PL118633B1 - Method of manufacture of novel derivatives of 1-/benzazolyl-alkyl/-piperidineil/-piperidina - Google Patents

Description

The invention relates to a process for preparing novel 1-(benzazolyl-alkyl)-piperidine derivatives and their pharmaceutically acceptable acid addition salts. Numerous piperidine derivatives substituted with benzazolyl-alkyl and indolyl-alkyl radicals, as well as certain benzazoles substituted with an aminoalkyl radical, have been known, some of which possess pharmacological activity, e.g., antidepressant, anticonvulsant, antihistaminic, or antispasmodic activity. Among other differences, the compounds prepared by the process of the invention differ from known compounds in the nature of the relevant benzazolyl and/or the substituted piperidine moiety. Some known compounds can be found in the following sources: Int. Pharmacopsychist. 1968 (1), p. 214; CA., 64, 2093b (1966); CA., 72, 111466 (1970); CA., 81 120632 b (1974); French patent specification No. 2042321 (derw. Fr. Week S 16, Pharm. p. 12) and Belgian patent specification No. 753472. The new derivatives of l-(benzazolyl-alkyl)-piperidine, prepared by the process according to the invention, are represented by the formula 1, wherein R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl radical or a trifluoromethyl radical, B represents a divalent group of the formula —N(L)—C(=O)—, wherein L represents a hydrogen atom, a lower alkyl radical, a lower alkylcarbonyl radical, a lower alkenyl radical or a protective group: or B represents a group of the formula —S—C(=O)—, —O—C(=O)—, —N=N— and —N=CH—, and the said divalent groups are linked to the ring a benzene heteroatom thereof; R3 is hydrogen or methyl; m and n are integers from 1 to 2 (inclusive); and a radical of formula 5 is: - a radical of formula 5a, in which R4 is hydrogen or a lower alkyl radical; and R6 and R6 each independently represent a hydrogen atom, a halogen atom, a lower alkyl radical or a trifluoromethyl radical; or - a radical of formula Sb, in which R7 and R8 each independently represent a hydrogen atom, a halogen atom, a lower alkyl radical or a trifluoromethyl radical; Y is oxygen or a sulfur atom; M represents a hydrogen atom, a lower alkyl radical or a lower alkylcarbonyl radical and the dashed line indicates a possible double bond between carbon atoms 3 and 4 of the piperidine ring, provided however that when Y represents a sulfur atom, there is only a single bond between carbon atoms 3 and 4 of the piperidine ring and M then represents a hydrogen atom; or - a radical of formula 5c, in which R9 is hydrogen, halogen, lower alkyl or trifluoromethyl, and R10 is hydrogen, halogen or trifluoromethyl. The term "lower alkyl" as used herein denotes straight or branched chain radicals of 1 to 5 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl and the like; "lower alkenyl" denotes straight or branched chain alkenyl radicals of 2 to 5 carbon atoms such as 1-methylethylene, propen-2-yl, buten-2-yl, buten-3-yl, penten-2-yl and the like; The term "halogen" includes halogens having an atomic weight of less than 127, i.e., fluorine, chlorine, bromine, and iodine. The compounds of formula I are prepared by reacting a reactive ester of formula II, wherein X is a reactive ester function of a suitable alcohol, such as, for example, halogen, methanesulfonyl, 4-methylbenzenesulfonyl, and the like, with a suitable piperidine derivative of formula III, wherein the group of formula V is as defined above. These reactions are illustrated in Scheme I. The above condensation reaction is preferably carried out in a suitable organic solvent, for example, a lower alcohol, such as methanol, ethanol, propanol, butanol, and the like; an aromatic hydrocarbon, for example, benzene, methylbenzene, dimethylbenzene, and the like; a ketone, such as 4-methyl-2-pentanone, ether, such as 1,4-dioxane, diethyl ether, and the like; N,N-dimethylformamide, nitrobenzene, and the like. Addition of a suitable base, such as an alkali metal or alkaline earth metal carbonate or bicarbonate, may be used to neutralize the acid evolved during the reaction. A small amount of a suitable metal iodide, for example Na2, or K2, may be added as a reaction medium, particularly when the reactive ester of formula II is a chloride. Elevated temperatures are suitable for increasing the rate of the reaction, and the reaction is preferably carried out at the reflux temperature of the reaction mixture. The reaction products are separated from the medium and, if necessary, further purified by methods known in the art. Compounds of formula I, which may be represented by formula IV, wherein R1, R2, R3, m, n, and the groups of formula V are as defined above, and L is a group by removing the above-mentioned protecting group using conventional, known methods, can be converted into compounds of formula 4, wherein L is hydrogen. Examples of such known protecting groups include, inter alia, lower alkyloxycarbonyl, 4-methylbenzenesulfonyl, methanesulfonyl and, preferably, substituted ethenyl of the formula R12 —CH=C(Rn)—, wherein R11 and R12 may represent different groups, but wherein Ru is preferably lower alkyl and R12 is preferably hydrogen, lower alkyl or phenyl. In the case where the protecting group is lower alkyloxycarbonyl, 4-methylbenzenesulfonyl or methanesulfonyl, it can be easily removed by alkaline hydrolysis, whereas when the protecting group is substituted by a ethenyl group, it is conveniently eliminated by subjecting the corresponding product of formula IV to acidic hydrolysis. A wide range of protic acids can be used for this acidic hydrolysis to remove the substituted ethenyl group from the compound of formula IV, including mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, and organic acids such as acetic, propionic, and the like. Furthermore, the reactions can be carried out in inert organic solvents commonly used in hydrolytic reactions of this type, for example, methanol, ethanol, 2-propanone, and the like. The starting materials used in the syntheses described herein can be prepared according to the methods described in Examples 1-28 below. The starting materials of formula III, represented by formulas 3a, 3b, and 3c, and methods for their preparation, can be found in the following texts, respectively: - the compound of formula 3a in US Patent No. 3,238,216; - the compound of formula 3b in US Patent No. 3,161,645 and Belgian Patent No. 830,403; - the compound of formula 3c in US Patent No. 3,518,276 and No. 3,575,990. The compounds of the invention can be converted into their therapeutically useful acid addition salts by treatment with a suitable acid, for example an inorganic acid, such as a hydrohalic acid, e.g., hydrochloric acid, hydrobromic acid, and the like; and sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid, such as acetic, propionic, hydroxyacetic, 2-hydroxypropionic, 2-ketopropionic, malonic, ethanedicarboxylic, maleic, fumaric, 2-hydroxyethanedicarboxylic, 1,2,3-dihydroxyethanedicarboxylic, 2-hydroxy-propanetricarboxylic-1,2,3-benzoic, β-phenylacrylic, α-hydroxyphenylacetic, 4-methylbenzenesulfonic, methanesulfonic, ethanesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Also, a compound in salt form can be converted into the free base form by treatment with alkali. It has been found that compounds of formula 1 and their therapeutically active acid addition salts possess a strong antiemetic effect, as proven by their ability to suppress morphine-induced vomiting in dogs. The method used was previously described by P.A.J. Janssen and C.J.E. Niemegeers in Arzneim-Forsch. (Drug Res), 9 765-767 (1959). The compounds listed below were administered subcutaneously to dogs in various doses and an hour later the animals were given a standard dose of morphine (subcutaneously) of 0.31 mg/kg. Tables MV give the ED50 values, representing the dose that protects 50% of the animals from vomiting. It is understood that the compounds given in Tables I-IV are not included to limit the invention to this, but only to exemplify The outstanding antiemetic properties of all compounds encompassed by Formula I are demonstrated. Given their useful antiemetic activity, the compounds of the invention may be formulated into various dosage forms for administration purposes. To prepare pharmaceutical compositions effective for antiemetic purposes, an amount of a particular compound in base or acid addition salt form as the active ingredient is combined with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of the drug desired for administration. The pharmaceutical compositions are desirably in a form suitable for unit dosage, preferably for oral, rectal, or parenteral injection. For example, in preparing oral dosage compositions, any of the usual pharmaceutical media such as water, glycols, oils, alcohols, and the like may be employed, in the case of Oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their convenience in administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are, of course, employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, may be formulated in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers are used. suspending agents and other similar substances. Acid addition salts of the compounds of formula I, due to their increased water solubility compared with the corresponding base form, are obviously more suitable for the preparation of aqueous compositions. It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form for convenience of administration and uniformity of dose. A unit dosage form refers to physically benign units suitable as unit doses, each containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, teaspoonfuls. Tablespoon and the like and packaged multiples thereof. The amount of active ingredient per daily dose will be 0.25 mg-100 mg, and preferably 1-30 mg. The following examples are illustrative of the invention but do not limit its scope. All parts in the description are by weight unless otherwise indicated. Example 1. A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)-benzene, 90 parts of 3-amino-1-propanol, and 200 parts of butanol is stirred at reflux and heated overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the mixture is acidified with HCl solution. The product is extracted with methylbenzene. The extract is dried, filtered, and evaporated. The solid residue The product is crystallized from petroleum ether. The product is filtered off and dried, yielding 141 parts (100%) of 3-[(2-nitro-4-(trifluoromethyl)phenyl)aminopropan-1-ol. Example 1. By proceeding as in Example 1 and using equivalent amounts of the appropriate starting materials, there are prepared: 3-((4-methyl-2-nitrophenyl)amino)propan-1-ol as a residue, 3-((4,5-dichloro-2-nitrophenyl)amino)propan-1-ol, m.p. 97°C, and 3-((2-chloro-6-nitrophenyl)amino)propan-1-ol as a residue. Example 3. A mixture of 70 parts 3-((4-Methyl-2-nitrophenyl)amino)-1-propanol and 400 parts of methanol are hydrogenated at normal pressure and room temperature with 10 parts of a 10% palladium-on-charcoal catalyst as a support. After the calculated amount of hydrogen has reacted, the catalyst is filtered off and the filtrate is evaporated, leaving 54 parts (91%) of 3-((2-amino-4-methylphenyl)amino)-1-propanol as a residue. Example 4. A mixture of 141 parts of 3-[(2-nitro-4-(trifluoromethyl)phenyl)amino]-1-propanol and 1200 parts of methanol is hydrogenated at normal pressure and room temperature with 15 parts of Raney nickel as a catalyst. After the calculated amount of hydrogen had reacted, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from isopropyl ether, yielding 110 parts (100%) of 3-[(2-amino-4-(trifluoromethyl)phenyl)amino]-propan-1-ol. Example V. By proceeding as in Example IV and using equivalent amounts of the appropriate starting materials, there were prepared: 3-((amino-4,5-dichlorophenyl)amino)propan-1-ol hydrochloride, melting point ±185°C, 3-((2-amino-6-chlorophenyl)amino-propan-1-ol as a residue and 3-((2-amino-4-chlorophenyl)amino)propan-1-ol as an oily residue.4 118633 Example VI. To a stirred and cooled solution of 54 parts of 3-((2-amino-4-methylphenyl)amino)-1-propanol in 30 parts of 10% HCl solution and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10°C. After complete addition, stirring is continued first for 1 hour at room temperature and then for 24 hours at reflux. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with 5% HCl solution, filtered and evaporated. The residue is crystallized from 4-methylpentanone-2, giving 19.5 parts (31%) of 1,3-dihydro-1-(3-)- 114.1°C. Example VII. By proceeding as in Example VI and using equivalent amounts of the appropriate starting materials, there were prepared: 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one, 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, mp 174.7°C, 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one and 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, mp 148.8°C. Example VIII. To a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane is added 11.9 parts of triethylamine. Then 11.5 parts of methanesulfonyl chloride are slowly added dropwise. After addition is complete, stirring is continued for 1 hour at reflux. After cooling, the reaction mixture is washed with water, dried, filtered, and evaporated. The solid residue is crystallized from 4-methylpentan-2-one, giving 15 parts (58%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate, melting point 125°C. Example IX. By proceeding as in Example 8 and using equivalent amounts of the appropriate starting materials, there were prepared: 3-(5,6-dichloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl methanesulfonate as an oily residue, 3-(7-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl methanesulfonate and 3-(5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl methanesulfonate, melting point ±140°C. Example 10 A mixture of 30 parts of 1H-benzimidazole, 49 parts of 2-(4-chlorobutoxy)tetrahydro-2H-pyran, 21 parts of KOH and 200 parts of ethanol are mixed and heated to reflux overnight. The reaction mixture is cooled to room temperature, filtered, and the filtrate is evaporated. The residue is stirred in water and acidified with dilute HCl solution. The mixture is stirred 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 made basic with NH3. The product is extracted with dichloromethane. The extract is dried, filtered, and evaporated, yielding 50 parts of 1H-benzimidazole-1-butanol as an oily residue. Example 11. To a mixture of 23 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)- 2H-benzimidazol-2-one in 150 parts of trichloromethane, stirred with a stirrer, 32 parts of sulfinyl chloride are added dropwise. After complete addition, the whole is heated to reflux and stirring is continued for 1 day at this temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from isopropyl ether, giving 14 parts (56%) of 1-(3-chloropropyl)-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one. Example XII. Proceeding as in Example XI and using an equivalent amount of the appropriate hydroxy compound as starting material, the following chlorides are prepared: 5-chloro-1-(3-chloropropyl)-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one 122° C., and 1-(4-chlorobutyl)-1H-benzimidazole as an oily residue. EXAMPLE 13. To a stirred and refluxing mixture of 35 parts of 4-fluoro-1,2-diaminobenzene in 270 parts of dimethylbenzene, a solution of 57 parts of ethyl α-acetylphenylacetate in 90 parts of dimethylbenzene was added dropwise over 2 hours, while at the same time the water and ethanol formed were distilled off (water separator). The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The mixture is filtered and purified by chromatography on silica gel, using a mixture of trichloromethane and methanol in the ratio (v/v) 98:2 as the eluent. The pure fractions are collected and the eluent is evaporated, yielding 11 parts of 6-fluoro-1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-one, melting point 190°C. Example 14. To a stirred solution of 8.5 parts of 1,1-dihydro-1-(1-methylethenyl)-2H-benzimidazol-one in 45 parts of N,N-dimethylformamide is added portionwise 1.7 parts of sodium hydride in a 78% suspension. After stirring for 1 hour at room temperature, the mixture is cooled to 0-5°C and 2H-benzimidazol-one is slowly added dropwise. 8.65 parts of 1-bromo-3-chloropropane. After complete addition, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, giving 5.5 parts (44%) of 1-(3-chloropropyl-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, melting point 115°C. Example XV. To a hot (55°C) mixture of 22.2 parts of 1,3-dihydro-5,6-dimethyl-3-(1-methyl- 2-phenylethenylO)-2H-benzimidazolone-2, 3 parts of N,N,N-triethylbenzylammonium chloride and 112.5 parts of 60% NaOH solution, stirred with a stirrer, 15.8 parts of 1-bromo-3-chloropropane are added dropwise (slightly exothermic reaction). After completion of this operation, stirring is continued for another 5 hours at 55°C. After cooling, water is added and the oily product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from isopropyl ether, yielding, after drying, 25 parts (88.5%) of 1-(3-chloropropyl)-1,3-dihydro-5,6- dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-one, m.p. 98°C. Example XVI. By proceeding as in Example XV and using equivalent amounts of the appropriate starting materials, there were prepared: 1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-one, as a residue, 1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methyl-ethenyl)-2H-benzimidazol-one, as a residue, and 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-ethenyl)-2H-benzimidazol-one, as a residue, and 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-ethenyl)-2H-benzimidazol-one, as a residue, and 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-ethenyl)-2H-benzimidazol-one, as a residue. -5-fluoro-1,3-dihydro-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-one, as an oily residue. Example XVII. A solution of 13 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one in 6 parts of HCl solution and 40 parts of ethanol was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the solid residue was crystallized from 2-propanol, yielding 9.5 parts (90%) of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-one, m.p. 115°C. Example XVIII. A mixture of 25 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one -1,3-Dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazolone-2, 165 parts of 6N HCl solution and 160 parts of ethanol are stirred at reflux temperature for 6 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from a mixture of isopropyl ether and 2-propanol, yielding, after drying, 16 parts (94.7%) of 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazolone-2, melting point 140°C. Example XIX. Solution of 180 parts 3-(2-Nitrophenyl)-1-propanol in 200 parts of methanol and 100 parts of 10 N HCl solution is hydrogenated under normal pressure and 50°C in the presence of 5 parts of a 10% palladium-on-charcoal catalyst. After the calculated amount of hydrogen (3 moles) has reacted, the hydrogenation reaction is stopped. The catalyst is filtered off, and the filtrate is evaporated. The residue (mainly 3-(2-aminophenyl)-1-propanol hydrochloride) is dissolved in 500 parts of water. To this solution is added a solution of 88.8 parts of potassium isocyanate in 150 parts of water, and the mixture is stirred under reflux for 15 hours. The reaction mixture is cooled. The product is extracted with trichloromethane. The extract is dried and evaporated. The residue is dissolved in 250 parts of boiling water, treated with activated charcoal, and crystallized at room temperature. The precipitate is filtered off and recrystallized from 400 parts of water, then recrystallized from ethyl acetate, yielding 58 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazolone-2-hydrate, melting point 48-65°C. To a solution of 52.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazolone-2-hydrate in 200 parts of pyridine is added 63 parts of methanesulfonyl chloride dropwise. The mixture is stirred and cooled in air for 2 hours. The pyridine is evaporated. 500 parts of water are added to the residue, and the resulting precipitate is filtered off. This is dissolved in 350 parts of trichloromethane. This solution is dried over magnesium sulfate and evaporated. The residue is crystallized from 40 parts of methylbenzene, yielding 25.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, melting point 118-120°C. To a solution of 0.5 part of sodium in 40 parts of absolute ethanol is added 5.4 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate while cold. The mixture is stirred until all the solid has gone into solution. The solution was stirred at reflux for 2 hours. After cooling, the reaction mixture was filtered to remove inorganic material, and the filtrate was evaporated. The residue was dissolved in 80 parts of methylbenzene, heated to boiling with activated charcoal, filtered, and the filtrate was evaporated again. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene, giving 2.6 parts of 3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole, m.p. 116.5-118.5°C. To a solution of 5.7 parts of 3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole in 80 parts of 2-propanone is added 5.7 parts of methyl iodide and the mixture is stirred at reflux for 2.5 hours. A second portion of 5.7 parts of methyl iodide is then added and the mixture is further stirred and refluxed for 2.5 hours. The solvent is evaporated to give 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one as an oily residue.6 118633 Example XX. A mixture of 84 parts of 4-((4-chloro-2-nitrophenyl)amino)piperidinecarboxylic acid-1-ethyl ester and 750 parts of a 48% HBr solution in water is stirred and heated under reflux for 4 hours. The precipitated product is filtered off, washed with water and petroleum ether and dried, yielding 71 parts (81%) of N-(4-chloro-2-nitrophenyl)-4-aminopiperidine hydrobromide, melting point 275°C. A mixture of 105 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazolone-2, 71 parts of N-(4-chloro-2-nitrophenyl)-4-aminopiperidine hydrobromide, 53 parts of Na2CO3, 0.2 part of KJ and 320 parts of 4-methylpentanone-2 is stirred under reflux with a water separator for 24 hours. The reaction mixture is cooled, water is added, and the layers are separated. The organic phase is dried, filtered, and evaporated, yielding 98.5 parts (100%) of 1-(3-[4-((4-chloro-2-nitrophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue. A solution of 98.5 parts of 1-(3-[4-((4-chloro-2-nitrophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 360 parts of methylbenzene is acidified with 2-propanol which has been previously saturated with gaseous hydrogen chloride. After boiling briefly, the oil is lost. The upper phase is decanted, and the remaining oil is dispersed in water. The suspension is basified with concentrated NH4OH solution. The product is extracted with methylbenzene. The extract is dried, filtered, and evaporated. The residue is crystallized from 4-methylpentanone-2. The product is filtered and dried, yielding 68 parts (75.5%) of 1-(3-[4-((4-chloro-2-nitrophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-2H-benzimidazol-2-one. A mixture of 21.5 parts of 1-(3-[4-((4-chloro-2-nitrophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and room temperature with 5 parts of Raney nickel as a catalyst. After the calculated amount of hydrogen had reacted, the catalyst was filtered off and the filtrate was evaporated, yielding 20 parts (100%) of 1-(3-[4-((2-amino-4-chlorophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-2H-benzimidazol-one as a residue. Example XXI. A mixture of 21.5 parts of 1-(3-[4-((4-chloro-2-nitrophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol was hydrogenated at normal pressure and room temperature with 10 parts of 10% palladium on charcoal. After the calculated amount of hydrogen had reacted, the catalyst was filtered off and the filtrate was evaporated, leaving 18.5 parts (90%) of 1-(3-[4-((2-amino-4-chlorophenyl)amino)piperidin-1-yl]propyl)-1,3-dihydro-2H-benzimidazol-2-one as a residue. Example 22. To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane was added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: temperature rose to 45°C). After completion of the dropwise addition, stirring was continued for a further 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N-(3-chloropropyl)-2-nitroaniline as residue. A mixture of 43 parts of N-(3-chloropropyl)-2-nitroaniline, 47.8 parts of 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-2-one, 30.3 parts of N,N-diethylethylamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100°C. The precipitated product is filtered off, washed with water and isopropyl ether and dried, yielding 64 parts (78.3%) of 5-chloro-1,3-dihydro-1-[1-(3-(2-nitrophenylamino)propyl)piperidin-4-yl]-2H-benzimidazol-one, melting point 220°C. A mixture of 64 parts of 5-chloro-1,3-dihydro-1-[1-(3-(2-nitrophenylamino)propyl)piperidin-4-yl]-2H-benzimidazol-one in 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and room temperature with 10 parts of Raney nickel as a catalyst. After the calculated amount of hydrogen had reacted, the catalyst was filtered off on a hyflo filter and the filtrate was evaporated. The residue was crystallized from a mixture of 2-propanol and ethanol. The product was filtered off and dried, yielding 42 parts (70.5%) of 1-(1-[3-(N-(2-aminophenyl)amino)propyl]piperidin-4-yl)-5-chloro-1,3-dihydro-2H-benzimidazol-2-one, melting point 196°C. Example XXIII. A mixture of 6.7 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazolone-2,4-methanesulfonate, 2 parts of 4-(4-chlorophenyl)piperidin-4-ol, 3.2 parts of Na2CO3 and 32 parts of 4-methylpentan-2-one is stirred and heated at 50-60°C for 1.5 hours. The reaction mixture is poured into ice-water. The precipitated product is filtered off and dissolved in trichloromethane. The solution is washed with water, dried, filtered, and evaporated. The solid residue is purified by chromatography on silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected, and the eluent is evaporated. The solid residue is stirred in a small amount of trichloromethane. The product is filtered off and crystallized from 4-methylpentanone-2, yielding 2 parts (24%) of 5-chloro-1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazolone-2, melting point 190.8°C. 118633 7 Example XXIV. A mixture of 3.58 parts of 1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one, 3.17 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of Na2CO3, 0.2 part of KI and 160 parts of 4-methyl-2-pentan-one is stirred and boiled under reflux in a water separator for 24 hours. After cooling, water is added and the layers are separated. The organic phase is dried, filtered, and evaporated. The residue is converted into the hydrochloride salt in methanol and 2-propanol. The salt is filtered off and dried, yielding 1.7 parts of 1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one hydrochloride, melting point 260.8°C. Example XXV A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.12 parts of 4-(4-chlorophenyl)piperidin-4-ol, 3.2 parts of Na2CC3, 0.1 part of KI, and 80 parts of 4-methylpentan-2-one is stirred and refluxed for 36 hours. After cooling to room temperature, water is added, and the layers are separated. The organic phase is dried, filtered, and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected, and the eluent is evaporated. The residue was crystallized from methylbenzene, yielding 1 part (26%) of 1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-one; melting point 134.2°C. Example XXVI. By proceeding as in Example XXV and using equivalent amounts of the appropriate starting materials, the following compounds were prepared: 6-chloro-1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-one; melting point 180.6°C; 1-(3-[4-(4-chloro-3-(trifluoromethyl)phenylH-hydroxy-piperidin-1-yl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 189.2°C; 1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-3-(propen-2-yl)-2H-benzimidazol-2-one; melting point 141.3°C; 1-[4-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)butyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 160.6°C and 1-(3- (1H-benzimidazol-1-yl)propyl)-4-(4-chlorophenyl)-4-piperidine; melting point 16°C. Example XXVII. A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidin-one, 5.3 parts of Na2O3 and 80 parts of 4-methylpentan-2-one is stirred and heated under reflux in a water separator for 48 hours. The reaction mixture is cooled to room temperature, water is added and the mixture is made alkaline with 15 parts of NaOH (60% solution). The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous HCl, and the mixture is stirred and heated under reflux for 15 minutes. The solvent is evaporated and the hydrochloride formed is dissolved in water. The free base is liberated by a conventional method, by treatment with dilute NaOH solution. The product is extracted with 4-methylpentanone-2. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of l-[3- (4-(4-fluorophenyl/4-hydroxy-piperidin-1-yIo)propyl]-1,3-dihydro-2H-benzimidazolone-2; melting point 135.4°C. Example XXVIII. Proceeding as in Example XXV and using equivalent amounts of appropriate starting materials, the following compounds were further prepared: 5-chloro-1-(3-[4-(4-chloro-3-(trifluoromethyl-phenyl-4-hydroxy-piperidin-1-yl]-propyl)-1,3-dihydro-2H-benzimidazolone-2; 5-chloro-1-[3-(4-/4-chlorophenyl)-4-hydroxy-piperidin-1-yl)-2-methylpropyl]-1,3-dihydro-2H-benzimidazolone-2; 5-bromo-1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one; 1-[3-(4-(4-bromophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one; 1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one; 1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-5,6-dichloro-1,3-dihydro -2H-benzimidazol-2-one and 5-chloro-1-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)propyl]-1,3-dihydro-3-(propen-2-yl)-2H-benzimidazol-2-one Preparation of compounds of formula 1: Example XXIX. A mixture of 4.6 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4,5]-4-decanene, 10 parts of Na2CO3, 0.2 part of KI and 80 parts of 4-methyl-2-pentan-one is stirred and refluxed overnight. After cooling, the precipitated product is filtered off. and triturated twice: first in a boiling mixture of 4-methylpentan-2-one and 2-propanol, and then in boiling methanol. The product was again filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 4.5 parts of 8-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl-propyl)-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]-4-decanone; melting point 215.4°C. Example XXX. Proceeding as in Example XXIX and using equivalent amounts of the appropriate starting materials, the following compounds were prepared: 8-(3-(6-chloro-2,3-dihydro-2-keto-1H-benzi-8-one hemihydrate) 118 633 midazol-1-yl(propyl)-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]-4-decanone; melting point 233°C; 1-(4-fluorophenyl)-8-(3-(2,3-dihydro-5,6-dimethyl-2-keto-1H-benzimidazol-1-yl)propyl)-1,3,8-triazaspiro[4,5]-4-decanone; melting point 245.2°C; 8-[3-(2,3-dihydro-2-keto-3-(propen-2-yl)-1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]-4-decanone; melting point 114°C; 8-(3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4,5]decan-4-one; melting point 198.2°C; 8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; melting point 228°C; 8-(3-(5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one; melting point 171.7°C; 8-(3-(6-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]4-decanone; melting point 255-256°C; 1-(4-fluorophenyl)-8-[3-(2,3-dihydro-2-keto-5-(trifluoromethyl)-1H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro[4,5]4-decanone; melting point 259.7°C; 8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]4-decanone; melting point 186°C; 1-(4-chloro-3-methylphenyl)-8-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl,3,8-triazaspiro[4,5]-4-decanone; m.p. 208.6°C and 8-(3-(1H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]-4-decanone; m.p. 191°C. Example XXXI. A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]-4-decanone; 4-[4,5]decanone, 10 parts of Na2CO3 and 80 parts of 4-methylpentanone-2 are stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and recrystallized twice from N,N-dimethylformamide/water, giving 0.8 part (17%) of 8-(3-(7-chloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]decanone-4, melting point 258.4°C. Example XXXII. Proceeding as in Example XXXI and carrying out the reaction in N,N-dimethylformamide as solvent, The following compounds were obtained from appropriate substrates: 8-(3-(5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]-4-decanone; melting point 233.7°C; 8-(3-(2,3-dihydro-5-methyl-2-keto-1H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]-4-decanone; melting point 255.5°C. Example XXXIII. A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-Phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 2.65 parts of Na2CC3 and 22.5 parts of N,N-dimethylformamide are stirred and heated for 2 hours at 70°C. The reaction mixture is cooled and poured into water, whereupon an oil precipitates. The upper aqueous phase is decanted and the remaining oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1 part of 8-(3-(1,3-dihydro-3-methyl-2-keto-2H-benzimidazol-1-yl)propyl)-1-[(3-(1,3-dihydro-3-methyl-2-oxo ... phenyl-1,3,8-triazaspiro[4,5]decan-4-one; melting point 164.4°C. Example XXXIV. A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 9.2 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and 90 parts of N,N-dimethylformamide is stirred and heated at 60°C for 1 hour. The reaction mixture is evaporated, and water is added to the residue. The mixture is made alkaline with NH4OH and the product is extracted with trichloromethane. The extract is dried, filtered, and evaporated. The residue is purified by chromatography on silica gel, using The product was filtered off and dried, yielding 2 parts of 8-(3-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4,5]-4-decan-one; m.p. 275.2°C. Example XXXV. A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.5 parts of 5 KI and 80 parts of 4-methylpentan-2-one was stirred and refluxed for 24 hours. The reaction mixture was cooled to room temperature and water was added. The insoluble product was filtered off and purified by chromatography on silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methylpentan-2-one. The product was filtered off and recrystallized from a mixture of N,N-dimethylformamide and water, yielding 1.3 parts (30%) of 5-chloro-1-[1-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; m.p. 242.5°C. Example XXXVI. Proceeding as in Example XXXVI, using equivalent amounts of starting materials, the following compounds were prepared: 5-chloro-1-(1-[3-(2,3-dihydro-3-(1-methylethenyl)-2-keto-1H-benzimidazol-1-yl)-2-methylopropyl]piperidin-4-yl) -1,3-dihydro- 2H-benzimidazolone-2, as oily residue; 6-chloro-1-[3-(4-/5-chloro-2,Dwuhydro-2-kcto-1H-benzimidazol-1-yl(piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazolone-2 hydrate; melting point 179.6°C; 1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-yl)propyl]-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one isopropanolate; melting point 159°C; 6-chloro-1,3-dihydro-1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-yl)propyl]-2H-benzimidazol-2-one; melting point 273°C; 1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 225°C; 1,3-dihydro-1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-yl)propyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; melting point 263.4°C; 5-chloro-1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-yl)propyl-1,3-dihydro-2H-benzimidazol-2-one; melting point 253-255°C; 5-chloro-1-[3-(2,3-dihydro-2-keto-3-(propen-2-yl)-1H-benzimidazol-1-yl)propyl]piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; melting point 153.4°C; 1-[3-(3,6-dihydro-4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 206.6°C; 5-chloro-1-(1-[3-(2,3-dihydro-3-(1-methylethenyl)-2-keto-1H-benzimidazol-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 165.2°C; 1-[1-(4-(1H-benzimidazol-1-yl)butyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 157.1°C Example XXXVII. A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-2-one, 6.4 parts of Na2CO3 and 200 parts of 4-methylpentan-2-one is stirred and heated to reflux under a water separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase was dried, filtered, and evaporated. The oily residue was purified by chromatography on silica gel using a 90:10 (v/v) mixture of trichloromethane and methanol as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (67%) of 1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)piperidin-1-7-yl)propyl]-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-1-one as an oily residue. Example XXXVIII. Proceeding as in Example XXXVII and using equivalent amounts of appropriate starting materials, the following compounds were prepared: 1-[3-(4-(5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl/piperidin-1-yl)-propyl]-1,3-dihydro-5-methyl-3- (1-methylethenyl)-2H-benzimidazolone-2, as oily residue; 3-[3-(4-/5-chloro-2,3Clwuhydro-2-keto-1H-benzimidazol-1-yl/piperidin-1-yl)-propyl]-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazolone-2, as oily residue; 1-[1-(3-(1H-benzimidazol-1-yl)propyl)-piperidin-4-yl]-5-chloro-1,3-dihydro-2H-benzimidazolone-2; melting point 224°C and 5-chloro-1-[1-(3-(3-/2-keto-3-/2H)-benzoxazol-3-yl/propyl)-f)iperidin-4-yIo]-1,3ndihydro -2H-benzimidazolone-2; melting point 212.3°C. Example XXXIX. A mixture of 5.4 parts of 3-(3-bromopropyl)-3H-benzimidazol-2-one, 4.5 parts of 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-2-one, 5.3 parts of Na2CO3, 0.1 part of KI, and 200 parts of 4-methyl-2-pentan-one is stirred and boiled under reflux with a water separator for 3 hours. After cooling, water is added, and the layers are separated. The organic phase is dried, filtered, and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentan-one and 2-propanone. The product is filtered off and dried to obtain 2.5 parts (31%) of 5-chloro-1,3-dihydro-1-[1-(3-(2-keto-(2H)-benzothiazol-3-10-propyl)piperidin-4-yl]-2H-benzimidazolone-2; melting point 184.1°C. Example XL. Proceeding as in Example XXXIX, 1-[1-(3-/1H-benzotriazol-1-yl/propyl)-piperidin-4-yl]-5-chloro-1,3-dihydro -2H-benzimidazolone-2 is prepared; melting point 203.4°C in the reaction of 1-(3-bromopropyl)-1H-benzotriazole with 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazolone-2 Example XLI. A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl-3-methyl-2H-benzimidazol-2-ru-2, 3.75 parts of 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-2-one, 2.65 parts of Na2Oa and 22.5 parts of N,N-dimethylformamide is stirred at 70-80°C for 2 hours. The reaction mixture is cooled, poured into water and the precipitated product is filtered off. It is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methylpentan-2-one, yielding 3 parts (43%) of 5-chloro-1-[1- (3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl)piperidin-1-yl]-1,3-dihydro-2H-benzimidazol-1-one; melting point 166.5°C. Example 42. A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-1-one methanesulfonate, 5 parts of 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-1-one, 5 parts of Na2CC3 and 63 parts of N,N-dimethylformamide is stirred and heated in an oil bath at 118°C. 50-60°C for 2 hours. The reaction mixture is poured into water. The precipitated product is filtered off, dried and purified by chromatography on silica gel using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methylpentan-2-one. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. It is filtered again and dissolved in a mixture of 4-methylpentan-2-one with a small amount of N,N-dimethylformamide. The solution is filtered until clear, and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried, yielding 1.27 parts of 5-chloro-1- [3-(4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-one; m.p. 229-236°C. Example 43. A mixture of 7 parts of 1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl)-2-phenylethenyl)-2H-benzimidazol-one, 5 parts of 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-one, 4.25 parts of K2CO3 and 0.1 part of KJ and 200 parts of 4-methylpentan-2-one is stirred and heated to reflux. overnight. The 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 and refluxed overnight with a solution of 55 parts of 6N HCl in 40 parts of ethanol. The solvent was evaporated, and the residue was taken up in water. The mixture was made basic with NH4OH, and the product was extracted with trichloromethane. The extract was dried, filtered, and evaporated. The residue was purified by chromatography on silica gel, using a 95:5 (v/v) mixture of trichloromethane and methanol as eluent. The pure fractions were collected, and the eluent was evaporated. The residue is converted into the hydrochloride salt in propanol-2. The salt is filtered and dried to obtain 1.2 parts of 1-[3-(4-(5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-piperidin-1-yl)propyl] hydrochloride. -5-fluoro-1,3-dihydro-2H-benzimidazolone-2; melting point 250°C. Example XLIV. Proceeding as in Example melting point 258°C in the reaction of 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one with 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-one with 5-chloro-1,3-dihydro-1-(piperidin-4-yl)-2H-benzimidazol-one and 1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-piperidin-4-yl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one; m.p. 174.3°C in the reaction of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-one with 1-(1-methylethyl)-3-(piperidin-4-yl)-2H-benzimidazol-one. Example 4LV. A mixture of 6 parts of 1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-piperidin-1-yl)propyl]-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-one, 12 parts of HCl solution, 30 parts of water and 40 parts of ethanol is stirred first for a short time at 50°C and then for an hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried, yielding 3.7 parts (40%) of 1-[3-(4-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-piperidin-1-yl)-propyl]-1,3-dihydro-5-methyl-2H-benzimidazol-1-one hydrochloride hydrate; melting point 251.4°C. Example 46 Proceeding as in Example -1,3-dihydro-2H-benzimidazolone-2; melting point 213.3°C; 5-chloro-1-[1-(3-/2,3-dihydro-6-methyl-2-keto-1H-benzimidazol-1-yl/propyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazolone-2 hemihydrate; 195.4°C and 5-chloro-1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-2-methylpropyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 244°C. Example XLVII. To a stirred solution of 1 part of 5-chloro-1-[1-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one in 32 parts of ethanol there is added a solution of 0.35 part of (±) 1,2-dihydroxy-ethanedicarboxylic acid-1,2-in 8 parts of ethanol. After stirring, the product is allowed to crystallize. It is filtered off and dried, yielding 1 part of (±)5-chloro-1-[1-(3-(1,2-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazo-2-nu, 1,2-dihydroxyethanedicarboxylate ethanolate; melting point 153.5°C. Example XLVIII. A stirred solution of 1 part of 5-chloro-1-[1-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-1-one in 20 parts of ethanol is saturated with HCl gas. The hydrochloride formed is allowed to crystallize with stirring. It is filtered off and dried, yielding 0.6 part (53%) of 5-chloro-1-[1-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-1-one hydrochloride hydrate; m.p. 195.7°C.118633 U Example XLIX. A solution of chloro-1-[1-(3-/1,3-dihydro-2-keto-2H-benzimidazol-1-yl/- ptopyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazolone-2 in 40 parts of ethanol is acidified with propanol-2, previously saturated with gaseous HC1. Upon cooling, the hydrochloride formed is allowed to crystallize, obtaining 1 part (83%) of 5-chloro-1-[1-(3-/1,3-dihydro-2-keto-2H-benzimidazol-1-yl/propyl)-piperidin-4-yl] hydrochloride ethanolate - 1,3-Dihydro-2H-benzimidazolone-2; melting point 213.7°C. Example L. 10.2 parts of 5-chloro-1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)piperidin-4-yl]-1,3'-dihydro-2H-benzimidazolone-2 is converted into the (±)-1,2-dihydroxyethanedicarboxylic acid salt in 100 parts of water at reflux temperature. The solution is treated for 10 minutes with a mixture of 0.5 parts of activated carbon and 0.2 parts of hyflo. The latter is filtered on hyflo, and the filtrate is cooled until an oily precipitate is formed. The oily product solidifies. The mixture is allowed to cool to room temperature and stirred at this temperature for 3 hours. The product is filtered off, washed with water and dried in vacuo for 18 hours at 60°C, yielding 10.24 parts (85.3%) of (R- /RX,RV) (+)-1,2-dihydroxyethanedicarboxylate, hemihydrate, 5-chloro-1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 184.1°C; [α]=+5.13° (c=1% CHjOH). Example LI. Proceeding as in Example XXIX and using equivalent amounts of appropriate starting materials, the following compounds are also prepared: 1-(4-chlorophenyl)-8-(3-/1,3-dihydro-2-keto-2H-benzimidazoI-1-yl/propyl-1,3,8-triazaspiro[4,5]decanone-4; 1-(4-chlorophenyl)-8- (3-/5-chloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl/propyl)-1,3,8-triazaspiro[4,5]decanone-4; -l-(4-fluorophenyl)-1,3,8- triazaspiro [4,5] 4-decanone; 8-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl-1-(4-fluorophenyl)-3-methyl-1,3,8-triazaspiro[4,5]-4-decanone; 8-(3-(1,3-dihydro-2-keto-2H-benzimidazol-1-yl)propyl)-3-ethyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]-4-decanone; 8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-(trifluoromethylphenyl)-1,3,8-triazaspiro[4,5]-4-decanone; melting point 237-244°C; 8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-(4-fluoro-3-methylphenyl)-1,3,8-triazaspiro[4,5]-4-decanone hydrate; melting point 167.6°C; 8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1-(3,4-dimethylphenyl)-1,3,8-triazaspiro[4,5]-4-decanone hemihydrate; melting point 185.9°C; 1-(4-bromophenyl)-8-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)propyl)-1,3,8-triazaspiro [4,5]decanone-4; melting point 197.4°C; 5-chloro-3-[1-(3-(3-/2,3-dihydro-2-keto-1H-benzimidazol-1-yl/-propyl)-piperidin-4-yl]-1,3-dihydro-4-methyl-2H-benzimidazolone-2 hydrochloride hydrate; melting point 298.4°C; 1-[1-(3-/2,3-dihydro-2-keto-1H-benzimidazol-1-yl/-propyl)-piperidin-4-yl]-1,3-dihydro-5-(trifluoromethyl)-2H-zolone-2 hydrochloride; melting point 233°C; 4-chloro-3- [l-(3-) hydrochloride dihydrate (2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-propyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 227.4°C; 1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-propyl)-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one; melting point 234°C; 5-chloro-1-[3-(4-(5-fluoro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one hemihydrate; melting point 219.1°C; 6-chloro-1-[1-(3-(2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-propyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride hemihydrate (2:1), melting point 256.2°C; 5-fluoro-1-[3-(4,5-fluoro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride isopropylate (2:1); melting point 243.7°C; 1-[1-(3-(2,3-dihydro-2-keto- 1H-benzimidazol-1-yl(-propyl)-piperidin-4-yIo]-1,3-dihydro-5,6-dimethyl-2H-benzimidazolone-2, melting point 300°C. Example LII. Proceeding as in Example XXXV and using equivalent amounts of appropriate starting materials, the following compounds were further prepared: 1-[3-(4-/5,6-dichloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl-/piperidin-1-yl)-propyl]- 1,3-dihydro-2H-benzimidazolone-2; melting point 263°C;12 118633 5-bromo-l-[3- (4- [5-chloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl]-piperidin-1-yl]-propyl]-1,3-dihydro-2H-benzimidazol-2-one; melting point 255.6°C and 1-[3-((5-bromo-1,3-dihydro-2-keto-2H-benzimidazol-1-yl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one, melting point 292.3°C. Claims 1. A method for preparing new derivatives and pharmaceutically acceptable acid addition salts of 1-(benzazolylalkyl)-piperidine of the general formula 1, wherein R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group or trifluoromethyl, Rj is a hydrogen atom or a methyl group, m and n are an integer of value 1, B is a divalent group of formula 0—N(L)—C—, in which L is a hydrogen atom, a lower alkyl group or a lower alkenyl group, this group being connected to the benzene ring by a nitrogen atom, and the group of formula 5 is a radical of formula S a, in which R 4 is a hydrogen atom or a lower alkyl group, R 5 is a hydrogen atom, a halogen atom or a trifluoromethyl group, R 6 is a hydrogen atom or a trifluoromethyl group, or the group of formula 5 is a radical of formula S b, in which R 7 and R* each independently are a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, Y is an oxygen atom, M is a hydrogen atom, and the dashed line optionally indicates a double bond between the 3rd and 4th carbon atoms a piperidine ring, or a group of formula S is a radical of formula Sc, in which R9 is a hydrogen atom or a halogen atom, and R10 is a hydrogen atom or a trifluoromethyl group, characterized in that a compound of formula 2, in which B, R1, R2, R1, m and n have the meanings given above and X is a reactive ester functional group, a derivative of the corresponding alcohol, is reacted with a compound of formula 3, in which the group of formula S has the meaning given above in an organic solvent. 2. A method for the preparation of new derivatives and pharmaceutically acceptable acid addition salts of 1-(benzazolylalkyl)piperidine of formula 1, in which R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl group, R1 is a hydrogen atom or a methyl group, m and n each represent an integer with a value of 1 or 2, B is a divalent group of the formula —N(L)—C—, in which L is a hydrogen atom, a lower alkyl group, a lower alkenyl group and either a lower alkylcarbonyl group, or B is a group of the formula —S—C—, —O—C—, —N=N—, —N=—CH—, these groups being linked to the benzene ring by a heteroatom, and the group of the formula 5 is a group of the formula S a, in which R 4 is a hydrogen atom or a lower alkyl group, R 5 and R 5 each independently is a hydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethyl group, or the group of the formula S is a group of the formula S b, in which R 7 and R 1 each independently is a hydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethyl group, Y is an oxygen or sulfur atom, M is an oxygen or sulfur atom a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group, the dashed line optionally denotes a double bond between the 3rd and 4th carbon atom of the piperidine ring, and if Y is a sulfur atom, there is a single bond between the 3rd and 4th carbon atom, and M is a hydrogen atom, or a group of formula S denotes a group of formula Sc, in which R9 is a hydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethyl group and R10 is a hydrogen atom or a halogen atom, and when B denotes a group of formula —N(L)—C—, in which L is a hydrogen atom, a lower alkyl group or a lower alkenyl group and the group of formula S denotes a group of formula S a, in which R4 is a hydrogen atom or a lower alkyl group, Rs is a hydrogen atom, a halogen atom or a trifluoromethyl group, R* denotes a hydrogen atom or a trifluoromethyl or a group of formula S means a radical of formula Sb, in which R7 and R1 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, Y represents an oxygen atom, M represents a hydrogen atom, and the dashed line optionally represents a double bond between carbon atoms 3 and 4 of the piperidine ring, or a group of formula S means a radical of formula Sc, in which R9 represents a hydrogen atom or a halogen atom, and R10 represents a hydrogen atom or a trifluoromethyl group, and m and n do not represent integers with value 1, characterized in that a compound of formula 2, in which B, R1, R2, R3m and n have the above-mentioned meaning, and X represents a reactive ester function derived from the corresponding alcohol, is reacted with a compound of formula 3, in which the group of formula S has the above-mentioned meaning, in an organic solvent and optionally the blocking group L.118 633 is cleaved off Table I c a I Compounds of formula 6 L H H H CH3 CH2 =CH-CH3 H H H H R1 H 5—a 5—HC3 H H H 5—O H H R4 H H H H H H H H CH3 R5 H H H H H 4—F 4—F 3—CF3 H Melting point °C 228° 233° 255.5° 164.4° 114.0° 215.4° 171.7° 198.2° 186.0° ED50 mg/kg s.c. 0.03 0.05 0.06 0.08 0.25 0.0l 0.015 0.025 0.015 Table 1 i c a II Compounds of formula 7 Melting point °C 225.0° 253.0° 159.0° 244° 242.5° 229-236° 166.5° 153.4° 206.6° 250° 213.3° 165.2° 251.4° L H H H H H H CH3 CH2 = CH- H H H C(CH3) = H -CH2 CH2 Rl H 5—a 5—CH3 H H 5—a H H H 5—F 5—CH3 H 5—CH3 R2 H H 6—CH3 H H H H H H H* H H H R3 H H H CH3 H H H H H H H 5-a H 5—a 5—a 5—a H Salt and solvate form — — CHj—CHOH—CH3 — — — — — — HClH2O HClH2O — HCl H2O ED50 mg/kg s.c. 0.02 0.10 1 0.45 0.06 0.01 0.12 0.16 0.12 0.04 0.004 0.12 0.20 0.20 Table III Compounds of formula U L H CH2=CH—CH2 R'° 4—a 4—a R9 H H Melting point °C 134.2° 141.3° ED50 mg/kg s.c. 0.06 0.50 H 4—O 3—CF3 189.2° 0.015118 633 Table IV Zuic|7ek formula 12 formula 13 formula 14 formula 15 formula 16 formula 17 formula 18 Melting point °C 191° I84.P 212.3° 266.6D 203.4° 248.5° 254.3° HD50 mg/kg .c. 0.25 0.001 0.03 0.004 0.06 0.025 0.004 R3 i BN-CCH2)-CH-CCH2)n-X^H-N A- Formula 3 R1 R2 Formula 2 - B N-fcH,k-CH-CCH,)-N^A 2yn R1 R' Formula 1 Scheme 1 -rTA IMformula 5118 633 O O II Formula 3a R5 R! HrC0-M H 2 R7 R8 Formula 3b 9 c R: L-N N-CCH^-CH-fCH^-N A r' R* tK\y 4 9 7^- R5 R6 Formula 5a R* I Y u \ L-^-CH2- CH-CHg-rQj^H R1 r2 Nzcr 7 0 I A R9 Rw Formula 5c Formula 6 R7 -o- -o- -o- L-N N-CHj-Ca-C^-N V I r Rs Formula 11 R'° R9118 633 O-^a- NH nJ Formula 12 0 0 Formula IZ 0 ^n-^-oXh MzOr 14 Cl S H hn^-Cc^-nT]/ *Vrdr 15 a o % 0 H HrrSi-CCHa)j- Printing Workshop UP PRL. Circulation 120 copies Price lOC PLN PL PL PL PL PL PL PL PL PL

Claims (1)

1.