KR810001715B1 - Process for preparing 5-4-(diarymethyl)-1-piperazinealkyl benaimidazole derivatives - Google Patents

Abstract

Title compds. [I; Ar1, Ar2 = phenyl, halophenyl, nitrophenyl, thienyl, pyridinyl; R = H, lower alkyl, aryl(lower alkyl); A: -N=C(R1a); R1a = lower alkyl, cycloalkyl, aryl, amino etc., n = 1, 2 useful as antihistaminics at 0.0025-0.16mg/ml in vitro and as antianaphylactics at 2.5mg/kg in vivo were prepd. Thus, compd. II was reacted with compd. III[D = O,NH; E = OH, 0-(lower alkyl) or NH2 To give compd. I

Description

Method for preparing 5- [4- (diarylmethyl) -1-piperazinylalkyl] benzimidazole derivative

The present invention relates to a process for the preparation of the novel 5- [4- (diarylmethyl) -1-piperazinylalkyl] benzimidazole derivatives having the following general formula.

In the food

Ar ¹ and Ar ² are each independently selected from phenyl, halophenyl, (lower alkyl) phenyl, (lower alkyloxy) phenyl, nitrophenyl, thienyl and pyridinyl.

R is hydrogen, lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl), cycloalkyl, (lower alkyl) carbonyloxy (lower alkyl), aroyloxy (lower alkyl), (lower alkyl) sulfonyloxy (Lower alkyl), halo (lower alkyl), arylthio (lower alkyl), and (lower alkyl) oxy (lower alkyl), wherein the aryl is selected from phenyl, substituted phenyl, thienyl and pyridinyl and is substituted Phenyl is phenyl with 1-2 substituents independently selected from halo, lower alkyl, and lower alkyloxy,

A is a divalent radical -N = C (R ¹ a)-, wherein the divalent radical has its nitrogen atom attached to benzenehex and R ¹ a is hydrogen, lower alkyl, aryl (lower alkyl), Hydroxy (lower alkyl) cycloalkyl, aryl, amino, (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl), aroyloxy (lower alkyl), (lower alkyl) oxycarbonylamino, (Lower alkyl) aminocarbonylamino and (lower alkyl) oxycarbonyl (lower alkyl) and said aryl is selected from phenyl, substituted phenyl, pyridinyl funnaryl, thienyl and halothienyl; Has 1-2 substituents independently selected from halo, lower alkyl and lower alkoxy,

n is an integer selected from 1-2 wherein if n is 2 the R is selected from hydrogen, lower alkyl and cycloalkyl and R ¹ is selected from hydrogen, lower alkyl, cycloalkyl and aryl.

"Lower alkyl" as used herein is a straight or branched chain hydrocarbon having 1-6 carbon molecules, for example methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-methylpropyl. , Butyl, pentyl, hexyl, "cycloalkyl" is a cyclic hydrocarbon radical having 3-6 carbon atoms means "cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl," the term "halo" is called fluoro, chloro, Halogens having an atomic weight of 127 or less, such as butomo and iodo.

Compound (I ') of general formula (I), wherein n is 1, starts with the following general formula (II) and cyclics it with a suitable cyclic agent, and then with R in general formula (I') obtained according to a known method. Prepared by modifying the R ¹ substituent.

In the above formula

Ar ¹ and Ar ² are as described above and Ra is selected from hydrogen, lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl) cycloalkyl and (lower alkyl) oxy (lower alkyl). The compound of the general formula (I ') prepared by directly cyclizing the benzenediamine of the general formula (II) is a compound of the following general formula (I'-a).

In the above formula

Ar ¹ and Ar ² are as described above and A ¹ represents a radical of the general formula —NH—C (O) — or —N═C (R ¹ a) —, wherein hydrogen, lower alkyl, aryl (lower alkyl) , Hydroxy (lower alkyl), cycloalkyl, aryl, amino, (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl), (lower alkyl) oxycarbonylamino, (lower alkyl) oxycar Selected from carbonyl (lower alkyl) and aroaloxy (lower alkyl).

The cyclization reaction of 1,2-benzenediamine to obtain benzimidazole and benzimidazole-2-silver is generally known and these are known benzimidazole and benzimidazole-2- starting from the corresponding benzeneamine. It carries out under the conditions described in the literature about preparation of silver. Depending on the nature of A ¹ in the compound (I′-a) to be prepared, for example the following cyclic agents are used.

Urea, carbonyldichloride or alkali as cyclic agent is used to prepare a compound of formula (I'-a) wherein A ¹ is -NH-C (O) -radical, ie, a compound of formula (I'-aI) Metal isocyanates are used.

Good results are obtained from urea in which case compound (I′-a-1) is obtained by stirring and heating the reactants together in the absence of any solvent.

Rings usable in the preparation of compounds of the general formula (I'-a) wherein A ¹ is a radical of the general formula -N = C (R ¹ a), ie, a compound represented by the following general formula (I'-a-2) The nature of the topic is in accordance with the nature of R ¹ a in formula (I'-a-2).

When R ¹ is a hydrogen formate or represent a suitable 1, 1 ', 1 "to use the methicillin naphthyridin-tris (oxy)] tris (lower alkyl). Suitable cyclization methods are achieved by stirring and heating a mixture of (II) and 1, 1 ′, 1 ′-[methiridinetris (oxy)] trisethane in vinegar acid.

When R ¹ a represents lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl), cycloalkyl or aryl, R ² represents lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl) cycloalkyl or aryl Carboxylic acids of the general formula R ² -COOH (III) or functional derivatives of acids such as acyl halides, esters, amides or nitriles, in which R ² is as defined above in general formula HNC (R ² ) -O- (lower) Amino esters of alkyl) (IV) or acid addition salts with aldehydes of the general formula 9P- @ Figure @ or alkali metal hydrogen sulfite compounds are used. When the cyclic agent is an aldehyde, an appropriate oxidizing agent such as nitrobenzene, mercury oxide, C ₁ (II) and Pb (II) salts or a suitable oxidizing agent known in the art is added to the reaction mixture, and an excessive amount of aldehyde is added. Act as. In carrying out the cyclic reaction, imino ester of the general formula (IV) is used, and the desired compound (I'-a-2) is reacted with the reactants at room temperature first, and then lower alkanes added with vinegar or a suitable acid, that is, hydrochloric acid. Prepared by stirring under elevated temperature in an acidic medium. When the imino ester (IV) is in the form of an acid addition salt, no additional acid needs to be added.

When R ¹ a is an amino group, the ring closure consists of cyanamides or their metal salts, in particular alkali or alkyra earth metal salts or BrCN, and ring closure to cyanamides, for example hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, vinegar Substituted benzenediamine in the presence of a suitable non-oxidant is carried out by stirring and heating with cyanamide. The reaction is carried out in an aqueous medium, but a reaction inert organic solvent such as a mixture of halogenated aliphatic and aromatic hydrocarbons and water such as nichloromethane, trichlorome 1, 2-dichloroethane, chlorobenzene and the like may be used.

Benzenediamine is first converted to acid addition salts and then reacted with cyanamide. When metal cyanamide is used as the cyclic agent, excess acid is added to liberate the free cyanamide from the salt. Ring closure to BrCN is carried out at room temperature in an aqueous medium and benzenediamine is used in the form of dihydrochloride or other salts. R ¹ a is (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl, aroyloxy (lower alkyl,), (lower alkyl) oxycarbonylamino or (lower alkyl) oxycarbonyl (lower) Alkyl) is used as a cyclic agent, and the reaction is carried out by stirring and heating the reactants together in the presence of a suitable acid, in particular (lower alkyl) carboxylic acid, such as vinegar, propionic acid, and the like. Conduct.

In the food

R ³ is (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl), aroyloxy (lower alkyl), (lower alkyl) oxycarbonylamino or (lower alkyl) oxycarbonyl (lower alkyl) )being. When R ³ in formula (VI) represents a (lower alkyl) carboxyylamino group, the reaction is carried out in a suitable organic solvent such as halogenated hydrocarbons such as dichloromethane, trichloromethane and the like.

When R ¹ a represents a (lower alkyl) oxycarbonylamino group, a compound of the general formula (VII) is used as a cyclic agent, and the cyclic reaction is performed by R ¹ a (lower alkyl) carbonylamino or (lower alkyl). The preparation is carried out in a similar manner as described for the preparation of the compound (I'-a-2) representing oxycarbonylamino.

Certain compounds of formula (I'-a-1) and (I'-a-2) may be modified by other compounds of formula (I ') by modification and substitution of the Ra and R1a groups according to the following known processes: Can be converted to

Compounds of formula (I ') wherein R ¹ represents an amino group are usually derived from compounds in which R ^{1 corresponds} to a (lower alkyl) oxycarbonylamino group by decarboxylation by treatment with a water soluble alkali. do.

Compounds of the general formula (I ') in which R ¹ represents a (lower alkyl) aminocarbonyl group, for example compounds containing R ¹ as amino groups in a suitable reaction inert organic solvent such as tetrahydrofuhan Lower alkyl) and by stirring and heating.

Compounds of the general formula (I ') in which R or R ¹ represent a (lower alkyl) carbonyloxy (lower alkyl) group or an aroyloxy (lower alkyl) group are suitable for the corresponding hydroxy (lower alkyl) substituted compound. Prepared by the 0-acylation reaction with a suitable acylating agent useful from acyl halides such as (lower alkyl) carboxylic acids or arylcarboxylic acids, especially chlorides. The acylation reaction is carried out according to standard procedures known in the art.

Compounds of the general formula (I ′) in which R and R ¹ represent hydroxy (lower alkyl) bonds are derived by reaction of their esters with lower alkyl- or arylcarboxylic acids by alkali hydrolysis.

In a similar manner, compounds (I) in which R represents (lower alkyl) sulfonyloxy (lower alkyl) are prepared by reacting the corresponding alcohol with the appropriate (lower alkanes) sulfonylchloride.

Compounds of the general formula (I ') in which R represents halo (lower alkyl) include those compounds in which R is hydroxy (lower alkyl) with suitable halogenating agents known in the art such as thioyl chloride, sulfonyl chloride, pentachloride Derived from the corresponding compounds by halogenation with phosphorus, phosphorus pentabromide, phosphorylchloride. Iodide is derived from the corresponding chloride or bromide by replacing the corresponding halogen with iodine.

Compounds of formula (I ') wherein R represents arylthio (lower alkyl) include, for example, lower alkanols such as methanol and ethanol, and N, N-dimethylformamide, N, N-dimethylacetamide, hexanemethylphosphoric tri Reaction of a suitable reactive ester derived from the corresponding hydroxy (lower alkyl) substituted compound with a suitable alkali metal arene thioate, in particular sodium salt, in a suitable reaction inert medium such as a mixture of relatively polar organic solvents such as amide, dimethyl sulfoxide Manufactured by Sikkim. Suitable reactive esters that can be used include halide and sulfonate esters such as methanesulfonate and 4-methylbenzenesulfonate. The preparation of halides and betanesulfonates has been described above and other reactive sulfonates are prepared according to the process for preparation with (lower alkyl) sulfonates using suitable sulfonyl chlorides as sulfonylating agents.

A is a radical of the formula -N = C (NH ₂ )-and r is lower alkyl, aryl (lower alkyl), cycloalkyl or (lower alkyl) oxy (lower alkyl), in which R is represented by R _b ( I ') compound (I'-c) is described in J. Gen Chem. According to the process described in USSR, 33, 2289 (1963), a suitable organic solvent such as N, N-dimethylbenzeneamine or dimethylbenzene can be used to obtain a compound (I'-b) in which A corresponds to -N = CH-. Prepared by amination, in which R preferably represents alkyl, phenyl (lower alkyl) or (lower alkyl) oxy (lower alkyl) and the latter is suitably R is cycloalkyl.

R is hydrogen, lower alkyl, aryl (lower alkyl), cycloalkyl or (lower alkyl) oxy (lower alkyl), represented by Rc and A is a radical of the formula -N = C (R ¹ )-wherein R ¹ is Hydrogen, lower alkyl, aryl (lower alkyl), cycloalkyl, amino, (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl) aroyloxy (lower alkyl) or aryl as R ¹ c Another process for preparing compound (I'-d) of one formula (I ') involves the reaction of a compound of formula (VIII) with a compound of formula (IX). In formulas (VIII) and (IX), Ar ¹ , Ar ² , Rc and R ¹ c are as described above and ^one of X and X ¹ is a 1-piperazinyl group and the other is for example halo especially chloro or bromo Or a reactive ester radical such as a sulfonyloxy group, in particular methyl sulfonyloxy or 4-methylphenyl sulfonyloxy.

The reaction of (VIII) and (IX) is a suitable reaction inert organic solvent such as lower alkanols such as methanol, ethanol, propanol, etc .: aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, 1, 4-dioxane, 2, 2 ' Ether and 4-methyl-2-penta, such as oxybispropane, are performed in organic solvents, such as ketone, N, N- dimethylformamide, and nitrobenzene. The addition of a suitable base, such as alkali or alkaline earth metal carbonates or intermediates, to the reaction mixture is used to remove the free acid during the reaction. Small amounts of suitable metal iodide, in particular sodium or potassium iodide, are added as reaction promoters and use a slightly elevated temperature to increase the reaction rate. The reaction is usually carried out at the reflux temperature of the reaction mixture.

Compound (I ') of formula (I) wherein n is 2 is prepared by the following reaction sequence.

A suitable benzenediamine of the general formula (X) wherein Ar ¹ and Ar ² are as described above and R _d is hydrogen, lower alkyl or cycloalkyl is described for the preparation of compound (I'-a) starting from (II). Depending on the process, a cyclization reaction is carried out with a suitable cyclic agent, and Ar ¹ , Ar ² and R _d are as described above, and A ² is -NH-C (O)-wherein R _d is hydrogen, lower alkyl, cycloalkyl or aryl. Intermediates of formula (XI) selected from -N = C (R ¹ _d ) are obtained and then reacted with a suitable chlorinating agent, in particular thionyl chloride, to obtain an intermediate of formula (XII). The desired compound (I ′) is prepared by reductive dehalogenation of (XII) by hydrogenation of the obtained (XII) in the presence of a suitable catalyst such as baladium-activated carbon. To avoid side reactions, small amounts of suitable catalyst-poison such as thioene are added to the reaction mixture.

The reactions are illustrated by the following schemes.

In the preparation the reaction product is separated from the reaction mixture and further purified according to standard procedures known in the art as required.

Benzene diamine of formula (II) used as starting material is prepared by the following reaction sequence.

As described above, Ar ¹ and Ar ² may be substituted with a suitable 1- (diarylmethyl) piperazine of general formula (XIII) in a lower alkanol such as a suitable organic solvent such as ethylene or propane. Intermediate of general formula (XIV) wherein R ⁴ is chloro or methoxy by reacting by heating and stirring with chloromethyl) -2X nitrobenzel or 4- (chloromethyl) -1-methoxy-2-nitrobenzene To obtain. The obtained (XIV) is reacted with a suitable amine of the general formula (XV) in which R _a has the above meaning to give an intermediate of the general formula (XVI). The reaction is carried out in a suitable organic solvent such as elkene dimeltin sulfoxide, N, N-dimethylformromide, N, N-dimethylacetamide and ethanol in a suitable organic solvent and when the amine reactant has the proper solvent properties, The temperature is slightly increased to increase the reaction rate.

The desired intermediates of formula (II) are subjected to standard processes of reducing nitro to amines by subjecting the intermediate (XVI) obtained in the previous step to hydrogenation of (XVI), or by catalytic hydrogenation using a suitable catalyst such as raninickel. By reduction accordingly.

The reaction sequence can be described by the following scheme.

Starting materials of the general formula (IX) are prepared according to the following reaction sequence.

Intermediate (XVIII) obtained by reacting 4-fluoro-3-nitrobenzoic acid with a suitable amine of the general formula (XVIII) as described above for the reaction of (XIV) with (XV) Reaction to reduce nitro to amine as described above yields an intermediate of formula (XIX); The obtained (XIX) is converted to the benz or imidazole derivative of the general formula (XX) by cyclizing with a suitable cyclic agent as described above for the preparation of the compound (I ') starting from (II). The carboxylic acid (XX) is converted to the corresponding carbonyl chloride (XXI) by reaction with a conventional method such as thionyl chloride and the obtained (XXI) is reacted with a suitable lower alkanol (XXII) to general formula (XXIII). Lower alkyl esters of are obtained.

The obtained (XXIII) is reduced to the corresponding alcohol (XXIV) as a suitable reducing agent such as, for example, sodium dihydrobis (2-methoxyethoxy) aluminate (Red-Al). The desired starting material (1X-a) of formula (IX), wherein X ¹ is represented by X ¹ _a in which X ¹ is a reactive ester group, is obtained by converting (XXIV) into a reactive ester according to known standard procedures. Halides are prepared by reacting (XXIV) with a suitable halogenating agent such as thionyl chloride, sulfaryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, and when the reactive ester is an iodide, the corresponding halogen is converted to iodine. It is prepared from chloride or bromide by replacement. Other reactive esters such as methanesulfonate and 4-methylbenzenesulfonate are obtained by reacting alcohols with suitable sulfonyl halides such as methanesulfonylchloride and 4-methylbenzenesulfonyl chloride.

The starting material (1X-b) of general formula (IX), wherein X ¹ is a piperazine moiety, is known N as described above for preparing compound (I'-d) by reacting (VIII) with (IX). Obtained by reacting (IX-a) with piperazine according to the alkylation process.

The process can be described as follows.

R _c is hydrogenyl. The starting materials (1X-a-1) and (1X-b-1) of the general formulas (IX-a) and (IX-b) are 4-amino-3-nitrobenzaldehyde by the following steps. Prepared from.

Iii) simultaneous reduction of aldehydes and nitro groups by catalytic hydrogenation in the presence of a suitable catalyst such as, for example, ranei-nickel, to give 3, 4-diaminobenzenemethanol.

Ii) cyclizing the obtained compound with a suitable cyclic agent as described above to obtain benzimidazole methanol of general formula (XXV)

V) conversion of the obtained compound to a reactive ester of the general formula (IX-a-1) by the conventional method as described above.

Iii) (IX-a-1) is reacted with piperazine as described above to give a piperazine derivative of the general formula (IX-b-1).

Starting materials of the general formula (X) can be prepared according to the following reaction sequence.

A suitable compound of formula (VIII) wherein X is a 1-piperazinyl radical (VIII-a) is first reacted with 2-bromo-1- (4-chloro-3-nitrophenyl) ethanone to formula (XXVI) An intermediate of (XXVI) is obtained and the corresponding alcohol is reduced as a suitable reducing agent such as sodium brohydride. (XXVII) obtained was reacted with a suitable amine (XXVIII) as described above for the preparation of (XVI) starting from (XIV) and (XV) with Rd and obtained of (XXIX) The nitro group is reacted to reduce nitro to amine to afford the desired starting material of formula (X).

The reactions are described by the following scheme.

Starting materials and precursors used in this process, which are not given a special preparation, are generally known and can be prepared according to known methods as described in the literature for the preparation of similar known compounds.

Compounds of formula (II) and (XVI) are considered novel and are an additional form of the invention as useful intermediates for the preparation of compounds of formula (I).

Compounds of general formula (I) are suitable acids such as hydrochloric acid, inorganic acids such as hydrochloric acid, bromic acid, inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, etc. or acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxyprotopanoic acid, 2-oxopro Panoic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid By treatment with organic acids such as cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like, it can be converted into pharmacologically active non-protic acid addition salts.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts have useful pharmacological activity, especially in very small dosages, strongly inhibiting vascular active kinetics such as histamine and serotonin. These useful pharmaceutical properties are evident because of their excellent activity in the next test step.

A. Laboratory Anti-Histamine Activity

Mormot ileum is suspended in 100 ml of Tyrode bath containing 0.75 g of preload at 37.5 ° C. and passed through 95% O ₂ and 5% CO ₂ gas.

The compound to be tested (5 min latency) and the inside of the round fruit family by kinematic recording with isotonic levers amplified by 5 times the seizure induced by histamine (0.5 mg / l). Study the action. When tested under these conditions, compounds of formula (I) and their pharmaceutically acceptable acid addition salts showed a 50% inhibition of histamine-induced career at a concentration of 0.0025-0.16 mg / ml.

B. Clinical Anti-Immunodeficiency and Anti-Histamine Effects

The anti-immune reduction and anti-histamine effects on the present compound (I) and their salts are clinically studied for mormot.

Morphants weighing 400-500 g were subcutaneously injected into the left fetal subcutaneous injection of 0.05 ml of immune serum to sensitize egg albumin and then saline (= comparative animals) or irradiated for 24 hours after sensing the animals. Certain dosages of the compound to be administered are administered orally.

Two hours after oral pretreatment with the compound, histamine injection (dose of 50 μg) is injected subcutaneously in the right fetal place. The diameter of both fetuses is measured before and 10 minutes after histamine injection, and animals are injected intravenously with 0.6 mg of egg albumin 30 minutes after histamine injection. All comparison animals develop traditional primary immunodeficiency shock signs (cough, shortness of breath, systemic spasms) and 85% of the comparison animals die within 15 minutes after egg albumin injection. Protection from death is used as a criterion for possible drug effects.

The median histamine edema in 200 comparative animals 10 minutes after histamine injection was 15 units (1 unit-0.1 mm) and the response of 10 units or less occurring below 5% of the control animals was effective in treating histamines in compound treated animals. Decide on suppression.

Compounds of formula (I) and their salts showed 100% activity against the reduction of morphot's immunity in a single oral dose of 2.5 mg / kg. At the same dose, they effectively reduced histamine-induced leg edema.

C. Activity against reduced skin immunity in rats.

Passive skin immunity reduction in rats is studied as a form of sensory hypersensitivity caused by "decidin" antibodies. For this test, serum containing this type of antibody is prepared according to the procedure described in Immunology 7,681 (1964) and subcutaneously injected into two different parts of the test animal and intravenously injected with egg albumin and triptanbur after 48 hours. The results are given independently by two observers for all reaction sites on the exposed inner skin by comparison with standard response intensity. The strongest result for a single reaction site is 4 and the best overall result for a unit rat is 16 (4 × 2 site × 2 observers). Treatment with the compound to be treated or with water (comparative animals) is given orally 2 hours prior to the injection of egg albumin and the effect of the treatment is to increase the intensity of the triphtan blue color at the reaction site of water-treated and compound treated rats. Evaluated by comparison. The results are expressed in terms of the ED ₅₀ value, the dosage required to achieve 50% inhibition of passive skin immunity reduction induced in rats, and the ED ₅₀ value determined for compounds of formula (I) and salts thereof is 0.16-5 mg / kg. Found.

As a result of the useful pharmaceutical properties, the compounds of the present invention (I) and their pharmaceutically acceptable acid addition salts are anti-histamine, anti-allergic and anti-allergic in doses ranging from 0.2-10 mm / kg body weight when administered systematically to silver blood animals. It has been found to be active as an asthma agent.

In view of their useful anti-histamine, anti-allergic and anti-asthmatic activity, the compounds of the present invention may be formulated in various pharmaceutical forms for feeding purposes. Combining effective anti-histamine, anti-immune or anti-asthmatic amounts of particular compounds in the form of bases or acid-addition salts as active ingredients to prepare the pharmaceutical compositions of the invention in admixture with pharmaceutically acceptable carriers The carrier may take a wide variety of forms depending on the form to be fed.

The pharmaceutical compositions are in unit dosage form suitable for administration by oral, pharmaceutical or parenteral injection. For example, any useful pharmaceutical medium may be used to prepare the composition in oral dosage form, e.g., oral liquids such as suspensions, seas, eggs and solutions, In the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, dispersants and the like are used. For ease of feeding tablets are used in the most suitable oral dosage unit form, in which case a solid pharmaceutical carrier is used. Carriers for parenteral compositions usually contain a number of incomes and may also include the following ingredients for increasing solubility. The carrier may also be prepared as an injectable solution comprising saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carrier dispersants may be employed. In order to increase their solubility in water, acid addition salts of (I) are more suitable for the preparation of water-soluble compositions than the corresponding base forms.

The pharmaceutical composition described above is preferably made in unit dosage form for ease of feeding and uniformity of dosage. As used herein, unit dosage form refers to units that are physically separated into unit dosages, each unit containing an amount of the active ingredient calculated to achieve the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such dosage units are tablets (including coated tablets) liquor, pills, powder packages, injectable solutions or suspensions, powdered tea or cutlery powder.

In addition to anti-histamine, anti-allergic and anti-asthmatic agents, compounds of formula (I) have vascular activity and consequently are used in the treatment of patients suffering from vascular disorders, particularly disorders of the vascular system.

Example I

4.64 parts 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -N ¹ -methyl-1, 2-benzenediamine, 3.71 parts methyl N, N'-bis (methoxycarbonyl) carbam After stirring and refluxing the mixture of imidothioate, 4.32 parts of vinegar acid and 150 parts of trichloromethane for 22 hours, the reaction mixture was cooled to room temperature, evaporated, the residue was dissolved in 100 parts of water, the precipitate formed was filtered Is alkalinized with ammonium hydroxide. The product is extracted with trichloromethane and the extract is washed with water, dried and filtered and then evaporated. The residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent and the pure fractions collected to evaporate the eluate. The residue was crystallized from 2-propanone and the product was filtered, washed with 2-propanol and 2, 2'-oxybispropane and dried to give 2.6 parts of methyl {5- [4- (diphenylmethyl ) -1-piperazinylmethyl] -1-methyl-1H-benzimidazol-2-yl} parbamate.

In a similar manner, the following compounds are prepared.

Methyl [5- {4-[(4-fluorophenyl) phenylmethyl] -1-piperazinmethyl} -1-methyl-1H-benzimidazol-2-yl] carbamate: Melting point: 191.2 ° C.

Methyl [5- {4- [bis (4-fluorophenyl) methyl] -1-piperazinylmethyl} -1-methyl-1H-benzimidazol-2-yl] carbamate monohydrate: melting point 156.4 ° C.

Methyl 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-propyl-1H-benzimidazol-2-yl} carbamate: Melted tablet: 139.5 ° C

Example II

4.64 parts of 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -methyl-1, a mixture of 2-benzenediamine and 1.2 parts of urea are stirred at 190 ° C. for 1.50 hours and then the reaction mixture is cooled to Dissolve in a mixture of 150 parts water and 6 parts 10N hydrochloric acid solution, treat the solution with activated charcoal, filter the activated charcoal and alkaline the filtrate with 5N sodium hydroxide. The product was extracted three times with dichloromethane, and the combined extracts were dried, filtered and evaporated. The residue was stirred in 20 parts of ethanol, and the product was filtered to give a mixture of trichloromethane and methanol (volume 97.5: 2.5) as eluent. Purify by column-chromatography on silica gel. Pure fractions were collected to evaporate the eluate, the solid residue was treated with 20 parts of ethanol, the product was filtered off, washed with a small amount of ethanol and dried, then 1.7 parts of 5- [4- (diphenylmethyl) -1 having a freezing point of 246 ° C. -Piperazinylmethine)]-1,3-dihydro-1-methyl-2H-benzimidazole-2-one.

In a similar manner, 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-1, 3-dihydro-2H-benzimidazole-2-one having a melting point of 239.8 ° C. is prepared. .

Example III

5 parts 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -N ¹ -propyl-1, 2-benzenediamine, 35 parts 1, 1 ', 1'-[methiridinetris (oxy) The mixture of trisethane and 1.5 parts of vinegar acid is stirred and refluxed for 2 hours, the reaction mixture is cooled and evaporated, the residue is added to 100 parts of water and 10N hydrochloric acid solution is added until all the solid is a solution. The solution is treated with activated charcoal and the activated charcoal is filtered and the filtrate is evaporated to dryness and filtered. The residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent and then pure fractions are collected to evaporate the eluate. The residue was crystallized from 4-methyl-2-pentanone, the product was filtered off, washed with a small amount of 4-methyl-2-pentanone and 2, 2'-oxybispropane, and dried. -[4- (diphenylmethyl) -1-piperazinylmethyl] -1-propyl-1H-benzoimidazole is obtained.

Example IV

Instead of 4- [4- (diphenylmethyl) -1-piperazinylmethyl-N'-propyl-1, 2-benzenediamine, following the process of Example III and used, an equivalent of appropriate 4- [4- (dia The following compounds are obtained in the form of hydrochloride after treating the base or free base with hydrochloric acid in a mixture of ethanol and 2-propanol using ylmethyl) -1-piperazinylmethyl-1, 2-benzenediamine.

Example V

Reacting 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -N1- (2-methoxyethyl) -1,2-phenzendiamine with trimethoxymethane according to the process of Example III To give 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1- (2-methoxyethyl) -1H-benzimidazole having a melting point of 161.7 ° C.

Example VI

A mixture of 4.6 parts of 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -N1-methyl-1, 2-benzenediamine, 1.48 parts of ethylethaneamidate hydrochloride and 80 parts of 2-propanol Slowly heat until the solid is a solution and first stir at room temperature for 1 hour and then at reflux for 3 hours. The reaction mixture is cooled to room temperature, filtered, the filtrate is evaporated and the hydrochloric acid solution is added until the residue is dissolved in water and all solids are in solution. The resulting solution is treated with activated charcoal and the activated charcoal is filtered and the filtrate is alkalined with 60% sodium hydroxide solution to extract the product with dichloromethane. The extract was washed with water, dried, filtered and evaporated and the residue was purified by column-chromatography on silica gel using a mixture of trichloromethane methanol and ammonium hydroxide (volume 97: 1) as eluent and then purified. Is collected to evaporate the eluate. The residue was crystallized from 2-propanol, the product was filtered off, washed with 2-propanol and 2, 2'-oxybispropane, and vacuum dried at 80 DEG C for one week. Phenylmethyl) -1-piperazinylmethyl] -1, 2-dimethyl-1H-benzimidazole.

In a similar manner, 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-2-phenyl-1H-benzimidazole having a melting point of 189.6 ° C. is prepared.

Example VII

Stir a mixture of 4.8 parts 4- [4- (diphenylmethyl) -1-piperazinylmethyl] -N1-ethyl-1, 2-benzenediamine and 25 parts vinegar acid at room temperature until all solids are in solution. 1.73 parts of ethyl ethaneimide hydrochloride were added, followed by stirring at room temperature for 1 hour and then at reflux for 1 hour. The reaction mixture is evaporated and the residue is stirred in water, then the whole is alkaline with sodium hydroxide solution to extract the product with dichloromethane and the extract is dried and filtered to evaporate. The residue was purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2 in volume) as eluent, the pure fractions collected, the eluate was evaporated, and the residue was 4-methyl-2-. Crystallized from pentanone, filtered and dried, 2.7 parts 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-2-methyl-1H-benzimi having a melting point of 152.9 ° C. Obtains the dazol.

Example VIII

Following the process of Example VII and using an equivalent of starting material in base form or after treatment with the free base with the appropriate acid, a compound having the following general formula in the form of an acid addition salt is obtained.

Example IX

The following compounds are prepared following the process of Example VII and using an equivalent of a suitable starting material.

Example X

5.6 parts 3-[{2-amino-4- [4- (diphenylmethyl) -1-piperazinylmethyl] phenyl} amino] -1-propanol, 2.8 parts ethyl benzenecarboximidate hydrochloride and 50 parts The mixture of vinegar acid is first stirred at room temperature overnight and at reflux for 1 hour, the solvent is evaporated in vacuo and the residue is stirred in water to alkalinize the whole to ammonium hydroxide. The product is extracted with trichloromethane, the extract is dried, filtered and evaporated and the residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2 in volume) as eluent. Collect the fraction with the maximum Rf value to evaporate the eluate and crystallize the residue with 35 parts 2,2'-oxybispropane. The next product is filtered and dried to have a melting point of 111.5 ° C of 1.8 (24.8%) parts [3- {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-phenyl-1H-benzimidazol-1-yl} propyl] acetate is obtained.

In a similar manner, the following compounds are prepared.

By reacting 3-[{2-amino-4- [4- (diphenylmethyl) -1-piperazinylmethyl] phenyl} amino] -1-propanol with ethyl ethaneimide hydrochloride: melting point 126.6 ° C.

N ¹ - butyl-4- [4- (diphenylmethyl) -1-piperazinyl-methyl] {1-by-1, 2-ben Sikkim jeldi Amen The ethyl 2-hydroxy ethane imidate hydrochloride and the reaction Butyl-5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-2-ylmethyl} acedate: melting point 151.2 ° C

Example XI

A mixture of 3.9 parts of 4- [4- (diphenylmethyl) -1-piperazinylmethyl [-N ¹ -methyl-1,2-benzeldiamine, 2.5 parts of 4-chlorobenzaldehyde and 18 parts of nitrobengels is oiled. The mixture was first stirred at 50 ° C. for 1 hour and then at 1.50 hours at 120 ° C., and the reaction mixture was allowed to stand for 1 night at room temperature under cooling. Then, about 100 parts of water was added, and the whole product was added with 2 N 2 hydrochloric acid solution. Extract with oxybipropane, treat the aqueous phase with activated charcoal, filter and alkaline the filtrate with 50% sodium hydroxide solution to extract the product with trichloromethane. The extract was washed with water, dried and filtered to evaporate and the residue was washed with 35 parts of 1,1'-oxybispropane and dried to obtain 1.3 parts having a melting point of 198.3 占 폚.

The following compounds are prepared following the procedure of Example XI.

2- (2-chloropinyl) -5 [4-diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazole: melting point 216.6 ° C.

2- (3-chlorophenyl) -5- [4- (dephenylmethyl) -1-piperazinyl methyl] -1-1H-methylbenzimidazole: melting point 149.4 ° C

5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-2- (2-methylphenyl) -1H-benzimidazole: melting point 200.2 deg.

5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-2- (4-pyridinyl) -1H-benzimidazole: melting point 149.6 ° C.

5- [4- (diphenylmethyl) -1-piperazinylmethyl] 2-(-2furanyl) -1-methyl-1H-benzimidazole hemihydrate: melting point 185.8 ° C

Example XIII

4.05 parts 1-[(4-pullorophenyl) phenylmethyl] piperazine, 3.9 parts 5- (chloromethyl) -2-methyl-1-propyl-1H-benzimidazole, 4.8 parts sodium carbonate and 45 parts N, The mixture of N-dimethylformamide was stirred at 50-60 ° C. for 3 hours, the N, N-dimethylformamide was evaporated, 100 parts of water was added to the residue, the product was extracted twice with methylbenzene, and the combined extracts were dried and Evaporate after filtration. The residue is converted to a hydrochloride salt in 2-propanol and the salt is filtered to liberate the organic base using conventional methods to ammonium hydroxide in water. The product was extracted twice with dichloromethane, the combined extracts were dried, filtered and evaporated and the residue was crystallized from 2,2'-oxybispropane at room temperature to yield 4.8 parts having a melting point of 105.1 占 폚.

Example XIV

The following compounds are obtained in the form of an organic base or in the form of an acid addition salt after treatment of the organic base with a suitable acid, following the process of Example XIII and using an equivalent of a suitable starting material.

Example XV

4.7 parts of methyl {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazol-2-yl} carba in a stirring solution of 4 parts sodium hydroxide in 50 parts of water Mate is added and the whole is stirred and refluxed for 3.50 hours. The reaction mixture was cooled and left to stand overnight, acidified with 10N hydrochloric acid solution, and the precipitated product was filtered, washed with water and boiled in ethanol. After cooling, the product was filtered, washed with ethanol and with 2, 2'-oxybispropane and then dried to give 2.5 parts 5- [4- (diphenylmethyl) -piperazinylmethyl] -1- with a melting point of 267.5 ° C. Obtain methyl-1H-benzimidazol-2-amine.

In a similar manner, the following compounds are prepared.

5- {4-[(4-fluorofluorophenyl) phenylmethyl] -1-piperazinylmethyl-1-methyl-1H-benzimidazol-2-amine: melting point 235.3 ° C

5- {4- [bis (4-Pluorophenyl) methyl] -1-piperazinylmethyl} -1-methyl-1H-benzimidazol-2-amine: residue

Example XVI

Stir a mixture of 4.1 parts 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-1H-benzimidazole, 1.2 parts sodium amide and 20 parts N, N-dimethylbenzeneamine While slowly heating to 135 ℃ and stirred at 135 ℃ 3 hours. The reaction mixture was cooled, poured into water, the product was extracted with trichloromethane, the extract was dried, filtered and evaporated. The residue was eluated with a mixture of trichloromethane and methanol (95: 5 in volume) and a small amount of ammonium hydroxide. Purified by column-chromatography on silica gel. Pure fractions were collected to evaporate the elution nuclei, the residue was crystallized from methylbenzene and the product was filtered and dried to yield 1.5 parts of 5- [4- (diphenylmethyl) -1-piperazinylmethyl]-with a melting point of 214.3 ° C. 1-ethyl-1H-benzimidazol-2-amine is obtained.

Example XVII

To a stirring mixture of 4.1 parts of 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazol-2-amine and 25 parts of pyridine 0.79 while cooling to 0-5 ° C. Partial acetyl chloride was added dropwise and stirred at 80 ° C for 1 hour. The reaction mixture is cooled to room temperature, poured into ice-water, alkalined with ammonium hydroxide, the product is extracted with methbenzene and the extract is washed with water, dried and filtered to evaporate. The residue was purified by column-chromatography on Silica phase using a mixture of trichloromethane and methane (95: 5 in volume) as eluent and the pure fractions collected to evaporate the eluate and the residue from 2-propanol. Crystallize and filter the product, then wash with 2-propanol and 2,2'-oxybispropane and dry, and 3 parts N- {5- [4- (diphenylmethyl) -1-piperazinyl having a melting point of 202.5 ° C Methyl] -1-methyl-1H-benzimidazol-2-yl} acetamide.

In a similar manner, the following compounds are prepared.

N- [5-[(4-diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-1H-benzimidazol-2-yl} acetamide: melting point 125.7 ° C

N- [5- {4-[(4-fluorofluorophenyl) phenylmethyl] -1piperazinyl methyl} -1-methyl-1H-benzimidazol-2-yl] acetamide: melting point 175.1 ° C

N- [5- {4-bis [(4-fluorofluorophenyl) methyl] -1-piperazinylmethyl} -1-methyl-1H-benzimidazol-2-yl] acetamide: Melting point 198.5 ° C

Example XVIII

Stirring a mixture of 1.9 parts of 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazole-2-methanol, 1.55 parts of anhydrous vinegar and 45 parts of methylbenzene for 2 hours And reflux and the reaction mixture is cooled, washed with dilute ammonium hydroxide solution, the layers are separated, the organic phase is dried, filtered and evaporated. The residue was crystallized from a mixture of methylbenzene and 2,2'-oxybispropane (20: 20 by volume), and the product was filtered and evaporated to give 1.5 parts (74.4%) of 5-4- (diphenyl) having a melting point of 201.1 占 폚. Methyl) -1-piperazinylmethyl-1-methyl-1H-benzimidazol-2-ylmethyl acetate is obtained.

Example XIX

Following the process of Example XVIII the following acetate is derived from the corresponding alcohol.

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-1H-benzimidazol-2-ylmethyl} acetate: Melting point 159.9 ° C

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-propyl-1H-benzimidazol-2-ylmethyl} acetate: Melting point 138.6 占 폚

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1- (1-methylethyl) -1H-benzimidazol-2-ylmethyl} acetate: melting point 142.1 ° C.

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1- (2-methylpropyl) -lH-benzimidazol-2-ylmethyl} acedate: melting point 238.9 ° C. (deck)

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-phenyl-1H-benzimidazol-2-ylmethyl} acetate: Melting point 148.4-153.2 ° C

{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-hexyl-1H-benzimidazol-2-ylmethyl] acedate: Melting point 144.7 ° C

[1-cyclopropyl-5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-2-ylmethyl} acetate: Melting point 142.4 ° C

[1-cyclopentyl-5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-2-ylmethyl} acetate: Melting point 190.2-193.2 ° C

[2- {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-1-yl} ethyl] acedate: melting point 152.2 ° C

[2- {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-methyl-1H-benzimidazol-1-yl} ethyl] acetate: Melting point 158 ° C

[2- {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-phenyl-1H-benzimidazol-1-yl} ethyl] acetate: Melting point 141.3 ° C

[3- [2- (acetyloxymethyl) -5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-1-yl} -propyl] acedate: melting point 100.8 ℃

Example XX

8.8 parts {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-2-ylmethyl} 13.5 parts 50% sodium hydroxide solution in a stirred mixture of benzoate and 120 parts methanol Was added and the whole was stirred and refluxed for 30 minutes, then the reaction mixture was evaporated and the residue was stirred in water. The product was extracted with dichloromethane, the extract was dried, filtered and evaporated and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent and collecting pure fractions. The eluate was evaporated and the residue was crystallized from 45 parts of ethylenebenzene. The product was filtered, washed with 2,2'-oxybisdrophan, dried and 4 parts (57%) of 5- [4- ( Diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazole-2-methanol is obtained.

Example XXI

4.1 parts 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazol-2-amine, 1 part 1-isocyanatobutane and 180 parts tetrahydrofuran The mixture was stirred for 1 week and refluxed, cooled to room temperature and the reaction mixture was filtered to evaporate the filtrate. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent and pure fractions are collected to evaporate the eluate. The residue was crystallized from ethanol to filter the product, washed with ethanol and with 2, 2'-oxybispropane and dried to 4.4 parts (66.7%) of N-butyl-N '-{5- [with a melting point of 195.8 ° C. 4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazol-2-yl} urea is obtained.

In a similar manner, N-butyl-N '-{5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-ethyl-1H-benzimidazol-2-yl} urea having a melting point of 186.4 ° C. To prepare.

Example XXII

To a stirring mixture of 4.4-part 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-methyl-1H-benzimidazole-1-ethanol in 25 parts pyridine was added 1.5 parts methanesulfonyl chloride. After adding drops, the pyridine was stirred at room temperature for 1 hour, and then 250 parts of water was added to the residue. The product was extracted three times with methinebenzene, and the combined extracts were dried, filtered and evaporated. The residue was stirred in 2, 2'-oxybispropane, and the solid product was filtered and dried. 4.4 parts (84.8%) having a melting point of 162.4 ° C. ) [2- {5-4- (diphenylmethyl) -1-piperazinylmethyl] -2-methyl-1H-benzimidazol-1-yl} ethyl] methanesulfonate.

Example XXIII

Acidification by injecting hydrogen chloride gas into a stirred mixture of 5.03 parts 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-phenyl-1H-benzimidazole-2-ethanol and 75 parts trichloromethane 2.4 parts thionyl chloride was added dropwise at room temperature, followed by stirring for 20 minutes under reflux. The reaction mixture is evaporated and 100 parts of water is added to the residue to alkalinize the whole with sodium bicarbonate, the product is extracted with dichloromethane and the extract is washed with water, dried and filtered to evaporate. The residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent and the pure fractions collected to evaporate the eluate. The residue was crystallized from methylbenzene and the product was filtered and dried to give 3.1 parts 1- (2-chloroethyl) -5- [4-diphenylmethyl-1-piperazinylmethyl] -2- with a melting point of 173.8-179.6 ° C. Obtain phenyl-1H-benzimidazole.

In a similar manner, 1- (2-chloroethyl) -5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazole having a melting point of 206.3 ° C. is prepared.

Example XXIV

To the stirring solution of 0.127 parts of sodium in 20 parts of methanol is added 0.61 parts of benzenetium, and the mixture is stirred for several minutes and then the methanol is evaporated. The residue was dissolved in 18 parts of methanol, the methanol was evaporated again and the residue was added to 22.5 parts of N, N-dimethylformamide and 2.6 parts of [2- {5-4- (diphenylmethyl) -1-piperazinylmethyl] -2-methyl-1H-benzimidazol-1-yl} ethyl] methanesulfonate is added. The reaction mixture is stirred for 30 minutes at room temperature, N, N-dimethylformamide is evaporated and 100 parts of water is added to the residue. The product is extracted twice with dichloromethane, the combined extracts are dried, filtered and then evaporated. The residue was crystallized from 2-propanol and the product was filtered and evaporated. 24 parts (90.1%) of 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-methyl-1 with a melting point of 170.3 ° C was obtained. -[2- (phenylthio) ethyl] -1 H-benzimidazole is obtained.

In a similar manner, the melting point is achieved by reacting 1- (2-chloroethyl) -5- [4- (diphenylmethyl) -1-piperazinylmethyl [-2-phenyl-1H-benzimidazole with benzenethiol. Melting point by reacting 1- (2-chloroethyl) -5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazole with benzenethiol 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1- [2- (phenylthio) ethyl] -1H-benzimidazole is prepared at 172 ° C.

Example XXV

9 parts 5- {1-chloro-2- [4- (diphenylmethyl) -1-piperazinyl] ethyl} -1-ethyl-2-methyl- 1H-benzimidazole trihydrochloride and 240 parts of methanol are added and the whole is hydrogenated at normal pressure and room temperature using 4 parts of 10% palladium-activated carbon catalyst, the calculated amount of hydrogen is taken, and the catalyst is filtered and evaporated. . The residue was dissolved in 100 parts of water, the whole was alkalined with almonium hydroxide, and the product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was eluent with trichloromethane and methanol (95 in volume). Purification by column-chromatography on silica gel using a mixture of: 5). Pure fractions were collected to evaporate the eluent, the residue was crystallized from 2-ctopanol and the product was filtered and dried to yield 2.4 parts (35.5% of 5- {2- [4- (diphenylmethyl) with a melting point of 95-105 ° ) -1-piperazinyl] ethyl} -1-ethyl-2-methyl-1H-benzimidazole monohydrate is hydrated.

In a similar manner, the following compounds are prepared.

5- {2- [4- (diphenylmethyl) -1-piperazinyl] ethyl} -2-methyl-1-propyl-1H-benzimidazole: melting point 115.6 ° C

5- {2- [4- (diphenylmethyl) -1-piperazinyl] ethyl} -2-ethyl-1-propyl-1H-benzimidazole trihydrochloride: 261.2 ° C

5- {2- [4- (diphenylmethyl) -1-piperazinyl] ethyl} -1,2-dipropyl-1H-benzimidazole trihydrochloride: Melting point 250-255 ° C

Example XXVI

To a stirring mixture of 5.03 parts of 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -2-phenyl-1H-benzimidazole-1-ethanol and 50 parts of pyridine, 3 parts of benzyl chloride are dropped at room temperature. Droplets are added and then stirred for 2 hours at room temperature. The reaction mixture is evaporated, water is added to the residue, the product is extracted with dichloromethane and the extract is washed with water, dried and filtered to evaporate. The residue was crystallized from 20 parts 2-propanol and the product was filtered, washed with 2-propanol and 2'-oxymispropane and dried to give 4 parts (66.5%) of [2- {5- [4 having a melting point of 164.1 ° C. -(Diphenylmethyl) -1-piperazinylmethyl] -2-phenyl-1H-benzimidazol-1-yl} ethyl] benzoate is obtained.

In a similar manner, [2- {5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1H-benzimidazol-1-yl} ethyl] benzoate 2-propanoate having a melting point of 214.6 ° C. (2: 1) is obtained.

Claims (1)

In a suitable solvent, the compound of formula (II)

A process for the preparation of 5- [4- (diarylmethyl) -1-piperazinylalkyl] benzimidazole derivatives of the general formula (I) below, characterized by reacting with a cyclic agent.

In the above formulas Ar ¹ and Ar ² are each independently selected from phenyl, halophenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, nitrophenyl, thienyl and pyridinyl, R is selected from hydrogen, lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl), cycloalkyl and (lower alkyl) oxy (lower alkyl) and said aryl is selected from phenyl, substituted phenyl, thienyl and pyridinyl And substituted phenyl is phenyl having 1-2 substituents independently selected from halo, lower alkyl and lower alkyloxy, A is a divalent radical-N = C (R ¹ _a ) where the divalent radicals have their nitrogen atoms attached to the benzene nucleus and R ¹ _a is hydrogen, lower alkyl, aryl (lower alkyl), hydroxy (lower alkyl) , Cycloalkyl, aryl, amino, (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl), aroyl oxy (lower alkyl), (lower alkyl) oxycarbonylamino and (lower alkyl) oxy Selected from carbonyl (lower alkyl) wherein the aryl is selected from phenyl, substituted phenyl, pyridinyl, furanyl, thienyl and halothienyl, wherein the substituted phenyl is independently selected from halo, lower alkyl and lower alkyloxy Having 1-2 substituents, n is an integer of 1-2 if n is 2 the R is selected from hydrogen, lower alkyl and cycloalkyl and R ¹ _a is selected from hydrogen, lower alkyl, cycloalkyl and aryl, D is O or NH E is OH, O- (lower alkyl) or NH ₂ or D and E together are N Iii) when D is NH, E is O- (lower alkyl) Ii) when R ¹ _a is hydrogen, D is O and E is OH Iv) D and E together are N when R ¹ _a is amino; Iii) R ¹ _a is (lower alkyl) carbonylamino, (lower alkyl) carbonyloxy (lower alkyl), aroyloxy (lower alkyl), (lower alkyl) oxycarbonylamino or (lower alkyl) oxycarbonyl When (lower alkyl) D is NH and E is O- (lower alkyl).