JPS6231707B2 - - Google Patents

Description

[Detailed description of the invention]

In the prior art, a large number of 1-
[(Heterocyclyl)alkyl]piperazines and numerous 1-substituted 4-(diarylmethyl)piperazines and 4-(diarylmethoxy)
Piperidine derivatives have been found. Such compounds are described in the following references: US Pat . The essential difference between the compounds of the present invention and the previous ones lies in the nature of the B-CnH ₂ n- group present in the 1-position of the piperazine or piperidine group and/or in the This is the nature of the diarylmethyl or diarylmethoxy group present at the 4-position. The present invention provides novel chemical compounds, particularly those of the formula piperazine and piperidine derivatives and pharmaceutically acceptable acid addition salts thereof, which are structurally represented by: where Ar ¹ and Ar ² each independently consist of phenyl, substituted phenyl and pyridinyl. wherein the substituted phenyl is phenyl having 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl, and nitro; m is an integer of 0 or 1, and A is a member selected from the group consisting of 〓N- and 〓CH-, provided that when A is 〓N-, m is 0, and A is 〓CH -, m is 1, n is an integer from 2 to 6, provided that
When CnH ₂ n represents a branched alkylene chain, at least two carbon atoms are present in the linear part of the chain connecting B and the piperidine or piperazine nitrogen atom, and B has the formula [In the formula, R ¹ and R ² are each independently hydrogen,
selected from the group consisting of halo, lower alkyl, and trifluoromethyl, and Y is a member selected from the group consisting of nitrogen substituted with 〓NL, where L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl,
is a member selected from the group consisting of hydroxymethyl and lower alkenyl. As used above and in the definitions below, the term "lower alkyl" means straight-chain and branched hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1 -dimethylethyl, propyl, butyl, pentyl, hexyl, etc., and the meaning of "lower alkenyl" includes straight chain and branched alkenyl groups having 2 to 6 carbon atoms, such as ethenyl, 1-methylethenyl, 1
-propenyl, 2-propenyl, 2-butenyl,
1-methyl-2-butenyl, 2-pentenyl, 2
-hexenyl, etc., "cycloalkyl" refers to a cyclic hydrocarbon radical having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the expression "CnH ₂ n" refers to the B group straight and branched alkylene chains of 2 to 6 carbon atoms having at least 2 carbon atoms in the linear part of the chain linking the piperidine or piperazine nitrogen, e.g. , 2-ethanediyl, 1,3-propanediyl, 2-methyl-1,3-propanediyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,
5-pentanediyl, 1,6-hexanediyl, etc., and the term "halo" generally refers to
Halogens with atomic number less than 127, namely fluoro, chloro, bromo and iodo. Compounds of the invention of formula () are suitable reactive esters of formula (), where n is as defined above and has the above definition, and W is derived from the corresponding alcohol. a suitable reactive ester functional group such as halo, methanesulfonyl, 4-methylbenzenesulfonyl, etc.] to a suitable piperidine or piperazine derivative of formula (where A, m, Ar ¹ and Ar ² are as defined above). It is conveniently produced by reacting with [as defined in]: Said condensation reaction is preferably carried out in a suitable organic solvent inert to the reaction, such as lower alkanols such as methanol, ethanol, propanol, butanol and similar alkanols; aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; ethers, e.g. 1,4-
Dioxane, 1,1′-oxybispropane, etc.;
Ketones, such as 4-methyl-2-pentanone;
N,N-dimethylformamide; nitrobenzene and the like. In order to take up the acid liberated during the course of the reaction, a suitable base can be added, for example an alkali metal or alkaline earth metal carbonate or hydrogen carbonate. Small amounts of suitable metal iodides, such as sodium or potassium iodide, can also be added as reaction promoters. To increase the reaction rate, somewhat elevated temperatures are suitable, and preferably the reaction is carried out at the reflux temperature of the reaction mixture. In this and the following preparations, the reaction product is separated from the reaction mixture and it is optionally further purified by applying methods commonly known in the art. On the other hand, formula (-c) The compound of formula () represented by [R ¹ , R ² , n, A, Ar ¹ and Ar ² are as defined above] is a 1,3-dihydro- It can be prepared by ring closure of the appropriate intermediate of formula () using a suitable cyclizing agent, as are methods known in the art for preparing 2H-benzimidazol-2-ones. Advantageous suitable cyclizing agents that can be used include, for example, urea, carbonyl dichloride, alkali metal isocyanates, and the cyclization reaction is carried out according to methods generally known in the art. For example, when using urea as the cyclizing agent, compound (-c) is easily obtained by stirring and heating the reaction together in the absence of a solvent. The above manufacturing method is shown below. The compound of formula (-c) has the corresponding formula () ^{In the general method} Therefore, it can be produced by removing the protecting group. Examples of such protecting groups include lower alkyloxycarbonyl and the formula Substituted ethenyl groups in which R ³ and R ⁴ represent different groups, R ³ is preferably lower alkyl and R ⁴ is preferably hydrogen, lower alkyl or phenyl; It will be done. When the protecting group is lower alkyloxycarbonyl it can be easily removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group it can be easily removed by acid hydrolysis of the appropriate intermediate (). It will be destroyed. In carrying out the acid hydrolysis to remove the substituted ethenyl group from , such as acetic acid, propanoic acid, ethanedionic acid, etc. moreover,
The reaction is carried out in an organic solvent inert to the reaction, such as is commonly used in such types of hydrolysis reactions, e.g. lower alkanols such as methanol, ethanol, 2-propanol, etc.
It can also be implemented. Formula (-f) [wherein R ¹ , R ² , n, A, m, Ar ¹ and Ar ² are as defined above, and L ¹ is lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl, -lower selected from the group consisting of alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl, and lower alkenyl, with the proviso that the unsaturation in the lower alkenyl is in a position other than α. c) It can be produced by introducing L ¹ into the compound. Depending on the nature of the L ¹ group added, the following methods can be used. When L ¹ represents lower alkyl, lower alkyloxycarbonyl-lower alkyl, phenylmethyl or lower alkenyl (using the symbol L ¹ a in this case), the introduction of L ¹ a into (-c) is
c) and a suitable reactive ester of the formula L ¹ a-W (), where L ¹ a is as defined above and W is as indicated in the definition of the starting material of formula (). It is carried out by the reaction ``has the same meaning as ''. The condensation of () and (-c) can be carried out under the same conditions as described above for the condensation of the reactive ester () and the intermediate product of formula (). In order to increase the reaction rate, small amounts of suitable macrocyclic polyethers, such as 2,3,11,12-dibenzo-
It is suitable to add 1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene. When the L ¹ group to be introduced is lower alkyloxycarbonylethyl, the introduction of the group is (-
c) with a (lower alkyl)2-propenoate of the formula () (lower alkyl)OOC-CH=CH ₂ (). The reaction is conveniently carried out in an organic solvent inert to the reaction, such as aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; ethers such as 1,1'-oxybisethane, 2,2' -oxybispropane, tetrahydrofuran, 1,4-dioxane, etc., preferably in the presence of a suitable aminium hydroxide such as, for example, N,N,N-triethylbenzene methanaminium hydroxide. Formula in which L ¹ represents carboxy-lower alkyl (
The compounds of -f) can be easily derived from the corresponding lower alkyloxycarbonyl-lower alkyl substituted compounds by hydrolyzing the latter in conventional manner, e.g. with aqueous alkali to liberate the acid from the ester. . When the L ¹ group is lower alkylcarbonyl, it is conveniently combined with (-c) and a suitable acylating agent derived from the corresponding lower alkylcarboxylic acid, such as a halide, preferably a chloride, or an anhydride. The reaction is introduced according to standard N-acylation methods. When L ¹ represents lower alkylaminocarbonyl, it can be dissolved in a suitable organic solvent which is inert towards the reaction, e.g. an ether, e.g. 1,1'-
In oxy-bisethane, 2,2'-oxybispropane, 1,4-dioxane,
c) with a suitable isocyanatoalkane. When L ¹ is a hydroxymethyl group, its introduction is conveniently carried out by reaction of (-c) with formaldehyde in a suitable organic solvent such as N,N-dimethylformamide. On the other hand, the formula (-g) [where B, n, Ar ¹ and Ar ² are as defined above] under the same conditions as described above for the preparation of compound () from () and (). The piperazine derivative of the formula () can be expressed as the formula (
) [where Ar ¹ , Ar ²
and W are as defined above]: A number of intermediates of formula () are known compounds, and some of them are described in U.S. Patent Application No. 597,793, filed July 21, 1975;
U.S. Patent Application No. 8, filed October 8, 1975
620727, and they can all be produced according to methods known per se.
Depending on the nature of B in the intermediates (), the following methods can be used for their preparation. Formula (-a) The intermediate product can be produced as follows. A suitable substituted 2-chloronitrobenzene of formula () is combined with a suitable aminoalkanol ()
and the reactants together in a suitable organic solvent inert to the reaction, such as a lower alkanol, such as ethanol, propanol, 2-propanol, butanol, etc., to give the formula (). of [(2-nitrophenyl)
The amino]alkanol is obtained, which is reduced by nitro-amine, for example by catalytic hydrogenation using a Raney-nickel catalyst. The intermediate product (XI) thus obtained is then reacted with a suitable cyclizing agent as described for the preparation of compound (-c) from () and the thus obtained The alcohol of formula () is then converted to the desired reactive ester (-a) by application of methods known in the art. Halide is simply (
) with sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, etc. When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by replacing its halogen with iodine. Other reactive esters, such as methanesulfonate and 4-methylbenzenesulfonate, are obtained by reaction of the alcohol with a suitable sulfonyl halide, such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively. The above reaction is clearly illustrated by the following schematic representation. On the other hand, the intermediate product of formula (-a) is obtained by converting the compound of formula () [wherein R ³ and R ⁴ are as defined above] into a compound of formula (
) with a haloalkanol of formula ( ) by conventional N-alkylation methods to obtain an alcohol of formula ( ), converting the hydroxyl function of ( ) to a reactive ester group by conventional methods as described above, and It is prepared by removing the substituted ethenyl group of () thus obtained by acid hydrolysis as described for the preparation of (-c) from (). The introduction of a hydroxyalkyl chain into () to obtain () converts () into the formula (
) with an appropriate 2-(haloalkyloxy)tetrahydro2H-pyran to form the formula ()
This is done by obtaining an intermediate product of which the ether function is hydrolytically removed, for example by treatment with aqueous hydrochloric acid. When the reactive ester (-a) is a halide (-a-1), it is prepared by treating () with an equal amount of a suitable dihaloalkane () in the presence of a suitable strong base such as sodium methoxide. or by the Mackosza method using an aqueous alkali and a quaternary ammonium catalyst, such as N,N,N-triethylbenzenemethanaminium chloride, to give an intermediate of formula (-a), which is then replaced by The desired halide (-a
-1). When the substituted ethenyl group is substituted with another suitable protecting group, the same methods apply except that its removal must be carried out according to the method appropriate for the removal of the particular included group. It should be noted that it is also possible to The above reaction is clearly illustrated by the following schematic representation. Formula (-b) [wherein R ¹ , R ² , n and W are as defined above, and L ² is lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower alkyl, phenyl, phenylmethyl and lower alkylaminocarbonyl. [selected from the group consisting of are prepared by introducing reactive ester side chains into the starting materials. Formula (-c) The intermediate products of are prepared from the corresponding (-a) by hydroxymethylation of the latter with formaldehyde in a conventional manner. Intermediate products of formula () are obtained by condensing a suitable reactive ester of formula () with piperazine or piperidine derivatives of formula (), and then replacing the nitro group of the intermediate product () thus obtained with an amino group. by reduction according to standard nitro-amine reduction methods, e.g. by reaction of the nitro compound with nascent hydrogen or by catalytic hydrogenation in the presence of a suitable catalyst, e.g. Raney-nickel. can get. The formula used here as starting material (
The reactive esters of ) are readily prepared from alcohols of formula ( ) by converting their hydroxyl functionality to reactive ester groups according to standard methods such as those described above. Intermediate products of formula () are obtained by condensing reactive esters of formula () with piperazine or piperidine derivatives of formula (). Reactive esters used as starting materials (
) is the CnH ₂ nW group according to the method described above with the formula () into the starting materials. Intermediates of formula () are prepared by reacting a reactive ester of formula () with a piperazine derivative of formula (), where Q is a suitable protecting group, e.g. phenylmethyl or lower alkyloxycarbonyl, and then From the intermediate product thus obtained ( ), the protecting group Q is removed according to standard methods known in the art, for example by catalytic hydrogenation using a palladium catalyst on charcoal when Q represents phenylmethyl. Alternatively, when Q represents lower alkyloxycarbonyl, it is produced by removing it by alkaline hydrolysis. Formula (-a) Intermediates of () are prepared by reacting () with () to obtain intermediates of formula (L), followed by removal of the protecting groups P and Q by suitable methods generally known in the art. Ru. Formula () where A is 〓N- and m is 0
The intermediate product (-a) is generally known,
And they are all manufactured by applying methods known in the art. Such intermediate products can be produced, for example, by first subjecting a suitable aroyl halide to a Friedel-Crafts reaction using a suitable allene to produce Ar ¹ ,
Ar ² -methanone is obtained, which is then processed in the usual manner by
For example, it is produced by reduction to the corresponding methanol using sodium borohydride. The latter is then converted into a reactive ester () according to standard methods for the production of reactive esters from alcohols.
and then reaction of () with piperazine gives the desired intermediate (-a). Intermediates (-b) of formula () in which A is 〓CH- and m is 1 are prepared by converting 4-piperidinol of formula (L), in which Q is a suitable protecting group as described above, into a suitable protecting group of formula (). It is easily prepared by O-alkylation using a reactive ester, followed by removal of the protecting group of (L) thus obtained by conventional methods. The main starting materials used in all the above-mentioned preparations are generally known and they are all prepared according to general methods known to those skilled in the art. Compounds of formula () may also be converted into therapeutically active non-toxic acid addition salt forms by treatment with suitable acids such as those listed below; examples of such acids include inorganic Acids, such as hydrohalic acids such as hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanonic acid, 2-oxopropanonic acid, etc. Nonacid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-
Hydroxybutenedioic acid, 2,3-dihydroxybutenedioic 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, cyclohexasulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and similar acids. Conversely, the salt form can also be converted to the free base form by treatment with an alkali. The compounds of the present invention of formula () and their pharmaceutically acceptable acid addition salts have strong antianaphylactic and antihistamine properties, and as such they are useful for human and animal therapy. It is a reagent. The useful antianaphylactic and antihistamine properties of the compounds of the invention are clearly demonstrated by the results obtained with the test method described below. The compounds listed in the accompanying table are not intended to limit the invention thereto, but rather include the useful antianaphylactic and antihistamine properties of all compounds within formula (). I would like to emphasize that these are listed for illustrative purposes. A. Materials and Methods a. In vivo anti-anaphylactic and anti-histamine effects The anti-anaphylactic and anti-histamine effects of the compound () of the present invention and its salts were studied in vivo in guinea pigs. Guinea pigs weighing 400-500 g were sensitized to ovalbumin by intraplantar injection of 0.05 ml of antiserum into the left hind paw. The animals were then fasted and 24 hours after sensitization were treated orally with saline (=control animals) or with specified doses of the compound. Two hours after pre-treatment with the compound, a histamine injection (at a dose of 50 μg) was given plantarly into the right hind paw.
The diameter of both hindpaws was measured before and 10 minutes after the histamine injection. Animals were given 0.6 mg ovalbumin intravenously 30 minutes after the histamine injection. All control animals exhibited typical early anaphylactic symptoms (cough, difficulty breathing, convulsions).
and 85% of these control animals died 15 minutes after ovalbumin injection. Protection against death was used as a criterion to examine the efficacy of the drug, and the estimated ED ₅₀ values, ie the oral dose at which 50% protection in guinea pigs was observed, are shown in the table below. Ten minutes after histamine injection, the average histamine-induced edema in the 200 control animals was 15 units (1 unit = 0.1 mm). An increase in paw diameter of less than 10 units was observed in less than 5% of control (saline treated) animals. The dose level that can reduce the increase in foot diameter to less than 10 units was defined as the effective dose and is listed in the table below. b Antihistamine activity in vitro A piece of guinea pig ileum was suspended in 100 ml of a 37.5° C. Tyrode bath with a preload of 0.75 g and exposed to a gas consisting of 95% O ₂ and 5% CO ₂ . supplied. Spasticity induced by histamine (0.5 mg/) was recorded by wave imaging using an isotonic criterion giving 5x magnification. The interaction of the compound to be tested with the working muscle (5 min incubation time) was investigated, and the effective concentration (mg/ml) of the various compounds was determined where a significant inhibition (50%) of histamine-induced contractions was determined. ) are shown in the table below. From the results of the above test, the compound of the present invention ()
and its pharmaceutically acceptable salts are generally found to be active as anti-allergic agents when administered systemically to warm-blooded animals at doses ranging from about 0.25 to about 20 mg/Kg body weight. Served. Because of their useful antihistamine and antianaphylactic activity, the compounds of the present invention can be formulated into a variety of pharmaceutical forms for administration. To prepare the pharmaceutical compositions of the present invention, an antihistamine or antianaphylactic effective amount of the specified compound in base or acid addition salt form as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier. The carrier may take a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in single dose form suitable for oral, rectal or parenteral injection administration. For example, in the preparation of compositions for oral dosage forms, any common pharmaceutical vehicle may be used, such as water, glycol, etc. in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions. ,
oil, alcohol, etc., and in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, leavening agents, etc. Because of their ease of administration, tablets and capsules represent the most useful oral dosage unit forms, in which case solid pharmaceutical carriers are employed. Carriers for parenteral administration will normally consist at least in large part of sterile water, although other ingredients may also be included, such as ingredients to aid solubility. Injectable solutions can also be prepared in which the carrier is a saline solution, a glucose solution, or a mixture of saline and glucose solutions.
Suitable liquid carriers, suspending agents and the like may also be used. The acid addition salts of () are clearly more suitable for the preparation of aqueous compositions than the corresponding base forms due to their greater water solubility. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used in the specification and claims, refers to physically discrete units suitable for single administration, each unit containing the desired pharmaceutical carrier(s). Contains a predetermined amount of active ingredient calculated to produce a therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packages, wafers, injectable solutions or suspensions,
These include tea spoon drops, tablespoon drops, etc., as well as their separated compounds.

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[Table] Note that 1,3-dihydro-1-[3-{4-[phenyl(2-pyridinyl)methyl-1-piperazinyl}] obtained in Example 27 below and generally called oxatomide Propyl]-2H
-About benzimidazol-2-one
The LD ₅₀ values were as follows: Dog: Oral: LD ₅₀ > 1280 mg/Kg (both sexes) Rat: Oral: LD ₅₀ > 2560 mg/Kg (male) LD ₅₀ = 1670 mg/Kg (female) Examples below are illustrative of the invention and are not intended to limit the scope of the invention. All parts are parts by weight unless otherwise noted. Example 1 54 parts of 1,3-dihydro-1-(phenylmethyl)-2H-benzimidazol-2-one,
450 parts of sodium hydroxide are added to a stirred hot mixture of 47.25 parts of 1-bromo-3-chloropropane and 6 parts of N,N,N-triethylbenzene methanaminium chloride at 60°C.
The 60% solution was added dropwise. After completion, stir at 60℃ for 6 hours.
It lasted for hours. The oily product was extracted with trichloromethane. The extracts were dried, filtered and evaporated. Crystallization of the residue from 2,2'-oxybispropane yields after drying 42 parts (58%) of 1-(3-chloro-propyl)-1,3-dihydro-3-(phenylmethyl)-2H-benzimidazole. -2-one was obtained. Similarly, the following compounds were prepared:

[Table] Example 2 5 parts of 4-chloro-1,3-dihydro-3-
To a stirred mixture of (3-hydroxypropyl)-2H-benzimidazol-2-one and 75 parts of trichloromethane was added dropwise 8 parts of sulfinyl chloride. After completion, stirring was continued for 3 hours at reflux temperature. The reaction mixture was cooled and evaporated. The residue was stirred in a small amount of 4-methyl-2-pentanone. The product was separated and dried to yield 3.5 parts of 4-chloro-3-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one. Example 3 A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts of butanol was stirred overnight and brought to reflux. . Butanol was removed by vacuum distillation and water was added to the residue. The product was extracted with 4-methyl-2-pentanone. The extract was washed 2-3 times with water, dried,
filtered and evaporated. the oily residue on silica gel,
It was purified by column chromatography using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was separated and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 31.7 parts of 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol ( A melting point of 97°C was obtained. Similarly, 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 2-{[2-nitro-4-(trifluoromethyl)
Phenyl]amino]ethanol (melting point 74.9°C) was produced. Example 4 To a stirred mixture of 39.2 parts of 3-(2-nitro-phenyl)amino-1-propanol and 225 parts of trichloromethane was added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: the temperature was 45℃
). After completion, stirring was continued for 6 hours at reflux temperature. Evaporation of the reaction mixture gave 43 parts (100%) of N-(3-chloro-propyl)-2-nitrobenzenamide as a residue. (
-1) In the same manner, the following was produced as a residue: N-(3-chloropropyl)-2-nitro-4-
(trifluoromethyl)benzenamine, 4,5
-dichloro-N-(3-chloropropyl.-2-nitrobenzeneamine (melting point 78°C), and N-(2-chloroethyl)-2-nitro-4-
(Trifluoromethyl)benzenamine. Example 5 21.5 parts of N-(3-chloropropyl)-2-nitrobenzeneamine, 22.68 parts of 1-(diphenylmethyl)-piperazine, 20 parts of N,N-diethylethanamine and 180 parts of N,N-dimethyl The acetamide mixture was stirred and heated at 100° C. for 6 hours. The reaction mixture was evaporated and the residue was taken into water. The oily product was extracted using trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The product was separated and dried to yield 15.5 parts (36.9%) of 4-(diphenylmethyl)-
N-(2-nitrophenyl)-1-piperazinepropanamine hydrochloride (melting point 228°C) was obtained. The following were prepared in the same way: N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine (residue), 4-(diphenylmethyl)-N-[ 2-Nitro-
4-(trifluoromethyl)-phenyl]-1-piperazinepropanamine (melting point 113.7°C) and 4-(diphenylmethyl)-N-[2-nitro-
4-(trifluoromethyl)-phenyl]-1-piperazinethanamine (melting point 152.1°C). Example 6 A mixture of 15 parts of 4-(diphenylmethyl)-N-(2-nitrophenyl)-1-piperazinepropanamine hydrochloride in 160 parts of methanol was reacted at normal pressure and room temperature with 5 parts of Raney-nickel catalyst. and hydrogenated. After the calculated amount of hydrogen had been absorbed, the catalyst was separated on Hyflo and the liquid was evaporated. The solid residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was separated and dried to yield 12 parts (78.9%) of N-
(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride (melting point
223.1℃) was obtained. Similarly, the following was prepared: 4,5-dichloro-N'-{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-
1,2-benzenamine (oily residue), N'-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenamine, and N'- {2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine (oily residue). Example 7 60.5 parts of 1-(3-chloropropyl)-1,3-
Dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 31.68 parts of 1-(phenylmethyl)piperazine, 21.2 parts of sodium carbonate, 0.1 part of potassium iodide and 400 parts of 4-methyl-2 - The mixture of pentanone was stirred and refluxed for 20 hours using a water separator. cool the reaction mixture;
Water was added and the layers were separated. The organic phase is dried, filtered and evaporated to give 70 parts (100%) of 1,3-dihydro-1-(1-methyl-ethenyl)-3-{3-[4-(phenylmethyl)-1- Piperazinyl]propyl}-2H-benzimidazol-2-one was obtained as a residue. Similarly, 1,3-dihydro-1-{2-[4-
(phenylmethyl)-1-piperazinyl]ethyl}
-2H-benzimidazol-2-one (melting point
136.5℃) was obtained. Example 8 70 parts of 1,3-dihydro-1-(1-methylethenyl)-3-{3-[4-(phenylmethyl)-1
-Piperazinyl]-propyl}-2H-benzimidazol-2-one in 240 parts of ethanol was added with stirring to a solution of 55 parts of N hydrochloric acid. The whole was stirred for 2 hours at 70-50°C. The reaction mixture was evaporated and the residue was taken into dilute ammonium hydroxide solution. The oily product was extracted using trichloromethane. The extract was dried, filtered and evaporated to yield 63 parts (100%) of 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazole-
2-one was obtained as a residue. Example 9 63 parts of 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-
A mixture of 2H-benzimidazol-2-one in 400 parts of methanol was hydrogenated at normal pressure and room temperature using 10 parts of 10% palladium on charcoal catalyst.
After the calculated amount of hydrogen had been absorbed, the catalyst was separated on Hyflo and the liquid was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product was separated and dried to yield 29.5 parts (63%) of 1,3-dihydro-1-[3-(1-piperazinyl)propyl].
-2H-benzimidazol-2-one (melting point
157.5℃) was obtained. Similarly, 1,3-dihydro-1-[2-(1
-piperazinyl)ethyl]-2H-benzimidazol-2-one (melting point 122.6°C) was obtained. Example 10 To a stirred mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene was added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. After completion, the mixture was heated to reflux and stirred at reflux temperature for 5 minutes. The reaction mixture was poured onto crushed ice and the product was extracted with 1,1'-oxybisethane. The extract was dried and evaporated to give 30 parts of (2,4-dichlorophenyl)(4-fluorophenyl)methanone as an oily residue. Similarly, (4-fluorophenyl)(4-pyridinyl.methanone) (melting point: 85.5°C) was produced. Example 11 23.4 parts of (4-
3.7 parts of sodium borohydride was added dropwise to the stirred and refluxing mixture containing chlorphenyl)(2-fluorophenyl)methanone, stirring for 2 hours at reflux temperature (±80°C).
It lasted for hours. The reaction mixture was cooled and decomposed by the addition of water. The 2-propanol was evaporated and the remaining product was extracted with trichloromethane. Drying, filtering and evaporating the extract yields 23.6
Part of 4-chloro-α(2-fluorophenyl)benzene methanol was obtained as a residue. Similarly, the following were prepared: 2,4-dichloro-α-(4-fluorophenyl)benzene methanol (residue), α-(4-fluorophenyl)-4-pyridine methanol (melting point 138.2°C), α-(4-fluorophenyl)-3-pyridinemethanol hydrochloride (melting point 158.8°C), and 4-methoxy-α-[3-(trifluoromethyl)phenyl]benzenemethanol (residue). Example 12 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzene methanol and 240 parts of 12N
The mixture of hydrochloric acid solution was stirred at room temperature for 40 hours. The reaction mixture was poured onto ice water and the product was extracted using trichloromethane. The extract was washed with water, dried, filtered and evaporated. Distilling the residue
13.2 parts of 2,4-dichloro-1-[chloro-(4-
fluorophenyl)methyl]benzene (boiling point 0.15
146°C at mm pressure) was obtained. Similarly, the following were prepared: 1-[α-chloro-α-(4-methoxyphenyl)methyl]-3-(trifluoromethyl)benzene (residue) and 1-[chloro-( 4-methylphenyl)methyl]
-4-fluorobenzene (residue). Example 13 23.6 parts of 4-chloro-α in 108 parts of benzene
24 parts of sulfinyl chloride were added dropwise to the stirred mixture containing -(2-fluorophenyl)benzene-methanol. After completion, the whole was heated to reflux and stirred, first at reflux temperature for 5 hours and then at room temperature for a further night. The benzene is evaporated and the residue is distilled to yield 16.5 parts of 1-chloro-
4-[α-chloro-α-(2-fluorophenyl)
-Methyl]benzene (boiling point, at 0.1 mm pressure
122-125°C) was obtained. The following were prepared in the same way: 3-[α-chloro-α-(4-fluorophenyl)methyl]pyridine hydrochloride (in the form of an oily residue), 3-[α-chloro-α-(4- chlorphenyl)
Methyl]pyridine hydrochloride (residue), 4-[α-chloro-α-(4-fluorophenyl)methyl]pyridine hydrochloride (melting point 198-200
°C), 1-(chlorophenylmethyl)-2,3-dimethylbenzene (boiling point, 137 at 0.7 mm pressure
°C), 1-(chlorophenylmethyl)-2,4-dimethylbenzene (boiling point 137 at 0.7 mm pressure)
℃), 2-(chlorophenylmethyl)-1,4-dimethylbenzene) boiling point 0.7 mm at 136℃), 1
-(Chlorphenylmethyl)-2-fluorobenzene (boiling point 108-109°C at 0.4 mm pressure). Example 14 121 parts of piperazine, 54 parts of 3-[α-chloro-
A mixture of α-(4-chlorophenyl)methyl]pyridine hydrochloride and 315 parts of N,N-dimethylformamide was stirred at room temperature for 20 minutes. The reaction mixture was evaporated and 250 parts of water were added to the residue. The product was extracted with methylbenzene. The organic phase was washed with water and extracted with 10% acetic acid solution. The acidic aqueous phase was made alkaline using 60% sodium hydroxide solution and the product was extracted again with methylbenzene. The extract was dried, filtered and evaporated. The oily residue was converted to the nitrate in ethanol. After separating the salt, washing with ethanol and 2,2'-oxybispropane, and crystallizing from ethanol,
48 parts of 1-[α-(4-chlorophenyl)-α-(3
-pyridinyl)methyl]piperazine trinitrate (melting point 132.9°C) was obtained. The following were prepared in the same way: 1-[α-(4-chlorophenyl)-α-(2-fluorophenyl)methyl]piperazine, 1-[α-(4-fluorophenyl)-α- (4-
pyridinyl)methyl]piperazine) melting point 108.4
℃), 1-[(2-chlorophenyl)(3-chlorophenyl)methyl]piperazine, 1-[(2-fluorophenyl)phenylmethyl]piperazine ethanedioate (1:1), (melting point 195.5℃), 1- [(4-fluorophenyl)(4-methoxyphenyl)methyl]piperazine ethanedioate (1:2), (melting point 280.1°C), and 1-[(4-nitrophenyl)phenylmethyl]
Piperazine dihydrochloride. Example 15 A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidine carboxylate, 35.2 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate was stirred in an oil bath at 140°C for 3 hours,
Heated. The reaction mixture was allowed to cool to room temperature;
Then added water. The product was extracted with methylbenzene. The extracts were washed successively with water, dilute hydrochloric acid solution and sodium bicarbonate solution, dried, filtered and evaporated. When the pre-distillate is removed by distillation (boiling point
29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidinecarboxylate were obtained in the form of an oily residue. Similarly, ethyl 4-(diphenylmethoxy)-1-piperidinecarboxylate (boiling point at 0.4 mm pressure)
150℃) was produced. Example 16 A mixture of 29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidine carboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol was heated for 4 hours. Stir and reflux. The solvent was evaporated and water was added to the residue. The product was extracted with methylbenzene. The extract was washed 2-3 times with water, dried, filtered and evaporated. The oily residue was converted to the hydrochloride salt in 4-methyl-2-pentanone and 2-propanol at room temperature. When salt is separated and dried, 20.5 parts (78%) of 4
-[Bis(4-fluorophenyl)-methoxy]piperazine hydrochloride (melting point 161.8°C) was obtained. Similarly, 4-(diphenylmethoxy)piperidine hydrochloride (melting point 209.8°C) was produced. Example 17 5.3 parts of 1-(3-chloropropyl)-1,3-
A mixture of dihydro-2H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate, and 200 parts of 4-methyl-2-pentanone was stirred and refluxed using a water separator. . After cooling water was added and the layers were separated. The 4-methyl-2-pentanone phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. When the product is separated and dried, 2
(23%) of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one (melting point 153.6 DEG C.) was obtained. In a similar manner, the following compounds were prepared in free base form:
or prepared in acid addition salt form after treatment of the free base with a suitable acid.

【table】

Table: Example 18 The following was prepared in a manner similar to that described in Example 23: 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazole-2- 1- by the reaction of 1-methanesulfonate with 1-[bis(4-fluorophenyl)methyl]piperazine.
[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one (melting point 197.3°C), 1,3-dihydro -1-(3-iodopropyl)-3-methyl-2H-benzimidazole-2
1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-methyl-2H-benzimidazol-2-one by reaction of -one with 1-(diphenylmethyl)piperazine Dihydrochloride hydrate (melting point 201.8°C), Example 19 6.95 parts of 1-(5-chloropentyl)-1,3-
Dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 5.15 parts of 1-(diphenylmethyl)piperazine, 5.30 parts of sodium carbonate, 0.1 part of potassium iodide and 160 parts of 4-
The mixture of methyl-2-pentanone was stirred and refluxed overnight using a water separator. The reaction mixture was cooled to room temperature, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was stirred with a solution of 12 parts of hydrochloric acid in 40 parts of ethanol and brought to reflux. Evaporation of the whole and crystallization of the residue from ethanol yields 5 parts (46%) of 1
-{5-[4-(diphenylmethyl)-1-piperazinyl]pentyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate (melting point
215.3℃) was obtained. The following were produced in the same way:

[Table] Example 20 76 parts of 1-{3-[4-
To a stirred solution containing (diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one is added a solution of 120 parts of hydrochloric acid and 250 parts of hydrochloric acid. of water was added. The whole was stirred at room temperature for 30 minutes. The product precipitated upon cooling in an ice bath. Apart from that, 2-propanone and 2,
Washing with 2'-oxybis-propane and drying yields 43 parts (55%) of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3
-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate (melting point 237.5°C) was obtained. The following were produced in the same way:

[Table] Example 21 3.6 parts of N'-{2-[4-(diphenylmethyl)-
A mixture of 1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine and 1.8 parts of urea was stirred in an oil bath at 190°C for 3 hours. The reaction mixture was cooled, water and trichloromethane were added, and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1.5 parts (41.5%) of 1-{2-
[4-(diphenylmethyl)-1piperazinyl]ethyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one (melting point 163.7°C) was obtained. Similarly, the following was prepared: 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-
(Trifluoromethyl)-2H-benzimidazol-2-one (melting point 152.7°C), 5,6-dichloro-1-{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-
1,3-dihydro-2H-benzimidazole-
2-one (melting point 214.7°C). Example 22 2.3 parts of 1-{3-[4-(diphenylmethyl)-
1-Piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 4.5 parts of a 40% formaldehyde solution and 45 parts of N,N-
The dimethylformamide mixture was stirred and heated at 100°C for 2 hours. The reaction mixture was cooled and diluted with water. The precipitated product is separated and crystallized from methylbenzene, yielding 1.5 parts (66
%) of 1-{3-[4-(diphenylmethyl)-1-
piperazinyl]-propyl}-1,3-dihydro-
3-(Hydroxymethyl)-2H-benzimidazol-2-one (melting point 102.5°C) was obtained. Example 23 1.55 parts acetic anhydride, 3 parts 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts methyl The benzene mixture was stirred and refluxed overnight. Water was added to the reaction mixture and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol as eluent. Collecting the pure fractions and evaporating the eluent,
1.1 parts (33.5%) of 1-acetyl-3-{3-[4
-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one (melting point 124.4°C) was obtained. Example 24 1.1 parts ethyl 2-propenoate, 3 parts 1
-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, N,N,N-trimethylbenzenemethanaminium hydroxide in methanol 40 2-3 drops of % solution, and 25 parts of 1,4-
The dioxane mixture was stirred and refluxed for 24 hours.
The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. Collect pure distillate,
The eluent was then evaporated. The residue was converted to the hydrochloride salt in 2-propanol and ethanol. Separate the salt and dry it, 1.4 parts (32.5%)
Ethyl 3-{3-[4-(diphenylmethyl)-1
-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-
Propanoate dihydrochloride dihydrate (melting point 204°C) was obtained. Example 25 3 parts of 1-{3-[4-(diphenylmethyl)-1
A mixture of 1 part isocyanatomethane and 25 parts 1,4-dioxane was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was purified on silica gel with a mixture of trichloromethane and methanol (95:
5) was used for purification by column chromatography. The pure fractions were collected and the eluent was evaporated. Crystallization of the residue from a mixture of methylbenzene and 2,2'-oxybispropane yields 0.8 parts (23.5%) of 3-{3-[4-(diphenylmethyl)
-1-Piperazinyl]-propyl}-2,3-dihydro-N-methyl-2-oxo-1H-benzimidazole-1-carboxamide (melting point 153.1
°C) was obtained. Example 26 9.4 parts of 1-{3-[4-(diphenylmethyl)-
1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 180
of methylbenzene into a stirred mixture of
0.8 part of a 75% dispersion of sodium hydride was added and the whole was stirred and heated at 90° C. for 60 minutes. After cooling to 30°C, 0.2 parts of 2, 3, 11, 12
-dibenzo-1,4,7,10.13,16-hexaoxacyclooctadeca-2,11-diene,
Stirring was then continued for 10 minutes. Then 4.2 parts of ethyl 2-bromoacetate were added and the mixture was stirred and refluxed overnight. The reaction mixture was cooled to 90°C, 50 parts of water were added, and the layers were separated hot. Evaporation of the organic phase yields 10 parts of ethyl 3-
{3-[4-(diphenylmethyl)-1-piperazinyl]-propyl}-2,3-dihydro-2-oxo-1H benzimidazole-1-acetate was obtained as a residue. 9.8 parts of ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate, 1.2 parts of sodium hydroxide and 150 The water mixture was stirred for 5 minutes and brought to reflux (±80° C.). The reaction mixture was filtered and the liquid was acidified with acetic acid to a pH of 5.8-6, forming a sticky precipitate. It was isolated and crystallized from ethanol and water. The product is separated and dried in vacuo at 100° C. for 3 hours to give 6 parts of 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo- 1H-benzimidazole-1-acetic acid hemihydrate (melting point 138.7°C) was obtained. Example 27 5.2 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 5.28 parts of 2-(chlorophenylmethyl)pyridine hydrochloride, 5.3 A mixture of 1 part sodium carbonate and 90 parts N,N-dimethylformamide was stirred and heated at 50 DEG C. overnight. The reaction mixture was cooled and poured onto ice water. The product was extracted with methylbenzene. Dry the extract
filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was separated and dried to yield 2 parts (23.4%) of 1,3-dihydro-1-
[3-{4-[phenyl(2-pyridinyl)methyl]-1-piperazinyl}propyl]-2H-benzimidazol-2-one (melting point 141.7°C) was obtained. The following were produced in the same way:

【table】

[Table] Example 28 13 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 12.4 parts of 1,1'-(brommethylene)bis A mixture of [benzene], 6.6 parts of sodium carbonate, and 200 parts of 4-methyl-2-pentanone was stirred overnight using a water separator and refluxed. After cooling to room temperature, water was added and the layers were separated. The organic layer was dried, filtered and evaporated. Crystallization of the residue from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol gives 1-
{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one (melting point 153°C) was obtained. Example 29 Following the procedure of Example 38 and using equal amounts of the appropriate starting materials, the following compound was prepared: 1-[2-{4-[bis(4-fluorophenyl)methyl]- 1-piperazinyl}ethyl]-1,
3-dihydro-2H-benzimidazole-2-
ion hemihydrate (melting point 131.5°C), 1-{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one (melting point 218°C), and 1-[3-{4-[bis(4-fluorophenyl)
Methyl]-1-piperazinyl}-propyl]-1,
3-dihydro-2H-benzimidazole-2-
on (melting point 198℃). Example 30 4.8 parts of 1-(3-chloropyropyl)-1,3-
Dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4
-Methyl-2-pentanone mixture was stirred overnight using a component separator and refluxed. The reaction mixture was cooled and water was added. The layers were separated and the 4-methyl-2-pentanone phase was dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. Crystallization of the residue from 4-methyl-2-pentanone yields 4.2 parts (48%) of 1-{3-[4-
(Diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one (melting point 149.2°C) was obtained. The following were produced in the same way:

[Table] Related aspects of the present invention are described below. 1 formula [wherein Ar ¹ and Ar ² are each independently selected from the group consisting of phenyl, substituted phenyl and pyridinyl, wherein the substituted phenyl is halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro phenyl having 1 to 2 substituents independently selected from the group consisting of, m is an integer of 0 or 1, and A is a member selected from the group consisting of 〓N- and 〓CH- , provided that when A is 〓N-, m is 0, and when A is 〓CH-, m is 1, and n is an integer from 2 to 6, provided that
When CnH ₂ n represents a branched alkylene chain, at least two carbon atoms are present in the linear part of the chain linking B and the piperidine or piperazine nitrogen atom, and B represents a formula (Here, R ¹ and R ² are each independently hydrogen,
is selected from the group consisting of halo, lower alkyl and trifluoromethyl, and Y is a member selected from the group consisting of oxygen, sulfur and substituted nitrogen of the formula N-L, and L is hydrogen, lower alkyl, a member selected from the group consisting of lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl; and a group having the formula b (Here, R ¹ and R ² are each independently hydrogen,
selected from the group consisting of halo, lower alkyl and trifluoromethyl, and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto,
is a member selected from the group consisting of lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino, and cycloalkyl having 3 to 6 carbon atoms) ] A method for producing a chemical compound selected from the group consisting of compounds having the formula a and pharmaceutically acceptable acid addition salts thereof, Preferably in the presence of a reaction-inert organic solvent and a suitable base and at elevated temperature to prepare a compound of the formula B'-CnH ₂ n-W [wherein B' is of the formula B as defined above except for the 2-amino-1H-benzimidazolyl-1-l group of and W is a suitable reactive ester function derived from the corresponding alcohol. Reactive ester formula or react with a compound of formula b Under hydrolysis conditions to produce the compound of formula or decarboxylate a compound of formula c or [wherein M ¹ is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl] is ring-closed by reaction of () with a suitable cyclizing agent by known methods using suitable cyclizing agents known in the art, or d To prepare the compound of formula The protecting group P is removed from the compound of formula e by a general method, or In order to prepare a compound of the above formula (-a)
A suitable compound of f is acylated by standard N-acylation methods or f formula [wherein L ¹ is selected from the group consisting of lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl, with the proviso that the lower alkenyl The unsaturation in is at a position other than α].
The group L ¹ is introduced into the compound of the formula g by a known method, or In order to prepare the compound, preferably in the presence of an organic solvent inert to the reaction and a suitable base,
and at elevated temperature Eq. Formula the compound of in which W is as defined above or by condensation with a suitable reactive ester of the formula from the corresponding -SH substituted congeners by known S-alkylation methods, and optionally preparing pharmaceutically acceptable acid addition salts of the products of steps a to h. How to do it. 2,1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one
- react with (diphenylmethyl)piperazine,
and optionally preparing a pharmaceutically acceptable acid addition salt of the product, 1-
the above selected from the group consisting of {3-[4-diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and pharmaceutically acceptable acid addition salts thereof; 1
A method of manufacturing a chemical compound according to. 3,1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate is reacted with 1-[bis(p-fluorophenyl)methyl]piperazine and optionally its 1-[3-, characterized in that it produces a pharmaceutically acceptable acid addition salt of the product.
{4-[bis(4-fluorophenyl)methyl]-
1-Piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and a pharmaceutically acceptable acid addition salt thereof. 4,1-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazolone-2-one is reacted with 1-[bis(p-fluorophenyl)methyl]piperazine and optionally the product is 1-[4-{4-[bis(4-fluoromethyl)methyl]-1-piperazinyl}butyl]-1, characterized in that it produces a pharmaceutically acceptable acid addition salt.
3-dihydro-2H-benzimidazole-2-
1. A method for producing a chemical compound according to 1 above selected from the group consisting of 1 and pharmaceutically acceptable acid addition salts thereof. 5,1-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazol-2-one to 1-
1-{4, characterized in that it reacts with (diphenylmethyl)piperazine and optionally prepares a pharmaceutically acceptable acid addition salt of the product.
- [4-(diphenylmethyl)-1-piperazinyl]butyl}-1,3-dihydro-2H-benzimidazol-2-one and a pharmaceutically acceptable acid addition salt thereof; A method of manufacturing a chemical compound according to. 1-{3-, characterized in that 6,1-(3-chloropropyl)-1H-benzimidazole is reacted with 1-(diphenylmethyl)piperazine.
[4-(diphenylmethyl)-1-piperazinyl]
A method for producing a chemical compound according to 1 above, selected from the group consisting of propyl}-1H-benzimidazole and pharmaceutically acceptable acid addition salts thereof. Reacting 7,1-(4-chlorobutyl)-1H-benzimidazole with 1-[(4-fluorophenyl)phenylmethyl]piperazine and producing a pharmaceutically acceptable acid addition salt of the product. From the group consisting of 1-[4-{4-[(4-fluorophenyl)phenylmethyl}-1-piperazinyl}butyl]-1H-benzimidazole and pharmaceutically acceptable acid addition salts thereof, characterized in that A method for producing a chemical compound selected according to 1 above. Reacting 8,1-(4-chlorobutyl)-1H-benzimidazole with 1-[bis(p-fluorophenyl)methyl]piperazine and optionally producing a pharmaceutically acceptable acid addition salt of the product. 1-[4-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}butyl]-1H-benzimidazole and a pharmaceutically acceptable acid addition salt thereof, characterized in that A method for producing a chemical compound according to 1 above, selected from the group consisting of:

Claims (1)

[Claims] 1 formula [wherein Ar ¹ and Ar ² are each independently selected from the group consisting of phenyl, substituted phenyl and pyridinyl, wherein the substituted phenyl is halo, lower alkyl, lower alkyloxy, trifluoromethyl and phenyl with 1 to 2 substituents independently selected from the group consisting of nitro, m is an integer of 0 or 1, and A is selected from the group consisting of 〓N- and 〓CH- member, provided that when A is 〓N-, m is 0, and when A is 〓CH-, m is 1, and n is an integer from 2 to 6, provided
When CnH ₂ n represents a branched alkylene chain, at least two carbon atoms are present in the linear part of the chain connecting B and the piperidine or piperazine nitrogen atom, and B is of the formula (Here, R ¹ and R ² are each independently hydrogen,
selected from the group consisting of halo, lower alkyl and trifluoromethyl, and Y is a substituted nitrogen of the formula N-L, where L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl) and pharmaceutically acceptable compounds thereof A compound selected from the group consisting of acid addition salts. 2 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H
- A compound according to claim 1 selected from the group consisting of benzimidazol-2-one and pharmaceutically acceptable acid addition salts thereof. 3 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-
1,3-dihydro-2H-benzimidazole-
2. A compound according to claim 1 selected from the group consisting of 2-one and pharmaceutically acceptable acid addition salts thereof. 4 1-[4-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}butyl]-1,
3-dihydro-2H-benzimidazole-2-
2. A compound according to claim 1 selected from the group consisting of 1 and pharmaceutically acceptable acid addition salts thereof. 5 1-{4-[4-(diphenylmethyl)-1-piperazinyl]butyl}-1,3-dihydro-2H-
A compound according to claim 1 selected from the group consisting of benzimidazol-2-ones and pharmaceutically acceptable acid addition salts thereof. 6 Inert carrier substance and antihistamine or antianaphylaxis as active ingredient - effective amount of the following formula: [wherein Ar ¹ is selected from the group consisting of phenyl, substituted phenyl and pyridinyl, wherein the substituted phenyl is 1 to 1 independently selected from the group consisting of halo, lower alkyl, and nitro.
phenyl having two substituents, ^Ar2 is phenyl optionally substituted with halo, m is an integer of 0 or 1, and A is selected from the group consisting of 〓N- and 〓CH- is _a member of represents a branched alkylene chain, at least two carbon atoms are present in the linear part of the chain linking the benzimidazolone group and the piperidine or piperazine nitrogen atom, and R ¹ is selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl, R ² is hydrogen or halo, and L is hydrogen, lower alkyl, acetyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, a member selected from the group consisting of benzyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl, and a compound selected from the group consisting of a compound having: and a pharmaceutically acceptable acid addition salt thereof. An antihistamine or antianaphylactic composition. 7 an inert carrier material and an antihistamine or antianaphylactic effective amount of 1- as the active ingredient.
selected from the group consisting of {3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and pharmaceutically acceptable acid addition salts thereof 7. A composition according to claim 6, comprising a compound.