonyl] -4,5, e, 7-tetrahydrobenzimidazole as a foaming substance.

[ate ⁰ = -16.5 ° (c = 1.13, methanol).

(c) (RM-1S-ld-methylindole-S-y-carbonyl) Me.Bey-tetrahydrobenzimidazole (0.56 g) obtained in the above (b) was treated with 0.21 g of fumaric acid in methanol / acetonitrile 0.64 g of (R) - (-) - 5 - [(1-methylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazole fumarate was obtained.

[a] = -28.1 ° l ° (c = 1.22; methanol) m.p .: 150.5 to 151.5 ⁰ C

Elemental analysis for C ₁₇ H ₁₇ N ₃ O · C ₄ H ₄ O ₄ · 0,35CH ₃ CN · 0.25H ₂ O Calculated (%). C 62.91; H 5.49; N 11.33 F (%): C, 62.94; H 5.41; N 11.35 Mass Spoktrum (El): m / z; 279 (m *, as free connection)

Example 44

In ethanol / ethyl acetate, 100 mg (RM-1-S-KI-methyl-S-indoly-D-carbonyl-M-e.ej-tetrahydro-benzimidazole obtained according to Example 43 (b) was dissolved.) A solution of hydrogen chloride in ethyl acetate was added.

The crystals formed were recovered and recrystallized from ethanol. There was obtained 70 mg of (R) - (-) - 5 - [(1-methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole hydrochloride.

(a) o = -42.9 ° (c = 1.02, methanol) F: 215-23O ⁰ C

Elemental analysis for CnHi ₇ NaO · HCl:

calc. (%): C, 64.66; H 5.75; N 13.31; Cl 11,23 gef. (%): C, 64.37; H 5.80; N 13:12; Cl 11.17 mass spectrum (El): m / z; 279 (M ⁺ , as a free connection)

Example 45

Optical resolution (2) of 5 - [(1-methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

(a) In the same manner as in Example 43 (a), using (-J-dibenzoyltartaric acid S1-l + 1S-KI-methylindol-S-yl) -carbonyl) -4,5,6,7-tetrahydrobenzimidazole (-) - dibenzoyl tartrate.

[α) "= -30.3 ° (c = 1.07, dimethylformamide) m.p .: 168.5 to 169.5 ⁰ C

Elemental Analysis for C) ₇ Hi ₇ N ₃ OC ₁₉ H ₁₄ O ₈ .H ₂ O:

calc. (%): C 64.12; H 5.07; N 6,41 gef. (%): CG4.13; H5.13; N6.71 Mass Spectrum (FAB): m / z; 280 (M ⁺ + 1, as free connection)

(b) In the same manner as in Example 43 (b), using the salt obtained in the above section (a), (S) - (+) - 5 - ((1-methylindole-S-y-carbonyl-acyl) tetrahydrobenzimidazole obtained as a foamy substance.

[α] έ ° = + 16.7 ° (c = 0.35, methanol)

(c) In the same manner as in Example 43 (c), using the (S) - (+) - 5 - [(1-methylindol-3-yl) carbonyl] -4 obtained in the above (b) , 5,6,7-tetrahydrobenzimidazole crystalline (S) - (+) - | (1-methylindol-3-yl) carbonyl) -4,5,6,7-tetrahydrobenzimidazol fumarate obtained.

[α] έ ° = + 28.3 ° (c = 1.14, methanol) mp: 151.0-152.0 ° C

Elemental analysis for C] ₇ Hi ₇ N ₃ OC ₄ H ₄ O ₄ · 0,35CH ₃ CN · 0.25 _H2 O:

calc. (%): C, 62.91; H 5.49; N Vi 33 gef. (%): C, 62.96; H 5.39; N 11.37 mass spectrum (El): m / z; 279 (M *, as a free connection)

COCI

^{> H} 2 ^SO 4 -H ₂ SO ₄

4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32g) was refluxed in 10ml of 1,2-dichloroethane along with 1.78g of thionyl chloride for 30 minutes. The excess thionyl chloride and the solvent were removed by distillation under reduced pressure. The residue was treated with 10 ml of 1,2-dichloroethane. Then, at 30 ° C or below with stirring 1.6 ml indoline was added dropwise. The mixture was then stirred for 2 hours at room temperature. Then, the reaction mixture was added successively once with 30 ml of water and twice with 20 ml of water. The combined aqueous phase was adjusted to a pH of 9-10 with aqueous 10% sodium hydroxide solution and then extracted with methylene chloride. The combined methyl chloride phase was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate. 1.1 g (82.7%) of 5 - [(2,3-dihydroindol-1-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole were obtained. Physicochemical properties: Q .: 175-178 ⁰ C

Mass spectrum (El): m / z; 267 (M ⁺ ) ¹ H NMR (CDClI-DMSO-de):

1.80-2.36 (m, 2H), 2.48-3.12 (m, 5H), 3.24 (t, 2H), 4.20 (t, 2H), 6.84-7 , 30 (m, 3H), 7.50 (s, 1H), 8.20 (dd, 1H) Elemental analysis for CuHi ₇ N ₃ O · 0.25H ₂ O calc. (%): C 70.70 ; H 6,49; N 15.46 gef. (%): C 70.79; H 6,37; N 15,19

Example 47

5-t (2,3-Dihydroindol-1-yl) carbonyl] -4,5,6,7-tetrahydrobonzimidazole obtained according to Example 46 was treated in the usual way with hydrochloric acid in ethanol. 5- (2,3-Dihydroindol-1-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole hydrochloride of the formula was obtained

HCl

Physicochemical properties:

Elemental analysis for Ci ₆ H ₁₀ N ₃ OCI:

calc. (%): C 63.26; H 5.97; N 13,83; Cl 11,67 gef. (%): C 63.15; H 5.97; N 13.80; Cl 11.78 Mass spectrum (El): m / z; 267 (M ⁺ , as a free connection)

Example 48

Optical resolution (1) of 5 - [(2,3-dlhydrolndol-1-yl) carbonyl] -4,5,6,7-tetrahydrobenzyldisazole

(a) 4 g of 5 - [(2,3-dihydroindol-1-yl) carbonyl] -4,5,6 _> 7-tetrahydrobenzimidazole obtained according to Example 46 were dissolved in 50 ml of methanol. A methanolic solution (250 ml) of 2,70 g (-) - dibenzoyltartaric acid was added. The crystals formed were collected by filtration and recrystallized twice from dimethylformamide / water. This gave 2.88 g of a (-) - dibenzoyl tartrate with an optical rotation of -34.0 ° (20 ° C, sodium D-line, c = 0.63 g / dl, dimethylformamide).

Physicochemical properties:

F .: 163.5-165.0 ° C

Elemental analysis for Ci ₆ H ₁₇ N ₃ O.C ₁₈ Ht ₄ O ₈ .0.7DMF.2.2H ₂ O:

calc. (%): C 60.59; H 5.66; N 7,22 gef. (%): C 60.53; H 5,28; N 7.26 Mass Spoktrum (El): m / z; 267 (M ⁺ , as a free connection)

(b) The above-prepared salt (2.65 g) was added to 2N hydrochloric acid. The solution was washed with ethyl acetate. The solution was then adjusted to pH 9 with sodium carbonate. The aqueous phase was extracted with chloroform / methanol (4: 1 by volume). The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. This gave 0.95 g of a base with an optical rotation of -6.3 ° (20 ⁰ C, sodium D-line, c = 1.05 g / dl, methanol) as a foamy substance!

Physicochemical properties:

F .: 100-106 ⁰ C

Elemental analysis for Ci ₆ H ₁₇ N ₃ O. 0.2 AcOEt. 0.5H ₂ O:

calc. (%): C, 68.64; H 6.72; N 14,29 gef. (%): C, 68.62; H 6,53; N, 14.30 mass spectrum (El): m / z; 267 (M ⁺ )

(c) The foamy base obtained above was dissolved in ethanol / ethyl acetate. The solution was treated with a solution of hydrogen chloride in ethyl acetate. This gave 0.94 g of crystalline hydrochloride with an optical rotation of + 19.1 ° (2O ⁰ C, sodium D-line, c = 1.06 g / dl, methanol).

Physicochemical properties:

F.: 241-244 ° C (Zers.) Elemental analysis for C ₁₉ H ₁₇ N ₃ O.HCl calc. (%): C, 63.26; H 5.97; N 13,83; Cl 11,67 gef. (%): C 63.18; H, 6.04; N 13,78; Cl 11.45 mass spectrum (El): m / z; 267 (M ⁺ , as a free connection)

Example 49 Optical resolution (2) of 5 - [(2,3-dlhydrolndol-1-vl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

(a) According to Example 48 (a), using (- t -) - dibenzoyltartaric acid, crystalline (+) - dibenzoyl tartrate with an optical rotation of + 33.4 ° (2O ⁰ C, sodium D-line, c = 0 , 60, dimethylformamide).

Physicochromic properties:

F .: 165.0-166.5-C

. Elemental analysis for C ₁₆ Hi ₇ N ₃ O · C ₁₈ Huo ₈ · 0,7DMF · 1,85H ₂ O Calculated (%): C 61.13; H 5.61; N, 7.28% (%): C, 61.12; H 5,28; N, 7.28 mass spectrum (El): m / z; 267 (M ⁺ , as a free connection)

(b) According to Example 48 (b), using the salt obtained in paragraph (a) above, a base with an optical rotation of + 7.9 ° (20 ° C, sodium D-line; c = 1.06, Methanol) as a foamy substance. Physicochemical properties:

F .: 98-103 ⁰ C

Elemental analysis for C ₁₆ Hi ₇ N ₃ O · 0.5H ₂ O · 0,15AcOEt:

calc. (%): C 68.86; H, 6.68; N 14.51 gef. (%): C, 68.65; H, 6.66; N 14,45 Mass spectrum (El): m / z; 267 (M ⁺ )

(c) According to Example 48 (c), using the foamy base obtained in paragraph (b) above, a crystalline hydrochloride having an optical rotation of -19.2 "(20 ° C, sodium D-line, c = 1, 07, methanol) Physicochemical properties:

. F.:239-242°C(Zers) Elemental analysis for C ₁₆ H ₁₇ N ₃ O HCl: Calculated (%): C, 63.26;. H 5.97; N 13,83; Cl 11,67 gef. (%): C 63.07; H 5.99; N 13,76; Cl 11.58 mass spectrum (El): m / z; 267 (M *, as a free connection)

Example 50

/ COOH «www

In 40 ml of acetonitrile, 5.00 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate were suspended. The suspension was treated with 2,75ml thionyl chloride and then stirred for 1 hour at 55 ⁰ C. Then, the solvent was distilled off under reduced pressure. The residue was treated with 20 ml of nitrobenzene and 1.80 ml of 2-methylbenzofuran. Then, 2.20 ml of tin tetrachloride was added. After stirring overnight at 85 ° C, 40 ml of 1M aqueous hydrochloric acid and 40 ml of ethyl ether were added. The organic phase was removed, 40 ml of chloroform were added and the solution was adjusted to pH with aqueous 10% sodium hydroxide solution. The reaction solution was filtered through celite and then extracted with chloroform containing 10% methanol. The organic phase was recovered and the solvent distilled off. The free base of the desired product obtained by treating the residue by column chromatography on silica gel

Using chloroform / methanol, the calculated amount of fumaric acid was added to convert it to the fumarate. It was then recrystallized from ethanol. 0.14 g of 5 - [(2-methylbenzofuran-3-yd-carbonyl-4,5, e, 7-tetrahydrobenzimidazole fumarate.

Physicochemical properties:

F .: 188-189 ° C

Elemental analysis for CjHi ₆ N ₂ O ₂ .C ₄ H ₄ O ₄ :

calc. (%): C 63.63; H 5.09; N 7.07 gef. (%): C, 63.47; H 5.06; N, 7.01 Mass Spectrum (El): m / z; 280 (M ⁺ , as a free connection)

Example 51 5 - [(Indolyl-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole

In the same manner as in Example 39, using indolezin instead of 2-methylindolizine, the above-mentioned compound was obtained.

Physicochemical properties:

F .: 210-212 ⁰ C

Elemental analysis for C ₁₆ Hi ₆ N ₃ O. 0.1 H ₂ O calc. (%): C, 71.94; H 5.74; N 15,73 gef. (%): C, 72.08; H 5.79; N 15.67 Mass Spectrum (El): m / z; 265 (M ⁺ )

Example 52 S-td-Methyllndolizln-a-yD-carbonyl- ^ S.ej-tetrahydrobenzimidazole

In the same manner as in Example 39, using 1-methylindolizine instead of 2-methylindolizine, the above-mentioned compound was obtained.

Physicochemical properties:

F .: 122-123 ° C

Elemental analysis for C _n Hi ₇ N ₃ O · 0.25C ₄ Hi ₀ O · 0.4H ₂ O Calculated (%): C70.87;. H 6.71; N 13.77 gef. (%): C, 70.88; H, 6.68; N 13.66 Mass Spectrum (El): m / z; 279 (M ⁺ )

Formulleri / iigsbeisplel 1 (tablets)

Compound of Example 44 (hereinafter referred to as Compound A) 0.2 mg of lactose 106.4 mg

Corn starch 48.0 mg

Hydroxypropylcellulose 4.8mg

Magnesium Stearate 0.6mg

Total: 160.0 mg / tablet

Compound A (200 g), lactose (106.4 g) and corn starch (48 g) were uniformly mixed and mixed with 48 ml of 10% aqueous hydroxypropylcellulose solution. The mixture was granulated by means of a granulator. The granules were mixed with 0.6 g of magnesium stearate. The mixture was compressed into 1000 tablets each weighing 160 mg.

-28- 291 Formulation Example 2 (Powder)

Compound A 0.4mg

Mannitol 770.0mq

Corn starch - 199,6mg

Polyvinylpyrrolidone 30.0 mg

Total: 1000.0 mg

Compound A (0.4 g), mannitol (770 g) and corn starch (199.6 g) were mixed uniformly. The mixture was mixed with 300 ml of 10% aqueous solution of polyvinylpyrrolidone and then granulated by means of a granulator. This gave 1 kg of powder.

Formulation Example 3 (Capsules)

Compound A 0.2 mg

Corn starch 198,8mg

Calcium stearate 1.0mg ·

Total: 200mg

Compound A (0.2 g), corn starch (198.8 g) and calcium stearate (1 g) were uniformly mixed. Each 200 mg of the mixture was filled into size # 3 capsules. One received 1000 capsules.

Formulierungsbelsplel 4 (syrup)

Compound A 0.2mg

Sucrose 8.0mg

pure water ad 5ml

Compound A (0.2 g) and sucrose (8 g) were dissolved in distilled water to make 5 liters of syrup. Formulation Example 5 (Injection Liquid)

Compound A 0.3mg

Sodium chloride 9mg

Distilled water for injections ad 1.0 ml

Compound A (300 mg) and sodium chloride (9 g) were dissolved in distilled water for injection. 1 000 ml of a solution was obtained. The solution was filtered and filled into ampoules in amounts of 1 ml each, displacing the atmosphere of the ampoules with nitrogen gas. The vials were sterilized by autoclaving.

Example 53

(1) 10 ml of dichloroethane are added with 1.08 g of S-pyrrolidinocarbonyl AS.e.sub.4 -tetrahydrobenzimidazole hydrochloride and 1.18 ml of phosphorus oxychloride, and the mixture is stirred at 80.degree. C. for one hour. At the same temperature, 0.69 g of 3-methylindolizine in 2 ml of dichloroethane are added dropwise over 15 minutes. The mixture is refluxed with stirring for 3 hours and then the mixture is poured into 20 ml of ice-water and then extracted at room temperature for 30 minutes. After the liquid-liquid separation, the aqueous layer is washed with 10 ml of dichloromethane. Subsequently, the aqueous layer is adjusted to a pH of about 9 with 20% sodium hydroxide solution and then extracted twice with 20 ml of chloroform-methanol (4: 1). The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is washed with 20 ml of dichloromethane-ethyl acetate (3: 1) to give 1.00 g of S-IO-methylindolizine-i-yD-carbonyl ^. E.ej-tetrahydrobenzimidazole.

Physicochemical properties:

Melting point: 219-221 ° C

Elemental analysis for Ci ₇ H ₁₇ N ₃ O. 0.05 AcOEt. 0.1 H ₂ O:

calc. (%): C 72.35; H 6.21; N 14.72

gef. (%): C, 72.42; H 8,16; N 14,84

Mass spectrum (El): m / z 279 (M ⁺ )

(2) Dissolve 0,56 of the compound obtained in (1) in 10 ml of ethyl acetate of ethyl acetate (4: 6) and add 0.5 ml of 4N hydrochloric acid-ethyl acetate solution to the solution. The resulting crystals are filtered off and recrystallized from ethanol to give 0.33 g of B-IO-methylindoline-i'yDcarbonyl ^ .S.ej-tetrahydrobenzimidazole'hydrochloride.

Physicochemical properties:

Melting point: 250-255 ⁰ C (decomposition) Elemental analysis for C ₁₇ H ₁₇ N ₃ O HCl Calculated (%). C 64.66; H 5.7; N 13.31; Cl 11,23 gef. (%): C, 64.43; H 5.85; N 13,21; Cl 11.14 Mass spectrum (El): m / z 279 (M ⁺ , as free compound)

Claims (14)

1. Process for the preparation of tetrahydrobenzimidazole derivatives of the formula (I) O ^H "- ^ XX> in which Het is a heterocyclic radical represented by 1 to 3 substituents selected from the group consisting of lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower-alkoxy, nitro, hydroxyl and lower alkoxycarbonyl radicals and halogen atoms may be substituted; and X represents a single bond or -NH- bonded to a carbon or nitrogen atom of the heterocyclic radical and pharmaceutically acceptable salts thereof, characterized in that
(a) for the preparation of compounds of formula (Ia). (La) in which Het is a heterocyclic radical represented by 1 to 3 substituents selected from the group lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl lower alkyl, aralkyl, lower alkoxy, nitro, hydroxyl and lower alkoxycarbonyl groups and halogen atoms may be substituted; and X ^{1 represents} a single bond attached to a nitrogen atom of the heterocyclic ring or an -NH group attached to a carbon atom of the heterocyclic ring,
an amine, amide or urea of the formula (III), Het-X'-H (ill) in the Het and X ^{1 has} the meaning defined above, with a carboxylic acid of the formula (II) HOOC " (II) or a reactive derivative dayon,
(B) for the preparation of compounds of formula (I b). Het-X ² -C> _ (Ib) in which Het is a heterocyclic radical which is substituted by 1 to 3 substituents selected from the group consisting of lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower-alkoxy, nitro, Hydroxyl and lower alkoxycarbonyl and halogen atoms may be substituted; and X ^{2 represents} a single bond connected to a carbon atom of the heterocyclic ring represented by Het, a heterocyclic compound of the formula (III a) in which Het and X ^{2 have} the meaning defined above, with a carboxylic acid of the formula (II) (II) or a reactive derivative thereof,
(c) for the preparation of compounds of formula (I c)
O wherein Het ^{2 is} a heterocyclic radical derived from Het ¹ which is a heterocyclic radical having the group -NH- in the ring, substituted by 1 to 3 substituents selected from the group lower alkyl, lower alkenyl, lower Alkynyl, cycloalkyl-lower-alkyl, aralkyl, lower alkoxy, nitro, hydroxyl and lower alkoxycarbonyl radicals and halogen atoms, where the group -NH of Het ¹ in Het ² belongs to the group -NR ⁴ R ^{4 is} a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower alkyl or aralkyl radical; and X represents a single bond or -NH group connected to a carbon atom or nitrogen atom of the heterocyclic ring, a compound of the formula (Id) _f
O Het'-X-C. in which Het ¹ and X ¹ are as defined above, subjecting to N-alkylation. 2. The method according to claim 1, characterized in that Het means a nitrogen-containing heterocyclic radical and X ^{1 is} a single bond. 3. The method according to claim 1, characterized in that Het is a heterocyclic radical of the formula R ^{1 represents} a hydrogen atom, a lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl or aralkyl radical; R ^{2 represents} a hydrogen atom, a lower alkyl, or aralkyl radical; and R ^{3 represents} a hydrogen atom, a lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl group or a halogen atom. 4. The method according to claim 2, characterized in that the nitrogen-containing heterocyclic radical has the formula: 5. The method according to claim 2, characterized in that the nitrogen-containing heterocyclic radical has the formula: 6. The method according to claim 3, characterized in that R ^{1 represents} a methyl group and R ² and R ³ each represent a hydrogen atom. 7. The method according to claim 3, characterized in that R ^{1 represents} a 2-propynyl group and R ² and R ³ each represent a hydrogen atom. 8. The method according to claim 1, characterized in that Het is a nitrogen-containing heterocyclic radical; and X represents a single bond linked to a nitrogen atom of the nitrogen-containing heterocyclic ring. 9. The method according to claim 1, characterized in that one prepares 5 - ((1-methylindol-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole. 10. The method according to claim 9, characterized in that it is the connection to the (R) compound. 11. The method according to claim 9, characterized in that it is the compound to the (S) compound. 12. The method according to claim 1, characterized in that one prepares 5 - [[1- (2-propynyl) -indol-3-yl] carbonyl] -4,5,6,7-tetrahydrobenzimidazole. 13. The method according to claim 8, characterized in that one prepares 5 - [(2,3-dihydroindol-1-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole. 14. The method according to claim 8, characterized in that one produces 1 - [(4,5,6,7-tetrahydrobenzirnidazol-5-yl-carbonyl] -2,3-dihydrobenzirnidazol-2-one.