PL106572B1 - METHOD OF MAKING NEW DERIVATIVES OF PIPERAZINE AND PIPERIDINE - Google Patents

Description

The subject of the invention is a process for the preparation of new piperazine and piperidine derivatives of the general formula I, in which Ar1 and Ar2, independently of each other, represent a phenyl radical, a substituted phenyl radical or a pyridinyl radical, the phenyl radical being substituted by 1-2 substituents from halogen, lower alkyl, lower alkoxy, trifluoromethyl and nitro, m is 0 or 1, A is N or CH, where when A is N, then m = 0 and when A is CH - then m = 1, n is inclusive of 2-6, whereby when CnH2n is a branched alkylene chain, then at least 2 carbon atoms are in the linear part of the chain linking the B substituent to the piperidine or piperazine nitrogen atom , B is a radical of formula 1A, in which R1 and R2 are independently of each other hydrogen, halogen, lower alkyl or trifluoromethyl radicals, Y is oxygen, sulfur or a group of formula N-L where L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alcoamino-carbonyl, hydroxymethyl or lower alkenyl, B is also a radical of formula IB, in which R1 and R2 independently represent a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl radical, M is a hydrogen atom, a lower alkyl, phenyl, phenylmethyl radical, mercaptan group, lower alkylthio, lower alkylcarbonate - nylamino, lower alkoxycarbonylamino or cycloalkyl radical of 3-6 carbon atoms. Piperazine and piperidine derivatives such as 1- [/ heterocyclyl / alkyl] piperazines, 1-substituted 4- (diarylmethyl) piperazines and 4- (diarylmethoxy / piperidines), having pharmaceutical and logical properties are described in U.S. Patent Nos. 3,362,956, 3,472854, 3369022, 2,882,271 and 3,956,328, and CA. The nature of the B — CnH2n group at the 1-position of the piperazine or piperidine group and / or the nature of the diarylmethoxy or diarylmethoxy group at the 4-position of the piperazine or piperidine is different from the aforementioned compounds. a straight and branched hydrocarbon chain containing 1-6 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like. "denotes a straight or branched chain alkenyl radical containing 2 to 6 carbon atoms, such as ethenyl, 1-methylethenium, 1-propenyl, 2-propenyl, 2-butenyl, 1-methyl-2- bu-106 572106 572 3-tenyl, 2-pentenyl, 2-hexenyl and the like. "Cycloalkyl" means a cyclic hydrocarbon radical of 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and c yklohexyl. The term "CnH2n" denotes a straight and branched alkylene chain containing 2 to 6 carbon atoms and having at least 2 carbon atoms in the straight line of the chain linking substituent B to the piperidine nitrogen atom or piperases, such as 1,2-etadienyl. , 1,3-propadienyl, 2-methyl-1,3-propadienyl, 1,4-butadienyl, 2-methyl-1,4-butadienyl, 1,5-pantadienes ". Iowa, 1,6- hexadienyl and the like. The term halogen denotes a halogen atom with an atomic weight below 127, i.e. fluorine, chlorine, bromine or iodine. Compounds of the general formula where A, Ar1, Ar2, B, before they have the meaning given above, are obtained by a reactive reaction ester of general formula II, in which B and n are as defined above and W is a reactive ester group, for example halogen, methanesulfonyl, 4-methylbenzenesulfonyl and the like, with a piperidine or piperazine derivative of general formula III in which A, m, Ar1 and Ar2 are as defined above. The condensation reactions shown in Scheme 1 are preferably carried out in a suitable inert organic solvent, such as a lower alkanol, for example methanol, ethanol, propanol , butanol; aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, ethers, such as 1,4-dioxane, 1,17-oxybispropane; ketones such as 4-methyl-pentanone-2, N, N-dimethylformamide, nitrobenzene and the like. The addition of a suitable base such as alkali metal or alkaline earth metal carbonate or bicarbonate can be used to bind the acid formed during the reaction. A small amount of a suitable metal iodide, for example sodium or potassium iodide, may be added as a reaction promoter. Increased temperature increases the reaction rate and preferably the reactions are carried out at the reflux temperature of the reaction mixture. The reaction products are separated from the reaction mixture and optionally further purified using methods commonly known in the art. Compounds of formula II are partially known, some of which are described in US Pat. Nos. 4,035,369 and 4,066,772 and all They can be obtained by known methods. Depending on the nature of the substituent B in the compounds of formula II, they can be prepared by the following methods. Compounds of formula 2-a can be prepared as outlined in Scheme 2. An appropriately substituted 2-chloronitrobenzene of formula IV is reacted with the appropriate aminoalkanol of formula H 2 N — CnH 2 n — OH while refluxing the reagents in an inert solvent. , such as a lower alkanol, i.e. ethanol, propanol, 2-propanol, butanol and the like, yielding an [(2-nitrophenyl) amino] alkanol of formula V which is reduced by converting a nitro group to an amino group by catalytic hydrogenation using Raney nickel as catalyst. The compound of formula VI thus obtained is then reacted with a suitable cyclizing medium and the resulting alcohol of formula VII is then converted to the corresponding ester of formula II by known methods. The halides are conveniently obtained by reacting the compound of formula VII. with a suitable halogenating agent such as sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentbromide, phosphoryl chloride and the like. If the reactive ester is iodide, the compound is preferably obtained from the corresponding chloride or bromide by quenching these halogens with iodine. Other reactive esters such as methanesulfonates and 4-methylbenZenesulfonates are prepared by reacting the alcohol with a suitable sulfonyl halide such as, for example, methanesulfonyl chloride and 4-methylbenZenesulfonyl. Compounds of Formula 2 - and may also be prepared as shown in Scheme 3. Compound of formula 8 where R3 and R4 may be different groups, but preferably R3 is lower alkyl and R4 is hydrogen, lower alkyl or phenyl are reacted with halo-C2H2n-OH haloalkanol by conventional N -alkylation to give the alcohol of formula 9. The hydroxy group in compound 9 is converted to a reactive ester group in the usual manner and the substituted ethenyl group in the resulting compound of formula 10 is removed by acid hydrolysis. The hydroxyalkyl chain can also be introduced into the compound. of formula 8, to obtain a compound of formula 9, by reacting a compound of formula 8 with the appropriate 2- (haloalkoxy) tetrahydro-2H-pyran to give a compound of formula VIII. Formula 11, in which the ether group is hydrolytically cleaved, for example by treatment with an aqueous solution of hydrochloric acid. When the reactive ester of the formula 2-a is the halide of the formula 2-a-1, it can also be obtained by reacting Formula 458 with an equivalent amount of the appropriate dichloroalkane (halo — C2H2n — halo) in the presence of a suitable strong base such as sodium methoxide or by reacting Macosz with an aqueous solution of the liquor and quaternary ammonium salt as A catalyst such as N, N, N-triethylbenzene methanammonium chloride gives an intermediate of Formula 10-a, in which the substituted ethenyl group is then removed by acidic hydrolysis to give the desired halide of Formula II-a-1. The same methods are also used when another suitable protecting group is present in place of the substituted ethenyl group, except that the method suitable for that particular group is removed. Compounds of formula 2-b, wherein R 1, R 2, n and W are as defined above and L 2 is a lower alkyl, lower alkenyl, lower alkoxycarbonyl-lower alkyl, phenyl, phenylmethyl or lower alkylaminocarbonyl radical, 65 to prepare by introducing a side lan-5 chain of a reactive ester to the starting compound of formula 12 in a similar manner to that already described in the preparation of the compounds. The compounds of formula II-c can be obtained from the corresponding compounds of formula II-a by hydroxymethylation in the usual manner with formaldehyde. Compounds of formula II-d, with the exception of those where M is mercaptan or lower alkylthio are obtained in a known manner by introducing the side chain of a reactive ester to the starting compound of formula 13. The CnHan-W group can be introduced in a similar manner as already described for the introduction of such a group to the starting compound of formula (8) Compounds of formula II, in which R1, R2, M1, n and W are as defined above, can be obtained by treating the corresponding alcohol of formula 14 with a ring-closure reaction with a suitable cyclizing agent, then undergoing the group hydroxyl of the resulting compound of formula 15 into a reactive ester group as shown in Scheme 4. The mercaptane group (formula 15-a) with the corresponding lower halogen alkane followed by conversion of the hydroxyl group in the resulting compound of formula 16 to a reactive ester group as shown in Scheme 5. Compounds of formula II-g can easily be obtained by N-acylation of the corresponding amino analog of formula 2-h by treating a compound of formula 2-hr in a known manner with the appropriate lower alkanecarbonyl halide or lower anhydride of an alkanoic acid. The compounds of formula III in which A is N-am = 0 (formula 3-a) are generally known and can be prepared by conventional methods. Compounds of formula III can be obtained, for example, by subjecting the corresponding aroyl halide to a Friedel-Crafts reaction with the appropriate arylene to give Ar1-, Ar2-methanone which is reduced in the usual way, for example with sodium borohydride to the corresponding methanol. This compound is in turn converted into the reactive ester of formula 17 by a known method for the preparation of reactive esters, starting from alcohols and the corresponding intermediates of formula 3 - a obtained by reacting compounds of formula 17 with piperazine. Compounds of formula 3 in which A is CH-am = 1 (Formula 3-b), easily obtained by O-alkylation of Piperidinol-4 of Formula 18, wherein Q is the appropriate protecting group, with the appropriate reactive ester of Formula 17, stepwise de-protecting in the resultant The compound of formula 19 in the usual manner as shown in Scheme 6. The starting compounds used in all described methods are generally known and can be obtained by methods known to those skilled in the art. The compounds of formula I can be converted into therapeutically active non-toxic acid addition salts by treatment with a suitable acid such as an inorganic acid, for example, a hydrohalic acid such as hydrochloric, hydrobromic and the like, sulfuric, nitric, phosphoric and the like, or an acid. organic such as acetic, propionic, 1-hydroxyacetic, 1-hydroxypropionic, 1-ketopropionic, malonic, amber, fumaric, maleic, 1-hydroxysuccinic, 1,2-dihydroxy succinic, citric, benzoic, 2-phenyl ethenecarboxylic , mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like. Salts can be converted into free bases by treatment with an alkali. The compounds of formula I and their pharmacologically acceptable acid addition salts have strong anti-anaphylactic and antihistamic properties and as such are useful in the treatment of humans and animals. The anti-anaphylactic and antihistamine properties of these compounds are clearly demonstrated by the results of the tests described below. The compounds listed in the tables do not limit the scope of the invention, as they are exemplified to demonstrate the anti-anaphylactic and antihistamine properties of all compounds falling under the general formula 1.A. Materials and Methods a) "In Vivo" Anti-Anaphylactic and Antihistaminic Activity The anti-anaphylactic and antihistamine activity of the compounds of formula I and their salts was tested "in vivo" in guinea pigs. Guinea pigs weighing 400- to 500 g were sensitized to ovalbumin by sub-plantar (s.p.) injection of 0.05 ml of antiserum into the left hind paw. The animals were then fasted 40 and 24 hours after sensitization, they were given a saline solution orally (control animals) or a special dose of the test compound. Histamine (at a dose of 50 ng) was injected (sp) into the right hind leg 2 hours after oral administration. relationship. The diameters of both hind legs were first measured prior to the histamine injection and again after 10 minutes. The animals were injected intravenously with 0.6 mg of ovalbumin 30 minutes after the injection of histamine. All control animals had the typical first symptoms of anaphylactic shock (coughing, difficulty breathing, convulsions) and 85% of these control animals died within 15 minutes of ovalbumin infection. Protection against death was used as a criterion of effectiveness. The obtained values of ED60, i.e. the oral dose which protects against death of 50% of guinea pigs, are given in Tables 1-5 below. The mean swelling of the paw induced 10 minutes after 60 injections was in 200 control animals units (1 unit = 0, 1 mm). Reactions of less than 10 units occur in less than 5% of the control animals and are defined as the inhibitory efficacy of histamine swelling in animals treated with the compounds. The amount of the oral dose for which the inhibitory effect is evident is also given in Tables 1-5. b) "In vitro" antihistamine action. Portions of a guinea pig mole were suspended in a 100 ml Tyrode bath at 37.5 ° C, with an initial content of 0.75 g, by passing a gas mixture of 95% Oz and 5% CO2. The developed histamine (0.5 mg / liter) contractions were recorded cymographically with an isotonic lever giving a 5-fold magnification. The relationship (incubation time 5 minutes) with the agonist (histamine) was investigated in the following tables. 1-5 gives the effective concentration (in mg / l) of the various compounds, which causes a significant inhibition (50%) of the contraction induced by histamine. On the basis of the above tests, it was found that the compounds of formula I and their pharmacologically acceptable Salts are generally active anti-allergic agents in doses from about 0.25 to about mg / kg body weight when administered systemically to warm-blooded animals. Due to their anti-anaphylactic and anti-histamine effects, the compounds of the invention may be prepared in various forms. pharmacological methods depending on the route of administration. The effective amount of a compound of formula I in the form of a base or acid addition salt is combined with a pharmaceutically acceptable carrier, the nature of which depends on the form of preparation desired. The pharmaceuticals are preferably prepared in unit dose forms suitable, in particular, for oral, rectal or parenteral injection. For example, in the preparation of compositions for oral administration, any of the usual pharmaceuticals such as water, glycols, oils, alcohols and the like may be used with oral solutions such as suspensions, syrups, elixirs and solutions, or carriers. steels such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. For ease of use, tablets and capsules are the most preferred form of oral preparations, in which case solid pharmaceutical carriers should be used. for example increasing solubility. The injection solutions may, for example, contain a saline solution, a glucose solution or a glucose-saline mixture as a carrier. Injection suspensions may also contain suitable liquid carriers, disintegrants and the like. The acid addition salts of the compounds of formula I, according to their increased water solubility over the corresponding base form, are more suitable for the preparation of aqueous preparations. It is particularly advantageous to prepare the aforementioned pharmaceuticals in easy dosing units. for "use and uniform dosing. The dosing units set forth in the specification and claims refer to physically discrete units suitable as dosing units. Each unit contains a specific amount of active compound calculated to produce the desired therapeutic effect in conjunction with Examples of such dosage units are tablets (scored and coated tablets only) capsules, pills, dosing powders, injection solutions or suspensions, teaspoon or tablespoon and the like, and specified multiples thereof. Table 1 Compounds o Formula 20 L1 HHHHHHHH R1 2 H —Cl H —CF8 —CH3 HHH —Cl R2 8 HH 6 — Cl HHHHHH CnH2n 4 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 CH2) 8 CH2) 8 R6 HHHHH 2 — F 4 ^ -FHH R7 6 HHHHHH 4 ^ -FHH Base or salt 7 base base base base base base 1 / 2H20 base base Histamine "in vitro" (mole) Effective concentration in mg / 1 8 0.01 0.01 0.02 0.02 0.01 0.02 0.02 0.005 0.01 Anaphylaxis in guinea pigs Effective oral dose in mg / kg of survival 9 0.63 0 , 63 2.5 0.31 1.25 0.31 0.63 0.10 0.63 histamine swelling 1.25 1.25 2.5 1.25 1.25 0.16 0.63 0.31 1.25106 572 9 10 Table 1 continued 1 1 HHHHHH CH2 = C (CH8) C2H5 — OOC— (CH2) 2 C6H5 — CH2 CHj- ^ CO— CHj — NH — CO— CH8— HOCH2— C6H5- HHHHHHHHHHHHHHHHHHHH HOOC — CHji 2 —CH8 HHH 6 — Cl 6 — CF8 HHHHHHH 6 — Cl HHHH —Cl HHHHHHHHHHHHHHHHH 3 OH 6 — Cl 6 — CH8 7 —CH8 7 —H HHHHHH 6H H 8HH2H HHHH 6H (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH 2) 8. (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (GH2) 8 (CH2) 8 (CH2) 8 (CH2) 4 (CH2) 4 (CH2) 5 (CH2) 5 "( CH ^ —CH2— —CH (CH8) - —CH2 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 HHHHHHHHHHHHHH 4 — F 4 —Cl 3 ^ -Cl 4 ^ -F 4 — F 4 ^ -Y 2 — FH 4 ^ FH 4 ^ -FH 4 — FH 4 — Cl "* HH 4 — FHHH 6 HHHHHHHHHHHHHHHH 4 — F 4 ^ -F 4— F 4 — Cl H 4 — FH 4-FH 4 — F 2 — Cl 4 — Cl 4 — Br 2 — F 4 — CH8 4 — CH8 4 — NOk H 7 base base base base base base 2HC1-2H2O 2HC1 base base 2HC1-H20 base rule 2HC1-1 / / 2H20 base base rule rule rule rule • H20 base base rule 2HC1-H20 1/2 C2H5OH 2HC1-H20 2HC1-H20 base rule rule rule rule rule rule rule rule 1/2 H20 8 0, 01 0.04 0.01 0.08 0.16 0.02 0.01 0.005 0.16 0.005 0.02 0.01 0.01 0.08 0.01 0.01 0.01 0.01 0, 04 0.02 0.02 0.01 0.01 0.01 0.01 0.01 0.02 0.08 0.16 0.16 0.02 0.16 0.08 0.16, 0.08 9 0.08 0.63 0/16 2.5 2.5 0.31 0.16 0.63 1.25 0.10 - 1.25 0.31 - 0.31 1.25 0.63 0, 31 1.25 0.63 0.31 0.16 0.16 0.63 1.25 1.25 1.25 - <2.5 <2.5 <2.5 <2 , 5 <2.5 <2.5 <2.5 1 0.16 0.63 0.31 - 2.5 0.31 0.31 0.63 1.25 0.31 - 2.5 0.31 - 0.31 0.63 1.25 0.16 1.25 1.25 1.25 0.31 0.31 2.5 2.5 2.5 1.25 -, <2.5 <2.5 <2.5 <2.5 <2.5 <2.5 <2.5 Table 2 Compounds of formula 21 M 1 HC * H5-H CH, —S— CH8 R1 2 HHHHS CnH2n 3 (CH2) 2 ( CH2) 2 (CH2) 8 (CH ^ a (CH2) 8 R6 4 HHHHH R7 HHHHH Base or salt 6 base 3HC1-H20 base 3HC1-H20 base Histamine "in vitro" (exciter) Effective concentration x mg / l 7 0.005 0.16 0.0025 0.16 0.02 Anaphylaxis in guinea pigs Effective oral dose in mg / kg survived 8 1.25 0.08 1.25 2.5 histamine edema 9 1.25 0.16 1, 25 2.5106 572 11 12 1 1 C2H5 HS— cyclohexyl C6H5 — CH2— CH2OOC — NH— CH8 — CO — NH— C2H5— cyclohexyl C2H6— C5H5 — CH2— CeHg— cyclohexyl HHHHH CH8 HHHHH 2 HHHH ^ HH —Cl. 6 — Cl 6 — Cl HHHHHHHHHHH 3 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 3 (CH2) ) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 4 (CH2) 4 (CH2) 4 (CH2) 4 (CH2) 4 CH2 — CH (CH8) CH2 CH2 —CH (CH8) CH2 4 HHHHH H H H H H H H 4-F 2-Cl 4-Cl 4-F H H 4-F 3-C1 4-F H 4-F H H H H. HHHHHHHHHHH 4-FHHH 'H 4-F II 4-F 6 base base 3HC1-H20 base 3HC1-H20 base 3HC1-H20 base 3HC1-H2O base base base 3HC12H20 base H20 base base base 3HC1-H20 base 1 / 2CH2CH OHCH8 base 3HC11 / 2H20 3HC11 / 2H20 7 0.08 0.01 0.16 0.16 <0.16 0.16 0.01 - 0.01 - - - (£ £ 05 0.01 0.01 0.02 0 . 0025 0.005 0.005 0.01 0.005 0.02 0.02 Table 2 continued 8 0.63 2.5 - 2.5 2.5 2.5 0.63 - 2.5 2.5 2.5 0, 31 1.25 0.08 0.16 0.16 1.25 0.08 1.25 0.31 - 0.63 9 1 1.25 2.5 - 2.5 - 2.5 2.5 - - - - 0.31 1.25 0.31 0.31 0.16 1.25 0.16 1.25 0.31 - 1.25 Table 3 Compounds of formula 22 YSO Base or salt 2 HCM / 2H2O 2 HCl Histamine "In vitro" (mole) Effective concentration in mg / l 0.01 0.01 Anaphylaxis in guinea pigs Effective oral dose in mg / kg Survival 1.25 0.63 Histamine edema 1.25 2.5 Table 4 Compounds of formula 23 B pattern 24 pattern 24 pattern 24 pattern 24 pattern 25 CnH2n (CH2) 2 (CH2) 8 (CH2) 4 (CH2) 2 (CH2) 8 (CH2) 8 R6 HHH 4-F 4-FH R7 HHH 4 -F 4-FH ¦ Base or salt HjCl base base - HCM / 2H20 HCM / 2H20 base Histamine "in vitro" (mole) Effective concentration in mg / l 0.0025 0.0025 0.005 0.0025 0.0025 0.0025 Anaphylaxis in guinea pigs Effective oral dose in mg / kg | survival 0.31 0.63 0.63 0.31 0.63 0.16 histamine swelling 0.16 1.25 0.31 0.31 0.63 0.1613 106 572 Table 5 Compounds of formula 26 14 Ar1 C6H5 C6H5 4-Cl-C6H4 4-F-C6H4 4-F-C6H4 Ar2 2-pyridinyl 3-pyridinyl 2,5- (CH3) 2-C6H3 3-pyridinyl 3-pyridinyl 4-pyridinyl Base or salt base base base base principle Histamine "in vitro" (mole) Effective concentration in mg / l 0.16 0.08 0.16 0.08 0.08 0.16 Anaphylaxis in guinea pigs Effective oral dose in mg / kg survived 1.25 <2.5 histamine edema 2.5 <2.5 2.5 <2.5 <2.5 The following examples illustrate the method of the invention, unless otherwise stated all parts are parts by weight. a mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene, while stirring, 20.5 parts of 2,4-dichlorobenzoyl chloride are dripped in, then the mixture is heated and stirred under reflux for minutes. on crushed ice and the product is extracted with 1,1'-oxybiseane. The extract is dried and evaporated to give some (2,4-dichlorophenyl) 4-fluorophenyl) methanone as an oily residue. Similarly, there is obtained (4-fluorophenyl) 4-pyridinyl / methanone, m.p. 85.5 ° C Example II. To a mixture of 23.4 parts (4-chlorophenyl) 2-fluorophenyl) methanone in 280 parts of 2-propanol, while stirring and heating under reflux, 3.7 parts of sodium borohydride are added in portions and then it is stirred for 2 hours under reflux (approx. 80 ° C). The mixture is cooled and decomposed by adding water. Propanol-2 is evaporated off and the residual product is extracted with trichloromethane. The extract is dried, filtered and evaporated to give 23.6 parts of chloro-α- (2-fluorophenyl) phenylmethanol as residue. melting point 138.2 ° C, α- (4-fluorophenyl) -3-pyridinemethanone hydrochloride, m.p. 158.3 ° C and 4-methoxy-α- [3- (trifluoromethyl) phenyl] phenylmethanol as a remainder Example III. A mixture of 22 parts of 2,4-dichloro-α- (4-fluorophenyl) phenylmethanol and 240 parts of a 12 N hydrochloric acid solution is stirred for 40 hours at room temperature. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled to give 13.2 parts of 2,4-dichloro-1- [chloro (4-fluorophenyl) methyl] benzene with a boiling point of 146 ° C at a pressure of 0.15 mm. a-chloro-α- (4-methoxyphenyl) methyl] -3- (trifluoromethyl) benzene as residue and 1- [chloro (4-methylphenyl) methyl-4-fluorobenzene as residue Example IV. 24 parts of sulfinyl chloride are added dropwise to a mixture of 23.6 parts of 4-chlorobenzene with stirring, then the whole is heated and stirred under reflux for 5 hours, then overnight at the temperature of room. The benzene is evaporated off and the residue is distilled to give 16.5 parts of 1-chloro-4- [α-chloro-α- (2-fluorophenyl) methyl] benzene with a boiling point of 122-125 ° C at a pressure of 0.1 mm. Similarly, there is obtained: 3- [α-chloro-α- (4-fluorophenyl) methyl] pyridine hydrochloride as an oily residue, 3- [α-chloro-α- (4-chlorophenyl) methyl] hydrochloride pyridine as residue, 4- [a-chloro-pyridine hydrochloride, m.p. 198-200 ° C. - (chlorophenylmethyl) -2,4-dimethylbenzene boiling point 137 ° C at 0.7 mm pressure, 2- (chlorophenylmethyl) -1,4-dimethylbenzene boiling point 136 ° C at 0.7 mm pressure 1- (chlorophenylmethyl) -2-fluorobenzene, boiling point 108-109 ° C. at 0.4 mm pressure. Example 5 A mixture of 121 parts of piperazine, 54 parts of 3- [phenyl / methyl] pyridine hydrochloride and 315 parts of N, N-dimethylformamide is stirred for 20 hours at room temperature. The reaction mixture was evaporated to 45 50 55 106. It is digested and 250 parts of water are added to the residue. The product is extracted with methylbenzene. The organic phase is washed with water and extracted with a% acetic acid solution. The acidic water phase is neutralized with a 60% sodium hydroxide solution and the product is again extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted into the nitrate salt in ethanol. The salt is filtered off, washed with ethanol and 2,2'-oxybispropane and crystallized in ethanol 1 (yielding 48 parts of 1- [α- (4-chlorophenyl) -a- (3-pyridinyl / methyl] piperazine trinitrate at the temperature of mp 132.9 ° C. Similarly, there are obtained: 1- [piperazine, 1- [times, m.p. 108.4 ° C, 1- [(2-chlorophenyl / 3-chlorophenyl) methyl] piperazine, oxalate ( 1: 1) 1 - [(2-fluorophenyl) phenylmeth-2Cyl] -piperazine, m.p. 195.5 ° C, 1 - [(4-fluorophenyl / 4-methyloxyphenyl) methyl oxalate (1: 2) ] piperazine, m.p. 280.1 ° C and 1- [(4-nitrophenyl) phenylmethyl] piperazine dihydrochloride. 2a Example VI. A mixture of 21.5 parts of ethyl 4-hydroxy-piperidinecarboxylate, 35.2 parts Bis (4-fluoro-phenyl) bromoethane and 8.6 parts of potassium carbonate are mixed and the oil bath is heated at 140 ° C for 3 hours. The reaction mixture is cooled to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed with another. with water, dilute hydrochloric acid solution, sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled (bp 143 ° C at 0.5-1 mm pressure) to give 29 parts of ethyl 4- [bis (4-fluorophenyl) methoxy] piperidinecarboxylate as an oily residue. (diphenylmethoxy) ethyl 1-piperidinecarboxylate having a boiling point of 150 ° C. and a pressure of 0.4 mm. Example VII. A mixture of 29 parts of ethyl 4- [bis (4- 45-fluorophenyl) methoxy] piperidinecarboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol is stirred at reflux for 4 hours. . The solvent is evaporated off until water is added to the residue. The product is extracted with methylbenzene. The extract is washed several times with water, dried, filtered and evaporated. The oily residue is converted into the hydrochloride in 2-methylpentanone-2 and 2-propanol at room temperature. The salt is filtered off and dried to give 20.5 parts (78%) of 4- [bis (4-fluorophenyl) methoxy] piperidine hydrochloride, m.p. 161.8 ° C. 4- (diphenylmethoxy) hydrochloride is likewise obtained. / piperidine with a melting point of 209.8 ° C. Example VIII. For a hot mixture of 54 parts of 1,3-dihydro-1- (phenylmethyl) -2H-benzimide-2, 47.25 parts of 1-bromo-3-chloropropane and 6 parts of N, N, N-chloride Triethylbenzene methane-ammonium chloride, while stirring, is added dropwise to 450 parts of a 60% solution of sodium hydroxide at 60 ° C, then stirred for 6 hours at this temperature. The reaction mixture is cooled and poured into water. The oily product is extracted with trichloromethane. The extract is dried. it drags, and evaporates. The residue is crystallized from 2,2'-oxybispropane to give 42 parts (58%) of 1- (3-chloropropyl) -1,3-dihydro-3- (phenylmethyl) -2H-benzimidazolone--2 after drying. compounds of formula 27 (Table 6) Table 6 Compounds of formula 27 L CH2 = C (CH8) CH2 = C (CH8) CeH CH2 = C (CH8) CH2 = C (CH3) CH2 = C (CH8) ^ R1 -CH8 6-CH8 -Cl HHH n 3 3 3 4 6 Boiling point 140 ° C / 0.015 mm 140 ° C / 0.02 mm - - - - Example IX. Following the procedure of Example VIII and using equivalent amounts of the appropriate 1 H benzimidazole starting product, the product of the compound of formula 28 (Table 7) is obtained. Table 7 Compounds of formula 28 CHj), (CH1), (CH2) S CH2-CH (CH1) - CH2 (CH1), _ (CH2) 4 Example X. Mixture of 20 parts of 3 - [/ 2-amino-4-chlorophenyl / amino] -propanol-1.5 parts acetic acid and 150 parts 4N hydrochloric acid solution are stirred under reflux overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is neutralized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-4-methyl-pentanone-2 and 2,2'-oxybispropane to give 6.5 parts (28%) of 5-chloro-2-methyl-1H-benzimidazole-1-propanol. 5-chloro-2-ethyl-1H-benimidazole-propanol-1 by reaction of 3 - [(2-amino-4-chlorophenyl) -amino] -propanol-1 with propionic acid. Example XI. To a mixture of 30 parts of 3 - [(2-amino-4-chlorophenyl) amino] -propanol-1 and 0.1 parts of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene, stirring at reflux temperature (with a separator water), a solution of 34 parts of cyclohexylformaldehyde in 45 parts of methylbenzene is added dropwise and then stirred for an hour at reflux with a water separator. The methylbenzene is removed by evaporation under vacuum and the residue is triturated with 2,2'-oxybispropane. The product is filtered off and dried to give 16.5 parts (38%) of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol, m.p. 95 ° C. Example XII. A mixture of 30 parts of sodium 3 - [(2-amino-4-chlorophenyl) amino] propanol-1.44.8 parts of α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred at reflux for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried and evaporated to give 45 parts (100%) of 5-chloro-2- (phenylmethyl) -1H-benimidazole-1-propanol-1 as a residue. propanol-1 9 mp 120.1 ° C. in the reaction of 3 - [(2-amino-5-chlorophenyl) (amino] propanol-1 with sodium α-hydroxycyclohexane methanesulfonate. Example XIII. 60.8 parts of carbon disulphide are added dropwise to a mixture of 93 parts of 1-3-(2-aminophenyl) amino-propanol, 45.5 parts of potassium hydroxide and 600 parts of 85% ethanol in water, while stirring. and it is stirred for 6 hours under reflux. The reaction mixture is evaporated and the residue is taken up to 1500 parts of water. The whole is sipped until the filtrate is acidified with acetic acid. The oily product solidifies. It is filtered off, washed with water and dried to give 92 parts (78.9%) of 2-mercapto-1H-benzimidazole-1-propanol, m.p. 110 ° C. A mixture of 20.8 parts of 2-mercapto-1H ^ benzimide- 1-sol-propanol, 15.62 parts iodomethane and 120 parts methanol are stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered and the filtrate is neutralized with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, suctioned and evaporated to give 19 parts (85.5%) of 2- (methylthio) -1H-benzimidazole-1-propanol as residual. To a mixture of 19 parts of 2- (methylthio) -1H- 1-benzimidazole-propanol, 15.2 parts of N, N-diethylethinamine and 195 parts of dichloromethane are added dropwise while stirring to 11.5 parts of methanesulfonyl chloride, and then stirring for an hour at reflux temperature. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated to give 19 parts of 3- [2 (methylthio) -1H-benzimidazoyl-1] propyl methanesulfonate as an oily residue. XIV. A mixture of 30 parts of 1H-benzimidazoles, 49 parts of 2- (4-chlorobutoxy) -tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred at reflux overnight. The reaction mixtures are cooled to room temperature, filtered, and the filtrate evaporated. The residue is mixed with water and acidified with a dilute hydrochloric acid solution. The whole is mixed and heated for 30 minutes in a water bath. After cooling to room temperature, the product is extracted with methylbenzene. The aqueous phase is separated and neutralized with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated to give 50 parts of 1H-benzimidazole-butanol-1 as the remaining oil. Example XV. 8 parts of sulfinyl chloride are added dropwise to a mixture of 5 parts of 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benimidazolone-2 and 75 parts of trichloromethane, while stirring, dropwise and then stirring. for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. The remainder is mixed with a small amount of 4-methyl-2-pentanone. The product is filtered off and dried to give 3.5 parts of 3-chloro-3- (3-chloropropyl) -1,3-dihydro-2H-2H-benzimidazolone-2. -1H-benzimidazoles of formula 29 (table 8). Table 8 Compounds of formula 29 M C5H5-CH2 CH8 C2H5 cyclohexyl CjH5-CH2 cyclohexyl C2H5 H n 3 3 3 3 3 3 2 4 R1 5hC1 -Cl -Cl -Cl H 6-Cl HH Base or salt base base base HCl base HCl base base Melting point ¦ - - - 211.7 ° C 112 ° C 227.5 ° C - - Example XVI. A mixture of 113.2 parts 1,2,4-trichloro-5-nitrobenzene, 75 parts 1-amino-propanol, 0.2 parts potassium iodide and 200 parts butanol was stirred under reflux overnight. The butanol is evaporated under vacuum and water is added to the residue. The product is extracted with 4-methylpentanone-2. The extract is washed several times with water, dried, filtered and evaporated. The oily residue is purified on a silica gel column chromatography using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated with 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give 31.7 parts of 3 - [(4,5-dichloro-2) -nitrophenyl / amino] -propanol-1, m.p. 97 ° C. 3 - {[2-nitro-4-) trifluoromethyl / phenyl] amino} -propanol-1 and 2 - {[2 -nitro-4- - (trifluoromethyl / phenyl] amino ethanol. Example XVII To a mixture of 39.2 parts of 3- (2-nitrophenyl) amino-propanol-1 and 225 parts of trichloromethane, 35.7 is added dropwise with stirring. parts of sulfinyl chloride (exothermic reaction: temperature rises to 45 ° C) and then stirred for 6 hours under reflux. The reaction mixture is evaporated to 43 parts (100%) N / 3 -chloropropyl / -2-nitrophenylamine as residue. Similarly, there is: N- (3-chloropropyl) -2-nitro-4- (trifluoromethyl) / phenylamine, 4,5-dichloro-N- (3-chloropropyl) - 2-nitrophenylamine, m.p. 78 ° C and N- (3-chloropropyl) -2-nitrile ro-4- (trifluoromethyl) phenylamine, Example XVIII. Mixture of 21.5 parts of N- (3-chloropropyl) -2-nitrophenylamine, 22.68 parts of 1- - (diphenylmethyl) -piperazine, 20 parts of N, N-diethylethanamine and 180 parts of N, N-dimethylacetamide it is stirred and heated for 6 hours to 100 ° C. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 4-oxybispropane. The product is filtered off and dried to give 15.5 parts (36.9%) of 4- (diphenylmethyl) hydrochloride -N- (2-nitrophenyl). -1-piperazinopropylamine, m.p. 228 ° C. Similarly, N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-piperazinopropylamine as residue, 4- (diphenylmethyl) -N- [2-nitro-4- (trifluoromethyl) -phenyl] -1-piperazinopropylamine, m.p. 113.7 ° C and 4- (diphenylmethyl) -N- [2-nitro-4-) trifluoromethyl / phenyl] -1-piperazineethylamine, melting point 152.1 ° C. Example XIX. A mixture of 15 parts of 4- (diphenylmethyl) -N- (2-nitrophenyl) -1-pyrazinopropylamine hydrochloride in 160 parts of methanol is hydrogenated under normal pressure at room temperature in the presence of 5 parts of Raney nickel as catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The solid residue crystallizes from a mixture of propane-2 and 2,2'-oxybis propane. The product is filtered off and dried to give 12 parts (78.9%) of N- (2-aminophenyl) -4- (diphenylmethyl) -1-pyrazinopropylamine hydrochloride, mp 223.1 ° C. Likewise the following is obtained: 4 , 5-dichloro-N1- 3- [4-diphenylmethyl) -1-piperazinyl] propyl} -benzenediamine-1,2 as an oily residue, N1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} 4- (trifluoromethyl) -benzenediamine-1,2 and N1- {2- [4- (diphenylmethyl) -1-piperazinyl] ethyl} - 4- (trifluoromethyl) -benzenediamine-1,2 as oleista Remnants. Example XX. Mixture of 5.3 parts 1- (3-chloropropyl) -1, 3-dihydro-2H-benzimidazolone-2, parts 1- (diphenylmethyl) piperazine, 6.4 parts sodium carbonate and 200 parts 4-methyl-pentanone- -2 is stirred overnight at reflux with a water separator. After cooling, water is added and the layers are separated. The 4-tyl-pentanone-2 layer is dried, filtered and evaporated. The residue is purified over a silica gel column chromatography using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue crystallizes from a mixture of 2,2'-oxybispropane and a small amount of propanol-2. The product is filtered off and dried to give 2 parts (23%) of 1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -1,3-dihydro-2H-benzimidazolone-2, m.p. 153 At 6 ° C, the following compounds (Table 9) were obtained in a similar manner as the free base or acid addition salt by treatment of the free base with an appropriate acid. (CH2) 8 (CH2) 8 (CH *), (CH2) 2 (CH2) 2 (CH2) 2 Table 9 Compounds of formula 30 Ar1 4 CeH5 C6H5 4-F-C6H4 C6H6 CeHg C6Hs Ar2 CeHfi C «H5 4- F-C6H4 4-F-C6H4 CeH * CgHs Base or salt 6 base base base 1 / 2H20 base base base Melting point in ° G 7 175 206.1 132 172.4 214.6 218 106 572 21 22 Table 9 continued 1 1 HHHHHHHHH C6H5-CH2 1 H 1 HHHHHH CA H. 2 HHH -Cl 6-C1 H 6-C1 -Cl HHHHHHHH 7-C1 -Cl H 3 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 4 (CH2) 2 ( CH2) 2 (CH2) 4 (CH2) S (CH2) 4 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 4 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 4 CeH5 CA 4-Cl-C6H4 4-F-C6H4 4-F-C6H4 CeH5 C6H5 C6H6 CeH * CeH5 4-F-C6H4 CeH5 4-OCH8-C6H4 Ce ^ 4-F-C6H4 C «H6 'CA CeH6 CeH5 _ 4-F -CA 4-Cl-CoH4 2-F-C6H4 4-F-C6H4 4-F-C6H4 CA C6H5 CeH5 CeH5 CeH5 4-F-C6H4 4-N02-C6H4 4-F-C6H4 4-Br-CeH4 2-F -C6H4 3-C ^ -CA CA CA CA 6 rule rule rule rule H20 rule rule rule rule 1 / 2H20 2HC1 2HC1-H20 base rule rule 2HC1-Ht0 base rule 2HC11 / 2H20 base • H20 7 1 153.6 180, 2 136 205.8 132.9 196.6 204.1 203.6 197.8 199.6 184.4 103.6 157.4 189.7 172.9 112.7 196.9 184.2 156.6 Example XXI. The following compounds are obtained in an analogous manner to Example XX: 1- [3- {4- [bis (4-fluorophenyl) methyl] -1-piperazinyl} propyl] -1,3-dihydro-2H-benzimidazolone -2 with a melting point of 197.3 ° C by reacting 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2 methanesulfonate with 1- [bis (4-fluorophenyl) methyl ] piperazine, 1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -1,3-dihydrogen-3-methyl-2H-benzimidazolone-2-dihydrochloride hydrate, m.p. 201.8 ° C by reactions of 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazolone-2 with 1- (diphenylmethyl) piperazine, 3- {3- [4- (diphenylmethylM-piperazinyl) dihydrochloride hemihydrate ] propyl} -2 (3H) -benzothiosolone, m.p. 186.1 ° C. by reacting 3- (3-bromopropyl) -2 (3H) -benzothiazolone with 1- (diphenylmethyl) piperazine and 3- dihydrochloride. {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -2 (3H) -benzothiosolone, m.p. 212.4 ° C by 3- (3-chloro reaction) - ropropyl (-2 (3H) -benzoxazolone from 1- (diphenylmethyl) piperazine. Example XXII. To a solution of 76 parts of 1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -1,3-dihydro-3-A-methylethenyl / -2H-benzimidazolone-2 in 280 parts of ethanol, stirring , 120 parts of hydrochloric acid solution and 250 parts of water are added. The mixture is stirred for 30 minutes at room temperature. After cooling in an ice bath, the product precipitates. It is filtered off, washed with 2-propanone and 2,2'-oxybispropane and dried to give 43 parts (55%) of 1- {3- [4-) diphenylmethylM-piperazinyl] propyl} -1,3-dihydrogen dihydrochloride hydrate. -2H-benzimidazolone-2, m.p. 237.5 ° C. Compounds of formula 31 (Table 10) are similarly prepared. Table 10 Compounds of formula 31 ) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 (CH2) 8 CH8-CH (CH8) -CH2 Ar1 3-pyridinyl 4-pyridinyl 4-Cl-C6H4 CA ca CA 4-F-CeH4 Ar * 4-C1-CA 4-FC «H4 4-OCH8-CeH4 2-F-CA CeH5. CA 4-F-CeH4 Melting point at ° C 160.2 183.2 199.3 157 / F 178.3 195.7 176/106 572 24 Example XXIII. A mixture of 4.9 parts of 1- (3-chloropropyl) -1H-benzimidazole, 5.76 parts of 1- [bis (4-fluorophenyl) methyl] piperazine, 5.3 parts of sodium carbonate, 0.1 parts of iodide of potassium and 200 parts of 4-methyl-2-pentanone are mixed at reflux with a water separator for 20 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-methylpentanone and 2,2'-oxybispropane. The product is filtered off and dried to give 5.5 parts (59.3%) of 1- [3- {4- [bis (4-fluorophenyl) methyl] -1-piperazinyl} propyl] -1H- hydrate. of benzimidazolone having a melting point of 108.4 ° C. Compounds of formula 32 (Table 11) are similarly prepared. Example XXIV. 1- {3- [4- (diphenylmethyl-M-piperazinyl] propyl} -2- (methylthio) -1H-benzimidazole trihydrate hydrate with a melting point of 203.4 ° C is obtained by reacting the methanesulfonate 3 by following the procedure of Example XXV. - [2- (Methylthio) -1H-benzimidazolyl-1] propyl from 1- (diphenylmethyl) piperazine. Example XXV. A mixture of 4.8 parts 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2, 6.1 parts 4- (diphenylmethyloxy / piperidine hydrochloride), 7.5 parts sodium carbonate and 200 Parts of the 4-methyl-pentanone-2 are stirred overnight at reflux with a water separator. The reaction mixture is cooled and water is added. The layers are separated, the 4-methylpentanone-2 phase is dried, filtered off and evaporated. The oily residue is purified on a silica gel column chromatography using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methylpentanone-2 to give 4.2 parts (48%) of 1- {3- [4- (diphenylmethoxy) -1-piperidinyl] propyl} -1,3-dihydrogen -2H- Benzimidazolone-2, m.p. 149.2 ° C. The compounds of formula 33 (Table 12) are similarly prepared. ; R1 HHH -Cl H -Cl H -Cl HH ff HHHHHH -Cl HHH -Clfi -Cl] 6-Cl H Table 11 Compounds of formula 32 CnH2n (CH,), (CH,), (CH,), fCHJ, (CH,), (CH,), (CH,), (CH,), (CH,), (CH,), (CH,), (CH,) 4 (CH,) 4 (CH,) 4 CH, -CH (CH,) - CH, CH, -CH (CH2 -CH,. (CH1), (CH2), (CH2 (CH1), (CH2), (CH2), (CH,), (CH,), (CH,), | Ar1 CA C6H5 CA CA CA ca CeH5 CA CA CA CA CA CA 4-F-CA CA 4-F-CA CA CA CA CA CA CA CA CA CA CA Ar * CA 3-Cl-CA CA CA C (A CA CgH5 CA CA 4-F-CA 4-Cl-C6H4 CA 4-F-CA 4-F-CA CA 4-F-CA C6H5 CA CA CA CA CA CA CA CA 3C1-CA Base or salt base 3HC1-H20 l / 2CH8-CHOH-CH8 base 3HC1-H20 base 3HC1-3H, 0 3HC1-H20 base base base base base base 3HC11 / 2H20 3HC11 / 2H20 base 3HC1H20 base 3 HCl 2 H 2 O 3 H Cl H 2 O 3 H Cl 2 H 2 O base base 3 H Cl 2 H 2 O Melting point at ° C 192.3 191.1 130.5 143.9 198.3 127.8 179.9 198.2 132.3 102.5 90. 8 106 114.9 86.3 237.3 223.4 121.2 226.4 118.7 208.5 224.4 233.1 106.5 114.9 173.6 182.925 106 572 Table 12 Compounds of formula 33 B j formula 24 j formula 24 j formula 24 formula 24 - formula 25 n 2 3 2 4 3 Ar1 C6H5 4-F-C6H4 4-F-C6H4 CeH5 C6H5 Ar2 CeH5 4-F-C6H4 4-F-C6H4 C6H5 C6H5 Base or salt * HC1 HC11 / 2H20 HC11 / 2H 2 O base base • Melting point in ° C 253.1 167.2 251.4 152 110.2 PL

Claims (2)

Claims 1. Process for the preparation of the new piperazine and piperidine derivatives of the general formula, in which Ar1 and Ar2 independently of each other represent a phenyl or halophenyl radical, m is a number 0 or 1, A is N- or CH-, where where, when A is N - then m = 0, and when A is CH - m = 1, n is 2-6 inclusive, whereby when CnH2n is a branched alkylene chain then at least 2 carbon atoms are present in the linear part of the chain connecting the substituent B to the nitrogen atom of piperidine or piperazine, B is a radical of formula oxygen, sulfur, or a moiety of the formula N-L, where L is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl, phenyl, phenylmethyl, lower alkylammonium, hydroxymethyl or lower alkyl ammonium. alkenyl , B is also a radical of formula IB, in which R 1 and R 2, independently of each other, represent a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl radical, and M represents a hydrogen atom, a lower alkyl, phenyl, phenylmethyl radical, mercaptan group, lower alkylthio, lower alkylcarbonylamino, lower alkoxycarbonylamino or a cycloalkyl radical containing 3-6 carbon atoms or their pharmacologically acceptable acid addition salts, characterized by the compound of general formula II, in which B is as defined above and W is reactive an ester group, is reacted with a compound of formula III in which A, Ar1, Ar2 and m are as defined above, preferably in the presence of an inert organic solvent and a suitable base at elevated temperature, to give a compound of formula I, which is optionally converted It forms suitable pharmacologically acceptable acid addition salts. 2. The method according to p. A process as claimed in claim 1, characterized in that for the preparation of 1- {3- [4- (diphenylmethyl) -1-piperazinyl] propyl} -1,3-dihydro-2H-benzimidazolone-2 or its pharmacologically acceptable addition salts with acids, 1- (3-chloropropyl) -1,3-dihydro-2H-benimidazolone-2 is reacted with 1- (diphenylmethyl) -piperazine and the resulting compound is optionally converted into an addition salt. 3. The method according to p. 2. A process as claimed in claim 1, characterized in that in the preparation of 1- [3- {4- [bis (4-fluorophenyl) p-methyl] -1-pyiperazinyl} propyl] -1,3-dihydro-2H-2H-benzimidazolone-2 or its pharmacologically acceptable acid addition oils are reacted with 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazólone-2 methanesulfonate with 1- [bis (p-fluorophenyl) methyl] piperazine and the resulting the compound optionally converts to an addition salt. 4. The method according to p. A process as claimed in claim 1, characterized in that for the preparation of 1- [4- {4- [bis (4-fluorophenyl / methyl] -1-piperazinyl} butyl] -1,3-dihydro-2H-benzimidazolone-2 and its pharmacologically acceptable acid addition salts, react 1- (4-chlorobutyl) -1,3-dihydro-2H-benzimidazolone-2 with 1- [bis (p-fluorophenyl) methyl] piperazine and the resulting compound is optionally converted into an addition salt. 5. The method according to p. A process as claimed in claim 1, characterized in that for the preparation of 1- {4- [4- (diphenylmethyl) -1-piperazinyl] butyl, 3-dihydro-2H-benzimidazolone-2 or its pharmacologically acceptable acid addition salts, 1- (4-chlorobutyl) -1,3-dihydro-2H-benzimidazolone-2 is reacted with 1- (diphenylmethyl) piperazine and the compound obtained is optionally converted into an addition salt. 6. The method according to p. The process of claim 1, wherein the preparation of 1- {3- [4- (diphenylmethyl) -1-piperazinyl] -propyl} -1H-benzimidazolone or its pharmacologically acceptable additive salts with acids is reacted with acids, (3-chlorophenyl) -1H-benzimidazole from 1- (diphenylmethyl) -piperazine and optionally converted to an addition salt. The method according to claim 55 6. The process of claim 1, wherein 1- [4- {4 - [(4-fluorophenyl)) phenylmethyl] -1-piperazinyl} butyl] -1H-benzimidazole or its pharmacologically acceptable acid addition salts is reacted to 60 1- (4-chlorobutyl) -1H-benzimidazole from 1- [(4-fluorophenyl) phenylmethyl] piperazine and the compound obtained is optionally converted into an addition salt. 8. The method according to p. A process as claimed in claim 1, characterized in that in the case of the preparation of 1- [4- {4- [bis (4-fluorophene)] -l-piperazinyl} butyl] -1H-benzimide - the sol or its pharmacologically acceptable acid addition salts are reacted with 1- (4-chlorobutyl) -1H-benzimidazol-2 zloty [bis (p-fluorophenyl) methyl] piperazine and the resulting compound is optionally converted into an addition salt . 9. The method for the preparation of the new piperazine and piperidine derivatives of the general formula I, in which Ar1 and Ar2 independently of each other represent a substituted phenyl radical or a pyridinyl radical, the phenyl radical being substituted by 1-2 substituents from among such substituents as a lower radical. alkyl, lower alkoxy, trifluoromethyl and nitro, m is 0 or 1, A is N or CH, where when a is N then m = 0 and when A is CH - m = l, n is a number from 2 to 6, inclusive, whereby when CnH2n is a branched alkylene chain, then at least 2 carbon atoms are located in the linear part of the chain connecting the substituent B to the nitrogen atom, piperidine or piperazine, B is the radical IA, in which R1 and R2 are independently of each other hydrogen, halogen, lower alkyl or trifluoromethyl and Y is oxygen, sulfur and N-L, where L is hydrogen, lower rhodium ¬ alkyl nickel, lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkyl aminocarbonyl, hydroxymethyl or lower alkenyl, B also denotes a radical of formula IB, in which R1 and R2 independently represent a hydrogen atom , halogen, lower alkyl or trifluoromethyl and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercaptan, lower alkylthio, lower alkylcarbonylamino, lower alkoxycarbonylamino, or a 3 to 6 carbon atoms or pharmacologically acceptable acid addition salts thereof, characterized in that a compound of general formula II wherein B and n is as defined above and W is a reactive ester group is reacted with a compound of general formula III wherein A, Ar1, Ar2 and m have the meaning given above, preferably in the presence of an inert organic solvent and a suitable base, at an elevated temperature. then, to obtain a compound of formula I, which is optionally converted into the corresponding pharmacologically acceptable acid addition salts. Ar1 BC ^ lQr (OVCH Ar2 B-C2H2n-W Formula 2 -Ar1 R1 R2 R1 R2 Formula 1A Formula IB HlfA-COlrCH m Formula 3 B-CnH2-W + HKyr (0) m-CH "XAr * V \ r2 Formula 2 Formula 3 Ar 'B-CnH2n- | ^ - (0) m-CH Formula 7 \ r Scheme 1106 572 R1 R2 Formula 4 H2N-CnH2n-OH 02NNH-CnH2n-OH j [j H2 / RgN ^ R1 R2 Formula 5 H ^ lNH-CnH2 ^ -0H // A closure / = \ rings R1 R2 Formula 6 0 II A o ii A HNN-CnH2irOH HNN-C "H2-nW // A formation of reactive ft \ R1 R2 Formula 7 Scheme 2. halo-OK-OH Tt '2n O II r-ch = c- ^ cjh R3 / A Formula 8 R' R halo - Cn n ^ - / K7 / o / w / o -C ^ rPt0? oo R1 R <IR 'R * Scheme 3 halo R' "R2 i106 572 cd of scheme 3 formation of the reactive ester H -h O uo tf-0 + Cl $ CJCnH2-Wu + H | Nl ^ -C ^ anW HN ^ -C ^ z- ^ io R1 R2 Formula 10 W A2 R ^ R2 Formula 2-ak R1 R2 Formula 2-a-1 Scheme 3 ou L * -N N-CnH2-W R1 R2 O II A H0CH2-NN-CnH2n-W A2 R1 R2 Formula 2-c M and Nf VcnH2n-W Formula 2-d. R) JH-co-tey) Nf% -CnH2n-W O II L2-N NH Rl R2 Formula 12 y NH2 A R1 R2 Formula 2-h Formula 2-g106 572 H2N NH-C2H2n-OH ^ ^ R1 Rz fi R 'R2 Formula 14 SH .// Cx R1 ^ V Formula f5 Scheme 4 Hzór2-e% - {nChower alkyl) S ~ (nusz «QlkU) NjJ -C ^ 2-0H hl Dl-C ^ s-OH fi 4 Hh & w alkylation _ ^ // \ formation of the reactive // \\ ester R'1 R2 Formula 15-a R1 R2 Formula IB * Scheme 5 R1 R2 Formula 2- f H OH / Tztfr 18 At 1 XAr2 / y ^ r 17 A1 W-CH —- Q - [^ T) -0-CH Ar Formula 19 removing group Q .Ar 'hO0_ch XAr2 Formula 3-b Scheme 6106 572 O ¥ R6 -R 'R Formula 21 0 II O Formula 22 B-CnH ^ CV0-CH ^' R7 R6 Formula 25 0 II / C \ HNN o Hf $ icVCH ^ tM \ 0 Formula 25 A1 Ar2 M Formula 26 L-NycH2) on rf rsi-CnH2n- ul rfV (aQ-ci R1 / fZ ^ ^ P106 572 0 A -. / Ar1 LN N-CnH2n-r (Jl ~ CH R1 W zór 30 0 "'/ Ar HM N-CnH2n-10l-CH Ar 2 R1 Formula 31 M • Ar1 D1 ^^ ^ B-CCH2) n- | Q-0-CH' \ Ar2 Ar2 PL