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

Description

The subject of the invention is a process for the preparation of new 1- (benzazolyl-alkyl) -piperidine derivatives and their pharmaceutically acceptable acid addition salts. Numerous benzazolyl-alkyl and indolyl-alkyl substituted piperidine derivatives and some aminoalkyl substituted benzazoles were known, some of which had pharmacological activity, e.g. antidepressant, anticonvulsant, antihistamine or antispasmodic activity. Among other differences, the compounds of the invention differ from the known compounds in the nature of the respective benzazolyl and / or a member of the substituted piperidine. Some known compounds can be found in the following sources: Int. Pharmacopsychist. 1968 (1), p. 214; CA., 64, 2093 b (1966); CA. 72, 111 466 (1970); CA., 81,120,632 b (1974); French Patent No. 2,042,321 (Der. Fr. Week S 16, Pharm. p. 12) and Belgian Patent No. 753,472. in which R1 and R2 each represent independently a hydrogen atom, a halogen atom, a lower alkyl radical or a trifluoromethyl radical, B is a divalent group of the formula -N (L) -C (= 0) -, in which L is a hydrogen atom, a lower alkyl radical, a lower alkylcarbonyl radical, a lower alkenyl radical or a protecting group: or B is a group of the formula —S — C (= O) -, —O — C (= O) -, —N = N— and —N = CH—, and the aforementioned divalent groups are combined with the benzene ring with their heteroatom; R3 represents a hydrogen atom or a methyl group; m and n are integers from 1 to 2 (inclusive); and the radical of formula 5 represents: - a radical of formula 5a in which R4 represents a hydrogen atom or a lower alkyl radical; and R 6 and R 6 are each independently hydrogen, halogen, lower alkyl or trifluoromethyl; or - a radical of formula Sb, in which R7 and R8 each independently represent a hydrogen atom, a halogen atom, a lower alkyl or a trifluoromethyl radical; Y is oxygen or sulfur; M represents a hydrogen atom, a lower alkyl radical or a lower alkylcarbonyl radical, and the dashed line indicates a possible double bond between the 3rd and 4th carbon atoms of the piperidine ring, provided, however, that when Y is sulfur, then there is only a single bond between the 3rd and 4th the carbon of the piperidine ring when M is then hydrogen; or - a radical of formula 5c, in which R9 represents a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl radical, and R10 represents a hydrogen atom or a halogen atom or a trifluoromethyl group. with 1-5 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl and the like; "Lower alkenyl" denotes straight or branched chain alkenyl radicals with 2 to 5 carbon atoms, such as 1-methylethylene, propen-2-yl, buten-2-yl, buten-3-yl, pentene-2 -yl and the like; the term "halogen" includes halogens with an atomic weight of less than 127, i.e., fluorine, chlorine, bromine and iodine. The compounds of formula 1 are prepared by reacting a reactive ester of formula 2 in which X represents a reactive ester functional group of a suitable alcohol such as, for example, halogen, methanesulfonyl, 4-methylbenzenesulfonyl and the like, with the corresponding piperidine derivative of formula 3 in which the group of formula 5 is as defined above. The above condensation reactions are 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. ie, dimethylbenzene and the like; in 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. The addition of a suitable base such as an alkali metal or alkaline earth metal carbonate or bicarbonate can be used to neutralize the acid generated during the reaction. As a reaction, a small amount of a suitable metal iodide, for example NaJ or KJ, may be added, especially when the reactive ester of formula II is chloride. For example, elevated temperatures are suitable for increasing the reaction rate, and the reaction is preferably carried out at the boiling point of the reaction mixture under reflux cooler. The reaction products are separated from the environment and, if necessary, further purified by known methods. Compounds of formula 1, which can be represented by formula 4, where R1, R2, R3, m, n and groups of formula 5 have the meaning given above, and L represents a protecting group; by removal of the above-mentioned protecting group using conventional known methods, it can be converted into compounds of formula IV in which L is hydrogen. Examples of such known protecting groups include, but are not limited to, lower alkyloxycarbonyl, 4-methylbenzenesulfonyl, methanesulfonyl, and a preferably substituted ethenyl group of the formula R12 — CH = C (Rn) - where R11 and R12 may represent different groups, but where Ru is preferably lower alkyl, and R12 is preferably hydrogen, lower alkyl or phenyl. In the case where the protecting group is a lower alkyloxycarbonyl, 4-methylbenzenesulfonyl or methanesulfonyl group it can be easily removed by alkaline hydrolysis, while when the protecting group is substituted with an ethenyl group it is conveniently eliminated by subjecting the corresponding product of formula 4 to acid hydrolysis. A wide variety of protic acids can be used for this acid hydrolysis to remove the substituted ethenyl group from Formula IV, including mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, and organic acids such as acetic, propionic and like them. In addition, the reactions can be carried out in inert organic solvents such as are commonly used in this type of hydrolytic reaction, for example methanol, ethanol, 2-propanone, and the like. in Examples I-XXVIII. The substrates of formula 3 represented by the formulas 3a, 3b and 3c and the methods of their preparation can be found in the following references, respectively: - the compound of formula 3a in US Patent No. No. 3,238,216; - the compound of formula 3b in US Patent No. PL No. 3,161,645 and Belgian Patent Specification No. 830,403; - a compound of formula IIIc in U.S. Patent Nos. 3,518,276 and No. 3,575,990. The compounds according to the invention can be converted into their acid addition salts for terepeutical use by treatment with a suitable acid, for example an inorganic acid. such as hydrohalic acid, for example hydrochloric, hydrobromic and the like; and sulfuric, nitric, phosphoric and the like; or an organic acid such as acetic, propionic, hydroxyacetic, 2-hydroxypropionic, 2-ketopropionic, malonic, ethane dicarboxylic, maleic, fumaric, 2-hydroxyethane dicarboxylic, 1,2,3-dihydroxyethane dicarboxylic, 2-hydroxy-propane-tricarboxylic acid, 2,3, benzoic, (J-phenyl) acrylic, α-hydroxyphenylacetic, 4-methylbenzenesulfonic, methanesulfonic, ethanesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Also, the salt compound can be converted to the free base form by treatment with an alkali. Compounds of formula I and their therapeutically active acid addition salts have been found to have a strong antiemetic effect, which has been proven 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 at various doses and one hour later the animals were given a normal dose of morphine (SC) of 0.31 mg / kg. 118633 3 The MV tables give the ED50 values represent the dose, which protects 50% of animals from vomiting It is understood that the compounds given in Tables I-IV are not included in order to limit the invention to this, but only to exemplify the outstanding antiemetic properties of all compounds covered by Formula 1 Consider the useful antiemetic activity, The compounds of the present invention can be formulated into various drug forms for administration purposes. In order to formulate antiemetic effective pharmaceutical formulations, the amount of a particular compound in the form of a base or acid addition salt as active ingredient is combined with a pharmaceutically acceptable carrier that can take a wide variety of forms depending on the form of the drug desired for administration. It is desirable that the pharmaceutical compositions be in a form suitable for unitary dosage, preferably for oral, rectal or parenteral injection. For example, in preparing formulations for oral dosing, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, and the like, may be used for oral liquid preparations such as suspensions, syrups, elixirs, and solutions. ; relatively solid carriers such as starch, sugars, kaolin, lubricants, binders, dispersants and the like in the case of powders, pills, capsules and tablets. Because of their convenience in administration, tablets and capsules are the most preferred forms for oral unitary dosing, and in this case, of course, solid pharmaceutical carriers are used. For parenteral formulas, the carrier will usually contain sterile water, at least in large part, although other ingredients may be formulated, for example, where the carrier contains saline, glucose solution, or a mixture of saline and glucose. Suitable liquid carriers, suspending agents and the like are suitable. The acid addition salts of the compounds of formula I, due to their increased solubility in water compared to the corresponding base form, are of course more suitable in the preparation of aqueous mixtures. It is particularly advantageous to formulate the above-mentioned pharmaceutical mixtures in unit dosage form for ease of administration and uniformity of dose. . Single-dose form refers to physically mild units suitable as unitary dosages containing each individual a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tables (including cut or coated tables), capsules, pills, powder packets, wafers, injection solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, and prepackaged thereof multiples. The amount of active ingredient per drinking dose will be 0.25 mg-100 mg, 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 stated. Example I. A mixture of 100 parts of 1-chloro-2-nitro-4 (trifluoromethyl) -benzene, 90 parts of 1-amino-propanol and 200 parts of butanol is mixed at the boiling point. under a reflux condenser and heated all night long. The reaction mixture is cooled and evaporated. Water is added to the residue and it is acidified with HCl solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue crystallizes out petroleum ether. The product was filtered off and dried to obtain 141 parts (100%) of 3 - [(2-nitro-4- (trifluoromethyl) phenyl) amino-propanol. Following the procedure of Example I and using equivalent amounts of the appropriate starting materials, the following is prepared: 3- (/ 4-methyl-2-nitrophenyl / amino) -propanol-1 as residue, -nitrophenyl) -amino) -propanol-1, m.p. 97 ° C and residue 3 - ((2-chloro-6-nitrophenyl) -amino) -propanol-1. Example III. A mixture of 70 parts of 3 - (4-methyl-2-nitrophenyl-amino) -propanol-1 and 400 parts of methanol is hydrogenated under normal pressure and room temperature with 10 parts of 10% palladium on charcoal as the carrier. . After the calculated amount of hydrogen had reacted, the catalyst was filtered off and the filtrate was evaporated to give 54 parts (91%) of residual 3 - (2-amino-4-methylphenyl) -propanol. A mixture of 141 parts of 3 - [(2-nitro-4- / trifluoromethyl / phenyl) amino] -propanol-1 and 1200 parts of methanol is hydrogenated under normal pressure and room temperature with 15 parts of Raney nickel catalyst. After the calculated amount of hydrogen has reacted, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from isopropyl ether to give 110 parts (100%) of 3 - [(2-amino-4- / trifluoromethyl / phenyl) amino] -propanol-1. - 3 - (/ Amino-4,5-dichlorophenyl / amino) -propanol-1 hydrochloride, m.p. ± 185 ° C, 3 - (/ 2-amino-6-chlorophenyl) aminoApropanol-1 as a residue and 3 - (2-amino-4-chlorophenyl / amino) -propanol-1 as an oily residue. 4 118633 Example VI. A solution of 28 parts of potassium cyanate in 50 parts of water is dripped into a mixed and cooled solution of 54 parts of 3 - (/ 2-amino-4-methylphenyl) amino / -propanol-1 in 30 parts of 10% HCl solution and 200 parts of water. temperature below 10 ° C. After completion of the dropwise 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 was crystallized from 2-4-methyl-pentanone to give 19.5 parts (31%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-2H-benzimidazolone-2, m.p. 114 , 1 ° C. Example VII. Proceeding as in Example VI and using equivalent amounts of the appropriate starting materials, the following is prepared: 1,3-Dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) -2H-benzimidazolone-2, 5,6-dichloro 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2, m.p. 174.7 ° C, 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazolone- 2 and 5-chloro-1,3-dihydro 1- (3-hydroxypropyl) -2H-benzimidazolone-2, mp 148.8 ° C. Example VIII. 11.9 parts of triethylamine are added to a mixed solution of 18.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazolone-2 in 325 parts of dichloromethane. Then 11.5 parts of triethylamine are slowly added dropwise. methanesulfonyl chloride. After completion of the dropwise addition, stirring is continued for 1 hour under reflux. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 2-methylpentanone-2 to give 15 parts (58%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-2H-benzimidazolone-2 methanesulfonate, m.p. 125 ° C. Example IX. Proceeding as in Example VIII and using equivalent amounts of the appropriate starting materials, the following is 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-benzimidazole methanesulfonate - 1-yl) propyl, melting point ± 140 ° C. Example X. 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 refluxed overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated. The residue is stirred in water and acidified with a dilute solution of HCl. The whole thing is mixed and heated for 30 minutes in a water bath. After cooling to room temperature, the product is extracted with methylbenzene. The water phase separates the whitefish alkalinizes NH2) H. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated to give 50 parts of 1H-benzimidazole-butanol-1 as an oily residue. Example XI. To a mixture of 23 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) - 2H-benzimidazolone-2 in 150 parts of trichloromethane, stirred with a stirrer, 32 parts of sulfinyl chloride are added dropwise. After completion of the dropwise addition, it is heated to reflux and stirring is continued for 1 day at this temperature. After cooling, the reaction mixture was evaporated and the residue crystallized from isopropyl ether to give 14 parts (56%) 1- (3-chloropropyl) -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazolone-2. Example XII. Following the procedure of Example 11 and using an equivalent amount of the appropriate hydroxy compound as substrate, the following chlorides are prepared: 5-chloro-1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2,6-chloro-1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2, m.p. 122 ° C, and 1- (4-chlorobutyl) -1H-benzimidazole as an oily residue. Example XIII. A mixture of 35 parts of 4-fluoro-1,2-diaminobenzene in 270 parts of dimethylbenzene, stirred under reflux under reflux, is added dropwise within 2 hours a solution of 57 parts of ethyl α-acetyl-phenylacetate in 90 parts of dimethylbenzene, while in the same formed water and ethanol (water separator) are distilled off over time. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and purified by chromatography on silica gel (silica gel), using a 98: 2 by volume mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated to give 11 parts of 6-fluoro-1,3-dihydro-1- (1-methyl-2-phenylethenyl) -2H-benzimidazolone-2, mp 190 ° C. Example XIV. To a mixed solution of 8.5 parts of 1, J-dihydro-1- (1-methylethenyl) -2H-2-benzimidazolone-2 in 45 parts of N, N-dimethylformamide is added 1.7 parts of sodium hydride in 78% suspension in portions. After stirring for 1 hour at room temperature, it is cooled to 0-5 ° C and 8.65 parts of 1-bromo-3-chloropropane are slowly added dropwise. After completion of the dropwise addition, stirring is continued for 3 hours at room temperature. The reaction mixture was poured onto crushed ice and the product was extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. It is crystallized from 2-propanol to give 5.5 parts (44%) of 1- (3-chloropropyl-1,3-dihydro-3- (1-methylethenyl) -2H. -benzimidazolone-2, m.p. 115 ° C. 118 633 5 Example 15 For a hot (55 ° C) mixture of 22.2 parts of 1,3-dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenylethylene) ) -2H-benzimidazolone-2, 3 parts of N, N, N-triethylbenzyl ammonium chloride and 112.5 parts of 60% NaOH solution, stirred with a stirrer, 15.8 parts of l-bromo-3-chloropropane are added dropwise (slightly exothermic reaction) After this operation is completed, stirring is continued for 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 to obtain, after drying, 25 parts (88.5%) l- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-3- (l-methyl-2-phenylethenyl) -2H-benzimidazolone-2, temperat mp 98 ° C. Example XVI. Following the procedure of Example XV and using an equal amount of the appropriate starting material, the following is obtained: 1- (3-chloropropyl) -1,3-dihydro-3- (2-propenyl) -2H-benzimidazolone-2 as a residue, 1- ( 3-chloro-2-methylpropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazolone-2 as a residue and 1- (3-chloropropyl) -5-fluoro-1,3- dihydro-3- (1-methyl-ethenyl) -2H-benzimidazolone-2 as residue and 1- (3-chloropropyl) -5-fluoro-1,3-dihydro-3- (1-methyl-2-phenylethenyl) ) -2H-benzimidazolone-2 as an oily residue. Example XVII. A solution of 13 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (I-methylethenyl) -2H-2H-benzimidazolone-2 in 6 parts of HCl solution and 40 parts of ethanol is stirred for 2 hours at room temperature. The reaction mixture was evaporated and the solid residue crystallized from propanol-2 to give 9.5 parts (90%) of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2, m.p. 115 ° C. Mixture of 25 parts of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-3- (I-methyl-2-phenylethenyl) -2H-benzimidazolone-2, 165 parts of 6N HCl solution and 160 parts of ethanol is stirred under reflux for 6 hours. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. This solution is dried, filtered and evaporated. The residue is crystallized from a mixture of isopropyl ether and 2H-propanol to give, after drying, 16 parts (94.7%) of 1- (3-oropropyl) -1,3-dihydro-5,6-dimethyl-2H-benzimidazolone -2, melting point 140 ° C. Example XIX. A solution of 180 parts of 3- / 2-nitrophenyl / amino) -propanol-1 in 200 parts of methanol and 100 parts of 10 N HCl solution is hydrogenated under normal pressure and a temperature of 50 ° C in the presence of 5 parts of 10% palladium catalyst mounted on charcoal. After the calculated amount of hydrogen (3 moles) had reacted, the hydrogenation reactions were stopped. The catalyst is drained off and the effluent is evaporated. Dissolve the residue (mainly 3- (2-aminophenyl / amino) -propanol-1 hydrochloride 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 whole is stirred under reflux for 15 hours. The reaction mixture is cooled and 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 ethyl acetate is recrystallized to give 58 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2 hydrate, mp 48-65 ° C. a solution of 52.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2 hydrate in 200 parts of pyridine is added dropwise to 63 parts of methanesulfonyl chloride. The mixture was stirred and air cooled for 2 hours. Pyridine evaporates. 500 parts of water are added to the residue and the resulting precipitate is filtered off. It is dissolved in 350 parts of trichloromethane. This solution is dried over magnesium sulfate and evaporated. The residue crystallizes from 40 parts of methylbenzene to give 25.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2 methanesulfonate, m.p. 118-120 ° C. To a solution of 0.5 part sodium in 40 parts of absolute ethanol are added in the cold, 5.4 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazole-2-mesylate. The whole thing is mixed until all the solid is in solution. The solution is stirred further at reflux for 2 hours. After cooling, the reaction mixture is filtered off the inorganic material and evaporated. The residue is dissolved in 80 parts of methylbenzene, heated to the boil (boiled) with activated carbon, sipped, and the filtrate evaporates again. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene to give 2.6 parts of 3,4-dihydro-2H- [1,3] oxazine [3,2-a] benzimidazole, mp 116.5-118.5 ° C. To a solution of 5.7 parts of 3.4 ^ iwuhydro-2H- [1,3] oxazine [3,2-a] benzimidazole in 80 parts of 2-propanone, 5.7 parts of methyl iodide are added and the whole is mixed in at reflux for 2.5 hours. A second portion of 5.7 parts of methyl iodide is then added and the whole is mixed with heating under reflux for 2.5 hours. The solvent is evaporated to give 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazolone-2 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% solution of HBr in water is stirred and refluxed for 4 hours. The precipitated product is filtered off, washed with water and petroleum ether and dried to give 71 parts (81%) of N- (4-chloro-2-nitrophenyl) -4-aminopiperidine hydrobromide, mp 275 ° C. A mixture of 105 parts I- (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 NaiCOa, 0, 2 KJ parts and 320 parts 4-methylpentanone-2 are mixed 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 to give 98.5 parts (100%) of 1- (3- [4- ((4-chloro -2-nitrophenyl) amino) -piperidin -1-yl] propyl) -1,3-dihydro 3- (1-Methylethenyl) -2H-benzimidazolone-2 as residue Solution 98.5 parts 1- (3- [4- (/ 4-chloro-2-nitrophenyl) -amino) -piperidin -1-yl] -propyl ) -1,3-dihydro-3- (1-methylethenyl) -2H-2-benzimidazolone-2 in 360 parts of methylbenzene is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. After cooking for a while, the oil turns into oil, the upper phase is decanted and the remaining oil is dispersed in the water. The suspension is made alkaline with a concentrated NH4OH solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue crystallizes from 2-methylpentanone. The product is filtered and dried to give 68 parts (75.5%) of 1- (3- [4- (/ 4-chloro-2-nitrophenyl / amino) -piperidin-1-yl] propyl) -1,3-dihydro -2H-benzimidazolone-2. Mixture of 21.5 parts 1- (3- [4- (/ 4-chloro-2-nitrophenyl / amino) -piperidin-1-yl] propyl) -1,3-dihydro -2H- Benzimidazolone-2 and 240 parts of methanol are hydrogenated at normal pressure and room temperature with 5 parts of Raney nickel as a catalyst. After the calculated amount of hydrogen has reacted, the catalyst is filtered off and the filtration is evaporated to give 20 parts (100%) of 1- (3- [4- (/ 2-amino-4-chlorophenyl / amino) -piperidin-1-yl] -propyl) -1,3-dihydro -2H-benzimidazolone-2 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-2-benzimidazolone and 240 parts of methanol is hydrogenated under normal pressure and at 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 to give 18.5 parts (M90%) of 1- (3- [4- ((2-amino-4-chlorophenyl) amino) -piperidin-1-yl ] -propyl) -1,3-dihydro-2H-benzimidazolone-2 as residue. Example XXII. 35.7 parts of sulfinyl chloride are added dropwise to a mixed mixture of 39.2 parts of 3- (2-nitrophenyl) amino-propanol-1 and 225 parts of trichloromethane (exothermic reaction: temperature rises to 45 ° C). After completion of the dropwise addition, stirring is continued for 6 hours at reflux temperature. The reaction mixture was evaporated to give 43 parts (100%) of N- (3-chloropropyl) -2-nitroaniline as a residue. A mixture of 43 parts of N- (3-chloropropyl) -2-nitroaniline, 47.8 parts 5- chloro-1,3-dihydro-1- (piperidin-4-yl) -2H-2-benzimidazolone, 30.3 parts of N, N-diethylethylamine and 180 parts of N, N-dimethylacetamide are mixed and heated for 6 hours at a temperature 100 ° C. The lost product is filtered off, washed with water and isopropyl ether and dried to give 64 parts (78.3%) of 5-chloro -1.3-dihydro 1- [1- (3- (2-nitrophenylamino / propyl) -piperidine -4-yl] -2H-benzimidazolone-2, m.p. 220 ° C. Mixture of 64 parts 5-chloro-1,3-dihydro -1- [1- (3- (2-nitrophenylamino / propyl) -piperidine -4 - ylo] -2H-benzimidazolone-2 in 200 parts methanol and 225 parts tetrahydrofuran is hydrated under normal pressure and room temperature with 10 parts Raney nickel as a catalyst. After the calculated amount of hydrogen has reacted, the catalyst is filtered off on a hyflo filter and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried to give 42 parts (70.5%) of 1- (1- [3- (N- (2-aminophenyl) amino) propyl] piperidin -4-yl) -5-chloro-1,3- dihydro - 2H-benzimidazolone-2, m.p. 196 ° C. Example XXIII. A mixture of 6.7 parts of 5-chloro -1.3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2.4.2 parts of 4- (4-chlorophenyl) piperidinol-4 methanesulfonate, 3.2 parts of NajCOa and 32 parts of 4-methylpentanone-2 are mixed 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 silica gel chromatography using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is mixed with a small amount of trichloromethane. The product is filtered off and crystallized from 2-methylpentanone to give 2 parts (24%) 5-chIoro-1- [3- (4- / 4-chlorophenyl) -4-hydroxy- piperidin-1-yl) propyl] -1,3-dihydro-2H-benzimidazolone-2, m.p. 190.8 ° C. 118633 7 Example XXIV. Mixture of 3.58 parts of 1- (3-chloro-propyl) -1,3-dihydro-5,6-dimethyl -2H-benzimidazolone-2, 3.17 parts of 4- (4-chlorophenyl) -piperidinol-4, 5 , 3 parts of Na2CO3, 0.2 parts KJ and 160 parts of 4-methylpentanone-2 are mixed and heated under reflux with 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 to the hydrochloride in methanol and propanol-2. The salt is filtered off and dried to give 1.7 parts of 1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) propyl] - hydrochloride 1,3-dihydro-5,6-dimethyl-2H-benzimidazolone-2, m.p. 260.8 ° C. Example XXV. A mixture of 2.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2, 2.12 parts of 4- (4-chlorophenyl) piperidinol-4, 3.2 parts of Na2CC3, 0.1 parts KJ and 80 parts of 4-methylpentanone-2 are mixed and heated under reflux 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 silica gel chromatography using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene to give 1 part (26%) of 1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidinyl! O) propyl] -1,3-dihydro-2H-benzimidazolone- 2; mp 134.2 ° C. Example XXVI. Following the procedure of example XXV and using equivalent amounts of the appropriate substrates, the following compounds are prepared: 6-chloro-1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-y! O) propyl] - 1,3-dihydro-2H-benzimidazolone-2; mp 180.6 ° C; 1- (3- [4- (4-chloro-3- (trifluoromethyl) phenylH-hydroxy-piperidin-1-yl) -propyl] -1,3-dihydro-2H-benzimidazolone-2; mp 189 * 2 ° C; 1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) propyl] -1,3-dihydro-3- (propen-2-yl) -2H-benzimidazolone-2 Melting point I41.3 ° C 1- [4- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) butyl] -1,3-dihydro-2H-benzimidazolone-2; melting point 160.6 ° C and 1- (3- (1H-benzimidazoI-1-yl) propyl) -4- (4-chlorophenyl) -piperidineI-4; mp 16 (fC. Example XXVII. Mixture of 5 parts 1) - (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-2-benzimidazolone, 3.9 parts 4- (4-fluorophenyl) piperidinol-4, 5.3 parts Na ^ Os and 80 parts of 4-methylpentanone-2 are mixed and refluxed with a water separator for 48 hours, the reaction mixture is cooled to room temperature, water is added and the whole is made alkaline with 15 parts NaOH (60% solution). The layers and are separated the organic phase is dried, filtered and evaporated. The residue is purified by silica gel chromatography using a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue dissolves in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous HCl, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated off and the hydrochloride formed is dissolved in water. The free base is released by the 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 crystallizes from methylbenzene. The product is filtered off and dried to give 2.5 parts of 1- [3- (4- (4-fluorophenyl) 4-hydroxy-piperidin-1-yl) propyl] -1,3-dihydro-2H -benzimidazolone-2; mp 135.4 ° C. Example XXVIII. The following compounds are also prepared by following the procedure of Example XXV and using equivalent amounts of the appropriate starting materials: 5-chloro-1- (3- [4- / 4-chloro-3- / trifluoromethylphenyl -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-2 H -benzimidazol-2; 1- [3- (4- (4-bromophenyl) -4-hydroxy-piperidin-1-yl) propyl] -1,3-dihydro-2H-benzimidazolone-2; 1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) propyl] -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazolone-2; 1- [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) propyl] -5,6-dichloro-1,3-dihydro -2H-benzimidazolone-2 and 5-chloro-1 - [3- (4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl) propyl] -1,3-dihydro-3- (propen-2-yl) -2H-benzimidazolone-2 Preparation of Formula 1: Example XXIX. A mixture of 4.6 parts 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazolone-2,5 parts of 1- (p-fluorophenyl) -1,3,8-triazaspiro [4,5] decanene-4 10 parts of Na2CO3, 0.2 parts KJ and 80 parts of 4-methylpentanone-2 are mixed and heated under reflux overnight. After cooling, the lost product is filtered off and triturated twice: first in a boiling mixture of 4-methylpentanone-2 and propanol-2 and then in boiling methanol. The product is recrystallized from a mixture of N, N-dimethylformamide with 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] decanone-4; mp 215.4 ° C. Example XXX. The following compounds are prepared by following the procedure of Example XXIX and using an equal amount of the appropriate substrates: yl) propyl) -1- (4-fluorophenyl) -1,3,8-triazaspiro [4,5] 4-decanone; mp 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] decanon-4; mp 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] decanone-4; mp 114 ° C; 8- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) -1- (3- (trifluoromethyl) phenyl) - 1,3,8-triazaspiro [4,5] decanone-4; mp. 198.2 ° C; 8- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) -1-phenyl-1,3,8-triazaspiro [4,5] decanone-4; mp 228 ° C; 8- (3- (5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl- (4-fluorophenyl) -1,3,8-triazaspiro [4,5] decanone- 4; mp 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] decanone-4; mp 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] decanone-4; mp 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] decanone-4; mp 186 ° C; 1- (4-chloro-3 -methyl-ophenyl) -8- (3- (2,3-dihydro-2-keto-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] decanone-4; mp 191 ° C. XXXI. A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) methanesulfonate ~ 2 H-benzimidazolone-2, 2.5 parts 1-phenyl-1,3,8-triazaspiro [4,5] decanone-4, 10 parts Na2CO3 and 80 parts 4-methylpentanone-2 are mixed and heated under reflux overnight. The reaction mixture was cooled and water was added to it. The lost product is filtered off and crystallized twice from a mixture of N, N-dimethylformamide with water, yielding 0.8 part (17%) of 8- (3- (7-chloro-1,3-dihydro-2-keto-2H-benzimidazole) -1-yl (propyl) -1-phenyl-1,3,8-triazaspiro [4,5] 4-decanone, melting point 258.4 ° C. Example XXXII. Following the procedure in Example XXXI and reacting in N, N-dimethylformamide as solvent, the following compounds are prepared from the corresponding stubs: 8- (3- (5-chloro-2,3-dihydro-2-keto-1H-benzimidazole) - 1-yl) propyl) -1-phenyl-1,3,8-triazaspiro [4,5] decanone-4; mp 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] decanone- 4; mp. 255.5 ° C. Example XXXIII. A mixture of 5 parts 1,3-dihydro-1- (3-iodoprop! O) -3-methyl-2H-benzimidazolone-2, 3,4 parts 1-phenyl-1,3,8-triazaspiro [4,5] decanone-4, 2.65 parts of Na 2 CO 3 and 22.5 parts of N, N-dimethylformamide are mixed and heated for 2 hours at 70 ° C. The reaction mixture was cooled and poured into water, whereupon the oil was precipitated. The upper water phase is decanted and the remaining oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by silica gel chromatography using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1 part 8- (3- (1,3-dihydro-3-methyl-2-keto-2H-benzimidazol-1-yl) propyl) -1-phenyl-1,3, 8-triazaspiro [4,5] decanone-4; mp 164.4 ° C. Example XXXIV. A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2, 9.2 parts of 1-phenyl-1,3,8-triazaspiro methanesulfonate [4,5] Decanone-4 and 90 parts N, N-dimethylformamide are mixed with heating at 60 ° C for 1 hour. The reaction mixture was evaporated and water was added to the residue. The whole 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 a mixture of trichloromethane and 10% methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is triturated in 4-methylpentanone-Z. The product is filtered off and dried to give 2 parts 8- (3- (5,6-dichloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl) propyl ) -1-phenyl-1,3,8-triazaspiro [4,5) decanone-4; mp 275.2 ° C. Example XXXV. A mixture of 2.3 parts 1- (3-chloropropyl) -1, 3-dihydro-2H-benzimidazolone-2, 2.5 parts 5 KJ and 80 parts 4-methylpentanone-2 is mixed and heated to reflux for 24 hours. hours. The reaction mixture was cooled to room temperature and water was added thereto. 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 are collected and the eluent is evaporated. The residue crystallizes from 4-methylpentanone-2. The product is filtered off and recrystallized from a mixture of N, N-dimethylformamide and water to give 1.3 parts (30%) 5-chloro-1- [1- (3- / l, 3- dihydro-2-keto-2H-benzimidazol-1-yl / propyl) piperidin-4-yl] -1,3-dihydro-2H-benzimidazolone-2; mp 242.5 ° C. Example XXXVI. Proceeding as in Example XXXVi, using an equal amount of the substrates, the following compounds are prepared: 5-chloro-1- (1- [3- (2,3-dihydro-3- (1-methylethenyl) -2-keto-1H-benzi- midazol-1-yl) -2-methylIopropyl] piperidin-4-yl) -1,3-dihydro-2H-benzimidazolone-2 as oily, residue 118633 9; 6-chloro-1- [3- (4- (5-chloro-2, hydro-2-ccto-1H-benzimidazol-1-yl) piperidin-1-yl) propyl] -1,3-dihydro-2H hydrate -benzimidazolone-2; mp. 179.6 ° C; isopropanolate 1- [3- (4- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) piperidin-1-yl) propyl] -1,3-dihydro-5,6-dimethyl -2H-benzimidazoyl-2; 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-benzimidazolone -2; mp 273 ° C; 1- [3- (4- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) piperidin-1-yl) propyl] -1,3-dihydro-2H-benzimidazolone-2; mp 225 ° C; 1,3-dihydro-1- [3- (4- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) piperidin-1-yl) propyl] -5- (trifluoromethyl) - 2H-benzimidazolone-2; mp 263.4 ° C .; 5-chloro-1- [3- (4- / 2,3-dihydro-2-keto-1H-benzimidazol-1-10 / piperidin-1-yl) -propyl- 1,3-dihydro-2H-benzimidazolone- 2; mp 253-255 ° C; 5-chloro-1- (1- [3- (2,3-dihydro-2-keto-3- (propen-2-yl) -1H-benzimidazol-1-yl) -propyl] piperidin-4-yl) - 1,3-dihydro-2H-benzimidazolone-2; mp. 153.4 ° C; 1- [3- (3,6-dihydro-4- / 2,3-dihydro-2-keto-1H-benzimidazol-1-yl / -2H) -piperidin-1-yl) -propyl] -1 , 3-dihydro-2H-benzimidazolone-2; mp. 206.6 ° C; 5-chloro-1- (1- [3- (2,3-dihydro-3- (I-methylethenyl) -2-keto-1H-benzimidazol-1-yl) propyliapperidin-4-yl) -1, 3-dihydro-2H-benzimidazolone-2; mp. 165.2 ° C; 1- [1- (4- (1H-benzimidazol-1-yl) butyl) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazolone-2; mp. 157.1 ° C. Example XXXVII. A mixture of 5.3 parts of 1- (3-chloropropyl) - 1,3-dihydro-5-methyl-3- (1-methylethenyl) -2H-2-benzimidazolone, 4.3 parts of 1,3-dihydro-1- ( piperidin-4-yl) -2H-benzimidazolone- 2, 6.4 parts of Na 2 CO 3 and 200 parts of 4-methylpentanone-2 are mixed and refluxed with a water separator. After cooling, water is added and the layers are separated. The 4-methylpentanone-2 phase is dried, filtered and evaporated. The oily residue is purified by silica gel chromatography using a 90:10 mixture of trichloromethane and methanol (by volume) as eluent. The pure fractions are collected and the eluent is evaporated to afford 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-benzimidazolone-2, as an oily residue. Example XXXVIII. Following the procedure of Example XXXVII and using equivalent amounts of the appropriate substrates, the following compounds are prepared: 1- [3- (4- (5-chloro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl / piperidines) -1-yl) propyl] -1,3-dihydro-5-methyl-3- (1-methylethenyl) -2H-benzimidazolone-2 as an oily residue; 3- [3- (4- (5-chloro-2,3Kl dihydro-2-keto-1H-benzimidazol-1-yl) piperidin-1-yl) propyl] -1,3-dihydro-5-methyl-1 - (1-methylethenyl) -2H-benzimidazolone-2 as an oily residue; 1- [1- (3- (1H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -5-chloro -1,3-dihydro-2H-benzimidazolone-2; mp. 224 ° C and 5-chloro-1- [1- (3- (2-keto-3- (2H) -benzoxazol-3-yl) propyl) -f) mustard-4-yl] -1,3nd dihydro -2H-benzimidazolone-2; mp 212.3 ° C. Example XXXIX. A mixture of 5.4 parts 3- (3-bromopropyl) 3H) -benzimidazolone-2, 4.5 parts 5-chloro-1,3-dihydro-1- (piperidin-4-yl) -2H-2,5-benzimidazolone-2, 5.3 parts of Na2CO3, 0.1 parts KJ and 200 parts of 4-methylpentanone-2 are mixed and refluxed 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 2-methylpentanone-2 and 2-propanone. The product is filtered off and dried to give 2.5 parts (31%) of 5-chloro-1,3-dihydro-1- [1- (3- (2-keto) (2H) -benzothiazol-3-yl) propyl ) piperidin-4-yl] -2H-benzimidazolone-2; mp 184.1 ° C. Class XL. Following the procedure of Example XXXIX, 1- [1- (3- (1H-benzotriazol-1-yl) propyl) -piperidin-4-yl] -5-chloro-1,3-dihydro -2H-benzimidazolone-2 is prepared. ; mp. 203.4 ° C in the reaction of 1- (3-bromopropyl) -1H-benzotriazole with 5-chloro-1,3-dihydro-1- (pipiyidin-4-yl) -2H-benzimidazolone-2. Example XLI. A mixture of 5 parts 1,3-dihydro-1- (3-iodopropyl-3-methyl-2H-benzimidazoline-2, 3.75 parts 5-chloro-1,3-dihydro-1- (piperidin-4-yl) ) -2H-benzimidazolone-2, 2.65 parts of Na 2 O and 22.5 parts of N, N-dimethylformamide are stirred at 70-80 ° C for 2 hours. The reaction mixture is cooled, poured into water and the lost product is filtered off It is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue crystallizes from 2-methylpentanone to give 3 parts (43%) 5-chloro-1- [1- (3- / l, 3- dihydro-3-methyl-2-keto-2H-benzimidazol-1-yl) propyl) -piperidin-1-yl] -1,3-dihydro-2H-benzimidazoyl-2, mp 166.5 ° C. Example XLII A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazolone-2, 5 parts of 5-chloro-1,3-dihydro-1- (piperidin- 4-yl) -2H-benzimidazolone-10 118 633 2.5 parts of Na 2 CO 3 and 63 parts of N, N-dimethylformamide are mixed and heated in an oil bath at 50-60 ° C for 2 reptiles. The reaction mixture is poured into water. The lost 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 crystallizes from 4-methylpentanone-2. The product is filtered off and recrystallized from a mixture of N, N-dimethylformamide with water. It is filtered again and dissolved in a mixture of 4-methylpentanone-2 with a small amount of N, N-dimethylformamide. The solution is drained to a clear state, and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The lost product is filtered off and dried to give 1.27 parts of 5-chloro-1- [3- (4- (5-chloro-1,3-dihydro-2-keto-2H-benzimidazol-1-yl / piperidin-1) -yl) propyl] -1,3-dihydro-2H-benzimidazolone-2; mp 229-236 ° C. Example XLIII. A mixture of 7 parts 1- (3-chloro-propyl) -5-fluoro-1,3-dihydro-3- (1-methyl) -2-phenylethenyl) -2H-benzimidazolone-2, 5 parts 5-chloro-1, 3-Dihydro-1- (piperidin-4-yl) -2H-benzimidazolone-2, 4.25 parts K2CO3 and 0.1 parts KJ and 200 parts 4-methylpentanone-2 are mixed and heated to reflux by night. The mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and refluxed overnight with a solution of 55 parts 6N HCl in 40 parts ethanol. The solvent is evaporated off and the residue is placed in water. The whole is made alkaline with NH4OH and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel chromatography using a 95: 5 mixture of trichloromethane and methanol (by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride in propanol-2. The salt is filtered and dried to give 1.2 parts of 1- [3- (4- / 5-chloro-2,3-dihydro-2-keto-1H-benzimidazole- 1- yl) -piperidin-1-yl) propyl] -5-fluoro-1,3-dihydro-2 H -benzimidazolone-2; melting point 250 ° C. Example XLIV. Proceeding as in Example XLIII produces: 5-chloro-1- [1- (4- (2,3-dihydro-2-keto-1H-benzimidazoI-1-yl) butyl) -piperidin-4-yl] - hemihydrate 1,3-dihydro-2H-benzimidazolone-2; mp. 258 ° C in the reaction of 1- (4-chlorobutyI) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-2H-benzimidazolone-2 with 5-chloro-1,3-dihydro-1- ( piperidin-4-yl) -2H-benzimidazolone-2 with 5-chloro-1,3-dihydro-1- (piperidin-4-yl) -2H-benzimidazolone-2 and 1- [1- (3- / 2, 3-dihydro-2-keto-1H-benzimidazol-1-yl / propyl) -piperidin-4-yl] -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazolone-2; melting point 174.3 ° C. in the reaction of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazolone-2 with 1- (1-methylethyl) -3- ( piperidin-4-yl) -2H-benzimidazolone-2. Example XLV. Mixture of 6 parts 1- [3- (4- (2,3-dihydro-2-keto-1H-benzimidazole -1-yl) - piperidin-1-yl) propyl] -1,3-dihydro-5-methyl The -3- (1-methylethenyl) -2H-2H-benzimidazolone-2, 12 parts of HCl solution, 30 parts of water and 40 parts of ethanol are first mixed briefly 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-methylpentanone-2 and 2-propanol-2. The product is filtered off and dried to give 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-2-benzimidazolone; mp 251.4 ° C. Example XLVI. The following suitably substituted (1-methylethenyl) -anogi is prepared by following the procedure of Example XLV: 5-chloro-1- [1- (3- (2,3-dihydro-5-methyl-2-keto-1H-) hydrochloride hydrate benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazolone-2; mp. 213.3 ° C; 5-chloro-1- [1- (3- (2,3-dihydro-6-methyl-2-keto-1H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-3 hemihydrate dihydro-2H-benzimidazolone-2; mp 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-benzimidazolone-2; mp 244 ° C. Example XLVII. For a mixed solution of 1 part 5-chloro-1- [1- (3- (1,3-dihydro-2-keto-2H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3- 2H-2H-benzimidazolone-2 dihydro in 32 parts of ethanol is added a solution of 0.35 parts (±) of 1,2-dihydroxy-1,2-dihydroxy-1,2-dicarboxylic acid in 8 parts of ethanol. After mixing, the product is allowed to crystallize. It is filtered off and dried to give 1 part of 1,2-dihydroxyethane dicarboxylate ethanolate (±) 5-chloro-1- [1- (3- (1,2-dihydro-2-keto-2H-benzimidazol-1-yl) propyl) ) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazocene-2; mp 153.5 ° C. Example XLVIII. Mixed solution of 1 part 5-chloro-1- [1- (3- 1,3-dihydro -2-keto -2H-benzimidazol-1-yl] -propyl-piperidin-4-yl] -1,3-dihydro - 2H-benzimidazolone-2 in 20 parts of ethanol is saturated with gaseous HCl. The hydrochloride formed is allowed to crystallize while stirring. It is filtered off and dried to give 0.6 parts (53%) of 5-chloro-l- [l- ( 3- (1,3-dihydro-2-keto-2H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazolone-2, m.p. 195.7 ° C.118633 U Example XLIX Solution of 5-chloro-1- [1- (3- (1,3-dihydro-2-keto-2H-benzimidazol-1-yl) -propyl) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazolone-2 in 40 parts of ethanol is acidified with propanol-2, previously saturated with gaseous HCl During cooling, the hydrochloride formed is allowed to crystallize, yielding 1 part (83%) of 5-chloro-1 hydrochloride ethanolate - [1- (3- (1,3-dihydro-2-keto-2H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-dihydro-2H-benzimidazo ! onu- 2; melting point 213.7 ° C. Example L. 10.2 parts 5-chloro-1- [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl / propyl) -piperidine- 4-yl] -1,3 ”dihydro-2H-benzimidazolone-2 is converted to the () 1,2-dihydroxyethane dicarboxylic acid salt in 100 parts of water under reflux. 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 drained over the hyflo and the filtrate is cooled until an oily deposit is formed. The oily product solidifies on short-term heating. The whole 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 under vacuum for 18 hours at 60 ° C to give 10.24 parts (85.3%) of the hemihydrate (R- / RX, RV) (+) - 1,2-dihydroxyethane dicarboxylate 5-chloro-1 [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-dihydro-2H- benzimidazolone-2; mp. 184.1 ° C; [a] = + 5.13 ° (c = 1% CH 2 OH). Example LI. The following compounds are also prepared by following the procedure of Example XXIX and using equivalent amounts of the appropriate substrates: 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-benzimidazole) -1-yl (propyl) -1,3,8-triazaspiro [4,5] decanone-4; 8- (3- (1,3-dihydro-2-keto-2H-benzimidazol-1-yl) < 2 > -metiopropyl) -1- (4-fluorophenyl) -1,3,8-triazaspiro [4,5] decanone-4; 8- (3- (1,3-dihydro-2-keto-2H-benzimidazol-1- yl) -propyl-1- (4-fluorophenyl) -3-methyl-1,3,8-triazaspiro [4,5] decanone-4; 8- (3- (1,3-dihydro-2-keto-2H) -benzimidazol-1-yl) propyl) -3-ethyl-1- (4-fluorophenyl) 1,3,8-triazaspiro [4,5] decanone-4; 8- (3- (2,3-dihydro-2) -keto-1H-benzimidazol-1-yl) -propyl) -1- (trifluoromethylphenyl) -1,3,8-triazaspiro [4,5] -decanone-4; mp 237-244 ° C; hydrate 8- ( 3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) -propyl) - (4-fluoro-3-methylphenes lo) -1,3,8-triazaspiro [4,5] decanone-4; mp. 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] hemihydrate decanone-4; mp. 185.9 ° C; 1- (4-bromophenyl) -8- (3- V2,3-dihydro-2-keto-1H-benzimidazol-1-yl / propyl) -1,3,8-triazaspiro [4,5] decanone-4 hydrate ; mp. 197.4 ° C; 5-chloro-3- [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) piperidin-4-yl] -1,3-dihydro hydrochloride hydrate 4-methyl -2H-benzimidazolone-2; mp. 298.4 ° C; 1- [1- (3- (2,3-Dihydro-2-keto-1H-benzimidazol-1-yl) -propyl) -piperidin-4-yl] -1,3-dihydro-5- (trifluoromethyl) hydrochloride -2H-zolone-2; mp 233 ° C; 4-chloro-3- [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) -piperidin-4-yl] -1,3-dihydro hydrochloride dihydrate 2H-benzimidazolone-2; mp. 227.4 ° C; 1- [1- (3- (2, M-dihydro-2-keto-1H-benzimidazol-1-yl) -propyl) -piperidin-4-yl] -5-fluoro-1,3-dihydro -2H-benzimidazolone- 2; mp 234 ° C; 5-chloro-1- [3- (4- (5-fluoro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl) -piperidin-1-yl) propyl] -1,3-dihydrate - dihydro-2H-benzimidazolone-2; mp. 219.1 ° C; 6-Chloro-1- [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) propyl) -piperidin-4- hydrochloride hemihydrate-isopropylate (2: 1) yl] -1,3-dihydro-2 H -benzimidazolone-2, m.p. 256.2 ° C; Hydrochloride isopropylate (2: 1) 5-fluoro-1- [3- (4V5-fluoro-2,3-dihydro-2-keto-1H-benzimidazol-1-yl) -piperidin-1-yl) -propyl] - 1,3-dihydro-2H-benzimidazolone-2; mp. 243.7 ° C; 1- [1- (3- (2,3-dihydro-2-keto-1H-benzimidazol-1-yl) -propyl) -piperidin-4-yl] -1,3-dihydro-5,6-dimethyl- 2H-benzimidazolone-2, m.p. 300 ° C. Example LII. The following compounds are further prepared by following the procedure of Example XXXV and using equivalent amounts of the appropriate substrates: 1- [3- (4- / 5,6-dichloro-1,3-dihydro-2-keto-2H-benzimidazole-1- yl- (piperidin-1-yl) propyl] -1,3-dihydro-2H-benzimidazolone-2; mp 263 ° C; 12 118633 5-bromo-1- [3- (4- (5-chloro-1,3-dihydro-2-keto-2H-benzimidazoI-1-yl) -piperidin-1-yl) -propyl] -1,3-dihydro-2H-benzimidazolone-2; mp. 255.6 ° C and 1- [3- (5-bromo-1,3-dihydro-2-keto-2H-benzimidazol-yl) -piperidin-1-yl) -propyl] -1.3- Dihydro-2H-benzimidazolone-2, melting point 292.3 ° C. Patent claims 1. Method for the preparation of new derivatives and pharmaceutically acceptable acid addition salts with 1- (benzazolylalkyl) -piperidine acids of general formula 1, in which R1 and R2 each independently represents a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl group, Rj is a hydrogen atom or a methyl group, m and n are an integer of 1, B is a divalent group of the formula 0 —N (L) —C—, where L is a hydrogen atom, a lower alkyl group or a lower alkenyl group, which group is connected to the benzene ring by a nitrogen atom, and the group of formula 5 is a radical of formula Sa, in which R4 is a hydrogen atom or a lower alkyl group, R5 is a hydrogen atom, halogen or a trifluoromethyl group, R6 is a hydrogen atom or a trifluoromethyl group b the group of formula 5 represents a radical of formula Sb, where R7 and R * 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 represents an optional double bond between the 3rd and 4th carbon of the piperidine ring, or the group of formula S is a radical of formula Sc, in which R9 is hydrogen or halogen, and R10 is hydrogen or trifluoromethyl, characterized by the compound of formula II in which B, R1, R2, R1, and min are as defined above and X is a reactive functional ester group, a derivative of the corresponding alcohol is reacted with a compound of formula III wherein the group of formula S is as defined above in an organic solvent. 2. A method for the preparation of new derivatives and pharmaceutically acceptable acid addition salts with 1- (benzazolylalkyl) -piperidine acids of formula 1, in which R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl group, Rj is a hydrogen atom or a group methyl, min each is an integer with a value of 1 or 2, B is a bivalent 0 group of the formula —N (L) —C—, where L is a hydrogen atom, a lower alkyl group, a lower alkenyl group 0 0 ii and or a lower group alkylcarbonyl or B is a group of the formula —S — C—, —O — C—, —N = N—, —N = —CH—, these groups being combined with the benzene ring with a heteroatom and the group of formula V is the group of formula Sa where R4 is hydrogen or a lower alkyl group, R5 and R5 each independently represent hydrogen, halogen, lower alkyl, or trifluoromethyl or the group of formula S is a group of formula Sb where R7 and R1 are each independently denotes a hydrogen atom, a ch atom halogen, lower alkyl or trifluoromethyl, Y is oxygen or sulfur, M is hydrogen, lower alkyl or lower alkylcarbonyl, the dashed line indicates an optional double bond between the 3rd and 4th carbon ring atoms of the piperidine ring, where if Y is an atom sulfur, there is a single bond between the 3rd and 4th carbon atom, and M is a hydrogen atom, or the group of formula S is a group of formula Sc, where R9 is hydrogen, halogen, lower alkyl or trifluoromethyl and R10 is hydrogen or a halogen atom, wherein when B is a group of the formula —N (L) —C— in which L is a hydrogen atom, a lower alkyl group or a lower alkenyl group and the group of the formula S is a group of the formula Sa, where R4 is a hydrogen atom or a lower alkyl group, Rs is a hydrogen atom, a halogen atom, or a trifluoromethyl group, R * is a hydrogen atom or a trifluoromethyl group, or the group of the formula S is the radical o Sb, where R7 and R1 are independently hydrogen, halogen, lower alkyl, trifluoromethyl, Y is oxygen, M is hydrogen, and the dashed line represents an optional double bond between the 3rd and 4th carbon atoms of the piperidine ring, or the group of the formula S represents a radical of the formula Sc, where R9 is a hydrogen atom or a halogen atom and R10 is a hydrogen atom or a trifluoromethyl group, m and n are not an integer with the value 1, characterized by the compound of formula 2, wherein B R 1, R 2, R 3 m, and n have the meaning as defined above, and X is a reactive ester functional group, derivative of the corresponding alcohol, is reacted with a compound of formula III in which the group of formula S is as defined above in an organic solvent and optionally cleaved from the group blocking L.118 633 Ta b I ca I Compounds of formula 6 LHHH CH3 CH2 = CH-CH3 HHHH Rl H 5 — a 5 — HC3 HHH 5 — OHH R4 HHHHHHHH CH3 R5 HHHHH 4 — F 4 — F 3 — CF3 H Te melting point ° C 228 ° 233 ° 255.5 ° 164.4 ° 114.0 ° 215.4 ° 171.7 ° 198.2 ° 186.0 ° ED 50 mg / kg s.c. 0.03 0.05 0.06 0.08 0.25 0.0l 0.015 0.025 0.015 Tab 1 ica 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 ° LHHHHHH CH3 CH2 = CH- HHHC (CH3) = H -CH2 CH2 R1 H 5— a 5 — CH3 HH 5 — a HHH 5 — F 5 — CH3 H 5 — CH3 R2 HH 6 — CH3 HHHHHHH * HHH R3 HHH CH3 HHHHHHHHH formula 8 formula 9 - - - - - - - formula 10 formula 9 - - * R7 HHH 5 — a 5 — a 5 — a 5-Cl 5-a H 5 — a 5 — a 5 — a H Salt and solvate form - - CHj — CHOH — CH3 - - - - - - HCIH2O HCIH2O - HCl H2O ED50 mg / kg sc 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 ULH CH2 = CH — CH2 R '° 4 — a 4 — a R9 HH Melting point ° C 134.2 ° 141.3 ° ED 50 mg / kg sc 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 temperature ° C 191 ° I84.P 212 , 3 ° 266.6 D 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 and BN-CCH2) -CH-CCH2) nX ^ HN A- Formula 3 R1 R2 Formula 2 - B N-fcH, k-CH-CCH,) - N ^ A 2yn R1 R 'Formula 1 Scheme 1 -rTA IM Pattern 5118 633 OO II Formula 3a R5 R! HrC0-M H 2 R7 R8 Formula 3b 9 c R: LN N-CCH ^ -CH-fCH ^ -NA r 'R * tK \ y 4 9 7 ^ - R5 R6 Formula 5a R * IY u \ L - ^ - CH2 - CH-CHg-rQj ^ H R1 r2 Nzcr 7 0 IA R9 Rw Formula 5c Formula 6 R7 -o- -o- -o- LN N-CHj-Ca-C ^ -NVI r Rs Formula 11 R '° R9118 633 O - ^ a- NH nJ Formula 12 0 0 Formula IZ 0 ^ n - ^ - oXh MzOr 14 Cl SH hn ^ -Cc ^ -nT] / * Vrdr 15 ao% 0 H HrrSi-CCHa) j- Printing Studio of the PRL. Mintage 120 copies Price LOC PLN PL PL

Claims (2)

1. Claims 1. A method for the preparation of new derivatives and pharmaceutically acceptable acid addition salts of 1- (benzazolylalkyl) -piperidine of the general formula 1, in which R1 and R2 are each independently hydrogen, halogen, lower alkyl or trifluoromethyl, Rj is a hydrogen atom or a methyl group, m and n are an integer with the value 1, B is a divalent group of the formula 0 —N (L) —C—, where L is a hydrogen atom, a lower alkyl group or a lower alkenyl group, the group being linked by is a nitrogen atom with a benzene ring, and the group of formula 5 is a radical of formula Sa, in which R4 is a hydrogen atom or a lower alkyl group, R5 is a hydrogen atom, a halogen atom or a trifluoromethyl group, R6 is a hydrogen atom or a trifluoromethyl group or a group of the formula 5 represents a radical of formula Sb, where R7 and R * each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, and Y is m oxygen, M represents a hydrogen atom, and the dashed line represents optionally a double bond between the 3rd and 4th carbon atoms of the piperidine ring, or the group of formula S represents a radical of the formula Sc, where R9 is hydrogen or halogen, and R10 is hydrogen or a trifluoromethyl group, characterized in that a compound of formula II, wherein B, R1, R2, R1, and min are as defined above and X is a reactive ester functional group, a derivative of the appropriate alcohol is reacted with a compound of formula III, wherein 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 with 1- (benzazolylalkyl) -piperidine acids of formula 1, in which R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl or trifluoromethyl group, Rj is a hydrogen atom or a group methyl, min each is an integer with a value of 1 or 2, B is a bivalent 0 group of the formula —N (L) —C—, where L is a hydrogen atom, a lower alkyl group, a lower alkenyl group 0 0 ii and or a lower group alkylcarbonyl or B is a group of the formula —S — C—, —O — C—, —N = N—, —N = —CH—, these groups being combined with the benzene ring with a heteroatom and the group of formula V is the group of formula Sa where R4 is hydrogen or a lower alkyl group, R5 and R5 each independently represent hydrogen, halogen, lower alkyl, or trifluoromethyl or the group of formula S is a group of formula Sb where R7 and R1 are each independently denotes a hydrogen atom, a ch atom halogen, lower alkyl or trifluoromethyl, Y is oxygen or sulfur, M is hydrogen, lower alkyl or lower alkylcarbonyl, the dashed line indicates an optional double bond between the 3rd and 4th carbon ring atoms of the piperidine ring, where if Y is an atom sulfur, there is a single bond between the 3rd and 4th carbon atom, and M is a hydrogen atom, or the group of formula S is a group of formula Sc, where R9 is hydrogen, halogen, lower alkyl or trifluoromethyl and R10 is hydrogen or a halogen atom, wherein when B is a group of the formula —N (L) —C— in which L is a hydrogen atom, a lower alkyl group or a lower alkenyl group and the group of the formula S is a group of the formula Sa, where R4 is a hydrogen atom or a lower alkyl group, Rs is a hydrogen atom, a halogen atom, or a trifluoromethyl group, R * is a hydrogen atom or a trifluoromethyl group, or the group of the formula S is the radical o Sb, where R7 and R1 are independently hydrogen, halogen, lower alkyl, trifluoromethyl, Y is oxygen, M is hydrogen, and the dashed line represents an optional double bond between the 3rd and 4th carbon atoms of the piperidine ring, or the group of the formula S represents a radical of the formula Sc, where R9 is a hydrogen atom or a halogen atom and R10 is a hydrogen atom or a trifluoromethyl group, m and n are not an integer with the value 1, characterized by the compound of formula 2, wherein B R 1, R 2, R 3 m, and n have the meaning as defined above, and X is a reactive ester functional group, derivative of the corresponding alcohol, is reacted with a compound of formula III in which the group of formula S is as defined above in an organic solvent and optionally cleaved from the group blocking L.118 633 Ta b I ca I Compounds of formula 6 LHHH CH3 CH2 = CH-CH3 HHHH Rl H 5 — a 5 — HC3 HHH 5 — OHH R4 HHHHHHHH CH3 R5 HHHHH 4 — F 4 — F 3 — CF3 H Te melting point ° C 228 ° 233 ° 255.5 ° 164.4 ° 114.0 ° 215.4 ° 171.7 ° 198.2 ° 186.0 ° ED 50 mg / kg s.c. 0.03 0.05 0.06 0.08 0.25 0.0l 0.015 0.025 0.015 Tab 1 ica 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 ° LHHHHHH CH3 CH2 = CH- HHHC (CH3) = H -CH2 CH2 R1 H 5— a 5 — CH3 HH 5 — a HHH 5 — F 5 — CH3 H 5 — CH3 R2 HH 6 — CH3 HHHHHHH * HHH R3 HHH CH3 HHHHHHHHH formula 8 formula 9 - - - - - - - formula 10 formula 9 - - * R7 HHH 5 — a 5 — a 5 — a 5-Cl 5-a H 5 — a 5 — a 5 — a H Salt and solvate form - - CHj — CHOH — CH3 - - - - - - HCIH2O HCIH2O - HCl H2O ED50 mg / kg sc 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 ULH CH2 = CH — CH2 R '° 4 — a 4 — a R9 HH Melting point ° C 134.2 ° 141.3 ° ED 50 mg / kg sc 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 temperature ° C 191 ° I84.P 212 , 3 ° 266.6 D 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 and BN-CCH2) -CH-CCH2) nX ^ HN A- Formula 3 R1 R2 Formula 2 - B N-fcH, k-CH-CCH,) - N ^ A 2yn R1 R 'Formula 1 Scheme 1 -rTA IM Pattern 5118 633 OO II Formula 3a R5 R! HrC0-M H 2 R7 R8 Formula 3b 9 c R: LN N-CCH ^ -CH-fCH ^ -NA r 'R * tK \ y 4 9 7 ^ - R5 R6 Formula 5a R * IY u \ L - ^ - CH2 - CH-CHg-rQj ^ H R1 r2 Nzcr 7 0 IA R9 Rw Formula 5c Formula 6 R7 -o- -o- -o- LN N-CHj-Ca-C ^ -NVI r Rs Formula 11 R '° R9118 633 O - ^ a- NH nJ Formula 12 0 0 Formula IZ 0 ^ n - ^ - oXh MzOr 14 Cl SH hn ^ -Cc ^ -nT] / * Vrdr 15 ao% 0 H HrrSi-CCHa) j- Printing Studio of the PRL. Mintage 120 copies Price LOC PLN PL PL